--- title: "L-Methylfolate (5-MTHF) — Evidence, Benefits & Where to Buy | Magellan" description: "L-Methylfolate (5-MTHF) — L-Methylfolate (also called 5-methyltetrahydrofolate, 5-MTHF, or levomefolic acid) is the biologically active, circulating form…" url: "https://magellanlongevity.com/p/130.md" canonical: "https://magellanlongevity.com/p/130.html" html: "https://magellanlongevity.com/p/130.html" type: "product" section: "Nutraceuticals & Cellular Energizers" evidence_grade: "Moderate evidence" evidence_tier: "moderate" citations: 21 product_id: 130 price_usd: 22 updated: 2026-09-02 author: "Gabriel Radu, DO" author_credentials: "Physiatrist (PM&R). NY medical license 275110. NPI 1376861765." publisher: "Magellan Longevity" content_format: "markdown" license: "Educational content — not medical advice" --- # L-Methylfolate (5-MTHF) [Home](https://magellanlongevity.com/) › [Nutraceuticals & Cellular Energizers](https://magellanlongevity.com/c/1.md) › L-Methylfolate (5-MTHF) **HTML version:** https://magellanlongevity.com/p/130.html · **In the Magellan app:** https://magellanlongevity.com/#/product/130 ## Key facts | Field | Value | | --- | --- | | Product | L-Methylfolate (5-MTHF) | | Category | [Nutraceuticals & Cellular Energizers](https://magellanlongevity.com/c/1.md) | | Evidence grade | Moderate evidence (B) | | Peer-reviewed citations | 21 | | Typical listed price | $22.00 (check the live price) | | Where to buy | [Search Amazon](https://www.amazon.com/s?k=L-Methylfolate%20%285-MTHF%29&tag=magellanlong-20) | | Catalog ID | 130 | ## What it is L-Methylfolate (also called 5-methyltetrahydrofolate, 5-MTHF, or levomefolic acid) is the biologically active, circulating form of the B-vitamin folate and the form that enters cells and the brain without further conversion. Unlike synthetic folic acid, it does not require reduction by dihydrofolate reductase or activation by methylenetetrahydrofolate reductase (MTHFR), so its bioavailability is not reduced by common MTHFR gene polymorphisms. Within one-carbon metabolism it donates a methyl group to convert homocysteine into methionine, supporting DNA methylation and neurotransmitter synthesis. ## Its role in longevity In human trials, both L-5-MTHF and folic acid raise blood folate and lower total homocysteine, an amino acid whose elevation is linked to cardiovascular and cognitive risk; head-to-head studies find L-5-MTHF at least as effective as folic acid, and sometimes better, at improving folate status. Evidence for hard clinical outcomes is more mixed: meta-analyses of folate supplementation show a modest (~10%) reduction in stroke risk but little effect on coronary heart disease or all-cause mortality, and B-vitamin trials have generally not slowed cognitive decline in older adults. As an adjunct to antidepressants, 15 mg/day L-methylfolate improved response in SSRI-resistant depression in randomized trials and a 2022 meta-analysis (about 25% higher response rates, NNT around 6, tolerability like placebo), with benefit concentrated in people with obesity, inflammation or certain folate-pathway genotypes; a 7.5 mg dose was ineffective. Depression augmentation is the best-tested use — longevity-specific indications are extrapolations, not tested. This evidence describes the folate compound and homocysteine mechanism itself, not this specific commercial product. ## Evidence grade: Moderate evidence - **What the grade means:** Curated grade based on the human and mechanistic evidence for this compound. - **Dose used in studies:** 15 mg/day as antidepressant adjunct (7.5 mg was ineffective) - **What this grade does not say:** It reliably raises folate status and lowers homocysteine, and randomized trials plus a 2022 meta-analysis show a modest adjunctive benefit in SSRI-resistant