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Director's Report to the National Advisory Council on Drug Abuse
May, 2002

Research Findings

Treatment Research and Development

Contingency Management to Enhance Naltrexone Treatment of Opioid Dependence: A Randomized Clinical Trial of Reinforcement Magnitude

Dr. Kathleen Carroll and colleagues at Yale University School of Medicine randomly assigned detoxified opioid-dependent individuals to 1 of 3 treatments delivered over 12 weeks: standard naltrexone maintenance, standard naltrexone plus low-value contingency management (CM), or standard naltrexone plus high-value CM. Results suggest that (a) assignment to either CM condition was associated with significant reductions in opioid use over time compared with standard naltrexone treatment; (b) contrasts of high- versus low-value reinforcement magnitude were not significant, suggesting no relative benefit of higher over lower value incentives in this population; (c) participants assigned to either CM group reported significant reductions in readiness to change compared with participants assigned to standard naltrexone treatment. These findings suggest that targeted behavioral therapies can play a substantial role in broadening the utility of available pharmacotherapies. Carroll, K.M., Sinha, R., Nich, C., Babuscio, T., and Rounsaville, B.J. Experimental and Clinical Psychopharmacology, 10, pp. 54-63, 2002.

Personality, Drug of Choice, and Co-morbid Psychopathology Among Substance Abusers

Researchers at Yale University investigated the association between substance abuse/dependence, drug of choice, and the personality traits of negative emotionality, positive emotionality, and constraint (disinhibition) as measured by the Multidimensional Personality Questionnaire. Of the sample of 325 subjects, a total of 205 (63%) met criteria for lifetime substance abuse/dependence, with the remainder comprising the comparison group. The substance abusers were placed into one of four predominant drug of abuse/dependence categories (opioid, cocaine or stimulants, marijuana or sedatives, or alcohol) based upon best-estimate diagnoses and one of five self-reported drug of preference groups (polysubstance, opioid, cocaine or stimulants, marijuana or sedatives, and alcohol). Findings demonstrated that individuals with substance abuse/dependence, compared to those without, scored lower on constraint even after adjusting for socio-demographic factors, comorbid psychiatric disorder, and current/remitted substance-use disorder. Individuals with substance abuse/dependence scored marginally higher on negative emotionality, but this difference was statistically significant only when co-morbid psychopathology was not controlled. Findings also showed that individuals who differ with respect to drug of choice-whether defined in terms of the predominant drug of abuse/dependence or self-reported drug of preference-vary in terms of constraint. After controlling for socio-demographic indicators and co-morbid psychopathology, scores on constraint generally decreased with the social deviance of the drug of choice, thereby underscoring a potentially important link between disinhibition and drug selection. Conway, K.P., Swendsen, J.D., Rounsaville, B.J., and Merikangas, K.R. Drug and Alcohol Dependence, 65, pp. 225-234, 2002.

Challenges In the Transfer of Contingency Management Techniques

Nancy Petry from the University of Connecticut critiqued the Therapeutic Workplace intervention. Strengths described include studying a patient population of major public health concern, expanding contingency management techniques to a vocational training setting, reinforcing gradual approximations, implementing the intervention for a long duration, and carefully designing and executing the experimental procedures. However, she emphasized many of these strengths also may be interpreted as weaknesses if the ultimate goal is to apply contingency management techniques in self-sustaining, community-based settings. She noted the need for long-term cost-effectiveness of these procedures, and discussed the difficulties in transferring contingency management techniques to real-world settings. Petry, N.M. Experimental and Clinical Psychopharmacology, 9, pp. 35-39, 2001.

A Promising Intervention For A Daunting Problem: Comment On Silverman Et Al. (2001)

Researcher Steve Higgins from the University of Vermont provided a commentary on Kenneth Silverman's Therapeutic Workplace Intervention. He asserted that the therapeutic workplace represents a creative and promising new approach to drug abuse treatment that to the author's knowledge, is the first intervention that has been shown in a randomized clinical trial to significantly reduce cocaine abuse among pregnant women. He commended the rigor of the work and the science-based approach that integrates concepts and principles from several behavioral science literatures. He remarked that the intervention offers a potentially practical way of extending incentive-based drug abuse treatments to community clinics and suggested that the report has the potential to provoke serious consideration of what more might be done to combat chronic unemployment and drug abuse in poor communities. Higgins, S.T. Experimental and Clinical Psychopharmacology, 9, pp. 27-28, 2001.

