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Director's Report to the National Advisory Council on Drug Abuse - February, 2005

Research Findings - Research on Pharmacotherapies for Drug Abuse

JDTic, a Novel Kappa-Opioid Antagonist, Shows Efficacy in Rat Model of Stress-Induced Relapse to Cocaine

Based on consultant advice, the NIDA Opioid Treatment Discovery Program (OTDP) has pursued the discovery of a developable kappa-opioid antagonist as its #1 goal. JDTic, a highly selective kappa-opioid antagonist that is undergoing DPMC-supported preclinical safety testing, advanced to development from the OTDP. The rationale for the original discovery effort stemmed from the hypothesis that relapse to opiate abuse reflects "self-medication" of an underlying dysphoric state, caused by mu-opioid agonist- (e.g., heroin-) induced sensitization of the brain to dysphoric effects of kappa-opioid agonists (e.g., dynorphin). While this hypothesis is still a reason for NIDA interest in JDTic, recent publications suggesting a role for the kappa-opioid system in mediating certain aspects of the stress response led to an expanded evaluation of JDTic. Within NIDA's highly successful Cocaine Treatment Discovery Program (CTDP), JDTic was sent for evaluation under a contract with Virginia Commonwealth University (Patrick Beardsley, PI) and the compound was found to block footshock-induced reinstatement - but not cocaine prime-induced reinstatement - of lever-pressing in extinguished cocaine self-administration rats. Because any CNS-active compound will impair lever-pressing at a high dose, the demonstrated selectivity of JDTic addresses an important go/no-go decision point within the CTDP and JDTic is viewed as a medication candidate for addressing the stress trigger of relapse to cocaine abuse. Similar findings in the past have generated interest in CRF-1 antagonists as potential addiction treatment medications; unfortunately, development of CRF-1 antagonists has been hampered within multiple pharmaceutical companies by unfavorable safety findings and pharmacokinetics issues. In vitro and in silico predictive safety tests, conducted under CTDP/OTDP contracts, suggest that JDTic is developable and that it may allow NIDA to conduct the type of clinical trials desired for CRF-1 antagonist. A manuscript describing JDTic effects in cocaine relapse models has been submitted by Drs. Carroll and Beardsley; the above mentioned data were presented by Dr. Carroll at a September, 2004 NIDA/AAPS meeting in Bethesda, MD.

A Double-Blind, Placebo-Controlled Trial of Modafinil for Cocaine Dependence

Despite years of active research, there are still no approved medications for the treatment of cocaine dependence. Modafinil is a glutamate-enhancing agent that blunts cocaine euphoria under controlled conditions, and the current study assessed whether modafinil would improve clinical outcome in cocaine-dependent patients receiving standardized psychosocial treatment. This was a randomized, double-blind, placebo-controlled trial conducted at a university outpatient center (from 2002 to 2003) on a consecutive sample of 62 (predominantly African American) cocaine-dependent patients (aged 25-63) free of significant medical and psychiatric conditions. After screening, eligible patients were randomized to a single morning dose of modafinil (400 mg), or matching placebo tablets, for 8 weeks while receiving manual-guided, twice-weekly cognitive behavioral therapy. The primary efficacy measure was cocaine abstinence based on urine benzoylecgonine levels. Secondary measures were craving, cocaine withdrawal, retention, and adverse events. Modafinil-treated patients provided significantly more BE-negative urine samples (p=0.03) over the 8-week trial when compared to placebos, and were more likely to achieve a protracted period (>/=3 weeks) of cocaine abstinence (p=0.05). There were no serious adverse events, and none of the patients failed to complete the study as a result of adverse events. This study provides preliminary evidence, which should be confirmed by a larger study, that modafinil improves clinical outcome when combined with psychosocial treatment for cocaine dependence. Dackis, C.A., Kampman, K.M., Lynch, K.G., Pettinati, H.M. and O'Brien, C.P. A Double-Blind, Placebo-Controlled Trial of Modafinil for Cocaine Dependence. Neuropsychopharmacology. 1, pp. 205-211, 2005.

Agonist-like, Replacement Pharmacotherapy for Stimulant Abuse and Dependence

Stimulant abuse and dependence are disproportionately problematic due to the combination of legal and social issues added to the serious behavioral and biological features of the disorders. These problems are compounded by adverse consequences for families and society. Illegality and stigma multiply the consequences of use and difficulties in providing treatment. Specific behavioral interventions have been demonstrated as useful in treatment of substance use disorders (SUDs). Medications also have an important role in treatment. Effective agonist and antagonist pharmacotherapies as well as symptomatic treatments exist for opioid and nicotine dependence. Neither agonists nor antagonists have been approved as uniquely effective for treatment of stimulant abuse or dependence. Still, promising results are emerging for an agonist-like or 'replacement' strategy paralleling that for nicotine and opioid dependence. Supporting data have emerged from both preclinical and clinical research environments. There are scientific, clinical, social, and legal impediments to application of an agonist-like approach to stimulant abuse and dependence. Some resemble past and current concerns about opioid replacement. Others are unique to the stimulant agents, effects, and clinical features. Here, the authors consider (1) agonist and antagonist pharmacotherapy strategies; (2) preclinical research, including methodological approaches, opioid and nicotine replacement, and agonists for stimulant dependence; (3) clinical reports with stimulant medications in cocaine dependence, and the amphetamine replacement strategy for amphetamine dependence; (4) application of agonist-like/replacement strategies, including clinical requirements and risks; and (5) directions for research. Grabowski, J., Shearer, J., Merrill, J. and Negus, S.S. Agonist-like, Replacement Pharmacotherapy for Stimulant Abuse and Dependence. Addict Behav. 29, pp. 1439-1464, 2004.

