Folate vs Folic Acid: MTHFR, Methylfolate and What the Evidence Shows
Folate is vitamin B9. Folic acid is the synthetic form in most supplements and fortified foods, and methylfolate (5-MTHF) is the form that circulates in blood. A popular claim holds that people with MTHFR gene variants cannot use folic acid and should switch to methylfolate. The trials do not bear that out: folic acid lowers homocysteine in people with the most-discussed MTHFR genotype, and it is the form proven to prevent neural tube defects.
- Folic acid is the synthetic form of vitamin B9 in most supplements and fortified foods; methylfolate (5-MTHF) is the form found in blood. Both supply folate.1,2
- In a 24-week randomized trial in healthy women, methylfolate and 400 µg of folic acid lowered homocysteine equally.3
- People with two copies of the MTHFR C677T variant (677TT) have higher homocysteine when folate intake is low, but in a randomized trial they responded to folic acid from fortified foods or a 400 µg supplement, needing more folate than others to reach the same level.4
- The US Preventive Services Task Force recommends that everyone who is planning to or could become pregnant take 400 to 800 µg of folic acid daily, an A-grade recommendation.5
- Unmetabolized folic acid appears in blood after folic acid supplements, but an NIH workshop found the evidence that it causes harm inconclusive and not strong enough to change public health advice.2,6
A common claim online holds that people with MTHFR gene variants cannot process folic acid and should take methylfolate instead. It deserves checking against the trials, because folic acid is also the form behind the most important folate recommendation there is, the prevention of neural tube defects.7 The short version: the form of folate matters less than the claim suggests, and getting enough folate matters more.
Folate, folic acid and methylfolate
All of folate's work in the body is done by tetrahydrofolate and its one-carbon derivatives. Folic acid, the synthetic form, is not significantly found in fresh natural foods; to be used, it must be converted to tetrahydrofolate by the enzyme dihydrofolate reductase. In liver samples from organ donors and surgery patients, this enzyme reduced folic acid at, on average, less than 2% of the rate seen in rat liver, and its activity varied almost fivefold between people.1
Whatever form goes in, the folate that circulates in blood is essentially 5-methyltetrahydrofolate (5-MTHF), the form sold as methylfolate or L-methylfolate.2 Methylfolate supplements provide that form directly, without the conversion step.
What MTHFR variants do
MTHFR makes the enzyme that produces 5-MTHF inside cells. Its best-known variant, C677T, makes a heat-sensitive enzyme with reduced activity, and people with two copies (677TT) have significantly higher blood homocysteine.8 Two copies are common in some populations: estimated from 1000 Genomes allele frequencies, about 13% of people of European ancestry, 22% of admixed American ancestry, 9% of East Asian ancestry and under 1% of African ancestry are 677TT.9
A second variant, A1298C, also lowers enzyme activity, but on its own it was not linked with higher homocysteine or lower folate. People carrying one copy of each variant, however, looked like 677TT carriers, with lower enzyme activity, higher homocysteine and lower folate.10 Their enzyme activity was 50 to 60% of normal in lymphocytes.11
For heart disease, the picture depends on folate intake. In a meta-analysis of 40 studies, 677TT carried 16% higher odds of coronary heart disease than 677CC, mainly when folate status was low; North American studies showed no excess, and the authors attributed the difference largely to folate status.12
Does folic acid work if you carry MTHFR variants?
The trials that tested it say yes. In a randomized trial of 126 healthy adults, 42 each with the TT, CT and CC genotypes, the TT group had homocysteine of 14.5 µmol/L on a diet that excluded folic acid-fortified foods, against 8.9 µmol/L in the CC group. A folate-rich diet including fortified foods, or a 400 µg folic acid supplement, effectively raised folate status, and the TT group responded, though it needed higher folate intakes than the CT and CC groups to reach the same homocysteine level.4
Head to head, the two forms performed alike. Over 24 weeks of supplementation in healthy women, methylfolate at 208 or 416 µg and folic acid at 400 µg lowered homocysteine equally, and the higher methylfolate dose was no more effective than the lower one.3 In a single-dose crossover study, methylfolate raised blood folate higher and faster than folic acid, in women with the TT genotype and in those with the CC genotype alike.2
Folic acid and pregnancy
Folic acid is the form used in the trials that established folate's protection against neural tube defects. In the Medical Research Council Vitamin Study, a randomized trial in 33 centres across seven countries, women with a previous affected pregnancy who took folic acid around conception had 72% fewer neural tube defects (relative risk 0.28), while a mix of seven other vitamins showed no significant protective effect.7
The US Preventive Services Task Force concludes with high certainty that folic acid supplementation has a substantial net benefit, and recommends that all persons planning to or who could become pregnant take a daily supplement containing 400 to 800 µg of folic acid.5 The recommendation applies to everyone in that group.
