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



Research Findings - Research on Pharmacotherapies for Drug Abuse

Infant Neurobehavior Following Prenatal Exposure to Methadone or Buprenorphine: Results from the Neonatal Intensive Care Unit Network Neurobehavioral Scale

This study examined the neurobehavioral functioning of neonates prenatally exposed to methadone (n = 11) or buprenorphine (n = 10), who underwent the Neonatal Intensive Care Unit Network Neurobehavioral Scale (NNNS) examinations on days 3, 5, 7, 10, and 14 post-delivery. Linear mixed model analyses revealed that NNNS scores of arousal and excitability showed significant differences between medications over time. Compared to neonates who did not require medication to treat neonatal abstinence syndrome (NAS), neonates receiving pharmacotherapy for NAS showed differences over time in quality of movement, excitability, and lethargy. Results suggest the NNNS may detect subtle differences over time between both neonates prenatally exposed to methadone or buprenorphine and neonates pharmacologically treated or untreated for NAS. Jones HE, O'Grady KE, Johnson RE, Velez M, Jansson LM. Infant neurobehavior following prenatal exposure to Methadone or Buprenorphine: results from the Neonatal Intensive Care Unit Network Neurobehavioral Scale. Subst Use Misuse. 2010 May 19. (Epub ahead of print).

Excretion of Methadone in Sweat of Pregnant Women Throughout Gestation After Controlled Methadone Administration

Sweat patches (n = 350) were collected throughout gestation from 29 opioid-dependent pregnant women participating in an outpatient methadone-assisted therapy program. Volunteers provided informed consent to participate in institutional review board-approved protocols. Methadone was eluted from sweat patches with sodium acetate buffer, followed by solid-phase extraction and quantification by gas chromatography mass spectrometry (limit of quantification >/= 10 ng/patch). Methadone was present in all weekly patches (n = 311) in concentrations ranging from 10.2 to 12,129.7 nanograms per patch and in 92.3% of short-term patches (n = 39, worn for 12 or 24 hours) in concentrations up to 3303.9 nanograms per patch. Correlation between patch concentrations and total amount of drug administered (r = 0.224), and concentrations and duration of patch wear (r = 0.129) were both weak. Although there were large intra- and intersubject variations in sweat drug concentrations, sweat testing was an effective alternative technique to qualitatively monitor illicit drug use and simultaneously document methadone medication-assisted treatment. Barnes AJ, Brunet BR, Choo RE, Mura P, Johnson RE, Jones HE, Huestis MA. Excretion of methadone in sweat of pregnant women throughout gestation after controlled methadone administration. Ther Drug Monit. 2010 June 29. (Epub ahead of print).

Clonidine Clearance Matures Rapidly During the Early Postnatal Period: A Population Pharmacokinetic Analysis in Newborns With Neonatal Abstinence Syndrome

The population pharmacokinetic (PK) profile of oral clonidine was characterized in newborns with neonatal abstinence syndrome, and significant covariates affecting its PK parameters were identified. Plasma clonidine concentration data were obtained from a clinical trial in which 36 newborns, aged 1 to 25 days (postnatal age, PNA) and weighing 2.1 to 3.9 kg, were enrolled to take multiple oral doses of clonidine. The population PK model of clonidine was developed by NONMEM, and significant covariates were identified, followed by nonparametric bootstraps (2000 replicates) and simulation experiments. A 1-compartment open linear PK model was chosen to describe plasma concentrations of clonidine, and body weight and PNA were significant covariates for apparent clearance (CL/F) as follows: CL/F (L/h) = 15.2 x [body weight (kg)/70](0.75) x [PNA (day)(0.441)/(4.06(0.441) + PNA (day)(0.441))]. Furthermore, CL/F of clonidine increased rapidly with PNA during the first month of life after body weight was adjusted. Any optimal dosage regimen for clonidine in term neonates should be based on infant's age and body weight, and 1.5 mug/kg every 4 hours is proposed starting the second week of life based on the simulation results. Xie HG, Cao YJ, Gauda EB, Agthe AG, Hendrix CW, Lee H. Clonidine clearance matures rapidly during the early postnatal period: a population pharmacokinetic analysis in newborns with neonatal abstinence syndrome. J Clin Pharmacol. 2010 May 19. (Epub ahead of print).

Effects of Repeated Tramadol and Morphine Administration on Psychomotor and Cognitive Performance in Opioid-Dependent Volunteers

Tramadol is an atypical, mixed mechanism analgesic used to treat moderate to severe pain. Based on evidence that tramadol has relatively low abuse potential and can relieve opioid withdrawal, tramadol may be useful for treating opioid dependence. The purpose of this study was to assess the performance side-effect profile of tramadol. Nine opioid-dependent volunteers completed a performance battery following 5-7 days of subcutaneous morphine (15mg, 4 times/day) and two doses of oral tramadol (50, 200mg, 4 times/day) in a within subject cross-over design. Morphine was always the first condition, and the order of the two tramadol doses was randomized and double blind. Performance was significantly worse in the morphine condition relative to one or both tramadol doses on measures of psychomotor speed/coordination (circular lights task), psychomotor speed/pattern recognition (DSST speed measure) and psychomotor speed/set shifting (trail-making tasks). There were no significant differences among conditions in DSST accuracy, simple reaction time, divided attention, working memory, episodic memory, metamemory, or time estimation. Neither tramadol dose was associated with worse performance than morphine on any measure. Although practice sessions were conducted prior to the first session to reduce order effects, the possibility that residual practice effects contributed to the differences between tramadol and morphine cannot be ruled out. The high tramadol dose produced worse performance than the low dose only on the balance measure. These findings suggest that tramadol is generally a safe medication with respect to cognitive and psychomotor measures and support tramadol's further evaluation as an opioid-dependence treatment. Mintzer, MZ, Lanier RK, Lofwall MR, Bigelow GE, Strain EC. Effects of repeated tramadol and morphine administration on psychomotor and cognitive performance in opioid-dependent volunteers. Drug Alcohol Depend. 2010 Jun 8. (Epub ahead of print).

Abuse Liability of Intravenous Buprenorphine/Naloxone and Buprenorphine Alone in Buprenorphine-Maintained Intravenous Heroin Abusers

Sublingual buprenorphine is an effective maintenance treatment for opioid dependence, yet intravenous buprenorphine misuse occurs. A buprenorphine/naloxone formulation was developed to mitigate this misuse risk. This randomized, double-blind, cross-over study was conducted to assess the intravenous abuse potential of buprenorphine/naloxone compared with buprenorphine in buprenorphine-maintained injection drug users (IDUs). Intravenous heroin users (n = 12) lived in the hospital for 8-9 weeks and were maintained on each of three different sublingual buprenorphine doses (2 mg, 8 mg, 24 mg). Under each maintenance dose, participants completed laboratory sessions during which the reinforcing and subjective effects of intravenous placebo, naloxone, heroin and low and high doses of buprenorphine and buprenorphine/naloxone were examined. Every participant received each test dose under the three buprenorphine maintenance dose conditions. The study results showed that intravenous buprenorphine/naloxone was self-administered less frequently than buprenorphine or heroin (P < 0.0005). Participants were most likely to self-administer drug intravenously when maintained on the lowest sublingual buprenorphine dose. Subjective ratings of 'drug liking' and 'desire to take the drug again' were lower for buprenorphine/naloxone than for buprenorphine or heroin (P = 0.0001). Participants reported that they would pay significantly less money for buprenorphine/naloxone than for buprenorphine or heroin (P < 0.05). Seven adverse events were reported; most were mild and transient. These data suggest that although the buprenorphine/ naloxone combination has intravenous abuse potential, that potential is lower than it is for buprenorphine alone, particularly when participants received higher maintenance doses and lower buprenorphine/naloxone challenge doses. Buprenorphine/naloxone may be a reasonable option for managing the risk for buprenorphine misuse during opioid dependence treatment Comer SD, Sullivan MA, Vosburg SK, Manubay J, Amass L, Cooper ZD, Saccone P, Kleber HD. Abuse liability of intravenous buprenorphine/naloxone and buprenorphine alone in buprenorphine-maintained intravenous heroin abusers. Addiction. 2010 April; 105(4): 709-718.

