Vitamin B12

Evidence-based effects and studies

← Back to Supplements
Effects
1045
Total evidences
1526

Effects and Evidences

Detailed analysis of research findings

relation to B-vitamins

1 evidences

In patients with hyperthyroidism, plasma homocysteine was low and inversely related to B-vitamins (including cobalamin); after antithyroid therapy homocysteine increased while folate and cobalamin decreased.

Trust comment: Observational longitudinal study with a reasonable sample size showing associations between B-vitamin status (including cobalamin) and homocysteine; causality limited.

Study Details

PMID:14535973
Participants:182
Impact:homocysteine inversely related to folate, cobalamin and riboflavin (stronger patterns in smokers for some vitamins)
Trust score:3/5

plasma 8-isoprostane (Iso-P)

1 evidences

In CAD patients with high homocysteine, B-vitamin therapy (folic acid, B6, B12) markedly lowered tHcy but had minimal effects on oxidative stress markers and only a small reduction in serum amyloid A.

Trust comment: Prospective randomized study with clear biochemical outcomes and reported pre/post values, though sample sizes in treated subgroup were modest.

Study Details

PMID:16006259
Participants:93
Impact:no significant change with vitamin therapy
Trust score:4/5

total plaque area (TPA)

1 evidences

In a randomized vitamin B therapy trial in diabetic nephropathy patients, 3D ultrasound vessel wall volume increased over time in one treatment group while IMT showed no between-group differences.

Trust comment: Randomized, double-blind study but small imaging subset and modest sample size reduce generalizability.

Study Details

PMID:18996639
Participants:71
Impact:no consistent between-group difference
Trust score:3/5

norepinephrine requirements (dose)

1 evidences

Prophylactic IV hydroxocobalamin in high-risk cardiac surgery patients reduced vasoplegia incidence and vasopressor needs while improving blood pressure and lactate.

Trust comment: Randomized placebo-controlled prospective single-center trial with clinically relevant endpoints but moderate sample size.

Study Details

PMID:40055025
Participants:60
Impact:decreased (significantly lower at 30 and 60 min; lower total dose)
Trust score:4/5

clinician-assessed total neuropathy score (TNS)

1 evidences

Pilot randomized placebo-controlled trial in cancer patients found no significant effect of a B-group vitamin on clinician-assessed neuropathy score, but patients reported less sensory neuropathy on patient questionnaires.

Trust comment: Randomized placebo-controlled pilot with objective and patient-reported outcomes but small analyzable sample and pilot design limit reliability.

Study Details

PMID:27612466
Participants:47
Impact:No significant reduction in TNS with B-group vitamin vs placebo (p=0.73)
Trust score:3/5

baseline B12/folate status

1 evidences

High-dose B-vitamin therapy (including 1 mg B12) in kidney transplant recipients lowered homocysteine and produced modest but significant improvements in processing speed and memory over ~3.3 years.

Trust comment: Large randomized, multi-site controlled trial ancillary with long follow-up and standardized cognitive testing, though most participants were B12/folate sufficient at baseline which may limit effect size interpretation.

Study Details

PMID:29182708
Participants:584
Impact:Most participants folate and B12 sufficient at baseline, limiting generalizability to deficient populations
Trust score:4/5

vitamin B-12 intake

1 evidences

Partially replacing animal proteins with plant proteins for 12 weeks lowered iodine intake and urinary iodine excretion in healthy adults.

Trust comment: Well-conducted 12-week randomized controlled trial with biomarker measurements, but relatively short duration for long-term status changes.

Study Details

PMID:34837522
Participants:136
Impact:ANIMAL 4.9 µg/d vs 50/50 3.4 µg/d vs PLANT 2.3 µg/d (PLANT < ANIMAL; P<0.001)
Trust score:4/5

total mortality

1 evidences

In hemodialysis patients, high-dose B-vitamin therapy including vitamin B12 did not reduce total mortality or cardiovascular events over ~2 years.

Trust comment: Large multicenter randomized double-blind trial with clinically important endpoints and adequate sample size.

Study Details

PMID:20231532
Participants:650
Impact:Active: 102/328 (31%) vs Placebo: 92/322 (28%); HR 1.13 (95% CI 0.85–1.50); P=0.51 (no reduction)
Trust score:5/5

movement and cognitive performance

1 evidences

Randomized, placebo-controlled trial of B-vitamin therapy (including B12) in elderly: biomarkers improved (tHcy and MMA) but short-term treatment did not improve movement or cognitive tests.

Trust comment: Double-blind randomized placebo-controlled trial with objective biochemical endpoints and clinical performance measures; sample size moderate for clinical outcomes.

Study Details

PMID:15883442
Participants:209
Impact:no improvement versus placebo after 4 months
Trust score:4/5

inflammatory and haemostasis markers (usCRP, IL-6, IL-8, IL-18, MCP-1, TF, TFPI)

1 evidences

B-vitamin supplementation (including B12 and folic acid) markedly lowered homocysteine but did not change markers of inflammation or haemostasis in PAOD patients over 6 weeks.

Trust comment: Randomized controlled trial with biomarker endpoints but modest sample size (n=65); strong internal validity for the measured outcomes.

Study Details

PMID:16634837
Participants:65
Impact:no change (no treatment effect)
Trust score:4/5

antidepressant treatment response

1 evidences

Large clinical-trial analysis found weak or no consistent relationships between one‑carbon biomarkers (including vitamin B12) and depression severity or antidepressant response.

Trust comment: Large sample (881) from randomized clinical trials; biomarker associations reported but effects were weak and inconsistent across trials.

Study Details

PMID:32787676
Participants:881
Impact:no significant association with pre-treatment vitamin B12 levels
Trust score:4/5

baseline correlation: folate status vs MN frequency

1 evidences

Across cross-sectional and short intervention studies, folate status correlated with chromosome stability but short-term supplementation (including a folate+B12+B6 arm) did not change micronucleus frequency or cell proliferation.

Trust comment: Includes cross-sectional data (n=99) and small short-term interventions (n≈29–30); appropriate methods but limited by short intervention duration and small sample sizes.

Study Details

PMID:16386942
Participants:99
Impact:negative correlation (higher folate associated with lower MN frequency; p<0.05)
Trust score:3/5

cancer mortality

1 evidences

Daily B-vitamin pill did not change overall cancer rates in people after stroke/TIA; diabetics had more and non-diabetics had fewer cancers with treatment in a post-hoc analysis.

Trust comment: Large randomized double-blind placebo-controlled trial (n=8164) with median 3.4-year follow-up, high internal validity.

Study Details

PMID:22474057
Participants:8164
Impact:2.35% vs 2.09% (+0.26 percentage points); RR 1.09, not significant
Trust score:5/5

serum/plasma vitamin B12 level

1 evidences

At 10 years after bariatric surgery, adherence to calcium–vitamin D supplements was associated with substantially lower prevalence of vitamin D insufficiency.

Trust comment: Predefined secondary analysis of a randomized trial with long (10-year) follow-up and objective lab measures, but supplement adherence was self-reported and some lab data were missing.

Study Details

PMID:40613787
Participants:178
Impact:no significant difference with vs without reported B12 supplements (398 vs 351 pmol/L; P=0.348)
Trust score:4/5

vitamin B12 supplement adherence

1 evidences

At 10 years after bariatric surgery, adherence to calcium–vitamin D supplements was associated with substantially lower prevalence of vitamin D insufficiency.

Trust comment: Predefined secondary analysis of a randomized trial with long (10-year) follow-up and objective lab measures, but supplement adherence was self-reported and some lab data were missing.

Study Details

PMID:40613787
Participants:178
Impact:overall 42% (LSG 29% vs LRYGB 56%; P<0.001)
Trust score:4/5

plasma/serum folate

1 evidences

In a long-term randomized trial subset, daily multivitamin/mineral (Centrum) increased plasma vitamin B12, folate, vitamin E and improved some other nutrient statuses versus placebo.

Trust comment: Large, long-duration double-blind randomized trial subset with objectively measured nutrient outcomes, though results reflect a multivitamin formulation rather than isolated B12.

Study Details

PMID:19636163
Participants:407
Impact:increased (P<0.005)
Trust score:4/5

blood glucose (glycemia)

1 evidences

120 women with type 2 diabetes on a low-calorie diet were given a multivitamin-mineral complex for 3 weeks; those receiving the complex showed greater improvements in some micronutrient levels and glycemia.

Trust comment: Controlled clinical diet study with adequate sample size but short duration and unclear randomization/allocation methods.

Study Details

PMID:25300112
Participants:120
Impact:-1.8 ±0.1 mmol/L (main group) vs -1.2 ±0.1 mmol/L (control) change
Trust score:3/5

muscular strength (convalescent children)

1 evidences

A 4-week vitamin supplement increased vitamin B12 and other vitamin levels in children; convalescent children also showed increases in appetite, weight and muscle strength.

Trust comment: Small randomized placebo-controlled study with short duration; biochemical increases shown but sample is small.

Study Details

PMID:10356941
Participants:40
Impact:+increased (p < 0.05)
Trust score:3/5

composite cardiovascular events

1 evidences

In patients with recent non-ST-elevation ACS, daily folic acid + vitamin B12 + vitamin B6 supplementation increased composite adverse cardiac events and rehospitalizations versus placebo over 6 months.

Trust comment: Randomized placebo-controlled trial (n=240) with clinical endpoints; supplement combined B12 with folate and B6 so B12-specific effects cannot be isolated.

Study Details

PMID:19515873
Participants:240
Impact:increased (significant) in supplement group
Trust score:4/5

serious re-hospitalization

1 evidences

In patients with recent non-ST-elevation ACS, daily folic acid + vitamin B12 + vitamin B6 supplementation increased composite adverse cardiac events and rehospitalizations versus placebo over 6 months.

Trust comment: Randomized placebo-controlled trial (n=240) with clinical endpoints; supplement combined B12 with folate and B6 so B12-specific effects cannot be isolated.

Study Details

PMID:19515873
Participants:240
Impact:increased (significant) in supplement group
Trust score:4/5

whole-body lean mass (WBLM)

1 evidences

In older adults doing resistance exercise, adding low-dose dairy protein plus micronutrients (including 200 IU vitamin D/day) increased muscle mass but did not further improve physical performance.

Trust comment: Randomized controlled trial with objective DXA measures (n=82); multi-nutrient supplement includes B12 so effects cannot be attributed solely to B12.

Study Details

PMID:29300423
Participants:82
Impact:+0.63 kg vs RE only (95% CI 0.31–0.95)
Trust score:4/5

femoral neck bone mineral density (FN BMD)

1 evidences

In this cohort of postmenopausal women, reduced BMD associated with the MTHFR TT genotype was observed only among women with low intake of B vitamins (including B12); supplementation would likely help a small subgroup.

Trust comment: Large observational cohort (n=1700) with genotype-diet analyses; associations are suggestive but cannot prove causality and rely on dietary intake estimates.

Study Details

PMID:15777680
Participants:1700
Impact:reduced in MTHFR TT genotype only in lowest quartile of vitamin B12 (and other B vitamins) intake
Trust score:3/5

riboflavin correlation with FN BMD in TT genotype

1 evidences

In this cohort of postmenopausal women, reduced BMD associated with the MTHFR TT genotype was observed only among women with low intake of B vitamins (including B12); supplementation would likely help a small subgroup.

Trust comment: Large observational cohort (n=1700) with genotype-diet analyses; associations are suggestive but cannot prove causality and rely on dietary intake estimates.

Study Details

PMID:15777680
Participants:1700
Impact:positive correlation (r=0.24, p<0.01); riboflavin identified as main predictor in stepwise model
Trust score:3/5

major depression (poststroke)

1 evidences

Long-term B-vitamin treatment after stroke was associated with a lower hazard of developing major depression compared with placebo.

Trust comment: Long-term randomized, double-blind placebo-controlled trial with clinically meaningful endpoints, though reported completer number is limited.

Study Details

PMID:20976769
Participants:273
Impact:18.4% (B-vitamins) vs 23.3% (placebo); adjusted HR=0.48 (95% CI 0.31–0.76)
Trust score:4/5

H3K79me2 (posttranslational histone modification)

1 evidences

In arsenic-exposed adults, vitamin B12 (an OCM index) showed sex-specific associations with certain histone modifications; folic acid supplementation (400 μg/d, 12 weeks) did not change global PTHMs.

Trust comment: Moderately sized observational/clinical trial dataset with adjusted analyses showing associations, but causality is not established.

Study Details

PMID:27765800
Participants:324
Impact:sex-specific association with vitamin B12 at baseline (association differed by sex)
Trust score:3/5

determinants of tHcy

1 evidences

In CKD stages 3–4, multivitamin supplementation (including folate, B6, B12) partially corrected hyperhomocysteinemia over one year; folate and B12 were major determinants of tHcy.

Trust comment: Large randomized dietary/protocol cohort with multivitamin repletion in CKD patients; B-vitamins included but not isolated, so moderate confidence for B12-specific effects.

Study Details

PMID:15780109
Participants:678
Impact:folate, vitamin B12 and GFR were major determinants of baseline tHcy levels
Trust score:3/5

tHcy reduction at 6 months

1 evidences

Daily hydrosoluble vitamin supplementation for 12 months reduced high homocysteine in hemodialysis patients but rarely normalized it.

Trust comment: Large human cohort with longitudinal follow-up and measured biomarkers, but supplementation was not a placebo-controlled single-agent B12 trial and some groups received additional folate.

Study Details

PMID:10916110
Participants:128
Impact:decreased to 23.5 μmol/L at 6 months (−9.8 μmol/L, −29.4% vs baseline, P<0.0001)
Trust score:4/5

added intravenous folic acid effect

1 evidences

Daily hydrosoluble vitamin supplementation for 12 months reduced high homocysteine in hemodialysis patients but rarely normalized it.

Trust comment: Large human cohort with longitudinal follow-up and measured biomarkers, but supplementation was not a placebo-controlled single-agent B12 trial and some groups received additional folate.

Study Details

PMID:10916110
Participants:128
Impact:greater mean tHcy reduction at 6 months with IV folic acid (12.2 vs 8.3 μmol/L, P<0.05) but no difference at 12 months
Trust score:4/5

micronutrient deficiency status (including vitamin B12)

1 evidences

Development and proof-of-concept double-blind RCT of a liposomal micronutrient-fortified massage oil in 444 infants showed overall improvements in micronutrient deficiency outcomes after implementation.

Trust comment: Proof-of-concept double-blind RCT described with reasonable sample, but this article focuses on development/implementation and lacks detailed efficacy numbers.

Study Details

PMID:33585378
Participants:444
Impact:reported improvement in deficiency levels (directional; no numeric values provided in this paper)
Trust score:3/5

parathormone (PTH)

1 evidences

One year of daily vitamin D3 (1200 IU) with calcium (with or without B vitamins) increased 25(OH)D, lowered PTH, and reduced multiple bone turnover markers in elderly subjects.

Trust comment: Randomized double-blind trial with objective biochemical endpoints and moderate sample size, though subgroup comparisons limit power for some bone markers.

Study Details

PMID:23183751
Participants:93
Impact:-28.3% (A), -41.2% (B)
Trust score:4/5

flow-mediated vasodilation (FMD)

1 evidences

Patients received rosuvastatin or B-vitamin supplementation (including B12) then combined therapy; vitamins lowered homocysteine and both treatments improved flow-mediated vasodilation, with additive effects when combined.

Trust comment: Randomized, double-blind study with objective endothelial function measures but small sample size limits generalizability.

Study Details

PMID:21884007
Participants:36
Impact:group R: +2.5% absolute (4.4→6.9%); group V: +1.5% absolute (4.9→6.4%); combined therapy further improved FMD to normal in most patients
Trust score:3/5

Schistosoma mansoni reinfection intensity

1 evidences

Multimicronutrient tablets (which included 5 µg vitamin D) modestly reduced Schistosoma mansoni reinfection intensity but did not affect other helminth reinfections.

Trust comment: Large randomized controlled trial in children but low tablet compliance (~46%) limits confidence.

Study Details

PMID:12886816
Participants:977
Impact:−31% (5.5 vs 7.7 eggs/g; P=0.047)
Trust score:3/5

serum amyloid A (S-AA)

1 evidences

In CAD patients with high homocysteine, B-vitamin therapy (folic acid, B6, B12) markedly lowered tHcy but had minimal effects on oxidative stress markers and only a small reduction in serum amyloid A.

Trust comment: Prospective randomized study with clear biochemical outcomes and reported pre/post values, though sample sizes in treated subgroup were modest.

Study Details

PMID:16006259
Participants:93
Impact:slightly reduced from 5.3 to 4.6 ng/L (small but significant)
Trust score:4/5

plasma Abeta40

1 evidences

In stroke patients given high- or low-dose B-vitamin formulations (including B12) for 2 years, homocysteine fell but plasma Abeta and cognition did not change between groups.

Trust comment: Large randomized double-blind trial with defined biochemical and cognitive endpoints; results are directly measured and reported.

Study Details

PMID:19153374
Participants:300
Impact:no change between treatment groups
Trust score:4/5

body composition

1 evidences

Eight-week randomized, double-blind trial (supplement contains 70 mg methylcobalamin) found some within-group gains in cognition and strength with PWS, but no consistent between-group advantages in body composition or most performance outcomes; supplements were well tolerated.

Trust comment: Well-powered randomized, double-blind, placebo-controlled trial with 80 completers and standardized training; internal validity strong though some effects were within-group only.

Study Details

PMID:28096757
Participants:80
Impact:No significant group differences in fat mass, fat-free mass, or % body fat after 8 weeks.
Trust score:5/5

mean arterial pressure

1 evidences

Prophylactic IV hydroxocobalamin in high-risk cardiac surgery patients reduced vasoplegia incidence and vasopressor needs while improving blood pressure and lactate.

Trust comment: Randomized placebo-controlled prospective single-center trial with clinically relevant endpoints but moderate sample size.

Study Details

PMID:40055025
Participants:60
Impact:increased (significant at 30 and 60 min after CPB separation)
Trust score:4/5

Systolic blood pressure

2 evidences

Randomized double-blind placebo-controlled ascending-dose trial showed hydroxocobalamin generally well tolerated but associated with transient BP increases and self-limited discoloration and rash.

Trust comment: Well-designed randomized, placebo-controlled safety trial with substantial sample and clear objective safety endpoints.

Study Details

PMID:16990190
Participants:136
Impact:mean max increase +22.6 to +27.0 mmHg across doses (vs 0.2–6.7 mmHg placebo)
Trust score:5/5

Randomized placebo-controlled trial of L-arginine plus B vitamins for 3–6 months in mildly hypertensive adults; intervention improved postprandial endothelial function, lowered homocysteine and reduced blood pressure.

Trust comment: Randomized double-blind placebo-controlled trial with objective vascular endpoints and sustained effects; B vitamins were part of a combination product so effects are combined.

Study Details

PMID:27817128
Participants:80
Impact:Decreased (to ~132.5 mmHg; ~6 mmHg reduction vs baseline)
Trust score:4/5

anemia association

1 evidences

Cross-sectional baseline data in early pregnancy showed high prevalence of vitamin B12 deficiency and that anemia was associated with B12 deficiency rather than iron deficiency.

Trust comment: Large, population-based baseline analysis with standard lab measures but observational design limits causal inference about B12 effects.

Study Details

PMID:21275915
Participants:740
Impact:Anemia (28%) associated with vitamin B12 deficiency (not iron deficiency)
Trust score:3/5

patient-reported sensory neuropathy (PNQ)

1 evidences

Pilot randomized placebo-controlled trial in cancer patients found no significant effect of a B-group vitamin on clinician-assessed neuropathy score, but patients reported less sensory neuropathy on patient questionnaires.

Trust comment: Randomized placebo-controlled pilot with objective and patient-reported outcomes but small analyzable sample and pilot design limit reliability.

Study Details

PMID:27612466
Participants:47
Impact:Patient-perceived sensory neuropathy improved with B-group vitamin at 12, 24, 36 weeks (p=0.03, 0.005, 0.021) and PNQ risk OR=5.78 (95% CI 1.63–20.5)
Trust score:3/5

vitamin B-12 status (holoTC)

1 evidences

Partially replacing animal proteins with plant proteins for 12 weeks lowered iodine intake and urinary iodine excretion in healthy adults.

Trust comment: Well-conducted 12-week randomized controlled trial with biomarker measurements, but relatively short duration for long-term status changes.

Study Details

PMID:34837522
Participants:136
Impact:PLANT 97.7 pmol/l vs 105.8 (50/50) vs 122.1 (ANIMAL); holoTC decreased ~23% in PLANT during trial (P<0.001)
Trust score:4/5

fatal and nonfatal cardiovascular events

1 evidences

In hemodialysis patients, high-dose B-vitamin therapy including vitamin B12 did not reduce total mortality or cardiovascular events over ~2 years.

Trust comment: Large multicenter randomized double-blind trial with clinically important endpoints and adequate sample size.

Study Details

PMID:20231532
Participants:650
Impact:Active: 83 (25%) vs Placebo: 98 (30%); HR 0.80 (95% CI 0.60–1.07); P=0.13 (no significant effect)
Trust score:5/5

small arterial elasticity index (SAEI)

1 evidences

In metformin-treated diabetic patients, supplementation with folate, vitamin B12 and B6 lowered homocysteine, raised B12 levels, and improved small-artery elasticity after 4 months.

Trust comment: Double-blind, placebo-controlled RCT with clear biomarker and functional endpoints but small sample size and short follow-up.

Study Details

PMID:18206891
Participants:60
Impact:Treatment 4.3±2.04 vs Placebo 3.2±1.1 ml/mmHg×100 (greater in treatment; P=0.01)
Trust score:4/5

markers of endothelial dysfunction (tPA, PAI, vWf)

1 evidences

In healthy volunteers, B-vitamin supplementation (including B12) lowered homocysteine by ~31% but did not change markers of endothelial dysfunction (tPA, PAI, vWf) over 8 weeks.

Trust comment: Randomized placebo-controlled study with adequate sample size and validated biomarkers, though short duration and surrogate outcomes.

Study Details

PMID:15543337
Participants:123
Impact:No significant change after supplementation
Trust score:4/5

sensory over-responsivity (SOR)

1 evidences

Randomized trial with placebo, B6 and B12 arms measuring sensory processing; Vitamin-B12 showed no reliable benefit on sensory over-responsivity or postural disorder in the high-score subgroups.

Trust comment: Randomized, double-blind design with a large overall sample but small subgroup sizes for the B12 comparisons, reducing precision of subgroup estimates.

Study Details

PMID:39180365
Participants:300
Impact:no significant change in Vitamin-B12 group (B12: baseline ~0.76 → post ~0.74; non-significant)
Trust score:4/5

vitamin B12 intake below DRI

1 evidences

Pre-operative assessment of bariatric surgery candidates found many did not meet dietary reference intakes; 48% had calcium intake below DRI.

Trust comment: Well-characterized cross-sectional assessment of 100 patients reporting intake and deficiency prevalence; observational design limits causal inference.

Study Details

PMID:26797718
Participants:100
Impact:14% of participants
Trust score:3/5

plasma cobalamin (vitamin B12) concentration

1 evidences

In this randomized substudy, antenatal multiple micronutrients (including vitamin D) improved maternal micronutrient biomarkers in late pregnancy but many deficiencies persisted.

Trust comment: Large, cluster-randomized trial substudy with robust measurements and adjustment; high-quality evidence that MM including B12 improved maternal B12 status relative to IFA.

Study Details

PMID:31006806
Participants:1526
Impact:+12 pmol/L mean difference (MM vs IFA) at 32 wk, p<0.0001
Trust score:5/5

unmetabolized folic acid (UMFA)

1 evidences

Elderly participants took folic acid or a B-complex (including B12) for ~23 days; B-complex led to lower unmetabolized folic acid than folic acid alone and both raised methylfolate.

Trust comment: Randomized single-blind trial with small elderly sample and short duration (~23 days); results credible but limited by size and short follow-up.

Study Details

PMID:25943647
Participants:58
Impact:higher after folic acid vs B-complex; B-complex caused lower post-intervention UMFA and lower prevalence of UMFA ≥0.21 nmol/L
Trust score:3/5

vitamin B12 supplementation need

1 evidences

In RYGB patients, a longer biliopancreatic limb (120 cm) did not improve weight loss or comorbidity remission but was associated with greater long-term requirements for vitamin B12 (and folic acid and vitamin A) supplementation.

Trust comment: Large prospective randomized clinical trial with long-term follow-up; clear outcome on supplementation needs though mechanism-based nutritional measures were not deeply detailed here.

Study Details

PMID:31104282
Participants:506
Impact:greater requirement in BPL 120 cm group vs BPL 70 cm during follow-up
Trust score:4/5

cancer incidence (diabetes subgroup)

1 evidences

Daily B-vitamin pill did not change overall cancer rates in people after stroke/TIA; diabetics had more and non-diabetics had fewer cancers with treatment in a post-hoc analysis.

Trust comment: Large randomized double-blind placebo-controlled trial (n=8164) with median 3.4-year follow-up, high internal validity.

Study Details

PMID:22474057
Participants:8164
Impact:5.35% vs 3.28% (adjusted RR 2.21; significant)
Trust score:5/5

plasma vitamin E

1 evidences

In a long-term randomized trial subset, daily multivitamin/mineral (Centrum) increased plasma vitamin B12, folate, vitamin E and improved some other nutrient statuses versus placebo.

Trust comment: Large, long-duration double-blind randomized trial subset with objectively measured nutrient outcomes, though results reflect a multivitamin formulation rather than isolated B12.

Study Details

PMID:19636163
Participants:407
Impact:increased (P<0.005)
Trust score:4/5

plasma vitamin C

1 evidences

Double-blind RCT of a multivitamin/mineral vs placebo in older adults on certain medications; MVMS increased folate and vitamin C status but did not significantly change serum calcium.

Trust comment: Randomized, double-blind controlled trial but small completed sample and short (16-week) duration; some reported B12 changes lacked detailed magnitude or significance in the text.

Study Details

PMID:33078646
Participants:54
Impact:increased (0.2 vs 0.0 mg/dL; P=0.004)
Trust score:3/5

iron deficiency incidence

1 evidences

After gastric bypass, vitamin B12 levels fell in both iron-supplemented and placebo groups over time; iron prevented iron deficiency but did not prevent B12 decline.

Trust comment: Prospective double-blind randomized trial with clear hematologic follow-up, though B12 was not the primary intervention focus.

Study Details

PMID:9688002
Participants:56
Impact:oral iron prevented iron deficiency (iron group) vs decreased ferritin in placebo
Trust score:4/5

death/nonfatal acute coronary syndrome

1 evidences

In patients with recent non-ST-elevation ACS, daily folic acid + vitamin B12 + vitamin B6 supplementation increased composite adverse cardiac events and rehospitalizations versus placebo over 6 months.

Trust comment: Randomized placebo-controlled trial (n=240) with clinical endpoints; supplement combined B12 with folate and B6 so B12-specific effects cannot be isolated.

Study Details

PMID:19515873
Participants:240
Impact:no reduction; included in increased composite endpoint
Trust score:4/5

median survival time

1 evidences

Large phase III RCT showed pemetrexed+cisplatin improved survival and progression outcomes versus cisplatin alone; folic acid and vitamin B12 supplementation given with pemetrexed significantly reduced treatment toxicities.

Trust comment: Large, well-conducted phase III RCT (n=456); vitamin B12 was co-administered with folic acid to reduce chemotherapy toxicity but its isolated effect is not separated.

Study Details

PMID:37068377
Participants:456
Impact:increased (12.1 vs 9.3 months) in pemetrexed/cisplatin arm
Trust score:4/5

time to progression

1 evidences

Large phase III RCT showed pemetrexed+cisplatin improved survival and progression outcomes versus cisplatin alone; folic acid and vitamin B12 supplementation given with pemetrexed significantly reduced treatment toxicities.

Trust comment: Large, well-conducted phase III RCT (n=456); vitamin B12 was co-administered with folic acid to reduce chemotherapy toxicity but its isolated effect is not separated.

Study Details

PMID:37068377
Participants:456
Impact:increased (5.7 vs 3.9 months) in pemetrexed/cisplatin arm
Trust score:4/5

appendicular lean mass (ALM)

1 evidences

In older adults doing resistance exercise, adding low-dose dairy protein plus micronutrients (including 200 IU vitamin D/day) increased muscle mass but did not further improve physical performance.

Trust comment: Randomized controlled trial with objective DXA measures (n=82); multi-nutrient supplement includes B12 so effects cannot be attributed solely to B12.

Study Details

PMID:29300423
Participants:82
Impact:+0.37 kg vs RE only (95% CI 0.16–0.58)
Trust score:4/5

leg lean mass (LLM)

1 evidences

In older adults doing resistance exercise, adding low-dose dairy protein plus micronutrients (including 200 IU vitamin D/day) increased muscle mass but did not further improve physical performance.

Trust comment: Randomized controlled trial with objective DXA measures (n=82); multi-nutrient supplement includes B12 so effects cannot be attributed solely to B12.

Study Details

PMID:29300423
Participants:82
Impact:+0.27 kg vs RE only (95% CI 0.10–0.46)
Trust score:4/5

iron status (ferritin/iron/transferrin saturation)

1 evidences

Daily microalgae smoothies for 14 days increased 25-hydroxyvitamin D2 (from Chlorella) but did not prevent seasonal 25(OH)D3 decline; short intervention also modified lipids and fatty acids.

Trust comment: Randomized controlled study (80 enrolled, 72 completed) with direct nutrient measurements; short duration (14 days) and healthy young cohort limit generalizability.

Study Details

PMID:37049486
Participants:72
Impact:decreased (worsened) in Chlorella group (p<0.05)
Trust score:4/5

serum 5-methyltetrahydrofolate (5-methylTHF)

1 evidences

Randomized older adults received B‑vitamin supplementation that included calcium carbonate in both arms; B‑vitamin arm raised folate forms and lowered homocysteine after 12 months.

Trust comment: Randomized trial with detailed biochemical measures though sample size is modest.

Study Details

PMID:25283139
Participants:59
Impact:increased from 19.6 to 49.1 nmol/L after 6 months
Trust score:4/5

whole-blood 5-methylTHF

1 evidences

Randomized older adults received B‑vitamin supplementation that included calcium carbonate in both arms; B‑vitamin arm raised folate forms and lowered homocysteine after 12 months.

Trust comment: Randomized trial with detailed biochemical measures though sample size is modest.

Study Details

PMID:25283139
Participants:59
Impact:increased from 616 to 1332 nmol/L after 6 months
Trust score:4/5

unmetabolized folic acid (UFA)

1 evidences

Randomized older adults received B‑vitamin supplementation that included calcium carbonate in both arms; B‑vitamin arm raised folate forms and lowered homocysteine after 12 months.

Trust comment: Randomized trial with detailed biochemical measures though sample size is modest.

Study Details

PMID:25283139
Participants:59
Impact:increased number of cases with detectable UFA after supplementation
Trust score:4/5

major or minor depression (end of trial)

1 evidences

Long-term B-vitamin treatment after stroke was associated with a lower hazard of developing major depression compared with placebo.

Trust comment: Long-term randomized, double-blind placebo-controlled trial with clinically meaningful endpoints, though reported completer number is limited.

Study Details

PMID:20976769
Participants:273
Impact:19.1% vs 27.7%; adjusted OR=0.58 (95% CI 0.31–1.09) — trend toward reduction
Trust score:4/5

effect of folic acid supplementation on PTHMs

1 evidences

In arsenic-exposed adults, vitamin B12 (an OCM index) showed sex-specific associations with certain histone modifications; folic acid supplementation (400 μg/d, 12 weeks) did not change global PTHMs.

Trust comment: Moderately sized observational/clinical trial dataset with adjusted analyses showing associations, but causality is not established.

Study Details

PMID:27765800
Participants:324
Impact:no change in global H3K36me2, H3K36me3, H3K79me2 after 12 weeks of 400 μg/d folic acid
Trust score:3/5

serum folate / folate deficiency

1 evidences

Subsample (n=740) from a randomized antenatal trial in rural Nepal: multiple micronutrient supplementation reduced the prevalence of vitamin D deficiency though mean serum 25‑hydroxyvitamin D concentrations were unchanged between first and third trimester.

Trust comment: Large randomized controlled trial with biochemical endpoints in humans; well-reported though functional health outcomes were not measured.

Study Details

PMID:16600929
Participants:740
Impact:folic acid alone or folic acid+iron reduced folate deficiency; MMN increased serum folate
Trust score:4/5

vitamin B12 (plasma)

1 evidences

A 12-week daily food-based snack intervention (green leafy vegetables, dried fruit, milk) produced a small but significant increase in circulating β-carotene but did not change vitamin B12 levels.

Trust comment: Randomized controlled food-based trial with objective nutrient assays but modest sample with some loss to follow-up and possible dietary behavior change confounding.

Study Details

PMID:25677713
Participants:170
Impact:no significant change (no treatment effect)
Trust score:4/5

MCP-1 level / VH-TCFA presence

1 evidences

Substudy of a randomized B‑vitamin trial: folic acid + vitamin B12 increased folate and cobalamin, lowered homocysteine (~2.8 µmol/L, ~29.5%) but did not change MCP‑1 levels or presence of VH‑TCFA.

Trust comment: Randomized trial sub-study with biochemical and imaging endpoints; well-conducted but B12 was given with folate so independent B12 effects are not isolated.

Study Details

PMID:23936148
Participants:102
Impact:no significant effect of folic acid/vitamin B12 treatment on MCP-1 levels or presence of VH‑TCFA lesions
Trust score:4/5

prevalence of hyperhomocysteinaemia

1 evidences

In Crohn's disease patients, elevated homocysteine was common and strongly associated with low bone mineral density and osteoporosis.

Trust comment: Moderate-sized observational study showing a strong association but cross-sectional design prevents causal inference and B12 measured only as a covariate.

Study Details

PMID:17373918
Participants:92
Impact:60% of patients had homocysteine >15 μmol/L
Trust score:3/5

LDL-C oxidation rate and lag time

1 evidences

In a 6-month randomized placebo-controlled trial a multivitamin containing vitamin B12 raised plasma B12 and improved homocysteine and LDL oxidation markers.

Trust comment: Randomized, placebo-controlled trial with objective biochemical endpoints and moderate sample size.

Study Details

PMID:14559932
Participants:182
Impact:oxidation rate −0.39 µmol/min/g protein (p<0.0003); lag time +11.3 min (p<0.003)
Trust score:4/5

GERD symptom regression

1 evidences

A single-blind randomized trial found a multi-ingredient supplement (including vitamin B12) produced complete symptom regression in all treated GERD patients versus 65.7% with omeprazole at 40 days.

Trust comment: Randomized single-blind trial with large sample, but multi-ingredient formula prevents attribution to vitamin B12 alone.

Study Details

PMID:16948779
Participants:351
Impact:100% complete regression in supplement group (176/176) vs 65.7% (115/175) with omeprazole; p<0.05
Trust score:3/5

major vascular events (stroke, MI, vascular death)

1 evidences

Large double-blind randomized trial of B-vitamin supplementation (including B12) after stroke/TIA found it was safe and produced a small, borderline reduction in major vascular events (not clearly clinically significant).

Trust comment: Large, multicenter double-blind placebo-controlled RCT with long follow-up and robust outcome assessment.

Study Details

PMID:20688574
Participants:8164
Impact:incidence 15% (B vitamins) vs 17% (placebo); RR 0.91 (95% CI 0.82–1.00), p=0.05; absolute risk reduction ~1.56%
Trust score:5/5

ferritin

1 evidences

Double-blind randomized trial in pregnant women showed that a micronutrient-fortified beverage (including iodine) increased hemoglobin and ferritin and reduced risk of anemia and iron deficiency.

Trust comment: Randomized double-blind controlled trial with clear biochemical endpoints but short supplementation duration and combined micronutrient formulation.

Study Details

PMID:12730420
Participants:259
Impact:+3 µg/L (end of 8 weeks)
Trust score:4/5

risk of anemia / iron deficiency anemia

1 evidences

Double-blind randomized trial in pregnant women showed that a micronutrient-fortified beverage (including iodine) increased hemoglobin and ferritin and reduced risk of anemia and iron deficiency.

Trust comment: Randomized double-blind controlled trial with clear biochemical endpoints but short supplementation duration and combined micronutrient formulation.

Study Details

PMID:12730420
Participants:259
Impact:risk reductions: anemia −51%, iron deficiency anemia −56%
Trust score:4/5

serum/ plasma B‑vitamin concentrations (folate, B6, B12)

1 evidences

In adults with prior CVD, daily low‑dose B‑vitamin supplementation (5‑methyl‑THF 560 μg, B6 3 mg, B12 20 μg) produced a large tHcy decrease after 1 year (~‑26.3%), raised vitamin biomarkers in year 1 (then plateaued), and the homocysteine response was modified by MTHFR genotype (TT showed larger initial decrease).

Trust comment: Large, multicenter, double‑blind randomized placebo‑controlled trial with long follow‑up and centralized assays; high internal validity for B‑vitamin effects on tHcy.

Study Details

PMID:29813097
Participants:2501
Impact:significant increase during first year (p<0.0001), then plateau
Trust score:5/5

homocysteine (Hcy)

4 evidences

In 120 AD patients, 6 months of daily folic acid plus vitamin B12 modestly improved some cognitive subtests, lowered homocysteine and TNFα, and raised B12 and SAM/ SAM:SAH.

Trust comment: Single-center randomized placebo-controlled trial with objective biochemical and cognitive endpoints; single-blind and moderate sample size limit generalizability.

Study Details

PMID:34101780
Participants:120
Impact:−3.10 µmol/L (β=−3.101; P<0.001)
Trust score:4/5

Randomized, unblinded 4-week dose-response trial in 30 long-term vegetarians testing roasted nori (5 g/day or 8 g/day) vs control; assessed serum B12, holoTC, Hcy, MMA and combined 4cB12 index.

Trust comment: Randomized food-based trial with comprehensive biomarkers showing short-term improvements, but small sample, short duration and lack of blinding to food limit strength and generalizability.

Study Details

PMID:39352476
Participants:30
Impact:Decreased (low-dose −1.7 µmol/L; high-dose −3.5 µmol/L; both vs control significant)
Trust score:3/5

In levodopa-treated Parkinson patients, combined vitamin B12 and folate supplementation significantly lowered plasma homocysteine compared with no supplementation.

Trust comment: Randomized controlled design but small sample size limits generalizability and precision.

Study Details

PMID:33992189
Participants:42
Impact:significant decrease with vitamin B12 + folate (P < 0.001)
Trust score:3/5

Pooled analyses from several randomized, double-blind trials and an open-label extension testing Souvenaid (Fortasyn Connect) versus control in mild/mild-to-moderate AD; measured plasma micronutrients and fatty acid incorporation.

Trust comment: Multiple randomized, double-blind clinical trials with centralized assays and consistent reproducible increases in circulating vitamin B12 and related biomarkers support high confidence in the finding.

Study Details

PMID:26213579
Participants:1199
Impact:decreased with active product (consistent with B-vitamin increases; P<0.001)
Trust score:5/5

Visual-constructional ability

1 evidences

Prospective case-control study of vitamin B12 in cognitive impairment: B12-treated patients showed improvements in attention/calculation and visuoconstruction vs control at 6 months.

Trust comment: Prospective, randomized case-control study with moderate sample size but limited reporting of effect sizes and blinding.

Study Details

PMID:37334792
Participants:115
Impact:Improved (p<0.05)
Trust score:3/5

Serum vitamin B12

51 evidences

Nine-month controlled school-based supplement delivering multiple micronutrients including B12 improved hemoglobin and serum vitamin B12 compared with control schools.

Trust comment: Controlled pre-post school study with substantial sample size but non-randomized cluster design limits causal inference.

Study Details

PMID:17542110
Participants:413
Impact:mean gain +687.6 pg/mL (experimental) vs +233.3 pg/mL (control) over 9 months; P<0.05
Trust score:3/5

In a large 7.3‑year randomized trial (n=3411), garlic increased serum folate and a vitamin+selenium supplement increased glutathione, but neither intervention changed serum vitamin B12 or homocysteine.

Trust comment: Large, long-term randomized trial with robust sample size for clinical endpoints though biochemical substudies involved selected samples.

Study Details

PMID:19056661
Participants:3411
Impact:no change after garlic or micronutrient supplementation over 7.3 years
Trust score:4/5

In 90 type 2 diabetic patients with neuropathy and low B12, 12 months of 1000 µg methylcobalamin normalized B12 and improved multiple neuropathy measures (nerve conduction, pain, sudomotor function) and quality of life.

Trust comment: Randomized, double-blind, placebo-controlled 1-year trial with objective neurophysiological outcomes; single-center and limited to metformin-treated diabetics.

Study Details

PMID:33513879
Participants:90
Impact:Increase from 232.0 to 776.7 pmol/L (+≈544.7 pmol/L)
Trust score:4/5

In this 4.3-year randomized placebo-controlled trial (initial n=390; 277 completed), metformin progressively lowered serum B12 and increased the risk of B12 deficiency and raised homocysteine in those who became deficient.

Trust comment: Large long-term randomized, placebo-controlled trial with frequent biochemical sampling and robust analyses; high internal validity for metformin effect on B12.

Study Details

PMID:20488910
Participants:277
Impact:Decreased ≈19% (−89.8 pmol/L) vs placebo (P<0.001)
Trust score:5/5

Combined and separate vitamin D3+B12 supplementation over 12 weeks raised serum 25(OH)D and B12; the single-tablet formulation produced larger average increases.

Trust comment: Randomized multicenter trial showing clear biochemical responses; open-label design, small completed sample (n=129) and short duration limit strength of clinical conclusions.

Study Details

PMID:39940277
Participants:129
Impact:Group A (compound) mean increase ~+120.5% (from 200.6 to 438.2), Group B (separate) +90.5% (both p<0.01)
Trust score:3/5

Children with severe acute malnutrition received RUTF and showed improved vitamin B12 biomarker status at discharge, though some remained deficient.

Trust comment: Randomized trial sub-study with objective biomarker measurements and moderate-to-large sample, though long storage of samples and sub-study design are limitations.

Study Details

PMID:37630687
Participants:361
Impact:Increase from admission to discharge (directional increase reported)
Trust score:4/5

Randomized, unblinded 4-week dose-response trial in 30 long-term vegetarians testing roasted nori (5 g/day or 8 g/day) vs control; assessed serum B12, holoTC, Hcy, MMA and combined 4cB12 index.

Trust comment: Randomized food-based trial with comprehensive biomarkers showing short-term improvements, but small sample, short duration and lack of blinding to food limit strength and generalizability.

Study Details

PMID:39352476
Participants:30
Impact:Increased (low-dose group median +49.8 pmol/L; high-dose +62 pmol/L; both vs control p≤0.005)
Trust score:3/5

Intranasal B12 given either as a loading regimen or every-3-day dosing raised blood B12 and corrected related metabolic markers; loading gave faster larger early rises.

Trust comment: Randomized controlled trial in elderly B12-deficient patients with repeated biomarker measurements and clear biomarker responses.

Study Details

PMID:38747399
Participants:60
Impact:rapid increase; loading: median 1090 pmol/L at day 14; no-loading: median 717 pmol/L at day 90 (declined to 530 pmol/L after weekly dosing by day 90)
Trust score:4/5

Daily use of B12-fortified toothpaste for 12 weeks increased circulating B12 markers and lowered MMA and homocysteine in vegans compared with placebo.

Trust comment: Double-blind, randomized, placebo-controlled trial in vegans with consistent biomarker improvements supports reliable effect.

Study Details

PMID:28052884
Participants:66
Impact:mean change +81 ±135 pmol/L (B12) vs −27 ±64 pmol/L (placebo)
Trust score:4/5

B12-enriched toothpaste used for 3 months raised serum B12 and holoTC and lowered homocysteine in elderly participants compared with placebo.

Trust comment: Well-conducted double-blind RCT in elderly with significant biomarker changes and clear reporting.

Study Details

PMID:30680547
Participants:92
Impact:post-intervention mean 368 vs 295 pmol/L; mean change +54 ±74 pmol/L (B12) vs +3 ±60 pmol/L (placebo)
Trust score:4/5

Adding folic acid plus vitamin B12 during isotretinoin therapy increased folate and B12 levels and lowered homocysteine compared with isotretinoin alone.

Trust comment: Randomized trial shows biochemical benefits but combined folic acid+B12 intervention and short duration limit attribution solely to B12.

Study Details

PMID:30207526
Participants:66
Impact:significant increase in supplementation group (P=0.0002)
Trust score:3/5

8-week double-blind RCT in adults at increased diabetes risk testing salmon fish protein supplement vs placebo and measuring blood micronutrient concentrations.

Trust comment: Well-conducted double-blind randomized trial with objective lab measures; secondary analysis but consistent biochemical findings.

Study Details

PMID:35362766
Participants:74
Impact:geometric mean increase from 304 to 359 pmol/L (adjusted effect logB 0.14; p=0.004)
Trust score:4/5

Intramuscular 1 mg B12 increased serum B12 but did not significantly lower plasma homocysteine over 3 months in haemodialysis patients.

Trust comment: Double-blind RCT but small sample (n=28) limits ability to detect modest homocysteine changes.

Study Details

PMID:14656250
Participants:28
Impact:significantly higher in treatment vs placebo (difference 217.7 pmol/L; 95% CI 103.0–332.5; P<0.001)
Trust score:3/5

A 4-week vegan diet rapidly lowered circulating holo-transcobalamin and serum B12 but did not change cellular markers (MMA, homocysteine) or cause clinical deficiency.

Trust comment: Well-conducted randomized controlled trial in healthy volunteers with objective biomarkers, but short duration and modest sample size.

Study Details

PMID:31752105
Participants:53
Impact:decreased 362.9 → 296.1 ng/mL in vegan group (p<0.001)
Trust score:4/5

People with relapsing-remitting MS on two dietary interventions plus supplements had improved mood over 24 weeks; serum B12 rose and homocysteine fell, but those blood changes did not explain the mood improvement.

Trust comment: Secondary analysis of a randomized trial with moderate sample size and repeated measures; results plausible though mediation analyses were negative.

Study Details

PMID:37148578
Participants:77
Impact:increase (significant at 12 and 24 weeks); serum homocysteine decreased (significant)
Trust score:4/5

In insulin-treated type 2 diabetics, 16 weeks of added metformin reduced serum folate and vitamin B12 and produced a modest increase in homocysteine compared with placebo.

Trust comment: Large randomized placebo-controlled trial with clear, clinically relevant biochemical endpoints and low risk of bias.

Study Details

PMID:14535967
Participants:353
Impact:decrease ~14% (95% CI -4.2 to -24%; P<0.0001)
Trust score:5/5

In hemodialysis patients, high-dose folic acid combined with 1 mg/day vitamin B12 (and higher folic acid dose) produced the largest reduction in plasma homocysteine over 8 weeks.

Trust comment: Small randomized study in HD patients showing biochemical effects; limited sample size lowers generalizability.

Study Details

PMID:19736473
Participants:36
Impact:significant increase in group IV (P=0.006)
Trust score:3/5

Substudy of a double-blind RCT: metformin (1 g twice daily) plus insulin modestly increased early orthostatic blood pressure drop versus placebo; metformin reduced serum B12 modestly.

Trust comment: Large double-blind randomized trial substudy with objective autonomic and biochemical measures; substudy analyses limit primary focus but methods are robust.

Study Details

PMID:32979921
Participants:372
Impact:decreased in metformin group by −19.9 pmol/L (95% CI −32.12; −7.72); P<0.01
Trust score:4/5

In older adults with mild cognitive impairment, 6 months of folic acid increased serum folate and vitamin B12, lowered homocysteine, and led to small improvements in some cognitive scores.

Trust comment: Randomized controlled trial with 159 completers showing biomarker and modest cognitive changes, though intervention was folic acid rather than B12 supplementation.

Study Details

PMID:26508298
Participants:159
Impact:increased (p=0.022) with folic acid treatment
Trust score:4/5

Moderate alcohol intake modestly decreased serum B12 and slightly increased homocysteine in healthy postmenopausal women.

Trust comment: Randomized, diet-controlled crossover trial with clear within-subject comparisons but modest sample size.

Study Details

PMID:15138463
Participants:53
Impact:-5% (461.45 vs 440.25 pg/mL; 0 to 30 g/day; P=0.03)
Trust score:4/5

Premenopausal Indian women taking a multi-micronutrient, protein-rich supplement containing calcium had improved bone turnover markers and some micronutrient status after 6 months.

Trust comment: Well-designed double-blind RCT with pre-specified primary endpoints and adequate reporting, though some between-group differences were not significant.

Study Details

PMID:33530298
Participants:102
Impact:increase (mean +50 pmol/L, ≈+35% in test group at 6 months; significant at month 3)
Trust score:4/5

One-month randomized trial in elderly inpatients showing 50 µg oral cyanocobalamin raises serum B12; 10 µg did not differ from placebo.

Trust comment: Randomized double-blind design but small sample and short duration limit generalizability.

Study Details

PMID:12028259
Participants:31
Impact:mean increase: +51.7% (50 µg group) vs +11.7% (placebo); 50 µg vs placebo P=0.044
Trust score:3/5

Young men with high homocysteine took B-vitamin supplements for 8 weeks; homocysteine fell but artery function did not change.

Trust comment: Double-blind randomized trial in 40 subjects with clear endpoints but modest sample size.

Study Details

PMID:12430779
Participants:40
Impact:increased (in hyperhomocysteinemic group)
Trust score:4/5

Compared dietary intake and biochemical markers in depressed patients vs controls; depressed group had poorer diet and lower serum B12 and folate.

Trust comment: Case-control study with direct biochemical measures but small sample size and self-reported diet data limit strength of inference.

Study Details

PMID:26413529
Participants:59
Impact:decreased (significant vs controls, p<0.05)
Trust score:3/5

In a randomized crossover herring intervention, serum vitamin B12 and selenium increased after 6 weeks of high fish intake while 25-hydroxy vitamin D3 did not change significantly.

Trust comment: Randomized cross-over with objective biomarker measurements and significant changes, but small sample size.

Study Details

PMID:24292746
Participants:32
Impact:+8.9% (p=0.008) after 6-week herring intervention
Trust score:4/5

Daily multivitamin supplementation for 8 weeks increased vitamin B12 and folate levels, lowered homocysteine, and improved contextual recognition memory in older men.

Trust comment: Well-controlled RCT but uses a multinutrient product, so improvements cannot be solely attributed to vitamin B12.

Study Details

PMID:22711385
Participants:51
Impact:increased (post-supplementation; no numeric value reported)
Trust score:3/5

Alternate supplementation with vitamin B12 and folic acid lowered homocysteine in dialysis patients; effect reversed after washout and B12 levels rose with diffusive haemodialysis.

Trust comment: Randomized, blinded study in 74 patients with clear measurements though results influenced by dialysis modality and washout.

Study Details

PMID:24652221
Participants:74
Impact:increased with diffusive haemodialysis
Trust score:4/5

In a randomized double-blind crossover pilot, both natural and synthetic B-complex supplements raised serum B vitamins (including B12) and reduced homocysteine and some metabolic markers.

Trust comment: Randomized double-blind crossover design but small pilot sample (n=30) limits precision and external validity.

Study Details

PMID:32189314
Participants:30
Impact:increased (+16% after first supplementation period for natural B complex)
Trust score:3/5

Cross-sectional study found common vitamin B12 and folate deficiencies and a high prevalence of elevated homocysteine among adolescent Afghan refugees; lower B12 associated with higher homocysteine.

Trust comment: Well-described cross-sectional human study showing strong associations but cannot prove causality.

Study Details

PMID:35565715
Participants:190
Impact:Lower serum B12 observed in participants with hyperhomocysteinemia; multivariable association OR 0.29 (95% CI 0.14–0.62, p < 0.01) for B12 vs hyperhomocysteinemia
Trust score:3/5

A prepared meal plan fortified with micronutrients (including recommended B12) for 10 weeks raised folate and vitamin B12 and reduced serum total homocysteine in high‑risk adults.

Trust comment: Large multicenter randomized trial with objective blood biomarkers and clear statistical significance supporting changes in homocysteine and B12.

Study Details

PMID:10539749
Participants:491
Impact:increased (significant vs self-selected diet)
Trust score:4/5

Men with type 2 diabetes given folic acid 5 mg/day for 8 weeks had lower homocysteine and malondialdehyde and improved total antioxidant capacity; serum folate and vitamin B12 levels also increased.

Trust comment: Randomized double-blind trial in humans with clear biomarker changes, but small sample size (n=68) and the intervention was folic acid rather than vitamin B12 directly.

Study Details

PMID:21896879
Participants:68
Impact:increased (reported improvement)
Trust score:3/5

16-week multivitamin (including B12) raised blood B12 and B6 and produced beneficial changes in homocysteine, CRP and some lipid/oxidative stress markers, but did not improve cognitive test performance in healthy 55–65 y olds.

Trust comment: Randomized double-blind placebo-controlled trials with objective blood biomarkers and adequate sample size by gender, providing credible evidence of B12 level increases from multivitamin supplementation.

Study Details

PMID:25996285
Participants:116
Impact:increased (women: 300 → 435 pmol/L; men: 265 → 342 pmol/L; p<0.001)
Trust score:4/5

Randomized trial in aged care residents: a daily multivitamin raised serum 25(OH)D and improved a heel ultrasound bone measure, with a trend to fewer falls.

Trust comment: Randomized controlled trial in institutionalized older adults with objective nutrient and bone outcomes; moderate sample size and clinically relevant biomarker changes.

Study Details

PMID:18043700
Participants:92
Impact:increased (mean difference +178.0 ±40.3 pmol/L; P<0.001)
Trust score:4/5

In non-diabetic men with CHD, metformin raised homocysteine and reduced serum B12 over 12–40 weeks.

Trust comment: Randomized prospective study with objective biochemical outcomes, though open-label and modest sample size.

Study Details

PMID:9350072
Participants:60
Impact:-13.4% at 12 weeks; -17.7% at 40 weeks (metformin vs control)
Trust score:4/5

Two randomized placebo-controlled trials in women with PCOS found metformin did not change homocysteine; nonpregnant women showed reductions in folate and B12.

Trust comment: Randomized placebo-controlled trials with clear biochemical outcomes; combined sample moderate in size.

Study Details

PMID:17364275
Participants:101
Impact:decreased with metformin in nonpregnant women
Trust score:4/5

A 2-year community nutrition program providing fortified foods did not significantly improve vitamin B12 status in older Chilean adults compared with control.

Trust comment: Large cluster randomized trial sub-study with substantial sample (351 analyzed) and intention-to-treat analysis; outcomes measured at baseline and 24 months but program adherence and dose may limit effectiveness.

Study Details

PMID:24016218
Participants:351
Impact:no significant difference (PACAM change −34.8 pmol/L vs control −43.4 pmol/L; multilevel model: no significant improvement)
Trust score:4/5

Randomized controlled study of low- vs high-dose hormone therapy versus control in postmenopausal women assessing fasting and post-methionine homocysteine and B-vitamin levels.

Trust comment: Randomized controlled design with clear biochemical outcomes, but small sample size and indirect focus on vitamin B12 (as an affected biomarker) limit strength for B12-specific conclusions.

Study Details

PMID:17000586
Participants:48
Impact:Decreased after low-dose HT by −12.2% (±6.6%; P<0.04) and after high-dose HT by −13.9% (±6.1%; P<0.01)
Trust score:3/5

High-dose folate supplementation markedly lowered very high homocysteine levels in peritoneal dialysis patients; serum B12 did not change.

Trust comment: Randomized clinical trial in a specific patient population with clear biochemical outcomes and reasonable sample size.

Study Details

PMID:11598393
Participants:59
Impact:no change
Trust score:4/5

In a controlled feeding RCT (n=118), a combination diet (fruits, vegetables, low‑fat dairy, reduced fat) modestly lowered fasting homocysteine compared with a control diet; changes in serum vitamin B12 were not associated with homocysteine change.

Trust comment: Randomized, controlled feeding trial with rigorous dietary control, moderate sample size and clear biochemical outcome reporting.

Study Details

PMID:10952952
Participants:118
Impact:no association with homocysteine change (P=0.64)
Trust score:4/5

28-day randomized placebo-controlled pilot tested folic acid, fish oil and calcium on cancer risk markers; vitamin B12 was measured but not supplemented.

Trust comment: Randomized placebo-controlled design with objective biochemical outcomes but short duration and modest sample size.

Study Details

PMID:16136044
Participants:98
Impact:+11% (treatment) vs -7% (control); P=0.0044
Trust score:4/5

Moderately malnourished pregnant women received one of three supplements for 10 weeks; RUSF limited the decline in vitamin B12 and produced the largest vitamin D increase.

Trust comment: Large randomized controlled trial sub-study with rigorous sampling and adjustments; some loss to follow-up and limited intervention duration reduce certainty.

Study Details

PMID:29986492
Participants:273
Impact:RUSF group: ~3% decrease from enrollment to week 10 vs CSB+UNIMMAP ~8% and CSB+IFA ~20% decrease (p=0.001); RUSF had significantly lower percent B12 deficient (p<0.001)
Trust score:4/5

Pregnant women given different iron doses (one tablet contained added zinc) showed no significant between-group differences in serum zinc during pregnancy.

Trust comment: Randomized allocation in humans with repeated biomarker monitoring, but small sample and limited scope for vitamin B12-specific effects.

Study Details

PMID:11787984
Participants:67
Impact:no statistically significant difference between 100 mg and 15 mg iron (with added micronutrients) groups during pregnancy
Trust score:3/5

In older adults doing resistance exercise, adding low-dose dairy protein plus micronutrients (including 200 IU vitamin D/day) increased muscle mass but did not further improve physical performance.

Trust comment: Randomized controlled trial with objective DXA measures (n=82); multi-nutrient supplement includes B12 so effects cannot be attributed solely to B12.

Study Details

PMID:29300423
Participants:82
Impact:+72.4 pg/mL (95% CI 12.9–131.9) vs RE only
Trust score:4/5

Daily microalgae smoothies for 14 days increased 25-hydroxyvitamin D2 (from Chlorella) but did not prevent seasonal 25(OH)D3 decline; short intervention also modified lipids and fatty acids.

Trust comment: Randomized controlled study (80 enrolled, 72 completed) with direct nutrient measurements; short duration (14 days) and healthy young cohort limit generalizability.

Study Details

PMID:37049486
Participants:72
Impact:increased from 244 to 281 nmol/L in Chlorella group (+37 nmol/L, p<0.05) but no significant between-group differences
Trust score:4/5

Nested case–control study measured serum folate, B6, B12, riboflavin, and homocysteine to assess associations with colon and rectal cancer risk in Finnish men.

Trust comment: Prospective nested case–control with matched controls and clear biomarker measurement; vitamin B12 showed no association with colorectal cancer risk.

Study Details

PMID:18990766
Participants:556
Impact:No association with colon or rectal cancer risk (no significant relationship detected)
Trust score:4/5

After weight loss and 64-week follow-up, higher reported protein intake correlated with greater weight-loss maintenance; the high-protein group showed higher serum vitamin B12 vs the high-carbohydrate group.

Trust comment: Long follow-up and completed sample but modest size and limited detail in abstract about randomization/control; observational relations within trial limit causal certainty for B12 finding.

Study Details

PMID:18175733
Participants:79
Impact:Higher serum vitamin B12 observed in the high-protein group versus high-carbohydrate group (no absolute values reported in abstract).
Trust score:3/5

12-week RCT in overweight/obese young women found lifestyle intervention produced greater weight and fat loss than metformin or placebo; serum vitamin B12 did not change significantly between groups.

Trust comment: Large randomized trial with clear weight/composition endpoints and reliable measurements; vitamin B12 was measured and showed no group differences.

Study Details

PMID:20163941
Participants:203
Impact:No significant time-by-group effects in serum vitamin B12 at 12 weeks across metformin, placebo, or lifestyle intervention groups.
Trust score:4/5

In haemodialysis patients, changing rHuEpo route did not alter measured vitamin B12 levels.

Trust comment: Small randomized study in humans with direct measurement of vitamin B12 but primary focus was erythropoietin administration rather than B12 effects.

Study Details

PMID:9681726
Participants:30
Impact:no change between IV and SC administration groups
Trust score:3/5

Fenofibrate increased homocysteine but this was not associated with changes in vitamin B12 levels.

Trust comment: Large clinical trial cohort (418) with angiographic outcomes and measured vitamin B12; secondary analysis appropriately reported.

Study Details

PMID:15050487
Participants:418
Impact:no change associated with fenofibrate-induced tHcy increase
Trust score:4/5

In obese women, a high-protein diet increased serum B12 while a high-carbohydrate diet decreased it.

Trust comment: Randomized dietary intervention with 100 completers and direct biochemical measurements showing significant differences in serum B12.

Study Details

PMID:15941879
Participants:100
Impact:+9% (high-protein diet) vs -13% (high-carbohydrate diet); P<0.0001 between diets
Trust score:4/5

46 bariatric surgery patients randomized to probiotics or placebo: at 4 months probiotics improved LBP, TNF-α, vitamin B12 and vitamin D3 and weight loss versus placebo, but most effects did not persist at 13 months except reduced MDA.

Trust comment: Double-blind randomized trial with objective biomarkers (n=46); modest sample size and some effects were transient, limiting long-term confidence.

Study Details

PMID:30612325
Participants:46
Impact:increased (month 4)
Trust score:3/5

pain score

2 evidences

In 90 type 2 diabetic patients with neuropathy and low B12, 12 months of 1000 µg methylcobalamin normalized B12 and improved multiple neuropathy measures (nerve conduction, pain, sudomotor function) and quality of life.

Trust comment: Randomized, double-blind, placebo-controlled 1-year trial with objective neurophysiological outcomes; single-center and limited to metformin-treated diabetics.

Study Details

PMID:33513879
Participants:90
Impact:Decreased (~7% reduction; p<0.001)
Trust score:4/5

Local injection of methylcobalamin plus lidocaine provided greater pain relief and reduced analgesic use compared with systemic methylcobalamin in subacute ophthalmic herpetic neuralgia.

Trust comment: Randomized phase III trial with clear endpoints and clinically meaningful differences; single-center limits external validity.

Study Details

PMID:32372561
Participants:105
Impact:LM group reduced from 6.7 to 2.8 vs IM 6.8→4.9 and OM 6.7→5.1 (LM superior)
Trust score:4/5

Anxiety (SCAARED)

1 evidences

In a general adult sample randomized to B6, B12, or placebo for ~1 month, vitamin B12 showed a small/near-significant reduction in self-reported anxiety and a trend toward increased visual contrast thresholds (greater surround suppression).

Trust comment: Large randomized double-blind trial but exploratory with multiple outcomes, variable completion per measure, short (≈1 month) supplementation and no serum B12 verification for participants.

Study Details

PMID:35851507
Participants:478
Impact:Reduced (group effect for B12: p=0.045; within-group trend p≈0.069)
Trust score:3/5

Risk of B12 deficiency

1 evidences

In this 4.3-year randomized placebo-controlled trial (initial n=390; 277 completed), metformin progressively lowered serum B12 and increased the risk of B12 deficiency and raised homocysteine in those who became deficient.

Trust comment: Large long-term randomized, placebo-controlled trial with frequent biochemical sampling and robust analyses; high internal validity for metformin effect on B12.

Study Details

PMID:20488910
Participants:277
Impact:Absolute risk +7.2 percentage points (number needed to harm ≈13.8 over 4.3 years; P=0.004)
Trust score:5/5

Serum vitamin B12 increase

1 evidences

In 80 children with nutritional macrocytic anemia, parenteral vitamin B12 produced larger increases in serum B12 and hemoglobin at 3 months than oral B12.

Trust comment: Randomized controlled pediatric trial showing greater biochemical and hematologic response with parenteral vs oral B12; single-center and open-label but randomized.

Study Details

PMID:35642923
Participants:80
Impact:Median rise: IM 600 pg/mL vs oral 399 pg/mL (P=0.016)
Trust score:4/5

plasma cobalamin/folate associations (observational)

1 evidences

Children given vitamin B12 and/or folic acid in early life showed no difference in cognition 6 years later.

Trust comment: Large randomized, double-blind trial with long follow-up and high re-enrollment (791) though outcomes were null; methods and follow-up are robust.

Study Details

PMID:32019814
Participants:791
Impact:associations with cognition in unadjusted models disappeared after adjustment
Trust score:4/5

plasma folate

5 evidences

Compared dolutegravir vs non-dolutegravir ART; measured folate, B12 and MCV — B12 levels did not differ between arms.

Trust comment: Randomized trial sub-study with prospective measurements and clear statistical adjustments, but outcome pertains to ART effects on B12/folate rather than B12 supplementation.

Study Details

PMID:37766505
Participants:229
Impact:higher in DTG arm: +1.6 ng/ml at week 4 and +2.7 ng/ml at ≥96 weeks (DTG vs SOC)
Trust score:4/5

Pre-op IV B-vitamin (including B12) massively raised B12/folate but did not prevent the nitrous oxide–induced rise in homocysteine.

Trust comment: Randomized study with objective biochemical outcomes and clear measurements, but modest sample size.

Study Details

PMID:20477781
Participants:59
Impact:+12-fold (first postoperative measurement)
Trust score:4/5

Rural and urban Mexican women ate model diets in a crossover; homocysteine and B12/folate were measured over 4 hours.

Trust comment: Controlled crossover with frequent sampling but small sample size limits generalizability.

Study Details

PMID:14559315
Participants:33
Impact:lower in rural vs urban (P<0.01)
Trust score:4/5

An 8-week multivitamin/mineral supplement raised B-vitamin levels (including B12) and lowered homocysteine in older adults.

Trust comment: Randomized, double-blind, placebo-controlled trial with clear biochemical outcomes, though intervention was a multivitamin rather than isolated B12.

Study Details

PMID:11110875
Participants:80
Impact:+41.6%
Trust score:4/5

28-day randomized placebo-controlled pilot tested folic acid, fish oil and calcium on cancer risk markers; vitamin B12 was measured but not supplemented.

Trust comment: Randomized placebo-controlled design with objective biochemical outcomes but short duration and modest sample size.

Study Details

PMID:16136044
Participants:98
Impact:+123% (treatment) vs +8% (control); P<0.000001
Trust score:4/5

vitamin B12 concentration

14 evidences

A fortified drink given 6 days/week for 8 weeks reduced vitamin B12 deficiency prevalence and increased vitamin B12 concentration and hemoglobin in schoolchildren.

Trust comment: Randomized, double-blind, placebo-controlled trial with adequate sample size and clear biomarker outcomes.

Study Details

PMID:23232585
Participants:246
Impact:increased (P<0.001)
Trust score:4/5

120 women with type 2 diabetes on a low-calorie diet were given a multivitamin-mineral complex for 3 weeks; those receiving the complex showed greater improvements in some micronutrient levels and glycemia.

Trust comment: Controlled clinical diet study with adequate sample size but short duration and unclear randomization/allocation methods.

Study Details

PMID:25300112
Participants:120
Impact:+significant increase after 3 weeks (main group)
Trust score:3/5

Compared dolutegravir vs non-dolutegravir ART; measured folate, B12 and MCV — B12 levels did not differ between arms.

Trust comment: Randomized trial sub-study with prospective measurements and clear statistical adjustments, but outcome pertains to ART effects on B12/folate rather than B12 supplementation.

Study Details

PMID:37766505
Participants:229
Impact:no difference at ≥96 weeks (difference −26 pg/ml, p=0.42)
Trust score:4/5

Daily low-dose folic acid, vitamin B6, vitamin B12 and betaine for 12 weeks reduced plasma homocysteine in Chinese adults with hyperhomocysteinemia compared with placebo.

Trust comment: Randomized, double-blind, placebo-controlled trial with objective biochemical endpoints though relatively small sample and short duration.

Study Details

PMID:36717385
Participants:86
Impact:Increase (reported +83 units at 12 weeks in supplement group vs baseline)
Trust score:4/5

In newly diagnosed type 2 diabetes, 6 weeks of metformin decreased vitamin B12 and folate and increased homocysteine; rosiglitazone decreased homocysteine and did not change B12 or folate.

Trust comment: Interventional treatment study with objective biochemical outcomes but short duration (6 weeks) and modest sample size.

Study Details

PMID:17331860
Participants:165
Impact:metformin: -20.17 pg/ml
Trust score:3/5

Randomized double-blind placebo-controlled trial in frail elderly showing enriched drink increased plasma B12, lowered homocysteine, and improved some cognitive test scores over 6 months.

Trust comment: Randomized, double-blind, placebo-controlled design but substantial attrition (67 completers), moderate sample for cognitive endpoints.

Study Details

PMID:15814873
Participants:67
Impact:increased (mean change ~+105 vs +8 pmol/L; p=0.003)
Trust score:4/5

Community-based case-control study comparing hypertensive patients and controls; found no difference in homocysteine but higher folate and B12 concentrations in hypertensive subjects.

Trust comment: Observational case-control design can show associations but not causation; sample size moderate and assays reported.

Study Details

PMID:11860783
Participants:297
Impact:higher in hypertensive subjects (magnitude not reported)
Trust score:3/5

In haemodialysis patients, alternating vitamin B12 and folic acid lowered homocysteine; effects depended on genotype and dialysis membrane type.

Trust comment: Randomized blinded crossover in 74 HD patients; moderate quality but small, specific population limits generalizability.

Study Details

PMID:17342693
Participants:74
Impact:increased in patients on diffusive haemodialysis (significant)
Trust score:3/5

In metformin-treated diabetic patients, supplementation with folate, vitamin B12 and B6 lowered homocysteine, raised B12 levels, and improved small-artery elasticity after 4 months.

Trust comment: Double-blind, placebo-controlled RCT with clear biomarker and functional endpoints but small sample size and short follow-up.

Study Details

PMID:18206891
Participants:60
Impact:Post-treatment B12 738.1±279.9 pg/ml vs Placebo 566.1±167.4 pg/ml (P=0.007)
Trust score:4/5

A targeted medical nutrition therapy increased folate (and B6 and B12) levels and substantially reduced serum lipids in hyperlipidemic patients, while plasma homocysteine was unchanged.

Trust comment: Randomized small trial with clear clinical endpoints and dietary counseling, but limited by modest sample size and short-term follow-up (12 weeks).

Study Details

PMID:19083486
Participants:40
Impact:increased in MNT group (statistically significant, P < .05)
Trust score:3/5

Three months of daily micronutrient packs increased vitamin D and other micronutrient levels and improved antioxidant markers in older institutionalized adults.

Trust comment: Randomized controlled trial with clear biochemical endpoints and significant changes, moderate sample size and short (3-month) follow-up.

Study Details

PMID:31464392
Participants:98
Impact:+128.8 ±34.8 pmol/L (intervention) vs +13.3 ±16.0 pmol/L (control) change over 3 months
Trust score:4/5

A 4-week vitamin supplement increased vitamin B12 and other vitamin levels in children; convalescent children also showed increases in appetite, weight and muscle strength.

Trust comment: Small randomized placebo-controlled study with short duration; biochemical increases shown but sample is small.

Study Details

PMID:10356941
Participants:40
Impact:+significant increase after 4 weeks
Trust score:3/5

After gastric bypass, vitamin B12 levels fell in both iron-supplemented and placebo groups over time; iron prevented iron deficiency but did not prevent B12 decline.

Trust comment: Prospective double-blind randomized trial with clear hematologic follow-up, though B12 was not the primary intervention focus.

Study Details

PMID:9688002
Participants:56
Impact:-significant decrease compared with preoperative values in both groups
Trust score:4/5

Daily Lactococcus cremoris on oat flakes reduced inflammatory marker hs‑CRP and cortisol and produced a small within‑group increase in vitamin B12, though between‑group B12 differences were not significant.

Trust comment: Randomized placebo‑controlled single‑blind trial with modest sample size; some significant within‑group changes but limited between‑group B12 effects.

Study Details

PMID:40572644
Participants:46
Impact:small within‑group increase in probiotic group (p = 0.036) but no between‑group difference (p = 0.762)
Trust score:3/5

early postoperative low back pain (VAS)

1 evidences

Epidural dexamethasone plus vitamin B12 after PEID reduced early postoperative pain and inflammatory markers and shortened hospital stay, with no long-term differences.

Trust comment: Randomized, double-blind RCT with complete 6-month follow-up but small sample (n=56) which limits precision and generalizability.

Study Details

PMID:39506779
Participants:56
Impact:reduced (POD1 −0.53 to −0.93 points range vs surgery alone; P<0.05)
Trust score:4/5

inflammatory markers (TNF-α, IL-6, PGE2)

1 evidences

Epidural dexamethasone plus vitamin B12 after PEID reduced early postoperative pain and inflammatory markers and shortened hospital stay, with no long-term differences.

Trust comment: Randomized, double-blind RCT with complete 6-month follow-up but small sample (n=56) which limits precision and generalizability.

Study Details

PMID:39506779
Participants:56
Impact:lower on POD3 in combined treatment (P<0.05)
Trust score:4/5

total homocysteine (tHcy)

28 evidences

Six-month early-life supplementation with vitamin B12 + folic acid led to lower homocysteine 6–7 years later; no overall effects on leptin/adiponectin.

Trust comment: Well-powered randomized factorial trial with long follow-up and robust lab methods; subsample analyses for adipokines were smaller and exploratory.

Study Details

PMID:36889645
Participants:791
Impact:decreased with B12+folic acid vs placebo: adjusted mean difference −1.19 μmol/L (95% CI −2.30, −0.09)
Trust score:4/5

Substudy of a cluster-RCT in rural China: daily fortified cereal or meat for 1 year increased serum B12 and lowered homocysteine; meat and fortified cereal groups had modestly higher cognitive scores versus local cereal.

Trust comment: Cluster-randomized intervention with objective biochemical endpoints and cognitive testing in a prespecified subsample (n=180), but nonblinded and limited subsample size.

Study Details

PMID:31519167
Participants:180
Impact:lower in meat and fortified cereal groups vs local (estimated differences −0.08 and −0.12; P≤0.005)
Trust score:4/5

Add-on methylcobalamin (alone or with folic acid) improved glycemic control and insulin-related markers in people with type 2 diabetes over 8 weeks.

Trust comment: Randomized multi-arm trial but small groups (n≈20 each) and open-label design limit confidence despite biomarker and clinical improvements.

Study Details

PMID:33066869
Participants:80
Impact:significant decline in all supplementation groups vs standard care
Trust score:3/5

B12-enriched toothpaste used for 3 months raised serum B12 and holoTC and lowered homocysteine in elderly participants compared with placebo.

Trust comment: Well-conducted double-blind RCT in elderly with significant biomarker changes and clear reporting.

Study Details

PMID:30680547
Participants:92
Impact:mean change −0.9 ±2.3 μmol/L (B12) vs +0.3 ±1.9 μmol/L (placebo)
Trust score:4/5

Adding folic acid plus vitamin B12 during isotretinoin therapy increased folate and B12 levels and lowered homocysteine compared with isotretinoin alone.

Trust comment: Randomized trial shows biochemical benefits but combined folic acid+B12 intervention and short duration limit attribution solely to B12.

Study Details

PMID:30207526
Participants:66
Impact:significant decrease after treatment in supplementation group (P=0.0004)
Trust score:3/5

In this community cohort of early-pregnancy women, about one quarter were cobalamin-deficient while folate deficiency was rare.

Trust comment: Large community-based cohort with validated biochemical assays and clear prevalence estimates, though cross-sectional so causal conclusions are limited.

Study Details

PMID:34422259
Participants:561
Impact:Mean 6.4 μmol/L with 7.7% above >10 μmol/L
Trust score:4/5

Twenty-four weeks of high-dose oral B12 (with or without folic acid) corrected biochemical deficiency but did not improve cognitive function.

Trust comment: Well-conducted double-blind randomized trial in older adults with biochemical correction but no cognitive benefit; moderate sample and 24-week duration.

Study Details

PMID:16895884
Participants:195
Impact:−36% with B12+folic acid
Trust score:4/5

Treatment-phase study in hemodialysis patients showing folate and added vitamin B12 lower but do not fully normalize homocysteine and MMA in ESRD.

Trust comment: Interventional study in a clinically relevant ESRD population with measurable biochemical endpoints, though normalization was not achieved.

Study Details

PMID:12601627
Participants:81
Impact:reduction: multivitamin with 1 mg folate lowered tHcy by 19.2%; further lowering with added 1 mg B12 (genotype-dependent)
Trust score:4/5

4-month randomized double-blind trial in elderly: oral B-vitamins raised cobalamin markers and tended to lower MMA and homocysteine, differences were not statistically strong.

Trust comment: Double-blind randomized trial with moderate sample size; biochemical improvements reported but were generally non-significant.

Study Details

PMID:18609169
Participants:209
Impact:decrease (greater in AG subjects, not statistically significant)
Trust score:3/5

In non-diabetic men with CHD, metformin raised homocysteine and reduced serum B12 over 12–40 weeks.

Trust comment: Randomized prospective study with objective biochemical outcomes, though open-label and modest sample size.

Study Details

PMID:9350072
Participants:60
Impact:+7.2% at 12 weeks; +13.8% at 40 weeks (metformin vs control)
Trust score:4/5

In stable CAD patients, B-vitamin regimens (including B12) lowered homocysteine but did not change inflammatory markers after 6 months.

Trust comment: Double-blind randomized 2x2 factorial trial with objective biomarkers but relatively small sample for clinical endpoints.

Study Details

PMID:17645592
Participants:90
Impact:-33% in patients receiving folic acid + vitamin B12 (groups A and B combined)
Trust score:4/5

Low-dose folic acid for 4 weeks decreased homocysteine but did not change plasma methionine or plasma vitamin B12 concentrations.

Trust comment: Randomized supplementation trial with moderate sample size and measured biochemical outcomes; directly reports no B12 change.

Study Details

PMID:10743479
Participants:144
Impact:significant decrease (no numeric percent given in abstract)
Trust score:4/5

In stroke patients, treatment with folic acid plus vitamin B12 for 2 months lowered homocysteine and CF6 levels compared with no vitamin treatment.

Trust comment: Randomized assignment to vitamin treatment vs no treatment, but folic acid and B12 were combined so effects cannot be attributed to B12 alone.

Study Details

PMID:20092401
Participants:59
Impact:decreased after 2 months of folic acid + B12 treatment
Trust score:3/5

Preoperative oral B‑vitamin complex (folate, B6, B12) given one week prevented nitrous oxide‑induced postoperative rises in homocysteine.

Trust comment: Randomized double‑blind trial showing clear prevention of tHcy rise, but intervention was a vitamin complex so B12 contribution cannot be isolated.

Study Details

PMID:11726432
Participants:39
Impact:vitamin group: −9.1% ±11% vs placebo group: +15% ±31% (P=0.035) — vitamins prevented postoperative tHcy increase
Trust score:3/5

Cross-sectional baseline biochemical analysis of infants (6–11 months) showing variable cobalamin status: depending on marker, a large proportion had functional indicators of low B12 while folate was adequate.

Trust comment: Well-conducted community-based biochemical assessment with multiple functional B12 markers; cross-sectional design limits causal inference.

Study Details

PMID:29783689
Participants:316
Impact:geometric mean 10.8 µmol/L; 53% >10 µmol/L (elevated)
Trust score:4/5

In 90 patients with suspected coronary disease, folic acid plus vitamin B12 rapidly and substantially lowered basal and postload homocysteine; vitamin B6 mainly lowered cystathionine.

Trust comment: Randomized 4-arm intervention with targeted biochemical endpoints and clear percentage changes, though sample size moderate.

Study Details

PMID:15321804
Participants:90
Impact:−31% basal and −22% post‑methionine with folic acid + B12
Trust score:4/5

Six‑week double‑blind randomized trial in postmenopausal women showed that soy protein with native phytate reduced total homocysteine and iron indices; vitamin B12 was measured as a covariate but not manipulated.

Trust comment: Short (6‑week) double‑blind RCT with small sample; B12 was measured as a covariate rather than the intervention, limiting direct inference about B12 effects.

Study Details

PMID:17023703
Participants:55
Impact:Soy protein with native phytate significantly reduced tHcy (P = 0.017)
Trust score:3/5

In stroke patients given high- or low-dose B-vitamin formulations (including B12) for 2 years, homocysteine fell but plasma Abeta and cognition did not change between groups.

Trust comment: Large randomized double-blind trial with defined biochemical and cognitive endpoints; results are directly measured and reported.

Study Details

PMID:19153374
Participants:300
Impact:decreased (significant)
Trust score:4/5

In stroke patients, B-vitamin therapy lowered homocysteine by about 3–5 μmol/L similarly across ethnic groups.

Trust comment: Large randomized trial with objective biochemical outcome measures, but limited numbers in non-Chinese subgroups.

Study Details

PMID:19372453
Participants:505
Impact:-3.8 μmol/L (Chinese), -4.9 μmol/L (Malay), -3.3 μmol/L (Indian) after 1 year vs baseline
Trust score:4/5

Six weeks of a B-complex (including 1000 μg B12) significantly reduced homocysteine; sublingual and oral delivery were equally effective.

Trust comment: Randomized, double-blind trial but small sample and short duration limit precision.

Study Details

PMID:17109579
Participants:41
Impact:significant reduction after 6 weeks of B-complex therapy
Trust score:3/5

Randomized older adults received B‑vitamin supplementation that included calcium carbonate in both arms; B‑vitamin arm raised folate forms and lowered homocysteine after 12 months.

Trust comment: Randomized trial with detailed biochemical measures though sample size is modest.

Study Details

PMID:25283139
Participants:59
Impact:decreased from mean 13.1 to 9.6 μmol/L after 1 year
Trust score:4/5

A combined nutraceutical (including 12.5 mg zinc) produced a larger reduction in homocysteine than high-dose folic acid alone over two months.

Trust comment: Randomized human trial but intervention was a combination product including B12, so effects cannot be attributed to B12 alone.

Study Details

PMID:27655522
Participants:104
Impact:Normocis: 21.5±8.7 → 10.0±1.7 µmol/L; control (5 mg folic acid): 22.6±6.2 → 14.3±2.8 µmol/L; greater reduction with Normocis (p<0.035)
Trust score:3/5

In CKD stages 3–4, multivitamin supplementation (including folate, B6, B12) partially corrected hyperhomocysteinemia over one year; folate and B12 were major determinants of tHcy.

Trust comment: Large randomized dietary/protocol cohort with multivitamin repletion in CKD patients; B-vitamins included but not isolated, so moderate confidence for B12-specific effects.

Study Details

PMID:15780109
Participants:678
Impact:Among those with hyperhomocysteinemia at baseline, 49% (study A) and 24% (study B) reduced tHcy to ≤15 µmol/L after 1 year of vitamin supplementation
Trust score:3/5

Substudy of a randomized B‑vitamin trial: folic acid + vitamin B12 increased folate and cobalamin, lowered homocysteine (~2.8 µmol/L, ~29.5%) but did not change MCP‑1 levels or presence of VH‑TCFA.

Trust comment: Randomized trial sub-study with biochemical and imaging endpoints; well-conducted but B12 was given with folate so independent B12 effects are not isolated.

Study Details

PMID:23936148
Participants:102
Impact:lowered by 2.8 µmol/L (≈29.5%) with folic acid/B12 supplementation (p<0.0001)
Trust score:4/5

In a 3-month open-label randomized study in hemodialysis patients, folic acid plus B-complex lowered homocysteine and CRP and increased albumin and vitamin B12.

Trust comment: Open-label randomized study with modest sample size and biochemical outcomes but potential bias due to lack of blinding.

Study Details

PMID:17605895
Participants:121
Impact:decrease (directional; significant)
Trust score:3/5

One year of daily vitamin D3 (1200 IU) with calcium (with or without B vitamins) increased 25(OH)D, lowered PTH, and reduced multiple bone turnover markers in elderly subjects.

Trust comment: Randomized double-blind trial with objective biochemical endpoints and moderate sample size, though subgroup comparisons limit power for some bone markers.

Study Details

PMID:23183751
Participants:93
Impact:-29.4% (group A receiving B vitamins; from 12.6 to 8.9 µmol/L)
Trust score:4/5

Patients received rosuvastatin or B-vitamin supplementation (including B12) then combined therapy; vitamins lowered homocysteine and both treatments improved flow-mediated vasodilation, with additive effects when combined.

Trust comment: Randomized, double-blind study with objective endothelial function measures but small sample size limits generalizability.

Study Details

PMID:21884007
Participants:36
Impact:decrease with B-group vitamin supplementation (no magnitude reported)
Trust score:3/5

Substudy of a large RCT in advanced CKD/ESRD testing high-dose B vitamins (including 2 mg B12) vs placebo: vitamins lowered homocysteine but did not improve cognitive outcomes.

Trust comment: Large randomized double-blind trial substudy with clear biochemical effect (tHcy lowering); cognitive assessments limited in timing but showed no benefit.

Study Details

PMID:19628319
Participants:659
Impact:-26.7% (treatment decreased tHcy by 26.7%)
Trust score:4/5

subgroup adipokine effects

1 evidences

Six-month early-life supplementation with vitamin B12 + folic acid led to lower homocysteine 6–7 years later; no overall effects on leptin/adiponectin.

Trust comment: Well-powered randomized factorial trial with long follow-up and robust lab methods; subsample analyses for adipokines were smaller and exploratory.

Study Details

PMID:36889645
Participants:791
Impact:beneficial effects on leptin/adiponectin ratios in underweight/stunted/wasted subgroups (subset analyses)
Trust score:4/5

Weight-for-age Z-score

1 evidences

Daily vitamin B12 supplementation for 6 months produced a small overall increase in weight-for-age and larger benefits in malnourished subgroups.

Trust comment: Large randomized, double-blind placebo-controlled trial with clear subgroup effects; effect sizes generally small but statistically supported.

Study Details

PMID:25802345
Participants:1000
Impact:increased by +0.07 mean z-score (95% CI 0.01 to 0.13) with vitamin B12
Trust score:4/5

restoration to adequate levels (B12 and D)

1 evidences

Combined and separate vitamin D3+B12 supplementation over 12 weeks raised serum 25(OH)D and B12; the single-tablet formulation produced larger average increases.

Trust comment: Randomized multicenter trial showing clear biochemical responses; open-label design, small completed sample (n=129) and short duration limit strength of clinical conclusions.

Study Details

PMID:39940277
Participants:129
Impact:higher proportions achieved adequacy with treated groups vs control (e.g., 69.4% restored adequate B12 in compound group)
Trust score:3/5

neurodevelopment (Bayley-III)

1 evidences

Daily 2 μg vitamin B12 for 12 months improved biochemical B12 status but did not change neurodevelopment, growth, or hemoglobin at end of study.

Trust comment: Large, double-blind, placebo-controlled RCT with high retention and robust biochemical and developmental assessments; null clinical outcomes despite clear metabolic response.

Study Details

PMID:33259482
Participants:572
Impact:no difference vs placebo (e.g., cognitive composite mean difference 0.73 points, 95% CI −0.55 to 2.02)
Trust score:5/5

vitamin B12 status (biomarkers, 3cB12/MMA/tHcy)

1 evidences

Daily 2 μg vitamin B12 for 12 months improved biochemical B12 status but did not change neurodevelopment, growth, or hemoglobin at end of study.

Trust comment: Large, double-blind, placebo-controlled RCT with high retention and robust biochemical and developmental assessments; null clinical outcomes despite clear metabolic response.

Study Details

PMID:33259482
Participants:572
Impact:improved metabolic status; larger improvements in those with poorer baseline status (e.g., reduced MMA in deficient subgroup)
Trust score:5/5

Functional biomarkers (tHcy and MMA)

1 evidences

Children with severe acute malnutrition received RUTF and showed improved vitamin B12 biomarker status at discharge, though some remained deficient.

Trust comment: Randomized trial sub-study with objective biomarker measurements and moderate-to-large sample, though long storage of samples and sub-study design are limitations.

Study Details

PMID:37630687
Participants:361
Impact:tHcy and MMA decreased from admission to discharge (directional decrease reported)
Trust score:4/5

Blood DMAs (bDMAs)

1 evidences

In 8–11 year-old children, 12 weeks of folic acid + B12 increased arsenic methylation capacity as shown by changes in blood and urine arsenic metabolites.

Trust comment: Well-conducted double-blind randomized placebo-controlled trial with objective arsenic speciation and high completion.

Study Details

PMID:38728816
Participants:236
Impact:+14% (95% CI: 5.0% to 25.0%) in supplementation vs placebo at 12 weeks
Trust score:5/5

Urinary %MMAs

1 evidences

In 8–11 year-old children, 12 weeks of folic acid + B12 increased arsenic methylation capacity as shown by changes in blood and urine arsenic metabolites.

Trust comment: Well-conducted double-blind randomized placebo-controlled trial with objective arsenic speciation and high completion.

