Loperamide is a peripheral opiate agonist able to inhibit ACTH secretion. In this work, the interactions between loperamide and two ACTH secretagogues, lysine vasopressin (LVP) and corticotropin-releasing hormone (CRH), were investigated in patients with Addison’s disease. After loperamide (16 mg orally) or placebo administration, 5 patients received LVP (0.06 IU/kg i.v. over 1 h) and 6 patients received oCRH (1 µg/kg i.v. as bolus). In all patients loperamide induced a significant fall in plasma ACTH levels. LVP increased ACTH levels after both loperamide (from 48 ± 17.3 to a peak of 95 + 21 pmol/l) and placebo (from 231 ± 59.5 to 365 ± 86.6 pmol/l): the interaction between treatments and time was not significant. CRH caused a rise in plasma ACTH after both loperamide (from 30 ± 16.6 to a peak of 108 ± 31 pmol/l) and placebo (from 98.5 ± 47 to 211 ± 61.7 pmol/l): the interaction between treatments and time was significant, and the first phase of CRH-induced ACTH secretion was significantly lower after loperamide. These data demonstrate that loperamide differently modifies the stimulatory action of LVP and CRH on ACTH secretion: namely, LVP and loperamide act in an additive manner, while CRH and loperamide interact in a non additive way. Although these findings might be explained by the involvement of different intracellular ACTH-secreting mechanisms, an influence of loperamide on some suprapituitary factors modulating the ACTH response is