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Director's Report to the National Advisory Council on Drug Abuse - February, 2008

Research Findings - Research on Pharmacotherapies for Drug Abuse

Bupropion for Methamphetamine Dependence, Clinical Trial

Bupropion was tested for efficacy in increasing weeks of abstinence in methamphetamine-dependent patients, compared to placebo. This was a double-blind placebo-controlled study, with 12 weeks of treatment and a 30-day follow-up. Five outpatient substance abuse treatment clinics located west of the Mississippi participated in the study. One hundred and fifty-one treatment-seekers with DSM-IV diagnosis of methamphetamine dependence were consented and enrolled. Seventy-two participants were randomized to placebo and 79 to sustained-release bupropion 150 mg twice daily. Patients were asked to come to the clinic three times per week for assessments, urine drug screens, and 90-min group psychotherapy. The primary outcome was the change in proportion of participants having a methamphetamine-free week. Secondary outcomes included: urine for quantitative methamphetamine, self-report of methamphetamine use, subgroup analyses of balancing factors and comorbid conditions, addiction severity, craving, risk behaviors for HIV, and use of other substances. The generalized estimating equation regression analysis showed that, overall, the difference between bupropion and placebo groups in the probability of a non-use week over the 12-week treatment period was not statistically significant (p<0.09). Mixed model regression was used to allow adjustment for baseline factors in addition to those measured (site, gender, level of baseline use, and level of symptoms of depression). This subgroup analysis showed that bupropion had a significant effect compared to placebo, among male patients who had a lower level of methamphetamine use at baseline (p<0.0001). Comorbid depression and attention-deficit/ hyperactivity disorder did not change the outcome. These data suggest that bupropion, in combination with behavioral group therapy, was effective for increasing the number of weeks of abstinence in participants with low-to-moderate methamphetamine dependence, mainly male patients, regardless of their comorbid condition. Elkashef, A.M., Rawson, R.A., Anderson, A. L., Li, S.H., Holmes, T., Smith, E. V., Chiang, N., Kahn, R., Vocci, F., Ling, W., Pearce, V.J., McCann, M., Campbell, J., Gorodetzky, C., Haning, W., Carlton, B., Mawhinney, J., and Weis, D. Bupropion for the Treatment of Methamphetamine Dependence. Neuropsychopharmacology (advance online publication), 20 June 2007.

Combination Therapy with Pergolide and Ondansetron as a Potential Approach for Reducing Relapse in Abstinent Methamphetamine Abusers

The authors have shown in earlier studies that the serotonin 5-HT3 receptor antagonist ondansetron reduces cocaine self-administration and cocaine-induced sensitization in rats if it is administered during cocaine withdrawal. The authors subsequently found that administration of the dopamine agonist pergolide followed by ondansetron, 3.5 h later, reversed cocaine sensitization and associated changes in NMDA and AMPA receptors. In their new study the authors tested this drug combination using a nose-poke task in 1) a methamphetamine sensitization model and 2) a reinstatement model following intravenous methamphetamine self-administration. They found that pergolide together with ondansetron administered on days 3-7 during methamphetamine withdrawal reversed methamphetamine-induced sensitization and attenuated reinstatement. Their hypothesis is that pergolide may evoke a methamphetamine-associated memory and that ondansetron disrupts its reconsolidation. These data support the hypothesis that combination treatment with pergolide plus ondansetron, two approved and clinically available human drugs, may hold potential as a therapeutic approach to reduce relapse in methamphetamine abusers. Davidson, C., Gopal, R., Ahn, C., Chen, Q., Mannelli, P., Patkar, A.A., Weese, G.D., Lee, T.H., and Ellinwood, E.H. Reduction in Methamphetamine Induced Sensitization and Reinstatement after Combined Pergolide plus Ondansetron Treatment during Withdrawal. Eur. J. Pharmacol., 565, pp. 113-118, 2007.

Treatment Retention for Buprenorphine Maintenance in "Real World"

The purpose of this study was to describe background characteristics, treatment process, outcomes and correlates of outcomes, for patients receiving buprenorphine maintenance in "real world" office-based settings in New York City. The study did not exclude patients with co-occurring psychiatric and non-opioid substance use disorders. A sample of six physicians completed anonymous chart abstraction forms for a total of 86 patients who began buprenorphine induction or who transferred to these practices during 2003-2005. The endpoint was the patient's current status or status at discharge from the index practice, presented in an intent-to-treat analysis. At the endpoint, 55% were retained in the index practice, 6% transferred to other buprenorphine practices, 7% transferred to other treatment, and 32% were lost to contact or out of any treatment, resulting in a total of 2/3 of patients remaining in an index practice or transferring to other treatment. Although co-occurring psychiatric disorders and polysubstance abuse at intake were common, these had no or minimal effect on study outcomes due to clinical attention for the disorders. Magura, S., Lee, S.J., Salsitz, E.A., Kolodny, A., Whitley, S.D., Taubes, T., Seewald, R., Joseph, H., Kayman, D.J., Fong, C., Marsch, L.A. and Rosenblum, A. Outcomes of Buprenorphine Maintenance in Office-Based Practice. J. Addict. Dis., 26(2), pp. 13-23, 2007.