Study Details

PMID:38728816
Participants:236
Impact:Week 1: −1.10% (95% CI: −1.73 to −0.48) greater decline in supplementation vs placebo
Trust score:5/5

Total sleep duration (day + night)

1 evidences

Daily vitamin B12 for one year in infants did not change night or total sleep duration or WASO; a small negative effect was reported for sleep onset latency.

Trust comment: Large double-blind randomized placebo-controlled trial using objective actigraphy measures; sleep was a predefined secondary outcome.

Study Details

PMID:34999324
Participants:600
Impact:No effect
Trust score:4/5

Human milk vitamin B12 at 7 months (postnatal supplement)

1 evidences

Prenatal high-dose maternal B12 increased human milk B12 at 6 weeks, and postnatal supplementation increased milk B12 at 7 months.

Trust comment: Randomized double-blind placebo-controlled trial with large sample and biochemical milk B12 outcomes measured at defined timepoints.

Study Details

PMID:38432714
Participants:412
Impact:+15.9% (95% CI: 1.91% to 31.9%) vs control
Trust score:5/5

Hemoglobin / hematocrit

1 evidences

In preterm infants receiving erythropoietin and iron, adding vitamin B12 + higher-dose folate modestly enhanced erythropoiesis over 4 weeks.

Trust comment: Randomized controlled neonatal trial with small sample and some baseline imbalances that limit certainty.

Study Details

PMID:16818564
Participants:64
Impact:Stable in treatment group vs decreased in control (directional difference reported)
Trust score:3/5

Serum vitamin B12 in cases vs controls

1 evidences

Case-control analysis found lower folate and B12 in neural tube defect pregnancies vs controls (not significant in this sample), and pooled literature showed lower serum B12 in cases.

Trust comment: Matched case-control analysis with small case numbers and non-significant primary comparisons in this sample; pooled review evidence supports association with lower B12.

Study Details

PMID:8605127
Participants:135
Impact:Lower in cases in this sample (not statistically significant); pooled literature estimate −38 ng/L (statistically significant)
Trust score:3/5

clinician-rated overall ASD symptoms (CGI-I)

1 evidences

8-week subcutaneous methyl B12 improved clinician-rated global autism symptoms and methylation markers but did not change parent-rated behavior or social responsiveness.

Trust comment: Randomized placebo-controlled trial in children with an objective primary outcome; moderate sample size (n=50 completed).

Study Details

PMID:26889605
Participants:50
Impact:-0.7 points (methyl B12 mean 2.4 vs placebo 3.1; p=0.005)
Trust score:4/5

handgrip strength

1 evidences

Two-year daily vitamin B12+folic acid (both arms received vitamin D) did not prevent decline in physical performance or handgrip strength or reduce fall risk in older adults overall; possible benefit on walking and in compliant >80y subgroup.

Trust comment: Large multicenter double-blind randomized placebo-controlled trial (n=2919) with 2-year follow-up and objective outcomes.

Study Details

PMID:26412463
Participants:2919
Impact:no significant difference; treatment effect 0.1 kg (95% CI −0.2 to 0.4)
Trust score:5/5

functional decline (ALSFRS-R)

1 evidences

Long-term intramuscular ultra-high-dose methylcobalamin did not meet primary endpoints overall, but a post-hoc subgroup diagnosed ≤12 months after onset showed prolonged time to death/ventilation and less functional decline.

Trust comment: Multicenter randomized double-blind trial with negative primary outcome; post-hoc subgroup (early diagnosis) showed benefit and should be interpreted cautiously.

Study Details

PMID:30636701
Participants:260
Impact:median decline placebo −24.0 vs −22.0 (25 mg) and −21.0 (50 mg); in early subgroup 50 mg vs placebo p=0.003
Trust score:4/5

serum vitamin B12 concentration

12 evidences

In 34 healthy adults, a liposomal multivitamin altered how some minerals and vitamins appeared in blood; serum calcium rose at 2 h after the liposomal MVM and some calcium PK markers (Tmax, absorption rate) differed; no side effects reported.

Trust comment: Well-controlled randomized crossover pharmacokinetic study but small sample and limited B12 PK data (PK calculable only for subset), so conclusions for B12 are cautious.

Study Details

PMID:37447400
Participants:34
Impact:no significant difference between liposomal and non-liposomal MVM over 6 h
Trust score:4/5

Substudy of a cluster-RCT in rural China: daily fortified cereal or meat for 1 year increased serum B12 and lowered homocysteine; meat and fortified cereal groups had modestly higher cognitive scores versus local cereal.

Trust comment: Cluster-randomized intervention with objective biochemical endpoints and cognitive testing in a prespecified subsample (n=180), but nonblinded and limited subsample size.

Study Details

PMID:31519167
Participants:180
Impact:fortified cereal 509.5 pg/mL vs meat 338.0 pg/mL vs local cereal 241.0 pg/mL (P < 0.001)
Trust score:4/5

12-week double-blind randomized trial in vegans/vegetarians with marginal B12 deficiency: weekly sublingual 350 μg and 2000 μg both restored serum B12 and improved related metabolic markers.

Trust comment: Double-blind randomized controlled trial but small sample (n=40) and short duration; biochemical endpoints improved in both arms.

Study Details

PMID:29499976
Participants:40
Impact:increased to adequate concentrations in both dose groups after 90 days
Trust score:3/5

Giving multiple micronutrients including vitamin B12 to HIV-infected children increased their blood B12 and folate levels over six months.

Trust comment: Randomized, double-blind multicenter RCT with objective biochemical assays but biochemical analysis limited to a 214-child subset and some missing samples.

Study Details

PMID:21600005
Participants:214
Impact:+90.5 pmol/L (median change over 6 months in MMS group; p<0.001)
Trust score:4/5

A 24‑week RCT of fortified milk (providing ~1008 mg Ca/day) plus exercise improved vitamin B‑12 and 25(OH)D levels and reduced bone turnover markers versus control.

Trust comment: Well-conducted RCT with good sample and biochemical measures, but intervention combined nutrition and exercise (effects not solely attributable to B12).

Study Details

PMID:32588047
Participants:163
Impact:intervention 345 ±119 → 484 ±136 pmol/L (+139 pmol/L; +40%) at 24 weeks; control 343 ±140 → 357 ±134 (+14 pmol/L)
Trust score:4/5

Two-week daily alcohol (red wine or vodka) decreased serum folate and vitamin B12 and produced a small increase in plasma homocysteine.

Trust comment: Randomized crossover trial with 78 healthy men and within-subject comparisons, but short intervention duration limits clinical generalizability.

Study Details

PMID:18790817
Participants:78
Impact:decrease (significant)
Trust score:4/5

In people with mild–moderate Alzheimer's on cholinesterase inhibitors, add-on multivitamin including mecobalamin (B12) for 26 weeks lowered homocysteine but produced no cognitive or ADL benefit.

Trust comment: Randomized double-blind placebo-controlled trial in humans with reported exact biomarker changes; moderate sample size supports reasonable trust.

Study Details

PMID:18042476
Participants:89
Impact:+536.9 pg/mL (mean difference vs placebo at 26 weeks; P<0.001)
Trust score:4/5

In 22 healthy women, serum vitamin B12 showed notable within-subject variability and was consistently lower in oral contraceptive users versus non-users.

Trust comment: Longitudinal study with standardized sampling and repeated measures but small, homogeneous sample of students limits generalizability.

Study Details

PMID:24067390
Participants:22
Impact:significantly lower in OCP users versus non-users (P=0.042; reported ~33% lower in discussion)
Trust score:4/5

Elderly people with food-bound B12 malabsorption given very low oral B12 doses for 30 days showed dose-related increases in serum B12.

Trust comment: Randomized double-blind trial with clear dose–response for serum B12 but moderate sample size.

Study Details

PMID:17237314
Participants:67
Impact:increased (log-dose response); ~5.9 µg/d estimated for +37 pmol/L)
Trust score:4/5

Oral high-dose B12 was as effective as intramuscular B12 for hematologic recovery in megaloblastic anemia over 90 days.

Trust comment: Randomized clinical trial showing similar clinical and laboratory recovery between oral and IM routes, but open-label and modest sample size.

Study Details

PMID:14749150
Participants:60
Impact:significant increase from baseline to day 90 (no numeric change reported)
Trust score:4/5

Subsample (n=740) from a randomized antenatal trial in rural Nepal: multiple micronutrient supplementation reduced the prevalence of vitamin D deficiency though mean serum 25‑hydroxyvitamin D concentrations were unchanged between first and third trimester.

Trust comment: Large randomized controlled trial with biochemical endpoints in humans; well-reported though functional health outcomes were not measured.

Study Details

PMID:16600929
Participants:740
Impact:decreased across pregnancy in control; multiple micronutrient (MMN) supplementation decreased prevalence of B12 deficiency
Trust score:4/5

Twelve weeks of fortified milk (including B-group vitamins and B12) in older adults increased circulating B vitamins (including B12), raised vitamin D, improved ω-3 status, and lowered homocysteine.

Trust comment: Double-blind crossover RCT with objective biochemical endpoints in older adults; small sample (n=48) but well-controlled.

Study Details

PMID:33266447
Participants:48
Impact:Significant increase after intervention (q = 0.0001)
Trust score:4/5

cognitive function (MMSE)

1 evidences

In an early PD cohort, low baseline B12 predicted greater worsening of mobility, whereas elevated homocysteine predicted greater cognitive decline on MMSE.

Trust comment: Observational analysis within a clinical trial cohort (DATATOP) with moderate sample size; associations are correlative and not proof of causation.

Study Details

PMID:29508904
Participants:456
Impact:elevated homocysteine associated with greater annualized MMSE decline: −1.96 vs 0.06 (P = 0.0001)
Trust score:3/5

Methylmalonic acid (MMA) and total brain volume

1 evidences

MRI substudy within an RCT of 2-year folic acid + vitamin B12 supplementation in older adults; investigated cross-sectional associations of B12/folate/Hcy biomarkers with grey, white and total brain volumes and compared brain volumes by supplementation group after 2 years.

Trust comment: High-quality imaging and biomarkers in a randomized parent trial, but MRI subgroup lacked baseline brain volumes and had age imbalance and selection (elevated Hcy), limiting causal inference.

Study Details

PMID:28029114
Participants:218
Impact:Inverse association (supplemented group β=−127.1 mL, p=0.02)
Trust score:3/5

Social quotient (Vineland)

1 evidences

Open-label, assessor-blinded randomized trial in infants with Infantile Tremor Syndrome comparing daily injectable B12 alone vs B12 plus multinutrients; primary outcome caregiver Likert score at 1 week and developmental scales at 1 week and 1 month.

Trust comment: Randomized, assessor-blinded noninferiority trial with objective developmental measures but modest sample size (n=72) limits precision.

Study Details

PMID:36048348
Participants:72
Impact:Greater improvement with B12 monotherapy (mean change 35.0 vs 23.5; p=0.01)
Trust score:4/5

Infant vitamin B12 concentration

2 evidences

Prospective analysis within a maternal supplementation trial examining associations between maternal B12 biomarkers during pregnancy and infant B12 status at 6 weeks (n=77 infants).

Trust comment: Prospective analysis with biochemical measures and adjustment for supplementation but small sample (n=77) and secondary analysis limits strength of causal claims.

Study Details

PMID:28402324
Participants:77
Impact:Higher maternal B12 in pregnancy associated with higher infant B12 at 6 weeks (adjusted association; p<0.05)
Trust score:3/5

Maternal dietary + MMN supplementation for 6 months increased maternal vitamin D concentrations modestly and reduced vitamin D deficiency prevalence compared with routine care.

Trust comment: Large randomized controlled trial with objective biochemical outcomes and good adherence; B12 was measured but part of a multi-micronutrient intervention.

Study Details

PMID:39324335
Participants:600
Impact:No significant change (adjusted mean diff +4.4 pg/ml; 95% CI −30.1 to 38.9)
Trust score:4/5

Problem-solving skills (ASQ-3)

1 evidences

Randomized, double-blind trial in 6–30 month-old Indian children testing daily vitamin B12 and/or folic acid for 6 months; developmental outcomes (ASQ-3) assessed in 422 children.

Trust comment: Large, well-conducted randomized, double-blind trial with good adherence and objective developmental screening, though some effects were modest or borderline and baseline differences required adjustment.

Study Details

PMID:26098427
Participants:422
Impact:Improved with B12+folic acid (mean diff +3.8 points vs placebo, p≈0.048)
Trust score:4/5

Corneal sensitivity (esthesiometry)

1 evidences

Single-centre randomized, double-blind trial testing topical citicoline + cyanocobalamin (vitamin B12) eyedrops vs placebo in patients with diabetes-related corneal nerve damage; primary outcomes nerve fiber length density and corneal sensitivity over 18 months.

Trust comment: Randomized double-blind pilot with objective confocal microscopy and sensitivity measures and low dropout, but small sample and single-centre limit generalizability.

Study Details

PMID:32738875
Participants:29
Impact:Larger improvement with Cit-B12 (approx. +150% vs +44% percent change; between-group p-values ≤0.01 at visits)
Trust score:4/5

Holotranscobalamin (holoTC)

6 evidences

Randomized, unblinded 4-week dose-response trial in 30 long-term vegetarians testing roasted nori (5 g/day or 8 g/day) vs control; assessed serum B12, holoTC, Hcy, MMA and combined 4cB12 index.

Trust comment: Randomized food-based trial with comprehensive biomarkers showing short-term improvements, but small sample, short duration and lack of blinding to food limit strength and generalizability.

Study Details

PMID:39352476
Participants:30
Impact:Increased in low-dose group (+27.3 pmol/L; p≈0.0035 vs control)
Trust score:3/5

Intranasal B12 given either as a loading regimen or every-3-day dosing raised blood B12 and corrected related metabolic markers; loading gave faster larger early rises.

Trust comment: Randomized controlled trial in elderly B12-deficient patients with repeated biomarker measurements and clear biomarker responses.

Study Details

PMID:38747399
Participants:60
Impact:rapid increase (normalized) in both regimens
Trust score:4/5

Daily use of B12-fortified toothpaste for 12 weeks increased circulating B12 markers and lowered MMA and homocysteine in vegans compared with placebo.

Trust comment: Double-blind, randomized, placebo-controlled trial in vegans with consistent biomarker improvements supports reliable effect.

Study Details

PMID:28052884
Participants:66
Impact:mean change +26 ±34 pmol/L (B12) vs −5 ±17 pmol/L (placebo)
Trust score:4/5

B12-enriched toothpaste used for 3 months raised serum B12 and holoTC and lowered homocysteine in elderly participants compared with placebo.

Trust comment: Well-conducted double-blind RCT in elderly with significant biomarker changes and clear reporting.

Study Details

PMID:30680547
Participants:92
Impact:mean change +21 ±34 pmol/L (B12) vs +2 ±32 pmol/L (placebo)
Trust score:4/5

In women with GDM, metformin treatment led to a greater decline in total serum B12 during pregnancy than insulin, though bioavailable B12 and homocysteine did not differ between groups.

Trust comment: Randomized comparison within a clinical trial cohort with clear biochemical measurements, moderate sample size.

Study Details

PMID:23402546
Participants:180
Impact:no significant difference between treatments
Trust score:4/5

Randomized trial comparing monthly high-dose oral cyanocobalamin vs weekly intramuscular hydroxocobalamin over 4 weeks; both routes improved B12 biomarkers but IM produced much larger early rises.

Trust comment: Randomized outpatient trial with direct biochemical outcomes but small sample size and nonblinded design limits precision.

Study Details

PMID:28421567
Participants:37
Impact:oral 49.0 → 156 pmol/L; IM 50.1 → 1269 pmol/L (both normalized by 4 weeks; greater increase with IM)
Trust score:4/5

Dose-response

1 evidences

Randomized, unblinded 4-week dose-response trial in 30 long-term vegetarians testing roasted nori (5 g/day or 8 g/day) vs control; assessed serum B12, holoTC, Hcy, MMA and combined 4cB12 index.

Trust comment: Randomized food-based trial with comprehensive biomarkers showing short-term improvements, but small sample, short duration and lack of blinding to food limit strength and generalizability.

Study Details

PMID:39352476
Participants:30
Impact:No clear additional benefit of 8 g/day vs 5 g/day over 4 weeks
Trust score:3/5

erythrocyte count

1 evidences

Adding 5 µg/day B12 during pregnancy modestly altered some blood markers and appeared to reduce risk of developing anemia compared with iron+folate alone.

Trust comment: Randomized trial with adequate sample size but modest, partly ambiguous hematologic changes and limited mechanistic detail.

Study Details

PMID:32302504
Participants:200
Impact:significant decrease post‑intervention in control only (suggesting relative preservation with B12)
Trust score:3/5

insulin resistance / plasma insulin

1 evidences

Add-on methylcobalamin (alone or with folic acid) improved glycemic control and insulin-related markers in people with type 2 diabetes over 8 weeks.

Trust comment: Randomized multi-arm trial but small groups (n≈20 each) and open-label design limit confidence despite biomarker and clinical improvements.

Study Details

PMID:33066869
Participants:80
Impact:significant improvement in Groups B and C vs standard care (no numeric values provided)
Trust score:3/5

MMA and tHcy

1 evidences

Daily use of B12-fortified toothpaste for 12 weeks increased circulating B12 markers and lowered MMA and homocysteine in vegans compared with placebo.

Trust comment: Double-blind, randomized, placebo-controlled trial in vegans with consistent biomarker improvements supports reliable effect.

Study Details

PMID:28052884
Participants:66
Impact:MMA change −0.169 ±0.340 μmol/L (B12) vs −0.036 ±0.544 (placebo); tHcy change −0.7 ±4.4 μmol/L (B12) vs +2.0 ±5.6 (placebo)
Trust score:4/5

infant cognitive composite score (Bayley) at 6 and 12 months

1 evidences

Large randomized trial in pregnant women: B12 improved maternal B12 status but did not change infant growth or cognitive scores.

Trust comment: Large, well-conducted double-blind randomized controlled trial with clear primary outcomes and intention-to-treat analyses.

Study Details

PMID:37031691
Participants:800
Impact:mean difference +0.5 (no meaningful change)
Trust score:5/5

steatosis score (imaging)

1 evidences

Small 12-week RCT in NAFLD patients: B12 (1000 µg/day) lowered homocysteine and improved some within-group markers but most liver/metabolic outcomes did not differ versus placebo.

Trust comment: Randomized double-blind trial but very small sample and short duration limit generalizability and power.

Study Details

PMID:35982162
Participants:33
Impact:decreased in both groups (no between-group difference)
Trust score:3/5

plasma total homocysteine (tHcy)

21 evidences

In acute ischemic stroke patients, short-term B‑group vitamin supplementation (including B12) was associated with reduced oxidative damage and inflammation markers compared with no supplementation.

Trust comment: Randomized small trial (n=48) with combined B‑vitamin intervention; results suggest antioxidant/anti-inflammatory effects but B12-specific effects cannot be isolated.

Study Details

PMID:15279619
Participants:48
Impact:decreased in both groups with no significant between-group cumulative difference
Trust score:3/5

In infants with biochemical B12 deficiency, a single IM hydroxycobalamin injection markedly improved B12 biomarkers and led to greater short-term gains in motor development versus placebo.

Trust comment: Randomized, double-blind intervention with objective biochemical and motor outcomes, though sample size of the intervention arm was small.

Study Details

PMID:26678525
Participants:31
Impact:decreased median −5.85 µmol/L (−61%) in cobalamin group
Trust score:4/5

In hemodialysis patients, high-dose folic acid combined with 1 mg/day vitamin B12 (and higher folic acid dose) produced the largest reduction in plasma homocysteine over 8 weeks.

Trust comment: Small randomized study in HD patients showing biochemical effects; limited sample size lowers generalizability.

Study Details

PMID:19736473
Participants:36
Impact:group IV (FA15 mg + B12 1 mg): −30.09% (significant, P=0.014); group III −14.54%; group II −6.99%; group I +1.35%
Trust score:3/5

Two-week daily alcohol (red wine or vodka) decreased serum folate and vitamin B12 and produced a small increase in plasma homocysteine.

Trust comment: Randomized crossover trial with 78 healthy men and within-subject comparisons, but short intervention duration limits clinical generalizability.

Study Details

PMID:18790817
Participants:78
Impact:+5% (red wine); +3% (vodka, NS)
Trust score:4/5

In 24 hemodialysis patients, weekly subcutaneous hydroxocobalamin substantially lowered plasma homocysteine and reduced serum methylmalonic acid over 16 weeks.

Trust comment: Prospective randomized controlled trial in a defined ESRD population with objective biochemical endpoints but small sample size.

Study Details

PMID:12077735
Participants:24
Impact:mean -32% after hydroxocobalamin (P<0.005)
Trust score:4/5

Vegetarian women received 500 μg oral B12 every other day for 6 weeks; B12 levels rose and homocysteine fell within 2 weeks and stayed lower.

Trust comment: Small randomized proof-of-principle trial with objective biochemical endpoints and high completer rate but limited size and duration.

Study Details

PMID:17215186
Participants:40
Impact:-5.0 μmol/L (18.0 → 13.0 μmol/L) within 2 weeks
Trust score:3/5

Older hospitalized patients given a mixed B‑vitamin drink had lower plasma homocysteine after 6 weeks, with partial return after stopping.

Trust comment: Well‑conducted randomized placebo‑controlled trial (n=236) but intervention was a mixed B‑vitamin formula (not B12 alone), limiting attribution to B12.

Study Details

PMID:23591663
Participants:236
Impact:-4.1 µmol/L at 6 weeks (mean vs placebo); +2.0 µmol/L increase between 6w and 6m after stopping
Trust score:3/5

In hemodialysis patients, consecutive folic acid and vitamin B12 treatments lowered homocysteine; the decrease depended on MTHFR genotype and was larger when starting with folic acid.

Trust comment: Randomized, blinded study in humans with clear outcomes and genotype stratification, though substantial mortality reduced numbers.

Study Details

PMID:16391331
Participants:148
Impact:decreased after consecutive vitamin therapies (folic acid and B12)
Trust score:4/5

In elderly people, combined cobalamin (B12) plus folic acid lowered homocysteine and raised betaine, but overall cognitive performance did not improve.

Trust comment: Double-blind, placebo-controlled randomized trial in humans with clear biochemical outcomes, though cognitive changes were not demonstrated.

Study Details

PMID:17537289
Participants:195
Impact:decreased by 36% with combined cobalamin + folic acid
Trust score:4/5

In folate-replete hemodialysis patients, oral vitamin B12 increased serum B12 but did not produce a greater reduction in plasma homocysteine compared with control over 6 weeks.

Trust comment: Small randomized open trial (n=28) with biochemical endpoints but limited power to detect between-group differences.

Study Details

PMID:12653261
Participants:28
Impact:no additional lowering with vitamin B12 versus control (both groups decreased; no between-group difference)
Trust score:3/5

B-vitamin supplementation lowered plasma homocysteine, with the largest reductions in men who had low B12 or high baseline homocysteine.

Trust comment: Two-year double-blind placebo-controlled RCT with clear biochemical endpoints; strong design though intervention was a B-vitamin combination.

Study Details

PMID:16373648
Participants:299
Impact:-6.74 μmol/L (B12-deficient subgroup, treatment vs control); -2.88 μmol/L (overall non-deficient comparison); -2.8 μmol/L (hyperhomocysteinaemia subgroup)
Trust score:5/5

Rural and urban Mexican women ate model diets in a crossover; homocysteine and B12/folate were measured over 4 hours.

Trust comment: Controlled crossover with frequent sampling but small sample size limits generalizability.

Study Details

PMID:14559315
Participants:33
Impact:rural 8.73 ±0.17 μM vs urban 9.27 ±0.13 μM (P=0.01)
Trust score:4/5

In older adults, a daily B-vitamin supplement (folate, B12, B6) lowered plasma total homocysteine but did not change plasma AdoHcy or AdoMet after 2 years.

Trust comment: Randomized placebo-controlled trial with moderate-to-large sample for older adults; measured subset (100) analyzed for these metabolites.

Study Details

PMID:20089204
Participants:100
Impact:-4.4 µmol/L at 2 years (vitamins vs placebo)
Trust score:4/5

Methylcobalamin plus folic acid lowered homocysteine but did not reduce global cognitive decline over 24 months; a subgroup with high baseline homocysteine had less decline in one cognitive domain.

Trust comment: Well-conducted randomized placebo-controlled trial with adequate duration and completion rate, though subgroup finding is secondary.

Study Details

PMID:21216507
Participants:140
Impact:reduced in supplement group (average reduced to 9.3 ± 2.7 μmol/L from baseline group mean ~14.1 μmol/L)
Trust score:4/5

Randomized trial in infants: a single intramuscular 400 μg cobalamin dose at 6 weeks raised serum cobalamin and normalized metabolic markers by 4 months.

Trust comment: Randomized, placebo-controlled trial with objective biochemical endpoints and moderate sample size; single-center limits generalizability.

Study Details

PMID:18595990
Participants:107
Impact:median tHcy decreased from 7.46 to 4.57 μmol/L in supplemented group (no change in controls)
Trust score:4/5

Six months of B‑vitamin supplementation (including cyanocobalamin/B12) lowered homocysteine and improved patients' general well‑being.

Trust comment: Double‑blind, placebo‑controlled multicentre RCT with moderate sample size and clear biochemical and clinical outcomes, though relatively small.

Study Details

PMID:19154566
Participants:57
Impact:median −34% (P<0.001)
Trust score:4/5

High-dose B-vitamin therapy (including 1 mg B12) in kidney transplant recipients lowered homocysteine and produced modest but significant improvements in processing speed and memory over ~3.3 years.

Trust comment: Large randomized, multi-site controlled trial ancillary with long follow-up and standardized cognitive testing, though most participants were B12/folate sufficient at baseline which may limit effect size interpretation.

Study Details

PMID:29182708
Participants:584
Impact:tHcy was lowered by high-dose B-vitamin therapy (reported in parent trial)
Trust score:4/5

Randomized, placebo-controlled trial of B-vitamin therapy (including B12) in elderly: biomarkers improved (tHcy and MMA) but short-term treatment did not improve movement or cognitive tests.

Trust comment: Double-blind randomized placebo-controlled trial with objective biochemical endpoints and clinical performance measures; sample size moderate for clinical outcomes.

Study Details

PMID:15883442
Participants:209
Impact:-32% with B-vitamin therapy (cyanocobalamin + folic acid + B6) versus baseline/placebo
Trust score:4/5

In adults with prior CVD, daily low‑dose B‑vitamin supplementation (5‑methyl‑THF 560 μg, B6 3 mg, B12 20 μg) produced a large tHcy decrease after 1 year (~‑26.3%), raised vitamin biomarkers in year 1 (then plateaued), and the homocysteine response was modified by MTHFR genotype (TT showed larger initial decrease).

Trust comment: Large, multicenter, double‑blind randomized placebo‑controlled trial with long follow‑up and centralized assays; high internal validity for B‑vitamin effects on tHcy.

Study Details

PMID:29813097
Participants:2501
Impact:‑26.3% after 1 year (p<0.0001); then +5.0% per year from year 1 to 5 (p<0.001)
Trust score:5/5

Elderly people with mild cognitive impairment received high-dose B-vitamin supplementation (folic acid, B6, B12) for 2 years; B-vitamin treatment lowered homocysteine and substantially slowed whole-brain atrophy versus placebo.

Trust comment: Large double-blind randomized trial with objective MRI endpoints and biochemical compliance data, though treatment was a B-vitamin combination so individual vitamin effects (including B12) are not isolated.

Study Details

PMID:20838622
Participants:168
Impact:Decreased by ≈22.5% in active group vs increased ≈7.7% in placebo
Trust score:5/5

In 8,164 patients with recent stroke or TIA randomized to daily B-vitamins (including B12) versus placebo, B-vitamin therapy lowered homocysteine but did not significantly change the incidence of osteoporotic fractures over ~3.4 years.

Trust comment: Large, well-conducted randomized double-blind trial with long follow-up and biochemical confirmation of homocysteine lowering, but underpowered for modest fracture effects.

Study Details

PMID:24004645
Participants:8164
Impact:Mean reduction ≈3.8 μmol/L in B-vitamins group vs placebo (10.5 vs 14.3 μmol/L; P < 0.001)
Trust score:5/5

low B12 prevalence

1 evidences

8-week double-blind RCT in adults at increased diabetes risk testing salmon fish protein supplement vs placebo and measuring blood micronutrient concentrations.

Trust comment: Well-conducted double-blind randomized trial with objective lab measures; secondary analysis but consistent biochemical findings.

Study Details

PMID:35362766
Participants:74
Impact:reduced in fish protein group (from 15.4% to 2.6% end-of-study)
Trust score:4/5

serum holotranscobalamin (bioactive B12)

1 evidences

Controlled feeding study (humans) and mouse experiments: higher maternal choline intake raised bioactive B12 (holotranscobalamin) in pregnant women and altered B12-related biomarkers.

Trust comment: Controlled feeding in a small human cohort with supporting animal data; human sample size is limited for broad inference.

Study Details

PMID:31473512
Participants:26
Impact:increased ≈24% with 2× choline supplementation (P=0.01)
Trust score:3/5

osteoporotic fractures in >80 y (per-protocol)

1 evidences

Large 2-year RCT in older adults with high homocysteine: combined B12+folic acid did not reduce overall osteoporotic fractures; exploratory subgroup suggested benefit in adherent >80-year-olds but cancer incidence was higher in the treatment arm.

Trust comment: Large, well-powered double-blind randomized trial with clear null primary outcome; subgroup and safety signals noted and reported.

Study Details

PMID:25411293
Participants:2919
Impact:reduced (HR 0.27; 95% CI 0.10–0.74) in compliant participants >80 y
Trust score:5/5

osteoporotic fracture incidence

1 evidences

Protocol and baseline description of a randomized trial (n=2919) testing vitamin B12+folic acid vs placebo in elderly; both groups received vitamin D (600 IU) and outcome results were not reported in this paper.

Trust comment: Well-designed, large randomized trial protocol with thorough measurements but this publication only reports design/baseline and no outcome results.

Study Details

PMID:22136481
Participants:2919
Impact:not reported
Trust score:3/5

bone mineral density (BMD)

2 evidences

Randomized trial in PD patients on levodopa showed homocysteine‑lowering therapy (5 mg folate + 1500 μg vitamin B12 daily) increased BMD at lumbar spine and femur vs control over 12 months.

Trust comment: Randomized controlled trial but small sample (n=42 randomized, 41 completed); results support benefit of folate+B12 regimen on BMD in this specific clinical population.

Study Details

PMID:19938151
Participants:41
Impact:Hcy‑lowering therapy increased BMD: lumbar spine +4.4%, total femur +2.8%, femur shaft +2.8% vs control (p=0.005–0.023).
Trust score:4/5

Protocol and baseline description of a randomized trial (n=2919) testing vitamin B12+folic acid vs placebo in elderly; both groups received vitamin D (600 IU) and outcome results were not reported in this paper.

Trust comment: Well-designed, large randomized trial protocol with thorough measurements but this publication only reports design/baseline and no outcome results.

Study Details

PMID:22136481
Participants:2919
Impact:not reported
Trust score:3/5

bone turnover markers (alkaline phosphatase, CTx)

1 evidences

Randomized double-blind trial in 31 women (65–93 y) giving folic acid (800 μg) + vitamin B12 (1000 μg) vs placebo for 4 months: homocysteine fell in the treated group but bone turnover markers did not change.

Trust comment: Randomized double-blind trial but very small sample (n=31) and short duration, limiting power for bone outcomes.

Study Details

PMID:23507227
Participants:31
Impact:no significant change vs placebo
Trust score:3/5

serum vitamin B12 status

1 evidences

Cluster randomized, double-blind protocol comparing 1 mg/day vitamin B12 delivered as fortified food vs pill vs routine PACAM (placebo arm) in older Chilean adults; outcomes planned include serum B12, nerve conduction and MMSE; this is a protocol paper (no results reported).

Trust comment: Well-described cluster RCT protocol with planned adequate sample size, but this publication is only the protocol without outcome data.

Study Details

PMID:21952034
Participants:300
Impact:not reported
Trust score:3/5

global cognition (MMSE)

3 evidences

Cluster randomized, double-blind protocol comparing 1 mg/day vitamin B12 delivered as fortified food vs pill vs routine PACAM (placebo arm) in older Chilean adults; outcomes planned include serum B12, nerve conduction and MMSE; this is a protocol paper (no results reported).

Trust comment: Well-described cluster RCT protocol with planned adequate sample size, but this publication is only the protocol without outcome data.

Study Details

PMID:21952034
Participants:300
Impact:not reported
Trust score:3/5

Two-year daily folic acid + vitamin B12 lowered homocysteine but did not improve cognitive domain scores; very small difference in global cognition possibly by chance.

Trust comment: Large multicenter double-blind RCT with objective outcomes and high sample size, providing high-quality evidence.

Study Details

PMID:25391305
Participants:2919
Impact:MMSE change -0.1 (B-vitamin) vs -0.3 (placebo); p=0.05; no clear benefit
Trust score:5/5

Randomized trial (VITACOG) in MCI patients: daily B-vitamin supplement (folic acid 0.8 mg, B12 0.5 mg, B6 20 mg) for ~2 years lowered homocysteine and prevented declines in several cognitive measures compared with placebo.

Trust comment: Randomized controlled trial with biochemical, cognitive and imaging measures in MCI patients; moderate sample size and well-characterized outcomes.

Study Details

PMID:33935094
Participants:196
Impact:Placebo group decline (28.2→27.7, p=0.029) not seen in B-vitamin group (no significant change)
Trust score:4/5

WPPSI-IV full scale IQ (FSIQ)

1 evidences

Follow-up of an RCT of daily 2 µg vitamin B12 vs placebo given in infancy (6–11 months) for 12 months (original n=600); at 42–47 months there was no overall effect on WPPSI-IV FSIQ or other neurodevelopmental outcomes.

Trust comment: Large randomized trial with high follow-up rates and validated developmental assessments; reports null overall effects with predefined subgroup analyses.

Study Details

PMID:35152918
Participants:533
Impact:Vitamin B12 84.4 vs placebo 85.0; mean difference −0.5 points (95% CI −1.97, 0.94), not significant
Trust score:4/5

subgroup: low birth weight — FSIQ

1 evidences

Follow-up of an RCT of daily 2 µg vitamin B12 vs placebo given in infancy (6–11 months) for 12 months (original n=600); at 42–47 months there was no overall effect on WPPSI-IV FSIQ or other neurodevelopmental outcomes.

Trust comment: Large randomized trial with high follow-up rates and validated developmental assessments; reports null overall effects with predefined subgroup analyses.

Study Details

PMID:35152918
Participants:533
Impact:vitamin group −4.54 points in low birth weight subgroup (95% CI 1.20, 7.88) — subgroup finding; may be chance
Trust score:4/5

normal serum vitamin B12 level at 3 months

1 evidences

After total gastrectomy, two oral B12 doses (500 µg vs 1500 µg/day) produced similar restoration of blood B12 and symptom improvement by 3 months.

Trust comment: Randomized multicenter phase II RCT with clear endpoints but prematurely closed for poor accrual, reducing power.

Study Details

PMID:35896261
Participants:74
Impact:91.7% (33/36) with 500 µg/day vs 100% (38/38) with 1,500 µg/day (p=0.3587)
Trust score:4/5

immediate memory (TICS-M immediate)

1 evidences

Daily folic acid (400 µg) plus vitamin B12 (100 µg) for 2 years produced small but significant improvements in global cognitive score and memory measures in older adults with distress.

Trust comment: Large randomized controlled trial (n=900) with 2-year follow-up showing modest cognitive benefits of combined supplementation.

Study Details

PMID:22170358
Participants:900
Impact:improved vs placebo (P=0.046; d=0.15 at 24 mo)
Trust score:5/5

hemoglobin

11 evidences

Fortified porridge given for 6 months raised hemoglobin and ferritin and improved motor development in infants.

Trust comment: Randomized trial with clear endpoints in infants but the intervention contained multiple micronutrients including B12, so effects cannot be isolated to B12.

Study Details

PMID:16280435
Participants:292
Impact:+9 g/L
Trust score:4/5

Nine-month controlled school-based supplement delivering multiple micronutrients including B12 improved hemoglobin and serum vitamin B12 compared with control schools.

Trust comment: Controlled pre-post school study with substantial sample size but non-randomized cluster design limits causal inference.

Study Details

PMID:17542110
Participants:413
Impact:mean gain +0.393 g/dL (experimental) vs loss -0.9556 g/dL (control); P<0.05
Trust score:3/5

Intravenous B12 (100 µg/mL twice weekly for 8 weeks) reduced median homocysteine and modestly increased hemoglobin and hematocrit in hemodialysis patients.

Trust comment: Randomized trial with moderate sample size (n=140) but limited detail on blinding and longer-term outcomes.

Study Details

PMID:26997378
Participants:140
Impact:mean 12.3 g/dL (intervention) vs 11.4 g/dL (control) at 8 weeks (P=0.003)
Trust score:3/5

Vegetarian women received 500 μg oral B12 every other day for 6 weeks; B12 levels rose and homocysteine fell within 2 weeks and stayed lower.

Trust comment: Small randomized proof-of-principle trial with objective biochemical endpoints and high completer rate but limited size and duration.

Study Details

PMID:17215186
Participants:40
Impact:+3 g/L (small increase)
Trust score:3/5

Fortifying foods with iron and vitamin B12 for 1 year worked similarly regardless of H. pylori infection status.

Trust comment: Large double-blind randomized controlled trial with objective biomarker outcomes, though fortification combined multiple micronutrients so attribution to B12 alone is limited.

Study Details

PMID:20683455
Participants:543
Impact:no difference in change after fortification between H. pylori+ and H. pylori- children
Trust score:4/5

Children given multiple-micronutrient fortified salt (includes iodine) had better blood nutrient markers and improved memory compared with iodized-salt controls.

Trust comment: Randomized controlled trial in residential schools with biochemical and cognitive endpoints and adequate sample size.

Study Details

PMID:20533221
Participants:402
Impact:+0.67 g/dL increase in experimental group vs control (p<0.05)
Trust score:4/5

Children with moderate acute malnutrition received food supplements; serum cobalamin rose during 3 months of supplementation but many remained marginal.

Trust comment: Large randomized factorial trial with objective biochemical and developmental measures; cobalamin was a secondary outcome and some serum data were missing.

Study Details

PMID:35263343
Participants:1548
Impact:Very low SC (<112 pmol/L) associated with −5.7 g/L hemoglobin (95% CI 3.0 to 8.3 g/L lower, p<0.001)
Trust score:4/5

Fortified salt containing iodine and other micronutrients given to children and women for 8 months improved iron and zinc status and reduced anemia; urinary iodine was maintained in the fortified group.

Trust comment: Randomized controlled trial with objective blood measures; however vitamin B12 was one of several micronutrients so effects cannot be attributed specifically to B12.

Study Details

PMID:33952731
Participants:212
Impact:+1.05 g/dL
Trust score:4/5

Caregiver education or provision of low‑protein foods reduced children's phenylalanine; micronutrients including vitamin B12 did not change significantly at 10 weeks.

Trust comment: Randomized trial with long follow-up in 44 children; well-described methods though small sample and multi-arm design limit attribution of micronutrient effects.

Study Details

PMID:34772434
Participants:44
Impact:Mean decreased in educational group (13.29 → 12.95 g/dL; p=0.041)
Trust score:4/5

Young women randomized to pork diet, iron supplement, or control for 12 weeks; iron supplementation raised ferritin and both pork and iron raised hemoglobin; B12 concentrations were not significantly changed (trend to increase with pork).

Trust comment: Randomized controlled trial with reasonable completion rate; B12 not significantly affected though measured.

Study Details

PMID:23204154
Participants:65
Impact:Increased in pork and iron groups vs control
Trust score:4/5

Children eating salt fortified with multiple micronutrients including iodine for one year showed better micronutrient status and improvements on several memory and attention tests.

Trust comment: Intervention showed benefits but was a school-based feeding intervention with multiple micronutrients and non-identical control conditions, limiting attribution to B12 specifically.

Study Details

PMID:17704033
Participants:129
Impact:increased (statistically significant vs control)
Trust score:3/5

atopic dermatitis severity (modified Six Area Six Sign score)

1 evidences

Topical vitamin B12 cream applied twice daily for 8 weeks reduced extent and severity of atopic dermatitis significantly compared with placebo and was well tolerated.

Trust comment: Randomized placebo-controlled multicenter phase III trial with within-patient control but small sample (n=49).

Study Details

PMID:15149512
Participants:49
Impact:greater reduction on vitamin B12–treated side vs placebo side (55.34 ± 5.74 vs 28.87 ± 4.86; P<0.001)
Trust score:4/5

homocysteine (tHcy)

1 evidences

In stroke/TIA patients, long-term B-vitamin (including B12) supplementation lowered homocysteine but did not change carotid thickness or endothelial function.

Trust comment: Randomized, double-blind sub-study with objective vascular measures and meta-analysis, but selection bias and lack of baseline vascular measures limit certainty.

Study Details

PMID:18803866
Participants:162
Impact:-3.7 μmol/L (adjusted mean difference)
Trust score:4/5

flow-mediated dilation (FMD)

1 evidences

In stroke/TIA patients, long-term B-vitamin (including B12) supplementation lowered homocysteine but did not change carotid thickness or endothelial function.

Trust comment: Randomized, double-blind sub-study with objective vascular measures and meta-analysis, but selection bias and lack of baseline vascular measures limit certainty.

Study Details

PMID:18803866
Participants:162
Impact:+0.5% (no significant change)
Trust score:4/5

diarrhea incidence

1 evidences

In Indian children 6–30 months, B12 and/or folic acid improved biochemical status but did not reduce diarrhea or respiratory infections; folic acid (alone or with B12) increased persistent diarrhea risk.

Trust comment: Large, randomized, double-blind trial with clear outcomes and adequate power, though increased persistent diarrhea was linked primarily to folic acid-containing arms.

Study Details

PMID:23902779
Participants:1000
Impact:no significant change
Trust score:4/5

persistent (prolonged) diarrhea

1 evidences

In Indian children 6–30 months, B12 and/or folic acid improved biochemical status but did not reduce diarrhea or respiratory infections; folic acid (alone or with B12) increased persistent diarrhea risk.

Trust comment: Large, randomized, double-blind trial with clear outcomes and adequate power, though increased persistent diarrhea was linked primarily to folic acid-containing arms.

Study Details

PMID:23902779
Participants:1000
Impact:increased risk (OR 2.1; 95% CI 1.1–3.8) associated with folic acid ± B12
Trust score:4/5

homocysteine

26 evidences

In a 6-month randomized placebo-controlled trial a multivitamin containing vitamin B12 raised plasma B12 and improved homocysteine and LDL oxidation markers.

Trust comment: Randomized, placebo-controlled trial with objective biochemical endpoints and moderate sample size.

Study Details

PMID:14559932
Participants:182
Impact:−1.45 µmol/L (8.38 → 6.93 µmol/L; p<0.0001; greater reduction vs placebo, p<0.008)
Trust score:4/5

Two double-blind RCTs (children and adults) showed B12-fortified foods substantially raised plasma B12 and reduced homocysteine compared with placebo.

Trust comment: Two double-blind, placebo-controlled trials with good adherence and objective biochemical endpoints support efficacy for raising B12 status.

Study Details

PMID:34189981
Participants:282
Impact:significant decrease with B12 supplementation
Trust score:4/5

High-dose folate, B6 and B12 lowered homocysteine but did not slow cognitive decline over 18 months and had more depression-related adverse events.

Trust comment: Large multicenter randomized double-blind controlled trial with intention-to-treat analysis and clear endpoints.

Study Details

PMID:18854539
Participants:340
Impact:mean decrease ≈2.42 µmol/L (active) vs 0.86 µmol/L (placebo); P<.001
Trust score:5/5

A 24-week randomized trial of L-methylfolate + methylcobalamin + PLP improved neuropathy symptoms and quality of life but did not change vibration perception threshold.

Trust comment: Well-designed randomized double-blind trial with clinically relevant symptom improvements but no change in primary physiologic measure (VPT).

Study Details

PMID:23218892
Participants:214
Impact:decrease by 2.7 ±3.0 µmol/L vs increase 0.5 ±2.4 µmol/L (P=.0001)
Trust score:4/5

A double-blind RCT of 1000 μg/day oral B12 vs placebo for one month in patients with borderline B12 showed rapid metabolic response (MMA fell) at 1 month but effects were not sustained after stopping therapy.

Trust comment: Randomized, double-blind placebo-controlled trial with validated biochemical outcomes but small sample and limited follow-up after treatment cessation.

Study Details

PMID:21232119
Participants:50
Impact:no significant change (Δ 0.04 μmol/l; p = 0.95)
Trust score:4/5

Two years of B-vitamin supplementation (including 500 μg B12) in elderly with elevated homocysteine lowered homocysteine but did not change arterial stiffness (PWV) or carotid IMT.

Trust comment: Large double-blind randomized controlled trial (2919 participants) with clear biochemical effect but no vascular benefit observed.

Study Details

PMID:26147383
Participants:2919
Impact:−3.6 μmol/L vs placebo
Trust score:4/5

In healthy older adults, adding probiotic VSL#3 to a personalized anti-inflammatory diet for 8 weeks increased plasma vitamin B12 and folate and decreased homocysteine compared with diet alone.

Trust comment: Open-label randomized multicenter study with small N (62) and short duration; biomarker changes significant but clinical relevance needs longer follow-up.

Study Details

PMID:25453395
Participants:62
Impact:decreased (p<0.001) with VSL#3
Trust score:3/5

In older adults with mild cognitive impairment, 6 months of folic acid increased serum folate and vitamin B12, lowered homocysteine, and led to small improvements in some cognitive scores.

Trust comment: Randomized controlled trial with 159 completers showing biomarker and modest cognitive changes, though intervention was folic acid rather than B12 supplementation.

Study Details

PMID:26508298
Participants:159
Impact:decreased (p=0.017) with folic acid treatment
Trust score:4/5

Moderate alcohol intake modestly decreased serum B12 and slightly increased homocysteine in healthy postmenopausal women.

Trust comment: Randomized, diet-controlled crossover trial with clear within-subject comparisons but modest sample size.

Study Details

PMID:15138463
Participants:53
Impact:+3% (trend; P=0.05)
Trust score:4/5

Folate plus B12 supplementation for 8 weeks improved coronary flow reserve and reduced homocysteine in elderly B12-deficient patients.

Trust comment: Randomized small trial in deficient elderly showing physiologic improvements, but small sample limits generalizability.

Study Details

PMID:20851295
Participants:44
Impact:decreased after supplementation
Trust score:3/5

Randomized trial comparing monthly high-dose oral cyanocobalamin vs weekly intramuscular hydroxocobalamin over 4 weeks; both routes improved B12 biomarkers but IM produced much larger early rises.

Trust comment: Randomized outpatient trial with direct biochemical outcomes but small sample size and nonblinded design limits precision.

Study Details

PMID:28421567
Participants:37
Impact:oral 14.8 → 13.8 µmol/L (−6.8%); IM 13.0 → 8.5 µmol/L (−34.6%)
Trust score:4/5

Two-year daily folic acid + vitamin B12 lowered homocysteine but did not improve cognitive domain scores; very small difference in global cognition possibly by chance.

Trust comment: Large multicenter double-blind RCT with objective outcomes and high sample size, providing high-quality evidence.

Study Details

PMID:25391305
Participants:2919
Impact:-5.0 µmol/L (B-vitamin) vs -1.3 µmol/L (placebo)
Trust score:5/5

Large randomized trial: daily B-vitamins (including 500 µg B12) lowered mean homocysteine but did not change MMSE scores or incidence of cognitive impairment over ~2.8–3.4 years.

Trust comment: Very large double-blind randomized trial with long follow-up and prespecified cognitive analysis, providing robust evidence.

Study Details

PMID:23765945
Participants:8164
Impact:mean tHcy 10.2 µmol/L (B-vitamins) vs 14.2 µmol/L (placebo); p<0.001
Trust score:5/5

In newly diagnosed type 2 diabetes, 6 weeks of metformin decreased vitamin B12 and folate and increased homocysteine; rosiglitazone decreased homocysteine and did not change B12 or folate.

Trust comment: Interventional treatment study with objective biochemical outcomes but short duration (6 weeks) and modest sample size.

Study Details

PMID:17331860
Participants:165
Impact:metformin: +2.36 μmol/l; rosiglitazone: -0.92 μmol/l
Trust score:3/5

Aged garlic extract plus B‑vitamin supplement for 1 year reduced coronary calcium progression and improved some vascular/oxidative biomarkers compared with placebo.

Trust comment: Randomized double-blind trial but small sample and the intervention combined multiple ingredients (including B12), so effects cannot be attributed to B12 alone.

Study Details

PMID:19573556
Participants:65
Impact:decreased in AGE+S vs placebo
Trust score:3/5

Men with type 2 diabetes given folic acid 5 mg/day for 8 weeks had lower homocysteine and malondialdehyde and improved total antioxidant capacity; serum folate and vitamin B12 levels also increased.

Trust comment: Randomized double-blind trial in humans with clear biomarker changes, but small sample size (n=68) and the intervention was folic acid rather than vitamin B12 directly.

Study Details

PMID:21896879
Participants:68
Impact:decreased (15.1 ±3.2 → 12.1 ±3.1 µmol/L; significant)
Trust score:3/5

In older men, serum B12 and folate were not associated with lung cancer risk; higher B6 associated with lower risk.

Trust comment: Prospective nested case-control within a cohort provides moderate-quality observational evidence but cannot prove causation and may have residual confounding.

Study Details

PMID:11282797
Participants:600
Impact:no significant association with lung cancer risk (no association reported)
Trust score:3/5

Large randomized trial in MI survivors includes a factorial randomization to folic acid plus 1 mg B12 vs placebo and achieved a modest homocysteine reduction.

Trust comment: Very large randomized trial design provides high-quality evidence on biomarker change, though reported here are trial characteristics and intermediate biomarker effects.

Study Details

PMID:17967584
Participants:12064
Impact:3–4 umol/L average reduction with folic acid 2 mg + vitamin B12 1 mg daily (vs placebo)
Trust score:4/5

In renal-transplant patients with high homocysteine, B-vitamin supplementation including B12 lowered homocysteine and reduced carotid artery thickness over 6 months.

Trust comment: Randomized placebo-controlled trial in humans (n=56) with clear, significant changes in homocysteine and cIMT over 6 months; single-center RTR population limits generalizability.

Study Details

PMID:12792513
Participants:56
Impact:21.8 → 9.3 µmol/L (absolute −12.5 µmol/L)
Trust score:4/5

In renal-transplant patients with high homocysteine, vitamin B treatment (including B12) lowered homocysteine and improved endothelium-dependent and -independent vasodilation over 6 months.

Trust comment: Small randomized controlled human trial (n=36) showing statistically significant biochemical and vascular function improvements; limited sample size.

Study Details

PMID:16083628
Participants:36
Impact:20 ± 5 → 13 ± 4 µmol/L (absolute ≈ −7 µmol/L)
Trust score:4/5

Case-control study measuring one-carbon metabolites in recurrent MDD found no clear association of vitamin B12 with MDD, though homocysteine was higher and vitamin B6 lower during depressive episodes.

Trust comment: Moderately sized observational case-control study (patients n=137, controls n=73) that measured multiple metabolites; associations are observational and state-dependent.

Study Details

PMID:25012419
Participants:210
Impact:increased during depressed state (statistically significant)
Trust score:3/5

Randomized trial in newly diagnosed cobalamin-deficient patients comparing daily oral (2 mg) versus intermittent intramuscular (1 mg) cyanocobalamin for 4 months; oral therapy was at least as effective and produced larger biochemical improvements.

Trust comment: Randomized human trial with objective biochemical and clinical endpoints but small sample size limits precision.

Study Details

PMID:9694707
Participants:33
Impact:decreased to 10.6 µmol/L (oral) vs 12.2 µmol/L (IM) at 4 months
Trust score:4/5

In a 6-month randomized placebo-controlled trial of folic acid (1 mg) in postmenopausal osteoporotic women, folic acid modestly affected homocysteine and bone markers and preserved vitamin B12 levels relative to placebo.

Trust comment: Double-blind RCT with biochemical measures but small single-center sample and limited power to detect small effects.

Study Details

PMID:25223378
Participants:31
Impact:Homocysteine decreased non-significantly in both groups; no significant between-group change (P=0.06)
Trust score:3/5

In undernourished psycho-geriatric patients, a multinutrient liquid supplement for 12 weeks increased body weight and improved multiple plasma nutrient levels including vitamin D.

Trust comment: Double-blind, placebo-controlled randomized trial in elderly patients with good completion and multiple measured biomarkers, though modest sample size.

Study Details

PMID:11960300
Participants:35
Impact:decreased in supplement group vs placebo (statistically significant)
Trust score:4/5

A multicomponent supplement (aged garlic extract plus B vitamins including vitamin B12) lowered homocysteine, increased brown/white epicardial adipose ratio and was associated with less coronary calcium progression over 12 months.

Trust comment: Randomized human study (n=60) of a multicomponent supplement that included vitamin B12; effects are real but cannot be attributed specifically to vitamin B12 alone.

Study Details

PMID:23453866
Participants:60
Impact:Decreased with AGE‑S vs placebo (significant, p<0.05)
Trust score:3/5

A 12-month randomized trial of a multi-component nutrition/diet protocol in ASD found improvements in many clinical and biomarker outcomes; the vitamin/mineral supplement increased some B-vitamin biomarkers.

Trust comment: Randomized, controlled human study with objective biomarker changes, but B12 was part of a multi-component intervention so attribution to B12 alone is uncertain.

Study Details

PMID:29562612
Participants:55
Impact:−29% (treatment) vs −7% (non-treatment); p=0.00002 (improvement consistent with B12/folate/B6 supplementation)
Trust score:3/5

negative symptoms (SANS)

1 evidences

Daily folic acid plus vitamin B12 for 16 weeks improved negative symptoms in schizophrenia when genetic folate-metabolism variants were considered; no change in positive or total symptoms.

Trust comment: Multicenter, randomized, placebo-controlled trial with pharmacogenetic analysis; credible but effect depended on genotype subgroup.

Study Details

PMID:23467813
Participants:140
Impact:improved: group difference -0.33 SANS points/week (significant when genotype included); greater effect in 484T homozygotes (-0.59/week)
Trust score:4/5

vitamin B12

1 evidences

Case-control study measuring one-carbon metabolites in recurrent MDD found no clear association of vitamin B12 with MDD, though homocysteine was higher and vitamin B6 lower during depressive episodes.

Trust comment: Moderately sized observational case-control study (patients n=137, controls n=73) that measured multiple metabolites; associations are observational and state-dependent.

Study Details

PMID:25012419
Participants:210
Impact:no clear association with recurrent MDD (no significant difference reported)
Trust score:3/5

Anxiety severity (HADS-A)

1 evidences

People with relapsing-remitting MS on two dietary interventions plus supplements had improved mood over 24 weeks; serum B12 rose and homocysteine fell, but those blood changes did not explain the mood improvement.

Trust comment: Secondary analysis of a randomized trial with moderate sample size and repeated measures; results plausible though mediation analyses were negative.

Study Details

PMID:37148578
Participants:77
Impact:decrease (significant at 12 and 24 weeks)
Trust score:4/5

Serum folate

16 evidences

Double-blind RCT of a multivitamin/mineral vs placebo in older adults on certain medications; MVMS increased folate and vitamin C status but did not significantly change serum calcium.

Trust comment: Randomized, double-blind controlled trial but small completed sample and short (16-week) duration; some reported B12 changes lacked detailed magnitude or significance in the text.

Study Details

PMID:33078646
Participants:54
Impact:increased (7.5 vs -1.6 ng/mL; P=0.007)
Trust score:3/5

In a large 7.3‑year randomized trial (n=3411), garlic increased serum folate and a vitamin+selenium supplement increased glutathione, but neither intervention changed serum vitamin B12 or homocysteine.

Trust comment: Large, long-term randomized trial with robust sample size for clinical endpoints though biochemical substudies involved selected samples.

Study Details

PMID:19056661
Participants:3411
Impact:+10.2% after garlic supplementation
Trust score:4/5

In insulin-treated type 2 diabetics, 16 weeks of added metformin reduced serum folate and vitamin B12 and produced a modest increase in homocysteine compared with placebo.

Trust comment: Large randomized placebo-controlled trial with clear, clinically relevant biochemical endpoints and low risk of bias.

Study Details

PMID:14535967
Participants:353
Impact:decrease ~7% (95% CI -1.4 to -13%; P=0.024)
Trust score:5/5

In people with low or marginal B12, 12 weeks of high-dose folic acid raised folate stores but did not change methylmalonic acid (a marker of B12 function).

Trust comment: Double-blind randomized placebo-controlled trial with validated assays and prespecified biochemical endpoints, though a substudy with some missing data and limited to middle-aged depressed patients.

Study Details

PMID:34510193
Participants:177
Impact:+21.6 μg/L (adjusted mean difference; P<0.001)
Trust score:4/5

A randomized crossover of whey (contains B12) vs soy protein in older adults with low B12 found WPI increased active B12 and folate (and those biochemical changes correlated with some cognitive improvements), but WPI did not produce a main cognitive benefit; soy improved some cognitive domains in females.

Trust comment: Randomized, double-blind crossover with biochemical and cognitive outcomes but small completer sample (n=44) and an active control (soy) that itself affected cognition in females.

Study Details

PMID:30577611
Participants:44
Impact:increase during WPI treatment (significant)
Trust score:4/5

In elderly people with low B12, whey protein isolate for 8 weeks increased active B12 and serum folate and prevented rises in MMA, homocysteine and genome instability seen with soy protein.

Trust comment: Randomized crossover trial with 56 participants, washout period, and objective biochemical endpoints.

Study Details

PMID:27981743
Participants:56
Impact:increased (p=0.0094) after WPI
Trust score:4/5

Daily consumption of spreads fortified with folic acid, vitamin B6 and vitamin B12 for 6 weeks raised B-vitamin status and significantly lowered plasma homocysteine in healthy volunteers.

Trust comment: Randomized, double-blind, placebo-controlled trial (n=150) with clear biomarker changes, but intervention combined multiple B-vitamins including B12.

Study Details

PMID:17151589
Participants:150
Impact:increase 48%–146% depending on sex and dose (P<0.05)
Trust score:4/5

Alternate supplementation with vitamin B12 and folic acid lowered homocysteine in dialysis patients; effect reversed after washout and B12 levels rose with diffusive haemodialysis.

Trust comment: Randomized, blinded study in 74 patients with clear measurements though results influenced by dialysis modality and washout.

Study Details

PMID:24652221
Participants:74
Impact:greater reduction with haemodialysis versus haemodiafiltration
Trust score:4/5

Randomized trial in aged care residents: a daily multivitamin raised serum 25(OH)D and improved a heel ultrasound bone measure, with a trend to fewer falls.

Trust comment: Randomized controlled trial in institutionalized older adults with objective nutrient and bone outcomes; moderate sample size and clinically relevant biomarker changes.

Study Details

PMID:18043700
Participants:92
Impact:increased (+13.4 ±2.8 nmol/L; P<0.001)
Trust score:4/5

Two randomized placebo-controlled trials in women with PCOS found metformin did not change homocysteine; nonpregnant women showed reductions in folate and B12.

Trust comment: Randomized placebo-controlled trials with clear biochemical outcomes; combined sample moderate in size.

Study Details

PMID:17364275
Participants:101
Impact:decreased with metformin in nonpregnant women
Trust score:4/5

Reproductive-aged Guatemalan women received weekly or daily folic acid (with B12 and minerals) for 12 weeks; folate improved and homocysteine fell in all groups, daily B12 raised serum B12.

Trust comment: Randomized, double-blind trial with adequate sample size and clear biochemical endpoints.

Study Details

PMID:18641196
Participants:459
Impact:mean increase 15.4 nmol/L (95% CI: 13.8, 16.9)
Trust score:4/5

A 2-year community nutrition program providing fortified foods did not significantly improve vitamin B12 status in older Chilean adults compared with control.

Trust comment: Large cluster randomized trial sub-study with substantial sample (351 analyzed) and intention-to-treat analysis; outcomes measured at baseline and 24 months but program adherence and dose may limit effectiveness.

Study Details

PMID:24016218
Participants:351
Impact:both groups decreased ≈ −8.3 nmol/L over 24 months
Trust score:4/5

Two-week controlled feeding in postmenopausal women showing serum nutrient concentrations (including vitamin B-12) reflect recent intake and can serve as biomarkers.

Trust comment: Well-controlled feeding study in humans (n=153) with objective biomarker measures; high internal validity for biomarker-intake relationships.

Study Details

PMID:28031191
Participants:153
Impact:biomarker correlated with intake (R²=0.49)
Trust score:4/5

Randomized double-blind trial showing short-term nitrous oxide anaesthesia reduced serum folate and produced minor hematological changes but did not alter serum cobalamin (vitamin B12) levels in analyzed patients.

Trust comment: Randomized double-blind trial in humans with complete-data n=51; relevant to vitamin B12 status though small sample and focused on anesthesia effects.

Study Details

PMID:10971777
Participants:51
Impact:significant decrease in nitrous oxide group (P<0.05)
Trust score:3/5

Pregnant women given different iron doses (one tablet contained added zinc) showed no significant between-group differences in serum zinc during pregnancy.

Trust comment: Randomized allocation in humans with repeated biomarker monitoring, but small sample and limited scope for vitamin B12-specific effects.

Study Details

PMID:11787984
Participants:67
Impact:remained ~15 µmol/L in multivitamin/mineral group but fell below 10 µmol/L in 100 mg iron group
Trust score:3/5

Drinking mineral water fortified with folic acid, vitamins (including D) and calcium for 8 weeks raised folate, lowered homocysteine, and increased urinary calcium excretion, indicating bioavailable calcium.

Trust comment: Randomized, double-blind, placebo-controlled trial with good completion (60) showing statistically significant biochemical effects, though intervention was a multi‑nutrient combination.

Study Details

PMID:14749760
Participants:60
Impact:increased by +16.1 nmol/L (P<0.001)
Trust score:4/5

Incident age-related cataract

1 evidences

In this large randomized trial of women at high CVD risk, daily folic acid+B6+B12 did not change incidence of age-related cataract but was associated with a higher rate of cataract extraction over ~7 years.

Trust comment: Large randomized, double-masked trial with long follow-up and objective outcomes; credible findings though extraction outcome may reflect clinical decision factors.

Study Details

PMID:26786311
Participants:3925
Impact:no significant change (HR 1.10; 95% CI 0.90–1.33; P=0.36)
Trust score:5/5

Target lesion revascularization

1 evidences

Six months of folic acid+B12+B6 after successful PCI lowered homocysteine and reduced 1-year major adverse events and target lesion revascularization compared with placebo.

Trust comment: Randomized double-blind placebo-controlled trial with moderate sample and clinically important endpoints showing statistically significant benefit.

Study Details

PMID:12190367
Participants:553
Impact:reduced from 16.0% to 9.9% (RR 0.62; 95% CI 0.40–0.97; P=0.03)
Trust score:5/5

Neonatal vitamin B12 status (deficiency rate)

1 evidences

Late cord clamping (60 s) was associated with higher neonatal FT3/FT4 and fewer neonates with low vitamin B12 compared with early clamping (≤10 s); urinary iodine results were measured but not emphasized.

Trust comment: Randomized but small study with limited power; outcome measurement appropriate but sample size restricts precision.

Study Details

PMID:34263919
Participants:60
Impact:higher rate of B12 values below normal in early clamping group (p=0.009)
Trust score:3/5

serum folate concentration

3 evidences

Giving multiple micronutrients including vitamin B12 to HIV-infected children increased their blood B12 and folate levels over six months.

Trust comment: Randomized, double-blind multicenter RCT with objective biochemical assays but biochemical analysis limited to a 214-child subset and some missing samples.

Study Details

PMID:21600005
Participants:214
Impact:+8.0 nmol/L (median change over 6 months in MMS group; p<0.001)
Trust score:4/5

Daily low-dose folic acid, vitamin B6, vitamin B12 and betaine for 12 weeks reduced plasma homocysteine in Chinese adults with hyperhomocysteinemia compared with placebo.

Trust comment: Randomized, double-blind, placebo-controlled trial with objective biochemical endpoints though relatively small sample and short duration.

Study Details

PMID:36717385
Participants:86
Impact:Increase +3.0 ng/mL at 12 weeks (supplement vs placebo)
Trust score:4/5

Two-week daily alcohol (red wine or vodka) decreased serum folate and vitamin B12 and produced a small increase in plasma homocysteine.

Trust comment: Randomized crossover trial with 78 healthy men and within-subject comparisons, but short intervention duration limits clinical generalizability.

Study Details

PMID:18790817
Participants:78
Impact:decrease (significant)
Trust score:4/5

migraine frequency

1 evidences

In a 2-month trial, combined vitamin B12 + magnesium plus high-intensity interval training reduced CGRP levels and improved migraine disability, frequency, intensity and duration more than other groups.

Trust comment: Randomized trial but small sample (n=60) and limited numeric detail in the provided text; registered but full methodological details and effect sizes not fully reported here.

Study Details

PMID:35112219
Participants:60
Impact:Reduced in the HIIT + supplement group compared with other groups (statistically significant)
Trust score:3/5

learning ability (memory)

1 evidences

Among patients with mild cognitive impairment, lower-normal vitamin B12 was associated with worse memory and reduced hippocampal microstructural integrity.

Trust comment: Well-characterized cross-sectional study with MRI and mediation analysis in MCI patients, but observational design limits causal inference.

Study Details

PMID:26912492
Participants:100
Impact:Worse in low-normal B12 group (P = 0.014)
Trust score:3/5

hippocampal microstructural integrity (mean diffusivity)

1 evidences

Among patients with mild cognitive impairment, lower-normal vitamin B12 was associated with worse memory and reduced hippocampal microstructural integrity.

Trust comment: Well-characterized cross-sectional study with MRI and mediation analysis in MCI patients, but observational design limits causal inference.

Study Details

PMID:26912492
Participants:100
Impact:Reduced in low-normal B12, partially mediating 32–48% of the memory effect (P = 0.029)
Trust score:3/5

predialysis total homocyst(e)ine

1 evidences

In hemodialysis patients with high homocysteine, adding oral vitamin B12 (1 mg/day) reduced homocysteine substantially over weeks.

Trust comment: Randomized, double-blind, placebo-controlled trial in ESRD patients showing significant homocysteine reductions with vitamin B12 plus folate; moderate sample size.

Study Details

PMID:11231366
Participants:81
Impact:Reduced by 16.7% (from 22.3 to 18.6 μmol/L) after 4 weeks of vitamin B12 1 mg/day (P < 0.001)
Trust score:4/5

plasma cobalamin concentration

3 evidences

In this community cohort of early-pregnancy women, about one quarter were cobalamin-deficient while folate deficiency was rare.

Trust comment: Large community-based cohort with validated biochemical assays and clear prevalence estimates, though cross-sectional so causal conclusions are limited.

Study Details

PMID:34422259
Participants:561
Impact:Mean 204.5 pmol/L with 24% of women <150 pmol/L (cobalamin-deficient)
Trust score:4/5

Measured plasma folate and cobalamin in young children and tracked diarrheal episodes; plasma B12 did not predict diarrhea.

Trust comment: Large prospective cohort with biomarker measurement and frequent follow-up, appropriate for associations though observational.

Study Details

PMID:22013199
Participants:2296
Impact:not a predictor of diarrheal morbidity
Trust score:4/5

Large community survey showing low plasma cobalamin common in young Indian children, especially in breastfed infants, with associated metabolic markers.

Trust comment: Large population-based sample with biochemical measures; cross-sectional design limits causal inference but data are robust for prevalence estimates.

Study Details

PMID:17991639
Participants:2482
Impact:Median 6–11 mo: breastfed 183 pmol/L vs nonbreastfed 334 pmol/L (breastfed lower)
Trust score:4/5

number of ulcers

1 evidences

Daily sublingual 1000 µg B12 for 6 months reduced ulcers, pain, and outbreak duration in people with recurrent mouth ulcers.

Trust comment: Randomized double-blind placebo-controlled trial but small sample (58), so moderate-high credibility.

Study Details

PMID:19124628
Participants:58
Impact:decrease (significant)
Trust score:4/5

pain level

1 evidences

Daily sublingual 1000 µg B12 for 6 months reduced ulcers, pain, and outbreak duration in people with recurrent mouth ulcers.

Trust comment: Randomized double-blind placebo-controlled trial but small sample (58), so moderate-high credibility.

Study Details

PMID:19124628
Participants:58
Impact:decrease (significant)
Trust score:4/5

cognitive decline (ADAS-cog)

1 evidences

High-dose folate, B6 and B12 lowered homocysteine but did not slow cognitive decline over 18 months and had more depression-related adverse events.

Trust comment: Large multicenter randomized double-blind controlled trial with intention-to-treat analysis and clear endpoints.

Study Details

PMID:18854539
Participants:340
Impact:no significant effect (0.401 vs 0.372 points/month; P=0.52)
Trust score:5/5

neuropathy symptom score (NTSS-6)

1 evidences

A 24-week randomized trial of L-methylfolate + methylcobalamin + PLP improved neuropathy symptoms and quality of life but did not change vibration perception threshold.

Trust comment: Well-designed randomized double-blind trial with clinically relevant symptom improvements but no change in primary physiologic measure (VPT).

Study Details

PMID:23218892
Participants:214
Impact:clinically significant improvement at week 16 and 24 (P=.013, P=.033)
Trust score:4/5

total serum vitamin B12 (TB12)

1 evidences

In women with GDM, metformin treatment led to a greater decline in total serum B12 during pregnancy than insulin, though bioavailable B12 and homocysteine did not differ between groups.

Trust comment: Randomized comparison within a clinical trial cohort with clear biochemical measurements, moderate sample size.

Study Details

PMID:23402546
Participants:180
Impact:greater decrease with metformin: −19.7 ±4.7 pmol/L vs −6.4 ±3.6 pmol/L (P=0.004)
Trust score:4/5

oxygen uptake kinetics (V'O2 time constant, MRT)

1 evidences

Small randomized double-blind trial in COPD patients; B12 supplementation produced modest improvements in exercise tolerance in more advanced COPD but no change in oxygen uptake kinetics.

Trust comment: Randomized double-blind design but very small completed sample (n=32) and subgroup effects were emphasized without precise quantified primary outcomes.

Study Details

PMID:27993287
Participants:32
Impact:no significant change (p > 0.05)
Trust score:3/5

colorectal cancer incidence

1 evidences

Large randomized placebo-controlled trial follow-up showing folic acid + vitamin B12 supplementation was associated with increased overall and colorectal cancer incidence.

Trust comment: Large multicenter randomized trial with long follow-up; findings statistically significant for colorectal cancer but reflect combined folic acid + B12 intervention.

Study Details

PMID:30341095
Participants:2524
Impact:+77% (HR 1.77; 3.4% vs 2.0%; P = 0.02)
Trust score:4/5

serum vitamin B12 concentration (MED group)

1 evidences

Dietary intervention (DIRECT PLUS) and lab analyses showed Mankai contains authentic bioactive B12 and long-term consumption in a green-Mediterranean diet increased serum B12 versus control.

Trust comment: Randomized dietary intervention with good retention and complementary lab evidence, though dietary changes (not isolated B12 supplement) and other B12 sources complicate attribution.

Study Details

PMID:33049929
Participants:294
Impact:+9.9% (mean +32.6 ± 76.2 pg/mL; p < 0.001 vs baseline)
Trust score:4/5

Mankai plant bioactive vitamin B12 content

1 evidences

Dietary intervention (DIRECT PLUS) and lab analyses showed Mankai contains authentic bioactive B12 and long-term consumption in a green-Mediterranean diet increased serum B12 versus control.

Trust comment: Randomized dietary intervention with good retention and complementary lab evidence, though dietary changes (not isolated B12 supplement) and other B12 sources complicate attribution.

Study Details

PMID:33049929
Participants:294
Impact:present (~3.23 µg/100 g dry weight)
Trust score:4/5

cognitive decline (CDR_SOB at 24 months)

1 evidences

Methylcobalamin (500 µg) + folic acid lowered homocysteine but did not reduce cognitive decline at 24 months; transient improvements in executive function and depressive symptoms at 12 months were not sustained.

Trust comment: Well-designed randomized placebo-controlled trial with clear biochemical effect but no durable clinical cognitive benefit.

Study Details

PMID:31787369
Participants:279
Impact:no significant difference
Trust score:4/5

fasting total homocysteine (Group B: FA alone)

1 evidences

In hemodialysis patients, oral folic acid normalized plasma homocysteine; adding IV methylcobalamin provided no additional benefit over folic acid alone.

Trust comment: Randomized trial but small sample; outcomes clearly measured and show folic acid efficacy while methylcobalamin alone had no effect.

Study Details

PMID:12021520
Participants:62
Impact:-8.7 µmol/L (19.9 → 11.2 µmol/L; p = 0.012)
Trust score:3/5

maternal elevated total homocysteine (tHcy) during pregnancy

1 evidences

Maternal oral B12 supplementation during pregnancy was associated with higher expressive language scores in children at 30 months.

Trust comment: Randomized maternal supplementation with measured child cognitive outcomes; moderate sample size and statistically significant domain-specific effect.

Study Details

PMID:30003521
Participants:218
Impact:associated with lower expressive language and gross motor scores (β ≈ -0.18 to -0.30; P ≤ 0.03)
Trust score:4/5

plasma homocysteine concentration

1 evidences

Two-year randomized trial in older adults: B-vitamin supplementation (including B12) lowered homocysteine but did not improve cognitive test scores.

Trust comment: Large double-blind randomized trial with clear biochemical lowering of homocysteine but no cognitive benefit, well-powered for the tested population.

Study Details

PMID:16807413
Participants:276
Impact:-4.36 µmol/L (mean difference vs placebo; P < 0.001)
Trust score:4/5

plasma methylmalonic acid (P-MMA)

2 evidences

Vitamin B12 lowered metabolic markers but did not change blood or clinical symptom scores over 3 months.

Trust comment: Randomized placebo-controlled trial with clear biochemical outcomes but limited clinical effects reported over short-term (3 months).

Study Details

PMID:11468228
Participants:140
Impact:decreased (P < 0.001)
Trust score:4/5

Lipid-based nutrient supplements given for 12 weeks to stunted children increased plasma cobalamin, reduced MMA, improved folate and hemoglobin, and lowered anemia risk.

Trust comment: Large randomized trial with objective biomarker improvements and high follow-up; provides strong evidence of improved B12 status though multinutrient context remains a consideration.

Study Details

PMID:38278366
Participants:736
Impact:reduced by 33% (95% CI: 27,39)
Trust score:4/5

clinical symptom scores (anemia, neurologic, gastroenterologic, neurological disability)

1 evidences

Vitamin B12 lowered metabolic markers but did not change blood or clinical symptom scores over 3 months.

Trust comment: Randomized placebo-controlled trial with clear biochemical outcomes but limited clinical effects reported over short-term (3 months).

Study Details

PMID:11468228
Participants:140
Impact:no significant change (P >= 0.21)
Trust score:4/5

overall psychosis symptoms (PANSS total)

1 evidences

Adjunctive B-vitamin supplementation lowered homocysteine but did not change overall symptoms or global cognition; attention/vigilance was preserved compared with decline in placebo.

Trust comment: Well-conducted randomized double-blind trial; biochemical and cognitive domain outcomes reported with subgroup analyses.

Study Details

PMID:30771856
Participants:120
Impact:no significant change (p = 0.749)
Trust score:4/5

neurocognition — attention/vigilance

1 evidences

Adjunctive B-vitamin supplementation lowered homocysteine but did not change overall symptoms or global cognition; attention/vigilance was preserved compared with decline in placebo.

Trust comment: Well-conducted randomized double-blind trial; biochemical and cognitive domain outcomes reported with subgroup analyses.

Study Details

PMID:30771856
Participants:120
Impact:improved/stabilized vs placebo decline (p = 0.024; effect size = 0.49)
Trust score:4/5

serum methylmalonic acid (MMA)

5 evidences

Methylcobalamin reduced MMA and homocysteine but did not prevent cognitive decline over 27 months in older diabetic adults with borderline B12.

Trust comment: Randomized placebo-controlled trial with adequate follow-up (27 months) and clinically relevant cognitive endpoints.

Study Details

PMID:27823800
Participants:271
Impact:decreased (P < 0.0001)
Trust score:4/5

Treatment-phase study in hemodialysis patients showing folate and added vitamin B12 lower but do not fully normalize homocysteine and MMA in ESRD.

Trust comment: Interventional study in a clinically relevant ESRD population with measurable biochemical endpoints, though normalization was not achieved.

Study Details

PMID:12601627
Participants:81
Impact:decreased with B12 supplementation but remained above normal (did not normalize)
Trust score:4/5

In 24 hemodialysis patients, weekly subcutaneous hydroxocobalamin substantially lowered plasma homocysteine and reduced serum methylmalonic acid over 16 weeks.

Trust comment: Prospective randomized controlled trial in a defined ESRD population with objective biochemical endpoints but small sample size.

Study Details

PMID:12077735
Participants:24
Impact:mean -19% after hydroxocobalamin (P<0.001)
Trust score:4/5

Six months of multivitamin supplementation including B6, B12 and folate in elderly women increased B12 and folate status and lowered homocysteine and methylmalonic acid.

Trust comment: Large randomized placebo-controlled double-blind trial in elderly women with clear biochemical endpoints supports reliability.

Study Details

PMID:15309436
Participants:220
Impact:decreased (median MMA lower than placebo after intervention)
Trust score:4/5

Randomized, placebo-controlled trial of B-vitamin therapy (including B12) in elderly: biomarkers improved (tHcy and MMA) but short-term treatment did not improve movement or cognitive tests.

Trust comment: Double-blind randomized placebo-controlled trial with objective biochemical endpoints and clinical performance measures; sample size moderate for clinical outcomes.

Study Details

PMID:15883442
Participants:209
Impact:-14% with B-vitamin therapy
Trust score:4/5

cognitive outcomes (CDR, NTB z-scores)

1 evidences

Methylcobalamin reduced MMA and homocysteine but did not prevent cognitive decline over 27 months in older diabetic adults with borderline B12.

Trust comment: Randomized placebo-controlled trial with adequate follow-up (27 months) and clinically relevant cognitive endpoints.

Study Details

PMID:27823800
Participants:271
Impact:no significant change at 27 months
Trust score:4/5

radionuclide glomerular filtration rate (GFR)

1 evidences

High-dose B-vitamin therapy (including B12) lowered homocysteine but was associated with greater GFR decline and more vascular events in diabetic nephropathy patients.

Trust comment: Multicenter randomized double-blind trial with clinically important adverse findings despite biochemical efficacy.

Study Details

PMID:20424250
Participants:238
Impact:greater decrease in B-vitamin group (mean difference -5.8 mL/min/1.73 m2; P = 0.02)
Trust score:4/5

composite vascular outcomes

1 evidences

High-dose B-vitamin therapy (including B12) lowered homocysteine but was associated with greater GFR decline and more vascular events in diabetic nephropathy patients.

Trust comment: Multicenter randomized double-blind trial with clinically important adverse findings despite biochemical efficacy.

Study Details

PMID:20424250
Participants:238
Impact:increased in B-vitamin group (HR 2.0; P = 0.04)
Trust score:4/5

subjective fatigue (CIS subscale)

1 evidences

High-dose oral B12 did not reduce subjective fatigue in IBS/IBD patients with normal B12 levels; a small improvement was seen in motivation subscale.

Trust comment: Randomized double-blind placebo-controlled trial with moderate size and clear null primary outcome.

Study Details

PMID:29460813
Participants:95
Impact:no significant difference (change ~ -8.1 vs -8.3)
Trust score:4/5

motivation (CIS subscale)

1 evidences

High-dose oral B12 did not reduce subjective fatigue in IBS/IBD patients with normal B12 levels; a small improvement was seen in motivation subscale.

Trust comment: Randomized double-blind placebo-controlled trial with moderate size and clear null primary outcome.

Study Details

PMID:29460813
Participants:95
Impact:improved (change -2.2; 95% CI -4.4 to -0.04)
Trust score:4/5

depression and quality of life

1 evidences

High-dose oral B12 did not reduce subjective fatigue in IBS/IBD patients with normal B12 levels; a small improvement was seen in motivation subscale.

Trust comment: Randomized double-blind placebo-controlled trial with moderate size and clear null primary outcome.

Study Details

PMID:29460813
Participants:95
Impact:no significant change
Trust score:4/5

venous thromboembolism incidence

1 evidences

B-vitamin therapy lowered homocysteine but did not change the incidence of venous thromboembolism over ~5 years.

Trust comment: Large randomized trial (secondary analysis) with reliable biochemical changes but VTE events not centrally adjudicated.

Study Details

PMID:17470822
Participants:5522
Impact:no significant change (HR 1.01; 95% CI 0.66–1.53)
Trust score:4/5

2-methylcitric acid concentration

1 evidences

In elderly people, intramuscular B12+folate+B6 given eight times over 3 weeks lowered several metabolic markers of B12 deficiency and normalized them in a higher proportion than placebo.

Trust comment: Prospective, multicentre double-blind placebo-controlled trial with objective biochemical outcomes and substantial sample size.

Study Details

PMID:7603218
Participants:285
Impact:Normalization rate +37 percentage points (62% vs 25% vitamin vs placebo)
Trust score:4/5

functional disability (Roland Morris score)

1 evidences

Randomized open-label study adding pyrimidine nucleotides plus vitamins B1 and B12 to standard care for painful radiculopathy showed no significant difference in pain VAS but some functional and global-clinical improvement versus control.

Trust comment: Randomized study but open-label with modest sample size and limited power for primary pain endpoint; secondary functional outcomes favored supplement.

Study Details

PMID:39683579
Participants:116
Impact:Greater functional improvement at final visit in experimental group (interaction −1.70 units; p=0.038)
Trust score:3/5

active vitamin B12 (holotranscobalamin)

1 evidences

A randomized crossover of whey (contains B12) vs soy protein in older adults with low B12 found WPI increased active B12 and folate (and those biochemical changes correlated with some cognitive improvements), but WPI did not produce a main cognitive benefit; soy improved some cognitive domains in females.

Trust comment: Randomized, double-blind crossover with biochemical and cognitive outcomes but small completer sample (n=44) and an active control (soy) that itself affected cognition in females.

Study Details

PMID:30577611
Participants:44
Impact:increase during WPI treatment (significant)
Trust score:4/5

electrophysiologic neurologic function

1 evidences

Cross-sectional analysis of older adults with moderately low B12 found no association between B12 status (total B12, holoTC, cB-12) and electrophysiologic or clinical neurologic measures.

Trust comment: Analysis uses high-quality baseline trial data and objective electrophysiologic measures but is cross-sectional and limited to moderately low (not severely deficient) older adults.

Study Details

PMID:27534645
Participants:201
Impact:no association with vitamin B12 status
Trust score:3/5

serum B12 and folate

1 evidences

Randomized trial comparing immediate vs 5–7 day prior folic acid+B12 supplementation in patients receiving pemetrexed-based chemotherapy; simultaneous supplementation was feasible and did not increase most hematologic toxicity.

Trust comment: Randomized multicenter trial with modified ITT and objective hematologic and biochemical measures; open-label but adequately powered for toxicity outcomes.

Study Details

PMID:30825389
Participants:150
Impact:increased after 5–7 days B12-FA in delayed arm (measured rise vs baseline)
Trust score:4/5

systolic orthostatic BP drop (30 s)

1 evidences

Substudy of a double-blind RCT: metformin (1 g twice daily) plus insulin modestly increased early orthostatic blood pressure drop versus placebo; metformin reduced serum B12 modestly.

Trust comment: Large double-blind randomized trial substudy with objective autonomic and biochemical measures; substudy analyses limit primary focus but methods are robust.

Study Details

PMID:32979921
Participants:372
Impact:worse with metformin: increased drop by +3.35 mmHg (95% CI 0.57–6.12); P=0.02
Trust score:4/5

serum vitamin B12 at 6 months

1 evidences

Randomized trial in metformin-treated type 2 diabetes patients with low B12 showed 3-month correction of B12 with either route; sublingual methylcobalamin produced higher serum B12 at 3 months but differences resolved by 6 months.

Trust comment: Randomized trial but small sample; biochemical outcome robust though limited by sample size and short follow-up.

Study Details

PMID:27355231
Participants:34
Impact:no significant difference between groups at 6 months (P=0.38)
Trust score:3/5

ICAM-1

1 evidences

In a 2-year randomized trial subsample, daily vitamin B12 (500 µg) plus folic acid did not change endothelial or inflammation biomarkers versus placebo in elderly with high homocysteine.

Trust comment: Large randomized trial subsample with measured biomarker outcomes; results show no significant effects.

Study Details

PMID:26774115
Participants:522
Impact:+36% vs +32% (no significant difference, p=0.72)
Trust score:4/5

Fasting plasma total homocysteine

1 evidences

Small randomized trial in renal transplant recipients: folic acid plus vitamin B12 reduced fasting homocysteine; vitamin B6 reduced post-methionine-loading increases.

Trust comment: Randomized controlled design but very small sample (n=29) limits precision and generalizability.

Study Details

PMID:9412311
Participants:29
Impact:−26.2% (folic acid + B12, p=0.027)
Trust score:3/5

Plasma total homocysteine (10 µg B12)

1 evidences

12-month randomized community trial: low-dose oral B12 (2 or 10 µg/day) significantly lowered plasma homocysteine compared to placebo; folic acid 200 µg/day also reduced homocysteine.

Trust comment: Well-conducted cluster randomized double-blind trial with adequate sample and clear biochemical outcomes.

Study Details

PMID:20216560
Participants:300
Impact:−7.1 µmol/L at 12 months (95% CI −8.9, −5.4)
Trust score:4/5

Intracerebral hemorrhage risk

1 evidences

Prospective cohort of male smokers: higher dietary folate (but not vitamin B12) intake was associated with lower risk of cerebral infarction; B12 intake showed no significant association with stroke subtypes.

Trust comment: Large prospective cohort with long follow-up; observational design limits causal inference for B12.

Study Details

PMID:18270369
Participants:26556
Impact:Vitamin B12: no significant association
Trust score:4/5

vitamin B12 serum level

1 evidences

An RCT of RYGB patients found that an optimized multivitamin (WLS Forte) produced fewer iron and B12 deficiencies versus standard MVS; both groups received substantial vitamin D (total ~1200 IU/day) with similar 25-OHD levels at 12 months.

Trust comment: Triple-blind randomized controlled trial with 148 patients and predefined biochemical outcomes; some participants received additional corrective supplements which may confound results.

Study Details

PMID:25437032
Participants:148
Impact:+44.1 pmol/L (WLS Forte) vs −38.9 pmol/L (sMVS) at 12 months
Trust score:4/5

vitamin B12 level

7 evidences

In obese adults on a weight-loss diet, synbiotic tablets increased vitamin D and B12 levels but both groups lost similar weight.

Trust comment: Randomized single-center trial with 110 participants and short follow-up; effects reported vs baseline without detailed absolute B12 change.

Study Details

PMID:40192559
Participants:110
Impact:increased (significant vs baseline)
Trust score:3/5

Caregiver education or provision of low‑protein foods reduced children's phenylalanine; micronutrients including vitamin B12 did not change significantly at 10 weeks.

Trust comment: Randomized trial with long follow-up in 44 children; well-described methods though small sample and multi-arm design limit attribution of micronutrient effects.

Study Details

PMID:34772434
Participants:44
Impact:No significant change at 10 weeks (educational ~722 → 756 pg/mL; food items ~760 → 740 pg/mL; p>0.05)
Trust score:4/5

Short-term high-dose folic acid improved endothelial function in young people with type 1 diabetes; vitamin B12 levels were measured and did not change.

Trust comment: Randomized crossover trial with direct measurement showing no change in B12, but B12 was not the intervention target.

Study Details

PMID:15069400
Participants:36
Impact:no change reported after folic acid intervention
Trust score:3/5

Identical twins randomized to vegan vs omnivorous diets for 8 weeks; vegans had lower LDL, insulin and weight; serum B12 fell numerically but was not significantly different.

Trust comment: Well-conducted randomized twin RCT with small sample and short duration; measured B12 but change was not statistically significant.

Study Details

PMID:38032644
Participants:42
Impact:−103 pg/mL (not significant)
Trust score:4/5

Secondary analysis of RCT data describing longitudinal micronutrient status after pancreaticoduodenectomy; documents prevalent vitamin D deficiency and related biochemical changes.

Trust comment: Prospective RCT-derived longitudinal data with moderate sample size; descriptive analysis shows B12 maintained postoperatively.

Study Details

PMID:34531424
Participants:47
Impact:Remained within normal range (no deficiency detected)
Trust score:3/5

Young women randomized to pork diet, iron supplement, or control for 12 weeks; iron supplementation raised ferritin and both pork and iron raised hemoglobin; B12 concentrations were not significantly changed (trend to increase with pork).

