The reversal of acute alcohol intoxication by naloxone is controversial. Naloxone increases cortisol secretion but there are no reports of this effect during acute alcohol intoxication. This study examines the effect of 20 mg naloxone on alcohol-induced intoxication using a balanced placebo design to investigate the role of cortisol, participant expectancy of treatment, and possible pharmacokinetic interactions during intoxication. Our results show differences in the time course of subjective self-evaluation of drunkenness in the presence of naloxone. Also, changes are observed in naloxone pharmacokinetic parameters with the ingestion of alcohol, specifically a decrease in plasma clearance. Whereas the cortisol response induced by naloxone was greater in the subgroup of participants with positive expectancy, in the presence of alcohol the naloxone effect on cortisol response was not observed. These observations may help explain the observed reversal of alcohol-induced coma by naloxone in a subgroup of patients.