Clinical Features of Pathological Gambling in an Addictions Treatment Cohort

Dr. James Langenbucher and colleagues at the Rutgers Center for Alcohol Studies examined the prevalence and descriptive psychopathology of pathological gambling in a heterogeneous treatment sample of 372 substance users. Of all participants, about 14% of men and 10% of women were identified by the South Oaks Gambling Screen (SOGS) as likely pathological gamblers (PGs). Compared with the 323 participants who were not pathological gamblers (NPGs), the 49 PGs showed more disturbance than NPGs on some measures of premorbid risk, pathological substance use, social consequences of use, and psychiatric comorbidity. Gambling status may be an important comorbid condition in addictions treatment settings and a significant covariate in research. Langenbucher, J., Bavly, L., Labouvie, E., Sanjuan, P.M., and Martin, C.S. Psychology of Addictive Behaviors, 15, pp. 77-79, 2002.

The Brief Abstinence Test: Effects of Continued Incentive Availability on Cocaine Abstinence

This study tested the efficacy of varying levels of incentives to initiate and sustain short-term abstinence from cocaine use. Cocaine-abusing methadone patients were randomized to one of 4 study conditions: In 3 conditions, patients could earn $100 for 2 days of cocaine abstinence; 2 of these conditions offered, on either a continuous or interrupted schedule, an additional $300 for evidence of sustained abstinence over the next 9 days. Patients in the 4th condition were offered no incentives. In the 3 incentive conditions, 70-80% of patients initiated abstinence, compared with 48% in the no-incentive condition. Both continuing reinforcement conditions produced higher rates of sustained abstinence than the single and no-voucher conditions. The study confirmed the utility of quantitative urine-testing methods combined with high valued incentives to promote cocaine abstinence initiation in methadone maintenance patients. Katz, E.C., Robles-Sotelo, E., Correia, C.J., Silverman, K., Stitzer, M.L., and Bigelow, G. Experimental & Clinical Psychopharmacology, 10, pp. 10-17, 2002.

Interest in and Obstacles to Pursuing Work Among Unemployed Dually Diagnosed Individuals

This study investigated interest in and perceived barriers to pursuing work, and the utilization of vocational rehabilitation services among 130 unemployed members of a dual recovery self-help fellowship. Members generally expressed high interest in working, although they perceived multiple barriers to attaining and maintaining employment. Based on a path model predicting interest in working, both substance use status and physical health rating were found to be significant contributors to interest in working. As expected, mental health symptoms and greater perceived obstacles (e.g., stigma, fear of failure, and insufficient skills) were significant contributors to perceived difficulty in pursuing work, whereas substance use, physical health, and recency of employment were not. Finally, perceived barriers to pursuing work, but not interest in work, were related to utilizing vocational rehabilitation services. There was also a significant gender difference, with men more likely than women to use these vocational rehabilitation services. Laudet, A.B., Magura, S., Vogel, H.S., Knight, E. L.. Substance Use & Misuse, 37, pp. 145-170, 2002.

Inhibition of Synthesis of Stress Hormones Does Not Reduce Drug Abuse

Stress plays an important role in substance abuse problems. For example, in studies with rodents stress induces reinstatement of opioid and cocaine self-administration. In addition, attenuation of the stress response by pharmacological adrenalectomy using ketoconazole, a cortisol synthesis inhibitor, reduces cocaine self-administration in rodents. In contrast, studies in primates and humans have produced conflicting results using cortisol synthesis inhibitors for attenuating cocaine-related behaviors and subjective effects. To explore the treatment implications of these findings, ketoconazole's (600-900 mg daily) ability to reduce heroin and cocaine use was compared with placebo in 39 methadone maintained patients with a history of cocaine abuse or dependence during a 12-week double blind trial. Contrary to the predicted effects, both heroin and cocaine use increased after patients were stabilized on methadone and ketoconazole. Depressive and withdrawal symptoms improved no more with ketoconazole than with placebo treatment, and side effects were greater on ketoconazole than placebo. As reported before with methadone treatment, morning cortisol levels were significantly lower than normal values throughout the clinical trial, but were not lower with ketoconazole than placebo treatment. Thus, in agreement with the negative results from acute dosing studies in primates and humans, chronic ketoconazole treatment does not appear to reduce cocaine or opioid use in humans maintained on methadone. Kosten, T.R., Oliveto, A., Sevarino, K.A., Gonsai, K.,and Feingold, A. Ketoconazole Increases Cocaine and Opioid Use in Methadone Maintained Patients. Drug Alcohol Depend., 66(2), pp.173-180, 2002.

