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Head-to-head evidence comparison — which supplement is right for you?
Methylfolate wins 1 of 3 categories. Both are solid choices — the best pick depends on your specific goals.
Verdict
Likely helps
13 of 15 studies with measurable effects showed benefit.
Top outcomes
Verdict
Mixed evidence
4 of 9 studies with measurable effects showed benefit.
Top outcomes
Shared outcomes (2)
Outcomes where both Methylfolate and St. John's Wort have evidence — compare verdict strength side-by-side.
400-800mcg daily
Morning with or without food, Consistent daily timing
L-Methylfolate (5-MTHF)
300mg 3x daily (900mg total)
With meals, Divided into 2-3 doses
Standardized extract (0.3% hypericin)
2-4 weeks
1-3 weeks
4-8 weeks
Days to weeks
4-6 weeks
4-8 weeks
During use
First 1-2 weeks
Efficacy of B-vitamins and vitamin D therapy in improving depressive and anxiety disorders: a systematic review of randomized controlled trials
Nutritional neuroscience (2023) · Systematic review · n=2256
Systematic review examining Methylfolate efficacy
Systematic Review and Meta-Analysis of L-Methylfolate Augmentation in Depressive Disorders
Pharmacopsychiatry (2022) · Meta analysis · n=6707
In the meta-analysis of categorical Hamilton Rating Scale for Depression-17 response, (three studies, N=483) adjunctive L-methylfolate was associated with a small effect versus antidepressant monotherapy (relative risk: 1.25, 95% confidence interval [CI]=1.08 to 1.46, p=0.004).
Folic acid/methylfolate for the treatment of psychopathology in schizophrenia: a systematic review and meta-analysis
Psychopharmacology (2018) · Meta analysis · n=925
Pooled FA + AP treatments were more effective than placebo + AP for negative symptoms (N = 5, n = 281; SMD = -0.25, 95% CI = -0.49, -0.01, p = 0.04, I2 = 0%).
St John's wort for major depression
Cochrane Database of Systematic Reviews (2008) · Meta analysis · n=5489
As effective as standard antidepressants for mild-moderate depression
Efficacy of Pharmacological Interventions in Milder Depression: A Systematic Review and Meta-Analysis
Neuropsychopharmacology reports (2025) · Meta analysis · n=1049
A meta-analysis found no significant difference in response rates between the two treatments (risk ratio [RR] = 0.96, 95% CI: 0.78-1.18) or dropout rates (RR = 1.08, 95% CI: 0.62-1.88).
Systematic Review and Network Meta-Analysis of the Effects of Plant Extracts on Cognitive Function and Quality of Life in Stroke Patients
Phytotherapy research : PTR (2025) · Meta analysis
John's Wort extract (SUCRA 71.2%) was the most effective in reducing NIHSS scores, Berberine (SUCRA 84.1%) was most effective in reducing mRS scores, and St.
Based on meta-analysis showing small effect size for adjunctive L-methylfolate. RCT showed efficacy at high doses but effectiveness appears modest. Risk increases with higher doses due to overmethylation symptoms.
Based on multiple meta-analyses (n>5000) showing efficacy comparable to SSRIs for mild-moderate depression. Effect plateau around 900-1200mg. Not effective for severe depression. Requires standardized extract (0.3% hypericin).
AI-estimated from published studies. Interpret as directional guidance.
Methylfolate has a higher evidence score (9/10 vs 9/10) and wins in 1 of 3 categories.
For support mood, St. John's Wort has a higher relevance score (92 vs 85).
No known interactions between Methylfolate and St. John's Wort have been documented in our database. However, always consult a healthcare provider before combining supplements.