SYS ONLINE
SUPPLEMENT_SCHOLAR
evidence · mechanism · dose
Supplements/Vitamin

Methylfolate (L-5-MTHF)

aka L-methylfolate · Quatrefolic · Metafolin

Bioactive folate that bypasses the MTHFR enzyme — preferred in MTHFR variants and pregnancy.

Mood & AnxietyFertilityWomen's HealthBrain & Cognitive

Overview

Bioactive folate that bypasses the MTHFR enzyme — preferred in MTHFR variants and pregnancy.

Natural sources
    Common forms

      Forms & variants of Folate (Vitamin B9)

      Different chemical forms of Folate (Vitamin B9) behave differently. Browse each form's mechanism, bioavailability, and best-use context.

      Parent
      Folate (Vitamin B9)

      One-carbon donor essential for DNA synthesis and neural tube development.

      Mechanism of action

      Skips dihydrofolate reductase and MTHFR — directly enters the methylation cycle as 5-MTHF.

      Pathways
      • · Methylation cycle
      • · Homocysteine remethylation
      • · Monoamine synthesis (BH4)

      Effects on the body

      Organ system effects

      Evidence-based benefits

      Augments SSRI response in depression

      Moderate evidence

      Prevents NTDs in pregnancy

      Strong evidence

      Potential side effects

      Common
      • · Anxiety/insomnia in overmethylators
      Rare
        Serious

          Drug interactions

          No notable interactions reported.

          Supplement interactions

          Pairs well with
          • Methylcobalamin (B12)
            Methyl trap prevention.
          Avoid combining with

          No specific avoidances listed.

          Dosing & bioavailability

          Typical dose
          400–1000 mcg DFE
          Study range
          Up to 15 mg in depression
          With food?
          Optional

          Where to buy

          Affiliate-style search links to reputable retailers. We don't endorse specific brands — verify third-party testing (USP, NSF, Informed Sport) before purchase.

          Vitamin
          Methylfolate…
          Amazon
          Wide selection · fast shipping
          Vitamin
          Methylfolate…
          iHerb
          Global delivery · curated brands
          Vitamin
          Methylfolate…
          Thorne
          Practitioner-grade · NSF tested

          Scientific evidence (9)

          RCTAm J Psychiatry · 2012

          L-methylfolate as adjunct in SSRI-resistant depression

          Papakostas GI, et al.

          60-day RCT of L-methylfolate in MDD.

          Key findings

          Significant improvement in HAM-D scores vs placebo.

          Open study
          Systematic reviewPubMed (NLM) · 1970

          PubMed: Methylfolate (L-5-MTHF) — Augments SSRI response in depression

          Live PubMed search

          Live results for "Methylfolate (L-5-MTHF) Augments SSRI response in depression" across the PubMed/MEDLINE peer-reviewed index.

          Key findings

          Opens current human and preclinical literature matching Methylfolate (L-5-MTHF) and "Augments SSRI response in depression". Filter by RCT, meta-analysis, or year on the results page.

          Open study
          Systematic reviewPubMed (NLM) · 1970

          PubMed: Methylfolate (L-5-MTHF) — Prevents NTDs in pregnancy

          Live PubMed search

          Live results for "Methylfolate (L-5-MTHF) Prevents NTDs in pregnancy" across the PubMed/MEDLINE peer-reviewed index.

          Key findings

          Opens current human and preclinical literature matching Methylfolate (L-5-MTHF) and "Prevents NTDs in pregnancy". Filter by RCT, meta-analysis, or year on the results page.

          Open study
          Systematic reviewPubMed (NLM) · 1970

          PubMed: Methylfolate (L-5-MTHF) — randomized controlled trial

          Live PubMed search

          Live results for "Methylfolate (L-5-MTHF) randomized controlled trial" across the PubMed/MEDLINE peer-reviewed index.

          Key findings

          Opens current human and preclinical literature matching Methylfolate (L-5-MTHF) and "randomized controlled trial". Filter by RCT, meta-analysis, or year on the results page.

          Open study
          Systematic reviewPubMed (NLM) · 1970

          PubMed: Methylfolate (L-5-MTHF) — meta-analysis

          Live PubMed search

          Live results for "Methylfolate (L-5-MTHF) meta-analysis" across the PubMed/MEDLINE peer-reviewed index.

          Key findings

          Opens current human and preclinical literature matching Methylfolate (L-5-MTHF) and "meta-analysis". Filter by RCT, meta-analysis, or year on the results page.

          Open study
          Systematic reviewPubMed (NLM) · 1970

          PubMed: Methylfolate (L-5-MTHF) — pharmacokinetics

          Live PubMed search

          Live results for "Methylfolate (L-5-MTHF) pharmacokinetics" across the PubMed/MEDLINE peer-reviewed index.

          Key findings

          Opens current human and preclinical literature matching Methylfolate (L-5-MTHF) and "pharmacokinetics". Filter by RCT, meta-analysis, or year on the results page.

          Open study
          Systematic reviewPubMed (NLM) · 1970

          PubMed: Methylfolate (L-5-MTHF) — safety adverse events

          Live PubMed search

          Live results for "Methylfolate (L-5-MTHF) safety adverse events" across the PubMed/MEDLINE peer-reviewed index.

          Key findings

          Opens current human and preclinical literature matching Methylfolate (L-5-MTHF) and "safety adverse events". Filter by RCT, meta-analysis, or year on the results page.

          Open study
          Systematic reviewPubMed (NLM) · 1970

          PubMed: Methylfolate (L-5-MTHF) — dose response

          Live PubMed search

          Live results for "Methylfolate (L-5-MTHF) dose response" across the PubMed/MEDLINE peer-reviewed index.

          Key findings

          Opens current human and preclinical literature matching Methylfolate (L-5-MTHF) and "dose response". Filter by RCT, meta-analysis, or year on the results page.

          Open study
          Systematic reviewGoogle Scholar · 1970

          Google Scholar: Methylfolate (L-5-MTHF) — clinical evidence

          Live Scholar search

          Cross-database citation index for Methylfolate (L-5-MTHF) as it relates to "clinical evidence".

          Key findings

          Includes preprints, theses, and journal articles. Useful for tracking citation counts and follow-on work.

          Open study
          Educational use only. This profile is not medical advice. Consult a qualified healthcare professional before starting any supplement, especially if you take prescription medication or have a chronic condition.