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Director's Report to the National Advisory Council on Drug Abuse - February, 2010



Research Findings - Research on Pharmacotherapies for Drug Abuse

Lasting Reduction of Cocaine Action in Neostriatum - A Hydrolase Gene Therapy Approach

The authors previously found that a quadruple mutant cocaine hydrolase derived from human butyrylcholinesterase [termed cocaine esterase (CocE)] can suppress or reverse cocaine toxicity and abolish drug-primed reinstatement in rats. Here, the authors examined whether gene transfer of CocE reduces cocaine actions in brain reward centers. Early experiments used a standard, early region 1-deleted adenoviral vector, which, after intravenous delivery of 1010 plaque-forming units, caused plasma cocaine hydrolase activity to rise 25,000-fold between day 4 and day 7. During this period, under a protocol that typically induces FosB expression in the caudate nucleus, these rats and unprotected controls given only empty vector or saline were subjected to repeated twice-daily injections of cocaine (30 mg/kg i.p.). Immunohistochemistry of the neostriatum on day 7 showed many FosB-reactive nuclei in unprotected rats but few if any in rats pretreated with active vector, which resembled rats never exposed to cocaine. Western blots confirmed this result. In contrast there was a more localized protection against cocaine-elicited FosB induction when hydrolase vector was injected directly into the ventral striatum, which generated high transgene expression in many neurons of the target area. Similar results were obtained with systemic and local injection of a more efficient helper-dependent adenoviral vector, which transduced high levels of hydrolase for at least 2 months, with lesser expression continued up to 1 year. Behavioral tests are now warranted to determine whether such effects can reduce drug-seeking behavior and lower the probability of relapse. Gao Y, Brimijoin S J. Pharmacol Exp Ther. 2009 Aug 330:449-457.

Cocaine Esterase Prevents Cocaine-Induced Toxicity and the Ongoing Intravenous Self-Administration of Cocaine in Rats

Cocaine esterase (CocE), a naturally occurring bacterial enzyme, is a very efficient protein catalyst for the hydrolysis of cocaine, and has previously been shown to protect rodents from the lethal effects of cocaine. The current studies were aimed at evaluating the capacity of a longer acting mutant form (CocE T172R/G173Q; DM CocE) of CocE to protect against the lethal effects of cocaine, and alter ongoing intravenous cocaine self-administration in rats. A dose-response analysis revealed a dose-dependent suppression of cocaine-reinforced responding with 1.0 mg of CocE T172R/G173Q producing saline-like rates of responding. The effects of 1.0 mg of CocE T172R/G173Q on cocaine-reinforced responding were then compared with responding when saline was available for injection, whereas the selectivity of CocE T172R/G173Q's effects was assessed by evaluating the effects of 1.0 mg of CocE T172R/G173Q on (-)-2β-carbomethoxy-3β-phenyltropane (WIN-35065-2)- and food-reinforced responding. Although 1.0 mg of CocE T172R/G173Q suppressed responding maintained by 0.1 mg/kg/injection cocaine, a significant increase in responding was observed when responding was maintained by 1.0 mg/kg/injection cocaine, resulting in a 10-fold rightward shift in the dose-response curve for cocaine self-administration at a dose that did not significantly alter responding maintained by either WIN-35065-2 or food. These findings demonstrate that a long-acting form of CocE is effective at abruptly reducing the ongoing self-administration of low doses of cocaine, and provides a robust antagonism of cocaine's reinforcing effects. Furthermore, these studies provide strong evidence for the potential usefulness of a suitable, stable, and long-acting form of CocE as a pharmacotherapy for cocaine abuse in humans. Collins GT, Brim RL, Narasimhan D, Ko MC, Sunahara RK, Zhan CG, Woods JH. J Pharmacol Exp Ther. 2009 Nov 331(2):445-455.

Thermostable Variants of Cocaine Esterase for Long-Time Protection Against Cocaine Toxicity

Enhancing cocaine metabolism by administration of cocaine esterase (CocE) has been recognized as a promising treatment strategy for cocaine overdose and addiction, because CocE is the most efficient native enzyme for metabolizing the naturally occurring cocaine yet identified. A major obstacle to the clinical application of CocE is the thermoinstability of native CocE with a half-life of only a few minutes at physiological temperature (37ĄC). Here the investigators report thermostable variants of CocE developed through rational design using a novel computational approach followed by in vitro and in vivo studies. This integrated computational-experimental effort has yielded a CocE variant with a 30-fold increase in plasma half-life both in vitro and in vivo. The novel design strategy can be used to develop thermostable mutants of any protein. Gao D, Narasimhan DL, Macdonald J, et al. Mol Pharmacol. 2009 Feb 75(2):318-323.

