Elevated levels of circulating corticosteroids are frequently associated with behavioral alterations in man, although the mechanisms by which corticosteroids may affect behavior are poorly understood. To evaluate possible effects of exogenous corticosteroids on brain electrophysiological functioning and the relationship of such effects to behavioral and biochemical changes, we administered prednisone (80 mg p.o. daily for 5 days) in a double-blind manner to 11 medically healthy volunteers. Quantitative electroencephalogram analysis was performed following 4 days of prednisone administration and during the preceding and ensuing placebo administration periods. Central theta wave brain electrical activity significantly increased following prednisone administration and returned to baseline following prednisone withdrawal. This effect was directly correlated with prednisone-induced increases in subjective sadness ratings and with decreases in self-rated energy and well-being. Prednisone-induced reductions in peak alpha wave activity were also directly correlated with increases in subjective sadness and Symptom Checklist-90 ratings and with decreases in self-rated 'hypomanic' symptoms. Further, prednisone-induced increases in theta activity were significantly correlated with prednisone-induced decreases in CSF levels of somatostatin-like immunoreactivity, and prednisone-induced decreases in peak alpha activity were significantly correlated with decreases in CSF levels of norepinephrine and with relative increases (or lesser decreases) in CSF levels of beta-endorphin and beta-lipotropic hormone. This preliminary report of the concomitant development of prednisone-induced changes in brain electrical activity, neurochemistry and behavior highlights areas for future exploration in the study of corticosteroid effects on behavior in man.