First Episode Schizophrenia-related Psychosis and Substance Use Disorders: Acute Response to Olanzapine and Haloperidol

Co-occurring substance use disorders, mostly involving alcohol, cannabis or cocaine, occur commonly in patients with schizophrenia and are associated with increased morbidity and mortality. Available but limited data suggest that substance use disorders (especially cannabis use disorders) may also be common in first-episode patients and appear linked to a poor outcome in these patients. Strategies to curtail substance use form an important dimension of the treatment program for both first-episode and chronic patients. This report describes rates of co-occurring substance use disorders in patients within their first episode of schizophrenia-related psychosis from a multi-center, international treatment trial of olanzapine vs. haloperidol. The study involved 262 patients (of 263 who were randomized and who returned for a post-randomization evaluation) within their first episode of psychosis (schizophrenia, schizoaffective disorder or schizophreniform disorder) recruited from 14 academic medical centers in North America and Western Europe. Patients with a history of substance dependence within 1 month prior to entry were excluded. Of this sample, 97 (37%) had a lifetime diagnosis of substance use disorder (SUD); of these 74 (28% of the total) had a lifetime cannabis use disorder (CUD) and 54 (21%) had a lifetime diagnosis of alcohol use disorder (AUD). Patients with SUD were more likely to be men. Those with CUD had a lower age of onset than those without. Patients with SUD had more positive symptoms and fewer negative symptoms than those without SUD, and they had a longer duration of untreated psychosis. The 12-week response data indicated that 27% of patients with SUD were responders compared to 35% of those without SUD. Patients with AUD were less likely to respond to olanzapine than those without AUD. These data suggest that first-episode patients are quite likely to have comorbid substance use disorders, and that the presence of these disorders may negatively influence response to antipsychotic medications, both typical and atypical antipsychotics, over the first 12 weeks of treatment. Green, A.I., Tohen, M.F., Hamer, R.M., Strakowski, S.M., Lieberman, J.A., Glick, I. and Clark, W.S. First Episode Schizophrenia-related Psychosis and Substance Use Disorders: Acute Response to Olanzapine and Haloperidol. Schizophr. Res. 66, pp. 125-135, 2004.

Therapeutic Vaccines for Substance Dependence

Immunotherapies are under development as a new approach to the treatment of substance dependence. The drugs of abuse currently being tested using this new approach are nicotine, cocaine, phencyclidine and methamphetamine. In laboratory animal models, a range of immunotherapies, including vaccines, monoclonal antibodies and catalytic antibodies, have been shown to reduce drug seeking. In human clinical trials, cocaine and nicotine vaccines have been shown to induce antibody titers while producing few side effects. Studies in humans determining how these vaccines interact in combination with their target drug are underway. Overall, immunotherapy offers a range of potential treatment options: drug treatment, as well as the treatment of overdose, prevention of brain or cardiac toxicity and fetal protection in pregnant drug abusers. Haney, M. and Kosten, T.R. Therapeutic Vaccines for Substance Dependence. Expert. Rev. Vaccines. 3, pp. 11-18, 2004.

Gabapentin Maintenance Decreases Smoked Cocaine-related Subjective Effects, but not Self-administration by Humans

Data from research with laboratory animals indicate that cocaine self-administration can be reduced by GABA agonists. Yet, the effectiveness of GABA agonists to decrease human cocaine self-administration has not been investigated under controlled laboratory conditions. The purpose of this study was to assess the effects of gabapentin, a GABA agonist, on cocaine-related behaviors, including self-administration, in human research participants under controlled laboratory conditions. During this 48-day double-blind, crossover design study, the effects of gabapentin (0, 600, and 1200 mg/d) maintenance on response to cocaine (0, 12, 25, and 50 mg) were investigated in seven cocaine abusers. Active cocaine significantly increased choice to self-administer cocaine, subjective-effect ratings (e.g., "Good Drug Effect"), blood pressure and heart rate (HR). Gabapentin did not reduce cocaine choice or cardiovascular measures, but it did decrease some subjective effects of cocaine (e.g., "Good Drug Effect" and "Anxious"). These data suggest that the cocaine-gabapentin combination was well tolerated, and because some cocaine-related subjective effects were reduced by maintenance on relatively low gabapentin doses, future studies should test higher gabapentin doses. Hart, C.L., Ward, A.S., Collins, E.D., Haney, M. and Foltin, R.W. Gabapentin Maintenance Decreases Smoked Cocaine-related Subjective Effects, but not Self-administration by Humans. Drug Alcohol Depend., 73, pp. 279-287, 2004.

Harm Reduction Approaches to Reducing Tobacco-related Mortality

Tobacco harm reduction approaches are gaining increased attention. Much of this attention is due to a growing concern that significant populations of smokers either do not want to quit or believe they are unable to quit smoking, and to a concern over tobacco-industry attempts to produce tobacco products that claim to result in less toxin exposure. Decreasing tobacco toxin exposure as a method for reducing mortality and morbidity may be a reasonable tobacco control strategy. However, the impact of this strategy must be explored both on individual and population levels. A significant amount of independent research is needed to inform policy decisions. Regulatory authority over potential reduced exposure products is also essential. Hatsukami, D.K., Henningfield, J.E. and Kotlyar, M. Harm Reduction Approaches to Reducing Tobacco-related Mortality. Annu. Rev. Public Health, 25, pp. 377-395, 2004.

Smokeless Tobacco Use: Harm Reduction or Induction Approach?

Smokeless tobacco (ST) substitution for cigarettes as a method to reduce harm has been actively debated. Use of ST as a smoking cessation method or as a means to reduce cigarettes has been proposed. The impact of using ST in these ways is relatively unknown. A review of the different issues and studies related to using smokeless tobacco as a method to reduce tobacco toxin exposure and harm is presented. The toxicity of the product itself varies by brand of ST and across countries. Of the existing studies, comparisons of consequences between cigarettes and ST show that cigarette smoking produces more negative health effects, is likely to have a higher addiction potential and more severe withdrawal, and leads to a higher rate of relapse than ST use. On the other hand, ST use facilitates the use of cigarettes, which is a deadly tobacco product. Additionally, ST is not a harmless product, and a less harmful product, medicinal nicotine, is available as an effective treatment approach. Furthermore, ST products are not under the same regulatory scrutiny as medicinal nicotine products. Considerably more research and product regulation is necessary prior to considering smokeless tobacco as a harm reduction method. Hatsukami, D.K., Lemmonds, C. and Tomar, S.L. Smokeless Tobacco Use: Harm Reduction or Induction Approach? Prev. Med., 38, pp. 309-317, 2004.

