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

Research Findings - Research on Pharmacotherapies for Drug Abuse

Oral Oxycodone, Hydrocodone and Hydromorphone Exhibit Similar Abuse Liabilities, Despite Dissimilar Analgesic Potencies

Abuse of prescription opioids has risen precipitously in the United States. Few controlled comparisons of the abuse liability of the most commonly abused opioids have been conducted. This outpatient study employed a double-blind, randomized, within-subject, placebo-controlled design to examine the relative abuse potential and potency of oral oxycodone (10, 20 and 40mg), hydrocodone (15, 30 and 45mg), hydromorphone (10, 17.5 and 25mg) and placebo. Healthy adult volunteers (n=9) with sporadic prescription opioid abuse participated in 11 experimental sessions (6.5h in duration) conducted in a hospital setting. All three opioids produced a typical mu opioid agonist profile of subjective (increased ratings of liking, good effects, high and opiate symptoms), observer-rated, and physiological effects (miosis, modest respiratory depression, exophoria and decrements in visual threshold discrimination) that were generally dose-related. Valid relative potency assays revealed that oxycodone was roughly equipotent to or slightly more potent than hydrocodone. Hydromorphone was only modestly more potent (less than two-fold) than either hydrocodone or oxycodone, which is inconsistent with prior estimates arising from analgesic studies. These data suggest that the abuse liability profile and relative potency of these three commonly used opioids do not differ substantially from one another and suggest that analgesic potencies may not accurately reflect relative differences in abuse liability of prescription opioids. Walsh, S.L., Nuzzo, P.A., Lofwall, M.R., and Holtman, J.R., Jr. The Relative Abuse Liability of Oral Oxycodone, Hydrocodone and Hydromorphone Assessed in Prescription Opioid Abusers. Drug Alcohol Depend., 2008, Jul 5. E-pub ahead of print.

A Review of Drug Self-administration Paradigms That Have Been Employed to Assess the Abuse Liability of Substances During Processes Drug Development

The purpose of this review is to illustrate the utility and value of employing human self-administration procedures in medication development, including abuse liability assessments of novel medications and evaluation of potential pharmacotherapies for substance use disorders. Traditionally, human abuse liability testing has relied primarily on subjective reports describing drug action by use of questionnaires; similarly, drug interactions between putative treatment agents and the drugs of abuse have relied on these measures. Subjective reports are highly valued because they provide qualitative and quantitative information about the characteristics of central and peripheral pharmacodynamic effects as well as safety and tolerability. However, self-administration procedures directly examine the behavior of interest - that is, drug taking. The present paper (1) reviews the most commonly used human self-administration procedures, (2) discusses the concordance of subjective reports and self-administration within the context of medications development for substance use disorders, focusing primarily on illustrative examples from development efforts with opioid and cocaine dependence, and (3) explores the utility of applying self-administration procedures to assess the abuse liability of novel compounds, including "abuse-deterrent" formulations (ADFs). The review will focus on opioid and cocaine dependence because a rich database from both clinical laboratory and clinical trial research exists for these two drug classes. The data reviewed suggest that drug-induced changes in self-administration and subjective effects are not always concordant. Therefore, assessment of self-administration in combination with subjective effects provides a more comprehensive picture that may have improved predictive validity for translating to the clinical setting. Comer, S.D., Ashworth, J.B., Foltin, R.W., Johanson, C.E., Zacny, J.P., and Walsh, S.L. The Role of Human Drug Self-administration Procedures in the Development of Medications. Drug Alcohol Depend. 96(1-2), pp. 1-15, 2008.

Oral Bupropion Does Not Increase Abstinence from Tobacco, Opioids, or Cocaine in Buprenorphine-stabilized (Opioid-dependent) Individuals, but Significantly Increases Treatment Non-compliance

In this double-blind, placebo-controlled trial, bupropion (BUPRO, 300 mg/day) was compared to placebo (PBO) for the concurrent treatment of opioid and tobacco addiction in 40 opioid-dependent smokers stabilized on buprenorphine (BUPRE, 24 mg/day). Participants received contingent, monetary reinforcement for abstinence from smoking, illicit opioids, and cocaine. Significant differences in treatment retention were observed (BUPRE+BUPRO, 58%; BUPRE+PBO, 90%). BUPRO treatment was not more effective than placebo for abstinence from tobacco, opioids, or cocaine in BUPRE-stabilized patients. These preliminary findings do not support the efficacy of BUPRO, in combination with BUPRE, for the concurrent treatment of opioid and tobacco addiction. Mooney, M.E., Poling, J., Gonzalez, G., Gonsai, K., Kosten, T., and Sofuoglu, M. Preliminary Study of Buprenorphine and Bupropion for Opioid-dependent Smokers. Am. J. Addict., 17(4), pp. 287-292, 2008.

Rural Opioid-using Pregnant Women Appear to Have Some Characteristics Associated With Better Treatment Outcomes

Historically, research on opioid use during pregnancy has occurred in urban settings and it is unclear how urban and rural populations compare. This study examined socio-demographic and other variables in opioid-using pregnant women seeking treatment and screened for participation in a multi-site randomized controlled trial. Women screened in rural Burlington, Vermont (n=54), were compared to those screened in urban Baltimore, Maryland (n=305). Rural opioid-using pregnant women appear to have some characteristics associated with better treatment outcomes (e.g., less severe drug use, greater employment). However, they may face additional barriers in accessing treatment (e.g., greater distance from treatment clinic). Heil, S.H., Sigmon, S.C., Jones, H.E., and Wagner, M. Comparison of Characteristics of Opioid-using Pregnant Women in Rural and Urban Settings. Am. J. Drug Alcohol Abuse, 34(4), pp. 463-471, 2008.

