Supplements
L-methylfolate treats mood disorder
Part of: 🧪 Folate & L-methylfolate
🧭 Read this score with how it was built in mindWe re-read the papers behind these claims and corrected how each one is counted
Rose for a reason worth knowing: rows recorded as contradicting it were re-read and found to be off-subject or duplicates, and one 2018 review's 15 mg subgroup turned out to be the same two trials already on the page, so it was counted twice. Fewer votes against, not more votes for. The supporting base is two trials from a small number of groups.
📅 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, Poweleit EA, Cox MO, Farrow JE, Strawn JR, Patino Duran LR, Prows CA, DelBello MP, Ramsey LB 2022 · J Affect Disord | observational | contradicts | low | Retrospective EHR, 412 youths with unipolar depression: among MTHFR C677T variant carriers, CGI-I change with vs without LMF 'did not significantly differ (p = 0.39)'; response not associated with LMF prescription (p = 0.17) or dose (p = 0.69). Authors: retrospective, 'heterogeneous patient population and limited data availability (e.g., adherence)', severely ill patients - confounding by indication, low quality. Indirect: pediatric, unscoped dose. |
| Siddique A, Khokhar MM, Waheed A, Naeem U, Aziz SA 2025 · BMC Pharmacol Toxicol | observational | tested-null | low | Open-label, non-randomized ('Randomization and blinding were not done'), n=44, methylfolate 800 µg/d added to mixed antidepressants for 28 d in unselected depressive disorder. PHQ-9 improvement 40.33% vs 26.43%, but the between-group test (Table 4) is mean difference 2.591, 95% CI -0.026 to 5.208, p = 0.052 - the abstract's 'p < 0.05' misreports it. Day 14 p = 0.26; remission 1.14% vs 2.27%. Underpowered trend toward the claim, graded tested-null per CONVENTIONS §5 (2026-09-26). Indirect: low dose, not SSRI-resistant. |
| Papakostas GI, Shelton RC, Zajecka JM, Etemad B, Rickels K, Clain A, Baer L, Dalton ED, Sacco GR, Schoenfeld D, Pencina M, Meisner A, Bottiglieri T, Nelson E, Mischoulon D, Alpert JE, Barbee JG, Zisook S, Fava M 2012 · Am J Psychiatry | RCT | supports | moderate | Two SPCD RCTs in SSRI-resistant MDD. Trial 2 (n=75, LMF 15 mg/d): 'significantly greater efficacy compared with continued SSRI therapy plus placebo on both primary outcome measures', NNT ~6. Trial 1 (n=148, randomized comparison at 7.5 mg): 'no significant difference'. Only one trial tested the scoped 15 mg dose; effect sizes not in abstract. |
| Liwinski T, Lang UE 2023 · Nutrients | 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 | Perspective, single author, funded by Alfasigma (LMF maker): 'This summary provides context for the role of L-methylfolate (LMF) in treating antidepressant non-responders.' Its efficacy figures (response 32.3 vs 14.6%, P = 0.04) re-describe the Papakostas 2012 trials already counted; the BMI/inflammation subgroup story is post-hoc, and the author says RCTs 'are necessary to confirm this hypothesis'. A review, not evidence. |
| Cheng YC, Huang WL, Chen WY, Huang YC, Kuo PH, Tu YK 2025 · Psychol Med | meta-analysis | mixed | moderate | NMA of 192 RCTs (17,437 patients, 44 nutraceuticals) in adults with depressive disorder. Only folate result in the main text: 'folate + ADT (0.64, 0.17–1.10)' SMD vs ADT alone; authors treat one-carbon chemicals 'such as folic acid' as different interventions and rate many comparisons low/very low (CINeMA). The word methylfolate does not appear; no L-methylfolate estimate - off-scope unless the supplement shows a separate node. |
| Roberts E, Carter B, Young AH 2018 · J Psychopharmacol | meta-analysis | supports | low | SR/MA of placebo-controlled RCTs (search to 1 May 2017; 7 RCTs, 966 participants). The claim-scoped 15 mg/day methylfolate subgroup pools two trials, Godfrey 1990 and Papakostas (II) = Papakostas 2012b: 'When this is restricted to a dose of 15mg/day methylfolate two trials of 99 participants demonstrate an effect size of -0.74 (95%CI: -1.19, -0.29; P=0.002; I2=2%; Figure 1d), which is of LOW quality'. Not purely SSRI: Table 1 lists Godfrey as 15 mg methylfolate 'an adjunct to undefined antidepressant treatment' in folate-deficient patients (red-cell folate below 200 µg/l). All-dose methylfolate (adds the 7.5 mg Papakostas (I) arm) is null: -0.34 (95% CI -1.08, 0.40; P=0.37; I2=81%), VERY LOW; the 7.5 mg arm alone 0.19 (-0.18, 0.57). 'All evidence was graded as low or very low quality for each outcome.' Papakostas 2012b is also counted separately on this claim - supersedes proposed. Full text: KCL author accepted manuscript. |
Disagree, or know a study we missed?
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Educational only, not medical advice. Grades and scores reflect published evidence weighted by study design and quality; see the methodology.