Methylfolate
Vitamin ·Exploratory record · not publication-reviewed ·Updated July 13, 2026
The active, methylated form of folate, essential for those with MTHFR variants.
Exploratory record, not a reviewed medical publication.
See the editorial and medical-review policies for the publication gate.
This generated database record has not completed a claim-level review by a qualified human medical reviewer. Bibliography links and evidence labels are not approval. The page remains available for reference and is excluded from search indexing.
What the research says.
A quick, data-only summary. The full evidence, dosing, and sources are below.
Methylfolate is a vitamin most often used for methylation support, mood, pregnancy health. NutriStack rates the overall evidence as strong. A typical adult dose is 400-1,000 mcg daily, commonly taken as quatrefolic (glucosamine salt of 5-mthf) or metafolin. This profile indexes 16 sources.
The bottom line
Evidence rating strong. Most-documented uses: methylation support, mood, pregnancy health. 16 sources indexed (2010–2026), with 0 interaction records on file.
How it works, mechanistically.
Core mechanism
Direct methyl donor in the methionine cycle via methionine synthase. Bypasses MTHFR enzyme entirely, crucial for the ~30-40% of population with MTHFR C677T or A1298C variants.6,1
Dosing & protocol.
What it actually costs.
Real-world pricing across three quality tiers. Assumes Methylfolate (5-MTHF).
Assumes 400-1,000 mcg/day. Methylfolate costs more than folic acid but is often the better value when MTHFR-related conversion issues are a concern. Updated 2026-04-02.
The same dose, as food.
How much you'd eat to match a supplemental dose.
Food provides folate, but methylfolate is the active supplement form rather than a direct food label category.
Full safety detail.
Side effects
- Overmethylation symptoms (anxiety, insomnia) if dose too high
Contraindications
- Undiagnosed B12 deficiency (can mask it)
Sources, by evidence tier.
Numbered references. Citations throughout the page link here.
Meta-analyses & systematic reviews
4- 1Folate supplementation as a beneficial add-on treatment in relieving depressive symptoms: A meta-analysis of meta-analysesPMIDZheng X et al. · Journal of Affective Disorders · 2024
Folate supplementation significantly relieved depression symptoms; active forms (L-methylfolate, SAMe) more beneficial than folic acid; MTHFR TT carriers particularly benefit.
- 2The Effects of Methylfolate on Cognitive Decline and Dementia: A Protocol for Systematic Review and Meta-AnalysisPMIDPrado LIA, Junger AL, Caixeta LF et al. · Journal of clinical medicine · 2023
Prado LIA, Junger AL, Caixeta LF et al.. The Effects of Methylfolate on Cognitive Decline and Dementia: A Protocol for Systematic Review and Meta-Analysis. Journal of clinical medicine. 2023
- 3Systematic Review and Meta-Analysis of L-Methylfolate Augmentation in Depressive DisordersPMIDJain R et al. · Journal of Clinical Psychiatry · 2021
Adjunctive L-methylfolate may have modest efficacy in antidepressant-treated adults with major depressive disorder.
- 4Association of the maternal MTHFR C677T polymorphism with susceptibility to neural tube defects in offsprings: evidence from 25 case-control studiesPMIDZhang T et al. · PLoS ONE · 2012
In 25 case-control studies (2429 cases, 3570 controls), maternal MTHFR C677T TT genotype increased NTD risk (OR 2.02, 95% CI 1.51-2.71).