Cocaine Vaccine (TA-CD) for the Treatment of Cocaine Dependence in Methadone-Maintained Patients

The purpose of this phase 2b, randomized, double-blind, placebo-controlled, 24-week clinical trial in 115 cocaine- and opioid-dependent persons was to evaluate the immunogenicity, safety, and efficacy of a novel cocaine vaccine to treat cocaine dependence. The study did not achieve a significant difference in complete abstinence with immunization; however, there was a significant reduction in cocaine use in patients who attained high IgG levels. Twenty-one vaccinated subjects (38%) who attained serum IgG anticocaine antibody levels of 43 ”g/ml or higher had significantly more cocaine-free urines than those with levels less than 43 ”g/ml and the placebo-receiving subjects during weeks 9 to 16 (45% vs. 35% cocaine-free urine samples, respectively). The proportion of subjects having a 50% reduction in cocaine use was significantly greater in the subjects with a high IgG level than in subjects with a low IgG level (53% of subjects vs. 23% of subjects, respectively). There were no treatment-related serious adverse events. The reported conclusion is that attaining high (ł 43 ”g/ml) IgG anticocaine antibody levels was associated with significantly reduced cocaine use, but only 38% of the vaccinated subjects attained those IgG levels and they had only 2 months of adequate cocaine blockade. Martell BA, Orson FM, Poling J, Mitchell E, Rossen RD, Gardner T, Kosten T. Arch Gen Psychiatry. 2009 66(10):1116-1123.

Cocaine-Specific Antibodies Blunt the Subjective Effects of Smoked Cocaine in Humans

Clinical data demonstrate that a cocaine vaccine (TA-CD) produces selective anticocaine antibodies, yet the impact of these antibodies on cocaine's direct effects is unknown. The objective of this human laboratory study was to measure the relationship between antibody titers and the effects of smoked cocaine on ratings of intoxication, craving, and cardiovascular effects. Ten cocaine-dependent men not seeking drug treatment spent 2 nights per week for 13 weeks inpatient where the effects of cocaine (0 mg, 25 mg, 50 mg) were determined before vaccination and at weekly intervals thereafter. Two doses of TA-CD (82 ”g, n = 4; 360 ”g, n = 6) were administered at weeks 1, 3, 5, and 9. The results showed that peak plasma antibody levels, which were highly variable, significantly predicted cocaine's effects. Those individuals in the upper half of antibody production had an immediate (within 4 minutes of cocaine smoking) and robust (55%-81%) reduction in ratings of good drug effect and cocaine quality, while those in the lower half showed only a nonsignificant attenuation (6%-26%). Self-reported cocaine use while participants were outpatient tended to decrease as a function of antibody titer (p < .12). By contrast, higher antibody levels predicted significantly greater cocaine-induced tachycardia. The investigators concluded that TA-CD vaccine substantially decreased smoked cocaine's intoxicating effects in those generating sufficient antibody. These data support further testing of cocaine immunotherapy as a treatment for cocaine dependence. Haney M, Gunderson EW, Jiang H, Collins ED, Foltin RW. Biol Psychiatry. 2010 Jan 1;67(1):59-65.

Cocaine Abuse Reduces White Matter Volume and Myelination Levels, Which Were Correlated With Diminished Motor and Executive Function

Recent studies demonstrated that diffusion tensor imaging (DTI) can provide information regarding white matter integrity of the corpus callosum (CC). In this study, DTI parameters were compared between cocaine dependent subjects (CDs) and non-drug using controls (NCs) in midsagittal CC. DTI images were acquired from19 CDs and 18 age-matched NCs. The midsagittal CC was segmented into: genu, rostral body, anterior midbody, posterior midbody, isthmus, and splenium. Linear mixed models analyses showed that, relative to NCs, CDs had lower fractional anisotropy (FA), higher radial diffusivity (λ⊥), and higher mean diffusivity (Dav) in the isthmus; higher λ⊥ and Dav in the rostral body; and lower FA in the splenium. After including mass of lifetime alcohol use in the mixed model analysis of covariance (ANCOVA) as a covariate, significant between group differences in λ⊥ in the rostral body and isthmus remained. These results suggest that alterations in λ⊥ in the rostral body and isthmus were mainly due to cocaine use, consistent with previous studies showing that cocaine may alter myelin integrity. Between group differences in FA in the isthmus and splenium, and Dav in the rostral body and isthmus became non-significant after inclusion of alcohol use as a covariate. This is suggestive of alcohol influencing these values, or may be related to the decreased degrees of freedom for these effects. Consistent with clinical data of greater severity of drug use in smoked versus intranasal cocaine, subjects who smoked cocaine showed lower FA and higher λ⊥ compared to intranasal CDs. Diffusion tensor imaging in cocaine dependence: regional effects of cocaine on corpus callosum and effect of cocaine administration route. Ma L, Hasan KM, Steinberg JL, et al. Drug Alcohol Depend. 2009 Oct 104(3): 262-267.

