To determine the effect of beta-endorphin on the pituitary-adrenal axis, human synthetic beta-endorphin was infused iv in 10 normal human subjects. Either beta-endorphin (0.3, 1.0, and 3.0 micrograms/kg . min, each dose for 30 min) or a control (sham) infusion of 5% dextrose water was administered in a blind fashion in the same subjects on 2 successive days. Plasma ACTH and cortisol and serum human GH and PRL levels were measured 30 min before and then every 30 min for 210 min during and after both the beta-endorphin and control infusions. In all subjects, cortisol levels decreased below the basal level in response to the infusion of beta-endorphin. The threshold dose was 1.0 micrograms/kg . min, with the mean control cortisol level (12 +/- 2 micrograms/dl) declining significantly to 7 +/- 1 micrograms/dl (1.0 micrograms/kg . min) and 6 +/- 1 micrograms/dl (3.0 micrograms/kg . min; P less than 0.01). ACTH levels also were significantly lower than the control value (48 +/- 6 pg/ml) at the 1.0 microgram/kg . min dose (32 +/- 4 pg/ml; P less than 0.05). The decline in ACTH and cortisol levels was also significantly different from levels obtained during the control infusions (P = 0.001 and P = 0.01, respectively). The results are consistent with short feedback loop inhibition of pituitary ACTH release or suppression of hypothalamic corticotropin-releasing factor release by beta-endorphin.