Physical Dependence Potential of Daily Tramadol Dosing in Humans

Tramadol is an atypical, mixed-mechanism analgesic involving both opioid and catecholamine processes that appears to have low abuse potential and may be useful as a treatment for opioid dependence. The current study assessed the level of physical dependence and opioid blockade efficacy produced by daily maintenance on oral tramadol. Nine residential opioid-dependent adults were maintained on two doses of daily oral tramadol (200 and 800 mg) for approximately 4-week intervals in a randomized, double-blind, crossover design. The acute effects of intramuscular placebo, naloxone (0.25, 0.5, and 1.0 mg), and hydromorphone (1.5, 3.0, and 6.0 mg) were tested under double-blind, randomized conditions. Outcomes included observer- and subject-rated measures and physiologic indices. Challenge doses of naloxone resulted in significantly higher mean peak withdrawal scores compared to placebo. Withdrawal intensity from naloxone was generally greater during 800 versus 200 mg/day tramadol maintenance. Mean peak ratings of agonist effects were elevated at higher hydromorphone challenge doses, but did not differ significantly between tramadol doses. Physiologic measures were generally affected by challenge conditions in a dose-dependent manner, with few differences between tramadol maintenance dose conditions. Chronic tramadol administration produces dose-related opioid physical dependence, without producing dose-related attenuation of agonist challenge effects. Tramadol may be a useful treatment for patients with low levels of opioid dependence or as a treatment for withdrawal during opioid detoxification, but does not appear to be effective as a maintenance medication due to a lack of opioid cross-tolerance. Lanier RK, Loftwall MR, Mintzer MZ, Bigelow GE, Strain EC. Physical dependence potential of daily tramadol dosing in humans. Psychopharmacology (Berl). 2010 Jun 30.(Epub ahead of print).

Feasibility and Acceptability of a Phase II Randomized Pharmacologic Intervention for Methamphetamine Dependence in High Risk Men Who Have Sex with Men

To determine whether actively using, methamphetamine (meth)-dependent men who have sex with men (MSM) could be enrolled and retained in a pharmacologic intervention trial, and the degree to which participants would adhere to study procedures, including medication adherence. This study was a phase 2 randomized, double-blind trial of bupropion vs. placebo. Thirty meth-dependent, sexually active MSM were randomized to receive daily bupropion XL 300 mg or placebo for 12 weeks. Participants received weekly substance use counseling, provided weekly urine specimens, and completed monthly audio-computer assisted self-interview (ACASI) behavioral risk assessments. Adherence was measured by medication event monitoring systems (MEMS) caps (the number of distinct MEMS cap openings divided by the number of expected doses) and self-report. Ninety percent completed the trial: 89% of monthly ACASIs were completed, 81% of study visits were attended, and 81% of urine samples were collected. Adherence by MEMS cap was 60% and by self-report was 81% and did not differ significantly by treatment assignment. The median number of positive urine samples was 5.5 out of a possible 11 (50%). Participants in both arms reported similar declines in the median number of sex partners (P = 0.52). No serious adverse events occurred and there were no significant differences in adverse events by treatment assignment (P = 0.11). It is feasible to enroll and retain actively using, meth-dependent MSM in a pharmacologic intervention. Bupropion was well tolerated. Study participation and retention rates were high, however, study drug medication adherence was only moderate. Findings support a larger trial with improved adherence support to evaluate the efficacy of bupropion and other pharmacologic interventions for meth dependence in this population. Das M, Santos D, Matheson T, Santos GM, Chu P, Vittinghoff E, Shoptaw S, Colfax GN. Feasibility and acceptability of a phase II randomized pharmacologic intervention for methamphetamine dependence in high risk men who have sex with men. AIDS. 2010 April 24;24(7): 991-1000.

The Angiotensin-converting Enzyme Inhibitor Perindopril Treatment Alters Cardiovascular and Subjective Effects of Methamphetamine in Humans

A variety of medications have been assessed for their potential efficacy for the treatment of methamphetamine dependence. This study was conducted in an attempt to evaluate the potential of a novel class of medications, angiotensin-converting enzyme inhibitors, as treatments for methamphetamine dependence. All participants met the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, third revision (DSM-IV-TR) criteria for methamphetamine abuse or dependence and were not seeking treatment at the time of study entry. The study was conducted using a double-blind design. Subjects received a baseline series of intravenous (IV) doses of methamphetamine (15mg and 30mg) and placebo. Subjects received a second identical series of methamphetamine doses 3 and 5 days after initiation of once-daily oral placebo or perindopril treatment. The dose of perindopril was 2mg, 4mg, or 8mg administered in the morning. Thirty participants completed the study. Perindopril treatment was tolerated well. There were no main effects of perindopril on methamphetamine-induced changes in cardiovascular or subjective effects. There were significant perindopril-methamphetamine interactions for diastolic blood pressure and for ratings of "Any Drug Effect", indicating inverted U dose-effect functions for these indices. Newton TF, De La Garza R 2nd, Grasing K. The agiotensin-converting enzyme inhibitor perindopril treatment alters cardiovascular and subjective effects of methamphetamine in humans. Psychiatry Res. 2010 May 19. (EPub ahead of print).

Estimating the Intake of Abused Methamphetamine Using Experimenter Administered Deuterium Labeled R-methamphetamine Selection of the R-methamphetamine Dose

All addictive drugs produce tolerance and addicts compensate by increasing drug exposure. Thus, the quantity of illicit drug ingested is related to the severity of addiction. Unfortunately, there are no objective methods to estimate intake for most addictive drugs. Using experimenter-administered doses of deuterium-labeled R-methamphetamine (R-[-]-MA-d3), a method was developed to estimate the amount of abused methamphetamine intake in addicts enrolled in clinical trials. This study assessed the pharmacokinetics, pharmacodynamics, and tolerability of single oral doses of R-MA in healthy adults to select a dose of R-MA-d3 to be used as a biomarker for estimating the amount of methamphetamine abuse. This was a five-session randomized, double-blind, placebo-controlled, balanced crossover study in eight subjects. Oral R-(-)-MA was dosed at 0 mg, 1 mg, 2.5 mg, 5 mg, or 10 mg; bioavailability was estimated by slow intravenous dosing (30 minutes) of 2.5 mg R-(-)-MA-d3 given with the 2.5 mg R-(-)-MA oral dose condition. Pharmacokinetic and pharmacodynamic measures were obtained. No serious adverse events occurred during the study and all doses of R-MA were well tolerated. Linear pharmacokinetics was observed within the oral dose range of 1 to 10 mg. Complete bioavailability and pharmacologic inactivity were found for all oral doses. These characteristics indicate the advantage of using a small oral R-(-)-MA-d3 dose as a biomarker to estimate exposure to abused methamphetamine. Based on these results, 5 mg R-(-)-MA-d3 has been selected as the biomarker dose in future studies. Preliminary findings from this study indicate that experimenter-administered oral R-(-)-MA-d3 may allow estimation of abused methamphetamine intake and exposure. Knowledge of the quantity of methamphetamine intake may allow better estimation of disease severity and treatment efficacy. Experience gained from this study also can be applied to the management of other drug dependence problems such as cocaine, cannabinoid, and opiate addiction. Li L, Lopez JC, Galloway GP, Baggott MJ, Everhart T, Mendelson J. Estimating the intake of abused methamphetamine using experimenter administered deuterium labeled R-methamphetamine selection of the R-methamphetamine dose. Ther Drug Monit. 2010 Jun 25. (Epub ahead of print).

Behavioral Effects of D-amphetamine in Humans: Influence of Subclinical Levels of Inattention and Hyperactivity

Several studies suggest a link between stimulant abuse and attention-deficit hyperactivity disorder (ADHD) symptoms (e.g., inattention and hyperactivity). To further assess the nature of this relationship, the present study examined the association between subclinical symptoms of inattention and hyperactivity and the behavioral effects of d-amphetamine. Participants were classified into a High- (n = 8) or Low-Score (n = 9) group based on their responses on a rating scale that assessed inattention and hyperactivity symptoms. The participants did not differ across the High-Score and Low-Score groups in their ability to discriminate d-amphetamine. The participants in the High-Score group were significantly more sensitive to the positive participant-rated effects of d-amphetamine (e.g., Good Effects, Like Drug), but less sensitive to drug-induced increases in blood pressure and heart rate. The selective increase in positive subjective effects of d-amphetamine suggests that individuals with subclinical inattention and hyperactivity symptoms may have increased vulnerability to stimulant abuse. Sevak RJ, Stoops WW, Rush CR. Am J Drug Alcohol Abuse. 2010 Jul;36(4): 220-227.

