Folate or folic acid?

What are folate, folic acid and methylfolate, and what is the difference?

According to the NIH, folate is the general term covering natural folates in foods and the forms in foods fortified with supplements (including folic acid). Folates in foods are in the tetrahydrofolate (THF) form and usually carry additional glutamate residues, forming polyglutamates. Some supplements, on the other hand, contain 5-MTHF, a single-glutamate form; this form is also referred to as L-5-MTHF, 5-methylfolate, L-methylfolate and methylfolate. ^[1]

Folic acid is the most common form in supplements and fortified foods; the NIH consumer page reports that folate in supplements is usually in the folic acid form and that methylfolate (5-MTHF) is also used. ^[2] The NIH’s emphasis is clear: folate, folic acid and 5-MTHF are not the same thing. ^[1]

Is methylfolate absorbed better than folic acid?

The NIH reports that the bioavailability of 5-MTHF in supplements is the same as or higher than that of folic acid. The same source also notes that conversion factors to µg DFE have not been officially established for 5-MTHF. ^[1] Therefore, how µg DFE values on labels are calculated for 5-MTHF products may differ from manufacturer to manufacturer.

Bioavailability and clinical outcome are different concepts, however. A higher blood level does not mean fewer neural tube defects, because the evidence for preventing neural tube defects comes from studies with folic acid. The Cochrane review, pooling five trials, reports that daily folic acid supplementation (alone or with other vitamins) reduced neural tube defects (RR 0.31; 95% CI 0.17–0.58). ^[6] The review’s neural tube defect results are reported for folic acid.

What is MTHFR, and what does the C677T variant mean?

The MTHFR gene provides instructions for making the MTHFR protein, which helps the body process folate. According to the CDC, the most common variant is C677T; this is the replacement of the expected “C” base at position 677 in the gene by “T”. Every person has two copies of the gene; the possible genotypes for position 677 are CC, CT and TT. Another common variant is A1298C; the CDC states that there is not enough evidence showing that this variant alone significantly affects folate processing. ^[3]

Variants are common: the CDC reports that in the US, people with one or two copies of the MTHFR C677T variant outnumber those without it; the variant is more frequent in some racial and ethnic groups than in others. ^[3]

Can people with an MTHFR variant use folic acid?

The CDC explicitly states that the claim “if there is an MTHFR variant, folic acid should be avoided and other folate types such as 5-MTHF should be taken” is not true: people with an MTHFR variant can process all folate types, including folic acid. The CDC also reports that, with the same amount of folic acid intake, the mean blood folate level in people with the MTHFR 677 TT genotype is only slightly lower (about 16%) than in the CC genotype, that 400 µg per day of folic acid increases blood folate regardless of genotype, and that folic acid intake is more important than genotype in determining blood folate level. ^[3]

The studies the CDC relied on in this assessment were conducted by CDC researchers. The systematic review and meta-analysis by Tsang and colleagues examined 40 studies in healthy women aged 12–49 years; in the meta-analysis of 6 studies using the recommended microbiological method, red blood cell folate was 16% higher (95% confidence interval 12–20%) and serum or plasma folate 13% higher (7–18%) in the CC genotype than in TT. The difference in serum or plasma folate measured by the protein-binding method was larger (20%), while the same pattern was not seen in red blood cell folate. The authors state that lower blood folate associated with this polymorphism may be meaningful at the population level for neural tube defect risk. ^[4]

In a double-blind study conducted in northern China (932 women of childbearing age, 6 months), 100, 400 or 4,000 µg per day and 4,000 µg per week of folic acid were given. The TT genotype remained associated with lower folate levels than CC even at the highest doses, and no significant interaction between genotype and dose was found; 100 µg per day and 4,000 µg per week did not lower high homocysteine levels in the TT genotype. ^[5] This study measured folate and homocysteine levels; it did not measure a birth outcome such as neural tube defects.

The NIH’s assessment is two-sided. The consumer page states that for some people with the MTHFR C677T variant, supplements containing 5-MTHF may be better than folic acid because the body can use this form more easily; however, it adds that all women who could become pregnant and adolescent girls, even with this variant, should get the 400 µg per day from folic acid and not from 5-MTHF. ^[2] The health professional page also reports that the TT genotype increases homocysteine level and neural tube defect risk, and that research on the benefit of supplementation in these people is inconclusive. ^[1]

Is “unmetabolized folic acid” harmful?

For folic acid, there is also a debate about “unmetabolized folic acid” (UMFA). According to the background section of a 2026 systematic review, because the DHFR enzyme in the liver reduces folic acid slowly, unmetabolized folic acid appears in the blood after mandatory fortification, and whether this alone has biological consequences is unresolved. The review’s findings are as follows: equimolar substitution of 5-MTHF reduced plasma unmetabolized folic acid (3 studies, low certainty); two studies on red blood cell folate point in opposite directions; no pooled estimate could be derived for homocysteine. ^[7]

The review concludes that associations between unmetabolized folic acid and outcomes in observational studies are inconsistent and influenced by total folate, that independent harm from unmetabolized folic acid has not been demonstrated, and that the clinical benefit of switching to 5-MTHF has not been demonstrated either. ^[7]

Upper limit and label: how are 5-MTHF products assessed?

In 2023, EFSA kept the tolerable upper intake levels for folate unchanged: 1,000 µg per day in adults, including pregnant and lactating women. This limit applies to the combined intake of folic acid and the approved (6S)-5-methyltetrahydrofolic acid glucosamine salt and L-5-methyltetrahydrofolic acid calcium salt. EFSA also states that exceeding the limit is unlikely in the European population, but that there may be exceptions for people who regularly use supplements containing high-dose folic acid or 5-methyltetrahydrofolic acid salt. ^[8] Therefore, marketing as “methyl” does not remove the need to consider the total amount when taken on the same day with another folate product.

Claims and evidence

This page does not recommend a personal form or dose choice. If there is pregnancy planning, medication use or a known genetic diagnosis, the folate form and amount are determined together with the relevant physician.