Synopsis

Source of validity: Scientific
Rating (out of 5): 2

Vitamin B9, particularly in its active form methylfolate (L-methylfolate), has some scientific rationale for use as an adjunctive treatment in schizophrenia, but the evidence is limited and not robust. Research has shown that individuals with schizophrenia often have lower folate levels, and some genetic variants (such as MTHFR polymorphisms) may impair folate metabolism, potentially influencing neurodevelopment and neurotransmitter synthesis. Several small studies and randomized controlled trials have investigated folate supplementation, sometimes alongside B12, in people with schizophrenia. Some of these studies reported modest improvements in negative symptoms—such as reduced emotional expression and social withdrawal—especially in patients with low baseline folate or certain genetic variants affecting folate metabolism. However, the overall effect sizes are small, and results are inconsistent across studies. A notable trial published in JAMA (2013) found that folate and B12 supplementation produced some benefit in negative symptoms, but only in a subgroup with relevant genetic backgrounds. Major guidelines do not recommend methylfolate as a primary treatment, but it may be considered as an adjunct in select patients, particularly those with folate deficiency or relevant genetic polymorphisms. In summary, while there is some scientific basis, the supporting evidence is limited, and further research is needed to establish efficacy and identify which patients may benefit most.

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