Diminished Brain Activity in Motor, Reward, and Cognitive Brain Regions of Cocaine-Dependent Subjects Versus Controls

Functional magnetic resonance imaging (fMRI) studies of early abstinence cocaine users offer information about the state of the brain when most cocaine users seek treatment. This study examined the relationship between pretreatment brain function and subsequent treatment response in 19 treatment-seeking early abstinence cocaine dependent (CD) subjects. These subjects and 14 non-drug using control subjects underwent fMRI while performing a working memory task with three levels of difficulty. CD subjects were then randomized to treatment studies. Results showed CD subjects had significantly lower (random effects, corrected for multiple 28 comparisons) brain activation in caudate, putamen, cingulate gyrus, middle and superior frontal gyri, inferior frontal gyrus pars triangularis and pars opercularis, precentral gyrus, and thalamus compared to non-drug using controls. Within CD subjects, thalamic activation significantly correlated with treatment response. This study shows CD subjects in early abstinence have alteration of brain function in frontal, striatal, and thalamic brain regions known to be part of a circuit associated with motor control, reward, and cognition. Subjects with pretreatment thalamic deactivation showed the poorest treatment response, possibly related to thalamic involvement in mesocortical and mesolimbic dopamine projections. Moeller FG, Steinberg JL, Schmitz JM, Ma L, Liu S, Kjome KL, Rathnayaka N, Kramer LA, Narayana PA. Psych Res: Neuroimaging.2010 Jan;175(1).

Influence of Verbal Recall of a Recent Stress Experience on Anxiety and Desire for Cocaine In Non-Treatment Seeking, Cocaine-Addicted Volunteers

It has long been postulated that stress increases the risk of drug abuse and relapse. The principal goal of this project was to evaluate the effects of verbal recall of a recent stress experience (specifically meaningful to each individual) on physiological and subjective measures in cocaine-addicted participants. Subjects described a recent stressful non-drug-related experience and a neutral non-stressful experience, and then completed mood and drug effect questionnaires, while heart rate and blood pressure were recorded. Participants (N = 25) were predominantly African American and male. As a group, participants used cocaine for more than 15 years and approximately 18 of the last 30 days, and a majority reported use of nicotine and/or alcohol. All participants were evaluated during a time in which they tested positive for cocaine metabolite. On a scale of 1-10, participants reported their verbal recall of a recent stress event as highly stressful and their verbal recall of a recent neutral event as non-stressful. The self-reported vividness of this recall was high (>8 out of 10) for both the stress and neutral events. Heart rate and systolic and diastolic blood pressure did not differ after verbal recall of either stress or neutral events. Similarly, self-reported subjective effects (including ratings of anxiety and craving for cocaine) did not differ after verbal recall of either stress or neutral events. In summary, despite the fact that participants recounted highly stressful and vivid memories, this experience did not elicit significant changes in cardiovascular or subjective effects. These data suggest that simply recalling a stressful event may not be a sufficient enough stimulus to contribute to craving or relapse in cocaine-addicted individuals. De La Garza R, Ashbrook LH, Evans SE, Jacobsen CA, Kalechstein AD, Newton TF. Am J Addict. 2009 Nov-Dec 18(6):481-487.

Mesocorticolimbic Activation of Cholinergic Receptors Appears Useful for the Treatment of Stimulant Addiction

Acetylcholine, the first neurotransmitter discovered, participates in many CNS functions, including sensory and motor processing, sleep, nociception, mood, stress response, attention, arousal, memory, motivation and reward. These diverse cholinergic effects are mediated by nicotinic- and muscarinic-type cholinergic receptors (nAChR and mAChR, respectively). The goal of this review is to synthesize a growing literature that supports the potential role of acetylcholine as a treatment target for stimulant addiction. Acetylcholine interacts with the dopaminergic reward system in the ventral tegmental area, nucleus accumbens and prefrontal cortex. In the ventral tegmental area, both nAChR and mAChR stimulate the dopaminergic system. In the nucleus accumbens, cholinergic interneurons integrate cortical and subcortical information related to reward. In the prefrontal cortex, the cholinergic system contributes to the cognitive aspects of addiction. Preclinical studies support a facilitative role of nicotinic receptor agonists in the development of stimulant addiction. In contrast, nonselective muscarinic receptor agonists seem to have an inhibitory role. In human studies, acetylcholinesterase inhibitors, which increase synaptic acetylcholine levels, have shown promise for the treatment of stimulant addiction. Further studies testing the efficacy of cholinergic medications for stimulant addiction are warranted. Sofuoglu M, Mooney M. CNS Drugs. 2009 Nov 23(11):939-952.

Atomoxetine Attenuates Dextroamphetamine Effects in Humans

The objectives of this study were to examine the effects of atomoxetine, a norepinephrine transporter inhibitor, on subjective, physiological, and plasma cortisol responses to dextroamphetamine in 10 healthy volunteers. Subjects were randomly assigned to a sequence of atomoxetine (40 mg/day) or placebo treatments, each lasting for 4 days. On day 4, responses to a single 20 mg/70 kg dose of dextroamphetamine were assessed. Atomoxetine treatment attenuated dextroamphetamine-induced increases in systolic and diastolic blood pressure and plasma cortisol as well as the self-report ratings of Ôstimulated', 'high', and Ôgood drug effects'. These findings are consistent with previous preclinical studies supporting the role of the noradrenergic system in mediating acute amphetamine responses, and support the potential use of atomoxetine as a treatment for stimulant addiction. Sofuoglu M, Poling J, Hill K, Kosten T. Am J Drug and Alcohol Abuse. 2009 35:412-416.

How Long Does Craving Predict Use of Methamphetamine?

