BACKGROUND This study evaluated the specificity of the ethanollike effects of the serotonergic receptor partial agonist m-chlorophenylpiperazine hydrochloride (MCPP) relative to the alpha 2-adrenergic receptor antagonist yohimbine hydrochloride and the placebo in recently detoxified alcoholics. It also examined the relationship between ethanollike discriminative properties and the induction of craving in these patients. Both MCPP and yohimbine are anxiogenic in humans; thus, this study evaluated the role of anxiogenic and ethanollike effects in the elicitation of craving. METHODS Twenty-two male inpatients who met DSM-III-R criteria for alcohol dependence and who had not consumed alcohol for 12 to 26 days prior to the study completed 3 days of testing that involved the intravenous infusion of MCPP (0.1 mg/kg), (0.1 mg/kg), yohimbine hydrochloride (0.4 mg/kg), or a saline solution over 2 weeks under double-blind conditions. Ethanollike subjective effects were assessed using the Sensation Scale and visual analog scales to measure the degree of similarity to the effects of ethanol, cocaine, and marijuana. Five components of craving for alcohol were assessed using visual analog scales. The effects of the drugs on mood were assessed using visual analog scales. Plasma levels of cortisol, prolactin, and 3-methoxy-4-hydroxyphenylethyleneglycol were also measured during the test days. RESULTS m-Chlorophenylpiperazine and yohimbine produced significant increases compared with placebo in Sensation Scale scores and the visual analog scale score for nervousness. However, the effects of MCPP were rated as more similar to those of ethanol, cocaine, and marijuana than were those of either yohimbine or placebo. Also, MCPP but not yohimbine or placebo significantly increased craving for alcohol. Yohimbine and MCPP increased plasma prolactin and cortisol levels relative to placebo, whereas only yohimbine increased plasma 3-methoxy-4-hydroxyphenylethleneglycol levels. CONCLUSIONS m-Chlorophenylpiperazine produced ethanollike effects and alcohol craving in recently detoxified alcoholics. Yohimbine increased Sensation Scale scores but was not recognized as ethanollike by patients. Although both drugs produced comparable levels of nervousness, yohimbine did not increase craving for alcohol. These data further implicate serotonergic systems in the discriminative properties of ethanol and may indicate a serotonergic contribution to craving. Noradrenergic systems contributed to the discriminative properties of ethanol but not to those features of ethanol response that were salient to craving in this population.