Six normal controls participated in two or three individual, intravenous challenges (each separated by 1 week) of saline or one of two doses of arecoline at 8 AM following ingestion of 1 mg dexamethasone at 12 midnight the previous evening. Individuals differed in their subjective and neuroendocrine responses to arecoline. At 2.1 micrograms/kg (n = 4) or 2.8 micrograms/kg (n = 1), four of five subjects evidenced dexamethone suppression test (DST) nonsuppression, which followed the rise in prolactin. Cholinergic side effects and nausea were minimal. At a dose of 4.2 micrograms/kg, four of five subjects evidenced cortisol escape from dexamethasone suppression, which was associated with a substantial rise in prolactin, some subjective cholinergic symptoms, and little to modest nausea. These data are consistent with the notion that cholinergic mechanisms are involved in the escape from dexamethasone suppression. Further, arecoline may be preferable to physostigmine as a cholinergic agonist, since it appears less likely to cause marked cholinergic side effects and significant nausea.