Evaluation of Carcinogen Exposure in People Who Used "Reduced Exposure" Tobacco Products

Although tobacco products with reportedly reduced carcinogen content are being marketed, carcinogen uptake in people who use these products has not been assessed systematically. Between June 2001 and November 2002, 54 users of smokeless tobacco and 51 cigarette smokers were randomly assigned to one of two groups. One used test products (Swedish snus for users of smokeless tobacco or OMNI cigarettes for smokers), while the other quit and used medicinal nicotine (the nicotine patch). All participants were assessed for urinary levels of total NNAL [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronide], metabolites of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Smokers were also assessed for levels of 1-hydroxypyrene (1-HOP), a biomarker of polycyclic aromatic hydrocarbon uptake. Assessments were made weekly during 2 weeks of baseline normal tobacco use and 4 weeks of treatment. Statistical tests were two-sided. Primary data analyses were conducted on 41 users of smokeless tobacco and 38 cigarette smokers who met the inclusion criteria. Total NNAL levels were statistically significantly lower in users of smokeless tobacco after they switched to snus or to nicotine patch (P<.001 for both groups) than they were before the switch, although the overall mean total NNAL level among subjects who used the nicotine patch was statistically significantly lower than that among those who used snus (mean = 1.2 and 2.0 pmol of NNAL/mg of creatinine, respectively; mean difference = 0.9 pmol of NNAL/mg of creatinine, 95% confidence interval [CI] = 0.2 to 1.5; P =.008). Compared with baseline levels, total NNAL levels (P =.003), but not 1-HOP levels, were statistically significantly reduced in cigarette smokers who switched to the OMNI cigarette, although both total NNAL levels and 1-HOP levels were statistically significantly reduced in smokers who switched to the nicotine patch (P<.001 for both). The overall mean total NNAL levels among smokers who used the nicotine patch was statistically significantly lower than that among smokers who used the OMNI cigarette (mean = 1.2 and 1.9 pmol of NNAL/mg of creatinine, respectively; mean difference = 0.6 pmol of NNAL/mg of creatinine, 95% CI = 0.1 to 1.1; P =. 022). Switching to reduced-exposure tobacco products or medicinal nicotine can decrease levels of tobacco-associated carcinogens, with greater reductions being observed with medicinal nicotine. Medicinal nicotine is a safer alternative than modified tobacco products. Hatsukami, D.K., Lemmonds, C., Zhang, Y., Murphy, S.E., Le, C., Carmella, S.G. and Hecht, S.S. Evaluation of Carcinogen Exposure in People Who Used "Reduced Exposure" Tobacco Products. J Natl. Cancer Inst., 96, pp. 844-852, 2004.

Effects of Sustained-release Bupropion Among Persons Interested in Reducing but not Quitting Smoking

The purpose of this study was to determine whether sustained-release bupropion promotes smoking reduction leading to smoking cessation among persons who wish to reduce their amount of smoking, but who are unwilling to quit or who perceive themselves as being unable to quit. Current smokers were assigned randomly to receive either sustained-release bupropion (150 mg twice daily) or matching placebo. During an initial 6-month smoking reduction phase, those who were willing to quit entered a 7-week cessation phase, during which study medication was continued. Four-week continuous abstinence rates were 14% (41/295) in the bupropion group and 8% (25/299) in the placebo group (P = 0.02) during treatment. However, this benefit did not continue after treatment was stopped; subsequent continuous abstinence rates were 7% (20/295) in the bupropion group and 5% (16/299) in the placebo group (P = 0.50). Similar proportions of subjects entered the cessation phase in both treatment groups (38% [n = 113] of those in the bupropion group and 34% [n = 101] of those in the placebo group), although the time until a cessation attempt was shorter for those taking bupropion (median, 64 days vs. 118 days, P = 0.008). The extent of smoking reduction (measured by urinary cotinine concentrations) among the 327 subjects who did not enter the cessation phase was significantly greater (P <0.05) in those treated with bupropion during the reduction treatment phase, but not during the month 12 follow-up visit (P = 0.25). Sustained-release bupropion, when used in smokers initially not willing to make a cessation attempt, can help sustain smoking reduction while subjects are on active medication, reduce the time until the next cessation attempt, and increase short-term abstinence rates. However, these benefits were modest and not sustained after bupropion was discontinued. Hatsukami, D.K., Rennard, S., Patel, M.K., Kotlyar, M., Malcolm, R., Nides, M.A., Dozier, G., Bars, M.P. and Jamerson, B.D. Effects of Sustained-release Bupropion Among Persons Interested in Reducing but not Quitting Smoking. Am. J Med., 116, pp. 151-157, 2004.

A Pilot Trial of Topiramate for the Treatment of Cocaine Dependence

Both GABAergic and glutamatergic neurons appear to be important modulators of the brain reward system and medications that affect GABA and glutamatergic neurotransmission may reduce the rewarding properties of cocaine and reduce cocaine craving. Topiramate, an anticonvulsant, raises cerebral GABA levels, facilitates GABAergic neurotransmission and inhibits glutamatergic activity at AMPA/kainate receptors. Thus, it may be useful for treating cocaine dependence. The efficacy of topiramate for cocaine dependence was tested in a 13-week, double-blind, placebo-controlled pilot trial (n = 40). Topiramate was titrated gradually over 8 weeks to a dose of 200 mg daily. The primary outcome measure was cocaine abstinence verified by twice weekly urine benzoylecgonine tests (UBT). Eighty-two percent of subjects completed the trial. Analysis of the UBT using a GEE model showed that after week 8, when the dose titration was completed, topiramate-treated subjects were more likely to be abstinent from cocaine compared to placebo-treated subjects (Z = 2.67, P = 0.01). Topiramate-treated subjects were also more likely to attain 3 weeks of continuous abstinence from cocaine (chi2 = 3.9, d.f. = 1, P = 0.05). Topiramate may be effective for the treatment of cocaine dependence. Kampman, K.M., Pettinati, H., Lynch, K. G., Dackis, C., Sparkman, T., Weigley, C. and O'Brien, C.P. A Pilot Trial of Topiramate for the Treatment of Cocaine Dependence. Drug Alcohol Depend., 75, pp. 233-240, 2004.