This study lays the foundation for a clinical prediction model based on methamphetamine craving intensity and its ability to predict the presence or absence of within-treatment methamphetamine use. The study used a random effects logistic approach for estimating repeated-measures, generalized linear mixed models (GLMM) using craving as the sole predictor of methamphetamine. The study investigated whether methamphetamine craving predicted subsequent use more accurately at intervals more proximal to versus those more distal to assessment, examining one-week periods ending one to seven weeks after assessment of craving. Analyses were based on data from 691 methamphetamine dependent outpatients enrolled in the MTP. Craving was assessed by self-report on a 0-100 scale. Self-reported methamphetamine use was toxicologically verified. Craving and drug use were assessed weekly for 8 weeks. Findings showed that in the univariate analysis craving predicted methamphetamine use in the week immediately following the craving report, with subject-specific use increasing 0.38% for each 1-point increase in craving on a 0-100 scale. In the multivariate analysis the probability of use decreased significantly by 2.45% for each week in treatment and increased significantly by 33.11% for previous methamphetamine use, the probability of methamphetamine use still increased significantly, rising 0.28% for each one-point increase in craving score. Predictive accuracy was strongest at the one-week time-lag and declined in magnitude the more distal the assessment period. The authors conclude that craving is a predictor of within-treatment methamphetamine use. Intensity of craving is appropriate for use as a surrogate marker in methamphetamine dependence. Galloway GP, Singleton EG. Subst Abuse 2009 Aug 26;1:63-79.

The Effects of Inhaled L-Methamphetamine on Athletic Performance While Riding a Stationary Bike: A Randomized Placebo-Controlled Trial

L-methamphetamine is banned in athletic competition because it may improve athletic performance, but there are no studies assessing its effects on performance. In the United States L-methamphetamine is formulated in the non-prescription Vick's Vapor Inhaler (VVI) nasal decongestant. VVIs sold elsewhere contain similar inactive ingredients but no L-methamphetamine. This study tested the effects of inhaled L-methamphetamine delivered from a widely available non-prescription product on athletic performance. In a 2-session double-blind placebo-controlled study 12 participants (ages 14-17) were dosed with 4 (session 1) and 12 (session 2) inhalations from VVIs with (USA) or without (UK) L-methamphetamine and then performed two 20 minute rides on a stationary bike with rides separated by a 30 minute rest. The main outcome measure was miles travelled during each 20 minute ride. Secondary outcome measures included postride urine toxicology; heart rate and blood pressure before, 1, 5 and 10 minutes postride; energy, performance, endurance, and ability to breathe; and VVI preference. Data were analysed using Excel statistical macros. After approximately 16 microg L-methamphetamine distance travelled was 5.26 vs. 5.30 miles with placebo. After approximately 48 microg L-methamphetamine distance travelled was 5.30 vs. 5.35 miles with placebo. The approximately 16 microg dose increased systolic blood pressure from 72.6 to 79.6 mm Hg at 5 minutes postride but there were no other differences in outcome. The authors conclude that modest doses of inhaled L-methamphetamine probably do not improve athletic performance but do minimally raise diastolic blood pressure. Dufka F, Galloway G, Baggott M, Mendelson J. Br J Sports Med. 2009 Nov 43(11):832-835.

Evaluation of Modafinil Effects on Cardiovascular, Subjective, and Reinforcing Effects of Methamphetamine In Methamphetamine-Dependent Volunteers

Methamphetamine is a highly addictive stimulant and long-term exposure leads to reductions in dopamine. One therapeutic strategy is to develop and test compounds that normalize dopamine. The primary aim of this study was to determine the safety of modafinil treatment during methamphetamine exposure in a controlled clinical setting. Methamphetamine-dependent volunteers (N=13), who were not seeking treatment, were randomized to receive either modafinil (200mg, PO) or matching placebo over three days (Days 1-3 or Days 8-10). On Day 1, subjects were randomized to modafinil or placebo in the morning, and then 3 and 6h later received infusions of methamphetamine (0 and 30mg, i.v.), after which cardiovascular and subjective effects were assessed. On Day 3, participants completed i.v. self-administration sessions during which they made 10 choices for low doses of methamphetamine (3mg, i.v.) or saline. Days 4-7 were used as a washout period. On Day 8 participants were assigned to the alternate study medication (placebo or modafinil), and the same testing procedures were repeated through Day 10. The data reveal that modafinil treatment was well-tolerated and not associated with increased incidence of adverse events. In general, modafinil reduced, by approximately 25%, ratings of methamphetamine-induced "Any Drug Effect", "High", and "Want Methamphetamine", and reduced total number of choices for methamphetamine and monetary value of methamphetamine, though none of these measures reached statistical significance. Given these encouraging, though non-significant trends, the primary conclusion is that it appears safe to proceed with modafinil in further clinical evaluations of therapeutic efficacy. De La Garza R, Zorick T, London ED, Newton TF. Drug Alcohol Depend. 2009 E-pub Sep 23.

