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B vitamins (vitamin B6, vitamin B12, folate) and memory: grade C

Limited evidence. Direction: No effect.

C Limited

Educational guidance, not medical advice

Why this grade

Rubric condition met: One positive RCT on a secondary endpoint in a selected population against null pooled domain analyses; not B because the positive result is not a prespecified primary outcome, and not N because the large RCT is positive

The FACIT trial (818 adults aged 50-70 with raised homocysteine, 800 µg folic acid daily for 3 years) found a better 3-year change in memory than placebo, but cognition was a secondary endpoint. A post hoc analysis found no interaction with omega-3 status for episodic memory. The Clarke meta-analysis of 4 cognitive-domain trials (folic acid with vitamin B12, 1,340 people) found no significant effect on any domain, and a meta-analysis of vitamin B12 alone or B complex found no effect on any cognitive subdomain; a 2024 meta-analysis of vitamin B12 trials found no effect on memory (8 trials).

How we grade evidence

Studies this grade rests on

EffectMixedNo effectSize shows participants (n)20052010201520202025Meta-analysisRCTClarke 2014, 2014: meta-analysis, n = 22,000, result not recordedMarkun 2021, 2021: meta-analysis, n = 6,276, result not recordedDurga 2007, 2007: RCT, n = 818, result not recordedPositive effects of folic 2021, 2021: RCT, n = 791, result not recordedAlzahrani 2024, 2024: meta-analysis, n not recorded, result not recorded
each study this grade rests on, by publication year and design. Solid: effect versus the comparator; half-filled: mixed; hollow: no effect; dashed: result not recorded yet. Larger marks had more participants.
Show the numbers
StudyYearDesignParticipantsResult
Durga 20072007RCT818result not recorded
Clarke 20142014meta-analysis22000result not recorded
Positive effects of folic 20212021RCT791result not recorded
Markun 20212021meta-analysis6276result not recorded
Alzahrani 20242024meta-analysisnot recordedresult not recorded

Assessment of Vitamin B12 Efficacy on Cognitive Memory Function and Depressive Symptoms: A Systematic Review and Meta-Analysis.

Alzahrani H. Assessment of Vitamin B12 Efficacy on Cognitive Memory Function and Depressive Symptoms: A Systematic Review and Meta-Analysis Cureus, 2024. PMID 39655146

Result not recorded
Design
Systematic review and meta-analysis of 9 RCTs
Population
Trial participants, some with mild cognitive impairment
Funding
No financial support received (author declaration)

Positive effects of folic acid supplementation on cognitive aging are dependent on ω-3 fatty acid status: a post hoc analysis of the FACIT trial.

van Soest APM, van de Rest O, Witkamp RF. Positive effects of folic acid supplementation on cognitive aging are dependent on ω-3 fatty acid status: a post hoc analysis of the FACIT trial Am J Clin Nutr, 2021. PMID 33564824

Result not recorded
Design
Post hoc analysis of a randomized placebo-controlled trial (FACIT)
Sample
n = 791
Population
Adults aged 50-70 with raised plasma homocysteine and serum vitamin B12 of 200 pmol/L or more
Funding
ZonMw (Crossref funder record)

Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial.

Durga J, van Boxtel MP, Schouten EG. Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial Lancet, 2007. PMID 17240287

Result not recorded
Design
Randomized, double-blind, placebo-controlled trial (cognition was a secondary endpoint)
Sample
n = 818
Population
Adults aged 50-70 in the Netherlands with raised plasma homocysteine and normal vitamin B12
Funding
Funding: not stated in the PubMed or Crossref record; full text not read.

Effects of Vitamin B12 Supplementation on Cognitive Function, Depressive Symptoms, and Fatigue: A Systematic Review, Meta-Analysis, and Meta-Regression.

Markun S, Gravestock I, Jäger L. Effects of Vitamin B12 Supplementation on Cognitive Function, Depressive Symptoms, and Fatigue: A Systematic Review, Meta-Analysis, and Meta-Regression Nutrients, 2021. PMID 33809274

Result not recorded
Design
Systematic review, meta-analysis and meta-regression of 16 RCTs
Sample
n = 6,276
Population
Adults without advanced neurological disorders or overt vitamin B12 deficiency
Funding
Funding: not stated in the PubMed or Crossref record; full text not read. Authors declare no conflict of interest.

Effects of homocysteine lowering with B vitamins on cognitive aging: meta-analysis of 11 trials with cognitive data on 22,000 individuals.

Clarke R, Bennett D, Parish S. Effects of homocysteine lowering with B vitamins on cognitive aging: meta-analysis of 11 trials with cognitive data on 22,000 individuals Am J Clin Nutr, 2014. PMID 24965307

Result not recorded
Design
Meta-analysis of 11 large placebo-controlled trials (individual trial data)
Sample
n = 22,000
Population
Adults in homocysteine-lowering trials, unselected for cognition-related disease other than heart attack or stroke
Funding
British Heart Foundation, UK Medical Research Council, Cancer Research UK, UK Food Standards Agency, Department of Health; authors declared no conflict of interest

Search and history

Search (): folic acid[ti] AND cognitive[ti] AND randomized controlled trial[pt] AND FACIT

  • Graded C (proposed): Proposed in the monograph draft
  • C to C (approved): Editor sign-off November 13, 2026: grade matches the editor-approved final page