L-Methylfolate (5-MTHF)

At a glance

Also calledMethylfolate, 5-MTHF, Metafolin, Deplin
5-MTHF; [6S]-5-methyltetrahydrofolate; 5-methyltetrahydrofolate; levomefolic acid; levomefolate calcium; L-methylfolate calcium; methylfolate; methylated folate. Metafolin and Deplin are branded preparations. It is both the form folate circulates as in the body and a supplement ingredient sold on that basis, which is the ambiguity most of its marketing runs on. Distinct from folic acid and from food folate; both are covered separately.
Typical doseAbout 400 micrograms a day as a supplement
Around 400 micrograms per day in supplement preparations; 416 micrograms was the dose tested head to head against 400 micrograms of folic acid, and 208 micrograms performed no worse on homocysteine (Lamers et al. 2004, DOI 10.1093/ajcn/79.3.473). Separately, 15 mg per day in the depression adjunct trials, roughly forty times the supplement dose and a prescription medical food rather than a supplement in the US (Papakostas et al. 2012, DOI 10.1176/appi.ajp.2012.11071114).
Upper limitNone set — folate's 1,000 micrograms a day is the nearest
None established specifically for L-methylfolate. The 1,000 microgram per day adult limit reported for folate (Merrell and Patel, StatPearls) is the nearest figure available, and it is stated for folate generally rather than for this form.
Found inMethylfolate capsules, methylated prenatals, medical foods
Standalone methylfolate capsules sold on the strength of MTHFR test results — commonly 400 micrograms to 1 mg. Prenatal vitamins marketed as methylated, substituting methylfolate for folic acid at a broadly similar microgram amount. Deplin and similar prescription medical foods for depression — 7.5 mg or 15 mg.

Myth check

If you carry the MTHFR gene variant you cannot process folic acid properly, so you need the methylated form instead.

Randomised head to head in healthy women, 416 micrograms of methylfolate lowered homocysteine no better than 400 micrograms of ordinary folic acid. Carrying the C677T variant does track with higher neural tube defect risk in pooled case-control data, but no trial has shown that carriers do better on methylfolate than on folic acid at preventing one. The trial built to compare the two forms before conception has not begun reporting.

The variant is real and the folate chemistry is real. What is missing is the step in between, the trial showing that swapping forms changes an outcome anyone cares about, and that missing step is where the price difference lives.

The findingsStrongest first

1↑

Sexual & reproductiveThe gene behind the supplement marketing is real

Across 19 case-control studies of 2228 affected babies and 4220 controls, the fetal C677T version of MTHFR, the enzyme that activates folate, was commoner in affected babies.

★★☆Support a healthy pregnancy

2↕

Mood & wellbeingTwo trials of the same design gave opposite answers

The first, in 148 people whose antidepressant had not worked, escalated the dose and found nothing. The second gave 75 people 15mg throughout and beat placebo on both main outcomes.

★☆☆CautionSupport mood

3–

OtherThe premium folate did not beat the cheap one

Over 24 weeks in 144 women, 416 micrograms of methylfolate lowered homocysteine no more than 400 micrograms of plain folic acid. Doubling the methylfolate dose did not move it further.

★☆☆Conflicting evidenceSupport a healthy pregnancy

Sources4 behind this page

Association of Fetal MTHFR C677T Polymorphism with Susceptibility to Neural Tube Defects: A Systematic Review and Update Meta-AnalysisTabatabaei RS et al., 2022DOI 10.1080/15513815.2020.1775734
Effect of Methylfolate, Pyridoxal-5'-Phosphate, and Methylcobalamin Supplementation on Homocysteine and Low-Density Lipoprotein Cholesterol Levels in Patients with MTHFR, MTR and MTRR Polymorphisms: A Randomized Controlled TrialPokushalov E et al., 2024DOI 10.3390/nu16111550
L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trialsPapakostas GI et al., 2012DOI 10.1176/appi.ajp.2012.11071114
Supplementation with [6S]-5-methyltetrahydrofolate or folic acid equally reduces plasma total homocysteine concentrations in healthy womenLamers Y, Prinz-Langenohl R, Moser R, Pietrzik K, 2004DOI 10.1093/ajcn/79.3.473

What we don't know

2 open questions

Contested — Only the positive trial tends to get quoted. The dose difference is the authors' own explanation for the split, but it is a comparison across two separate studies rather than a randomised test of dose, and the trial that worked had 75 patients. The 15mg used is roughly forty times a periconceptional folate dose and is a prescription medical food in the United States, not the supplement sold to consumers on the same reasoning.
Conflicting — Whether methylfolate beats plain folic acid in carriers of the MTHFR variant, a folate-activating enzyme gene, is not shown. The trial cited for it had no folic acid arm; the one that compared the two forms found no advantage.