Tiagabine and Disulfiram for Cocaine Dependence

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Comorbid cocaine dependence among methadone maintained patients interferes with treatment outcomes. Disulfiram (DbetaH inhibitor) and Tiagabine (GAT-1 blocker) have shown promising results in the treatment of cocaine dependence. While inhibition of DbetaH activity is hypothesized to increase dopamine neurotransmission primarily in the neocortex and to intensify the dysphoric experience of cocaine use, the selective inhibition of GABA reuptake is hypothesized to attenuate dopamine neurotransmission primarily in the nucleus accumbens and to reduce the reinforcing effects of cocaine use. The objective of this proposal is to determine to what extend does prospective screening for a functional polymorphism of dopamine beta hydroxylase (DBH-1021C->T) predict the treatment efficacy of disulfiram and tiagabine among newly admitted methadone treated patients. DBH -1021C->T regulates plasma DbetaH levels by influencing DBH gene expression. Based on our pilot studies, we hypothesize that carriers of the low-DbetaH associated T allele will have significant reductions in cocaine use, because they are more susceptible to inhibition of DbetaH by disulfiram. In contrast, carriers of the high-DpH associated C allele will have little reduction in cocaine use with disulfiram, but may have significant reductions with tiagabine, because of tiagabine's contrasting action in reducing dopamine release. This 14-week double-blind, placebo controlled randomized clinical trial will provide treatment for 150 cocaine-dependent opioid dependent patients. Participants, aged 18-65 years, will be randomized to receive disulfiram 250mg/day, tiagabine 24mg/day, or placebo while concurrently receiving treatment with methadone. All participants receive weekly 1-hour psychotherapy (Cognitive Behavioral Treatment). The primary outcomes will be reduction in opioid and cocaine use, as assessed by self-report and confirmed by thrice-weekly urinalyses. The proposed study is expected to provide a better understanding of the role of the DbetaH inhibitor disulfiram and the selective GABA reuptake inhibitor tiagabine on cocaine using behavior among distinct DBH -1021C->T genotypes.