Comparison of Heroin and Prescription Opioid Dependent Patients in Primary Care Office-Based Buprenorphine Treatment

Although prescription opioid dependence is increasing, treatment outcomes with office-based buprenorphine/naloxone among these patients remains to be described. This study compared demographic, clinical characteristics and treatment outcomes among 200 patients in a trial of primary care office-based buprenorphine/naloxone treatment, stratifying on those reporting exclusive heroin use (n = 124), heroin and prescription opioid use (n = 47), or only prescription opioid use (n = 29). Compared to heroin-only patients, prescription-opioid-only patients were younger, had fewer years of opioid use, less drug treatment history, more likely to be white, earned more income, and were less likely to have Hepatitis C antibodies. Prescription-opioid-only patients were more likely to complete treatment (59% vs. 30%), remained in treatment longer (21.0 vs. 14.2 weeks) and had a higher percent of opioid-negative urine samples than heroin-only patients (56.3% vs. 39.8%), all p values < .05. Patients who used both heroin and prescription opioids had outcomes that were intermediate between heroin-only and prescription-opioid-only patients. The study conclusion was that individuals dependent on prescription opioids have an improved treatment response to buprenorphine/naloxone maintenance in an office-based setting compared to those who exclusively or episodically use heroin. Moore, B.A., Fiellin, D.A., Barry, D.T., Sullivan, L.E., Chawarski, M.C., O'Connor, P.G. and Schottenfeld, R.S. Primary Care Office-Based Buprenorphine Treatment: Comparison of Heroin and Prescription Opioid Dependent Patients. J. Gen. Intern. Med., 22(4), pp. 527-30, 2007.

Intranasal Methamphetamine Produces Predictable Effects on Multiple Behavioral and Physiological Measures Before Peak Plasma Levels are Observed

This study investigated the acute effects of intranasal methamphetamine, the abuse of which has dramatically increased in the past decade. The effects of single-dose intranasal methamphetamine administration on a broad range of behavioral and physiological measures was examined in an inpatient, double-blind study in 11 non-treatment seeking methamphetamine abusers. During each session, one of four intranasal methamphetamine doses (0, 12, 25, and 50 mg/70 kg) was administered and methamphetamine plasma concentrations, cardiovascular, subjective, and psychomotor/cognitive performance effects were assessed before and after drug administration. Following drug administration, methamphetamine plasma concentrations systematically increased for 4h postdrug administration, then declined. Methamphetamine dose-dependently increased cardiovascular measures and positive subjective effects, with peaks occurring 5 - 15 minutes after drug administration, when plasma levels were still ascending. Cognitive performance on less complicated tasks was improved by all active methamphetamine doses, whereas performance on more complicated tasks was improved by intermediate (12 and 25 mg) doses. These results showed that intranasal methamphetamine produced predictable effects on multiple behavioral and physiological measures before peak plasma levels were observed. The dissociation between methamphetamine plasma concentrations and cardiovascular measures and positive subjective effects might have important implications for potential toxicity after repeated doses. Acute Physiological and Behavioral Effects of Intranasal Methamphetamine in Humans. Hart, C., Gunderson, E., Perez, A., Kirkpatrick, M., Thurmond, A., Comer, S., and Foltin, R. Neuropsychopharm., pp. 1-9 (2007) (advance online publication).

Effects of Intranasal Methamphetamine on Metacognition of Agency This study investigated the acute effects of intranasal methamphetamine on complex cognitive performance (a computerized task measuring metacognition of agency) in 10 non-treatment seeking methamphetamine abusers. In this four-session, within-participant, double-blind laboratory study, participants received one of four doses (0, 12, 25, or 50 mg/kg) and completed the metacognition of agency task. Following placebo, judgments of agency were greater under optimal task conditions compared with less than optimal task conditions. Relative to placebo, the 12 mg dose improved task performance, increased judgments of agency under the optimal condition, and decreased judgments of agency under the less than optimal condition. By contrast, the larger doses (25 and 50 mg) increased judgments of agency only under the optimal condition but disrupted performance under the less than optimal condition. These data show that a low intranasal methamphetamine dose enhanced judgments of agency and performance, while larger doses produced limited effects. Effects of Intranasal Methamphetamine on Metacognition of Agency. Kirkpatrick, M.G., Metcalfe, J., Greene, M.J., and Hart, C.L. Psychopharm. 2007 (e-pub ahead of print).

Difference in Attentional Bias Towards Cocaine Cues Between Treatment Seeking and Nontreatment Seeking Cocaine-Dependent Individuals

Cocaine-dependent individuals demonstrate attentional bias when measured by Stroop color-naming tasks that have been modified to include cocaine-related words. This study explored the relationship between attentional bias and the treatment-seeking status of cocaine-dependent individuals. The purpose of the study was to compare attentional bias towards cocaine-related verbal stimuli between treatment-seeking and nontreatment-seeking cocaine abusers. Performance on a Stroop task modified to include drug-related words was examined in 17 cocaine-dependent treatment-seeking male participants and 20 cocaine-dependent nontreatment-seeking male participants. Treatment seekers reported less experience with cocaine than nontreatment seekers but exhibited increased response latency and made more errors when identifying the colors of cocaine-related words, relative to neutral words (p < .05), whereas nontreatment seekers did not. The conclusions were that factors other than a high frequency of cocaine use may contribute to the difference in attentional bias towards cocaine cues between these subgroups of cocaine users. Attentional Bias Towards Cocaine-Related Stimuli: Relationship to Treatment-Seeking for Cocaine Dependence. Vadhan, N.P., Carpenter, K.M., Copersino, M.L., Hart, C.L., Foltin, R.W. and Nunes, E.V. Am. J. Drug and Alcohol Abuse, 33, pp. 727-736, 2007.

