Synopsis

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

L-5-methyltetrahydrofolate (5-MTHF), the biologically active form of folate, has a moderate amount of scientific evidence supporting its adjunctive use in schizophrenia treatment. Schizophrenia is a complex neuropsychiatric disorder, and several studies have shown that individuals with schizophrenia often have lower folate levels and impaired one-carbon metabolism. These deficiencies are associated with more severe negative symptoms and poorer treatment response. Genetic polymorphisms, especially in the MTHFR gene (notably the C677T variant), further impair folate metabolism, which can exacerbate symptoms or reduce the efficacy of antipsychotic medications. Clinical trials have investigated the use of folate supplementation—specifically 5-MTHF, which bypasses common genetic mutations that impair folic acid metabolism—as an adjunct to standard antipsychotic therapy. Some randomized controlled trials (e.g., Roffman et al., JAMA Psychiatry 2013) have found that adjunctive 5-MTHF or folic acid can improve negative symptoms (such as social withdrawal or blunted affect) in patients with schizophrenia, particularly in those with low baseline folate or relevant genetic variants. However, results are mixed, and benefits appear most pronounced when supplementation is personalized based on genetic and nutritional status. While 5-MTHF is not a standalone treatment for schizophrenia, there is scientific validation for its adjunctive use, especially in genetically susceptible or folate-deficient individuals. The overall evidence is moderate (rated 3/5), and further studies are ongoing to clarify which subgroups benefit most.

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