Supplements

Folate (Folic Acid)

Updated · 25 sources

Folate is vitamin B9, a water-soluble B vitamin the body needs to make DNA, divide cells and recycle the amino acid homocysteine. Folic acid is the synthetic form used in supplements and fortified grains, and L-methylfolate (5-MTHF) is the active form found in blood. Folic acid taken before and in early pregnancy prevents neural tube defects, but in large trials it did not prevent heart attacks or improve semen quality, and the US upper limit for adults is 1,000 mcg/day from supplements and fortified foods.

Folate is marketed to lifters in “fertility,” “methylation” and “MTHFR” products, often at doses far above the RDA. The best-designed male fertility trial, FAZST, gave 5 mg of folic acid plus 30 mg of zinc daily to 1,185 men and found no gain in live births or semen quality, with a small rise in sperm DNA damage. The main safety concern with high folic acid intake is that it can hide the anemia of vitamin B12 deficiency while nerve damage continues.

This page summarizes what the National Academies, the NIH Office of Dietary Supplements, the European Food Safety Authority and clinical trials report. It is for education only and is not medical advice.

Property Detail
Type Essential water-soluble vitamin (B9); dietary supplement, food fortificant and prescription drug ingredient
Main forms Food folate (polyglutamates); folic acid (synthetic, fully oxidized); 5-methyltetrahydrofolate (5-MTHF, L-methylfolate)
Adult RDA (US) 400 mcg DFE/day; 600 mcg DFE in pregnancy; 500 mcg DFE in lactation
Upper limit US and EU: 1,000 mcg/day for adults from folic acid (EU: plus authorized 5-MTHF salts); no limit for food folate
Conversion 1 mcg DFE = 1 mcg food folate = 0.6 mcg folic acid with food = 0.5 mcg folic acid on an empty stomach
Typical US intake 602 mcg DFE/day from food in men aged 20+ and 455 mcg DFE/day in women (NHANES 2013–2014)
Doses in cited trials 400–800 mcg/day (neural tube defect prevention, stroke); 1 mg/day (colon polyps); 2.5 mg/day (heart trials); 5 mg/day (FAZST); 7.5–15 mg/day L-methylfolate (depression)
Half-life No single value; total body folate is about 15–30 mg, half of it in the liver
WADA status Not on the 2026 Prohibited List

What it is

“Folate” is the umbrella term for a family of related molecules. The Institute of Medicine (IOM) describes folate as a coenzyme in “single-carbon transfers,” reactions that move one-carbon units to build DNA bases and amino acids (IOM 1998). The three forms people run into are:

Form Where it comes from Key points
Food folate Leafy greens, legumes, liver and other foods Mostly polyglutamates (several glutamate units attached). Must be trimmed in the gut before absorption; about 50% bioavailable
Folic acid Supplements and fortified grains Synthetic, stable, fully oxidized monoglutamate. About 85% bioavailable with food and close to 100% on an empty stomach. Must be reduced by the enzyme dihydrofolate reductase before use
5-MTHF (L-methylfolate, levomefolate) Main form in blood; sold as calcium L-methylfolate and other salts Already in the active methylated form, so it bypasses dihydrofolate reductase and the MTHFR step

The ODS notes that dihydrofolate reductase activity varies greatly between people. When its capacity is exceeded, unmetabolized folic acid appears in the blood. The main form of folate in plasma is 5-MTHF, and the body holds an estimated 15 to 30 mg in total, about half in the liver (NIH ODS).

Dietary folate equivalents

Because folic acid is absorbed better than food folate, US intake values are set in dietary folate equivalents (DFE). The IOM conversion is: 1 mcg DFE = 1 mcg food folate = 0.6 mcg folic acid from fortified food or a supplement taken with meals = 0.5 mcg folic acid on an empty stomach (IOM 1998). So 400 mcg of folic acid taken with food counts as about 680 mcg DFE.