Cocaine Choice in Humans During D-amphetamine Maintenance

The results of preclinical laboratory experiments and clinical trials indicate that agonist replacements such as d-amphetamine may be a viable option for managing cocaine dependence. This study determined the effects of d-amphetamine maintenance on cocaine choice behavior in human participants. It was predicted that d-amphetamine maintenance would reduce cocaine choice. Nine cocaine-dependent participants completed the study. Two d-amphetamine maintenance conditions were completed in a counterbalanced order (0 and 40 mg/d). After 3 to 5 days of placebo or d-amphetamine maintenance, the participants completed 5 experimental sessions. During these sessions, the participants first sampled the placebo (i.e., 4 mg of intranasal cocaine) identified as drug A. The participants then sampled a second intranasal drug dose (4, 10, 20, or 30 mg of cocaine) identified as drug B. The participants then made 6 discrete choices between drugs A and B. Drug choices were separated by 45 minutes. The primary outcome measure was the number of cocaine choices. All doses of cocaine were chosen significantly more than placebo during both maintenance conditions (i.e., placebo and d-amphetamine). Choice of the 20-mg dose of cocaine was significantly lower during d-amphetamine maintenance relative to when this cocaine dose was tested during placebo-d-amphetamine maintenance. Cocaine produced prototypical subject-rated drug effects (eg., good effects, like drug, willing to take again). These effects were not altered to a significant degree by d-amphetamine maintenance. Cocaine was well tolerated during D-amphetamine maintenance, and no unexpected or serious adverse events occurred. These results are concordant with those of previous preclinical experiments, human laboratory studies, and clinical trials that suggest that agonist replacement therapy may be a viable strategy for managing cocaine dependence. Rush CR, Stoops WW, Sevak RJ, Hays LR. Cocaine choice in humans during D-amphetamine maintenance. J Clin Psychopharmacol. 2010; 30(2): 152-159.

Intranasal Cocaine Functions as a Reinforcer on a Progressive Ratio Schedule in Humans

Cocaine dependence continues to be a worldwide public health concern. Although the majority of individuals reporting cocaine use do so via the intranasal route, relatively few laboratory experiments have examined the reinforcing effects of cocaine administered intranasally. The purpose of this experiment was to measure the reinforcing effects of intranasal cocaine using a progressive ratio schedule in which eight cocaine-using subjects chose between doses of cocaine (4 [placebo], 15, 30 and 45mg) and an alternative reinforcer ($0.25). During each session, subjects first sampled the dose of cocaine available that day and then made six choices between that dose and money, which were available on concurrent progressive ratio schedules of responding. Break points for active cocaine doses were higher than those for placebo but no statistically significant active versus placebo dose effects were observed on subject-rated or physiological measures. These data demonstrate that intranasal cocaine functions as a reinforcer under a progressive ratio schedule in humans. Future research should test higher cocaine doses and larger values of the alternative reinforcer. These procedures may be useful for examining the influence of putative pharmacological and behavioral interventions on intranasal cocaine self-administration. Stoops WW, Lile JA, Glaser PE, Hays LR, Rush CR. Eur J Pharmacol. 2010 Jul 15. (Epub ahead of print).

Review of Treatment for Cocaine Dependence

Cocaine dependence is a complicated, destructive, and often chronic illness that is difficult to treat. This article reviews the challenges in treating cocaine dependence, as well as recent developments and future directions in psychosocial and pharmacological treatment relevant to treatment of cocaine dependence. Cocaine is one of the most addictive drugs because of its immediate and powerful rewarding effects. Often, cocaine dependent individuals experience difficulty abstaining due to cognitive impairments from repeated cocaine use, strong use-related social and environmental cues, and high levels of life stress. Cocaine use also affects areas of the brain related to motor function, learning, emotion, and memory, further complicating the administration of effective interventions. In addition, development of treatments for cocaine dependence has been complicated by the tendency for abusers not to complete treatment programs and their propensity for relapse. Despite these challenges, some treatment approaches, such as cognitive behavioral therapy (CBT) and medications have shown promise in successfully treating cocaine dependence. However, individually, each of these treatments exhibit weakness in longitudinal studies where long-term abstinence is the primary outcome of interest. Although other treatments are being explored, thus far, the combination of CBT and pharmacotherapy has elicited the best results for treating cocaine dependence with respect to patient retention and relapse prevention following abstinence. No treatment method has yet been shown to completely and effectively treat cocaine dependence. More research is necessary to test treatment programs and garner further information in order to better understand and treat cocaine dependence. Penberthy JK, Ait-Daoud N, Vaughan M, Fanning T. Curr Drug Abuse Rev. 2010 Mar;3(1): 49-62.

Contingency Management and Levodopa-Carbidopa for Cocaine Treatment: A Comparison of Three Behavioral Targets

New data support use of levodopa pharmacotherapy with behavioral contingency management (CM) as one efficacious combination in cocaine dependence disorder treatment. A potential mechanism of the combined treatment effects may be related to dopamine-induced enhancement of the saliency of contingently delivered reinforcers. Evidence to support this mechanism was sought by evaluating levodopa-enhancing effects across distinct CM conditions that varied in behavioral targets. A total of 136 treatment-seeking, cocaine dependent subjects participated in this 12-week, randomized, placebo-controlled trial of levodopa (vs. placebo) administered in combination with one of three behavioral CM conditions. In the CM-URINE condition, subjects received cash-valued vouchers contingent on cocaine-negative urine toxicology results. In the CM-ATTEND condition, the same voucher schedule was contingent on attending thrice weekly clinic visits. In the CM-MEDICATION condition, the same voucher schedule was contingent on Medication Event Monitoring Systems- and riboflavin-based evidence of pill-taking behavior. Primary outcomes associated with each CM target behavior were analyzed using generalized linear mixed models for repeated outcomes. CM responding in the CM-ATTEND and CM-MEDICATION conditions showed orderly effects, with each condition producing corresponding changes in targeted behaviors, regardless of medication condition. In contrast, CM responding in the CM-URINE condition was moderated by medication, with levodopa-treated subjects more likely to submit cocaine-negative urines. These findings specify the optimal target behavior for CM when used in combination with levodopa pharmacotherapy. Schmitz JM, Lindsay JA, Stotts AL, Green CE, Moeller FG. Contingency management and levodopa-carbidopa for cocaine treatment: a comparison of three behavioral targets. Exp Clin Psychopharmacol. 2010 June 18(3): 238-244.

Association Analysis Between Polymorphisms in the Dopamine D2 Receptor (DRD2) and Dopamine Transporter (DAT1) Genes With Cocaine Dependence

Genetic research on cocaine dependence (CD) may help clarify in understanding the disorder as well as provide novel insights for effective treatment. Since dopamine neurotransmission has been shown to be involved in drug reward, related genes are plausible candidates for susceptibility to CD. The dopamine receptor D(2) (DRD2) protein and dopamine transporter (DAT1) protein play regulatory roles in dopamine neurotransmission. The TaqI A single-nucleotide polymorphism (SNP) in the DRD2 gene and the 3' variable number tandem repeat (VNTR) polymorphism in the DAT1 gene have been implicated in psychiatric disorders and drug addictions. In this study, the investigators hypothesized that these polymorphisms contribute to increased risk for CD. Cocaine-dependent individuals (n=347) and unaffected controls (n=257) of African descent were genotyped for the polymorphisms in the DRD2 and DAT1 genes. No statistically significant differences or trends in allele or genotype frequencies between cases and controls for either of the tested polymorphisms were observed. The study suggests that there is no association between the DRD2 and DAT1 polymorphisms and CD. However, additional studies using larger sample sizes and clinically homogenous populations are necessary before confidently excluding these variants as contributing genetic risk factors for CD. Lohoff FW, Bloch PJ, Hodge R, Nall AH, Ferraro TN, Kampman KM, Dackis CA, O'Brien CP, Pettinati HM, Oslin DW. Association analysis between polymorphisms in the dopamine D2 receptor (DRD2) and dopamine transporter (DAT1) genes with cocaine dependence. Neuroscience Letters. 2010 473: 87-91.

Opioid Antagonism Enhances Marijuana's Effects in Heavy Marijuana Smokers

Preclinical studies in rats suggest that there may be reciprocal modulation of the opioidergic and endocannabinoid systems, a relationship that has not been demonstrated in humans. This study sought to clarify this interaction by assessing how a range of naltrexone doses altered the subjective, cognitive, and cardiovascular effects of marijuana. The sample was 29 daily marijuana smokers in a within-subject, randomized, double-blind, placebo-controlled study. Naltrexone (0, 12, 25, 50, or 100 mg) was administered before active or inactive marijuana (3.27 or 0% THC) was smoked. Active marijuana increased subjective ratings of marijuana 'Strength', 'High', and positive subjective ratings of marijuana quality and drug effect including 'Liking', 'Good', and 'Take Again' compared to inactive marijuana. Naltrexone alone decreased ratings of 'Liking', 'Take Again' and 'Stimulated' compared with placebo, but increased ratings of drug 'Strength', 'High', 'Good', 'Liking', 'Stimulated' and 'Take Again' when administered under active marijuana conditions. Active marijuana did not affect performance on cognitive tasks relative to inactive marijuana, whereas naltrexone decreased performance when administered alone or in combination with active marijuana. Active marijuana increased heart rate compared to inactive marijuana under placebo naltrexone conditions. Although naltrexone alone decreased heart rate, it further increased marijuana's cardiovascular effect. The conclusions from the study were that in heavy marijuana smokers opioid-receptor blockade enhanced the subjective and cardiovascular effects of marijuana, suggesting that endogenous opioids dampen cannabinoid effects in this population. These findings demonstrate that a broad range of clinically used doses of naltrexone potentially increases the abuse liability and cardiovascular effects of cannabinoids. Cooper ZD, Haney M. Opioid antagonism enhances marijuana's effects in heavy marijuana smokers. Psychopharmacology. 2010 211: 141-148.

