Cocaethylene Formation Following Ethanol and Cocaine Administration by Different Routes Ellen D. Herbst University of California, San Francisco Debra S. Harris University of Cincinnati E. Thomas Everhart University of California, San Francisco John Mendelson Addiction and Pharmacology Research Laboratory, California Pacific Medical Center Research Institute, St Luke’s Hospital, San Francisco, California Peyton Jacob University of California, San Francisco Reese T. Jones University of California, San Francisco Ethanol alters the hepatic biotransformation of cocaine, resulting in transesterification to a novel active metabolite, cocaethylene. Because of first pass metabolism, oral drug administration might be expected to produce relatively larger concentrations of cocaethylene than would intravenous or smoked administration. We, therefore, compared the effects of route of cocaine administration on the formation and elimination of cocaethylene. Six experienced cocaine users were tested in 6 sessions, approximately 1 week apart. Deuterium-labeled cocaine (d 5 ) was administered in all conditions. Oral cocaine-d 5 2.0 mg/kg, intravenous cocaine-d 5 1.0 mg/kg, and smoked cocaine-d 5 (200 mg) were administered after oral ethanol 1.0g/kg or placebo. A small, intravenous dose of deuterated cocaethylene (d 3 ) also was administered with all conditions for determination of cocaethylene formation. Physiologic and subjective effects were recorded and plasma cocaine-d 5 , cocaethylene-d 5 , cocaethylene-d 3 , and benzoylecgonine-d 5 were measured by gas chromatogra- phy-mass spectrometry. About 24% ( 11) of intravenous cocaine was converted to cocaethyl- ene. The oral route (34%  20) was significantly greater than from the smoked route (18%  11) and showed a trend toward significance for greater formation of cocaethylene compared to the intravenous route. Within each route, the cocaine-ethanol combination produced greater increases in heart rate and rate-pressure product than cocaine alone. Global intoxication effects across time after smoking or intravenous administration were significantly greater when cocaine and ethanol were both given. Administration of cocaine by different routes alters the amount of cocaethylene formed through hepatic first-pass effects. Increased cardiovascular and subjective effects might explain the toxicity and popularity of the combined drugs. Keywords: cocaine, alcohol, cocaethylene, first-pass metabolism, routes of administration The prevalence of concurrent use of and dual dependence on cocaine and ethanol among cocaine abusers is very high (Grant & Harford, 1990). In a sample of cocaine-dependent participants, more than half also met criteria for alcohol dependence (Higgins, Budney, Bickel, Foerg, & Badger, 1994). Cocaine use is also common among alcohol depen- dent individuals; in a national sample of 6,059 alcohol dependent respondents of the National Survey on Drug Use and Health, 19% reported past year cocaine use (Hedden et al., 2010). The toxic effects of the cocaine-alcohol combination have been observed in emergency room settings and med- ical inpatient units. A 1996 study found that ethanol- and cocaine-positive patients had the greatest percentage of Ellen D. Herbst, E. Thomas Everhart, Peyton Jacob, and Reese T. Jones, San Francisco Dept. of Veterans Affairs Med- ical Center and Department of Psychiatry, University of Cali- fornia, San Francisco; Debra S. Harris, Cincinnati Dept. of Veterans Affairs Medical Center and Department of Psychiatry, University of Cincinnati; and John Mendelson, Addiction and Pharmacology Research Laboratory, California Pacific Medical Center Research Institute, St Luke’s Hospital, San Francisco, California. This work was supported by United States Public Health Service Grants DA01696, DA12393, and DA00053 awarded by the Na- tional Institute on Drug Abuse, National Institutes of Health, and carried out in part in the General Clinical Research Center at the University of California, San Francisco, with support of the Divi- sion of Research Resources, National Institutes of Health (Grant 5 M01 RR– 00079). The authors have no financial or personal rela- tionships which could be perceived as influencing the described research. Correspondence concerning this article should be addressed to Ellen D. Herbst, San Francisco Dept. of Veterans Affairs Medical Center and Department of Psychiatry, University of California, San Francisco, CA 94121. E-mail: ellen.herbst@va.gov Experimental and Clinical Psychopharmacology © 2011 American Psychological Association 2011, Vol. 19, No. 2, 95–104 1064-1297/11/$12.00 DOI: 10.1037/a0022950 95 This document is copyrighted by the American Psychological Association or one of its allied publishers. This article is intended solely for the personal use of the individual user and is not to be disseminated broadly.