A Nicotine Antagonist, Mecamylamine, Reduces Cue-Induced Cocaine Craving in Cocaine-Dependent Subjects Malcolm S. Reid, Ph.D., Joanne D. Mickalian, M.S., Kevin L. Delucchi, Ph.D., and S. Paul Berger, M.D. We have previously shown that nicotine enhances cue- cue measures. Cue exposure also produced an increase in induced cocaine craving. In the present study, the effects of skin conductance and decrease in skin temperature. The a nicotine antagonist, mecamylamine, on cue-induced cue-induced increase in cocaine craving was reduced, cocaine craving were investigated. Twenty-three cocaine- while the cue-induced skin conductance and temperature dependent patients, all cigarette smokers, were randomly responses were unaffected, by mecamylamine. These assigned to mecamylamine (2.5 mg tablet) or placebo in a findings show that cue-induced cocaine craving is single-dose, placebo-controlled, crossover, double-blind attenuated by mecamylamine. Further study on the use study. Craving and anxiety were measured before and after of mecamylamine in relapse prevention programs cocaine cues with visual analog scales for desire to use are suggested. cocaine and mood. Skin conductance, skin temperature and [Neuropsychopharmacology 20:297–307, 1999] heart rate were recorded before and during cocaine cues. © 1999 American College of Neuropsychopharmacology. Following exposure to cocaine cues, all patients reported an Published by Elsevier Science Inc. increase in cocaine craving and anxiety relative to the pre- KEY WORDS: Cocaine; Craving; Mecamylamine; Nicotine; and cocaine paraphernalia handling (Ehrman et al. Addiction 1992; Reid et al. 1998). The cocaine cue procedure ap- pears to be contextually specific because opiate-related Over the past several years, numerous studies have cues are less effective whereas cues specific to the sub- demonstrated that environmental cues previously asso- ject’s mode of cocaine use are most effective (Ehrman et ciated with cocaine use will consistently induce cocaine al. 1992; O’Brien et al. 1990, 1992). Furthermore, cocaine craving in cocaine-dependent subjects (Ehrman et al. cue reactivity persists inpatients who have not used co- 1992; O’Brien et al. 1990; Berger et al. 1996; Reid et al. caine for several months (Rohsenow et al. 1991; O’Brien 1998). This behavior is readily elicited in a clinical labo- et al. 1990). In recent years, this model has been used to ratory setting by means of a standardized cocaine cue investigate medications for their ability to reduce cue- procedure involving both visual/audio presentation induced cocaine craving, and consequently, it has been proposed as a screening mechanism for identifying po- From the Psychiatry Services NYVAMC (MSR), New York Uni- tentially therapeutic compounds for the treatment of versity Medical Center, New York, New York; and Psychiatry Ser- vices SFVAMC (JDM, KLD, SPB), University of California, San cocaine addiction (Berger et al. 1996; Robbins et al. 1992; Francisco, California. Kranzler and Bauer 1992; Satel et al. 1995). Address correspondence to: Malcolm S. Reid, Psychiatry Ser- Studies investigating the pharmacological modula- vices, NYVAMC 116A, 423 East 23rd Street, New York, NY 10010. Received February 3, 1998; revised July 20, 1998; accepted July 22, tion of cue-induced cocaine craving have tested a wide 1998. variety of compounds. These include bromocriptine NEUROPSYCHOPHARMACOLOGY 1999–VOL. 20, NO. 3 © 1999 American College of Neuropsychopharmacology Published by Elsevier Science Inc. 0893-133X/99/$–see front matter 655 Avenue of the Americas, New York, NY 10010 PII S0893-133X(98)00076-1 298 M.S. Reid et al. NEUROPSYCHOPHARMACOLOGY 1999–VOL. 20, NO. 3 (Kranzler and Bauer 1992), amantadine (Robbins et al. done over the phone, followed by a screening interview 1992), haloperidol (Berger et al. 1996) and nicotine (Reid at the SFVAMC with a SAT trained psychology techni- et al. 1998), as well as tryptophan depletion, which re- cian with experience in cocaine abuse diagnosis and duces serotonin levels (Satel et al. 1995). Most of these treatment. Patients were included if they were: (1) studies found either a reduction (haloperidol, tryp- males or nonpregnant/nursing females, (2) 18–65 years tophan depletion) or no change (bromocriptine, aman- of age, (3) regular (10 cigarettes/day) cigarette smokers, tadine) in self-reported cocaine craving and have led to (4) “crack” cocaine was their drug of choice, (5) had the suggestion that dopamine may be involved in medi- smoked “crack” cocaine within the last 3 months and ating cocaine craving (Berger et al. 1996; Wickelgren (6) cocaine-dependent within the last 3 months accord- 1997). More recently, we found that nicotine produced ing to DSM-IV criteria from the Structural Clinical In- an