The effect of acute oral administration of loperamide (4, 8 and 16 mg), a peripheral opiate agonist used in the treatment of diarrhoea, on several metabolic and endocrine variables has been evaluated in healthy volunteers in comparison with placebo. Plasma glucose was significantly raised by all three doses, whereas serum IRI and C-peptide were decreased and serum FFA was significantly increased only after loperamide 8 and 16 mg; serum PRL, GH, LH and FSH did not change. The data suggest that opiates may be involved in the regulation of glycaemia, probably by modifying islet hormone secretion by acting at a peripheral site, since loperamide does not cross the blood-brain barrier. Although the precise mechanism of these actions is unknown, it is suggested that the effects of loperamide are mediated either by stimulation of opiate receptors per se, or by suppression of acetylcholine release from cholinergic nerve endings. The lack of change in pituitary hormone secretion by loperamide is in agreement with previous observations indicating that opiate effects on PRL, GH and gonadotropins occur at the level of the central nervous system.