Depression, More Than Marijuana Use Per Se, Leads Abusers To Seek Treatment

A post hoc analysis examined depressive symptoms in regular marijuana smokers interested in non-treatment, laboratory studies, and marijuana-dependent treatment-seekers considering clinical trial participation. Among marijuana-dependent treatment-seeking patients screened for a clinical trial, the mean Beck Depression Inventory Score (BDI) was significantly higher than for marijuana-using volunteers screened for non-treatment laboratory studies. Mean self-reported baseline marijuana use was not significantly different between groups, and BDI score was not correlated with use. Although the methods by which the two groups were selected influenced their characteristics (i.e., treatment-seekers are more likely to be experiencing some degree of clinical distress), it is notable that treatment-seeking, and not marijuana use per se, is associated with significantly higher rates of depression. Mariani JJ, Haney M, Hart CL, Vosburg SK, Levin FR. J Subst Abuse Treat. 2009;37(4): 431-434.

Buspirone-Treated Subjects Tended To Have Fewer Positive Marijuana Urine Drug Screens Than Controls

The present study investigated the potential efficacy of buspirone for treating marijuana dependence. Participants received either buspirone (maximum 60mg/day) (n=23) or matching placebo (n=27) for 12 weeks, each in conjunction with motivational interviewing. In the modified intention-to-treat analysis, the percentage of negative UDS results in the buspirone-treatment group was 18 percentage points higher than the placebo-treatment group (95% CI: -2% to 37%, p=0.071). On self-report, participants receiving buspirone reported not using marijuana 45.2% of days and participants receiving placebo reported not using 51.4% of days (p=0.55). An analysis of participants that completed the 12-week trial showed a significant difference in the percentage negative UDS (95% CI: 7-63%, p=0.014) and a trend for participants randomized to the buspirone-treatment group who completed treatment to achieve the first negative UDS result sooner than those participants treated with placebo (p=0.054). Further study with buspirone in this population may be warranted; however, strategies to enhance study retention and improve outcome measurement should be considered in future trials. McRae-Clark AL, Carter RE, Killeen TK, Carpenter MJ, Wahlquist AE, Simpson SA, Brady KT. Drug Alcohol Depend. 2009 Nov 105(1-2): 132-138.

Medications, Particularly In Combination With Evidence-Based Psychosocial Treatments, Are Needed To Achieve Sustained Abstinence From Marijuana

Cannabis is the most widely used illicit drug in the world. Treatment admissions for cannabis use disorders have risen considerably in recent years, and the identification of medications that can be used to improve treatment outcomes among this population is a priority for researchers and clinicians. To date, several medications have been investigated for indications of clinically desirable effects among cannabis users (e.g. reduced withdrawal, attenuation of subjective or reinforcing effects, reduced relapse). Medications studied have included those: (i) known to be effective in the treatment of other drug use disorders; (ii) known to alleviate symptoms of cannabis withdrawal (e.g. dysphoric mood, irritability); or (iii) that directly affect endogenous cannabinoid receptor function. Results from controlled laboratory studies and small open-label clinical studies indicate that buspirone, dronabinol, fluoxetine, lithium and lofexidine may have therapeutic benefit for those seeking treatment for cannabis-related problems. However, controlled clinical trials have not been conducted and are needed to both confirm the potential clinical efficacy of these medications and to validate the laboratory models being used to study candidate medications. Although the recent increase in research towards the development of pharmacotherapy for cannabis use disorders has yielded promising leads, well-controlled clinical trials are needed to support broad clinical use of these medications to treat cannabis use disorders. Vandrey R, Haney M. CNS Drugs. 2009 Nov 23(7): 543-553.

Varenicline Attenuates Some of the Subjective and Physiological Responses To Nicotine In Smokers

Varenicline, a partial nicotinic acetylcholine receptor (nAChR) agonist, is approved for smoking cessation. A few preclinical studies examined the pharmacological effects of varenicline, alone or in combination with nicotine. How varenicline affects the pharmacological effects of pure nicotine has not been examined in humans. The goal of this study was to characterize varenicline's actions on nicotine's dose-dependent effects in abstinent smokers. Six male and six female smokers participated in a double-blind, placebo-controlled, crossover study. Smokers had two 4-day treatment periods, assigned in random sequence, to varenicline (1 mg/day) or placebo treatment. On day 4 of each treatment phase, smokers had an experimental session, where they received three escalating doses of intravenous (IV) nicotine (0.1, 0.4, and 0.7 mg/70 kg), in 30-min intervals. Varenicline's effects were assessed through subjective, physiological, and cognitive performance outcomes to nicotine administered via IV route. In response to IV nicotine, varenicline treatment attenuated the rating of drug strength, high, head rush, and stimulated. Varenicline also attenuated nicotine-induced increases in heart rate. Varenicline had mixed effects on cognitive performance. Smokers under varenicline treatment, compared with placebo, reported enhanced positive mood measured with the Positive and Negative Affect Schedule. These findings provide new insights into the mechanisms of action of varenicline in smoking cessation. Sofuoglu M, Herman AI, Mooney M, Waters AJ. Psychopharmacology. 2009 Nov 207(1):153-162.

