SummaryOBJECTIVEThe central serotoninergic system is known to modulate the activity of the hypothalamic‐pituitary‐adrenal axis, but the effect of fenfluramine, a serotonin reuptake inhibitor, on ACTH and cortisol secretion is not well understood. We have therefore evaluated its effects on the hypothalamic‐pituitary‐adrenal axis in healthy controls.DESIGNEpisodic secretion of ACTH and cortisol was Investigated in 6 healthy volunteers under basal conditions and again during treatment with 20 and 60 mg fenfluramine given orally every 8 hours. On all occasions blood samples were obtained at 10‐minute Intervals for 24 hours and the mode of hormone secretion was analysed by three different methods (PULSAR, CLUSTER, DESADE). In addition ACTH and cortisol responses to CRH were tested at the end of the sampling period.RESULTSAt the lower dose fenfluramine had no effect on ACTH and cortisol secretion. At the higher dose a significant increase of mean plasma ACTH (+ 85%) and cortisol (+129%) levels as well as of urinary free cortisol secretion (+44%) was observed. Fenfluramine did not modulate the frequency, but increased the amplitudes of ACTH and cortisol secretory episodes. ACTH and cortisol responses to CRH injection remained unchanged. Maximum plasma levels ofd‐fenfluramine andd‐nortenfluramine were documented 2–4 hours after the ingestlon of the drug.CONCLUSIONFenfluramine stimulates the activity of the hypothalamic‐pituitary‐adrenal axis at a suprapituitary level by modulating the amplitude of ACTH and cortis