Cocaine Dependence Severity Predicts Outcome in Outpatient Detoxification from Cocaine and Alcohol

This study compared the effects of alcohol and cocaine dependence severity on the outcome of outpatient detoxification from alcohol and cocaine. Subjects included 84 subjects with both alcohol and cocaine dependence admitted for outpatient detoxification. Fifty-three of the 84 subjects (63%) completed detoxification. Baseline cocaine use, cocaine craving, and cocaine withdrawal symptoms predicted detoxification outcome, whereas alcohol use, alcohol craving, and alcohol withdrawal symptoms did not. Among cocaine- and alcohol-dependent subjects, cocaine dependence severity appears to be a more important predictor of detoxification success than alcohol dependence severity. Kampman, K.M., Pettinati, H.M., Volpicelli, J.R., Oslin, D.M., Lipkin, C., Sparkman, T. and O'Brien, C.P. Cocaine Dependence Severity Predicts Outcome in Outpatient Detoxification from Cocaine and Alcohol. Am. J Addict, 13, pp. 74-82, 2004.

Naltrexone for Heroin Dependence Treatment in St. Petersburg, Russia

Naltrexone may be more effective for treating opioid (heroin) dependence in Russia than in the U.S. because patients are mostly young and living with their parents, who can control medication compliance. In this pilot study in St. Petersburg were 52 randomized consenting patients who completed detoxification to a double blind, 6-month course of biweekly drug counseling and naltrexone, or counseling and placebo naltrexone. Significant differences in retention and relapse favoring naltrexone were seen beginning at 1 month and continuing throughout the study. At the end of 6 months, 12 of the 27 naltrexone patients (44.4%) remained in treatment and had not relapsed as compared to 4 of 25 placebo patients (16%; p<0.05). Since heroin dependence is the main vector for HIV transmission in Russia, naltrexone is likely to improve treatment outcome and help reduce the spread of HIV if it can be made more widely available. Krupitsky, E.M., Zvartau, E.E., Masalov, D.V., Tsoi, M.V., Burakov, A.M., Egorova, V.Y., Didenko, T.Y., Romanova, T.N., Ivanova, E.B., Bespalov, A.Y., Verbitskaya, E.V., Neznanov, N.G., Grinenko, A.Y., O'Brien, C.P. and Woody, G.E. Naltrexone for Heroin Dependence Treatment in St. Petersburg, Russia. J Subst.Abuse Treat. 26, pp. 285-294, 2004.

Characteristics of Cigarette Smokers Seeking Treatment for Cessation Versus Reduction

Comparisons were made between cigarette smokers seeking treatment to quit smoking and cigarette smokers seeking treatment to reduce the number of cigarettes they smoke. Potential subjects were recruited from the local metropolitan area by advertisement in the local media. A total of 665 cigarette smokers telephoned seeking treatment for smoking cessation and 565 cigarette smokers telephoned to seek treatment to gradually reduce the number of cigarettes they smoke but not quit smoking. Potential subjects were instructed to call the clinic to find out additional information about the studies, and while on the telephone they were asked questions pertaining to tobacco use and health status. The results show that the two populations are similar in many respects with the following exceptions: smokers seeking treatment to reduce cigarette use tend to smoke more cigarettes per day, are less motivated to quit, make fewer quit attempts, drink more alcoholic beverages per day, and have more health problems (Ps<.05). These results indicate that cigarette smokers seeking treatment for smoking reduction but not cessation may be more dependent smokers who experience more medical disorders. Lemmonds, C.A., Mooney, M., Reich, B. and Hatsukami, D. Characteristics of Cigarette Smokers Seeking Treatment for Cessation Versus Reduction. Addict Behav. 29, pp. 357-364, 2004.

Impact of Attention-Deficit Hyperactivity Disorder and Other Psychopathology on Treatment Retention Among Cocaine Abusers in a Therapeutic Community

Although there are some data suggesting that individuals with depressive disorders may be more likely to remain in treatment than those without depressive disorders, it is less clear how well other psychiatric subgroups compare to those without psychiatric comorbidity. This sample is a follow-up study of 135 individuals who were admitted into a therapeutic community. Individuals with attention-deficit hyperactivity disorder (ADHD), other Axis I disorders (no ADHD), and no Axis I disorders were compared. Although individuals with other Axis I disorders had a strikingly low early drop-out rate, after a prolonged time in treatment, the drop-out rate increased substantially, such that these individuals were found to complete treatment at a lower rate (17%) than those with no Axis I disorders (29%). Furthermore, individuals with ADHD were less likely to graduate treatment than those with other Axis I or no Axis I disorders (0%, 9%, and 19%, respectively). Future investigations may be useful to determine whether pharmacologic or non-pharmacologic interventions might improve treatment outcome. Levin, F.R., Evans, S.M., Vosburg, S.K., Horton, T., Brooks, D. and Ng, J. Impact of Attention-Deficit Hyperactivity Disorder and Other Psychopathology on Treatment Retention Among Cocaine Abusers in a Therapeutic Community. Addict Behav., 29, pp. 1875-1882, 2004.

Pharmacotherapy for Marijuana Dependence: A Double-blind, Placebo-controlled Pilot Study of Divalproex Sodium

There is a noticeable lack of targeted treatment options for marijuana dependence, in particular pharmacologic approaches. This is the first study evaluating a targeted pharmacologic approach for marijuana dependence. The goals of the study were to determine if such patients would seek pharmacologic treatment, whether these patients could be retained in treatment using a design previously developed for cocaine-dependent patients, and especially whether divalproex sodium showed promise as a treatment agent for marijuana dependence. It was found that marijuana-dependent patients will seek treatment, and such patients can be adequately maintained in a pharmacologic trial. Regardless of treatment group, patients reported a significant reduction in their frequency and amount of marijuana use as well as a reduction in irritability. Given the lack of proven effective treatments for marijuana dependence, pharmacotherapies should be sought. The design of a preliminary clinical trial should include a psychosocial/behavioral intervention emphasizing motivation and medication compliance and a placebo control group. Levin, F.R., McDowell, D., Evans, S.M., Nunes, E., Akerele, E., Donovan, S. and Vosburg, S.K. Pharmacotherapy for Marijuana Dependence: A Double-blind, Placebo-controlled Pilot Study of Divalproex Sodium. Am. J Addict, 13, pp. 21-32, 2004.