For 5-MTHF, the US has no formally established DFE factor, and the FDA lets manufacturers use 1.7 (the folic acid factor) or their own factor up to 1.7 (NIH ODS). In 2022, EFSA proposed using 1.7 for 5-MTHF at intakes below 400 mcg/day and 2.0 at 400 mcg/day or more, because 5-MTHF was more bioavailable than folic acid at the higher dose (EFSA NDA Panel, EFSA J 2022).

Dietary reference intakes

Group RDA (mcg DFE/day) UL (mcg/day, folic acid from supplements or fortified food)
Children 1–3 y 150 300
Children 4–8 y 200 400
Ages 9–13 y 300 600
Ages 14–18 y 400 800
Adults 19 y and older 400 1,000
Pregnancy 600 800–1,000 (by age)
Lactation 500 800–1,000 (by age)

Sources: IOM 1998; NIH ODS. The adult Estimated Average Requirement is 320 mcg DFE/day, and the RDA is set at 120% of it.

The UL is stated in mcg, not mcg DFE, and applies only to synthetic folate. No UL exists for folate from ordinary food, because high food intakes have not been reported to cause harm. 1,000 mcg of folic acid equals about 1,667 mcg DFE (NIH ODS).

European values are similar in structure but lower for intake:

  • Population reference intake. In 2014, EFSA set an average requirement of 250 mcg DFE/day and a population reference intake of 330 mcg DFE/day for adults, with an adequate intake of 600 mcg DFE/day in pregnancy (EFSA NDA Panel, EFSA J 2014).
  • Upper limit. In 2023, EFSA reviewed the evidence again and kept the adult UL at 1,000 mcg/day. The limit now covers folic acid plus the authorized 5-MTHF salts combined. The critical effect is still the risk of worsening nerve damage in people with vitamin B12 deficiency. EFSA found the evidence insufficient to link folate intake to cognitive decline or to colorectal or prostate cancer (EFSA NDA Panel, EFSA J 2023).

Fortification and intake

Since January 1998, the FDA has required 140 mcg of folic acid per 100 g in enriched breads, cereals, flours, pasta, rice and other grain products. This raised average US folic acid intake by about 190 mcg/day. Canada requires 150 mcg/100 g. US neural tube defect rates have fallen by 28% since fortification began (NIH ODS).

Most Americans get enough. About 35% of US adults take a supplement with folic acid, and supplement users get a mean of 712 mcg DFE from supplements alone. About 5% of adults aged 51–70 exceed the UL, mainly because of supplements (NIH ODS).

How it works in the body

Folate carries one-carbon units in two linked cycles (IOM 1998; NIH ODS):

  • DNA building. Folate is needed to make thymidine and purines, the building blocks of DNA. Fast-dividing cells, such as red blood cell precursors and the cells of an early embryo, are most sensitive to a shortage.
  • Homocysteine recycling. 5-MTHF gives its methyl group to homocysteine to make methionine. The enzyme that does this, methionine synthase, also needs vitamin B12. Methionine then becomes S-adenosylmethionine, the body’s main methyl donor.

When folate is short, homocysteine builds up in the blood. A cut-off of 16 micromol/L is most often used for elevated homocysteine, though 12–14 micromol/L is also used. Homocysteine is not specific to folate, because low B12, poor kidney function and other deficiencies also raise it (NIH ODS). For the B12 side of this pathway, see Vitamin B12. Another methyl donor that lowers homocysteine through a separate enzyme is betaine (TMG).

Deficiency

Isolated folate deficiency is uncommon and usually occurs alongside poor diet, alcohol use disorder or malabsorption. Its main clinical sign is megaloblastic anemia, with large, abnormal red cells. Symptoms include weakness, fatigue, poor concentration, headache, palpitations and shortness of breath. Alcohol interferes with folate absorption and speeds its breakdown and urinary loss. Celiac disease, inflammatory bowel disease and stomach surgery also raise risk (NIH ODS).

MTHFR variants

MTHFR (methylenetetrahydrofolate reductase) is the enzyme that makes 5-MTHF. A common gene variant, 677C>T, produces a less active enzyme. According to the ODS, about 25% of Hispanics, 10% of Caucasians and Asians, and 1% of African Americans carry two copies (are homozygous). Homozygous people tend to have higher homocysteine and lower folate levels (NIH ODS). The IOM noted that in one study, homocysteine was raised in TT carriers only when plasma folate was low (IOM 1998).

