This Center for Medications Development (MDU) has a theme of developing new GABA enhancingmedications and using genetic approaches to optimally match successful cocaine pharmacotherapies suchas disulfiram and the GABA reuptake blocker tiagabine to subgroups of cocaine dependent patients. We areconducting two outpatient randomized clinical trials and a series of five laboratory screening studies for newGABA enhancers. Project 1 is a randomized, placebo-controlled, 12-week clinical trial examining 150cocaine-dependent methadone-stabilized patients in a trial of disulfiram and the GABA reuptake blockertiagabine. These patients will be stratified based on a functional dopamine beta hydroxylase (DBH)polymorphism with the prediction of a treatment response to disulfiram only in those with the genetichaplotype that leads to low DBH levels and relatively higher dopamine (DA) levels. Project 2 includes 140depressed, recently abstinent, cocaine-dependent patients in a randomized, placebo-controlled, 12-weekrelapse trial with four treatment groups: placebo, sertraline, sertraline + tiagabine and sertraline +gabapentin. This trial includes an initial 2 weeks of inpatient abstinence. The patients in both Projects 1 and2 will undergo genetic screening of GABA related polymorphisms as potential predictors of treatmentresponse to GABA enhancers in future studies. Project 3 will use cocaine administration to humans in alaboratory in order to screen five GABA enhancers for their potential utility as pharmacotherapies. Thesethree projects involve examination of nine different potential cocaine pharmacotherapies in clinical trials andthe human laboratory. These clinical trials offer an interesting contrast in DA enhancement by disulfiram .orthe DA reuptake blocker sertraline versus DA reduction by the GABA enhancers - tiagabine and gabapentin.Overall, over 300 patients will be studied in this Center and eight different agents in either outpatient Phase IItrials or human laboratory studies.
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