Folate

If you could become pregnant, take 400 µg of folic acid a day — that advice is settled. Otherwise, if you need folate, either form works. Keep folic acid and methylfolate from supplements and fortified foods under 1,000 µg a day combined.

What it is

Folate is one of the eight B vitamins. With vitamins B6 and B12 it clears homocysteine, an amino acid that builds up when B-vitamin status is poor.

Folic acid does nothing until the body converts it, in several steps. The first enzyme in that chain, dihydrofolate reductase, has low and variable capacity in humans, so high intakes can outrun it and leave unmetabolised folic acid circulating in the blood. What that means long term is uncertain. 5-MTHF, the form that circulates in the blood, needs no conversion.

Folate and B12: the masking problem

Plenty of folic acid can hide the anaemia that would normally signal a hidden vitamin B12 deficiency, which delays the diagnosis. There is a second interaction: when B12 status is low, a high blood folate has been associated with worse cognition and higher levels of homocysteine and methylmalonic acid, a marker of B12 shortfall.^[1] With so much food fortified, adequate B12 matters more, not less.

The MTHFR question

A large share of people carry a common variant in the MTHFR gene that slows the conversion of folate to its active form; in the United States, more people carry one or two copies of the C677T variant than don't. This is the usual argument for methylfolate. But the US Centers for Disease Control and Prevention (CDC) states that people with these variants can still process all types of folate, including folic acid, and that the variant is not a reason to avoid it. A US medical genetics society advises against MTHFR testing as part of a routine work-up for clotting risk.^[2][3]

Head to head, the forms perform alike. In a randomised trial in 144 healthy women, 5-MTHF lowered homocysteine about as well as folic acid.^[4] Methylfolate's real advantages are that it skips the conversion step and leaves no unmetabolised folic acid. In a small single-dose study of one 5-MTHF salt in 24 healthy adults, funded by the salt's maker, it was absorbed better than folic acid and unmetabolised folic acid did not rise.^[5] No trial shows better health outcomes with it. It is a reasonable choice, not a necessity.

Pregnancy: where the evidence is strongest

Women who could become pregnant should make sure they get enough folate to prevent neural-tube defects, birth defects of the brain and spine. Folic acid is the form with the deepest evidence here. When Canada made fortification mandatory, neural-tube defects fell by 46%, from 1.58 to 0.86 per 1,000 births, and other fortifying countries saw falls of roughly a quarter to a half.^[6]

Folic acid and cancer

A randomised polyp-prevention trial in 1,021 people found that 1 mg a day of folic acid did not prevent colorectal polyps (adenomas), and was associated with more advanced and multiple lesions.^[7] The wider trial evidence is reassuring. A pooled analysis of 13 randomised trials, about 50,000 people mostly in heart-disease prevention trials, found that folic acid at doses roughly ten times what fortification provides made no significant difference to colorectal or overall cancer rates over about five years of treatment.^[8] High doses warrant some caution, but no colorectal-cancer effect has been shown in trials.

Folic acid also has a trial-backed benefit for stroke: a small cut, where food is not fortified; see Homocysteine.

What to do

1. If you could become pregnant, take 400 µg of folic acid a day.
2. Otherwise, take folate only if you need it, and in either form. You don't need an MTHFR test to choose.
3. Stay under 1,000 µg a day of folic acid and methylfolate combined, from supplements and fortified foods. The limit covers both forms; folate naturally present in food doesn't count.
4. If you take a lot of folate, make sure your B12 is adequate, especially if you are vegan, take metformin or acid-suppressing drugs, or are over about 60.

Further reading

• Lamers 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.^[9]
• Hickey SE et al. ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing. Genet Med 2013.^[10]
• De Wals P et al. Reduction in neural-tube defects after folic acid fortification in Canada. N Engl J Med 2007.^[11]
• Cole BF et al. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA 2007.^[12]
• Vollset SE 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.^[13]