Trust comment: Randomized controlled trial with reasonable completion rate; B12 not significantly affected though measured.

Study Details

PMID:23204154
Participants:65
Impact:No significant change (trend increase in pork group)
Trust score:4/5

Elderly women took a multivitamin for 16 weeks and showed faster spatial working memory and improved some blood nutrient markers.

Trust comment: Randomized double-blind placebo-controlled trial with clear cognitive and biochemical outcomes but modest sample size.

Study Details

PMID:22006207
Participants:56
Impact:increased (statistically significant)
Trust score:4/5

carotid intima-media thickness

2 evidences

Two years of B-vitamin supplementation (including 500 μg B12) in elderly with elevated homocysteine lowered homocysteine but did not change arterial stiffness (PWV) or carotid IMT.

Trust comment: Large double-blind randomized controlled trial (2919 participants) with clear biochemical effect but no vascular benefit observed.

Study Details

PMID:26147383
Participants:2919
Impact:no change vs placebo
Trust score:4/5

Cross-sectional study measuring homocysteine metabolism markers and carotid intima-media thickness in people with and without type 2 diabetes.

Trust comment: Well-characterized cross-sectional human cohort measuring B12 and related metabolites, but observational design prevents causal inference.

Study Details

PMID:12921985
Participants:231
Impact:+0.07 mm (homocysteine >12 μmol/L) in diabetic individuals; -0.004 mm in non-diabetic individuals
Trust score:3/5

cognitive function (selected tests)

1 evidences

In older adults with mild cognitive impairment, 6 months of folic acid increased serum folate and vitamin B12, lowered homocysteine, and led to small improvements in some cognitive scores.

Trust comment: Randomized controlled trial with 159 completers showing biomarker and modest cognitive changes, though intervention was folic acid rather than B12 supplementation.

Study Details

PMID:26508298
Participants:159
Impact:improved (Full Scale IQ, Digit Span, Block Design; small effect sizes)
Trust score:4/5

hearing loss (pure-tone average)

1 evidences

Higher MMA was linked to hearing loss; short-term B12 did not improve hearing.

Trust comment: Moderate-sized clinical study with measured biomarkers but limited intervention duration and observational associations.

Study Details

PMID:18032219
Participants:93
Impact:associated with elevated MMA (worse ear only)
Trust score:3/5

choline metabolites (betaine, dimethylglycine)

1 evidences

Vitamin B12 intervention did not change plasma TMAO or related choline metabolites in vegetarians.

Trust comment: Controlled intervention in vegetarians with repeated measures and reported ICCs; moderate sample size.

Study Details

PMID:27562778
Participants:171
Impact:no effect from vitamin B12 intervention
Trust score:4/5

executive function (CLOX)

1 evidences

B-vitamin treatment (including B12) lowered homocysteine and slowed some cognitive decline, especially in those with high baseline homocysteine.

Trust comment: Double-blind randomized trial with adequate sample and clear biomarker and cognitive endpoints, though effects concentrated in subgroup.

Study Details

PMID:21780182
Participants:266
Impact:stabilized vs placebo (P=0.015)
Trust score:4/5

serum vitamin B12 concentration (oral)

1 evidences

Randomized trial comparing monthly high-dose oral cyanocobalamin vs weekly intramuscular hydroxocobalamin over 4 weeks; both routes improved B12 biomarkers but IM produced much larger early rises.

Trust comment: Randomized outpatient trial with direct biochemical outcomes but small sample size and nonblinded design limits precision.

Study Details

PMID:28421567
Participants:37
Impact:158 → 354 pmol/L (+196 pmol/L; +124%) at 4 weeks
Trust score:4/5

serum PINP (bone formation marker)

1 evidences

A 24‑week RCT of fortified milk (providing ~1008 mg Ca/day) plus exercise improved vitamin B‑12 and 25(OH)D levels and reduced bone turnover markers versus control.

Trust comment: Well-conducted RCT with good sample and biochemical measures, but intervention combined nutrition and exercise (effects not solely attributable to B12).

Study Details

PMID:32588047
Participants:163
Impact:intervention median 41.0 → 29.0 µg/L (decrease) by 24 weeks
Trust score:4/5

role limitations due to emotional problems (SF-36)

1 evidences

Ancillary analysis of a large RCT of low-dose B-vitamin supplementation (including B12) in CVD survivors found no overall QOL benefit and a small worsening in emotional role limitations.

Trust comment: Large randomized trial but this is an ancillary QOL analysis with low B12 dose and composite B-vitamin treatment, limiting attribution to B12 alone.

Study Details

PMID:24465438
Participants:2029
Impact:mean difference +3.8 points (worse) for B vitamins vs no B vitamins; 95% CI: 0.4 to 7.1, p=0.029
Trust score:3/5

plasma methylmalonic acid (MMA) reduction

1 evidences

Double-blind randomized dose-finding trial in older adults with mild B12 deficiency showing dose-dependent reductions in methylmalonic acid; high oral doses required to approximate maximal biochemical response.

Trust comment: Randomized, double-blind dose-finding RCT with clear biochemical endpoints, though limited to mild deficiency and 16-week duration.

Study Details

PMID:15911731
Participants:120
Impact:2.5 µg: −16%; 100 µg: −16%; 250 µg: −23%; 500 µg: −33%; 1000 µg: −33% over 16 weeks
Trust score:4/5

folate level and treatment response (context)

1 evidences

Observational analysis in fluoxetine-resistant MDD patients: baseline low folate predicted poor response, whereas low serum vitamin B12 did not predict treatment outcome.

Trust comment: Small clinical sample with baseline biomarker associations; informative but limited power to detect B12 effects on antidepressant response.

Study Details

PMID:15323594
Participants:55
Impact:low folate associated with lower response rate (7.1% vs 44.7%) — included as contextual comparator
Trust score:3/5

Serum vitamin B-12 concentration

1 evidences

One-year daily 1 mg oral B12 in older adults raised blood B12 but did not improve nerve conduction or cognitive tests.

Trust comment: Large, double-blind randomized trial with high adherence and objective outcomes; low risk of bias.

Study Details

PMID:26135351
Participants:191
Impact:+177%
Trust score:5/5

Maternal–infant plasma vitamin B12 correlation (Cambodia)

1 evidences

In two cohorts, maternal and infant blood B12 concentrations correlated; milk B12 correlated with infant B12 in Canada but not in Cambodia, and most mothers and infants had adequate B12 status.

Trust comment: Secondary analysis of two trials with valid laboratory methods but limited and non-representative samples and some missing measures across specimens.

Study Details

PMID:28287490
Participants:168
Impact:significant (p<0.001)
Trust score:3/5

Route comparison (sublingual vs oral)

1 evidences

Daily 500 μg cobalamin given sublingually or orally for 4 weeks similarly corrected low serum B12 concentrations.

Trust comment: Randomized study but small sample (n=30) and short duration; results on biochemical correction are clear but limited by size.

Study Details

PMID:14616423
Participants:30
Impact:no difference between routes
Trust score:3/5

Global cognitive function (MoCA total)

1 evidences

In 120 AD patients, 6 months of daily folic acid plus vitamin B12 modestly improved some cognitive subtests, lowered homocysteine and TNFα, and raised B12 and SAM/ SAM:SAH.

Trust comment: Single-center randomized placebo-controlled trial with objective biochemical and cognitive endpoints; single-blind and moderate sample size limit generalizability.

Study Details

PMID:34101780
Participants:120
Impact:+1.03 points (β=1.033; P=0.029)
Trust score:4/5

serum TNF-α

1 evidences

In 120 AD patients, 6 months of daily folic acid plus vitamin B12 modestly improved some cognitive subtests, lowered homocysteine and TNFα, and raised B12 and SAM/ SAM:SAH.

Trust comment: Single-center randomized placebo-controlled trial with objective biochemical and cognitive endpoints; single-blind and moderate sample size limit generalizability.

Study Details

PMID:34101780
Participants:120
Impact:−37.11 pg/mL (β=−37.105; P<0.001)
Trust score:4/5

Attention / calculation (neuropsychological)

1 evidences

Prospective case-control study of vitamin B12 in cognitive impairment: B12-treated patients showed improvements in attention/calculation and visuoconstruction vs control at 6 months.

Trust comment: Prospective, randomized case-control study with moderate sample size but limited reporting of effect sizes and blinding.

Study Details

PMID:37334792
Participants:115
Impact:Improved (p<0.01)
Trust score:3/5

Sural nerve conduction / neurophysiological indices

1 evidences

In 90 type 2 diabetic patients with neuropathy and low B12, 12 months of 1000 µg methylcobalamin normalized B12 and improved multiple neuropathy measures (nerve conduction, pain, sudomotor function) and quality of life.

Trust comment: Randomized, double-blind, placebo-controlled 1-year trial with objective neurophysiological outcomes; single-center and limited to metformin-treated diabetics.

Study Details

PMID:33513879
Participants:90
Impact:Improved (significant between-group changes; p≤0.001 for several indices)
Trust score:4/5

Visual contrast surround suppression

1 evidences

In a general adult sample randomized to B6, B12, or placebo for ~1 month, vitamin B12 showed a small/near-significant reduction in self-reported anxiety and a trend toward increased visual contrast thresholds (greater surround suppression).

Trust comment: Large randomized double-blind trial but exploratory with multiple outcomes, variable completion per measure, short (≈1 month) supplementation and no serum B12 verification for participants.

Study Details

PMID:35851507
Participants:478
Impact:Trend toward elevated contrast thresholds with B12 (p≈0.055)
Trust score:3/5

hemoglobin increase

1 evidences

In 80 children with nutritional macrocytic anemia, parenteral vitamin B12 produced larger increases in serum B12 and hemoglobin at 3 months than oral B12.

Trust comment: Randomized controlled pediatric trial showing greater biochemical and hematologic response with parenteral vs oral B12; single-center and open-label but randomized.

Study Details

PMID:35642923
Participants:80
Impact:Median rise: IM +2.7 g/dL vs oral +0.5 g/dL (P=0.001)
Trust score:4/5

cognitive outcomes

1 evidences

Children given vitamin B12 and/or folic acid in early life showed no difference in cognition 6 years later.

Trust comment: Large randomized, double-blind trial with long follow-up and high re-enrollment (791) though outcomes were null; methods and follow-up are robust.

Study Details

PMID:32019814
Participants:791
Impact:no difference vs placebo
Trust score:4/5

RBC folate

2 evidences

Compared dolutegravir vs non-dolutegravir ART; measured folate, B12 and MCV — B12 levels did not differ between arms.

Trust comment: Randomized trial sub-study with prospective measurements and clear statistical adjustments, but outcome pertains to ART effects on B12/folate rather than B12 supplementation.

Study Details

PMID:37766505
Participants:229
Impact:higher in DTG arm: +73 ng/ml at ≥96 weeks (adjusted)
Trust score:4/5

In people with low or marginal B12, 12 weeks of high-dose folic acid raised folate stores but did not change methylmalonic acid (a marker of B12 function).

Trust comment: Double-blind randomized placebo-controlled trial with validated assays and prespecified biochemical endpoints, though a substudy with some missing data and limited to middle-aged depressed patients.

Study Details

PMID:34510193
Participants:177
Impact:+461 μg/L (adjusted mean difference; P<0.001)
Trust score:4/5

MCV

1 evidences

Compared dolutegravir vs non-dolutegravir ART; measured folate, B12 and MCV — B12 levels did not differ between arms.

Trust comment: Randomized trial sub-study with prospective measurements and clear statistical adjustments, but outcome pertains to ART effects on B12/folate rather than B12 supplementation.

Study Details

PMID:37766505
Participants:229
Impact:no difference in change from baseline between arms
Trust score:4/5

early postoperative leg pain (VAS)

1 evidences

Epidural dexamethasone plus vitamin B12 after PEID reduced early postoperative pain and inflammatory markers and shortened hospital stay, with no long-term differences.

Trust comment: Randomized, double-blind RCT with complete 6-month follow-up but small sample (n=56) which limits precision and generalizability.

Study Details

PMID:39506779
Participants:56
Impact:reduced (POD1 −0.93 points; POD3 −1.00 points; POD7 −0.57 points vs surgery alone; P<0.05)
Trust score:4/5

postoperative hospital stay

1 evidences

Epidural dexamethasone plus vitamin B12 after PEID reduced early postoperative pain and inflammatory markers and shortened hospital stay, with no long-term differences.

Trust comment: Randomized, double-blind RCT with complete 6-month follow-up but small sample (n=56) which limits precision and generalizability.

Study Details

PMID:39506779
Participants:56
Impact:shorter by −1.07 days (5.14 vs 6.21 days; p=0.028)
Trust score:4/5

leptin and adiponectin (overall)

1 evidences

Six-month early-life supplementation with vitamin B12 + folic acid led to lower homocysteine 6–7 years later; no overall effects on leptin/adiponectin.

Trust comment: Well-powered randomized factorial trial with long follow-up and robust lab methods; subsample analyses for adipokines were smaller and exploratory.

Study Details

PMID:36889645
Participants:791
Impact:no difference vs placebo
Trust score:4/5

growth in wasted/underweight/stunted children

1 evidences

Daily vitamin B12 supplementation for 6 months produced a small overall increase in weight-for-age and larger benefits in malnourished subgroups.

Trust comment: Large randomized, double-blind placebo-controlled trial with clear subgroup effects; effect sizes generally small but statistically supported.

Study Details

PMID:25802345
Participants:1000
Impact:significant increases in weight-for-age and height-for-age in these subgroups (reported subgroup effects)
Trust score:4/5

25(OH)D3

1 evidences

Combined and separate vitamin D3+B12 supplementation over 12 weeks raised serum 25(OH)D and B12; the single-tablet formulation produced larger average increases.

Trust comment: Randomized multicenter trial showing clear biochemical responses; open-label design, small completed sample (n=129) and short duration limit strength of clinical conclusions.

Study Details

PMID:39940277
Participants:129
Impact:increased (Group A +69.1%, Group B +59.5%, p<0.01); compound group had greater percent rise (borderline p=0.052)
Trust score:3/5

growth (length, weight)

1 evidences

Daily 2 μg vitamin B12 for 12 months improved biochemical B12 status but did not change neurodevelopment, growth, or hemoglobin at end of study.

Trust comment: Large, double-blind, placebo-controlled RCT with high retention and robust biochemical and developmental assessments; null clinical outcomes despite clear metabolic response.

Study Details

PMID:33259482
Participants:572
Impact:no difference vs placebo (e.g., length change mean difference 0.09 cm, p>0.05)
Trust score:5/5

3cB12 (combined B12 status)

1 evidences

Children with severe acute malnutrition received RUTF and showed improved vitamin B12 biomarker status at discharge, though some remained deficient.

Trust comment: Randomized trial sub-study with objective biomarker measurements and moderate-to-large sample, though long storage of samples and sub-study design are limitations.

Study Details

PMID:37630687
Participants:361
Impact:+20 percentage points adequate (16% → 36%); marked/severe deficiency −23 percentage points (32% → 9%)
Trust score:4/5

Blood secondary methylation index (bSMI)

1 evidences

In 8–11 year-old children, 12 weeks of folic acid + B12 increased arsenic methylation capacity as shown by changes in blood and urine arsenic metabolites.

Trust comment: Well-conducted double-blind randomized placebo-controlled trial with objective arsenic speciation and high completion.

Study Details

PMID:38728816
Participants:236
Impact:Absolute increase +0.19 (95% CI: 0.09 to 0.35) in supplementation vs placebo
Trust score:5/5

Night sleep duration

1 evidences

Daily vitamin B12 for one year in infants did not change night or total sleep duration or WASO; a small negative effect was reported for sleep onset latency.

Trust comment: Large double-blind randomized placebo-controlled trial using objective actigraphy measures; sleep was a predefined secondary outcome.

Study Details

PMID:34999324
Participants:600
Impact:No effect
Trust score:4/5

Sleep onset latency (SOL)

1 evidences

Daily vitamin B12 for one year in infants did not change night or total sleep duration or WASO; a small negative effect was reported for sleep onset latency.

Trust comment: Large double-blind randomized placebo-controlled trial using objective actigraphy measures; sleep was a predefined secondary outcome.

Study Details

PMID:34999324
Participants:600
Impact:Small significant negative effect reported (direction reported as 'negative' in study)
Trust score:4/5

Human milk vitamin B12 at 6 weeks (prenatal supplement)

1 evidences

Prenatal high-dose maternal B12 increased human milk B12 at 6 weeks, and postnatal supplementation increased milk B12 at 7 months.

Trust comment: Randomized double-blind placebo-controlled trial with large sample and biochemical milk B12 outcomes measured at defined timepoints.

Study Details

PMID:38432714
Participants:412
Impact:+34.4% (95% CI: 17.0% to 54.5%) vs control
Trust score:5/5

Prevalence low milk B12

1 evidences

Prenatal high-dose maternal B12 increased human milk B12 at 6 weeks, and postnatal supplementation increased milk B12 at 7 months.

Trust comment: Randomized double-blind placebo-controlled trial with large sample and biochemical milk B12 outcomes measured at defined timepoints.

Study Details

PMID:38432714
Participants:412
Impact:High prevalence: 73.3% at 6 wk and 68.4% at 7 mo (baseline/contextual finding)
Trust score:5/5

Red blood cell count (erythropoiesis)

1 evidences

In preterm infants receiving erythropoietin and iron, adding vitamin B12 + higher-dose folate modestly enhanced erythropoiesis over 4 weeks.

Trust comment: Randomized controlled neonatal trial with small sample and some baseline imbalances that limit certainty.

Study Details

PMID:16818564
Participants:64
Impact:+10% in RBC counts in B12+folate group vs control over 4 weeks
Trust score:3/5

Serum and red cell folate

1 evidences

Case-control analysis found lower folate and B12 in neural tube defect pregnancies vs controls (not significant in this sample), and pooled literature showed lower serum B12 in cases.

Trust comment: Matched case-control analysis with small case numbers and non-significant primary comparisons in this sample; pooled review evidence supports association with lower B12.

Study Details

PMID:8605127
Participants:135
Impact:Lower in cases than controls in this sample (not statistically significant in this dataset; pooled literature shows significant folate deficit)
Trust score:3/5

cellular methylation capacity (SAM/SAH ratio)

1 evidences

8-week subcutaneous methyl B12 improved clinician-rated global autism symptoms and methylation markers but did not change parent-rated behavior or social responsiveness.

Trust comment: Randomized placebo-controlled trial in children with an objective primary outcome; moderate sample size (n=50 completed).

Study Details

PMID:26889605
Participants:50
Impact:improved (correlated with clinical improvement; p=0.007)
Trust score:4/5

physical performance score

1 evidences

Two-year daily vitamin B12+folic acid (both arms received vitamin D) did not prevent decline in physical performance or handgrip strength or reduce fall risk in older adults overall; possible benefit on walking and in compliant >80y subgroup.

Trust comment: Large multicenter double-blind randomized placebo-controlled trial (n=2919) with 2-year follow-up and objective outcomes.

Study Details

PMID:26412463
Participants:2919
Impact:no significant difference; treatment effect 0.1 (95% CI −0.1 to 0.3)
Trust score:5/5

fall risk

1 evidences

Two-year daily vitamin B12+folic acid (both arms received vitamin D) did not prevent decline in physical performance or handgrip strength or reduce fall risk in older adults overall; possible benefit on walking and in compliant >80y subgroup.

Trust comment: Large multicenter double-blind randomized placebo-controlled trial (n=2919) with 2-year follow-up and objective outcomes.

Study Details

PMID:26412463
Participants:2919
Impact:no significant difference; HR 1.0 (95% CI 0.9 to 1.2)
Trust score:5/5

time to death or ventilation support (primary event)

1 evidences

Long-term intramuscular ultra-high-dose methylcobalamin did not meet primary endpoints overall, but a post-hoc subgroup diagnosed ≤12 months after onset showed prolonged time to death/ventilation and less functional decline.

Trust comment: Multicenter randomized double-blind trial with negative primary outcome; post-hoc subgroup (early diagnosis) showed benefit and should be interpreted cautiously.

Study Details

PMID:30636701
Participants:260
Impact:no significant benefit overall (HR total active 0.88); in early-diagnosed subgroup median time increased from 570 days (placebo) to 1087/1197 days (25/50 mg); combined HR 0.57 (95% CI 0.35–0.92)
Trust score:4/5

cognitive score (BSID III)

1 evidences

Substudy of a cluster-RCT in rural China: daily fortified cereal or meat for 1 year increased serum B12 and lowered homocysteine; meat and fortified cereal groups had modestly higher cognitive scores versus local cereal.

Trust comment: Cluster-randomized intervention with objective biochemical endpoints and cognitive testing in a prespecified subsample (n=180), but nonblinded and limited subsample size.

Study Details

PMID:31519167
Participants:180
Impact:meat vs local estimated difference +0.99 (95% CI 0.21–1.76; p=0.013); fortified vs local p=0.051
Trust score:4/5

related metabolic markers (homocysteine and blood counts)

1 evidences

12-week double-blind randomized trial in vegans/vegetarians with marginal B12 deficiency: weekly sublingual 350 μg and 2000 μg both restored serum B12 and improved related metabolic markers.

Trust comment: Double-blind randomized controlled trial but small sample (n=40) and short duration; biochemical endpoints improved in both arms.

Study Details

PMID:29499976
Participants:40
Impact:improved in both dose groups during the 12-week follow-up
Trust score:3/5

ambulatory capacity (mobility)

1 evidences

In an early PD cohort, low baseline B12 predicted greater worsening of mobility, whereas elevated homocysteine predicted greater cognitive decline on MMSE.

Trust comment: Observational analysis within a clinical trial cohort (DATATOP) with moderate sample size; associations are correlative and not proof of causation.

Study Details

PMID:29508904
Participants:456
Impact:low baseline B12 tertile (<234 pmol/L) associated with greater annualized worsening of ambulatory capacity (exact effect size not provided)
Trust score:3/5

Total brain volume

1 evidences

MRI substudy within an RCT of 2-year folic acid + vitamin B12 supplementation in older adults; investigated cross-sectional associations of B12/folate/Hcy biomarkers with grey, white and total brain volumes and compared brain volumes by supplementation group after 2 years.

Trust comment: High-quality imaging and biomarkers in a randomized parent trial, but MRI subgroup lacked baseline brain volumes and had age imbalance and selection (elevated Hcy), limiting causal inference.

Study Details

PMID:28029114
Participants:218
Impact:−8.7 mL in B-vitamin group vs non-supplemented after adjustment (1063.6 vs 1072.3 mL; p=0.03)
Trust score:3/5

Homocysteine (Hcy) and total brain volume

1 evidences

MRI substudy within an RCT of 2-year folic acid + vitamin B12 supplementation in older adults; investigated cross-sectional associations of B12/folate/Hcy biomarkers with grey, white and total brain volumes and compared brain volumes by supplementation group after 2 years.

Trust comment: High-quality imaging and biomarkers in a randomized parent trial, but MRI subgroup lacked baseline brain volumes and had age imbalance and selection (elevated Hcy), limiting causal inference.

Study Details

PMID:28029114
Participants:218
Impact:Inverse association (stronger in supplemented group; β=−4.9 mL per µmol/L, p<0.01)
Trust score:3/5

Caregiver-rated improvement (Likert)

1 evidences

Open-label, assessor-blinded randomized trial in infants with Infantile Tremor Syndrome comparing daily injectable B12 alone vs B12 plus multinutrients; primary outcome caregiver Likert score at 1 week and developmental scales at 1 week and 1 month.

Trust comment: Randomized, assessor-blinded noninferiority trial with objective developmental measures but modest sample size (n=72) limits precision.

Study Details

PMID:36048348
Participants:72
Impact:No significant difference between B12 monotherapy and B12+multinutrients (mean 16.1 vs 14.9; p=0.237)
Trust score:4/5

Infant B12 deficiency risk

1 evidences

Prospective analysis within a maternal supplementation trial examining associations between maternal B12 biomarkers during pregnancy and infant B12 status at 6 weeks (n=77 infants).

Trust comment: Prospective analysis with biochemical measures and adjustment for supplementation but small sample (n=77) and secondary analysis limits strength of causal claims.

Study Details

PMID:28402324
Participants:77
Impact:Infants of B12-deficient mothers had ~2-fold greater risk of B12 deficiency after adjusting for supplementation
Trust score:3/5

Gross motor function (ASQ-3)

1 evidences

Randomized, double-blind trial in 6–30 month-old Indian children testing daily vitamin B12 and/or folic acid for 6 months; developmental outcomes (ASQ-3) assessed in 422 children.

Trust comment: Large, well-conducted randomized, double-blind trial with good adherence and objective developmental screening, though some effects were modest or borderline and baseline differences required adjustment.

Study Details

PMID:26098427
Participants:422
Impact:Improved with combined B12+folic acid (mean diff +6.5 points vs placebo, p<0.01) and with B12 alone (+4.0 points vs placebo, p<0.05)
Trust score:4/5

ASQ-3 total score

1 evidences

Randomized, double-blind trial in 6–30 month-old Indian children testing daily vitamin B12 and/or folic acid for 6 months; developmental outcomes (ASQ-3) assessed in 422 children.

Trust comment: Large, well-conducted randomized, double-blind trial with good adherence and objective developmental screening, though some effects were modest or borderline and baseline differences required adjustment.

Study Details

PMID:26098427
Participants:422
Impact:Borderline higher in B12+folic acid group (+12.6 points vs placebo; p=0.071)
Trust score:4/5

Corneal subbasal nerve fiber length (FLD)

1 evidences

Single-centre randomized, double-blind trial testing topical citicoline + cyanocobalamin (vitamin B12) eyedrops vs placebo in patients with diabetes-related corneal nerve damage; primary outcomes nerve fiber length density and corneal sensitivity over 18 months.

Trust comment: Randomized double-blind pilot with objective confocal microscopy and sensitivity measures and low dropout, but small sample and single-centre limit generalizability.

Study Details

PMID:32738875
Participants:29
Impact:Greater percent improvement with Cit-B12 vs placebo at 18 months (33% vs 15%; p=0.04)
Trust score:4/5

Methylmalonic acid (MMA) and 4cB12 score

1 evidences

Randomized, unblinded 4-week dose-response trial in 30 long-term vegetarians testing roasted nori (5 g/day or 8 g/day) vs control; assessed serum B12, holoTC, Hcy, MMA and combined 4cB12 index.

Trust comment: Randomized food-based trial with comprehensive biomarkers showing short-term improvements, but small sample, short duration and lack of blinding to food limit strength and generalizability.

Study Details

PMID:39352476
Participants:30
Impact:MMA decreased and 4cB12 score improved (low-dose +0.9; high-dose +0.51; both vs control significant for 4cB12)
Trust score:3/5

methylmalonic acid (MMA) and total homocysteine (tHcy)

2 evidences

Intranasal B12 given either as a loading regimen or every-3-day dosing raised blood B12 and corrected related metabolic markers; loading gave faster larger early rises.

Trust comment: Randomized controlled trial in elderly B12-deficient patients with repeated biomarker measurements and clear biomarker responses.

Study Details

PMID:38747399
Participants:60
Impact:initially high values normalized in both regimens
Trust score:4/5

A 4-week vegan diet rapidly lowered circulating holo-transcobalamin and serum B12 but did not change cellular markers (MMA, homocysteine) or cause clinical deficiency.

Trust comment: Well-conducted randomized controlled trial in healthy volunteers with objective biomarkers, but short duration and modest sample size.

Study Details

PMID:31752105
Participants:53
Impact:no significant change between groups after 4 weeks
Trust score:4/5

haptoglobin

1 evidences

Adding 5 µg/day B12 during pregnancy modestly altered some blood markers and appeared to reduce risk of developing anemia compared with iron+folate alone.

Trust comment: Randomized trial with adequate sample size but modest, partly ambiguous hematologic changes and limited mechanistic detail.

Study Details

PMID:32302504
Participants:200
Impact:significant decrease post‑intervention in B12 group
Trust score:3/5

hematocrit

2 evidences

Adding 5 µg/day B12 during pregnancy modestly altered some blood markers and appeared to reduce risk of developing anemia compared with iron+folate alone.

Trust comment: Randomized trial with adequate sample size but modest, partly ambiguous hematologic changes and limited mechanistic detail.

Study Details

PMID:32302504
Participants:200
Impact:decreased in both groups (decrease within reference in control; larger decrease reported in intervention)
Trust score:3/5

Intravenous B12 (100 µg/mL twice weekly for 8 weeks) reduced median homocysteine and modestly increased hemoglobin and hematocrit in hemodialysis patients.

Trust comment: Randomized trial with moderate sample size (n=140) but limited detail on blinding and longer-term outcomes.

Study Details

PMID:26997378
Participants:140
Impact:mean 37.9% (intervention) vs 35.3% (control) at 8 weeks (P=0.02)
Trust score:3/5

HbA1c

1 evidences

Add-on methylcobalamin (alone or with folic acid) improved glycemic control and insulin-related markers in people with type 2 diabetes over 8 weeks.

Trust comment: Randomized multi-arm trial but small groups (n≈20 each) and open-label design limit confidence despite biomarker and clinical improvements.

Study Details

PMID:33066869
Participants:80
Impact:Group B (B12): median −1.2% (≈−13 mmol/mol); Group C (B12+folate): median −1.5% (≈−16 mmol/mol) vs standard care
Trust score:3/5

serum folic acid

3 evidences

Adding folic acid plus vitamin B12 during isotretinoin therapy increased folate and B12 levels and lowered homocysteine compared with isotretinoin alone.

Trust comment: Randomized trial shows biochemical benefits but combined folic acid+B12 intervention and short duration limit attribution solely to B12.

Study Details

PMID:30207526
Participants:66
Impact:significant increase in supplementation group (P=0.0026); decreased in isotretinoin-only group
Trust score:3/5

In hemodialysis patients, high-dose folic acid combined with 1 mg/day vitamin B12 (and higher folic acid dose) produced the largest reduction in plasma homocysteine over 8 weeks.

Trust comment: Small randomized study in HD patients showing biochemical effects; limited sample size lowers generalizability.

Study Details

PMID:19736473
Participants:36
Impact:no significant change overall
Trust score:3/5

Compared dietary intake and biochemical markers in depressed patients vs controls; depressed group had poorer diet and lower serum B12 and folate.

Trust comment: Case-control study with direct biochemical measures but small sample size and self-reported diet data limit strength of inference.

Study Details

PMID:26413529
Participants:59
Impact:decreased (significant vs controls, p<0.05)
Trust score:3/5

infant length-for-age Z score at 12 months

1 evidences

Large randomized trial in pregnant women: B12 improved maternal B12 status but did not change infant growth or cognitive scores.

Trust comment: Large, well-conducted double-blind randomized controlled trial with clear primary outcomes and intention-to-treat analyses.

Study Details

PMID:37031691
Participants:800
Impact:mean difference −0.02 (no meaningful change)
Trust score:5/5

maternal vitamin B12 status

1 evidences

Large randomized trial in pregnant women: B12 improved maternal B12 status but did not change infant growth or cognitive scores.

Trust comment: Large, well-conducted double-blind randomized controlled trial with clear primary outcomes and intention-to-treat analyses.

Study Details

PMID:37031691
Participants:800
Impact:increased (substantially improved)
Trust score:5/5

serum homocysteine

10 evidences

Small 12-week RCT in NAFLD patients: B12 (1000 µg/day) lowered homocysteine and improved some within-group markers but most liver/metabolic outcomes did not differ versus placebo.

Trust comment: Randomized double-blind trial but very small sample and short duration limit generalizability and power.

Study Details

PMID:35982162
Participants:33
Impact:decreased −2.1 µmol/L (between-group significant, p≈0.036)
Trust score:3/5

Intravenous B12 (100 µg/mL twice weekly for 8 weeks) reduced median homocysteine and modestly increased hemoglobin and hematocrit in hemodialysis patients.

Trust comment: Randomized trial with moderate sample size (n=140) but limited detail on blinding and longer-term outcomes.

Study Details

PMID:26997378
Participants:140
Impact:median reduced to 22.2 µmol/L in B12 group vs 28.4 µmol/L in control after 8 weeks (P=0.006)
Trust score:3/5

Methylcobalamin (500 µg) + folic acid lowered homocysteine but did not reduce cognitive decline at 24 months; transient improvements in executive function and depressive symptoms at 12 months were not sustained.

Trust comment: Well-designed randomized placebo-controlled trial with clear biochemical effect but no durable clinical cognitive benefit.

Study Details

PMID:31787369
Participants:279
Impact:-4.6 µmol/L (13.9 → 9.3 µmol/L at month 24)
Trust score:4/5

Randomized trial comparing immediate vs 5–7 day prior folic acid+B12 supplementation in patients receiving pemetrexed-based chemotherapy; simultaneous supplementation was feasible and did not increase most hematologic toxicity.

Trust comment: Randomized multicenter trial with modified ITT and objective hematologic and biochemical measures; open-label but adequately powered for toxicity outcomes.

Study Details

PMID:30825389
Participants:150
Impact:no change with 5–7 days B12-FA (unchanged vs baseline)
Trust score:4/5

In people with mild–moderate Alzheimer's on cholinesterase inhibitors, add-on multivitamin including mecobalamin (B12) for 26 weeks lowered homocysteine but produced no cognitive or ADL benefit.

Trust comment: Randomized double-blind placebo-controlled trial in humans with reported exact biomarker changes; moderate sample size supports reasonable trust.

Study Details

PMID:18042476
Participants:89
Impact:−2.25 μmol/L (between-group difference vs placebo at 26 weeks; P=0.008)
Trust score:4/5

Two randomized placebo-controlled trials in women with PCOS found metformin did not change homocysteine; nonpregnant women showed reductions in folate and B12.

Trust comment: Randomized placebo-controlled trials with clear biochemical outcomes; combined sample moderate in size.

Study Details

PMID:17364275
Participants:101
Impact:no change with metformin (nonpregnant and pregnant)
Trust score:4/5

Reproductive-aged Guatemalan women received weekly or daily folic acid (with B12 and minerals) for 12 weeks; folate improved and homocysteine fell in all groups, daily B12 raised serum B12.

Trust comment: Randomized, double-blind trial with adequate sample size and clear biochemical endpoints.

Study Details

PMID:18641196
Participants:459
Impact:geometric mean decreased by 9.8% (95% CI: -12.3, -7.1)
Trust score:4/5

Postmenopausal women on hormone therapy plus folic acid had lowered homocysteine, whereas hormone therapy alone increased homocysteine; control group had no change.

Trust comment: Randomized, placebo-controlled trial with additional non-randomized control group; small sample but clear biochemical outcomes and reported p-values.

Study Details

PMID:16390760
Participants:55
Impact:HT + folic acid: −1.04 µmol/L (from 9.96 to 8.92; −~10.4%); HT alone: +0.58 µmol/L (from 9.64 to 10.22; +~6%); control: no significant change
Trust score:4/5

In levodopa-treated Parkinson patients, folate plus vitamin B12 decreased homocysteine over 6 weeks while entacapone did not.

Trust comment: Randomized double-blind placebo-controlled trial though small sample size limits precision.

Study Details

PMID:16801668
Participants:35
Impact:decreased with folate 1 mg + vitamin B12 500 μg versus placebo
Trust score:4/5

16‑week double‑blind randomized placebo‑controlled trial of a multivitamin (high‑dose B‑vitamins including B12) versus placebo in healthy adults; measured B12, homocysteine and diurnal cortisol outcomes.

Trust comment: Randomized double‑blind placebo‑controlled trial with objective blood measures and appropriate analyses, though multivitamin contains many constituents so effects are not fully attributable to B12 alone.

Study Details

PMID:24284609
Participants:138
Impact:Multivitamin group decreased: baseline 10.84→9.86 μmol/L (8 wk, Δ −0.99) and →9.22 μmol/L (16 wk, Δ −1.62); MV < placebo (p<0.01 at 8 and 16 wk)
Trust score:4/5

fasting blood glucose

1 evidences

Small 12-week RCT in NAFLD patients: B12 (1000 µg/day) lowered homocysteine and improved some within-group markers but most liver/metabolic outcomes did not differ versus placebo.

Trust comment: Randomized double-blind trial but very small sample and short duration limit generalizability and power.

Study Details

PMID:35982162
Participants:33
Impact:within-group decrease in B12 group (median −5 mg/dL) but not significant vs placebo
Trust score:3/5

serum cobalamin

7 evidences

In infants with biochemical B12 deficiency, a single IM hydroxycobalamin injection markedly improved B12 biomarkers and led to greater short-term gains in motor development versus placebo.

Trust comment: Randomized, double-blind intervention with objective biochemical and motor outcomes, though sample size of the intervention arm was small.

Study Details

PMID:26678525
Participants:31
Impact:increased median +254% after injection (cobalamin group)
Trust score:4/5

In elderly subjects, a 12-week supplement containing folic acid and cobalamin improved B-vitamin status and lowered homocysteine, with greater effect in those with higher baseline Hcy.

Trust comment: Randomized double-blind 12-week trial (n=133) with significant biochemical improvements and appropriate subgroup analyses.

Study Details

PMID:36715360
Participants:133
Impact:+63 ± 48 pmol/L
Trust score:4/5

Intravenous cobalamin with folate and B6 markedly raised serum B12 and reduced serum homocysteine when given two or three times weekly in hemodialysis patients.

Trust comment: Small (n=33) intervention with three dosing regimens; biochemical outcomes reported but limited sample size and short follow-up.

Study Details

PMID:11426667
Participants:33
Impact:marked increase (e.g., group3 548 -> 77,961 pg/ml)
Trust score:3/5

Daily 1000 µg crystalline cobalamin for 12 weeks (milk or capsule) effectively increased serum cobalamin and lowered MMA and homocysteine in mildly deficient elderly.

Trust comment: Randomized double-blind interventions showing consistent biochemical improvement in cobalamin-deficient elderly over 12 weeks.

Study Details

PMID:16155269
Participants:112
Impact:Increase +250 ±96 pmol/L (mean) in fortified-milk group vs placebo
Trust score:4/5

Randomized trial in newly diagnosed cobalamin-deficient patients comparing daily oral (2 mg) versus intermittent intramuscular (1 mg) cyanocobalamin for 4 months; oral therapy was at least as effective and produced larger biochemical improvements.

Trust comment: Randomized human trial with objective biochemical and clinical endpoints but small sample size limits precision.

Study Details

PMID:9694707
Participants:33
Impact:increased to 1005 pg/mL (oral) vs 325 pg/mL (IM) at 4 months
Trust score:4/5

Women with PCOS on metformin experienced a decrease in serum cobalamin after six months, but other functional markers (holoTC, MMA) did not indicate deficiency.

Trust comment: Direct human study measuring multiple cobalamin biomarkers with appropriate assays but limited by small sample size and short follow-up.

Study Details

PMID:23857221
Participants:29
Impact:Significant decline after 6 months of metformin (p=0.003)
Trust score:4/5

Children with moderate acute malnutrition received food supplements; serum cobalamin rose during 3 months of supplementation but many remained marginal.

Trust comment: Large randomized factorial trial with objective biochemical and developmental measures; cobalamin was a secondary outcome and some serum data were missing.

Study Details

PMID:35263343
Participants:1548
Impact:Mean increase +72 pmol/L at 3 months (95% CI 65 to 79, p<0.001); mean increase +26 pmol/L at 6 months (16 to 37, p<0.001)
Trust score:4/5

AIMS gross motor score

1 evidences

In infants with biochemical B12 deficiency, a single IM hydroxycobalamin injection markedly improved B12 biomarkers and led to greater short-term gains in motor development versus placebo.

Trust comment: Randomized, double-blind intervention with objective biochemical and motor outcomes, though sample size of the intervention arm was small.

Study Details

PMID:26678525
Participants:31
Impact:median increase +7 points (36%) vs +5 points (23%) in placebo; between-group p=0.02
Trust score:4/5

serum selenium

2 evidences

8-week double-blind RCT in adults at increased diabetes risk testing salmon fish protein supplement vs placebo and measuring blood micronutrient concentrations.

Trust comment: Well-conducted double-blind randomized trial with objective lab measures; secondary analysis but consistent biochemical findings.

Study Details

PMID:35362766
Participants:74
Impact:increased from 1.18 to 1.30 µmol/L (adjusted effect 0.10; p=0.002)
Trust score:4/5

In a randomized crossover herring intervention, serum vitamin B12 and selenium increased after 6 weeks of high fish intake while 25-hydroxy vitamin D3 did not change significantly.

Trust comment: Randomized cross-over with objective biomarker measurements and significant changes, but small sample size.

Study Details

PMID:24292746
Participants:32
Impact:+4.6% (p=0.02) after 6-week herring intervention
Trust score:4/5

serum methylmalonic acid (MMA) and genetic effects

1 evidences

Controlled feeding study (humans) and mouse experiments: higher maternal choline intake raised bioactive B12 (holotranscobalamin) in pregnant women and altered B12-related biomarkers.

Trust comment: Controlled feeding in a small human cohort with supporting animal data; human sample size is limited for broad inference.

Study Details

PMID:31473512
Participants:26
Impact:certain CHDH/BHMT variants associated with higher MMA (~31%) or lower holoTC (~34%) (P≈0.03)
Trust score:3/5

BMI

1 evidences

RCT (n=70 allocated, 68 completed) of tailored progressive dietary advice plus new complete dentures vs standard care in edentulous elders, assessing nutritional status (MNA) and nutrient intake at 3 months.

Trust comment: Single-blind RCT, registered and completed with 68 participants; outcomes well-reported though dietary intake changes (including vitamin B12) were not significant, limiting conclusions about B12 specifically.

Study Details

PMID:40227937
Participants:68
Impact:changed (intervention group mean change −0.55; p=0.003 in paired test; ANCOVA p=0.03)
Trust score:4/5

osteoporotic fracture incidence (primary)

1 evidences

Large 2-year RCT in older adults with high homocysteine: combined B12+folic acid did not reduce overall osteoporotic fractures; exploratory subgroup suggested benefit in adherent >80-year-olds but cancer incidence was higher in the treatment arm.

Trust comment: Large, well-powered double-blind randomized trial with clear null primary outcome; subgroup and safety signals noted and reported.

Study Details

PMID:25411293
Participants:2919
Impact:no significant reduction (HR 0.84; 95% CI 0.58–1.21)
Trust score:5/5

incident cancer

1 evidences

Large 2-year RCT in older adults with high homocysteine: combined B12+folic acid did not reduce overall osteoporotic fractures; exploratory subgroup suggested benefit in adherent >80-year-olds but cancer incidence was higher in the treatment arm.

Trust comment: Large, well-powered double-blind randomized trial with clear null primary outcome; subgroup and safety signals noted and reported.

Study Details

PMID:25411293
Participants:2919
Impact:higher in intervention group (63 vs 42; HR 1.56; 95% CI 1.04–2.31)
Trust score:5/5

plasma homocysteine

66 evidences

In men with mildly elevated homocysteine, B‑group vitamin supplementation (including cyanocobalamin) reduced plasma homocysteine over 8 weeks.

Trust comment: Randomized double-blind controlled trial with 8-week intervention and 101 completers; reasonably powered for biochemical outcome.

Study Details

PMID:9583842
Participants:101
Impact:-27.9% (reduction over 8 weeks)
Trust score:4/5

Randomized double-blind trial in 31 women (65–93 y) giving folic acid (800 μg) + vitamin B12 (1000 μg) vs placebo for 4 months: homocysteine fell in the treated group but bone turnover markers did not change.

Trust comment: Randomized double-blind trial but very small sample (n=31) and short duration, limiting power for bone outcomes.

Study Details

PMID:23507227
Participants:31
Impact:10.6 μmol/L (vitamin) vs 18.5 μmol/L (placebo); decrease −7.9 μmol/L (≈ −43%) in vitamin group
Trust score:3/5

Two-year randomized trial in older adults (subgroup with baseline homocysteine >15 μmol/L n=135) showing B‑vitamin supplementation lowered homocysteine but did not change bone turnover biomarkers.

Trust comment: Large, long-duration randomized controlled trial with clear biochemical outcomes and subgroup biomarker measurements.

Study Details

PMID:17284744
Participants:135
Impact:reduced by 5.2 μmol/L (vitamin vs placebo; 95% CI 3.9–6.6; P<0.001)
Trust score:5/5

Protocol and baseline description of a randomized trial (n=2919) testing vitamin B12+folic acid vs placebo in elderly; both groups received vitamin D (600 IU) and outcome results were not reported in this paper.

Trust comment: Well-designed, large randomized trial protocol with thorough measurements but this publication only reports design/baseline and no outcome results.

Study Details

PMID:22136481
Participants:2919
Impact:not reported
Trust score:3/5

Factorial RCT in elderly patients with ischemic vascular disease testing folic acid + vitamin B12 (and other B vitamins); folic acid + B12 lowered homocysteine by ~5.0 μmol/L but produced no significant improvement in fibrinogen, vWF, or cognitive tests over one year.

Trust comment: Randomized, placebo-controlled, double-blind factorial trial with moderate sample size and measured clinical and biomarker outcomes; homocysteine reduction was clear but clinical cognitive benefit was not observed.

Study Details

PMID:16332666
Participants:185
Impact:decrease −5.0 μmol/L (95% CI 3.8, 6.2) with folic acid + vitamin B12
Trust score:4/5

In insulin-treated type 2 diabetics, 16 weeks of added metformin reduced serum folate and vitamin B12 and produced a modest increase in homocysteine compared with placebo.

Trust comment: Large randomized placebo-controlled trial with clear, clinically relevant biochemical endpoints and low risk of bias.

Study Details

PMID:14535967
Participants:353
Impact:increase ~4% (95% CI 0.2 to 8%; P=0.039)
Trust score:5/5

In women with GDM, metformin treatment led to a greater decline in total serum B12 during pregnancy than insulin, though bioavailable B12 and homocysteine did not differ between groups.

Trust comment: Randomized comparison within a clinical trial cohort with clear biochemical measurements, moderate sample size.

Study Details

PMID:23402546
Participants:180
Impact:no significant difference between treatments
Trust score:4/5

Adjunctive B-vitamin supplementation lowered homocysteine but did not change overall symptoms or global cognition; attention/vigilance was preserved compared with decline in placebo.

Trust comment: Well-conducted randomized double-blind trial; biochemical and cognitive domain outcomes reported with subgroup analyses.

Study Details

PMID:30771856
Participants:120
Impact:decreased (p = 0.003; effect size = -0.65)
Trust score:4/5

Methylcobalamin reduced MMA and homocysteine but did not prevent cognitive decline over 27 months in older diabetic adults with borderline B12.

Trust comment: Randomized placebo-controlled trial with adequate follow-up (27 months) and clinically relevant cognitive endpoints.

Study Details

PMID:27823800
Participants:271
Impact:decreased (P < 0.0001)
Trust score:4/5

6-month randomized double-blind trial of combined folic acid, B6 and B12 in migraine with aura showed marked homocysteine lowering and reduced migraine disability in supplemented patients, with genotype-modified response.

Trust comment: Randomized double-blind trial but small sample and intervention combined multiple vitamins (cannot ascribe effects to B12 alone); genotype-related subgroup findings reduce generalizability.

Study Details

PMID:19384265
Participants:52
Impact:decreased ≈39% (~4 µmol/L) vs baseline; greater reduction than placebo (P=0.001)
Trust score:3/5

Randomized phase 2 trial found that adding folic acid and vitamin B12 to gemcitabine/cisplatin did not significantly change response rate, time to progression, or overall survival, though homocysteine fell with supplementation.

Trust comment: Randomized multicenter phase 2 trial but open-label and modest sample size; biological markers changed but no clinical efficacy benefit shown.

Study Details

PMID:29696360
Participants:78
Impact:lower in supplemented patients (mean 6.9 µM vs 12.5 µM; P<0.001)
Trust score:3/5

Randomized 4-week intervention in lactovegetarians comparing low-dose CN‑B12 capsules vs cow or buffalo milk (natural HO‑B12): all three modestly improved B12 biomarkers with similar combined-index changes at 3.5 weeks.

Trust comment: Randomized prospective trial with frequent biomarker sampling and combined indicator analysis; short duration and low dose limit conclusions about full replenishment.

Study Details

PMID:30717112
Participants:67
Impact:decreased in all groups (metabolic marker improved across interventions)
Trust score:4/5

Two-year treatment with folate plus mecobalamin (vitamin B12) lowered homocysteine and substantially reduced hip fracture incidence in elderly post-stroke patients.

Trust comment: Large randomized trial with 2-year follow-up showing clinically meaningful fracture reduction, though intervention combined folate and B12 (not B12 alone).

Study Details

PMID:15741530
Participants:559
Impact:−38% (treatment) vs +31% (placebo)
Trust score:4/5

Long-term combined B-vitamin treatment lowered homocysteine but did not change plasma markers of inflammation or endothelial dysfunction.

Trust comment: Large, long-duration randomized substudy (7.3 years) with robust biomarker measurements; high internal validity for the null biomarker findings.

Study Details

PMID:29776960
Participants:300
Impact:−18.3% (active group)
Trust score:5/5

Fortified rice increased plasma vitamin B12, lowered homocysteine, and improved physical performance in school children after 6 months.

Trust comment: Randomized double-blind controlled trial in 258 children with biochemical and performance endpoints; good design though limited to one setting.

Study Details

PMID:22437556
Participants:258
Impact:decreased (significant, P<0.001)
Trust score:4/5

In MI survivors, folic acid plus B12 lowered homocysteine but did not reduce major vascular events, stroke, or mortality over ~6.7 years.

Trust comment: Large, long-term double-blind randomized trial (12,064 participants) with hard clinical endpoints; high reliability.

Study Details

PMID:20571015
Participants:12064
Impact:reduced by 3.8 μmol/L (≈28%)
Trust score:5/5

In patients with advanced CKD/ESRD, high-dose folic acid plus B vitamins including cyanocobalamin (B12) lowered homocysteine but did not reduce mortality or major vascular events over ~3.2 years.

Trust comment: Large, multicenter double-blind randomized trial with hard clinical endpoints and long follow-up, high credibility.

Study Details

PMID:17848650
Participants:2056
Impact:−6.3 μmol/L (−25.8% at 3 months vs baseline; P<0.001)
Trust score:5/5

One-month randomized trial in elderly inpatients showing 50 µg oral cyanocobalamin raises serum B12; 10 µg did not differ from placebo.

Trust comment: Randomized double-blind design but small sample and short duration limit generalizability.

Study Details

PMID:12028259
Participants:31
Impact:decrease in cyanocobalamin groups but not statistically significant
Trust score:3/5

Dietary-protein intervention trial found that plasma homocysteine was inversely associated with vitamin B12 intake at 3 months (observational within trial).

Trust comment: Well-controlled dietary trial but B12 effects were observational associations within the diet intervention and sample size was modest.

Study Details

PMID:12450883
Participants:65
Impact:inverse association with vitamin B12 intake (significant; vitamin B12 explained ~2% of variation at 3 months, P=0.02)
Trust score:3/5

Large randomized trial of folic acid, vitamin B6 and vitamin B12 in high-risk women: homocysteine fell but there was no reduction in cardiovascular events or mortality.

Trust comment: Large randomized double-blind placebo-controlled trial with long follow-up and objective outcomes; high-quality evidence despite null clinical results.

Study Details

PMID:18460663
Participants:5442
Impact:decreased −18.5% (95% CI 12.5%–24.1%; P<0.001, substudy n=150)
Trust score:5/5

Large randomized trial after acute MI showed folic acid plus vitamin B12 lowered homocysteine markedly but did not reduce recurrent cardiovascular events; possible harm suggested in combined-vitamin arm.

Trust comment: Large, well-conducted randomized trial with robust endpoints; high-quality evidence showing biochemical effect without clinical benefit.

Study Details

PMID:16531614
Participants:3749
Impact:decreased −27% (mean) with folic acid + vitamin B12 (significant)
Trust score:5/5

Large RCT: folic acid+B6+B12 lowered homocysteine and reduced stroke incidence but did not affect stroke severity or disability.

Trust comment: Large, high-quality randomized trial showing reduced stroke incidence with homocysteine-lowering B-vitamin therapy but no effect on severity or disability.

Study Details

PMID:19228852
Participants:5522
Impact:decrease (~2.2 μmol/L vs +0.8 μmol/L for placebo)
Trust score:5/5

6-month RCT in hemodialysis patients with hyperhomocysteinemia: high-dose B-vitamin regimen significantly lowered homocysteine but did not change carotid IMT.

Trust comment: Randomized trial with modest sample showing clear homocysteine reduction; underpowered for structural IMT outcomes.

Study Details

PMID:17048428
Participants:54
Impact:decrease (from 27.94 to 22.71; p=0.009; between-group p=0.002)
Trust score:4/5

Women with migraine took a daily vitamin tablet (1 mg folic acid + B6 + B12) for 6 months; B12 levels rose but homocysteine and migraine outcomes did not change significantly.

Trust comment: Randomized double-blind trial with moderate sample and modified ITT; outcomes largely non-significant and treatment was a combination so B12-specific effects are not isolated.

Study Details

PMID:27339806
Participants:189
Impact:-0.9 μmol/L (9.4 → 8.5 μmol/L) in treatment group (not significant, P=0.2)
Trust score:3/5

In this pilot randomized trial, adding folic acid/vitamin B12 lowered homocysteine while simvastatin reduced LDL, and there was no antagonistic interaction.

Trust comment: Randomized pilot study with clear biochemical endpoints but short duration and modest size limits generalizability.

Study Details

PMID:11079257
Participants:141
Impact:-23.1% with vitamins alone; -25.3% in combination group
Trust score:3/5

Daily multivitamin supplementation for 8 weeks increased vitamin B12 and folate levels, lowered homocysteine, and improved contextual recognition memory in older men.

Trust comment: Well-controlled RCT but uses a multinutrient product, so improvements cannot be solely attributed to vitamin B12.

Study Details

PMID:22711385
Participants:51
Impact:decreased (post-supplementation; no numeric value reported)
Trust score:3/5

Adding folic acid plus vitamin B12 (and probucol in one arm) to antihypertensive therapy lowered plasma homocysteine and ADMA over 12 weeks in hypertensive patients.

Trust comment: Randomized 3-arm trial with clear biochemical endpoints but limited detail on blinding and long-term outcomes in provided excerpt.

Study Details

PMID:23363713
Participants:120
Impact:21.51 → 12.54 μmol/L at 12 weeks (≈−41.7%) in folic acid + B12 group
Trust score:3/5

In depressed patients, adding folic acid to fluoxetine reduced homocysteine and improved depression scores, while vitamin B12 levels did not change.

Trust comment: Small randomized trial with clinical and biochemical endpoints but limited sample size (27) reducing precision.

Study Details

PMID:18716414
Participants:27
Impact:Significant decrease after folic acid (p=0.02); exact magnitude not provided in excerpt
Trust score:3/5

Three-arm randomized trial (drink powder with betaine + B‑vitamins, UNIMMAP multivitamin, control) in 298 women; both supplements substantially lowered plasma homocysteine versus control, drink powder > UNIMMAP.

Trust comment: Well-powered randomized controlled trial with objective biochemical primary outcome, high compliance, and appropriate analyses.

Study Details

PMID:31408467
Participants:298
Impact:drink powder −23.6% vs control at 12 wk; UNIMMAP −15.5% vs control at 12 wk (drink powder −8.8% vs UNIMMAP)
Trust score:5/5

Randomized double-blind placebo-controlled trial in frail elderly showing enriched drink increased plasma B12, lowered homocysteine, and improved some cognitive test scores over 6 months.

Trust comment: Randomized, double-blind, placebo-controlled design but substantial attrition (67 completers), moderate sample for cognitive endpoints.

Study Details

PMID:15814873
Participants:67
Impact:decreased (mean change ~−6.3 μmol/L vs −0.3; p<0.001)
Trust score:4/5

After coronary angioplasty, patients given folic acid, vitamin B12 and B6 had lower homocysteine and less restenosis and revascularization vs placebo.

Trust comment: Prospective double-blind randomized trial (n=205) showing significant clinical and biomarker effects but intervention was a combined folate/B12/B6 formula so effects cannot be attributed to B12 alone.

Study Details

PMID:11757505
Participants:205
Impact:-3.9 μmol/L (11.1→7.2 μmol/L; ~-35%)
Trust score:4/5

In nursing-home residents, adding oat-bran reduced laxative use and was associated with slower decline in plasma B12 compared with control; homocysteine fell in both groups.

Trust comment: Small controlled parallel intervention (n=30) with objective measures but limited sample size and indirect effect on B12 (dietary fiber influence rather than B12 supplementation).

Study Details

PMID:20191257
Participants:30
Impact:decreased in both groups (p<0.05)
Trust score:3/5

Cross-sectional study found common vitamin B12 and folate deficiencies and a high prevalence of elevated homocysteine among adolescent Afghan refugees; lower B12 associated with higher homocysteine.

Trust comment: Well-described cross-sectional human study showing strong associations but cannot prove causality.

Study Details

PMID:35565715
Participants:190
Impact:Median 12.2 μmol/L; 25% ≥15 μmol/L (hyperhomocysteinemia); homocysteine decreased significantly with higher vitamin B12
Trust score:3/5

Type 2 diabetes patients randomized to folic acid, methylcobalamin, both, or control for 12 weeks: methylcobalamin (and combinations) reduced plasma homocysteine and increased HTase/PON activity, with the greatest homocysteine reduction seen with methylcobalamin alone.

Trust comment: Randomized human trial with 120 participants showing substantial, dose-specific biochemical effects of methylcobalamin and folic acid; moderate-to-high internal validity though group sizes were modest (n≈30).

Study Details

PMID:17425871
Participants:120
Impact:decreased (Group III methylcobalamin −37.3%; Group II folic acid −14.0%; Group IV combo −21.7%)
Trust score:4/5

In 50 hemodialysis patients with high homocysteine, regimens including monthly B12 injections plus folic acid and B6 significantly lowered plasma homocysteine; high and low B-vitamin dose regimens had similar efficacy.

Trust comment: Randomized prospective study with clear biochemical endpoints but modest sample size (N=50); results internally consistent.

Study Details

PMID:15115259
Participants:50
Impact:reduced to 21.2 µmol/L (group A) and 18.6 µmol/L (group B) (significant)
Trust score:4/5

Older women took daily high-dose folic acid, B6 and B12 or placebo for ~7 years; supplementation lowered homocysteine but did not reduce depression risk.

Trust comment: Large randomized controlled trial with long follow-up and clinically relevant outcomes.

Study Details

PMID:25573400
Participants:4331
Impact:significantly reduced with supplementation
Trust score:5/5

Schizophrenic patients with high homocysteine received B vitamins and showed lower homocysteine and better clinical and cognitive scores versus placebo.

Trust comment: Randomized double-blind placebo-controlled crossover in human patients; good design and reported significant clinical and cognitive improvements.

Study Details

PMID:16412989
Participants:42
Impact:decrease (significant)
Trust score:4/5

In RA patients randomized to SSZ, MTX, or combination, MTX (and especially combination) produced persistent rises in plasma homocysteine; SSZ caused only a slight temporary rise.

Trust comment: Large (n=105) randomized double-blind 52-week trial measuring homocysteine and related biomarkers; solid design.

Study Details

PMID:10343521
Participants:105
Impact:increase with MTX (persistent); greater increase with MTX+SSZ; slight temporary increase with SSZ
Trust score:4/5

B-vitamin combination (including 1000 µg B12) for 6 months lowered homocysteine and improved endothelium-dependent and -independent vasodilation in renal transplant recipients.

Trust comment: Randomized small trial with clear physiological outcomes, but used combined B-vitamin therapy so effects cannot be attributed solely to B12.

Study Details

PMID:18206175
Participants:36
Impact:decrease from 20.1±5.4 to 12.6±3.9 µmol/L (−7.5 µmol/L, ~−37%, p<0.01)
Trust score:3/5

Short-term folic acid with methylcobalamin markedly lowered homocysteine and increased HTase/PON activity in type 2 diabetes.

Trust comment: Randomized short-term biochemical trial with clear lab endpoints, but very short duration and biochemical surrogate outcomes.

Study Details

PMID:18781288
Participants:90
Impact:Group with folic acid + methylcobalamin: -37.3% reduction over 2 weeks (vs -14% with folic acid alone; -2.75% with no supplement)
Trust score:3/5

Daily folate + B12 + B6 lowered homocysteine but did not change blood pressure in older adults over 2 years.

Trust comment: Large double-blind randomized placebo-controlled trial with long follow-up and objective measures.

Study Details

PMID:17449579
Participants:276
Impact:-4.4 μmol/L (Vitamins vs placebo) at 2 years (also -4.3 μmol/L at 1 year)
Trust score:5/5

In kidney transplant patients with high homocysteine, folic acid plus vitamin B12 lowered homocysteine and suggested improved blood vessel function.

Trust comment: Small, non-blinded treatment subgroup (n=29) with statistically significant homocysteine reduction but preliminary vascular findings.

Study Details

PMID:16386537
Participants:29
Impact:-5.6 μmol/L (from 19.05 to 13.45 μmol/L; ≈-29%)
Trust score:3/5

In older adults with CKD, daily B-vitamin therapy including vitamin B12 lowered homocysteine but did not reduce cardiovascular events and was associated with increased hospitalizations for some cardiac conditions.

Trust comment: Large randomized, placebo-controlled trial (n=619) with long follow-up and hard clinical endpoints.

Study Details

PMID:18003666
Participants:619
Impact:-4.0 μmol/L (from 15.9 to 11.9 μmol/L; ≈-25%)
Trust score:5/5

Cross-sectional study measuring homocysteine metabolism markers and carotid intima-media thickness in people with and without type 2 diabetes.

Trust comment: Well-characterized cross-sectional human cohort measuring B12 and related metabolites, but observational design prevents causal inference.

Study Details

PMID:12921985
Participants:231
Impact:Homocysteine >12 μmol/L associated with increased IMT in diabetics (+0.07 mm)
Trust score:3/5

Daily 1000 µg crystalline cobalamin for 12 weeks (milk or capsule) effectively increased serum cobalamin and lowered MMA and homocysteine in mildly deficient elderly.

Trust comment: Randomized double-blind interventions showing consistent biochemical improvement in cobalamin-deficient elderly over 12 weeks.

Study Details

PMID:16155269
Participants:112
Impact:Median decrease −4.0 µmol/L (5th–95th: −7.3, 3.0) vs placebo
Trust score:4/5

High-dose folate supplementation markedly lowered very high homocysteine levels in peritoneal dialysis patients; serum B12 did not change.

Trust comment: Randomized clinical trial in a specific patient population with clear biochemical outcomes and reasonable sample size.

Study Details

PMID:11598393
Participants:59
Impact:decrease from 54 ± 32 to 23 ± 14 μmol/L after 2 months (≈ −31 μmol/L, >50% reduction)
Trust score:4/5

Randomized study adding mecobalamin to standard care in ischemic stroke patients with H-type hypertension and measuring homocysteine, inflammation, plaques and function over 6 months.

Trust comment: Randomized clinical study with adequate sample size (n=224) showing consistent biomarker changes, but some reporting ambiguities and lack of detailed magnitude limit certainty.

Study Details

PMID:30304141
Participants:224
Impact:significant decrease vs control at 4 weeks–6 months (P<0.05)
Trust score:3/5

Randomized trial of a 16-week combined training exercise program in PLHIV assessing homocysteine and oxidative stress markers; vitamin levels were measured but not supplemented.

Trust comment: Randomized exercise trial with clear pre/post biomarker changes in a small PLHIV subgroup (n randomized=30); vitamin B12 was measured but not the intervention, so B12-specific effects are indirect.

Study Details

PMID:30861351
Participants:30
Impact:32% reduction in PLHIV with hyperhomocysteinemia after exercise; mean −5.6 ± 3.2 µmol/L reported in that subgroup
Trust score:3/5

6-month randomized, double-blind placebo-controlled trial of daily B-vitamin supplementation (B6, B9, B12) in women with migraine with aura, assessing homocysteine and migraine outcomes and genotype effects.

Trust comment: Well-designed double-blind randomized trial (n=206) showing clinically relevant reductions in homocysteine and migraine outcomes, with genotype-stratified effects increasing credibility.

Study Details

PMID:22926161
Participants:206
Impact:significant reduction with B-vitamin supplementation
Trust score:4/5

In PCI patients, baseline ADMA and TML were independently associated with angiographic CAD progression; moderate-dose folic acid plus vitamin B12 lowered homocysteine but did not change median ADMA or TML.

Trust comment: Well-conducted randomized trial sub-study with objective angiographic measures and biomarker assays; moderate sample size and appropriate analyses.

Study Details

PMID:23734218
Participants:183
Impact:reduced by 24.8% in FA/B12 group at sub-study end
Trust score:4/5

Six‑month randomized, double‑blind trial of methylfolate + P5P + methylcobalamin showed large reductions in homocysteine and modest reductions in LDL‑C versus placebo, with greater effects in homozygous minor‑allele genotype subgroup.

Trust comment: Double‑blind randomized placebo‑controlled trial with clear biochemical effects; sample size modest but pre‑specified and analyses appropriate.

Study Details

PMID:38892484
Participants:54
Impact:Treatment: −30.0% (95% CI −39.7% to −20.3%) vs Placebo: +1.8% (95% CI −4.8% to 6.8%); between‑group difference 31.8% (p<0.01)
Trust score:4/5

Controlled trial testing multivitamin (including hydroxycobalamin) or individual vitamins on plasma homocysteine in patients and volunteers.

Trust comment: Randomized controlled design but interventions were combined multivitamins (folic acid likely main driver); cobalamin-alone subgroup small and showed only modest effect.

Study Details

PMID:9514403
Participants:316
Impact:High-dose multivitamin normalized homocysteine in 26/30 vs 7/30 placebo; median reduction ~30% in normohomocysteinemic subjects
Trust score:3/5

A 6-month RCT of a multivitamin/trace element formula increased cobalamin and other vitamins and reduced homocysteine in healthy volunteers.

Trust comment: Randomized double-blind trial with objective biomarkers and good completion, but multicomponent supplement limits attribution to B12 alone.

Study Details

PMID:25789594
Participants:142
Impact:decreased at 3 and 6 months (p<0.001, p<0.025)
Trust score:3/5

In a 24-month randomized trial of B vitamins (methylcobalamin + folic acid), cognitive decline was slowed in MCI patients with greater left frontal lobe atrophy; homocysteine was lowered.

Trust comment: Large randomized trial with objective outcomes, but the cognitive benefit is from a post-hoc subgroup analysis which lowers strength of inference.

Study Details

PMID:36057827
Participants:279
Impact:significantly decreased with B vitamin supplementation
Trust score:4/5

28-day randomized placebo-controlled pilot tested folic acid, fish oil and calcium on cancer risk markers; vitamin B12 was measured but not supplemented.

Trust comment: Randomized placebo-controlled design with objective biochemical outcomes but short duration and modest sample size.

Study Details

PMID:16136044
Participants:98
Impact:-3% (treatment) vs +7% (control); P=0.096 (ns)
Trust score:4/5

Six months of high-dose B-group multivitamin supplementation increased blood B12 and B6 and lowered homocysteine; brain metabolite concentrations did not change significantly in this small neuroimaging sub-study.

Trust comment: Randomized double-blind trial with objective biochemical and MRS measures; neuroimaging sub-sample was small and some data were excluded, limiting power for brain outcomes.

Study Details

PMID:30513795
Participants:33
Impact:Plasma homocysteine decreased with treatment (group×time interaction, p<0.001; b=−0.68)
Trust score:4/5

B-vitamin supplementation (including B12 and folic acid) markedly lowered homocysteine but did not change markers of inflammation or haemostasis in PAOD patients over 6 weeks.

Trust comment: Randomized controlled trial with biomarker endpoints but modest sample size (n=65); strong internal validity for the measured outcomes.

Study Details

PMID:16634837
Participants:65
Impact:−33% mean reduction vs ~−1% placebo
Trust score:4/5

Drinking mineral water fortified with folic acid, vitamins (including D) and calcium for 8 weeks raised folate, lowered homocysteine, and increased urinary calcium excretion, indicating bioavailable calcium.

Trust comment: Randomized, double-blind, placebo-controlled trial with good completion (60) showing statistically significant biochemical effects, though intervention was a multi‑nutrient combination.

Study Details

PMID:14749760
Participants:60
Impact:decreased by 1.6 μmol/L (P<0.001)
Trust score:4/5

A targeted medical nutrition therapy increased folate (and B6 and B12) levels and substantially reduced serum lipids in hyperlipidemic patients, while plasma homocysteine was unchanged.

Trust comment: Randomized small trial with clear clinical endpoints and dietary counseling, but limited by modest sample size and short-term follow-up (12 weeks).

Study Details

PMID:19083486
Participants:40
Impact:no change (P = .98)
Trust score:3/5

Daily vitamin B-complex for 12 weeks lowered homocysteine and improved blood sugar and kidney markers in adolescents with type 1 diabetes and microalbuminuria.

Trust comment: Small randomized controlled trial (n=80), short duration (12 weeks), but randomized and controlled; moderate quality.

Study Details

PMID:30704890
Participants:80
Impact:significant decrease vs placebo (p<0.001)
Trust score:3/5

4110 kidney transplant recipients randomized to high- vs low-dose folic acid/B6/B12: homocysteine was reduced but there was no reduction in composite cardiovascular outcomes over ~4 years.

Trust comment: Large, double-blind randomized trial with long follow-up showing robust null clinical outcome despite biochemical change.

Study Details

PMID:21482964
Participants:4110
Impact:significantly reduced by high-dose vitamins (no percent given)
Trust score:5/5

Daily fortified milk (including phytosterols) plus lifestyle counselling for 3 months improved several CVD-related markers (lower homocysteine, higher folate/B12) and tended to improve LDL:HDL; effects are from combined intervention.

Trust comment: Randomized intervention but contains multiple added nutrients and lifestyle counselling, so effects cannot be attributed to vitamin B12 alone.

Study Details

PMID:23249766
Participants:101
Impact:significant decrease in enriched milk group vs placebo and control (P<0.001)
Trust score:3/5

6-week randomized trial of B-vitamin (including B12) plus folic acid in PAD patients: homocysteine fell and B12/folate rose, but ADMA did not change.

Trust comment: Randomized placebo-controlled trial (n=49) with clear biochemical outcomes and appropriate measures, but short duration and moderate sample size.

Study Details

PMID:15634723
Participants:49
Impact:decreased
Trust score:4/5

In dialysis patients, adding supraphysiologic B-vitamin doses including 1 mg B12 significantly lowered plasma homocysteine over 4–8 weeks compared with placebo.

Trust comment: Small randomized placebo-controlled human trial with objective biomarker outcomes but limited sample size.

Study Details

PMID:8770960
Participants:27
Impact:-29.8% at 4 weeks; -25.8% at 8 weeks (active vs placebo); 5/15 treated vs 0/12 placebo normalized (<15 μmol/L)
Trust score:3/5

In elderly people, a folate-rich diet with or without B12/B6 supplements significantly reduced blood homocysteine.

Trust comment: Randomized, prospective, simple-blind trial with completed n=44 and clear homocysteine outcome; modest sample size.

Study Details

PMID:11152929
Participants:44
Impact:-10.8 µmol/L (mean decrease; 95% CI 9.4–12.5)
Trust score:4/5

Randomized placebo-controlled trial of L-arginine plus B vitamins for 3–6 months in mildly hypertensive adults; intervention improved postprandial endothelial function, lowered homocysteine and reduced blood pressure.

Trust comment: Randomized double-blind placebo-controlled trial with objective vascular endpoints and sustained effects; B vitamins were part of a combination product so effects are combined.

Study Details

PMID:27817128
Participants:80
Impact:−1.61 µmol/L (intervention vs placebo)
Trust score:4/5

peripheral nerve conduction velocity

1 evidences

Cluster randomized, double-blind protocol comparing 1 mg/day vitamin B12 delivered as fortified food vs pill vs routine PACAM (placebo arm) in older Chilean adults; outcomes planned include serum B12, nerve conduction and MMSE; this is a protocol paper (no results reported).

Trust comment: Well-described cluster RCT protocol with planned adequate sample size, but this publication is only the protocol without outcome data.

Study Details

PMID:21952034
Participants:300
Impact:not reported
Trust score:3/5

Bayley-III cognitive and motor composite scores

1 evidences

Follow-up of an RCT of daily 2 µg vitamin B12 vs placebo given in infancy (6–11 months) for 12 months (original n=600); at 42–47 months there was no overall effect on WPPSI-IV FSIQ or other neurodevelopmental outcomes.

Trust comment: Large randomized trial with high follow-up rates and validated developmental assessments; reports null overall effects with predefined subgroup analyses.

Study Details

PMID:35152918
Participants:533
Impact:no significant differences between groups
Trust score:4/5

cognitive performance (Letter Digit Coding Test, TICS)

1 evidences

Factorial RCT in elderly patients with ischemic vascular disease testing folic acid + vitamin B12 (and other B vitamins); folic acid + B12 lowered homocysteine by ~5.0 μmol/L but produced no significant improvement in fibrinogen, vWF, or cognitive tests over one year.

Trust comment: Randomized, placebo-controlled, double-blind factorial trial with moderate sample size and measured clinical and biomarker outcomes; homocysteine reduction was clear but clinical cognitive benefit was not observed.

Study Details

PMID:16332666
Participants:185
Impact:no significant change vs control over 1 year
Trust score:4/5

pain intensity (VAS)

5 evidences

Randomized open-label study adding pyrimidine nucleotides plus vitamins B1 and B12 to standard care for painful radiculopathy showed no significant difference in pain VAS but some functional and global-clinical improvement versus control.

Trust comment: Randomized study but open-label with modest sample size and limited power for primary pain endpoint; secondary functional outcomes favored supplement.

Study Details

PMID:39683579
Participants:116
Impact:No statistically significant difference between groups (estimate ~+3.1 mm, p=0.416 mITT)
Trust score:3/5

In 100 patients with chronic postthoracotomy pain, pregabalin plus methylcobalamin improved pain and neuropathic symptom scores compared with diclofenac, with minimal side effects.

Trust comment: Randomized prospective study in humans with clear patient-reported outcomes but modest sample size and some reporting parts in the text are unclear.

Study Details

PMID:27916242
Participants:100
Impact:reduced vs diclofenac (greater pain relief)
Trust score:3/5

Gabapentin combined with vitamins B1 and B12 reduced neuropathic pain similarly to pregabalin, with some differences in adverse events and sleep improvements.

Trust comment: Large randomized multicenter trial with ITT/PPP populations and appropriate analyses; open-label design and combination therapy limit attribution to B12 alone.

Study Details

PMID:26885528
Participants:270
Impact:decreased in both groups; ≥30% response 78% (GBP+B1/B12) vs 85% (pregabalin); no significant between-group difference
Trust score:4/5

Adding B vitamins (thiamine, pyridoxine, cyanocobalamin) to dexketoprofen produced faster and slightly greater pain relief and reduced disability over 7 days compared with dexketoprofen alone.

Trust comment: Well-conducted randomized double-blind multicentre RCT (n=170) with prespecified pain and disability outcomes; short follow-up (7 days) limits long-term inference.

Study Details

PMID:38842764
Participants:170
Impact:Day 5 mean 2.4 vs 3.3 cm (difference −0.9 cm); Day 7 mean 1.3 vs 1.9 cm (difference −0.6 cm); final % change −79.6% vs −74.5%
Trust score:4/5

In an open randomized trial, adding neuromultivit (multivitamin containing B vitamins) to standard therapy for L5-S1 vertebrogenic radiculopathy produced greater improvements in pain and disability than basic therapy alone.

Trust comment: Randomized but open-label trial with limited reported numeric outcomes and single-country report; risk of bias from lack of blinding.

Study Details

PMID:29171487
Participants:100
Impact:Greater reduction vs control (reported p<0.05); exact magnitudes not provided
Trust score:3/5

clinical symptoms of B12 deficiency

1 evidences

After total gastrectomy, two oral B12 doses (500 µg vs 1500 µg/day) produced similar restoration of blood B12 and symptom improvement by 3 months.

Trust comment: Randomized multicenter phase II RCT with clear endpoints but prematurely closed for poor accrual, reducing power.

Study Details

PMID:35896261
Participants:74
Impact:similar degree of improvement between 500 µg and 1,500 µg arms
Trust score:4/5

plasma total homocysteine

15 evidences

Intramuscular 1 mg B12 increased serum B12 but did not significantly lower plasma homocysteine over 3 months in haemodialysis patients.

Trust comment: Double-blind RCT but small sample (n=28) limits ability to detect modest homocysteine changes.

Study Details

PMID:14656250
Participants:28
Impact:no significant reduction (difference 3.08 µmol/L; 95% CI −4.44–10.61; P=0.406)
Trust score:3/5

Vitamin B12 lowered metabolic markers but did not change blood or clinical symptom scores over 3 months.

Trust comment: Randomized placebo-controlled trial with clear biochemical outcomes but limited clinical effects reported over short-term (3 months).

Study Details

PMID:11468228
Participants:140
Impact:decreased (P < 0.001)
Trust score:4/5

High-dose B-vitamin therapy (including B12) lowered homocysteine but was associated with greater GFR decline and more vascular events in diabetic nephropathy patients.

Trust comment: Multicenter randomized double-blind trial with clinically important adverse findings despite biochemical efficacy.

Study Details

PMID:20424250
Participants:238
Impact:decreased (mean difference -4.8 μmol/L; P < 0.001)
Trust score:4/5

B-vitamin therapy lowered homocysteine but did not change the incidence of venous thromboembolism over ~5 years.

Trust comment: Large randomized trial (secondary analysis) with reliable biochemical changes but VTE events not centrally adjudicated.

Study Details

PMID:17470822
Participants:5522
Impact:decreased (geometric mean decreased by 2.2 μmol/L in vitamin group)
Trust score:4/5

Young men with high homocysteine took B-vitamin supplements for 8 weeks; homocysteine fell but artery function did not change.

Trust comment: Double-blind randomized trial in 40 subjects with clear endpoints but modest sample size.

Study Details

PMID:12430779
Participants:40
Impact:decreased (significant)
Trust score:4/5

Young women given folic acid with or without B12 for 4 weeks: all vitamin treatments lowered homocysteine, and adding B12 produced larger reductions.

Trust comment: Controlled supplementation trial with 150 participants and clear quantitative homocysteine outcomes.

Study Details

PMID:9808229
Participants:150
Impact:folic acid alone -11%; folic acid +6 µg B12 -15%; folic acid +400 µg B12 -18% (largest reduction)
Trust score:4/5

Haemodialysis patients given folinic/folic acid plus vitamin B6 and weekly oral B12 experienced large, sustained reductions in plasma homocysteine over 6 months.

Trust comment: Randomized controlled trial in 60 patients with clear homocysteine reductions, but B12 was given to all groups so its isolated effect is unclear.

Study Details

PMID:11981075
Participants:60
Impact:decreased (mean reductions at 6 months ~42–46% across groups)
Trust score:3/5

In 60 maintenance hemodialysis patients, two daily vitamin regimens (both containing B12) reduced plasma homocysteine substantially over 12 months.

Trust comment: Randomized, double-blind trial in 60 patients with repeated biochemical measures and 12-month follow-up.

Study Details

PMID:16053010
Participants:60
Impact:−23.6% at 1 month; maximal −28.3% at 6 months (32.4 → 22.7 μmol/L)
Trust score:4/5

In a factorial randomized trial, B-vitamin supplementation including vitamin B12 (1 mg) lowered plasma homocysteine by ~30% in people at high risk of dementia after 12 weeks.

Trust comment: Randomized factorial trial with biochemical endpoints and moderate sample size (n=149); results robust for homocysteine lowering though cognitive outcomes unchanged.

Study Details

PMID:12823643
Participants:149
Impact:reduced by ~30% with B-vitamin (folic acid + vitamin B12) supplementation (P < 0.0001)
Trust score:4/5

Giving B12 alone modestly lowered homocysteine; combining B12 with folic acid lowered it much more.

Trust comment: Randomized clinical trial with clear biochemical outcomes and adequate sample size; high internal validity.

Study Details

PMID:12220694
Participants:191
Impact:-10.9% (vitamin B12 alone); -38.5% (vitamin B12 + folic acid)
Trust score:4/5

Daily B-vitamin (folic acid, B6, B12) vs placebo in 8164 patients after stroke/TIA: overall no significant reduction in major vascular events, but subgroup not on antiplatelet therapy showed fewer events; B-vitamins lowered homocysteine.

Trust comment: Large, randomized double-blind multicentre trial with robust biochemical and clinical outcomes; subgroup post-hoc analysis so exploratory.

Study Details

PMID:22554931
Participants:8164
Impact:Decreased by −3.18 μmol/L in B-vitamins group (p<0.0001)
Trust score:4/5

In patients with hyperthyroidism, plasma homocysteine was low and inversely related to B-vitamins (including cobalamin); after antithyroid therapy homocysteine increased while folate and cobalamin decreased.

Trust comment: Observational longitudinal study with a reasonable sample size showing associations between B-vitamin status (including cobalamin) and homocysteine; causality limited.

Study Details

PMID:14535973
Participants:182
Impact:low in hyperthyroid state and increased after antithyroid therapy
Trust score:3/5

In CAD patients with high homocysteine, B-vitamin therapy (folic acid, B6, B12) markedly lowered tHcy but had minimal effects on oxidative stress markers and only a small reduction in serum amyloid A.

Trust comment: Prospective randomized study with clear biochemical outcomes and reported pre/post values, though sample sizes in treated subgroup were modest.

Study Details

PMID:16006259
Participants:93
Impact:reduced from 17.4 to 9.2 µmol/L (~47% decrease; p<0.0001)
Trust score:4/5

A single intramuscular hydroxycobalamin injection in infants with biochemical B12 impairment rapidly corrected biomarkers and improved motor scores and regurgitation.

Trust comment: Double-blind randomized controlled trial in humans with objective biochemical and clinical outcomes and clear effects.

Study Details

PMID:24025626
Participants:79
Impact:decreased by 54%
Trust score:5/5

PCOS patients on metformin who received B-group vitamins had reduced rises in homocysteine compared to metformin alone over 12 weeks.

Trust comment: Randomized trial with clear biochemical outcomes but small sample size and short duration limit generalizability.

Study Details

PMID:15790610
Participants:60
Impact:metformin alone: +26.5% at 12 weeks; metformin + B-vitamins: -21.17%; metformin + folic acid: -8.33%
Trust score:3/5

holotranscobalamin (holo-TC)

1 evidences

A 4-week vegan diet rapidly lowered circulating holo-transcobalamin and serum B12 but did not change cellular markers (MMA, homocysteine) or cause clinical deficiency.

Trust comment: Well-conducted randomized controlled trial in healthy volunteers with objective biomarkers, but short duration and modest sample size.

Study Details

PMID:31752105
Participants:53
Impact:decreased 67.3 → 43.6 pmol/L (−23.7 pmol/L; p<0.001) in vegan group
Trust score:4/5

global cognitive function (TICS-M total)

1 evidences

Daily folic acid (400 µg) plus vitamin B12 (100 µg) for 2 years produced small but significant improvements in global cognitive score and memory measures in older adults with distress.

Trust comment: Large randomized controlled trial (n=900) with 2-year follow-up showing modest cognitive benefits of combined supplementation.

Study Details

PMID:22170358
Participants:900
Impact:improved vs placebo (P=0.032; effect size d=0.17 at 24 mo)
Trust score:5/5

delayed recall (TICS-M delayed)

1 evidences

Daily folic acid (400 µg) plus vitamin B12 (100 µg) for 2 years produced small but significant improvements in global cognitive score and memory measures in older adults with distress.

Trust comment: Large randomized controlled trial (n=900) with 2-year follow-up showing modest cognitive benefits of combined supplementation.

Study Details

PMID:22170358
Participants:900
Impact:improved vs placebo (P=0.013; d=0.18 at 24 mo)
Trust score:5/5

carotid intima-media thickness (CIMT)

2 evidences

In stroke/TIA patients, long-term B-vitamin (including B12) supplementation lowered homocysteine but did not change carotid thickness or endothelial function.

Trust comment: Randomized, double-blind sub-study with objective vascular measures and meta-analysis, but selection bias and lack of baseline vascular measures limit certainty.

Study Details

PMID:18803866
Participants:162
Impact:0.01 mm (no significant change)
Trust score:4/5

In renal-transplant patients with high homocysteine, B-vitamin supplementation including B12 lowered homocysteine and reduced carotid artery thickness over 6 months.

Trust comment: Randomized placebo-controlled trial in humans (n=56) with clear, significant changes in homocysteine and cIMT over 6 months; single-center RTR population limits generalizability.

Study Details

PMID:12792513
Participants:56
Impact:mean −32.2% (0.95 mm → 0.64 mm)
Trust score:4/5

acute lower respiratory infection incidence

1 evidences

In Indian children 6–30 months, B12 and/or folic acid improved biochemical status but did not reduce diarrhea or respiratory infections; folic acid (alone or with B12) increased persistent diarrhea risk.

Trust comment: Large, randomized, double-blind trial with clear outcomes and adequate power, though increased persistent diarrhea was linked primarily to folic acid-containing arms.

Study Details

PMID:23902779
Participants:1000
Impact:no significant change
Trust score:4/5

tinnitus severity (VAS/THI)

1 evidences

In patients with idiopathic tinnitus, one month of vitamin B12 did not reduce tinnitus severity compared with placebo at one and three months.

Trust comment: Double-blind randomized trial with moderate sample size, but short treatment duration and subjective outcomes limit strength of evidence.

Study Details

PMID:37647778
Participants:140
Impact:no significant change
Trust score:3/5

plasma vitamin B12 concentration

8 evidences

Daily low-dose B vitamins (including B12) for 12 months reduced Framingham risk score and increased HDL, with effects reversing after stopping.

Trust comment: Large double-blind RCT with clinically relevant endpoints and sustained follow-up, though combined B-vitamin formulation confounds B12-specific effects.

Study Details

PMID:24916013
Participants:390
Impact:+80% at 6 months
Trust score:4/5

In a 6-month randomized placebo-controlled trial a multivitamin containing vitamin B12 raised plasma B12 and improved homocysteine and LDL oxidation markers.

Trust comment: Randomized, placebo-controlled trial with objective biochemical endpoints and moderate sample size.

Study Details

PMID:14559932
Participants:182
Impact:increase (p<0.0001)
Trust score:4/5

Two double-blind RCTs (children and adults) showed B12-fortified foods substantially raised plasma B12 and reduced homocysteine compared with placebo.

Trust comment: Two double-blind, placebo-controlled trials with good adherence and objective biochemical endpoints support efficacy for raising B12 status.

Study Details

PMID:34189981
Participants:282
Impact:children +91 pmol/L (B12 alone) / +82 pmol/L (B12+MMN); adults +38 pmol/L
Trust score:4/5

In non-diabetic high-risk breast cancer patients, 6 months of metformin reduced plasma vitamin B12 levels and increased biochemical B12 deficiency without causing anemia.

Trust comment: Large randomized trial with centralized assays and paired samples; clear objective measures though secondary analysis of first 492 paired samples.

Study Details

PMID:28447237
Participants:492
Impact:metformin median -70 pmol/L (390 → 320) at 6 months; placebo median +10 pmol/L (370 → 380); p=0.0001
Trust score:4/5

Women with migraine took a daily vitamin tablet (1 mg folic acid + B6 + B12) for 6 months; B12 levels rose but homocysteine and migraine outcomes did not change significantly.

Trust comment: Randomized double-blind trial with moderate sample and modified ITT; outcomes largely non-significant and treatment was a combination so B12-specific effects are not isolated.

Study Details

PMID:27339806
Participants:189
Impact:+~167 pmol/L (baseline 289.3 → 456.8 pmol/L) in treatment group
Trust score:3/5

Vegetarian women received 500 μg oral B12 every other day for 6 weeks; B12 levels rose and homocysteine fell within 2 weeks and stayed lower.

Trust comment: Small randomized proof-of-principle trial with objective biochemical endpoints and high completer rate but limited size and duration.

Study Details

PMID:17215186
Participants:40
Impact:+90 pmol/L (125 → 215 pmol/L)
Trust score:3/5

Giving B12 alone modestly lowered homocysteine; combining B12 with folic acid lowered it much more.

Trust comment: Randomized clinical trial with clear biochemical outcomes and adequate sample size; high internal validity.

Study Details

PMID:12220694
Participants:191
Impact:increased (not quantified)
Trust score:4/5

Pooled analyses from several randomized, double-blind trials and an open-label extension testing Souvenaid (Fortasyn Connect) versus control in mild/mild-to-moderate AD; measured plasma micronutrients and fatty acid incorporation.

Trust comment: Multiple randomized, double-blind clinical trials with centralized assays and consistent reproducible increases in circulating vitamin B12 and related biomarkers support high confidence in the finding.