What this means in practice:

  • Folic acid still works. The CDC recommends 400 mcg/day of folic acid, not 5-MTHF, for people who could become pregnant, even with the 677C>T variant, and the ODS states that this dose helps prevent neural tube defects in women with the variant (NIH ODS).
  • Testing has limited value. The American College of Medical Genetics advises that MTHFR testing has minimal clinical utility and should not be part of routine evaluation for blood clotting disorders. It noted that meta-analyses have disproven a link between MTHFR status and venous blood clots (Hickey et al., Genet Med 2013).
  • 5-MTHF raises blood folate faster. In a crossover study of 24 women with the TT or normal CC genotype, a single dose of 416 mcg 5-MTHF raised plasma folate more than 400 mcg of folic acid in both genotypes. Unmetabolized folic acid appeared regularly after folic acid but rarely after 5-MTHF (Prinz-Langenohl et al., Br J Pharmacol 2009).
  • Homocysteine lowering is similar. Over 24 weeks in 144 women, 400 mcg folic acid, 416 mcg 5-MTHF and 208 mcg 5-MTHF lowered homocysteine by similar amounts (Lamers et al., Am J Clin Nutr 2004).

Approved medical uses

  • Neural tube defect prevention. In the MRC Vitamin Study, 1,817 women who had a previous pregnancy affected by a neural tube defect (a birth defect of the brain or spine, such as spina bifida) were randomized. Folic acid gave a 72% protective effect (relative risk 0.28; 95% CI 0.12–0.71), while a mix of seven other vitamins did not (MRC Vitamin Study, Lancet 1991). The US Preventive Services Task Force recommends that all people planning to or who could become pregnant take 0.4 to 0.8 mg (400–800 mcg) of folic acid daily, an “A” recommendation (USPSTF, JAMA 2023). Women with a previously affected pregnancy are often advised to take 4,000–5,000 mcg daily under medical supervision (NIH ODS).
  • Treating folate deficiency and megaloblastic anemia, after B12 deficiency has been ruled out.
  • Methotrexate side effects. Methotrexate blocks folate metabolism. In rheumatoid arthritis, a meta-analysis of 7 trials (709 patients) found that folate cut elevated liver enzymes (OR 0.15), nausea and vomiting (OR 0.71) and drop-outs (OR 0.29) (Liu et al., J Clin Rheumatol 2019). People taking methotrexate for cancer should not add folate without their oncologist, because it could blunt the drug’s effect (NIH ODS).

What the research shows

Homocysteine and heart disease

Folic acid reliably lowers homocysteine, but lowering it has not prevented heart attacks:

Evidence Population Result
Clarke et al., Arch Intern Med 2010 Individual data from 8 trials, 37,485 people at high cardiovascular risk Homocysteine fell 25% on average, but no effect on major vascular events (RR 1.01), coronary events (RR 1.03), stroke (RR 0.96), cancer or death over a median 5 years
Martí-Carvajal et al., Cochrane 2017 15 trials, 71,422 people No effect on heart attack (RR 1.02) or death (RR 1.01); a small reduction in stroke (4.3% vs 5.1%; RR 0.90; 95% CI 0.82–0.99)
Huo et al., JAMA 2015 (CSPPT) 20,702 adults with high blood pressure in China, where grain is not fortified Enalapril plus 0.8 mg folic acid vs enalapril alone: first stroke 2.7% vs 3.4% (HR 0.79; 95% CI 0.68–0.93). No effect on heart attack or death

The ODS concludes that folic acid may mainly benefit people with low folate status, which is less common in countries with fortification such as the US (NIH ODS).

Cancer

Concern that high folic acid intake might speed the growth of precancerous lesions came partly from a polyp prevention trial. In 1,021 people with a history of colorectal adenomas (polyps), 1 mg/day of folic acid did not reduce new adenomas. At the second colonoscopy, advanced lesions occurred in 11.6% on folic acid vs 6.9% on placebo (RR 1.67; 95% CI 1.00–2.80; P = .05), and folic acid was linked to more people with 3 or more adenomas (Cole et al., JAMA 2007).