A Randomized, Placebo-controlled Trial of Buspirone for the Treatment of Anxiety in Opioid-dependent Individuals

Anxiety symptoms are common among opioid-dependent individuals. Buspirone, a non-benzodiazepine anxiolytic, has been used successfully for the treatment of anxiety in alcoholic patients. Its efficacy in opioid-dependent patients has not been previously examined. A twelve-week, randomized, placebo-controlled trial of buspirone in 36 subjects receiving methadone-maintenance treatment who presented with anxiety symptoms was conducted. Measures of anxiety, depression, and substance use were obtained repeatedly during treatment. Buspirone treatment did not significantly reduce anxiety symptoms in opioid-dependent patients. However, buspirone treatment was associated with trends toward reduction in depression scale scores and a slower return to substance use. McRae, A.L., Sonne, S.C., Brady, K.T., Durkalski, V. and Palesch, Y. A Randomized, Placebo-controlled Trial of Buspirone for the Treatment of Anxiety in Opioid-dependent Individuals. Am. J Addict, 13, pp. 53-63, 2004.

The Blind Spot in the Nicotine Replacement Therapy Literature: Assessment of the Double-blind in Clinical Trials

While clinical trials of medications often use a double-blind procedure, the integrity of the blind and its relationship to treatment outcome is seldom examined. In this review, 73 double-blind, placebo-controlled clinical trials of the nicotine replacement therapies (NRTs) in smoking cessation were identified. Seventeen articles were found that assessed blindness integrity, demonstrating major variations in the assessment, analysis, and reporting of blindness integrity. Although 12 studies found that subjects accurately judged treatment assignment at a rate significantly above chance, the available literature does not permit definitive conclusions about blindness integrity. Recommendations for the assessment, analysis, and reporting of blindness integrity are made. Mooney, M., White, T. and Hatsukami, D. The Blind Spot in the Nicotine Replacement Therapy Literature: Assessment of the Double-Blind in Clinical Trials. Addict Behav. 29, pp. 673-684, 2004.

A Comparison of Urinary Biomarkers of Tobacco and Carcinogen Exposure in Smokers

Recently, several potential harm reduction strategies, such as reduction in the number of cigarettes smoked and the use of modified cigarette products, have been discussed as possible means by which to reduce tobacco-related disease. To assess any potential reduction in harm by either of these approaches requires an accurate assessment of tobacco toxin exposure. Urine samples were collected at four time points and analyzed for 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), and its glucuronide, 1-hydroxypyrene, anatabine, free nicotine, total nicotine (free plus glucuronidated), free cotinine, total cotinine (free plus glucuronidated), and total trans-3'-hydroxycotinine (free plus glucuronidated). Anatabine is a minor alkaloid that may be useful in assessing tobacco exposure in individuals using nicotine replacement therapies. Urinary anatabine levels were well correlated (P < 0.0001) with both free and total nicotine (r = 0.753 and 0.773, respectively). Anatabine levels were also correlated with free cotinine (r = 0.465; P < 0.001), total cotinine (r = 0.514; P < 0.001), and total NNAL (r = 0.633; P < 0.001). These data support the role of anatabine as a biomarker of tobacco exposure. 1-Hydroxypyrene is a biomarker of polycyclic aromatic hydrocarbon exposure, but unlike NNAL it is not tobacco specific. Whereas urinary concentrations of 1-hydroxypyrene were consistent across the four visits, the levels were not correlated with NNAL, anatabine, nicotine, or any nicotine metabolites. Murphy, S.E., Link, C.A., Jensen, J., Le, C., Puumala, S.S., Hecht, S.S., Carmella, S.G., Losey, L. and Hatsukami, D.K. A Comparison of Urinary Biomarkers of Tobacco and Carcinogen Exposure in Smokers. Cancer Epidemiol. Biomarkers Prev., 13, pp. 1617-1623, 2004.

Antidepressant Treatment of Co-occurring Depression and Alcohol Dependence

The use of antidepressant pharmacotherapy to treat patients with co-occurring depression and alcohol dependence is controversial. There is a stigma attached to giving medications to alcohol-dependent persons. Also, empirical evidence is sparse and inconsistent, which discourages the use of antidepressants in these patients. Historically, it has been a challenge to accurately diagnose a depressive disorder in the presence of alcohol dependence. In addition, early clinical studies were fraught with methodological problems; however, improved diagnostic assessments are now available, and in the last decade, from well-controlled trials appear to support the use of antidepressants in this patient population in the specific role of relieving depressive symptoms. The majority of these trials also demonstrate that antidepressants have relatively little impact on reducing heavy drinking in this patient population, even though the medications reduce depressive symptoms. Newer approaches to treating patients with co-occurring depression and alcohol dependence suggest adding to the antidepressant a pharmacotherapy that directly impacts drinking. The findings from this review better define the action of antidepressants in patients with co-occurring depression and alcohol dependence as specific to reducing depressive symptoms, and these medications and their action on mood have little impact on treating the co-occurring alcohol dependence. Pettinati, H.M. Antidepressant Treatment of Co-occurring Depression and Alcohol Dependence. Biol. Psychiatry, 56, pp. 785-792, 2004.

Smoking Cessation Services in U.S. Methadone Maintenance Facilities

Most patients in drug treatment smoke cigarettes. This study established the prevalence and types of nicotine dependence services offered in methadone and other opioid treatment clinics in the United States. A cross-sectional survey was conducted of all outpatient methadone maintenance clinics in the United States. One person in a leadership position from each clinic was surveyed. The 20-minute survey was collected by phone, fax, or mail, according to responder preference. Fifty-nine percent of the clinics (408 of 697 clinics) responded. The sample was very similar to all outpatient methadone maintenance clinics in the United States in size, region, and ownership. In the 30 days before the survey, respondents reported that their clinics provided the following services to at least one patient: 73 percent provided brief advice to quit, 18 percent offered individual or group smoking cessation counseling, and 12 percent prescribed nicotine replacement therapy. However, the services were provided to very few patients. Clinics with written guidelines that required them to address smoking were much more likely to provide services than those without guidelines. Private for-profit clinics were significantly less likely than public or private nonprofit clinics to treat nicotine dependence. Most respondents (77 percent) reported that their staffs were interested in receiving training in nicotine dependence treatment, and more than half (56 percent) had at least one staff member ("champion") with a strong interest in treating nicotine dependence. A vast majority of methadone patients smoke; yet in the 30 days before the survey only one out of three facilities provided counseling to any patients and only one out of ten prescribed nicotine replacement therapy to any patients. A dual strategy of requiring clinics to provide comprehensive nicotine dependence services and training staff to provide these services may provide the incentive and support necessary for the widespread adoption of treatment for nicotine dependence in methadone facilities. Richter, K.P., Choi, W.S., McCool, R.M., Harris, K.J. and Ahluwalia, J.S. Smoking Cessation Services in U.S. Methadone Maintenance Facilities. Psychiatr. Serv., 55, pp. 1258-1264, 2004.