Study Details

PMID:26213579
Participants:1199
Impact:increased in active (Fortasyn Connect) vs control from baseline to week 24 (e.g., RCT2: 289.5 → 322.0 pM; P<0.001)
Trust score:5/5

positive and total symptoms

1 evidences

Daily folic acid plus vitamin B12 for 16 weeks improved negative symptoms in schizophrenia when genetic folate-metabolism variants were considered; no change in positive or total symptoms.

Trust comment: Multicenter, randomized, placebo-controlled trial with pharmacogenetic analysis; credible but effect depended on genotype subgroup.

Study Details

PMID:23467813
Participants:140
Impact:no significant change
Trust score:4/5

Depression severity (HADS-D)

1 evidences

People with relapsing-remitting MS on two dietary interventions plus supplements had improved mood over 24 weeks; serum B12 rose and homocysteine fell, but those blood changes did not explain the mood improvement.

Trust comment: Secondary analysis of a randomized trial with moderate sample size and repeated measures; results plausible though mediation analyses were negative.

Study Details

PMID:37148578
Participants:77
Impact:decrease (significant at 12 and 24 weeks)
Trust score:4/5

Cataract extraction

1 evidences

In this large randomized trial of women at high CVD risk, daily folic acid+B6+B12 did not change incidence of age-related cataract but was associated with a higher rate of cataract extraction over ~7 years.

Trust comment: Large randomized, double-masked trial with long follow-up and objective outcomes; credible findings though extraction outcome may reflect clinical decision factors.

Study Details

PMID:26786311
Participants:3925
Impact:increase (HR 1.28; 95% CI 1.01–1.63; P=0.04)
Trust score:5/5

Composite major adverse cardiac events (death, MI, repeat revascularization)

1 evidences

Six months of folic acid+B12+B6 after successful PCI lowered homocysteine and reduced 1-year major adverse events and target lesion revascularization compared with placebo.

Trust comment: Randomized double-blind placebo-controlled trial with moderate sample and clinically important endpoints showing statistically significant benefit.

Study Details

PMID:12190367
Participants:553
Impact:reduced from 22.8% to 15.4% at 1 year (RR 0.68; 95% CI 0.48–0.96; P=0.03)
Trust score:5/5

Maternal–neonatal vitamin B12 correlation

1 evidences

Late cord clamping (60 s) was associated with higher neonatal FT3/FT4 and fewer neonates with low vitamin B12 compared with early clamping (≤10 s); urinary iodine results were measured but not emphasized.

Trust comment: Randomized but small study with limited power; outcome measurement appropriate but sample size restricts precision.

Study Details

PMID:34263919
Participants:60
Impact:positive correlation (r=0.334; p=0.009)
Trust score:3/5

haemoglobin

2 evidences

Giving multiple micronutrients including vitamin B12 to HIV-infected children increased their blood B12 and folate levels over six months.

Trust comment: Randomized, double-blind multicenter RCT with objective biochemical assays but biochemical analysis limited to a 214-child subset and some missing samples.

Study Details

PMID:21600005
Participants:214
Impact:+0.3 g/dL (median change in MMS group)
Trust score:4/5

Weekly iron+folic acid with or without added vitamin B12 for 26 weeks raised haemoglobin; addition of B12 improved ferritin and reduced B12 deficiency more than IFA alone.

Trust comment: Large randomized double-blind community RCT with good completion (373), appropriate biochemical outcomes, though single-centre and limited to 26 weeks.

Study Details

PMID:26695724
Participants:373
Impact:+9.7 g/l (Group A IFA only) and +7.5 g/l (Group B IFA + B12) increase from baseline to end
Trust score:4/5

plasma methylmalonic acid (MMA)

3 evidences

In people with low or marginal B12, 12 weeks of high-dose folic acid raised folate stores but did not change methylmalonic acid (a marker of B12 function).

Trust comment: Double-blind randomized placebo-controlled trial with validated assays and prespecified biochemical endpoints, though a substudy with some missing data and limited to middle-aged depressed patients.

Study Details

PMID:34510193
Participants:177
Impact:No significant change (adjusted mean difference −0.009 μmol/L; P=0.71)
Trust score:4/5

Daily 1000 µg crystalline cobalamin for 12 weeks (milk or capsule) effectively increased serum cobalamin and lowered MMA and homocysteine in mildly deficient elderly.

Trust comment: Randomized double-blind interventions showing consistent biochemical improvement in cobalamin-deficient elderly over 12 weeks.

Study Details

PMID:16155269
Participants:112
Impact:Median decrease −0.19 µmol/L (5th–95th: −0.76, −0.04) vs placebo
Trust score:4/5

Randomized trial in infants: a single intramuscular 400 μg cobalamin dose at 6 weeks raised serum cobalamin and normalized metabolic markers by 4 months.

Trust comment: Randomized, placebo-controlled trial with objective biochemical endpoints and moderate sample size; single-center limits generalizability.

Study Details

PMID:18595990
Participants:107
Impact:median MMA decreased from 0.58 to 0.20 μmol/L in supplemented group (no change in controls)
Trust score:4/5

serum calcitonin gene-related peptide (CGRP)

1 evidences

In a 2-month trial, combined vitamin B12 + magnesium plus high-intensity interval training reduced CGRP levels and improved migraine disability, frequency, intensity and duration more than other groups.

Trust comment: Randomized trial but small sample (n=60) and limited numeric detail in the provided text; registered but full methodological details and effect sizes not fully reported here.

Study Details

PMID:35112219
Participants:60
Impact:Significant decrease in the HIIT + supplement group versus other groups (no numeric value reported)
Trust score:3/5

migraine disability (MIDAS) / intensity / duration

1 evidences

In a 2-month trial, combined vitamin B12 + magnesium plus high-intensity interval training reduced CGRP levels and improved migraine disability, frequency, intensity and duration more than other groups.

Trust comment: Randomized trial but small sample (n=60) and limited numeric detail in the provided text; registered but full methodological details and effect sizes not fully reported here.

Study Details

PMID:35112219
Participants:60
Impact:Reduced in the HIIT + supplement group compared with other groups (statistically significant)
Trust score:3/5

recognition performance (memory)

1 evidences

Among patients with mild cognitive impairment, lower-normal vitamin B12 was associated with worse memory and reduced hippocampal microstructural integrity.

Trust comment: Well-characterized cross-sectional study with MRI and mediation analysis in MCI patients, but observational design limits causal inference.

Study Details

PMID:26912492
Participants:100
Impact:Worse in low-normal B12 group (P = 0.008)
Trust score:3/5

Methylmalonic acid (MMA)

12 evidences

In this community cohort of early-pregnancy women, about one quarter were cobalamin-deficient while folate deficiency was rare.

Trust comment: Large community-based cohort with validated biochemical assays and clear prevalence estimates, though cross-sectional so causal conclusions are limited.

Study Details

PMID:34422259
Participants:561
Impact:Mean 0.24 μmol/L and 32.8% had MMA >0.26 μmol/L (indicator of functional B12 insufficiency)
Trust score:4/5

Pregnant women randomized to 250 μg/day B12 vs placebo showed higher maternal and infant B12 status and lower MMA; maternal vaccine IgA responses improved and some infant inflammation markers decreased.

Trust comment: Blinded, placebo-controlled randomized trial with biomarker and clinical immune measures, moderate sample size (n=68).

Study Details

PMID:25648738
Participants:68
Impact:decrease in mothers, neonates and infants at 3 months (p < 0.05)
Trust score:4/5

A double-blind RCT of 1000 μg/day oral B12 vs placebo for one month in patients with borderline B12 showed rapid metabolic response (MMA fell) at 1 month but effects were not sustained after stopping therapy.

Trust comment: Randomized, double-blind placebo-controlled trial with validated biochemical outcomes but small sample and limited follow-up after treatment cessation.

Study Details

PMID:21232119
Participants:50
Impact:-0.13 μmol/l at 1 month versus placebo (CI95% -0.19 to -0.06; p < 0.001)
Trust score:4/5

A randomized crossover of whey (contains B12) vs soy protein in older adults with low B12 found WPI increased active B12 and folate (and those biochemical changes correlated with some cognitive improvements), but WPI did not produce a main cognitive benefit; soy improved some cognitive domains in females.

Trust comment: Randomized, double-blind crossover with biochemical and cognitive outcomes but small completer sample (n=44) and an active control (soy) that itself affected cognition in females.

Study Details

PMID:30577611
Participants:44
Impact:no significant change (did not reach significance)
Trust score:4/5

Higher MMA was linked to hearing loss; short-term B12 did not improve hearing.

Trust comment: Moderate-sized clinical study with measured biomarkers but limited intervention duration and observational associations.

Study Details

PMID:18032219
Participants:93
Impact:elevated MMA associated with greater hearing loss prevalence
Trust score:3/5

Randomized trial comparing monthly high-dose oral cyanocobalamin vs weekly intramuscular hydroxocobalamin over 4 weeks; both routes improved B12 biomarkers but IM produced much larger early rises.

Trust comment: Randomized outpatient trial with direct biochemical outcomes but small sample size and nonblinded design limits precision.

Study Details

PMID:28421567
Participants:37
Impact:oral 304 → 168 nmol/L (−44.7%); IM 321 → 156 nmol/L (−51.4%; normalized by 4 weeks)
Trust score:4/5

In older or at-risk patients with low B12, both oral (1000 µg/day) and IM regimens normalized serum cobalamin in all patients; oral B12 showed lower MMA at day 91.

Trust comment: Randomized comparative study with near-complete follow-up and objective biochemical endpoints, though small and open-label.

Study Details

PMID:21600388
Participants:48
Impact:mean MMA lower in oral B12 vs IM at day 91 (p=0.033)
Trust score:4/5

4-month randomized double-blind trial in elderly: oral B-vitamins raised cobalamin markers and tended to lower MMA and homocysteine, differences were not statistically strong.

Trust comment: Double-blind randomized trial with moderate sample size; biochemical improvements reported but were generally non-significant.

Study Details

PMID:18609169
Participants:209
Impact:decrease (greater in AG subjects, not statistically significant)
Trust score:3/5

Randomized trial in newly diagnosed cobalamin-deficient patients comparing daily oral (2 mg) versus intermittent intramuscular (1 mg) cyanocobalamin for 4 months; oral therapy was at least as effective and produced larger biochemical improvements.

Trust comment: Randomized human trial with objective biochemical and clinical endpoints but small sample size limits precision.

Study Details

PMID:9694707
Participants:33
Impact:decreased to 169 nmol/L (oral) vs 265 nmol/L (IM) at 4 months
Trust score:4/5

Cross-sectional baseline biochemical analysis of infants (6–11 months) showing variable cobalamin status: depending on marker, a large proportion had functional indicators of low B12 while folate was adequate.

Trust comment: Well-conducted community-based biochemical assessment with multiple functional B12 markers; cross-sectional design limits causal inference.

Study Details

PMID:29783689
Participants:316
Impact:geometric mean 0.50 µmol/L; 75% >0.28 µmol/L (elevated)
Trust score:4/5

Women with PCOS on metformin experienced a decrease in serum cobalamin after six months, but other functional markers (holoTC, MMA) did not indicate deficiency.

Trust comment: Direct human study measuring multiple cobalamin biomarkers with appropriate assays but limited by small sample size and short follow-up.

Study Details

PMID:23857221
Participants:29
Impact:Small decline after 4 months (p=0.02); overall no increase indicating no functional deficiency
Trust score:4/5

In elderly with cobalamin deficiency, high-dose oral cyanocobalamin lowered SAH, MMA, and homocysteine.

Trust comment: Direct cobalamin intervention with biochemical endpoints in a convenience sample; methods solid but generalizability limited.

Study Details

PMID:17158426
Participants:149
Impact:decreased (significant) with high‑dose oral cobalamin
Trust score:3/5

carotid intima-media thickness (IMT)

2 evidences

6-month RCT in hemodialysis patients with hyperhomocysteinemia: high-dose B-vitamin regimen significantly lowered homocysteine but did not change carotid IMT.

Trust comment: Randomized trial with modest sample showing clear homocysteine reduction; underpowered for structural IMT outcomes.

Study Details

PMID:17048428
Participants:54
Impact:no significant change
Trust score:4/5

Double-blind randomized trial: combined folic acid + B6 + B12 for 1 year reduced homocysteine and decreased carotid intima-media thickness compared with placebo.

Trust comment: Double-blind randomized design with statistically significant results, but modest sample size (n=50).

Study Details

PMID:15939064
Participants:50
Impact:-0.08 mm absolute change in treatment group (1.50 to 1.42 mm); mean between-group difference -0.15 mm (P = 0.019)
Trust score:4/5

outbreak duration

1 evidences

Daily sublingual 1000 µg B12 for 6 months reduced ulcers, pain, and outbreak duration in people with recurrent mouth ulcers.

Trust comment: Randomized double-blind placebo-controlled trial but small sample (58), so moderate-high credibility.

Study Details

PMID:19124628
Participants:58
Impact:decrease (significant)
Trust score:4/5

depression adverse events

1 evidences

High-dose folate, B6 and B12 lowered homocysteine but did not slow cognitive decline over 18 months and had more depression-related adverse events.

Trust comment: Large multicenter randomized double-blind controlled trial with intention-to-treat analysis and clear endpoints.

Study Details

PMID:18854539
Participants:340
Impact:increase (more events in treatment group)
Trust score:5/5

vibration perception threshold (VPT)

2 evidences

A 24-week randomized trial of L-methylfolate + methylcobalamin + PLP improved neuropathy symptoms and quality of life but did not change vibration perception threshold.

Trust comment: Well-designed randomized double-blind trial with clinically relevant symptom improvements but no change in primary physiologic measure (VPT).

Study Details

PMID:23218892
Participants:214
Impact:no significant change
Trust score:4/5

Randomized placebo-controlled trial (n=73) of a 10-ingredient tablet including vitamin B12; active group had marked reduction in neuropathic pain and improvements in some nerve-function measures and vitamin B12 levels.

Trust comment: Randomized, placebo-controlled study with objective measures and adequate reporting, but the multi-ingredient tablet prevents isolating vitamin B12-specific effects.

Study Details

PMID:39339645
Participants:73
Impact:improved (significant) in active group
Trust score:4/5

colorectal adenoma occurrence

1 evidences

In women at high cardiovascular risk, combined folate, B6 and B12 supplementation did not change the risk of colorectal adenoma over follow-up.

Trust comment: Large randomized double-blind placebo-controlled trial subset analysis with adequate follow-up, yielding null results for adenoma risk.

Study Details

PMID:23066166
Participants:1470
Impact:no significant difference: 24.3% (treatment) vs 24.0% (placebo); RR=1.00 (95% CI 0.83–1.20)
Trust score:4/5

cycle ergometer endurance

1 evidences

Small randomized double-blind trial in COPD patients; B12 supplementation produced modest improvements in exercise tolerance in more advanced COPD but no change in oxygen uptake kinetics.

Trust comment: Randomized double-blind design but very small completed sample (n=32) and subgroup effects were emphasized without precise quantified primary outcomes.

Study Details

PMID:27993287
Participants:32
Impact:+ discrete improvement (advanced COPD subgroup; not quantified)
Trust score:3/5

prevalence of vitamin B12 deficiency

2 evidences

Small randomized double-blind trial in COPD patients; B12 supplementation produced modest improvements in exercise tolerance in more advanced COPD but no change in oxygen uptake kinetics.

Trust comment: Randomized double-blind design but very small completed sample (n=32) and subgroup effects were emphasized without precise quantified primary outcomes.

Study Details

PMID:27993287
Participants:32
Impact:baseline prevalence 34.4%
Trust score:3/5

At 10 years after bariatric surgery, adherence to calcium–vitamin D supplements was associated with substantially lower prevalence of vitamin D insufficiency.

Trust comment: Predefined secondary analysis of a randomized trial with long (10-year) follow-up and objective lab measures, but supplement adherence was self-reported and some lab data were missing.

Study Details

PMID:40613787
Participants:178
Impact:low (~2%)
Trust score:4/5

overall cancer incidence

1 evidences

Large randomized placebo-controlled trial follow-up showing folic acid + vitamin B12 supplementation was associated with increased overall and colorectal cancer incidence.

Trust comment: Large multicenter randomized trial with long follow-up; findings statistically significant for colorectal cancer but reflect combined folic acid + B12 intervention.

Study Details

PMID:30341095
Participants:2524
Impact:+25% (HR 1.25; 13.6% vs 11.3%; P = 0.05)
Trust score:4/5

serum vitamin B12 concentration (green-MED/low-meat group)

1 evidences

Dietary intervention (DIRECT PLUS) and lab analyses showed Mankai contains authentic bioactive B12 and long-term consumption in a green-Mediterranean diet increased serum B12 versus control.

Trust comment: Randomized dietary intervention with good retention and complementary lab evidence, though dietary changes (not isolated B12 supplement) and other B12 sources complicate attribution.

Study Details

PMID:33049929
Participants:294
Impact:+15.4% (mean +48.8 ± 124.9 pg/mL; p < 0.001 vs baseline)
Trust score:4/5

executive function and depressive symptoms (month 12)

1 evidences

Methylcobalamin (500 µg) + folic acid lowered homocysteine but did not reduce cognitive decline at 24 months; transient improvements in executive function and depressive symptoms at 12 months were not sustained.

Trust comment: Well-designed randomized placebo-controlled trial with clear biochemical effect but no durable clinical cognitive benefit.

Study Details

PMID:31787369
Participants:279
Impact:transient improvement at 12 months (significant) but not sustained at 24 months
Trust score:4/5

fasting total homocysteine (Group A: Me-Cbl + FA)

1 evidences

In hemodialysis patients, oral folic acid normalized plasma homocysteine; adding IV methylcobalamin provided no additional benefit over folic acid alone.

Trust comment: Randomized trial but small sample; outcomes clearly measured and show folic acid efficacy while methylcobalamin alone had no effect.

Study Details

PMID:12021520
Participants:62
Impact:-12.3 µmol/L (22.5 → 10.2 µmol/L; p = 0.003)
Trust score:3/5

fasting total homocysteine (Me-Cbl alone)

1 evidences

In hemodialysis patients, oral folic acid normalized plasma homocysteine; adding IV methylcobalamin provided no additional benefit over folic acid alone.

Trust comment: Randomized trial but small sample; outcomes clearly measured and show folic acid efficacy while methylcobalamin alone had no effect.

Study Details

PMID:12021520
Participants:62
Impact:no significant change
Trust score:3/5

child expressive language score (30 months)

1 evidences

Maternal oral B12 supplementation during pregnancy was associated with higher expressive language scores in children at 30 months.

Trust comment: Randomized maternal supplementation with measured child cognitive outcomes; moderate sample size and statistically significant domain-specific effect.

Study Details

PMID:30003521
Participants:218
Impact:higher (β = 0.14; P = 0.03)
Trust score:4/5

cognitive performance

2 evidences

Two-year randomized trial in older adults: B-vitamin supplementation (including B12) lowered homocysteine but did not improve cognitive test scores.

Trust comment: Large double-blind randomized trial with clear biochemical lowering of homocysteine but no cognitive benefit, well-powered for the tested population.

Study Details

PMID:16807413
Participants:276
Impact:no significant improvement after 1–2 years
Trust score:4/5

Three months of folic acid plus small doses of B-vitamins including B12 improved folate and lowered homocysteine in children but did not change cognitive test scores.

Trust comment: Double-blind randomized controlled trial in children with biochemical outcomes and adequate sample but short intervention duration for cognitive effects.

Study Details

PMID:24481688
Participants:237
Impact:no relevant differences between supplement and control groups after 3 months
Trust score:4/5

homocysteine concentration

10 evidences

Randomized trial in PD patients on levodopa showed homocysteine‑lowering therapy (5 mg folate + 1500 μg vitamin B12 daily) increased BMD at lumbar spine and femur vs control over 12 months.

Trust comment: Randomized controlled trial but small sample (n=42 randomized, 41 completed); results support benefit of folate+B12 regimen on BMD in this specific clinical population.

Study Details

PMID:19938151
Participants:41
Impact:Plasma Hcy decreased to ~35% of baseline (≈−65%) in Hcy‑lowering group versus increases in other groups.
Trust score:4/5

In elderly people, intramuscular B12+folate+B6 given eight times over 3 weeks lowered several metabolic markers of B12 deficiency and normalized them in a higher proportion than placebo.

Trust comment: Prospective, multicentre double-blind placebo-controlled trial with objective biochemical outcomes and substantial sample size.

Study Details

PMID:7603218
Participants:285
Impact:Normalization rate +72 percentage points (92% vs 20% vitamin vs placebo)
Trust score:4/5

Daily low-dose folic acid, vitamin B6, vitamin B12 and betaine for 12 weeks reduced plasma homocysteine in Chinese adults with hyperhomocysteinemia compared with placebo.

Trust comment: Randomized, double-blind, placebo-controlled trial with objective biochemical endpoints though relatively small sample and short duration.

Study Details

PMID:36717385
Participants:86
Impact:−3.87 μmol/L (mean group difference); −10.1% reduction (P<0.001)
Trust score:4/5

In CAD patients, B-vitamin/folic acid supplementation lowered plasma total homocysteine but did not change fibrin clot structure/function (clot lysis time or maximum absorbance); other sulfur metabolites were linked to clot properties and outcomes.

Trust comment: Large randomized trial/cohort with long follow-up and extensive biochemical and clinical endpoints; valid negative finding for clot properties despite tHcy lowering.

Study Details

PMID:36301961
Participants:1952
Impact:Decreased with B-vitamin supplementation (significant reduction vs placebo)
Trust score:4/5

Double-blind randomized trial: combined folic acid + B6 + B12 for 1 year reduced homocysteine and decreased carotid intima-media thickness compared with placebo.

Trust comment: Double-blind randomized design with statistically significant results, but modest sample size (n=50).

Study Details

PMID:15939064
Participants:50
Impact:-3.94 µmol/L (10.50 to 6.56 µmol/L), ≈-37.5% (P < 0.0001)
Trust score:4/5

Community-based case-control study comparing hypertensive patients and controls; found no difference in homocysteine but higher folate and B12 concentrations in hypertensive subjects.

Trust comment: Observational case-control design can show associations but not causation; sample size moderate and assays reported.

Study Details

PMID:11860783
Participants:297
Impact:no significant difference (10.56 µmol/L in hypertensives vs 10.34 µmol/L in controls)
Trust score:3/5

In metformin-treated diabetic patients, supplementation with folate, vitamin B12 and B6 lowered homocysteine, raised B12 levels, and improved small-artery elasticity after 4 months.

Trust comment: Double-blind, placebo-controlled RCT with clear biomarker and functional endpoints but small sample size and short follow-up.

Study Details

PMID:18206891
Participants:60
Impact:Treatment decreased from 10.0±4.4 to 7.6±2.5 µmol/l (P=0.002); no change in placebo)
Trust score:4/5

In healthy volunteers, B-vitamin supplementation (including B12) lowered homocysteine by ~31% but did not change markers of endothelial dysfunction (tPA, PAI, vWf) over 8 weeks.

Trust comment: Randomized placebo-controlled study with adequate sample size and validated biomarkers, though short duration and surrogate outcomes.

Study Details

PMID:15543337
Participants:123
Impact:Mean reduction ~31% in B-vitamin group vs ~3% in placebo (95% CI 22.7–39.1)
Trust score:4/5

High-dose B-vitamin supplementation lowered homocysteine (~27.7%) in healthy volunteers but produced no clear changes in clotting activation markers (F1+2, TAT); D-dimer showed a non-significant reduction.

Trust comment: Randomized intervention with biomarker outcomes in healthy subjects; reasonable sample size but surrogate endpoints and short duration.

Study Details

PMID:12195694
Participants:118
Impact:~27.7% reduction in B-vitamin group vs placebo (P<0.0001)
Trust score:4/5

Twelve weeks of fortified milk (including B-group vitamins and B12) in older adults increased circulating B vitamins (including B12), raised vitamin D, improved ω-3 status, and lowered homocysteine.

Trust comment: Double-blind crossover RCT with objective biochemical endpoints in older adults; small sample (n=48) but well-controlled.

Study Details

PMID:33266447
Participants:48
Impact:Decreased from 15.2 to 11.6 µmol/L (−~23.7%; q < 0.0001)
Trust score:4/5

methylmalonic acid (MMA) concentration

1 evidences

In elderly people, intramuscular B12+folate+B6 given eight times over 3 weeks lowered several metabolic markers of B12 deficiency and normalized them in a higher proportion than placebo.

Trust comment: Prospective, multicentre double-blind placebo-controlled trial with objective biochemical outcomes and substantial sample size.

Study Details

PMID:7603218
Participants:285
Impact:Normalization rate +62 percentage points (82% vs 20% vitamin vs placebo)
Trust score:4/5

fibrin clot lysis time (CLT)

1 evidences

In CAD patients, B-vitamin/folic acid supplementation lowered plasma total homocysteine but did not change fibrin clot structure/function (clot lysis time or maximum absorbance); other sulfur metabolites were linked to clot properties and outcomes.

Trust comment: Large randomized trial/cohort with long follow-up and extensive biochemical and clinical endpoints; valid negative finding for clot properties despite tHcy lowering.

Study Details

PMID:36301961
Participants:1952
Impact:No significant change with B-vitamin/folate therapy
Trust score:4/5

fibrin maximum absorbance (Absmax)

1 evidences

In CAD patients, B-vitamin/folic acid supplementation lowered plasma total homocysteine but did not change fibrin clot structure/function (clot lysis time or maximum absorbance); other sulfur metabolites were linked to clot properties and outcomes.

Trust comment: Large randomized trial/cohort with long follow-up and extensive biochemical and clinical endpoints; valid negative finding for clot properties despite tHcy lowering.

Study Details

PMID:36301961
Participants:1952
Impact:No significant change with B-vitamin/folate therapy
Trust score:4/5

clinical global impression (CGI)

1 evidences

Randomized open-label study adding pyrimidine nucleotides plus vitamins B1 and B12 to standard care for painful radiculopathy showed no significant difference in pain VAS but some functional and global-clinical improvement versus control.

Trust comment: Randomized study but open-label with modest sample size and limited power for primary pain endpoint; secondary functional outcomes favored supplement.

Study Details

PMID:39683579
Participants:116
Impact:Higher odds of improvement in experimental group (OR = 0.20; p=0.003; ~5× more likely to improve)
Trust score:3/5

memory function

1 evidences

In older adults at high cardiovascular risk, higher serum B12 was correlated with better memory only among those with high adherence to the Mediterranean diet.

Trust comment: Nested cohort analysis with modest sample size and observational design; association observed only in subgroup with high Mediterranean diet adherence.

Study Details

PMID:37948836
Participants:170
Impact:Positive correlation with serum vitamin B12 in high Mediterranean diet adherence subgroup (r2=0.57, P=0.028)
Trust score:3/5

vitamin B12 (serum)

1 evidences

Six months of a protein/HMB-containing oral nutritional supplement (which included vitamin D) improved multiple biochemical and hematological indices compared with placebo in older adults at risk of malnutrition.

Trust comment: Large double-blind randomized placebo-controlled trial with pre-specified biochemical endpoints and good methodology (findings reflect multi-nutrient product rather than isolated B12 effect).

Study Details

PMID:39125374
Participants:811
Impact:significant increase in intervention group at day 90 and day 180 (p≤0.010)
Trust score:5/5

maternal and breast milk B12

1 evidences

Pregnant women randomized to 250 μg/day B12 vs placebo showed higher maternal and infant B12 status and lower MMA; maternal vaccine IgA responses improved and some infant inflammation markers decreased.

Trust comment: Blinded, placebo-controlled randomized trial with biomarker and clinical immune measures, moderate sample size (n=68).

Study Details

PMID:25648738
Participants:68
Impact:increase (p < 0.05)
Trust score:4/5

H1N1-specific maternal IgA response

1 evidences

Pregnant women randomized to 250 μg/day B12 vs placebo showed higher maternal and infant B12 status and lower MMA; maternal vaccine IgA responses improved and some infant inflammation markers decreased.

Trust comment: Blinded, placebo-controlled randomized trial with biomarker and clinical immune measures, moderate sample size (n=68).

Study Details

PMID:25648738
Participants:68
Impact:increase (significant)
Trust score:4/5

serum cobalamin (vitamin B12)

9 evidences

A double-blind RCT of 1000 μg/day oral B12 vs placebo for one month in patients with borderline B12 showed rapid metabolic response (MMA fell) at 1 month but effects were not sustained after stopping therapy.

Trust comment: Randomized, double-blind placebo-controlled trial with validated biochemical outcomes but small sample and limited follow-up after treatment cessation.

Study Details

PMID:21232119
Participants:50
Impact:+101.6 pM/l at 1 month (CI95% 60.1 to 143.2; p < 0.001)
Trust score:4/5

In Danish lactating mothers, supplemental oral B12 (variable doses) did not change serum B12 or binding proteins over 9 months.

Trust comment: Prospective 9‑month follow‑up (n=89) with mixed supplementation regimens; direct measurements but variable dosing and observational design limit causal inference.

Study Details

PMID:16900082
Participants:89
Impact:no significant change (3 weeks → 9 months) between supplemented and unsupplemented groups
Trust score:3/5

Six months of multivitamin supplementation including B6, B12 and folate in elderly women increased B12 and folate status and lowered homocysteine and methylmalonic acid.

Trust comment: Large randomized placebo-controlled double-blind trial in elderly women with clear biochemical endpoints supports reliability.

Study Details

PMID:15309436
Participants:220
Impact:increased significantly after 6 months
Trust score:4/5

Randomized trial in infants: a single intramuscular 400 μg cobalamin dose at 6 weeks raised serum cobalamin and normalized metabolic markers by 4 months.

Trust comment: Randomized, placebo-controlled trial with objective biochemical endpoints and moderate sample size; single-center limits generalizability.

Study Details

PMID:18595990
Participants:107
Impact:median serum cobalamin +75% at 4 months in supplemented infants (vs no change in controls)
Trust score:4/5

Randomized double-blind trial showing short-term nitrous oxide anaesthesia reduced serum folate and produced minor hematological changes but did not alter serum cobalamin (vitamin B12) levels in analyzed patients.

Trust comment: Randomized double-blind trial in humans with complete-data n=51; relevant to vitamin B12 status though small sample and focused on anesthesia effects.

Study Details

PMID:10971777
Participants:51
Impact:no significant change
Trust score:3/5

In patients with hyperthyroidism, plasma homocysteine was low and inversely related to B-vitamins (including cobalamin); after antithyroid therapy homocysteine increased while folate and cobalamin decreased.

Trust comment: Observational longitudinal study with a reasonable sample size showing associations between B-vitamin status (including cobalamin) and homocysteine; causality limited.

Study Details

PMID:14535973
Participants:182
Impact:decreased after restoration of euthyroidism
Trust score:3/5

Substudy of a randomized B‑vitamin trial: folic acid + vitamin B12 increased folate and cobalamin, lowered homocysteine (~2.8 µmol/L, ~29.5%) but did not change MCP‑1 levels or presence of VH‑TCFA.

Trust comment: Randomized trial sub-study with biochemical and imaging endpoints; well-conducted but B12 was given with folate so independent B12 effects are not isolated.

Study Details

PMID:23936148
Participants:102
Impact:increased by ~191.3 pmol/L with supplementation (p<0.001)
Trust score:4/5

In healthy adults, 6-week supplementation with natural or synthetic B-complex raised blood B-vitamin levels; natural B-complex showed a decrease in homocysteine and larger increases in antioxidant capacity in this small pilot.

Trust comment: Double-blind randomized pilot crossover but small sample and carryover/period effects limited planned analyses, so results are exploratory.

Study Details

PMID:31915511
Participants:29
Impact:+16% (natural) and +15% (synthetic) at end of supplementation; natural group maintained ~+9% after washout
Trust score:3/5

Food-based supplement providing substantial B12 increased dietary B12 intake (>2-fold) but did not change circulating serum cobalamin or improve birth outcomes.

Trust comment: Randomized trial with substantial sample but higher attrition and no biomarker changes despite intake increases, limiting observed efficacy.

Study Details

PMID:32469870
Participants:317
Impact:no difference among trial groups at mid or late pregnancy (no change)
Trust score:4/5

clinical neurologic markers

1 evidences

Cross-sectional analysis of older adults with moderately low B12 found no association between B12 status (total B12, holoTC, cB-12) and electrophysiologic or clinical neurologic measures.

Trust comment: Analysis uses high-quality baseline trial data and objective electrophysiologic measures but is cross-sectional and limited to moderately low (not severely deficient) older adults.

Study Details

PMID:27534645
Participants:201
Impact:no association with vitamin B12 status
Trust score:3/5

any-grade hematologic toxicity

1 evidences

Randomized trial comparing immediate vs 5–7 day prior folic acid+B12 supplementation in patients receiving pemetrexed-based chemotherapy; simultaneous supplementation was feasible and did not increase most hematologic toxicity.

Trust comment: Randomized multicenter trial with modified ITT and objective hematologic and biochemical measures; open-label but adequately powered for toxicity outcomes.

Study Details

PMID:30825389
Participants:150
Impact:no difference (IA 87.0% vs DA 87.7%; P=0.90)
Trust score:4/5

thrombocytopenia incidence

1 evidences

Randomized trial comparing immediate vs 5–7 day prior folic acid+B12 supplementation in patients receiving pemetrexed-based chemotherapy; simultaneous supplementation was feasible and did not increase most hematologic toxicity.

Trust comment: Randomized multicenter trial with modified ITT and objective hematologic and biochemical measures; open-label but adequately powered for toxicity outcomes.

Study Details

PMID:30825389
Participants:150
Impact:higher with immediate start: IA 31.2% vs DA 16.4% (P=0.04); ≈+14.8% absolute
Trust score:4/5

hemoglobin concentration

5 evidences

A fortified drink given 6 days/week for 8 weeks reduced vitamin B12 deficiency prevalence and increased vitamin B12 concentration and hemoglobin in schoolchildren.

Trust comment: Randomized, double-blind, placebo-controlled trial with adequate sample size and clear biomarker outcomes.

Study Details

PMID:23232585
Participants:246
Impact:increased (P<0.001)
Trust score:4/5

Double-blind randomized trial in pregnant women showed that a micronutrient-fortified beverage (including iodine) increased hemoglobin and ferritin and reduced risk of anemia and iron deficiency.

Trust comment: Randomized double-blind controlled trial with clear biochemical endpoints but short supplementation duration and combined micronutrient formulation.

Study Details

PMID:12730420
Participants:259
Impact:+4.16 g/L (end of 8 weeks)
Trust score:4/5

Randomized placebo-controlled trial in young children found that 6 months of vitamin B12 and/or folic acid did not improve hemoglobin concentrations.

Trust comment: Well-conducted randomized placebo-controlled trial in children with adequate sample size and biochemical measures; outcome negative and directly relevant.

Study Details

PMID:27486122
Participants:262
Impact:no improvement; mean Hb decreased in all groups over 6 months (no benefit of B12 or folate)
Trust score:4/5

Cross-sectional analysis in early pregnancy: higher plasma vitamin B12 was positively associated with hemoglobin concentration.

Trust comment: Observational biochemical sub-study with moderate sample size; association reported but no causality established.

Study Details

PMID:23469947
Participants:285
Impact:Positive association with plasma vitamin B12 (p<0.05)
Trust score:3/5

Cluster-RCTs in Kenya and Bangladesh delivering LNSs (containing B12) plus counseling increased hemoglobin, reduced anemia and improved vitamin B12 status in young children compared with control.

Trust comment: Large, well-conducted cluster-randomized trials with objective biomarker endpoints and high adherence to LNS, though some attrition and timing issues occurred.

Study Details

PMID:30624600
Participants:2120
Impact:increase ~2.4–4.4 g/L in nutrition arms (varied by site/arm)
Trust score:5/5

diastolic orthostatic BP drop (30 s)

1 evidences

Substudy of a double-blind RCT: metformin (1 g twice daily) plus insulin modestly increased early orthostatic blood pressure drop versus placebo; metformin reduced serum B12 modestly.

Trust comment: Large double-blind randomized trial substudy with objective autonomic and biochemical measures; substudy analyses limit primary focus but methods are robust.

Study Details

PMID:32979921
Participants:372
Impact:worse with metformin: increased drop by +1.30 mmHg (95% CI 0.30–2.57); P=0.045
Trust score:4/5

distal peripheral neuropathy measures

1 evidences

Substudy of a double-blind RCT: metformin (1 g twice daily) plus insulin modestly increased early orthostatic blood pressure drop versus placebo; metformin reduced serum B12 modestly.

Trust comment: Large double-blind randomized trial substudy with objective autonomic and biochemical measures; substudy analyses limit primary focus but methods are robust.

Study Details

PMID:32979921
Participants:372
Impact:no between-group difference (no metformin effect)
Trust score:4/5

migraine disability prevalence

1 evidences

6-month randomized double-blind trial of combined folic acid, B6 and B12 in migraine with aura showed marked homocysteine lowering and reduced migraine disability in supplemented patients, with genotype-modified response.

Trust comment: Randomized double-blind trial but small sample and intervention combined multiple vitamins (cannot ascribe effects to B12 alone); genotype-related subgroup findings reduce generalizability.

Study Details

PMID:19384265
Participants:52
Impact:reduced from 60% to 30% after 6 months in supplement group (P=0.01)
Trust score:3/5

headache frequency and severity

1 evidences

6-month randomized double-blind trial of combined folic acid, B6 and B12 in migraine with aura showed marked homocysteine lowering and reduced migraine disability in supplemented patients, with genotype-modified response.

Trust comment: Randomized double-blind trial but small sample and intervention combined multiple vitamins (cannot ascribe effects to B12 alone); genotype-related subgroup findings reduce generalizability.

Study Details

PMID:19384265
Participants:52
Impact:reduced (reported but not quantified here; text indicates reduction vs baseline/placebo)
Trust score:3/5

response rate

1 evidences

Randomized phase 2 trial found that adding folic acid and vitamin B12 to gemcitabine/cisplatin did not significantly change response rate, time to progression, or overall survival, though homocysteine fell with supplementation.

Trust comment: Randomized multicenter phase 2 trial but open-label and modest sample size; biological markers changed but no clinical efficacy benefit shown.

Study Details

PMID:29696360
Participants:78
Impact:no significant difference (supplemented RR 42.1% vs unsupplemented RR 32.4%; P=0.4)
Trust score:3/5

overall survival

3 evidences

Randomized phase 2 trial found that adding folic acid and vitamin B12 to gemcitabine/cisplatin did not significantly change response rate, time to progression, or overall survival, though homocysteine fell with supplementation.

Trust comment: Randomized multicenter phase 2 trial but open-label and modest sample size; biological markers changed but no clinical efficacy benefit shown.

Study Details

PMID:29696360
Participants:78
Impact:no significant difference (median OS 10.0 vs 7.7 months; P=0.9)
Trust score:3/5

In a large phase III trial, adding folic acid and vitamin B12 to chemotherapy reduced treatment toxicity without harming survival outcomes.

Trust comment: Large randomized phase III trial with clear outcomes; vitamin supplementation was added prospectively and toxicity reduction was significant.

Study Details

PMID:12860938
Participants:456
Impact:no adverse effect from vitamin supplementation
Trust score:5/5

Prospective ancillary study evaluating supplement use during chemotherapy; vitamin B12 use before and during treatment was associated with poorer disease-free survival.

Trust comment: Large prospective ancillary study but supplement use was self-reported and observational associations are susceptible to confounding.

Study Details

PMID:31855498
Participants:1134
Impact:similar trend toward worse survival (reported as similar to disease-free survival)
Trust score:3/5

free (non-protein bound) plasma platinum

1 evidences

Randomized phase 2 trial found that adding folic acid and vitamin B12 to gemcitabine/cisplatin did not significantly change response rate, time to progression, or overall survival, though homocysteine fell with supplementation.

Trust comment: Randomized multicenter phase 2 trial but open-label and modest sample size; biological markers changed but no clinical efficacy benefit shown.

Study Details

PMID:29696360
Participants:78
Impact:increased with supplementation: 4.7 µM vs 3.6 µM (P<0.05)
Trust score:3/5

combined B12 status (4cB12)

1 evidences

Randomized 4-week intervention in lactovegetarians comparing low-dose CN‑B12 capsules vs cow or buffalo milk (natural HO‑B12): all three modestly improved B12 biomarkers with similar combined-index changes at 3.5 weeks.

Trust comment: Randomized prospective trial with frequent biomarker sampling and combined indicator analysis; short duration and low dose limit conclusions about full replenishment.

Study Details

PMID:30717112
Participants:67
Impact:endpoint increases: +0.30 (CN-capsule), +0.25 (cow milk), +0.22 (buffalo milk); no significant difference between groups (P=0.49)
Trust score:4/5

total plasma B12

1 evidences

Randomized 4-week intervention in lactovegetarians comparing low-dose CN‑B12 capsules vs cow or buffalo milk (natural HO‑B12): all three modestly improved B12 biomarkers with similar combined-index changes at 3.5 weeks.

Trust comment: Randomized prospective trial with frequent biomarker sampling and combined indicator analysis; short duration and low dose limit conclusions about full replenishment.

Study Details

PMID:30717112
Participants:67
Impact:greater and more rapid increase with CN-B12 capsules (steeper rise) vs milk (more gradual)
Trust score:4/5

serum vitamin B12 at 3 months

1 evidences

Randomized trial in metformin-treated type 2 diabetes patients with low B12 showed 3-month correction of B12 with either route; sublingual methylcobalamin produced higher serum B12 at 3 months but differences resolved by 6 months.

Trust comment: Randomized trial but small sample; biochemical outcome robust though limited by sample size and short follow-up.

Study Details

PMID:27355231
Participants:34
Impact:higher with sublingual tablets: mean 372.1 pmol/L vs injection 251.7 pmol/L; difference ≈+120 pmol/L (ANCOVA P=0.002)
Trust score:3/5

Vitamin B12 deficiency prevalence

8 evidences

A fortified drink given 6 days/week for 8 weeks reduced vitamin B12 deficiency prevalence and increased vitamin B12 concentration and hemoglobin in schoolchildren.

Trust comment: Randomized, double-blind, placebo-controlled trial with adequate sample size and clear biomarker outcomes.

Study Details

PMID:23232585
Participants:246
Impact:reduced by 5% (relative reduction; P<0.01)
Trust score:4/5

Among the first 127 participants in a micronutrient RCT, vitamin D insufficiency/deficiency was common and treatment adherence to the capsule regimen was high (~88%).

Trust comment: Blinded RCT with validated measures but this is a mid-study subanalysis of a multi-micronutrient intervention so B12-specific causal effects are not isolated.

Study Details

PMID:24465617
Participants:127
Impact:2.4% participants <133 pmol/L
Trust score:3/5

Four-month randomized placebo-controlled trial in elderly people showing B-vitamin supplementation lowers markers of B12/folate deficiency.

Trust comment: Double-blind placebo-controlled RCT in 209 elderly subjects with clear biochemical endpoints and statistically significant results.

Study Details

PMID:14576756
Participants:209
Impact:observed in 7.2% at baseline; biochemical indices improved with supplementation
Trust score:4/5

Weekly iron+folic acid with or without added vitamin B12 for 26 weeks raised haemoglobin; addition of B12 improved ferritin and reduced B12 deficiency more than IFA alone.

Trust comment: Large randomized double-blind community RCT with good completion (373), appropriate biochemical outcomes, though single-centre and limited to 26 weeks.

Study Details

PMID:26695724
Participants:373
Impact:-22.9 percentage points (63.3% → 40.4%) in B12-supplemented group
Trust score:4/5

Community-randomized trial: provision of a lipid-based nutrient supplement containing vitamin B12 reduced the proportion of young children classified as B12-deficient at 6 months compared with controls.

Trust comment: Cluster-randomized controlled trial with moderate sample size (n=300) and objective biochemical outcomes; some cluster design complexities but overall reliable.

Study Details

PMID:24628577
Participants:300
Impact:reduced by ~24.1 percentage points in intervention vs control at 6 months (43.6% vs 67.7%; P=0.03)
Trust score:4/5

Cross-sectional baseline data in early pregnancy showed high prevalence of vitamin B12 deficiency and that anemia was associated with B12 deficiency rather than iron deficiency.

Trust comment: Large, population-based baseline analysis with standard lab measures but observational design limits causal inference about B12 effects.

Study Details

PMID:21275915
Participants:740
Impact:46% of women were vitamin B12 deficient at ~14 weeks gestation
Trust score:3/5

Pre-operative assessment of bariatric surgery candidates found many did not meet dietary reference intakes; 48% had calcium intake below DRI.

Trust comment: Well-characterized cross-sectional assessment of 100 patients reporting intake and deficiency prevalence; observational design limits causal inference.

Study Details

PMID:26797718
Participants:100
Impact:0%
Trust score:3/5

Double-blind RCT (n=139) comparing an optimized multivitamin vs standard supplement in sleeve gastrectomy patients found improvements in folic acid, vitamin B1, PTH and anemia rates with the optimized supplement but no difference in vitamin D deficiency prevalence.

Trust comment: Double-blind RCT with adequate sample and 12-month follow-up; outcomes biochemical and clinically relevant though supplementation regimes are multinutrient.

Study Details

PMID:31776782
Participants:139
Impact:no difference between optimized multivitamin (WLS Optimum) and standard multivitamin groups
Trust score:4/5

Correlation: serum B12 with CD4 count

1 evidences

Among the first 127 participants in a micronutrient RCT, vitamin D insufficiency/deficiency was common and treatment adherence to the capsule regimen was high (~88%).

Trust comment: Blinded RCT with validated measures but this is a mid-study subanalysis of a multi-micronutrient intervention so B12-specific causal effects are not isolated.

Study Details

PMID:24465617
Participants:127
Impact:r=0.20, p=0.007 (positive correlation)
Trust score:3/5

Household salt use (weighed)

1 evidences

Women evaluated taste/acceptability of salt fortified with iodine and other micronutrients; QFS was well accepted.

Trust comment: Well-designed randomized crossover with objective and subjective acceptability measures but small sample and only acceptability (no health outcomes) assessed.

Study Details

PMID:39490799
Participants:77
Impact:No difference by salt type
Trust score:3/5

Probability of adequate serum B12 (≥200 pmol/L)

1 evidences

Cross-sectional analysis in older Dutch adults linking vitamin B12 intake from different food sources to serum B12 and related biomarkers.

Trust comment: Large sample with validated FFQ and biochemical measures supports associations, but cross-sectional design limits causal inference.

Study Details

PMID:26389945
Participants:600
Impact:Top vs bottom tertile total intake PR=1.20 (1.06–1.35, model 3)
Trust score:4/5

Folic acid effect on CKD progression (low B12)

1 evidences

Post hoc analysis of a CKD substudy evaluating whether baseline B12 status modifies the effect of folic acid treatment on CKD progression.

Trust comment: Large randomized parent trial, but this is a post hoc subgroup analysis with low event rates so findings are hypothesis-generating rather than definitive.

Study Details

PMID:31629573
Participants:1374
Impact:OR 1.21 (95% CI 0.51–2.85) among B12 <248 pmol/L (no significant benefit)
Trust score:3/5

Modification by change in B12 over 12 months

1 evidences

Secondary analysis of the OPEN RCT intervention arm testing whether baseline or change in B12 status modified neurological response to B12 supplementation in older adults.

Trust comment: High-quality parent RCT data but small secondary-analysis sample and heterogeneous, inconsistent outcome associations reduce confidence.

Study Details

PMID:28225050
Participants:91
Impact:No evidence that change in B12 altered neurological outcomes
Trust score:3/5

Epigenetic age (Horvath clock)

1 evidences

Secondary analysis of intervention datasets: folic acid + vitamin B12 supplementation altered global DNA methylation patterns and reduced epigenetic age in a genotype- and sex-dependent manner (notably in women with MTHFR 677CC).

Trust comment: Small secondary analysis of existing methylation datasets with subgroup effects; hypothesis-generating rather than definitive.

Study Details

PMID:30350398
Participants:44
Impact:Reduced in women with MTHFR 677CC genotype after folic acid + B12 supplementation
Trust score:3/5

serum folate and MMA

1 evidences

Moderate alcohol intake modestly decreased serum B12 and slightly increased homocysteine in healthy postmenopausal women.

Trust comment: Randomized, diet-controlled crossover trial with clear within-subject comparisons but modest sample size.

Study Details

PMID:15138463
Participants:53
Impact:no significant change
Trust score:4/5

association with hunger/animal-source food/B12 intake

1 evidences

Cross-sectional study of lactating Kenyan women found low breast milk B12 concentrations in most women and no association with reported household hunger or recent animal-source food or B12 intake.

Trust comment: Well-conducted cross-sectional measurement with adequate sample but observational design and dietary-report limitations restrict causal inference.

Study Details

PMID:27075905
Participants:286
Impact:no significant association with Household Hunger Scale, recent animal-source food score, or 24-h estimated B12 intake
Trust score:3/5

major vascular events

1 evidences

In MI survivors, folic acid plus B12 lowered homocysteine but did not reduce major vascular events, stroke, or mortality over ~6.7 years.

Trust comment: Large, long-term double-blind randomized trial (12,064 participants) with hard clinical endpoints; high reliability.

Study Details

PMID:20571015
Participants:12064
Impact:no significant change (RR 1.04; 25.5% vs 24.8%)
Trust score:5/5

percent transmethylation remethylated to methionine

1 evidences

In pregnant women with low B12, combined B12 plus protein-energy supplementation tended to increase homocysteine remethylation rates in late pregnancy.

Trust comment: Randomized intervention in pregnant women with metabolic tracer outcomes; moderate sample size and mechanistic endpoints.

Study Details

PMID:28446631
Participants:93
Impact:M+B-12: 49.5% vs M+P: 42.3% (trend, P=0.053)
Trust score:4/5

vascular outcomes (recurrent stroke, CHD, death)

1 evidences

Large randomized trial found a modestly greater homocysteine reduction with high-dose B-vitamins but no effect on recurrent stroke, coronary events, or death over 2 years.

Trust comment: Large multicenter double-blind RCT with clinically important endpoints and adequate sample size, supporting high trustworthiness.

Study Details

PMID:14762035
Participants:3680
Impact:no treatment effect; unadjusted risk ratio 1.0 for stroke/CHD/death over 2 years
Trust score:5/5

urinary methylmalonic acid (uMMA) / plasma MMA

1 evidences

Double-blind randomized placebo-controlled trial in elderly people showed dose-dependent biomarker improvements with B12 supplements, but even 500 μg/day for 8 weeks left a minority with persistent metabolic abnormalities.

Trust comment: Double-blind randomized controlled intervention with clear biomarker endpoints in humans (n=100); good internal validity for biomarker effects.

Study Details

PMID:23236022
Participants:100
Impact:15–25% still showed metabolic deficiency after 500 μg/d for 8 weeks
Trust score:4/5

carboxylated/undercarboxylated osteocalcin ratio (c-OC/uc-OC)

1 evidences

Premenopausal Indian women taking a multi-micronutrient, protein-rich supplement containing calcium had improved bone turnover markers and some micronutrient status after 6 months.

Trust comment: Well-designed double-blind RCT with pre-specified primary endpoints and adequate reporting, though some between-group differences were not significant.

Study Details

PMID:33530298
Participants:102
Impact:increase: +53% in test group at 6 months (P<0.001)
Trust score:4/5

clinical/haematologic parameters (MMSE, red cell indices)

1 evidences

One-month randomized trial in elderly inpatients showing 50 µg oral cyanocobalamin raises serum B12; 10 µg did not differ from placebo.

Trust comment: Randomized double-blind design but small sample and short duration limit generalizability.

Study Details

PMID:12028259
Participants:31
Impact:no significant change over 1 month
Trust score:3/5

executive function (TMT-B)

1 evidences

Eight-week randomized controlled trial of an antioxidant mix (including vitamin B12) in older adults showing improved executive function and reduced oxidative stress markers versus placebo.

Trust comment: Randomized double-blind RCT with clear cognitive and biomarker endpoints, but the active product is a multi-ingredient mix so effects cannot be attributed to B12 alone.

Study Details

PMID:33375429
Participants:80
Impact:improvement: active group −17.63 s vs control +3.46 s; treatment difference −21.01 s (P<0.0001)
Trust score:4/5

other HRQOL domains (7/8)

1 evidences

In people with biochemical signs of B12 deficiency, B12 injections produced improvement in one SF-36 domain (general health) but no change in seven other quality-of-life dimensions.

Trust comment: Randomized placebo-controlled double-blind study with clear outcome measures but modest sample size and limited to individuals with only biochemical signs of deficiency.

Study Details

PMID:12542554
Participants:140
Impact:no change after B12 treatment
Trust score:4/5

plasma folate concentration

1 evidences

Large community survey showing low plasma cobalamin common in young Indian children, especially in breastfed infants, with associated metabolic markers.

Trust comment: Large population-based sample with biochemical measures; cross-sectional design limits causal inference but data are robust for prevalence estimates.

Study Details

PMID:17991639
Participants:2482
Impact:Median 6–11 mo: breastfed 20.3 nmol/L vs nonbreastfed 5.3 nmol/L (breastfed higher)
Trust score:4/5

red blood cell folate

1 evidences

A 12‑week multimicronutrient plus n‑3 PUFA supplement (including cholecalciferol) increased vitamin D status and reduced a composite low‑grade inflammation score versus placebo.

Trust comment: Well-conducted RCT with objective endpoints, but multinutrient formulation and omega-3 co-intervention limit attribution to B12 alone.

Study Details

PMID:40644954
Participants:112
Impact:increased (P<0.001)
Trust score:3/5

composite CVD events (MI, stroke, revascularization, CVD death)

1 evidences

Large randomized trial of folic acid, vitamin B6 and vitamin B12 in high-risk women: homocysteine fell but there was no reduction in cardiovascular events or mortality.

Trust comment: Large randomized double-blind placebo-controlled trial with long follow-up and objective outcomes; high-quality evidence despite null clinical results.

Study Details

PMID:18460663
Participants:5442
Impact:no significant change (RR 1.03; 95% CI 0.90–1.19; P=0.65)
Trust score:5/5

memory

1 evidences

One-year RCT in older adults with MCI: vitamin B (with folate and B6) did not improve cognition.

Trust comment: Randomized placebo-controlled trial with good compliance; well-conducted but found no cognitive benefit from FA/B12/B6 supplementation.

Study Details

PMID:18308888
Participants:152
Impact:no significant change
Trust score:4/5

total cobalamins

1 evidences

4-month randomized double-blind trial in elderly: oral B-vitamins raised cobalamin markers and tended to lower MMA and homocysteine, differences were not statistically strong.

Trust comment: Double-blind randomized trial with moderate sample size; biochemical improvements reported but were generally non-significant.

Study Details

PMID:18609169
Participants:209
Impact:increase (greater in AG subjects, not statistically significant)
Trust score:3/5

restenosis rate

2 evidences

Multicenter double-blind RCT after coronary stenting: folate/B6/B12 therapy increased angiographic restenosis and repeat revascularization compared with placebo.

Trust comment: Large, double-blind multicenter RCT showing a statistically significant adverse effect of folate/B-vitamin therapy on restenosis outcomes.

Study Details

PMID:15215483
Participants:636
Impact:increase (34.5% vs 26.5%; +8.0 percentage points, P=0.05)
Trust score:5/5

After coronary angioplasty, patients given folic acid, vitamin B12 and B6 had lower homocysteine and less restenosis and revascularization vs placebo.

Trust comment: Prospective double-blind randomized trial (n=205) showing significant clinical and biomarker effects but intervention was a combined folate/B12/B6 formula so effects cannot be attributed to B12 alone.

Study Details

PMID:11757505
Participants:205
Impact:-18.0 percentage points (37.6%→19.6%)
Trust score:4/5

Peripheral motor conduction time (PMCT, lower extremities)

1 evidences

Cross-sectional study of older adults comparing low vs normal B12: no central motor conduction differences, but peripheral motor conduction delay in lower limbs with low B12.

Trust comment: Well-conducted cross-sectional neurophysiology study in older adults but observational design limits causal inference.

Study Details

PMID:24694205
Participants:53
Impact:Significant delay/increase in low B12 group (p=0.014)
Trust score:3/5

transcobalamin (TC / holoTC)

1 evidences

In Danish lactating mothers, supplemental oral B12 (variable doses) did not change serum B12 or binding proteins over 9 months.

Trust comment: Prospective 9‑month follow‑up (n=89) with mixed supplementation regimens; direct measurements but variable dosing and observational design limit causal inference.

Study Details

PMID:16900082
Participants:89
Impact:total TC decreased over time but no difference by supplementation status
Trust score:3/5

PASI score (psoriasis severity)

1 evidences

Topical vitamin B12 ointment applied twice daily to one hemi‑body significantly reduced psoriasis severity (PASI) and itching versus control emollient.

Trust comment: Randomized intra‑patient left/right controlled trial with direct topical B12 intervention but small sample (n=24); single‑blind design limits blinding.

Study Details

PMID:29048238
Participants:24
Impact:M‑treated: mean decrease 4.47 at 2 weeks; overall baseline→12 weeks −5.92 (M) vs −1.07 (control) (all timepoints P<0.001)
Trust score:4/5

complete early & end‑of‑treatment viral responses (cEVR, ETR)

1 evidences

Adding oral vitamin B12 to standard peg‑interferon plus ribavirin increased early and sustained virological response rates in treatment‑naïve chronic HCV patients.

Trust comment: Randomized study (n=94) with direct B12 supplementation and multivariate analysis supporting effect, though sample size is modest.

Study Details

PMID:22810757
Participants:94
Impact:both higher with B12 (p=0.03)
Trust score:4/5

postmethionine-load total homocysteine (PML tHcy)

1 evidences

Baseline plasma betaine strongly predicted the post-methionine-load rise in homocysteine; B-vitamin supplementation weakened this relation.

Trust comment: Randomized human study with repeated measures and statistical reporting; relevant to B12 as part of multi-vitamin supplementation.

Study Details

PMID:14699020
Participants:90
Impact:PML increase in tHcy inversely related to plasma betaine (baseline beta=-0.29, P=0.02; PML beta=-0.47, P<0.001)
Trust score:4/5

pain score (visual analogue scale)

1 evidences

Vitamin B12 injections reduced pain, paresthesia and tingling more than nortriptyline in people with painful diabetic neuropathy.

Trust comment: Randomized single-blind trial with 100 completers and statistically strong differences (P<0.001), though single-blind and comparator is an active drug.

Study Details

PMID:19212856
Participants:100
Impact:-3.66 units (vitamin B12 group)
Trust score:4/5

inflammatory markers (e.g., hs-CRP, IL-6)

1 evidences

In patients with prior TIA/stroke, B-vitamin therapy lowered homocysteine but did not change measured blood markers of inflammation, endothelial dysfunction, or hypercoagulability at 6 months.

Trust comment: Well-powered randomized substudy (n=285) with objective laboratory endpoints; negative results are plausible and clearly reported.

Study Details

PMID:15569860
Participants:285
Impact:no significant change
Trust score:4/5

cGMP

1 evidences

In metabolic syndrome patients, combined folate and B12 therapy lowered homocysteine and improved insulin resistance and several measures of endothelial function over 1 month of B-vitamin treatment.

Trust comment: Randomized double-blind parallel study (n=50) with clear biochemical and functional endpoints, though sample size is modest.

Study Details

PMID:15476449
Participants:50
Impact:+13.6%
Trust score:4/5

plasma ADMA

2 evidences

Adding folic acid plus vitamin B12 (and probucol in one arm) to antihypertensive therapy lowered plasma homocysteine and ADMA over 12 weeks in hypertensive patients.

Trust comment: Randomized 3-arm trial with clear biochemical endpoints but limited detail on blinding and long-term outcomes in provided excerpt.

Study Details

PMID:23363713
Participants:120
Impact:0.20 → 0.18 μmol/L at 12 weeks (≈−10%) in folic acid + B12 group
Trust score:3/5

6-week randomized trial of B-vitamin (including B12) plus folic acid in PAD patients: homocysteine fell and B12/folate rose, but ADMA did not change.

Trust comment: Randomized placebo-controlled trial (n=49) with clear biochemical outcomes and appropriate measures, but short duration and moderate sample size.

Study Details

PMID:15634723
Participants:49
Impact:no change
Trust score:4/5

word learning test (WLT)

1 evidences

Randomized double-blind placebo-controlled trial in frail elderly showing enriched drink increased plasma B12, lowered homocysteine, and improved some cognitive test scores over 6 months.

Trust comment: Randomized, double-blind, placebo-controlled design but substantial attrition (67 completers), moderate sample for cognitive endpoints.

Study Details

PMID:15814873
Participants:67
Impact:improved (change ~+0.9 vs −0.1; p=0.014)
Trust score:4/5

bone turnover markers (bone-specific ALP)

1 evidences

Two-year randomized trial in older adults (subgroup with baseline homocysteine >15 μmol/L n=135) showing B‑vitamin supplementation lowered homocysteine but did not change bone turnover biomarkers.

Trust comment: Large, long-duration randomized controlled trial with clear biochemical outcomes and subgroup biomarker measurements.

Study Details

PMID:17284744
Participants:135
Impact:no significant change
Trust score:5/5

flow-mediated dilation (endothelial function)

1 evidences

Eight weeks of folic acid plus vitamin B12 lowered homocysteine and improved endothelial (flow-mediated) dilation in men with coronary heart disease.

Trust comment: Controlled trial with placebo comparison in CHD patients showing biomarker and functional vascular improvement; sample moderate (n=89) and intervention combined folate+B12.

Study Details

PMID:11076820
Participants:89
Impact:+1.5 percentage points (2.5%→4.0%)
Trust score:4/5

free plasma homocysteine

1 evidences

Eight weeks of folic acid plus vitamin B12 lowered homocysteine and improved endothelial (flow-mediated) dilation in men with coronary heart disease.

Trust comment: Controlled trial with placebo comparison in CHD patients showing biomarker and functional vascular improvement; sample moderate (n=89) and intervention combined folate+B12.

Study Details

PMID:11076820
Participants:89
Impact:-1.3 μmol/L (4.3→3.0 μmol/L)
Trust score:4/5

Neuropsychiatric Inventory (caregiver report)

1 evidences

A multi-nutrient formulation including vitamin B12 produced short-term improvements in some cognitive test scores vs placebo in patients with Alzheimer's disease.

Trust comment: Double-blind randomized phase II trial with positive cognitive outcomes, but formulation contained multiple active agents so effects cannot be ascribed to B12 specifically.

Study Details

PMID:25589719
Participants:106
Impact:non-significant improvement reported
Trust score:3/5

total plasma homocysteine (tHcy)

6 evidences

Alternate supplementation with vitamin B12 and folic acid lowered homocysteine in dialysis patients; effect reversed after washout and B12 levels rose with diffusive haemodialysis.

Trust comment: Randomized, blinded study in 74 patients with clear measurements though results influenced by dialysis modality and washout.

Study Details

PMID:24652221
Participants:74
Impact:decreased during alternate B12/folate supplementation; increased after washout
Trust score:4/5

In 132 hemodialysis patients, supplementation with folate and/or B12 lowered homocysteine, with the magnitude and timing of response differing by C677T MTHFR genotype.

Trust comment: Randomized supplementation in a moderate-sized HD cohort with genotype stratification provides credible genotype-treatment interaction data.

Study Details

PMID:26559681
Participants:132
Impact:decreased significantly with B12 and/or folate supplementation; response magnitude depended on C677T MTHFR genotype
Trust score:4/5

In a randomized double-blind crossover pilot, both natural and synthetic B-complex supplements raised serum B vitamins (including B12) and reduced homocysteine and some metabolic markers.

Trust comment: Randomized double-blind crossover design but small pilot sample (n=30) limits precision and external validity.

Study Details

PMID:32189314
Participants:30
Impact:decreased (marked reduction reported)
Trust score:3/5

Six months of multivitamin supplementation including B6, B12 and folate in elderly women increased B12 and folate status and lowered homocysteine and methylmalonic acid.

Trust comment: Large randomized placebo-controlled double-blind trial in elderly women with clear biochemical endpoints supports reliability.

Study Details

PMID:15309436
Participants:220
Impact:decreased significantly after 6 months
Trust score:4/5

In haemodialysis patients, alternating vitamin B12 and folic acid lowered homocysteine; effects depended on genotype and dialysis membrane type.

Trust comment: Randomized blinded crossover in 74 HD patients; moderate quality but small, specific population limits generalizability.

Study Details

PMID:17342693
Participants:74
Impact:decreased (statistically significant during alternate vitamin therapy; greater decrease in MTHFR T/T genotype and when starting with folic acid)
Trust score:3/5

Long-term B-vitamin therapy (including B12 0.5 mg) lowered plasma homocysteine but did not change arterial wall inflammation by FDG-PET.

Trust comment: Randomized double-blind trial with long follow-up but small sample size limits generalizability.

Study Details

PMID:19202330
Participants:30
Impact:decreased (vitamins mean 8.4 μmol/L vs placebo mean 11.6 μmol/L; p = 0.002)
Trust score:4/5

flow-mediated dilation (brachial artery)

1 evidences

In unstable angina patients with high homocysteine, folic acid supplementation markedly lowered homocysteine and improved brachial artery flow-mediated dilation over 8 weeks.

Trust comment: Controlled clinical measurements with vascular outcome but subgroup treated (n≈22) and modest sample for endothelial measures.

Study Details

PMID:19491420
Participants:82
Impact:increased from 6.4% to 9.0% at 8 weeks (+2.6 percentage points)
Trust score:3/5

vibration perception threshold

2 evidences

A 12-week randomized double-blind trial found benfotiamine plus B6/B12 improved peroneal nerve conduction in diabetic polyneuropathy with trends in vibration sense.

Trust comment: Double-blind randomized design but very small sample (n=24) limits generalizability.

Study Details

PMID:8886748
Participants:24
Impact:trend toward improvement
Trust score:3/5

In patients with painful diabetic neuropathy, Milgamma (contains mecobalamin/cyanocobalamin) produced significant pain relief and improved vibration perception versus comparator over 3 months.

Trust comment: Small 3-month trial with randomized assignment but limited sample size and unclear blinding; results suggest benefit but need larger trials.

Study Details

PMID:9575643
Participants:45
Impact:median improvement 1.56 on biothesiometer scale (P<0.01)
Trust score:3/5

olfactory function improvement

1 evidences

Randomized nonblinded trial found mecobalamin (vitamin B12) produced improvement in post-infectious olfactory dysfunction similar to tokishakuyakusan.

Trust comment: Randomized clinical trial directly testing mecobalamin, but nonblinded design and small sample limit confidence.

Study Details

PMID:37120318
Participants:82
Impact:Improvement rate 59% in mecobalamin group (vs 56% in TSS group); improvement seen by self-report and olfactory testing
Trust score:3/5

behavioral symptoms of autism

1 evidences

A 12-week double-blind crossover trial of injectable methyl B12 in children with autism found no significant group-level behavioral or glutathione changes, though a subgroup (~30%) showed clinical improvement with increased glutathione.

Trust comment: Double-blind crossover design is strong but small sample size (n=30) and pilot scope limit generalizability.

Study Details

PMID:20804367
Participants:30
Impact:no significant mean group-level improvement with methyl B12 over placebo (overall negative)
Trust score:3/5

HTase/PON activity

2 evidences

Type 2 diabetes patients randomized to folic acid, methylcobalamin, both, or control for 12 weeks: methylcobalamin (and combinations) reduced plasma homocysteine and increased HTase/PON activity, with the greatest homocysteine reduction seen with methylcobalamin alone.

Trust comment: Randomized human trial with 120 participants showing substantial, dose-specific biochemical effects of methylcobalamin and folic acid; moderate-to-high internal validity though group sizes were modest (n≈30).

Study Details

PMID:17425871
Participants:120
Impact:increased (Group IV +17.6%; other intervention groups +3.4–8.0%)
Trust score:4/5

Short-term folic acid with methylcobalamin markedly lowered homocysteine and increased HTase/PON activity in type 2 diabetes.

Trust comment: Randomized short-term biochemical trial with clear lab endpoints, but very short duration and biochemical surrogate outcomes.

Study Details

PMID:18781288
Participants:90
Impact:+17.59% increase in group receiving folic acid + methylcobalamin over 2 weeks
Trust score:3/5

infant vitamin B-12 deficiency prevalence

1 evidences

Maternal multiple micronutrient supplements reduced the rate of infant B12 deficiency at 6 months versus standard iron+folic acid.

Trust comment: Large randomized trial with biochemical measures in a sizable infant subset, though effect reported as subgroup comparison.

Study Details

PMID:20053938
Participants:1066
Impact:MMS 26.1% vs Fe30Fol 36.5% (absolute -10.4 percentage points)
Trust score:4/5

hematologic recovery (hemoglobin, MCV, WBC, platelets)

1 evidences

Oral high-dose B12 was as effective as intramuscular B12 for hematologic recovery in megaloblastic anemia over 90 days.

Trust comment: Randomized clinical trial showing similar clinical and laboratory recovery between oral and IM routes, but open-label and modest sample size.

Study Details

PMID:14749150
Participants:60
Impact:significant improvement from baseline by days 30 and 90; similar recovery patterns oral vs IM
Trust score:4/5

dose comparison

1 evidences

In 50 hemodialysis patients with high homocysteine, regimens including monthly B12 injections plus folic acid and B6 significantly lowered plasma homocysteine; high and low B-vitamin dose regimens had similar efficacy.

Trust comment: Randomized prospective study with clear biochemical endpoints but modest sample size (N=50); results internally consistent.

Study Details

PMID:15115259
Participants:50
Impact:no difference in Hcy reduction between high and low B12 dose regimens
Trust score:4/5

prevalence of severe+moderate B12 deficiency

1 evidences

Undernourished Kenyan schoolchildren ate a daily school meal with meat, milk, or energy for one year; meat and milk raised B12 status.

Trust comment: Large randomized school-meal trial with measured biochemical outcomes though infections may have confounded some effects.

Study Details

PMID:14672298
Participants:555
Impact:Meat: 80.7% → 64.1%; Milk: 71.6% → 45.1%
Trust score:4/5

neuropathy symptom scores

1 evidences

Diabetic neuropathy patients receiving electroacupuncture plus methylcobalamin injection had better nerve conduction and symptom scores than those receiving methylcobalamin injection alone.

Trust comment: Randomized 60-patient clinical observation with clear outcome measures but likely unblinded and both groups received methylcobalamin, limiting attribution solely to B12.

Study Details

PMID:21823284
Participants:60
Impact:lower scores with combined therapy (significant)
Trust score:3/5

overall neuropathy symptom score

1 evidences

Benfotiamine (alone or with B6 and B12) improved vibration perception, motor function and overall neuropathy symptoms in patients with alcoholic polyneuropathy over 8 weeks.

Trust comment: Multicenter, randomized, placebo-controlled double-blind trial with 84 completers supports moderate-high reliability.

Study Details

PMID:9872352
Participants:84
Impact:significant improvement during study
Trust score:4/5

grade III neurotoxicity incidence

1 evidences

Adding mecobalamin to glutathione during FOLFOX4 chemo reduced nerve toxicity compared with glutathione alone.

Trust comment: Randomized human trial with objective neurotoxicity outcomes and statistically significant differences, moderate sample size.

Study Details

PMID:27531486
Participants:94
Impact:-11.3 percentage points at 6 cycles (13.3% -> 2.0%); -14.6 percentage points at 9 cycles (18.9% -> 4.26%)
Trust score:4/5

sensory nerve electrophysiologic indices (nonparetic side)

1 evidences

Oral mecobalamin for 2 years improved electrophysiologic measures of sensory median nerve function in the nonparetic hands of stroke patients.

Trust comment: Randomized prospective study with objective neurophysiologic endpoints and long follow-up, but open-label design.

Study Details

PMID:15792815
Participants:135
Impact:Significant improvement after 2 years in treated group versus untreated (sensory conduction velocity, SNAPs and latencies improved)
Trust score:4/5

hospitalization for heart failure

1 evidences

In older adults with CKD, daily B-vitamin therapy including vitamin B12 lowered homocysteine but did not reduce cardiovascular events and was associated with increased hospitalizations for some cardiac conditions.

Trust comment: Large randomized, placebo-controlled trial (n=619) with long follow-up and hard clinical endpoints.

Study Details

PMID:18003666
Participants:619
Impact:increased (RR 1.98; P=0.007)
Trust score:5/5

late cerebral potentials

1 evidences

Healthy volunteers received B‑vitamins for 1 week before testing pain; no detectable effect of B‑vitamins on analgesia was found.

Trust comment: Well-designed placebo-controlled double-blind crossover in healthy volunteers (n=38) with objective measures, but small sample and negative result for B‑vitamins.

Study Details

PMID:7609864
Participants:38
Impact:no effect detected (analgesic changes observed were independent of B‑vitamin pretreatment)
Trust score:4/5

performance IQ

1 evidences

Older adults with low cobalamin received IM cyanocobalamin or no treatment; cognitive results were mixed with no clear consistent benefit.

Trust comment: Randomized trial in older adults (n=50) with biochemical deficiency but small sample, no placebo control, and mixed/weak effects limits strength of conclusions.

Study Details

PMID:9777425
Participants:50
Impact:improved in supplement group but not significantly more than controls
Trust score:3/5

pain score (cumulative)

1 evidences

Acupoint injection of 2000 µg VitB12 showed higher response rates and greater pain reduction than oral carbamazepine for trigeminal neuralgia in this randomized trial.

Trust comment: Randomized clinical observation with reasonable sample (104) but limited methodological detail reported and possible regional publication bias.

Study Details

PMID:17926620
Participants:104
Impact:greater reduction in B12 injection group (P<0.01)
Trust score:3/5

mucosal injury severity

1 evidences

Inhalation of a vitamin B12 mixed solution improved symptoms of acute radiation-induced mucosal injury and facilitated uninterrupted radiotherapy compared with gentamycin inhalation.

Trust comment: Moderate-sized comparative clinical study (n=122) but methodological details and randomization/blinding not fully described.

Study Details

PMID:16624769
Participants:122
Impact:clinical improvement: relieved pain, improved appetite, less weight loss (favorable response with B12 inhalation)
Trust score:3/5

global cognitive function

1 evidences

Ancillary analysis of a large randomized trial (n=1748) found no overall cognitive benefit after 4 years of B-vitamin (including B12) and/or omega-3 supplementation; a subgroup with prior stroke showed reduced odds of decline in temporal orientation (OR 0.43).

Trust comment: Large, randomized trial with long follow-up; subgroup/ancillary findings warrant cautious interpretation.

Study Details

PMID:21593490
Participants:1748
Impact:no significant effect after 4 years
Trust score:4/5

hematological cell counts

1 evidences

Randomized trial in infants (n=107) giving 400 μg cobalamin at 6 weeks improved biochemical markers of cobalamin function but did not change hematological cell counts at 4 months.

Trust comment: Double-blind randomized trial with clear biochemical endpoints; hematological outcomes were unchanged.

Study Details

PMID:23770919
Participants:107
Impact:no change at 4 months (no effect)
Trust score:4/5

Cyanocobalamin (vitamin B12) and suicide attempts

1 evidences

In a large pharmacoepidemiologic within-person study, folic acid fills associated with fewer suicide attempts, and the negative-control analysis found cyanocobalamin (B12) had no association with suicide attempts.

Trust comment: Very large claims-based within-person study reducing between-person confounding, but observational design limits causal inference and B12 was a negative-control analysis.

Study Details

PMID:36169979
Participants:866586
Impact:No association: HR 1.01 (95% CI 0.80–1.27)
Trust score:3/5

first ischemic stroke risk (baseline B12/folate > median)

1 evidences

Large randomized trial of folic acid in hypertensive adults showing baseline higher B12 (and folate) associated with lower first ischemic stroke risk and that folic acid supplementation reduced stroke risk especially in subgroups defined by low B12/folate and MTHFR genotype.

Trust comment: Large randomized trial with long follow-up and prespecified endpoints; strong evidence of interaction between B12/folate status and stroke risk/treatment effect.

Study Details

PMID:31932513
Participants:20702
Impact:lower risk HR 0.74 (95% CI 0.57–0.96) among those not receiving folic acid
Trust score:5/5

plasma folate insufficiency threshold (pf-IT)

1 evidences

Population-based randomized folic acid trial in women of reproductive age that estimated a plasma folate threshold for NTD prevention; vitamin B12 deficiency substantially modified the plasma–RBC folate relation and the estimated plasma threshold.

Trust comment: Randomized supplementation trial with robust modeling showing that vitamin B12 status modifies folate biomarkers and thresholds relevant to NTD prevention.

Study Details

PMID:31005964
Participants:1673
Impact:median pf-IT 25.5 nmol/L overall; higher in women with B12 deficiency (34.6 nmol/L) vs sufficient (25.6 nmol/L)
Trust score:4/5

hypozincemia

1 evidences

Compared quintuply-fortified salt (including iodine) versus iodized salt in nonpregnant reproductive-age women; QFS improved several micronutrient deficiencies versus iodized salt.

Trust comment: Large, double-blind randomized community trial with objective biomarker endpoints and sustained 12-month follow-up.

Study Details

PMID:40610127
Participants:998
Impact:odds −38% (OR 0.62) at 6 months vs iodized salt
Trust score:5/5

blood homocysteine

1 evidences

In lactating women, daily multiple micronutrient supplement (including vitamin D, DHA, lutein) for ~12 weeks increased milk DHA and raised maternal blood levels of several nutrients including 25-OH-vitamin D; well tolerated.

Trust comment: Randomized, double-blind trial with targeted biochemical endpoints but modest sample size and limited population diversity.

Study Details

PMID:33339438
Participants:65
Impact:decrease with MMS (placebo group showed an increase; exact magnitude not reported)
Trust score:4/5

total pregabalin use

1 evidences

Mecobalamin (a form of B12) improved foot/ankle function at 3 months and reduced pregabalin use over 12 months, but benefits were not sustained at later follow-ups.

Trust comment: Randomized trial with objective functional outcomes but small sample and transient effect limit confidence.

Study Details

PMID:39297877
Participants:47
Impact:reduced ~39% over 12 months in mecobalamin group
Trust score:3/5

adverse events

4 evidences

In 100 patients with chronic postthoracotomy pain, pregabalin plus methylcobalamin improved pain and neuropathic symptom scores compared with diclofenac, with minimal side effects.

Trust comment: Randomized prospective study in humans with clear patient-reported outcomes but modest sample size and some reporting parts in the text are unclear.

Study Details

PMID:27916242
Participants:100
Impact:minimal, no major safety signals reported
Trust score:3/5

Ultrahigh‑dose intramuscular methylcobalamin slowed functional decline over 16 weeks in early ALS compared with placebo, with similar adverse event rates.

Trust comment: Multicenter, double-blind, placebo-controlled phase 3 RCT with adequate randomization and completion rates.

Study Details

PMID:35532908
Participants:126
Impact:no difference vs placebo
Trust score:5/5

Adding diclofenac-cholestyramine to nucleotides + hydroxycobalamin for 10 days reduced pain and improved function versus nucleotides + hydroxycobalamin alone.

Trust comment: Randomized double-blind RCT with clear pain and function effects, but vitamin B12 (hydroxycobalamin) was present in both arms so B12-specific effects are not isolated.

Study Details

PMID:22128442
Participants:81
Impact:no significant difference between groups (p=0.587)
Trust score:4/5

Randomized double-blind placebo-controlled ascending-dose trial showed hydroxocobalamin generally well tolerated but associated with transient BP increases and self-limited discoloration and rash.

Trust comment: Well-designed randomized, placebo-controlled safety trial with substantial sample and clear objective safety endpoints.

Study Details

PMID:16990190
Participants:136
Impact:common: chromaturia, skin reddening, rash, headache; 2 immediate allergic reactions managed successfully
Trust score:5/5

serum glutathione

1 evidences

In a large 7.3‑year randomized trial (n=3411), garlic increased serum folate and a vitamin+selenium supplement increased glutathione, but neither intervention changed serum vitamin B12 or homocysteine.

Trust comment: Large, long-term randomized trial with robust sample size for clinical endpoints though biochemical substudies involved selected samples.

Study Details

PMID:19056661
Participants:3411
Impact:+13.4% after vitamin+selenium supplementation
Trust score:4/5

Survey of Autonomic symptoms (SAS)

1 evidences

In an 8-week RCT, mecobalamin intramuscular injections improved corneal small-fiber measures and autonomic symptom scores more than oral mecobalamin in mild–moderate diabetic peripheral neuropathy.

Trust comment: Small single-center open-label but assessor-blind RCT with objective imaging endpoints; limited sample size and short duration.

Study Details

PMID:34282267
Participants:32
Impact:injection change -2.13 ±1.85 vs tablet -0.18 ±0.81 (P<0.01)
Trust score:3/5

sleep duration

1 evidences

Gabapentin combined with vitamins B1 and B12 reduced neuropathic pain similarly to pregabalin, with some differences in adverse events and sleep improvements.

Trust comment: Large randomized multicenter trial with ITT/PPP populations and appropriate analyses; open-label design and combination therapy limit attribution to B12 alone.

Study Details

PMID:26885528
Participants:270
Impact:increased from baseline in both groups (statistically significant)
Trust score:4/5

PDE4C CpG methylation

1 evidences

In older adults, adding B-vitamins to vitamin D plus calcium changed methylation at some aging-related CpG sites and was associated with higher odds of accelerated epigenetic aging after 1 year.

Trust comment: Randomized supplementation trial but small sample and modest effect sizes; results are preliminary and require replication.

Study Details

PMID:29395637
Participants:63
Impact:change +1.95 vs 0.22 (borderline difference; adjusted p=0.062)
Trust score:3/5

pain (McGill pain questionnaire)

1 evidences

In an open randomized trial, adding neuromultivit (multivitamin containing B vitamins) to standard therapy for L5-S1 vertebrogenic radiculopathy produced greater improvements in pain and disability than basic therapy alone.

Trust comment: Randomized but open-label trial with limited reported numeric outcomes and single-country report; risk of bias from lack of blinding.

Study Details

PMID:29171487
Participants:100
Impact:More pronounced improvement vs control (p<0.05)
Trust score:3/5

AMI risk (per 1 SD increase in log Hcy‑thiolactone/creatinine)

1 evidences

Higher urinary Hcy-thiolactone (normalized to creatinine) predicted increased risk of incident acute myocardial infarction in CAD patients; folic acid and B‑vitamin supplementation did not change urinary Hcy-thiolactone.

Trust comment: Large prospective cohort (n>2000) with robust adjustment and consistent findings; high reliability for the biomarker–outcome association.

Study Details

PMID:30193001
Participants:2049
Impact:HR 1.22 (95% CI 1.05–1.41)
Trust score:5/5

plasma ADMA (vitamin E effect)

1 evidences

A multistep strategy including pravastatin, vitamin E and B‑vitamins had no overall effect on plasma ADMA in stage 2–4 CKD; vitamin E alone was associated with a small ADMA decrease.

Trust comment: Randomized placebo-controlled trial but secondary analysis with small sample and limited power for ADMA outcomes.

Study Details

PMID:18786751
Participants:93
Impact:Vitamin E associated with ≈4% decrease in ADMA (multiple adjusted P = 0.02)
Trust score:3/5

corneal nerve width

1 evidences

Oral vitamin B1 plus mecobalamin improved corneal subbasal nerve parameters and several dry eye symptoms over 1–3 months compared with artificial tears alone.

Trust comment: Randomized, double-blind controlled trial with objective IVCM measures and consistent symptom improvements; follow-up relatively short (3 months).

Study Details

PMID:36145126
Participants:199
Impact:Increased at 1 and 3 months (p<0.05)
Trust score:4/5

plasma total homocysteine (tHcy) reduction

1 evidences

Long-term folic acid–based multivitamin therapy consistently lowered plasma total homocysteine by ~3–4 μmol/L at 6 months across recruitment periods despite rising baseline folate status.

Trust comment: Randomized double-blind placebo-controlled trial with measured biomarkers and adequate sample for biochemical endpoints.

Study Details

PMID:15608435
Participants:285
Impact:Difference vs placebo at 6 months by quartile: −4.1, −4.1, −3.1, −3.6 μmol/L (no significant attenuation over time)
Trust score:4/5

vitamin A deficiency prevalence

1 evidences

Children given multiple-micronutrient fortified salt (includes iodine) had better blood nutrient markers and improved memory compared with iodized-salt controls.

Trust comment: Randomized controlled trial in residential schools with biochemical and cognitive endpoints and adequate sample size.

Study Details

PMID:20533221
Participants:402
Impact:Reduced from 57.1% to 16% post-intervention (p<0.05)
Trust score:4/5

Ischaemic stroke (no antiplatelet)

1 evidences

Daily B-vitamin (folic acid, B6, B12) vs placebo in 8164 patients after stroke/TIA: overall no significant reduction in major vascular events, but subgroup not on antiplatelet therapy showed fewer events; B-vitamins lowered homocysteine.

Trust comment: Large, randomized double-blind multicentre trial with robust biochemical and clinical outcomes; subgroup post-hoc analysis so exploratory.

Study Details

PMID:22554931
Participants:8164
Impact:Adjusted HR 0.65 (95% CI 0.46–0.91) — ~35% relative reduction
Trust score:4/5

acute diarrhea

1 evidences

Measured plasma folate and cobalamin in young children and tracked diarrheal episodes; plasma B12 did not predict diarrhea.

Trust comment: Large prospective cohort with biomarker measurement and frequent follow-up, appropriate for associations though observational.

Study Details

PMID:22013199
Participants:2296
Impact:small positive association with high total homocysteine (adjusted OR = 1.14)
Trust score:4/5

arterial wall FDG uptake (mean SUV)

1 evidences

Long-term B-vitamin therapy (including B12 0.5 mg) lowered plasma homocysteine but did not change arterial wall inflammation by FDG-PET.

Trust comment: Randomized double-blind trial with long follow-up but small sample size limits generalizability.

Study Details

PMID:19202330
Participants:30
Impact:no significant change with B-vitamin treatment (p = 0.65)
Trust score:4/5

pain (VAS >30 mm responders)

1 evidences

Adding diclofenac-cholestyramine to nucleotides + hydroxycobalamin for 10 days reduced pain and improved function versus nucleotides + hydroxycobalamin alone.

Trust comment: Randomized double-blind RCT with clear pain and function effects, but vitamin B12 (hydroxycobalamin) was present in both arms so B12-specific effects are not isolated.

Study Details

PMID:22128442
Participants:81
Impact:87.5% (DN) vs 51.23% (NB); +36.3 percentage points (DN vs NB) after 10 days
Trust score:4/5

low birth weight prevalence (per-protocol)

1 evidences

Large randomized food-based trial: overall no effect on birth weight in intention-to-treat, but per-protocol (supplement ≥90 d preconception) showed +48 g birth weight and reduced low birth weight.

Trust comment: Very large, individually randomized trial with supervised supplementation and robust measurements; partial blinding and loss to follow-up are limitations but overall high quality.

Study Details

PMID:25332324
Participants:6513
Impact:34% (treatment) vs 41% (control); −7 percentage points; OR 0.76; P=0.03
Trust score:5/5

L‑homocysteine

1 evidences

In a crossover feeding study, a traditional Korean diet higher in one‑carbon nutrients (including B12) reduced homocysteine more than the control diet and increased global DNA methylation in peripheral blood mononuclear cells.

Trust comment: Controlled crossover dietary intervention with objective methylation and metabolite measures; small sample but within‑subject design strengthens internal validity.

Study Details

PMID:38867083
Participants:52
Impact:Greater decrease with K‑diet: −70.7 ± 85.0 vs −39.3 ± 69.4 (K‑diet vs control); p<0.0168
Trust score:4/5

non-elective readmission rate

1 evidences

Daily oral multi-nutrient supplements for 6 weeks improved nutrition and reduced non-elective readmissions in older hospitalized patients.

Trust comment: Large randomized double-blind RCT with clear clinical endpoints, but used a multi-nutrient supplement so effects cannot be attributed to B12 specifically.

Study Details

PMID:16887416
Participants:445
Impact:-11 percentage points (29% vs 40%)
Trust score:4/5

WMH volume change in severe CSVD subgroup

1 evidences

Two years of daily B-vitamin supplementation did not significantly reduce overall progression of ischemic brain lesions versus placebo, but a predefined subgroup with severe small vessel disease showed less white-matter lesion progression.

Trust comment: Randomized double-blind substudy with objective MRI outcomes; overall null results with a positive effect in a prespecified severe-subgroup limit generalizability.

Study Details

PMID:23093615
Participants:359
Impact:-1.4 cm3 (0.3 vs 1.7 cm3; P=0.039)
Trust score:4/5

Psychological general well‑being (PGWB)

1 evidences

Six months of B‑vitamin supplementation (including cyanocobalamin/B12) lowered homocysteine and improved patients' general well‑being.

Trust comment: Double‑blind, placebo‑controlled multicentre RCT with moderate sample size and clear biochemical and clinical outcomes, though relatively small.

