L-methylfolate, also known as methylfolate or 5-methyltetrahydrofolate (5-MTHF), is the primary active form of folate found in the body, and it directly participates as a coenzyme in metabolic pathways. Since L-methylfolate does not require enzymes like DHFR and MTHFR for activation (unlike folic acid), it has been suggested as an alternative way to supplement folate, particularly in people with genetic mutations that reduce the effectiveness of these enzymes.[1]
Research suggests that L-methylfolate supplementation can increase plasma and red blood cell folate levels to a similar or greater extent than folic acid when given at equivalent doses and can comparably reduce plasma homocysteine levels.[2][3][4] Additionally, unlike folic acid supplementation, L-methylfolate is both less likely to mask a vitamin B12 deficiency and avoids the unknown potential consequences of unmetabolized folic acid in the body.[5]
Despite the promising features of L-methylfolate, folic acid has been used in the vast majority of clinical trials, and it hasn’t been established that L-methylfolate provides the same benefits as folic acid — including for the prevention of NTDs. An exception to this is folate supplementation for depression: there is evidence to suggest that L-methylfolate may be more effective than folic acid.[6][7]