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Research · Supplements

Folate

Folic acid taken around conception cut neural tube defects by about 69% in a Cochrane review. Pooled trials found 10% fewer strokes and no change in coronary heart disease or cognition. Cancer did not change overall in 13 trials. One adenoma trial found more advanced lesions on 1 mg a day. High folate with low B12 tracked with anemia.

Add to Bio HackChecked 2026-11-09
Status
Dietary supplement in the US. Folic acid 1 mg tablets are prescription.
Also called
folic acid, vitamin B9, methylfolate, L-methylfolate, 5-MTHF, 5-methyltetrahydrofolate, L-5-MTHF, folinic acid, prenatal vitamin
Taken for
preventing birth defects, pregnancy, fertility, heart health, stroke, memory, mood, depression, MTHFR gene variants, homocysteine

Strong several reviews agree · Moderate one review or consistent trials · Limited one or a few small studies · Untested no study in people, listed with what it rests on

Shown to help7

Reported risks4

What people take it for, and what was found

Shown to help7

Strong

Neural tube defects

Shown to lower neural tube defects about 69% with daily folic acid, including recurrence after an affected pregnancy. 400 µg did as well as higher doses.

The numbers and sources
Effect
Daily folic acid, alone or with other vitamins and minerals, lowered neural tube defects against no folate (RR 0.31, 95% CI 0.17 to 0.58, 5 trials, 6,708 births). Recurrence in women with a previous affected pregnancy was also lower (RR 0.34, 95% CI 0.18 to 0.64, 4 trials, 1,846 births). The effect did not differ between 400 µg a day and higher doses [1]. A 2026 umbrella review found the same pattern, with RR 0.31 (95% CI 0.16 to 0.60, I² 0%) for neural tube defects at birth and RR 0.30 (95% CI 0.14 to 0.65) for recurrence [2].
Population
7,391 women in 5 trials, 2,033 of them with a previous pregnancy affected by a neural tube defect [1]; systematic reviews of trials and observational studies [2].
Sources
[1], [2]
Caveats
Only one of the five trials was at low risk of bias. The authors graded the main result high quality [1]. The one trial measuring first occurrence alone did not reach significance (RR 0.07, 95% CI 0.00 to 1.32) because there were no events in the folic acid group [1]. The two reviews draw on overlapping trials [1][2].
Strong

Stroke and cardiovascular disease

Shown to lower stroke about 10% in adults, with no change in coronary heart disease. Effects were larger in people with low blood folate.

The numbers and sources
Effect
Across 30 RCTs with 82,334 participants, folic acid lowered stroke (RR 0.90, 95% CI 0.84 to 0.96) and overall cardiovascular disease (RR 0.96, 95% CI 0.92 to 0.99). Coronary heart disease did not change (RR 1.04, 95% CI 0.99 to 1.09) [3]. In the largest single trial, first stroke occurred in 2.7% on enalapril plus folic acid and 3.4% on enalapril alone (HR 0.79, 95% CI 0.68 to 0.93) [4]. A Cochrane review of B vitamin trials found the same 10% stroke reduction and no change in heart attack [5].
Population
Adults with and without cardiovascular disease [3][5]; 20,702 adults with high blood pressure in China, median 4.5 years [4].
Sources
[3], [4], [5]
Caveats
Stroke and overall cardiovascular effects were larger in people with lower blood folate at baseline and without existing cardiovascular disease [3]. The Chinese trial gave folic acid with enalapril and compared it with enalapril alone [4].
Limited

Depression, as an add-on to antidepressants

Small trials found L-methylfolate added to antidepressants raised response and lowered symptoms in adults with major depression.

The numbers and sources
Effect
Added to antidepressants, L-methylfolate raised response on the Hamilton scale (RR 1.25, 95% CI 1.08 to 1.46, 3 studies, 483 patients) and lowered depressive symptom scores (SMD -0.38, 95% CI -0.59 to -0.17, 4 studies, 507 patients) against antidepressants alone [7].
Population
Adults with major depressive disorder already taking antidepressants [7].
Sources
[7]
Caveats
Few small studies. No trial in that review tested methylfolate alone against placebo as the only treatment.
Moderate

Methylfolate in place of folic acid

Shown to raise blood folate and lower unmetabolized folic acid more than folic acid in women of childbearing age. These are blood markers, not health outcomes.