Quetiapine Treatment of Zolpidem Dependence

This is a case study of a 52-year old male with a lifelong history of substance use disorders who developed a dependence on zolpidem, and was successfully treated with quetiapine. The patient received a prescription for zolpidem 10 mg/day from his internist. Over a six-month period his use escalated to a minimum of 40 mg per day to a maximum of as much as 250 mg, which resulted in intoxication and amnesia. The patient was admitted to an inpatient detoxification unit and treated with clonazepam over a five-day period. After discharge, the patient experienced severe insomnia and craving for zolpidem. A trial of trazodone up to 200 mg QHS was initially effective, but the patient developed tolerance to the sedating effects. A trial of gabapentin followed, with initial efficacy, then a rapid development of tolerance. Quetiapine treatment was initiated at 50 mg QHS and titrated to higher doses as the patient developed tolerance to the sedating effects. The patient eventually stabilized at quetiapine 800 mg each night, with good hypnotic effects and no craving for zolpidem. Six months after detoxification from zolpidem, the patient has maintained abstinence from zolpidem and reports no craving. This case history suggests that, although zolpidem has relatively low abuse potential, patients with substance abuse histories may be at risk for abuse. In the case of zolpidem abuse or dependence, the use of another sedating agent with lower abuse potential should be considered. Quetiapine Treatment of Zolpidem Dependence. Mariani, J.J. and Levin, F.R. Am. J. on Addictions, 16, p. 426, 2007.

Comparison of Olanzapine to Risperidone in Substance-abusing Individuals with Schizophrenia

Drs. Akerele and Levin report the results of a 14-week double blind study that compared the efficacy of olanzapine to risperidone in reducing marijuana/cocaine craving and use in individuals with schizophrenia. The study consisted of three phases: a two-week assessment phase, a two-week cross-taper phase onto olanzapine/risperidone, and a ten-week period of maintenance on olanzapine/risperidone. The proportion of cocaine-positive urines decreased over time for both groups with a trend for a greater reduction for the olanzapine group compared to risperidone group. In the last six weeks, marijuana craving was more likely for the risperidone group compared to the olanzapine group, although there was no group difference in the proportion of negative marijuana urines. The data suggest some potential for the utility of olanzapine for the treatment of cocaine dependence in individuals with schizophrenia. Akerele, E. and Levin, F.R. Comparison of Olanzapine to Risperidone in Substance-abusing Individuals with Schizophrenia. Am. J.Addict., 16, pp. 260-268, 2007.

Sustained-release Naltrexone: Novel Treatment for Opioid Dependence

At present, several different maintenance medications exist for treating opioid dependence, including methadone, buprenorphine and naltrexone. Of these, naltrexone is the only one that possesses no opioid agonist effects. Instead, naltrexone occupies opioid receptors and prevents or reverses the effects produced by opioid agonists. Despite its clear pharmacologic effectiveness, its clinical effectiveness in treating opioid dependence has been disappointing, primarily due to non-compliance with taking the medication. However, the recent availability of sustained-release formulations of naltrexone has renewed interest in this medication. The present paper describes the development of sustained-release naltrexone formulations and discusses the clinical issues associated with their use in treating opioid dependence. Comer, S.D., Sullivan, M.A., and Hulse, G.K. Sustained-release Naltrexone: Novel Treatment for Opioid Dependence. Expert. Opin. Investig. Drugs, 16, pp. 1285-1294, 2007.

Relevance of Rodent Models of Intravenous MDMA Self-administration to Human MDMA Consumption Patterns

Despite decades of research specifying harmful effects produced by 3,4-methylenedioxymethamphetamine (MDMA; a principal component of 'ecstasy' pills), young people (and adults) continue to use it. In an attempt to model human MDMA consumption patterns, preclinical investigators have sought to establish reliable patterns of intravenous MDMA self-administration in rodents. The objective of this report is to offer a critical review of published data that reveal MDMA self-administration in rodents. The data indicate that MDMA serves as a reinforcer in rodents, though the responses are not similar to those previously reported for psychostimulants (i.e., cocaine). Important differences between rodent models and human use patterns include frequency of dosing and dosage exposure, routes of administration, tolerance that develops to MDMA after repeated exposure, polydrug use in humans but not by rodents, limits on the repertoire of behaviors that can be exhibited by rodents undergoing IV self-administration procedures, and the question of neurotoxicity as it relates to models of self-administration. While MDMA is not as potent a reinforcer as other drugs of abuse, the fact remains that young people and adults continue to use the drug, and therefore, additional research is needed to determine why drugs with low reinforcing effects continue to be abused. De La, G.R., Fabrizio, K.R., and Gupta, A. Relevance of Rodent Models of Intravenous MDMA Self-administration to Human MDMA Consumption Patterns. Psychopharmacology, 189, pp. 425-434, 2007.

A 12-week Double-blind, Placebo-controlled Study of Bupropion SR Added to High-dose Dual Nicotine Replacement Therapy for Smoking Cessation or Reduction in Schizophrenia

