L-Methylfolate (5-MTHF)
Commonly used for
MoodFocus
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What is it? / Overview
MTHFR converts folic acid to 5-MTHF, the form actually used to make the mood-relevant neurotransmitters serotonin, dopamine, and norepinephrine; people with reduced-function MTHFR variants convert folic acid less efficiently, so supplying preformed 5-MTHF bypasses that bottleneck. It also crosses the blood-brain barrier more readily than folic acid. Clinical trials support 5-MTHF as a helpful adjunct in depression that hasn't fully responded to standard treatment, particularly in people with elevated inflammatory/metabolic markers.
How is it used? / Administration
Form: L-5-methyltetrahydrofolate (levomefolate, often as the calcium or glucosamine salt) -- the already-active, circulating form of folate that bypasses the MTHFR conversion step folic acid requires
Typical dose studied: 7.5-15 mg/day as an adjunct for mood support (15 mg was the effective dose in supporting trials) -- a much higher dose than the existing Folate entry's general-repletion range
Timing: Daily, with or without food
Distinct from the existing Folate entry (see that separate entry) -- that entry already lists L-methylfolate as its preferred form but at general-repletion doses (400-800 mcg/day) for pregnancy/anemia use; this entry is the same active molecule at a roughly 10-20x higher dose specifically for the mood-support adjunct use-case, which has its own separate trial evidence. Folinic acid (leucovorin) is a related but pharmacologically distinct reduced-folate form used clinically to rescue methotrexate toxicity -- a prescription/oncology context, not a self-directed wellness use, so it isn't carried as its own database entry here. Only folic acid has large-RCT proof specifically for neural-tube-defect prevention; that's the existing Folate/Prenatal Multivitamin entries' domain, not this one's.
How well does it work? / Evidence
~ Moderate evidence
Who should avoid it?
Avoid with: Vitamin B12 deficiency; Cancer — active or within past 12 months
Interacts with: Methotrexate and other antifolate/antiepileptic drugs -- folate can reduce their efficacy and vice versa; do not combine without direct medical guidance
Already taking it? Reasonable to continue if genuinely supporting mood, but always pair with adequate B12 -- high-dose folate can mask the blood-count signs of a B12 deficiency while nerve damage from that deficiency continues to progress silently.
Research & references
Fava M, Mischoulon D (2010). Folate in Depression: Efficacy, Safety, Differences in Formulations, and Clinical Issues. Journal of Clinical Psychiatry. Lam NSK et al. (2022). The Potential Use of Folate and Its Derivatives in Treating Psychiatric Disorders: A Systematic Review. Biomedicine & Pharmacotherapy. Skavinska O et al. (2026). Comparative Analysis of Treatment With Folate Forms in Clinical Practice. Nutrition Reviews.
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