Study Details

PMID:19154566
Participants:57
Impact:significant improvement overall (P<0.01); Anxiety and Depressed Mood improved in those with poor well‑being (P<0.05)
Trust score:4/5

fine motor z-score

1 evidences

Children with moderate acute malnutrition received food supplements; serum cobalamin rose during 3 months of supplementation but many remained marginal.

Trust comment: Large randomized factorial trial with objective biochemical and developmental measures; cobalamin was a secondary outcome and some serum data were missing.

Study Details

PMID:35263343
Participants:1548
Impact:SC <112 pmol/L associated with −0.21 in fine motor z-score (95% CI −0.41 to −0.01, p=0.04)
Trust score:4/5

plasma cystatin C

1 evidences

In hyperhomocysteinaemic individuals, 3 months of B-vitamin treatment increased plasma cystatin C and cystatin C mRNA in PBMCs compared with placebo.

Trust comment: Randomized, placebo-controlled double-blind trial showing biochemical changes; small sample size limits generalizability but design is strong.

Study Details

PMID:19682403
Participants:37
Impact:increased after B-vitamin treatment vs placebo
Trust score:4/5

clinical dementia rating scale sum of boxes (CDR_SOB)

1 evidences

In a 24-month randomized trial of B vitamins (methylcobalamin + folic acid), cognitive decline was slowed in MCI patients with greater left frontal lobe atrophy; homocysteine was lowered.

Trust comment: Large randomized trial with objective outcomes, but the cognitive benefit is from a post-hoc subgroup analysis which lowers strength of inference.

Study Details

PMID:36057827
Participants:279
Impact:improved (lower CDR_SOB) at 24 months in patients with above-median left frontal lobe atrophy (post-hoc subgroup effect)
Trust score:4/5

intima-media thickness (IMT)

1 evidences

In a randomized vitamin B therapy trial in diabetic nephropathy patients, 3D ultrasound vessel wall volume increased over time in one treatment group while IMT showed no between-group differences.

Trust comment: Randomized, double-blind study but small imaging subset and modest sample size reduce generalizability.

Study Details

PMID:18996639
Participants:71
Impact:no difference between treatment groups
Trust score:3/5

total cholesterol

2 evidences

A targeted medical nutrition therapy increased folate (and B6 and B12) levels and substantially reduced serum lipids in hyperlipidemic patients, while plasma homocysteine was unchanged.

Trust comment: Randomized small trial with clear clinical endpoints and dietary counseling, but limited by modest sample size and short-term follow-up (12 weeks).

Study Details

PMID:19083486
Participants:40
Impact:−20.9% after MNT vs control
Trust score:3/5

Daily microalgae smoothies for 14 days increased 25-hydroxyvitamin D2 (from Chlorella) but did not prevent seasonal 25(OH)D3 decline; short intervention also modified lipids and fatty acids.

Trust comment: Randomized controlled study (80 enrolled, 72 completed) with direct nutrient measurements; short duration (14 days) and healthy young cohort limit generalizability.

Study Details

PMID:37049486
Participants:72
Impact:decreased in Chlorella group by −0.82 mmol/L (p<0.05)
Trust score:4/5

incidence of vasoplegic shock syndrome

1 evidences

Prophylactic IV hydroxocobalamin in high-risk cardiac surgery patients reduced vasoplegia incidence and vasopressor needs while improving blood pressure and lactate.

Trust comment: Randomized placebo-controlled prospective single-center trial with clinically relevant endpoints but moderate sample size.

Study Details

PMID:40055025
Participants:60
Impact:decreased (statistically significant)
Trust score:4/5

offspring insulin resistance (HOMA-IR)

1 evidences

Maternal B12 deficiency in pregnancy was linked to higher insulin resistance in school-aged offspring; antenatal micronutrient supplements (including groups that contained zinc) did not significantly alter this outcome.

Trust comment: Large cohort with biomarker data and long follow-up showing a robust association, though observational in nature.

Study Details

PMID:21865563
Participants:1132
Impact:+26.7% HOMA-IR in children of mothers B12-deficient in early pregnancy (P=0.02)
Trust score:4/5

total body iron (TBI)

1 evidences

Fortifying school meals with a multinutrient premix for 8 months improved vitamin A and folate status, increased total body iron, and lessened the decline in vitamin B12 among schoolchildren.

Trust comment: Large, cluster-randomized placebo-controlled trial with objective biomarkers, but B12 was a low-dose component of a multi-micronutrient mix limiting attribution to B12 alone.

Study Details

PMID:20410083
Participants:499
Impact:TBI increased in both groups, greater increase in treatment vs control (P<0.05)
Trust score:4/5

PCC brain metabolites (NAA, choline, creatine)

1 evidences

Six months of high-dose B-group multivitamin supplementation increased blood B12 and B6 and lowered homocysteine; brain metabolite concentrations did not change significantly in this small neuroimaging sub-study.

Trust comment: Randomized double-blind trial with objective biochemical and MRS measures; neuroimaging sub-sample was small and some data were excluded, limiting power for brain outcomes.

Study Details

PMID:30513795
Participants:33
Impact:No significant group×time changes in PCC metabolite concentrations (p>0.05)
Trust score:4/5

processing speed and memory

1 evidences

High-dose B-vitamin therapy (including 1 mg B12) in kidney transplant recipients lowered homocysteine and produced modest but significant improvements in processing speed and memory over ~3.3 years.

Trust comment: Large randomized, multi-site controlled trial ancillary with long follow-up and standardized cognitive testing, though most participants were B12/folate sufficient at baseline which may limit effect size interpretation.

Study Details

PMID:29182708
Participants:584
Impact:Modest but significant improvements in processing speed and memory in the supplement group vs control (p≤0.05)
Trust score:4/5

vitamin B12 absorption

1 evidences

Olestra intake reduced some fat-soluble nutrient levels but did not affect vitamin B12 absorption or status over 8 weeks in healthy adults.

Trust comment: Controlled dose-response study with objective measures in healthy adults, but modest sample size and short duration for some nutrients.

Study Details

PMID:9237961
Participants:90
Impact:No change in vitamin B12 absorption (measured wk 0 and 8)
Trust score:3/5

D-dimer

1 evidences

High-dose B-vitamin supplementation lowered homocysteine (~27.7%) in healthy volunteers but produced no clear changes in clotting activation markers (F1+2, TAT); D-dimer showed a non-significant reduction.

Trust comment: Randomized intervention with biomarker outcomes in healthy subjects; reasonable sample size but surrogate endpoints and short duration.

Study Details

PMID:12195694
Participants:118
Impact:~10.4% reduction (P=0.08; not statistically significant)
Trust score:4/5

vitamin B12 deficiency prevalence (anaemic children)

1 evidences

Community study of preschool children found high anaemia prevalence and that vitamin B12 deficiency (alone or with iron) was a notable contributor to anaemia in this population.

Trust comment: Community-based prevalence and etiology study with reasonable sample size but observational design and subset diagnostic workups.

Study Details

PMID:9701895
Participants:300
Impact:14.4% with B12 deficiency alone; 22.2% with B12 deficiency combined with iron deficiency (evaluated among 90 anaemic children)
Trust score:3/5

serum vitamin D

1 evidences

Moderately malnourished pregnant women received one of three supplements for 10 weeks; RUSF limited the decline in vitamin B12 and produced the largest vitamin D increase.

Trust comment: Large randomized controlled trial sub-study with rigorous sampling and adjustments; some loss to follow-up and limited intervention duration reduce certainty.

Study Details

PMID:29986492
Participants:273
Impact:RUSF +6.4 ng/mL vs CSB+IFA +1.7 ng/mL and CSB+UNIMMAP +2.7 ng/mL (p<0.001)
Trust score:4/5

breastmilk Vitamin B12 (MMN/LNS vs IFA)

1 evidences

In a randomized maternal supplementation trial (>700 women), breastmilk Vitamin B12 concentration was positively associated with attention and executive function; MMN/LNS arms had higher breastmilk B12 than IFA.

Trust comment: Large randomized trial with biomarker substudy showing consistent associations between breastmilk B12 and cognitive outcomes, though B12 was not isolated as sole causal agent.

Study Details

PMID:29098783
Participants:712
Impact:increase (reported higher in MMN and LNS vs IFA; magnitude unspecified)
Trust score:4/5

depression severity

1 evidences

Large clinical-trial analysis found weak or no consistent relationships between one‑carbon biomarkers (including vitamin B12) and depression severity or antidepressant response.

Trust comment: Large sample (881) from randomized clinical trials; biomarker associations reported but effects were weak and inconsistent across trials.

Study Details

PMID:32787676
Participants:881
Impact:weak inverse correlation with serum vitamin B12 (significant only in paroxetine study)
Trust score:4/5

plasma malondialdehyde (MDA)

1 evidences

In acute ischemic stroke patients, short-term B‑group vitamin supplementation (including B12) was associated with reduced oxidative damage and inflammation markers compared with no supplementation.

Trust comment: Randomized small trial (n=48) with combined B‑vitamin intervention; results suggest antioxidant/anti-inflammatory effects but B12-specific effects cannot be isolated.

Study Details

PMID:15279619
Participants:48
Impact:decreased in treatment group versus increase in controls (P=0.05)
Trust score:3/5

% polychromatic erythrocytes (PCE)

1 evidences

Across cross-sectional and short intervention studies, folate status correlated with chromosome stability but short-term supplementation (including a folate+B12+B6 arm) did not change micronucleus frequency or cell proliferation.

Trust comment: Includes cross-sectional data (n=99) and small short-term interventions (n≈29–30); appropriate methods but limited by short intervention duration and small sample sizes.

Study Details

PMID:16386942
Participants:99
Impact:no significant change after supplementation
Trust score:3/5

cancer incidence (overall)

1 evidences

Daily B-vitamin pill did not change overall cancer rates in people after stroke/TIA; diabetics had more and non-diabetics had fewer cancers with treatment in a post-hoc analysis.

Trust comment: Large randomized double-blind placebo-controlled trial (n=8164) with median 3.4-year follow-up, high internal validity.

Study Details

PMID:22474057
Participants:8164
Impact:4.04% vs 4.59% (−0.55 percentage points); RR 0.86, not significant
Trust score:5/5

renal markers (UAE, cystatin C)

1 evidences

Daily vitamin B-complex for 12 weeks lowered homocysteine and improved blood sugar and kidney markers in adolescents with type 1 diabetes and microalbuminuria.

Trust comment: Small randomized controlled trial (n=80), short duration (12 weeks), but randomized and controlled; moderate quality.

Study Details

PMID:30704890
Participants:80
Impact:significant decrease vs placebo (p<0.001)
Trust score:3/5

Study treatment adherence (pill count)

1 evidences

Among the first 127 participants in a micronutrient RCT, vitamin D insufficiency/deficiency was common and treatment adherence to the capsule regimen was high (~88%).

Trust comment: Blinded RCT with validated measures but this is a mid-study subanalysis of a multi-micronutrient intervention so B12-specific causal effects are not isolated.

Study Details

PMID:24465617
Participants:127
Impact:Mean 88% adherence
Trust score:3/5

Sensory discrimination (triangle tests)

1 evidences

Women evaluated taste/acceptability of salt fortified with iodine and other micronutrients; QFS was well accepted.

Trust comment: Well-designed randomized crossover with objective and subjective acceptability measures but small sample and only acceptability (no health outcomes) assessed.

Study Details

PMID:39490799
Participants:77
Impact:Rice samples with QFS, DFS, iodized salt not distinguishable
Trust score:3/5

Dietary source potency (meat and dairy)

1 evidences

Cross-sectional analysis in older Dutch adults linking vitamin B12 intake from different food sources to serum B12 and related biomarkers.

Trust comment: Large sample with validated FFQ and biochemical measures supports associations, but cross-sectional design limits causal inference.

Study Details

PMID:26389945
Participants:600
Impact:Upper tertile meat PR=1.22 (1.08–1.37); dairy PR=1.24 (1.10–1.39) for adequate serum B12
Trust score:4/5

Interaction B12 × folic acid

1 evidences

Post hoc analysis of a CKD substudy evaluating whether baseline B12 status modifies the effect of folic acid treatment on CKD progression.

Trust comment: Large randomized parent trial, but this is a post hoc subgroup analysis with low event rates so findings are hypothesis-generating rather than definitive.

Study Details

PMID:31629573
Participants:1374
Impact:P for interaction = 0.001
Trust score:3/5

Plasma total homocysteine (2 µg B12)

1 evidences

12-month randomized community trial: low-dose oral B12 (2 or 10 µg/day) significantly lowered plasma homocysteine compared to placebo; folic acid 200 µg/day also reduced homocysteine.

Trust comment: Well-conducted cluster randomized double-blind trial with adequate sample and clear biochemical outcomes.

Study Details

PMID:20216560
Participants:300
Impact:−5.9 µmol/L at 12 months (95% CI −7.8, −4.1)
Trust score:4/5

Cerebral infarction risk

1 evidences

Prospective cohort of male smokers: higher dietary folate (but not vitamin B12) intake was associated with lower risk of cerebral infarction; B12 intake showed no significant association with stroke subtypes.

Trust comment: Large prospective cohort with long follow-up; observational design limits causal inference for B12.

Study Details

PMID:18270369
Participants:26556
Impact:Vitamin B12: no significant association (folate, but not B12, associated with lower risk)
Trust score:4/5

pulse wave velocity (arterial stiffness)

1 evidences

Two years of B-vitamin supplementation (including 500 μg B12) in elderly with elevated homocysteine lowered homocysteine but did not change arterial stiffness (PWV) or carotid IMT.

Trust comment: Large double-blind randomized controlled trial (2919 participants) with clear biochemical effect but no vascular benefit observed.

Study Details

PMID:26147383
Participants:2919
Impact:no change vs placebo
Trust score:4/5

active vitamin B12 (serum)

1 evidences

In elderly people with low B12, whey protein isolate for 8 weeks increased active B12 and serum folate and prevented rises in MMA, homocysteine and genome instability seen with soy protein.

Trust comment: Randomized crossover trial with 56 participants, washout period, and objective biochemical endpoints.

Study Details

PMID:27981743
Participants:56
Impact:increased (p<0.0001) after WPI
Trust score:4/5

methylmalonic acid (MMA) / homocysteine

1 evidences

In elderly people with low B12, whey protein isolate for 8 weeks increased active B12 and serum folate and prevented rises in MMA, homocysteine and genome instability seen with soy protein.

Trust comment: Randomized crossover trial with 56 participants, washout period, and objective biochemical endpoints.

Study Details

PMID:27981743
Participants:56
Impact:no increase with WPI (increases observed with soy control)
Trust score:4/5

plasma TMAO

1 evidences

Vitamin B12 intervention did not change plasma TMAO or related choline metabolites in vegetarians.

Trust comment: Controlled intervention in vegetarians with repeated measures and reported ICCs; moderate sample size.

Study Details

PMID:27562778
Participants:171
Impact:no effect from vitamin B12 intervention
Trust score:4/5

total homocysteine

18 evidences

B-vitamin treatment (including B12) lowered homocysteine and slowed some cognitive decline, especially in those with high baseline homocysteine.

Trust comment: Double-blind randomized trial with adequate sample and clear biomarker and cognitive endpoints, though effects concentrated in subgroup.

Study Details

PMID:21780182
Participants:266
Impact:-30% (mean decrease vs placebo)
Trust score:4/5

Large randomized trial found a modestly greater homocysteine reduction with high-dose B-vitamins but no effect on recurrent stroke, coronary events, or death over 2 years.

Trust comment: Large multicenter double-blind RCT with clinically important endpoints and adequate sample size, supporting high trustworthiness.

Study Details

PMID:14762035
Participants:3680
Impact:~2 µmol/L greater reduction in high-dose vs low-dose group
Trust score:5/5

Randomized trial (VITACOG) in MCI patients: daily B-vitamin supplement (folic acid 0.8 mg, B12 0.5 mg, B6 20 mg) for ~2 years lowered homocysteine and prevented declines in several cognitive measures compared with placebo.

Trust comment: Randomized controlled trial with biochemical, cognitive and imaging measures in MCI patients; moderate sample size and well-characterized outcomes.

Study Details

PMID:33935094
Participants:196
Impact:Decreased from 11.8±3.4 μM to 8.9±2.2 μM in B-vitamin group (Δ ≈ −2.9 μM; p≈7E-13)
Trust score:4/5

In patients with prior TIA/stroke, B-vitamin therapy lowered homocysteine but did not change measured blood markers of inflammation, endothelial dysfunction, or hypercoagulability at 6 months.

Trust comment: Well-powered randomized substudy (n=285) with objective laboratory endpoints; negative results are plausible and clearly reported.

Study Details

PMID:15569860
Participants:285
Impact:-3.7 μmol/L
Trust score:4/5

In older adults, B-vitamin supplementation lowered homocysteine but did not change plasma long-chain n-3 PUFA proportions after 2 years.

Trust comment: Double-blind randomized trial with adequate sample (n=253) and objective biochemical outcomes; methods and results are clearly reported.

Study Details

PMID:18287365
Participants:253
Impact:-4.4 μmol/L
Trust score:4/5

In metabolic syndrome patients, combined folate and B12 therapy lowered homocysteine and improved insulin resistance and several measures of endothelial function over 1 month of B-vitamin treatment.

Trust comment: Randomized double-blind parallel study (n=50) with clear biochemical and functional endpoints, though sample size is modest.

Study Details

PMID:15476449
Participants:50
Impact:-27.8% (12.2 → 8.8 μmol/L)
Trust score:4/5

In elderly subjects, a 12-week supplement containing folic acid and cobalamin improved B-vitamin status and lowered homocysteine, with greater effect in those with higher baseline Hcy.

Trust comment: Randomized double-blind 12-week trial (n=133) with significant biochemical improvements and appropriate subgroup analyses.

Study Details

PMID:36715360
Participants:133
Impact:-3.6 ± 5.7 μmol/L
Trust score:4/5

A prepared meal plan fortified with micronutrients (including recommended B12) for 10 weeks raised folate and vitamin B12 and reduced serum total homocysteine in high‑risk adults.

Trust comment: Large multicenter randomized trial with objective blood biomarkers and clear statistical significance supporting changes in homocysteine and B12.

Study Details

PMID:10539749
Participants:491
Impact:decreased (10.8 → 9.3 µmol/L; p<0.0001, ≈−13.9%)
Trust score:4/5

16-week multivitamin (including B12) raised blood B12 and B6 and produced beneficial changes in homocysteine, CRP and some lipid/oxidative stress markers, but did not improve cognitive test performance in healthy 55–65 y olds.

Trust comment: Randomized double-blind placebo-controlled trials with objective blood biomarkers and adequate sample size by gender, providing credible evidence of B12 level increases from multivitamin supplementation.

Study Details

PMID:25996285
Participants:116
Impact:decreased in men (≈−9.3%; treatment effect observed)
Trust score:4/5

In haemodialysis patients receiving high‑dose folic acid, adding methylcobalamin (intravenous) produced large reductions in fasting total homocysteine (normalization in combined methylcobalamin groups).

Trust comment: Randomized intervention in a clinical population showing large, physiologically meaningful reductions in homocysteine with methylcobalamin plus folic acid; small sample (n=21) but strong biochemical effects.

Study Details

PMID:11981084
Participants:21
Impact:substantially decreased (Group II −57.4% with methylcobalamin+folic acid; Group III −59.9% with methylcobalamin+folic acid+B6; Group I folic acid alone −17.3%)
Trust score:4/5

In chronic hemodialysis patients given folic acid and B vitamins for 3 months, homocysteine and hsCRP fell significantly in non-diabetic patients but not in diabetic patients.

Trust comment: Pre-post treatment in a modest-sized clinical sample with subgroup analysis; useful but not randomized.

Study Details

PMID:21439275
Participants:61
Impact:decreased from 33.63 ±14.13 to 18.94 ±8.46 μmol/L in non-DM (p<0.001); non-significant decrease in DM (34.97 to 29.53 μmol/L, p=0.057)
Trust score:3/5

In recent ischemic stroke patients, one year of folic acid, vitamin B12 and B6 lowered mean plasma homocysteine by 3.8 μmol/L compared with placebo, and MTHFR variants did not modify this benefit.

Trust comment: Large randomized trial in stroke patients with clear endpoints and genotype analysis supports high reliability.

Study Details

PMID:16397167
Participants:443
Impact:mean at 1 year 10.7 μmol/L (vitamin) vs 14.5 μmol/L (placebo); difference 3.8 μmol/L (p<0.0001)
Trust score:5/5

In a controlled feeding RCT (n=118), a combination diet (fruits, vegetables, low‑fat dairy, reduced fat) modestly lowered fasting homocysteine compared with a control diet; changes in serum vitamin B12 were not associated with homocysteine change.

Trust comment: Randomized, controlled feeding trial with rigorous dietary control, moderate sample size and clear biochemical outcome reporting.

Study Details

PMID:10952952
Participants:118
Impact:−0.34 μmol/L with combination diet vs control (P=0.03)
Trust score:4/5

An 8-week multivitamin/mineral supplement raised B-vitamin levels (including B12) and lowered homocysteine in older adults.

Trust comment: Randomized, double-blind, placebo-controlled trial with clear biochemical outcomes, though intervention was a multivitamin rather than isolated B12.

Study Details

PMID:11110875
Participants:80
Impact:-9.6%
Trust score:4/5

In elderly with cobalamin deficiency, high-dose oral cyanocobalamin lowered SAH, MMA, and homocysteine.

Trust comment: Direct cobalamin intervention with biochemical endpoints in a convenience sample; methods solid but generalizability limited.

Study Details

PMID:17158426
Participants:149
Impact:decreased (significant) with high‑dose oral cobalamin
Trust score:3/5

Elderly participants took folic acid or a B-complex (including B12) for ~23 days; B-complex led to lower unmetabolized folic acid than folic acid alone and both raised methylfolate.

Trust comment: Randomized single-blind trial with small elderly sample and short duration (~23 days); results credible but limited by size and short follow-up.

Study Details

PMID:25943647
Participants:58
Impact:declined: median −1.6 µmol/L (FA) and −1.3 µmol/L (B-complex)
Trust score:3/5

Large double-blind randomized trial of B-vitamin supplementation (including B12) after stroke/TIA found it was safe and produced a small, borderline reduction in major vascular events (not clearly clinically significant).

Trust comment: Large, multicenter double-blind placebo-controlled RCT with long follow-up and robust outcome assessment.

Study Details

PMID:20688574
Participants:8164
Impact:decrease (intended biochemical effect; reported lowering vs placebo)
Trust score:5/5

In healthy adults, 6-week supplementation with natural or synthetic B-complex raised blood B-vitamin levels; natural B-complex showed a decrease in homocysteine and larger increases in antioxidant capacity in this small pilot.

Trust comment: Double-blind randomized pilot crossover but small sample and carryover/period effects limited planned analyses, so results are exploratory.

Study Details

PMID:31915511
Participants:29
Impact:-13% at end of supplementation in the natural B group (remained −11% after washout)
Trust score:3/5

coronary flow reserve (CFR)

1 evidences

Folate plus B12 supplementation for 8 weeks improved coronary flow reserve and reduced homocysteine in elderly B12-deficient patients.

Trust comment: Randomized small trial in deficient elderly showing physiologic improvements, but small sample limits generalizability.

Study Details

PMID:20851295
Participants:44
Impact:+0.4 absolute (from 1.7 ± 0.2 to 2.1 ± 0.2; P<0.001)
Trust score:3/5

insulin resistance

1 evidences

Folate plus B12 supplementation for 8 weeks improved coronary flow reserve and reduced homocysteine in elderly B12-deficient patients.

Trust comment: Randomized small trial in deficient elderly showing physiologic improvements, but small sample limits generalizability.

Study Details

PMID:20851295
Participants:44
Impact:improved after supplementation
Trust score:3/5

vitamin B12 level and treatment response

1 evidences

Observational analysis in fluoxetine-resistant MDD patients: baseline low folate predicted poor response, whereas low serum vitamin B12 did not predict treatment outcome.

Trust comment: Small clinical sample with baseline biomarker associations; informative but limited power to detect B12 effects on antidepressant response.

Study Details

PMID:15323594
Participants:55
Impact:no significant association between low vitamin B12 and clinical response to subsequent treatments (p>0.05)
Trust score:3/5

Maternal–infant plasma vitamin B12 correlation (Canada)

1 evidences

In two cohorts, maternal and infant blood B12 concentrations correlated; milk B12 correlated with infant B12 in Canada but not in Cambodia, and most mothers and infants had adequate B12 status.

Trust comment: Secondary analysis of two trials with valid laboratory methods but limited and non-representative samples and some missing measures across specimens.

Study Details

PMID:28287490
Participants:168
Impact:milk–infant correlation r=0.108 (weak); p<0.001
Trust score:3/5

Serum cobalamin concentration

1 evidences

Daily 500 μg cobalamin given sublingually or orally for 4 weeks similarly corrected low serum B12 concentrations.

Trust comment: Randomized study but small sample (n=30) and short duration; results on biochemical correction are clear but limited by size.

Study Details

PMID:14616423
Participants:30
Impact:+~178–195 pmol/L (mean increase)
Trust score:3/5

cognitive function

3 evidences

Twenty-four weeks of high-dose oral B12 (with or without folic acid) corrected biochemical deficiency but did not improve cognitive function.

Trust comment: Well-conducted double-blind randomized trial in older adults with biochemical correction but no cognitive benefit; moderate sample and 24-week duration.

Study Details

PMID:16895884
Participants:195
Impact:no improvement (no benefit)
Trust score:4/5

In stroke patients given high- or low-dose B-vitamin formulations (including B12) for 2 years, homocysteine fell but plasma Abeta and cognition did not change between groups.

Trust comment: Large randomized double-blind trial with defined biochemical and cognitive endpoints; results are directly measured and reported.

Study Details

PMID:19153374
Participants:300
Impact:no association / no change
Trust score:4/5

Substudy of a large RCT in advanced CKD/ESRD testing high-dose B vitamins (including 2 mg B12) vs placebo: vitamins lowered homocysteine but did not improve cognitive outcomes.

Trust comment: Large randomized double-blind trial substudy with clear biochemical effect (tHcy lowering); cognitive assessments limited in timing but showed no benefit.

Study Details

PMID:19628319
Participants:659
Impact:No improvement in cognitive outcomes (initial or 1-year follow-up)
Trust score:4/5

vascular/nonvascular mortality

1 evidences

In MI survivors, folic acid plus B12 lowered homocysteine but did not reduce major vascular events, stroke, or mortality over ~6.7 years.

Trust comment: Large, long-term double-blind randomized trial (12,064 participants) with hard clinical endpoints; high reliability.

Study Details

PMID:20571015
Participants:12064
Impact:no significant difference between groups
Trust score:5/5

eczema severity

1 evidences

Double-blind intraindividual RCT in children showed topical vitamin B12 improved eczema significantly more than placebo at 2 and 4 weeks.

Trust comment: Double-blind randomized design supports validity but small sample (n=21) limits precision and generalizability.

Study Details

PMID:19368512
Participants:21
Impact:significant improvement vs placebo at 2 weeks (p=0.02) and 4 weeks (p=0.01)
Trust score:3/5

ocular surface oxidative stress (lipid peroxidation)

1 evidences

Clinical study in cataract surgery patients: dry eye patients randomized to hyaluronic acid 0.15% plus vitamin B12 eye drops versus no treatment; treatment reduced oxidative stress markers and improved dry-eye clinical scores.

Trust comment: Small randomized clinical study with objective oxidative stress and symptom measures, but limited sample and surgical population context.

Study Details

PMID:25398660
Participants:103
Impact:Significantly reduced after hyaluronic acid + vitamin B12 eye drops compared with untreated dry eye
Trust score:3/5

all-cause mortality

3 evidences

In patients with advanced CKD/ESRD, high-dose folic acid plus B vitamins including cyanocobalamin (B12) lowered homocysteine but did not reduce mortality or major vascular events over ~3.2 years.

Trust comment: Large, multicenter double-blind randomized trial with hard clinical endpoints and long follow-up, high credibility.

Study Details

PMID:17848650
Participants:2056
Impact:no significant difference (448 vs 436 deaths; HR 1.04, 95% CI 0.91–1.18)
Trust score:5/5

4110 kidney transplant recipients randomized to high- vs low-dose folic acid/B6/B12: homocysteine was reduced but there was no reduction in composite cardiovascular outcomes over ~4 years.

Trust comment: Large, double-blind randomized trial with long follow-up showing robust null clinical outcome despite biochemical change.

Study Details

PMID:21482964
Participants:4110
Impact:no effect (HR 1.04; 95% CI 0.86–1.26)
Trust score:5/5

Large prospective cohort showing calcium channel blocker (CCB) use was associated with higher long-term all-cause and CVD mortality; associations were attenuated in patients receiving B-vitamin treatment.

Trust comment: Large, well-characterized prospective cohort with long follow-up and multivariable adjustment, but observational design with possible residual confounding.

Study Details

PMID:37121550
Participants:3991
Impact:CCB-associated HR 1.86 (B‑vitamin non-treated) vs HR 1.16 (B‑vitamin treated) in model 1; association attenuated in treated group
Trust score:4/5

plasma total homocysteine (P-tHcys)

1 evidences

Four-month randomized placebo-controlled trial in elderly people showing B-vitamin supplementation lowers markers of B12/folate deficiency.

Trust comment: Double-blind placebo-controlled RCT in 209 elderly subjects with clear biochemical endpoints and statistically significant results.

Study Details

PMID:14576756
Participants:209
Impact:significant decrease (P<0.001)
Trust score:4/5

plasma homocysteine (background effect)

1 evidences

Large randomized trial protocol in high-risk adults testing folic acid + vitamins B6 and B12 versus placebo with cardiovascular events as the primary outcome.

Trust comment: Large, well-powered randomized trial protocol across many centers; this paper reports design and baseline data rather than outcomes.

Study Details

PMID:16450017
Participants:5522
Impact:expected/observed reduction with combined therapy: ≈25–30% (reported from prior data/assumptions)
Trust score:4/5

8-isoprostane (oxidative stress marker)

1 evidences

Eight-week randomized controlled trial of an antioxidant mix (including vitamin B12) in older adults showing improved executive function and reduced oxidative stress markers versus placebo.

Trust comment: Randomized double-blind RCT with clear cognitive and biomarker endpoints, but the active product is a multi-ingredient mix so effects cannot be attributed to B12 alone.

Study Details

PMID:33375429
Participants:80
Impact:decrease: active group −63.65 pg/mL vs control −4.14 pg/mL; treatment difference −65.31 pg/mL (P<0.0001)
Trust score:4/5

time to complete recovery

1 evidences

Methylcobalamin (vitamin B12 form) shortened time to full facial recovery and improved facial nerve scores compared with steroid alone.

Trust comment: Small randomized open trial showing large effects, but limited by small size and open (non-blinded) design.

Study Details

PMID:8749227
Participants:60
Impact:methylcobalamin 1.95±0.51 wk, methylcobalamin+steroid 2.05±1.23 wk vs steroid 9.60±7.79 wk (≈7.6 wk shorter with methylcobalamin vs steroid)
Trust score:3/5

depressive symptoms (GDS)

1 evidences

Long-term low-dose B-vitamin supplementation (including B12) had no effect on depressive symptoms in cardiovascular disease survivors.

Trust comment: Large randomized factorial trial with long follow-up and adequate sample for secondary analysis (2000), but analysis is ancillary.

Study Details

PMID:22648722
Participants:2000
Impact:no association/no benefit after median 4.7 years of B-vitamin supplementation
Trust score:4/5

folate concentration

1 evidences

In newly diagnosed type 2 diabetes, 6 weeks of metformin decreased vitamin B12 and folate and increased homocysteine; rosiglitazone decreased homocysteine and did not change B12 or folate.

Trust comment: Interventional treatment study with objective biochemical outcomes but short duration (6 weeks) and modest sample size.

Study Details

PMID:17331860
Participants:165
Impact:metformin: -1.04 ng/ml; rosiglitazone: no change
Trust score:3/5

remission of major depression (52 weeks)

1 evidences

Adjunctive B-vitamin supplementation did not change 12-week antidepressant remission but improved sustained response over 52 weeks and reduced relapse risk.

Trust comment: Randomized, double-blind, placebo-controlled trial with adequate follow-up and clinically relevant endpoints.

Study Details

PMID:25257064
Participants:153
Impact:absolute ~+9.7 percentage points (75.8% placebo → 85.5% vitamins); OR=2.49 over 52 weeks
Trust score:5/5

SCORAD index (AD severity)

1 evidences

In 22 mild atopic dermatitis patients using a within-person design, a topical vitamin B12 cream produced a larger reduction in SCORAD than a standard emollient.

Trust comment: Small, single-blind intra-patient randomized trial showing large effect size but limited sample and short-term follow-up.

Study Details

PMID:28677237
Participants:22
Impact:77.6% reduction with B12 cream vs 33.5% with standard emollient at week 12
Trust score:3/5

basal coronary blood flow

1 evidences

Stable CAD patients randomized to folic acid plus vitamin B12 showed increased basal and adenosine-induced coronary blood flow after 24 months versus placebo.

Trust comment: Randomized trial with invasive physiological measures and long follow-up; small sample size reduces generalizability.

Study Details

PMID:21389855
Participants:40
Impact:increased (significant vs placebo at 24 months, p<0.02)
Trust score:4/5

attention

1 evidences

One-year RCT in older adults with MCI: vitamin B (with folate and B6) did not improve cognition.

Trust comment: Randomized placebo-controlled trial with good compliance; well-conducted but found no cognitive benefit from FA/B12/B6 supplementation.

Study Details

PMID:18308888
Participants:152
Impact:no significant change
Trust score:4/5

minimal luminal diameter

1 evidences

Multicenter double-blind RCT after coronary stenting: folate/B6/B12 therapy increased angiographic restenosis and repeat revascularization compared with placebo.

Trust comment: Large, double-blind multicenter RCT showing a statistically significant adverse effect of folate/B-vitamin therapy on restenosis outcomes.

Study Details

PMID:15215483
Participants:636
Impact:decrease (mean 1.59 mm vs 1.74 mm; difference −0.15 mm, P=0.008)
Trust score:5/5

MEP latency/amplitude

1 evidences

Cross-sectional study of older adults comparing low vs normal B12: no central motor conduction differences, but peripheral motor conduction delay in lower limbs with low B12.

Trust comment: Well-conducted cross-sectional neurophysiology study in older adults but observational design limits causal inference.

Study Details

PMID:24694205
Participants:53
Impact:No significant differences
Trust score:3/5

Incidence of age-related macular degeneration (AMD)

1 evidences

Large randomized double-blind trial of folic acid + B6 + B12 vs placebo over ~7.3 years showed reduced incidence of AMD and visually significant AMD in the treatment group.

Trust comment: Large, long-duration randomized double-blind trial showing statistically significant reductions in AMD outcomes with combined B-vitamin therapy.

Study Details

PMID:19237716
Participants:5205
Impact:Reduced (55 cases treatment vs 82 placebo); RR 0.66 (95% CI 0.47–0.93), P=0.02
Trust score:4/5

angiographic progression (minimum lumen diameter / diameter stenosis)

1 evidences

Folic acid/vitamin B12 lowered homocysteine but did not improve angiographic measures and was associated in post hoc analysis with increased odds of rapid progression.

Trust comment: Randomized trial substudy with objective angiographic and biochemical measures and adequate sample, though some findings arise from post hoc analyses.

Study Details

PMID:20494665
Participants:348
Impact:no overall improvement in minimum lumen diameter or diameter stenosis; mean Δ MLD -0.16 mm, Δ stenosis +4.4%
Trust score:4/5

haptocorrin (HC / holoHC)

1 evidences

In Danish lactating mothers, supplemental oral B12 (variable doses) did not change serum B12 or binding proteins over 9 months.

Trust comment: Prospective 9‑month follow‑up (n=89) with mixed supplementation regimens; direct measurements but variable dosing and observational design limit causal inference.

Study Details

PMID:16900082
Participants:89
Impact:total HC increased over time but no difference by supplementation status
Trust score:3/5

itch (pVAS)

1 evidences

Topical vitamin B12 ointment applied twice daily to one hemi‑body significantly reduced psoriasis severity (PASI) and itching versus control emollient.

Trust comment: Randomized intra‑patient left/right controlled trial with direct topical B12 intervention but small sample (n=24); single‑blind design limits blinding.

Study Details

PMID:29048238
Participants:24
Impact:reduced (highly significant improvement during treatment)
Trust score:4/5

rapid viral response (RVR)

1 evidences

Adding oral vitamin B12 to standard peg‑interferon plus ribavirin increased early and sustained virological response rates in treatment‑naïve chronic HCV patients.

Trust comment: Randomized study (n=94) with direct B12 supplementation and multivariate analysis supporting effect, though sample size is modest.

Study Details

PMID:22810757
Participants:94
Impact:no difference between groups
Trust score:4/5

plasma betaine concentration

2 evidences

In elderly people, combined cobalamin (B12) plus folic acid lowered homocysteine and raised betaine, but overall cognitive performance did not improve.

Trust comment: Double-blind, placebo-controlled randomized trial in humans with clear biochemical outcomes, though cognitive changes were not demonstrated.

Study Details

PMID:17537289
Participants:195
Impact:increased by 38% with combined cobalamin + folic acid
Trust score:4/5

Baseline plasma betaine strongly predicted the post-methionine-load rise in homocysteine; B-vitamin supplementation weakened this relation.

Trust comment: Randomized human study with repeated measures and statistical reporting; relevant to B12 as part of multi-vitamin supplementation.

Study Details

PMID:14699020
Participants:90
Impact:median baseline 36.9 μmol/L; increased 15% after methionine loading
Trust score:4/5

effect of B-vitamin supplementation on betaine–tHcy relation

1 evidences

Baseline plasma betaine strongly predicted the post-methionine-load rise in homocysteine; B-vitamin supplementation weakened this relation.

Trust comment: Randomized human study with repeated measures and statistical reporting; relevant to B12 as part of multi-vitamin supplementation.

Study Details

PMID:14699020
Participants:90
Impact:relation between PML tHcy and PML betaine weakened after 3 months of B-vitamin intervention (beta=-0.33, P=0.007)
Trust score:4/5

paresthesia score

1 evidences

Vitamin B12 injections reduced pain, paresthesia and tingling more than nortriptyline in people with painful diabetic neuropathy.

Trust comment: Randomized single-blind trial with 100 completers and statistically strong differences (P<0.001), though single-blind and comparator is an active drug.

Study Details

PMID:19212856
Participants:100
Impact:-2.98 units (vitamin B12 group)
Trust score:4/5

holoTC diagnostic accuracy (AUC)

1 evidences

Holotranscobalamin (holoTC) performed well as a diagnostic marker for early B12 deficiency; a randomized subset received B12 or placebo but primary focus was test evaluation.

Trust comment: Large diagnostic cohort with a randomized injection subset (n=140) but primary aim was assay performance rather than clinical endpoints of supplementation.

Study Details

PMID:15715686
Participants:140
Impact:AUC 0.90 for identifying likely B12 deficiency
Trust score:3/5

plasma total homocysteine (Vit B12 group)

1 evidences

In hemodialysis patients, weekly IV vitamin B12 reduced homocysteine substantially and was similarly effective as low-dose folinic acid; combining both gave the largest decrease.

Trust comment: Randomized trial in 75 chronic HD patients with clear numeric outcomes, though specific long-term clinical endpoints were not reported.

Study Details

PMID:19462276
Participants:75
Impact:-29.3% after 3 months
Trust score:4/5

endothelial dysfunction markers (e.g., VCAM-1, ICAM-1, vWF)

1 evidences

In patients with prior TIA/stroke, B-vitamin therapy lowered homocysteine but did not change measured blood markers of inflammation, endothelial dysfunction, or hypercoagulability at 6 months.

Trust comment: Well-powered randomized substudy (n=285) with objective laboratory endpoints; negative results are plausible and clearly reported.

Study Details

PMID:15569860
Participants:285
Impact:no significant change
Trust score:4/5

holo-transcobalamin (Holo-TC)

1 evidences

In elderly subjects, a 12-week supplement containing folic acid and cobalamin improved B-vitamin status and lowered homocysteine, with greater effect in those with higher baseline Hcy.

Trust comment: Randomized double-blind 12-week trial (n=133) with significant biochemical improvements and appropriate subgroup analyses.

Study Details

PMID:36715360
Participants:133
Impact:+17 ± 19 pmol/L
Trust score:4/5

blood pressure / pulse

1 evidences

Three-arm randomized trial (drink powder with betaine + B‑vitamins, UNIMMAP multivitamin, control) in 298 women; both supplements substantially lowered plasma homocysteine versus control, drink powder > UNIMMAP.

Trust comment: Well-powered randomized controlled trial with objective biochemical primary outcome, high compliance, and appropriate analyses.

Study Details

PMID:31408467
Participants:298
Impact:no meaningful change compared with control
Trust score:5/5

bone resorption marker (collagen fragments)

1 evidences

Two-year randomized trial in older adults (subgroup with baseline homocysteine >15 μmol/L n=135) showing B‑vitamin supplementation lowered homocysteine but did not change bone turnover biomarkers.

Trust comment: Large, long-duration randomized controlled trial with clear biochemical outcomes and subgroup biomarker measurements.

Study Details

PMID:17284744
Participants:135
Impact:no significant change
Trust score:5/5

need for target lesion revascularization

1 evidences

After coronary angioplasty, patients given folic acid, vitamin B12 and B6 had lower homocysteine and less restenosis and revascularization vs placebo.

Trust comment: Prospective double-blind randomized trial (n=205) showing significant clinical and biomarker effects but intervention was a combined folate/B12/B6 formula so effects cannot be attributed to B12 alone.

Study Details

PMID:11757505
Participants:205
Impact:-11.5 percentage points (22.3%→10.8%)
Trust score:4/5

laxative use

1 evidences

In nursing-home residents, adding oat-bran reduced laxative use and was associated with slower decline in plasma B12 compared with control; homocysteine fell in both groups.

Trust comment: Small controlled parallel intervention (n=30) with objective measures but limited sample size and indirect effect on B12 (dietary fiber influence rather than B12 supplementation).

Study Details

PMID:20191257
Participants:30
Impact:decreased in fiber group (p<0.001)
Trust score:3/5

plasma vitamin B12 (baseline)

1 evidences

In unstable angina patients with high homocysteine, folic acid supplementation markedly lowered homocysteine and improved brachial artery flow-mediated dilation over 8 weeks.

Trust comment: Controlled clinical measurements with vascular outcome but subgroup treated (n≈22) and modest sample for endothelial measures.

Study Details

PMID:19491420
Participants:82
Impact:lower in UA patients versus controls at baseline
Trust score:3/5

therapy-specific adverse effects

1 evidences

A 12-week randomized double-blind trial found benfotiamine plus B6/B12 improved peroneal nerve conduction in diabetic polyneuropathy with trends in vibration sense.

Trust comment: Double-blind randomized design but very small sample (n=24) limits generalizability.

Study Details

PMID:8886748
Participants:24
Impact:none observed
Trust score:3/5

pain (Visual Analogue Scale)

1 evidences

Intramuscular methylcobalamin given three times weekly for two weeks improved pain and disability at two months versus placebo in chronic nonspecific low back pain.

Trust comment: Double-blind randomized controlled trial with low dropout (58 reviewed) showing clinically relevant patient-reported outcomes.

Study Details

PMID:22159928
Participants:58
Impact:decreased (significant vs placebo at 2 months)
Trust score:4/5

dietary vitamin B12 intake

3 evidences

Six-month lifestyle modification program with structured nutrition counseling increased intake of multiple micronutrients including vitamin B12 and improved glycemic indices in adults with prediabetes.

Trust comment: Interventional lifestyle study with measured dietary intake showing a significant increase in vitamin B12 intake, though intake was assessed by dietary recall rather than biomarkers.

Study Details

PMID:31731609
Participants:139
Impact:increase (significant; between-group P=0.041)
Trust score:3/5

Cluster-RCT assessing dietary intakes over 12 months in children given LNS (contains multiple micronutrients) vs control; dietary recalls used.

Trust comment: Cluster-randomized trial with repeated dietary recalls showing improved nutrient intakes; intake changes documented but clinical outcomes not provided.

Study Details

PMID:25819697
Participants:298
Impact:Increased from baseline more in the LNS arm than in controls across follow-up visits (magnitude not specified)
Trust score:3/5

In a small randomized subsample, an 8-week whole-food plant-based diet reduced weight, HbA1c and several cardiometabolic risk factors but decreased intake of some micronutrients including vitamin D and calcium.

Trust comment: Randomized trial but this analysis is a small subsample (n=37) using self-reported dietary records, limiting precision for intake estimates.

Study Details

PMID:36364858
Participants:37
Impact:significantly decreased in plant-based group and fell below D-A-CH recommended intake (below DRI)
Trust score:3/5

complete recovery rate of oculomotor nerve palsy

1 evidences

In patients with oculomotor nerve palsy after PcomA embolization, adding mecobalamin to embolization was associated with higher complete recovery rates at one year compared with embolization alone.

Trust comment: Non-randomized comparative treatment groups with one-year follow-up and statistically significant differences, but potential for selection bias and limited sample (n=55).

Study Details

PMID:26221889
Participants:55
Impact:higher with embolization + mecobalamin: 71.4% vs 40.7% (difference ≈ +30.7 percentage points; p<0.05)
Trust score:3/5

plasma glutathione (GSH/GSSG)

1 evidences

A 12-week double-blind crossover trial of injectable methyl B12 in children with autism found no significant group-level behavioral or glutathione changes, though a subgroup (~30%) showed clinical improvement with increased glutathione.

Trust comment: Double-blind crossover design is strong but small sample size (n=30) and pilot scope limit generalizability.

Study Details

PMID:20804367
Participants:30
Impact:increased in clinical responders (≈30% of participants); responders showed associated clinical improvement
Trust score:3/5

serum folic acid / methylcobalamin levels

1 evidences

Type 2 diabetes patients randomized to folic acid, methylcobalamin, both, or control for 12 weeks: methylcobalamin (and combinations) reduced plasma homocysteine and increased HTase/PON activity, with the greatest homocysteine reduction seen with methylcobalamin alone.

Trust comment: Randomized human trial with 120 participants showing substantial, dose-specific biochemical effects of methylcobalamin and folic acid; moderate-to-high internal validity though group sizes were modest (n≈30).

Study Details

PMID:17425871
Participants:120
Impact:increased (significant)
Trust score:4/5

methionine-loading test normalization

1 evidences

In haemodialysis patients receiving high‑dose folic acid, adding methylcobalamin (intravenous) produced large reductions in fasting total homocysteine (normalization in combined methylcobalamin groups).

Trust comment: Randomized intervention in a clinical population showing large, physiologically meaningful reductions in homocysteine with methylcobalamin plus folic acid; small sample (n=21) but strong biochemical effects.

Study Details

PMID:11981084
Participants:21
Impact:normalized in groups receiving methylcobalamin (post-treatment)
Trust score:4/5

inflammatory markers (neopterin, sCD40L, IL-6, CRP)

1 evidences

In stable CAD patients, B-vitamin regimens (including B12) lowered homocysteine but did not change inflammatory markers after 6 months.

Trust comment: Double-blind randomized 2x2 factorial trial with objective biomarkers but relatively small sample for clinical endpoints.

Study Details

PMID:17645592
Participants:90
Impact:no significant change after 6 months
Trust score:4/5

neuropathy symptom scores (TCSS, TSS, VAS)

1 evidences

In 40 diabetic neuropathy patients, both methylcobalamin and alpha-lipoic acid reduced neuropathy symptoms over 2 weeks; ALA improved antioxidant markers while methylcobalamin improved some sensory deficits.

Trust comment: Randomized small trial (N=40) with short 2-week follow-up and both subjective and objective measures; limited duration and sample size.

Study Details

PMID:27901334
Participants:40
Impact:decreased (significant) after 2 weeks
Trust score:3/5

depressive symptoms (CES-D score)

1 evidences

Women given folic-acid-containing multi-micronutrients (including zinc) for 12 weeks had lower average depressive symptoms and lower depression prevalence; no difference between weekly vs daily dosing and no baseline association between zinc and depression.

Trust comment: Large randomized controlled trial (N=459) but used combined micronutrient interventions, so independent effect of B12 cannot be isolated.

Study Details

PMID:19886513
Participants:459
Impact:decreased by 2.3 points (mean) post-intervention
Trust score:4/5

MTHFR genotype response

1 evidences

In 50 hemodialysis patients with high homocysteine, regimens including monthly B12 injections plus folic acid and B6 significantly lowered plasma homocysteine; high and low B-vitamin dose regimens had similar efficacy.

Trust comment: Randomized prospective study with clear biochemical endpoints but modest sample size (N=50); results internally consistent.

Study Details

PMID:15115259
Participants:50
Impact:greater percent reduction in homozygous thermolabile MTHFR (58% decrease) vs heterozygous (34% decrease)
Trust score:4/5

other micronutrients (iron, zinc, vitamin A, riboflavin)

1 evidences

Undernourished Kenyan schoolchildren ate a daily school meal with meat, milk, or energy for one year; meat and milk raised B12 status.

Trust comment: Large randomized school-meal trial with measured biochemical outcomes though infections may have confounded some effects.

Study Details

PMID:14672298
Participants:555
Impact:no significant improvement vs control
Trust score:4/5

vitamin B6

1 evidences

Case-control study measuring one-carbon metabolites in recurrent MDD found no clear association of vitamin B12 with MDD, though homocysteine was higher and vitamin B6 lower during depressive episodes.

Trust comment: Moderately sized observational case-control study (patients n=137, controls n=73) that measured multiple metabolites; associations are observational and state-dependent.

Study Details

PMID:25012419
Participants:210
Impact:decreased during depressed state (statistically significant)
Trust score:3/5

hemoglobin rise

1 evidences

Adding cobalamin to iron and folic acid in children produced a greater hemoglobin increase compared with iron and folic acid alone.

Trust comment: Randomized pediatric trial with clear hematologic endpoints and adequate sample, but limited reporting of exact magnitude in abstract.

Study Details

PMID:22415494
Participants:150
Impact:Greater Hb increase at 2, 4 and 8 weeks with cobalamin added; significant difference at 4 and 8 weeks (percent Hb rise significantly higher, p≈0.00)
Trust score:4/5

spontaneous pain

1 evidences

Mecobalamin treatment improved neuropathic symptoms and some nerve function measures in diabetic patients versus control vitamin B12 regimen.

Trust comment: Randomized clinical trial with clear symptom improvements, but details on blinding and full methodology are limited in the excerpt.

Study Details

PMID:11798619
Participants:108
Impact:improved in 73% (mecobalamin) vs 36% (control) — approx +37 percentage points
Trust score:3/5

stimulus-induced EEG delta power

1 evidences

Healthy volunteers received B‑vitamins for 1 week before testing pain; no detectable effect of B‑vitamins on analgesia was found.

Trust comment: Well-designed placebo-controlled double-blind crossover in healthy volunteers (n=38) with objective measures, but small sample and negative result for B‑vitamins.

Study Details

PMID:7609864
Participants:38
Impact:no effect detected (changes attributable to diclofenac, independent of B‑vitamin)
Trust score:4/5

motor function scores

1 evidences

Older adults with low cobalamin received IM cyanocobalamin or no treatment; cognitive results were mixed with no clear consistent benefit.

Trust comment: Randomized trial in older adults (n=50) with biochemical deficiency but small sample, no placebo control, and mixed/weak effects limits strength of conclusions.

Study Details

PMID:9777425
Participants:50
Impact:some motor scores worse in supplement group at follow‑up
Trust score:3/5

platelet monoamine oxidase B (MaoB) expression

1 evidences

Randomized dietary intervention in healthy young men comparing usual vs high-protein meat diet and measuring platelet proteome, cognitive function, and methylation-cycle components including vitamin B12.

Trust comment: Randomized intervention with controlled diet and biochemical measures but small sample size limits generalizability.

Study Details

PMID:21424576
Participants:23
Impact:-26% (significant decrease) after high-protein diet
Trust score:3/5

reaction time (cognitive performance)

1 evidences

Randomized dietary intervention in healthy young men comparing usual vs high-protein meat diet and measuring platelet proteome, cognitive function, and methylation-cycle components including vitamin B12.

Trust comment: Randomized intervention with controlled diet and biochemical measures but small sample size limits generalizability.

Study Details

PMID:21424576
Participants:23
Impact:Shortened (improved) and correlated with decrease in MaoB (r=0.477)
Trust score:3/5

incidence of grade ≥2 hand-foot syndrome

1 evidences

Multicentre double-blind randomized placebo-controlled phase 3 trial testing oral methylcobalamin versus placebo to prevent grade ≥2 capecitabine-induced hand-foot syndrome in women with HER2-negative early breast cancer.

Trust comment: Large multicentre double-blind randomized phase 3 trial with clear primary endpoint and robust statistics, providing high-quality evidence for methylcobalamin's preventive effect.

Study Details

PMID:40935571
Participants:234
Impact:Methylcobalamin 12.0% vs placebo 24.8%; risk difference −12.8% (95% CI −22.6% to −3.0%)
Trust score:5/5

treatment-related dose reduction/discontinuation due to hand-foot syndrome

1 evidences

Multicentre double-blind randomized placebo-controlled phase 3 trial testing oral methylcobalamin versus placebo to prevent grade ≥2 capecitabine-induced hand-foot syndrome in women with HER2-negative early breast cancer.

Trust comment: Large multicentre double-blind randomized phase 3 trial with clear primary endpoint and robust statistics, providing high-quality evidence for methylcobalamin's preventive effect.

Study Details

PMID:40935571
Participants:234
Impact:Lower in methylcobalamin group (7.7% vs 13.7% total reduction/discontinuation related to HFS) but not statistically significant for overall capecitabine modifications
Trust score:5/5

CMAP amplitude (compound muscle action potential)

1 evidences

Ultrahigh-dose methylcobalamin increased compound muscle action potential amplitudes in ALS patients at 4 weeks; low-dose showed no change.

Trust comment: Double-blind controlled trial but small sample (24) and short follow-up limits generalizability.

Study Details

PMID:9843082
Participants:24
Impact:+ significant increase at 4 weeks with ultrahigh-dose; no significant change with low-dose
Trust score:3/5

serum homocyst(e)ine

1 evidences

Intravenous cobalamin with folate and B6 markedly raised serum B12 and reduced serum homocysteine when given two or three times weekly in hemodialysis patients.

Trust comment: Small (n=33) intervention with three dosing regimens; biochemical outcomes reported but limited sample size and short follow-up.

Study Details

PMID:11426667
Participants:33
Impact:decrease: -39.8%±31.9% (twice weekly) and -30.1%±26.9% (three times weekly); no reduction with once weekly
Trust score:3/5

radiotherapy interruption

1 evidences

Inhalation of a vitamin B12 mixed solution improved symptoms of acute radiation-induced mucosal injury and facilitated uninterrupted radiotherapy compared with gentamycin inhalation.

Trust comment: Moderate-sized comparative clinical study (n=122) but methodological details and randomization/blinding not fully described.

Study Details

PMID:16624769
Participants:122
Impact:allowed uninterrupted radiotherapy in B12 group vs 8 suspensions in gentamycin group
Trust score:3/5

urinary function (URF)

1 evidences

Randomized trial comparing mecobalamin (1,500 µg/day) versus no mecobalamin after nerve-sparing prostatectomy; no significant improvement in urinary or sexual function, with a non-significant early urinary recovery trend.

Trust comment: Small randomized controlled trial with objective endpoints but likely underpowered; results were mostly non-significant.

Study Details

PMID:19198223
Participants:54
Impact:+18.8 points at 3 months (85.7 vs 66.9); no significant difference overall
Trust score:3/5

temporal orientation (prior stroke subgroup)

1 evidences

Ancillary analysis of a large randomized trial (n=1748) found no overall cognitive benefit after 4 years of B-vitamin (including B12) and/or omega-3 supplementation; a subgroup with prior stroke showed reduced odds of decline in temporal orientation (OR 0.43).

Trust comment: Large, randomized trial with long follow-up; subgroup/ancillary findings warrant cautious interpretation.

Study Details

PMID:21593490
Participants:1748
Impact:reduced odds of decline (OR 0.43)
Trust score:4/5

Red blood cell (RBC) transfusions

1 evidences

An ultra-short preoperative combination (IV iron, erythropoietin, subcutaneous B12, oral folic acid) reduced perioperative transfusions and raised early haemoglobin and reticulocyte markers.

Trust comment: Large randomized trial with clinically meaningful endpoints, but effects derive from a multi-agent combination so B12-specific contribution is not isolated.

Study Details

PMID:31036337
Participants:1006
Impact:Median first 7 days: placebo 1 unit (IQR 0–3) vs treatment 0 units (0–2); OR 0.70 for transfusion thresholds, p=0.036
Trust score:4/5

effect of folic acid in participants with low folate and B12

1 evidences

Large randomized trial of folic acid in hypertensive adults showing baseline higher B12 (and folate) associated with lower first ischemic stroke risk and that folic acid supplementation reduced stroke risk especially in subgroups defined by low B12/folate and MTHFR genotype.

Trust comment: Large randomized trial with long follow-up and prespecified endpoints; strong evidence of interaction between B12/folate status and stroke risk/treatment effect.

Study Details

PMID:31932513
Participants:20702
Impact:reduced stroke incidence 2.3% vs 3.6%; HR 0.62 (95% CI 0.46–0.86)
Trust score:5/5

modification by vitamin B12 status

1 evidences

Population-based randomized folic acid trial in women of reproductive age that estimated a plasma folate threshold for NTD prevention; vitamin B12 deficiency substantially modified the plasma–RBC folate relation and the estimated plasma threshold.

Trust comment: Randomized supplementation trial with robust modeling showing that vitamin B12 status modifies folate biomarkers and thresholds relevant to NTD prevention.

Study Details

PMID:31005964
Participants:1673
Impact:low B12 substantially increases pf-IT (i.e., alters plasma–RBC folate relation)
Trust score:4/5

arterial stiffness (PWV)

1 evidences

Cross-sectional analysis in older adults (n=567) found no association between B‑vitamin biomarkers (including B12) or a genetic hyperhomocysteinemia score and arterial stiffness (PWV); observed a homocysteine–gene interaction.

Trust comment: Well-characterized cross‑sectional baseline analysis with moderate sample size but observational design limits causal inference.

Study Details

PMID:24656138
Participants:567
Impact:no association with vitamin B12 or folate levels
Trust score:3/5

pain intensity

2 evidences

Randomized trial found that local methylcobalamin plus lidocaine injections (especially if given 4–7 days after rash onset) reduced pain faster and improved quality of life in acute herpetic neuralgia versus control regimens.

Trust comment: Well-conducted randomized trial with adequate sample and clear, clinically relevant outcomes using methylcobalamin (direct B12 form).

Study Details

PMID:26814241
Participants:204
Impact:mean pain scores decreased (IE-Tr 2.4 ±0.7; ES-Tr 1.3 ±0.7) — significant vs controls
Trust score:4/5

Local methylcobalamin plus lidocaine injections shortened healing times, produced large and sustained pain reductions, and reduced postherpetic neuralgia incidence in acute ophthalmic herpetic neuralgia.

Trust comment: Randomized controlled trial with clear clinical endpoints and significant effects, though single-center and short-term.

Study Details

PMID:26200815
Participants:98
Impact:mean pain reduced to 2.6 (A1) vs 7.0 (A0) and 1.2 (B1) vs 5.6 (B0) (significant)
Trust score:4/5

NSS+NDS (neuropathy symptoms + disability)

1 evidences

Multicenter double-blind RCT showed methylcobalamin (MC) was effective in improving neuropathic symptom and disability scores and neurophysiological parameters in diabetic peripheral neuropathy and was non-inferior to acetyl-L-carnitine.

Trust comment: High-quality multicenter, randomized, double-blind trial directly testing methylcobalamin with robust outcomes and low dropout.

Study Details

PMID:27180954
Participants:204
Impact:decrease from baseline to week 24: MC group -3.46 ±3.43 (significant)
Trust score:5/5

worst pain severity

2 evidences

Single-center RCT found local methylcobalamin injections reduced pain and improved quality of life in subacute herpetic neuralgia versus oral or lidocaine comparators.

Trust comment: Direct methylcobalamin intervention in an RCT, but single-center and modest sample size with limited numeric detail reported here.

Study Details

PMID:23566267
Participants:98
Impact:significant reduction vs comparators (P<0.05)
Trust score:3/5

Randomized trial in 90 postherpetic neuralgia patients showing TENS plus local cobalamin injections reduced pain and improved activities of daily living and quality of life.

Trust comment: Randomized controlled trial in humans with clear, clinically relevant outcomes and significant results; single-center and moderate sample size limits generalizability.

Study Details

PMID:24196971
Participants:90
Impact:Mean endpoint pain 4.0±1.4 (TENS+cobalamin); 28 participants achieved ≥30% pain reduction in cobalamin group; comparator (TENS+lidocaine) endpoint mean 6.1±1.2 with 6 participants ≥30% reduction.
Trust score:4/5

hs-CRP (inflammation)

2 evidences

Randomized study adding mecobalamin to standard care in ischemic stroke patients with H-type hypertension and measuring homocysteine, inflammation, plaques and function over 6 months.

Trust comment: Randomized clinical study with adequate sample size (n=224) showing consistent biomarker changes, but some reporting ambiguities and lack of detailed magnitude limit certainty.

Study Details

PMID:30304141
Participants:224
Impact:significantly lower in treatment group at 4 weeks–6 months (P<0.01)
Trust score:3/5

In a 3-month open-label randomized study in hemodialysis patients, folic acid plus B-complex lowered homocysteine and CRP and increased albumin and vitamin B12.

Trust comment: Open-label randomized study with modest sample size and biochemical outcomes but potential bias due to lack of blinding.

Study Details

PMID:17605895
Participants:121
Impact:decrease (directional; significant)
Trust score:3/5

lipid oxidative damage (lipid hydroperoxide)

1 evidences

Randomized trial of a 16-week combined training exercise program in PLHIV assessing homocysteine and oxidative stress markers; vitamin levels were measured but not supplemented.

Trust comment: Randomized exercise trial with clear pre/post biomarker changes in a small PLHIV subgroup (n randomized=30); vitamin B12 was measured but not the intervention, so B12-specific effects are indirect.

Study Details

PMID:30861351
Participants:30
Impact:reduction observed in hyperhomocysteinemic PLHIV after exercise
Trust score:3/5

global cognitive score

1 evidences

In older women with CVD/risk factors, combined B-vitamin supplementation did not change cognitive decline overall; possible benefit in those with low dietary B-vitamin intake.

Trust comment: Large randomized placebo-controlled trial sub-study with repeated measures; results are robust though findings limited to a subgroup for dietary intake.

Study Details

PMID:19064521
Participants:2009
Impact:difference in change 0.03 (95% CI -0.03 to 0.08), P=0.30 (no significant effect)
Trust score:4/5

plasma homocysteine normalization

1 evidences

In hemodialysis patients, adding methylcobalamin to folate normalized homocysteine more often and reduced ADMA and arterial stiffness more than folate alone over 3 weeks.

Trust comment: Small randomized trial with objective biomarker endpoints but open-label, short duration and no long-term clinical outcomes.

Study Details

PMID:20430500
Participants:40
Impact:90% (18/20) vs 30% (6/20) (P<0.001) favoring methylcobalamin
Trust score:3/5

TML level

1 evidences

In PCI patients, baseline ADMA and TML were independently associated with angiographic CAD progression; moderate-dose folic acid plus vitamin B12 lowered homocysteine but did not change median ADMA or TML.

Trust comment: Well-conducted randomized trial sub-study with objective angiographic measures and biomarker assays; moderate sample size and appropriate analyses.

Study Details

PMID:23734218
Participants:183
Impact:baseline TML associated with DS progression (multivariate); FA/B12 did not alter TML percentiles (no median change)
Trust score:4/5

vertigo (adverse event)

1 evidences

Gabapentin combined with vitamins B1 and B12 reduced neuropathic pain similarly to pregabalin, with some differences in adverse events and sleep improvements.

Trust comment: Large randomized multicenter trial with ITT/PPP populations and appropriate analyses; open-label design and combination therapy limit attribution to B12 alone.

Study Details

PMID:26885528
Participants:270
Impact:less frequent with GBP+B1/B12 versus pregabalin (statistically significant, p=0.014)
Trust score:4/5

accelerated epigenetic aging (biological > chronological age)

1 evidences

In older adults, adding B-vitamins to vitamin D plus calcium changed methylation at some aging-related CpG sites and was associated with higher odds of accelerated epigenetic aging after 1 year.

Trust comment: Randomized supplementation trial but small sample and modest effect sizes; results are preliminary and require replication.

Study Details

PMID:29395637
Participants:63
Impact:higher odds with D+Ca+B vs D+Ca (OR 5.26; 95% CI 1.51–18.28)
Trust score:3/5

disability (QBPDS / ABPS)

1 evidences

In an open randomized trial, adding neuromultivit (multivitamin containing B vitamins) to standard therapy for L5-S1 vertebrogenic radiculopathy produced greater improvements in pain and disability than basic therapy alone.

Trust comment: Randomized but open-label trial with limited reported numeric outcomes and single-country report; risk of bias from lack of blinding.

Study Details

PMID:29171487
Participants:100
Impact:Greater improvement vs control (p<0.05)
Trust score:3/5

effect of B‑vitamin supplementation on Hcy‑thiolactone

1 evidences

Higher urinary Hcy-thiolactone (normalized to creatinine) predicted increased risk of incident acute myocardial infarction in CAD patients; folic acid and B‑vitamin supplementation did not change urinary Hcy-thiolactone.

Trust comment: Large prospective cohort (n>2000) with robust adjustment and consistent findings; high reliability for the biomarker–outcome association.

Study Details

PMID:30193001
Participants:2049
Impact:No significant change in urinary Hcy‑thiolactone/creatinine after 12 or 38 months of folic acid and/or B‑vitamin supplementation
Trust score:5/5

homocysteine-lowering (B‑vitamins added)

1 evidences

A multistep strategy including pravastatin, vitamin E and B‑vitamins had no overall effect on plasma ADMA in stage 2–4 CKD; vitamin E alone was associated with a small ADMA decrease.

Trust comment: Randomized placebo-controlled trial but secondary analysis with small sample and limited power for ADMA outcomes.

Study Details

PMID:18786751
Participants:93
Impact:B‑vitamin component did not produce an overall ADMA change in this cohort
Trust score:3/5

neuromas (number)

1 evidences

Oral vitamin B1 plus mecobalamin improved corneal subbasal nerve parameters and several dry eye symptoms over 1–3 months compared with artificial tears alone.

Trust comment: Randomized, double-blind controlled trial with objective IVCM measures and consistent symptom improvements; follow-up relatively short (3 months).

Study Details

PMID:36145126
Participants:199
Impact:Improved (reduced) at 1 and 3 months (p<0.05)
Trust score:4/5

folate status

2 evidences

Long-term folic acid–based multivitamin therapy consistently lowered plasma total homocysteine by ~3–4 μmol/L at 6 months across recruitment periods despite rising baseline folate status.

Trust comment: Randomized double-blind placebo-controlled trial with measured biomarkers and adequate sample for biochemical endpoints.

Study Details

PMID:15608435
Participants:285
Impact:Baseline red cell folate rose over 1998–2002, but tHcy-lowering effect of therapy remained
Trust score:4/5

Fortifying school meals with a multinutrient premix for 8 months improved vitamin A and folate status, increased total body iron, and lessened the decline in vitamin B12 among schoolchildren.

Trust comment: Large, cluster-randomized placebo-controlled trial with objective biomarkers, but B12 was a low-dose component of a multi-micronutrient mix limiting attribution to B12 alone.

Study Details

PMID:20410083
Participants:499
Impact:Fewer children with low folate in treatment vs control (OR 0.47, 95% CI 0.26–0.84)
Trust score:4/5

memory (cognitive tests)

1 evidences

Children given multiple-micronutrient fortified salt (includes iodine) had better blood nutrient markers and improved memory compared with iodized-salt controls.

Trust comment: Randomized controlled trial in residential schools with biochemical and cognitive endpoints and adequate sample size.

Study Details

PMID:20533221
Participants:402
Impact:Significant improvement in memory tests in experimental vs control (p<0.05)
Trust score:4/5

number of arterial 'hot spots' on PET

1 evidences

Long-term B-vitamin therapy (including B12 0.5 mg) lowered plasma homocysteine but did not change arterial wall inflammation by FDG-PET.

Trust comment: Randomized double-blind trial with long follow-up but small sample size limits generalizability.

Study Details

PMID:19202330
Participants:30
Impact:no significant change with treatment (p = 0.65)
Trust score:4/5

patient functionality (>5-point improvement)

1 evidences

Adding diclofenac-cholestyramine to nucleotides + hydroxycobalamin for 10 days reduced pain and improved function versus nucleotides + hydroxycobalamin alone.

Trust comment: Randomized double-blind RCT with clear pain and function effects, but vitamin B12 (hydroxycobalamin) was present in both arms so B12-specific effects are not isolated.

Study Details

PMID:22128442
Participants:81
Impact:80% (DN) vs 29.3% (NB); +50.7 percentage points (DN vs NB) after 10 days
Trust score:4/5

other nutritional markers (folate, ferritin, zinc)

1 evidences

In adults with overweight/obesity, two high-protein meal-replacement programs (with or without alternate day fasting) produced similar ~11% weight loss and improved metabolic markers; vitamin D levels decreased modestly in both groups by week 16.

Trust comment: Randomized controlled trial with objective biochemical measures showing increased B12 (meal replacements supplied B12); B12 effect is intervention-associated but not isolated.

Study Details

PMID:30142886
Participants:164
Impact:significant increases at week 16 vs baseline (p<0.05)
Trust score:4/5

elevated plasma homocysteine prevalence

1 evidences

Cross‑sectional comparison found vegans had lower plasma vitamin B12 and higher prevalence of elevated homocysteine compared with omnivores and vegetarians.

Trust comment: Observational cross‑sectional study with modest sample sizes; associations plausible but cannot infer causality.

Study Details

PMID:16988496
Participants:118
Impact:66% of vegans vs ~45–50% of omnivores and vegetarians had elevated homocysteine
Trust score:3/5

global DNA methylation

1 evidences

In a crossover feeding study, a traditional Korean diet higher in one‑carbon nutrients (including B12) reduced homocysteine more than the control diet and increased global DNA methylation in peripheral blood mononuclear cells.

Trust comment: Controlled crossover dietary intervention with objective methylation and metabolite measures; small sample but within‑subject design strengthens internal validity.

Study Details

PMID:38867083
Participants:52
Impact:increased from 6.70% to 9.45% in K‑diet group (p<0.0001)
Trust score:4/5

length of hospital stay

1 evidences

Daily oral multi-nutrient supplements for 6 weeks improved nutrition and reduced non-elective readmissions in older hospitalized patients.

Trust comment: Large randomized double-blind RCT with clear clinical endpoints, but used a multi-nutrient supplement so effects cannot be attributed to B12 specifically.

Study Details

PMID:16887416
Participants:445
Impact:-0.7 days (9.4 vs 10.1 days)
Trust score:4/5

gingival index

1 evidences

A two-month adjunctive multi-vitamin supplement reduced gingival inflammation and probing depths in patients with chronic periodontitis compared with placebo.

Trust comment: Randomized trial but small sample and multi-ingredient supplement limit attribution to B12 specifically.

Study Details

PMID:11913269
Participants:63
Impact:decrease (statistically significant)
Trust score:3/5

cobalamin bound to haptocorrin (Cbl-HC)

1 evidences

Women with PCOS on metformin experienced a decrease in serum cobalamin after six months, but other functional markers (holoTC, MMA) did not indicate deficiency.

Trust comment: Direct human study measuring multiple cobalamin biomarkers with appropriate assays but limited by small sample size and short follow-up.

Study Details

PMID:23857221
Participants:29
Impact:Significant decrease (4 months p=0.012; 6 months p=0.0009)
Trust score:4/5

milk cobalamin concentration

1 evidences

A single bolus maternal lipid-based nutrient supplement increased milk cobalamin concentration and infant cobalamin intake over 8 hours compared with control.

Trust comment: Randomized crossover design with objective milk and intake measures in 26 dyads; small sample but within-subject design increases reliability.

Study Details

PMID:32649760
Participants:26
Impact:+32% (0.041 → 0.054 μg·min⁻¹·mL⁻¹; Bolus vs Control; P=0.039)
Trust score:4/5

gross motor z-score

1 evidences

Children with moderate acute malnutrition received food supplements; serum cobalamin rose during 3 months of supplementation but many remained marginal.

Trust comment: Large randomized factorial trial with objective biochemical and developmental measures; cobalamin was a secondary outcome and some serum data were missing.

Study Details

PMID:35263343
Participants:1548
Impact:SC <112 pmol/L associated with −0.24 in gross motor z-score (95% CI −0.42 to −0.06, p=0.01)
Trust score:4/5

serum cobalamin (cobalamin)

1 evidences

A 6-month RCT of a multivitamin/trace element formula increased cobalamin and other vitamins and reduced homocysteine in healthy volunteers.

Trust comment: Randomized double-blind trial with objective biomarkers and good completion, but multicomponent supplement limits attribution to B12 alone.

Study Details

PMID:25789594
Participants:142
Impact:increased (p=0.001)
Trust score:3/5

antioxidant markers (e.g., tocopherol)

1 evidences

A 6-month RCT of a multivitamin/trace element formula increased cobalamin and other vitamins and reduced homocysteine in healthy volunteers.

Trust comment: Randomized double-blind trial with objective biomarkers and good completion, but multicomponent supplement limits attribution to B12 alone.

Study Details

PMID:25789594
Participants:142
Impact:increased (p<0.001)
Trust score:3/5

PBMC cystatin C mRNA

1 evidences

In hyperhomocysteinaemic individuals, 3 months of B-vitamin treatment increased plasma cystatin C and cystatin C mRNA in PBMCs compared with placebo.

Trust comment: Randomized, placebo-controlled double-blind trial showing biochemical changes; small sample size limits generalizability but design is strong.

Study Details

PMID:19682403
Participants:37
Impact:increased after B-vitamin treatment vs placebo
Trust score:4/5

fasting insulin

1 evidences

Identical twins randomized to vegan vs omnivorous diets for 8 weeks; vegans had lower LDL, insulin and weight; serum B12 fell numerically but was not significantly different.

Trust comment: Well-conducted randomized twin RCT with small sample and short duration; measured B12 but change was not statistically significant.

Study Details

PMID:38032644
Participants:42
Impact:−2.9 μIU/mL
Trust score:4/5

Diastolic blood pressure

1 evidences

Randomized double-blind placebo-controlled ascending-dose trial showed hydroxocobalamin generally well tolerated but associated with transient BP increases and self-limited discoloration and rash.

Trust comment: Well-designed randomized, placebo-controlled safety trial with substantial sample and clear objective safety endpoints.

Study Details

PMID:16990190
Participants:136
Impact:mean max increase +14.3 to +25.4 mmHg across doses (vs -3.0 to +3.8 mmHg placebo)
Trust score:5/5

zinc deficiency prevalence

1 evidences

Cross-sectional baseline data in early pregnancy showed high prevalence of vitamin B12 deficiency and that anemia was associated with B12 deficiency rather than iron deficiency.

Trust comment: Large, population-based baseline analysis with standard lab measures but observational design limits causal inference about B12 effects.

Study Details

PMID:21275915
Participants:740
Impact:55% zinc deficient
Trust score:3/5

vitamin B12 intake

9 evidences

Randomized trial comparing GUMLi formula vs cows' milk in toddlers; reports nutrient intake differences including higher vitamin D intake in the GUMLi group.

Trust comment: Multi-centre, double-blind randomized trial with 160 infants and repeated dietary measures; direct dietary intake assessed.

Study Details

PMID:30912737
Participants:160
Impact:decreased (intervention vs control)
Trust score:4/5

6-week RCT in healthy men replacing most red/processed meat with legumes; studied nutrient intakes and biomarkers including iodine intake and urinary iodine excretion.

Trust comment: Well-conducted randomized dietary trial with good compliance and nutritional biomarkers, but short duration (6 weeks) limits long-term conclusions about B12 status.

Study Details

PMID:40828321
Participants:102
Impact:Vitamin B12 intake lower in LEGUME vs MEAT at endpoint (4.7 vs 7.1 µg/d, P<0.001)
Trust score:4/5

Overweight adults ate one of three diets for 6 months; vitamin B12 intake was lower on the high-simple carbohydrate diet but still met recommendations.

Trust comment: Randomized controlled dietary intervention in humans with clear intake assessment (7-day weighed food record) but modest sample size.

Study Details

PMID:14749754
Participants:46
Impact:decreased on SCHO vs CCHO and CD (statistically significant, P=0.025 and P=0.012) but remained above recommended levels
Trust score:4/5

Increasing milk intake in older adults raised vitamin B12 intake and eliminated B12 inadequacy in women over 12 weeks.

Trust comment: Randomized controlled trial (n=204) with clear dietary intervention and measured nutrient intake changes; B12 increase is direct and quantifiable.

Study Details

PMID:10916520
Participants:204
Impact:increased; prevalence of B12 inadequacy in women decreased from 6% to 0% at 12 weeks
Trust score:4/5

RCT (n=70 allocated, 68 completed) of tailored progressive dietary advice plus new complete dentures vs standard care in edentulous elders, assessing nutritional status (MNA) and nutrient intake at 3 months.

Trust comment: Single-blind RCT, registered and completed with 68 participants; outcomes well-reported though dietary intake changes (including vitamin B12) were not significant, limiting conclusions about B12 specifically.

Study Details

PMID:40227937
Participants:68
Impact:increased (higher in intervention vs control but not statistically significant)
Trust score:4/5

Twelve weeks of a nutrient-dense drink (contains 250 mg calcium/serving) increased energy and micronutrient intake and improved body weight and some muscle mass in older outpatients at risk of malnutrition.

Trust comment: Randomized controlled trial, registered and with low dropout and good compliance; not double-blind but outcomes objectively measured and statistically significant for nutrient intake.

Study Details

PMID:40154078
Participants:101
Impact:+1.3 mcg/day (intervention delta vs control, p<0.001)
Trust score:4/5

Provision of one egg daily to infants increased several nutrient intakes—including vitamin B12—and reduced B12 inadequacy compared with controls, though many micronutrient gaps remained.

Trust comment: Large randomized controlled trial (n=660) with rigorous dietary assessment and appropriate statistical modelling; findings on B12 intake and adequacy are direct and reliable.

Study Details

PMID:33974324
Participants:660
Impact:+0.24 µg/day (midline, egg vs control); +0.34 µg/day (endline); prevalence of inadequacy midline 1% vs 16%, endline 0% vs 14% (egg vs control)
Trust score:5/5

Randomized 22-week trial in people with type 2 diabetes comparing a low-fat vegan diet vs ADA diet; both groups reported decreased vitamin D intake and the vegan group improved overall diet quality.

Trust comment: Randomized controlled dietary trial with clear reporting of nutrient-intake changes including vitamin B12, though B12 was assessed as intake (not biomarkers) and no supplementation was tested.

Study Details

PMID:18926128
Participants:99
Impact:decrease (significant) in vegan group (reported reduction; exact value not provided)
Trust score:3/5

A 4-week low FODMAP diet delivered by a dietitian altered some nutrient intakes in IBS patients, including higher reported vitamin B12 intake.

Trust comment: Randomized trials with dietitian-delivered interventions measured nutrient intake; B12 intake increase was reported but not clinical B12 status.

Study Details

PMID:31029650
Participants:130
Impact:6.1 μg/day on low FODMAP vs 3.9 μg/day habitual (+2.2 μg/day) and vs 4.7 μg/day sham (+1.4 μg/day)
Trust score:3/5

vitamin B12 effect (trend)

1 evidences

Pilot randomized placebo-controlled trial in cancer patients found no significant effect of a B-group vitamin on clinician-assessed neuropathy score, but patients reported less sensory neuropathy on patient questionnaires.

Trust comment: Randomized placebo-controlled pilot with objective and patient-reported outcomes but small analyzable sample and pilot design limit reliability.

Study Details

PMID:27612466
Participants:47
Impact:Trend suggesting B12 may reduce onset/severity of CIPN (not conclusive)
Trust score:3/5

Overall sensory acceptability

1 evidences

Women evaluated taste/acceptability of salt fortified with iodine and other micronutrients; QFS was well accepted.

Trust comment: Well-designed randomized crossover with objective and subjective acceptability measures but small sample and only acceptability (no health outcomes) assessed.

Study Details

PMID:39490799
Participants:77
Impact:QFS mean 7.8 vs DFS 7.7 on 9-point scale (P=0.68; no difference)
Trust score:3/5

Serum vitamin B12 concentration (total intake)

1 evidences

Cross-sectional analysis in older Dutch adults linking vitamin B12 intake from different food sources to serum B12 and related biomarkers.

Trust comment: Large sample with validated FFQ and biochemical measures supports associations, but cross-sectional design limits causal inference.

Study Details

PMID:26389945
Participants:600
Impact:Adjusted mean increased from 250 to 287 pmol/L across tertiles of total B12 intake (P for trend=0.009)
Trust score:4/5

Folic acid effect on CKD progression (high B12)

1 evidences

Post hoc analysis of a CKD substudy evaluating whether baseline B12 status modifies the effect of folic acid treatment on CKD progression.

Trust comment: Large randomized parent trial, but this is a post hoc subgroup analysis with low event rates so findings are hypothesis-generating rather than definitive.

Study Details

PMID:31629573
Participants:1374
Impact:OR 0.17 (95% CI 0.07–0.40) for enalapril+folic acid vs enalapril alone among B12 ≥248 pmol/L
Trust score:3/5

Modification of neurological response by baseline B12

1 evidences

Secondary analysis of the OPEN RCT intervention arm testing whether baseline or change in B12 status modified neurological response to B12 supplementation in older adults.

Trust comment: High-quality parent RCT data but small secondary-analysis sample and heterogeneous, inconsistent outcome associations reduce confidence.

Study Details

PMID:28225050
Participants:91
Impact:No consistent evidence that baseline B12 status modified neurological response to supplementation
Trust score:3/5

depression score

2 evidences

Randomized placebo-controlled trial in adults with elevated MMA testing whether B12 treatment improved cognitive scores or depression over 3 months.

Trust comment: Randomized placebo-controlled design with biomarker-selected participants is strong, but short 3-month follow-up limits detection of longer-term effects.

Study Details

PMID:15337331
Participants:140
Impact:No improvement; P = 0.18 (treatment vs placebo)
Trust score:4/5

A multivitamin containing B12 improved depressive symptoms but did not change anxiety in men receiving methadone maintenance.

Trust comment: Double‑blind randomized trial but small, male‑only sample and limited reporting of effect sizes.

Study Details

PMID:37256965
Participants:70
Impact:improved (significant between‑group difference favoring multivitamin)
Trust score:3/5

C-reactive protein (CRP)

2 evidences

In acute ischemic stroke patients, short-term B‑group vitamin supplementation (including B12) was associated with reduced oxidative damage and inflammation markers compared with no supplementation.

Trust comment: Randomized small trial (n=48) with combined B‑vitamin intervention; results suggest antioxidant/anti-inflammatory effects but B12-specific effects cannot be isolated.

Study Details

PMID:15279619
Participants:48
Impact:lower in treatment group compared with controls (P<0.05)
Trust score:3/5

In a 2-year randomized trial subsample, daily vitamin B12 (500 µg) plus folic acid did not change endothelial or inflammation biomarkers versus placebo in elderly with high homocysteine.

Trust comment: Large randomized trial subsample with measured biomarker outcomes; results show no significant effects.

Study Details

PMID:26774115
Participants:522
Impact:+26% vs +36% (no significant difference, p=0.70)
Trust score:4/5

Global DNA methylation (CpG islands/shores)

1 evidences

Secondary analysis of intervention datasets: folic acid + vitamin B12 supplementation altered global DNA methylation patterns and reduced epigenetic age in a genotype- and sex-dependent manner (notably in women with MTHFR 677CC).

Trust comment: Small secondary analysis of existing methylation datasets with subgroup effects; hypothesis-generating rather than definitive.

Study Details

PMID:30350398
Participants:44
Impact:Increased after folic acid + B12 supplementation (in unmethylated regions)
Trust score:3/5

ferritin / iron deficiency incidence

1 evidences

An RCT of RYGB patients found that an optimized multivitamin (WLS Forte) produced fewer iron and B12 deficiencies versus standard MVS; both groups received substantial vitamin D (total ~1200 IU/day) with similar 25-OHD levels at 12 months.

Trust comment: Triple-blind randomized controlled trial with 148 patients and predefined biochemical outcomes; some participants received additional corrective supplements which may confound results.

Study Details

PMID:25437032
Participants:148
Impact:1.3% (WLS Forte) vs 10.7% (sMVS); mean ferritin −18.4 μg/L (sMVS) vs stable (WLS Forte)
Trust score:4/5

weight / BMI

1 evidences

In obese adults on a weight-loss diet, synbiotic tablets increased vitamin D and B12 levels but both groups lost similar weight.

Trust comment: Randomized single-center trial with 110 participants and short follow-up; effects reported vs baseline without detailed absolute B12 change.

Study Details

PMID:40192559
Participants:110
Impact:decreased in both groups with no difference between groups
Trust score:3/5

folate plasma level

1 evidences

In healthy older adults, adding probiotic VSL#3 to a personalized anti-inflammatory diet for 8 weeks increased plasma vitamin B12 and folate and decreased homocysteine compared with diet alone.

Trust comment: Open-label randomized multicenter study with small N (62) and short duration; biomarker changes significant but clinical relevance needs longer follow-up.

Study Details

PMID:25453395
Participants:62
Impact:increased (p=0.007) with VSL#3
Trust score:3/5

high-density lipoprotein (HDL) cholesterol

1 evidences

Daily low-dose B vitamins (including B12) for 12 months reduced Framingham risk score and increased HDL, with effects reversing after stopping.

Trust comment: Large double-blind RCT with clinically relevant endpoints and sustained follow-up, though combined B-vitamin formulation confounds B12-specific effects.

Study Details

PMID:24916013
Participants:390
Impact:+9.2% at 12 months (0.11 increase; P=0.003)
Trust score:4/5

uncoupling ratio (formation/resorption)

1 evidences

A 24‑week RCT of fortified milk (providing ~1008 mg Ca/day) plus exercise improved vitamin B‑12 and 25(OH)D levels and reduced bone turnover markers versus control.

Trust comment: Well-conducted RCT with good sample and biochemical measures, but intervention combined nutrition and exercise (effects not solely attributable to B12).

Study Details

PMID:32588047
Participants:163
Impact:greater in intervention (median 0.70) vs control (median −0.11), p<0.001
Trust score:4/5

serum vitamin B12 concentration (biomarker response)

1 evidences

Ancillary analysis of a large RCT of low-dose B-vitamin supplementation (including B12) in CVD survivors found no overall QOL benefit and a small worsening in emotional role limitations.

Trust comment: Large randomized trial but this is an ancillary QOL analysis with low B12 dose and composite B-vitamin treatment, limiting attribution to B12 alone.

Study Details

PMID:24465438
Participants:2029
Impact:~+35% increase in serum vitamin B12 associated with B-vitamin treatment at end of trial (reported as biomarker change)
Trust score:3/5

breast milk vitamin B12 concentration

2 evidences

Cross-sectional study of lactating Kenyan women found low breast milk B12 concentrations in most women and no association with reported household hunger or recent animal-source food or B12 intake.

Trust comment: Well-conducted cross-sectional measurement with adequate sample but observational design and dietary-report limitations restrict causal inference.

Study Details

PMID:27075905
Participants:286
Impact:median 113 pmol/L (IQR 61–199); 89% <310 pmol/L (estimated adequacy cutoff)
Trust score:3/5

Measured multiple vitamins in breast milk including B12 and found that most vitamins (except thiamin after fortification) were low relative to infant Adequate Intakes, implying low milk B12 concentrations for many mothers.

Trust comment: Direct measurement study with modest sample size and clear reporting of milk vitamin concentrations.

Study Details

PMID:32211800
Participants:68
Impact:many samples below infant Adequate Intake (insufficient for infants)
Trust score:3/5

Neurologic and cognitive function

1 evidences

One-year daily 1 mg oral B12 in older adults raised blood B12 but did not improve nerve conduction or cognitive tests.

Trust comment: Large, double-blind randomized trial with high adherence and objective outcomes; low risk of bias.

Study Details

PMID:26135351
Participants:191
Impact:no change
Trust score:5/5

Hip fracture incidence

2 evidences

Two-year treatment with folate plus mecobalamin (vitamin B12) lowered homocysteine and substantially reduced hip fracture incidence in elderly post-stroke patients.

Trust comment: Large randomized trial with 2-year follow-up showing clinically meaningful fracture reduction, though intervention combined folate and B12 (not B12 alone).