depression at 15 mg/day with placebo-like tolerability, likely concentrated in inflammatory or metabolic subgroups. But homocysteine lowering has not translated into clear cardiovascular or cognitive outcome benefits, and longevity uses are extrapolations, not tested. ## Where it comes from without a bottle Food, exercise and behaviour routes to the same pathway, each with its citation. | Natural source | How it works | Citation | | --- | --- | --- | | Leafy greens & legumes (natural folate = same active molecule) | L-methylfolate (5-MTHF) is not exotic: it's the exact active folate form your body already makes from the folate in food and the only folate normally circulating in your blood. Eat dietary folate from leafy greens and legumes and you generate this same molecule internally; the supplement just skips the conversion steps. | Clinical Pharmacokinetics 2010 [PMID 20608755](https://pubmed.ncbi.nlm.nih.gov/20608755/) | | Legumes, dark leafy vegetables, asparagus & citrus | Whole-food folate is concentrated in legumes (lentils, beans, chickpeas), dark leafy greens, asparagus, and oranges - low intake of exactly these foods is the leading cause of folate deficiency. A folate-rich plate is the natural equivalent; 5-MTHF capsules help when intake, pregnancy needs, or MTHFR genetics fall short. | Food and Nutrition Bulletin 2008 [PMID 18709879](https://pubmed.ncbi.nlm.nih.gov/18709879/) | ### What those papers actually say 1. **Leafy greens & legumes (natural folate = same active molecule)** Clinical Pharmacokinetics 2010 · [PMID 20608755](https://pubmed.ncbi.nlm.nih.gov/20608755/) · [DOI 10.2165/11532990-000000000-00000](https://doi.org/10.2165/11532990-000000000-00000) > L-5-methyl-THF is the predominant form of dietary folate and the only species normally found in the circulation. 2. **Legumes, dark leafy vegetables, asparagus & citrus** Food and Nutrition Bulletin 2008 · [PMID 18709879](https://pubmed.ncbi.nlm.nih.gov/18709879/) · [DOI 10.1177/15648265080292S105](https://doi.org/10.1177/15648265080292S105) > The primary cause of folate deficiency is low intake of sources rich in the vitamin, such as legumes and green leafy vegetables. ## In the news - **L-Methylfolate Forte Uses, Side Effects & Warnings** — Drugs.com 2025 [Read it](https://www.drugs.com/mtm/l-methylfolate-forte.html) > L-Methylfolate Forte is a medical food for use in people who have conditions related to folate deficiency. L-Methylfolate Forte is also used in people with major depressive disorder who have folate deficiency, or in people with schizophrenia who have hyperhomocysteinemia related to folate deficiency. ## The research Peer-reviewed studies on the active compound. Quotes are verbatim from the cited abstract. Research describes the active mechanism and is not a claim about this specific product. ### Cited studies 1. **Evidence: active folate, methylation cofactor** Clin Nutr ESPEN 2023 · [PMID 38056998](https://pubmed.ncbi.nlm.nih.gov/38056998/) · [DOI 10.1016/j.clnesp.2023.09.002](https://doi.org/10.1016/j.clnesp.2023.09.002) > serum folate increased while total homocysteine decreased significantly 2. **Effect of adjunctive L-methylfolate 15 mg among inadequate responders to SSRIs in depressed patients** J Clin Psychiatry 2014 · [PMID 24813065](https://pubmed.ncbi.nlm.nih.gov/24813065/) · [DOI 10.4088/JCP.13m08947](https://doi.org/10.4088/JCP.13m08947) > greater pooled mean change with L-methylfolate versus placebo 3. **Comparison of the effect of low-dose supplementation with L-5-methyltetrahydrofolate or folic acid on plasma homocysteine: a randomized placebo-controlled study.