In a double-blind, crossover design, 10 mg of methadone or an inert placebo were administered intramuscularly to nine acutely manic patients in identical experimental sessions separated by 1 day. Standardized behavioral observations, self-ratings of mood and affect, and blood samples for prolactin and cortisol were obtained at baseline and 30, 60, and 120 minutes after the administration of methadone or placebo. Methadone decreased symptoms of euphoria, elation, and grandiosity in these manics. There was a significant rise in prolactin, peaking at 60 minutes, and a significant decrease in cortisol, maximal at 120 minutes following methadone administration. There appeared to be a correlational consistency between the subduing effects of methadone on behavior and its effect upon prolactin and cortisol secretion. These findings, together with data from previous studies of our own and others, suggest that a potentially important interrelationship may exist between the central endogenous opioid peptide systems, various neuroendocrine regulatory factors, and the pathophysiology of affective disorder.