Drug and Alcohol Dependence 48 (1997) 159–165 Enhancing cocaine metabolism with butyrylcholinesterase as a treatment strategy David A. Gorelick * NIH/NIDA Diision of Intramural Research, Treatment Branch, 5500 Nathan Shock Drie, Baltimore, MD 21224, USA Received 10 March 1997; accepted 7 August 1997 Abstract Existing pharmacodynamic approaches to cocaine abuse treatment have not been widely successful. An alternative, pharma- cokinetic, approach is to enhance cocaine metabolism by administration of butyrylcholinesterase (BChE), a major cocaine-metab- olizing enzyme in primates. Initial studies in rodents suggest that BChE pretreatment can substantially reduce the acute physiological and behavioral effects of cocaine, at enzyme doses that themselves have no behavioral or toxic effects. A single enzyme injection may increase plasma BChE activity for several days, suggesting that exogenous administration may be practical. BChE treatment may also produce a favorable pattern of cocaine metabolites. Further research is needed to evaluate the long-term effects of BChE administration. © 1997 Elsevier Science Ireland Ltd. Keywords: Cocaine; Butyrylcholinesterase; Pharmacokinetics; Metabolites 1. Introduction Pharmacologic treatment for cocaine abuse and de- pendence is widely used in the United States, although no medication has consistently demonstrated efficacy in controlled clinical trials (Halikas et al., 1994; Wilkins and Gorelick, 1994; Gorelick, 1995). Whether adminis- tered short-term to treat acute cocaine intoxication, or longer term to treat cocaine withdrawal or dependence, all currently used medications use a pharmacodynamic approach, i.e. they interact with one or more neuronal binding sites to influence neurotransmitter systems, with the goal of blocking or counteracting cocaine’s neu- ropharmacological actions. A pharmacodynamic ap- proach has not yet proven successful, either because the appropriate neuronal binding sites at which to intervene have not yet been identified or because existing pharma- cologic agents have inadequate efficacy or specificity for the appropriate site of action. In addition, since phar- macodynamic agents themselves exert pharmacologic effects, they have the potential for producing side-ef- fects, drug interactions, and abuse liability. An alternative approach to pharmacologic treatment is pharmacokinetic, i.e. to act directly on the cocaine molecule itself to block its actions and/or speed up its clearance from the body. The former approach could be implemented by administration of a molecule, such as a cocaine antibody, which bound tightly to the cocaine molecule so as to prevent cocaine from crossing the blood-brain barrier or binding to its neuronal sites of action (Fox et al., 1996). The latter could be imple- mented by administration of an enzyme or catalytic antibody that enhanced cocaine metabolism in the body. Since the pharmacokinetic agent, in theory, has no direct pharmacodynamic action of its own, there is little or no potential for side-effects, drug interactions, or abuse liability. * Tel.: +1 410 5501478; fax: +1 410 5501528. 0376-8716/97/$17.00 © 1997 Elsevier Science Ireland Ltd. All rights reserved. PII S0376-8716(97)00119-1