"Who Gets In?" Recruitment and Screening Processes of Outpatient Substance Abuse Trials

A brief telephone-screening interview was conducted with 1759 callers seeking treatment for substance abuse at the Treatment Research Clinic (TRC) over a 16-month period. The purpose of this study was to examine the effectiveness of various recruitment strategies in attracting eligible participants and to identify screening variables that characterized eligible and ineligible callers. Callers referred by friends and family were more likely to be eligible than callers from other referral sources. Callers seeking treatment for cocaine abuse who reported more severe alcohol/substance problems were more likely to be eligible for treatment protocols, while those with severe problems in other psychosocial areas (legal, medical, and psychiatric) were more often excluded. Alcohol- and nicotine-dependent callers reporting severe alcohol problems were more likely to be eligible but otherwise were not different from callers who were ineligible. The effectiveness of recruitment may not be the same for different types of substance use disorders. This study underscores the importance of having a sensitive screening assessment for recruiting a homogeneous yet representative sample for outpatient substance abuse clinical trials. Sayre, S.L., Evans, M., Hokanson, P.S., Schmitz, J.M., Stotts, A.L., Averill, P. and Grabowski, J. Who Gets In?" Recruitment and Screening Processes of Outpatient Substance Abuse Trials. Addict Behav., 29, pp. 389-398, 2004.

A Randomized Controlled Trial of Pemoline for Attention-Deficit/Hyperactivity Disorder in Substance-Abusing Adolescents

In adolescents with substance use disorder (SUD), comorbid attention-deficit/hyperactivity disorder (ADHD) is associated with greater severity of substance abuse, conduct problems, and worse treatment outcomes. Although many controlled trials have established the efficacy of psychostimulants, including pemoline, for ADHD in children and adolescents, none have been conducted in adolescents with SUD. This randomized, placebo-controlled trial, conducted between 1996 and 2000, evaluated the safety and efficacy of pemoline on substance abuse and conduct problems. Sixty-nine adolescents (aged 13-19) with conduct disorder (CD), SUD, and ADHD were recruited from the community and randomly assigned to a 12-week clinical trial of pemoline (n = 35) or placebo (n = 34), titrated over 4 weeks to a single morning dose of 75 to 112.5 mg as tolerated. Pemoline had greater efficacy than placebo for ADHD as determined by significantly more Clinician's Global Impression-Improvement (CGI-I) ratings of 1 (very much improved) or 2 (much improved) at the study endpoint (n = 69; p <.05). There was also greater reduction in ADHD severity on the parent-rated Conners Hyperactivity-Impulsivity scale in pemoline-treated study completers compared to placebo-treated completers (pemoline, n = 17; placebo, n = 16; p <.01), but no difference between groups in the intent-to-treat analysis (n = 68; p <.13). Substance use did not decline in either group, and there was no difference between groups in baseline to study endpoint change in substance use or CD symptoms. Overall, pemoline was well tolerated, demonstrating a good safety profile and no elevation in liver enzyme levels. Pemoline was efficacious for ADHD but did not have an impact on CD or substance abuse in the absence of specific treatment for SUD. Riggs, P.D., Hall, S.K., Mikulich-Gilbertson, S.K., Lohman, M. and Kayser, A. A Randomized Controlled Trial of Pemoline for Attention-Deficit/Hyperactivity Disorder in Substance-abusing Adolescents. J Am. Acad. Child Adolesc.Psychiatry, 43, pp. 420-429, 2004.

Attention-Deficit/Hyperactivity Disorder and the Substance Use Disorders: The Nature of the Relationship, Subtypes at Risk, and Treatment Issues

There is a strong literature supporting a relationship between ADHD and SUD. Clearly, ADHD adolescents with conduct or bipolar disorder as part of their clinical picture are at the highest risk for SUD. ADHD without comorbidity appears to confer an intermediate risk factor for SUD that appears to manifest in young adults and college students. Both family genetic and self-medication influences may be operational in the development and continuation of SUD in ADHD subjects: however, systematic data are lacking. Patients with ADHD and SUD require multi-modal interventions incorporating addiction and mental health treatment. Pharmacotherapy in individuals with ADHD and SUD needs to take into consideration abuse liability, potential drug interactions, and compliance concerns. Although the existing literature has provided important information on the relationship of ADHD and SUD, it also points to a number of areas in need of further study. The mechanism by which untreated ADHD leads to SUD and the risk reduction of ADHD treatment on later SUD, needs to be understood better. The influence of adequateness of treatment of ADHD on later SUD needs to be delineated. Given the prevalence and major morbidity and impairment caused by SUD and ADHD. Prevention and treatment strategies for these patients need to be developed and evaluated further. Wilens, T.E. Attention-Deficit/Hyperactivity Disorder and the Substance Use Disorders: The Nature of the Relationship, Subtypes at Risk, and Treatment Issues. Psychiatr. Clin. North Am., 27, pp. 283-301, 2004.