The numbers and sources
Effect
Over 24 weeks, 113 µg a day of L-methylfolate lowered homocysteine 14.6% and 100 µg of folic acid 9.3% against placebo. Red blood cell folate rose 23% and 31% [8]. A 2025 meta-analysis of 11 RCTs in women of childbearing age found that active folate, compared with folic acid, raised plasma folate (p 0.04) and red blood cell folate (p 0.01) and lowered unmetabolized folic acid (p below 0.0001), with no difference in homocysteine or B12. In women with a history of adverse pregnancy outcomes, it was linked to higher later pregnancy rates and fewer adverse outcomes [9]. A 2026 systematic review found that 5-MTHF in place of folic acid reduced unmetabolized folic acid in 3 trials (SMD 0.99, 95% CI 0.20 to 1.79, GRADE low), and showed no difference in homocysteine [10]. A 2024 review reported a lack of clinical studies testing methylfolate for preventing neural tube defects [11].
Population
167 healthy volunteers [8]; women of childbearing age in 11 RCTs [9]; trials and observational studies in two reviews [10][11].
Sources
[8], [9], [10], [11]
Caveats
Most results are blood markers, not health outcomes. The 2025 meta-analysis notes low study quality and short treatment [9]. The 2026 review found the two trials of red blood cell folate pointed in opposite directions, and found no evidence that unmetabolized folic acid causes harm on its own. Its authors disclosed ties to a company developing a folinic acid drug [10]. [11] is a narrative review funded by ITF Research Pharma.
Strong

Homocysteine

Shown to lower homocysteine in adults with high levels, kidney disease or type 2 diabetes. In kidney disease, cardiovascular events did not fall.

The numbers and sources
Effect
In 36 RCTs of adults with high homocysteine, folic acid alone lowered homocysteine (SMD -0.99, 95% CI -1.15 to -0.83, I² 90%), with the largest effects at 5 to 15 mg a day and after 6 months or more [12]. In 14 RCTs in chronic kidney disease, folate-based supplements lowered homocysteine by 8.09 µmol/L (95% CI -11.54 to -4.63, I² 98%), while cardiovascular events (RR 0.88, 95% CI 0.68 to 1.13), all-cause mortality and cardiovascular mortality did not change [13]. In 29 studies in type 2 diabetes, folic acid with B12 lowered homocysteine (SMD -2.77, 95% CI -3.23 to -2.30) [14].
Population
Adults with high homocysteine [12]; 8,625 adults with chronic kidney disease in 37 studies [13]; adults with type 2 diabetes [14].
Sources
[12], [13], [14]
Caveats
Heterogeneity was high in all three. The high-homocysteine review found substantial risk of bias and likely overestimation from small-study effects and publication bias, and no included trial reported adjudicated heart attacks, strokes or cardiovascular deaths [12]. The type 2 diabetes estimate is about three times the size of the other review's and combined folic acid with B12 [14]. Lower homocysteine did not translate into fewer cardiovascular events in kidney disease [13].
Moderate

Miscarriage and pregnancy rate (high dose against standard dose)

Shown to raise pregnancy rates slightly with 4 to 5 mg a day before conception against 0.4 mg. Fewer miscarriages appeared only among women who conceived.

The numbers and sources
Effect
Across 3 RCTs (5,144 women trying to conceive), 4 to 5 mg a day of folic acid before conception, against 0.4 mg, was linked to fewer miscarriages among the 1,488 who became pregnant (RR 0.73, 95% CI 0.56 to 0.94, I² 0%). Counting all randomized women, the reduction was not significant (RR 0.79, 95% CI 0.61 to 1.04). Pregnancy rate was higher on the high dose (RR 1.10, 95% CI 1.02 to 1.18) [15].
Population
Nonpregnant women of reproductive age [15].
Sources
[15]
Caveats
Certainty was rated low to moderate. Restricting to women who became pregnant breaks randomization [15].
Moderate

Autism and neurodevelopment in children (use in pregnancy)

Linked to about 30% lower autism risk and lower ADHD odds in children whose mothers took folic acid, in observational studies.