Along With Individual Measures, A Better Understanding of Impulsivity and Compulsion Are Critical For Improved Addiction Treatment

Addictions are among the most costly disorders, estimated at over $500 billion annually. The multidimensional construct of impulsivity has received increased attention recently as a potential endophenotype for addictions. As questions relating to how best to define and categorize addictions are being discussed in anticipation of DSM-V, a growing role for empirical, neurobiological understandings of addictions exists. Given that this process involves gathering, analyzing, and synthesizing data from multiple lines of investigation, the importance of translational, interdisciplinary research has never been greater. Here, the investigators highlight how the manuscripts in this issue inform a translational neurobiological understanding of impulsivity in addiction and identify existing challenges that await future investigation. Potenza MN, Taylor JR. Found in translation: Understanding impulsivity and related constructs through integrative preclinical and clinical research. Biol Psychiatry. 2009 Oct 66(8): 714-716.

Oral Progesterone Enhanced the Negative Effects of Nicotine and Diminished the Urge to Smoke Cigarettes In Smokers

Previous studies suggest possible modulatory effects of progesterone on nicotine addiction. The goal of this study was to determine the effects of progesterone, on acute physiological and subjective responses to intravenous (IV) nicotine in overnight abstinent male and female smokers. Twelve smokers, six males and six females, participated in a double-blind, placebo-controlled, crossover study, which consisted of two experimental sessions. Before each session, subjects were treated orally with a single dose of either 200 mg progesterone or placebo. Starting 2 h following the medication treatment, subjects received an IV saline injection, followed by 0.5 and 1.0 mg/70 kg IV nicotine. Progesterone treatment, compared to placebo, enhanced the ratings of "bad effects," from IV nicotine and attenuated the rating of "drug liking." Progesterone also enhanced suppression of smoking urges by nicotine as assessed by the Brief Questionnaire on Smoking Urges (BQSU). These results suggest that progesterone may alter the subjective effects of nicotine as well as urges to smoke cigarettes. Further studies are warranted to examine the modulation of nicotine's effects by gonadal hormones. Sofuoglu M, Mitchell E, Mooney M. Progesterone effects on subjective and physiological responses to intravenous nicotine in male and female smokers. Hum Psychopharmacol. 2009 Oct 24(7): 559-564.

Treatment of Depression With Bupropion and CBT Reduces the Relapse Risk To Smoking

Bupropion and cognitive-behavioral treatment (CBT) for depression have been used as components of treatments designed to alleviate affective disturbance during smoking cessation. Studies of treatment-related changes in pre-cessation affect or urges to smoke are needed to evaluate the proposed mechanisms of these treatments. The present report examines affective trajectories and urges to smoke prior to, on quit day, and after quitting in a sample of 524 smokers randomized to receive bupropion versus placebo and CBT versus standard smoking cessation CBT. Bupropion and/or CBT did not affect the observed decreases in positive affect and increases in negative affect prior to cessation. However, on quit day, observed levels of negative affect and urges to smoke were diminished significantly among individuals receiving bupropion. Decreases in positive affect prior to quitting, lower levels of positive affect, and increased levels of negative affect and urges to smoke on quit day were each related to higher risk of smoking lapse. Depression proneness was an independent predictor of lower positive affect and higher negative affect but did not moderate the effects of bupropion on outcomes. In mediational analyses, the effect of bupropion was accounted for in part by lower negative affect and urges to smoke on quit day. Results support the efficacy of bupropion in reducing relapse risk associated with urges to smoke and negative affect and suggest the need to better understand the role of low positive affect as a risk factor for early lapse. Strong DR, Kahler CW, Leventhal AM, et al. Nicotine Tob Res. 2009 Oct 11(10):1142-1153.

Relationship Between Cigarette Use and Mood/Anxiety Disorders Among Pregnant Methadone-Maintained Patients

This study investigates the association between cigarette use and current mood/anxiety disorders among pregnant opioid-dependent patients. Pregnant methadone-maintained women (N = 122) completed the Addiction Severity Index and Structured Clinical Interview for DSM-IV. Participants were categorized based on past 30 days cigarette use: no (n = 15) and any smoking (n = 107); this latter group was then subdivided into light (one to ten cigarettes/day; n = 55), and heavy smokers (11+ cigarettes/day; n = 52). Any smoking was significantly associated with any current mood/anxiety disorder, any current mood disorder, and any current anxiety disorder. No significant association was found between specific level of cigarette use and mood/anxiety disorders. This association between smoking and psychiatric disorders has implications for the mental and physical health of methadone-maintained women and their children, and may contribute to the understanding of the physiological mechanisms underlying smoking and nicotine dependence. Chisolm MS, Tuten M, Brigham EC, Strain EC, Jones HE. Am J Addict. 2009 Sep-Oct 18(5):422-429.