Predictive Validity of the CSSA and Urine Toxicology Results in Drug Abuse Treatment

Both cocaine withdrawal symptoms, measured by an instrument called the Cocaine Selective Severity Assessment (CSSA), and urine toxicology results obtained at the start of treatment have been shown to predict treatment outcome in outpatient cocaine dependence treatment. This study further evaluates the predictive validity of the CSSA and urine toxicology results, alone and in combination. Subjects included 76 cocaine-dependent individuals who participated in 7-week, outpatient, pilot medication trials for cocaine dependence. Predictor variables included CSSA scores and results from a urine toxicology screen obtained on the first day of medication treatment. Successful outcome was defined as 3 continuous weeks of self-reported abstinence from cocaine confirmed by urine toxicology screens. Predictive validity was assessed by logistic regression analysis. Both the urine toxicology screen and the CSSA scores were significant predictors of 3 weeks of continuous abstinence from cocaine, and the inclusion of both variables significantly improved the predictive validity of either variable alone. Urine toxicology results and CSSA scores obtained at treatment entry are useful predictors of outcome in outpatient cocaine dependence treatment. Kampman, K.M., Volpicelli, J.R., Mulvaney, F., Rukstalis, M., Alterman, A.I., Pettinati, H., Weinrieb, R.M., and O'Brien, C.P. Cocaine Withdrawal Severity and Urine Toxicology Results from Treatment Entry Predict Outcome in Medication Trials for Cocaine Dependence. Addict Behav., 27(2), pp. 251-260, 2002.

Depot Formulation of Naltrexone Provides a Safe, Effective, Long-lasting Antagonism of the Effects of Heroin

Naltrexone, an opioid antagonist, is currently approved as a treatment for heroin dependence. However, naltrexone is generally not well accepted by patients, and medication non-compliance is a difficult obstacle to treatment. A sustained-release form of naltrexone may improve compliance. The present study was designed to evaluate the time course, safety, and effectiveness of a depot formulation of naltrexone (Depotrex). Twelve heroin-dependent individuals participated in an 8-week inpatient study. After a 1-week detoxification period, six participants received 192 mg naltrexone base and six participants received 384 mg naltrexone base. For safety, the low dose of depot naltrexone was tested before the high dose. The effects of heroin (0, 6.25, 12.5, 18.75, 25 mg, ivy.) were evaluated for the next 6 weeks. One dose of heroin was tested per day on Mondays through Fridays, and the entire dose range was tested each week. Active heroin doses were administered in ascending order during the week, while placebo could be administered on any day. Subjective, performance, and physiological effects were measured both before and after heroin administration. The hypotheses were that depot naltrexone would antagonize the effects of heroin, and that the high dose of depot naltrexone would produce a more effective and longer-lasting antagonism than the low dose. The low and high doses of depot naltrexone antagonized heroin-induced subjective ratings for 3 and 5 weeks, respectively. Plasma levels of naltrexone remained above 1 ng/ml for approximately 3 and 4 weeks after administration of 192 mg and 384 mg naltrexone. Other than the initial discomfort associated with the injection of depot naltrexone, there were no untoward side effects. These results suggest that this depot formulation of naltrexone provides a safe, effective, long-lasting antagonism of the effects of heroin. Comer, S.D., Collins, E.D., Kleber, H.D., Nuwayser, E.S., Kerrigan, J.H., and Fischman, M.W. Depot Naltrexone: Long-lasting Antagonism of the Effects of Heroin in Humans. Psychopharmacology (Berl); 159(4), pp. 351-360, 2002.

