Metafolin® for optimal folate assimilation

By Kelly C. Heim, Ph.D.

Folate is a general term referring to folic acid (pteroylglutamic acid) and its reduced derivatives. Reduced, or activated folate is the coenzyme that participates in numerous methylation reactions, which include biosynthesis of nucleic acids, neuronal membrane components and neurotransmitters. Importantly, methylation of chromatin and DNA by reduced folate is an important aspect of the maintenance of healthy gene expression.

Folic acid is a synthetic, oxidized folate that requires enzymatic reduction in order to function as a methyl donor. Reductive activation of folic acid is a multi-step process. Recent evidence indicates that the efficiency of this conversion may be low and variable, possibly explaining the high plasma levels of oxidized folic acid observed in subjects receiving supplemental folic acid 1,2. The long-term effects of sustained tissue exposure to oxidized folic acid are unknown 3.

In food, folate naturally occurs primarily in the activated form, (L)-5-methyl-THF (5-MTHF). While synthetic folic acid can be converted to 5-MTHF in the body, this process requires the enzyme 5,10-methylene tetrahydrofolate reductase (MTHFR). Highly prevalent genetic variations in MTHFR compromise the efficiency of 5-MTHF synthesis 4,5. MTHFR comprises a pivotal node in folate biochemistry, transferring methyl groups to maintain essential biosynthetic and genomic regulatory processes.

Metafolin® ((L)-5-MTHF) is stereochemically identical to naturally occurring 5-MTHF. Metafolin® does not require modification and can therefore execute the beneficial effects of folate regardless of MTHFR genotype. Metafolin® is also efficiently absorbed and assimilated. In a double-blind, randomized, placebo-controlled intervention study of 144 women, 5-MTHF supplementation resulted in a greater accumulation of 5-MTHF in red blood cells than equimolar doses of folic acid 6. Another advantage of Metafolin® is that 5-MTHF is the sole substrate for methionine synthase, which converts homocysteine to methionine to maintain vascular and neuronal health. In a placebo-controlled study of 30 women, 5-MTHF supplementation supported healthy homocysteine levels over a 3-week period 7. Contrary to folic acid, 5-MTHF readily traverses the blood-brain barrier to support neurological health. In a placebo-controlled trial of 123 individuals, 5-MTHF administered over 6 months promoted emotional well-being. 8

Over the past three decades, epidemiologic evidence has demonstrated positive associations between folate-rich diets and cellular and cardiovascular health. As an active coenzyme, 5-MTHF circumvents rate-limiting enzymatic steps to directly participate in life-sustaining methyl transfer reactions. Optimizing the efficiency of these reactions is an important dimension of diverse nutritional strategies for the maintenance of cardiovascular, hematopoietic and neurological health.


  1. Bailey 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.
  2. Kelly P, McPartlin J, Goggins M, et al. Unmetabolized folic acid in serum: Acute studies in subjects consuming fortified food and supplements. Am J Clin Nutr. 1997;65:1790�95.
  3. Troen AM, Mitchell B, Sorensen B, 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.
  4. Sharp L, Little J. Polymorphisms in genes involved in folate metabolism and colorectal neoplasia: a HuGE review. Am J Epidemiol. 2004; 159(5):423-43.
  5. Meshkin B, Blum K. Folate nutrigenomics: a convergence of dietary folate metabolism, folic acid supplementation, and folate antagonist pharmacogenetics. Drug Metab Lett. 2007;1(1):55-60.
  6. Lamers Y, Prinz-Langenohl R, Br�mswig S, et al. Red blood cell folate concentrations increase more after supplementation with [6S]-5-methyltetrahydrofolate than with folic acid in women of childbearing age. Am J Clin Nutr. 2006;84(1):156-61.
  7. Cagnacci A, Cannoletta M, Volpe A. High-dose short-term folate administration modifies ambulatory blood pressure in postmenopausal women. A placebo-controlled study. Eur J Clin Nutr. 2009;1-3.
  8. Godfrey PS, Toone BK, Carney MW, et al. Enhancement of recovery from psychiatric illness by methylfolate. Lancet. 1990; 336(8712):392-5.

Metafolin® is a registered trademark of Merck KGaA, Darmstadt, Germany.