Suicidality, Aggression, and Other Treatment Considerations Among Pregnant, Substance-Dependent Women With Posttraumatic Stress Disorder

Posttraumatic stress disorder (PTSD) and other Axis I comorbidity among women with substance use disorders (SUDs) appear similarly prevalent and are associated with comparable negative clinical profiles and treatment outcomes. The relative contribution of comorbid PTSD vs other Axis I psychiatric disorders to clinical characteristics is largely unexamined, however, despite theory and empirical data indicating that PTSD and SUDs may have a unique relationship that confers specific risk for clinical severity and poor treatment outcome. In a sample of pregnant, opioid- and/or cocaine-dependent women entering substance abuse treatment, women with PTSD (SUD-PTSD; n = 23) were compared to those with other Axis I comorbidity (SUD-PSY; n = 45) and those without Axis I comorbidity (SUD-only; n = 37). Data were collected via face-to-face interviews and urinalysis drug assays. Although the study groups had similar substance use severity, the SUD-PTSD group was more likely to report suicidality, aggression, and psychosocial impairment than both the SUD-PSY and SUD-only groups. Findings indicate treatment considerations for substance-dependent women with PTSD are broader and more severe than those with other Axis I conditions or substance dependence alone. Eggleston AM, Calhoun PS, Svikis DS, Tuten M, Chisolm MS, Jones HE. Compr Psychiatry. 2009 Sep-Oct 50(5):415-423.

PTSD Contributes To Teen and Young Adult Cannabis Use Disorders

Previous studies involving adults suggest that Post Traumatic Stress Disorder (PTSD) increases the prevalence of cannabis use disorders (CUD) (cannabis dependence and cannabis abuse). However, little work with PTSD and CUD has been conducted involving adolescents, despite the fact that CUD typically have their onset during adolescence. This study addresses the effect of PTSD on CUD among teenagers transitioning to young adulthood. The subjects in this study were the offspring of adult men with a lifetime history of a substance use disorder (SUD) (SUD+probands, N=343) vs those with no lifetime history of a SUD (SUD-probands, N=350). The participants were initially recruited when the index sons of these fathers were 10-12 years of age, and subsequent assessments were conducted at age 12-14, 16, 19, 22, and 25. Other variables examined were an index of behavioral undercontrol associated with future risk for developing SUD, known as the Transmissible Liability Index, or TLI, and affiliation with deviant peers. Multivariate logistic regression and path analyses were conducted. Of these 693 subjects, 31 subjects were diagnosed with PTSD, and 161 were diagnosed with a CUD. The CUD subjects included 136 male participants and 25 female participants, including 103 (64%) Caucasian participants and 58 (36%) participants of other races. Logistic regression demonstrated that the development of a CUD was associated with deviance of peers (Wald=63.4, p=0.000), the TLI (Wald=28.8, p=0.000), African American race (Wald=14.2, p=0.000), PTSD (Wald=12.7, p=0.000), male gender (Wald=12.0, p=0.001), household SES (Wald=9.2, p=0.002), and being an offspring of a SUD+proband (Wald=6.9, p=0.009). Path analyses demonstrated that PTSD is directly associated with the presence of a CUD and with peer deviance, that higher peer deviance is associated with the presence of a CUD, and that PTSD mediated the association between peer deviance and CUD. These findings suggest that PTSD contributes to the etiology of CUD among teenagers making the transition to young adulthood beyond the effects of deviant peers, the TLI (Transmissible Liability Index, a measure of risk for SUD), and demographic factors. Cornelius JR, Kirisci L, Reynolds M, Clark DB, Hayes J, Tarter R. Addict Behav. 2010 Feb;35(2):91-94. Epub 2009 Sep 11.

Smoking Expectancies and Intention To Quit In Smokers With Schizophrenia, Schizoaffective Disorder and Non-Psychiatric Controls

Cigarette smoking expectancies are systematically related to intention to quit smoking in adult smokers without psychiatric illness, but little is known about these relationships in smokers with serious mental illness. In this study, the investigators compared positive and negative smoking expectancies, and examined relationships between expectancies and intention to quit smoking, in smokers with schizophrenia (n=46), smokers with schizoaffective disorder (n=35), and smokers without psychiatric illness (n=71). In all three groups, reduction of negative affect was rated as the most important smoking expectancy and intention to quit smoking was systematically related to concerns about the health effects and social consequences of smoking. Compared to the other groups of smokers, those with schizoaffective disorder were more concerned with social expectancies and with the immediate negative physical effects of smoking. Results of this study suggest that challenging positive smoking expectancies and providing more tailored information about the negative consequences of smoking might increase motivation to quit smoking in smokers with schizophrenia and schizoaffective disorder, as has been found with non-psychiatric smokers. Tidey JW, Rohsenow DJ. Schizophr Res. 2009 Dec;115(2-3):310-316.

Predicting Adherence To Treatment For Methamphetamine Dependence From Neuropsychological and Drug Use Variables

Although some individuals who abuse methamphetamine have considerable cognitive deficits, no prior studies have examined whether neurocognitive functioning is associated with outcome of treatment for methamphetamine dependence. In an outpatient clinical trial of bupropion combined with cognitive behavioral therapy and contingency management (Shoptaw, S., Heinzerling, K.G., Rotheram-Fuller, E., Steward, T., Wang, J., Swanson, A.N., De La Garza, R., Newton, T., Ling, W., 2008. Randomized, placebo-controlled trial of bupropion for the treatment of methamphetamine dependence. Drug Alcohol Depend 96, 222-232.), 60 methamphetamine-dependent adults completed three tests of reaction time and working memory at baseline. Other variables that were collected at baseline included measures of drug use, mood/psychiatric functioning, employment, social context, legal status, and medical status. The investigators evaluated the relative predictive value of all baseline measures for treatment outcome using Classification and Regression Trees (CART; Breiman, L., Friedman, J.H., Olshen, R.A., Stone, C.J., 1984.