The objective of this study was to examine whether there is a benefit of adding bupropion SR to high-dose combination nicotine replacement therapy (NRT) and weekly group cognitive behavioral therapy (CBT) for smoking reduction or cessation in schizophrenia. Fifty-one adult smokers with schizophrenia were randomly assigned to a 12-week trial of bupropion SR 300 mg/d or placebo added to transdermal nicotine patch, nicotine polacrilex gum, and CBT. The treatment goal was smoking cessation. The primary outcome measure was biochemically confirmed 7-day point-prevalence of 50% -100% smoking reduction at week 12. Secondary outcomes were biochemically confirmed tobacco abstinence and change from baseline in expired air carbon monoxide (CO) and psychiatric symptoms. Subjects on bupropion + NRT had a greater rate of 50% to 100% smoking reduction at weeks 12 (60% vs. 31%; P=0.036) and 24, a lower expired air CO in the treatment and follow-up periods, (F=13.8; P< 0.001) and a greater continuous abstinence rate at week 8, before NRT taper, (52% vs. 19%; P=0.014). However, relapse rates in subjects on bupropion + dual NRT were 31% during NRT taper (weeks 8-12) and 77% at the 12-month follow-up. Abstinence rates did not differ by treatment group at weeks 12 (36% vs. 19%), 24 (20% vs. 8%), or 52 (12% vs. 8%). Because abstinence rates were high during treatment with combination pharmacotherapy and relapse rates were very high during taper and after discontinuation of treatment, study of longer term treatment with combination pharmacotherapy and CBT for sustained abstinence is warranted in those who attain initial abstinence with this intervention. Evins, A., Cather, C., Culhane, M., Birnbaum, A., Horowitz, J., Hsieh, E. et al. A 12-week Double-blind, Placebo-controlled Study of Bupropion SR Added to High-dose Dual Nicotine Replacement Therapy for Smoking Cessation or Reduction in Schizophrenia. J.Clin.Psychopharm., 27, pp. 380-386, 2007.

A Naturalistic Study of the Effects of Pharmacotherapy on Substance Use Disorders Among ADHD Adults

Studies of adults with attention deficit hyperactivity disorder (ADHD) show an elevated prevalence of substance use disorders (SUDs) and the substance abuse literature shows that ADHD is elevated in substance users. Some researchers postulate that stimulant treatment of ADHD increases the risk for SUD in ADHD patients but follow-up studies suggest treatment protects patients from subsequent SUDs. This report uses retrospective data to assess the impact of prior ADHD pharmacotherapy on SUDs in 206 ADHD adults (n=79 late-onset ADHD, n=127 full ADHD) grouped by lifetime history of ADHD treatment (no treatment, past treatment, current and past treatment). Structured Clinical Interview for DSM-IV (SCID) data were used to establish abuse and dependence, and Drug Use Screening Inventory (DUSI) responses were used to establish prevalence of use, preference for cigarettes, alcohol and drugs of abuse, complications from use, and motivation for use (get high, change mood, sleep better). No differences were found in the prevalence of cigarette smoking, alcohol or drug abuse or dependence, as well as no significant differences in 1-month prevalence of any use or use more than 20 times. No differences were found in complications of drug or alcohol use across groups. Subjects with current treatment rated getting high as a motivating factor significantly more frequently than subjects in the past treatment group; this result lost significance when the authors included ADHD diagnostic category. The results are consistent across substances and ADHD diagnoses, and support the hypothesis that pharmaco-therapy does not cause subsequent SUDs. Faraone, S.V., Biederman, J., Wilens, T.E., and Adamson, J. A Naturalistic Study of the Effects of Pharmacotherapy on Substance Use Disorders Among ADHD Adults. Psychol. Med., 37, pp. 1743-1752, 2007.

Sublingual Buprenorphine/Naloxone Precipitated Withdrawal in Subjects Maintained on Methadone

Buprenorphine is available in many countries for use as a sublingual medication that is effective in the treatment of opioid dependence. When administered to opioid dependent persons, it can precipitate withdrawal under certain experimental and clinical conditions. Buprenorphine-related precipitated withdrawal is thought to occur due to its partial mu agonist effects. The risk of buprenorphine-precipitated withdrawal is increased as a function of three parameters: higher doses of buprenorphine, a shorter time interval between the exposure to the full agonist and buprenorphine administration (which may vary as a function of the half life of the full agonist), and higher levels of physical dependence. The purpose of this study was to examine the relationship between buprenorphine delivery and occurrence of buprenorphine-induced precipitated withdrawal in 16 subjects. Participants were adult male and female volunteers eligible for methadone maintenance treatment. Participants were initially stabilized as outpatients on methadone 100 mg/day for an average of 25 days. The findings have implications for the use of buprenorphine/naloxone. Specifically, findings suggest that patients with high levels of physical dependence, including those maintained on daily doses of methadone of up to 100mg, may receive repeated small doses of buprenorphine/naloxone and not experience significant precipitated withdrawal. The administration of repeated, small doses of buprenorphine/naloxone may by the optimal mechanism for transitioning patients with higher levels of opioid physical dependence onto sublingual buprenorphine/naloxone. Rosado, J., Walsh, S.L., Bigelow, G.E., and Strain, E.C., Sublingual Buprenorphine/Naloxone Preciptitated Withdrawal in Subjects Maintained on 100mg of Daily Methadone. Drug and Alcohol Dep., 90, pp. 261-269, 2007.

Buprenorphine and Norbuprenorphine in Hair of Pregnant Women and Their Infants after Controlled Buprenorphine Administration

