Ketoconazole attenuates the cortisol response but not the subjective effects of smoked cocaine in humans

Attenuation of hypothalamo pituitary-adrenal (HPA) function in laboratory r odents has been found to reduce the reinforcing effects of cocaine. To exam ine whether attenuation of HPA function reduces the effects of cocaine in h umans, one female and seven male 'crack' cocaine abusers were pretreated wi th three doses of ketoconazole (0, 600, 1200 mg), an inhibitor of adrenocor ticoid biosynthesis, 1 h before receiving cocaine. Three doses of smoked co caine (0, 12, 50 mg) were administered in counterbalanced order under each ketoconazole condition. Ketoconazole dose-dependently reduced cocaine-induc ed cortisol, but not adrenocorticotropin (ACTH) release, and attenuated the cocaine-induced increase in heart rate and blood pressure. Plasma ACTH lev els were more predictive of blood pressure changes than either cocaine or c ortisol levels. Suppression of cortisol secretion was not associated with a reduction in ratings of the subjective effects of cocaine. These results s upport a role for the HPA axis in the cardiovascular effects of cocaine, bu t do not support a role for the HPA axis in the subjective effects of cocai ne. To the extent that self-administration can be predicted by subjective e ffects, these results further argue that the HPA axis does not play a criti cal role in cocaine self-administration by humans. Behav Pharmacol 1998; 9: 577-586 (C) 1998 Lippincott Williams & Wilkins.