Randomized controlled trials
7- 5Feasibility of a randomized clinical trial comparing 5-methyltetrahydrofolate and folic acid prenatal multivitamins in couples with recurrent pregnancy lossPMIDLedowsky C, Scarf V, Rogers K et al. · Nutrition research (New York, N.Y.) · 2026
Ledowsky C, Scarf V, Rogers K et al.. Feasibility of a randomized clinical trial comparing 5-methyltetrahydrofolate and folic acid prenatal multivitamins in couples with recurrent pregnancy loss. Nutrition research (New York, N.Y.). 2026
- 6Effect of Methylfolate, Pyridoxal-5'-Phosphate, and Methylcobalamin (Soloways(TM)) Supplementation on Homocysteine and Low-Density Lipoprotein Cholesterol Levels in Patients with Methylenetetrahydrofolate Reductase, Methionine Synthase, and Methionine Synthase Reductase Polymorphisms: A Randomized Controlled TrialPMIDPokushalov E, Ponomarenko A, Bayramova S et al. · Nutrients · 2024
Pokushalov E, Ponomarenko A, Bayramova S et al.. Effect of Methylfolate, Pyridoxal-5'-Phosphate, and Methylcobalamin (Soloways(TM)) Supplementation on Homocysteine and Low-Density Lipoprotein Cholesterol Levels in Patients with Methylenetetrahydrofolate Reductase, Methionine Synthase, and Methionine Synthase Reductase Polymorphisms: A Randomized Controlled Trial. Nutrients. 2024
- 75-MTHF enhances the portal pressure reduction achieved with propranolol in patients with cirrhosis: A randomized placebo-controlled trialPMIDVukotic R, Di Donato R, Roncarati G et al. · Journal of hepatology · 2023
Vukotic R, Di Donato R, Roncarati G et al.. 5-MTHF enhances the portal pressure reduction achieved with propranolol in patients with cirrhosis: A randomized placebo-controlled trial. Journal of hepatology. 2023
- 8Suitability and safety of L-5-methyltetrahydrofolate as a folate source in infant formula: A randomized-controlled trialPMIDTroesch B, Demmelmair J, Gimpfl M et al. · PloS one · 2019
Troesch B, Demmelmair J, Gimpfl M et al.. Suitability and safety of L-5-methyltetrahydrofolate as a folate source in infant formula: A randomized-controlled trial. PloS one. 2019
- 9Does L-Methylfolate Supplement Methylphenidate Pharmacotherapy in Attention-Deficit/Hyperactivity Disorder?: Evidence of Lack of Benefit From a Double-Blind, Placebo-Controlled, Randomized Clinical TrialPMIDSurman C, Ceranoglu A, Vaudreuil C et al. · Journal of clinical psychopharmacology · 2019
Surman C, Ceranoglu A, Vaudreuil C et al.. Does L-Methylfolate Supplement Methylphenidate Pharmacotherapy in Attention-Deficit/Hyperactivity Disorder?: Evidence of Lack of Benefit From a Double-Blind, Placebo-Controlled, Randomized Clinical Trial. Journal of clinical psychopharmacology. 2019
- 10Biochemical, physiological and clinical effects of l-methylfolate in schizophrenia: a randomized controlled trialPMIDRoffman JL, Petruzzi LJ, Tanner AS et al. · Molecular psychiatry · 2018
Roffman JL, Petruzzi LJ, Tanner AS et al.. Biochemical, physiological and clinical effects of l-methylfolate in schizophrenia: a randomized controlled trial. Molecular psychiatry. 2018
- 11L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trialsPMIDPapakostas GI et al. · American Journal of Psychiatry · 2012
Adjunctive L-methylfolate at 15 mg/day showed significantly greater efficacy vs placebo for response rate and symptom severity in SSRI-resistant MDD.
Reviews & position papers
3- 12Active Folate Versus Folic Acid: The Role of 5-MTHF (Methylfolate) in Human HealthPMIDSamblas M et al. · Nutrients · 2022
5-MTHF bypasses MTHFR enzyme entirely; bioavailability unaffected by genetic polymorphisms; better option than folic acid for MTHFR variant carriers.
- 13MTHFR polymorphisms and disease: a reviewSource linkedPMIDLiew SC, Gupta ED · Biomed J · 2015
- 14Folic acid and L-5-methyltetrahydrofolate: comparison of clinical pharmacokinetics and pharmacodynamicsPMIDPietrzik K et al. · Clinical Pharmacokinetics · 2010
L-5-MTHF and folic acid have comparable physiological activity at equimolar doses, but 5-MTHF's bioavailability is not affected by metabolic defects.
Reference material
2- 15Sakuma K, Matsunaga S, Nomura I et al.. Folic acid/methylfolate for the treatment of psychopathology in schizophrenia: a systematic review and meta-analysis. Psychopharmacology. 2018Source linkedPMID
- 16Maletic V, Shelton R, Holmes V. A Review of l-Methylfolate as Adjunctive Therapy in the Treatment of Major Depressive Disorder. The primary care companion for CNS disorders. 2023Source linkedPMID
Common questions.
Quick answers about Methylfolate, drawn from the data on this page.
What is Methylfolate?
The active, methylated form of folate, essential for those with MTHFR variants.
What is Methylfolate used for?
Commonly cited benefits of Methylfolate include: Methylation support; Mood; Pregnancy health; MTHFR support. NutriStack rates the overall evidence as strong.
What is a typical dose of Methylfolate?
A typical adult dose of Methylfolate is 400-1,000 mcg daily. The commonly recommended form is Quatrefolic (glucosamine salt of 5-MTHF) or Metafolin. These are general ranges, not personalized advice; confirm the right dose with a clinician.
What are the side effects of Methylfolate?
Reported side effects include overmethylation symptoms (anxiety, insomnia) if dose too high. This is educational information; check with a healthcare professional before use.
How strong is the evidence for Methylfolate?
NutriStack rates this as Strong, meaning multiple high-quality meta-analyses or systematic reviews converge on the same finding. Full tier criteria are at https://nutristackapp.com/methodology/evidence-tiers.
Use this with your stack
Methylfolate in NutriStack.
Add it to your stack, see how it interacts with everything else you take, and get a Stack Score that updates the moment it does.