Buprenorphine is under investigation as a pharmacotherapeutic agent for treating opioid dependence in pregnant women. The investigators hypothesized that there would be a relationship between the cumulative maternal dose of buprenorphine during pregnancy and the concentration of buprenorphine and norbuprenorphine in maternal and infant hair. This study examined buprenorphine and norbuprenorphine concentrations in hair obtained from 9 buprenorphine-maintained pregnant women and 4 of their infants. Specimens were analyzed by liquid chromatography-tandem mass spectrometry with limits of quantification of 3.0 pg/mg. All maternal hair specimens were washed with methylene chloride before analysis, and when sufficient amounts of maternal hair were available, specimens also were analyzed without washing. Infant hair specimens were not washed. Buprenorphine concentrations were significantly greater in unwashed hair than washed hair (P = 0.031). Norbuprenorphine concentrations were significantly greater than buprenorphine concentrations in both maternal (P = 0.0097) and infant hair (P = 0.0033). There were statistically significant associations between the cumulative maternal dose of buprenorphine administered and the concentrations of buprenorphine (washed, P <0.0001; unwashed, P = 0.0004), norbuprenorphine (washed, P <0.0001; unwashed, P = 0.0005), and buprenorphine plus norbuprenorphine (washed, P <0.0001; unwashed, P = 0.0005) for both washed and unwashed maternal hair specimens. There was a significant positive association between concentrations of buprenorphine and norbuprenorphine in maternal hair (washed, P <0.0001; unwashed, P = 0.0003), a trend for this association in infant hair (P = 0.08), and an association between buprenorphine concentrations in maternal unwashed hair and infant hair (P = 0.0002). The buprenorphine:norbuprenorphine ratio increased in distal segments. Buprenorphine treatment during gestation provides an opportunity for monitoring drug disposition in maternal and fetal tissues under controlled conditions. Goodwin, R.S., Wilkins, D.G., Averin, O., Choo, R.E., Schroeder, J.R., Jasinski, D.R. et al. Buprenorphine and Norbuprenorphine in Hair of Pregnant Women and Their Infants after Controlled Buprenorphine Administration. Clin. Chem. (e-pub ahead of print, 2007).

Behavioral Economic Analysis of Drug Preference Using Multiple Choice Procedure Data

The multiple choice procedure has been used to evaluate preference for psychoactive drugs, relative to money amounts (price), in human subjects. The present re-analysis shows that MCP data are compatible with behavioral economic analysis of drug choices. Demand curves were constructed from studies with intravenous fentanyl, intramuscular hydromorphone and oral methadone in opioid-dependent individuals; oral d-amphetamine, oral MDMA alone and during fluoxetine treatment, and smoked marijuana alone or following naltrexone pretreatment in recreational drug users. For each participant and dose, the MCP crossover point was converted into unit price (UP) by dividing the money value ($) by the drug dose (mg/70kg). At the crossover value, the dose ceases to function as a reinforcer, so "0" was entered for this and higher UPs to reflect lack of drug choice. At lower UPs, the dose functions as a reinforcer and "1" was entered to reflect drug choice. Data for UP vs. average percent choice were plotted in log-log space to generate demand functions. Rank of order of opioid inelasticity (slope of non-linear regression) was: fentanyl>hydromorphone (continuing heroin users)>methadone> hydromorphone (heroin abstainers). Rank order of psychostimulant inelasticity was d-amphetamine>MDMA>MDMA+fluoxetine. Smoked marijuana was more inelastic with high-dose naltrexone. These findings show this method translates individuals' drug preferences into estimates of population demand, which has the potential to yield insights into pharmacotherapy efficacy, abuse liability assessment, and individual differences in susceptibility to drug abuse. Greenwald, M.K. Behavioral Economic Analysis of Drug Preference Using Multiple Choice Procedure Data. Drug Alcohol Depend. (e-pub ahead of print, 2007).

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

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. Opioid Antagonism of Cannabinoid Effects: Differences between Marijuana Smokers and Nonmarijuana Smokers. Neuropsychopharmacology, 32, pp. 1391-1403, 2007.

Dronabinol and Marijuana in HIV-positive Marijuana Smokers: Caloric Intake, Mood, and Sleep

Individuals with HIV constitute the largest group using cannabinoids for medicinal reasons; yet, no studies have directly compared the tolerability and efficacy of smoked marijuana and oral dronabinol maintenance in HIV-positive marijuana smokers. This placebo-controlled within-subjects study evaluated marijuana and dronabinol across a range of behaviors: eating topography, mood, cognitive performance, physiologic measures, and sleep. HIV-positive marijuana smokers (n = 10) completed 2 16-day inpatient phases. Each dronabinol (5 and 10 mg) and marijuana (2.0% and 3.9% Delta9-tetrahydrocannabinol [THC]) dose was administered 4 times daily for 4 days, but only 1 drug was active per day, thereby maintaining double-blind dosing. Four days of placebo washout separated each active cannabinoid condition. As compared with placebo, marijuana and dronabinol dose dependently increased daily caloric intake and body weight in HIV-positive marijuana smokers. All cannabinoid conditions produced significant intoxication, except for low-dose dronabinol (5 mg); the intoxication was rated positively (eg, "good drug effect") with little evidence of discomfort and no impairment of cognitive performance. Effects of marijuana and dronabinol were comparable, except that only marijuana (3.9% THC) improved ratings of sleep. These data suggest that for HIV-positive marijuana smokers, both dronabinol (at doses 8 times current recommendations) and marijuana were well tolerated and produced substantial and comparable increases in food intake. Haney, M., Gunderson, E.W., Rabkin, J., Hart, C.L., Vosburg, S.K., Comer, S.D. et al. Dronabinol and Marijuana in HIV-positive Marijuana Smokers. Caloric Intake, Mood, and Sleep. J. Acquir. Immune. Defic. Syndr., 45, pp. 545-554, 2007.

