The effects of castration on liver alcohol dehydrogenase (ADH) activity and the in vivo metabolism of ethanol were examined in the male Sprague-Dawley-derived rat. It was found that castration led to immediate (24 hr) increases in the ADH-dependent metabolism of ethanol which persisted for at least 6 weeks postcastration. Testosterone completely reversed the effects of castration. Moreover, when increases in liver ADH activity and the metabolism of ethanol were allowed to develop to maximal levels (2 weeks), a single s.c. injection of testosterone promptly reversed the effects of castration, such that by 24 hr castrated animals were indistinguishable from controls. Thus, it appears that in the male Sprague-Dawley-derived rat liver ADH activity and the in vivo metabolism of ethanol are under the control of testosterone. Because narcotics have also been shown to depress serum testosterone levels, and there is good evidence of significant pharmacological and biochemical interactions between the narcotics and ethanol, we examined whether chronic administration of morphine led to testosterone-reversible increases in the ADH-dependent metabolic disposition of ethanol. We found that chronic morphine administration, at doses sufficient to markedly depress serum testosterone levels (> 85%), produced large increases in liver ADH activity and the clearance of ethanol. Concurrent administration of testosterone completely abolished this effect. These data may, therefore, provide the first evidence of a biochemical mechanism involved in the interactions between morphine and ethanol. Furthermore, our results suggest that drug-induced reductions in serum testosterone may serve as an important mechanism involved in the cross-tolerance observed between ethanol and many abused, sedative-hypnotic drugs which share the common ability to decrease serum testosterone.