Classification and Regression Trees

Wadsworth, Belmont, CA.), a nonparametric statistical technique that produces easily interpretable decision rules for classifying subjects that are particularly useful in clinical settings. Outcome measures were whether or not a participant completed the trial and whether or not most urine tests showed abstinence from methamphetamine abuse. Urine-verified methamphetamine abuse at the beginning of the study was the strongest predictor of treatment outcome; two psychosocial measures (e.g., nicotine dependence and Global Assessment of Functioning) also offered some predictive value. A few reaction time and working memory variables were related to treatment outcome, but these cognitive measures did not significantly aid prediction after adjusting for methamphetamine usage at the beginning of the study. On the basis of these findings, the investigators recommend that research groups seeking to identify new predictors of treatment outcome compare the predictors to methamphetamine usage variables to assure that unique predictive power is attained. Dean AC, London ED, Sugar CA, Kitchen CM, et al. Drug Alcohol Depend. 2009 Nov 1;105(1-2):48-55.

Concurrent Validation of the Clinical Opiate Withdrawal Scale (COWS) and Single-Item Indices Against the Clinical Institute Narcotic Assessment (CINA) Opioid Withdrawal Instrument

The Clinical Opiate Withdrawal Scale (COWS) is an 11-item clinician-administered scale assessing opioid withdrawal. Though commonly used in clinical practice, it has not been systematically validated. The present study validated the COWS in comparison to the validated Clinical Institute Narcotic Assessment (CINA) scale. Opioid-dependent volunteers were enrolled in a residential trial and stabilized on morphine 30 mg given subcutaneously four times daily. Subjects then underwent double-blind, randomized challenges of intramuscularly administered placebo and naloxone (0.4 mg) on separate days, during which the COWS, CINA, and visual analog scale (VAS) assessments were concurrently obtained. Subjects completing both challenges were included (N=46). Correlations between mean peak COWS and CINA scores as well as self-report VAS questions were calculated. Mean peak COWS and CINA scores of 7.6 and 24.4, respectively, occurred on average 30 min post-injection of naloxone. Mean COWS and CINA scores 30 min after placebo injection were 1.3 and 18.9, respectively. The Pearson's correlation coefficient for peak COWS and CINA scores during the naloxone challenge session was 0.85 (p<0.001). Peak COWS scores also correlated well with peak VAS self-report scores of bad drug effect (r=0.57, p<0.001) and feeling sick (r=0.57, p<0.001), providing additional evidence of concurrent validity. Placebo was not associated with any significant elevation of COWS, CINA, or VAS scores, indicating discriminant validity. Cronbach's alpha for the COWS was 0.78, indicating good internal consistency (reliability). COWS, CINA, and certain VAS items are all valid measurement tools for acute opiate withdrawal. Tompkins DA, Bigelow GE, Harrison JA, et al. Drug Alcohol Depend. 2009 Nov 1;105(1-2):154-159.

The Cardiovascular and Subjective Effects of Methamphetamine Combined With Gamma-Vinyl-Gamma-Aminobutyric Acid (GVG) In Non-Treatment Seeking Methamphetamine-Dependent Volunteers

Gamma-vinyl-gamma-aminobutyric acid (GVG) elevates central nervous system gamma-aminobutyric acid (GABA) levels by irreversibly inhibiting GABA transaminase. An open-label clinical trial in humans suggested that GVG may reduce cocaine and methamphetamine use. To test safety and to obtain preliminary data on efficacy of GVG for treating methamphetamine dependence, the investigators conducted a double-blind, placebo-controlled, parallel group study of GVG interaction with the cardiovascular and subjective effects produced by methamphetamine. Non-treatment seeking methamphetamine-dependent volunteers received either GVG (N=8) or placebo (N=9) by random assignment. GVG treatment was initiated at 1 g/day and increased to 5 g/day. After reaching the target dose of 5 g/day, participants received methamphetamine (15+30 mg, IV), and cardiovascular and subjective effects were assessed. No serious adverse events were noted, and the total number of adverse events was similar between the treatment groups. Considering the full time course and peak effects independently, no significant differences were detected between the groups for systolic or diastolic blood pressures, or heart rate, following methamphetamine exposure. Some methamphetamine-induced cardiovascular changes approached significance (p<0.10) and may warrant attention in future trials. Methamphetamine-induced subjective effects ("any drug effect", "high", "crave methamphetamine") were statistically similar between GVG and placebo treatment groups. Pharmacokinetic data indicate that GVG treatment did not alter methamphetamine or amphetamine plasma levels, and there was no association between methamphetamine or amphetamine plasma levels and peak cardiovascular effects. Taken together, the data indicate that GVG treatment is generally well tolerated but not efficacious in attenuating the positive subjective effects of methamphetamine in the laboratory. De La Garza R 2nd, Zorick T, Heinzerling KG, et al. Pharmacol Biochem Behav. 2009 Nov;94(1):186-193.


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