** Am J Clin Nutr 2003 · [PMID 12600857](https://pubmed.ncbi.nlm.nih.gov/12600857/) · [DOI 10.1093/ajcn/77.3.658](https://doi.org/10.1093/ajcn/77.3.658) > L-MTHF was more effective than was folic acid in lowering tHcy (P < 0.05). At 24 wk, the increases in plasma folate and RCF concentrations did not differ significantly between the 2 supplemented groups. 4. **The folic acid metabolite L-5-methyltetrahydrofolate effectively reduces total serum homocysteine level in orthotopic liver transplant recipients: a double-blind placebo-controlled study.** Eur J Clin Nutr 2007 · [PMID 17522618](https://pubmed.ncbi.nlm.nih.gov/17522618/) · [DOI 10.1038/sj.ejcn.1602778](https://doi.org/10.1038/sj.ejcn.1602778) > We observed only a significant decrease of total serum HCY in the L-5-MTHF group during the study period (at week 0: 15+/-7.7 microM; after 8 weeks treatment: 9.41+/-2.6 microM, P<0.001). 5. **l-5-Methyltetrahydrofolate Supplementation Increases Blood Folate Concentrations to a Greater Extent than Folic Acid Supplementation in Malaysian Women.** J Nutr 2018 · [PMID 29878267](https://pubmed.ncbi.nlm.nih.gov/29878267/) · [DOI 10.1093/jn/nxy057](https://doi.org/10.1093/jn/nxy057) > These findings suggest differential effects of l-5-MTHF compared with folic acid supplementation on blood folate concentrations but no differences on plasma total homocysteine lowering in Malaysian women. 6. **Supplementation with [6S]-5-methyltetrahydrofolate or folic acid equally reduces serum homocysteine concentrations in older adults.** Int J Food Sci Nutr 2017 · [PMID 28460586](https://pubmed.ncbi.nlm.nih.gov/28460586/) · [DOI 10.1080/09637486.2017.1320536](https://doi.org/10.1080/09637486.2017.1320536) > Supplementation with [6 S]-5-MTHF was slightly less effective, but not significantly, in Hcy lowering than FA (p = .243 between the groups), that is, by 7.8% and 13.4%, respectively. The [6 S]-5-MTHF was shown to be an adequate alternative to FA in reducing Hcy concentrations. 7. **Folate, folic acid and 5-methyltetrahydrofolate are not the same thing.** Xenobiotica 2014 · [PMID 24494987](https://pubmed.ncbi.nlm.nih.gov/24494987/) · [DOI 10.3109/00498254.2013.845705](https://doi.org/10.3109/00498254.2013.845705) > Naturally occurring 5-MTHF has important advantages over synthetic folic acid - it is well absorbed even when gastrointestinal pH is altered and its bioavailability is not affected by metabolic defects. 8. **MTHFR 677 C>T Polymorphism reveals functional importance for 5-methyltetrahydrofolate, not homocysteine, in regulation of vascular redox state and endothelial function in human atherosclerosis.** Circulation 2009 · [PMID 19398669](https://pubmed.ncbi.nlm.nih.gov/19398669/) · [DOI 10.1161/CIRCULATIONAHA.108.808675](https://doi.org/10.1161/CIRCULATIONAHA.108.808675) > Vascular 5-MTHF, rather than plasma or vascular homocysteine, is a key regulator of endothelial nitric oxide synthase coupling and nitric oxide bioavailability in human vessels, suggesting that plasma homocysteine is an indirect marker of 5-MTHF rather than a primary regulator of endothelial function. 9. **Is 5-methyltetrahydrofolate an alternative to folic acid for the prevention of neural tube defects?** J Perinat Med 2013 · [PMID 23482308](https://pubmed.ncbi.nlm.nih.gov/23482308/) · [DOI 10.1515/jpm-2012-0256](https://doi.org/10.1515/jpm-2012-0256) > Carriers of certain polymorphisms in genes related to folate metabolism or absorption can better benefit from 5-methylTHF instead of FA. 10. **5-MTHF enhances the portal pressure reduction achieved with propranolol in patients with cirrhosis: A randomized placebo-controlled trial.** J Hepatol 2023 · [PMID 37482222](https://pubmed.ncbi.nlm.nih.gov/37482222/) · [DOI 10.1016/j.jhep.2023.06.017](https://doi.org/10.1016/j.jhep.2023.06.017) > In patients with cirrhosis and portal hypertension, 5-MTHF administration significantly enhanced the HVPG reduction achieved with propranolol. This effect appears to be mediated by improved nitric oxide bioavailability in the hepatic microcirculation. 