Similar Exposure to a Tobacco-specific Carcinogen in Smokeless Tobacco Users and Cigarette Smokers

Smokeless tobacco has been proposed as a reduced risk substitute for smoking, but no large studies have investigated exposure to the powerful carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in smokeless tobacco users versus smokers. The purpose of this study was to carry out such a comparison. Levels of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides (total NNAL), a biomarker of NNK exposure, and cotinine, a biomarker of nicotine exposure, were quantified in the urine of 420 smokers and 182 smokeless tobacco users who were participants in studies designed to reduce their use of these products. The measurements were taken at baseline, before intervention. Levels of total NNAL per milliliter of urine were significantly higher in smokeless tobacco users than in smokers (P < 0.0001). When adjusted for age and gender, levels of total NNAL per milligram of creatinine were also significantly higher in smokeless tobacco users than in smokers (P < 0.001). Levels of cotinine per milliliter of urine and per milligram of creatinine were significantly higher in smokeless tobacco users than in smokers (P < 0.001). These results show similar exposures to the potent tobacco-specific carcinogen NNK in smokeless tobacco users and smokers. These findings do not support the use of smokeless tobacco as a safe substitute for smoking. Hecht, S.S., Carmella, S.G., Murphy, S.E., Riley, W.T., Le, C., Luo, X. et al. Similar Exposure to a Tobacco-specific Carcinogen in Smokeless Tobacco Users and Cigarette Smokers. Cancer Epidemiol. Biomarkers Prev., 16, pp. 1567-1572, 2007.

Effects of Major Depressive Disorder and Attention-Deficit/Hyperactivity Disorder on the Outcome of Treatment for Cocaine Dependence

Co-occurring psychiatric disorders have been associated with poor prognosis among substance-dependent patients, but few studies have examined this association among patients with cocaine dependence (CD). The authors compared baseline characteristics and treatment outcome between cocaine-dependent patients with major depressive disorder (MDD; n = 66), those with attention-deficit/hyperactivity disorder (ADHD; n = 53), and those with CD without comorbid disorders (CD alone; n = 48) who had been randomized to the placebo arms of clinical trials with venlafaxine, methylphenidate, and gabapentin, respectively. The three groups differed significantly in racial makeup, with more Caucasians and Hispanics among patients with MDD and those with ADHD but more African Americans among those with CD alone. The groups did not differ significantly in treatment retention, with retention rates ranging from 42% to 47%; neither did they differ in the rates of achieving 2 consecutive weeks of urinalysis-confirmed abstinence, with rates ranging from 40% to 50%. Using logistic regression for repeated measures with general estimating equations, modeling the likelihood of a cocaine-positive week over time in treatment, the authors found the diagnostic group to interact with the baseline level of cocaine use and time. Among cocaine-dependent patients who achieved abstinence at baseline, those with MDD and those with ADHD had better outcome over time as compared with patients with CD alone. However, among patients with cocaine-positive urine specimens at baseline, those with MDD and those with ADHD were associated with poor outcome as compared with patients with CD alone. The findings suggest that diagnosis and treatment of co-occurring disorders such as depression and ADHD may be important components of treatment planning for CD and that the baseline level of cocaine use should be included as a covariate in studies evaluating the impact of such treatment. Levin, F., Bisaga, A., Raby, W., Aharonovich, E., Rubin, E., Mariani, J. et al. Effects of Major Depressive Disorder and Attention-Deficit/Hyperactivity Disorder on the Outcome of Treatment for Cocaine Dependence. J. Subst. Abuse Treat (e-pub ahead of print, 2007).

Gender Differences with High-dose Naltrexone in the Patients with Co-occurring Cocaine and Alcohol Dependence

This is a randomized, double-blind, placebo-controlled clinical trial that evaluated the efficacy of a higher-than-typical daily dose of naltrexone (150 mg/day), taken for 12 weeks, in 164 patients (n = 116 men and n = 48 women) with co-occurring cocaine and alcohol dependence. Patients were stratified by gender and then randomly assigned to either naltrexone or placebo, and to either cognitive-behavioral therapy or a type of medical management. The two primary outcomes were cocaine use and alcohol use. Significant Gender x Medication interactions were found for cocaine use via urine drug screens (three way, with time) and self-reports (two way) for drug severity (two way) and alcohol use (two way). The type of psychosocial treatment did not affect outcomes. Thus, 150 mg/day naltrexone added to a psychosocial treatment resulted in reductions in cocaine and alcohol use and drug severity in men, compared to higher rates of cocaine and alcohol use and drug severity in women. Pettinati, H., Kampman, K., Lynch, K., Suh, J., Dackis, C., Oslin, D. et al. Gender Differences with High-dose Naltrexone in the Patients with Co-occurring Cocaine and Alcohol Dependence. J. Subst. Abuse Treat. (e-pub ahead of print, 2007).

Nicotine Replacement and Behavioral Therapy for Smoking Cessation in Pregnancy

This study examines whether adding nicotine replacement therapy (NRT) to cognitive-behavioral therapy (CBT) for pregnant smokers increases rates of smoking cessation. An open-label randomized trial (Baby Steps, n=181) of CBT-only versus CBT+NRT (choice of patch, gum, or lozenge; 1:2 randomization) was used. Data were collected from 2003 through 2005; analyses were conducted in 2006 and 2007. Outcomes were biochemically validated self-reported smoking status at 7 weeks post-randomization, 38 weeks gestation, and 3 months postpartum. Women in the CBT+NRT arm were almost three times more likely than women in the CBT-only arm to have biochemically validated cessation at both pregnancy time points (after 7 weeks: 24% vs 8%, p=0.02; at 38 weeks gestation: 18% vs 7%, p=0.04), but not at 3 months postpartum (20% vs 14%, p=0.55). Recruitment was suspended early by an Independent Data and Safety Monitoring Board when an interim analysis found a higher rate of negative birth outcomes in the CBT+NRT arm than in the CBT-only arm. In the final analysis, the difference between the arms in rate of negative birth outcomes was 0.09 (p=0.26), when adjusted for previous history of preterm birth. The addition of NRT to CBT promoted smoking cessation in pregnant women. This effect did not persist postpartum. More data are needed to determine safety parameters and to confirm the efficacy of NRT use during pregnancy. Pollak, K.I., Oncken, C.A., Lipkus, I.M., Lyna, P., Swamy, G.K., Pletsch, P.K. et al. Nicotine Replacement and Behavioral Therapy for Smoking Cessation in Pregnancy. Am. J. Prev. Med., 33, pp. 297-305, 2007.

