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



Research Findings - Research on Pharmacotherapies for Drug Abuse

Disulfiram Effects on Responses to Intravenous Cocaine Administration

Disulfiram has been studied as a treatment for cocaine dependence. Authors report results of a randomized, double-blind, placebo-controlled, within-subject study to examine the interaction of disulfiram with intravenous cocaine. Non-treatment-seeking, cocaine-dependent, volunteers participated in serial experiments in which they received disulfiram placebo, 62.5 or 250mg/day on days 1-6. On days 4-6, participants received a morning disulfiram dose 2h prior to a scheduled session in which they were administered intravenous cocaine placebo, 0.25mg/kg (n=9) or 0.5mg/kg (n=3) over 1 min. Blood, cardiovascular and subjective measures were collected. Seven days of washout occurred between disulfiram conditions. Following active disulfiram treatments and cocaine 0.25mg/kg administration, plasma cocaine AUC (0-480min) was increased (p=0.003 and 0.001) and cocaine clearance decreased (p<0.001). Disulfiram treatments also decreased cocaine clearance for the 0.5mg/kg cocaine dose (p=0.002 and<0.001). Neither disulfiram dose with cocaine altered cardiovascular responses relative to cocaine alone. Following cocaine 0.25mg/kg, 'any high' (p=0.021 and 0.019), 'cocaine high' (p=0.017 and 0.018) and 'rush' (p=0.013 and 0.047) significantly decreased with either disulfiram dose. Disulfiram decreased cocaine clearance without toxicity. Cocaine 'high' and 'rush' were diminished. Disulfiram may be a promising pharmacotherapy in selected cocaine dependent individuals. Baker, J.R., Jatlow, P., and McCance-Katz, E.F. Drug Alcohol Depend. September 15, 2006 [Epub ahead of print].

Marijuana Use and the Risk of Lung and Upper Aerodigestive Tract Cancers: Results of a Population-Based Case-Control Study

Despite several lines of evidence suggesting the biological plausibility of marijuana being carcinogenic, epidemiologic findings are inconsistent. Authors conducted a population-based case-control study of the association between marijuana use and the risk of lung and upper aerodigestive tract cancers in Los Angeles. This study included 1,212 incident cancer cases and 1,040 cancer-free controls matched to cases on age, gender, and neighborhood. Subjects were interviewed with a standardized questionnaire. The cumulative use of marijuana was expressed in joint-years, where 1 joint-year is equivalent to smoking one joint per day for 1 year. Although using marijuana for > or =30 joint-years was positively associated in the crude analyses with each cancer type (except pharyngeal cancer), no positive associations were observed when adjusting for several confounders including cigarette smoking. The adjusted odds ratio estimate (and 95% confidence limits) for > or =60 versus 0 joint-years was 1.1 (0.56, 2.1) for oral cancer, 0.84 (0.28, 2.5) for laryngeal cancer, and 0.62 (0.32, 1.2) for lung cancer; the adjusted odds ratio estimate for > or =30 versus 0 joint-years was 0.57 (0.20, 1.6) for pharyngeal cancer, and 0.53 (0.22, 1.3) for esophageal cancer. No association was consistently monotonic across exposure categories, and restriction to subjects who never smoked cigarettes yielded similar findings. These results may have been affected by selection bias or error in measuring lifetime exposure and confounder histories; but they suggest that the association of these cancers with marijuana, even long-term or heavy use, is not strong and may be below practically detectable limits. Hashibe, M., Morgenstern, H., Cui, Y., Tashkin, D.P., Zhang, Z.F., Cozen, W., Mack, T.M., and Greenland, S. Cancer Epidemiol Biomarkers Prev. 15(10), pp. 1829-1834, 2006.

Oral Delta-9-Tetrahydrocannabinol Suppresses Cannabis Withdrawal Symptoms

This study assessed whether oral administration of delta-9-tetrahydrocannbinol (THC) effectively suppressed cannabis withdrawal in an outpatient environment. The primary aims were to establish the pharmacological specificity of the withdrawal syndrome and to obtain information relevant to determining the potential use of THC to assist in the treatment of cannabis dependence. Eight adult, daily cannabis users who were not seeking treatment participated in a 40-day, within-subject ABACAD study. Participants administered daily doses of placebo, 30mg (10mg/tid), or 90mg (30mg/tid) oral THC during three, 5-day periods of abstinence from cannabis use separated by 7-9 periods of smoking cannabis as usual. Comparison of withdrawal symptoms across conditions indicated that (1) the lower dose of THC reduced withdrawal discomfort, and (2) the higher dose produced additional suppression in withdrawal symptoms such that symptom ratings did not differ from the smoking-as-usual conditions. Minimal adverse effects were associated with either active dose of THC. This demonstration of dose-responsivity replicates and extends prior findings of the pharmacological specificity of the cannabis withdrawal syndrome. The efficacy of these doses for suppressing cannabis withdrawal suggests oral THC might be used as an intervention to aid cannabis cessation attempts. Budney, A.J., Vandrey, R.G., Hughes, J.R., Moore, B.A., and Bahrenburg, B. Drug Alcohol Depend. 86(1), pp. 22-29, 2007.