Buprenorphine May Have Abuse Liability in Nonopioid-dependent Individuals who Abuse Heroin

Several sources indicate that intravenously administered buprenorphine may have significant abuse liability in humans. The present study evaluated the reinforcing effects of intravenously administered buprenorphine (0, 2, and 8 mg) in detoxified heroin-dependent participants during a 7.5-week inpatient study. Participants (n = 6) were detoxified from heroin over a 1.5-week period immediately after admission. Testing subsequently occurred in three 2-week blocks. During the first week of each 2-week block, the reinforcing effects of buprenorphine were evaluated. Participants first received a dose of buprenorphine and $20 and then were given either the opportunity to self-administer the dose or $20 during choice sessions. During the second week of each 2-week block, the direct effects of heroin were measured to evaluate potential long-lasting antagonist effects of buprenorphine. Progressive ratio break-point values were significantly higher after 2 and 8 mg of buprenorphine compared with placebo. Correspondingly, several positive subjective ratings increased after administration of active buprenorphine relative to placebo. Although there were few differences in peak effects produced by 2 versus 8 mg of buprenorphine, the higher buprenorphine dose generally produced longer-lasting effects. Heroin also produced dose-related increases in several subjective effects. Peak ratings produced by heroin were generally higher than peak ratings produced by buprenorphine. There was little evidence of residual antagonism produced by buprenorphine. These results demonstrate that buprenorphine served as a reinforcer under these conditions, and that it may have abuse liability in nonopioid-dependent individuals who abuse heroin. Comer, S.D., Collins, E.D., and Fischman, M.W. Intravenous Buprenorphine Self-administration by Detoxified Heroin Abusers. J Pharmacol Exp Ther., 301(1), pp. 266-276, 2002.

Prefrontal Dysfunction in Methamphetamine-Dependent Subjects

Paulus and colleagues at the Department of Psychiatry, University California, San Diego used fMRI to demonstrate decision-making deficits in a two-choice prediction task and reduced task-related neural activation in different prefrontal areas in subjects dependent on methamphetamine. The performance of 10 methamphetamine abusers during early stages of abstinence was compared to ten age- and education-matched, non-drug using controls. Relative to comparison subjects methamphetamine abusers more influenced by the immediately preceding outcome during the two-choice prediction task, i.e. relied on stimulus-contingent response selection. Methamphetamine-dependent subjects failed to activate ventromedial cortex (BA 10,11) during the task, and exhibited less task related activation of the dorsolateral prefrontal cortex (BA 9) than the comparison subjects. These results demonstrate that decision-making deficits in methamphetamine abusers are related to orbitofrontal and dorsolateral prefrontal dysfunction. Paulus, M.P. et al., Neuropsychopharmacology, 26, pp. 53-63, 2002.

Prefrontal and Anterior Cingulate Activity during Decision-Making Depend on Error Rate and Outcome Predictability

Paulus and colleagues at the Department of Psychiatry, University California, San Diego used fMRI to demonstrate that the rate of errors during decision-making differentially affects activation of the prefrontal and cingulate cortex in normal, healthy subjects. BOLD fMRI scans were obtained while normal, healthy subjects performed a two-choice prediction task across 90-s blocks with 20, 50, or 80% error rates. As reported previously, activation of the right dorsolateral (BA 9, 46), inferior prefrontal (BA 44), and precuneus (BA 7) was observed when error rates were set at chance level (50%). In contrast, premotor (BA 6) and parahippocampal (BA 36) areas were relatively more active at high error rates. During low error rates, the dorsolateral (BA 9, 46) and inferior prefrontal cortex (BA 44) as well as parietal (BA 40) and cingulate cortex (BA 25, 32) were more active. In addition, error rate or outcome predictability influenced the relationship activation in the dorsolateral prefrontal cortex and the anterior cingulate and the dominant strategy underlying decision-making (e.g., win-stay/lose-shift). These results suggest that these structures maintain a representation of the reinforcement history and available response alternatives that contribute to selection of optimal decision-making strategies. Paulus, M.P., Hozack, N., Frank, L., and Brown, G.G. Neuroimage, 15(4), pp. 836-846, 2002.

Reward Prediction Errors Selectively Activate Ventral Striatum in Humans

Berns and colleagues in the Department of Psychiatry at Emory University used fMRI to test whether the ventral striatum plays a specific role of signaling errors in the prediction of rewards in normal, healthy subjects. Subjects performed either a simple operant conditioning task involving delivery of small quantities of fruit juice rewards or a control task where the outcome event was a neutral visual stimulus instead of juice. Increased BOLD signal in the ventral striatum occurred when the juice was withheld at the expected time of delivery, but not when the visual outcome stimulus was unexpectedly withheld. These data provide evidence for time-locked processing of reward prediction errors in human ventral striatum. Pagnoni, G. et al., Nature Neuroscience, 5, pp. 97-98, 2002.