A larger pooled analysis was reassuring. Individual data from 13 trials with 49,621 participants showed that folic acid, over an average of 5.2 years, had no significant effect on overall cancer (RR 1.06; 95% CI 0.99–1.13) or on cancers of the bowel, prostate, lung or breast (Vollset et al., Lancet 2013). EFSA’s 2023 review likewise found the evidence insufficient to show that folate intake causes colorectal or prostate cancer (EFSA 2023).

Sperm and male fertility (FAZST)

Folate is needed for DNA synthesis in rapidly dividing sperm-forming cells, and small trials suggested a benefit:

  • Early trial. In 87 Dutch men, 5 mg/day folic acid plus 66 mg/day zinc sulfate for 26 weeks raised sperm concentration in subfertile men. FSH, testosterone and inhibin B did not change (Ebisch et al., Int J Androl 2006).
  • Meta-analyses of small trials. A 2017 meta-analysis of 7 trials found higher sperm concentration with folate or folate plus zinc, with no effect on serum testosterone, but warned of major differences between studies (Irani et al., Urol J 2017). A 2020 meta-analysis of 4 trials of 5 mg/day found a nonsignificant rise in sperm concentration (3.54 million/mL; 95% CI −1.40 to 8.48) (Hoek et al., Mol Nutr Food Res 2020).

The Folic Acid and Zinc Supplementation Trial (FAZST) was the definitive test (Schisterman et al., JAMA 2020):

FAZST feature Detail
Who 2,370 couples planning infertility treatment at 4 US centers, enrolled 2013–2017; men’s mean age 33
What 5 mg folic acid plus 30 mg elemental zinc daily, or placebo, for 6 months
Live birth 34% vs 35% (risk difference −0.9%; 95% CI −4.7% to 2.8%)
Semen quality No significant difference in concentration, motility, shape, volume or total motile count
DNA fragmentation Higher with supplements: 29.7% vs 27.2% (mean difference 2.4%; 95% CI 0.5%–4.4%)
Side effects More abdominal pain (6% vs 3%), nausea (4% vs 2%) and vomiting (3% vs 1%)

The authors concluded that the findings do not support folic acid and zinc for male partners in infertility treatment. A 2025 meta-analysis of 50 trials found that zinc plus folic acid improved sperm concentration in smaller studies but that no supplement improved pregnancy or live birth, with low or very low certainty (Michaelsen et al., Nutrients 2025). For the zinc side of this trial, see Zinc.

Testosterone and training

We found no trial showing that folic acid or L-methylfolate raises testosterone, muscle mass or strength. In the fertility trials that measured hormones, folic acid with zinc did not change serum testosterone (Ebisch et al. 2006; Irani et al. 2017). For lifters, folate matters as part of an adequate diet and for anyone planning a pregnancy with a partner, not as a performance aid.

L-methylfolate as an antidepressant add-on

L-methylfolate at prescription-strength doses has been studied with antidepressants. In two trials in people whose depression had not responded to an SSRI, 7.5 mg/day (then 15 mg/day) showed no benefit in the first trial (148 patients), while 15 mg/day improved response in the second (75 patients), with a number needed to treat of about 6 (Papakostas et al., Am J Psychiatry 2012). These are milligram doses, far above dietary intakes, and were given alongside antidepressants under medical care.

Side effects and risks

Hiding vitamin B12 deficiency

This is the main reason the UL exists. Folic acid can correct the anemia of B12 deficiency but not the nerve damage. In people with undiagnosed B12 deficiency, high-dose folic acid can therefore delay diagnosis while damage to the spinal cord and nerves progresses. The IOM based the adult UL on more than 100 case reports of neurological progression in patients with pernicious anemia at folate doses of 5 mg/day or more. It divided that lowest-observed-adverse-effect level of 5 mg by an uncertainty factor of 5 to reach 1,000 mcg/day, noting that the damage “may be serious, irreversible, and crippling” (IOM 1998).

