Methylfolate

L-5-methyltetrahydrofolate (5-MTHF)

Evidence: Strong

Methylfolate is the biologically active form of folate, essential for DNA synthesis, cell division, and repair. It is paramount for cell turnover, including intestinal epithelial cells, supporting gut lining integrity and absorption. This form is also crucial for healthy fetal development.

There are 73,988 peer-reviewed scientific studies on this ingredient.

Selected Study 1/2:

Carboni, L. (2022). Active Folate Versus Folic Acid: The Role of 5-MTHF (Methylfolate) in Human Health. Integrative Medicine: A Clinician's Journal, 21(3), 36. https://pmc.ncbi.nlm.nih.gov/articles/PMC9380836/

Summary:

Study Summary:

Study type: A 2022 narrative review in Integrative Medicine synthesizes previous pharmacokinetic experiments and clinical trials comparing synthetic folic acid with the bio-active folate 5-methyltetrahydrofolate (5-MTHF); it enrolls no new participants. Roughly 40 % of the global population carries MTHFR gene variants that slow folic-acid activation, making the question clinically relevant.

Observed benefits: Across cited studies 5-MTHF is absorbed more efficiently than folic acid and does not leave unmetabolized folic acid in the blood. In a 104-patient hypertensive trial, 400 µg 5-MTHF plus vitamins B6/B12 reduced mean homocysteine from 21.5 µmol/L to 10 µmol/L—better than 5 mg folic acid. Other research shows 5-MTHF works regardless of MTHFR genotype and may offer stronger neural-tube-defect protection when taken pre-conception.

Mechanisms of action: 5-MTHF arrives pre-methylated, so it slots straight into one-carbon metabolism, recycling homocysteine to methionine and refilling the S-adenosyl-methionine pool without relying on the rate-limiting DHFR or MTHFR enzymes. This bypass not only lowers homocysteine but also avoids the accumulation of unmetabolized folic acid that can compete for folate transporters.

Side effects: The review notes no adverse events at typical supplemental doses of 5-MTHF, whereas very high folic-acid intakes can leave unmetabolized folic acid in plasma and may mask vitamin-B₁₂ deficiency.

Strength of evidence: Mechanistic plausibility is strong and several small RCTs confirm superior bioavailability and homocysteine lowering, yet most human data are limited in size or manufacturer-sponsored, and no large independent trials have linked 5-MTHF to fewer cardiovascular events or birth defects. Overall, evidence is moderate—encouraging for people with MTHFR variants but not yet definitive.

Selected Study 2/2:

Tate C, Shuman A, Nice S, Salehi P. The Critical Role of Folate in Prenatal Health and a Proposed Shift from Folic Acid to 5-Methyltetrahydrofolate Supplementation. Georgetown Medical Review. 2024;8(1). doi:10.52504/001c.124570

Study Summary:

Study type: This is a 2024 narrative review that collates and critiques the existing basic, epidemiological and clinical literature on prenatal folate; it compares synthetic folic acid with the active form 5-methyltetrahydrofolate (5-MTHF) and enrolls no new participants.

Observed benefits: The review reiterates that periconceptional folic-acid intake of about 400 µg/day prevents most neural-tube defects (NTDs) and supports fetal neuro-ocular development, maternal haematological status and possibly lowers risks of pre-eclampsia and infant food allergy. It argues that formulating prenatal vitamins with 5-MTHF could add further advantages: greater bioavailability regardless of DHFR or MTHFR enzyme activity, consistently larger homocysteine reductions and retrospective evidence of fewer hypertensive disorders of pregnancy.

Mechanisms of action: Only 5-MTHF can donate the methyl group that recycles homocysteine to methionine and fuels DNA methylation; folic acid must first be reduced by DHFR and MTHFR, creating a metabolic bottleneck in people with low enzyme activity or common MTHFR variants. Supplying 5-MTHF directly bypasses this step, sustains one-carbon metabolism and avoids build-up of unmetabolized folic acid (UMFA) that competes with active folate for cellular transporters.

Side effects: Physiological doses of either form are generally safe; the review flags theoretical hazards associated with chronic UMFA—masking vitamin-B12 deficiency and uncertain immune effects—which 5-MTHF would avert, while reporting no unique adverse events for 5-MTHF itself.

Strength of evidence: Folic-acid efficacy is underpinned by large RCTs and decades of fortification data; the case for wholesale replacement with 5-MTHF rests on sound biochemical logic, pharmacokinetics and small observational or interventional studies. Direct head-to-head pregnancy trials powered for NTDs or long-term child outcomes are still lacking, so the proposed shift is biologically plausible but supported by only moderate-quality clinical evidence at present.