Psychobiology /992, 20 (3), /79-/84 The interaction of alcohol and cocaine: A review

JACKIE DIAL Colorado State University, Fort Collins, Colorado

Alcohol and cocaine are often ingested simultaneously, as recreational drugs. What is their combined effect on humans? Because cocaine is a stimulant and alcohol a depressant, one might expect that concurrent use of cocaine and alcohol would attenuate certain attributes of both; how­ ever, each drug achieves its effects through an assortment of mechanisms. The effects of these combined mechanisms are routinely discounted by the user and often by professionals as well. Recent information on the mechanisms and psychopharmacology of their interaction is reviewed.

Alcohol is a central nervous system depressant that has tion typical of chronic alcoholism. Because cocaine is a long been a popular substance in society. In certain so­ stimulant and alcohol a depressant, one might expect that cial circles the use of cocaine, a central nervous system concurrent use of cocaine and alcohol would attenuate cer­ stimulant, has become more prevalent. How does their tain attributes of both; however, each drug achieves its combined ingestion affect the human body and mind? particular effects through assorted mechanisms and, in ad­ Among exogenous substances, shared mechanisms and dition, ethanol is known to potentiate the effects of many metabolic routes greatly increase the likelihood of addi­ drugs (Church, Dintcheff, & Gessner, 1988). Despite tive or synergistic effects (Jones, 1987). For obvious ethi­ their differences, both cocaine and ethanol are hepato­ cal reasons, research on the physiological effects of these toxins, and results thus far accumulated on their combined drugs has been confined primarily to animal models, and effects are included in this paper. Future research may pharmaceutical literature often is confined primarily to show even more explicitly how their combination impacts descriptions and forensics. Because of differences in drug systems in ways of which neither is capable when acting metabolism among and within species, and even between alone. sexes, generalizing must be limited. Nevertheless, within this constraint and with the human data available, knowl­ ALCOHOL EFFECTS edge has accrued. This paper reviews existing literature pertaining to effects of the interaction of alcohol and Ethanol, or ethyl alcohol, is a social drug of the cocaine. sedative-hypnotic class (Lee & Becker, 1989). Although it affects a multiplicity of systems, alcohol displays its MECHANISMS OF DRUG INTERACTIONS most remarkable activity within the central nervous sys­ tem, particularly cell membranes and brain enzymes. Al­ Drug interactions are considered to occur through one cohol may also affect receptor and transport molecules of three mechanisms: pharmacokinetic, the movement of and sodium-dependent calcium uptake. Hardly a neuro­ drugs within a system; pharmacodynamic, the system's transmitter is not implicated. Its effects on cells and tis­ responses to exogenous substances; or synergic (Hansten, sues, especially in the central nervous system, can vary 1989). The use of more than one drug that has an adverse as a function of dose and site, low doses initially impair­ effect on a structure can damage that structure, even if ing inhibitory pathways and progressively affecting higher the amount of each drug administered falls short of the centers with increased concentrations (Seixas, 1975). toxic range. Particular drugs can enhance the toxic ef­ Ethanol is metabolized in the body to acetaldehyde by fects of other drugs, even in the absence of inherent tox­ means of one of two pathways, determined in part by al­ icity of the enhancing drug. cohol concentration (Correia & Castagnoli, 1989; Lee & Certain attributes of drugs affect the probability of their Becker, 1989). It is thought that at low alcohol concen­ interacting with other drugs (Hansten, 1989). Attributes trations the main oxidizing system is alcohol dehydroge­ increasing the likelihood of drug interaction with alcohol nase, whereas at higher concentrations of alcohol the include the inhibited drug metabolism that occurs with mixed-function oxidase system (also called the microsomal acute alcohol intoxication (regardless of intoxication fre­ ethanol oxidizing system, or MEOS) becomes predomi­ quency) and the enzyme induction and hepatic dysfunc- nant. In this event, increases in smooth endoplasmic retic­ ula are of long duration. Induction of enzymes can be a mixed blessing. By accelerating metabolism, enzyme in­ Correspondence should be addressed to J. Dial, Department of Anat­ omy and Neurobiology, Colorado State University, Fort Collins, duction decreases the pharmacologic effect of the induc­ CO 80521 (e-mail: [email protected]). ing agent and also of coadministered drugs. However,

