We assessed the efficacy of pexacerfont, a CRF1 antagonist, for the treatment of withdrawal symptoms. In this randomized, double-blind, placebo-controlled clinical trial, male patients with amphetamine or opioid dependence, on the basis of the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR), in the age range 18–55 years, received either pexacerfont or placebo (300, 200, and 100 mg/day in the first, second, and third week, respectively). No antidepressants, behavioral interventions, or substitution therapy were administered. Candidates were excluded if they had DSM-IV-TR axis I or II disorders (other than depressive/anxiety disorders). The primary outcomes were difference in the distribution of positive urine test results for heroin and methamphetamine at the end of the trial, and the mean difference in the change in the Visual Analog Scale (VAS) score for craving from the baseline to the endpoint between the two groups. No significant difference was detected for urine test results, but a significant difference was observed for craving scores. Also, significant time×treatment interactions were found for all the scales including VAS craving, VAS temptation severity, frequency of temptation, Clinical Opiate Withdrawal Scale, Amphetamine Withdrawal Questionnaire, Beck Anxiety Inventory, and Beck Depression Inventory II. Our findings favor pexacerfont as a potential treatment for withdrawal from drug dependence; however, further comprehensive studies are warranted.