11. **Influence of Dietary Supplementation for Hyperhomocysteinemia Treatments.** Nutrients 2020 · [PMID 32630031](https://pubmed.ncbi.nlm.nih.gov/32630031/) · [DOI 10.3390/nu12071957](https://doi.org/10.3390/nu12071957) > Every supplementation induced significant (range <0.05-0.0001) reductions of Hcy level and Cys concentration after the three protocols adopted. 12. **Homocysteine lowering interventions for peripheral arterial disease and bypass grafts.** Cochrane Database Syst Rev 2013 · [PMID 23881650](https://pubmed.ncbi.nlm.nih.gov/23881650/) · [DOI 10.1002/14651858.CD003285.pub2](https://doi.org/10.1002/14651858.CD003285.pub2) > Currently, no recommendation can be made regarding the value of treatment of hyperhomocysteinaemia in peripheral arterial disease. 13. **L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials.** Am J Psychiatry 2012 · [PMID 23212058](https://pubmed.ncbi.nlm.nih.gov/23212058/) · [DOI 10.1176/appi.ajp.2012.11071114](https://doi.org/10.1176/appi.ajp.2012.11071114) > In the second trial, adjunctive L-methylfolate at 15 mg/day showed significantly greater efficacy compared with continued SSRI therapy plus placebo on both primary outcome measures (response rate and degree of change in depression symptom score) and two secondary outcome measures of symptom severity. 14. **A Review of l-Methylfolate as Adjunctive Therapy in the Treatment of Major Depressive Disorder.** Prim Care Companion CNS Disord 2023 · [PMID 37192264](https://pubmed.ncbi.nlm.nih.gov/37192264/) · [DOI 10.4088/PCC.22nr03361](https://doi.org/10.4088/PCC.22nr03361) > These studies support the use of LMF as an adjunctive treatment in patients with MDD not responding to antidepressant monotherapy. The most effective dose tested was 15 mg/day. 15. **Folic Acid Supplementation and the Risk of Cardiovascular Diseases: A Meta-Analysis of Randomized Controlled Trials.** J Am Heart Assoc 2016 · [PMID 27528407](https://pubmed.ncbi.nlm.nih.gov/27528407/) · [DOI 10.1161/JAHA.116.003768](https://doi.org/10.1161/JAHA.116.003768) > Our meta-analysis indicated a 10% lower risk of stroke and a 4% lower risk of overall CVD with folic acid supplementation. 16. **Efficacy of folic acid supplementation in cardiovascular disease prevention: an updated meta-analysis of randomized controlled trials.** Eur J Intern Med 2012 · [PMID 22884409](https://pubmed.ncbi.nlm.nih.gov/22884409/) · [DOI 10.1016/j.ejim.2012.07.004](https://doi.org/10.1016/j.ejim.2012.07.004) > This meta-analysis suggests that there might be a potentially modest benefit of folic acid supplementation in stroke prevention. 17. **The effect of folate fortification on folic acid-based homocysteine-lowering intervention and stroke risk: a meta-analysis.** Public Health Nutr 2014 · [PMID 25323814](https://pubmed.ncbi.nlm.nih.gov/25323814/) · [DOI 10.1017/S1368980014002134](https://doi.org/10.1017/S1368980014002134) > Folic acid supplementation might have a modest benefit on stroke prevention in regions without folate fortification. 18. **Homocysteine versus the vitamins folate, B6, and B12 as predictors of cognitive function and decline in older high-functioning adults: MacArthur Studies of Successful Aging.** Am J Med 2005 · [PMID 15694902](https://pubmed.ncbi.nlm.nih.gov/15694902/) · [DOI 10.1016/j.amjmed.2004.08.019](https://doi.org/10.1016/j.amjmed.2004.08.019) > In high-functioning older adults, low folate levels appear to be a risk factor for cognitive decline. The risk of developing cognitive decline might be reduced through dietary folate intake. 19. **Effect of Vitamin Intake on Cognitive Decline in Older Adults: Evaluation of the Evidence.