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Director's Report to the National Advisory Council on Drug Abuse - September, 2009

Research Findings - Research on Pharmacotherapies for Drug Abuse

Dual Dopamine/Serotonin Releasers: Potential Treatment Agents for Stimulant Addiction

The evidence supporting the utility of dual releaser during cocaine and alcohol withdrawal was summarized. Data demonstrating the "antistimulant" role of 5-HT-sub(2C) receptors were presented and the mechanisms of potential adverse effects discussed. PAL-287, a novel DA/5-HT releaser, suppressed cocaine self-administration without reinforcing properties by itself. This report demonstrated that DA/5-HT releasers could be useful adjunct therapy for cocaine and alcohol addictions and potential medication for obesity, attention-deficit disorder, and depression. Rothman RB, Blough BE, Baumann MH. Dual dopamine/serotonin releasers: potential treatment agents for stimulant addiction. Exp Clin Psychopharmacol. 2008; Dec;16(6):458-474.

(1R, 3S)-(-)-trans-PAT: A Novel Full-efficacy Serotonin 5-HT2C Receptor Agonist with 5-HT2A and 5-HT2B Receptor Inverse Agonist/antagonist Activity

This paper reports 5-HT2 receptor affinity and function of (1R,3S)-(-)-trans-PAT, a small molecule that produces anorexia and weight-loss after peripheral administration to mice. It is a stereoselective agonist at 5-HT2C receptor and an inverse agonist and competitive antagonist at 5-HT2A/2B (Ki=37, 410, 1200 nM, respectively and EC50/IC50=20, 490 and 1,000 nM, respectively). In addition to being a tool for studying 5-HT(2) receptor structure and function, (-)-trans-PAT is a novel medication compound for treating obesity and neuropsychiatric disorders. Booth RG, Fang L, Huang Y, Wilczynski A, Sivendran S. (1R, 3S)-(-)-trans-PAT: a novel full-efficacy serotonin 5-HT2C receptor agonist with 5-HT2A and 5-HT2B receptor inverse agonist/antagonist activity. Eur J Pharmacol. 2009; Aug 1;615(1-3):1-9.

Effects of the Monoamine Uptake Inhibitors RTI-112 and RTI-113 on Cocaine- and Food-Maintained Responding in Rhesus Monkeys

The present study compared the effects of a non-selective monoamine uptake inhibitor (RTI-112) and a dopamine-selective uptake inhibitor (RTI-113) on cocaine- and food-maintained responding in rhesus monkeys. Both produced dose-dependent, sustained and nearly complete elimination of cocaine self-administration. The potency to cocaine was similar to that to food. These findings do not support the hypothesis that pharmacological selectivity to block dopamine uptake is associated with behavioral selectivity to decrease cocaine- vs. food-maintained responding in rhesus monkeys. Negus SS, Mello NK, Kimmel HL, Howell LL, Carroll FI. Effects of the monoamine uptake inhibitors RTI-112 and RTI-113 on cocaine- and food-maintained responding in rhesus monkeys. Pharmacol Biochem Behav. 2009; Jan;91(3):333-338.

Attenuation of Methamphetamine-induced Effects Through the Antagonism of Sigma (Sigma) Receptors: Evidence from In Vivo and In Vitro Studies

In the present study, AC927, a sigma receptor antagonist, had preferential affinity for sigma receptors compared to 29 other receptors, transporters and ion channels. Pretreatment of mice with AC927 significantly attenuated METH-induced locomotor stimulation, striatal dopamine depletions, striatal dopamine transporter reductions, and hyperthermia. Co-incubation with AC927 in cells mitigated METH-induced cytotoxicity. Matsumoto RR, Shaikh J, Wilson LL, Vedam S, Coop A. Attenuation of methamphetamine-induced effects through the antagonism of sigma (sigma) receptors: Evidence from in vivo and in vitro studies. Eur Neuropsychopharmacol. 2008; Dec;18(12):871-881.

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

A major obstacle to the clinical application of cocaine esterase (CocE) against cocaine toxicity is the thermoinstability of native CocE with a half-life of only a few minutes at physiological temperature (37 degrees C). An integrated computational-experimental effort has yielded a CocE variant with a approximately 30-fold increase in plasma half-life both in vitro and in vivo. The novel design strategy can be applicable to progein mutants in general in improving their thermostability. Gao D, Narasimhan DL, Macdonald J, Brim R, Ko MC, Landry DW, Woods JH, Sunahara RK, Zhan CG. Thermostable variants of cocaine esterase for long-time protection against cocaine toxicity. Mol Pharmacol. 2009; Feb;75(2):318-323.