Disulfiram Enhances Both the Rewarding- and Aversive Subjective Effects of Acute Dextroamphetamine in Normal Subjects, Without Significantly Increasing Heart Rate or Blood Pressure

Disulfiram has shown promise in several clinical trials for cocaine addiction, but its potential utility in the treatment of amphetamine addiction has not been examined. The goal of this study was to determine the effects of disulfiram on acute physiological and subjective responses to dextroamphetamine in healthy volunteers. Five male and 5 female subjects participated in an outpatient double-blind, placebo-controlled, crossover study. Subjects were randomly assigned to a sequence of disulfiram (250 mg/day) or placebo treatments each lasting for 4 days. Day four of each treatment period was the experimental session, in which subjects orally ingested a single dose of dextroamphetamine (20 mg/70 kg). Outcome measures included heart rate, blood pressure, plasma cortisol and prolactin, subjective and performance on the Sustained Attention to Response Test (SART). Disulfiram did not affect dextroamphetamine-induced increases in heart rate, blood pressure, cortisol, or prolactin. Disulfiram did enhance some of the subjective effects of dextroamphetamine including ratings of "high," "anxious," "bad drug effects," "want more drug" and "drug liking" and was also associated with decreased performance in the SART test. How these enhanced subjective amphetamine responses affect cocaine use behavior remains to be determined in future clinical trials. Sofuoglu, M., Poling, J., Waters, A., Sewell, A., Hill, K., and Kosten, T. Disulfiram Enhances Subjective Effects of Dextroamphetamine in Humans. Pharmacol. Biochem. Behav. 90(3), pp. 394-398, 2008.

Bupropion Hydrochloride versus Placebo, in Combination with Cognitive Behavioral Therapy, for the Treatment of Cocaine Abuse/Dependence

This article describes a randomized, double-blind, placebo controlled trial comparing outpatient treatment with bupropion (N=37) and placebo (N=33) in combination with standard cognitive behavioral therapy (CBT) in cocaine dependent subjects. Bupropion was tested because it is a dopamine and norepinephrine reuptake inhibitor, and might have potential as an effective treatment for cocaine dependence due to its ability to reverse deficits in dopaminergic functioning that occur in chronic cocaine users. There were no statistically significant differences between bupropion and placebo in treatment outcomes, including measures of urine drug screen results (Joint Probability Index at 16 weeks: 0.43 for bupropion and 0.38 for placebo), treatment retention, cocaine craving ratings, and assessments of depressive symptoms. The results of this study suggest that further testing of bupropion for the treatment of cocaine dependence is not warranted. Shoptaw, S., Heinzerling, K.G., Rotherham-Fuller, E., Kao, U.H., Wang, P.C., Bholat, M.A., and Ling, W. Bupropion Hydrochloride versus Placebo, in Combination with Cognitive Behavioral Therapy, for the Treatment of Cocaine Abuse/Dependence. J. Addict. Dis., 27(1), pp. 13-23, 2008.

A Double-blind, Placebo-controlled Trial That Combines Disulfiram and Naltrexone for Treating Co-occurring Cocaine and Alcohol Dependence

This is a double blind, placebo-controlled trial that evaluated the efficacy of disulfiram, naltrexone and their combination in patients with co-occurring cocaine and alcohol dependence. 208 patients were randomized to disulfiram (250 mg/day), naltrexone (100 mg/day), the combination, or placebo for 11 weeks. Outcomes were in-trial abstinence from cocaine and/or alcohol. Few safety concerns were reported, although medication adherence was low in a number of patients for both medications, alone or in combination. In the primary analyses (GEE modeling), abstinence from cocaine as measured by cocaine-negative urines and days of self-reported abstinence from cocaine or alcohol did not differ between placebo and any of the medication groups. However, patients taking disulfiram (alone or in combination) were most likely to achieve combined abstinence from cocaine and alcohol. Secondary analyses revealed that patients taking the disulfiram-naltrexone combination were most likely to achieve 3 consecutive weeks of abstinence from cocaine and alcohol. There was an association between disulfiram treatment and abstinence from cocaine and alcohol. More patients taking the disulfiram-naltrexone combination achieved 3 consecutive weeks of abstinence in treatment than placebo-treated patients. Pettinati, H.M., Kampman, K.M., Lynch, K.G., Xie, H., Dackis, C., Rabinowitz, A.R., and O'Brien, C.P. A Double Blind, Placebo-Controlled Trial that Combines Disulfiram and Naltrexone for Treating Co-occurring Cocaine and Alcohol Dependence. Addict. Behav., 33, pp. 651-667, 2008.

Agonist-replacement Therapies May Have Implications as Treatments for Stimulant Dependence

Two experiments were conducted to determine whether methylphenidate or modafinil, two potential pharmacotherapies for stimulant dependence, would impair inhibitory behavior in cocaine users. Eleven cocaine abusers were administered methylphenidate (0, 15, 30, and 45 mg) or modafinil (0, 150, 300, and 450 mg) across four experimental sessions. A cued go-no-go task was used to measure response execution and inhibition. Subjective and cardiovascular measures were collected. Neither methylphenidate nor modafinil impaired inhibitory control, but produced prototypical subject-rated and cardiovascular effects. The results of these studies may have implications for the use of these drugs as agonist-replacement therapies for stimulant dependence. Vansickel, A.R., Fillmorex, M.T., Hays, L.R., and Rush, C.R. Effects of Potential Agonist-replacement Therapies for Stimulant Dependence on Inhibitory Control in Ccaine Ausers. Am. J. Drug Alcohol Abuse, 34(3), pp. 293-305, 2008.