Study Details

PMID:15741530
Participants:559
Impact:reduced (RR 0.20; absolute risk reduction 7.1%; NNT=14)
Trust score:4/5

In 8,164 patients with recent stroke or TIA randomized to daily B-vitamins (including B12) versus placebo, B-vitamin therapy lowered homocysteine but did not significantly change the incidence of osteoporotic fractures over ~3.4 years.

Trust comment: Large, well-conducted randomized double-blind trial with long follow-up and biochemical confirmation of homocysteine lowering, but underpowered for modest fracture effects.

Study Details

PMID:24004645
Participants:8164
Impact:34 (0.83%) B-vitamins vs 36 (0.88%) placebo; RR 0.94 (95% CI 0.59–1.50), not significant
Trust score:5/5

plasma vitamin B-12

2 evidences

Fortified rice increased plasma vitamin B12, lowered homocysteine, and improved physical performance in school children after 6 months.

Trust comment: Randomized double-blind controlled trial in 258 children with biochemical and performance endpoints; good design though limited to one setting.

Study Details

PMID:22437556
Participants:258
Impact:increased (significant, P<0.001)
Trust score:4/5

Undernourished Kenyan schoolchildren ate a daily school meal with meat, milk, or energy for one year; meat and milk raised B12 status.

Trust comment: Large randomized school-meal trial with measured biochemical outcomes though infections may have confounded some effects.

Study Details

PMID:14672298
Participants:555
Impact:increased (significant) in Meat and Milk groups
Trust score:4/5

physical performance

2 evidences

Fortified rice increased plasma vitamin B12, lowered homocysteine, and improved physical performance in school children after 6 months.

Trust comment: Randomized double-blind controlled trial in 258 children with biochemical and performance endpoints; good design though limited to one setting.

Study Details

PMID:22437556
Participants:258
Impact:improved (significant, P<0.05)
Trust score:4/5

In older adults doing resistance exercise, adding low-dose dairy protein plus micronutrients (including 200 IU vitamin D/day) increased muscle mass but did not further improve physical performance.

Trust comment: Randomized controlled trial with objective DXA measures (n=82); multi-nutrient supplement includes B12 so effects cannot be attributed solely to B12.

Study Details

PMID:29300423
Participants:82
Impact:no additional improvement vs RE only
Trust score:4/5

homocysteine remethylation rate

1 evidences

In pregnant women with low B12, combined B12 plus protein-energy supplementation tended to increase homocysteine remethylation rates in late pregnancy.

Trust comment: Randomized intervention in pregnant women with metabolic tracer outcomes; moderate sample size and mechanistic endpoints.

Study Details

PMID:28446631
Participants:93
Impact:M+B-12: 5.1±1.7 vs M+P: 4.1±1.0 and P: 5.0±1.4 μmol·kg⁻¹·h⁻¹ (trend, P=0.057)
Trust score:4/5

cognitive domains (memory, attention, processing, executive)

1 evidences

Two-year daily folic acid + vitamin B12 lowered homocysteine but did not improve cognitive domain scores; very small difference in global cognition possibly by chance.

Trust comment: Large multicenter double-blind RCT with objective outcomes and high sample size, providing high-quality evidence.

Study Details

PMID:25391305
Participants:2919
Impact:no significant between-group differences over 2 years
Trust score:5/5

attention/processing speed (SDMT)

1 evidences

Randomized trial (VITACOG) in MCI patients: daily B-vitamin supplement (folic acid 0.8 mg, B12 0.5 mg, B6 20 mg) for ~2 years lowered homocysteine and prevented declines in several cognitive measures compared with placebo.

Trust comment: Randomized controlled trial with biochemical, cognitive and imaging measures in MCI patients; moderate sample size and well-characterized outcomes.

Study Details

PMID:33935094
Participants:196
Impact:Placebo group decline (37.1→35.4, p=0.002) prevented in B-vitamin group (no significant change)
Trust score:4/5

Ocular Surface Disease Index (OSDI) symptom score

1 evidences

Clinical study in cataract surgery patients: dry eye patients randomized to hyaluronic acid 0.15% plus vitamin B12 eye drops versus no treatment; treatment reduced oxidative stress markers and improved dry-eye clinical scores.

Trust comment: Small randomized clinical study with objective oxidative stress and symptom measures, but limited sample and surgical population context.

Study Details

PMID:25398660
Participants:103
Impact:Significant decrease after treatment vs untreated dry eye
Trust score:3/5

cognition (ADAS-cog)

1 evidences

In people with mild–moderate Alzheimer's on cholinesterase inhibitors, add-on multivitamin including mecobalamin (B12) for 26 weeks lowered homocysteine but produced no cognitive or ADL benefit.

Trust comment: Randomized double-blind placebo-controlled trial in humans with reported exact biomarker changes; moderate sample size supports reasonable trust.

Study Details

PMID:18042476
Participants:89
Impact:no significant change vs placebo at 26 weeks
Trust score:4/5

serum holotranscobalamin (holoTC)

1 evidences

Double-blind randomized placebo-controlled trial in elderly people showed dose-dependent biomarker improvements with B12 supplements, but even 500 μg/day for 8 weeks left a minority with persistent metabolic abnormalities.

Trust comment: Double-blind randomized controlled intervention with clear biomarker endpoints in humans (n=100); good internal validity for biomarker effects.

Study Details

PMID:23236022
Participants:100
Impact:improved with dose; after 500 μg/d, 12% remained abnormal
Trust score:4/5

activities of daily living / quality of life

1 evidences

Single-center randomized trial of local injections for herpetic itching found injected cobalamin (B12) significantly relieved pain and improved daily activities and quality of life compared with controls.

Trust comment: Randomized controlled single-center trial with small groups (n≈20 per arm); results suggest benefit but sample size and single-center design limit generalizability.

Study Details

PMID:23887347
Participants:80
Impact:improved in cobalamin and combination groups (P<0.001)
Trust score:3/5

serum CTX-1 (s-CTX-1)

1 evidences

Premenopausal Indian women taking a multi-micronutrient, protein-rich supplement containing calcium had improved bone turnover markers and some micronutrient status after 6 months.

Trust comment: Well-designed double-blind RCT with pre-specified primary endpoints and adequate reporting, though some between-group differences were not significant.

Study Details

PMID:33530298
Participants:102
Impact:decrease: −33% (test) vs −23% (control) at 6 months
Trust score:4/5

general health (SF-36)

1 evidences

In people with biochemical signs of B12 deficiency, B12 injections produced improvement in one SF-36 domain (general health) but no change in seven other quality-of-life dimensions.

Trust comment: Randomized placebo-controlled double-blind study with clear outcome measures but modest sample size and limited to individuals with only biochemical signs of deficiency.

Study Details

PMID:12542554
Participants:140
Impact:significant improvement vs placebo (P=0.03)
Trust score:4/5

plasma methylmalonic acid

2 evidences

Elderly people with food-bound B12 malabsorption given very low oral B12 doses for 30 days showed dose-related increases in serum B12.

Trust comment: Randomized double-blind trial with clear dose–response for serum B12 but moderate sample size.

Study Details

PMID:17237314
Participants:67
Impact:between-subject differences (not a log-dose effect reported)
Trust score:4/5

A single intramuscular hydroxycobalamin injection in infants with biochemical B12 impairment rapidly corrected biomarkers and improved motor scores and regurgitation.

Trust comment: Double-blind randomized controlled trial in humans with objective biochemical and clinical outcomes and clear effects.

Study Details

PMID:24025626
Participants:79
Impact:decreased by 84%
Trust score:5/5

overall cognition

1 evidences

One-year RCT in older adults with MCI: vitamin B (with folate and B6) did not improve cognition.

Trust comment: Randomized placebo-controlled trial with good compliance; well-conducted but found no cognitive benefit from FA/B12/B6 supplementation.

Study Details

PMID:18308888
Participants:152
Impact:no significant change
Trust score:4/5

repigmentation rate

1 evidences

Randomized study in stable vitiligo patients: narrowband UVB effective; adding B12+folic acid provided no additional benefit.

Trust comment: Small randomized study showing no added effect of B12+folate on UVB-induced repigmentation; limited power due to small sample.

Study Details

PMID:12430737
Participants:27
Impact:no significant difference (UVB vs UVB+ B12/folate)
Trust score:3/5

Central motor conduction time (CMCT)

1 evidences

Cross-sectional study of older adults comparing low vs normal B12: no central motor conduction differences, but peripheral motor conduction delay in lower limbs with low B12.

Trust comment: Well-conducted cross-sectional neurophysiology study in older adults but observational design limits causal inference.

Study Details

PMID:24694205
Participants:53
Impact:No significant difference between low and normal B12 groups
Trust score:3/5

Depressive symptoms (PHQ-9)

2 evidences

Older adults received folic acid + vitamin B12 or placebo (factorial RCT); folic acid + B12 did not reduce depressive symptoms over follow-up.

Trust comment: Large factorial randomized controlled trial with good follow-up showing no preventive effect of folic acid+B12 on depressive symptoms.

Study Details

PMID:20592433
Participants:909
Impact:No significant reduction at 6 weeks, 6, 12, or 24 months
Trust score:4/5

Community older adults received folic acid+B12 or placebo; supplementation did not clearly enhance antidepressant effects on depressive symptoms.

Trust comment: Randomized trial with adequate sample size and repeated measures though effect sizes were small.

Study Details

PMID:20805005
Participants:900
Impact:no significant interaction of supplement with antidepressant use over time
Trust score:4/5

LDL cholesterol

4 evidences

In this pilot randomized trial, adding folic acid/vitamin B12 lowered homocysteine while simvastatin reduced LDL, and there was no antagonistic interaction.

Trust comment: Randomized pilot study with clear biochemical endpoints but short duration and modest size limits generalizability.

Study Details

PMID:11079257
Participants:141
Impact:-55.2% (combination) and -51.5% (simvastatin alone)
Trust score:3/5

6-week RCT in healthy men replacing most red/processed meat with legumes; studied nutrient intakes and biomarkers including iodine intake and urinary iodine excretion.

Trust comment: Well-conducted randomized dietary trial with good compliance and nutritional biomarkers, but short duration (6 weeks) limits long-term conclusions about B12 status.

Study Details

PMID:40828321
Participants:102
Impact:LDL cholesterol decreased in LEGUME group and increased in MEAT group (between-group P<0.001)
Trust score:4/5

A targeted medical nutrition therapy increased folate (and B6 and B12) levels and substantially reduced serum lipids in hyperlipidemic patients, while plasma homocysteine was unchanged.

Trust comment: Randomized small trial with clear clinical endpoints and dietary counseling, but limited by modest sample size and short-term follow-up (12 weeks).

Study Details

PMID:19083486
Participants:40
Impact:−14.5% after MNT vs control
Trust score:3/5

Identical twins randomized to vegan vs omnivorous diets for 8 weeks; vegans had lower LDL, insulin and weight; serum B12 fell numerically but was not significantly different.

Trust comment: Well-conducted randomized twin RCT with small sample and short duration; measured B12 but change was not statistically significant.

Study Details

PMID:38032644
Participants:42
Impact:−13.9 mg/dL
Trust score:4/5

sustained viral response (SVR)

1 evidences

Adding oral vitamin B12 to standard peg‑interferon plus ribavirin increased early and sustained virological response rates in treatment‑naïve chronic HCV patients.

Trust comment: Randomized study (n=94) with direct B12 supplementation and multivariate analysis supporting effect, though sample size is modest.

Study Details

PMID:22810757
Participants:94
Impact:SVR significantly higher with B12 supplementation (p=0.001); vitamin B12 supplementation independently associated with SVR (OR=6.9, 95% CI 2.0–23.6)
Trust score:4/5

relative contribution of B12

1 evidences

In hemodialysis patients, consecutive folic acid and vitamin B12 treatments lowered homocysteine; the decrease depended on MTHFR genotype and was larger when starting with folic acid.

Trust comment: Randomized, blinded study in humans with clear outcomes and genotype stratification, though substantial mortality reduced numbers.

Study Details

PMID:16391331
Participants:148
Impact:vitamin B12 provided a secondary (smaller) contribution to lowering tHcy compared with folic acid
Trust score:4/5

coagulation measures (INR, APTT, PT)

1 evidences

Patients given folic acid plus B12 had lower homocysteine, improved coagulation parameters and much lower DVT recurrence than untreated patients.

Trust comment: Randomized clinical comparison with clear clinical endpoints but single-center and limited methodological detail reported.

Study Details

PMID:28617530
Participants:90
Impact:INR first standard/stable times higher in treatment; APTT and PT lower in treatment group (p<0.05)
Trust score:3/5

plasma homocysteine (tHcy)

2 evidences

Three months of folic acid plus small doses of B-vitamins including B12 improved folate and lowered homocysteine in children but did not change cognitive test scores.

Trust comment: Double-blind randomized controlled trial in children with biochemical outcomes and adequate sample but short intervention duration for cognitive effects.

Study Details

PMID:24481688
Participants:237
Impact:decreased by 1.1 μmol/L compared to baseline in the intervention group (P<0.0001)
Trust score:4/5

In unstable angina patients with high homocysteine, folic acid supplementation markedly lowered homocysteine and improved brachial artery flow-mediated dilation over 8 weeks.

Trust comment: Controlled clinical measurements with vascular outcome but subgroup treated (n≈22) and modest sample for endothelial measures.

Study Details

PMID:19491420
Participants:82
Impact:-20.3% at 4 weeks; -55.3% at 8 weeks (in UA patients with hyperhomocysteinaemia)
Trust score:3/5

contextual recognition memory

1 evidences

Daily multivitamin supplementation for 8 weeks increased vitamin B12 and folate levels, lowered homocysteine, and improved contextual recognition memory in older men.

Trust comment: Well-controlled RCT but uses a multinutrient product, so improvements cannot be solely attributed to vitamin B12.

Study Details

PMID:22711385
Participants:51
Impact:improved (p < 0.05)
Trust score:3/5

post-ischemic maximal hyperemic vasodilation

1 evidences

In metabolic syndrome patients, combined folate and B12 therapy lowered homocysteine and improved insulin resistance and several measures of endothelial function over 1 month of B-vitamin treatment.

Trust comment: Randomized double-blind parallel study (n=50) with clear biochemical and functional endpoints, though sample size is modest.

Study Details

PMID:15476449
Participants:50
Impact:+29.8%
Trust score:4/5

depression severity (HDRS)

1 evidences

In depressed patients, adding folic acid to fluoxetine reduced homocysteine and improved depression scores, while vitamin B12 levels did not change.

Trust comment: Small randomized trial with clinical and biochemical endpoints but limited sample size (27) reducing precision.

Study Details

PMID:18716414
Participants:27
Impact:Lower HDRS at 6 weeks with folic acid (7.43 vs 11.43; between-group difference ≈−4.0 points)
Trust score:3/5

Dementia Rating Scale

1 evidences

A multi-nutrient formulation including vitamin B12 produced short-term improvements in some cognitive test scores vs placebo in patients with Alzheimer's disease.

Trust comment: Double-blind randomized phase II trial with positive cognitive outcomes, but formulation contained multiple active agents so effects cannot be ascribed to B12 specifically.

Study Details

PMID:25589719
Participants:106
Impact:improved vs placebo (p=0.0266; 95% CI [0.1722,2.7171])
Trust score:3/5

grade 4 neutropenia incidence

1 evidences

Folate plus vitamin B12 given with pemetrexed was associated with a tolerable safety profile in Japanese patients and allowed an increased MTD and recommended dose compared with historic non‑supplemented data.

Trust comment: Phase I open-label trial with small treated cohort (n=31); findings show improved tolerability with folate/B12 co‑administration but lack randomized control and rely on historical comparisons.

Study Details

PMID:16940981
Participants:31
Impact:3% (1/31 patients experienced grade 4 neutropenia)
Trust score:3/5

peroneal nerve conduction velocity

1 evidences

A 12-week randomized double-blind trial found benfotiamine plus B6/B12 improved peroneal nerve conduction in diabetic polyneuropathy with trends in vibration sense.

Trust comment: Double-blind randomized design but very small sample (n=24) limits generalizability.

Study Details

PMID:8886748
Participants:24
Impact:increased (significant, p=0.006)
Trust score:3/5

other B vitamins (B1, B2, B6, B9)

1 evidences

In a randomized double-blind crossover pilot, both natural and synthetic B-complex supplements raised serum B vitamins (including B12) and reduced homocysteine and some metabolic markers.

Trust comment: Randomized double-blind crossover design but small pilot sample (n=30) limits precision and external validity.

Study Details

PMID:32189314
Participants:30
Impact:increased (varied by natural vs synthetic preparations)
Trust score:3/5

quantitative heel ultrasound (bone measure)

1 evidences

Randomized trial in aged care residents: a daily multivitamin raised serum 25(OH)D and improved a heel ultrasound bone measure, with a trend to fewer falls.

Trust comment: Randomized controlled trial in institutionalized older adults with objective nutrient and bone outcomes; moderate sample size and clinically relevant biomarker changes.

Study Details

PMID:18043700
Participants:92
Impact:increased (adjusted mean difference +3.0 dB·MHz⁻¹ vs −2.9 in placebo; P=0.041)
Trust score:4/5

depressed/anxious mood

1 evidences

Lower blood B12 levels were associated with higher self-reported and clinically rated depression and anxiety.

Trust comment: Moderate-quality observational study showing associations in a defined sample but cannot prove causation.

Study Details

PMID:10719135
Participants:159
Impact:inverse association (lower B12 associated with greater depression/anxiety; not quantified)
Trust score:3/5

neuropsychological performance (Wisconsin Card Sort)

1 evidences

Schizophrenic patients with high homocysteine received B vitamins and showed lower homocysteine and better clinical and cognitive scores versus placebo.

Trust comment: Randomized double-blind placebo-controlled crossover in human patients; good design and reported significant clinical and cognitive improvements.

Study Details

PMID:16412989
Participants:42
Impact:improved (significant)
Trust score:4/5

motor and sensory nerve conduction velocity (MCV, SCV)

1 evidences

Diabetic neuropathy patients receiving electroacupuncture plus methylcobalamin injection had better nerve conduction and symptom scores than those receiving methylcobalamin injection alone.

Trust comment: Randomized 60-patient clinical observation with clear outcome measures but likely unblinded and both groups received methylcobalamin, limiting attribution solely to B12.

Study Details

PMID:21823284
Participants:60
Impact:greater increase with combined therapy (significant)
Trust score:3/5

motor function

1 evidences

Benfotiamine (alone or with B6 and B12) improved vibration perception, motor function and overall neuropathy symptoms in patients with alcoholic polyneuropathy over 8 weeks.

Trust comment: Multicenter, randomized, placebo-controlled double-blind trial with 84 completers supports moderate-high reliability.

Study Details

PMID:9872352
Participants:84
Impact:significant improvement during study
Trust score:4/5

MTHFR genotype interaction

1 evidences

In recent ischemic stroke patients, one year of folic acid, vitamin B12 and B6 lowered mean plasma homocysteine by 3.8 μmol/L compared with placebo, and MTHFR variants did not modify this benefit.

Trust comment: Large randomized trial in stroke patients with clear endpoints and genotype analysis supports high reliability.

Study Details

PMID:16397167
Participants:443
Impact:no significant modification of tHcy-lowering effect by C677T or A1298C
Trust score:5/5

MGMT promoter methylation (CpG4)

1 evidences

Among elderly Chileans exposed to folic acid fortification, high serum folate was associated with increased DNA methylation in specific CpG sites of p16, MLH1 and MGMT, while low vitamin B12 showed no significant association with methylation.

Trust comment: Well-characterized cross-sectional study with comprehensive assays but observational design limits causal inference.

Study Details

PMID:28748002
Participants:249
Impact:high folate associated with OR 3.91 for increased methylation (CpG4); low vitamin B12 showed no significant association
Trust score:3/5

Depressive symptoms

2 evidences

Hospitalised older patients given a daily oral nutritional supplement (including vitamins) had improved depressive symptoms at 6 months but no cognitive change.

Trust comment: Well-conducted double-blind RCT with clear outcome on depressive symptoms, though effect is from a multinutrient supplement rather than isolated B12.

Study Details

PMID:17662509
Participants:225
Impact:significant reduction at 6 months (between-group p=0.021)
Trust score:4/5

Dietary advice improved depressive symptoms but did not increase serum vitamin B12 after six months, likely due to poor adherence.

Trust comment: Randomized trial but small sample and insufficient adherence limited detectable changes in micronutrient levels.

Study Details

PMID:25726209
Participants:77
Impact:improved in intervention group (+)
Trust score:3/5

grade I-II neurotoxicity incidence

1 evidences

Adding mecobalamin to glutathione during FOLFOX4 chemo reduced nerve toxicity compared with glutathione alone.

Trust comment: Randomized human trial with objective neurotoxicity outcomes and statistically significant differences, moderate sample size.

Study Details

PMID:27531486
Participants:94
Impact:-20.9 percentage points at 6 cycles (55.6% -> 34.7%); -25.7 percentage points at 9 cycles (70.3% -> 44.6%)
Trust score:4/5

endothelial function (endothelium-dependent dilation)

1 evidences

In kidney transplant patients with high homocysteine, folic acid plus vitamin B12 lowered homocysteine and suggested improved blood vessel function.

Trust comment: Small, non-blinded treatment subgroup (n=29) with statistically significant homocysteine reduction but preliminary vascular findings.

Study Details

PMID:16386537
Participants:29
Impact:improved (preliminary/qualitative)
Trust score:3/5

composite cardiovascular events (death, MI, stroke)

1 evidences

In older adults with CKD, daily B-vitamin therapy including vitamin B12 lowered homocysteine but did not reduce cardiovascular events and was associated with increased hospitalizations for some cardiac conditions.

Trust comment: Large randomized, placebo-controlled trial (n=619) with long follow-up and hard clinical endpoints.

Study Details

PMID:18003666
Participants:619
Impact:no reduction (RR 1.19; P=0.25)
Trust score:5/5

neurogenic claudication distance

1 evidences

In lumbar spinal stenosis patients, methylcobalamin plus standard care did not change pain or neurologic signs but improved walking distance for neurogenic claudication.

Trust comment: Randomized single-blind trial with moderate sample size (70 in methylcobalamin arm); single-blind design limits blinding.

Study Details

PMID:10998833
Participants:70
Impact:improved (statistically significant)
Trust score:4/5

pain rating

1 evidences

Healthy volunteers received B‑vitamins for 1 week before testing pain; no detectable effect of B‑vitamins on analgesia was found.

Trust comment: Well-designed placebo-controlled double-blind crossover in healthy volunteers (n=38) with objective measures, but small sample and negative result for B‑vitamins.

Study Details

PMID:7609864
Participants:38
Impact:no effect detected (no additive effect of B‑vitamins)
Trust score:4/5

erythrocyte S-adenosylmethionine (SAM)

1 evidences

Cross-sectional study measuring homocysteine metabolism markers and carotid intima-media thickness in people with and without type 2 diabetes.

Trust comment: Well-characterized cross-sectional human cohort measuring B12 and related metabolites, but observational design prevents causal inference.

Study Details

PMID:12921985
Participants:231
Impact:High SAM (>4000 nmol/L) associated with smaller IMT: -0.04 mm in diabetics (NS) and -0.12 mm in non-diabetics (P=0.005)
Trust score:3/5

post-methionine homocysteine increase

1 evidences

Randomized controlled study of low- vs high-dose hormone therapy versus control in postmenopausal women assessing fasting and post-methionine homocysteine and B-vitamin levels.

Trust comment: Randomized controlled design with clear biochemical outcomes, but small sample size and indirect focus on vitamin B12 (as an affected biomarker) limit strength for B12-specific conclusions.

Study Details

PMID:17000586
Participants:48
Impact:Low-dose HT produced a steeper reduction in post-load homocysteine response than high-dose HT (regression slopes: low −1.637x vs high −0.304x)
Trust score:3/5

plasma S-adenosylmethionine (AdoMet)

1 evidences

In older adults, a daily B-vitamin supplement (folate, B12, B6) lowered plasma total homocysteine but did not change plasma AdoHcy or AdoMet after 2 years.

Trust comment: Randomized placebo-controlled trial with moderate-to-large sample for older adults; measured subset (100) analyzed for these metabolites.

Study Details

PMID:20089204
Participants:100
Impact:no significant change (+4%, ns)
Trust score:4/5

therapeutic effective rate

1 evidences

Acupoint injection of 2000 µg VitB12 showed higher response rates and greater pain reduction than oral carbamazepine for trigeminal neuralgia in this randomized trial.

Trust comment: Randomized clinical observation with reasonable sample (104) but limited methodological detail reported and possible regional publication bias.

Study Details

PMID:17926620
Participants:104
Impact:treatment 98.2% vs control 80.9% (effective rate); cured+markedly effective 82.5% vs 57.4%
Trust score:3/5

neuropathic pain

1 evidences

Randomized placebo-controlled trial (n=73) of a 10-ingredient tablet including vitamin B12; active group had marked reduction in neuropathic pain and improvements in some nerve-function measures and vitamin B12 levels.

Trust comment: Randomized, placebo-controlled study with objective measures and adequate reporting, but the multi-ingredient tablet prevents isolating vitamin B12-specific effects.

Study Details

PMID:39339645
Participants:73
Impact:-33% (significant reduction in active group vs placebo)
Trust score:4/5

vitamin B12 blood level

1 evidences

Randomized placebo-controlled trial (n=73) of a 10-ingredient tablet including vitamin B12; active group had marked reduction in neuropathic pain and improvements in some nerve-function measures and vitamin B12 levels.

Trust comment: Randomized, placebo-controlled study with objective measures and adequate reporting, but the multi-ingredient tablet prevents isolating vitamin B12-specific effects.

Study Details

PMID:39339645
Participants:73
Impact:increased (significant) in active group
Trust score:4/5

biochemical markers of cobalamin function

1 evidences

Randomized trial in infants (n=107) giving 400 μg cobalamin at 6 weeks improved biochemical markers of cobalamin function but did not change hematological cell counts at 4 months.

Trust comment: Double-blind randomized trial with clear biochemical endpoints; hematological outcomes were unchanged.

Study Details

PMID:23770919
Participants:107
Impact:improved after supplementation
Trust score:4/5

TCSS neuropathy score

1 evidences

Injecting mecobalamin at the Zusanli acupoint improved nerve imaging markers and symptoms modestly compared with intramuscular injection over 14 days.

Trust comment: Small single-center randomized study with objective imaging endpoints but short treatment (14 days) and limited sample size.

Study Details

PMID:35765223
Participants:40
Impact:AI 9.31→7.12 (−2.19); MI 9.34→7.86 (−1.48); between-group P>0.05
Trust score:3/5

Ferritin deficiency

2 evidences

Daily supervised iron+folic acid with or without vitamin B12 for 90 days increased hemoglobin and corrected deficiencies, but adding B12 did not improve hemoglobin.

Trust comment: Cluster-randomized, supervised supplementation with biochemical outcomes; however only a subset (200) completed 90 supervised doses reported here.

Study Details

PMID:33828241
Participants:200
Impact:Alleviated in >96% of girls post-intervention
Trust score:4/5

After RYGB surgery, use of an optimized multivitamin (WLS Forte) resulted in fewer vitamin B12, ferritin and anemia deficiencies than a standard multivitamin over 3 years.

Trust comment: Triple-blind randomized controlled trial cohort with 3-year follow-up and objective biomarkers, though some loss to follow-up and supplement discontinuation occurred.

Study Details

PMID:26947791
Participants:137
Impact:sMVS 14% vs WLS Forte 3% (higher in sMVS; P=0.043)
Trust score:4/5

folate insufficiency

1 evidences

Compared quintuply-fortified salt (including iodine) versus iodized salt in nonpregnant reproductive-age women; QFS improved several micronutrient deficiencies versus iodized salt.

Trust comment: Large, double-blind randomized community trial with objective biomarker endpoints and sustained 12-month follow-up.

Study Details

PMID:40610127
Participants:998
Impact:odds −86% (OR 0.14) at 6 months vs iodized salt
Trust score:5/5

blood vitamin B12

1 evidences

In lactating women, daily multiple micronutrient supplement (including vitamin D, DHA, lutein) for ~12 weeks increased milk DHA and raised maternal blood levels of several nutrients including 25-OH-vitamin D; well tolerated.

Trust comment: Randomized, double-blind trial with targeted biochemical endpoints but modest sample size and limited population diversity.

Study Details

PMID:33339438
Participants:65
Impact:increase (significant vs placebo; exact magnitude not reported in text)
Trust score:4/5

FAAM-sport score

1 evidences

Mecobalamin (a form of B12) improved foot/ankle function at 3 months and reduced pregabalin use over 12 months, but benefits were not sustained at later follow-ups.

Trust comment: Randomized trial with objective functional outcomes but small sample and transient effect limit confidence.

Study Details

PMID:39297877
Participants:47
Impact:improvement at 3 months: mecobalamin 56.3 vs placebo 43.4 (≈+12.9 points; P<.05)
Trust score:3/5

malondialdehyde (MDA)

3 evidences

Antioxidant vitamins, with or without B-group vitamins (including B12), improved antioxidant capacity, lowered oxidative damage markers and reduced CRP after acute ischemic stroke; B vitamins reduced homocysteine.

Trust comment: Randomized trial with relevant biochemical endpoints and adequate sample size for an acute intervention study.

Study Details

PMID:16517955
Participants:96
Impact:significant reduction in treatment groups vs increase in control
Trust score:4/5

Three months of daily micronutrient packs increased vitamin D and other micronutrient levels and improved antioxidant markers in older institutionalized adults.

Trust comment: Randomized controlled trial with clear biochemical endpoints and significant changes, moderate sample size and short (3-month) follow-up.

Study Details

PMID:31464392
Participants:98
Impact:-1.5 ±0.2 nmol/mL (intervention) vs +0.2 ±0.3 nmol/mL (control) change over 3 months
Trust score:4/5

46 bariatric surgery patients randomized to probiotics or placebo: at 4 months probiotics improved LBP, TNF-α, vitamin B12 and vitamin D3 and weight loss versus placebo, but most effects did not persist at 13 months except reduced MDA.

Trust comment: Double-blind randomized trial with objective biomarkers (n=46); modest sample size and some effects were transient, limiting long-term confidence.

Study Details

PMID:30612325
Participants:46
Impact:decreased (month 13)
Trust score:3/5

neuropathic symptoms (LANSS)

1 evidences

In 100 patients with chronic postthoracotomy pain, pregabalin plus methylcobalamin improved pain and neuropathic symptom scores compared with diclofenac, with minimal side effects.

Trust comment: Randomized prospective study in humans with clear patient-reported outcomes but modest sample size and some reporting parts in the text are unclear.

Study Details

PMID:27916242
Participants:100
Impact:improved vs diclofenac
Trust score:3/5

cystathionine

1 evidences

In 90 patients with suspected coronary disease, folic acid plus vitamin B12 rapidly and substantially lowered basal and postload homocysteine; vitamin B6 mainly lowered cystathionine.

Trust comment: Randomized 4-arm intervention with targeted biochemical endpoints and clear percentage changes, though sample size moderate.

Study Details

PMID:15321804
Participants:90
Impact:−31% basal and −42% post‑methionine with vitamin B6
Trust score:4/5

plasma DHA

1 evidences

In 163 infants, one egg/day for 6 months increased plasma choline and DHA biomarkers and had no effect on plasma vitamin B12 concentrations.

Trust comment: Randomized controlled trial with biomarker endpoints in infants and appropriate analytic adjustments, moderate sample size for biochemical analyses.

Study Details

PMID:29092879
Participants:163
Impact:endline 1.32 vs 1.14 μg/mL in egg vs control (+0.18 μg/mL; effect size ~0.43)
Trust score:4/5

progression-free/overall survival

1 evidences

Small randomized trial where high-dose IV methylcobalamin added to bortezomib therapy reduced the incidence of bortezomib-induced peripheral neuropathy compared with control.

Trust comment: Direct intervention with a B12 form (mecobalamin) but single-centre trial with small sample size limits confidence.

Study Details

PMID:28446297
Participants:65
Impact:no significant difference
Trust score:3/5

promoter methylation

1 evidences

6-month randomized trial in patients with prior colorectal adenomas comparing folic acid + vitamin B12 vs placebo; biomarkers in rectal DNA were measured.

Trust comment: Randomized human trial (n=86) but used high-dose folic acid together with B12 and most effects were borderline or non-significant, limiting attribution to B12 alone.

Study Details

PMID:17709451
Participants:86
Impact:↑ more frequent in intervention (OR 1.67; P=0.08, tendency)
Trust score:3/5

vitamin B6 concentration

1 evidences

120 women with type 2 diabetes on a low-calorie diet were given a multivitamin-mineral complex for 3 weeks; those receiving the complex showed greater improvements in some micronutrient levels and glycemia.

Trust comment: Controlled clinical diet study with adequate sample size but short duration and unclear randomization/allocation methods.

Study Details

PMID:25300112
Participants:120
Impact:+significant increase (main group)
Trust score:3/5

migraine disability (high-disability percentage)

1 evidences

6-month randomized, double-blind placebo-controlled trial of daily B-vitamin supplementation (B6, B9, B12) in women with migraine with aura, assessing homocysteine and migraine outcomes and genotype effects.

Trust comment: Well-designed double-blind randomized trial (n=206) showing clinically relevant reductions in homocysteine and migraine outcomes, with genotype-stratified effects increasing credibility.

Study Details

PMID:22926161
Participants:206
Impact:significant reduction in proportion with high disability (genotype-dependent)
Trust score:4/5

postherpetic neuralgia incidence

1 evidences

Local methylcobalamin plus lidocaine injections shortened healing times, produced large and sustained pain reductions, and reduced postherpetic neuralgia incidence in acute ophthalmic herpetic neuralgia.

Trust comment: Randomized controlled trial with clear clinical endpoints and significant effects, though single-center and short-term.

Study Details

PMID:26200815
Participants:98
Impact:2.04% at 3 months (reduced incidence)
Trust score:4/5

corneal nerve fibre length (CNFL)

1 evidences

In an 8-week RCT, mecobalamin intramuscular injections improved corneal small-fiber measures and autonomic symptom scores more than oral mecobalamin in mild–moderate diabetic peripheral neuropathy.

Trust comment: Small single-center open-label but assessor-blind RCT with objective imaging endpoints; limited sample size and short duration.

Study Details

PMID:34282267
Participants:32
Impact:injection +3.26 ±4.01 mm/mm² vs tablet +0.08 ±4.64 (P=0.048)
Trust score:3/5

mean arterial pressure (MAP)

1 evidences

In healthy volunteers, high-dose intravenous hydroxocobalamin caused a short-lived rise in blood pressure that paralleled plasma cobalamin exposure.

Trust comment: Controlled pharmacokinetic study in healthy volunteers with clear physiologic measurements but small sample and single-dose design.

Study Details

PMID:18584369
Participants:41
Impact:transient increase during infusion, returned near baseline by 4 hours; change correlated with plasma total and free cobalamin AUC (r>0.7)
Trust score:3/5

analgesic use

1 evidences

Local injection of methylcobalamin plus lidocaine provided greater pain relief and reduced analgesic use compared with systemic methylcobalamin in subacute ophthalmic herpetic neuralgia.

Trust comment: Randomized phase III trial with clear endpoints and clinically meaningful differences; single-center limits external validity.

Study Details

PMID:32372561
Participants:105
Impact:LM reduced from 94% at baseline to 6% at endpoint (large reduction)
Trust score:4/5

ASPA CpG methylation

1 evidences

In older adults, adding B-vitamins to vitamin D plus calcium changed methylation at some aging-related CpG sites and was associated with higher odds of accelerated epigenetic aging after 1 year.

Trust comment: Randomized supplementation trial but small sample and modest effect sizes; results are preliminary and require replication.

Study Details

PMID:29395637
Participants:63
Impact:change +1.40 (D+Ca+B) vs -0.96 (D+Ca); adjusted p=0.046
Trust score:3/5

AMI risk (urine Hcy‑thiolactone/creatinine, T3 vs T1)

1 evidences

Higher urinary Hcy-thiolactone (normalized to creatinine) predicted increased risk of incident acute myocardial infarction in CAD patients; folic acid and B‑vitamin supplementation did not change urinary Hcy-thiolactone.

Trust comment: Large prospective cohort (n>2000) with robust adjustment and consistent findings; high reliability for the biomarker–outcome association.

Study Details

PMID:30193001
Participants:2049
Impact:HR ≈ 1.58 (95% CI ~1.10–2.27) in multivariate models
Trust score:5/5

plasma ADMA (overall multistep strategy)

1 evidences

A multistep strategy including pravastatin, vitamin E and B‑vitamins had no overall effect on plasma ADMA in stage 2–4 CKD; vitamin E alone was associated with a small ADMA decrease.

Trust comment: Randomized placebo-controlled trial but secondary analysis with small sample and limited power for ADMA outcomes.

Study Details

PMID:18786751
Participants:93
Impact:No overall effect after 24 months (beta = −0.006; P = 0.27)
Trust score:3/5

corneal nerve length

1 evidences

Oral vitamin B1 plus mecobalamin improved corneal subbasal nerve parameters and several dry eye symptoms over 1–3 months compared with artificial tears alone.

Trust comment: Randomized, double-blind controlled trial with objective IVCM measures and consistent symptom improvements; follow-up relatively short (3 months).

Study Details

PMID:36145126
Participants:199
Impact:Increased at 1 and 3 months vs baseline (p<0.05)
Trust score:4/5

Serum zinc

1 evidences

Children given multiple-micronutrient fortified salt (includes iodine) had better blood nutrient markers and improved memory compared with iodized-salt controls.

Trust comment: Randomized controlled trial in residential schools with biochemical and cognitive endpoints and adequate sample size.

Study Details

PMID:20533221
Participants:402
Impact:+50 μg/dL increase (p<0.05)
Trust score:4/5

Primary composite in patients not on antiplatelet therapy

1 evidences

Daily B-vitamin (folic acid, B6, B12) vs placebo in 8164 patients after stroke/TIA: overall no significant reduction in major vascular events, but subgroup not on antiplatelet therapy showed fewer events; B-vitamins lowered homocysteine.

Trust comment: Large, randomized double-blind multicentre trial with robust biochemical and clinical outcomes; subgroup post-hoc analysis so exploratory.

Study Details

PMID:22554931
Participants:8164
Impact:Adjusted HR 0.71 (95% CI 0.55–0.90) — ~29% relative reduction
Trust score:4/5

persistent diarrhea

1 evidences

Measured plasma folate and cobalamin in young children and tracked diarrheal episodes; plasma B12 did not predict diarrhea.

Trust comment: Large prospective cohort with biomarker measurement and frequent follow-up, appropriate for associations though observational.

Study Details

PMID:22013199
Participants:2296
Impact:no association with plasma cobalamin
Trust score:4/5

MDRS construction domain in high-tHCY subgroup

1 evidences

Methylcobalamin plus folic acid lowered homocysteine but did not reduce global cognitive decline over 24 months; a subgroup with high baseline homocysteine had less decline in one cognitive domain.

Trust comment: Well-conducted randomized placebo-controlled trial with adequate duration and completion rate, though subgroup finding is secondary.

Study Details

PMID:21216507
Participants:140
Impact:smaller decline in supplement group (median 0 vs 2 points, p = 0.003)
Trust score:4/5

birth weight (per-protocol ≥90 d before pregnancy)

1 evidences

Large randomized food-based trial: overall no effect on birth weight in intention-to-treat, but per-protocol (supplement ≥90 d preconception) showed +48 g birth weight and reduced low birth weight.

Trust comment: Very large, individually randomized trial with supervised supplementation and robust measurements; partial blinding and loss to follow-up are limitations but overall high quality.

Study Details

PMID:25332324
Participants:6513
Impact:+48 g (per-protocol); P=0.046
Trust score:5/5

homocysteine in homozygous minor allele carriers

1 evidences

Six‑month randomized, double‑blind trial of methylfolate + P5P + methylcobalamin showed large reductions in homocysteine and modest reductions in LDL‑C versus placebo, with greater effects in homozygous minor‑allele genotype subgroup.

Trust comment: Double‑blind randomized placebo‑controlled trial with clear biochemical effects; sample size modest but pre‑specified and analyses appropriate.

Study Details

PMID:38892484
Participants:54
Impact:−48.3% (95% CI −62.3% to −34.3%) in homozygous subgroup
Trust score:4/5

iron status (ferritin, transferrin saturation)

1 evidences

Six‑week double‑blind randomized trial in postmenopausal women showed that soy protein with native phytate reduced total homocysteine and iron indices; vitamin B12 was measured as a covariate but not manipulated.

Trust comment: Short (6‑week) double‑blind RCT with small sample; B12 was measured as a covariate rather than the intervention, limiting direct inference about B12 effects.

Study Details

PMID:17023703
Participants:55
Impact:Native phytate reduced transferrin saturation (P = 0.027) and ferritin (P = 0.029)
Trust score:3/5

incident lacunes

1 evidences

Two years of daily B-vitamin supplementation did not significantly reduce overall progression of ischemic brain lesions versus placebo, but a predefined subgroup with severe small vessel disease showed less white-matter lesion progression.

Trust comment: Randomized double-blind substudy with objective MRI outcomes; overall null results with a positive effect in a prespecified severe-subgroup limit generalizability.

Study Details

PMID:23093615
Participants:359
Impact:+2.1 percentage points (8.0% vs 5.9%; not significant)
Trust score:4/5

NIH-CPSI score

1 evidences

Randomized single-center trial: Deprox 500 (pollen extract plus multiple B vitamins including B12) improved prostatitis symptom scores more than Serenoa repens after 6 weeks.

Trust comment: Small, single-center RCT without placebo and with a multi-vitamin product — cannot attribute effects specifically to B12 and risk of bias exists.

Study Details

PMID:30488800
Participants:63
Impact:mean change −17.3 ± 3.1 (Deprox) vs −13.6 ± 4.8 (Serenoa); Deprox improvement ~84.5%
Trust score:3/5

B vitamins

1 evidences

Two-year follow-up of stroke patients with confluent WMH found that clinical and imaging factors predicted cognitive decline, while B vitamin measures were not associated with decline.

Trust comment: Prospective cohort (n=100) with multivariate analysis; B vitamins measured but found not to predict cognitive decline, moderate quality.

Study Details

PMID:22651941
Participants:100
Impact:no association with cognitive decline over 2 years
Trust score:3/5

effect of cobalamin alone

1 evidences

Controlled trial testing multivitamin (including hydroxycobalamin) or individual vitamins on plasma homocysteine in patients and volunteers.

Trust comment: Randomized controlled design but interventions were combined multivitamins (folic acid likely main driver); cobalamin-alone subgroup small and showed only modest effect.

Study Details

PMID:9514403
Participants:316
Impact:Hydroxycobalamin alone produced modest median reduction ~10% (range −21% to 41%)
Trust score:3/5

holotranscobalamin (B12 marker)

1 evidences

A 12‑week multimicronutrient plus n‑3 PUFA supplement (including cholecalciferol) increased vitamin D status and reduced a composite low‑grade inflammation score versus placebo.

Trust comment: Well-conducted RCT with objective endpoints, but multinutrient formulation and omega-3 co-intervention limit attribution to B12 alone.

Study Details

PMID:40644954
Participants:112
Impact:increased (P<0.001)
Trust score:3/5

INFLA score (low-grade inflammation)

1 evidences

A 12‑week multimicronutrient plus n‑3 PUFA supplement (including cholecalciferol) increased vitamin D status and reduced a composite low‑grade inflammation score versus placebo.

Trust comment: Well-conducted RCT with objective endpoints, but multinutrient formulation and omega-3 co-intervention limit attribution to B12 alone.

Study Details

PMID:40644954
Participants:112
Impact:decreased vs placebo (P=0.036)
Trust score:3/5

3D vessel wall volume (VWV CCA+ICA)

1 evidences

In a randomized vitamin B therapy trial in diabetic nephropathy patients, 3D ultrasound vessel wall volume increased over time in one treatment group while IMT showed no between-group differences.

Trust comment: Randomized, double-blind study but small imaging subset and modest sample size reduce generalizability.

Study Details

PMID:18996639
Participants:71
Impact:group B +53 mm^3/yr vs group A −12 mm^3/yr (p=0.034) — increase in group B
Trust score:3/5

motor development (AIMS score)

1 evidences

A single intramuscular hydroxycobalamin injection in infants with biochemical B12 impairment rapidly corrected biomarkers and improved motor scores and regurgitation.

Trust comment: Double-blind randomized controlled trial in humans with objective biochemical and clinical outcomes and clear effects.

Study Details

PMID:24025626
Participants:79
Impact:median increase +7 points (vs +4.5 in placebo; P=0.003)
Trust score:5/5

bone resorption (β cross laps)

1 evidences

In a 6-month randomized placebo-controlled trial of folic acid (1 mg) in postmenopausal osteoporotic women, folic acid modestly affected homocysteine and bone markers and preserved vitamin B12 levels relative to placebo.

Trust comment: Double-blind RCT with biochemical measures but small single-center sample and limited power to detect small effects.

Study Details

PMID:25223378
Participants:31
Impact:Increase in β cross laps greater in control than treatment (P=0.01)
Trust score:3/5

vitamin B12 status (holoTC)

1 evidences

6-week RCT in healthy men replacing most red/processed meat with legumes; studied nutrient intakes and biomarkers including iodine intake and urinary iodine excretion.

Trust comment: Well-conducted randomized dietary trial with good compliance and nutritional biomarkers, but short duration (6 weeks) limits long-term conclusions about B12 status.

Study Details

PMID:40828321
Participants:102
Impact:Serum holoTC lower in LEGUME vs MEAT at endpoint and declined within LEGUME group (P=0.022); more participants with marginal holoTC in LEGUME group (16%)
Trust score:4/5

anemia (clinical diagnosis)

1 evidences

After RYGB surgery, use of an optimized multivitamin (WLS Forte) resulted in fewer vitamin B12, ferritin and anemia deficiencies than a standard multivitamin over 3 years.

Trust comment: Triple-blind randomized controlled trial cohort with 3-year follow-up and objective biomarkers, though some loss to follow-up and supplement discontinuation occurred.

Study Details

PMID:26947791
Participants:137
Impact:sMVS 16% vs WLS Forte 3% (higher in sMVS; P=0.021)
Trust score:4/5

prothrombin fragments 1+2 and TAT

1 evidences

High-dose B-vitamin supplementation lowered homocysteine (~27.7%) in healthy volunteers but produced no clear changes in clotting activation markers (F1+2, TAT); D-dimer showed a non-significant reduction.

Trust comment: Randomized intervention with biomarker outcomes in healthy subjects; reasonable sample size but surrogate endpoints and short duration.

Study Details

PMID:12195694
Participants:118
Impact:No significant change after supplementation
Trust score:4/5

verbal fluency

1 evidences

In a randomized maternal supplementation trial (>700 women), breastmilk Vitamin B12 concentration was positively associated with attention and executive function; MMN/LNS arms had higher breastmilk B12 than IFA.

Trust comment: Large randomized trial with biomarker substudy showing consistent associations between breastmilk B12 and cognitive outcomes, though B12 was not isolated as sole causal agent.

Study Details

PMID:29098783
Participants:712
Impact:+0.14 z-score (association with higher breastmilk Vitamin B12)
Trust score:4/5

micronucleus frequency (fMN-Trf-Ret)

1 evidences

Across cross-sectional and short intervention studies, folate status correlated with chromosome stability but short-term supplementation (including a folate+B12+B6 arm) did not change micronucleus frequency or cell proliferation.

Trust comment: Includes cross-sectional data (n=99) and small short-term interventions (n≈29–30); appropriate methods but limited by short intervention duration and small sample sizes.

Study Details

PMID:16386942
Participants:99
Impact:no significant change after 1-week supplementation with folic acid alone or folic acid+B12+B6
Trust score:3/5

triacylglycerol

1 evidences

A targeted medical nutrition therapy increased folate (and B6 and B12) levels and substantially reduced serum lipids in hyperlipidemic patients, while plasma homocysteine was unchanged.

Trust comment: Randomized small trial with clear clinical endpoints and dietary counseling, but limited by modest sample size and short-term follow-up (12 weeks).

Study Details

PMID:19083486
Participants:40
Impact:−30.8% after MNT vs control
Trust score:3/5

glycemic control (HbA1c / fasting glucose)

1 evidences

Daily vitamin B-complex for 12 weeks lowered homocysteine and improved blood sugar and kidney markers in adolescents with type 1 diabetes and microalbuminuria.

Trust comment: Small randomized controlled trial (n=80), short duration (12 weeks), but randomized and controlled; moderate quality.

Study Details

PMID:30704890
Participants:80
Impact:significant decrease vs placebo (p<0.001)
Trust score:3/5

Cognitive function (CAMCOG total score)

1 evidences

Randomized placebo-controlled trial in adults with elevated MMA testing whether B12 treatment improved cognitive scores or depression over 3 months.

Trust comment: Randomized placebo-controlled design with biomarker-selected participants is strong, but short 3-month follow-up limits detection of longer-term effects.

Study Details

PMID:15337331
Participants:140
Impact:No improvement; P = 0.43 (treatment vs placebo)
Trust score:4/5

VCAM-1

1 evidences

In a 2-year randomized trial subsample, daily vitamin B12 (500 µg) plus folic acid did not change endothelial or inflammation biomarkers versus placebo in elderly with high homocysteine.

Trust comment: Large randomized trial subsample with measured biomarker outcomes; results show no significant effects.

Study Details

PMID:26774115
Participants:522
Impact:+27% vs +25% (no significant difference, p=0.39)
Trust score:4/5

Post-methionine-loading plasma total homocysteine increase

1 evidences

Small randomized trial in renal transplant recipients: folic acid plus vitamin B12 reduced fasting homocysteine; vitamin B6 reduced post-methionine-loading increases.

Trust comment: Randomized controlled design but very small sample (n=29) limits precision and generalizability.

Study Details

PMID:9412311
Participants:29
Impact:−22.1% (vitamin B6 effect on post-load increase, p=0.042)
Trust score:3/5

Plasma total homocysteine (folic acid 200 µg)

1 evidences

12-month randomized community trial: low-dose oral B12 (2 or 10 µg/day) significantly lowered plasma homocysteine compared to placebo; folic acid 200 µg/day also reduced homocysteine.

Trust comment: Well-conducted cluster randomized double-blind trial with adequate sample and clear biochemical outcomes.

Study Details

PMID:20216560
Participants:300
Impact:−4.8 µmol/L at 12 months (95% CI −6.3, −3.3)
Trust score:4/5

Subarachnoid hemorrhage risk

1 evidences

Prospective cohort of male smokers: higher dietary folate (but not vitamin B12) intake was associated with lower risk of cerebral infarction; B12 intake showed no significant association with stroke subtypes.

Trust comment: Large prospective cohort with long follow-up; observational design limits causal inference for B12.

Study Details

PMID:18270369
Participants:26556
Impact:Vitamin B12: no significant association
Trust score:4/5

vitamin B12 deficiency incidence

3 evidences

An RCT of RYGB patients found that an optimized multivitamin (WLS Forte) produced fewer iron and B12 deficiencies versus standard MVS; both groups received substantial vitamin D (total ~1200 IU/day) with similar 25-OHD levels at 12 months.

Trust comment: Triple-blind randomized controlled trial with 148 patients and predefined biochemical outcomes; some participants received additional corrective supplements which may confound results.

Study Details

PMID:25437032
Participants:148
Impact:1.6% (WLS Forte) vs 7.9% (sMVS) at 12 months
Trust score:4/5

Sixty bariatric patients were randomized to two surgery types and followed for 3 years; vitamin B12 deficiency occurred more often after Roux-en-Y gastric bypass than after sleeve gastrectomy.

Trust comment: Randomized surgical trial with 3-year follow-up but small sample for nutritional outcomes and B12 was an observed postoperative deficiency rather than a tested intervention.

Study Details

PMID:21818647
Participants:60
Impact:Higher after LRYGB vs LSG (statistically significant, P = 0.05)
Trust score:3/5

At 1 year after RYGB variants, vitamin D deficiency was common and patients with very long Roux limb RYGB had significantly lower vitamin D levels than standard RYGB patients.

Trust comment: Large multicentre randomized surgical trial with laboratory-measured nutrient outcomes at 1 year, though some reporting inconsistencies and relatively short follow-up for long-term deficiency outcomes.

Study Details

PMID:32077402
Participants:423
Impact:Approximately 9.0–9.9% of patients at 1 year postoperative
Trust score:4/5

HOMA-IR

1 evidences

In obese adults on a weight-loss diet, synbiotic tablets increased vitamin D and B12 levels but both groups lost similar weight.

Trust comment: Randomized single-center trial with 110 participants and short follow-up; effects reported vs baseline without detailed absolute B12 change.

Study Details

PMID:40192559
Participants:110
Impact:decreased (significant vs baseline; larger decrease in synbiotic group)
Trust score:3/5

vitamin B12 plasma level

1 evidences

In healthy older adults, adding probiotic VSL#3 to a personalized anti-inflammatory diet for 8 weeks increased plasma vitamin B12 and folate and decreased homocysteine compared with diet alone.

Trust comment: Open-label randomized multicenter study with small N (62) and short duration; biomarker changes significant but clinical relevance needs longer follow-up.

Study Details

PMID:25453395
Participants:62
Impact:increased (p=0.001) with VSL#3
Trust score:3/5

short-term vitamin B12 supplementation

1 evidences

Higher MMA was linked to hearing loss; short-term B12 did not improve hearing.

Trust comment: Moderate-sized clinical study with measured biomarkers but limited intervention duration and observational associations.

Study Details

PMID:18032219
Participants:93
Impact:no improvement in hearing status in B12-deficient individuals
Trust score:3/5

intra-individual variation of TMAO

1 evidences

Vitamin B12 intervention did not change plasma TMAO or related choline metabolites in vegetarians.

Trust comment: Controlled intervention in vegetarians with repeated measures and reported ICCs; moderate sample size.

Study Details

PMID:27562778
Participants:171
Impact:low intra-individual variation (ICC 0.819)
Trust score:4/5

global cognition in high-homocysteine subgroup

1 evidences

B-vitamin treatment (including B12) lowered homocysteine and slowed some cognitive decline, especially in those with high baseline homocysteine.

Trust comment: Double-blind randomized trial with adequate sample and clear biomarker and cognitive endpoints, though effects concentrated in subgroup.

Study Details

PMID:21780182
Participants:266
Impact:improved (MMSE P<0.001)
Trust score:4/5

Framingham Risk Score (FRS)

1 evidences

Daily low-dose B vitamins (including B12) for 12 months reduced Framingham risk score and increased HDL, with effects reversing after stopping.

Trust comment: Large double-blind RCT with clinically relevant endpoints and sustained follow-up, though combined B-vitamin formulation confounds B12-specific effects.

Study Details

PMID:24916013
Participants:390
Impact:-7.6% at 12 months (mean difference -0.77; P=0.033)
Trust score:4/5

serum vitamin B12 concentration (IM)

1 evidences

Randomized trial comparing monthly high-dose oral cyanocobalamin vs weekly intramuscular hydroxocobalamin over 4 weeks; both routes improved B12 biomarkers but IM produced much larger early rises.

Trust comment: Randomized outpatient trial with direct biochemical outcomes but small sample size and nonblinded design limits precision.

Study Details

PMID:28421567
Participants:37
Impact:164 → 2796 pmol/L (+2632 pmol/L; +1604%) at 4 weeks
Trust score:4/5

serum CTX (bone resorption marker)

1 evidences

A 24‑week RCT of fortified milk (providing ~1008 mg Ca/day) plus exercise improved vitamin B‑12 and 25(OH)D levels and reduced bone turnover markers versus control.

Trust comment: Well-conducted RCT with good sample and biochemical measures, but intervention combined nutrition and exercise (effects not solely attributable to B12).

Study Details

PMID:32588047
Participants:163
Impact:intervention median 276 → 239 pg/mL (decrease) by 24 weeks
Trust score:4/5

physical component summary (PCS)

1 evidences

Ancillary analysis of a large RCT of low-dose B-vitamin supplementation (including B12) in CVD survivors found no overall QOL benefit and a small worsening in emotional role limitations.

Trust comment: Large randomized trial but this is an ancillary QOL analysis with low B12 dose and composite B-vitamin treatment, limiting attribution to B12 alone.

Study Details

PMID:24465438
Participants:2029
Impact:no significant change (0.0 points, 95% CI −0.8 to 0.8)
Trust score:3/5

estimated effective oral dose to achieve 80–90% maximal MMA reduction

1 evidences

Double-blind randomized dose-finding trial in older adults with mild B12 deficiency showing dose-dependent reductions in methylmalonic acid; high oral doses required to approximate maximal biochemical response.

Trust comment: Randomized, double-blind dose-finding RCT with clear biochemical endpoints, though limited to mild deficiency and 16-week duration.

Study Details

PMID:15911731
Participants:120
Impact:~647–1032 µg/day (authors' estimate)
Trust score:4/5

Holotranscobalamin concentration

1 evidences

One-year daily 1 mg oral B12 in older adults raised blood B12 but did not improve nerve conduction or cognitive tests.

Trust comment: Large, double-blind randomized trial with high adherence and objective outcomes; low risk of bias.

Study Details

PMID:26135351
Participants:191
Impact:+331%
Trust score:5/5

Prevalence of adequate B12 status

1 evidences

In two cohorts, maternal and infant blood B12 concentrations correlated; milk B12 correlated with infant B12 in Canada but not in Cambodia, and most mothers and infants had adequate B12 status.

Trust comment: Secondary analysis of two trials with valid laboratory methods but limited and non-representative samples and some missing measures across specimens.

Study Details

PMID:28287490
Participants:168
Impact:≥97% mothers; ≥84% infants adequate (>221 pmol/L)
Trust score:3/5

Inflammation and endothelial biomarkers (CRP, IL-6, ICAM-1, fibrinogen)

1 evidences

Long-term combined B-vitamin treatment lowered homocysteine but did not change plasma markers of inflammation or endothelial dysfunction.

Trust comment: Large, long-duration randomized substudy (7.3 years) with robust biomarker measurements; high internal validity for the null biomarker findings.

Study Details

PMID:29776960
Participants:300
Impact:no change vs placebo
Trust score:5/5

serum cobalamin normalization

1 evidences

In older or at-risk patients with low B12, both oral (1000 µg/day) and IM regimens normalized serum cobalamin in all patients; oral B12 showed lower MMA at day 91.

Trust comment: Randomized comparative study with near-complete follow-up and objective biochemical endpoints, though small and open-label.

Study Details

PMID:21600388
Participants:48
Impact:100% of patients in both groups achieved ≥350 pg/mL by day 61 (and by day 15 all reached ≥350 pg/mL)
Trust score:4/5

holotranscobalamin (active B12)

1 evidences

In older or at-risk patients with low B12, both oral (1000 µg/day) and IM regimens normalized serum cobalamin in all patients; oral B12 showed lower MMA at day 91.

Trust comment: Randomized comparative study with near-complete follow-up and objective biochemical endpoints, though small and open-label.

Study Details

PMID:21600388
Participants:48
Impact:all patients had ≥40 pmol/L on day 61 and day 91
Trust score:4/5

cognitive impairment (MMSE)

1 evidences

Large randomized trial: daily B-vitamins (including 500 µg B12) lowered mean homocysteine but did not change MMSE scores or incidence of cognitive impairment over ~2.8–3.4 years.

Trust comment: Very large double-blind randomized trial with long follow-up and prespecified cognitive analysis, providing robust evidence.

Study Details

PMID:23765945
Participants:8164
Impact:no difference in MMSE change (difference 0.03 points) and no difference in incidence of cognitive impairment (5.51% vs 5.47%)
Trust score:5/5

incidence of clinically significant depression (proportion remaining free)

1 evidences

2-year randomized placebo-controlled trial in men ≥75 y testing daily B12 (400 μg) + folic acid (2 mg?) + B6; found no benefit of B-vitamin treatment vs placebo on depressive symptom severity or incidence of clinically significant depression.

Trust comment: Placebo-controlled randomized trial in older men with low dropout; direct clinical outcome measured.

Study Details

PMID:18557664
Participants:241
Impact:Vitamin group 84.3% vs placebo 79.1% free of clinically significant symptoms at 2 years; difference not statistically significant
Trust score:4/5

verbal episodic memory (HVLT-DR)

1 evidences

Randomized trial (VITACOG) in MCI patients: daily B-vitamin supplement (folic acid 0.8 mg, B12 0.5 mg, B6 20 mg) for ~2 years lowered homocysteine and prevented declines in several cognitive measures compared with placebo.

Trust comment: Randomized controlled trial with biochemical, cognitive and imaging measures in MCI patients; moderate sample size and well-characterized outcomes.

Study Details

PMID:33935094
Participants:196
Impact:Placebo group decline (7.4→6.9, p=0.046) prevented in B-vitamin group (no significant change)
Trust score:4/5

interaction with DHA

1 evidences

Post-hoc analysis of an RCT of folic acid + B12 (2-year intervention) showing that benefit of B-vitamin supplementation on global cognition was present in participants with high baseline plasma DHA (high-tertile) but not in lower DHA tertiles.

Trust comment: Post-hoc subset analysis of an RCT (exploratory, limited sample); suggests DHA-modified effect but not prespecified.

Study Details

PMID:35704085
Participants:191
Impact:Overall interaction between B-vitamins and DHA status significant/trending (p=0.06); no interaction with EPA or total omega-3
Trust score:3/5

Break Up Time (BUT)

1 evidences

Clinical study in cataract surgery patients: dry eye patients randomized to hyaluronic acid 0.15% plus vitamin B12 eye drops versus no treatment; treatment reduced oxidative stress markers and improved dry-eye clinical scores.

Trust comment: Small randomized clinical study with objective oxidative stress and symptom measures, but limited sample and surgical population context.

Study Details

PMID:25398660
Participants:103
Impact:Significant increase after treatment vs untreated dry eye
Trust score:3/5

Plasma vitamin B12

23 evidences

In a long-term randomized trial subset, daily multivitamin/mineral (Centrum) increased plasma vitamin B12, folate, vitamin E and improved some other nutrient statuses versus placebo.

Trust comment: Large, long-duration double-blind randomized trial subset with objectively measured nutrient outcomes, though results reflect a multivitamin formulation rather than isolated B12.

Study Details

PMID:19636163
Participants:407
Impact:increased (P<0.005)
Trust score:4/5

Double-blind randomized placebo-controlled trial in elderly people showed dose-dependent biomarker improvements with B12 supplements, but even 500 μg/day for 8 weeks left a minority with persistent metabolic abnormalities.

Trust comment: Double-blind randomized controlled intervention with clear biomarker endpoints in humans (n=100); good internal validity for biomarker effects.

Study Details

PMID:23236022
Participants:100
Impact:dose-dependent increase; after 500 μg/d, 8% remained below normalization
Trust score:4/5

Fortifying foods with iron and vitamin B12 for 1 year worked similarly regardless of H. pylori infection status.

Trust comment: Large double-blind randomized controlled trial with objective biomarker outcomes, though fortification combined multiple micronutrients so attribution to B12 alone is limited.

Study Details

PMID:20683455
Participants:543
Impact:no difference in response to fortification between H. pylori+ and H. pylori- children
Trust score:4/5

Pre-op IV B-vitamin (including B12) massively raised B12/folate but did not prevent the nitrous oxide–induced rise in homocysteine.

Trust comment: Randomized study with objective biochemical outcomes and clear measurements, but modest sample size.

Study Details

PMID:20477781
Participants:59
Impact:+35-fold (first postoperative measurement)
Trust score:4/5

In obese knee osteoarthritis patients, a low-energy formula diet (containing vitamin D) and weight loss increased serum 25‑OH vitamin D, lowered PTH, and produced a small increase in BMD over 16 weeks.

Trust comment: Large prospective cohort (175 completers) with measured biochemical endpoints and clear pre/post comparisons.

Study Details

PMID:22190136
Participants:175
Impact:+43.7 pmol/L (≈+14.9%)
Trust score:4/5

In depressed patients, adding folic acid to fluoxetine reduced homocysteine and improved depression scores, while vitamin B12 levels did not change.

Trust comment: Small randomized trial with clinical and biochemical endpoints but limited sample size (27) reducing precision.

Study Details

PMID:18716414
Participants:27
Impact:No significant change
Trust score:3/5

In nursing-home residents, adding oat-bran reduced laxative use and was associated with slower decline in plasma B12 compared with control; homocysteine fell in both groups.

Trust comment: Small controlled parallel intervention (n=30) with objective measures but limited sample size and indirect effect on B12 (dietary fiber influence rather than B12 supplementation).

Study Details

PMID:20191257
Participants:30
Impact:declined faster in control than fiber group (fiber preserved B12; p<0.05)
Trust score:3/5

Low-dose folic acid for 4 weeks decreased homocysteine but did not change plasma methionine or plasma vitamin B12 concentrations.

Trust comment: Randomized supplementation trial with moderate sample size and measured biochemical outcomes; directly reports no B12 change.

Study Details

PMID:10743479
Participants:144
Impact:no change after 4 weeks of low-dose folic acid supplementation
Trust score:4/5

Rural and urban Mexican women ate model diets in a crossover; homocysteine and B12/folate were measured over 4 hours.

Trust comment: Controlled crossover with frequent sampling but small sample size limits generalizability.

Study Details

PMID:14559315
Participants:33
Impact:no difference between rural and urban; no subjects with low B12
Trust score:4/5

Hospitalised older patients given a daily oral nutritional supplement (including vitamins) had improved depressive symptoms at 6 months but no cognitive change.

Trust comment: Well-conducted double-blind RCT with clear outcome on depressive symptoms, though effect is from a multinutrient supplement rather than isolated B12.

Study Details

PMID:17662509
Participants:225
Impact:significant increase (supplement vs placebo)
Trust score:4/5

Randomized dietary intervention in healthy young men comparing usual vs high-protein meat diet and measuring platelet proteome, cognitive function, and methylation-cycle components including vitamin B12.

Trust comment: Randomized intervention with controlled diet and biochemical measures but small sample size limits generalizability.

Study Details

PMID:21424576
Participants:23
Impact:Increased with high-protein diet (significant; exact % not reported)
Trust score:3/5

In 163 infants, one egg/day for 6 months increased plasma choline and DHA biomarkers and had no effect on plasma vitamin B12 concentrations.

Trust comment: Randomized controlled trial with biomarker endpoints in infants and appropriate analytic adjustments, moderate sample size for biochemical analyses.

Study Details

PMID:29092879
Participants:163
Impact:no significant change vs control
Trust score:4/5

In adults with overweight/obesity, two high-protein meal-replacement programs (with or without alternate day fasting) produced similar ~11% weight loss and improved metabolic markers; vitamin D levels decreased modestly in both groups by week 16.

Trust comment: Randomized controlled trial with objective biochemical measures showing increased B12 (meal replacements supplied B12); B12 effect is intervention-associated but not isolated.

Study Details

PMID:30142886
Participants:164
Impact:significant increase at week 16 vs baseline (p<0.05)
Trust score:4/5

Cross‑sectional comparison found vegans had lower plasma vitamin B12 and higher prevalence of elevated homocysteine compared with omnivores and vegetarians.

Trust comment: Observational cross‑sectional study with modest sample sizes; associations plausible but cannot infer causality.

Study Details

PMID:16988496
Participants:118
Impact:vegans had significantly lower mean plasma B12 than omnivores and vegetarians (reported as significantly lower; no absolute value given in excerpt)
Trust score:3/5

Six‑week double‑blind randomized trial in postmenopausal women showed that soy protein with native phytate reduced total homocysteine and iron indices; vitamin B12 was measured as a covariate but not manipulated.

Trust comment: Short (6‑week) double‑blind RCT with small sample; B12 was measured as a covariate rather than the intervention, limiting direct inference about B12 effects.

Study Details

PMID:17023703
Participants:55
Impact:measured at baseline and included in analyses as a contributor to tHcy; no treatment effect reported
Trust score:3/5

Six months of high-dose B-group multivitamin supplementation increased blood B12 and B6 and lowered homocysteine; brain metabolite concentrations did not change significantly in this small neuroimaging sub-study.

Trust comment: Randomized double-blind trial with objective biochemical and MRS measures; neuroimaging sub-sample was small and some data were excluded, limiting power for brain outcomes.

Study Details

PMID:30513795
Participants:33
Impact:Plasma B12 increased significantly with treatment (group×time interaction, p<0.001; b=42.74)
Trust score:4/5

In undernourished psycho-geriatric patients, a multinutrient liquid supplement for 12 weeks increased body weight and improved multiple plasma nutrient levels including vitamin D.

Trust comment: Double-blind, placebo-controlled randomized trial in elderly patients with good completion and multiple measured biomarkers, though modest sample size.

Study Details

PMID:11960300
Participants:35
Impact:increased in supplement group vs placebo (statistically significant)
Trust score:4/5

PCOS patients on metformin who received B-group vitamins had reduced rises in homocysteine compared to metformin alone over 12 weeks.

Trust comment: Randomized trial with clear biochemical outcomes but small sample size and short duration limit generalizability.

Study Details

PMID:15790610
Participants:60
Impact:increased with B-group vitamin supplementation (reported alongside Hcy change)
Trust score:3/5

Single meals of Mankai duckweed raised certain amino acids and produced a larger short-term increase in plasma vitamin B12 compared with cheese or peas in healthy men.

Trust comment: Randomized meal study in 36 healthy men; small sample and short-term measurements but directly assesses B12 bioavailability.

Study Details

PMID:30591380
Participants:36
Impact:greater acute increase after Mankai vs cheese (p=0.007) and vs peas (p=0.047)
Trust score:3/5

Elderly people with mild cognitive impairment received high-dose B-vitamin supplementation (folic acid, B6, B12) for 2 years; B-vitamin treatment lowered homocysteine and substantially slowed whole-brain atrophy versus placebo.

Trust comment: Large double-blind randomized trial with objective MRI endpoints and biochemical compliance data, though treatment was a B-vitamin combination so individual vitamin effects (including B12) are not isolated.

Study Details

PMID:20838622
Participants:168
Impact:Increased from ~330 to ~672 pmol/L in active group (doubling; P < 0.001)
Trust score:5/5

A locally made RUTF produced greater weight gain than the local fortified cereal milk and increased plasma zinc, vitamin B12, albumin, and hemoglobin in malnourished preschoolers.

Trust comment: Randomized controlled trial with modest sample size and reported improvements in B12 and other biomarkers, but exact B12 magnitude was not detailed in the abstract.

Study Details

PMID:20972285
Participants:96
Impact:increase reported (exact numeric change not provided)
Trust score:3/5

Daily fortified milk (including phytosterols) plus lifestyle counselling for 3 months improved several CVD-related markers (lower homocysteine, higher folate/B12) and tended to improve LDL:HDL; effects are from combined intervention.

Trust comment: Randomized intervention but contains multiple added nutrients and lifestyle counselling, so effects cannot be attributed to vitamin B12 alone.

Study Details

PMID:23249766
Participants:101
Impact:significant increase in enriched milk group vs placebo and control (P<0.001)
Trust score:3/5

6-week randomized trial of B-vitamin (including B12) plus folic acid in PAD patients: homocysteine fell and B12/folate rose, but ADMA did not change.

Trust comment: Randomized placebo-controlled trial (n=49) with clear biochemical outcomes and appropriate measures, but short duration and moderate sample size.

Study Details

PMID:15634723
Participants:49
Impact:increased
Trust score:4/5

itch severity

1 evidences

Single-center randomized trial of local injections for herpetic itching found injected cobalamin (B12) significantly relieved pain and improved daily activities and quality of life compared with controls.

Trust comment: Randomized controlled single-center trial with small groups (n≈20 per arm); results suggest benefit but sample size and single-center design limit generalizability.

Study Details

PMID:23887347
Participants:80
Impact:cobalamin primarily reduced pain (itch relief seen with thiamine and with combination; B12 alone less on itch)
Trust score:3/5

vitamin B12 status

6 evidences

Double-blind RCT of a multivitamin/mineral vs placebo in older adults on certain medications; MVMS increased folate and vitamin C status but did not significantly change serum calcium.

Trust comment: Randomized, double-blind controlled trial but small completed sample and short (16-week) duration; some reported B12 changes lacked detailed magnitude or significance in the text.

Study Details

PMID:33078646
Participants:54
Impact:improved but remained within normal range (no magnitude reported)
Trust score:3/5

Fortifying school meals with a multinutrient premix for 8 months improved vitamin A and folate status, increased total body iron, and lessened the decline in vitamin B12 among schoolchildren.

Trust comment: Large, cluster-randomized placebo-controlled trial with objective biomarkers, but B12 was a low-dose component of a multi-micronutrient mix limiting attribution to B12 alone.

Study Details

PMID:20410083
Participants:499
Impact:Decrease in serum B12 in both groups but magnitude of decrease smaller in treatment vs control (P<0.05)
Trust score:4/5

In a 6-month randomized placebo-controlled trial of folic acid (1 mg) in postmenopausal osteoporotic women, folic acid modestly affected homocysteine and bone markers and preserved vitamin B12 levels relative to placebo.

Trust comment: Double-blind RCT with biochemical measures but small single-center sample and limited power to detect small effects.

Study Details

PMID:25223378
Participants:31
Impact:Serum B12 decreased in both groups but was significantly lower in control vs treatment at 6 months (P=0.01) — treatment preserved B12
Trust score:3/5

Olestra intake reduced some fat-soluble nutrient levels but did not affect vitamin B12 absorption or status over 8 weeks in healthy adults.

Trust comment: Controlled dose-response study with objective measures in healthy adults, but modest sample size and short duration for some nutrients.

Study Details

PMID:9237961
Participants:90
Impact:No effect on overall vitamin B12 status over 8 weeks
Trust score:3/5

Compared to standard enteral nutrition, immunomodulatory enteral nutrition after GI cancer surgery reduced some post-surgical complications and improved immune markers and nutritional parameters including vitamin B12 status.

Trust comment: Randomized surgical nutrition trial with 100 patients but used a multi-nutrient immunonutrition formula, so effects cannot be attributed specifically to vitamin B12.

Study Details

PMID:40374110
Participants:100
Impact:improved (better nutritional parameters related to vitamin B12)
Trust score:3/5

Double-blind RCT of a multinutrient (including B12 50 µg) for 12 weeks; B vitamin biomarkers (B1, B6, B12) increased with active treatment and modest cognitive attention benefits were seen in a diet-defined subgroup.

Trust comment: Well-powered double-blind RCT with biochemical confirmation of B vitamin uptake; cognitive benefits were modest and subgroup-specific.

Study Details

PMID:36501109
Participants:116
Impact:Significant increase (active vs placebo)
Trust score:4/5

relationship glycine–MMA

1 evidences

Treatment-phase study in hemodialysis patients showing folate and added vitamin B12 lower but do not fully normalize homocysteine and MMA in ESRD.

Trust comment: Interventional study in a clinically relevant ESRD population with measurable biochemical endpoints, though normalization was not achieved.

Study Details

PMID:12601627
Participants:81
Impact:positive correlation between plasma glycine and MMA (P<.05)
Trust score:4/5

serum ferritin deficiency prevalence

1 evidences

Weekly iron+folic acid with or without added vitamin B12 for 26 weeks raised haemoglobin; addition of B12 improved ferritin and reduced B12 deficiency more than IFA alone.

Trust comment: Large randomized double-blind community RCT with good completion (373), appropriate biochemical outcomes, though single-centre and limited to 26 weeks.

Study Details

PMID:26695724
Participants:373
Impact:-30.1 percentage points in B12 group (36.5% → 6.4%); IFA-only -23.9 pp (39.1% → 15.2%)
Trust score:4/5

concomitant symptom improvement

1 evidences

Methylcobalamin (vitamin B12 form) shortened time to full facial recovery and improved facial nerve scores compared with steroid alone.

Trust comment: Small randomized open trial showing large effects, but limited by small size and open (non-blinded) design.

Study Details

PMID:8749227
Participants:60
Impact:greater improvement in methylcobalamin-treated groups vs steroid alone (qualitative)
Trust score:3/5

biochemical vitamin B12 deficiency rate

1 evidences

In non-diabetic high-risk breast cancer patients, 6 months of metformin reduced plasma vitamin B12 levels and increased biochemical B12 deficiency without causing anemia.

Trust comment: Large randomized trial with centralized assays and paired samples; clear objective measures though secondary analysis of first 492 paired samples.

Study Details

PMID:28447237
Participants:492
Impact:increased after 6 months of metformin (higher incidence vs placebo)
Trust score:4/5

within-subject variability of vitamin B12

1 evidences

In 22 healthy women, serum vitamin B12 showed notable within-subject variability and was consistently lower in oral contraceptive users versus non-users.

Trust comment: Longitudinal study with standardized sampling and repeated measures but small, homogeneous sample of students limits generalizability.

Study Details

PMID:24067390
Participants:22
Impact:high (RCV ~49.8% for vitamin B12)
Trust score:4/5

body weight / waist circumference / BMI

1 evidences

Compared dietary intake and biochemical markers in depressed patients vs controls; depressed group had poorer diet and lower serum B12 and folate.

Trust comment: Case-control study with direct biochemical measures but small sample size and self-reported diet data limit strength of inference.

Study Details

PMID:26413529
Participants:59
Impact:increased (significant vs controls, p<0.05)
Trust score:3/5

stroke severity/disability

1 evidences

Large RCT: folic acid+B6+B12 lowered homocysteine and reduced stroke incidence but did not affect stroke severity or disability.

Trust comment: Large, high-quality randomized trial showing reduced stroke incidence with homocysteine-lowering B-vitamin therapy but no effect on severity or disability.

Study Details

PMID:19228852
Participants:5522
Impact:no significant change
Trust score:5/5

pain severity (VAS)

1 evidences

Breast cancer patients receiving docetaxel got either Goshajinkigan or mecobalamin (B12); the mecobalamin (B12) group had a much higher rate and greater severity of neuropathy than GJG group.

Trust comment: Randomized open-label trial with small sample; shows higher neuropathy incidence and severity in the mecobalamin group compared with GJG, but open design and small size limit conclusions.

Study Details

PMID:24377531
Participants:60
Impact:Mean VAS 4.9 ± 2.4 in B12 group vs 2.7 ± 2.2 in GJG group (worse in B12 group)
Trust score:3/5

total plasma homocysteine

5 evidences

Antioxidant vitamins, with or without B-group vitamins (including B12), improved antioxidant capacity, lowered oxidative damage markers and reduced CRP after acute ischemic stroke; B vitamins reduced homocysteine.

Trust comment: Randomized trial with relevant biochemical endpoints and adequate sample size for an acute intervention study.

Study Details

PMID:16517955
Participants:96
Impact:decrease in B-group vitamin recipients (versus rise with antioxidants alone)
Trust score:4/5

Pre-op IV B-vitamin (including B12) massively raised B12/folate but did not prevent the nitrous oxide–induced rise in homocysteine.

Trust comment: Randomized study with objective biochemical outcomes and clear measurements, but modest sample size.

Study Details

PMID:20477781
Participants:59
Impact:+18% (≈+1.9 μmol/L) increase after nitrous oxide despite B-vitamin infusion
Trust score:4/5

Folic acid/vitamin B12 lowered homocysteine but did not improve angiographic measures and was associated in post hoc analysis with increased odds of rapid progression.

Trust comment: Randomized trial substudy with objective angiographic and biochemical measures and adequate sample, though some findings arise from post hoc analyses.

Study Details

PMID:20494665
Participants:348
Impact:-22% with folic acid/vitamin B12 treatment
Trust score:4/5

Eight weeks of folic acid plus vitamin B12 lowered homocysteine and improved endothelial (flow-mediated) dilation in men with coronary heart disease.

Trust comment: Controlled trial with placebo comparison in CHD patients showing biomarker and functional vascular improvement; sample moderate (n=89) and intervention combined folate+B12.

Study Details

PMID:11076820
Participants:89
Impact:-3.7 μmol/L (13.0→9.3 μmol/L)
Trust score:4/5

In a short randomized study, hydrochlorothiazide raised plasma homocysteine and markers of renal function, whereas captopril did not.

Trust comment: Randomized prospective study but small, short-duration and preliminary, limiting generalizability.

Study Details

PMID:12647260
Participants:40
Impact:increase +16% with hydrochlorothiazide (P = .003)
Trust score:3/5

temperature rebound (vascular reactivity)

1 evidences

Aged garlic extract plus B‑vitamin supplement for 1 year reduced coronary calcium progression and improved some vascular/oxidative biomarkers compared with placebo.

Trust comment: Randomized double-blind trial but small sample and the intervention combined multiple ingredients (including B12), so effects cannot be attributed to B12 alone.

Study Details

PMID:19573556
Participants:65
Impact:increased (favorable) in AGE+S vs placebo
Trust score:3/5

hyperhomocysteinemia prevalence

1 evidences

Older hospitalized patients given a mixed B‑vitamin drink had lower plasma homocysteine after 6 weeks, with partial return after stopping.

Trust comment: Well‑conducted randomized placebo‑controlled trial (n=236) but intervention was a mixed B‑vitamin formula (not B12 alone), limiting attribution to B12.

Study Details

PMID:23591663
Participants:236
Impact:supplement group 55%→29% at end of treatment (baseline→6 weeks)
Trust score:3/5

serum vitamin B12 level

1 evidences

Dietary advice improved depressive symptoms but did not increase serum vitamin B12 after six months, likely due to poor adherence.

Trust comment: Randomized trial but small sample and insufficient adherence limited detectable changes in micronutrient levels.

Study Details

PMID:25726209
Participants:77
Impact:no significant change after 6 months
Trust score:3/5

genotype-dependent response (MTHFR)

1 evidences

In hemodialysis patients, consecutive folic acid and vitamin B12 treatments lowered homocysteine; the decrease depended on MTHFR genotype and was larger when starting with folic acid.

Trust comment: Randomized, blinded study in humans with clear outcomes and genotype stratification, though substantial mortality reduced numbers.

Study Details

PMID:16391331
Participants:148
Impact:greater tHcy decrease in T/T genotype; larger decrease when treatment started with folic acid
Trust score:4/5

DVT recurrence rate

1 evidences

Patients given folic acid plus B12 had lower homocysteine, improved coagulation parameters and much lower DVT recurrence than untreated patients.

Trust comment: Randomized clinical comparison with clear clinical endpoints but single-center and limited methodological detail reported.

Study Details

PMID:28617530
Participants:90
Impact:reduced from 28.9% (non-treatment) to 4.4% (treatment) (p<0.05)
Trust score:3/5

blood folate

1 evidences

Three months of folic acid plus small doses of B-vitamins including B12 improved folate and lowered homocysteine in children but did not change cognitive test scores.

Trust comment: Double-blind randomized controlled trial in children with biochemical outcomes and adequate sample but short intervention duration for cognitive effects.

Study Details

PMID:24481688
Participants:237
Impact:median blood folate increased by ~50% with supplementation (P<0.0001)
Trust score:4/5

association between biochemical markers and symptoms

1 evidences

Holotranscobalamin (holoTC) performed well as a diagnostic marker for early B12 deficiency; a randomized subset received B12 or placebo but primary focus was test evaluation.

Trust comment: Large diagnostic cohort with a randomized injection subset (n=140) but primary aim was assay performance rather than clinical endpoints of supplementation.

Study Details

PMID:15715686
Participants:140
Impact:no association observed
Trust score:3/5

plasma total homocysteine (combination group)

1 evidences

In hemodialysis patients, weekly IV vitamin B12 reduced homocysteine substantially and was similarly effective as low-dose folinic acid; combining both gave the largest decrease.

Trust comment: Randomized trial in 75 chronic HD patients with clear numeric outcomes, though specific long-term clinical endpoints were not reported.

Study Details

PMID:19462276
Participants:75
Impact:-38.9% after 3 months
Trust score:4/5

n-3 long-chain PUFA proportion (plasma phosphatidylcholine)

1 evidences

In older adults, B-vitamin supplementation lowered homocysteine but did not change plasma long-chain n-3 PUFA proportions after 2 years.

Trust comment: Double-blind randomized trial with adequate sample (n=253) and objective biochemical outcomes; methods and results are clearly reported.

Study Details

PMID:18287365
Participants:253
Impact:no significant change (e.g., EPA/DPA/DHA differences ≈ 0 mol%)
Trust score:4/5

HOMA (insulin resistance)

1 evidences

In metabolic syndrome patients, combined folate and B12 therapy lowered homocysteine and improved insulin resistance and several measures of endothelial function over 1 month of B-vitamin treatment.

Trust comment: Randomized double-blind parallel study (n=50) with clear biochemical and functional endpoints, though sample size is modest.

Study Details

PMID:15476449
Participants:50
Impact:-27%
Trust score:4/5

Body weight

4 evidences

In obese knee osteoarthritis patients, a low-energy formula diet (containing vitamin D) and weight loss increased serum 25‑OH vitamin D, lowered PTH, and produced a small increase in BMD over 16 weeks.

Trust comment: Large prospective cohort (175 completers) with measured biochemical endpoints and clear pre/post comparisons.

Study Details

PMID:22190136
Participants:175
Impact:−14.0 kg (≈−13.7%)
Trust score:4/5

In adults with overweight/obesity, two high-protein meal-replacement programs (with or without alternate day fasting) produced similar ~11% weight loss and improved metabolic markers; vitamin D levels decreased modestly in both groups by week 16.

Trust comment: Randomized controlled trial with objective biochemical measures showing increased B12 (meal replacements supplied B12); B12 effect is intervention-associated but not isolated.

Study Details

PMID:30142886
Participants:164
Impact:Week 16 weight change: −10.7 ± 0.5 kg (ADF+DER) and −11.2 ± 0.6 kg (DER); no difference between groups
Trust score:4/5

In undernourished psycho-geriatric patients, a multinutrient liquid supplement for 12 weeks increased body weight and improved multiple plasma nutrient levels including vitamin D.

Trust comment: Double-blind, placebo-controlled randomized trial in elderly patients with good completion and multiple measured biomarkers, though modest sample size.

Study Details

PMID:11960300
Participants:35
Impact:+2.2 kg difference vs placebo after 12 weeks (P=0.03)
Trust score:4/5

Identical twins randomized to vegan vs omnivorous diets for 8 weeks; vegans had lower LDL, insulin and weight; serum B12 fell numerically but was not significantly different.

Trust comment: Well-conducted randomized twin RCT with small sample and short duration; measured B12 but change was not statistically significant.

Study Details

PMID:38032644
Participants:42
Impact:−1.9 kg
Trust score:4/5

iron status

1 evidences

Providing a daily animal-source snack for 6 months markedly reduced the prevalence of low zinc intake among women and improved several micronutrient intakes/status markers.

Trust comment: Randomized intervention with biochemical measures and 6-month follow-up, moderate completion (89/117).

Study Details

PMID:28424257
Participants:89
Impact:Improved iron status (biomarker change reported by study; exact magnitude not provided in excerpt)
Trust score:4/5

Clox-1 (cognitive test)

1 evidences

A multi-nutrient formulation including vitamin B12 produced short-term improvements in some cognitive test scores vs placebo in patients with Alzheimer's disease.

Trust comment: Double-blind randomized phase II trial with positive cognitive outcomes, but formulation contained multiple active agents so effects cannot be ascribed to B12 specifically.

Study Details

PMID:25589719
Participants:106
Impact:improved vs placebo (p=0.0083; 95% CI [0.4481,2.9343])
Trust score:3/5

plasma homocysteine (females)

1 evidences

Daily consumption of spreads fortified with folic acid, vitamin B6 and vitamin B12 for 6 weeks raised B-vitamin status and significantly lowered plasma homocysteine in healthy volunteers.

Trust comment: Randomized, double-blind, placebo-controlled trial (n=150) with clear biomarker changes, but intervention combined multiple B-vitamins including B12.

Study Details

PMID:17151589
Participants:150
Impact:spread1 -1.4±1.2 μmol/L (-14.2%); spread2 -2.4±2.0 μmol/L (-23.3%)
Trust score:4/5

recommended dose (RD) for phase II

1 evidences

Folate plus vitamin B12 given with pemetrexed was associated with a tolerable safety profile in Japanese patients and allowed an increased MTD and recommended dose compared with historic non‑supplemented data.

Trust comment: Phase I open-label trial with small treated cohort (n=31); findings show improved tolerability with folate/B12 co‑administration but lack randomized control and rely on historical comparisons.

Study Details

PMID:16940981
Participants:31
Impact:1000 mg/m^2 determined as RD
Trust score:3/5

serum folate and vitamin B12

1 evidences

In 132 hemodialysis patients, supplementation with folate and/or B12 lowered homocysteine, with the magnitude and timing of response differing by C677T MTHFR genotype.

Trust comment: Randomized supplementation in a moderate-sized HD cohort with genotype stratification provides credible genotype-treatment interaction data.

Study Details

PMID:26559681
Participants:132
Impact:levels changed with supplementation (increased corresponding to given vitamin)
Trust score:4/5

adverse reactions

1 evidences

Intramuscular methylcobalamin given three times weekly for two weeks improved pain and disability at two months versus placebo in chronic nonspecific low back pain.

