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Trends in Psychopharmacology

Why L-Methylfolate Rather Than Folic Acid for Depression?


January 21, 2008

Stephen M. Stahl, MD, PhD


Adjunct Professor of Psychiatry, University of California, San Diego

First published in Psychiatry Weekly, Volume 3, Issue 3, on January 21, 2008


Folate is one of the 13 essential vitamins. Dihydrofolate, a mixture of polyglutamates (ie, a number of glutamatic acid entities) is the form of folate obtained from dietary intake of green vegetables, yeast, liver, kidney, and egg yolk. Folic acid is the synthetic form of folate contained in over-the-counter vitamin supplements (usually mixed with several other vitamins and nutrients and present in low doses). Folic acid is also the synthetic form of folate contained in prescriptions written by a licensed practitioner in higher doses for medical use.

Dihydrofolate and folic acid are converted to monoglutamate entites by the enzyme alpha-L-glutamyl transferase in the intestinal wall as they are absorbed. Once absorbed, monoglutamate entities are converted to L-methylfolate (MTHF), the form of folate that passes into the brain and is utilized by trimonoamine neurons to facilitate neurotransmitter synthesis (Figure). Normally, ingesting folate from dihydrofolate in the diet or from folic acid in synthetic supplements will result in adequate delivery of MTHF levels to the brain, especially in those individuals with the more efficient genotype (C677C) producing up to 100% of the enzyme methylene tetrahydrofolate reductase and who do not have depression.

However, robust levels of MTHF in the brain, which may be necessary to maximize the chances of boosting trimonoamine neurotransmitter synthesis, are more likely attained after administration of MTHF rather than folic acid (Figure). Thus, administration of MTHF may have significant advantages over administration of folic acid as a trimonoamine modulator to augment antidepressants in depressed patients who do not respond adequately to their antidepressant treatment. Such patients may or may not be folate deficient, may or may not have the inefficient form of the genotype (C677T, T677T) producing 35% to 71% of the MTHF enzyme, and may or may not be taking various anticonvulsant mood stabilizers that interfere with folic acid absorption or MTHF formation, such as lamotrigine, carbamazepine, and others (Figure). Further research is needed to identify those depressed patients most likely to respond to MTHF augmentation, including studies of both unipolar and bipolar depression.

In terms of what is known about treatment with folic acid versus MTHF, it may take as much as 7 mg of oral folic acid to generate the same plasma levels of MTHF as giving 1 mg of oral MTHF. How much folic acid is this? The recommended daily allowance of folic acid from food or dietary supplements is 0.4 mg (0.8 mg for pregnant women); over-the-counter multivitamin supplements typically provide between 0.25 and 1 mg of folic acid; normal “prescription strength” folic acid is 1 mg pure folic acid; high-dose prescription folic acid for treating pregnant women to reduce the risk of neural tube defects is between 4 mg and 5 mg. By comparison, the lowest dose of MTHF studied in depression to augment antidepressant treatment is 7.5 mg, roughly equivalent to 52 mg of folic acid.

Disclosure: Dr. Stahl is a consultant to, is on the speaker’s bureaus of, or receives grant/research support from Acadia, Amylin, AstraZeneca, Biolaunch, Biovail, Bristol-Myers Squibb, Boehringer-Ingelheim, Cephalon, CSC Pharmaceuticals, Cyberonics, Cypress, Eli Lilly, Epix, Forest, GlaxoSmithKline, Janssen, Neurocrine, Neuromolecular, Neuronetics, NovaDel, Novartis, Organon, Otsuka, Pfizer, Pierre Fabre, Sanofi, ScheringPlough, Sepracor, Solvay, Shire, Somaxon, Tetragenix, and Wyeth.