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Director's Report to the National Advisory Council on Drug Abuse - May, 2007



Research Findings - Research on Pharmacotherapies for Drug Abuse

Urine Drug Screens (UDS) and Cocaine Selective Severity Assessment (CSSA) Scores are Powerful Outcome Predictors in Cocaine Dependence Treatment Trials

This study extended findings based on current predictors of response to psychosocial treatment, i.e., cocaine withdrawal symptom severity and results of a urine drug screen (UDS), by examining outcome predictors in a large number (n=402) of subjects participating in a series of outpatient cocaine pharmacotherapy trials while selecting three separate criteria to define successful outcome. Predictor variables included results from the baseline Addiction Severity Index (ASI), initial UDS results, and cocaine withdrawal symptom severity at treatment entry, as measured by scores on the Cocaine Selective Severity Assessment (CSSA). Baseline variables that most consistently predicted treatment outcome were the initial UDS results and initial CSSA scores, indicating that baseline UDS results and CSSA scores are powerful predictors of outcome and should be used as stratifying variables in outpatient cocaine medication trials. Ahmadi, J., Kampman, K. and Dackis, C. Outcome Predictors in Cocaine Dependence Treatment Trials. Am J Addiction, 15, pp. 434-439, 2006.

Benztropine Does Not Alter Cocaine-induced Effects

In this human laboratory study, benztropine was evaluated for its ability to block cocaine's physiological and subjective effects in 16 healthy, adult male volunteers who were recreational users of cocaine. Placebo or benztropine (1, 2, and 4 mg orally) was given 2 hours before subjects self-administered 0.9 mg/kg cocaine intranasally. Measurements (increases in heart rate and alterations in self-reports measured by visual analog scales) were made 2 hours following cocaine administration and plasma cocaine and cocaine metabolites were assayed. Benztropine alone did not produce changes on these measures, and responses to cocaine with and without benztropine pretreatment were similar. The results of this study suggest that benztropine does not alter cocaine-induced effects, and does not produce adverse behavioral or physiological effects. Penetar, D., Looby, A.R., Su, Z., Lundahl, L.H., Eroes-Sarnyai, M., McNeil, J.F., and Lukas, S.E. Benztropine Pretreatment Does Not Affect Responses to Acute Cocaine Administration in Human Volunteers. Hum Psychopharmacol Clin Exp, 21, pp. 549-559, 2006.

Divalproex May Be A Possible Treatment for Patients with Comorbidity of Bipolar Disorder and Primary Cocaine Dependence

This report describes the result of an open-label pilot study with divalproex to evaluate its utility in decreasing cocaine use and stabilizing mood symptoms in 15 adult subjects with a DSM-IV diagnosis of comorbid bipolar disorder and cocaine dependence. Patients were started on open-label divalproex. After stabilization, weekly assessments, with counseling, were undertaken for 8 weeks. The results showed significant improvement on % cocaine abstinent days, dollars spent on cocaine, ASI's drug use severity index, % alcohol abstinent days, drinks per drinking day, marijuana use and cigarette smoking. Results also showed significant improvement on manic, depressive, and sleep symptoms and on functioning, with no reported adverse events, or increases in liver function tests. Double-blind, placebo-controlled studies to fully evaluate the efficacy of divalproex in this patient population are warranted, based on the results of this pilot study. Salloum, I.M., Douaihy, A., Cornelius, J.R., Kirisci, L., Kelly, T.M. and Hayes, J. Divalproex Utility in Bipolar Disorder With Co-occurring Cocaine Dependence: A Pilot Study. Addictive Beh, 32, pp. 410-415, 2007.

