Supplements
L-methylfolate decreases homocysteine
Part of: 🧪 Folate & L-methylfolate
📅 Last reviewed: 2026-07-15 ⓘ
Evidence ladder
How far up the ladder this claim has climbed. A high consensus on a low rung means "consistent so far," not "proven in people."
Top evidence so far: All trials, pooled (Meta-analysis)
How the studies fall
What the evidence shows
L-methylfolate is superior to folic acid for lowering homocysteine.
The evidence (8)
| Source | Grade | Stance | Quality | Finding |
|---|---|---|---|---|
| Xie M, Qing X, Huang H, Zhang J 2025 · Medicine | meta-analysis | contradicts | moderate | 11 RCTs, active folate vs equimolar folic acid: active form ↑plasma folate (P=.04), ↑RBC folate (P=.01), but NO significant difference in homocysteine, B12, or betaine. |
| Venn BJ, Green TJ, Moser R, Mann JI 2003 · Am J Clin Nutr | RCT | mixed | moderate | RCT: low-dose L-5-MTHF and folic acid lowered tHcy comparably (no superiority) |
| lamers-2004 2004 · The American journal of clinical nutrition | RCT | tested-null | moderate | 5-MTHF and folic acid EQUAL for homocysteine lowering (no superiority). |
| Mazza A, Cicero AF, Ramazzina E, Lenti S, Schiavon L, Casiglia E, Gussoni G 2016 · Clin Nutr | RCT | supports | moderate | 5-MTHF nutraceutical lowered homocysteine in hypertensives |
| Willems FF, Boers GH, Blom HJ, Aengevaeren WR, Verheugt FW 2004 · Br J Pharmacol | RCT | mixed | moderate | Randomised two-way crossover PK study (CAD patients, single 5 mg dose): 5-MTHF bioavailability HIGHER than folic acid, peak ~7x, irrespective of MTHFR genotype. RELEVANCE GATE: the endpoint is folate PHARMACOKINETICS, not homocysteine - it does not test this claim's outcome. Superior bioavailability does not establish superior homocysteine lowering (cf. Lamers 2004, which found the two EQUAL on homocysteine). |
| Song J, Lan R, Yin D, Wang L, Gong H 2025 · Technology and health care : official journal of the European Society for Engineering and Medicine | RCT | mixed | low | Methylfolate vs synthetic folic acid in high-HCY/adverse-pregnancy-history cohort: methylfolate 'efficiently reduced' HCY and lower adverse-pregnancy incidence, but no comparative HCY statistic vs folic-acid arm reported. |
| Coppola A, D'Angelo A, Fermo I, Mazzola G, Di Minno MN, Cajani A, Sala A, Folco G, Tremoli E, Di Minno G 2005 · Br J Haematol | observational | supports | low | 5-MTHF supplementation lowered tHcy in 677TT early-thrombosis patients, durable effect |
| Bostom AG, Shemin D, Bagley P, Massy ZA, Zanabli A, Christopher K, Spiegel P, Jacques PF, Dworkin L, Selhub J 2000 · Circulation | RCT | mixed | moderate | Block-randomized, 50 hemodialysis patients, 12 wk, folic acid 15 mg/d vs equimolar L-5-MTHF 17 mg/d (both + B6/B12, no placebo). 'The mean percent reductions (+/-95% CIs) in predialysis tHcy were not significantly different: MTHF, 17.0% (12.0% to 22.0%); FA, 14.8% (9.6% to 20.1%); P=0.444'. Null on superiority (contradicts under the scope reading); within-arm fall supports the bare SPO. Held mixed pending claim re-encoding. |
Disagree, or know a study we missed?
We grade by evidence, not opinions. The way to weigh in is to point us to a study we haven't cited (check the evidence table above first), or to flag a problem with one we have. Every submission is reviewed; if it holds up, the grade updates and shows in Science Changes Its Mind.
Opens a short form. You'll sign in with Google so submissions are tied to a real account — we don't display your identity, and we only accept a link we can verify (PubMed, DOI, ClinicalTrials.gov).
Educational only, not medical advice. Grades and scores reflect published evidence weighted by study design and quality; see the methodology.