Substance Use and Psychosocial Outcomes Following Participation in Residential

Laboratory Studies of Marijuana, Methamphetamine and Zolpidem Non-therapeutic research with drugs of abuse in humans is important for a more comprehensive understanding of substance abuse and for the development of more effective treatments. However, the administration of substances from drug classes with abuse potential to human volunteers raises ethical questions regarding potential risk to study volunteers. The purpose of this study was to assess the psychosocial functioning and reported drug-taking behavior of volunteers before and after participating in a residential laboratory study, during which either marijuana, methamphetamine or zolpidem was administered. Twenty-two volunteers were administered Addiction Severity Index (ASI) interviews at intake and approximately six months following their study participation. No significant differences between intake and follow-up assessments were found on any ASI composite or drug/alcohol-taking variable. These preliminary data suggest that participation in residential laboratory studies involving the administration of drugs from classes with abuse potential does not alter subsequent psychosocial functioning or reported drug use. Vadhan, N.P., Hart, C.L., Roe, B., Colley, J., Haney, M., and Foltin, R.W. Am J Drug Alcohol Abuse. 32(4), pp. 589-597, 2006.

Opioid Antagonism of Cannabinoid Effects: Differences between Marijuana Smokers and Nonmarijuana Smokers

In non-human animals, opioid antagonists block the reinforcing and discriminative-stimulus effects of Delta(9)-tetrahydrocannabinol (THC), while in human marijuana smokers, naltrexone (50 mg) enhances the reinforcing and subjective effects of THC. The objective of this study was to test a lower, more opioid-selective dose of naltrexone (12 mg) in combination with THC. The influence of marijuana-use history and sex was also investigated. Naltrexone (0, 12 mg) was administered 30 min 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 (Study 1; n=22) and in nonmarijuana smoking (Study 2; n=21) men and women. The results show 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 shifted THC's effects in the opposite direction, enhancing the intoxicating effects of a low THC dose (2.5 mg) and decreasing 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. These data demonstrate that the interaction between opioid antagonists and cannabinoid agonists varies as a function of marijuana use history. Haney, M. Neuropsychopharmacology, advance online publication, 8 November 2006.

Cocaine Withdrawal Symptoms Predict Medication Response in Cocaine Users

The influence of cocaine withdrawal symptoms on addiction severity and treatment outcomes was evaluated 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 support the clinical utility of cocaine withdrawal symptoms in predicting treatment response to medications. Sofuoglu, M., Poling, J., Gonzalez, G., Gonsai, K., and Kosten, T. Am. J. of Drug and Alcohol Abuse, 32, pp. 617-627, 2006.

Smoked Cocaine Self-Administration by Humans is Not Reduced by Large Gabapentin Maintenance Doses

This study follows a previous study reporting that gabapentin significantly reduced the 'positive' subjective effects of cocaine without reducing cocaine self-administration. This study examined the effects of larger gabapentin maintenance doses (0, 2400, and 3200 mg/day) on cocaine-related effects, including self-administration in six cocaine-dependent, non-treatment seeking, individuals. Gabapentin did not decrease cocaine self-administration, cardiovascular measures, or most subjective effects of cocaine. These findings suggest that gabapentin does not show promise as a treatment medication for cocaine dependence. Hart, C.L., Haney, M., Collins, E.D., Rubin, E. and Foltin, R.W. Drug and Alcohol Dep, 86, pp. 274-277, 2007.

Safety, Tolerability and Efficacy of Levodopa-Carbidopa Treatment for Cocaine Dependence: Two Double-blind, Randomized, Clinical Trials

Based on the fact that cocaine use can significantly alter dopaminergic functioning through depletion of dopamine and changes in receptor functioning, two studies were designed to test the hypothesis that L-dopa pharmacotherapy may be helpful in reducing or abolishing cocaine use by evaluating the safety, tolerability and efficacy of L-dopa as a treatment for cocaine dependence. In Study 1, 67 cocaine-dependent subjects received either placebo or 400 mg L-dopa plus 100 mg carbidopa. In Study 2, 122 cocaine-dependent subjects received either placebo , 400mg/100mg L-dopa/carbidopa, or 800mg/200mg L-dopa/carbidopa. L-dopa was found to be well tolerated with similar retention and medication adherence rates compared to placebo, and had no effect on cocaine use, cocaine craving, or mood. Mooney, M.E., Schmitz, J.M., Moeller, F.G., and Grabowski, J. E-publication, Drug and Alcohol Dep., accepted 26 October, 2006.