A 2024 review adds that people with low B12 and high folate have lower cognitive scores and higher homocysteine and methylmalonic acid than people with low B12 and normal folate. The authors note this evidence is mostly correlational but call for vigilance in older adults, vegans and people with B12 malabsorption who take high-dose folic acid (Miller et al., Food Nutr Bull 2024). Long-term metformin use is one known cause of low B12, according to its label.

Unmetabolized folic acid

In NHANES 2007–2008, unmetabolized folic acid was detectable in more than 95% of US serum samples, in both supplement users and non-users, and was above 1 nmol/L in 33.2% of people (Pfeiffer et al., J Nutr 2015). Single doses of 300–400 mcg produce detectable levels, while 100–200 mcg do not. Unmetabolized folic acid has been linked to lower natural killer cell activity, but the health consequences are not established (NIH ODS).

Other effects

  • Stomach upset. In FAZST, 5 mg folic acid plus zinc roughly doubled rates of abdominal pain, nausea and vomiting (Schisterman et al. 2020).
  • Pregnancy at high doses. Periconception intakes of 1,000 mcg/day or more from supplements have been associated with lower scores on some child development tests at age 4–5, compared with 400–999 mcg/day (NIH ODS).

Interactions

The ODS lists these (NIH ODS):

  • Methotrexate. A folate antagonist; folate may interfere with its anticancer effect but reduces side effects at low arthritis or psoriasis doses.
  • Antiepileptic drugs (phenytoin, carbamazepine, valproate). These can lower serum folate, and folate supplements may lower blood levels of the drugs.
  • Sulfasalazine. Blocks folate absorption in the gut and can cause deficiency.

In the US, folic acid and L-methylfolate are sold as dietary supplements. Folic acid is also a required fortificant in enriched US grain products. Folate is not named on the WADA 2026 Prohibited List. Multi-ingredient “methylation” or fertility stacks can still be contaminated, so tested athletes rely on third-party certification.

Key takeaways

  • Three forms, one vitamin. Food folate, synthetic folic acid and active L-methylfolate (5-MTHF) all supply folate; folic acid is absorbed best per microgram.
  • RDA 400 mcg DFE, UL 1,000 mcg. The upper limit applies to folic acid from supplements and fortified foods, not to food folate.
  • Prevents neural tube defects. Folic acid before conception cut recurrence by 72% in the MRC trial, and the USPSTF recommends 400–800 mcg/day for anyone who could become pregnant.
  • Lowers homocysteine but not heart attacks. Large trials show no effect on heart attacks or death, with a modest stroke benefit mainly where folate status is low.
  • MTHFR is overhyped. The 677C>T variant raises homocysteine when folate is low, but folic acid still works and routine testing is not advised.
  • FAZST was negative. 5 mg folic acid plus 30 mg zinc did not improve semen quality or live births and slightly raised sperm DNA damage.
  • Watch B12. High-dose folic acid can hide B12 deficiency while nerve damage progresses.