The numbers and sources
Effect
A 2025 umbrella review of 23 systematic reviews found maternal folic acid linked to lower odds of autism (OR 0.66, 95% CI 0.55 to 0.79), ADHD (OR 0.86, 95% CI 0.78 to 0.95) and behavioral problems (OR 0.75). Motor, cognitive and language development showed no association [16]. A second umbrella review of 8 meta-analyses (101 studies, over 3 million mother and child pairs) found folic acid linked to 30% lower autism risk (RR 0.70, 95% CI 0.60 to 0.83) [17].
Population
Mother and child pairs in observational studies [16][17].
Sources
[16], [17]
Caveats
All underlying studies were observational, so they cannot show cause. Half the reviews in [16] were rated very low quality. A 2026 review of excess intake linked high folic acid and high blood folate in pregnancy with adverse neurodevelopment in offspring [18].

Not shown to help1

Moderate

Memory and cognitive decline

Not shown to change memory or cognitive scores in adults across 9 placebo-controlled trials.

The numbers and sources
Effect
Across 9 placebo-controlled trials (2,835 participants, median 6 months), folic acid with or without other B vitamins changed cognitive scores by an SMD of 0.01 (95% CI -0.08 to 0.10). Memory, speed, language and executive function each showed no effect [6].
Population
Adults in 9 RCTs [6].
Sources
[6]
Caveats
Trials ran up to 3 years. None recorded dementia incidence [6].

Doses studied

Neural tube defect trials used 400 µg (0.4 mg) a day or more [1]. The Chinese stroke trial used 0.8 mg with enalapril [4]. The adenoma trial used 1 mg a day [19]. The methylfolate comparison used 100 µg folic acid or 113 µg L-methylfolate [8]. The miscarriage trials compared 4 to 5 mg a day with 0.4 mg [15]. EFSA sets a tolerable upper intake level of 1,000 µg a day for adults, including during pregnancy. It applies to folic acid and the two methylfolate salts added to foods or supplements, and not to folate naturally in food [20].

Risks

Reported risks4

LimitedVery common

Advanced colorectal adenomas

One trial found advanced colorectal lesions in 11.6% on 1 mg a day against 6.9% on placebo, in people with past adenomas.

The numbers and sources
How common
Very common: more than 1 in 10 people.
Effect
At the second colonoscopy, at least one advanced lesion was found in 11.6% on 1 mg folic acid a day and 6.9% on placebo (RR 1.67, 95% CI 1.00 to 2.80). Adenomas of any kind did not differ. Three or more adenomas and noncolorectal cancers were more common on folic acid [19].
Population
1,021 people with a recent history of colorectal adenomas, with colonoscopies at 3 years and again 3 or 5 years later [19].
Sources
[19]
Caveats
One trial. Only 59.5% had the second colonoscopy [19].
Why limited
This rests on one trial, of 1,021 people. Strength counts independent studies that agree, so one trial is limited at any size.
LimitedHow often is not known

High folate with low B12

Limited evidence: in older adults with low B12, high blood folate was linked to anemia and cognitive impairment. With normal B12 it went with less impairment.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
Among older adults with low B12, serum folate above 59 nmol/L was associated with anemia (OR 3.1, 95% CI 1.5 to 6.6) and cognitive impairment (OR 2.6, 95% CI 1.1 to 6.1). With normal B12, high folate went with less cognitive impairment (OR 0.4, 95% CI 0.2 to 0.9) [23].
Population
1,459 seniors in the US NHANES survey, 1999 to 2002 [23].
Sources
[23]
Caveats
Cross-sectional. The authors note that a trial of this question would be unethical [23].
ModerateHow often is not known

Gestational diabetes with high or long use

Linked to higher odds of gestational diabetes at 800 µg a day or more, or with use beyond 3 to 6 months, in observational studies.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
A 2025 systematic review of 12 observational studies found that 800 µg a day or more, or use beyond 3 to 6 months, may be associated with higher odds of gestational diabetes, especially when started before conception. About 400 µg a day appeared neutral or protective in some populations. High folate with low B12 was linked to higher risk [24]. A 2026 systematic review linked excess folic acid intake and high blood folate in pregnancy with gestational diabetes, large-for-gestational-age infants and higher birth weight [18].
Population
Pregnant women in cohort and case-control studies [24][18].
Sources
[24], [18]
Caveats
Observational studies, no pooled estimate. The first review calls the evidence inconclusive [24].
LimitedHow often is not known

Cardiovascular events at 15 mg a day

Limited evidence: trials at 15 mg a day reported more cardiovascular events in people with high homocysteine, with none at 10 mg or less.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
In a meta-analysis of 36 RCTs in high homocysteine, no cardiovascular adverse events were observed at 10 mg a day or less, while trials using 15 mg a day reported more (3 studies, 35 events) [12].
Population
Adults with high homocysteine [12].
Sources
[12]
Caveats
Few events in 3 trials. The events were not adjudicated, and the authors call all dose findings hypothesis-generating [12].