179 Copyright 1992 Psychonomic Society, Inc. 180 DIAL metabolism of drugs into reactive intermediates can ag­ been self-administered to every vertebrate species tested gravate their toxicity. As will be discussed below, this (Johanson, 1988). It is a reinforcing substance regardless may bear upon alcohol's recognized propensity to inter­ of the route of administration, be it intravenous, gastric, act with other drugs metabolized by MEOS. intramuscular, oral, or inhaled. It is at once anorectic and The central nervous system appears to contain no spe­ psychostimulant, local anesthetic and convulsant (Bates, cific receptor sites for alcohol (Seixas, 1975); alcohol, 1988; Koob & Hubnet, 1988). It produces profound sym­ as well as barbituates and sedatives, has a general action pathetic stimulation, both centrally and peripherally involving cell membranes, or neurotransmitter metabo­ (DiGregorio, 1990). The central stimulation appears lism, or both. Ethanol molecules dissolve in the lipid responsible for behavioral sensitization and kindling bilayer of cells, affecting receptors and ion channels in (Koob & Hubnet, 1988; Post & Weiss, 1988). Centrally, a process known as fluidization (Lee & Becker, 1989). cocaine affects monoamine metabolism, particularly that Although there appears to be a relationship between lipid of dopamine. Cocaine appears to assist in the transmis­ solubility and membrane-disordering effects (yY allace, sion of catecholamines by reducing their reuptake, and 1988), research in this area has been inconclusive. There possibly by facilitating their release (Hollister, 1973; Kat­ are correlations concerning alcohol and brain neurotrans­ zung, 1989; Porrino & Kornetsky, 1988). The euphoria mitters. Decreased serotonin is associated with alcohol reported by humans is thought to be mediated by activa­ craving in rats, and increasing the amount of brain seroto­ tion of these dopamine circuits in the brain (Dackis & nin decreases alcohol consumption in animals and humans Gold, 1990). The intensity of its euphoria both reinforces (yYallace, 1988). Decreased levels of norepinephrine cor­ continuing use and depletes dopaminergic reserves, thus relate as well with alcohol craving in alcoholics abstinent inducing craving and intense psychologic dependence for lengthy periods of time, while dopamine transmission (Cregler & Mark, 1986; Dackis & Gold, 1990). How­ appears to be biphasically affected by alcohol adminis­ ever, because dopamine blockers do not always preclude tration. Some evidence indicates that transmitter dispari­ cocaine effects, its ability to reinforce probably involves ties may antecede abuse. Two of the esteemed effects of other neurochemical systems as well (Balstar, 1988). alcohol, decreased anxiety and increased composure, can Cocaine appears to decrease synthesis of 5-hydroxy­ be linked to alcohol's enhancement of gamma amino bu­ typtamine (Woolverton & Kleven, 1988) and to inhibit tyric acid transmission. acetylcholine (Dackis & Gold, 1990). Membrane-bound receptors with a high specific affinity for cocaine have Alcohol's Interactions with Other Drugs not thus far been identified, although cocaine receptors In its interactions, alcohol achieves its effects through appear to be associated with the dopamine transport sys­ changes involving absorption, metabolism, synergy with tem (Jones, 1986; Kuhar, Ritz, & Sharkey, 1988; Madras the coadministered drug, self-contained congeners, and et al., 1990). secondary consequences of alcohol metabolism (Seixas, Cocaine is a lipid-soluble, low-molecular-weight alka­ 1975). The absorption of alcohol is delayed by epine­ loid (benzoylmethylecgonine, C17H21N04) capable of phrine, amphetamines, antimuscurinic drugs such as atro­ penetrating both the blood-brain and placental barriers pine, and similar drugs. Because of its solvent effect, on (Church et aI., 1988; Cregler & Mark, 1986). In the hu­ the other hand, alcohol can accelerate the absorption of man body, cocaine is metabolized either by hydrolytic less soluble agents such as nitroglycerine and toxic heavy splitting of ester bonds or by the oxidation-reduction pro­ metals. The primary hepatic metabolizer of alcohol, al­ cess described above (Correia & Castagnoli, 1989; Kloss, cohol dehydrogenase (ADH), also metabolizes other Rosen, & Rauckman, 1984; Smolen & Smolen, 1990; drugs, the by-products of which are sometimes toxic. Al­ Stewart, Inaba, Tang, & Kalow, 1977). In the former, cohol's most notable synergy occurs with sedatives and normally the major pathway, plasma and liver cholinester­ anesthetics. This is probably associated with alcohol's in­ ases rapidly reduce cocaine to inactive, water-soluble duction of the MEOS system, and induction, through metabolites. But levels of blood cholinesterases can be increases in the smooth endoplasmic reticulum, may pro­ notably less active in babies, elderly men, pregnant duce synergistic interactions even in the absence of alco­ women, and those with liver disease. When cholinester­ hol. Alcohol can enhance the undesirable effects of other ase amounts are insufficient or enzyme induction has oc­ drugs as well. Large quantities of alcohol affect concen­ curred, cocaine metabolism occurs enzymatically, through trations of components of blood plasma and alter glucose oxidation reduction. This pathway produces toxic metabo­ metabolism. Use of monoamine-oxidase inhibitors can lites, such as the free radical norcocaine nitroxide, be­ leave unmetabolized such congeners as the tyramine in lieved responsible for liver damage. The histopathology Chianti wines, causing a surfeit of norepinephrine and sub­ of liver toxicity from human cocaine ingestion has been sequent hypertensive crisis. confirmed (Cregler & Mark, 1986; Freeman & Harbi­ son, 1978a; Kanel, Cassidy, Shuster, & Reynolds, 1990; COCAINE EFFECTS Kloss et al., 1984; Wanless et al., 1990). Its metabolite norcocaine has also been located in the brain of the rat Unlike alcohol, the taste for which in animals must at (Misra, Nayak, Patel, Vadlamani, & Mule, 1974). Co­ least be induced or genetically engineered, cocaine has caine and its metabolite have been implicated in a host ALCOHOL AND COCAINE INTERACTION 181 of other unsavory consequences, both central and periph­ Twin, adoption, and family studies unequivocally sup­ eral, including carcinogenic potential (Rosenkranz & port the heritable basis of alcoholic tendencies (Miller Klopman, 1990). et al., 1989). Preexisting differences in brain neuro­ chemistry have been reported in animal studies of alco­ THE INTERACTION OF holism (Wallace, 1988). Genetic predisposition to poly­ ALCOHOL AND COCAINE drug abuse is implied by positive family histories of alcoholism in cocaine addicts and by the prevalence of When substance abuse includes more than one sub­ cocaine abuse by young alcoholics (McCaul, Turkkan, stance, alcohol and cocaine are drugs quite likely to be Svikis, Bigelow, & Cromwell, 1990; Miller & Gold, paired (De Milio, 1989; Jones, 1986; Masur, Souza­ 1988; Miller et al., 1989; Shulman, 1987; Wallace, Formigoni, & Pires, 1989; Miller, Gold, Belkin, & Klahr, 1988). Diagnosis of alcohol dependence in the family his­ 1989; Smith, 1986). Alcohol may be used either to govern tory of cocaine abusers is common, and it may in fact the stimulation, or to enhance the euphoria, of cocaine. be more common than the family history of alcoholism The reason for the popularity of the pairing is open to in alcoholics. Those dependent on alcohol may be primed question. Abuse of illicit drugs occurs more often in heavy for discovery of cocaine or other drugs genetically or by users of alcohol than in those who drink little or no alco­ a vulnerability induced by existing intoxication (Miller hol (Kaufman, 1975). More drug addicts appear also to . et al., 1989). A person's perception of the effect of sun­ be intemperate drinkers than not, although only a minority dry drugs can be similar, particularly when the user is of one sample presenting for cocaine treatment were des­ already under the influence of one, and so one might in­ ignated severely alcohol dependent (Walfish, Massey, & fer that drugs possessing different properties may invoke Krone, 1989). As the author of that report pointed out, a similar response in the user. To be determined more however, the study was a retrospective one, fraught with concretely is whether partiality for cocaine is consonant certain limitations. It is, of course, difficult to gather reli­ with proclivity for alcohol, or indicative of a generalized able data in this area, and thus the attempt to untangle predilection for substance abuse. the web of drug abuse is enigmatic and uncertain. In any event, to titrate stimulant side effects with alcohol or