A Double-Blind, Placebo-Controlled Trial of Amantadine, Propranolol, and Their Combination for the Treatment of Cocaine Dependence in Patients with Severe Cocaine Withdrawal Symptoms

This trial evaluated the effects of Amantadine, propranolol, and their combination in 199 cocaine dependent patients with severe cocaine withdrawal symptoms. The results of this study showed no significant differences between the four medication groups in treatment retention. In highly medication-adherent patients, treatment retention and rates of cocaine abstinence were significantly better in the propranolol group compared to the placebo group. None of the active treatments was significantly more effective than placebo in promoting cocaine abstinence in patients with more severe cocaine withdrawal symptoms. Kampman, K. M., Dackis, C., Lynch, K. G., Pettinati, H., Tirado, C., Gariti, P. et al. Drug Alcohol Depend. 85, pp. 129-137, 2006.

Six-Month Trial of Bupropion With Contingency Management for Cocaine Dependence in a Methadone-Maintained Population

This placebo-controlled, double-blind trial compared the efficacy of bupropion and contingency management (CM) for reducing cocaine use in 106 opiate-dependent, cocaine-abusing individuals. Participants were randomly assigned to one of four conditions: CM and placebo; CM and 300 mg/d bupropion (CMB); voucher control and placebo (VCP) or voucher control and bupropion (VCB). In this study, CMB was an effective treatment for cocaine abuse in the methadone-maintained population. CM alone was also effective in reducing cocaine use relative to VCP, but only during the last half of the study. Poling, J., Oliveto, A., Petry, N., Sofuoglu, M., Gonsai, K., Gonzalez, G., Martell, B., and Kosten, T. Arch Gen Psychiatry, 63, pp. 219-228, 2006.

Randomized, Placebo-Controlled Trial of Baclofen and Gabapentin for the Treatment of Methamphetamine Dependence

This trial evaluated the effects of two GABAergic medications, baclofen (20 mg tid) and gabapentin (800 mg tid) for the treatment of methamphetamine dependence in 88 methamphetamine-dependent patients. The results of this study showed no statistically significant effects for either baclofen or gabapentin in reducing methamphetamine use. Heinzerling, K.G., Shoptaw, S., Peck, J.A., Yang, X., Liu, J., Roll, J., and Ling, W. Drug and Alcohol Dependence 85, pp. 177-184, 2006.

Randomized, Placebo-Controlled Trial of Sertraline and Contingency Management for the Treatment of Methamphetamine Dependence

This study evaluated the effects of sertraline, sertraline plus contingency management (CM), placebo plus CM, or placebo only, in 229 methamphetamine-dependent patients. The study results did not show any efficacy for sertraline or CM in reducing methamphetamine use. Sertraline conditions produced significantly more adverse events than placebo conditions. Shoptaw, S., Huber, A., Peck, J.A., Yang, X., Liu, J., Dang, J., Roll, J., Shapiro, B., Rotherham-Fuller, E., and Ling, W. Drug and Alcohol Dependence 85, pp. 12-18, 2006.

A Low Dose of Aripiprazole Attenuates the Subject-Rated Effects of d-Amphetamine

A previous study carried out by this group found that 20 mg aripiprazole attenuated many of the behavioral effects of d-amphetamine, but also impaired performance on a computerized version of the DSST when administered alone, indicating that the attenuation observed might be due to functional, rather than receptor mediated, effects. The present study in 6 healthy adults examined the effects of a lower dose of aripiprazole (10 mg) on the discriminative-stimulus, subject-rated, and physiological effects of d-amphetamine without impairing performance. The results of this study indicate that 10 mg aripiprazole attenuated some abuse-related behavioral effects of d-amphetamine and showed no significant performance impairment. These findings suggest that 10 mg aripiprazole would be a reasonable starting dose for the treatment of stimulant abuse and dependence. Stoops. W.W., Lile, J.A., Glaser, P.E.A., and Rush, C. Drug and Alcohol Dependence 84, pp. 206-209, 2006.

Injectable, Sustained-Release Naltrexone for the Treatment of Opioid Dependence

Oral naltrexone can completely antagonize the effects produced by opioid agonists, but poor compliance with this medication has been an obstacle to its use in the treatment of opioid dependency. This study evaluated the safety and efficacy of a sustained-release depot formulation of naltrexone in treating opioid dependence in a randomized, double-blind, placebo-controlled trial in 60 patients at 2 medical centers. The main outcome measures were treatment retention and percentage of opioid-negative urines. In this study, the injectable, sustained-release depot formulation of naltrexone was well tolerated and produced a robust, dose-related increase in treatment retention. Comer, S., Sullivan, M.A., Yu, E., Rothenberg, J.L., Kleber, H.D., Kampman, K., Dackis, C., and O'Brien, C. Archives of General Psychiatry 63, pp. 210-218, 2006.


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