Supplements
L-methylfolate treats mood disorder
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 (15 mg/d) augments antidepressant response in SSRI-resistant depression.
The evidence (7)
| Source | Grade | Stance | Quality | Finding |
|---|---|---|---|---|
| Bopp EA et al 2022 · study_type: observational | observational | contradicts | moderate | Retrospective EHR, n=412 youth: CGI-I change did not differ by L-methylfolate prescription (p=0.39); response not assoc. w/ Rx (p=0.17) or dose (p=0.69), regardless of MTHFR C677T genotype |
| Siddique A et al 2025 · study_type: RCT | observational | mixed | low | Open-label, n=44, methylfolate 800µg add-on: 40.33% vs 26.43% symptom improvement (p<0.05) at d28; remission rate NOT significant; day-14 time-lag NOT significant |
| papakostas-2012 2012 | RCT | supports | moderate | L-methylfolate 15 mg augmented SSRI response in resistant MDD (2 RCTs). |
| Liwinski T et al 2023 · study_type: observational | observational | supports | low | Narrative review: 'findings have been mixed' but concludes evidence 'generally supports' folic acid/L-methylfolate as adjunct/stand-alone in depression |
| Macaluso M 2022 · Front Psychiatry | observational | mixed | low | DESIGN NOTE: a single-author narrative summary ('this summary provides context'), NOT a trial - graded observational/low per CONVENTIONS narrative-review rule. Argues LMF benefit concentrates in antidepressant non-responders with elevated BMI/inflammation; that stratified rationale remains post-hoc and hypothesis-level. L-methylfolate is a commercial product, so weigh authorship interest. |
| Cheng 2025 2025 · Psychol Med | meta-analysis | mixed | moderate | network MA: methylfolate efficacy ranking modest/uncertain |
| Roberts 2018 2018 · J Psychopharmacol | meta-analysis | contradicts | high | SR/MA: folate-derivative evidence in depression weak/contradictory |
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.
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Educational only, not medical advice. Grades and scores reflect published evidence weighted by study design and quality; see the methodology.