Gender Differences With High-dose Naltrexone in 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.M., Kampman, K.M., Lynch, K.G., Suh, J.J., Dackis, C.A., Oslin, D.W., and O'Brien, C.P. Gender Differences with High-dose Naltrexone in Patients with Co-occurring Cocaine and Alcohol Dependence. J. Subst. Abuse Treat., 34, pp. 378-390, 2008.

Randomized, Placebo-controlled Trial of Bupropion for the Treatment of Methampheta-mine Dependence

This study compared bupropion to placebo for reducing methamphetamine use, increasing retention, and reducing the severity of depressive symptoms and methamphetamine cravings in 73 treatment-seeking methamphetamine dependent participants, with a secondary objective of comparing bupropion to placebo for reducing cigarette smoking among study participants. Participants were randomly assigned to bupropion SR (150 mg twice daily, N=36) or placebo (twice daily, N=37) for 12 weeks under double-blind conditions. Participants attended clinic thrice weekly to provide urine samples, complete research measures and assessments, and to receive contingency management and weekly cognitive behavioral therapy sessions. Results of this study showed that there were no statistically significant effects for bupropion relative to placebo on methamphetamine use, for reducing the severity of depressive symptoms or methamphetamine cravings, or on study retention. In a post hoc analysis, there was a statistically significant effect of bupropion treatment on methamphetamine use among participants with lighter (0-2 methamphetamine positive urines but not heavier (3 - 6 methamphetamine positive urines) during baseline. Bupropion treatment was associated with significantly reduced cigarette smoking. The post hoc findings of an effect for bupropion among baseline light, but not heavy, methamphetamine users suggests further evaluation of bupropion for light methamphetamine users is warranted. Shoptaw, S., Heinzerling, K.G., Rotherham-Fuller, E., Steward, T., Wang, J., Swanson, A-N., De La Garza, R., Newton, T., and Ling, W. Randomized, Placebo-controlled Trial of Bupropion for the Treatment of Methamphetamine Dependence. Drug and Alc. Dep., 96, pp. 222-232, 2008.

Predictors of Cardiovascular Response to Methamphetamine Administration in Methamphetamine-dependent Individuals May Help in the Prevention and Treatment of Cardiovascular Events in a Population at High Risk

The goal of this study was to determine predictors of cardiovascular response to methamphetamine administrated in the laboratory. Heart rate (HR) and blood pressure (BP) were measured at baseline and at several time points following the administration of methamphetamine or saline placebo. One-way ANOVA was used to determine the differences between female and male subjects in their cardiovascular response. In male subjects, linear regression and one-way ANOVA were used to determine the influence of potential predictors on cardiovascular response, including age, weight, drug use indicators, concurrent use of other substances, route of administration, and race. Methamphetamine administration provoked significant increases in HR and BP, as compared to placebo. Female gender was associated with larger peak change in diastolic BP following administration. Baseline HR and BP were found to be strong predictors of cardiovascular response to methamphetamine administration in male subjects. Lifetime use and recent use of methamphetamine and nicotine did not predict cardiovascular response to methamphetamine. Recent alcohol use was associated with increased peak change in diastolic BP. Also, current use of cannabis was negatively correlated with peak HR change. Male cannabis users show lower peak change in HR as compared to non-cannabis users. As compared to methamphetamine smokers, intravenous users demonstrated higher peak change in diastolic BP following drug administration. Race did not have a significant effect on cardiovascular response. Taken together, these findings may help in the prevention and treatment of cardiovascular events in a population at high risk of premature morbidity and mortality. Fleury, G., DeLaGarza, R., Mahoney, J.J., Evans, S.E., and Newton, T.F. Predictors of Cardiovascular Response to Methamphetamine Administration in Methamphetamine-dependent Individuals. Am. J. Addict. Mar-Apr;17(2) pp. 103-110, 2008.

Pharmacological Manipulations That Enhance Brain ACh Warrant Continued Investigation as Potential Treatments for Methamphetamine Addiction

Acetylcholine (ACh) has been implicated in the reinforcing and locomotor-activating effects produced by methamphetamine (Meth). Of interest, recent data suggest that acetylcholinesterase (AChE) inhibitors attenuate Meth-seeking behaviour in rats. This study was conducted in order to determine the safety (adverse events, mood changes, cardiovascular effects) and preliminary efficacy (subjective effects) of the AChE inhibitor rivastigmine (Riv) when tested in combination with Meth. Twenty-three non-treatment-seeking Meth-dependent participants resided in an in-patient unit at UCLA for 2 wk, and completed this double-blind, between-subjects, placebo-controlled study. The data analyses compared across-study measures of adverse events and mood, and a post-randomization analysis of cardiovascular and subjective effects (on day 11). The data reveal that rivastigmine was not associated with increased adverse events or alterations in mood. As expected, acute Meth exposure (30 mg i.v.) increased heart rate and blood pressure, as well as several positive subjective effects, Addiction Research Center Inventory (ARCI) ratings, and reported monetary value (p<0.05). The data indicated that Riv, at 3 mg, significantly attenuated Meth-induced increases in diastolic blood pressure, and self-reports of 'anxious' and 'desire' (p<0.05). Taken together, the findings in the current report suggest that pharmacological manipulations that enhance brain ACh warrant continued investigation as potential treatments for Meth addiction. DeLaGarza, R., Shoptaw, S. and Newton, T.F. Evaluation of the Cardiovascular and Subjective Effects of Rivastigmine in Combination with Methamphetamine in Methamphet-amine-dependent Human Volunteers. Int. J. Neuropsychopharm. Feb 4, pp. 1-13, 2008.

