The hypothalamo-pituitary-adrenal (HPA) axis is known to relate with energy homeostasis. Appetite and food intake are assumed to be regulated by the HPA axis. Among lots of medicines that act gastrointestinal system, we focused proton pump inhibitors, which are widely used to treat peptic ulcer, gastro esophageal reflux disease and eradication of Helicobacter pylori. In this study, we investigated that the effect of three proton pump inhibitors (omeprazole, lansoprazole and rabeprazole) on plasma adrenocorticotropic hormone (ACTH) and cortisol levels in healthy human subjects. Five healthy male volunteers were treated to omeprazole, lansoprazole, rabeprazole or placebo. Venous blood samples were taken repetitively from a forearm vein before and after administration. Plasma ACTH-like immunoreactive substance (IS) levels were measured using a sensitive enzyme immunoassay, and plasma cortisol levels were measured using a fluorescence polarization immunoassay. Single administration of lansoprazole caused significant (P<0.05) increase of ACTH-IS at 60 and 120-180 min, and cortisol at 180-240 min after administration, compared with placebo group. Rabeprazole also caused significant increase of ACTH-IS at 120 min and cortisol at 240-360 min, compared with placebo group. Omeprazole had no effect on plasma ACTH-IS and cortisol levels. Lansoprazole and rabeprazole increased plasma ACTH-IS and cortisol levels. Therefore, we hypothesized that the medicines might activate the HPA axis, and have effect to promote feeding. We considered that these results might be relevant to the development of new therapeutics in the treatment of psychiatric disorders involving dysregulation of appetite.