Progesterone Effects on Cocaine Use in Male Cocaine Users Maintained on Methadone: A Randomized, Double-blind, Pilot Study

Previously, the authors reported that progesterone treatment attenuated reports of cocaine-induced high in male and female cocaine users. In this pilot clinical trial, the authors tested the safety and efficacy of oral progesterone as a treatment for cocaine dependence in methadone-stabilized male cocaine users. This was a 10-week, randomized, double-blind, placebo-controlled trial. Forty-five male methadone-stabilized cocaine users were randomized to receive placebo (n=15) or progesterone (n=30) for 9 weeks. The progesterone dose was gradually increased from 100 mg to 300 mg twice daily by Week 4 and maintained through Week 10. Treatment retention for the clinical trial was 80%, without significant group differences (log rank=2.4, p=.12). Hierarchical linear modeling estimates of obtaining a cocaine positive urine result across 10 weeks showed a very slight reduction in cocaine use for the progesterone group (Z=-2.89, p<.004). The placebo group showed a slight increase in cocaine use from Week 1 to Week 10 (Z=2.72, p<.007). These slopes significantly differed from each other (Z=-3.83, p<.0001). Overall, the placebo group showed significantly lower probability of having a cocaine positive urine result at treatment's end (Weeks 9 and 10) compared with the progesterone group (0.60 vs. 0.73; U=4837, p<.04). These preliminary findings do not support the efficacy of progesterone in male cocaine users. The efficacy of progesterone in female cocaine users remains to be determined in future studies. Sofuoglu, M., Poling, J., Gonzalez, G., Gonsai, K., Oliveto, A., and Kosten, T.R. Progesterone Effects on Cocaine Use in Male Cocaine Users Maintained on Methadone: A Randomized, Double-blind, Pilot Study. Exp. Clin. Psychopharmacol., 15, pp. 453-460, 2007.

Modafinil and Nicotine Interactions in Abstinent Smokers

In this study, the authors examined the effects of a wakefulness-promoting medication, modafinil, alone and with the nicotine lozenge, on subjective, physiological and cognitive measures as well as on nicotine withdrawal in overnight abstinent cigarette smokers. Nineteen smokers, 13 male and 6 female, participated in a double-blind, placebo-controlled, crossover study. In each of three experimental sessions, subjects were treated orally with a single 200 mg or 400 mg dose of modafinil or placebo. Two hours and 10 min following the medication treatment, subjects received a single 2 mg nicotine lozenge. Both doses of modafinil alone increased the rating of elated-depressed on the Profile of Mood States (POMS) subscale in the direction of depressed and increased ratings of negative affect on the Positive and Negative Affect Schedule (PANAS). In contrast, the 200 mg modafinil dose combined with a 2 mg nicotine lozenge, increased the rating of energetic-tired in the direction of energetic on the POMS subscale. Modafinil attenuated self-reported rating of 'drug strength' in response to the nicotine lozenge. Modafinil, alone or in combination with the nicotine lozenge, did not affect tobacco withdrawal symptoms. There was an increase in baseline heart rate and systolic blood pressure under modafinil treatment. In addition, modafinil speeded reaction times on a modified Stroop task. The clinical utility of modafinil for smoking cessation needs to be determined in future studies. Sofuoglu, M., Waters, A.J., and Mooney, M. Modafinil and Nicotine Interactions in Abstinent Smokers. Hum. Psychopharmacol. (e-pub ahead of print, 2007).

Management of Relapse in Naltrexone Maintenance for Heroin Dependence

This paper identifies critical determinants of lapses to opioid use during naltrexone maintenance. Time retained in treatment was examined as a function of whether lapses to opioid use occurred while adherent to naltrexone (blocked use), or after having missed naltrexone doses (unblocked). Participants (N=83) met DSM-IV criteria for opioid dependence and identified a significant other willing to participate in their treatment. Following inpatient detoxification, participants were enrolled in a 26-week outpatient course of therapy and naltrexone maintenance. Patients with unblocked use had a very high rate of dropout (10% retained at 6 months), dropout usually occurring within 2 weeks after unblocked use. Patients with only blocked use had less dropout (33% retained at 6 months). However, episodes of blocked use were often followed by unblocked use and dropout. During naltrexone maintenance for opioid dependence unblocked opioid use calls for immediate intervention, such as detoxification or switching to the partial agonist buprenorphine. Episodes of blocked use warrant increased clinical attention, such as direct observation of naltrexone ingestion, increased dose, or increased intensity of treatment contact. Maintenance on oral naltrexone is a fragile treatment because it is so easily undermined by episodes of opioid use while non-compliant. New long-acting injectable or implantable formulations of naltrexone may address this limitation and should be investigated for treatment of opioid dependence. Sullivan, M.A., Garawi, F., Bisaga, A., Comer, S.D., Carpenter, K., Raby, W. N. et al. Management of Relapse in Naltrexone Maintenance for Heroin Dependence. Drug Alcohol Depend., 91, pp. 289-292, 2007.