The Acute Behavioral Effects of Methamphetamine, d-amphetamine, and Methylphenidate Overlap Extensively in Humans

Methamphetamine abuse is a significant public health concern. Although widely studied in laboratory animals, little is known about the abuse-related behavioral effects of methamphetamine relative to other abused stimulants in controlled laboratory settings in humans. The aim of this study was to examine the discriminative stimulus, subject-rated, performance, and cardiovascular effects of methamphetamine in humans. In the present study, subjects first learned to discriminate 10 mg of oral methamphetamine from placebo. After acquiring the discrimination, a range of oral doses of methamphetamine, d-amphetamine, methylphenidate, and triazolam were tested. Methamphetamine functioned as a discriminative stimulus and produced prototypical stimulant-like subject-rated effects. d-Amphetamine and methylphenidate produced dose-related increases in methamphetamine-appropriate responding, whereas triazolam did not. d-Amphetamine and methylphenidate produced stimulant-like behavioral effects, whereas triazolam produced sedative-like effects. Methamphetamine, but no other drug, increased heart rate, systolic pressure, and diastolic pressure significantly above placebo levels. Performance in the Digit-Symbol Substitution Test was not affected by any of the drugs tested. Overall, these results demonstrate that the acute behavioral effects of methamphetamine, d-amphetamine, and methylphenidate overlap extensively in humans, which is concordant with findings from preclinical studies. Future studies should assess whether the similarity in the behavioral effects of methamphetamine and related stimulants can be extended to other behavioral assays, such as measures of reinforcement, in humans. Sevak RJ, Stoops WW, Hays LR, Rush CR, Discriminative stimulus and subject-rated effects of methamphetamine, d-amphetamine, methylphenidate and triazolamin methamphetamine-trained humans. J Pharmacol Exp Ther. 2009; Mar;328(3):1007-1018.

Evaluation of Subjective Effects of Aripiprazole and Methamphetamine in Methamphetamine -dependent Volunteers

This study investigated the safety and potential efficacy of aripiprazole in 16 methamphetamine-dependent patients as a treatment for methamphetamine addiction. The study was a double-blind in-patient clinical pharmacology study to assess potential interactions between intravenous methamphetamine (15 mg and 30 mg) and oral aripiprazole (15 mg). Following baseline methamphetamine dosing, subjects received 2 weeks treatment with aripiprazole (n=8) or placebo (n=8). Participants then completed cue exposure sessions using neutral and methamphet-amine-related cues, and methamphetamine dosing was then repeated. Aripiprazole treatment had no effect on cue-induced methamphetamine craving or on daily baseline craving assessed over the course of medication treatment, although treatment was associated with increased craving independent of methamphetamine dosing. Aripiprazole treatment did not alter the pharmaco-kinetics of methamphetamine, and reduced increase in systolic blood pressure following methamphetamine dosing. The findings indicate that aripiprazole treatment appears safe in volunteers with methamphetamine dependence, although it increases some of the rewarding and stimulatory effects produced by methamphetamine, indicating that 15 mg aripiprazole is unlikely to be efficacious for the treatment of methamphetamine dependence. Newton TF, Reid MS, De La Garza R, Mahoney JJ, Abad A, Condos R, et al., Evaluation of Subjective Effects of Aripiprazole and Methamphetamine in Methamphetamine-dependent volunteers. Int. J. Neuropsychopharm. 2008;11:1037-1045.

Methamphetamine Self-Administration by Humans Subjected to Abrupt Shift and Sleep Schedule Changes

Methamphetamine attenuates disruptions that occur after changes in work shifts. The reinforcing effects of the drug during shift work have yet to be characterized. This study examined methamphetamine-related mood, performance, and reinforcing effects during simulated shift work. In this 19-day study, ten volunteers were given an opportunity to self-administer 10 mg oral methamphetamine or receive a $1 voucher before and after an 8-hour work period for four consecutive days under two shift conditions. Night-shift work disrupted psycho-motor task performance and some ratings of mood, especially on the first night. Participants chose to take methamphetamine significantly more often on the first night-shift night compared with the first day-shift day. Participants selected markedly more methamphetamine doses before the work period than after it. The data showed that methamphetamine self-administration occurred more often before work than after work, suggesting that the use of methamphetamine by shift workers may be one strategy employed to meet behavioral demands, especially under conditions engendering poor performance, fatigue, and/or sleep disruptons. Kirkpatrick MG, Haney M, Vosburg SK, Comer SD, Foltin RW, Hart CL. Methamphetamine self-administration by humans subjects to abrupt shift and sleep schedule changes. Psychopharmacology. 2009;203:771-780.