Cocaine Withdrawal Symptoms May Predict Treatment Response to Medications

This study examined the influence of cocaine withdrawal symptoms on addiction severity and treatment outcomes in 85 methadone-stabilized cocaine users who participated in pharmacotherapy trials using GABA medications. Subjects who fulfilled DSM-IV cocaine withdrawal criteria (n=45) compared to those who did not (n=40) showed a greater increase in cocaine free urines in response to pharmacotherapy with GABA medications. The results of this and previous studies support the clinical utility of cocaine withdrawal symptoms in predicting treatment response to GABA medications, while high withdrawal severity may predict better response to adrenergic blockers. Sofuoglu, M., Poling, J., Gonzalez, G., Gonsai, K., and Kosten, T. Cocaine Withdrawal Symptoms Predict Medication Response in Cocaine Users. Am J Drug Alcohol Abuse, 32, pp. 617-627, 2006.

Gabapentin Does Not Reduce Smoked Cocaine Self-administration

This 48-day inpatient/outpatient study examined the effects of gabapentin maintenance on cocaine self-administration using a purchase-cocaine choice procedure in 12 nontreatment- seeking cocaine abusers maintained on gabapentin (0, 600, 1200 mg.day). Four doses of cocaine (0, 12, 25, 50 mg) were each tested twice under each gabapentin condition. Participants were provided with 25 dollars before the start of each session, and smoked the sample cocaine dose once. Subsequently, participants were given five opportunities to purchase the sampled dose of cocaine at 5 dollars per dose or to keep 5 dollars for that choice trial. Choice to self-administer cocaine increased significantly with escalating cocaine doses. Gabapentin maintenance did not alter choice to self-administer cocaine. Along with other study results, the data indicate that gabapentin does not show promise as a treatment medication for cocaine dependence. Hart, C.L., Haney, M., Vosburg, S.K., Rubin, E., and Foltin, R.W. Gabapentin Does Not Reduce Smoked Cocaine Self-Administration: Employment of a Novel Self-Administration Procedure. Behav Pharmacol, 18, pp. 71-5, 2007.

No Associations Between Polymorphisms in the Par-4 Gene and the Cocaine-dependent Phenotype

The purpose of this study was to test the hypothesis that polymorphisms in the human Par-4 gene contribute to the etiology of cocaine dependence, based on other studies which have investigated the genes underlying dopamine, serotonin and glutamine neurotransmitter systems in order to find a genetic basis for the pathology of cocaine dependence. The study employed a case-control design in which the genotype and allele frequencies for five single nucleotide polymorphisms in the human Par-4 gene were compared between 172 cocaine-dependent individuals and 92 controls, of African descent. The genotype results failed to detect any associations between polymorphisms in the Par-r gene and the cocaine-dependent phenotype, suggesting that variations in the human Par-4 gene are unlikely to play a major role in the pathophysiology of cocaine dependence. The authors suggest that the study should be repeated in larger cocaine-dependent and control populations to determine if this is the case. Weller, A.E., Dahl, J.P., Lohoff, F.W., Kampman, K.M., Oslin, D.W., Dackis, C., Ferraro, T.N., O'Brien, C.P., and Berrettini, W.H. No Association Between Polymorphisms in the Prostate Apoptosis Factor-4 Gene and Cocaine Dependence. Psychiatric Genetics, 16, pp. 193-196, 2006.

Characteristics of Individuals Presenting for Substance Abuse Treatment Can Provide Important Information to Help Focus Treatment Services

In this study, demographic and clinical characteristics of individuals presenting for medication trials for the treatment of cocaine or marijuana dependence were compared, to highlight the significant impairments associated with marijuana and cocaine dependence. In general, marijuana-dependent subjects were younger than cocaine-dependent subjects, more likely to be Caucasian, and completed more years of education. Marijuana-dependent subjects also reported significantly more days using than cocaine-dependent subjects and higher levels of craving. Cocaine-dependent subjects were more likely to report anxiety symptoms and marijuana-dependent subjects, more past depressive episodes. Past and current other drug use was similar between the two groups. McRae, A.L., Hedden, S.L., Malcolm, R.J., Carter, R.E., and Brady, K.T. Characteristics of Cocaine- and Marijuana-Dependent Subjects Presenting for Medication Treatment Trials. Addictive Behaviors, 2006 (e-publication ahead of print).