Changes in Gene Expression Linked to Methamphetamine-Induced Dopaminergic Neurotoxicity

The effects of the mRNA synthesis inhibitor, actinomycin-D, and the protein synthesis inhibitor, cycloheximide, were examined by Dr. Ricaurte and colleagues at the Johns Hopkins School of Medicine. Both agents afforded complete protection against methamphetamine- (METH) induced DA neurotoxicity and did so independently of effects on core temperature, DA transporter function, or METH brain levels, suggesting that gene transcription and mRNA translation play a role in METH neurotoxicity. Next, microarray technology, in combination with an experimental approach designed to facilitate recognition of relevant gene expression patterns, was used to identify gene products linked to METH-induced DA neurotoxicity. This led to the identification of genes in the ventral midbrain associated with the neurotoxic process, including genes for energy metabolism [cytochrome c oxidase subunit 1 (COX1), reduced nicotinamide adenine dinucleotide ubiquinone oxidoreductase chain 2, and phosphoglycerate mutase B], ion regulation (members of sodium/ hydrogen exchanger and sodium/bile acid cotransporter family), signal transduction (adenylyl cyclase III), and cell differentiation and degeneration (N-myc downstream-regulated gene 3 and tau protein). It was elected to further examine the increase in COX1 expression, because of data implicating energy utilization in METH neurotoxicity and the known role of COX1 in energy metabolism. On the basis of time course studies, Northern blot analyses, in situ hybridization results, and temperature studies, it was shown that increased COX1 expression in the ventral midbrain is linked to METH-induced DA neuronal injury. The precise role of COX1 and other genes in METH neurotoxicity remains to be elucidated. Xie, T., Tong, L., Barrett, T., Yuan, J., Hatzidimitriou, G., McCann, U.D., Becker K.G., Donovan, D.M. and Ricaurte, G.A. Changes in Gene Expression Linked to Methamphetamine-Induced Dopaminergic Neurotoxicity. Journal of Neuroscience, 22(1), pp. 274-281, 2002.

Altered Prolactin Response to M-chlorophenylpiperazine in Monkeys Treated Previously with 3,4-Methylenedioxymethamphetamine (Ecstasy, MDMA) and Fenfluramine

3,4-Methylenedioxymethamphetamine (ecstasy, MDMA) and fenfluramine are potent brain serotonin (5-HT) neurotoxins in animals. There is concern that humans previously exposed to these amphetamine derivatives may have incurred brain 5-HT neurotoxicity. To determine whether MDMA- and/or fenfluramine-induced 5-HT neurotoxicity can be detected during life using neuroendocrine methods, groups of monkeys previously treated with neurotoxic regimens of MDMA or fenfluramine underwent neuroendocrine challenge with the direct 5-HT agonist and 5-HT-releasing drug, m-chlorophenylpiperazine (m-CPP). Animals treated 2 weeks previously with MDMA exhibited a nonsignificant reduction in the prolactin response to m-CPP. In contrast, monkeys treated 3 1/2 years previously with MDMA or 2 years previously with fenfluramine exhibited significantly increased prolactin responses to m-CPP. No significant differences in cortisol concentrations were noted between groups at any time point. These data indicate that neuroendocrine challenge with m-CPP is capable of detecting substituted amphetamine-induced 5-HT neurotoxicity in living primates, but that the recency of drug exposure is an important consideration. Changes in the neuroendocrine response to m-CPP over time in animals with substituted amphetamine-induced neurotoxicity may be related to aberrant 5-HT reinnervation of the basal forebrain that occurs over time in monkeys previously treated with neurotoxic doses of MDMA or fenfluramine. Hatzidimitriou, G., Tsai, E.H., McCann, U.D., and Ricaurte, G.A. Altered Prolactin Response to M-chlorophenylpiperazine in Monkeys Previously Treated with 3,4-methylenedioxymethamphetamine (MDMA) or Fenfluramine. Synapse, 44(1), pp. 51-57, 2002.

