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L-methylfolate May Offer Benefit in Schizophrenia

March 27, 2017

Supplementation with L-methylfolate produced positive physiological changes and some symptom improvement in patients with schizophrenia, researchers found in a study published online in Molecular Psychiatry.

L-methylfolate is the fully reduced and bioactive form of folate.

“Folic acid supplementation confers modest benefit in schizophrenia,” researchers explained, “but its effectiveness is influenced by common genetic variants in the folate pathway that hinder conversion to its active form.”

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To gauge the effects of L-methylfolate, the double-blind trial randomized 55 outpatients with schizophrenia to 15 milligrams of the supplement or to placebo for 12 weeks. Patients continued to take stable doses of antipsychotic medications throughout the study. The primary outcome was change in plasma methylfolate.

Patients who received L-methylfolate had increased plasma methylfolate levels at the end of the study, compared with patients who received placebo, researchers found.

In addition, the L-methylfolate group had improved Positive and Negative Syndrome Scale (PANSS) Total scores and PANSS Negative and General Psychopathology subscales, compared with the placebo group. PANSS Total and General Psychopathology changes were affected by genotype, although “significant PANSS Negative changes occurred regardless of genotype,” researchers reported.

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No treatment differences were evident on the Scale for Assessment of Negative Symptoms, Calgary Depression Scale for Schizophrenia, or the Measurement and Treatment Research to Improve Cognition in Schizophrenia composite.

In other findings, magnetic resonance imaging revealed convergent changes in ventromedial prefrontal physiology in patients who received L-methylfolate, researchers reported. Changes included increased task-induced deactivation, altered limbic connectivity, and increased cortical thickness.

Researchers said the results warrant larger clinical trials to further investigate the potential benefits of L-methylfolate supplementation in the schizophrenia patient population.

Jolynn Tumolo


Roffman JL, Petruzzi LJ, Tanner AS, et al. Biochemical, physiological and clinical effects of l-methylfolate in schizophrenia: a randomized controlled trial. Molecular Psychiatry. 2017 March 14;[Epub ahead of print].

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