increase in cue-induced cocaine craving (Reid et al. terview (SCID). Patient were excluded if they were: (1) 1998). This findings is consistent with previous investi- currently abusing opiates or in a methadone mainte- gations of cocaine–nicotine interactions. Thus, epidemi- nance program, (2) had undergone alcohol or drug ological studies have reported that cigarette smoking is detoxification within the last 30 days, (3) taking pre- significantly more prevalent in cocaine-dependent indi- scribed psychoactive medication, (4) taking prescribed viduals (Budney et al. 1993; Sees and Clark 1991), that antibiotics, (5) had coronary heart disease or high blood cocaine-dependent smokers reported an earlier age of pressure, or (6) had previously suffered from a serious onset and more frequent use of cocaine than cocaine- head injury (trauma) or stroke. The psychiatric status of dependent nonsmokers (Budney et al. 1993) and that all patients was initially evaluated by a Master’s degree smoking is predictive of the abuse of psychoactive level SAT psychologist. Those with erratic behavior drugs such as cocaine (Henningfield et al. 1990; U.S. De- were interviewed by an SAT psychiatrist, and if they partment of Health and Human Services 1988). Indeed, met criteria for an axis I psychiatric disorder (other than anecdotal reports by patients claim that smoking men- substance abuse), they were excluded from the study. tholated cigarettes prolongs the cocaine high and can Following the screening interview, written informed even substitute for cocaine during periods of abstinence consent was obtained, and all study participants under- (Sees and Clark 1991). Finally, animal studies have went an intake assessment including a demographic shown that subchronic pretreatment with nicotine in- questionnaire, the drug and alcohol sections of SCID for creases the subsequent acquisition and rate of cocaine DSM-IV (First et al. 1996), the Addiction Severity Index self-administration in rats (Horger et al. 1992). These (ASI) (McLellan et al. 1980), the Fagerström Nicotine studies indicate that nicotine could stimulate the use of Tolerance Questionnaire (Fagerström 1978) and the cocaine and possibly increase the risk of relapse in co- Profile of Mood States (POMS) (McNair et al. 1971), and caine-dependent individuals during rehabilitation. More- test dates for two separate sessions (at least 72 h apart) over, this suggests that a nicotine antagonist could reduce were scheduled. cue-induced cocaine craving and, consequently, could Descriptive data of the patient population derived be of therapeutic value in the treatment of cocaine addic- from the screening interview, ASI, POMS, and Fager- tion. Mecamylamine is a clinically available, centrally ström Nicotine Tolerance Questionnaire are shown in active nicotine antagonist with known therapeutic value Table 1. All patients abused cocaine by smoking in smoking cessation; it reduces relapse in cigarette “crack” cocaine, 14 of them had used within the last 30 smokers when combined with nicotine patch treatment days, 10 were currently in the SAT outpatient program, (Rose et al. 1994). Therefore, in the present study, we and all were current cigarette smokers. have investigated the effects of mecamylamine on cue- induced cocaine craving in cocaine-dependent “crack” Study Design: Methodological Considerations smokers. All patients were instructed to abstain from smoking from midnight before each test day. (Studies began at METHODS 9:30 A.M. and were completed by approximately 1:30 P.M.) Compliance was verified on each test day using a Participants carbon monoxide (CO) breath monitor (15 PPM cut-off This human study was approved by an independent, level). All patients were also instructed to abstain form University of California research council: Committee on cocaine use for at least 2 days before each test day, Human Research. Individuals were recruited from the which was verified with qualitative urine screens for transition group at the Substance Abuse Treatment cocaine (300 ng/ml cut-off). (SAT) clinic at the San Francisco Veterans Affairs Medi- Mecamylamine (2.5 mg tablet, Merck) or placebo cal Center (SFVAMC), as well as by word of mouth at (lactose tablet) were administered in gelcaps in a dou- other outpatient treatment clinics in the San Francisco ble-blind, randomized, counterbalanced design. All pa- metropolitan area. Initial contact and recruitment were tients served in all conditions resulting in a within-patient NEUROPSYCHOPHARMACOLOGY 1999–VOL. 20, NO. 3 Mecamylamine Reduces Conditioned Cocaine Craving 299 Table 1. Subject Demographics and Drug Use History Frequency Mean (SD) Demographics Race African American 19 Caucasian 4 Gender Male 20 Female 3 Age 40.6 (5.1) Income in last 30 days