Synopsis

Source of validity: Scientific
Rating (out of 5): 3

L-5-methyltetrahydrofolate glucosamine salt (5-MTHF) is the bioactive form of folate, a B-vitamin involved in one-carbon metabolism and methylation processes in the brain. Its use in supporting or treating depression is primarily justified by scientific evidence, though the strength of the evidence is moderate (rated 3 out of 5). Several studies have noted that individuals with major depressive disorder often have lower levels of folate in their blood. Low folate status is associated with poorer outcomes in depression and reduced response to standard antidepressant treatments. 5-MTHF, as the active form, bypasses common genetic polymorphisms (such as MTHFR C677T) that may impair folic acid conversion, ensuring effective folate metabolism and neurotransmitter synthesis, particularly of serotonin, dopamine, and norepinephrine.

Randomized controlled trials have shown that adjunctive use of L-methylfolate (typically 15 mg/day) with antidepressants can improve depressive symptoms, especially in individuals who do not fully respond to antidepressants alone. For example, two double-blind, placebo-controlled trials (Papakostas et al., 2012, 2014) demonstrated a statistically significant benefit for L-methylfolate in treatment-resistant depression. L-methylfolate is sometimes prescribed as a medical food (e.g., Deplin®) in psychiatric practice. However, large-scale studies are limited, and some meta-analyses call for more robust evidence before recommending universal use. In summary, 5-MTHF’s application in depression is grounded in scientific rationale and moderate-quality clinical evidence, but it is not yet considered a first-line standalone therapy.

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