** J Nutr Health Aging 2015 · [PMID 26193858](https://pubmed.ncbi.nlm.nih.gov/26193858/) · [DOI 10.1007/s12603-015-0539-3](https://doi.org/10.1007/s12603-015-0539-3) > Evaluation of the totality of the currently available evidence indicates that intake of the above vitamins, either as a monotherapy, or in combination with other vitamins, has no clinically-relevant effect on delaying cognitive decline or delaying the onset of dementia in older adults. 20. **Meta-analysis of folic acid supplementation trials on risk of cardiovascular disease and risk interaction with baseline homocysteine levels.** Am J Cardiol 2010 · [PMID 20691310](https://pubmed.ncbi.nlm.nih.gov/20691310/) · [DOI 10.1016/j.amjcard.2010.03.064](https://doi.org/10.1016/j.amjcard.2010.03.064) > Overall, FA supplementation did not affect primary cardiovascular clinical end points (relative risk 1.02, 95% confidence interval [CI] 0.93 to 1.13, p = 0.66) or stroke (relative risk 0.95, 95% CI 0.84 to 1.08, p = 0.43). 21. **Systematic Review and Meta-Analysis of L-Methylfolate Augmentation in Depressive Disorders.** Pharmacopsychiatry 2022 · [PMID 34794190](https://pubmed.ncbi.nlm.nih.gov/34794190/) > Adjunctive L-methylfolate modestly improved antidepressant response versus placebo (RR 1.25 for HAMD-17 response; SMD −0.38), supporting the 15 mg/day trial findings. ## Where to buy [Search Amazon for L-Methylfolate (5-MTHF)](https://www.amazon.com/s?k=L-Methylfolate%20%285-MTHF%29&tag=magellanlong-20) — affiliate search link. ## Structured data ```json {"@context":"https://schema.org","@graph":[{"@type":"ItemPage","@id":"https://magellanlongevity.com/p/130.html#page","url":"https://magellanlongevity.com/p/130.html","name":"L-Methylfolate (5-MTHF)","description":"L-Methylfolate (also called 5-methyltetrahydrofolate, 5-MTHF, or levomefolic acid) is the biologically active, circulating form of the B-vitamin folate…","inLanguage":"en","isPartOf":{"@type":"WebSite","name":"Magellan Longevity","url":"https://magellanlongevity.com/"},"author":{"@type":"Person","name":"Gabriel Radu, DO","jobTitle":"Physiatrist (PM&R)","identifier":[{"@type":"PropertyValue","name":"NPI","value":"1376861765"},{"@type":"PropertyValue","name":"NY medical license","value":"275110"}]},"publisher":{"@type":"Organization","name":"Magellan Longevity","url":"https://magellanlongevity.com/"},"encoding":{"@type":"MediaObject","encodingFormat":"text/markdown","contentUrl":"https://magellanlongevity.com/p/130.md"},"dateModified":"2026-09-02"},{"@type":"BreadcrumbList","itemListElement":[{"@type":"ListItem","position":1,"name":"Home","item":"https://magellanlongevity.com/"},{"@type":"ListItem","position":2,"name":"Nutraceuticals & Cellular Energizers","item":"https://magellanlongevity.com/c/1.html"},{"@type":"ListItem","position":3,"name":"L-Methylfolate (5-MTHF)","item":"https://magellanlongevity.com/p/130.html"}]},{"@type":"Product","@id":"https://magellanlongevity.com/p/130.html#product","name":"L-Methylfolate (5-MTHF)","category":"Nutraceuticals & Cellular Energizers","url":"https://magellanlongevity.com/p/130.html","description":"L-Methylfolate (also called 5-methyltetrahydrofolate, 5-MTHF, or levomefolic acid) is the biologically active, circulating form of the B-vitamin folate and the form that enters cells and the brain without further conversion. 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Nothing here is intended to diagnose, treat, cure, or prevent any disease. Talk to your physician before starting any supplement or device, especially if you are pregnant, nursing, or taking medication. Editorial firewall: evidence grades are assigned from the published research and are independent of any affiliate commission. As an Amazon Associate, Magellan Longevity earns from qualifying purchases. Reviewed for accuracy by a board-certified physician (DO).