L-Methylfolate (5-MTHF): What It Is, Medical-Food Use and Evidence
L-methylfolate (5-MTHF) is the form of folate found in blood. What it is, how FDA treats medical foods, what trials in depression and blood-level studies found, and the limits.
Content last updated . This page has not been medically reviewed.
Quick answer
L-methylfolate, also written 5-MTHF or 5-methyltetrahydrofolate, is a form of folate. It is the primary form of folate found in blood. [1] Products containing it are sold, and some may carry a medical-food label (explained below). Evidence that it works better than folic acid for health outcomes in the general public is limited, and one use in depression has been studied only as an add-on to prescribed treatment. This page is information only. Do not use it to replace any prescribed medicine, and ask a clinician or pharmacist before starting it.
What it is
Folate is the B vitamin found in foods. Folic acid is the man-made form used in supplements and fortified foods. [2] A review of folic acid versus 5-MTHF in pregnancy states that folic acid is inactive in the body and must be converted by the liver into 5-MTHF, which does not require activation. [3] That review was supported by a company grant, so read its conclusions with care. [3] For the full comparison of forms see Folate vs folic acid vs methylfolate.What "medical food" means
In the US a medical food is defined in law as a food formulated to be consumed or administered enterally under the supervision of a physician, for the specific dietary management of a disease or condition with distinctive nutritional requirements. [4] The FDA says it generally does not approve medical foods and that they do not undergo premarket approval. [5] So the words "medical food" on a label do not mean FDA approval of the product for a disease. We did not find a source we could read that lists which L-methylfolate products carry that label, so we make no claim about specific products.What the research found
| Question | What the source found | Strength of evidence |
|---|---|---|
| Blood levels versus folic acid | In a crossover study of coronary artery disease patients with the 677TT variant, a single 5 mg dose of 5-MTHF gave higher bioavailability than 5 mg of folic acid. [6] | Biomarker only |
| Add-on to antidepressants (SSRI) | Two trials (148 and 75 patients) tested L-methylfolate in major depression that had not responded to SSRIs. The first showed no significant difference. The second found 15 mg/day better than placebo on both primary outcomes, with a number needed to treat of about six. [7] Amounts here are study amounts, not advice. | Promising but limited |
| Pooled analysis of the add-on use | A 2022 meta-analysis found a small effect: relative risk 1.25 for response in three studies (483 people). [8] | Promising but limited |
| Folate (folic acid or L-methylfolate) as an add-on | A separate 2021 meta-analysis of six randomized trials found lower depression scores and better response rates with the add-on, combining both forms. [9] | Mixed (forms combined) |
| Preventing neural tube defects | The trials in the Cochrane review tested folic acid, and the review states that effects of different forms are unclear. [10] | Proper evidence not found for 5-MTHF alone |
| Health benefit of choosing it because of a gene result | See MTHFR variants and folate. | Insufficient evidence |
Higher blood levels are not a health outcome. A depression trial in people who have not responded to other treatment does not apply to people without depression, and trials of one folate form should not be moved to another.
Intake figures
Health Canada's table gives folate RDAs in dietary folate equivalents (DFE): 400 micrograms for adults and 600 in pregnancy (ages 19 to 30). Its upper limit of 1,000 micrograms applies only to synthetic folic acid. [11] So that table does not set an upper limit for L-methylfolate. Product labels may list amounts in different units, so read them carefully.Frequently asked questions
Is L-methylfolate the same as folate?
It is one form of folate, the primary form in blood. [1]
Is it better than folic acid?
It reaches higher blood levels in one small study. [6] Proper evidence not found that this gives better health outcomes in the general public.
Is "medical food" an FDA approval?
No. The FDA says it generally does not approve medical foods. [5]
Does it help depression?
As an add-on to antidepressants, a trial and meta-analyses found modest benefits. [7][8] It is a question for your prescriber.
Is it safe in pregnancy?
Official pregnancy advice names folic acid. Ask your midwife or doctor before changing form. [14]
More details: evidence, limits and cautions
The details behind this page: cautions, limits of the evidence and where sources disagree. Open any note to read it.
How to read the evidence labels
Labels used on this page: established nutritional role, promising but limited, mixed, insufficient evidence and Proper evidence not found.
Safety and who should ask first
- Medicines: the NHS lists some anticonvulsants, colestyramine, sulfasalazine and methotrexate among medicines that reduce folate or make it harder to absorb. [12] Do not change them yourself. Ask your prescriber or pharmacist, and see How medication interactions work.
- Vitamin B12: folic acid above 1 mg a day can mask B12 deficiency. [2] We did not find a source we could read that shows whether L-methylfolate does the same. An NIH expert workshop listed whether elevated folate from any form affects vitamin B12 function as an open research question, so ask a clinician. [13]
- Pregnancy: official advice names folic acid. See Folic acid and folate before and during pregnancy.
- Depression: if you have low mood, see a clinician. Do not stop or replace an antidepressant. [7]
- Quality varies: see Quality testing and certifications.
References
- MedlinePlus Genetics, US National Library of Medicine. MTHFR gene. Read 2026-10-23.
- NHS (UK). Vitamins and minerals: B vitamins and folic acid. Page last reviewed 3 August 2020. Read 2026-10-23.
- Ferrazzi E, Tiso G, Di Martino D. Folic acid versus 5-methyl tetrahydrofolate supplementation in pregnancy. Eur J Obstet Gynecol Reprod Biol 2020;253:312-319. The paper declares company funding.
- US Code, Title 21, section 360ee (definition of medical food), via Cornell Legal Information Institute. Read 2026-10-23.
- US Food and Drug Administration. It's really FDA-approved? (consumer update). Read 2026-10-23.
- Willems FF, et al. Pharmacokinetic study on the utilisation of 5-methyltetrahydrofolate and folic acid in patients with coronary artery disease. Br J Pharmacol 2004;141(5):825-830.
- Papakostas GI, et al. L-methylfolate as adjunctive therapy for SSRI-resistant major depression. Am J Psychiatry 2012;169(12):1267-1274.
- Maruf AA, et al. Systematic review and meta-analysis of L-methylfolate augmentation in depressive disorders. Pharmacopsychiatry 2022;55(3):139-147.
- Folate as adjunct therapy to SSRI/SNRI for major depressive disorder: systematic review and meta-analysis. Complement Ther Med 2021;61:102770.
- De-Regil LM, et al. Effects and safety of periconceptional oral folate supplementation for preventing birth defects. Cochrane Database Syst Rev 2015;(12):CD007950.
- Health Canada. Dietary reference intakes tables: Reference values for vitamins. Page dated 2025-11-19. Read 2026-10-23 through a web-fetch tool.
- NHS (UK). Vitamin B12 or folate deficiency anaemia: Causes. Page last reviewed 20 February 2023. Read 2026-10-23.
- Maruvada P, et al. Knowledge gaps in understanding the metabolic and clinical effects of excess folates/folic acid: a summary from an NIH workshop. Am J Clin Nutr 2020;112(5):1390-1403.
- US Preventive Services Task Force. Folic acid supplementation to prevent neural tube defects: reaffirmation recommendation statement. JAMA 2023;330(5):454-459.
Education, not medical advice. This page is for general information. It does not diagnose or treat any condition and is not a substitute for care from a qualified health professional. Natural does not automatically mean safe. Ask a clinician or pharmacist before changing your care, especially if you take medication, are pregnant or breastfeeding, or have a health condition.