Effects of Baclofen and Mirtazapine on a Laboratory Model of Marijuana Withdrawal and Relapse

Only a small percentage of individuals seeking treatment for their marijuana use achieves sustained abstinence, suggesting more treatment options are needed. The objective of this study was to investigate the effects of baclofen (study 1) and mirtazapine (study 2) in a human laboratory model of marijuana intoxication, withdrawal, and relapse. In study 1, daily marijuana smokers (n = 10), averaging 9.4 (+/-3.9) marijuana cigarettes/day, were maintained on placebo and each baclofen dose (60, 90 mg/day) for 16 days. In study 2, daily marijuana smokers (n = 11), averaging 11.9 (+/-5.3) marijuana cigarettes/day, were maintained on placebo and mirtazapine (30 mg/day) for 14 days each. Medication administration began outpatient prior to each 8-day inpatient phase. On the first inpatient day of each medication condition, participants smoked active marijuana (study 1: 3.3% THC; study 2: 6.2% THC). For the next 3 days, they could self-administer placebo marijuana (abstinence phase), followed by 4 days in which they could self-administer active marijuana (relapse phase); participants paid for self-administered marijuana using study earnings. The results of study 1 showed that during active marijuana smoking, baclofen dose-dependently decreased craving for tobacco and marijuana, but had little effect on mood during abstinence and did not decrease relapse. Baclofen also worsened cognitive performance regardless of marijuana condition. In study 2, mirtazapine improved sleep during abstinence, and robustly increased food intake, but had no effect on withdrawal symptoms and did not decrease marijuana relapse. The conclusions are that, overall, this human laboratory study did not find evidence to suggest that either baclofen or mirtazapine showed promise for the potential treatment of marijuana dependence. Haney M, Hart CL, Vosburg SK, Comer SD, Reed SC, Cooper ZD, Foltin RW. Effects of baclofen and mirtazapine on a laboratory model of marijuana withdrawal and relapse. Psychopharmacology 2010; 211: 233-244.

Behavioral Effects of Gamma-hydroxybutyrate in Humans

Despite the therapeutic use and abuse potential of gamma-hydroxybutyrate (GHB or Xyrem), relatively few studies have examined the behavioral effects of GHB in humans under controlled laboratory conditions. This eight-session study examined in 10 non-substance-abusing volunteers the behavioral effects of GHB at each of the following doses: 0, 0.32, 0.56, 0.75, 1.0, 1.8, 2.4, 3.2 g/70 kg, orally. Order of dose testing was random, except that the first two participants received active doses in ascending order and 2.4 g/70 kg was always tested before 3.2 g/70 kg. Before drug administration and at several post-drug time points, self-report, observer report, physiological, and psychomotor performance measures were obtained. Analyses based on area under the curve showed that GHB produced dose-related increases in subjective ratings of sedative-like, stimulant-like, positive mood, and dissociative effects, but no changes in psychomotor performance measures or blood pressure. Analyses based on peak effects generally showed dose-related increases in ratings indicating sedative-like, dissociative, and drug liking, although some measures showed U-shaped dose-related changes. These initial findings suggest that GHB at doses of 0.32-3.2 g/70 kg produces dissociative, sedating and some stimulant-like effects in humans without a history of sedative abuse. Oliveto A, Gentry WB, Pruzinsky R, Gonsai K, Kosten TR, Martell B, Poling J. Behavioral effects of gamma-hydroxybutyrate in humans. Behav Pharmacol 2010 June 3. (Epub ahead of print).

A Double-Blind, Placebo-Controlled Study of N-acetyl Cysteine Plus Naltrexone for Methamphetamine Dependence

Reducing both glutamatergic and dopaminergic drive in the nucleus accumbens may offer complementary mechanisms by which to reduce drug cravings. This 8-week study sought to examine the efficacy of a combination of a glutamate modulator, N-acetyl cysteine (NAC), plus the opioid antagonist, naltrexone, compared to placebo in the treatment of methamphetamine dependence. Thirty-one subjects with methamphetamine dependence (mean age 36.8+/-7.12years; 29% female) were randomly assigned in a 1:1 fashion to NAC plus naltrexone or placebo and returned for one post-baseline visit. The Penn Craving Scale was the primary outcome measure. Self-report methamphetamine use frequency and urine toxicology were secondary measures. NAC plus naltrexone failed to demonstrate statistically significant differences from placebo on primary and secondary outcomes. The current study failed to demonstrate greater efficacy for NAC plus naltrexone compared to placebo. Given the small sample size, the statistical power to detect significant effects of active treatment versus placebo was limited. The question of whether a larger, well-powered sample would have detected differences between NAC plus naltrexone and placebo deserves further examination. Grant JE, Odlaug BL, Kim SW. A double-blind, placebo-controlled study of N-acetyl cysteine plus naltrexone for methamphetamine dependence. Eur Neuropsychopharmacol. 2010 Jul 21. [Epub ahead of print].

Introduction to Behavioral Addictions

Several behaviors, besides psychoactive substance ingestion, produce short-term reward that may engender persistent behavior, despite knowledge of adverse consequences, i.e., diminished control over the behavior. These disorders have historically been conceptualized in several ways. One view posits these disorders as lying along an impulsive-compulsive spectrum, with some classified as impulse control disorders. An alternate, but not mutually exclusive, conceptualization considers the disorders as non-substance or "behavioral" addictions. The authors review data illustrating similarities and differences between impulse control disorders or behavioral addictions and substance addictions. This topic is particularly relevant to the optimal classification of these disorders in the forthcoming fifth edition of the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders (DSM-V). Growing evidence suggests that behavioral addictions resemble substance addictions in many domains, including natural history, phenomenology, tolerance, comorbidity, overlapping genetic contribution, neurobiological mechanisms, and response to treatment, supporting the DSM-V Task Force proposed new category of Addiction and Related Disorders encompassing both substance use disorders and non-substance addictions. Current data suggest that this combined category may be appropriate for pathological gambling and a few other better studied behavioral addictions, e.g., Internet addiction. There is currently insufficient data to justify any classification of other proposed behavioral addictions. Conclusions and Scientific Significance: Proper categorization of behavioral addictions or impulse control disorders has substantial implications for the development of improved prevention and treatment strategies. Grant, JE, Potenza, MN, Weinstein, A, Gorelick, DA. Introduction to Behavioral Addictions. Am J Drug Alcohol Abuse. 2010 Jun 21. [Epub ahead of print].

Monetary Incentives Promote Smoking Abstinence In Adults With Attention Deficit Hyperactivity Disorder (ADHD)

Individuals with attention deficit hyperactivity disorder (ADHD) smoke at rates significantly higher than the general population and have more difficulty quitting than non-diagnosed individuals. Currently, there are no evidence-based approaches for reducing smoking specifically in individuals with ADHD. Adult regular smokers with or without ADHD participated in a study of extended smoking withdrawal where monetary incentives were used to promote abstinence. Participants were paid according to an escalating schedule for maintaining abstinence measured as self-report of no smoking and an expired air carbon monoxide (CO) level of < or=4 parts per million. Sixty-four percent (14/22) of smokers with ADHD and 50% (11/22) of smokers without ADHD maintained complete abstinence for the 2-week duration of the study. Twenty-two percent (5/22) and 9% (2/22) of smokers with ADHD and without ADHD, respectively, maintained continued abstinence for up to 10 days following the removal of the contingencies. Though abstinence rates were higher for the smokers with ADHD, the group differences were not statistically significant. Results suggest that monetary incentives may be a useful approach for promoting abstinence in adult smokers with ADHD, perhaps owing to altered reinforcement processes in these individuals. Kollins SH, McClernon FJ, Van Voorhees EE. Monetary incentives promote smoking abstinence in adults with attention deficit hyperactivity disorder (ADHD). Exp Clin Psychopharmacol. 2010; 18(3): 221-228.

