Supplement evidence

061 / 575Vitamin form

L-methylfolate (5-MTHF)

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The short answer

A bioactive folate form that can meet folate needs; prescription doses are also studied as adjunctive depression treatment.

Evidence and scope: Established for an indicated use
This status does not grade the ingredient for every goal, outcome, or person.
Important limitation: The benefit is tied to the stated indication, dose, and population; it is not evidence of broader disease prevention or longer life.
Before deciding: Key concern: Evaluate B12 status; high-dose psychiatric use requires prescriber oversight and bipolar screening.

01 / PRACTICAL GUIDE

Dose, absorption, and combinations

These are indication-specific reference or studied ranges—not a personalized prescription. Start with the objective, then check the form, label, medicines, and health conditions.

Reference range by objective

Meeting usual needs400 mcg DFE-equivalent/day for usual needs

Reference or studied range—not a personalized prescription. The product label or a clinician may specify a different dose.

Dose source ↗

Mood symptoms7.5–15 mg/day is prescription-level adjunctive research

Reference or studied range—not a personalized prescription. The product label or a clinician may specify a different dose.

Dose source ↗

More is not automatically better. A clinician or product label may specify a different amount.

Absorption / solubilityWater-soluble

Water-soluble or readily water-dispersible. This does not mean excess is always harmless.

How it is commonly taken

May be taken with or without food.

Do not combine casually

Evaluate B12 status; high-dose psychiatric use requires prescriber oversight and bipolar screening.

Dose and use source ↗

Dose and use links lead to primary or official source material. Search links are discovery tools, not proof that every returned paper applies.

02 / EVIDENCE

What the research says

We keep supportive, mixed, negative, safety, and contextual findings together. The headline never replaces the underlying papers.

4research papers in this ledger

5unique primary studies represented

482unique participants represented

These are audited counts for this JIVANA collection, not search-result totals. Participants are counted once when multiple papers use the same cohort; review papers are not added again to participant totals.

Open the research timelineResearch timeline

Entries are ordered by publication year. A study period appears only when the source reports it.

2024

Mixed or qualifiedPMID 37649241

Folic acid versus 5-methyltetrahydrofolate supplementation in pregnancy

Red-cell and serum folate did not differ between forms, while unmetabolized folic acid was lower with 5-MTHF. The trial was not designed to show whether that biochemical difference changes maternal or infant clinical outcomes.

Published: 2024Duration: 16 weeksn=60 participants

Study design and methods

Design: Randomized controlled trial
Population: 60 pregnant participants enrolled at 8–21 weeks; 54 completed endline assessment
Intervention: Folic acid 0.6 mg/day or L-5-MTHF 0.6 mg/day
Outcome: Red-cell and serum folate and unmetabolized folic acid

Open research record ↗

2018

Mixed or qualifiedPMID 28289280 · NCT01091506

L-Methylfolate Supplementation in Schizophrenia

Plasma methylfolate rose and PANSS total, negative, and general psychopathology scores improved selectively, but other symptom scales and cognition did not differ. The small adjunctive trial does not establish broad schizophrenia benefit.

Published: 2018Duration: 12 weeksn=55 participants

Study design and methods

Design: Randomized, double-blind, placebo-controlled trial
Population: 55 outpatients with schizophrenia receiving stable antipsychotic treatment
Intervention: L-methylfolate 15 mg/day or placebo
Outcome: Plasma methylfolate, PANSS symptoms, other symptom scales, and cognition

Open research record ↗

2012

Mixed or qualifiedPMID 23212058 · NCT00321152 · NCT00955955

L-methylfolate as adjunctive therapy for SSRI-resistant major depression

Trial 1 did not differ from placebo. In trial 2, 15 mg/day improved response and symptom scores with a reported number needed to treat near 6; adverse-event rates were similar. The positive result applies to prescription-dose adjunctive treatment, not general mood enhancement.

Published: 2012Duration: 60 days in each of two trialsn=223 participants2 primary studies represented

Study design and methods

Design: Two multicenter randomized, double-blind, placebo-controlled, parallel-sequential trials
Population: 223 adults with major depressive disorder and inadequate response to a stable SSRI: 148 in trial 1 and 75 in trial 2
Intervention: Adjunctive L-methylfolate 7.5 then 15 mg/day in trial 1 or 15 mg/day in trial 2, versus adjunctive placebo
Outcome: Depression response and symptom-score change, discontinuation, and adverse events

Open research record ↗

2006

Supports a specific usePMID 16825690

A comparison of folic acid and L-5-methyltetrahydrofolate for red-cell folate concentration

Equimolar 416 μg L-5-MTHF increased red-cell folate more than 400 μg folic acid. This supports folate-status efficacy but did not test neural-tube defects, pregnancy outcomes, or other clinical events.

Published: 2006Duration: 24 weeksn=144 participants

Study design and methods

Design: Randomized, double-blind, placebo-controlled dose-comparison trial
Population: 144 healthy women aged 19–33
Intervention: Folic acid 400 μg/day, L-5-MTHF 416 μg/day, L-5-MTHF 208 μg/day, or placebo
Outcome: Red-cell folate and plasma folate

Open research record ↗

Unscreened discovery appendix—not evidence241 candidate publicationsSearch run: Aug 21, 2026

Complete for the displayed PubMed query at the search timestamp—not for all databases or every possible synonym. Candidates can be irrelevant, duplicate the same study, or report negative findings. They are never summed as evidence or participants until screened.

03 / SOURCES

Start with the source material

Official evidence overviewPubMed bounded human-evidence search Live PubMed discovery searchNational Library of Medicine

The live search is for discovery only. Search-result counts change and are not included in the audited totals above.

Recent PubMed discovery recordsDirect links to the first 12 records returned by the reproducible search. These are discovery candidates—not reviewed summaries or a count of supportive findings.

04 / EXPERT CONTEXT

Expert context—not evidence

Expert positions are dated context—not scientific evidence. They never raise the evidence status or become consensus by repetition.

No direct, source-verified endorsement is currently recorded. Research authorship or discussion alone is not treated as endorsement.