Interaction Between Opioid Antagonists and Cannabinoid Agonists Varies as a Function of Marijuana Use History

The purpose of this study was to test whether a low dose of naltrexone (12 mg) in combination with THC has the same reported reinforcing effect as a higher (50 mg) dose of naltrexone. Naltrexone (0, 12 mg) was administered 30 minutes before oral THC (0-40 mg) or methadone (0--10 mg) capsules, and subjective effects, task performance, pupillary diameter, and cardiovascular parameters were assessed in marijuana smoking (n=22) and nonmarijuana smoking (n=21) men and women. The results showed that in marijuana smokers, low-dose naltrexone blunted the intoxicating effects of a low THC dose (20 mg) while increasing ratings of anxiety at a higher THC dose (40 mg). In nonmarijuana smokers, low-dose naltrexone enhanced the intoxicating effects of a low THC dose (2.5 mg) and decreased anxiety ratings following a high dose of THC (10 mg). There were no sex differences in these interactions, although among nonmarijuana smokers, men were more sensitive to the effects of THC alone than women. To conclude, a low, opioid-selective dose of naltrexone blunted THC intoxication in marijuana smokers, while in nonmarijuana smokers, naltrexone enhanced THC intoxication. Haney, M. Opioid Antagonism of Cannabinoid Effects: Differences Between Marijuana Smokers and Nonmarijuana Smokers. Neuropsychopharmacology 2006 (e-publication ahead of print).

Mood Disorders Affect Drug Treatment Success of Drug-dependent Pregnant Women

This study examined the impact of co-occurring Axis I disorders on drug treatment outcomes of drug-dependent pregnant women. Participants (N =106) were women who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for opioid dependence and were receiving methadone. Based on DSM-IV Axis I criteria, participants were categorized into three groups: (1) absence of mood/anxiety disorder (ND, n = 29), (2) primary mood disorder (MD, n = 39), or (3) primary anxiety disorder (AD, n = 38). Demographically, the groups were similar. The MD group was significantly more likely to be positive for drugs while in treatment compared with both the ND and AD groups. The MD and AD groups had more psychosocial impairment and higher incidence of suicidal ideation compared with the ND group. Interestingly, the AD group spent more days in treatment compared with the ND or MD group. These findings highlight the need to treat co-occurring Axis I disorders, particularly given the higher relapse risk for those with mood disorders. Fitzsimons, H.E., Tuten, M., Vaidya, V., and Jones, HE. Mood Disorders Affect Drug Treatment Success of drug-dependent pregnant women. J Subst Abuse Treat. 32(1), pp. 19-25, 2007. Epub 2006 October 13, 2006.

Simultaneous Determination of Buprenorphine, Norbuprenorphine and the Enantiomers of Methadone and its Metabolite (EDDP) in Human Plasma by Liquid Chromatography/ Mass Spectrometry

