This competitive renewal examines further the influence of dopamine beta-hydroxylase enzyme activity on the clinical efficacy of the novel pharmacotherapy, disulfiram, for treating cocaine dependence in 160 cocaine-dependent patients, some of whom are opioid dependent and maintained on an FDA-approved opioid agonist. Cocaine dependent as well as co-morbid cocaine dependence in opioid-dependent individuals is associated with more public health issues and poorer treatment prognosis when admitted to methadone maintenance. However, to date, no effective pharmacotherapies have been developed to treat cocaine dependence. One novel pharmacotherapy, disulfiram, has shown some promise as a treatment for this disorder in several clinical trials at a dose of 250 mg/day or more (e.g., Carroll et al., 1998, 2004). This 14-week, randomized, double blind clinical trial will provide treatment for 160 cocaine-dependent opioid addicts, aged 18-65 years. Participants will be stabilized on methadone maintenance during the first 2 weeks and baseline cocaine use will be assessed; participants will be stratified by DBH genotype and randomly assigned to receive one of the following: placebo disulfiram (0 mg/day), disulfiram at 250 mg/day, disulfiram at 375 mg/day, or disulfiram at 500 mg/day. During induction onto methadone or buprenorphine for opioid dependent individuals, participants are administered increasing doses of opioid agonist on a daily basis until maintenance doses of opioid agonist are attained. At the beginning of week 3, participants receive opioid agonist, if relevant, plus disulfiram or placebo disulfiram according to their randomized assignments, and are maintained on study medication(s) through week 14. At the end of the study, participants will undergo detoxification from the opioid agonist, if relevant, and active/placebo medication over a 4- to 6-week period. All participants receive weekly 1-hour psychotherapy (Cognitive Behavioral Treatment) with experienced clinicians specifically trained to deliver the therapy and who will receive ongoing supervision.

Participants undergo a delay discounting session during week 1. The primary outcomes will be retention, reduction in opioid and cocaine use, as assessed by self-report and confirmed by thrice-weekly urinalyses, and disulfiram side-effects profile. Secondary outcomes will include reductions in other illicit drug and alcohol use, and improvements in psychosocial functioning. The prognostic relevance of genotype at the DBH locus, DβH activity, etc., on response to disulfiram will be examined.