A Comprehensive Review of Two Common Club Drugs

Evidence indicates that 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) is toxic to serotonergic neurons in animals and may be a neurotoxin in humans as well. The use of gamma-hydroxybutyrate (GHB), although not as popular as MDMA, is also a significant problem. The pharmacokinetics of MDMA and GHB, appear to be nonlinear, making it difficult to estimate a dose-response relationship. Symptoms of an MDMA toxic reaction include tachycardia, sweating, and hyperthermia. Occasional severe sequelae include disseminated intravascular coagulation, rhabdomyolysis, and acute renal failure. Treatment includes lowering the body temperature and maintaining adequate hydration. Symptoms of GHB intoxication include coma, respiratory depression, unusual movements, confusion, amnesia, and vomiting. Treatment includes cardiac and respiratory support. Because of the popularity of these agents and their potentially dangerous effects, health care professionals must be familiar with these substances and the treatment options for patients who present with symptoms of a toxic reaction. Because of the increasing popularity of club drugs and their dangerous adverse effects, health care professionals must be familiar with these substances. No standard treatment protocols exist for the intoxication syndromes associated with MDMA or GHB, and supportive care is currently the standard of treatment. Teter, C.J., and Guthrie, S.K., A Comprehensive Review of MDMA and GHB: Two Common Club Drugs. Pharmacotherapy, 21(12), pp. 1486-1513, 2001.

Risperidone Pre-Treatment Reduces the Euphoric Effects of Experimentally Administered Cocaine

The effects of stimulants seem to be critically dependent on dopaminergic (DA) neurotransmission in preclinical research; however, stimulant challenge studies using volunteers treated with DA antagonists have generally failed to demonstrate a reduction of subjective effects. To further test the role of DA, a study to determine whether repeated dosing with risperidone reduced the subjective effects of experimentally administered cocaine was conducted. Nine non-treatment seeking hospitalized cocaine-dependent volunteers received 40 mg cocaine IV before and following 5 days of treatment with 2 mg per day of risperidone, a D2 antagonist. Risperidone pre-treatment reduced the self-rated `high' produced by cocaine. Repeated, rather than single dosing may be necessary to reduce the subjective effects produced by cocaine. The degree of D2 receptor blockade produced by risperidone appears to be greater than the reduction in euphoric effects produced by cocaine, suggesting that mechanisms other than those involving D2 receptors may be important in drug-induced euphoria. Newton, T.F., Ling, W., Kalechstein, A.D., Uslaner, J., and Tervo, K. Risperidone Pre-Treatment Reduces the Euphoric Effects of Experimentally Administered Cocaine. Biology Psychiatry, 102, pp. 227-233, 2001.

Sensitivity of Prefrontal Cortex to Changes in Target Probability: A Functional MRI Study

Electrophysiological studies suggest sensitivity of the prefrontal cortex to changes in the probability of an event. The purpose of this study by Dr. Steven Forman and colleagues at the University of Pittsburgh was to determine if subregions of the prefrontal cortex respond differentially to changes in target probabilities using functional magnetic resonance imaging (fMRI). Ten right-handed adults were scanned using a gradient-echo, echo planar imaging sequence during performance of an oddball paradigm. Subjects were instructed to respond to any letter but X. The frequency of targets (i.e., any letter but X) varied across trials. The results showed that dorsal prefrontal regions were active during infrequent events and ventral prefrontal regions were active during frequent events. Further, we observed an inverse relation between the dorsal and ventral prefrontal regions such that when activity in dorsal prefrontal regions increased, activity in ventral prefrontal regions decreased, and vice versa. This finding may index competing cognitive processes or capacity limitations. Most importantly, these findings taken as a whole suggest that any simple theory of prefrontal cortex function must take into account the sensitivity of this region to changes in target probability. Casey, B.J., Forman, S.D., Franzen, P., Berkowitz, A., Braver, T.S., Nystrom, L.E., Thomas, K.M., and Noll, D.C. Sensitivity of Prefrontal Cortex to Changes in Target Probability: A Functional MRI Study. Human Brain Mapping, 13, pp. 26-33, 2001.