any Central Nervous System Effects other depressant can spawn a secondary drug pattern with Ingested chemicals have various effects upon the brain, its own set of problems. the one most coveted being the diversion to be found in altered consciousness. Regular use of recreational doses Adjuncts of Polydrug Abuse eventually initiates an equilibrium that is subject to dis­ Although certainty eludes us in the quest for reliable ruption by withdrawal. Profound or persistent intoxica­ indicators of potential or active drug abusers, predictors tion can damage brain tissue, and an individual's behavior can be discerned. These predictors can be categorized may become permanently altered by habitual drug abuse, roughly as environmental and genetic. Environmental and even when drugs are not being ingested. Alcohol and co­ psychological precursors of polydrug abuse are thought caine both affect the brain and almost certainly share ef­ to include parental role models, cycles of drug availabil­ fects upon one or more neurotransmitters. ity, sexual or social dysfunction, and psychopathology A likely candidate for shared effects is dopamine. (Kaufman, 1975). Dopaminergic neuronal activity has been found in studies In the person acquainted with the sensation of both, use of rats and mice to react biphasically to alcohol adminis­ of either alcohol or cocaine can inspire a yearning for the tration, depending upon dose (Wallace, 1988). With­ other (Smith, 1986; Wallace, 1988). The temptation may drawal after heavy alcohol consumption appears to deplete arise from organic or psychologic factors, or a combina­ levels of dopamine. Cocaine is a powerful agonist of dopa­ tion. Indeed, the degree to which any particular drug is mine, to the point of depletion. Wallace (1988) specu­ reinforcing seems to be complicated by factors other than lates that the craving for cocaine varies with mood changes pharmacology (Falk & Tang, 1989; George, 1990). In that occur in response to the consumption of alcohol. Al­ animal studies, although genotypic preference for alcohol cohol appears to have complex effects upon brain seroto­ appears to correlate highly with preference for cocaine nin (Cocores, Miller, Pottash, & Gold, 1988; Wallace, and opiates, reinforcement value and neurosensitivity have 1988). The combination of alcohol and cocaine may de­ been found to exhibit very little correlation (George, plete catecholamines while increasing acetylcholine turn­ 1990). Thus, a person's inherent preference for a sub­ over (Cocores et al., 1988). stance may not coincide with hislher ability to handle its In the presence of a large quantity of alcohol, general effects. Denial or minimization devices may differ be­ analeptics administered for stimulation of the central ner­ tween abusers of alcohol and cocaine (Smith, 1986). As vous system can cause convulsions (Seixas, 1975). Milder to dual abuse, it is important to recognize that, although central nervous system stimulants such as amphetamines primary dependence may be recognized and lamented by are more limited in their antagonism of alcohol's effects, the user, the individual may be inclined to believe that but share mechanisms with alcohol that interact synergisti­ the secondary drug poses no problem and that its con­ cally. Among other things, synergy may increase dramat­ trolled use is a viable alternative. ically the risk of psychotic experiences in users (Tien & 182 DIAL

Anthony, 1990). Alcohol and cocaine have both been as­ first-pass metabolism appears to be gastric, and normal sociated with aggressive behavior in users during intoxi­ activity of the enzyme protects against rapid penetration cation and withdrawal (Miller & Potter-Efron, 1990). of alcohol into the bloodstream. However, first-pass metabolism is decreased in alcoholics because of dimin­ Cardiovascular Features ished gastric ADH activity, and gastric ADH also tends Both ethanol and cocaine are individual risk factors for to be lower in women. Ethanol absorption occurs more cardiovascular problems (Billman, 1990; Jones, 1987; rapidly from the small intestine than from the stomach, Kabas et al., 1990; Leissinger, 1990). Both stimulate the but the sympathetic stimulation of cocaine can be expected sympathetic nervous system, affecting catecholamine to slow gastric emptying. It is conceivable that the coin­ levels and blood pressure and increasing the potential for cidence of these events interferes with alcohol metabolism arrhythmia. In rare cases, ingestion of alcohol can precipi­ and complicates