Buprenorphine (Bu) is a semi-synthetic oripavine derivative which is 25-50 times more potent than morphine. In humans, Bu is N-dealkylated by cytochrome P450 3A4 to form norbuprenorphine (norBu). A previously reported enantioselective LC-MS assay for the determination of (R)- and (S)-methadone [Met] and (R)- and (S)-2-ethylidene-1,5-dimethyl-3,3-diphenyl-pyrrolidine [EDDP] (the primary metabolite of Met) has been adapted for use in the simultaneous determination of the plasma concentrations of Met, EDDP, buprenorphine (Bu) and norbuprenorphine (norBu). All of the target compounds were separated within 15min using an alpha(1)-acid glycoprotein chiral stationary phase, a mobile phase composed of acetonitrile: ammonium acetate buffer [10mM, pH 7.0] in a ratio of 18:82 (v/v), a flow rate of 0.9ml/min at 25 degrees C. Deuterium labeled compounds were used as internal standards [d(4)-Bu, d(3)-norBu, (R,S)-d(3)-Met and (R,S)-d(3)-EDDP] and linear relationships between peak height ratios and drug concentrations were obtained for Bu and norBu in the range 0.2-12ng/ml with correlation coefficients greater than 0.999. The relative standard deviations (%R.S.D.) for the intra- and inter-day precision of the method were <4.5% and for accuracy was <4.0%. The bioanalytical assay reported in this manuscript is a simple, sensitive, accurate, rapid and reproducible LC/MS method for the simultaneous determination of Bu, norBu and the enantiomers of Met and EDDP in human plasma obtained from opioid dependent methadone-maintained adults. The method was validated and used to analyze plasma samples obtained from opioid dependent methadone-maintained adults enrolled in a research study. Rodriguez-Rosas, M.E., Lofwall, M.R., Strain, E.C., Siluk, D., and Wainer, I.W. Simultaneous Determination of Buprenorphine, Norbuprenorphine and the Enantiomers of Methadone and its Metabolite (EDDP) in Human Plasma by Liquid Chromatography/Mass Spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci., November 30, 2006 [Epub ahead of print].

Lofexidine May have Potential in Reducing Stress-Related Opioid Craving and Relapse Outcomes in Humans

This preliminary study examined whether lofexidine decreases stress-induced and cue-induced opioid craving and improves opioid abstinence in naltrexone-treated opioid-dependent individuals. Eighteen opioid-dependent patients were stabilized for 4 weeks with naltrexone (50 mg/day) and lofexidine (2.4 mg bid) before entering a 4-week randomized, double-blind placebo-controlled discontinuation study where one group continued on lofexidine for an additional 4 weeks, and the second was tapered to placebo. Ten patients also participated in guided imagery exposure to stress, drug cue, and neutral scenarios in a single laboratory session. The results showed that lofexidine-naltrexone patients had higher opioid abstinence rates and improved relapse outcomes as compared to the placebo-naltrexone group, as well as significantly lower heart rates and an attenuated stress and drug cue-induced opioid craving response in the laboratory as compared to the placebo-naltrexone group. Further development of lofexidine to address stress-related opioid craving and relapse is warranted. Sinha, R., Kimmerling, A., Doebrick, C., and Kosten, T.R. Effects of Lofexidine on Stress-Induced and Cue-Induced Opioid Craving and Opioid Abstinence Rates: Preliminary Findings. Psychopharmacology, 190, pp. 569-574, 2007.

Effects of Acute Abstinence, Reinstatement, and Mecamylamine on Biochemical and Behavioral Measures of Cigarette Smoking in Schizophrenia

Schizophrenics have higher rates of smoking than the general population, and more difficulty with smoking cessation. However, there has been little study of differences between schizophrenics and controls with respect to biochemical and behavioral indices of smoking. This study compared smokers with schizophrenia (SS; n=27) and control smokers (CS; n=26) on smoking and psychiatric outcomes at baseline, during acute smoking abstinence and reinstatement, and with pre-treatment using the nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine (MEC) in a human laboratory setting. Biochemical (e.g., plasma nicotine) and behavioral (e.g., craving, withdrawal) outcomes were assessed at baseline, after overnight abstinence, and after smoking reinstatement during three consecutive test weeks. Each week, participants received one of three doses of MEC (0.0, 5.0, or 10.0 mg/dayx3 days) in a randomized, counterbalanced manner. Compared to CS, SS displayed similar levels of craving and withdrawal, but higher plasma nicotine and cotinine levels, and cotinine/CPD ratio. During reinstatement, SS consumed significantly more cigarettes than CS, but MEC did not significantly alter indices of smoking, psychiatric symptoms, or cigarette consumption during reinstatement. 1) The reinforcing effects of smoking may be increased in SS versus CS after overnight abstinence; 2) the lack of effects of nAChR antagonism may suggest that non-nicotinic components of cigarettes may contribute to the behavioral effects of smoking in both SS and CS; and 3) consistent with previous studies, SS may exhibit higher baseline levels of nicotine and cotinine, and greater extraction of nicotine per cigarette than CS. Weinberger, A.H., Sacco, K.A., Creeden, C.L., Vessicchio, J.C., Jatlow, P.I., and George, T.P. Effects of Acute Abstinence, Reinstatement, and Mecamylamine on Biochemical and Behavioral Measures of Cigarette Smoking in Schizophrenia. Schizophr Res. 91(1-3), pp. 217-225, 2007.