Checked, no increase found1

Moderate

Cancer

Cancer was about as common as on placebo across 13 trials over about 5 years. The upper limit allows up to a 13% increase.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
Across 13 trials with 49,621 participants, folic acid quadrupled blood folic acid and did not significantly change cancer incidence (1,904 against 1,809 cancers, RR 1.06, 95% CI 0.99 to 1.13) over a weighted average of 5.2 years. No specific site differed [21]. A 2025 umbrella review found folic acid supplement use linked to lower colorectal cancer risk in observational data (RR 0.83, 95% CI 0.77 to 0.90, low quality). In people with a past adenoma, adenoma recurrence on folic acid was RR 1.05 (95% CI 0.86 to 1.29, high quality), and high blood folate was linked to advanced-stage tumors (OR 1.95, 95% CI 1.18 to 3.22, very low quality) [22].
Population
Participants in 10 cardiovascular prevention trials and 3 colorectal adenoma trials [21]; meta-analyses of trials and observational studies [22].
Sources
[21], [22]
Caveats
Covers the treatment period only. The upper confidence limit allows up to a 13% increase.

Claims tested and not found

  1. That folic acid slows cognitive decline. Nine trials found no effect on any cognitive domain [6].
  2. That folic acid prevents heart attacks. Coronary heart disease did not change in 30 pooled trials [3].
  3. That folic acid prevents colorectal adenomas. At 1 mg a day, adenoma rates did not differ from placebo [19].