Quantitative EEG (QEEG) Defined a Group of Treatment-receptive Cocaine-Dependent Males and Females

Dr. Leslie Prichep and colleagues at NYU School of Medicine used EEG analyzed by sophisticated quantitative measures and somatosensory evoked potential features to group 16 female and 41 male cocaine-dependent subjects into three clusters. All subjects were in treatment and had been drug free for 5 to 14 days. The clusters were compared on a median split of length-of-stay (</> 25 weeks) in treatment. Eighty percent of the subjects in one cluster remained in treatment more than 25 weeks, while only 22% and 35% of the subjects in the other clusters did. There were no differences among the clusters in length or amount of cocaine use. The EEG patterns of the clusters differed in a number of ways of relative and absolute power in various frequency bands. Understanding the bases of these electrocortigrams will aid in understanding the individual differences among recovering cocaine-dependent individuals. Prichep, L.S., Alper, K.R., Sverdlov, L., Kowalik, S.C., John, E.R., Merkin, H., Tom, M.L., Howard, B., and Rosenthal, M.S. Clin Electroenceph, 33(1), pp. 8-20, 2002.

Fluoxetine was Shown to Reduce the Probability of Dropout and Increase the Probability of Abstinence in Smoking Cessation Treatment

Hitsman and colleagues demonstrated in a two-level dose (30 mg and 60 mg) of fluoxetine that there was a dose-response improvement in dropout and abstinence rates and a behavioral treatment paradigm. The study was devised to answer questions of whether side effects to such treatment would have the opposite, deleterious effect or would have a positive effect at the lower dose and a negative effect at the higher dose. In further analysis it was shown that the probability of improved performance was correlated linearly with blood levels (for moderate levels and above) for both men and women, though men had an overall better outcome. Hitsman, B., Spring, B., Borelli, B., Niura, R., and Papandonatos, G.D., Exptl Clin Psychopharm, 9(4), pp. 355-362, 2001.

Impulsivity Has an Important Role in Severity of Drug Use and in Retention in Treatment

Moeller and colleagues assessed treatment-seeking cocaine-dependent subjects on a questionnaire (BIS-11) measurement of impulsivity. The subjects then participated in a 12-week double-blind placebo-controlled trial of buspirone. Both amount of cocaine use and severity of withdrawal were significantly correlated with impulsivity scores. While the effect of buspirone was modest and not significant in percentage of subjects who remained in the trial, scores on the impulsivity measure were: higher scores predicted early drop-outs with 25% remaining at 12 weeks compared to 70% with low impulsivity scores. While the numbers in the study were small (n=35), the results suggest that impulsivity is an important consideration for both cocaine use and for treatment outcome. Moeller, F.G., Dougherty, D.M., Barrattt, E.S., Schmitz, J.M., Swann, A.C., and Grabowski, J. J Subst Abuse Treat., 21, pp. 193-198, 2001.

Serum Prolactin, as a Measure of Central Dopamine, Is Related to Some Successful Outcomes in Treatment

Dr. Ashwin Patkar and associates assayed serum prolactin and found that cocaine-dependent subjects with levels above the median in treatment had fewer negative urine screens and received less favorable ratings by the treatment counselors. While it was true that neither discharge status nor retention in treatment were related to prolactin levels, the results do indicate activity of cerebral activity-presumably in the dopaminergic system-modulate treatment goals. It should be noted that prolactin levels in the cocaine patients were significantly higher than controls by nearly 30% (9.12 vs. 7.14 ng/ml). Patkar, A.A., Hill, K.P., Sterling, R.C., Gottheil, E., Berrettinin, W.H., and Weinstein, S.P. Addiction Biology, 7(1), pp. 45-53, 2002.

Preliminary Evidence Suggests an Allele of the Serotonin Transporter is Related to Cocaine Abuse

Dr. Patkar and colleagues compared Long (L) and Short (S) alleles of the serotonin transporter between cocaine-dependent subjects and controls in an association study. The alleles differed by a 44-bp insertion or deletion involving repeat elements. Those with an L-allele (and those with the LL genotype) were more frequent among the cocaine patients; the SS genotype was less frequent. All the patients were African-American (N=197); these results were significant only when compared to a heterogeneous control group (N=101) while failing to reach significance when compared only to the African-American controls (N=61). There were no differences between the groups in allele frequencies and it is tentatively concluded that the failure to reach significance was due to reduced sample size, since the trends were the same. These results therefore suggest that allelic variants of the serotonin transporter may be related to cocaine susceptibility. Patkar, A.A., Berrettini, W.H., Hoehe, M., Hill, K.P., Sterling, R.C., Gottheil, E., and Weinstein, S.P. Addiction Biology, 6, pp. 337-345, 2001.

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