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OBJECTIVE: The efficacy of the branched-chain amino acids in the treatment of tardive dyskinesia in men with psychiatric disorders was tested. METHOD: Public-sector psychiatric patients with long histories of antipsychotic treatment and presumably long-standing tardive dyskinesia were randomly assigned to receive branched-chain amino acids or placebo. Treatment frequency was three times a day, 7 days a week for 3 weeks. The efficacy measure was a frequency count of videotaped tardive dyskinesia movements. RESULTS: A robust and highly significant difference was observed between patients who received high-dose branched-chain amino acids (222 mg/kg of body weight t.i.d.) (N=18) and those who received placebo (N=18) in the percent change in tardive dyskinesia symptoms from baseline to the end of the 3-week trial. Significant and marked differences were seen between the two groups at the ≥30% and ≥60% levels of decrease in tardive dyskinesia symptoms. No clinically significant differences were seen between the pre- and posttrial results of physical examinations and laboratory screening tests. Minimal gastrointestinal symptoms occurred during the trial. The reduction in tardive dyskinesia symptoms in the amino acids group was not related to changes in antipsychotic and glucose plasma levels. A mechanism of response related to decreased amine neurotransmitter synthesis was suggested by the significant positive correlations observed between decreases in tardive dyskinesia symptoms and decreases in aromatic amino acid plasma concentrations over the course of the trial. CONCLUSIONS: Branched-chain amino acids constitute a novel, safe treatment for tardive dyskinesia, with a strong potential for providing significant improvement in the diseased physiognomy of the afflicted person.