The role of the endogenous opioid system in humans was studied using three clinical research strategies. High doses of the opiate antagonist naloxone (up to 4 mg/kg) were administered to normal volunteers. Dose-dependent increases in self-ratings of tension-anxiety and anger-hostility were observed, supporting the hypothesized involvement of the endogenous opioid system in the modulation of human mood and feelings of well-being. Accompanying dose-dependent increases in systolic blood pressure and respiratory rate were found, suggesting that the lower doses of naloxone utilized in previous clinical studies were not sufficient to block the endogenous opioid system. CSF opioid activity in psychiatric patients and normals was measured using a sensitive radioreceptor assay developed by the authors. Results suggest diminished endogenous opioid system activity in some schizophrenics, and a relationship between opioid activity and state change in manic-depressive illness and anorexia nervosa. A complex but consistently observed relationship between ratings of anxiety and CSF opioid activity in normals and patients is consistent with basic science and clinical data suggesting interactions between CNS noradrenergic and opioid systems. General surgery was used as a strategy for studying the relationship of the endogenous opioid system to stress in humans; robust increases in levels of plasma beta-endorphin immunoreactivity accompanying surgical stress and an inverse relationship between patient levels of plasma beta-endorphin immunoreactivity and postoperative analgesic requirement were observed. These data support the involvement of the endogenous opioid system in the human stress response and suggest that hormonal stress response and endogenous opioid system activity may relate to human endogenous analgesic mechanisms.