5-Methyltetrahydrofolate vs. folic acid: which is the optimal choice for human health?

Folic acid and 5-Methyltetrahydrofolate (5-MTHF) are two primary supplement forms of folate. 5-MTHF is the predominant natural dietary folate and the principal form of folate in plasma and cerebrospinal fluid. Synthetic folic acid, used in food fortification and most supplements, must be converted enzymatically into 5-MTHF. Unfortunately, this bioconversion process may be incomplete in some people.

Folic acid fortification has been successful from a public health perspective. However, at doses commonly used for supplementation (>200 mcg per day), some folic acid remains unmetabolized and enters the peripheral circulation. Circulating folic acid has been found in nearly all children and adults, raising concerns about potential long-term health effects.⁸ Folic acid can compete with 5-MTHF for transport into human cells, umbilical cord blood, and human milk. Consequently, breast milk samples with high folic acid levels have reduced levels of 5-MTHF. Alternatively, supplementation with 5-MTHF directly raises plasma folate levels more rapidly than an equivalent dose of folic acid even in individuals with impaired folate metabolism (MTHFR polymorphism C677T).^†9-11 Folic acid can also mask vitamin B₁₂ deficiency, a problem that is completely avoided with the use of MTHF.

Moreover, some children on the spectrum have cerebral folate deficiency (CFD) as a result of autoantibodies that block folate transport into the brain via folate receptor-α (FR-α).¹² Because folic acid competes with 5-MTHF for uptake by FR-α, folic acid is not recommended for individuals with CFD. Studies show that 5-MTHF can be transported into the brain via alternative pathways.^13,14

As the preferred folate supplement form, 5-MTHF avoids the known and potential drawbacks associated with folic acid.