Intravenous Oxycodone, Hydrocodone, and Morphine In Recreational Opioid Users: Abuse Potential and Relative Potencies

Nonmedical use and abuse of prescription opioids is an increasing public health problem. Intravenous (IV) administration of opioid analgesics intended for oral use is not uncommon; yet, little is known about the relative abuse potential of these drugs when administered intravenously to recreational opioid abusers without physical dependence. This inpatient study employed a double-blind, randomized, within-subject, placebo-controlled design to examine the relative abuse potential of IV doses of oxycodone, hydrocodone, and morphine. Nine healthy adult participants reporting recreational opioid use and histories of IV opioid use completed 11 experimental sessions, including one active-dose practice session. IV doses were infused over 5 min and included three identical doses of each opioid (5, 10, and 20 mg/10 ml) and saline placebo. Physiological, subjective, and performance effects were collected before and for 6 h after drug administration. All three opioids produced prototypical mu agonist effects (e.g., miosis; increased ratings of liking) that were generally dose-related. Pharmacodynamic effects were observed within 5 min of IV administration. Physiological effects were more prolonged than subjective effects for all three drugs. While the magnitude of effects was generally comparable across drugs and qualitatively similar, valid potency assays indicated the following potency relationship: oxycodone > morphine > hydrocodone. There were modest potency differences between oxycodone, hydrocodone, and morphine, but their overall profile of effects was similar, indicating significant abuse potential when administered intravenously. Stoops WW, Hatton KW, Lofwall MR, Nuzzo PA, Walsh SL. Intravenous oxycodone, hydrocodone, and morphine in recreational opioid users: abuse potential and relative potencies. Psychopharmacology (Berl). 2010 Jul 28. [Epub ahead of print].

Behavioral Effects of D-Amphetamine In Humans: Influence of Subclinical Levels of Inattention and Hyperactivity

Several studies suggest a link between stimulant abuse and attention-deficit hyperactivity disorder (ADHD) symptoms (e.g., inattention and hyperactivity). To further assess the nature of this relationship, the present study examined the association between subclinical symptoms of inattention and hyperactivity and the behavioral effects of d-amphetamine. Participants were classified into a High- (n = 8) or Low-Score (n = 9) group based on their responses on a rating scale that assessed inattention and hyperactivity symptoms. The participants did not differ across the High-Score and Low-Score groups in their ability to discriminate d-amphetamine. The participants in the High-Score group were significantly more sensitive to the positive participant-rated effects of d-amphetamine (e.g., Good Effects, Like Drug), but less sensitive to drug-induced increases in blood pressure and heart rate. The selective increase in positive subjective effects of d-amphetamine suggests that individuals with subclinical inattention and hyperactivity symptoms may have increased vulnerability to stimulant abuse. Sevak RJ, Stoops WW, Rush CR. Behavioral effects of d-amphetamine in humans: influence of subclinical levels of inattention and hyperactivity. Am J Drug Alcohol Abuse. 2010; 36(4): 220-227.

Acute Effects of Intramuscular and Sublingual Buprenorphine and Buprenorphine/ Naloxone In Non-Dependent Opioid Abusers

Buprenorphine is a partial mu opioid receptor agonist with clinical efficacy as a pharmacotherapy for opioid dependence. A sublingual combination formulation was developed containing buprenorphine and naloxone with the intent of decreasing abuse liability in opioid-dependent individuals. However, the addition of naloxone may not limit abuse potential of this medication when taken by individuals without opioid physical dependence. The present study investigated the effects of buprenorphine alone and in combination with naloxone administered intramuscularly and sublingually to non-dependent opioid abusers. In a within-subject crossover design, non-dependent opioid-experienced volunteers (N = 8) were administered acute doses of buprenorphine (4, 8, and 16 mg) and buprenorphine/naloxone (4/1, 8/2, and 16/4 mg) via both intramuscular and sublingual routes, intramuscular hydromorphone (2 and 4 mg as an opioid agonist control), and placebo, for a total of 15 drug conditions. Laboratory sessions were conducted twice per week using a double-blind, double-dummy design. Buprenorphine and buprenorphine/ naloxone engendered effects similar to hydromorphone. Intramuscular administration produced a greater magnitude of effects compared to the sublingual route at the intermediate dose of buprenorphine and at both the low and high doses of the buprenorphine/naloxone combination. The addition of naloxone did not significantly alter the effects of buprenorphine. These results suggest that buprenorphine and buprenorphine/naloxone have similar abuse potential in non-dependent opioid abusers, and that the addition of naloxone at these doses and in this dose ratio confers no evident advantage for decreasing the abuse potential of intramuscular or sublingual buprenorphine in this population. Duke AN, Correia CJ, Walsh SL, Bigelow GE, Strain EC. Acute effects of intramuscular and sublingual buprenorphine and buprenorphine/naloxone in non-dependent opioid abusers. Psychopharmacology (Berl). 2010 Jun 25. [Epub ahead of print].

Does the Response to Cocaine Differ as a Function of Sex or Hormonal Status In Human and Non-Human Primates?

Stimulant abuse continues to be a growing problem among women. Over the last 10-15 years, an increasing number of studies have focused on factors that may be implicated in stimulant abuse in women as compared to men, including the role of hormonal fluctuations across the menstrual cycle. Numerous preclinical studies have documented that female rodents are more sensitive than male rodents to the behavioral effects of stimulant administration and the hormone estradiol is involved in the enhanced response to stimulants observed in females. In contrast, fewer studies have been conducted in humans and non-human primates addressing the role of sex and gonadal hormones on the effects of cocaine. This review paper presents a recent update on data collected in our Human Cocaine Challenge Laboratory and our Non-human Primate Laboratory, including analysis of cocaine pharmacokinetics, sex differences, the menstrual cycle, and the role of progesterone in modulating the response to cocaine. Our studies indicate that there is minimal evidence that the response to intranasal cocaine varies across the menstrual cycle or between men and women. In contrast, the response to smoked cocaine is greater in the follicular phase than the luteal phase and differences between men and women generally only emerge when men are compared to women in the luteal phase. In terms of potential hormonal mechanisms for these differences, the hormone progesterone attenuates the subjective response to cocaine. With respect to cocaine self-administration, there are minimal changes across the menstrual cycle in both humans and non-human primates. Thus, there is converging evidence across a range of species that the behavioral effects of cocaine (1) differ between males and females, (2) differ in relation to hormonal fluctuations, (3) can be attenuated by progesterone (at least in females), and (4) do not appear to be related to differences in cocaine pharmacokinetics. Evans SM, Foltin RW. Does the response to cocaine differ as a function of sex or hormonal status in human and non-human primates? Horm Behav. 2010; 58(1): 13-21. [Epub 2009 Sep 4].

A Placebo-Controlled Trial of Memantine For Cocaine Dependence With High-Value Voucher Incentives During A Pre-Randomization Lead-In Period

Preclinical findings suggest that the inhibition of NMDA glutamatergic neurotransmission may have beneficial effects in the treatment of cocaine dependence. The authors hypothesized that memantine, a low potency, uncompetitive NMDA receptor antagonist, would be safe and effective in the treatment of cocaine dependence, particularly in preventing relapse to cocaine use in abstinent individuals. Cocaine dependent patients (N=112) were enrolled. The trial began with a 2-week placebo lead-in period during which patients received high-value voucher contingency management to induce abstinence. Participants were then randomized to receive either memantine 20mg bid (N=39) or placebo (N=42) for 12-weeks in combination with individual relapse-prevention therapy. The randomization was stratified by abstinence status during the lead-in period. The primary outcome was the weekly proportion of days of cocaine use. There were no significant differences in cocaine use outcome between the groups treated with memantine versus placebo. Thus, the efficacy of memantine 40mg/d for the treatment of cocaine dependence was not supported. Urine-confirmed abstinence during the lead-in period was achieved by 44% of participants, and was a strong predictor of subsequent cocaine abstinence during the trial. This suggests that this clinical trial design, an intensive behavioral intervention during a lead-in period, resolves cocaine dependent patients into two subgroups, one that rapidly achieves sustained abstinence and may not need a medication, and another that displays persistent cocaine use and would most likely benefit from a medication to help induce abstinence. Targeting the latter subgroup may advance medication development efforts. Bisaga A, Aharonovich E, Cheng WY, Levin FR, Mariani JJ, Raby WN, Nunes EV. A placebo-controlled trial of memantine for cocaine dependence with high-value voucher incentives during a pre-randomization lead-in period. Drug Alcohol Depend. 2010 May 25. [Epub ahead of print].