Impact of ADHD and its Treatment on Substance Abuse in Adults

Attention-deficit/hyperactivity disorder (ADHD) is a risk factor for substance abuse in adults. Additional psychiatric comorbidity increases this risk. ADHD is associated with different characteristics of substance abuse: substance abuse transitions more rapidly to dependence, and lasts longer in adults with ADHD than those without ADHD. Self-medication may be a factor in the high rate of substance abuse in adults with ADHD. While previous concerns arose whether stimulant therapy would increase the ultimate risk for substance abuse, recent studies have indicated that pharmacologic treatment appears to reduce the risk of substance abuse in individuals with ADHD. When treating adults with ADHD and substance abuse, clinicians should assess the relative severity of the substance abuse, the symptoms of ADHD, and any other comorbid disorders. Generally, stabilizing or addressing the substance abuse should be the first priority when treating an adult with substance abuse and ADHD. Treatment for adults with ADHD and substance abuse should include a combination of addiction treatment/psychotherapy and pharmacotherapy. The clinician should begin pharmacotherapy with medications that have little likelihood of diversion or low liability, such as bupropion and atomoxetine, and, if necessary, progress to the stimulants. Careful monitoring of patients during treatment is necessary to ensure compliance with the treatment plan. Wilens, T.E. Impact of ADHD and its Treatment on Substance Abuse in Adults. J Clin. Psychiatry, 65 Suppl 3, pp. 38-45, 2004.

Risk of Substance Use Disorders in Adolescents with Bipolar Disorder

Previous work in adults and youths has suggested that juvenile onset bipolar disorder (BPD) is associated with an elevated risk of substance use disorders (SUD). Considering the public health importance of this issue, the authors now report on a controlled study of adolescents with and without BPD to evaluate the risk of SUD. Probands with DSM-IV BPD (n=57, mean age +/- SD=13.3 +/- 2.4 years) and without DSM-IV BPD (n=46, 13.6 +/- 2.2 years) were studied. Structured psychiatric interviews and multiple measures of SUD were collected. Bipolar disorder was associated with a highly significant risk factor for SUD (32% versus 7%, Z=2.9, p=.004) that was not accounted for by conduct disorder (adjusted odds ratio=5.4, p=.018). Adolescent-onset BPD (> or =13 years) was associated with a higher risk of SUD compared with those with child-onset BPD (chi1=9.3, p=.002). These findings strongly indicate that BPD, especially adolescent onset, is a significant risk factor for SUD independently of conduct disorder. Wilens, T.E., Biederman, J., Kwon, A., Ditterline, J., Forkner, P., Moore, H., Swezey, A., Snyder, L., Henin, A., Wozniak, J. and Faraone, S.V. Risk of Substance Use Disorders in Adolescents with Bipolar Disorder. J Am. Acad. Child Adolesc. Psychiatry, 43, pp. 1380-1386, 2004.

A Clinical Perspective of Attention-Deficit/Hyperactivity Disorder into Adulthood

Attention-deficit/hyperactivity disorder (ADHD) is a common psychiatric disorder that affects all age groups. Recent data on the clinical presentation, comorbidity, neurobiology, and treatment are reviewed. Using the search term ADHD, a selective PubMed review of the clinical literature was undertaken to evaluate recent data relevant to ADHD with attention to a life span perspective of the disorder. A growing literature indicates that ADHD is more persistent than previously thought and has a developmental variability in its presentation. The disorder impairs academic, social, and occupational functioning and is often associated with comorbidity, including cigarette smoking and substance abuse. Considerable evidence suggests that the disorder has a strong genetic component and a biological underpinning; the pathophysiology includes dysfunction in both noradrenergic and dopaminergic systems. Both psychosocial therapy and pharmacotherapy have been shown effective in the treatment of the disorder throughout the life span. The therapeutic effectiveness of pharmacologic agents in the treatment of ADHD has been attributed to noradrenergic and/or dopaminergic effects. ADHD is associated with impairment and comorbidity throughout the life span. Growing evidence suggests the importance of short- and long-term management of the disorder. While the long-term treatment of ADHD is expected to lessen the individual's impairment, the outcome for adults who have received treatment since childhood requires further research. Wilens, T.E. and Dodson, W. A Clinical Perspective of Attention-Deficit/Hyperactivity Disorder into Adulthood. J Clin. Psychiatry, 65, pp. 1301-1313, 2004.

Methylphenidate Has Some Potential for Abuse

Methylphenidate is used to treat Attention Deficit Hyperactivity Disorder in children and adolescents. However, its abuse potential has not been well characterized, although it produces behavioral effects similar to those observed with other abused stimulants, such as d-amphetamine and cocaine. Investigators at the University of Kentucky, Lexington, KY, aimed to characterize the abuse potential of oral methylphenidate relative to oral d-amphetamine. Ten drug-abusing volunteers were recruited to participate in this study, which consisted of seven dose conditions: methylphenidate (16, 32 and 48 mg), d-amphetamine (8, 16 and 24 mg) and placebo. The reinforcing effects of these drugs were assessed during a self-administration session with a modified progressive-ratio procedure. Subject-rated, performance and physiological effects were assessed concurrently during both the sampling and self-administration sessions. The intermediate dose of methylphenidate and d-amphetamine increased responding significantly above placebo levels. Both methylphenidate and d-amphetamine produced dose-dependent increases in stimulant-like subject ratings (e.g. Active, Alert, or Energetic and High). These findings are consistent with epidemiological data and previous findings from laboratory studies that suggest methylphenidate has at least some abuse potential. Stoops, W.W., Glaser, P.E., Fillmore, M.T. and Rush, C.R. Reinforcing, Subject-rated, Performance and Physiological Effects of Methylphenidate and D-amphetamine in Stimulant Abusing Humans. J Psychopharmacology, 18(4), pp. 534-543, 2004.

Reinforcing Effects of Methylphenidate, Like D-amphetamine and Cocaine, are Influenced by Behavioral Demands

The reinforcing effects of stimulant drugs such as d-amphetamine, caffeine, and cocaine are modulated by behavioral demands following drug administration. Investigators at the University of Kentucky, Lexington, aimed to assess the reinforcing effects of methylphenidate under different behavioral demands using a modified progressive-ratio procedure. The effects of oral methylphenidate (0, 10, 20, and 40 mg) were assessed in seven healthy adult volunteers under both performance and relaxation conditions. Performance sessions required volunteers to complete simple arithmetic problems. Relaxation sessions required volunteers to sit quietly in a semi-reclined position in a darkened room. The results showed that methylphenidate significantly increased break point and number of capsules earned on the modified progressive-ratio procedure as an increasing function of dose under the performance, but not the relaxation, condition. Methylphenidate produced comparable stimulant-like subject ratings under both the performance and relaxation conditions. These findings suggest that the reinforcing effects of methylphenidate, like d-amphetamine and cocaine, are influenced by behavioral demands following drug administration. Stoops, W.W., Lile, J.A., Fillmore, M.T., Glaser, P.E. and Rush, C.R. Reinforcing Effects of Methylphenidate: Influence of Dose and Behavioral Demands Following Drug Administration. Psychopharmacology (Berlin), 177, pp. 349-355, 2005.