The Prevalence of Antisocial Behaviors Syndromes is Similar Within Either Cannabis- or Cocaine-dependent Populations of Patients

Antisocial personality disorder (ASPD) is highly associated with substance use disorders (SUD). In addition to the full ASPD syndrome, which requires both childhood conduct disorder and the adult features, other antisocial behavioral syndromes, including conduct disorder (CD) alone without the adult syndrome, and the adult antisocial behavioral syndrome without childhood CD (AABS) are also frequently diagnosed in patients with SUD. The aim of this study was to compare the rates of these various ASPD syndromes between cocaine- and cannabis-dependent individuals seeking treatment. A structured interview for ASPD excluding symptoms that occurred solely in the context of substance use was conducted in 241 outpatients (cocaine dependence, n = 111; cannabis dependence, n = 130). Overall, the proportion of substance-dependent individuals in this study with AABS was significantly larger than the proportion with ASPD (30.9% vs. 17.3%). A diagnosis of CD-only, where CD did not progress to ASPD, was uncommon. No significant differences in the prevalence of antisocial behavioral syndrome diagnoses were found between cocaine- and cannabis-dependent patients. Antisocial behavioral syndrome diagnosis did not influence treatment retention. Antisocial behavioral syndromes are commonly diagnosed in patients with SUD and future research should evaluate prognostic implications of AABS compared to ASPD in a variety of clinical treatment settings. Mariani, J.J., Horey, J., Bisaga, A., Aharonovich, E., Raby, W., Cheng, W.Y., Nunes, E., and Levin, F.R. Antisocial Behavioral Syndromes in Cocaine and Cannabis Dependence. Am. J. Drug Alcohol Abuse, 34(4), pp. 405-414, 2008.

Cannabis Reinforcement and Dependence: Role of the Cannabinoid CB1 Receptor

Awareness of cannabis dependence as a clinically relevant issue has grown in recent years. Clinical and laboratory studies demonstrate that chronic marijuana smokers can experience withdrawal symptoms upon cessation of marijuana smoking and have difficulty abstaining from marijuana use. This paper reviews data implicating the cannabinoid CB1 receptor in regulating the behavioral effects of Delta(9)-tetrahydrocannobinol (THC), the primary psychoactive component of cannabis, across a range of species. The behavioral effects discussed included those that directly contribute to the maintenance of chronic marijuana smoking, such as reward, subjective effects, and the positive and negative reinforcing effects of marijuana, THC and synthetic cannabinoids. The role of the CB1 receptor in the development of marijuana dependence and expression of withdrawal was also discussed. Lastly, treatment options that may alleviate withdrawal symptoms and promote marijuana abstinence will be considered. Cooper, Z.D. and Haney, M.. Cannabis Reinforcement and Dependence: Role of the Cannabinoid CB1 Receptor. Addict. Biol., 13, pp. 188-195, 2008.

Under Certain Conditions, Psychostimulants May be a Pharmacologic Option in the Treatment of Patients With Co-morbid ADHD and SUD

This review addresses the relationship between attention-deficit/hyperactivity disorder (ADHD) and substance use disorders (SUDs), with an emphasis on factors that determine the potential for psychostimulant abuse. Strategies for identification and treatment of patients with ADHD who are at risk for, or have, co-morbid SUD are also addressed. The article was based on a qualitative review of current literature addressing co-morbid ADHD and SUD. Adolescent and adult patients with ADHD are at increased risk for SUD, as well as a number of other psychiatric disorders. Psychostimulant agents like methylphenidate (MPH) and mixed amphetamine salts (MAS) are effective first-line pharmacotherapies for ADHD; however, they are Schedule II controlled substances with a potential for abuse. Evidence suggests that treatment of ADHD during childhood with stimulant agents may reduce the risk of developing SUD later on. Factors associated with the highest risk of SUD in patients with ADHD include co-morbid antisocial personality disorder, bipolar disorder, an eating disorder, severe ADHD and/or antisocial behavior symptoms, and dropping out of school. Treatment initiation during adolescence or young adulthood also has been linked to increased risk of polydrug use and non-medical stimulant use, a pattern of behavior consistent with a risk of SUD development. Treatment plans for patients with ADHD and co-morbid SUD should include behavioral interventions, careful monitoring, and when appropriate, pharmacotherapy. When oral formulations of psychostimulants are used at recommended doses and frequencies, they are unlikely to yield effects consistent with abuse potential in patients with ADHD. Long-acting stimulant formulations and non-stimulants, like atomoxetine or bupropion, have a lower potential for abuse, and provide several safe and effective treatment options for the development of a comprehensive management plan for patients with co-morbid ADHD and SUD. Patients with ADHD are at increased risk for SUD. Under certain conditions, psychostimulants may be a pharmacologic option in the treatment of patients with co-morbid ADHD and SUD. However, clinicians should be mindful of the risks and benefits of this treatment approach in a high-risk population and should also bear in mind the labeling guidelines when working with this co-morbidity. Kollins, S.H. A Qualitative Review of Issues Arising in the Use of Psycho-stimulant Medications in Patients with ADHD and Co-morbid Substance Use Disorders. Curr. Med. Res. Opin. 24(5) pp. 1345-1357. E-pub 2008 Apr 1.