A Comparison of Psychosocial and Cognitive Functioning Between Depressed and Non-Depressed Patients With Cannabis Dependence

Cannabis use and depressive disorders are thought to impair cognitive performance and psychosocial functioning. Both disorders co-occurring may compound the negative effects of these diagnoses. In this study, the authors used the California Computerized Assessment Package as the cognitive performance measure and the Addiction Severity Index as the psychosocial functioning measure to compare individuals who were cannabis dependent and either depressed or not depressed (N= 108: 54 cannabis dependent only, 54 cannabis dependent and depressed or dysthymic). As predicted, cannabis dependent individuals with comorbid depression showed more psychosocial impairment than individuals with cannabis dependence alone. However, contrary to the authors' hypothesis, individuals who were cannabis dependent with comorbid depression showed less cognitive impairment in some California Computerized Assessment Package modules than individuals with cannabis dependence alone. Based on the authors' results, they concluded that the additive effects of cannabis dependency and depression may only be limited to psychosocial domains and may not extend to cognitive functioning. Secora AM, Eddie D, Wyman BJ, Brooks DJ, Mariani JJ, Levin FR. A comparison of psychosocial and cognitive functioning between depressed and non-depressed patients with cannabis dependence. J Addict Dis. 2010;29(3): 325-337.

Long-Acting Injectable Versus Oral Naltrexone Maintenance Therapy With Psychosocial Intervention For Heroin Dependence: A Quasi-Experiment

A quasi-experimental comparison of early clinical outcomes between injectable, sustained-release, depot naltrexone formulation versus oral naltrexone maintenance therapy in individuals with opiate dependence was conducted. Early retention in treatment and urine-confirmed opiate use in the first 8 weeks post-detoxification were compared between patients (diagnosed as opiate-dependent according to DSM-IV criteria) participating in 2 concurrently run randomized clinical trials of oral (n = 69; patients treated from September 1999 to May 2002) and long-acting injectable (n = 42; patients treated from November 2000 to June 2003) naltrexone maintenance therapy with psychosocial therapy. Long-acting injectable naltrexone produced significantly better outcome than oral naltrexone on days retained in treatment (F(1,106) = 6.49, P = .012) and for 1 measure of opiate use (F(1,106) = 5.26, P = .024); other measures were not significantly different, but differences were in the same direction. In subanalyses, there were interaction effects between baseline heroin use severity and type of treatment. In subanalyses, heroin users with more severe baseline use showed better retention with oral naltrexone maintenance therapy combined with intensive psychotherapy (behavioral naltrexone therapy) as compared to retention shown by severe heroin users treated with long-acting naltrexone injections combined with standard cognitive-behavioral therapy (chi(2)(1) = 9.31, P = .002); less severe heroin users evidenced better outcomes when treated with long-acting injectable naltrexone. This quasi-experimental analysis provides tentative indications of superior outcomes for heroin-dependent patients treated with long-acting injectable naltrexone compared to oral naltrexone. The finding that heroin users with more severe baseline use achieved better outcomes with oral naltrexone is most probably attributable to the intensive nature of the psychosocial treatments provided and points to the opportunity for continued research in augmenting injectable naltrexone with psychosocial strategies to further improve outcome, especially in individuals with more severe use. The results should be considered exploratory given the quasi-experimental nature of the study. Brooks AC, Comer SD, Sullivan MA, Bisaga A, Carpenter KM, Raby WM, Yu E, O'Brien CP, Nunes EV. Long-acting injectable versus oral naltrexone maintenance therapy with psychosocial intervention for heroin dependence: a quasi-experiment. J Clin Psychiatry. 2010 Jul 13 [Epub ahead of print].

Progesterone Improves Cognitive Performance and Attenuates Smoking Urges In Abstinent Smokers

Progesterone, a steroid hormone, has been implicated in many CNS functions including reward, cognition, and neuroprotection. The goal of this study was to examine the dose-dependent effects of progesterone on cognitive performance, smoking urges, and smoking behavior in smokers. Thirty female and thirty-four male smokers participated in a double-blind, placebo-controlled study. Female smokers were in the early follicular phase of their menstrual cycle during study participation. Smokers were randomly assigned to either 200 or 400mg/day of progesterone or placebo, given in two separate doses, during clinic visit. The first 3 days of the treatment period, smokers abstained from smoking, which was verified with breath CO levels. Smokers attended an experimental session on day 4 where the number of cigarettes smoked were recorded starting 2h after the medication treatment. Progesterone treatment, 200mg/day, significantly improved cognitive performance in the Stroop and the Digit Symbol Substitution Test. Progesterone at 400mg/day was associated with reduced urges for smoking but did not change ad lib smoking behavior. These findings suggest a potential therapeutic value of progesterone for smoking cessation. Sofuoglu M, Mouratidis M, Mooney M. Progesterone improves cognitive performance and attenuates smoking urges in abstinent smokers. Psychoneuroendocrinology. 2010 Jul 30. [Epub ahead of print].

Comparison of Available Treatments For Tobacco Addiction

Cigarette smoking is a major public health problem that causes more than 5 million deaths annually worldwide. Cigarette smoking is especially common among individuals with psychiatric comorbidity, including individuals with primary psychiatric disorders and other addictions. Effective behavioral and pharmacologic treatments for smoking cessation are available. Behavioral treatments including brief (< 3 min) counseling by physicians are effective. Seven first-line pharmacologic treatments are currently available: five nicotine replacement therapies, bupropion, and varenicline. In addition, clonidine and nortriptyline are second-line treatments for smoking cessation. These treatments increase the chances of quitting smoking by two- to threefold, supporting their use in smokers who are motivated to quit. However, effective treatments for many subpopulations, including smokers with psychiatric comorbidities as well as adolescent, pregnant, or postpartum smokers, remain to be developed and represent an important challenge. Herman AI, Sofuoglu M. Comparison of Available Treatments for Tobacco Addiction. Curr Psychiatry Rep. 2010 Jul 10. [Epub ahead of print].

Cognitive Effects of Nicotine: Genetic Moderators

Cigarette smoking is the main preventable cause of death in developed countries, and the development of more effective treatments is necessary. Cumulating evidence suggests that cognitive enhancement may contribute to the addictive actions of nicotine. Several studies have demonstrated that nicotine enhances cognitive performance in both smokers and non-smokers. Genetic studies support the role of both dopamine (DA) and nicotinic acetylcholine receptors (nAChRs) associated with nicotine-induced cognitive enhancement. Based on knockout mice studies, beta2 nAChRs are thought to be essential in mediating the cognitive effects of nicotine. alpha7nAChRs are associated with attentional and sensory filtering response, especially in schizophrenic individuals. Genetic variation in D2 type DA receptors and the catechol-O-methyltransferase enzyme appears to moderate cognitive deficits induced by smoking abstinence. Serotonin transporter (5-HTT) gene variation also moderates nicotine-induced improvement in spatial working memory. Less is known about the contribution of genetic variation in DA transporter and D4 type DA receptor genetic variation on the cognitive effects of nicotine. Future research will provide a clearer understanding of the mechanism underlying the cognitive-enhancing actions of nicotine. Herman AI, Sofuoglu M. Cognitive effects of nicotine: genetic moderators. Addict Biol. 2010;15(3): 250-265. Epub 2010 Apr 29.

Influence of Cocaine Dependence and Early Life Stress on Pituitary-Adrenal Axis Responses to CRH and the Trier Social Stressor

Long-term changes in the hypothalamic-pituitary-adrenal (HPA) axis as a result of early life stress could be related to the development of substance use disorders during adulthood. In this study, the neuroendocrine, physiologic (HR), and subjective responses to corticotropin releasing hormone (CRH) and the Trier Social Stress Task (TSST) in individuals with cocaine dependence, with (n=21)/without early life stress (n=21), non-dependent individuals with early life stress (n=22), and a control group were examined (n=21). CRH increased cortisol and ACTH levels in all groups. However, a significant effect of early life stress on ACTH was observed indicating that the increase in ACTH was greatest in subjects with a history of childhood stress. Post hoc analysis indicated the early life stress/non-cocaine dependent individuals exhibited significantly higher levels of ACTH as compared to the early life stress/cocaine-dependent group. Despite the elevated ACTH response there was no difference between the groups in the cortisol response to CRH. The TSST produced a significant elevation in ACTH and cortisol all study groups. No significant group differences were observed. The subjective stress and peak heart rate responses to the TSST were greatest in cocaine-dependent subjects without early life stress. In response to CRH, subjective stress and craving were positively correlated in cocaine-dependent subjects regardless of early life stress history, while stress and craving following the TSST were correlated only in cocaine-dependent subjects without a history of early life stress. Findings support previous studies demonstrating that subjects with a history of childhood adversity exhibit elevated ACTH and blunted cortisol levels in response to stress. In contrast, HR and subjective stress in response to the TSST were greatest in cocaine-dependent subjects without a history of early life stress, suggesting that childhood adversity may desensitize autonomic and subjective responding to social stress in adults with cocaine dependence. Maria MM, McRae-Clark AL, Back SE, Desantis SM, Baker NL, Spratt EG, Simpson AN, Brady KT. Influence of cocaine dependence and early life stress on pituitary-adrenal axis responses to CRH and the Trier social stressor. Psychoneuroendocrinology. 2010 May 31. [Epub ahead of print].

