Cholecystokinin (CCK) is an abundant neurotransmitter in brain. Its functional significance in humans is incompletely understood, but it may modulate activity in the hypothalamic-pituitary-adrenal (HPA) axis. To explore this hypothesis, we examined the effects of varying doses (0 to 0.8 microgram/kg) of the CCK-B agonist pentagastrin on adrenocorticotropin (ACTH) and cortisol release in healthy human subjects. We also examined anxiety, heart rate (HR), and blood pressure (BP) responses. Pentagastrin induced large (up to 520% increase over baseline), significant and very rapid, dose-dependent elevations in ACTH and cortisol levels. Significant elevations in HR and BP were seen at all doses, without clear dose-response relationships. Anxious distress and symptom responses were also somewhat dose dependent; but hormonal responses were more robustly linked to pentagastrin dose than to these subjective measures. The HPA axis response to the CCK-B agonist pentagastrin may be a direct pharmacological effect. Further work is needed to determine the mechanisms and the physiological significance of CCK-mediated modulation of the human neuroendocrine stress axis.