Sex and Opioid Maintenance Dose Influence Response to Naloxone in Opioid-dependent Humans

Pooled self-report and physiological data from 32 male and 15 female methadone or LAAM maintained volunteers were retrospectively analyzed for individual differences in response to naloxone (0.15 mg/70 kg, IM) and placebo at 20 and 40 minutes post-injection. Males and females were each divided by the median split methadone maintenance dose (MMD, in mg/kg body weight) into high and low MMD groups and MMD was used as a factor in the analysis, along with sex, drug, and time post-drug. Females in the low, but not high, MMD group showed naloxone-induced increases in ratings on the Antagonist and Mixed-Action subscales of the Adjective Rating Scale, and the LSD sub-scale of the Addiction Research Center Inventory at 20 minutes post-injection. Males in the high MMD group showed significant naloxone-induced increases in scores of these measures at both post-injection time points. In addition, low MMD subjects showed more short-lived naloxone-induced increases on Visual Analogue Scale Bad and Any drug effects ratings than high MMD subjects. These results suggest that those on a lower MMD, especially women, experience a more intense, but short-lived, response to naloxone, whereas those on a higher MMD experience a more modest, but long lasting effect. Chopra, M.P., Feldman, Z., Mancino, M.J., and Oliveto, A. Sex and Opioid Maintenance Dose Influence Response to Naloxone in Opioid-dependent Humans. Pharm. Biochem. Behav., 2008 (E-pub ahead of print).

Buprenorphine for Opioid-dependent Patients in Office Practice

The profile of opioid dependence in the United States is changing. Abuse of prescription opioids is more common than that of illicit opioids: Recent data indicate that approximately 1.6 million persons abuse or are dependent on prescription opioids, whereas 323,000 abuse or are dependent on heroin. Despite this prevalence, nearly 80% of opioid-dependent persons remain untreated. One option for expanding treatment is the use of buprenorphine and the buprenorphine-naloxone combination. Buprenorphine is a partial opioid agonist that can be prescribed by trained physicians and dispensed at pharmacies. This article addresses the clinical presentation of a patient with opioid dependence and describes the relatively new practice of office-based treatment with buprenorphine-naloxone. The different components of treatment; the role of the physician who provides this treatment; and the logistics of treating this growing, multifaceted patient population are also examined. Sullivan, LE. and Fiellin, D.A. Narrative Review: Buprenorphine for Opioid-dependent Patients in Office Practice. Ann. Intern. Med., 148, pp. 662-670, 2008.

Pharmacogenetic Treatments for Drug Addiction: Alcohol and Opiates

Psychiatric pharmacogenetics involves the use of genetic tests that can predict the effectiveness of treatments for individual patients with mental illness such as drug dependence. This review article covers the developments in the pharmacotherapy of alcohol and opiates, addictive drugs for which the majority of FDA-approved pharmacotherapies exists. The results of an extensive literature review conclude that alcohol's physiological and subjective effects are associated with enhanced ss-endorphin release. Naltrexone increases baseline ss-endorphin release blocking further release by alcohol. Naltrexone's action as an alcohol pharmacotherapy is facilitated by a putative functional single nucleotide polymorphism (SNP) in the opioid mu receptor gene (A118G) which alters receptor function. Patients with this SNP have significantly lower relapse rates to alcoholism when treated with naltrexone. Caucasians with various forms of the CYP2D6 enzyme results in a 'poor metabolizer' phenotype and appear to be protected from developing opioid dependence. Others with a 'ultra-rapid metabolizer' phenotype do poorly on methadone maintenance and have frequent withdrawal symptoms. These patients can do well using buprenorphine because it is not significantly metabolized by CYP2D6. The authors conclude that pharmacogenetics has a great potential for improving treatment outcome as gene variants are identified that affect pharmacodynamic and pharmacokinetic factors. These mutations guide pharmacotherapeutic agent choice for optimum treatment of alcohol and opiate abuse and subsequent relapse. Haile, C., Kosten, T.A., and Kosten, T.R. Pharmacogenetic Treatments for Drug Addiction: Alcohol and Opiates. Am. J. Drug Alcohol Abuse, 34, pp. 355-381, 2008.

Impact of a Brief Training on Medical Resident Screening for Alcohol Misuse and Illicit Drug Use

Educational initiatives are needed to improve primary care substance use screening. This study assesses the impact on 24 medical residents of a 2.5-day curriculum combining experiential and manual-based training on screening for alcohol misuse and illicit drug use. A retrospective chart review of new primary care outpatients demonstrated that nearly all were asked about current alcohol use before and after curriculum participation. Adherence to national screening guidelines on quantification of alcohol consumption modestly improved (p < .05), as did inquiry about current illicit drug use (p < .05). Continued efforts are needed to enhance educational initiatives for primary care physicians. Gunderson, E.W., Levin, F.R., and Owen, P. Impact of a Brief Training on Medical Resident Screening for Alcohol Misuse and Illicit Drug Use. Am. J. Addict., 17, pp. 149-154, 2008.