Methylphenidate Transdermal System in Adults With Past Stimulant Misuse: An Open-Label Trial--Investigator-Supported Trial Funded by Shire Pharmaceuticals

This 8-week, open-label trial assessed the efficacy of methylphenidate transdermal system (MTS) in 14 adult individuals diagnosed with ADHD and with a history of stimulant misuse, abuse, or dependence. The primary efficacy endpoint was the Wender-Reimherr Adult ADHD Scale (WRAADS), and secondary efficacy endpoints included the Clinical Global Impression (CGI) ratings and substance abuse as quantified by urine drug screens and self-reported use. Significant improvements from baseline were found on both the WRAADS and CGI measurements. No abuse of the study medication was observed. The findings suggested that MTS may improve ADHD symptoms in adults with a history of stimulant misuse; however, there were limitations. The study data showed the need for subsequent randomized studies that further explore findings made in this study. McRae-Clark AL, Brady KT, Hartwell KJ, White K, Carter RE. Methylphenidate Transdermal System in Adults With Past Stimulant Misuse: An Open-Label Trial--Investigator-Supported Trial Funded by Shire Pharmaceuticals. J Atten Disord. 2010 Jun 10. [Epub ahead of print].

Extinction of Drug Cue Reactivity In Methamphetamine-Dependent Individuals

Conditioned responses to drug-related environmental cues (such as craving) play a critical role in relapse to drug use. Animal models demonstrate that repeated exposure to drug-associated cues in the absence of drug administration leads to the extinction of conditioned responses, but the few existing clinical trials focused on extinction of conditioned responses to drug-related cues in drug-dependent individuals show equivocal results. The current study examined drug-related cue reactivity and response extinction in a laboratory setting in methamphetamine-dependent individuals. Methamphetamine cue-elicited craving was extinguished during two sessions of repeated (3) within-session exposures to multi-modal (picture, video, and in-vivo) cues, with no evidence of spontaneous recovery between sessions. A trend was noted for a greater attenuation of response in participants with longer (4-7 day) inter-session intervals. These results indicate that extinction of drug cue conditioned responding occurs in methamphetamine-dependent individuals, offering promise for the development of extinction- based treatment strategies. Price KL, Saladin ME, Baker NL, Tolliver BK, Desantis SM, McRae-Clark AL, Brady KT. Extinction of drug cue reactivity in methamphetamine-dependent individuals. Behav Res Ther. 2010 Sep;48(9): 860-865. Epub 2010 May 19.

Naltrexone to Treat Opioid Addiction in a Country in Which Methadone and Buprenorphine Are Not Available

Opioid dependence is one of the most severe drug dependencies. Naltrexone is a medication that completely blocks the subjective and other effects of opioids and, when administered to detoxified opioid addicts and taken as directed, prevents relapse and helps maintain abstinence. The major problem with naltrexone is poor compliance, particularly in countries in which there is a treatment alternative based on substitution of illicit opioids such as heroin with orally administered opioid agonists (methadone) or partial agonist/antagonists (buprenorphine). In Russia, substitution therapy is forbidden by law, and naltrexone is the only available pharmacotherapy for heroin dependence. Due to the lack of alternatives to naltrexone and stronger family control of compliance (adherence), naltrexone is more effective for relapse prevention and abstinence stabilization in Russia than in Western countries. Long-acting, sustained-release formulations (injectable and implantable) seem particularly effective compared with oral formulations. This article summarizes the results of studies conducted in Russia during the past 10 years that demonstrate these points. Krupitsky E, Zvartau E, Woody G. Use of Naltrexone to Treat Opioid Addiction in a Country in Which Methadone and Buprenorphine Are Not Available. Curr Psychiatry Rep. 2010 Jul 17. [Epub ahead of print].

Cost-Effectiveness of Extended Buprenorphine-Naloxone Treatment for Opioid-Dependent Youth: Data From a Randomized Trial

The objective is to estimate cost, net social cost and cost-effectiveness in a clinical trial of extended buprenorphine-naloxone (BUP) treatment versus brief detoxification treatment in opioid-dependent youth. Economic evaluation of a clinical trial conducted at six community out-patient treatment programs from July 2003 to December 2006, who were randomized to 12 weeks of BUP or a 14-day taper (DETOX). BUP patients were prescribed up to 24 mg per day for 9 weeks and then tapered to zero at the end of week 12. DETOX patients were prescribed up to 14 mg per day and then tapered to zero on day 14. All were offered twice-weekly drug counseling. Participants were 152 patients aged 15-21 years. Data were collected prospectively during the 12-week treatment and at follow-up interviews at months 6, 9 and 12. The 12-week out-patient study treatment cost was $1514 (P < 0.001) higher for BUP relative to DETOX. One-year total direct medical cost was only $83 higher for BUP (P = 0.97). The cost-effectiveness ratio of BUP relative to DETOX was $1376 in terms of 1-year direct medical cost per quality-adjusted life year (QALY) and $25,049 in terms of out-patient treatment program cost per QALY. The acceptability curve suggests that the cost-effectiveness ratio of BUP relative to DETOX has an 86% chance of being accepted as cost-effective for a threshold of $100,000 per QALY. Extended BUP treatment relative to brief detoxification is cost effective in the US health-care system for the outpatient treatment of opioid-dependent youth. Polsky D, Glick HA, Yang J, Subramaniam GA, Poole SA, Woody GE. Cost-effectiveness of extended buprenorphine-naloxone treatment for opioid-dependent youth: data from a randomized trial. Addiction. 2010 Jul 12. [Epub ahead of print].

Diffusion Tensor Imaging and Decision Making In Cocaine Dependence

Chronic stimulant abuse is associated with both impairment in decision making and structural abnormalities in brain gray and white matter. Recent data suggest these structural abnormalities may be related to functional impairment in important behavioral processes. In 15 cocaine-dependent and 18 control subjects, relationships were examped between decision-making performance on the Iowa Gambling Task (IGT) and white matter integrity as measured by diffusion tensor imaging (DTI). Whole brain voxelwise analyses showed that, relative to controls, the cocaine group had lower fractional anisotropy (FA) and higher mean of the second and third eigenvalues (lambda perpendicular) in frontal and parietal white matter regions and the corpus callosum. Cocaine subjects showed worse performance on the IGT, notably over the last 40 trials. Importantly, FA and lambda perpendicular values in these regions showed a significant relationship with IGT performance on the last 40 trials. Compromised white matter integrity in cocaine dependence may be related to functional impairments in decision making. Lane SD, Steinberg JL, Ma L, Hasan KM, Kramer LA, Zuniga EA, Narayana PA, Moeller FG. Diffusion tensor imaging and decision making in cocaine dependence. PLoS One. 2010; 5(7): e11591.

Effect of Cocaine on Structural Changes In Brain: MRI Volumetry Using Tensor-Based Morphometry

Magnetic resonance imaging (MRI) was performed in cocaine-dependent subjects to determine the structural changes in brain compared to non-drug using controls. Cocaine-dependent subjects and controls were carefully screened to rule out brain pathology of undetermined origin. Magnetic resonance images were analyzed using tensor-based morphometry (TBM) and voxel-based morphometry (VBM) without and with modulation to adjust for volume changes during normalization. For TBM analysis, unbiased atlases were generated using two different inverse consistent and diffeomorphic nonlinear registration techniques. Two different control groups were used for generating unbiased atlases. Independent of the nonlinear registration technique and normal cohorts used for creating the unbiased atlases, our analysis failed to detect any statistically significant effect of cocaine on brain volumes. These results show that cocaine-dependent subjects do not show differences in regional brain volumes compared to non-drug using controls. Narayana PA, Datta S, Tao G, Steinberg JL, Moeller FG. Effect of cocaine on structural changes in brain: MRI volumetry using tensor-based morphometry. Drug Alcohol Depend. 2010 May 28. [Epub ahead of print].