the interactive effects of the drugs. tate sudden cardiac death in drug abusers (Garfia, Val­ Intestinal ischemia has occasionally been attributed to verde, Borondo, Candenas, & Lucena, 1990). abuse of cocaine (Cregler & Mark, 1986). Garfia et al. (1990) documented one fatality from intestinal ischemia Hepatotoxicity after ingestion of alcohol and cocaine. They attributed the Ample evidence has accrued as to the detrimental ef­ ischemia to arteriolar lesioning in the intestinal submucosa fects of alcohol and cocaine on the liver. As noted above, induced by spasm, which drastically reduced blood flow cytosolic ADH is the primary metabolizer of ethanol un­ and induced platelet aggregation. til something, such as chronic alcohol intake, causes liver microsomes to oxidize ethanol without ADH (Boyer & Maternal and Fetal Effects Petersen, 1990; Lieber, 1990; Shuster, Garhart, Powers, The risk of fetal alcohol syndrome in children of Grunfeld, & Kanel, 1988; Smith, Freeman, & Harbison, alcohol-abusing mothers has been well documented. 1981). Liver microsomes and the cytochrome P-450 they Women who abuse cocaine may become amenorrheic, yet employ are considered a distinct method of biotransfor­ be able to conceive (Smith, 1986). Cocaine easily passes mation called the mixed-function oxidase system, as the placental barrier, and, as noted above, pregnant described above. Once MEOS has been induced, alcohol women tend to have lower levels of plasma cholinester­ metabolism competes with and presently inhibits ases with which to disarm toxins (Stewart et al., 1977). metabolism of xenobiotics. The microsomes respond to Prenatal exposure to alcohol and cocaine independently this increased metabolic demand by accelerating biotrans­ increases chances of placental abruption, fetal edema, formation of both alcohol and drugs, and the increase in cephalic hemorrhage, and physical deformity (Bates, drug metabolism activates metabolites toxic to the liver. 1988; Howard, 1989; Johanson, 1988; Krug, 1989; Ku­ Cocaine damages the liver in a dose- and time-dependent har et al., 1988; Smith & Asch, 1987; Smolen & Smo­ manner directly correlated with mixed-function oxidase len, 1990; Van Dyke & Fox, 1990). Pregnant cocaine activity (Smith et al., 1981). Biotransformation of cocaine abusers may not eat enough, as cocaine suppresses the produces the metabolite norcocaine, which is a more po­ appetite (Smith, 1986). Church et al. (1988) researched tent destroyer of liver tissue than its parent and which, the combined toxicity of alcohol and cocaine in pregnant indeed, requires no prior induction of MEOS for initia­ rats. Although no synergistic effects were noted, their re­ tion of its effects (Freeman & Harbison, 1978b; Lieber, sults demonstrated that the drug combination is more toxic 1990). The location of intralobular necrosis occurring than the use of either drug alone. The connection between after cocaine administration depends upon the inducing fetal exposure to alcohol and learning problems in school­ agent (Shuster et aI., 1988; Smith et al., 1981). Hepatic aged children is clear; that between fetal exposure to poly­ necrosis also occurs when liver and serum esterase ac­ drug abuse and later learning deficits has yet to be tivities are inhibited (Freeman & Harbison, 1978a). Thus, _ documented. both inducers of the mixed-function oxidase system and inhibitors of esterase activity cause a higher percentage Sexual Effects of any agent to be metabolized by MEOS. When the agent Ever-popular are substances reputed to enhance the sex­ is cocaine, its bioactivation induces hepatic cellular ual act. The rise in popularity of cocaine has been accom­ damage and eventual frank necrosis. Serum glutamate­ panied, and perhaps propelled, by testimonials as to its pyruvate transaminase levels are also significantly elevated sexual efficacy. In at least one study, both males and fe­ in ethanol-pretreated animals that receive just one injec­ males favored the combination of alcohol and cocaine for tion of cocaine. Induction thus appears not only to increase sexual enhancement (Smith, Wesson, & Apter-Marsh, the risk of damage to the liver through cocaine, but may 1984). However, there is general consensus among ad­ complicate interactions between cocaine and other sub­ diction and sexual counselors that the sexual enhancement stances, whether therapeutic or abused. associated with psychoactive drugs is a transient thing, fading with continued use, and that sexual dysfunction Gastric and Intestinal Impact among