Trust comment: Double-blind randomized controlled trial with low dropout (58 reviewed) showing clinically relevant patient-reported outcomes.

Study Details

PMID:22159928
Participants:58
Impact:minor local reactions reported
Trust score:4/5

plasma total cobalamin

1 evidences

Oral vitamin B12 (with/without folic acid) produced rapid changes in cobalamin biomarkers, with holo-transcobalamin rising markedly within 3 days.

Trust comment: Randomized placebo-controlled human trial with serial biomarker measurements and clear, early biochemical effects of oral B12.

Study Details

PMID:12324494
Participants:88
Impact:+28% at 3 days with further increases by 84 days
Trust score:4/5

Pain (VAS)

1 evidences

In a crossover trial comparing duloxetine vs oral vitamin B12 (1.5 mg/day) for chemotherapy-induced peripheral neuropathy, duloxetine produced greater reductions in numbness and pain than vitamin B12 over 4 weeks.

Trust comment: Small (n=34), open-label randomized crossover with clear outcome measures but limited sample size and blinding.

Study Details

PMID:25762165
Participants:34
Impact:smaller decrease with vitamin B12 vs duloxetine (duloxetine superior; between-group difference at 4 weeks, p=0.04)
Trust score:3/5

red cell/serum folate

1 evidences

A prepared meal plan fortified with micronutrients (including recommended B12) for 10 weeks raised folate and vitamin B12 and reduced serum total homocysteine in high‑risk adults.

Trust comment: Large multicenter randomized trial with objective blood biomarkers and clear statistical significance supporting changes in homocysteine and B12.

Study Details

PMID:10539749
Participants:491
Impact:increased (significant)
Trust score:4/5

total antioxidant capacity

1 evidences

Men with type 2 diabetes given folic acid 5 mg/day for 8 weeks had lower homocysteine and malondialdehyde and improved total antioxidant capacity; serum folate and vitamin B12 levels also increased.

Trust comment: Randomized double-blind trial in humans with clear biomarker changes, but small sample size (n=68) and the intervention was folic acid rather than vitamin B12 directly.

Study Details

PMID:21896879
Participants:68
Impact:increased (significant)
Trust score:3/5

CRP (inflammation)

1 evidences

16-week multivitamin (including B12) raised blood B12 and B6 and produced beneficial changes in homocysteine, CRP and some lipid/oxidative stress markers, but did not improve cognitive test performance in healthy 55–65 y olds.

Trust comment: Randomized double-blind placebo-controlled trials with objective blood biomarkers and adequate sample size by gender, providing credible evidence of B12 level increases from multivitamin supplementation.

Study Details

PMID:25996285
Participants:116
Impact:decreased (women; significant)
Trust score:4/5

lung cancer risk

1 evidences

In older men, serum B12 and folate were not associated with lung cancer risk; higher B6 associated with lower risk.

Trust comment: Prospective nested case-control within a cohort provides moderate-quality observational evidence but cannot prove causation and may have residual confounding.

Study Details

PMID:11282797
Participants:600
Impact:no significant association with serum vitamin B12
Trust score:3/5

oxidative stress markers (SOD, MDA)

1 evidences

In 40 diabetic neuropathy patients, both methylcobalamin and alpha-lipoic acid reduced neuropathy symptoms over 2 weeks; ALA improved antioxidant markers while methylcobalamin improved some sensory deficits.

Trust comment: Randomized small trial (N=40) with short 2-week follow-up and both subjective and objective measures; limited duration and sample size.

Study Details

PMID:27901334
Participants:40
Impact:SOD increased and MDA decreased with alpha-lipoic acid; no change with methylcobalamin
Trust score:3/5

vitamin B12 status and depression

1 evidences

Women given folic-acid-containing multi-micronutrients (including zinc) for 12 weeks had lower average depressive symptoms and lower depression prevalence; no difference between weekly vs daily dosing and no baseline association between zinc and depression.

Trust comment: Large randomized controlled trial (N=459) but used combined micronutrient interventions, so independent effect of B12 cannot be isolated.

Study Details

PMID:19886513
Participants:459
Impact:no association detected
Trust score:4/5

psychological distress (K-10)

1 evidences

Community older adults received folic acid+B12 or placebo; supplementation did not clearly enhance antidepressant effects on depressive symptoms.

Trust comment: Randomized trial with adequate sample size and repeated measures though effect sizes were small.

Study Details

PMID:20805005
Participants:900
Impact:small interaction detected (p=0.041) but clinical relevance unclear
Trust score:4/5

schizophrenia symptoms (PANSS score)

1 evidences

Schizophrenic patients with high homocysteine received B vitamins and showed lower homocysteine and better clinical and cognitive scores versus placebo.

Trust comment: Randomized double-blind placebo-controlled crossover in human patients; good design and reported significant clinical and cognitive improvements.

Study Details

PMID:16412989
Participants:42
Impact:decrease (significant)
Trust score:4/5

effective rate

1 evidences

Diabetic neuropathy patients receiving electroacupuncture plus methylcobalamin injection had better nerve conduction and symptom scores than those receiving methylcobalamin injection alone.

Trust comment: Randomized 60-patient clinical observation with clear outcome measures but likely unblinded and both groups received methylcobalamin, limiting attribution solely to B12.

Study Details

PMID:21823284
Participants:60
Impact:90.0% vs 63.3% (combined vs injection alone); +26.7 percentage points
Trust score:3/5

vibration perception

1 evidences

Benfotiamine (alone or with B6 and B12) improved vibration perception, motor function and overall neuropathy symptoms in patients with alcoholic polyneuropathy over 8 weeks.

Trust comment: Multicenter, randomized, placebo-controlled double-blind trial with 84 completers supports moderate-high reliability.

Study Details

PMID:9872352
Participants:84
Impact:significant improvement during study
Trust score:4/5

MLH1 promoter methylation (CpG2)

1 evidences

Among elderly Chileans exposed to folic acid fortification, high serum folate was associated with increased DNA methylation in specific CpG sites of p16, MLH1 and MGMT, while low vitamin B12 showed no significant association with methylation.

Trust comment: Well-characterized cross-sectional study with comprehensive assays but observational design limits causal inference.

Study Details

PMID:28748002
Participants:249
Impact:high folate associated with OR 3.73 for increased methylation (CpG2)
Trust score:3/5

endothelium-independent vasodilatation

2 evidences

In renal-transplant patients with high homocysteine, vitamin B treatment (including B12) lowered homocysteine and improved endothelium-dependent and -independent vasodilation over 6 months.

Trust comment: Small randomized controlled human trial (n=36) showing statistically significant biochemical and vascular function improvements; limited sample size.

Study Details

PMID:16083628
Participants:36
Impact:12% → 18% (≈ +6 percentage points)
Trust score:4/5

B-vitamin combination (including 1000 µg B12) for 6 months lowered homocysteine and improved endothelium-dependent and -independent vasodilation in renal transplant recipients.

Trust comment: Randomized small trial with clear physiological outcomes, but used combined B-vitamin therapy so effects cannot be attributed solely to B12.

Study Details

PMID:18206175
Participants:36
Impact:increase from 12.2%±4.7% to 17.6%±3.9% (+5.4 percentage points, p<0.01)
Trust score:3/5

red-cell folate

1 evidences

Hospitalised older patients given a daily oral nutritional supplement (including vitamins) had improved depressive symptoms at 6 months but no cognitive change.

Trust comment: Well-conducted double-blind RCT with clear outcome on depressive symptoms, though effect is from a multinutrient supplement rather than isolated B12.

Study Details

PMID:17662509
Participants:225
Impact:significant increase (supplement vs placebo)
Trust score:4/5

plasma CF6

1 evidences

In stroke patients, treatment with folic acid plus vitamin B12 for 2 months lowered homocysteine and CF6 levels compared with no vitamin treatment.

Trust comment: Randomized assignment to vitamin treatment vs no treatment, but folic acid and B12 were combined so effects cannot be attributed to B12 alone.

Study Details

PMID:20092401
Participants:59
Impact:decreased after 2 months of folic acid + B12 treatment
Trust score:3/5

hypoesthesia

1 evidences

Mecobalamin treatment improved neuropathic symptoms and some nerve function measures in diabetic patients versus control vitamin B12 regimen.

Trust comment: Randomized clinical trial with clear symptom improvements, but details on blinding and full methodology are limited in the excerpt.

Study Details

PMID:11798619
Participants:108
Impact:improved in 55% vs 25% — approx +30 percentage points
Trust score:3/5

pain

2 evidences

In lumbar spinal stenosis patients, methylcobalamin plus standard care did not change pain or neurologic signs but improved walking distance for neurogenic claudication.

Trust comment: Randomized single-blind trial with moderate sample size (70 in methylcobalamin arm); single-blind design limits blinding.

Study Details

PMID:10998833
Participants:70
Impact:no significant change
Trust score:4/5

In patients with mild–moderate carpal tunnel syndrome awaiting surgery, a twice-daily multi-nutrient supplement (including B vitamins and B12) for 60 days improved symptoms and pain versus no treatment.

Trust comment: Randomized prospective trial but open-label, single-center with modest sample and multi-nutrient formulation (B12 not isolated), limiting attribution to B12 specifically.

Study Details

PMID:37366197
Participants:147
Impact:Significant reduction with supplement (p<0.05)
Trust score:3/5

erythrocyte folate

1 evidences

Drinking mineral water fortified with folic acid, vitamins (including D) and calcium for 8 weeks raised folate, lowered homocysteine, and increased urinary calcium excretion, indicating bioavailable calcium.

Trust comment: Randomized, double-blind, placebo-controlled trial with good completion (60) showing statistically significant biochemical effects, though intervention was a multi‑nutrient combination.

Study Details

PMID:14749760
Participants:60
Impact:increased by +199 nmol/L (P<0.001)
Trust score:4/5

fasting plasma homocysteine

1 evidences

Randomized controlled study of low- vs high-dose hormone therapy versus control in postmenopausal women assessing fasting and post-methionine homocysteine and B-vitamin levels.

Trust comment: Randomized controlled design with clear biochemical outcomes, but small sample size and indirect focus on vitamin B12 (as an affected biomarker) limit strength for B12-specific conclusions.

Study Details

PMID:17000586
Participants:48
Impact:Reduced by both HT doses; reduction inversely related to pretreatment homocysteine levels (regression slope reported)
Trust score:3/5

plasma S-adenosylhomocysteine (AdoHcy)

1 evidences

In older adults, a daily B-vitamin supplement (folate, B12, B6) lowered plasma total homocysteine but did not change plasma AdoHcy or AdoMet after 2 years.

Trust comment: Randomized placebo-controlled trial with moderate-to-large sample for older adults; measured subset (100) analyzed for these metabolites.

Study Details

PMID:20089204
Participants:100
Impact:no significant change (-1%, ns)
Trust score:4/5

sexual bother (SXB)

1 evidences

Randomized trial comparing mecobalamin (1,500 µg/day) versus no mecobalamin after nerve-sparing prostatectomy; no significant improvement in urinary or sexual function, with a non-significant early urinary recovery trend.

Trust comment: Small randomized controlled trial with objective endpoints but likely underpowered; results were mostly non-significant.

Study Details

PMID:19198223
Participants:54
Impact:trend toward improvement throughout follow-up (no significant difference reported)
Trust score:3/5

DTI apparent diffusion coefficient (ADC, tibial & peroneal)

1 evidences

Injecting mecobalamin at the Zusanli acupoint improved nerve imaging markers and symptoms modestly compared with intramuscular injection over 14 days.

Trust comment: Small single-center randomized study with objective imaging endpoints but short treatment (14 days) and limited sample size.

Study Details

PMID:35765223
Participants:40
Impact:AI: peroneal 1.44 vs MI 1.61 (−0.17×10⁻³ mm²/s); tibial 1.54 vs MI 1.60 (−0.06×10⁻³ mm²/s); P<0.05 (lower in acupoint injection)
Trust score:3/5

Serum vitamin B12 deficiency prevalence

1 evidences

Daily supervised iron+folic acid with or without vitamin B12 for 90 days increased hemoglobin and corrected deficiencies, but adding B12 did not improve hemoglobin.

Trust comment: Cluster-randomized, supervised supplementation with biochemical outcomes; however only a subset (200) completed 90 supervised doses reported here.

Study Details

PMID:33828241
Participants:200
Impact:Reduced to 2.5% in the experimental group post-intervention
Trust score:4/5

Risk of cognitive impairment/dementia

1 evidences

Two-year randomized double-blind trial found no cognitive benefit from daily B12/B6/folic acid supplementation in hypertensive men aged ≥75.

Trust comment: Well-conducted randomized, double-blind placebo-controlled trial with objective cognitive outcomes and adequate follow-up.

Study Details

PMID:20861451
Participants:299
Impact:Nonsignificant ~28% lower risk (OR/HR 0.72) but confidence intervals crossed 1
Trust score:5/5

plasma cobalamin (geometric mean)

1 evidences

Cross-sectional baseline biochemical analysis of infants (6–11 months) showing variable cobalamin status: depending on marker, a large proportion had functional indicators of low B12 while folate was adequate.

Trust comment: Well-conducted community-based biochemical assessment with multiple functional B12 markers; cross-sectional design limits causal inference.

Study Details

PMID:29783689
Participants:316
Impact:271.6 pmol/L
Trust score:4/5

vitamin B12 insufficiency

1 evidences

Compared quintuply-fortified salt (including iodine) versus iodized salt in nonpregnant reproductive-age women; QFS improved several micronutrient deficiencies versus iodized salt.

Trust comment: Large, double-blind randomized community trial with objective biomarker endpoints and sustained 12-month follow-up.

Study Details

PMID:40610127
Participants:998
Impact:odds −80% (OR 0.20) at 6 months vs iodized salt
Trust score:5/5

milk DHA content

1 evidences

In lactating women, daily multiple micronutrient supplement (including vitamin D, DHA, lutein) for ~12 weeks increased milk DHA and raised maternal blood levels of several nutrients including 25-OH-vitamin D; well tolerated.

Trust comment: Randomized, double-blind trial with targeted biochemical endpoints but modest sample size and limited population diversity.

Study Details

PMID:33339438
Participants:65
Impact:LS mean difference +0.15 wt% total fatty acids (increase from 0.25% to 0.35% vs decrease to 0.21%; p<0.0001)
Trust score:4/5

FAAM activities of daily living (ADL) score

1 evidences

Mecobalamin (a form of B12) improved foot/ankle function at 3 months and reduced pregabalin use over 12 months, but benefits were not sustained at later follow-ups.

Trust comment: Randomized trial with objective functional outcomes but small sample and transient effect limit confidence.

Study Details

PMID:39297877
Participants:47
Impact:improvement at 3 months: mecobalamin 74.5 vs placebo 62.2 (≈+12.3 points; P<.05)
Trust score:3/5

total plasma antioxidant capacity (TAOC)

1 evidences

Antioxidant vitamins, with or without B-group vitamins (including B12), improved antioxidant capacity, lowered oxidative damage markers and reduced CRP after acute ischemic stroke; B vitamins reduced homocysteine.

Trust comment: Randomized trial with relevant biochemical endpoints and adequate sample size for an acute intervention study.

Study Details

PMID:16517955
Participants:96
Impact:increase in antioxidant treatment groups vs decline in controls
Trust score:4/5

ALS functional status (ALSFRS-R)

1 evidences

Ultrahigh‑dose intramuscular methylcobalamin slowed functional decline over 16 weeks in early ALS compared with placebo, with similar adverse event rates.

Trust comment: Multicenter, double-blind, placebo-controlled phase 3 RCT with adequate randomization and completion rates.

Study Details

PMID:35532908
Participants:126
Impact:+1.97 points (less decline) at week 16 vs placebo (-2.66 vs -4.63)
Trust score:5/5

plasma choline

1 evidences

In 163 infants, one egg/day for 6 months increased plasma choline and DHA biomarkers and had no effect on plasma vitamin B12 concentrations.

Trust comment: Randomized controlled trial with biomarker endpoints in infants and appropriate analytic adjustments, moderate sample size for biochemical analyses.

Study Details

PMID:29092879
Participants:163
Impact:endline 2.00 vs 1.77 μg/mL in egg vs control (+0.23 μg/mL; effect size ~0.35)
Trust score:4/5

overall clinical effective rate

1 evidences

Small randomized trial where high-dose IV methylcobalamin added to bortezomib therapy reduced the incidence of bortezomib-induced peripheral neuropathy compared with control.

Trust comment: Direct intervention with a B12 form (mecobalamin) but single-centre trial with small sample size limits confidence.

Study Details

PMID:28446297
Participants:65
Impact:77.78% (HDIME) vs 73.68% (control), P>0.05 (ns)
Trust score:3/5

quality of life score

1 evidences

Randomized trial found that local methylcobalamin plus lidocaine injections (especially if given 4–7 days after rash onset) reduced pain faster and improved quality of life in acute herpetic neuralgia versus control regimens.

Trust comment: Well-conducted randomized trial with adequate sample and clear, clinically relevant outcomes using methylcobalamin (direct B12 form).

Study Details

PMID:26814241
Participants:204
Impact:higher in treatment groups (IE-Tr 81.2 ±6.9; ES-Tr 88.3 ±8.6) vs controls
Trust score:4/5

nerve conduction velocity / amplitude

1 evidences

Multicenter double-blind RCT showed methylcobalamin (MC) was effective in improving neuropathic symptom and disability scores and neurophysiological parameters in diabetic peripheral neuropathy and was non-inferior to acetyl-L-carnitine.

Trust comment: High-quality multicenter, randomized, double-blind trial directly testing methylcobalamin with robust outcomes and low dropout.

Study Details

PMID:27180954
Participants:204
Impact:improved in multiple nerves (e.g., median sensory NCV +6.42 ±12.73 m/s in MC group for those measured)
Trust score:5/5

uracil incorporation in DNA

1 evidences

6-month randomized trial in patients with prior colorectal adenomas comparing folic acid + vitamin B12 vs placebo; biomarkers in rectal DNA were measured.

Trust comment: Randomized human trial (n=86) but used high-dose folic acid together with B12 and most effects were borderline or non-significant, limiting attribution to B12 alone.

Study Details

PMID:17709451
Participants:86
Impact:+5.37 fmol/µg DNA (increase in treated group; change from baseline ~+4.01 fmol/µg, tendency vs placebo)
Trust score:3/5

migraine pain severity

1 evidences

6-month randomized, double-blind placebo-controlled trial of daily B-vitamin supplementation (B6, B9, B12) in women with migraine with aura, assessing homocysteine and migraine outcomes and genotype effects.

Trust comment: Well-designed double-blind randomized trial (n=206) showing clinically relevant reductions in homocysteine and migraine outcomes, with genotype-stratified effects increasing credibility.

Study Details

PMID:22926161
Participants:206
Impact:significant reduction in severity with supplementation (genotype-dependent)
Trust score:4/5

category fluency

1 evidences

In older women with CVD/risk factors, combined B-vitamin supplementation did not change cognitive decline overall; possible benefit in those with low dietary B-vitamin intake.

Trust comment: Large randomized placebo-controlled trial sub-study with repeated measures; results are robust though findings limited to a subgroup for dietary intake.

Study Details

PMID:19064521
Participants:2009
Impact:no significant change (overall)
Trust score:4/5

Arterial stiffness (augmentation index)

1 evidences

In hemodialysis patients, adding methylcobalamin to folate normalized homocysteine more often and reduced ADMA and arterial stiffness more than folate alone over 3 weeks.

Trust comment: Small randomized trial with objective biomarker endpoints but open-label, short duration and no long-term clinical outcomes.

Study Details

PMID:20430500
Participants:40
Impact:decrease only in methylcobalamin group (P=0.03)
Trust score:3/5

healing time (eye opening/crusting)

1 evidences

Local methylcobalamin plus lidocaine injections shortened healing times, produced large and sustained pain reductions, and reduced postherpetic neuralgia incidence in acute ophthalmic herpetic neuralgia.

Trust comment: Randomized controlled trial with clear clinical endpoints and significant effects, though single-center and short-term.

Study Details

PMID:26200815
Participants:98
Impact:time to start/full eye opening and start/full crusting significantly reduced (P<0.05)
Trust score:4/5

inferior whorl length (IWL)

1 evidences

In an 8-week RCT, mecobalamin intramuscular injections improved corneal small-fiber measures and autonomic symptom scores more than oral mecobalamin in mild–moderate diabetic peripheral neuropathy.

Trust comment: Small single-center open-label but assessor-blind RCT with objective imaging endpoints; limited sample size and short duration.

Study Details

PMID:34282267
Participants:32
Impact:injection +4.00 ±3.09 mm/mm² vs tablet -0.22 ±3.92 (P=0.002)
Trust score:3/5

clinically relevant pain reduction (>30%)

1 evidences

Local injection of methylcobalamin plus lidocaine provided greater pain relief and reduced analgesic use compared with systemic methylcobalamin in subacute ophthalmic herpetic neuralgia.

Trust comment: Randomized phase III trial with clear endpoints and clinically meaningful differences; single-center limits external validity.

Study Details

PMID:32372561
Participants:105
Impact:91% in LM vs 66% IM vs 57% OM
Trust score:4/5

adverse events (severity)

1 evidences

Adding B vitamins (thiamine, pyridoxine, cyanocobalamin) to dexketoprofen produced faster and slightly greater pain relief and reduced disability over 7 days compared with dexketoprofen alone.

Trust comment: Well-conducted randomized double-blind multicentre RCT (n=170) with prespecified pain and disability outcomes; short follow-up (7 days) limits long-term inference.

Study Details

PMID:38842764
Participants:170
Impact:Fewer moderate adverse events with dexketoprofen/vitamin B (6.2% vs 41.4% moderate AE in dexketoprofen group)
Trust score:4/5

Major vascular events (stroke, MI, vascular death) - primary composite

1 evidences

Daily B-vitamin (folic acid, B6, B12) vs placebo in 8164 patients after stroke/TIA: overall no significant reduction in major vascular events, but subgroup not on antiplatelet therapy showed fewer events; B-vitamins lowered homocysteine.

Trust comment: Large, randomized double-blind multicentre trial with robust biochemical and clinical outcomes; subgroup post-hoc analysis so exploratory.

Study Details

PMID:22554931
Participants:8164
Impact:−1.56% absolute risk reduction (B-vitamins 15% vs placebo 17%); RR 0.91 (95% CI 0.82–1.00), p=0.05
Trust score:4/5

Plasma vitamin B6 (PLP) and adenoma risk

1 evidences

Nested analysis in a trial of 1,084 individuals with prior adenomas found no significant association between plasma vitamin B12 and risk of new colorectal adenomas.

Trust comment: Large, nested analysis within a randomized trial; observational associations limit causal inference for B12.

Study Details

PMID:18708408
Participants:1084
Impact:Borderline inverse association (Q4 vs Q1 adjusted RR 0.78; Ptrend=0.08)
Trust score:3/5

global cognitive decline (MDRS)

1 evidences

Methylcobalamin plus folic acid lowered homocysteine but did not reduce global cognitive decline over 24 months; a subgroup with high baseline homocysteine had less decline in one cognitive domain.

Trust comment: Well-conducted randomized placebo-controlled trial with adequate duration and completion rate, though subgroup finding is secondary.

Study Details

PMID:21216507
Participants:140
Impact:no significant difference between groups overall
Trust score:4/5

Quality of life

1 evidences

Randomized trial in 90 postherpetic neuralgia patients showing TENS plus local cobalamin injections reduced pain and improved activities of daily living and quality of life.

Trust comment: Randomized controlled trial in humans with clear, clinically relevant outcomes and significant results; single-center and moderate sample size limits generalizability.

Study Details

PMID:24196971
Participants:90
Impact:Improved at study endpoint in cobalamin-containing groups (statistically significant, P<0.05).
Trust score:4/5

birth weight (intention-to-treat)

1 evidences

Large randomized food-based trial: overall no effect on birth weight in intention-to-treat, but per-protocol (supplement ≥90 d preconception) showed +48 g birth weight and reduced low birth weight.

Trust comment: Very large, individually randomized trial with supervised supplementation and robust measurements; partial blinding and loss to follow-up are limitations but overall high quality.

Study Details

PMID:25332324
Participants:6513
Impact:+26 g (treatment 2624 g vs control 2598 g); not significant (P=0.22)
Trust score:5/5

LDL‑cholesterol

1 evidences

Six‑month randomized, double‑blind trial of methylfolate + P5P + methylcobalamin showed large reductions in homocysteine and modest reductions in LDL‑C versus placebo, with greater effects in homozygous minor‑allele genotype subgroup.

Trust comment: Double‑blind randomized placebo‑controlled trial with clear biochemical effects; sample size modest but pre‑specified and analyses appropriate.

Study Details

PMID:38892484
Participants:54
Impact:Treatment: −7.5% vs Placebo: +2.6%; between‑group difference 10.1% (p<0.01)
Trust score:4/5

white matter hyperintensities (WMH) volume change

1 evidences

Two years of daily B-vitamin supplementation did not significantly reduce overall progression of ischemic brain lesions versus placebo, but a predefined subgroup with severe small vessel disease showed less white-matter lesion progression.

Trust comment: Randomized double-blind substudy with objective MRI outcomes; overall null results with a positive effect in a prespecified severe-subgroup limit generalizability.

Study Details

PMID:23093615
Participants:359
Impact:-0.05 cm3 (0.08 vs 0.13 cm3; not significant)
Trust score:4/5

duration of RAS episodes

1 evidences

Daily multivitamin at 100% RDI (including vitamin D among others) did not reduce number or duration of recurrent mouth ulcers compared with placebo over up to 365 days.

Trust comment: Well-designed randomized double-masked trial but used a broad multivitamin, so effects cannot be isolated to B12.

Study Details

PMID:22467697
Participants:160
Impact:-0.33 days (8.66 vs 8.99; not significant)
Trust score:4/5

attachment levels

1 evidences

A two-month adjunctive multi-vitamin supplement reduced gingival inflammation and probing depths in patients with chronic periodontitis compared with placebo.

Trust comment: Randomized trial but small sample and multi-ingredient supplement limit attribution to B12 specifically.

Study Details

PMID:11913269
Participants:63
Impact:no significant change
Trust score:3/5

IPSS score

1 evidences

Randomized single-center trial: Deprox 500 (pollen extract plus multiple B vitamins including B12) improved prostatitis symptom scores more than Serenoa repens after 6 weeks.

Trust comment: Small, single-center RCT without placebo and with a multi-vitamin product — cannot attribute effects specifically to B12 and risk of bias exists.

Study Details

PMID:30488800
Participants:63
Impact:mean change −12.7 ± 4.3 (Deprox) vs −7.8 ± 4.7 (Serenoa); Deprox improvement ~74.5%
Trust score:3/5

low cobalamin prevalence

1 evidences

Large community survey showing low plasma cobalamin common in young Indian children, especially in breastfed infants, with associated metabolic markers.

Trust comment: Large population-based sample with biochemical measures; cross-sectional design limits causal inference but data are robust for prevalence estimates.

Study Details

PMID:17991639
Participants:2482
Impact:Plasma cobalamin <150 pmol/L in 36% of breastfed vs 9% of nonbreastfed children
Trust score:4/5

incidence of acute diarrhea (effect of zinc)

1 evidences

Daily zinc reduced the risk of prolonged diarrhea primarily in children with low cobalamin (vitamin B12) status.

Trust comment: Large randomized double-blind trial with prespecified biomarker subgroup analysis, providing robust evidence for effect modification by cobalamin status.

Study Details

PMID:21525251
Participants:2296
Impact:no modification by cobalamin status (no meaningful change)
Trust score:5/5

S-adenosylhomocysteine (SAH)

1 evidences

In elderly with cobalamin deficiency, high-dose oral cyanocobalamin lowered SAH, MMA, and homocysteine.

Trust comment: Direct cobalamin intervention with biochemical endpoints in a convenience sample; methods solid but generalizability limited.

Study Details

PMID:17158426
Participants:149
Impact:decreased (significant) with high‑dose oral cobalamin
Trust score:3/5

vitamin B12 deficiency

1 evidences

After RYGB surgery, use of an optimized multivitamin (WLS Forte) resulted in fewer vitamin B12, ferritin and anemia deficiencies than a standard multivitamin over 3 years.

Trust comment: Triple-blind randomized controlled trial cohort with 3-year follow-up and objective biomarkers, though some loss to follow-up and supplement discontinuation occurred.

Study Details

PMID:26947791
Participants:137
Impact:WLS Forte: 5 cases vs standard MVS: 15 cases (fewer with WLS Forte; P=0.001)
Trust score:4/5

holoTC below deficiency threshold

1 evidences

Partially replacing animal proteins with plant proteins for 12 weeks lowered iodine intake and urinary iodine excretion in healthy adults.

Trust comment: Well-conducted 12-week randomized controlled trial with biomarker measurements, but relatively short duration for long-term status changes.

Study Details

PMID:34837522
Participants:136
Impact:ANIMAL 1 (2.2%), 50/50 5 (10.9%), PLANT 4 (9.1%) at end point
Trust score:4/5

postural disorder (PD)

1 evidences

Randomized trial with placebo, B6 and B12 arms measuring sensory processing; Vitamin-B12 showed no reliable benefit on sensory over-responsivity or postural disorder in the high-score subgroups.

Trust comment: Randomized, double-blind design with a large overall sample but small subgroup sizes for the B12 comparisons, reducing precision of subgroup estimates.

Study Details

PMID:39180365
Participants:300
Impact:no significant change in Vitamin-B12 group (non-significant)
Trust score:4/5

infant serum vitamin B12

1 evidences

Randomized trial in HIV-infected mothers: maternal multivitamin supplementation (including B12) increased infant serum B12 and reduced infant B12 deficiency at 6 weeks and 6 months.

Trust comment: Large randomized clinical trial with objective biomarker outcomes measured in infants at two timepoints.

Study Details

PMID:15956998
Participants:716
Impact:+176 pmol/L at 6 weeks and +127 pmol/L at 6 months (multivitamin vs placebo; P<0.0001)
Trust score:4/5

digit span forward

1 evidences

In a randomized maternal supplementation trial (>700 women), breastmilk Vitamin B12 concentration was positively associated with attention and executive function; MMN/LNS arms had higher breastmilk B12 than IFA.

Trust comment: Large randomized trial with biomarker substudy showing consistent associations between breastmilk B12 and cognitive outcomes, though B12 was not isolated as sole causal agent.

Study Details

PMID:29098783
Participants:712
Impact:+0.12 z-score (association with higher breastmilk Vitamin B12)
Trust score:4/5

prevalence of vitamin B12 deficiency (<150 pmol/L)

1 evidences

In this randomized substudy, antenatal multiple micronutrients (including vitamin D) improved maternal micronutrient biomarkers in late pregnancy but many deficiencies persisted.

Trust comment: Large, cluster-randomized trial substudy with robust measurements and adjustment; high-quality evidence that MM including B12 improved maternal B12 status relative to IFA.

Study Details

PMID:31006806
Participants:1526
Impact:−19% prevalence (PRR 0.81; p=0.002) in MM vs IFA at 32 wk
Trust score:5/5

serum (6S)-5-methyltetrahydrofolate

1 evidences

Elderly participants took folic acid or a B-complex (including B12) for ~23 days; B-complex led to lower unmetabolized folic acid than folic acid alone and both raised methylfolate.

Trust comment: Randomized single-blind trial with small elderly sample and short duration (~23 days); results credible but limited by size and short follow-up.

Study Details

PMID:25943647
Participants:58
Impact:increased: median +9.2 nmol/L (FA) and +6.5 nmol/L (B-complex) vs baseline
Trust score:3/5

folic acid supplementation need

1 evidences

In RYGB patients, a longer biliopancreatic limb (120 cm) did not improve weight loss or comorbidity remission but was associated with greater long-term requirements for vitamin B12 (and folic acid and vitamin A) supplementation.

Trust comment: Large prospective randomized clinical trial with long-term follow-up; clear outcome on supplementation needs though mechanism-based nutritional measures were not deeply detailed here.

Study Details

PMID:31104282
Participants:506
Impact:greater requirement in BPL 120 cm group vs BPL 70 cm during follow-up
Trust score:4/5

postoperative vitamin B12 level

1 evidences

After gastric bypass, daily probiotics reduced bacterial overgrowth and were associated with higher postoperative vitamin B12 levels and greater early weight loss.

Trust comment: Small randomized prospective trial (n=44) with objective measures but limited sample size and follow-up duration; moderate quality.

Study Details

PMID:19381735
Participants:44
Impact:significantly higher in probiotic group vs control (timepoint post-op; reported as significant)
Trust score:3/5

treatment toxicity

2 evidences

In a large phase III trial, adding folic acid and vitamin B12 to chemotherapy reduced treatment toxicity without harming survival outcomes.

Trust comment: Large randomized phase III trial with clear outcomes; vitamin supplementation was added prospectively and toxicity reduction was significant.

Study Details

PMID:12860938
Participants:456
Impact:-significantly reduced with folic acid + vitamin B12 supplementation
Trust score:5/5

Large phase III RCT showed pemetrexed+cisplatin improved survival and progression outcomes versus cisplatin alone; folic acid and vitamin B12 supplementation given with pemetrexed significantly reduced treatment toxicities.

Trust comment: Large, well-conducted phase III RCT (n=456); vitamin B12 was co-administered with folic acid to reduce chemotherapy toxicity but its isolated effect is not separated.

Study Details

PMID:37068377
Participants:456
Impact:decreased (significant) with folic acid + vitamin B12 supplementation in pemetrexed arm
Trust score:4/5

maternal plasma vitamin B-12 concentration

1 evidences

In pregnant women, an MMN supplement containing 15 mg zinc produced maternal plasma zinc concentrations similar to standard iron–folic acid regimens at week 30; MMN increased vitamin B12 but did not change zinc vs controls.

Trust comment: Large randomized prenatal trial with measured biomarkers and good adherence assessment; direct biochemical outcome.

Study Details

PMID:27798335
Participants:641
Impact:MMN 119 pmol/L at 30 wk; MMN vs Fe60F: +9 pmol/L; MMN vs Fe30F: +18 pmol/L (significant, P<0.01)
Trust score:4/5

depressive symptom severity (BDI score)

1 evidences

2-year randomized placebo-controlled trial in men ≥75 y testing daily B12 (400 μg) + folic acid (2 mg?) + B6; found no benefit of B-vitamin treatment vs placebo on depressive symptom severity or incidence of clinically significant depression.

Trust comment: Placebo-controlled randomized trial in older men with low dropout; direct clinical outcome measured.

Study Details

PMID:18557664
Participants:241
Impact:No significant difference over 2 years (F=0.76, p=0.384)
Trust score:4/5

global cognition (Z-score) — high DHA tertile

1 evidences

Post-hoc analysis of an RCT of folic acid + B12 (2-year intervention) showing that benefit of B-vitamin supplementation on global cognition was present in participants with high baseline plasma DHA (high-tertile) but not in lower DHA tertiles.

Trust comment: Post-hoc subset analysis of an RCT (exploratory, limited sample); suggests DHA-modified effect but not prespecified.

Study Details

PMID:35704085
Participants:191
Impact:Treatment effect ΔZ = +0.24 ± 0.07 in high DHA tertile (p=0.01)
Trust score:3/5

Schirmer's test (tear production)

1 evidences

Clinical study in cataract surgery patients: dry eye patients randomized to hyaluronic acid 0.15% plus vitamin B12 eye drops versus no treatment; treatment reduced oxidative stress markers and improved dry-eye clinical scores.

Trust comment: Small randomized clinical study with objective oxidative stress and symptom measures, but limited sample and surgical population context.

Study Details

PMID:25398660
Participants:103
Impact:Significant increase after treatment vs untreated dry eye
Trust score:3/5

major vascular events (MI/stroke/amputation)

1 evidences

In patients with advanced CKD/ESRD, high-dose folic acid plus B vitamins including cyanocobalamin (B12) lowered homocysteine but did not reduce mortality or major vascular events over ~3.2 years.

Trust comment: Large, multicenter double-blind randomized trial with hard clinical endpoints and long follow-up, high credibility.

Study Details

PMID:17848650
Participants:2056
Impact:no significant differences vs placebo
Trust score:5/5

pain severity

1 evidences

Single-center randomized trial of local injections for herpetic itching found injected cobalamin (B12) significantly relieved pain and improved daily activities and quality of life compared with controls.

Trust comment: Randomized controlled single-center trial with small groups (n≈20 per arm); results suggest benefit but sample size and single-center design limit generalizability.

Study Details

PMID:23887347
Participants:80
Impact:significant analgesic effect for locally injected cobalamin (18 patients achieved ≥30% pain reduction in B12 group)
Trust score:3/5

serum methylmalonic acid (S-MMA)

1 evidences

Four-month randomized placebo-controlled trial in elderly people showing B-vitamin supplementation lowers markers of B12/folate deficiency.

Trust comment: Double-blind placebo-controlled RCT in 209 elderly subjects with clear biochemical endpoints and statistically significant results.

Study Details

PMID:14576756
Participants:209
Impact:significant decrease (P=0.009)
Trust score:4/5

major cardiovascular events (trial primary outcome)

1 evidences

Large randomized trial protocol in high-risk adults testing folic acid + vitamins B6 and B12 versus placebo with cardiovascular events as the primary outcome.

Trust comment: Large, well-powered randomized trial protocol across many centers; this paper reports design and baseline data rather than outcomes.

Study Details

PMID:16450017
Participants:5522
Impact:trial designed to assess effect over ~5 years (no outcome results in this paper)
Trust score:4/5

letter verbal fluency (VFT)

1 evidences

Eight-week randomized controlled trial of an antioxidant mix (including vitamin B12) in older adults showing improved executive function and reduced oxidative stress markers versus placebo.

Trust comment: Randomized double-blind RCT with clear cognitive and biomarker endpoints, but the active product is a multi-ingredient mix so effects cannot be attributed to B12 alone.

Study Details

PMID:33375429
Participants:80
Impact:increase: active group +5.28 words vs control +1.07 words; treatment difference +4.33 words (P=0.0009)
Trust score:4/5

facial nerve score

1 evidences

Methylcobalamin (vitamin B12 form) shortened time to full facial recovery and improved facial nerve scores compared with steroid alone.

Trust comment: Small randomized open trial showing large effects, but limited by small size and open (non-blinded) design.

Study Details

PMID:8749227
Participants:60
Impact:significantly better at 1–3 weeks in methylcobalamin-treated groups (p<0.001)
Trust score:3/5

relapse risk after initial remission

1 evidences

Adjunctive B-vitamin supplementation did not change 12-week antidepressant remission but improved sustained response over 52 weeks and reduced relapse risk.

Trust comment: Randomized, double-blind, placebo-controlled trial with adequate follow-up and clinically relevant endpoints.

Study Details

PMID:25257064
Participants:153
Impact:reduced (OR=0.33; 95% CI 0.12–0.94)
Trust score:5/5

anemia prevalence

3 evidences

Double-blind RCT (n=139) comparing an optimized multivitamin vs standard supplement in sleeve gastrectomy patients found improvements in folic acid, vitamin B1, PTH and anemia rates with the optimized supplement but no difference in vitamin D deficiency prevalence.

Trust comment: Double-blind RCT with adequate sample and 12-month follow-up; outcomes biochemical and clinically relevant though supplementation regimes are multinutrient.

Study Details

PMID:31776782
Participants:139
Impact:lower anemia rates with WLS Optimum (1/38 vs 11/63 in sMVS per protocol analysis)
Trust score:4/5

Cluster-RCTs in Kenya and Bangladesh delivering LNSs (containing B12) plus counseling increased hemoglobin, reduced anemia and improved vitamin B12 status in young children compared with control.

Trust comment: Large, well-conducted cluster-randomized trials with objective biomarker endpoints and high adherence to LNS, though some attrition and timing issues occurred.

Study Details

PMID:30624600
Participants:2120
Impact:reduction of ~12–22 percentage points in Kenya (N, WSH+N) and ~9 percentage points in Bangladesh; relative reductions ~26–50% depending on site
Trust score:5/5

Fortified salt containing iodine and other micronutrients given to children and women for 8 months improved iron and zinc status and reduced anemia; urinary iodine was maintained in the fortified group.

Trust comment: Randomized controlled trial with objective blood measures; however vitamin B12 was one of several micronutrients so effects cannot be attributed specifically to B12.

Study Details

PMID:33952731
Participants:212
Impact:-38.4 percentage points (67.5% → 29.1%)
Trust score:4/5

endothelium-dependent dilatation

1 evidences

Young men with high homocysteine took B-vitamin supplements for 8 weeks; homocysteine fell but artery function did not change.

Trust comment: Double-blind randomized trial in 40 subjects with clear endpoints but modest sample size.

Study Details

PMID:12430779
Participants:40
Impact:no change
Trust score:4/5

adenosine-induced coronary blood flow

1 evidences

Stable CAD patients randomized to folic acid plus vitamin B12 showed increased basal and adenosine-induced coronary blood flow after 24 months versus placebo.

Trust comment: Randomized trial with invasive physiological measures and long follow-up; small sample size reduces generalizability.

Study Details

PMID:21389855
Participants:40
Impact:increased (significant vs placebo at 24 months, p<0.05)
Trust score:4/5

composite cardiovascular events (recurrent MI, stroke, sudden coronary death)

1 evidences

Large randomized trial after acute MI showed folic acid plus vitamin B12 lowered homocysteine markedly but did not reduce recurrent cardiovascular events; possible harm suggested in combined-vitamin arm.

Trust comment: Large, well-conducted randomized trial with robust endpoints; high-quality evidence showing biochemical effect without clinical benefit.

Study Details

PMID:16531614
Participants:3749
Impact:no significant change (risk ratio 1.08; 95% CI 0.93–1.25; P=0.31)
Trust score:5/5

stroke incidence

1 evidences

Large RCT: folic acid+B6+B12 lowered homocysteine and reduced stroke incidence but did not affect stroke severity or disability.

Trust comment: Large, high-quality randomized trial showing reduced stroke incidence with homocysteine-lowering B-vitamin therapy but no effect on severity or disability.

Study Details

PMID:19228852
Participants:5522
Impact:reduced (HR 0.75; ~25% relative risk reduction)
Trust score:5/5

late luminal loss

1 evidences

Multicenter double-blind RCT after coronary stenting: folate/B6/B12 therapy increased angiographic restenosis and repeat revascularization compared with placebo.

Trust comment: Large, double-blind multicenter RCT showing a statistically significant adverse effect of folate/B-vitamin therapy on restenosis outcomes.

Study Details

PMID:15215483
Participants:636
Impact:increase (mean 0.90 mm vs 0.76 mm; difference +0.14 mm, P=0.004)
Trust score:5/5

High migraine disability (proportion)

1 evidences

Women with migraine took a daily vitamin tablet (1 mg folic acid + B6 + B12) for 6 months; B12 levels rose but homocysteine and migraine outcomes did not change significantly.

Trust comment: Randomized double-blind trial with moderate sample and modified ITT; outcomes largely non-significant and treatment was a combination so B12-specific effects are not isolated.

Study Details

PMID:27339806
Participants:189
Impact:-34 percentage points (79% → 45% in treatment group; difference vs placebo not significant)
Trust score:3/5

Incidence of neuropathy

1 evidences

Breast cancer patients receiving docetaxel got either Goshajinkigan or mecobalamin (B12); the mecobalamin (B12) group had a much higher rate and greater severity of neuropathy than GJG group.

Trust comment: Randomized open-label trial with small sample; shows higher neuropathy incidence and severity in the mecobalamin group compared with GJG, but open design and small size limit conclusions.

Study Details

PMID:24377531
Participants:60
Impact:88.9% in mecobalamin (B12) group vs 39.3% in GJG group (p<0.01)
Trust score:3/5

Visually significant AMD

1 evidences

Large randomized double-blind trial of folic acid + B6 + B12 vs placebo over ~7.3 years showed reduced incidence of AMD and visually significant AMD in the treatment group.

Trust comment: Large, long-duration randomized double-blind trial showing statistically significant reductions in AMD outcomes with combined B-vitamin therapy.

Study Details

PMID:19237716
Participants:5205
Impact:Reduced (26 cases treatment vs 44 placebo); RR 0.59 (95% CI 0.36–0.95), P=0.03
Trust score:4/5

iron status (serum ferritin/total body iron)

1 evidences

Fortifying foods with iron and vitamin B12 for 1 year worked similarly regardless of H. pylori infection status.

Trust comment: Large double-blind randomized controlled trial with objective biomarker outcomes, though fortification combined multiple micronutrients so attribution to B12 alone is limited.

Study Details

PMID:20683455
Participants:543
Impact:no difference in change after fortification between H. pylori+ and H. pylori- children
Trust score:4/5

coronary artery calcium progression

1 evidences

Aged garlic extract plus B‑vitamin supplement for 1 year reduced coronary calcium progression and improved some vascular/oxidative biomarkers compared with placebo.

Trust comment: Randomized double-blind trial but small sample and the intervention combined multiple ingredients (including B12), so effects cannot be attributed to B12 alone.

Study Details

PMID:19573556
Participants:65
Impact:significantly lower progression in AGE+S vs placebo (p<0.05)
Trust score:3/5

rapid angiographic progression (post hoc)

1 evidences

Folic acid/vitamin B12 lowered homocysteine but did not improve angiographic measures and was associated in post hoc analysis with increased odds of rapid progression.

Trust comment: Randomized trial substudy with objective angiographic and biochemical measures and adequate sample, though some findings arise from post hoc analyses.

Study Details

PMID:20494665
Participants:348
Impact:increased odds ratio 1.84 (95% CI 1.07–3.18) with folic acid/vitamin B12
Trust score:4/5

folate level

1 evidences

In haemodialysis patients, alternating vitamin B12 and folic acid lowered homocysteine; effects depended on genotype and dialysis membrane type.

Trust comment: Randomized blinded crossover in 74 HD patients; moderate quality but small, specific population limits generalizability.

Study Details

PMID:17342693
Participants:74
Impact:reduced at end of study in haemodialysis patients
Trust score:3/5

plasma homocysteine (Hcy)

1 evidences

Patients given folic acid plus B12 had lower homocysteine, improved coagulation parameters and much lower DVT recurrence than untreated patients.

Trust comment: Randomized clinical comparison with clear clinical endpoints but single-center and limited methodological detail reported.

Study Details

PMID:28617530
Participants:90
Impact:significant decrease with folic acid + B12 treatment (p<0.05)
Trust score:3/5

cognitive performance (memory and other domains)

1 evidences

In elderly people, combined cobalamin (B12) plus folic acid lowered homocysteine and raised betaine, but overall cognitive performance did not improve.

Trust comment: Double-blind, placebo-controlled randomized trial in humans with clear biochemical outcomes, though cognitive changes were not demonstrated.

Study Details

PMID:17537289
Participants:195
Impact:no overall improvement; borderline better memory in those with largest betaine increases (p=0.07)
Trust score:4/5

tingling sensation score

1 evidences

Vitamin B12 injections reduced pain, paresthesia and tingling more than nortriptyline in people with painful diabetic neuropathy.

Trust comment: Randomized single-blind trial with 100 completers and statistically strong differences (P<0.001), though single-blind and comparator is an active drug.

Study Details

PMID:19212856
Participants:100
Impact:-3.48 units (vitamin B12 group)
Trust score:4/5

plasma vitamin B12 diagnostic accuracy (AUC)

1 evidences

Holotranscobalamin (holoTC) performed well as a diagnostic marker for early B12 deficiency; a randomized subset received B12 or placebo but primary focus was test evaluation.

Trust comment: Large diagnostic cohort with a randomized injection subset (n=140) but primary aim was assay performance rather than clinical endpoints of supplementation.

Study Details

PMID:15715686
Participants:140
Impact:AUC 0.85
Trust score:3/5

plasma total homocysteine (folinic acid group)

1 evidences

In hemodialysis patients, weekly IV vitamin B12 reduced homocysteine substantially and was similarly effective as low-dose folinic acid; combining both gave the largest decrease.

Trust comment: Randomized trial in 75 chronic HD patients with clear numeric outcomes, though specific long-term clinical endpoints were not reported.

Study Details

PMID:19462276
Participants:75
Impact:-16.4% after 3 months
Trust score:4/5

insulin level

1 evidences

In metabolic syndrome patients, combined folate and B12 therapy lowered homocysteine and improved insulin resistance and several measures of endothelial function over 1 month of B-vitamin treatment.

Trust comment: Randomized double-blind parallel study (n=50) with clear biochemical and functional endpoints, though sample size is modest.

Study Details

PMID:15476449
Participants:50
Impact:-~25.6% (19.9 → 14.8 μU/mL)
Trust score:4/5

plasma 25-OH vitamin D

1 evidences

In obese knee osteoarthritis patients, a low-energy formula diet (containing vitamin D) and weight loss increased serum 25‑OH vitamin D, lowered PTH, and produced a small increase in BMD over 16 weeks.

Trust comment: Large prospective cohort (175 completers) with measured biochemical endpoints and clear pre/post comparisons.

Study Details

PMID:22190136
Participants:175
Impact:+15.3 nmol/L (≈+31.3%)
Trust score:4/5

dietary vitamin B12 intake (below EAR)

1 evidences

Providing a daily animal-source snack for 6 months markedly reduced the prevalence of low zinc intake among women and improved several micronutrient intakes/status markers.

Trust comment: Randomized intervention with biochemical measures and 6-month follow-up, moderate completion (89/117).

Study Details

PMID:28424257
Participants:89
Impact:Intakes below EAR eliminated in ASF group (reduced to 0%)
Trust score:4/5

compliance / adverse events

1 evidences

Three-arm randomized trial (drink powder with betaine + B‑vitamins, UNIMMAP multivitamin, control) in 298 women; both supplements substantially lowered plasma homocysteine versus control, drink powder > UNIMMAP.

Trust comment: Well-powered randomized controlled trial with objective biochemical primary outcome, high compliance, and appropriate analyses.

Study Details

PMID:31408467
Participants:298
Impact:very high compliance (~98%); low and similar AEs across interventions
Trust score:5/5

plasma homocysteine (males)

1 evidences

Daily consumption of spreads fortified with folic acid, vitamin B6 and vitamin B12 for 6 weeks raised B-vitamin status and significantly lowered plasma homocysteine in healthy volunteers.

Trust comment: Randomized, double-blind, placebo-controlled trial (n=150) with clear biomarker changes, but intervention combined multiple B-vitamins including B12.

Study Details

PMID:17151589
Participants:150
Impact:spread1 -0.7±1.5 μmol/L (-6.8%); spread2 -1.7±1.7 μmol/L (-17.6%)
Trust score:4/5

maximum tolerated dose (MTD) of pemetrexed

1 evidences

Folate plus vitamin B12 given with pemetrexed was associated with a tolerable safety profile in Japanese patients and allowed an increased MTD and recommended dose compared with historic non‑supplemented data.

Trust comment: Phase I open-label trial with small treated cohort (n=31); findings show improved tolerability with folate/B12 co‑administration but lack randomized control and rely on historical comparisons.

Study Details

PMID:16940981
Participants:31
Impact:1200 mg/m^2 with folate and B12 co‑administration
Trust score:3/5

disability (Oswestry Disability Index)

1 evidences

Intramuscular methylcobalamin given three times weekly for two weeks improved pain and disability at two months versus placebo in chronic nonspecific low back pain.

Trust comment: Double-blind randomized controlled trial with low dropout (58 reviewed) showing clinically relevant patient-reported outcomes.

Study Details

PMID:22159928
Participants:58
Impact:decreased (significant vs placebo at 2 months)
Trust score:4/5

holo-transcobalamin (holo-TC) and TC saturation

1 evidences

Oral vitamin B12 (with/without folic acid) produced rapid changes in cobalamin biomarkers, with holo-transcobalamin rising markedly within 3 days.

Trust comment: Randomized placebo-controlled human trial with serial biomarker measurements and clear, early biochemical effects of oral B12.

Study Details

PMID:12324494
Participants:88
Impact:holo-TC +54% and TC saturation +82% at 3 days versus control
Trust score:4/5

overall macro- and micronutrient intake

1 evidences

Cluster-RCT assessing dietary intakes over 12 months in children given LNS (contains multiple micronutrients) vs control; dietary recalls used.

Trust comment: Cluster-randomized trial with repeated dietary recalls showing improved nutrient intakes; intake changes documented but clinical outcomes not provided.

Study Details

PMID:25819697
Participants:298
Impact:Larger increases in energy, fat, protein and multiple micronutrients in LNS arm vs control over 12 months
Trust score:3/5

numbness (VAS)

1 evidences

In a crossover trial comparing duloxetine vs oral vitamin B12 (1.5 mg/day) for chemotherapy-induced peripheral neuropathy, duloxetine produced greater reductions in numbness and pain than vitamin B12 over 4 weeks.

Trust comment: Small (n=34), open-label randomized crossover with clear outcome measures but limited sample size and blinding.

Study Details

PMID:25762165
Participants:34
Impact:smaller decrease with vitamin B12 vs duloxetine (duloxetine superior; between-group difference at 4 weeks, p=0.03)
Trust score:3/5

sleep timing and sleep-related symptoms

1 evidences

Methylcobalamin (3 mg/day) did not improve sleep timing, daytime mood, or sleep logs versus placebo in delayed sleep phase syndrome.

Trust comment: Double-blind randomized trial but small sample and short duration; negative result with reasonable internal validity.

Study Details

PMID:9413873
Participants:50
Impact:no significant difference between methylcobalamin and placebo (no numeric change reported)
Trust score:4/5

pressure and pinprick abnormal points

1 evidences

In 40 diabetic neuropathy patients, both methylcobalamin and alpha-lipoic acid reduced neuropathy symptoms over 2 weeks; ALA improved antioxidant markers while methylcobalamin improved some sensory deficits.

Trust comment: Randomized small trial (N=40) with short 2-week follow-up and both subjective and objective measures; limited duration and sample size.

Study Details

PMID:27901334
Participants:40
Impact:decreased with methylcobalamin only
Trust score:3/5

depression prevalence

1 evidences

Women given folic-acid-containing multi-micronutrients (including zinc) for 12 weeks had lower average depressive symptoms and lower depression prevalence; no difference between weekly vs daily dosing and no baseline association between zinc and depression.

Trust comment: Large randomized controlled trial (N=459) but used combined micronutrient interventions, so independent effect of B12 cannot be isolated.

Study Details

PMID:19886513
Participants:459
Impact:decreased from 49.3% to 37.7% (-11.6 percentage points)
Trust score:4/5

incident depression

1 evidences

Older women took daily high-dose folic acid, B6 and B12 or placebo for ~7 years; supplementation lowered homocysteine but did not reduce depression risk.

Trust comment: Large randomized controlled trial with long follow-up and clinically relevant outcomes.

Study Details

PMID:25573400
Participants:4331
Impact:no difference (adjusted RR 1.02, 95% CI 0.86–1.21)
Trust score:5/5

serum vitamin B-12

2 evidences

Reproductive-aged Guatemalan women received weekly or daily folic acid (with B12 and minerals) for 12 weeks; folate improved and homocysteine fell in all groups, daily B12 raised serum B12.

Trust comment: Randomized, double-blind trial with adequate sample size and clear biochemical endpoints.

Study Details

PMID:18641196
Participants:459
Impact:daily supplementation: +20% (95% CI: 8, 33.2); weekly: no effect
Trust score:4/5

Two-week controlled feeding in postmenopausal women showing serum nutrient concentrations (including vitamin B-12) reflect recent intake and can serve as biomarkers.

Trust comment: Well-controlled feeding study in humans (n=153) with objective biomarker measures; high internal validity for biomarker-intake relationships.

Study Details

PMID:28031191
Participants:153
Impact:biomarker correlated with intake (R²=0.51)
Trust score:4/5

hsCRP

1 evidences

In chronic hemodialysis patients given folic acid and B vitamins for 3 months, homocysteine and hsCRP fell significantly in non-diabetic patients but not in diabetic patients.

Trust comment: Pre-post treatment in a modest-sized clinical sample with subgroup analysis; useful but not randomized.

Study Details

PMID:21439275
Participants:61
Impact:decreased from 0.58 to 0.22 mg/dL in non-DM (p<0.001); no significant change in DM
Trust score:3/5

p16 promoter methylation (CpG5)

1 evidences

Among elderly Chileans exposed to folic acid fortification, high serum folate was associated with increased DNA methylation in specific CpG sites of p16, MLH1 and MGMT, while low vitamin B12 showed no significant association with methylation.

Trust comment: Well-characterized cross-sectional study with comprehensive assays but observational design limits causal inference.

Study Details

PMID:28748002
Participants:249
Impact:high folate (>45.3 nmol/L) associated with OR 4.17 for increased methylation (CpG5)
Trust score:3/5

endothelium-dependent vasodilatation

2 evidences

In renal-transplant patients with high homocysteine, vitamin B treatment (including B12) lowered homocysteine and improved endothelium-dependent and -independent vasodilation over 6 months.

Trust comment: Small randomized controlled human trial (n=36) showing statistically significant biochemical and vascular function improvements; limited sample size.

Study Details

PMID:16083628
Participants:36
Impact:9% → 12% (≈ +3 percentage points)
Trust score:4/5

B-vitamin combination (including 1000 µg B12) for 6 months lowered homocysteine and improved endothelium-dependent and -independent vasodilation in renal transplant recipients.

Trust comment: Randomized small trial with clear physiological outcomes, but used combined B-vitamin therapy so effects cannot be attributed solely to B12.

Study Details

PMID:18206175
Participants:36
Impact:increase from 8.8%±5.2% to 12.2%±4.6% (+3.4 percentage points, p<0.01)
Trust score:3/5

blood pressure (systolic/diastolic)

1 evidences

Daily folate + B12 + B6 lowered homocysteine but did not change blood pressure in older adults over 2 years.

Trust comment: Large double-blind randomized placebo-controlled trial with long follow-up and objective measures.

Study Details

PMID:17449579
Participants:276
Impact:No meaningful change versus placebo (mean differences ≤1 mm Hg)
Trust score:5/5

numbness

1 evidences

Mecobalamin treatment improved neuropathic symptoms and some nerve function measures in diabetic patients versus control vitamin B12 regimen.

Trust comment: Randomized clinical trial with clear symptom improvements, but details on blinding and full methodology are limited in the excerpt.

Study Details

PMID:11798619
Participants:108
Impact:improved in 75% vs 45% — approx +30 percentage points
Trust score:3/5

MMSE in demented subgroup

1 evidences

Older adults with low cobalamin received IM cyanocobalamin or no treatment; cognitive results were mixed with no clear consistent benefit.

Trust comment: Randomized trial in older adults (n=50) with biochemical deficiency but small sample, no placebo control, and mixed/weak effects limits strength of conclusions.

Study Details

PMID:9777425
Participants:50
Impact:3 of 7 demented subjects improved MMSE scores (inconsistent across other tests)
Trust score:3/5

urinary bother (URB)

1 evidences

Randomized trial comparing mecobalamin (1,500 µg/day) versus no mecobalamin after nerve-sparing prostatectomy; no significant improvement in urinary or sexual function, with a non-significant early urinary recovery trend.

Trust comment: Small randomized controlled trial with objective endpoints but likely underpowered; results were mostly non-significant.

Study Details

PMID:19198223
Participants:54
Impact:+21.8 points at 3 months (85.7 vs 63.9); no significant difference overall
Trust score:3/5

DTI fractional anisotropy (tibial & peroneal nerves)

1 evidences

Injecting mecobalamin at the Zusanli acupoint improved nerve imaging markers and symptoms modestly compared with intramuscular injection over 14 days.

Trust comment: Small single-center randomized study with objective imaging endpoints but short treatment (14 days) and limited sample size.

Study Details

PMID:35765223
Participants:40
Impact:AI: peroneal 0.36 vs MI 0.31 (+0.05); tibial 0.38 vs MI 0.34 (+0.04); P<0.05 (higher in acupoint injection)
Trust score:3/5

Hemoglobin change

1 evidences

Daily supervised iron+folic acid with or without vitamin B12 for 90 days increased hemoglobin and corrected deficiencies, but adding B12 did not improve hemoglobin.

Trust comment: Cluster-randomized, supervised supplementation with biochemical outcomes; however only a subset (200) completed 90 supervised doses reported here.

Study Details

PMID:33828241
Participants:200
Impact:Experimental (IFA+B12) +1.3 ±1.0 g/dL; Control (IFA+placebo) +1.6 ±1.2 g/dL; addition of B12 showed no benefit on Hb
Trust score:4/5

ADAS-cog change (cognition)

1 evidences

Two-year randomized double-blind trial found no cognitive benefit from daily B12/B6/folic acid supplementation in hypertensive men aged ≥75.

Trust comment: Well-conducted randomized, double-blind placebo-controlled trial with objective cognitive outcomes and adequate follow-up.

Study Details

PMID:20861451
Participants:299
Impact:No difference: vitamins group +0.7 (SD 3.4) vs placebo +0.8 (SD 4.0) over 24 months
Trust score:5/5

Haematologic response (Hb & reticulocytes)

1 evidences

An ultra-short preoperative combination (IV iron, erythropoietin, subcutaneous B12, oral folic acid) reduced perioperative transfusions and raised early haemoglobin and reticulocyte markers.

Trust comment: Large randomized trial with clinically meaningful endpoints, but effects derive from a multi-agent combination so B12-specific contribution is not isolated.

Study Details

PMID:31036337
Participants:1006
Impact:Higher haemoglobin, higher reticulocyte count and reticulocyte haemoglobin content in treatment group during first 7 days (p≤0.001)
Trust score:4/5

hematologic and neurologic abnormalities

1 evidences

Randomized trial in newly diagnosed cobalamin-deficient patients comparing daily oral (2 mg) versus intermittent intramuscular (1 mg) cyanocobalamin for 4 months; oral therapy was at least as effective and produced larger biochemical improvements.

Trust comment: Randomized human trial with objective biochemical and clinical endpoints but small sample size limits precision.

Study Details

PMID:9694707
Participants:33
Impact:clinical correction prompt and indistinguishable between oral and IM
Trust score:4/5

combined cobalamin indicator (3cB12)

1 evidences

Cross-sectional baseline biochemical analysis of infants (6–11 months) showing variable cobalamin status: depending on marker, a large proportion had functional indicators of low B12 while folate was adequate.

Trust comment: Well-conducted community-based biochemical assessment with multiple functional B12 markers; cross-sectional design limits causal inference.

Study Details

PMID:29783689
Participants:316
Impact:mean −0.70; 58% classified as low cobalamin status
Trust score:4/5

genotype-specific effects (MTHFR C677T)

1 evidences

Large randomized trial of folic acid in hypertensive adults showing baseline higher B12 (and folate) associated with lower first ischemic stroke risk and that folic acid supplementation reduced stroke risk especially in subgroups defined by low B12/folate and MTHFR genotype.

Trust comment: Large randomized trial with long follow-up and prespecified endpoints; strong evidence of interaction between B12/folate status and stroke risk/treatment effect.

Study Details

PMID:31932513
Participants:20702
Impact:treatment effect varied by genotype (e.g., CC: HR 0.24 in certain subgroups; TT responded better when both nutrients high)
Trust score:5/5

renal function markers (creatinine, cystatin C)

1 evidences

In a short randomized study, hydrochlorothiazide raised plasma homocysteine and markers of renal function, whereas captopril did not.

Trust comment: Randomized prospective study but small, short-duration and preliminary, limiting generalizability.

Study Details

PMID:12647260
Participants:40
Impact:increase with hydrochlorothiazide (P = .025 and P = .004)
Trust score:3/5

genetic risk score for homocysteine

1 evidences

Cross-sectional analysis in older adults (n=567) found no association between B‑vitamin biomarkers (including B12) or a genetic hyperhomocysteinemia score and arterial stiffness (PWV); observed a homocysteine–gene interaction.

Trust comment: Well-characterized cross‑sectional baseline analysis with moderate sample size but observational design limits causal inference.

Study Details

PMID:24656138
Participants:567
Impact:no direct association with PWV; interaction with measured homocysteine present
Trust score:3/5

incidence of bortezomib-induced peripheral neuropathy

1 evidences

Small randomized trial where high-dose IV methylcobalamin added to bortezomib therapy reduced the incidence of bortezomib-induced peripheral neuropathy compared with control.

Trust comment: Direct intervention with a B12 form (mecobalamin) but single-centre trial with small sample size limits confidence.

Study Details

PMID:28446297
Participants:65
Impact:29.63% (HDIME) vs 55.26% (control) — absolute reduction 25.63 percentage points
Trust score:3/5

time to satisfactory response

1 evidences

Randomized trial found that local methylcobalamin plus lidocaine injections (especially if given 4–7 days after rash onset) reduced pain faster and improved quality of life in acute herpetic neuralgia versus control regimens.

Trust comment: Well-conducted randomized trial with adequate sample and clear, clinically relevant outcomes using methylcobalamin (direct B12 form).

Study Details

PMID:26814241
Participants:204
Impact:median 6 days (ES-Tr) and 11 days (IE-Tr)
Trust score:4/5

neuropathy symptom score (NSS)

1 evidences

Multicenter double-blind RCT showed methylcobalamin (MC) was effective in improving neuropathic symptom and disability scores and neurophysiological parameters in diabetic peripheral neuropathy and was non-inferior to acetyl-L-carnitine.

Trust comment: High-quality multicenter, randomized, double-blind trial directly testing methylcobalamin with robust outcomes and low dropout.

Study Details

PMID:27180954
Participants:204
Impact:MC group change -2.11 ±2.48 from baseline to week 24 (significant)
Trust score:5/5

quality of life / interference with ADL

1 evidences

Single-center RCT found local methylcobalamin injections reduced pain and improved quality of life in subacute herpetic neuralgia versus oral or lidocaine comparators.

Trust comment: Direct methylcobalamin intervention in an RCT, but single-center and modest sample size with limited numeric detail reported here.

Study Details

PMID:23566267
Participants:98
Impact:improved after 28 days of local methylcobalamin
Trust score:3/5

carotid artery plaques

1 evidences

Randomized study adding mecobalamin to standard care in ischemic stroke patients with H-type hypertension and measuring homocysteine, inflammation, plaques and function over 6 months.

Trust comment: Randomized clinical study with adequate sample size (n=224) showing consistent biomarker changes, but some reporting ambiguities and lack of detailed magnitude limit certainty.

Study Details

PMID:30304141
Participants:224
Impact:significant reduction at 3 and 6 months vs control (P<0.05)
Trust score:3/5

verbal memory

1 evidences

In older women with CVD/risk factors, combined B-vitamin supplementation did not change cognitive decline overall; possible benefit in those with low dietary B-vitamin intake.

Trust comment: Large randomized placebo-controlled trial sub-study with repeated measures; results are robust though findings limited to a subgroup for dietary intake.

Study Details

PMID:19064521
Participants:2009
Impact:no significant change (overall)
Trust score:4/5

ADMA level

2 evidences

In hemodialysis patients, adding methylcobalamin to folate normalized homocysteine more often and reduced ADMA and arterial stiffness more than folate alone over 3 weeks.

Trust comment: Small randomized trial with objective biomarker endpoints but open-label, short duration and no long-term clinical outcomes.

Study Details

PMID:20430500
Participants:40
Impact:mean decrease 25.4% ±10.2 vs 13.2% ±11.2 (P<0.001) favoring methylcobalamin
Trust score:3/5

In PCI patients, baseline ADMA and TML were independently associated with angiographic CAD progression; moderate-dose folic acid plus vitamin B12 lowered homocysteine but did not change median ADMA or TML.

Trust comment: Well-conducted randomized trial sub-study with objective angiographic measures and biomarker assays; moderate sample size and appropriate analyses.

Study Details

PMID:23734218
Participants:183
Impact:baseline ADMA associated with greater DS progression; FA/B12 did not alter median ADMA (except small increase at 10th percentile: +0.040 µmol/L)
Trust score:4/5

neuropathic pain (background and peak)

1 evidences

In patients with painful diabetic neuropathy, Milgamma (contains mecobalamin/cyanocobalamin) produced significant pain relief and improved vibration perception versus comparator over 3 months.

Trust comment: Small 3-month trial with randomized assignment but limited sample size and unclear blinding; results suggest benefit but need larger trials.

Study Details

PMID:9575643
Participants:45
Impact:statistically significant relief in Milgamma-treated patients (reported significant decrease vs comparator)
Trust score:3/5

disability (NPQ)

1 evidences

Adding B vitamins (thiamine, pyridoxine, cyanocobalamin) to dexketoprofen produced faster and slightly greater pain relief and reduced disability over 7 days compared with dexketoprofen alone.

Trust comment: Well-conducted randomized double-blind multicentre RCT (n=170) with prespecified pain and disability outcomes; short follow-up (7 days) limits long-term inference.

Study Details

PMID:38842764
Participants:170
Impact:Day 7 median 7.5% vs 7.9% (p=0.028); greater reduction with vitamin B combination
Trust score:4/5

symptom score (OSDI)

1 evidences

Oral vitamin B1 plus mecobalamin improved corneal subbasal nerve parameters and several dry eye symptoms over 1–3 months compared with artificial tears alone.

Trust comment: Randomized, double-blind controlled trial with objective IVCM measures and consistent symptom improvements; follow-up relatively short (3 months).

Study Details

PMID:36145126
Participants:199
Impact:Improved at 3 months (p=0.029)
Trust score:4/5

treatment durability

1 evidences

Long-term folic acid–based multivitamin therapy consistently lowered plasma total homocysteine by ~3–4 μmol/L at 6 months across recruitment periods despite rising baseline folate status.

Trust comment: Randomized double-blind placebo-controlled trial with measured biomarkers and adequate sample for biochemical endpoints.

Study Details

PMID:15608435
Participants:285
Impact:Homocysteine-lowering effect sustained at 6 months across time quartiles
Trust score:4/5

Risk of new colorectal adenomas (plasma vitamin B12)

1 evidences

Nested analysis in a trial of 1,084 individuals with prior adenomas found no significant association between plasma vitamin B12 and risk of new colorectal adenomas.

Trust comment: Large, nested analysis within a randomized trial; observational associations limit causal inference for B12.

Study Details

PMID:18708408
Participants:1084
Impact:No significant association
Trust score:3/5

activities of daily living

1 evidences

Randomized trial in 90 postherpetic neuralgia patients showing TENS plus local cobalamin injections reduced pain and improved activities of daily living and quality of life.

Trust comment: Randomized controlled trial in humans with clear, clinically relevant outcomes and significant results; single-center and moderate sample size limits generalizability.

Study Details

PMID:24196971
Participants:90
Impact:Improved at study endpoint in cobalamin-containing groups (statistically significant, P<0.05).
Trust score:4/5

riboflavin status

1 evidences

Cross‑sectional comparison found vegans had lower plasma vitamin B12 and higher prevalence of elevated homocysteine compared with omnivores and vegetarians.

Trust comment: Observational cross‑sectional study with modest sample sizes; associations plausible but cannot infer causality.

Study Details

PMID:16988496
Participants:118
Impact:riboflavin deficiency more common in vegans (over 30%) vs ~10% in omnivores/vegetarians)
Trust score:3/5

vitamin B12 intake (dietary)

2 evidences

In a crossover feeding study, a traditional Korean diet higher in one‑carbon nutrients (including B12) reduced homocysteine more than the control diet and increased global DNA methylation in peripheral blood mononuclear cells.

Trust comment: Controlled crossover dietary intervention with objective methylation and metabolite measures; small sample but within‑subject design strengthens internal validity.

Study Details

PMID:38867083
Participants:52
Impact:K‑diet consumed more vitamin B12 (reported higher intake vs control; no absolute value in excerpt)
Trust score:4/5

Food-based supplement providing substantial B12 increased dietary B12 intake (>2-fold) but did not change circulating serum cobalamin or improve birth outcomes.

Trust comment: Randomized trial with substantial sample but higher attrition and no biomarker changes despite intake increases, limiting observed efficacy.

Study Details

PMID:32469870
Participants:317
Impact:increased markedly (≈>2-fold increase in intake in supplemented groups)
Trust score:4/5

mortality at 6 months

1 evidences

Daily oral multi-nutrient supplements for 6 weeks improved nutrition and reduced non-elective readmissions in older hospitalized patients.

Trust comment: Large randomized double-blind RCT with clear clinical endpoints, but used a multi-nutrient supplement so effects cannot be attributed to B12 specifically.

Study Details

PMID:16887416
Participants:445
Impact:+5 percentage points (14% vs 9%)
Trust score:4/5

number of RAS episodes

1 evidences

Daily multivitamin at 100% RDI (including vitamin D among others) did not reduce number or duration of recurrent mouth ulcers compared with placebo over up to 365 days.

Trust comment: Well-designed randomized double-masked trial but used a broad multivitamin, so effects cannot be isolated to B12.

Study Details

PMID:22467697
Participants:160
Impact:-0.41 episodes (4.19 vs 4.60; not significant)
Trust score:4/5

periodontal pocket depth

1 evidences

A two-month adjunctive multi-vitamin supplement reduced gingival inflammation and probing depths in patients with chronic periodontitis compared with placebo.

Trust comment: Randomized trial but small sample and multi-ingredient supplement limit attribution to B12 specifically.

Study Details

PMID:11913269
Participants:63
Impact:decrease (statistically significant in pockets ≥4 mm)
Trust score:3/5

recurrent venous thrombosis (DVT/PE)

1 evidences

Large randomized double-blind trial: daily B-vitamin supplementation (folic acid, B6, B12) lowered homocysteine but did not significantly reduce recurrent DVT/PE over 2.5 years.

Trust comment: Large, double-blind randomized trial with clinical endpoints and adequate follow-up; high-quality evidence that B-vitamin regimen did not prevent recurrence of DVT/PE.

Study Details

PMID:16960155
Participants:701
Impact:43/353 events in vitamin group vs 50/348 in placebo; hazard ratio 0.84 (95% CI 0.56–1.26), not statistically significant
Trust score:5/5

incidence of prolonged diarrhea (effect of zinc)

1 evidences

Daily zinc reduced the risk of prolonged diarrhea primarily in children with low cobalamin (vitamin B12) status.

Trust comment: Large randomized double-blind trial with prespecified biomarker subgroup analysis, providing robust evidence for effect modification by cobalamin status.

Study Details

PMID:21525251
Participants:2296
Impact:OR 0.53 in low cobalamin group (≈47% relative reduction); OR 0.90 in higher cobalamin group (no significant reduction)
Trust score:5/5

infant cobalamin intake over 8 h

1 evidences

A single bolus maternal lipid-based nutrient supplement increased milk cobalamin concentration and infant cobalamin intake over 8 hours compared with control.

Trust comment: Randomized crossover design with objective milk and intake measures in 26 dyads; small sample but within-subject design increases reliability.

Study Details

PMID:32649760
Participants:26
Impact:+53% (0.015 → 0.023 μg; Bolus vs Control; P=0.001)
Trust score:4/5

effect of supplement matrix (LNS vs CSB)

1 evidences

Children with moderate acute malnutrition received food supplements; serum cobalamin rose during 3 months of supplementation but many remained marginal.

Trust comment: Large randomized factorial trial with objective biochemical and developmental measures; cobalamin was a secondary outcome and some serum data were missing.

Study Details

PMID:35263343
Participants:1548
Impact:LNS vs CSB overall +16 pmol/L (95% CI 3 to 29, p=0.02); LNS with soy isolate vs CSB with SI: +39 pmol/L (20 to 57, p<0.001)
Trust score:4/5

vitamin B-12 concentration

1 evidences

An 8-week multivitamin/mineral supplement raised B-vitamin levels (including B12) and lowered homocysteine in older adults.

Trust comment: Randomized, double-blind, placebo-controlled trial with clear biochemical outcomes, though intervention was a multivitamin rather than isolated B12.

Study Details

PMID:11110875
Participants:80
Impact:+13.8%
Trust score:4/5

plasma cobalamin (P-Cob)

1 evidences

Lipid-based nutrient supplements given for 12 weeks to stunted children increased plasma cobalamin, reduced MMA, improved folate and hemoglobin, and lowered anemia risk.

Trust comment: Large randomized trial with objective biomarker improvements and high follow-up; provides strong evidence of improved B12 status though multinutrient context remains a consideration.

Study Details

PMID:38278366
Participants:736
Impact:increased by 138 pmol/L (95% CI: 111,164)
Trust score:4/5

hemoglobin / anemia

1 evidences

Lipid-based nutrient supplements given for 12 weeks to stunted children increased plasma cobalamin, reduced MMA, improved folate and hemoglobin, and lowered anemia risk.

Trust comment: Large randomized trial with objective biomarker improvements and high follow-up; provides strong evidence of improved B12 status though multinutrient context remains a consideration.

Study Details

PMID:38278366
Participants:736
Impact:Hb increased by 3.8 g/L (95% CI: 1.7,6.0); odds of anemia reduced by 55% (OR 0.45)
Trust score:4/5

bacterial overgrowth (H2 breath test)

1 evidences

After gastric bypass, daily probiotics reduced bacterial overgrowth and were associated with higher postoperative vitamin B12 levels and greater early weight loss.

Trust comment: Small randomized prospective trial (n=44) with objective measures but limited sample size and follow-up duration; moderate quality.

Study Details

PMID:19381735
Participants:44
Impact:significant reduction (sum H2 change: probiotics −32.13 ppm vs controls 0.80 ppm)
Trust score:3/5

superoxide dismutase (SOD) activity

1 evidences

Three months of daily micronutrient packs increased vitamin D and other micronutrient levels and improved antioxidant markers in older institutionalized adults.

Trust comment: Randomized controlled trial with clear biochemical endpoints and significant changes, moderate sample size and short (3-month) follow-up.

Study Details

PMID:31464392
Participants:98
Impact:+14.3 ±2.4 U/mL (intervention) vs -2.1 ±2.4 U/mL (control) change over 3 months
Trust score:4/5

body weight and appetite (convalescent children)

1 evidences

A 4-week vitamin supplement increased vitamin B12 and other vitamin levels in children; convalescent children also showed increases in appetite, weight and muscle strength.

Trust comment: Small randomized placebo-controlled study with short duration; biochemical increases shown but sample is small.

Study Details

PMID:10356941
Participants:40
Impact:+increased (p < 0.05)
Trust score:3/5

serum ferritin

3 evidences

Fortified porridge given for 6 months raised hemoglobin and ferritin and improved motor development in infants.

Trust comment: Randomized trial with clear endpoints in infants but the intervention contained multiple micronutrients including B12, so effects cannot be isolated to B12.

Study Details

PMID:16280435
Participants:292
Impact:+9.4 μg/L
Trust score:4/5

Fortified salt containing iodine and other micronutrients given to children and women for 8 months improved iron and zinc status and reduced anemia; urinary iodine was maintained in the fortified group.

Trust comment: Randomized controlled trial with objective blood measures; however vitamin B12 was one of several micronutrients so effects cannot be attributed specifically to B12.

Study Details

PMID:33952731
Participants:212
Impact:+6.97 μg/L
Trust score:4/5

Young women randomized to pork diet, iron supplement, or control for 12 weeks; iron supplementation raised ferritin and both pork and iron raised hemoglobin; B12 concentrations were not significantly changed (trend to increase with pork).

Trust comment: Randomized controlled trial with reasonable completion rate; B12 not significantly affected though measured.

Study Details

PMID:23204154
Participants:65
Impact:Increased with iron supplement (significant)
Trust score:4/5

delivery route efficacy

1 evidences

Six weeks of a B-complex (including 1000 μg B12) significantly reduced homocysteine; sublingual and oral delivery were equally effective.

Trust comment: Randomized, double-blind trial but small sample and short duration limit precision.

Study Details

PMID:17109579
Participants:41
Impact:no significant difference between sublingual and oral delivery
Trust score:3/5

serum riboflavin and vitamin B6 deficiencies

1 evidences

Subsample (n=740) from a randomized antenatal trial in rural Nepal: multiple micronutrient supplementation reduced the prevalence of vitamin D deficiency though mean serum 25‑hydroxyvitamin D concentrations were unchanged between first and third trimester.

Trust comment: Large randomized controlled trial with biochemical endpoints in humans; well-reported though functional health outcomes were not measured.

Study Details

PMID:16600929
Participants:740
Impact:MMN decreased prevalence of riboflavin and B6 deficiencies
Trust score:4/5

folic acid / serum folate

1 evidences

Double-blind RCT (n=139) comparing an optimized multivitamin vs standard supplement in sleeve gastrectomy patients found improvements in folic acid, vitamin B1, PTH and anemia rates with the optimized supplement but no difference in vitamin D deficiency prevalence.

Trust comment: Double-blind RCT with adequate sample and 12-month follow-up; outcomes biochemical and clinically relevant though supplementation regimes are multinutrient.

Study Details

PMID:31776782
Participants:139
Impact:higher serum folate in WLS Optimum users
Trust score:4/5

proportion reaching ideal homocysteine (<10 µmol/L)

1 evidences

A combined nutraceutical (including 12.5 mg zinc) produced a larger reduction in homocysteine than high-dose folic acid alone over two months.

Trust comment: Randomized human trial but intervention was a combination product including B12, so effects cannot be attributed to B12 alone.

Study Details

PMID:27655522
Participants:104
Impact:55.8% in Normocis group vs lower in controls (p<0.05)
Trust score:3/5

serum total homocysteine (tHcy)

1 evidences

Daily hydrosoluble vitamin supplementation for 12 months reduced high homocysteine in hemodialysis patients but rarely normalized it.

Trust comment: Large human cohort with longitudinal follow-up and measured biomarkers, but supplementation was not a placebo-controlled single-agent B12 trial and some groups received additional folate.

Study Details

PMID:10916110
Participants:128
Impact:-11.6 μmol/L (33.3 → 21.7 μmol/L), −34.8% at 12 months (significant, P<0.0001)
Trust score:4/5

association with osteoporosis

1 evidences

In Crohn's disease patients, elevated homocysteine was common and strongly associated with low bone mineral density and osteoporosis.

Trust comment: Moderate-sized observational study showing a strong association but cross-sectional design prevents causal inference and B12 measured only as a covariate.

Study Details

PMID:17373918
Participants:92
Impact:hyperhomocysteinaemia associated with osteoporosis (OR 61.4; 95% CI 23–250; P<0.001)
Trust score:3/5

serum albumin

1 evidences

In a 3-month open-label randomized study in hemodialysis patients, folic acid plus B-complex lowered homocysteine and CRP and increased albumin and vitamin B12.

Trust comment: Open-label randomized study with modest sample size and biochemical outcomes but potential bias due to lack of blinding.

Study Details

PMID:17605895
Participants:121
Impact:increase (directional; significant)
Trust score:3/5

MTHFR C677T genotype effect on tHcy response

1 evidences

In adults with prior CVD, daily low‑dose B‑vitamin supplementation (5‑methyl‑THF 560 μg, B6 3 mg, B12 20 μg) produced a large tHcy decrease after 1 year (~‑26.3%), raised vitamin biomarkers in year 1 (then plateaued), and the homocysteine response was modified by MTHFR genotype (TT showed larger initial decrease).

Trust comment: Large, multicenter, double‑blind randomized placebo‑controlled trial with long follow‑up and centralized assays; high internal validity for B‑vitamin effects on tHcy.

Study Details

PMID:29813097
Participants:2501
Impact:TT genotype had greater initial tHcy reduction (interaction p<0.02); baseline TT ~+19% tHcy vs CC
Trust score:5/5

plasma 25-hydroxyvitamin D (25(OH)D)

1 evidences

One year of daily vitamin D3 (1200 IU) with calcium (with or without B vitamins) increased 25(OH)D, lowered PTH, and reduced multiple bone turnover markers in elderly subjects.

Trust comment: Randomized double-blind trial with objective biochemical endpoints and moderate sample size, though subgroup comparisons limit power for some bone markers.

Study Details

PMID:23183751
Participants:93
Impact:+87.6% (group A: D3+B vitamins), +133.3% (group B: D3 only)
Trust score:4/5

Schistosoma mansoni reinfection rate

1 evidences

Multimicronutrient tablets (which included 5 µg vitamin D) modestly reduced Schistosoma mansoni reinfection intensity but did not affect other helminth reinfections.

Trust comment: Large randomized controlled trial in children but low tablet compliance (~46%) limits confidence.

Study Details

PMID:12886816
Participants:977
Impact:OR 0.7 (borderline significance P=0.09)
Trust score:3/5

Hookworm/Ascaris/Trichuris reinfection (rates/intensity)

1 evidences

Multimicronutrient tablets (which included 5 µg vitamin D) modestly reduced Schistosoma mansoni reinfection intensity but did not affect other helminth reinfections.

Trust comment: Large randomized controlled trial in children but low tablet compliance (~46%) limits confidence.

Study Details

PMID:12886816
Participants:977
Impact:no significant change
Trust score:3/5

Composite cardiovascular outcome

1 evidences

4110 kidney transplant recipients randomized to high- vs low-dose folic acid/B6/B12: homocysteine was reduced but there was no reduction in composite cardiovascular outcomes over ~4 years.

Trust comment: Large, double-blind randomized trial with long follow-up showing robust null clinical outcome despite biochemical change.

Study Details

PMID:21482964
Participants:4110
Impact:no effect (HR 0.99; 95% CI 0.84–1.17)
Trust score:5/5

blood pressure

1 evidences

2501 patients with prior CVD took B-vitamins (including B12 20 µg) or placebo for ~5 years; supplementation did not change blood pressure.

Trust comment: Large, double-blind randomized trial with long follow-up and objective measures showing null effect on BP.

Study Details

PMID:21801476
Participants:2501
Impact:no significant change with B-vitamin supplementation over ~5 years
Trust score:4/5

Vitamin B-12 concentration/status

1 evidences

Cluster-RCTs in Kenya and Bangladesh delivering LNSs (containing B12) plus counseling increased hemoglobin, reduced anemia and improved vitamin B12 status in young children compared with control.

Trust comment: Large, well-conducted cluster-randomized trials with objective biomarker endpoints and high adherence to LNS, though some attrition and timing issues occurred.

Study Details

PMID:30624600
Participants:2120
Impact:increased ~11–21% in nutrition arms (site- and arm-specific increases)
Trust score:5/5

Change in homocysteine vs BP

1 evidences

2501 patients with prior CVD took B-vitamins (including B12 20 µg) or placebo for ~5 years; supplementation did not change blood pressure.

Trust comment: Large, double-blind randomized trial with long follow-up and objective measures showing null effect on BP.

Study Details

PMID:21801476
Participants:2501
Impact:no association between homocysteine change and BP change
Trust score:4/5

5STS (Five Times Sit-to-Stand) performance

1 evidences

In older women at risk of sarcopenia, micronutrient intake modified strength-training responses; higher vitamin D intake was associated with poorer 5STS performance improvements.

Trust comment: Randomized clinical trial with dietary assessment showing associations between nutrient status and strength outcomes, but exact quantitative B12 effect sizes were not provided.

Study Details

PMID:39999641
Participants:80
Impact:Worse performance associated with B12 deficiency (negative association)
Trust score:4/5

muscle strength gains

1 evidences

In older women at risk of sarcopenia, micronutrient intake modified strength-training responses; higher vitamin D intake was associated with poorer 5STS performance improvements.

Trust comment: Randomized clinical trial with dietary assessment showing associations between nutrient status and strength outcomes, but exact quantitative B12 effect sizes were not provided.

Study Details

PMID:39999641
Participants:80
Impact:Reduced when vitamin B12 deficient (negative association)
Trust score:4/5

plasma vitamin B-12 concentration

1 evidences

Supplement users had higher plasma vitamin B-12 levels and generally healthier behaviors compared with nonusers.

Trust comment: Large observational cohort with measured B12 levels showing associations but cannot establish causation.

Study Details

PMID:15987865
Participants:1776
Impact:Higher in supplement users (no numeric change reported)
Trust score:3/5

Body mass index (BMI)

1 evidences

Supplement users had higher plasma vitamin B-12 levels and generally healthier behaviors compared with nonusers.

Trust comment: Large observational cohort with measured B12 levels showing associations but cannot establish causation.

Study Details

PMID:15987865
Participants:1776
Impact:Lower in supplement users (no numeric change reported)
Trust score:3/5

physical activity (behavior)

1 evidences

Supplement users had higher plasma vitamin B-12 levels and generally healthier behaviors compared with nonusers.

Trust comment: Large observational cohort with measured B12 levels showing associations but cannot establish causation.

Study Details

PMID:15987865
Participants:1776
Impact:More common among supplement users (association)
Trust score:3/5

motor development score

1 evidences

Fortified porridge given for 6 months raised hemoglobin and ferritin and improved motor development in infants.

Trust comment: Randomized trial with clear endpoints in infants but the intervention contained multiple micronutrients including B12, so effects cannot be isolated to B12.

Study Details

PMID:16280435
Participants:292
Impact:+1.1 items (mean difference: 15.5 vs 14.4)
Trust score:4/5

Left ventricular volumes

1 evidences

In elderly patients with chronic heart failure, long-term high-dose multiple micronutrient supplementation (including vitamin D) improved left ventricular volumes, increased LVEF and improved quality-of-life versus placebo.