Acute Administration of Tiagabine Does Not Alter the Effects of Oral Cocaine

Drugs enhancing central gamma-aminobutyric acid (GABA) systems appear promising in the treatment of cocaine addiction. The investigators from the University of Kentucky, Lexington, KY, examined if tiagabine, a GABA reuptake inhibitor, has an ability to modify the discriminative-stimulus, reinforcing, subjective, performance and cardiovascular effects of oral cocaine in non-treatment seeking cocaine users. Initially, acute doses of 4 mg tiagabine were tested alone and in combination with oral cocaine in four participants to establish the safety of drug combinations. A higher dose of tiagabine (8 mg) was then tested in 6 patients. Participants learned to discriminate 150 mg of oral cocaine. The effects of cocaine (0-150 mg, p.o.) administered alone and in combination with tiagabine were then determined using the Multiple-Choice Procedure. Cocaine alone produced prototypical behavioral and physiological effects (i.e., functioned as a discriminative and reinforcing stimulus, produced stimulant-like subject-rated effects, improved performance and increased heart rate), but acute administration of tiagabine did not alter these effects. These findings suggest that tiagabine would not be effective at preventing continued cocaine use by blocking its acute, abuse-related effects. Lile, J.A., Stoops, W.W., Glaser, P.E., Hays, L.R. and Rush, C.R. Acute Administration of the GABA Reuptake Inhibitor Tiagabine Does Not Alter the Effects of Oral Cocaine in Humans. Drug and Alcohol Dependence, 76(1), pp. 81-91, 2004.

Ketoconazole, a Cytochrome P450 3A4 Inhibitor Increases Concentrations of Levo-Acetyl-Alpha-Methadol in Opioid-naive Individuals

Levo-acetyl-alpha-methadol (LAAM) exerts most of it mu-agonist activity through the action of its 2 N-demethylation metabolites, norLAAM and dinorLAAM. This reaction is primarily performed by cytochrome P450s (CYP) in the 3A family. Investigators from the University of Utah in Salt Lake City examined the effect of in vivo inhibition of CYP3A on the pharmacokinetics and pharmacodynamics of LAAM. Oral LAAM (5 mg/70 kg) was administered on 2 occasions in a single-blind, randomized crossover design to 13 opioid-naive subjects 1 hour after pretreatment with 400 mg ketoconazole or placebo. Blood and urine samples were collected at defined intervals over 240- and 96-hour periods, respectively; LAAM, norLAAM, and dinorLAAM concentrations were determined by liquid chromatography-tandem mass spectrometry. Physiologic and subjective measures were collected for up to 72 hours. This study showed that a single dose of ketoconazole causes a significant pharmacokinetic drug interaction with a single dose of LAAM that results in increased LAAM concentrations relative to norLAAM and dinorLAAM. Co-administration also results in prolongation of the appearance of its active metabolites and a prolongation of miosis, a sensitive dynamic index of mu-opioid action. The clinically relevant increase in LAAM concentrations and prolongation of plasma LAAM metabolites may affect physiologic function, such as QT intervals, suggesting that co-administration of LAAM and CYP3A4 inhibitors should be contraindicated. Moody, D.E., Walsh, S.L., Rollins, D.E., Neff, J.A. and Huang, W. Ketoconazole, a Cytochrome P450 3A4 Inhibitor, Markedly Increases Concentrations of Levo-Acetyl-Alpha-Methadol in Opioid-naive Individuals. Clinical Pharmacology and Therapeutics. 76(2), pp. 154-166, 2004.

Sex Influences Responses to Disulfiram Treatment in Cocaine-dependent Individuals

Sex and gender influences many physiological and behavioral responses to treatments. Investigators from Yale University and VA Connecticut Health Care System aimed to examine the differential response to disulfiram treatment of cocaine dependence by sex. Sex by treatment interactions from two pooled randomized clinical trials involving 191 cocaine-dependent subjects (36% female) were evaluated. Primary outcomes were days of abstinence and percentage of drug-free urine specimens. Men treated with disulfiram had better outcomes than those who were not. Women had an intermediate outcome regardless of whether they received disulfiram. Sex differences in response to disulfiram treatment may have important clinical and theoretical implications. Reasons for this apparent difference in sex-based response are not clear, but possible mechanisms worthy of greater study include differences in alcohol use by sex as well as differences in dopamine-mediated responses to cocaine and disulfiram. Nich, C., McCance-Katz, E.F., Petrakis, I.L., Cubells, J.F., Rounsaville, B.J. and Carroll, K.M. Sex Differences in Cocaine-dependent Individuals' Response to Disulfiram Treatment. Addictive Behaviors, 29(6), pp. 1123-1128, 2004.

Cocaine Addicts with Conduct Disorder have Altered Secretion of Adrenal Steroids

There is evidence that children with antisocial behaviors have increased plasma levels of the adrenal androgen dehydroepiandrosterone sulfate (DHEA-S) and either a decreased level of cortisol, or a decreased cortisol responsivity to stress. Low levels of cortisol have also been reported in antisocial adults but their levels of DHEA-S have not been studied. The investigators from New York Harbor Healthcare System, NY, assessed blood levels of DHEA-S and cortisol in adult cocaine addicts as a function of a diagnosis of antisocial personality disorder and of a retrospective diagnosis of conduct disorder (CD). Basal cortisol and DHEA-S were determined in the plasma samples of 40 hospitalized men. The patients' cortisol responsivity was also assessed while they were being exposed to a stressful situation. Patients who had a retrospective CD diagnosis had significantly increased DHEA-S levels and secreted less cortisol when stressed, confirming observations made in children and indicating that mechanisms underlying adrenal steroid alterations in childhood could still be at play in adulthood. Buydens-Branchey, L. and Branchey, M. Cocaine Addicts with Conduct Disorder are Typified by Decreased Cortisol Responsivity and High Plasma Levels of DHEA-S. Neuropsychobiology, 50(2), pp. 161-166, 2004.


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