To investigate the effect of cyproheptadine on ACTH and cortisol secretion, we obtained blood samples at 10-min intervals for 24 h in six healthy volunteers under basal conditions and under treatment with 16 mg day-1 cyproheptadine. Cyproheptadine caused significant decreases in mean plasma ACTH and cortisol levels in 30% and 19% of samples, respectively, mainly in the afternoon and evening. Analysis of episodic hormone secretion by three different methods demonstrated that the drug did not modulate the frequency but lowered the amplitudes of ACTH and cortisol secretory episodes. ACTH and cortisol responses following ovine CRH injection at 20.00 h were unchanged. We conclude that in the afternoon and evening central serotoninergic mechanisms influence the activity of the hypothalamic-pituitary-adrenal axis at the hypothalamic level by modulating the amplitude of the secretory hormonal bursts, but do not influence the increase in ACTH and cortisol secretion in the morning.