A Placebo-controlled Randomized Clinical Trial of Naltrexone in the Context of Different Levels of Psychosocial Intervention

Naltrexone is approved for the treatment of alcohol dependence when used in conjunction with a psychosocial intervention. This study was undertaken to examine the impact of 3 types of psychosocial treatment combined with either naltrexone or placebo treatment on alcohol dependency over 24 weeks of treatment: (1) Cognitive-Behavioral Therapy (CBT) + medication clinic, (2) BRENDA (an intervention promoting pharmacotherapy) + medication clinic, and (3) a medication clinic model with limited therapeutic content. Two hundred and forty alcohol-dependent subjects were enrolled in a 24-week double-blind placebo-controlled study of naltrexone (100 mg/d). Subjects were also randomly assigned to 1 of 3 psychosocial interventions. All patients were assessed for alcohol use, medication adherence, and adverse events at regularly scheduled research visits. There was a modest main treatment effect for the psychosocial condition favoring those subjects randomized to CBT. Intent-to-treat analyses suggested that there was no overall efficacy of naltrexone and no medication by psychosocial intervention interaction. There was a relatively low level of medication adherence (50% adhered) across conditions, and this was associated with poor outcome. Results from this 24-week treatment study demonstrate the importance of the psychosocial component in the treatment of alcohol dependence. Moreover, results demonstrate a substantial association between medication adherence and treatment outcomes. The findings suggest that further research is needed to determine the appropriate use of pharmacotherapy in maximizing treatment response. Oslin, D.W., Lynch, K.G., Pettinati, H.M., Kampman, K.M., Gariti, P., Gelfand, L., Ten Have, T., Wortman, S., Dundon, W., Dackis, C., Volpicelli, J.R., and O'Brien, C.P. A Placebo-controlled Randomized Clinical Trial of Naltrexone in the Context of Different Levels of Psychosocial Intervention. Alcohol Clin. Exp. Res., 32, pp. 1299-1308, 2008.

Stability of the Nicotine Metabolite Ratio in Ad Libitum and Reducing Smokers

The ratio of two nicotine metabolites, cotinine and trans-3'-hydroxycotinine (3-HC), has been validated as a method of phenotyping the activity of the liver enzyme cytochrome P450 (CYP) 2A6 and, thus, the rate of nicotine metabolism. The objective of this study was to evaluate the correlates and stability of the 3-HC to cotinine ratio in ad libitum and reducing smokers, using nicotine replacement therapy (NRT), over a period of months. Smokers (n = 123, 94% Caucasian) participated in a smoking reduction study, where one-third of the sample smoked ad libitum for 8 weeks (Waitlist phase), before joining the rest of the participants for 12 weeks of cigarette reduction (Reduction phase) using NRT. Urinary nicotine, cotinine, and 3-HC were measured at each visit. The baseline 3-HC to cotinine ratio was significantly but weakly correlated with cigarettes per day (r = 0.19), BMI (r = -0.27), and waking at night to smoke (r = 0.23). As assessed by repeated measure ANOVA, the 3-HC to cotinine ratio was stable in the Waitlist phase [coefficient of variation for 3 to 4 measurements, 38% (range, 5-110%)], whereas minor variation was noted in the Reduction phase [coefficient of variation for 3-5 measurements, 35% (range, 10-107%)]. In nonreducing ad libitum smokers, the 3-HC to cotinine ratio was generally stable, whereas during smoking reduction using NRT, some small variation was detected. Although the current findings are suggestive of the stability of the 3-HC to cotinine ratio in a predominantly Caucasian sample smoking freely or reducing smoking with NRT, additional research is needed in more diverse populations. Mooney, M.E., Li, Z.Z., Murphy, S.E., Pentel, P.R., Le, C., and Hatsukami, D.K. Stability of the Nicotine Metabolite Ratio in ad libitum and Reducing Smokers. Cancer Epidemiol. Biomarkers Prev., 17, pp. 1396-1400, 2008.

Exposure to Nicotine and a Tobacco-specific Carcinogen Increase With Duration of Use of Smokeless Tobacco

Smokeless tobacco is an efficient delivery vehicle for nicotine and can contain significant amounts of carcinogens. However, few studies have examined factors that might moderate levels of nicotine or carcinogen exposure. The purpose of this study was to determine the effect of duration of smokeless tobacco use on the uptake of nicotine and a tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Questionnaires on use of smokeless tobacco were administered, and urine samples from 212 smokeless tobacco users were analysed for biomarkers of uptake of nicotine and NNK. The biomarkers were cotinine and total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL). Male smokeless tobacco users were recruited for studies designed to investigate methods of reducing smokeless tobacco use. The questionnaire and biomarker data were obtained at baseline, prior to reduction. Levels of cotinine (p<0.001) and total NNAL (p<0.001) were significantly correlated with duration (in years) of use of smokeless tobacco products. Median cotinine and total NNAL were 2.4 and 2.1 times higher, respectively, in the > or = 21 years of use than in the 0-5 years of use category. Smokeless tobacco users adjust their intensity of use with experience in order to increase their nicotine dose, resulting in a corresponding increase in exposure to NNK, a powerful carcinogen. These results indicate the importance of educating smokeless tobacco users about the effects of prolonged use of these products. Hecht, S.S., Carmella, S.G., Edmonds, A., Murphy, S.E., Stepanov, I., Luo, X., and Hatsukami, D.K. Exposure to Nicotine and a Tobacco-specific Carcinogen Increase with Duration of Use of Smokeless Tobacco. Tob. Control, 17, pp. 128-131, 2008.