Sources

  1. Institute of Medicine. Folate. In: Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: National Academies Press; 1998. National Academies Press.
  2. National Institutes of Health Office of Dietary Supplements. Folate: fact sheet for health professionals. Updated November 30, 2022. NIH ODS.
  3. EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA). Scientific opinion on dietary reference values for folate. EFSA J. 2014;12(11):3893. EFSA.
  4. EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA), Turck D, Bohn T, et al. Scientific opinion on the tolerable upper intake level for folate. EFSA J. 2023;21(11):e08353. PubMed.
  5. EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA), Turck D, Bohn T, et al. Conversion of calcium-L-methylfolate and (6S)-5-methyltetrahydrofolic acid glucosamine salt into dietary folate equivalents. EFSA J. 2022;20(8):e07452. PubMed.
  6. Prinz-Langenohl R, Brämswig S, Tobolski O, et al. [6S]-5-methyltetrahydrofolate increases plasma folate more effectively than folic acid in women with the homozygous or wild-type 677C→T polymorphism of methylenetetrahydrofolate reductase. Br J Pharmacol. 2009;158(8):2014–2021. PubMed.
  7. Lamers Y, Prinz-Langenohl R, Moser R, Pietrzik K. Supplementation with [6S]-5-methyltetrahydrofolate or folic acid equally reduces plasma total homocysteine concentrations in healthy women. Am J Clin Nutr. 2004;79(3):473–478. PubMed.
  8. Hickey SE, Curry CJ, Toriello HV. ACMG practice guideline: lack of evidence for MTHFR polymorphism testing. Genet Med. 2013;15(2):153–156. PubMed.
  9. MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet. 1991;338(8760):131–137. PubMed.
  10. US Preventive Services Task Force, Barry MJ, Nicholson WK, et al. Folic acid supplementation to prevent neural tube defects: US Preventive Services Task Force reaffirmation recommendation statement. JAMA. 2023;330(5):454–459. PubMed.
  11. Liu L, Liu S, Wang C, et al. Folate supplementation for methotrexate therapy in patients with rheumatoid arthritis: a systematic review. J Clin Rheumatol. 2019;25(5):197–202. PubMed.
  12. Clarke R, Halsey J, Lewington S, et al. Effects of lowering homocysteine levels with B vitamins on cardiovascular disease, cancer, and cause-specific mortality: meta-analysis of 8 randomized trials involving 37 485 individuals. Arch Intern Med. 2010;170(18):1622–1631. PubMed.
  13. Martí-Carvajal AJ, Solà I, Lathyris D, Dayer M. Homocysteine-lowering interventions for preventing cardiovascular events. Cochrane Database Syst Rev. 2017;8(8):CD006612. PubMed.
  14. Huo Y, Li J, Qin X, et al. Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China: the CSPPT randomized clinical trial. JAMA. 2015;313(13):1325–1335. PubMed.
  15. Cole BF, Baron JA, Sandler RS, et al. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA. 2007;297(21):2351–2359. PubMed.
  16. 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. Lancet. 2013;381(9871):1029–1036. PubMed.
  17. Ebisch IM, Pierik FH, De Jong FH, et al. Does folic acid and zinc sulphate intervention affect endocrine parameters and sperm characteristics in men? Int J Androl. 2006;29(2):339–345. PubMed.
  18. Irani M, Amirian M, Sadeghi R, et al. The effect of folate and folate plus zinc supplementation on endocrine parameters and sperm characteristics in sub-fertile men: a systematic review and meta-analysis. Urol J. 2017;14(5):4069–4078. PubMed.
  19. Hoek J, Steegers-Theunissen RPM, Willemsen SP, Schoenmakers S. Paternal folate status and sperm quality, pregnancy outcomes, and epigenetics: a systematic review and meta-analysis. Mol Nutr Food Res. 2020;64(9):e1900696. PubMed.
  20. Schisterman EF, Sjaarda LA, Clemons T, et al. Effect of folic acid and zinc supplementation in men on semen quality and live birth among couples undergoing infertility treatment: a randomized clinical trial. JAMA. 2020;323(1):35–48. PubMed.
  21. Michaelsen MP, Poulsen M, Bjerregaard AA, et al. The effect of dietary supplements on male infertility in terms of pregnancy, live birth, and sperm parameters: a systematic review and meta-analysis. Nutrients. 2025;17(10):1710. PubMed.
  22. Papakostas GI, Shelton RC, Zajecka JM, et al. L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials. Am J Psychiatry. 2012;169(12):1267–1274. PubMed.
  23. Miller JW, Smith A, Troen AM, Mason JB, Jacques PF, Selhub J. Excess folic acid and vitamin B12 deficiency: clinical implications? Food Nutr Bull. 2024;45(1 Suppl):S67–S72. PubMed.
  24. Pfeiffer CM, Sternberg MR, Fazili Z, et al. Unmetabolized folic acid is detected in nearly all serum samples from US children, adolescents, and adults. J Nutr. 2015;145(3):520–531. PubMed.
  25. World Anti-Doping Agency. The 2026 Prohibited List. WADA 2026 Prohibited List.