L-Methylfolate and Depression: Dose and Evidence
L-methylfolate is the active form of folate, the form that crosses into the brain without needing further conversion. It has been studied as an addition to antidepressant treatment, most notably in a 2012 trial in which 15 mg a day improved response over an SSRI alone. The form is what distinguishes it from an ordinary folic acid supplement, and the clinical guidelines treat the two differently.
The folate form matters
L-methylfolate
Folic acid
What is L-methylfolate?
Folate from food and from ordinary folic acid supplements has to be converted by the body before it can be used in the brain. L-methylfolate, also written as (6S)-5-methyltetrahydrofolate, is already in that active form. The enzyme responsible for the final conversion step is methylenetetrahydrofolate reductase, usually shortened to MTHFR. [6][7] Because L-methylfolate arrives already converted, it does not depend on that enzyme step in the way folic acid does.
What dose has been studied?
Two randomised, double-blind trials were reported together in the American Journal of Psychiatry in 2012, testing L-methylfolate added to an SSRI in people whose depression had not responded adequately to the SSRI alone. The trial using 15 mg a day found a benefit over placebo. [1] The systematic review of adjunctive nutraceuticals in the same journal records methylfolate doses of 15 or 30 mg a day across the trials it assessed. [2] The 2022 WFSBP and CANMAT clinician guidelines give adjunctive methylfolate a positive recommendation in unipolar depression, and do not recommend plain folic acid, which is the distinction Hedonia’s use of the methylated form rests on. [3]
Is methylfolate supported for use alongside an antidepressant?
Yes. A systematic review and meta-analyses in the American Journal of Psychiatry concluded that current evidence supports the adjunctive use of SAMe, methylfolate and omega-3 with antidepressants to reduce depressive symptoms, and found primarily positive results in replicated studies for all three. [2] The 2022 WFSBP and CANMAT clinician guidelines assess adjunctive methylfolate among the nutraceuticals reviewed for unipolar depression. [3] A meta-review in World Psychiatry reports positive findings from trials of high-dose methylfolate. [4]
What is MTHFR, and do I need a genetic test?
MTHFR is the gene encoding the enzyme that carries out the last step in activating folate. Common variants in this gene reduce how efficiently the enzyme works. [6][7] Testing is a separate question from supplementation. The American College of Medical Genetics and Genomics advises against MTHFR polymorphism testing, in a practice guideline addressing thrombophilia and recurrent pregnancy loss. [8] Taking folate in its already-active form does not require knowing your MTHFR status.
Which products provide L-methylfolate at that dose?
Deplin is a medical food that provides L-methylfolate on its own. Hedonia is a medical food that provides L-methylfolate in combination with two other nutrients, i.e. EPA omega-3 and SAMe. Four Hedonia capsules a day provide 15 mg of L-methylfolate, from 20 mg of Quatrefolic® L-methylfolate glucosamine. Anyone comparing products should compare the amount of active L-methylfolate per day rather than the amount of the branded salt per capsule, since the two figures differ and are not always labelled clearly.
Where Hedonia sits
Hedonia provides 15 mg of L-methylfolate a day across four capsules, matching the dose that carried the positive result in the 2012 trials, alongside 1,440 mg of EPA omega-3 and 1,200 mg of SAMe. It is a medical food for the dietary management of the nutritional requirements associated with depression, intended for use under medical supervision alongside a physician-directed treatment plan.
References
- Papakostas GI, Shelton RC, Zajecka JM, Etemad B, Rickels K, Clain A, et al. L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials. Am J Psychiatry. 2012;169(12):1267-1274. PMID 23212058. PubMed
- Sarris J, Murphy J, Mischoulon D, Papakostas GI, Fava M, Berk M, Ng CH. Adjunctive nutraceuticals for depression: a systematic review and meta-analyses. Am J Psychiatry. 2016;173(6):575-587. PMID 27113121. PubMed
- Sarris J, Ravindran A, Yatham LN, et al. WFSBP and CANMAT Taskforce clinician guidelines. World J Biol Psychiatry. 2022;23(6):424-455. PMID 35311615. PubMed
- Firth J, Teasdale SB, Allott K, et al. The efficacy and safety of nutrient supplements in the treatment of mental disorders. World Psychiatry. 2019;18(3):308-324. Open access
- Tobin D, Vuckovic A, Sarris J. Targeting divergent pathways in the nutritional management of depression. Nutrients. 2024;16(16):2806. PMID 39203943. Open access
- MedlinePlus Genetics. MTHFR gene. National Library of Medicine. MedlinePlus
- National Center for Biotechnology Information. Methylenetetrahydrofolate reductase deficiency. Medical Genetics Summaries. NBK66131. NCBI Bookshelf
- American College of Medical Genetics and Genomics. ACMG practice guideline: lack of evidence for MTHFR polymorphism testing. Genet Med. 2013;15(2):153-156. Reaffirmed 2020. PubMed