Combined Active and Passive Immunization Enhances the Efficacy of Immunotherapy Against Nicotine in Rats

Vaccination against nicotine reduces the behavioral effects of nicotine in rats, and it is under clinical evaluation as a treatment for tobacco addiction. Efficacy is limited by the need for high serum nicotine-specific antibody (NicAb) levels, and currently available nicotine vaccines do not uniformly generate the required NicAb levels. Passive immunization with a nicotine-specific monoclonal antibody (Nic311) has also shown efficacy in rats. The principal aim of this study was to determine whether the combined use of vaccination and passive immunization would produce greater effects than vaccination alone on nicotine pharmacokinetics and locomotor sensitization (LMS) to nicotine. Rats were treated with vaccination alone, Nic311 alone, both, or neither, and then they were administered 10 daily injections of 0.3 mg/kg nicotine s.c. Treatment with Nic311 or vaccination alone increased the binding of nicotine in serum, reduced the unbound serum nicotine concentration and nicotine distribution to brain, and attenuated the development of LMS. Combined use of vaccination and passive immunization produced higher total serum NicAb levels, greater changes in nicotine pharmacokinetics, and a greater attenuation of LMS than either treatment alone. The total serum NicAb concentration was significantly correlated with brain nicotine levels and locomotor activity. These data indicate that providing higher serum NicAb concentrations improves the efficacy of immunotherapy against nicotine and that supplementing vaccination with passive immunization is a potential strategy to accomplish this. Roiko, S.A., Harris, A.C., Keyler, D.E., LeSage, M.G., Zhang, Y., and Pentel, P.R.. Combined Active and Passive Immunization Enhances the Efficacy of Immunotherapy Against Nicotine in Rats. J. Pharmacol. Exp. Ther., 325, pp. 985-993, 2008.

Prelude to Passion: Limbic Activation By "Unseen" Drug and Sexual Cues

The human brain responds to recognizable signals for sex and for rewarding drugs of abuse by activation of limbic reward circuitry. Does the brain respond in similar way to such reward signals even when they are "unseen", i.e., presented in a way that prevents their conscious recognition? Can the brain response to "unseen" reward cues predict the future affective response to recognizable versions of such cues, revealing a link between affective/motivational processes inside and outside awareness? The investigators exploited the fast temporal resolution of event-related functional magnetic resonance imaging (fMRI) to test the brain response to "unseen" (backward-masked) cocaine, sexual, aversive and neutral cues of 33 milliseconds duration in male cocaine patients (n = 22). Two days after scanning, the affective valence for visible versions of each cue type was determined using an affective bias (priming) task. They demonstrated, for the first time, limbic brain activation by "unseen" drug and sexual cues of only 33 msec duration. Importantly, increased activity in a large interconnected ventral pallidum/amygdala cluster to the "unseen" cocaine cues strongly predicted future positive affect to visible versions of the same cues in subsequent off-magnet testing, pointing both to the functional significance of the rapid brain response, and to shared brain substrates for appetitive motivation within and outside awareness. These findings represent the first evidence that brain reward circuitry responds to drug and sexual cues presented outside awareness. The results underscore the sensitivity of the brain to "unseen" reward signals and may represent the brain's primordial signature for desire. The limbic brain response to reward cues outside awareness may represent a potential vulnerability in disorders (e.g., the addictions) for whom poorly-controlled appetitive motivation is a central feature. Childress, A.R., Ehrman, R.N., Wang, Z., Li, Y., Sciortino, N., Hakun, J., Jens, W., Suh, J., Listerud, J., Marquez, K., Franklin, T., Langleben, D., Detre, J., and O'Brien, C.P. Prelude to Passion: Limbic Activation by "Unseen" Drug and Sexual Cues. PLoS.ONE., 3, e1506, 2008.

Changes in Mood, Cognitive Performance and Appetite in the Late Luteal and Follicular Phases of the Menstrual Cycle in Women With and Without PMDD (Premenstrual Dysphoric Disorder)

Although it's been reported that women with premenstrual dysphoric disorder (PMDD) have increased negative mood, appetite (food cravings and food intake), alcohol intake and cognitive deficits premenstrually, few studies have examined these changes concurrently within the same group of women or compared to women without PMDD. Thus, to date, there is not a clear understanding of the full range of PMDD symptoms. The present study concurrently assessed mood and performance tasks in 29 normally cycling women (14 women who met DSM-IV criteria for PMDD and 15 women without PMDD). Women had a total of ten sessions: two practice sessions, 4 sessions during the follicular phase and 4 sessions during the late luteal phase of the menstrual cycle. Each session, participants completed mood and food-related questionnaires, a motor coordination task, performed various cognitive tasks and ate lunch. There was a significant increase in dysphoric mood during the luteal phase in women with PMDD compared to their follicular phase and compared to Control women. Further, during the luteal phase, women with PMDD showed impaired performance on the Immediate and Delayed Word Recall Task, the Immeate and Delayed Digit Recall Task and the Digit Symbol Substitution Test compared to Control women. Women with PMDD, but not Control women, also showed increased desire for food items high in fat during the luteal phase compared to the follicular phase and correspondingly, women with PMDD consumed more calories during the luteal phase (mostly derived from fat) compared to the follicular phase. In summary, women with PMDD experience dysphoric mood, a greater desire and actual intake of certain foods and show impaired cognitive performance during the luteal phase. An altered serotonergic system in women with PMDD may be the underlying mechanism for the observed symptoms; correspondingly, treatment with specific serotonin reuptake inhibitors (SSRIs) remains the preferred treatment at this time. Reed, S.C., Levin, F.R., and Evans, S.M. Changes in Mood, Cognitive Performance and Appetite in the Late Luteal and Follicular Phases of the Menstrual Cycle in Women With and Without PMDD (Premenstrual Dysphoric Disorder). Horm. Behav., 54, pp. 185-193, 2008.

