Methylfolate
Research reviewed: Up until 03/2026
Methylfolate (5-Methyltetrahydrofolate (5-MTHF)) is a dietary supplement with 8 published peer-reviewed studies involving 1,870 participants, researched for Depression & Mood, MTHFR Gene Support, Cardiovascular Health and 1 more areas.
Evidence at a Glance
Strength is scored by study design, sample size, study type, and outcomes
Depression & Mood
StrongMTHFR Gene Support
ModerateCardiovascular Health
StrongPregnancy Health
ModerateResearch Visualised
Visual breakdown of the clinical data.
Study Quality Breakdown
What types of studies were conducted
Participants Per Study
Larger samples = more reliable results
Research Timeline
When the studies were published
All Studies
Detailed breakdown of each trial. Click to expand.
Depression & Mood
To evaluate L-methylfolate as adjunctive therapy in patients with major depressive disorder (MDD) not responding to antidepressants.
Study Type
Randomised, double-blind, placebo-controlled
Purpose
To evaluate L-methylfolate as adjunctive therapy in patients with major depressive disorder (MDD) not responding to antidepressants.
Dose
15 mg/day L-methylfolate
Participants
148 patients with SSRI-resistant MDD
Duration
30 days
Results
L-methylfolate as adjunct to SSRI therapy significantly improved response rates (32.3% vs 14.6%) and produced greater HAM-D score reductions. Effects were more pronounced in patients with MTHFR polymorphisms.
How They Measured It
HAM-D, MADRS, response and remission rates
To evaluate folate and methylfolate supplementation for depression.
Study Type
Systematic review
Purpose
To evaluate folate and methylfolate supplementation for depression.
Dose
Various (0.4-15 mg/day)
Participants
Pooled from 11 RCTs
Duration
Various
Results
Folate and methylfolate supplementation significantly improved response to antidepressant treatment and reduced depressive symptoms. 5-MTHF appears superior to folic acid in patients with MTHFR variants.
How They Measured It
Pooled response and remission rates across RCTs of folate/methylfolate in depression
MTHFR Gene Support
To compare 5-MTHF vs folic acid supplementation on homocysteine reduction in adults with MTHFR C677T polymorphism.
Study Type
Randomised, double-blind, crossover
Purpose
To compare 5-MTHF vs folic acid supplementation on homocysteine reduction in adults with MTHFR C677T polymorphism.
Dose
400 µg/day 5-MTHF vs 400 µg/day folic acid
Participants
131 healthy adults with MTHFR variants
Duration
8 weeks each arm
Results
5-MTHF was significantly more effective than folic acid at reducing homocysteine in adults with MTHFR C677T variant. Plasma 5-MTHF levels were 1.7-fold higher with direct 5-MTHF supplementation.
How They Measured It
Serum homocysteine, plasma 5-MTHF levels, MTHFR genotype
To determine whether 5-MTHF is superior to folic acid for raising blood folate in women with MTHFR polymorphisms.
Study Type
Randomised, controlled trial
Purpose
To determine whether 5-MTHF is superior to folic acid for raising blood folate in women with MTHFR polymorphisms.
Dose
400 µg/day 5-MTHF vs folic acid
Participants
184 women of childbearing age
Duration
16 weeks
Results
5-MTHF supplementation raised red blood cell folate more effectively than folic acid, particularly in women with MTHFR 677TT genotype. 5-MTHF is recommended over folic acid for those with MTHFR variants.
How They Measured It
Red blood cell folate, plasma homocysteine, MTHFR genotype
Cardiovascular Health
To evaluate the effect of methylfolate supplementation on homocysteine and cardiovascular risk.
Study Type
Meta-analysis
Purpose
To evaluate the effect of methylfolate supplementation on homocysteine and cardiovascular risk.
Dose
0.5-5 mg/day folate/methylfolate
Participants
Pooled data from multiple RCTs (>12,000 participants)
Duration
Various
Results
Folate/methylfolate supplementation significantly reduced homocysteine levels by 25-30%. Meta-analyses showed modest but significant reduction in stroke risk with homocysteine lowering.
How They Measured It
Serum homocysteine, cardiovascular events across RCTs
Pregnancy Health
To compare 5-MTHF vs folic acid supplementation during pregnancy on maternal and neonatal folate status.
Study Type
Randomised, double-blind, controlled
Purpose
To compare 5-MTHF vs folic acid supplementation during pregnancy on maternal and neonatal folate status.
Dose
400 µg/day 5-MTHF vs folic acid
Participants
136 pregnant women
Duration
Weeks 12-36 of pregnancy
Results
Both 5-MTHF and folic acid effectively raised maternal and neonatal folate levels. 5-MTHF showed superior bioavailability in women with MTHFR variants, supporting its use as an alternative to folic acid in prenatal supplementation.
How They Measured It
Maternal and cord blood folate, neonatal health outcomes
To evaluate the evidence for 5-MTHF vs folic acid in periconceptional supplementation for neural tube defect prevention.
Study Type
Review
Purpose
To evaluate the evidence for 5-MTHF vs folic acid in periconceptional supplementation for neural tube defect prevention.
Dose
400-800 µg/day
Participants
Multiple study populations
Duration
N/A
Results
5-MTHF prevents neural tube defects as effectively as folic acid and bypasses the MTHFR enzymatic step, making it particularly suitable for women with reduced MTHFR activity. No risk of masking B12 deficiency.
How They Measured It
Review of mechanistic and clinical evidence
To compare the efficacy of 5-MTHF vs folic acid in preventing neural tube defects in a folate-sensitive mouse model.
Study Type
Animal study
Purpose
To compare the efficacy of 5-MTHF vs folic acid in preventing neural tube defects in a folate-sensitive mouse model.
Dose
Dietary supplementation with 5-MTHF or folic acid
Participants
Splotch mice (Pax3 mutant model of NTDs)
Duration
Gestational period
Results
Both 5-MTHF and folic acid reduced neural tube defect incidence compared to no supplementation. 5-MTHF achieved prevention at lower doses, consistent with its superior bioavailability.
How They Measured It
Neural tube defect incidence, embryonic folate levels
Frequently Asked Questions
Common questions about Methylfolate research
There are currently 10 peer-reviewed studies on Methylfolate (5-Methyltetrahydrofolate (5-MTHF)), involving 1,870 total participants. Research covers Depression & mood, MTHFR gene support, Cardiovascular health and 1 more areas. The overall evidence strength is rated as Very Strong.
The evidence is currently rated as "Very Strong Evidence". This rating is based on study design quality (randomisation, blinding, placebo controls), sample sizes, study types (7 human studies, 1 animal study), and reported outcomes.
Methylfolate has been researched for: Depression & mood, MTHFR gene support, Cardiovascular health, Pregnancy health. Each area has its own body of evidence which you can explore in the study breakdowns above.
Yes, 7 out of 10 studies are human trials. The remaining 1 is an animal study. Human trials carry more weight in our evidence scoring system.
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