Unmetabolized folic acid
Because the conversion enzyme works slowly in people, folic acid that is not converted can turn up in blood and urine, and very high doses may saturate the enzyme.1 Unmetabolized folic acid occurs regularly after folic acid supplements, but rarely after methylfolate.2
Whether it matters for health is unsettled. In a study of 105 healthy postmenopausal women, unmetabolized folic acid was found in 78% of fasting blood samples, and natural killer cell activity, a measure of immune function, was about 23% lower in women with detectable levels. In the same study, women with low-folate diets who took folic acid supplements had higher natural killer activity.13 An NIH workshop that reviewed the research concluded that reported adverse effects of excess folic acid, high folate status and unmetabolized folic acid remain inconclusive and do not provide the evidence needed to change public health recommendations.6
What this means in practice
For most adults, getting enough folate matters more than its form. Food folate, folic acid and methylfolate all supply it, and in a 24-week trial methylfolate and folic acid lowered homocysteine equally.3
If you could become pregnant, the Task Force recommendation is 400 to 800 µg of folic acid a day.5 Carrying an MTHFR variant does not stop folic acid from working: 677TT carriers responded to it in a randomized trial.4
If you prefer methylfolate, it is a reasonable alternative. It lowered homocysteine as well as folic acid did, and the trial's authors noted it is unlikely to mask the symptoms of vitamin B12 deficiency.3 Effects on vitamin B12 deficiency were the original concern about high folic acid intake.6
Testing your MTHFR genotype adds little. The American College of Medical Genetics advises against MTHFR testing as part of routine evaluations for clotting risk, because it has minimal clinical utility.14 A homocysteine blood test measures the outcome these variants affect.
Put this research into practice: Gene Variant Lookup · Supplement Evidence Database
References
- 1Bailey SW, Ayling JE. "The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake." Proc Natl Acad Sci U S A. 2009;106(36):15424-9. PubMed · DOI
- 2Prinz-Langenohl R, 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):2014-21. PubMed · DOI
- 3Lamers Y, et al. "Supplementation with [6S]-5-methyltetrahydrofolate or folic acid equally reduces plasma total homocysteine concentrations in healthy women." Am J Clin Nutr. 2004;79(3):473-8. PubMed · DOI
- 4Ashfield-Watt PA, et al. "Methylenetetrahydrofolate reductase 677C-->T genotype modulates homocysteine responses to a folate-rich diet or a low-dose folic acid supplement: a randomized controlled trial." Am J Clin Nutr. 2002;76(1):180-6. PubMed · DOI
- 5Barry MJ, 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 · DOI
- 6Maruvada P, et al. "Knowledge gaps in understanding the metabolic and clinical effects of excess folates/folic acid: a summary, and perspectives, from an NIH workshop." Am J Clin Nutr. 2020;112(5):1390-1403. PubMed · DOI
- 7 "Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. MRC Vitamin Study Research Group." Lancet. 1991;338(8760):131-7. PubMed
- 8Frosst P, et al. "A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase." Nat Genet. 1995;10(1):111-3. PubMed · DOI
- 9Auton A, et al. "A global reference for human genetic variation." Nature. 2015;526(7571):68-74. PubMed · DOI
- 10van der Put NM, et al. "A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects?" Am J Hum Genet. 1998;62(5):1044-51. PubMed · DOI
- 11Weisberg I, et al. "A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity." Mol Genet Metab. 1998;64(3):169-72. PubMed · DOI
- 12Klerk M, et al. "MTHFR 677C-->T polymorphism and risk of coronary heart disease: a meta-analysis." JAMA. 2002;288(16):2023-31. PubMed · DOI
- 13Troen AM, et al. "Unmetabolized folic acid in plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal women." J Nutr. 2006;136(1):189-94. PubMed · DOI
- 14Hickey SE, et al. "ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing." Genet Med. 2013;15(2):153-6. PubMed · DOI