A Cocaine Hydrolase Engineered from Human Butyrylcholinesterase Selectively Blocks Cocaine Toxicity and Reinstatement of Drug Seeking in Rats

In this report, the authors describe the effectiveness of engineered cocaine hydrolase from human butyrylcholinesterase in rats and its potential clinical application in humans. Successive rational mutations of human butyrylcholinesterase (BChE) followed by fusion to human serum albumin have yielded an efficient hydrolase that offers realistic options for therapy of cocaine overdose and abuse. This albumin-BChE prevented seizures in rats given a normally lethal cocaine injection (100 mg/kg, i.p.), lowered brain cocaine levels even when administered after the drug, and provided rescue after convulsions commenced. Moreover, it selectively blocked cocaine-induced reinstatement of drug seeking in rats that had previously self-administered cocaine. The enzyme treatment was well tolerated and may be worth exploring for clinical application in humans. Brimijoin, S., Gao, Y., Anker, J.J., Gliddon, L.A., LaFleur, D., Shah, R., Zhao, Q., Singh, M. and Carrol, M.E. Neuropsychopharmacology, advance online publication, 16 Jan. 2008.

Rational Design of an Enzyme Mutant for Anti-cocaine Therapeutics

This article described the computational design of high-activity mutants of human butyrylcholinesterase (BChE) against (-)-cocaine. The computational design of BChE mutants have been based on not only the structure of the enzyme, but also the detailed catalytic mechanisms for BChE-catalyzed hydrolysis of (-)-cocaine and (+)-cocaine. By using the computational insights into the catalytic mechanisms, a unique design strategy based on the simulation of the rate-determining transition state has led to the exciting discovery of BChE mutants with a considerably improved catalytic efficiency against (-)-cocaine. One of the discovered BChE mutants has an approximately 456-fold improved catalytic efficiency against (-)-cocaine. The encouraging outcome demonstrates that the computational design approach based on the transition-state simulation is promising for rational enzyme redesign and drug discovery. Zheng, F., and Zhan, C.G. J. Comput. Aided Mol. Des. Nov 8, 2007.

A Neutral CB1 Receptor Antagonist Reduces Weight Gain in Rat

This study examined the effect of a neutral CB1 antagonist, AM4113, on food intake, weight gain, and emesis. The Ki value of AM4113 was 100-fold more selective for CB1 over CB2 receptors. AM4113 significantly reduced food intake and weight gain in rat. Compared with AM251, higher doses of AM4113 were needed to produce similar effects on food intake and body weight. Unlike AM251, a highly anorectic dose of AM4113 did not significantly potentiate emesis. The results show that a centrally active neutral CB1 receptor antagonist shares the appetite suppressant and weight loss effects of inverse agonists. They could be developed into a new class of antiobesity agents. Chambers, A.P., Vemuri, V.K., Peng, Y., Wood, J.T., Olszewska, T., Pittman, Q.J., Makriyannis, A., and Sharkey, K.A. Am. J. Physiol. Regul. Integr. Comp. Physiol. 293(6), pp. R2185-R2193, 2007.

Antidepressant-like Effects of the Novel Kappa Opioid Antagonist MCL-144B in the Forced-swim Test

Previous studies have demonstrated that kappa opioid receptor (KOR) antagonists reduce stress- and depression-like behaviors. The authors hypothesized that administration of a novel opioid mixed agonist/antagonist capable of antagonist activity at the KOR would attenuate forced-swim stress (FSS)-induced immobility, an animal model of depression-like behavior. Mice were exposed to repeated FSS after pretreatment with a graded dose of a novel bivalent morphinan compound, MCL-144B. In support of the hypothesis, pretreatment with MCL-144B dose-dependently attenuated stress-induced antinociception and immobility in the forced-swim test. Reindl, J.D., Rowan, K., Carey, A.N., Peng, X., Neumeyer, J.L., and McLaughlin, J.P. Pharmacology, 81(3), pp. 229-235, 2008.

Novel Sigma Receptor Agonists Produce Antidepressant-like Effects in Mice

In this study, two novel sigma receptor agonists (UMB23, UMB82) were evaluated for antidepressant-like activity in mice. First, radioligand binding studies confirmed that the novel compounds had preferential affinity for sigma receptors. Second, the forced swim test, a well established animal model for screening potential antidepressant drugs, showed that both compounds dose-dependently reduced immobility time. The sigma receptor antagonist BD1047 attenuated the antidepressant-like effects of UMB23 and UMB82. Third, locomotor activity suggested that the effects of UMB23 and UMB82 in the forced swim test were not due to non-specific motor activating effects. Together, the data provide further evidence that sigma receptor agonists represent a possible new class of antidepressant medication. Wang, J., Mack, A.L., Coop, A., and Matsumoto, R.R. Eur. Neuropsychopharmacol. 17(11), pp. 708-716, 2007.


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