Trust comment: Small double-blind randomized trial with clinical endpoints but used a multivitamin combination so effects cannot be attributed to vitamin B12 alone.

Study Details

PMID:16081469
Participants:28
Impact:-13.1% (intervention) vs +3.8% (placebo) at study end
Trust score:3/5

left ventricular ejection fraction (LVEF)

1 evidences

In elderly patients with chronic heart failure, long-term high-dose multiple micronutrient supplementation (including vitamin D) improved left ventricular volumes, increased LVEF and improved quality-of-life versus placebo.

Trust comment: Small double-blind randomized trial with clinical endpoints but used a multivitamin combination so effects cannot be attributed to vitamin B12 alone.

Study Details

PMID:16081469
Participants:28
Impact:+5.3% (intervention) vs no change (placebo)
Trust score:3/5

quality-of-life (QoL) score

1 evidences

In elderly patients with chronic heart failure, long-term high-dose multiple micronutrient supplementation (including vitamin D) improved left ventricular volumes, increased LVEF and improved quality-of-life versus placebo.

Trust comment: Small double-blind randomized trial with clinical endpoints but used a multivitamin combination so effects cannot be attributed to vitamin B12 alone.

Study Details

PMID:16081469
Participants:28
Impact:+9.5% (intervention) vs -1.1% (placebo)
Trust score:3/5

Rate of whole-brain atrophy

1 evidences

Elderly people with mild cognitive impairment received high-dose B-vitamin supplementation (folic acid, B6, B12) for 2 years; B-vitamin treatment lowered homocysteine and substantially slowed whole-brain atrophy versus placebo.

Trust comment: Large double-blind randomized trial with objective MRI endpoints and biochemical compliance data, though treatment was a B-vitamin combination so individual vitamin effects (including B12) are not isolated.

Study Details

PMID:20838622
Participants:168
Impact:Active 0.76%/yr vs placebo 1.08%/yr (≈29.6% reduction; P = 0.001)
Trust score:5/5

Any osteoporotic fracture incidence

1 evidences

In 8,164 patients with recent stroke or TIA randomized to daily B-vitamins (including B12) versus placebo, B-vitamin therapy lowered homocysteine but did not significantly change the incidence of osteoporotic fractures over ~3.4 years.

Trust comment: Large, well-conducted randomized double-blind trial with long follow-up and biochemical confirmation of homocysteine lowering, but underpowered for modest fracture effects.

Study Details

PMID:24004645
Participants:8164
Impact:67/4089 (1.64%) B-vitamins vs 78/4075 (1.91%) placebo; RR 0.86 (95% CI 0.62–1.18), not significant
Trust score:5/5

blood vitamin B12 status

1 evidences

In a 17-week RCT in frail elderly people, nutrient-dense (micronutrient-enriched) foods corrected multiple micronutrient deficiencies including 25‑hydroxy vitamin D deficiency, whereas exercise alone did not.

Trust comment: Randomized 2x2 factorial trial with 145 participants and measured biochemical outcomes; B12 changes are direct biochemical findings though functional outcomes unchanged.

Study Details

PMID:10539780
Participants:145
Impact:deficiencies corrected after 17 wk in groups receiving nutrient-dense foods; no change in control/exercise
Trust score:4/5

arsenic methylation (to DMA)

1 evidences

Arsenic methylation to DMA improved during early pregnancy, and this improvement was not associated with vitamin B12 status.

Trust comment: Longitudinal study with 324 pregnant women showing clear negative result (no association) between B12 status and arsenic methylation.

Study Details

PMID:21078382
Participants:324
Impact:improvement during pregnancy with no association to vitamin B12 status
Trust score:3/5

cardiovascular events

1 evidences

In hemodialysis patients, homocysteine-lowering vitamin B (primarily folate per protocol) therapy was associated with fewer cardiovascular events versus untreated patients.

Trust comment: Single-center prospective trial with 114 patients showing fewer events in treated group, but intervention emphasized folate and attribution to B12 specifically is unclear.

Study Details

PMID:16755160
Participants:114
Impact:treated: 41% (26/63) vs untreated: 63% (32/51); absolute difference -22 percentage points
Trust score:3/5

natural killer (NK) cell activity

1 evidences

A multi-nutrient supplement that included vitamin B12 preserved certain immune functions and was associated with fewer infections in elderly subjects.

Trust comment: Randomized small trial (n=60) showing immune benefits for a combined supplement including B12, but effects cannot be isolated to B12 alone.

Study Details

PMID:15449576
Participants:60
Impact:increased in supplemented subjects vs decreased in controls
Trust score:3/5

infection rate (scheduled visits)

1 evidences

A multi-nutrient supplement that included vitamin B12 preserved certain immune functions and was associated with fewer infections in elderly subjects.

Trust comment: Randomized small trial (n=60) showing immune benefits for a combined supplement including B12, but effects cannot be isolated to B12 alone.

Study Details

PMID:15449576
Participants:60
Impact:reduced: 13% in supplemented vs 22% in controls (p = 0.02)
Trust score:3/5

IL-2 production by PBMC

1 evidences

A multi-nutrient supplement that included vitamin B12 preserved certain immune functions and was associated with fewer infections in elderly subjects.

Trust comment: Randomized small trial (n=60) showing immune benefits for a combined supplement including B12, but effects cannot be isolated to B12 alone.

Study Details

PMID:15449576
Participants:60
Impact:maintained in supplemented subjects vs decreased in controls
Trust score:3/5

newborn cobalamin (vitamin B-12)

1 evidences

Cord-blood substudy (n=333) of a large cluster-randomized trial comparing antenatal multiple micronutrient (MM) supplementation (includes vitamin D) versus iron–folic acid (IFA); MM increased newborn vitamin D, ferritin, and zinc vs IFA.

Trust comment: Large, double-blinded cluster-RCT with high-quality biomarker assays; MM included B12 but the intervention effect on newborn B12 was small and not statistically significant.

Study Details

PMID:32844185
Participants:333
Impact:+8.0% (MM vs IFA; 95% CI −3.5, 21.0; P=0.17; NS)
Trust score:5/5

maternal→newborn cobalamin association

1 evidences

Cord-blood substudy (n=333) of a large cluster-randomized trial comparing antenatal multiple micronutrient (MM) supplementation (includes vitamin D) versus iron–folic acid (IFA); MM increased newborn vitamin D, ferritin, and zinc vs IFA.

Trust comment: Large, double-blinded cluster-RCT with high-quality biomarker assays; MM included B12 but the intervention effect on newborn B12 was small and not statistically significant.

Study Details

PMID:32844185
Participants:333
Impact:+31.3% per 1‑SD higher maternal cobalamin (95% CI 24.6, 38.3; P<0.0001)
Trust score:5/5

oxidative stress markers (f2-isoprostane, protein carbonyl)

1 evidences

In hemodialysis patients, an antioxidant cocktail that included vitamin B12 did not change markers of oxidative stress or inflammation over 8 weeks.

Trust comment: Randomized placebo-controlled trial but small sample (n=37) and vitamins were given as a combined cocktail, so individual B12 effects cannot be isolated.

Study Details

PMID:19397224
Participants:37
Impact:no change at 4 and 8 weeks
Trust score:3/5

inflammatory markers (CRP, IL-6)

1 evidences

In hemodialysis patients, an antioxidant cocktail that included vitamin B12 did not change markers of oxidative stress or inflammation over 8 weeks.

Trust comment: Randomized placebo-controlled trial but small sample (n=37) and vitamins were given as a combined cocktail, so individual B12 effects cannot be isolated.

Study Details

PMID:19397224
Participants:37
Impact:no change at 4 and 8 weeks
Trust score:3/5

vitamin B12 adherence (pharmacy refill)

1 evidences

Randomized trial testing a smartphone app to improve adherence to prescribed supplements (including calcium/vitamin D) after bariatric surgery: the app did not improve objective pharmacy-based adherence or biochemical deficiency rates at 1 year.

Trust comment: Randomized controlled trial with objective pharmacy-refill adherence data and moderate sample size (n=140); measures adherence to prescribed B12 but not direct physiological outcomes.

Study Details

PMID:36050801
Participants:140
Impact:change −9.6% (intervention) vs −9.3% (control); no significant difference (P=0.48) — mean adherence fell from ~93% to ~84% (intervention)
Trust score:4/5

attained child weight at 24 months

1 evidences

Giving HIV-infected mothers multivitamins (including B12) during pregnancy and postpartum improved their children's weight at 24 months.

Trust comment: Large randomized placebo-controlled trial (n=886) with clear anthropometric outcomes; multivitamin regimen included B12 but effects cannot be attributed to B12 alone.

Study Details

PMID:15817867
Participants:886
Impact:+459 g (95% CI 35, 882; P=0.03)
Trust score:5/5

weight-for-age z score at 24 months

1 evidences

Giving HIV-infected mothers multivitamins (including B12) during pregnancy and postpartum improved their children's weight at 24 months.

Trust comment: Large randomized placebo-controlled trial (n=886) with clear anthropometric outcomes; multivitamin regimen included B12 but effects cannot be attributed to B12 alone.

Study Details

PMID:15817867
Participants:886
Impact:+0.42 (95% CI 0.07, 0.77; P=0.02)
Trust score:5/5

weight-for-length z score at 24 months

1 evidences

Giving HIV-infected mothers multivitamins (including B12) during pregnancy and postpartum improved their children's weight at 24 months.

Trust comment: Large randomized placebo-controlled trial (n=886) with clear anthropometric outcomes; multivitamin regimen included B12 but effects cannot be attributed to B12 alone.

Study Details

PMID:15817867
Participants:886
Impact:+0.38 (95% CI 0.07, 0.68; P=0.01)
Trust score:5/5

weight gain

1 evidences

A locally made RUTF produced greater weight gain than the local fortified cereal milk and increased plasma zinc, vitamin B12, albumin, and hemoglobin in malnourished preschoolers.

Trust comment: Randomized controlled trial with modest sample size and reported improvements in B12 and other biomarkers, but exact B12 magnitude was not detailed in the abstract.

Study Details

PMID:20972285
Participants:96
Impact:RUTF mean gain 0.54 kg vs HCCM 0.38 kg at 3 months (P=0.047)
Trust score:3/5

Clinical effective rate (medication group)

1 evidences

Compared intramuscular methyl vitamin B12 injections, acupuncture, and their combination for diabetic paralytic squint over 28 days; acupuncture (alone or with medication) had higher effective rates than medication alone.

Trust comment: Randomized trial including a methyl B12 medication arm, but limited reporting on randomization details and small group sizes reduce confidence.

Study Details

PMID:18405147
Participants:72
Impact:54.5%
Trust score:3/5

Clinical effective rate (acupuncture group)

1 evidences

Compared intramuscular methyl vitamin B12 injections, acupuncture, and their combination for diabetic paralytic squint over 28 days; acupuncture (alone or with medication) had higher effective rates than medication alone.

Trust comment: Randomized trial including a methyl B12 medication arm, but limited reporting on randomization details and small group sizes reduce confidence.

Study Details

PMID:18405147
Participants:72
Impact:87.5%
Trust score:3/5

Clinical effective rate (acupuncture + medication)

1 evidences

Compared intramuscular methyl vitamin B12 injections, acupuncture, and their combination for diabetic paralytic squint over 28 days; acupuncture (alone or with medication) had higher effective rates than medication alone.

Trust comment: Randomized trial including a methyl B12 medication arm, but limited reporting on randomization details and small group sizes reduce confidence.

Study Details

PMID:18405147
Participants:72
Impact:95.7%
Trust score:3/5

carotid intima-media thickness progression

1 evidences

Double-blind RCT of high-dose B vitamins (folic acid, B12, B6) vs placebo for ~3.1 years found no overall effect on carotid IMT progression but reduced IMT progression in participants with baseline homocysteine ≥9.1 µmol/L.

Trust comment: Large, double-blind randomized trial with rigorous imaging outcomes, but vitamins were given combined so effects cannot be ascribed solely to B12.

Study Details

PMID:19118243
Participants:506
Impact:no significant difference overall; significantly lower progression in subgroup with baseline tHcy ≥9.1 µmol/L (P=0.02)
Trust score:4/5

Aortic and coronary artery calcification progression

1 evidences

Double-blind RCT of high-dose B vitamins (folic acid, B12, B6) vs placebo for ~3.1 years found no overall effect on carotid IMT progression but reduced IMT progression in participants with baseline homocysteine ≥9.1 µmol/L.

Trust comment: Large, double-blind randomized trial with rigorous imaging outcomes, but vitamins were given combined so effects cannot be ascribed solely to B12.

Study Details

PMID:19118243
Participants:506
Impact:no effect
Trust score:4/5

postoperative complications (fistula, sepsis, diarrhea)

1 evidences

Compared to standard enteral nutrition, immunomodulatory enteral nutrition after GI cancer surgery reduced some post-surgical complications and improved immune markers and nutritional parameters including vitamin B12 status.

Trust comment: Randomized surgical nutrition trial with 100 patients but used a multi-nutrient immunonutrition formula, so effects cannot be attributed specifically to vitamin B12.

Study Details

PMID:40374110
Participants:100
Impact:decreased (lower frequency)
Trust score:3/5

lymphocyte count (immune markers)

1 evidences

Compared to standard enteral nutrition, immunomodulatory enteral nutrition after GI cancer surgery reduced some post-surgical complications and improved immune markers and nutritional parameters including vitamin B12 status.

Trust comment: Randomized surgical nutrition trial with 100 patients but used a multi-nutrient immunonutrition formula, so effects cannot be attributed specifically to vitamin B12.

Study Details

PMID:40374110
Participants:100
Impact:increased (higher lymphocyte number)
Trust score:3/5

fetal loss

1 evidences

Maternal multiple micronutrient supplements (which included 10 µg vitamin D) did not reduce overall fetal loss or early infant mortality; effects of vitamin D alone were not separable.

Trust comment: Large, double-blind, cluster-randomized trial with robust sample size; vitamin B12 was included only within a multi-micronutrient mix so effects are not isolated to B12.

Study Details

PMID:14668283
Participants:4926
Impact:no change (no reduction)
Trust score:4/5

3-month infant mortality in preterm infants

1 evidences

Maternal multiple micronutrient supplements (which included 10 µg vitamin D) did not reduce overall fetal loss or early infant mortality; effects of vitamin D alone were not separable.

Trust comment: Large, double-blind, cluster-randomized trial with robust sample size; vitamin B12 was included only within a multi-micronutrient mix so effects are not isolated to B12.

Study Details

PMID:14668283
Participants:4926
Impact:decreased with folic acid alone (RR 0.36) and folic acid+iron (RR 0.53)
Trust score:4/5

term infant mortality with multiple micronutrients

1 evidences

Maternal multiple micronutrient supplements (which included 10 µg vitamin D) did not reduce overall fetal loss or early infant mortality; effects of vitamin D alone were not separable.

Trust comment: Large, double-blind, cluster-randomized trial with robust sample size; vitamin B12 was included only within a multi-micronutrient mix so effects are not isolated to B12.

Study Details

PMID:14668283
Participants:4926
Impact:increased (MNs RR 1.74; borderline, needs further evaluation)
Trust score:4/5

MNA score (nutritional status)

1 evidences

RCT (n=70 allocated, 68 completed) of tailored progressive dietary advice plus new complete dentures vs standard care in edentulous elders, assessing nutritional status (MNA) and nutrient intake at 3 months.

Trust comment: Single-blind RCT, registered and completed with 68 participants; outcomes well-reported though dietary intake changes (including vitamin B12) were not significant, limiting conclusions about B12 specifically.

Study Details

PMID:40227937
Participants:68
Impact:increased (+1.08 mean change; p<0.001)
Trust score:4/5

protein intake

1 evidences

Twelve weeks of a nutrient-dense drink (contains 250 mg calcium/serving) increased energy and micronutrient intake and improved body weight and some muscle mass in older outpatients at risk of malnutrition.

Trust comment: Randomized controlled trial, registered and with low dropout and good compliance; not double-blind but outcomes objectively measured and statistically significant for nutrient intake.

Study Details

PMID:40154078
Participants:101
Impact:+23.9 g/day (between-group change after 12 weeks, p<0.001)
Trust score:4/5

vitamin B12 biomarker

1 evidences

Secondary analysis of a 2-year RCT in adults with type 2 diabetes comparing very low‑carb vs high‑carb diets found micronutrient biomarkers (including calcium) remained within normal ranges with no differences between diets.

Trust comment: Two-year randomized dietary trial with measured blood biomarkers; moderate completer number (61) and rigorous biomarker follow-up supports reliability for B12 status under these diets.

Study Details

PMID:33058957
Participants:61
Impact:no significant change between diet groups over time (remained within normal range)
Trust score:4/5

other micronutrient biomarkers

1 evidences

Secondary analysis of a 2-year RCT in adults with type 2 diabetes comparing very low‑carb vs high‑carb diets found micronutrient biomarkers (including calcium) remained within normal ranges with no differences between diets.

Trust comment: Two-year randomized dietary trial with measured blood biomarkers; moderate completer number (61) and rigorous biomarker follow-up supports reliability for B12 status under these diets.

Study Details

PMID:33058957
Participants:61
Impact:no differential response between groups over time
Trust score:4/5

clinical nutritional adequacy

1 evidences

Secondary analysis of a 2-year RCT in adults with type 2 diabetes comparing very low‑carb vs high‑carb diets found micronutrient biomarkers (including calcium) remained within normal ranges with no differences between diets.

Trust comment: Two-year randomized dietary trial with measured blood biomarkers; moderate completer number (61) and rigorous biomarker follow-up supports reliability for B12 status under these diets.

Study Details

PMID:33058957
Participants:61
Impact:maintained (no clinical deficiencies reported)
Trust score:4/5

mfERG R1 RAD (central macular function)

1 evidences

Randomized double-blind trial of Macuprev (multi-ingredient supplement including vitamin D3 800 IU) vs placebo in 30 patients with intermediate AMD (28 completed): after 6 months the active supplement increased central mfERG amplitudes (R1 and R2) without OCT structural changes.

Trust comment: Double-blind randomized placebo-controlled trial with 28 completers and objective electrophysiological endpoints, but the supplement contained many compounds so B12-specific effects cannot be isolated.

Study Details

PMID:31243641
Participants:28
Impact:increased (mean +23.50 nV/degree^2; 61.52 → 85.02; p=0.010)
Trust score:4/5

mfERG R2 RAD

1 evidences

Randomized double-blind trial of Macuprev (multi-ingredient supplement including vitamin D3 800 IU) vs placebo in 30 patients with intermediate AMD (28 completed): after 6 months the active supplement increased central mfERG amplitudes (R1 and R2) without OCT structural changes.

Trust comment: Double-blind randomized placebo-controlled trial with 28 completers and objective electrophysiological endpoints, but the supplement contained many compounds so B12-specific effects cannot be isolated.

Study Details

PMID:31243641
Participants:28
Impact:increased (mean +8.13 nV/degree^2; 26.65 → 34.78; p=0.044)
Trust score:4/5

SD-OCT structural parameters

1 evidences

Randomized double-blind trial of Macuprev (multi-ingredient supplement including vitamin D3 800 IU) vs placebo in 30 patients with intermediate AMD (28 completed): after 6 months the active supplement increased central mfERG amplitudes (R1 and R2) without OCT structural changes.

Trust comment: Double-blind randomized placebo-controlled trial with 28 completers and objective electrophysiological endpoints, but the supplement contained many compounds so B12-specific effects cannot be isolated.

Study Details

PMID:31243641
Participants:28
Impact:no change (no significant morphological differences)
Trust score:4/5

normal spermiogram proportion

1 evidences

Six months of a multi-component supplement (including vitamin B12) improved sperm parameters: a higher proportion of men achieved normal spermiograms and spontaneous pregnancy rates increased compared with placebo.

Trust comment: Double-blind, placebo-controlled multicenter RCT with all 83 participants completing the study; however, the supplement was multi-component so benefits cannot be attributed solely to vitamin B12.

Study Details

PMID:32330373
Participants:83
Impact:increased (verum 69.0% [29/42] vs placebo 22.0% [9/41] at month 4; p<0.001)
Trust score:4/5

spontaneous pregnancy rate

1 evidences

Six months of a multi-component supplement (including vitamin B12) improved sperm parameters: a higher proportion of men achieved normal spermiograms and spontaneous pregnancy rates increased compared with placebo.

Trust comment: Double-blind, placebo-controlled multicenter RCT with all 83 participants completing the study; however, the supplement was multi-component so benefits cannot be attributed solely to vitamin B12.

Study Details

PMID:32330373
Participants:83
Impact:increased (verum 23.8% [10/42] vs placebo 4.9% [2/41]; p=0.017)
Trust score:4/5

sperm quality (concentration, motility, morphology)

1 evidences

Six months of a multi-component supplement (including vitamin B12) improved sperm parameters: a higher proportion of men achieved normal spermiograms and spontaneous pregnancy rates increased compared with placebo.

Trust comment: Double-blind, placebo-controlled multicenter RCT with all 83 participants completing the study; however, the supplement was multi-component so benefits cannot be attributed solely to vitamin B12.

Study Details

PMID:32330373
Participants:83
Impact:improved (more participants met normal thresholds)
Trust score:4/5

serum vitamin B6

1 evidences

Nested case–control study measured serum folate, B6, B12, riboflavin, and homocysteine to assess associations with colon and rectal cancer risk in Finnish men.

Trust comment: Prospective nested case–control with matched controls and clear biomarker measurement; vitamin B12 showed no association with colorectal cancer risk.

Study Details

PMID:18990766
Participants:556
Impact:Highest vs lowest quintile associated with lower colon cancer risk (OR 0.30)
Trust score:4/5

energy intake

1 evidences

Twelve weeks of a nutrient-dense drink (contains 250 mg calcium/serving) increased energy and micronutrient intake and improved body weight and some muscle mass in older outpatients at risk of malnutrition.

Trust comment: Randomized controlled trial, registered and with low dropout and good compliance; not double-blind but outcomes objectively measured and statistically significant for nutrient intake.

Study Details

PMID:40154078
Participants:101
Impact:+336 kcal/day (between-group change after 12 weeks, p<0.001)
Trust score:4/5

Peak eosinophil count (PEC)

1 evidences

In a small study of adults with EoE, higher calcium intake (and certain dairy products) tended to associate with lower esophageal inflammation.

Trust comment: Small observational study with appropriate dietary assessment and biopsy-based outcome; associations are hypothesis-generating and not proof of causality.

Study Details

PMID:38456617
Participants:40
Impact:Inverse association with vitamin B12 intake (standardized β = -0.319, p = 0.039)
Trust score:3/5

Plasma vitamin B12 level

2 evidences

6-month randomized placebo-controlled trial of oral vs transdermal estrogen+progesterone; oral estrogen significantly reduced plasma vitamin B12 levels vs placebo, transdermal did not.

Trust comment: Randomized placebo-controlled design with moderate sample size and clear biochemical outcome; effect on B12 quantified and statistically significant for oral route.

Study Details

PMID:15135267
Participants:196
Impact:Oral ERT decreased vitamin B12 by -11.7% relative to placebo over 6 months (mean relative variation difference -11.7%, 95% CI -21 to -2%)
Trust score:4/5

In this feasibility RCT of metformin vs placebo in people with non-diabetic hyperglycaemia, metformin was associated with a small but statistically significant reduction in plasma vitamin B12 levels.

Trust comment: Randomized controlled trial reporting a measurable decrease in plasma B12 with metformin; direct measurement and clear numerical effect increase confidence.

Study Details

PMID:29652246
Participants:249
Impact:−16.4 ng/L (mean change vs placebo; 95% CI −32.9 to −0.01 ng/L)
Trust score:4/5

Plasma vitamin B12 level (transdermal)

1 evidences

6-month randomized placebo-controlled trial of oral vs transdermal estrogen+progesterone; oral estrogen significantly reduced plasma vitamin B12 levels vs placebo, transdermal did not.

Trust comment: Randomized placebo-controlled design with moderate sample size and clear biochemical outcome; effect on B12 quantified and statistically significant for oral route.

Study Details

PMID:15135267
Participants:196
Impact:No significant change vs placebo
Trust score:4/5

Phenylalanine level

1 evidences

Caregiver education or provision of low‑protein foods reduced children's phenylalanine; micronutrients including vitamin B12 did not change significantly at 10 weeks.

Trust comment: Randomized trial with long follow-up in 44 children; well-described methods though small sample and multi-arm design limit attribution of micronutrient effects.

Study Details

PMID:34772434
Participants:44
Impact:Decreased (educational: 8.77 → 5.33 at 24 months; food items: 12.20 → 7.48 at 24 months; significant reductions, 10-week P<0.001)
Trust score:4/5

bEAT/wEAT ratio (brown:white epicardial fat)

1 evidences

A multicomponent supplement (aged garlic extract plus B vitamins including vitamin B12) lowered homocysteine, increased brown/white epicardial adipose ratio and was associated with less coronary calcium progression over 12 months.

Trust comment: Randomized human study (n=60) of a multicomponent supplement that included vitamin B12; effects are real but cannot be attributed specifically to vitamin B12 alone.

Study Details

PMID:23453866
Participants:60
Impact:Increased with AGE‑S vs placebo (significant, p<0.05)
Trust score:3/5

Coronary artery calcium (CAC) progression

1 evidences

A multicomponent supplement (aged garlic extract plus B vitamins including vitamin B12) lowered homocysteine, increased brown/white epicardial adipose ratio and was associated with less coronary calcium progression over 12 months.

Trust comment: Randomized human study (n=60) of a multicomponent supplement that included vitamin B12; effects are real but cannot be attributed specifically to vitamin B12 alone.

Study Details

PMID:23453866
Participants:60
Impact:Reduced risk of CAC progression with AGE‑S vs placebo (significant, p<0.05)
Trust score:3/5

MOT latency (psychomotor response speed)

1 evidences

A 6‑month multinutrient supplement (includes vitamin B12 among other nutrients) improved psychomotor response speed, immediate verbal memory and habitual walking speed in older women; effects cannot be ascribed to vitamin B12 alone.

Trust comment: Randomized, double‑blind pilot RCT with clear outcomes but small sample (27 completers) and industry funding; multinutrient composition prevents isolating vitamin B12 effects.

Study Details

PMID:26265727
Participants:27
Impact:Improved (shorter) with supplement vs placebo; adjusted mean difference ~−118 ms (p=0.038)
Trust score:3/5

Verbal recognition memory (immediate free recall)

1 evidences

A 6‑month multinutrient supplement (includes vitamin B12 among other nutrients) improved psychomotor response speed, immediate verbal memory and habitual walking speed in older women; effects cannot be ascribed to vitamin B12 alone.

Trust comment: Randomized, double‑blind pilot RCT with clear outcomes but small sample (27 completers) and industry funding; multinutrient composition prevents isolating vitamin B12 effects.

Study Details

PMID:26265727
Participants:27
Impact:Increased with supplement vs placebo (+1.3 words immediate recall; p=0.029)
Trust score:3/5

Habitual walking speed (HW)

1 evidences

A 6‑month multinutrient supplement (includes vitamin B12 among other nutrients) improved psychomotor response speed, immediate verbal memory and habitual walking speed in older women; effects cannot be ascribed to vitamin B12 alone.

Trust comment: Randomized, double‑blind pilot RCT with clear outcomes but small sample (27 completers) and industry funding; multinutrient composition prevents isolating vitamin B12 effects.

Study Details

PMID:26265727
Participants:27
Impact:Increased with supplement vs placebo (+0.07 m/s adjusted mean difference; p=0.031)
Trust score:3/5

Breast‑milk vitamin B12 concentration

1 evidences

In Malawian HIV‑infected mothers, lipid‑based nutrient supplements (LNS) increased breast‑milk B vitamins including B12, while antiretroviral therapy lowered some milk B vitamins and attenuated the supplementation benefit.

Trust comment: Large randomized human study (n=537) with detailed measurement of milk B vitamins showing clear effects of supplementation and interaction with antiretrovirals.

Study Details

PMID:26537941
Participants:537
Impact:Increased with maternal LNS supplementation; decreased with antiretroviral therapy and ARVs attenuated LNS effect
Trust score:4/5

Other B vitamins in milk

1 evidences

In Malawian HIV‑infected mothers, lipid‑based nutrient supplements (LNS) increased breast‑milk B vitamins including B12, while antiretroviral therapy lowered some milk B vitamins and attenuated the supplementation benefit.

Trust comment: Large randomized human study (n=537) with detailed measurement of milk B vitamins showing clear effects of supplementation and interaction with antiretrovirals.

Study Details

PMID:26537941
Participants:537
Impact:LNS increased most B vitamins (except thiamin); ARVs decreased nicotinamide and pyridoxal and offset LNS increases for several vitamins
Trust score:4/5

Overall milk B vitamin levels

1 evidences

In Malawian HIV‑infected mothers, lipid‑based nutrient supplements (LNS) increased breast‑milk B vitamins including B12, while antiretroviral therapy lowered some milk B vitamins and attenuated the supplementation benefit.

Trust comment: Large randomized human study (n=537) with detailed measurement of milk B vitamins showing clear effects of supplementation and interaction with antiretrovirals.

Study Details

PMID:26537941
Participants:537
Impact:Concentrations were lower than typical reference values but were raised by maternal LNS (except thiamin); ARVs reduced some concentrations
Trust score:4/5

plaque lipid content

1 evidences

Patients with severe carotid stenosis took aspirin plus Aterofisiol (multi-ingredient supplement including vitamin B12) or aspirin plus placebo; plaques removed at surgery were analyzed.

Trust comment: Randomized, double-blind trial with good sample size and significant results, but the supplement contained multiple active ingredients so effects cannot be attributed specifically to vitamin B12.

Study Details

PMID:26229448
Participants:202
Impact:-34.8% (0.356 → 0.232 mg/mg dry weight)
Trust score:3/5

plaque cholesterol content

1 evidences

Patients with severe carotid stenosis took aspirin plus Aterofisiol (multi-ingredient supplement including vitamin B12) or aspirin plus placebo; plaques removed at surgery were analyzed.

Trust comment: Randomized, double-blind trial with good sample size and significant results, but the supplement contained multiple active ingredients so effects cannot be attributed specifically to vitamin B12.

Study Details

PMID:26229448
Participants:202
Impact:-32.1% (0.053 → 0.036 mg/mg dry weight)
Trust score:3/5

incidence of neurological symptoms

1 evidences

Patients with severe carotid stenosis took aspirin plus Aterofisiol (multi-ingredient supplement including vitamin B12) or aspirin plus placebo; plaques removed at surgery were analyzed.

Trust comment: Randomized, double-blind trial with good sample size and significant results, but the supplement contained multiple active ingredients so effects cannot be attributed specifically to vitamin B12.

Study Details

PMID:26229448
Participants:202
Impact:-12.4 percentage points (20/99 → 8/103; 20.2% → 7.8%)
Trust score:3/5

brain atrophy rate

1 evidences

Randomized placebo-controlled trial of high-dose B vitamins in elderly with MCI; B vitamins slowed brain atrophy by 40% over 2 years but only in those with high baseline plasma ω‑3 levels.

Trust comment: Well-conducted randomized placebo-controlled trial with MRI outcomes; subgroup interaction reduces generalizability.

Study Details

PMID:25877495
Participants:168
Impact:−40% with B vitamins vs placebo in subjects with high baseline ω‑3 (>590 μmol/L) over 2 years
Trust score:4/5

treatment effect by plasma ω‑3

1 evidences

Randomized placebo-controlled trial of high-dose B vitamins in elderly with MCI; B vitamins slowed brain atrophy by 40% over 2 years but only in those with high baseline plasma ω‑3 levels.

Trust comment: Well-conducted randomized placebo-controlled trial with MRI outcomes; subgroup interaction reduces generalizability.

Study Details

PMID:25877495
Participants:168
Impact:benefit observed only in high ω‑3 subgroup; no significant effect in low ω‑3 subgroup (<390 μmol/L)
Trust score:4/5

LDL:HDL cholesterol ratio

1 evidences

Daily fortified milk (including phytosterols) plus lifestyle counselling for 3 months improved several CVD-related markers (lower homocysteine, higher folate/B12) and tended to improve LDL:HDL; effects are from combined intervention.

Trust comment: Randomized intervention but contains multiple added nutrients and lifestyle counselling, so effects cannot be attributed to vitamin B12 alone.

Study Details

PMID:23249766
Participants:101
Impact:favourable change in enriched milk group (trend, P=0.066)
Trust score:3/5

resting energy expenditure (VO2/VCO2/RER)

1 evidences

Acute ingestion of the pre-workout supplement (contains 70 mg methylcobalamin) increased short-term metabolism and improved cognitive scores and perceived energy with minimal safety signals in young trained adults.

Trust comment: Randomized, double-blind, crossover human trial with rigorous methods but small sample (n=25) limits generalizability.

Study Details

PMID:28096758
Participants:25
Impact:+5.6% VO2 (PWS), +8.6% VO2 (PWS+S) vs +1.4% (PLA); VCO2 and RER AUC significantly higher in PWS and PWS+S vs PLA (p<0.01).
Trust score:4/5

cognitive function (Stroop Word/Color/Word-Color)

1 evidences

Acute ingestion of the pre-workout supplement (contains 70 mg methylcobalamin) increased short-term metabolism and improved cognitive scores and perceived energy with minimal safety signals in young trained adults.

Trust comment: Randomized, double-blind, crossover human trial with rigorous methods but small sample (n=25) limits generalizability.

Study Details

PMID:28096758
Participants:25
Impact:Increased Stroop counts +7–12 counts in PWS/PWS+S vs baseline; several timepoints significantly > PLA (p<0.05).
Trust score:4/5

perceived vigor/optimism (VAS)

1 evidences

Acute ingestion of the pre-workout supplement (contains 70 mg methylcobalamin) increased short-term metabolism and improved cognitive scores and perceived energy with minimal safety signals in young trained adults.

Trust comment: Randomized, double-blind, crossover human trial with rigorous methods but small sample (n=25) limits generalizability.

Study Details

PMID:28096758
Participants:25
Impact:VAS ratings of vigor/optimism increased ~+0.4–0.6 points at 1 hour in PWS and PWS+S vs PLA (p<0.05).
Trust score:4/5

cognitive function (Stroop)

1 evidences

Eight-week randomized, double-blind trial (supplement contains 70 mg methylcobalamin) found some within-group gains in cognition and strength with PWS, but no consistent between-group advantages in body composition or most performance outcomes; supplements were well tolerated.

Trust comment: Well-powered randomized, double-blind, placebo-controlled trial with 80 completers and standardized training; internal validity strong though some effects were within-group only.

Study Details

PMID:28096757
Participants:80
Impact:Word/Color/Word-Color counts increased over 8 weeks; PWS and PWS+S showed earlier/larger within-group increases (e.g., Word +7.6 counts PWS, +9.9 PWS+S by wk8) though differences versus placebo were not sustained for all measures.
Trust score:5/5

maximal strength (1RM bench & leg press)

1 evidences

Eight-week randomized, double-blind trial (supplement contains 70 mg methylcobalamin) found some within-group gains in cognition and strength with PWS, but no consistent between-group advantages in body composition or most performance outcomes; supplements were well tolerated.

Trust comment: Well-powered randomized, double-blind, placebo-controlled trial with 80 completers and standardized training; internal validity strong though some effects were within-group only.

Study Details

PMID:28096757
Participants:80
Impact:Bench press 1RM increased within PWS by +14.36 kg and PWS+S +13.84 kg at 8 weeks (PLA +7.18 kg); no significant between-group differences at wk8.
Trust score:5/5

weight change with protein intake

1 evidences

After weight loss and 64-week follow-up, higher reported protein intake correlated with greater weight-loss maintenance; the high-protein group showed higher serum vitamin B12 vs the high-carbohydrate group.

Trust comment: Long follow-up and completed sample but modest size and limited detail in abstract about randomization/control; observational relations within trial limit causal certainty for B12 finding.

Study Details

PMID:18175733
Participants:79
Impact:Mean weight loss similar by group (HP 4.6±5.5 kg vs HC 4.4±6.1 kg); higher protein intake (upper tertile ~88 g/d) associated with greater weight loss (6.5 vs 3.4 kg, p=0.03).
Trust score:3/5

cardiometabolic risk markers

1 evidences

After weight loss and 64-week follow-up, higher reported protein intake correlated with greater weight-loss maintenance; the high-protein group showed higher serum vitamin B12 vs the high-carbohydrate group.

Trust comment: Long follow-up and completed sample but modest size and limited detail in abstract about randomization/control; observational relations within trial limit causal certainty for B12 finding.

Study Details

PMID:18175733
Participants:79
Impact:Lipids, glucose, insulin, CRP and homocysteine improved with weight loss with no differences between diet groups.
Trust score:3/5

homocysteine and osteoporosis

1 evidences

Cross-sectional study found higher plasma homocysteine associated with osteoporosis in postmenopausal women with T2D; association remained after adjustment for serum folate and vitamin B12.

Trust comment: Large cross-sectional hospital-based study with adjustment for B12 and other confounders; observational design limits causal inference.

Study Details

PMID:24366622
Participants:258
Impact:Subjects with osteoporosis had higher Hcy (10.4±2.4 vs 9.5±2.0 μmol/L, p=0.001); per 5 μmol/L Hcy increase OR for osteoporosis 1.42 (1.07–1.96), p=0.027, independent of serum vitamin B12.
Trust score:3/5

weight and body composition

1 evidences

12-week RCT in overweight/obese young women found lifestyle intervention produced greater weight and fat loss than metformin or placebo; serum vitamin B12 did not change significantly between groups.

Trust comment: Large randomized trial with clear weight/composition endpoints and reliable measurements; vitamin B12 was measured and showed no group differences.

Study Details

PMID:20163941
Participants:203
Impact:Lifestyle intervention: weight −4.2±0.4 kg vs metformin −1.0±0.4 kg and placebo −0.2±0.3 kg (p<0.001); greater reductions in waist and fat mass in lifestyle group.
Trust score:4/5

vitamin B12 intake (proportion inadequate)

1 evidences

Among people with RRMS, the Wahls diet increased the proportion not getting enough calcium from food; supplements did not fully correct this shortfall.

Trust comment: Randomized parallel-group trial with weighed food records and specified supplement regimen; modest completer sample (77) but rigorous dietary assessment.

Study Details

PMID:34684508
Participants:77
Impact:+17.4% (Wahls group vs baseline at 12 weeks); Swank had higher inadequate B12 after inclusion of supplements (p=0.02)
Trust score:4/5

hypovitaminosis B12 incidence

1 evidences

RYGB led to major weight loss and hypertension improvements; some patients developed low vitamin B12 after surgery.

Trust comment: High-quality randomized trial reporting B12 deficiency as an adverse outcome, but B12 was not the primary focus.

Study Details

PMID:32805133
Participants:100
Impact:13 patients developed hypovitaminosis B12 (RYGB group)
Trust score:3/5

blood vitamin B12 level

1 evidences

16-week multivitamin raised B vitamins and lowered homocysteine in men; modest, mainly non-significant cognitive improvements in men only.

Trust comment: Randomized double-blind placebo-controlled trial with 116 completers; biochemical increases clear but cognitive effects were limited and partly non-significant.

Study Details

PMID:24424708
Participants:116
Impact:+substantial increase
Trust score:4/5

vibration perception threshold (big toe)

1 evidences

Vitamin B complex (with or without folic acid) improved vibration perception and sensory symptoms in alcoholic polyneuropathy over 12 weeks.

Trust comment: Randomized double-blind placebo-controlled trial showing clear benefit of a vitamin B complex (includes B12), but effects cannot be attributed to B12 alone.

Study Details

PMID:16926172
Participants:253
Impact:significant improvement vs placebo
Trust score:4/5

gastrointestinal cancer incidence

1 evidences

Folic acid given with monthly intramuscular vitamin B12 was associated with fewer GI cancers and improved gastric precancerous lesions versus placebo.

Trust comment: Randomized trial showing benefit of folic acid with monthly B12 injection, but B12 was co-administered and the sample size was limited.

Study Details

PMID:12667380
Participants:216
Impact:reduced in folic acid + monthly B12 group vs placebo (FA group 0 cases vs placebo 3; P=0.04)
Trust score:3/5

global cognition (TICS-M)

1 evidences

In older adults with MCI, B-vitamin supplementation (including B12) slowed cognitive decline and reduced risk of worse clinical dementia ratings, but benefits were mainly observed in those with high baseline omega-3 status.

Trust comment: Randomized controlled trial in humans with 2-year follow-up and objective cognitive outcomes; interaction/subgroup analyses were tertiary and based on baseline omega-3 tertiles.

Study Details

PMID:26757190
Participants:266
Impact:+2.85 points difference between 3rd and 1st omega-3 tertiles (enhanced effect of B vitamins); significant B vitamin effect in 3rd DHA tertile (~+2.78 points)
Trust score:4/5

pre-treatment vitamin B12 level (predictor)

1 evidences

Among children with ADHD treated with a broad-spectrum micronutrient formula, pre-treatment serum calcium levels did not meaningfully predict clinical response; overall, serum nutrient levels had limited value as predictors.

Trust comment: Exploratory secondary analysis of a small clinical trial subset; associations for B12 were weak and inconsistent.

Study Details

PMID:30217770
Participants:71
Impact:Lower B12 weakly associated with greater improvement on some outcomes (predictive value weak)
Trust score:3/5

Attention (incongruent Stroop)

1 evidences

Double-blind RCT of a multinutrient (including B12 50 µg) for 12 weeks; B vitamin biomarkers (B1, B6, B12) increased with active treatment and modest cognitive attention benefits were seen in a diet-defined subgroup.

Trust comment: Well-powered double-blind RCT with biochemical confirmation of B vitamin uptake; cognitive benefits were modest and subgroup-specific.

Study Details

PMID:36501109
Participants:116
Impact:Improved in 'optimal' diet subgroup after 12 weeks (significant)
Trust score:4/5

non-cardiovascular mortality

1 evidences

Large prospective cohort showing calcium channel blocker (CCB) use was associated with higher long-term all-cause and CVD mortality; associations were attenuated in patients receiving B-vitamin treatment.

Trust comment: Large, well-characterized prospective cohort with long follow-up and multivariable adjustment, but observational design with possible residual confounding.

Study Details

PMID:37121550
Participants:3991
Impact:CCB-associated HR 1.65 (B‑vitamin non-treated) vs HR 1.21 (B‑vitamin treated) in model 1; trend to attenuation in treated group
Trust score:4/5

spatial working memory speed

1 evidences

Elderly women took a multivitamin for 16 weeks and showed faster spatial working memory and improved some blood nutrient markers.

Trust comment: Randomized double-blind placebo-controlled trial with clear cognitive and biochemical outcomes but modest sample size.

Study Details

PMID:22006207
Participants:56
Impact:improved (statistically significant)
Trust score:4/5

third-trimester weight gain

1 evidences

Among HIV-positive pregnant women, daily multivitamins increased third-trimester weight gain and reduced risk of low weight gain.

Trust comment: Large randomized placebo-controlled trial (2x2 factorial) with robust sample size and clear weight outcomes.

Study Details

PMID:12399282
Participants:1075
Impact:+304 g on average (95% CI: 17 to 590; P=0.04)
Trust score:5/5

electrophysiological measures / glycemic control

1 evidences

Type 2 diabetic patients given micronutrient formulas (one including B-vitamins) reported reduced neuropathy symptom scores, but objective measures did not differ between groups.

Trust comment: Randomized double-blind trial but small sample, multiple-nutrient formulas make attribution to B12 uncertain and between-group differences were not significant for examinations.

Study Details

PMID:21496936
Participants:67
Impact:no significant change vs placebo
Trust score:3/5

MMSE cognitive score

1 evidences

Alzheimer patients treated with donepezil plus an antioxidant/B‑vitamin formula showed decreased oxidative stress and homocysteine and some cognitive improvements versus donepezil plus placebo.

Trust comment: Small randomized double-blind cohort using a combined antioxidant/B‑vitamin formula alongside donepezil; combination therapy and small N limit attribution to B12 alone.

Study Details

PMID:20224285
Participants:48
Impact:some improvements observed in donepezil + formula F group (vs placebo + donepezil)
Trust score:3/5

fasting total homocysteine (tHcy)

1 evidences

High‑dose folic acid–based B‑vitamin supplementation (including B12) produced only a modest (~1 μmol/L) reduction in fasting homocysteine in CAD patients in a folic‑acid‑fortified setting.

Trust comment: Randomized factorial trial in CAD patients but relatively small sample and only modest effects in a fortified background.

Study Details

PMID:11884295
Participants:131
Impact:-~1.0 μmol/L (modest but statistically significant, P<0.05)
Trust score:3/5

hs-CRP

1 evidences

Daily Lactococcus cremoris on oat flakes reduced inflammatory marker hs‑CRP and cortisol and produced a small within‑group increase in vitamin B12, though between‑group B12 differences were not significant.

Trust comment: Randomized placebo‑controlled single‑blind trial with modest sample size; some significant within‑group changes but limited between‑group B12 effects.

Study Details

PMID:40572644
Participants:46
Impact:decreased (significant vs control at 12 weeks; p = 0.002)
Trust score:3/5

cortisol

1 evidences

Daily Lactococcus cremoris on oat flakes reduced inflammatory marker hs‑CRP and cortisol and produced a small within‑group increase in vitamin B12, though between‑group B12 differences were not significant.

Trust comment: Randomized placebo‑controlled single‑blind trial with modest sample size; some significant within‑group changes but limited between‑group B12 effects.

Study Details

PMID:40572644
Participants:46
Impact:reduced within probiotic group at weeks 6 and 12 (p = 0.003 and p = 0.002) but no between‑group difference
Trust score:3/5

Milk vitamin B12 concentration (deficient subgroup)

1 evidences

Giving mothers MMS raised iodine in breast milk but did not change infant growth at 3 months.

Trust comment: Randomized, cluster-designed substudy with blinded outcome assessment and robust lab methods, but underpowered (did not reach planned sample) and not primarily designed for vitamin B12 effects on growth.

Study Details

PMID:40409469
Participants:186
Impact:MMS vs standard among samples <87 pmol/L: +11 pmol/L (55 vs 44 pmol/L; P=0.007)
Trust score:4/5

Dietary vitamin B12 intake adequacy

1 evidences

Cross-sectional dietary assessment of 291 hemodialysis patients using 4-day recall; evaluated adequacy of energy, macronutrients and micronutrient intakes relative to recommendations.

Trust comment: Representative cross-sectional dietary recall with moderate sample size and clear findings on inadequate B12 intake, but subject to recall bias and no biochemical B12 status confirmation.

Study Details

PMID:22111822
Participants:291
Impact:61% of patients had vitamin B12 intake below recommended intakes
Trust score:3/5

Correlation: B12 change vs MN frequency

1 evidences

Six months of resistance training plus protein and vitamin (including B12) supplementation increased plasma B12 and folate and tended to reduce chromosomal damage, with B12 change correlated with reduced MN frequency.

Trust comment: Human intervention with objective biomarkers but small sample and mainly non-significant reductions in chromosomal damage; correlation supports a link.

Study Details

PMID:25747997
Participants:97
Impact:negative correlation in RTS group (r = −0.584, p = 0.009)
Trust score:3/5

total vitamin B12

1 evidences

Ancillary randomized, double-blind study comparing high- (4 mg) versus low-dose folic acid in pregnancy; measured multiple 1-carbon biomarkers including total vitamin B12 and found no evidence that high-dose folic acid altered 1-carbon metabolism or vitamin B12 status.

Trust comment: Randomized, double-blind design with measured biomarkers but small ancillary sample limits precision.

Study Details

PMID:33675351
Participants:50
Impact:no difference between high- and low-dose folic acid groups
Trust score:4/5

homocysteine (men)

1 evidences

16-week multivitamin raised B vitamins and lowered homocysteine in men; modest, mainly non-significant cognitive improvements in men only.

Trust comment: Randomized double-blind placebo-controlled trial with 116 completers; biochemical increases clear but cognitive effects were limited and partly non-significant.

Study Details

PMID:24424708
Participants:116
Impact:- decreased
Trust score:4/5

major cardiovascular events (CVD)

1 evidences

Secondary analysis found no consistent effect modification by baseline nutritional factors, including vitamin D intake, on multivitamin effects for major cardiovascular events.

Trust comment: Large randomized double-blind trial; secondary analysis signals with baseline B12 intake were inconsistent and likely reflect multiple testing.

Study Details

PMID:28384735
Participants:13316
Impact:no effect of long-term multivitamin use on CVD risk
Trust score:4/5

pain intensity and sensory function

1 evidences

Vitamin B complex (with or without folic acid) improved vibration perception and sensory symptoms in alcoholic polyneuropathy over 12 weeks.

Trust comment: Randomized double-blind placebo-controlled trial showing clear benefit of a vitamin B complex (includes B12), but effects cannot be attributed to B12 alone.

Study Details

PMID:16926172
Participants:253
Impact:significant improvement vs placebo
Trust score:4/5

gastric mucosal lesion reversal

1 evidences

Folic acid given with monthly intramuscular vitamin B12 was associated with fewer GI cancers and improved gastric precancerous lesions versus placebo.

Trust comment: Randomized trial showing benefit of folic acid with monthly B12 injection, but B12 was co-administered and the sample size was limited.

Study Details

PMID:12667380
Participants:216
Impact:improvement/reversal of atrophy, inflammation, and dysplasia in FA group (+)
Trust score:3/5

bench press recovery muscular endurance (repetitions to failure)

1 evidences

Randomized double-blind crossover trial in recreationally active resistance-trained adults testing a ready-to-drink pre-workout (contains B12 among other ingredients); acute and short-term ingestion improved recovery from resistance exercise with no safety concerns.

Trust comment: Well-conducted randomized double-blind crossover trial but B12 was one ingredient among many, so effects cannot be attributed to B12 specifically.

Study Details

PMID:28763003
Participants:25
Impact:Less decline vs placebo (~+1.8 reps on Day 1 recovery)
Trust score:4/5

plasma holotranscobalamin (active B12)

1 evidences

Daily consumption of micronutrient-fortified cereal with milk for 12 weeks increased vitamin D intake and maintained serum 25(OH)D compared with unfortified cereal, where 25(OH)D declined.

Trust comment: Randomized, placebo‑controlled trial with objective biomarker measurement showing improved active B12 status from fortified cereal; well-conducted for the question addressed.

Study Details

PMID:27418034
Participants:71
Impact:Fortified group: increased from 35.3 to 42.8 pmol/L (Δ +7.5 pmol/L; significant vs unfortified, p<0.001)
Trust score:4/5

clinical dementia rating (CDR > 0)

1 evidences

In older adults with MCI, B-vitamin supplementation (including B12) slowed cognitive decline and reduced risk of worse clinical dementia ratings, but benefits were mainly observed in those with high baseline omega-3 status.

Trust comment: Randomized controlled trial in humans with 2-year follow-up and objective cognitive outcomes; interaction/subgroup analyses were tertiary and based on baseline omega-3 tertiles.

Study Details

PMID:26757190
Participants:266
Impact:Adjusted OR 0.31 for worse CDR in B vitamin vs placebo in highest combined omega-3 tertile (p=0.043); CDR-sum-of-boxes mean difference −0.53 in 3rd tertile
Trust score:4/5

apolipoprotein A1 (ApoA1)

1 evidences

In older adults with diabetes who took methylcobalamin (B12) in a prior randomized trial, B12 supplementation showed no significant effect on HDL function measures or on cognitive decline over follow-up.

Trust comment: Randomized placebo-controlled trial with long follow-up but substantial attrition; analyses adjusted for group assignment and relevant covariates.

Study Details

PMID:35731136
Participants:222
Impact:no significant change with B12 supplementation (P>0.05 at months 9,27,72)
Trust score:4/5

reticulocyte count (hematopoiesis)

1 evidences

Six months of a protein/HMB-containing oral nutritional supplement (which included vitamin D) improved multiple biochemical and hematological indices compared with placebo in older adults at risk of malnutrition.

Trust comment: Large double-blind randomized placebo-controlled trial with pre-specified biochemical endpoints and good methodology (findings reflect multi-nutrient product rather than isolated B12 effect).

Study Details

PMID:39125374
Participants:811
Impact:absolute reticulocyte count and percentage significantly increased in intervention group (p≤0.044)
Trust score:5/5

β-carotene

1 evidences

A 12-week daily food-based snack intervention (green leafy vegetables, dried fruit, milk) produced a small but significant increase in circulating β-carotene but did not change vitamin B12 levels.

Trust comment: Randomized controlled food-based trial with objective nutrient assays but modest sample with some loss to follow-up and possible dietary behavior change confounding.

Study Details

PMID:25677713
Participants:170
Impact:treatment effect +47 nmol/L (~12% of baseline), P=0.023
Trust score:4/5

body mass index

1 evidences

Thai schoolchildren given zinc plus multivitamins (which included vitamin D) for 6 months had greater height gain than placebo.

Trust comment: Randomized controlled trial (n=140) with clear primary outcome and significant result for height; reasonably high quality though B12 was part of a multinutrient intervention.

Study Details

PMID:27083763
Participants:140
Impact:no significant change
Trust score:4/5

overall ADHD symptom improvement

1 evidences

Among children with ADHD treated with a broad-spectrum micronutrient formula, pre-treatment serum calcium levels did not meaningfully predict clinical response; overall, serum nutrient levels had limited value as predictors.

Trust comment: Exploratory secondary analysis of a small clinical trial subset; associations for B12 were weak and inconsistent.

Study Details

PMID:30217770
Participants:71
Impact:Inconsistent; clinician-rated improvements in some domains but no consistent parent/teacher-rated benefit
Trust score:3/5

D-QoL belonging (feelings of belonging)

1 evidences

In older adults with MCI, daily folate/B12/B6 pills for 1 year did not improve overall quality of life and were associated with a small negative effect on feelings of belonging.

Trust comment: Well-powered randomized, double-blind placebo-controlled trial with high compliance and intent-to-treat analyses, though QoL was a secondary/exploratory outcome.

Study Details

PMID:17616840
Participants:152
Impact:−0.18 points (beta; 95% CI −0.29 to −0.07; P < 0.01)
Trust score:4/5

Vitamin B1 and B6 status

1 evidences

Double-blind RCT of a multinutrient (including B12 50 µg) for 12 weeks; B vitamin biomarkers (B1, B6, B12) increased with active treatment and modest cognitive attention benefits were seen in a diet-defined subgroup.

Trust comment: Well-powered double-blind RCT with biochemical confirmation of B vitamin uptake; cognitive benefits were modest and subgroup-specific.

Study Details

PMID:36501109
Participants:116
Impact:Significant increases (active vs placebo)
Trust score:4/5

cardiovascular mortality

1 evidences

Large prospective cohort showing calcium channel blocker (CCB) use was associated with higher long-term all-cause and CVD mortality; associations were attenuated in patients receiving B-vitamin treatment.

Trust comment: Large, well-characterized prospective cohort with long follow-up and multivariable adjustment, but observational design with possible residual confounding.

Study Details

PMID:37121550
Participants:3991
Impact:CCB-associated HR 2.17 (B‑vitamin non-treated) vs HR 1.11 (B‑vitamin treated) in model 1; no association in treated group
Trust score:4/5

risk of low rate of weight gain

1 evidences

Among HIV-positive pregnant women, daily multivitamins increased third-trimester weight gain and reduced risk of low weight gain.

Trust comment: Large randomized placebo-controlled trial (2x2 factorial) with robust sample size and clear weight outcomes.

Study Details

PMID:12399282
Participants:1075
Impact:reduced (RR 0.73; ~27% lower risk)
Trust score:5/5

C-reactive protein (CRP) level

1 evidences

In a 6-month randomized trial subgroup, multivitamin use was associated with lower CRP levels compared with placebo.

Trust comment: Post-hoc subgroup analysis of an RCT with modest sample size; results relevant to multivitamin use but not specifically attributable to B12.

Study Details

PMID:14693322
Participants:87
Impact:between-group difference −0.91 mg/L (95% CI: −1.52 to −0.30; P=0.005)
Trust score:3/5

treatment success (sufficient pain reduction)

1 evidences

Adding B‑vitamins (including B12) to diclofenac led to faster and greater pain relief and improved mobility in acute low back pain.

Trust comment: Large randomized double‑blind controlled trial with a clear primary outcome and statistically significant results.

Study Details

PMID:19731994
Participants:372
Impact:+17.5 percentage points (46.5% vs 29% terminated after 3 days; p=0.0005)
Trust score:4/5

anxiety score

1 evidences

A multivitamin containing B12 improved depressive symptoms but did not change anxiety in men receiving methadone maintenance.

Trust comment: Double‑blind randomized trial but small, male‑only sample and limited reporting of effect sizes.

Study Details

PMID:37256965
Participants:70
Impact:no significant change versus placebo
Trust score:3/5

Milk vitamin B12 concentration (overall)

1 evidences

Giving mothers MMS raised iodine in breast milk but did not change infant growth at 3 months.

Trust comment: Randomized, cluster-designed substudy with blinded outcome assessment and robust lab methods, but underpowered (did not reach planned sample) and not primarily designed for vitamin B12 effects on growth.

Study Details

PMID:40409469
Participants:186
Impact:no difference between MMS and standard of care (adjusted P≈0.36)
Trust score:4/5

micronucleus frequency (chromosomal damage)

1 evidences

Six months of resistance training plus protein and vitamin (including B12) supplementation increased plasma B12 and folate and tended to reduce chromosomal damage, with B12 change correlated with reduced MN frequency.

Trust comment: Human intervention with objective biomarkers but small sample and mainly non-significant reductions in chromosomal damage; correlation supports a link.

Study Details

PMID:25747997
Participants:97
Impact:tendency to decrease (cells with MN −15%; total MN −20%) but no significant time-effect overall
Trust score:3/5

dietary vitamin B12 intake (week 9)

1 evidences

Post-hoc analysis of an RCT comparing fasting + plant-based diet vs guideline diet in RA patients; both groups had dietary calcium below recommendations, with the guideline (DGE) group having higher calcium intake than the PBD group.

Trust comment: Randomized trial with direct dietary intake measurement but small, female-only sample and B12 was measured as intake not as an isolated intervention.

Study Details

PMID:36839208
Participants:50
Impact:DGE vs PBD: +1.9 µg/day (2.3 vs 0.4 µg/day); both below RDI
Trust score:3/5

vitamin B12 status (baseline)

1 evidences

In a multinational cohort of ART‑naïve HIV‑infected adults, vitamin D deficiency was common at baseline and mean vitamin concentrations rose after 48 weeks of ART but prevalence of deficiency changed little.

Trust comment: Multicountry observational analysis with direct B12 measurement at baseline; abstract does not report a clear B12-specific prevalence or post-ART change, limiting direct conclusions about B12 effects.

Study Details

PMID:25703452
Participants:270
Impact:measured at baseline (no post-ART change reported for B12 in abstract)
Trust score:3/5

selective attention/response inhibition (Stroop incongruent)

1 evidences

16-week multivitamin raised B vitamins and lowered homocysteine in men; modest, mainly non-significant cognitive improvements in men only.

Trust comment: Randomized double-blind placebo-controlled trial with 116 completers; biochemical increases clear but cognitive effects were limited and partly non-significant.

Study Details

PMID:24424708
Participants:116
Impact:trend improvement in men (p=0.01 unadjusted; not significant after multiple comparison)
Trust score:4/5

CVD mortality / total mortality interaction with baseline vitamin B12 intake

1 evidences

Secondary analysis found no consistent effect modification by baseline nutritional factors, including vitamin D intake, on multivitamin effects for major cardiovascular events.

Trust comment: Large randomized double-blind trial; secondary analysis signals with baseline B12 intake were inconsistent and likely reflect multiple testing.

Study Details

PMID:28384735
Participants:13316
Impact:statistically significant interaction observed but patterns inconsistent across tertiles (likely multiple testing)
Trust score:4/5

safety

1 evidences

Vitamin B complex (with or without folic acid) improved vibration perception and sensory symptoms in alcoholic polyneuropathy over 12 weeks.

Trust comment: Randomized double-blind placebo-controlled trial showing clear benefit of a vitamin B complex (includes B12), but effects cannot be attributed to B12 alone.

Study Details

PMID:16926172
Participants:253
Impact:no significant safety differences vs placebo
Trust score:4/5

leg press recovery repetitions to failure

1 evidences

Randomized double-blind crossover trial in recreationally active resistance-trained adults testing a ready-to-drink pre-workout (contains B12 among other ingredients); acute and short-term ingestion improved recovery from resistance exercise with no safety concerns.

Trust comment: Well-conducted randomized double-blind crossover trial but B12 was one ingredient among many, so effects cannot be attributed to B12 specifically.

Study Details

PMID:28763003
Participants:25
Impact:+4.0 reps (Day 1 recovery; RTD) vs PLA −2.6 reps
Trust score:4/5

% below holoTC threshold (<37 pmol/L)

1 evidences

Daily consumption of micronutrient-fortified cereal with milk for 12 weeks increased vitamin D intake and maintained serum 25(OH)D compared with unfortified cereal, where 25(OH)D declined.

Trust comment: Randomized, placebo‑controlled trial with objective biomarker measurement showing improved active B12 status from fortified cereal; well-conducted for the question addressed.

Study Details

PMID:27418034
Participants:71
Impact:Fortified group: decreased from 53% pre-intervention to 36% post-intervention (significant)
Trust score:4/5

height gain

1 evidences

Thai schoolchildren given zinc plus multivitamins (which included vitamin D) for 6 months had greater height gain than placebo.

Trust comment: Randomized controlled trial (n=140) with clear primary outcome and significant result for height; reasonably high quality though B12 was part of a multinutrient intervention.

Study Details

PMID:27083763
Participants:140
Impact:+1.3 cm (4.9 vs 3.6 cm) increased over 6 months
Trust score:4/5

homocysteine level

3 evidences

Alzheimer patients treated with donepezil plus an antioxidant/B‑vitamin formula showed decreased oxidative stress and homocysteine and some cognitive improvements versus donepezil plus placebo.

Trust comment: Small randomized double-blind cohort using a combined antioxidant/B‑vitamin formula alongside donepezil; combination therapy and small N limit attribution to B12 alone.

Study Details

PMID:20224285
Participants:48
Impact:decreased (statistically significant in conjunction with other marker changes)
Trust score:3/5

In RA patients with elevated homocysteine, 12 months of B-vitamin treatment (including B12) significantly lowered homocysteine levels compared with placebo.

Trust comment: Double-blind randomized trial showing a clear biochemical effect (Hcy reduction) though sample size was modest (n=62).

Study Details

PMID:14626626
Participants:62
Impact:decreased (significant vs placebo over 12 months)
Trust score:4/5

Elderly women took a multivitamin for 16 weeks and showed faster spatial working memory and improved some blood nutrient markers.

Trust comment: Randomized double-blind placebo-controlled trial with clear cognitive and biochemical outcomes but modest sample size.

Study Details

PMID:22006207
Participants:56
Impact:decreased (statistically significant)
Trust score:4/5

lactate production during exercise

1 evidences

Healthy adults given a vitamin B-complex (including B12) for 28 days showed reduced exercise fatigue markers and improved endurance time compared with placebo.

Trust comment: Randomized double-blind crossover trial with clear biochemical and performance endpoints but small sample size (n=32) and the supplement was a multicomponent B-complex product.

Study Details

PMID:37786445
Participants:32
Impact:reduced during exercise and faster post-exercise recovery (significant)
Trust score:4/5

ω-3 index (EPA+DHA in erythrocytes)

1 evidences

Twelve weeks of fortified milk (including B-group vitamins and B12) in older adults increased circulating B vitamins (including B12), raised vitamin D, improved ω-3 status, and lowered homocysteine.

Trust comment: Double-blind crossover RCT with objective biochemical endpoints in older adults; small sample (n=48) but well-controlled.

Study Details

PMID:33266447
Participants:48
Impact:Increased from 5.6% to 7.3% (+1.7 percentage points; q < 0.0001)
Trust score:4/5

D-QoL sumscore (overall QoL)

1 evidences

In older adults with MCI, daily folate/B12/B6 pills for 1 year did not improve overall quality of life and were associated with a small negative effect on feelings of belonging.

Trust comment: Well-powered randomized, double-blind placebo-controlled trial with high compliance and intent-to-treat analyses, though QoL was a secondary/exploratory outcome.

Study Details

PMID:17616840
Participants:152
Impact:no significant change (beta −0.06; P = 0.07)
Trust score:4/5

vitamin D level

1 evidences

After gastric bypass, the investigational multivitamin produced higher vitamin D and thiamine levels and lower PTH at 3 months compared with the standard multivitamin.

Trust comment: Randomized trial but small sample with losses to follow-up and multiple endpoints; B12 effects not clearly reported separately.

Study Details

PMID:29500675
Participants:47
Impact:Higher at 3 months in investigational arm (p=0.033)
Trust score:3/5

neuropathic symptom score (MNSI)

1 evidences

Type 2 diabetic patients given micronutrient formulas (one including B-vitamins) reported reduced neuropathy symptom scores, but objective measures did not differ between groups.

Trust comment: Randomized double-blind trial but small sample, multiple-nutrient formulas make attribution to B12 uncertain and between-group differences were not significant for examinations.

Study Details

PMID:21496936
Participants:67
Impact:decreased by 2.81 points in MVB group (3.45→0.64); no significant difference vs placebo in between-group comparisons
Trust score:3/5

oxidative stress (plasma hydroperoxides)

1 evidences

Alzheimer patients treated with donepezil plus an antioxidant/B‑vitamin formula showed decreased oxidative stress and homocysteine and some cognitive improvements versus donepezil plus placebo.

Trust comment: Small randomized double-blind cohort using a combined antioxidant/B‑vitamin formula alongside donepezil; combination therapy and small N limit attribution to B12 alone.

Study Details

PMID:20224285
Participants:48
Impact:decreased (statistically significant in formula F group)
Trust score:3/5

post‑methionine tHcy response

1 evidences

High‑dose folic acid–based B‑vitamin supplementation (including B12) produced only a modest (~1 μmol/L) reduction in fasting homocysteine in CAD patients in a folic‑acid‑fortified setting.

Trust comment: Randomized factorial trial in CAD patients but relatively small sample and only modest effects in a fortified background.

Study Details

PMID:11884295
Participants:131
Impact:no significant reduction versus placebo
Trust score:3/5

hypertension during pregnancy

1 evidences

Daily multivitamins (including B12) during pregnancy reduced the risk of hypertension in HIV‑positive women.

Trust comment: Large double‑blind randomized controlled trial with a clear, clinically important outcome and significant effect.

Study Details

PMID:15987864
Participants:1078
Impact:-38% risk (RR 0.62; 95% CI 0.40–0.94; P = 0.03)
Trust score:4/5

Vitamin B12 intake (general)

1 evidences

Dietary modelling using national survey data showed adding one serving of common milk products would substantially reduce population nutrient inadequacy, including calcium.

Trust comment: Large, nationally representative dietary dataset and modeling provide plausible estimates of improved B12 intake from fortified milk, but results are theoretical (modeling) rather than interventional.

Study Details

PMID:33138121
Participants:3864
Impact:increased with YCM/PCM fortification scenarios (improved adequacy across age groups; exact % change varied by scenario and age)
Trust score:3/5

Risk of vitamin B12 inadequacy (Ornish diet)

1 evidences

Randomized comparison of four popular weight-loss diets showed diet-specific changes in micronutrient adequacy; the Ornish diet increased risk of B12 inadequacy at 8 weeks.

Trust comment: Randomized diet trial with moderate sample size using 24‑h recalls (self-report) which can limit micronutrient precision.

Study Details

PMID:20573800
Participants:291
Impact:increased risk at 8 weeks
Trust score:3/5

Prevalence of suboptimal B12 status

1 evidences

Eight-week double-blind RCT in older adults showed multivitamin supplementation increased plasma B12 and reduced prevalence of suboptimal B12 status.

Trust comment: Double-blind, placebo-controlled RCT with objective plasma measures; sample moderate but design is strong.

Study Details

PMID:11022875
Participants:80
Impact:reduced (statistically significant reduction in prevalence)
Trust score:4/5

1-carbon metabolism biomarkers

1 evidences

Ancillary randomized, double-blind study comparing high- (4 mg) versus low-dose folic acid in pregnancy; measured multiple 1-carbon biomarkers including total vitamin B12 and found no evidence that high-dose folic acid altered 1-carbon metabolism or vitamin B12 status.

Trust comment: Randomized, double-blind design with measured biomarkers but small ancillary sample limits precision.

Study Details

PMID:33675351
Participants:50
Impact:no alteration with high-dose folic acid
Trust score:4/5

disease-free survival

1 evidences

Prospective ancillary study evaluating supplement use during chemotherapy; vitamin B12 use before and during treatment was associated with poorer disease-free survival.

Trust comment: Large prospective ancillary study but supplement use was self-reported and observational associations are susceptible to confounding.

Study Details

PMID:31855498
Participants:1134
Impact:adjHR 1.83 (↑83% hazard of recurrence) associated with vitamin B12 use before and during chemotherapy
Trust score:3/5

lipopolysaccharide-binding protein (LBP)

1 evidences

46 bariatric surgery patients randomized to probiotics or placebo: at 4 months probiotics improved LBP, TNF-α, vitamin B12 and vitamin D3 and weight loss versus placebo, but most effects did not persist at 13 months except reduced MDA.

Trust comment: Double-blind randomized trial with objective biomarkers (n=46); modest sample size and some effects were transient, limiting long-term confidence.

Study Details

PMID:30612325
Participants:46
Impact:improved (month 4)
Trust score:3/5

total combined lifting volume (kg/kg FFM)

1 evidences

Randomized double-blind crossover trial in recreationally active resistance-trained adults testing a ready-to-drink pre-workout (contains B12 among other ingredients); acute and short-term ingestion improved recovery from resistance exercise with no safety concerns.

Trust comment: Well-conducted randomized double-blind crossover trial but B12 was one ingredient among many, so effects cannot be attributed to B12 specifically.

Study Details

PMID:28763003
Participants:25
Impact:+21.06 kg/kgFFM (Day 1 recovery) vs PLA −13.12
Trust score:4/5

serum vitamin B12 (cyanocobalamin)

1 evidences

16‑week double‑blind randomized placebo‑controlled trial of a multivitamin (high‑dose B‑vitamins including B12) versus placebo in healthy adults; measured B12, homocysteine and diurnal cortisol outcomes.

Trust comment: Randomized double‑blind placebo‑controlled trial with objective blood measures and appropriate analyses, though multivitamin contains many constituents so effects are not fully attributable to B12 alone.

Study Details

PMID:24284609
Participants:138
Impact:Multivitamin group mean B12 ~289→371 pmol/L at 8 weeks (+~82 pmol/L) and →392 pmol/L at 16 weeks (+~103 pmol/L); MV > placebo (p≤0.049 at 8 wk; p=0.001 at 16 wk)
Trust score:4/5

Cortisol Awakening Response (CAR)

1 evidences

16‑week double‑blind randomized placebo‑controlled trial of a multivitamin (high‑dose B‑vitamins including B12) versus placebo in healthy adults; measured B12, homocysteine and diurnal cortisol outcomes.

Trust comment: Randomized double‑blind placebo‑controlled trial with objective blood measures and appropriate analyses, though multivitamin contains many constituents so effects are not fully attributable to B12 alone.

Study Details

PMID:24284609
Participants:138
Impact:Treatment×visit interaction significant (p=0.045); MV showed an increase in CAR over time with MV>placebo at 16 wk approaching significance (p≈0.054)
Trust score:4/5

cholesterol efflux capacity (CEC)

1 evidences

In older adults with diabetes who took methylcobalamin (B12) in a prior randomized trial, B12 supplementation showed no significant effect on HDL function measures or on cognitive decline over follow-up.

Trust comment: Randomized placebo-controlled trial with long follow-up but substantial attrition; analyses adjusted for group assignment and relevant covariates.

Study Details

PMID:35731136
Participants:222
Impact:no significant change with B12 supplementation (P>0.05 at months 9,27,72)
Trust score:4/5

prealbumin

1 evidences

Six months of a protein/HMB-containing oral nutritional supplement (which included vitamin D) improved multiple biochemical and hematological indices compared with placebo in older adults at risk of malnutrition.

Trust comment: Large double-blind randomized placebo-controlled trial with pre-specified biochemical endpoints and good methodology (findings reflect multi-nutrient product rather than isolated B12 effect).

Study Details

PMID:39125374
Participants:811
Impact:significant increase in intervention group over 180 days (p≤0.010)
Trust score:5/5

vitamin B12 (blood)

1 evidences

Post-hoc analysis of a randomized nutraceutical trial found EPA/DHA increases correlated with clinical response; measured B12 and folate were not associated with symptom improvement.

Trust comment: Post-hoc biomarker analysis of an RCT with moderate sample size; negative finding for B12 but not a primary prespecified B12 outcome.

Study Details

PMID:31555976
Participants:158
Impact:no association with antidepressant treatment response (no predictive/correlative effect reported)
Trust score:3/5

vitamin B12 dietary adequacy

1 evidences

Modeling of infant diets showed baseline complementary feeding often provided less than recommended vitamin B12 and some formulated products did not fill nutrient gaps.

Trust comment: Cross-sectional dietary data and LP modeling (n=78) providing useful population-level dietary adequacy results but not an intervention testing B12 effects.

Study Details

PMID:24153341
Participants:78
Impact:optimal diets achieved 14–91% of RNI for vitamin B12 (inadequate in many scenarios)
Trust score:3/5

time to exhaustion

1 evidences

Healthy adults given a vitamin B-complex (including B12) for 28 days showed reduced exercise fatigue markers and improved endurance time compared with placebo.

Trust comment: Randomized double-blind crossover trial with clear biochemical and performance endpoints but small sample size (n=32) and the supplement was a multicomponent B-complex product.

Study Details

PMID:37786445
Participants:32
Impact:+3.26 min (15.82 vs 12.56 min; ~+26%)
Trust score:4/5

total antioxidant capacity (TAC)

1 evidences

In healthy adults, 6-week supplementation with natural or synthetic B-complex raised blood B-vitamin levels; natural B-complex showed a decrease in homocysteine and larger increases in antioxidant capacity in this small pilot.

Trust comment: Double-blind randomized pilot crossover but small sample and carryover/period effects limited planned analyses, so results are exploratory.

Study Details

PMID:31915511
Participants:29
Impact:+26% in natural B group vs +6% in synthetic group at end of supplementation
Trust score:3/5

thiamine level

1 evidences

After gastric bypass, the investigational multivitamin produced higher vitamin D and thiamine levels and lower PTH at 3 months compared with the standard multivitamin.

Trust comment: Randomized trial but small sample with losses to follow-up and multiple endpoints; B12 effects not clearly reported separately.

Study Details

PMID:29500675
Participants:47
Impact:Higher at 3 months in investigational arm (p=0.009)
Trust score:3/5

memory and attention test scores

1 evidences

Children eating salt fortified with multiple micronutrients including iodine for one year showed better micronutrient status and improvements on several memory and attention tests.

Trust comment: Intervention showed benefits but was a school-based feeding intervention with multiple micronutrients and non-identical control conditions, limiting attribution to B12 specifically.

Study Details

PMID:17704033
Participants:129
Impact:improved on 4/7 memory tests and letter cancellation (statistically significant)
Trust score:3/5

vitamin B6 / vitamin C association with CRP

1 evidences

In a 6-month randomized trial subgroup, multivitamin use was associated with lower CRP levels compared with placebo.

Trust comment: Post-hoc subgroup analysis of an RCT with modest sample size; results relevant to multivitamin use but not specifically attributable to B12.

Study Details

PMID:14693322
Participants:87
Impact:inverse association observed for B6 and C (B12 not shown to be associated)
Trust score:3/5

Methylcobalamin (vitamin B12 form)

1 evidences

A 12-month randomized trial of a multi-component nutrition/diet protocol in ASD found improvements in many clinical and biomarker outcomes; the vitamin/mineral supplement increased some B-vitamin biomarkers.

Trust comment: Randomized, controlled human study with objective biomarker changes, but B12 was part of a multi-component intervention so attribution to B12 alone is uncertain.

Study Details

PMID:29562612
Participants:55
Impact:no significant change reported
Trust score:3/5

Vitamin B12 inadequacy (age 3–4 years)

1 evidences

Dietary modelling using national survey data showed adding one serving of common milk products would substantially reduce population nutrient inadequacy, including calcium.

Trust comment: Large, nationally representative dietary dataset and modeling provide plausible estimates of improved B12 intake from fortified milk, but results are theoretical (modeling) rather than interventional.

Study Details

PMID:33138121
Participants:3864
Impact:reduced from 44% to 25% (−19 percentage points) with one serving of preschool children milk (PCM) per day
Trust score:3/5

Human milk 25-hydroxyvitamin D3 concentration

1 evidences

Maternal supplement (intervention vs control) given from preconception through pregnancy raised vitamin D in breast milk but did not change B‑vitamin levels.

Trust comment: Large double-blind RCT with repeated measures and objective assays; results are reliable though effect limited to vitamin D.

Study Details

PMID:38411017
Participants:338
Impact:+20% (95% CI 8%–33%) over first 3 months of lactation
Trust score:4/5

Vitamin B12 intake (overall)

1 evidences

Randomized comparison of four popular weight-loss diets showed diet-specific changes in micronutrient adequacy; the Ornish diet increased risk of B12 inadequacy at 8 weeks.

Trust comment: Randomized diet trial with moderate sample size using 24‑h recalls (self-report) which can limit micronutrient precision.

Study Details

PMID:20573800
Participants:291
Impact:varied by diet (Ornish group showed decreased adequacy)
Trust score:3/5

postpartum blood loss

1 evidences

Secondary analysis of a large prenatal RCT found that higher plasma myo-inositol (not B12) was associated with reduced postpartum blood loss; plasma vitamin B12 showed no association with blood loss in fully adjusted models.

Trust comment: Large, well-conducted randomized trial with longitudinal nutrient measurements; B12 was directly measured and showed no association with the studied outcome after adjustment.

Study Details

PMID:38999805
Participants:583
Impact:vitamin B12 — no association in fully adjusted models (no effect)
Trust score:4/5

episodic memory (HVLT-DR)

1 evidences

In older adults with MCI, B-vitamin supplementation (including B12) slowed cognitive decline and reduced risk of worse clinical dementia ratings, but benefits were mainly observed in those with high baseline omega-3 status.

Trust comment: Randomized controlled trial in humans with 2-year follow-up and objective cognitive outcomes; interaction/subgroup analyses were tertiary and based on baseline omega-3 tertiles.

Study Details

PMID:26757190
Participants:266
Impact:+2.08 points in highest omega-3 tertile (B vitamins vs placebo) at 24 months; longitudinal increase ≈+0.46 points/year in highest tertile with B vitamins
Trust score:4/5

cognitive decline (executive and memory function)

1 evidences

In older adults with diabetes who took methylcobalamin (B12) in a prior randomized trial, B12 supplementation showed no significant effect on HDL function measures or on cognitive decline over follow-up.

Trust comment: Randomized placebo-controlled trial with long follow-up but substantial attrition; analyses adjusted for group assignment and relevant covariates.

Study Details

PMID:35731136
Participants:222
Impact:no significant effect of B12 supplementation on cognitive decline (previously reported)
Trust score:4/5

plasma Aβ40 (beta-amyloid 1-40)

1 evidences

In a 2-year randomized trial in older men, daily B-vitamin treatment (folate/B6/B12) attenuated the rise in plasma Aβ40 compared with placebo.

Trust comment: Large randomized trial in humans with clear, measured biomarker change; outcome is surrogate (plasma Aβ40) not clinical dementia.

Study Details

PMID:17113685
Participants:299
Impact:vitamin group +7.0 pg/ml (4.9%) vs placebo +26.8 pg/ml (18.5%) after 2 years (smaller increase with B-vitamins)
Trust score:4/5

Weight change

1 evidences

Thai schoolchildren given zinc plus multivitamins (which included vitamin D) for 6 months had greater height gain than placebo.

Trust comment: Randomized controlled trial (n=140) with clear primary outcome and significant result for height; reasonably high quality though B12 was part of a multinutrient intervention.

Study Details

PMID:27083763
Participants:140
Impact:no significant change
Trust score:4/5

inflammation markers association

1 evidences

In RA patients with elevated homocysteine, 12 months of B-vitamin treatment (including B12) significantly lowered homocysteine levels compared with placebo.

Trust comment: Double-blind randomized trial showing a clear biochemical effect (Hcy reduction) though sample size was modest (n=62).

Study Details

PMID:14626626
Participants:62
Impact:baseline Hcy associated with IL-2sRα; Hcy change associated with CRP and MTX in multivariate analysis
Trust score:4/5

blood ammonia (NH3)

1 evidences

Healthy adults given a vitamin B-complex (including B12) for 28 days showed reduced exercise fatigue markers and improved endurance time compared with placebo.

Trust comment: Randomized double-blind crossover trial with clear biochemical and performance endpoints but small sample size (n=32) and the supplement was a multicomponent B-complex product.

Study Details

PMID:37786445
Participants:32
Impact:reduced during exercise and faster recovery (significant)
Trust score:4/5

maternal vitamin B12 concentration

1 evidences

Maternal dietary + MMN supplementation for 6 months increased maternal vitamin D concentrations modestly and reduced vitamin D deficiency prevalence compared with routine care.

Trust comment: Large randomized controlled trial with objective biochemical outcomes and good adherence; B12 was measured but part of a multi-micronutrient intervention.

Study Details

PMID:39324335
Participants:600
Impact:No significant change (adjusted mean diff +6.9 pg/ml; 95% CI −13.9 to 27.7)
Trust score:4/5

maternal ferritin concentration

1 evidences

Maternal dietary + MMN supplementation for 6 months increased maternal vitamin D concentrations modestly and reduced vitamin D deficiency prevalence compared with routine care.

Trust comment: Large randomized controlled trial with objective biochemical outcomes and good adherence; B12 was measured but part of a multi-micronutrient intervention.

Study Details

PMID:39324335
Participants:600
Impact:Increased (adjusted mean diff +14.7 ng/ml; 95% CI 9.3 to 20.2; P<0.001)
Trust score:4/5

SF12-MCS (mental component)

1 evidences

In older adults with MCI, daily folate/B12/B6 pills for 1 year did not improve overall quality of life and were associated with a small negative effect on feelings of belonging.

Trust comment: Well-powered randomized, double-blind placebo-controlled trial with high compliance and intent-to-treat analyses, though QoL was a secondary/exploratory outcome.

Study Details

PMID:17616840
Participants:152
Impact:no significant main effect
Trust score:4/5

Reactive hyperaemia index (endothelial function)

1 evidences

Randomized placebo-controlled trial of L-arginine plus B vitamins for 3–6 months in mildly hypertensive adults; intervention improved postprandial endothelial function, lowered homocysteine and reduced blood pressure.

Trust comment: Randomized double-blind placebo-controlled trial with objective vascular endpoints and sustained effects; B vitamins were part of a combination product so effects are combined.

Study Details

PMID:27817128
Participants:80
Impact:ΔΔRHI +0.371 (intervention vs placebo) - improved endothelial function
Trust score:4/5

symptom severity (BCTQ total and symptoms subscale)

1 evidences

In patients with mild–moderate carpal tunnel syndrome awaiting surgery, a twice-daily multi-nutrient supplement (including B vitamins and B12) for 60 days improved symptoms and pain versus no treatment.

Trust comment: Randomized prospective trial but open-label, single-center with modest sample and multi-nutrient formulation (B12 not isolated), limiting attribution to B12 specifically.

Study Details

PMID:37366197
Participants:147
Impact:Significant improvement with supplement (p<0.05)
Trust score:3/5

function (BCTQ function subscale / Michigan Hand Questionnaire)

1 evidences

In patients with mild–moderate carpal tunnel syndrome awaiting surgery, a twice-daily multi-nutrient supplement (including B vitamins and B12) for 60 days improved symptoms and pain versus no treatment.

Trust comment: Randomized prospective trial but open-label, single-center with modest sample and multi-nutrient formulation (B12 not isolated), limiting attribution to B12 specifically.

Study Details

PMID:37366197
Participants:147
Impact:No significant improvement
Trust score:3/5

parathyroid hormone (PTH)

1 evidences

After gastric bypass, the investigational multivitamin produced higher vitamin D and thiamine levels and lower PTH at 3 months compared with the standard multivitamin.

Trust comment: Randomized trial but small sample with losses to follow-up and multiple endpoints; B12 effects not clearly reported separately.

Study Details

PMID:29500675
Participants:47
Impact:Lower at 3 months in investigational arm (p=0.042)
Trust score:3/5

urinary iodine

1 evidences

Children eating salt fortified with multiple micronutrients including iodine for one year showed better micronutrient status and improvements on several memory and attention tests.

Trust comment: Intervention showed benefits but was a school-based feeding intervention with multiple micronutrients and non-identical control conditions, limiting attribution to B12 specifically.

Study Details

PMID:17704033
Participants:129
Impact:increased (statistically significant)
Trust score:3/5

pain reduction and mobility/functionality

1 evidences

Adding B‑vitamins (including B12) to diclofenac led to faster and greater pain relief and improved mobility in acute low back pain.

Trust comment: Large randomized double‑blind controlled trial with a clear primary outcome and statistically significant results.

Study Details

PMID:19731994
Participants:372
Impact:greater pain reduction and improved mobility/functionality (statistically significant)
Trust score:4/5

Infant growth (LAZ, WAZ, WLZ, HCZ)

1 evidences

Giving mothers MMS raised iodine in breast milk but did not change infant growth at 3 months.

Trust comment: Randomized, cluster-designed substudy with blinded outcome assessment and robust lab methods, but underpowered (did not reach planned sample) and not primarily designed for vitamin B12 effects on growth.

Study Details

PMID:40409469
Participants:186
Impact:no difference between MMS and standard of care at 3 months; however, infants fed milk with all 5 micronutrients below MAEs had lower LAZ (β −0.39) and lower HCZ (β −0.32)
Trust score:4/5

Cyanocobalamin (vitamin B12 biomarker)

1 evidences

A 12-month randomized trial of a multi-component nutrition/diet protocol in ASD found improvements in many clinical and biomarker outcomes; the vitamin/mineral supplement increased some B-vitamin biomarkers.

Trust comment: Randomized, controlled human study with objective biomarker changes, but B12 was part of a multi-component intervention so attribution to B12 alone is uncertain.

Study Details

PMID:29562612
Participants:55
Impact:+44% (treatment) vs −5% (non-treatment); p=0.006
Trust score:3/5

Human milk B‑vitamin concentrations (including B12)

1 evidences

Maternal supplement (intervention vs control) given from preconception through pregnancy raised vitamin D in breast milk but did not change B‑vitamin levels.

Trust comment: Large double-blind RCT with repeated measures and objective assays; results are reliable though effect limited to vitamin D.

Study Details

PMID:38411017
Participants:338
Impact:no change (no observed intervention effect)
Trust score:4/5

Plasma vitamin B12 (cobalamin)

2 evidences

Six months of resistance training plus protein and vitamin (including B12) supplementation increased plasma B12 and folate and tended to reduce chromosomal damage, with B12 change correlated with reduced MN frequency.

Trust comment: Human intervention with objective biomarkers but small sample and mainly non-significant reductions in chromosomal damage; correlation supports a link.

Study Details

PMID:25747997
Participants:97
Impact:increased (statistically significant increase over 6 months)
Trust score:3/5

Eight-week double-blind RCT in older adults showed multivitamin supplementation increased plasma B12 and reduced prevalence of suboptimal B12 status.

Trust comment: Double-blind, placebo-controlled RCT with objective plasma measures; sample moderate but design is strong.

Study Details

PMID:11022875
Participants:80
Impact:increased from 286 to 326 pmol/L (+40 pmol/L, ≈+14%)
Trust score:4/5

dietary vitamin B12 intake (week 4)

1 evidences

Post-hoc analysis of an RCT comparing fasting + plant-based diet vs guideline diet in RA patients; both groups had dietary calcium below recommendations, with the guideline (DGE) group having higher calcium intake than the PBD group.

Trust comment: Randomized trial with direct dietary intake measurement but small, female-only sample and B12 was measured as intake not as an isolated intervention.

Study Details

PMID:36839208
Participants:50
Impact:DGE vs PBD: +2.4 µg/day (3.0 vs 0.6 µg/day); both below RDI
Trust score:3/5

CD4 recovery post-cART

1 evidences

Pre-cART vitamin D deficiency was associated with smaller CD4 count recovery over 96 weeks after starting antiretroviral therapy.

Trust comment: Well-characterized secondary analysis with direct baseline B12 measurement but B12 was not found to be associated with the primary immunologic outcome in adjusted models.

Study Details

PMID:29885777
Participants:270
Impact:vitamin B12 — no significant association reported with CD4 recovery
Trust score:3/5