Nicotine Dependence, Symptoms and Oxidative Stress in Male Patients with Schizophrenia

The high rate of smoking in schizophrenia may reflect patients' attempts to reduce the side effects of antipsychotic medications, and one mechanism for this reduction may be a decrease in oxidative stress and free radical-mediated brain damage that may contribute to schizophrenic symptoms and to complications of its treatment. Symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS), side effects were assessed with the Simpson and Angus Rating Scale (SAS), and malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) activities were measured in plasma. All of these measures were compared in 130 male inpatients with DSM-IV schizophrenia: 104 smokers and 26 non-smokers. The results showed that the positive PANSS symptoms were lower in smokers than non-smokers (14.5 vs 17.5), while the negative symptoms were lower in those who smoked more cigarettes (r=-0.23). The SAS showed no differences. The CAT activity was correlated with both GSH-Px and SOD activities. Of the three enzymes only the CAT activity was significantly higher in smokers than non-smokers (2.9 vs 1.6 U/ml), but greater SOD activity was correlated with more cigarettes smoked (r=0.24). Consistent with some protection against oxidative stress, MDA also was significantly lower in smokers than non-smokers (9.2 vs 14.4 nmol/ml). The fewer positive symptoms in smokers and fewer negative symptoms in those who smoked more cigarettes may be a selection bias, but appears to be associated with decreased oxidative stress and lipid peroxidation in schizophrenics who smoke tobacco. Zhang, X.Y., Tan, Y.L., Zhou, D.F., Haile, C.N., Wu, G.Y., Cao, L.Y., Kosten, T.A., and Kosten, T.R. Nicotine Dependence, Symptoms and Oxidative Stress in Male Patients with Schizophrenia. Neuropsychopharmacology advance online publication, January 17, 2007.

Effects of High Dose Transdermal Nicotine Replacement in Cigarette Smokers

Nicotine replacement therapies (NRT) have been evaluated to facilitate cigarette smoking reduction in smokers unwilling or unable to quit. In most of these studies, only conventional doses of NRT have been tested and higher doses may be required to result in significant reductions in smoking and in biomarkers of exposure. The purpose of this study was to determine if higher NRT doses in conjunction with smoking are safe and may promote significant reductions in cigarette smoking and biomarkers of exposure. A dose-ranging, within-subject design was implemented to evaluate the effects of 15, 30 and 45 mg nicotine-patch treatment on measures of safety and the extent of smoking reduction and biomarker exposure per cigarette in smokers (N=20 completers) not immediately interested in quitting. Concurrent smoking and NRT were generally tolerated and resulted in no changes in blood pressure or heart rate. Slightly less than 10% of the study sample was not given the highest dose of NRT due to side effects. Self-reported cigarette smoking decreased with increasing doses of nicotine replacement and significant reductions were observed for total NNAL (a carcinogen biomarker) and carbon monoxide. However, even at the 45 mg dose, increased carbon monoxide and total NNAL per cigarette occurred, even though cotinine levels increased on average, 69.3% from baseline. The present results suggest that the use of high dose NRT is safe, leads to significant reductions in smoking (-49%), significant but less reductions in total NNAL (-24%) and carbon monoxide (-37%) due to compensatory smoking. Hatsukami, D. Mooney, M., Murphy, S., LeSage, M., Babb, D. and Hecht, S. Effects of High Dose Transdermal Nicotine Replacement in Cigarette Smokers. Pharmacol Biochem Behav. 86(1), pp. 132-139, 2007.


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