addicted individuals is the rule. Although the primary metabolizer of ethanol is the liver, Neurochemistry may well be involved. Homeostatis is ADH exists in the digestive tracts of rats and humans (Lie­ quite naturally involved in balanced sexual functioning, ber, 1990). Lieber reported that in fact the main site of and abuse of alcohol and cocaine alters the major brain ALCOHOL AND COCAINE INTERACTION 183 neurotransmitters (Cocores et al., 1988; Hollister, 1973; mediated hepatotoxicity by acute and chronic ethanol. Alcoholism, Wallace, 1988). Serotonin is considered a central nervous 14,28-31. system sexual suppressant, and alcohol is believed to in­ CHURCH, M. W., DINTCHEFF, B. A., It GESSNER, P. K. (1988). The interactive effects of alcohol and cocaine on maternal and fetal toxic­ crease serotonin in the brain. Dopamine appears to be as­ ity in the Long-Evans rat. Neurotoxicology & Teralology, 10, 355-361. sociated with sexual function, and, as discussed above, COCORES, J. A., MILLER, N. S., POTTASH, A. C., It GoLD, M. S. alcohol in the proper dose may increase dopamine levels (1988). Sexual dysfunction in abusers of cocaine and alcohol. Ameri­ as well, whereas alcohol withdrawal depletes that trans­ can Journal of Drug & Alcohol Abuse, 14, 169-173. CORREIA, M. A., It CASTAGNOU, N., JR. (1989). Drug biotransforma­ mitter. Cocaine is a powerful agonist of dopamine, to the tion. In B. G. Katzung (Ed.), Basic and clinical phormacology point that brain dopamine becomes depleted. Cocores (4th ed., pp. 41-50). Norwalk, CT: Appleton & Lange. et al. (1988) reported that the catecholamine depletion CREGLER, L. L., It MARK, H. (1986). Special report: Medical com­ provoked by use of alcohol and cocaine may activate plications of cocaine abuse. New England Journal of Medidne, 315, acetylcholine, which furthers sexual dysfunction. Com­ 1495-1500. DACKIS, C. A., It GoLD, M. S. (1990). Addictiveness of central plicating the situation is the craving for alcohol induced stimulants. Advances in Alcohol and Substance Abuse, 9, 9-26. by depleted catecholamine levels and the perpetuation that DEMIUO, L. (1989). Psychiatric syndromes in adolescent substance is implied. abusers. American Journal of Psychiatry, 146, 1212-1214. Of course, the periphery is affected as well. Cocaine DIGREGORIO, G. J. (1990). Cocaine update: Abuse and therapy. Ameri­ alters testosterone levels in the rat following intraperi­ can Family Physidan, 41, 247-250. . FALK, J. L., It TANG, M. (1989). Schedule-induced chlordiazepoxide toneal injection (Gordon, Mostofsky, & Gordon, 1980), intake: Differential effect of cocaine and ethanol histories. Pharma­ and both alcohol and its metabolite, acetaldehyde, curb cology, Biochemistry & Behavior, 33, 393-396. the synthesis of testosterone (Smith & Asch, 1987). Acute FREEMAN, R. W., It HARBISON, R. D. (1978a). Cocaine-induced hepatic consumption of alcohol also increases hepatic clearance necrosis. Toxicology & Applied Pharmacology, 45, 355. FREEMAN, R. W., It HARBISON, R. D. (l978b). Norcocaine-induced of testosterone. In women, cocaine alters levels of leu­ hepatic necrosis. Pharmacologist, 20, 193. tinizing hormone and prolactin, whereas chronic alcohol GARFlA, A., VALVERDE, J. L., BoRONDO, J. C., CANDENAS, I., It Lu­ abuse is associated with reproductive disorders. It is CENA, J. (1990). Vascular lesions in intestinal ischemia induced by worthy of note that a functional liver is germane to cocaine-alcohol abuse: Report of a fatal case due to overdose. Jour­ nal of Forensic Sdence, 35, 740-745. reproductive fitness, and liver disease alters the pattern GEORGE, F. R. (1990). Genetic approaches to studying drug abuse: of circulating sex steroids. Correlates of drug self-administration. Alcohol, 7, 207-211. GoRDON, L. A., MOSTOFSKY, D. I., It GoRDON, G. G. (1980). Changes The Bottom Line on Drug Abuse in testosterone levels in the rat following intraperitoneal cocaine My interest in the subject of alcohol/cocaine abuse be­ hydrochloride. Intemationallournal of Neurosdence, 11, 139-141. HANSTEN, P. D. (1989). Appendix I: Important drug interactions. In gan personally when, despite my support and belief in B. G. Katzung (Ed.), Basic and clinical pharmacology (4th ed., him, a friend gradually and seemingly inexorably suc­ pp. 831-839). Norwalk, CT: Appleton & Lange. cumbed to its siren. In an attempt to understand, I sought HOLUSTER, L. E. (1973). Human pharmacology of drugs ofabuse with assistance from the literature, but found to my surprise emphasis on neuroendocrine