Relationship Between Impulsivity and Decision Making In Cocaine Dependence

Impulsivity and decision making are associated on a theoretical level in that impaired planning is a component of both. However, few studies have examined the relationship between measures of decision making and impulsivity in clinical populations. The purpose of this study was to compare cocaine-dependent subjects to controls on a measure of decision making (the Iowa Gambling Task or IGT), a questionnaire measure of impulsivity (the Barratt Impulsiveness Scale or BIS-11) and a measure of behavioural inhibition (the immediate memory task or IMT), and to examine the interrelationship among these measures. Results of the study showed that cocaine-dependent subjects made more disadvantageous choices on the IGT, had higher scores on the BIS and more commission errors on the IMT. Cognitive model analysis showed that choice consistency factors on the IGT differed between cocaine-dependent subjects and controls. However, there was no significant correlation between IGT performance and the BIS total score or subscales or IMT commission errors. These results suggest that in cocaine-dependent subjects there is little overlap between decision making as measured by the IGT and impulsivity/ behavioral inhibition as measured by the BIS and IMT. Kjome KL, Lane SD, Schmitz JM, Green C, Ma L, Prasla I, Swann AC, Moeller FG. Relationship between impulsivity and decision making in cocaine dependence. Psychiatry Res. 2010 Jul 30;178(2): 299-304. Epub 2010 May 15.

Dopamine D4 Receptor Gene Variation Moderates the Efficacy of Bupropion For Smoking Cessation

Smokers (>/=10 cigarettes per day, N=331) of European ancestry taking part in a double-blind placebo-controlled randomized trial of 12 weeks of treatment with bupropion along with counseling for smoking cessation were genotyped for a variable number of tandem repeats polymorphism in exon III of the dopamine D4 receptor gene. Generalized estimating equations predicting point-prevalence abstinence at end of treatment and 2, 6 and 12 months after the end of treatment indicated that bupropion (vs placebo) predicted increased odds of abstinence. The main effect of Genotype was not significant. A Genotype x Treatment interaction (P=0.005) showed that bupropion predicted increased odds of abstinence in long-allele carriers (odds ratios (OR)=1.31, P<0.0001), whereas bupropion was not associated with abstinence among short-allele homozygotes (OR=1.06, P=0.23). The Genotype x Treatment interaction remained when controlling for demographic and clinical covariates (P=0.01) and in analyses predicting continuous abstinence (P'sSmoking Expectancies, Weight Concerns, and Dietary Behaviors In Adolescence

The objective of this study was to examine the association of cigarette smoking and weight concerns in adolescents, given that adolescents may begin smoking or have difficulty quitting because of their expectancies of the effects of smoking on body weight. This study used data from a cross-sectional survey of 4523 Connecticut high school adolescents to assess the influence of gender, smoking intensity, and dietary-restrictive behavior on smoking-related weight concerns. Heavy smokers were significantly less likely to engage in healthy dietary restrictions than nonsmokers; however, light smokers did not differ from nonsmokers. Both light and heavy smokers were significantly more likely to engage in unhealthy dietary restriction when compared with nonsmokers. In the model that was used to examine smokers only, heavy smokers were significantly less likely to engage in healthy dietary restriction than light smokers, but smoking level was not associated with unhealthy dietary restrictions. Dietary restrictions are significantly associated with smoking-related weight concerns; however, this seems to be related to type of dietary-restrictive behavior, with greater weight concerns observed only in those smokers who engaged in unhealthy dietary restrictions and not in those who engaged in healthy dietary restrictions or no restrictions. Although limited by its cross-sectional nature, the findings from this large, geographically diverse sample have clinical implications for smoking prevention and cessation interventions in adolescents. Cavallo DA, Smith AE, Schepis TS, Desai R, Potenza MN, Krishnan-Sarin S. Smoking expectancies, weight concerns, and dietary behaviors in adolescence. Pediatrics. 2010 Jul;126(1): e66-72. Epub 2010 Jun 14.

Drug-Induced Plasticity Contributing To Heightened Relapse Susceptibility: Neurochemical Changes and Augmented Reinstatement In High-Intake Rats

Previous studies have demonstrated that increased extracellular glutamate, but not dopamine, in the nucleus accumbens core (NAcc) is necessary for cocaine-induced reinstatement. In this study, rats were assigned to self-administer cocaine under conditions resulting in low or high levels of drug intake. Approximately 19 d after the last session, extracellular levels of glutamate and dopamine in the NAcc were measured. Contrary to what has beeng reported, high-intake rats exhibited an increase in extracellular levels of dopamine but not glutamate. Further, increased reinstatement in high-intake rats was no longer observed when the D(1) receptor antagonist SCH-23390 was infused into the NAcc. The sensitized dopamine response to cocaine in high-intake rats may involve blunted cystine-glutamate exchange by system x(c(-)). Reduced (14)C-cystine uptake through system x(c(-)) was evident in NAcc tissue slices obtained from high-intake rats, and the augmented dopamine response in these rats was no longer observed when subjects received the cysteine prodrug N-acetyl cysteine. Madayag A, Kau KS, Lobner D, Mantsch JR, Wisniewski S, Baker DA. J Neurosci. 2010; 30(1): 210-217.

Behavioral and Neurochemical Effects of Amphetamine Analogs That Release Monoamines In the Squirrel Monkey

Previous preclinical and clinical studies have shown that continuous treatment with the monoamine releaser amphetamine reduces cocaine self-administration, but amphetamine selectively targets the dopamine system and is reinforcing. In the present study, the consequences of administration of amphetamine and three structurally related analogs that vary in their potencies for releasing dopamine and serotonin on behavioral-stimulant effects and nucleus accumbens dopamine levels in squirrel monkeys were examined. These results demonstrate that increasing serotonergic activity attenuates dopamine release and dopamine-mediated behavioral effects of monoamine releasers. These results support further investigation of PAL-313 and similar compounds as a potential medication for treating psychostimulant abuse. Kimmel HL, Manvich DF, Blough BE, Negus SS, Howell LL. Pharmacol Biochem Behav. 2009; 94(2): 278-284.

Synthetic Studies and Pharmacological Evaluations on the MDMA ('Ecstasy') Antagonist Nantenine

(R)- and (S)-nantenine were prepared and evaluated in a food-reinforced operant task in rats. Pretreatment with either nantenine enantiomer (0.3mg/kg ip) completely blocked the behavioral suppression induced upon administration of 3.0mg/kg MDMA. (+/-)-Nantenine displayed high affinity and selectivity for the alpha(1A) adrenergic receptor among several other receptors suggesting that this alpha(1) subtype may be significantly involved in the anti-MDMA effects of the enantiomers. Legendre O, Pecic S, Chaudhary S, Zimmerman SM, Fantegrossi WE, Harding WW. Bioorg Med Chem Lett. 2010; 20(2): 628-631.

A Novel Substituted Piperazine, CM156, Attenuates the Stimulant and Toxic Effects of Cocaine In Mice

In the present study, CM156, a novel compound, was developed and tested for interactions with sigma receptors using radioligand binding studies. It was also evaluated against cocaine-induced effects in behavioral studies. The results showed that CM156 has nanomolar affinities for each of the sigma receptor subtypes in the brain and much weaker affinities for non-sigma binding sites. Pretreatment of male Swiss-Webster mice with CM156, before administering either a convulsive or locomotor stimulant dose of cocaine, led to a significant attenuation of these acute effects. CM156 also significantly reduced the expression of behavioral sensitization and place conditioning evoked by subchronic exposure to cocaine. Xu YT, Kaushal N, Shaikh J, Wilson LL, Mésangeau C, McCurdy CR, Matsumoto RR. J Pharmacol Exp Ther. 2010; 333(2): 491-500.

A Thermally Stable Form of Bacterial Cocaine Esterase: A Potential Therapeutic Agent For Treatment of Cocaine Abuse

Rhodococcal cocaine esterase (CocE) is an attractive potential treatment for both cocaine overdose and cocaine addiction. The most thermostable form of this enzyme to date, CocE-L169K/G173Q were characterized. In vitro kinetic analyses reveal that CocE-L169K/G173Q displays a half-life of 2.9 days at 37 degrees C, which represents a 340-fold improvement over wild type (wt) and is 15-fold greater than previously reported mutants. In vivo rodent studies reveal that intravenous pretreatment with CocE-L169K/G173Q in mice provides protection from cocaine-induced lethality and prevents self-administration of cocaine in a time-dependent manner. Termination of the in vivo effects of CoCE seems to be dependent on, but not proportional to, its clearance from plasma as its half-life is approximately 2.3 h and similar to that of wt CocE (2.2 h). Brim RL, Nance MR, Youngstrom DW, Narasimhan D, Zhan CG, Tesmer JJ, Sunahara RK, Woods JH. Mol Pharmacol. 2010; 77(4): 593-600.


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