Sources

  1. De-Regil LM, Peña-Rosas JP, Fernández-Gaxiola AC, et al. Effects and safety of periconceptional oral folate supplementation for preventing birth defects. Cochrane Database of Systematic Reviews. 2015. https://doi.org/10.1002/14651858.CD007950.pub3
  2. Yoo S, Montazeri A, Bennett D, et al. Folate and global health umbrella review series, part 1: methodological framework and syntheses on anaemia and neural tube defects. Journal of Global Health. 2026. https://doi.org/10.7189/jogh.16.04014
  3. Li Y, Huang T, Zheng Y, et al. Folic Acid Supplementation and the Risk of Cardiovascular Diseases: A Meta-Analysis of Randomized Controlled Trials. Journal of the American Heart Association. 2016. https://doi.org/10.1161/JAHA.116.003768
  4. Huo Y, Li J, Qin X, et al. Efficacy of Folic Acid Therapy in Primary Prevention of Stroke Among Adults With Hypertension in China. JAMA. 2015. https://doi.org/10.1001/jama.2015.2274
  5. Martí-Carvajal AJ, Solà I, Lathyris D, et al. Homocysteine-lowering interventions for preventing cardiovascular events. Cochrane Database of Systematic Reviews. 2017. https://doi.org/10.1002/14651858.CD006612.pub5
  6. Wald DS, Kasturiratne A, Simmonds M. Effect of Folic Acid, with or without Other B Vitamins, on Cognitive Decline: Meta-Analysis of Randomized Trials. The American Journal of Medicine. 2010. https://doi.org/10.1016/j.amjmed.2010.01.017
  7. Maruf AA, Poweleit EA, Brown LC, et al. Systematic Review and Meta-Analysis of L-Methylfolate Augmentation in Depressive Disorders. Pharmacopsychiatry. 2022. https://doi.org/10.1055/a-1681-2047
  8. Venn BJ, Green TJ, Moser R, et al. Comparison of the effect of low-dose supplementation with L-5-methyltetrahydrofolate or folic acid on plasma homocysteine: a randomized placebo-controlled study. The American Journal of Clinical Nutrition. 2003. https://doi.org/10.1093/ajcn/77.3.658
  9. Xie M, Qing X, Huang H, et al. The effectiveness and safety of the active form of folate on biochemical parameters in women of childbearing age: A systematic review and meta-analysis. Medicine. 2025. https://doi.org/10.1097/MD.0000000000046564
  10. Frye RE, Rossignol DA. Unmetabolized Folic Acid: Biology, Epidemiology, and Clinical Consequences: A Systematic Review. Nutrients. 2026. https://doi.org/10.3390/nu18172887
  11. Samaniego-Vaesken ML, Morais-Moreno C, Carretero-Krug A, et al. Supplementation with Folic Acid or 5-Methyltetrahydrofolate and Prevention of Neural Tube Defects: An Evidence-Based Narrative Review. Nutrients. 2024. https://doi.org/10.3390/nu16183154
  12. Long Z, Wang C, Sun F, et al. Efficacy and safety of folic acid on homocysteine and cardiovascular surrogate biomarkers in hyperhomocysteinemia: a systematic review and meta-analysis of RCTs. BMC Nutrition. 2026. https://doi.org/10.1186/s40795-026-01343-y
  13. Chan WL, Jiao Y, Chim KCY, et al. Effect of Folate-Based Supplementation in Kidney Disease: A Systematic Review and Meta-analysis of Kidney, Cardiovascular, and Mortality Outcomes. Nutrition Reviews. 2026. https://doi.org/10.1093/nutrit/nuag038
  14. Yin Y, Zhao Z, Wang X, et al. Effects of folic acid with vitamin B12/vitamin B6 intervention on serum homocysteine metabolism and complications in patients with type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Frontiers in Nutrition. 2025. https://doi.org/10.3389/fnut.2025.1701310
  15. Vinti D, Fiore A, Fornelli G, et al. High versus standard dose folic acid supplementation for miscarriage prevention: systematic review and meta-analysis of randomized controlled trials. American Journal of Obstetrics & Gynecology MFM. 2026. https://doi.org/10.1016/j.ajogmf.2026.101934
  16. Yu M, Hu Y, Hou L, et al. The Effect of Maternal Folic Acid Supplementation on Neurodevelopmental Disorders in Offspring: An Umbrella Review of Systematic Reviews and Meta-Analyses. Nutrients. 2025. https://doi.org/10.3390/nu17213443
  17. Abate BB, Tusa BS, Sendekie AK, et al. The association between maternal prenatal folic acid and multivitamin supplementation and autism spectrum disorders in offspring: An umbrella review. PLOS One. 2025. https://doi.org/10.1371/journal.pone.0334852
  18. Ledowsky C, Scarf V, Sobczyńska-Malefora A, et al. Effects of excess folic acid and high blood folate during preconception and pregnancy: systematic review. Reproductive BioMedicine Online. 2026. https://doi.org/10.1016/j.rbmo.2025.105240
  19. Cole BF, Baron JA, Sandler RS, et al. Folic Acid for the Prevention of Colorectal Adenomas. JAMA. 2007. https://doi.org/10.1001/jama.297.21.2351
  20. European Food Safety Authority. Overview on Tolerable Upper Intake Levels as derived by the Scientific Committee on Food (SCF) and the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA). Version 11. 2025. https://www.efsa.europa.eu/sites/default/files/assets/UL_Summary_tables.pdf
  21. Vollset SE, Clarke R, Lewington S, et al. Effects of folic acid supplementation on overall and site-specific cancer incidence during the randomised trials: meta-analyses of data on 50 000 individuals. The Lancet. 2013. https://doi.org/10.1016/S0140-6736(12)62001-7
  22. Li T, Yin L, Li Y, et al. Folate exposures and risk of colorectal cancer: an umbrella review of meta-analyses of observational studies and randomised controlled trials. BMJ Open. 2025. https://doi.org/10.1136/bmjopen-2025-103637
  23. Morris MS, Jacques PF, Rosenberg IH, et al. Folate and vitamin B-12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification. The American Journal of Clinical Nutrition. 2007. https://doi.org/10.1093/ajcn/85.1.193
  24. Gómez-Cabrera AS, González-Santiago AE, Castañeda-Arellano R, et al. Folic Acid Supplementation and Risk of Gestational Diabetes Mellitus: A Systematic Review of the Literature. International Journal of Molecular Sciences. 2025. https://doi.org/10.3390/ijms26167977

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