effects. Progress in Brain Research, 39, 373-381. that not much specifically concerned with the drug com­ HOWARD, J. (1989). Cocaine and its effects on the newborn. Develop­ bination seems to have been published. That which has mental & Child Neurology, 31, 255-257. been done begs the question of whether the substrate for JOHANSON, C. E. (1988). Behavioral studies of the reinforcing proper­ drug abuse is biology or psychology, chemistry or be­ ties of cocaine. In D. Clouet, K. Asghar, & R. Brown (Eds.), Mech­ havior, physical deprivation or psychic trauma. Perhaps anisms of cocaine abuse and toxicity (NIDA Research Monograph 88, pp. 107-124). Washington, DC: U.S. Govenunent Printing Office. that issue is of no import. For whatever reason, the drug JONES, R. T. (1986). Cocaine and other drug interactions: Strategy con­ abuser seeks to engender a change in his/her subjective siderations. In M. C. Braude & H. M. Ginzburg (Eds.), Strategies state. This change in attitude is irrevocably accompanied for research on the interactions of drugs of abuse (NIDA Research by physical adjustments that are often overlooked by the Monograph 68, pp. 142-153). Washington, DC: U.S. Government user and relatively unexplored in the fields of medicine Printing Office. JONES, R. T. (1987). Psychopharmacology of cocaine. In A. M. and psychology. More consideration of the diffuse effects Washton & M. S. Gold (Eds.), Cocaine: A clinician's handbook of drug combinations might be valuable as a base from (pp. 55-72). Wiley, NY: Guilford. which to derive competent treatment. And perhaps as a KABAS, J. S., BLANCHARD, S. M., MATSUYAMA, Y., loNG, J. D., corollary of this wisdom, other personal tragedies will HOFFMAN, G. W., JR., ELUNWOOD, E. H., SMITH, P. K., It STRAUSS, H. C. (1990). Cocaine-mediated impairment of cardiac conduction be avoided. in the dog: A potential mechanism for sudden death after cocaine. Journal of Pharmacology & Experiments in Therapy, 252,185-191. REFERENCES KANEL, G. C., CASSIDY, W., SHUSTER, L., It REYNOLDS, T. B. (1990). Cocaine-induced liver cell injury: Comparison of morphological fea­ BALSTAR, R. L. (1988). Pharmacological effects of cocaine relevant to tures in man and experimental models. Hepatology, 11, 646-651. its abuse. In D. Clouet, K. Asghar, & R. Brown (Eds.), Mechanisms KATZUNG, B. G. (1989). Introduction. In B. G. Katzung (Ed.), Basic of cocaine abuse and toxidty (NIDA Research Monograph 88, pp. 1- and clinical pharmacology (4th ed., pp. 1-9). Norwalk, CT: Apple­ 13). Washington, DC: U.S. Government Printing Office. ton & Lange. BATES, C. K. (1988). Medical risks of cocaine use [Specialty Confer­ KAUFMAN, E. (1975). Polydrug abuse or multidrug misuse: It's here ence]. Western Journal of Medidne, 148, 440-444. to stay. In A. Schecter, H. Aiksne, & E. Kaufman (Eds.), Drug abuse: BILLMAN, G. E. (1990). Mechanisms responsible for the cardiotoxic Modem trends, issues, and perspectives (pp. 124-141). New York: effects of cocaine. FASEB Journal, 4, 2469-2475. Marcel Dekker. BoYER, C. S., It PETERSEN, D. R. (1990). Potentiation of cocaine- KLOSS, M. W., ROSEN, G. M., It RAUCKMAN, E. I. (1984). Cocaine- 184 DIAL

mediated hepatotoxicity: A critical review. Biochemical Pharmacol­ ROSENKRANZ, H. S., '" KWPMAN, G. (1990). Tbe carcinogenic potential ogy,33, 169-173. of cocaine. Cancer Leners, 52, 243-246. KooB, G. F., '" HUBNET, C. B. (1988). Reinforcement pathways for SEIXAS, F. A. (1975). Alcohol and its drug interactions. Annals of In­ cocaine. In D. Clouet, K. Asghar, & R. Brown (Eds.) Mechanisms ternal Medicine, 83, 86-92. ofcocaine abuse and toxicity (NIDA Research Monograph 88, pp. 137- SHULMAN, G. (1987). Alcoholism and cocaine addition: Similarities, 159). Washington, DC: U.S. Government Printing Office. differences, treatment implications. Alcoholism Treatment Quarterly, KRUG, S. E. (1989). Cocaine abuse: Historical, epidemiologic, and clin­ 4, 31-40. ical perspectives for pediatricians. Advances in Pediatrics, 36, 369406. SHUSTER, L., GARHART, C. A., POWERS, J., GRUNFELD, Y., '" KUHAR, M. J., RITZ, M. C., '" SHARKEY, J. (1988). Cocaine recep­ KANEL, G. (1988). In D. Clouet, K. Asghar, & R. Brown (Eds.), tors in dopamine transporters mediate cocaine-reinforced behavior. Mechanisms of cocaine abuse and toxicity (NIDA Research Mono­ In D. Clouet, K. Asghar, & R. Brown (Eds.), Mechanisms ofcocaine graph 88, pp. 250-275). Washington, DC: U.S. Government Print­ abuse and toxicity (NIDA Research Monograph 88, pp. 14-22). ing Office. Washington, DC: U.S. Government Printing