The combined abuse of cocaine and alcohol is a common occurrence. Epidemiological studies have shown that at least 62% of cocaine abusers and possibly up to 90% in some populations are concomitant alcohol abusers. Patterns of cocaine and alcohol use vary in individuals. The association between cocaine use and alcohol use and the successful treatment of alcoholism with disulfiram led us to hypothesize that disulfiram might be efficacious in the treatment of cocaine addiction, and cocaine addiction which is accompanied by alcohol abuse. Furthermore, above and beyond it's direct effect on alcohol consumption, disulfiram may potentiate serotonergic neurotransmission by inhibition of serotonin metabolism which may be important to diminishing cocaine- induced euphoria or to modulation of dysphoria associated with cocaine administration. The major aim of this project is to assess the potential efficacy of disulfiram as a treatment for cocaine addiction and cocaine addiction complicated by alcohol abuse and to examine possible mechanisms, especially the contribution of serotonergic neurotransmission to cocaine effects. We propose to explore this by conducting the following inpatient studies: 1. a pharmacologic challenge in which physiological and behavioral effects of cocaine in humans will be determined in a dose response in which several doses of cocaine and disulfiram are studied and 2. a pharmacologic challenge in which the acute effects of cocaine administration following chronic administration of disulfiram (using the best dose of disulfiram as determined in Study 1) are determined. These studies will include assessment of direct effects of disulfiram on cocaine metabolism to determine the potential for toxicity in humans. In Study 3 we will use cocaethylene as a pharmacologic probe in an attempt to determine the relative contribution of dopamine and serotonin to cocaine effects and to develop an understanding of possible mechanisms by which disulfiram may modify drug effects. Cocaethylene has been shown to have much greater selectivity for the dopamine transporter than does cocaine. As such, cocaethylene may be used as a tool to sort out the role of serotonin versus dopamine in mediating the actions of disulfiram on cocaine effects. The study consists of a pharmacologic challenge in which cocaethylene will be administered prior to and following chronic treatment with disulfiram. Cocaine will be used as a comparator. Study 4 consists of a pharmacologic challenge in which the behavioral, physiological, and pharmacokinetic effects of cocaine administration following chronic treatment with disulfiram is ascertained in subjects with chronic schizophrenia and cocaine or cocaine-alcohol abuse. This study is important to determination of efficacy and safety of disulfiram treatment for this high risk population.
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