Neuronal Nicotinic Receptor Agonists for the Treatment of Attention-Deficit/Hyperactivity Disorder: Focus on Cognition

Attention deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed neurobehavioral disorder in children and adolescents, and in about half of these patients, significant symptomology continues into adulthood. Although impulsivity and hyperactivity are the most salient features of ADHD, cognitive deficits, particularly impairments in attention and executive function, are an important component, particularly in adolescents and adults, with over 90% of adults seeking treatment for ADHD manifesting cognitive dysfunction. Currently available medications treat the core ADHD symptoms but typically do not adequately address cognitive aspects of ADHD, underscoring the need for new therapeutics. Dopamine and norepinephrine are hypothesized to be particularly important in ADHD, but there is emerging evidence that cholinergic neurotransmission, particularly involving neuronal nicotinic acetylcholine receptors (nAChRs), may play a role in the pathophysiology of ADHD. Nicotine has demonstrated procognitive effects in both humans and experimental animals and has produced signals of efficacy in small proof-of-concept adult ADHD trials. Although adverse effects associated with nicotine preclude its development as a therapeutic, a number of novel nAChR agonists with improved safety/tolerability profiles have been discovered. Of these, ABT-418 and ABT-089 have both demonstrated signals of efficacy in adults with ADHD. Notably, tolerability issues that might be expected of a nAChR agonist, such as nausea and emesis, were not observed at efficacious doses of ABT-089. Further understanding of the effects of novel neuronal nAChR agonists on specific aspects of cognitive functioning in ADHD is required to assess the full potential of this approach. Wilens, T.E. and Decker, M.W. Neuronal Nicotinic Receptor Agonists for the Treatment of Attention-Deficit/Hyperactivity Disorder: Focus on Cognition. Biochem. Pharmacol., 74, pp. 1212-1223, 2007.

When ADHD and Substance Use Disorders Intersect: Relationship and Treatment Implications

In this report, the authors describe the developmental relationship between ADHD and SUDs. ADHD alone and in combination with co-occurring psychopathology is a risk factor for the development of SUDs in adulthood. Conversely, approximately one fifth of adults with SUDs have ADHD. Pharmacotherapeutic treatment of ADHD in children reduces the risk for later cigarette smoking and SUDs in adulthood. In contrast, medication treatment alone of adults with ADHD and current SUD is inadequate for both ADHD and SUD. Stimulant diversion continues to be of concern, particularly in older adolescents and young adults. Wilens, T.E. and Fusillo, S. When ADHD and Substance Use Disorders Intersect: Relationship and Treatment Implications. Curr. Psychiatry Rep., 9, pp. 408-414, 2007.

The Novel Cannabinoid CB(1) Receptor Neutral Antagonist AM4113 Suppresses Food Intake and Food-Reinforced Behavior but Does not Induce Signs of Nausea in Rats

CB1 inverse agonists have been shown to suppress food intake, but they also appear to induce nausea and malaise. The present studies characterized the behavioral effects of AM4113, a CB1 neutral antagonist. AM4113 binds to CB1 receptors, but does not show inverse agonist properties (i.e. no effects on cyclic-AMP production). In tests of spontaneous locomotion and analgesia, AM4113 reversed the effects of the CB1 agonist AM411. It suppressed food-reinforced operant responding in rats on high-fat, high-carbohydrate, and lab chow diets in a dose-dependent manner. AM4113 did not induce conditioned gaping, which is a sign of nausea and food-related malaise in rats. Sink, K.S., McLaughlin, P.J., Wood, J.A., Brown, C., Fan, P., Vemuri, V.K., Pang, Y., Olzewska, T., Thakur, G.A., Makriyannis, A., Parker, L.A., Salamone, J.D. Neuropsychopharmacology, June 20, 2007 (e-pub ahead of print).

Antibody-Catalyzed Oxidation of Delta(9)- Tetrahydrocannabinol

Catalytic antibodies capable of oxidatively degrading the major psychoactive component of marijuana, Delta9-tetrahydrocannabinol (Delta9-THC), are presented. The antibodies generate reactive oxygen species from singlet oxygen (1O2*), using riboflavin (vitamin B2) and visible light as the 1O2* source. Cannabitriol was identified as the major degradation product of this reaction, demonstrating the ability of an antibody to catalyze a complex chemical transformation with therapeutic implications for treating marijuana abuse. Brogan, A.P., Eubanks, L.M., Koob, G.F., Dickerson, T.J., and Janda, K.D. J. Am. Chem. Soc. 129(12), pp. 3698-3702, 2007.

Effects of UMB24 and (+/-)-SM 21, Putative Sigma2-Preferring Antagonists, on Behavioral Toxic and Stimulant Effects of Cocaine in Mice

Earlier studies have demonstrated that antagonism of sigma1 receptors attenuates the convulsive, lethal, locomotor stimulatory and rewarding actions of cocaine in mice. In contrast, the contribution of sigma2 receptors is unclear because experimental tools to selectively target this subtype are unavailable. The authors characterized UMB24 (1-(2-phenethyl)-4-(2-pyridyl)-piperazine) and (+/-)-SM 21 (3alpha-tropanyl-2-(4-chorophenoxy)butyrate) in receptor binding and behavioral studies, which confirmed their preferential affinity for sigma2 over sigma1 receptors. In behavioral studies, pretreatment of mice with these compounds significantly attenuated cocaine-induced convulsions and locomotor activity, but not lethality. Compared with saline, (+/-)-SM 21 produced no significant effects, but UMB24 had locomotor depressant actions. Together, the data suggest that sigma2 receptor antagonists have the potential to attenuate some of the behavioral effects of cocaine, and further development of more selective, high affinity ligands are warranted. Matsumoto, R.R., Pouw, B., Mack, A.L., Daniels, A., and Coop, A. Pharmacol. Biochem. Behav. 86(1), pp. 86-91, 2007.


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