Office. SMITH, A. C., FREEMAN, R. W., '" HARBISON, R. D. (1981). Ethanol LEE, N. M., '" BECKER, C. E. (1989). The alcohols. In B. G. Katzung enhancement of cocaine-induced hepatotoxicity. Biochemical Phar­ (Ed.), Basic and clinical pharmacology (4th ed., pp. 278-286). Nor­ macology, 30, 453-458. walk, CT: Appleton & Lange. SMITH, C. G., '" ASCH, R. H. (1987). Drug abuse and reproduction. LEISSINGER, C. A. (1990). Severe thrombocytopenia associated with Fertility & Sterility, 48, 355-373. cocaine use. Annals of Internal Medicine, 112,708-710. SMITH, D. E. (1986). Cocaine-alcohol abuse: Epidemiological, diag­ LIEBER, C. S. (1990). Interaction of ethanol with drugs, hepatotoxic nostic and treatment considerations. Journal of Psychoactive Drugs, agents, carcinogens and vitamins. Alcohol & Alcoholism, 25,157-176. 18, 117-129. MADRAS, B. K., KAMIEN, J. B., FAHEY, M. A., CANFIELD, D. R., SMITH, D. E., WESSON, D. R., '" APTER-MARSH, M. (1984). Cocaine­ MIUUS, R. A., SAHA, J. K., NEUMEYER, J. L., '" SPEALMAN, R. D. and alcohol-induced sexual dysfunction in patients with addictive dis­ (1990). N-modified fluorophenyltropane analogs of cocaine with high ease. Journal of Psychoactive Drugs, 16, 359-361. affinity for cocaine receptors. Pharmacology, Biochemistry & Be­ SMOLEN, T. N., '" SMOLEN, A. (1990). Developmental expression of havior, 35, 949-953. cocaine hepatotoxicity in the mouse. Pharmacology, Biochemistry & MASUR, J., SOUZA-FoRMIGONI, M. L. 0., '" PIRES, M. L. N. (1989). Behavior, 36, 333-338. Increased stimulatory effect by the combined administration of co­ STEWART, D. J., INABA, T., TANG, B. K., '" KAWW, W. (1977). caine and alcohol in mice. Alcohol, 6, 181-182. Hydrolysis of cocaine in human plasma by cholinesterase. Life Sci­ MCCAUL, M. E., TURKKAN, J. S., SVIIUS, D. S., BIGEWW, G. E., ences, 20, 1557-1564. '" CROMWELL, C. C. (1990). Alcohol and drug use by college males TIEN, A. Y., '" ANTHONY, J. C. (1990). Epidemiological analysis of as a function of family alcoholism history. Alcoholism: Clinical & alcohol and drug use as risk factors for psychotic experiences. Jour­ Experimental Research, 14, 467-471. nal of Nervous & Mental Disease, 178, 473-480. MILLER, M. M., '" POTTER-EFRON, R. T. (1990). Aggression and vio­ VAN DYKE, D. C., '" Fox, A. A. (1990). Fetal drug exposure and its lence associated with substance abuse. Journal of Chemical Depen­ possible implications for learning in the preschool and school-age popu­ dency Treatment, 3, 1-36. lation. Journal of Learning Disabilities, 23, 160-163. MILLER, N. S., '" GOLD, M. S. (1988). Cocaine and alcoholism: Dis­ WALFlSH, S., MASSEY, R., '" KRONE, A. (1989). Levels of alcohol de­ tinct or part of a spectrum. Psychiatric Annals, 18, 538-539. pendence in cocaine addicts: Some clinical implications. Psychology MILLER, N. S., GoLD, M. S., BELKIN, B. M., '" KLAHR, A. L. (1989). of Addictive Behaviors, 3(2), 65-68. Family history and diagnosis of alcohol dependence in cocaine de­ WALLACE, J. (1988). The relevance to clinical care of recent research pendence. Psychiatry Research, 29, 113-121. in neurobiology. Journal of Substance Abuse Treatment, 5, 207-217. MISRA, A. L., NAYAK, P. K., PATEL, M. N., VADLAMANI, N. L., '" WANLESS, I. R., DORE, S., GoPiNATH, N., TAN, J., CAMERON, R., MULE, S. J. (1974). Identification of norcocaine as a metabolite of HEATHCOTE, E. J., BLENDlS, L. M., '" LEVY, G. (1990). Histopathol­ [,Hl-cocaine in rat brain. Experienta, 30, 1312-1314. ogy of cocaine hepatotoxicity. Report of four patients. Gastroenterol­ PORRlNO, L. J., '" KORNETSKY, C. (1988). The effects of cocaine on ogy, 98, 497-501. local cerebral metabolic activity. In D. Clouet, K. Asghar, & WOOLVERTON, W. L., '" KLEVEN, M. S. (1988). Multiple dopamine R. Brown (Eds.), Mechanisms of cocaine abuse and toxicity (NIDA receptors and the behavioral effects of cocaine. In D. Clouet, K. As­ Research Monograph 88, pp. 92-106). Washington, DC: U.S. Govern­ ghar, & R. Brown (Eds.), Mechanisms of cocaine abuse and toxicity ment Printing Office. (NIDA Research Monograph 88, pp. 160-184). Washington, DC: U.S. POST, R. M., '" WEISS, S. R. B. (1988). Psychomotor stimulant versus Government Printing Office. local anesthetic properties of cocaine: Role of behavioral sensitiza­ tion and kindling. In D. Clouet, K. Asghar, & R. Brown (Eds.), Mechanisms of cocaine abuse and toxicity (NIDA Research Mono­ graph 88, pp. 217-238). Washington, DC: U.S. Government Print­ (Manuscript received January 6, 1992; ing Office. revision accepted for publication April 28, 1992.)