Unrestricted Access to Methamphetamine or Cocaine in the Past is Associated with Increased Current Use

Laboratory animals allowed to self-administer stimulants for extended periods of time escalate drug intake compared to animals that self-administer under temporally limited conditions. This phenomenon has not been systematically investigated in humans. Investigators interviewed 106 (77 male, 29 female) methamphetamine (Meth) and 96 (81 male, 15 female) cocaine (Coc) users to determine if they had experienced discrete period(s) of unrestricted access to unlimited quantities of Meth or Coc in the past. Fifty-eight Meth users and 53 Coc users reported having a discrete period of unrestricted access in the past, but not in the present. Meth-using participants with a prior history of unrestricted access reported significantly more current Meth use, compared to Meth users with no prior history of unrestricted access. Specifically, these participants reported more days used in the past 30 d, more days of use per week, greater use per day and greater total use per week (p<0.05 for each). Coc-using participants with a prior history of unrestricted access also reported significantly more current Coc use, compared to Coc users with no prior history of unrestricted access. This was true across all measures of current use for these participants, including more days used in the past 30 days, more days of use per week, greater use per day, and higher total use per week (p<0.02 for each). Taken together, these results suggest that a history of unrestricted access to stimulants is associated with long-lasting increases in stimulant use. Culbertson C, De La Garza R, Costello M, Newton TF, Unrestricted access to methamphetamine or cocaine in the past is associated with increased current use. Int J Neuropsychopharmacol. 2009;Jun;12(5):677-685.

Atomoxetine Treatment for Cocaine Abuse and Adult Attention-Deficit Hyperactivity Disorder (ADHD): A Preliminary Open Trial

The purpose of this 12-week open trial was to evaluate the potential utility of atomoxetine for the treatment of attention deficit hyperactivity disorder (ADHD) in cocaine-dependent treatment seekers. The sample consisted of 20 participants with all participants meeting DSM-IV-TR criteria for ADHD and cocaine dependence (CD). Using several measures to assess ADHD, there was a significant reduction in ADHD symptoms. There was no significant decrease in cocaine use throughout the trial. Taken together, although cocaine-dependent individuals showed some reduction in ADHD symptoms while receiving atomoxetine, the high drop-out rate and lack of impact on cocaine use may limit its utility in ADHD adults who are currently abusing cocaine. Levin FR, Mariani JJ, Secora A, Brooks D, Cheng WY, Bisaga A, Nunes E, Aharonovich E, Raby W, Hennessy G. J. Dual Diagn. 2009 Jan 1;5(1):41-56.

Repeated Dosing with Oral Cocaine in Humans: Assessment of Direct Effects, Withdrawal, and Pharmacokinetics

Cocaine withdrawal symptoms are thought to play a role in relapse; studies characterizing the symptomatology have yielded mixed findings. This study sought to examine the pharmacodynamic/pharmacokinetic profile of repeated high dose exposure to oral cocaine and characterize acute and protracted withdrawal in cocaine abusers. This study employed a repeated-dosing, single-blind design in which subjects (n = 9), resided for 40 days on a closed ward. They were maintained for two 4-day cocaine exposure periods (Days 1-4 & Days 9-12, cocaine 175 mg, p.o.; 5 hourly doses; 875 mg/day) separated by a 4-day matched placebo exposure period (Days 5-8). After these 12 days, an additional period of 28 days of placebo maintenance followed (Days 13-40). Test sessions were conducted during each phase; measures of mood, drug effects, sleep, pharmacokinetics, and prolactin were collected throughout the study. The dosing regimen produced cocaine plasma concentrations (Cmax of 680 ng/mL) two to threefold higher than typically seen in acute dose studies. Prototypic psychostimulant effects, including subjective ratings of euphoric effects (liking, high, good effects) and significant cardiopressor effects, were sustained during the active dosing periods, corresponding to the rise and fall of plasma cocaine. Withdrawal-like symptoms (i.e., disruptions of sleep, increased ratings of anxiety, irritability, crashing) were observed within 24-hr after cessation of dosing. Cocaine reduced prolactin acutely, but no sustained alterations were observed for this measure or for other signs or symptoms during the 28-day abstinence period. These findings indicate that exposure to controlled high doses of cocaine produces modest symptoms consistent with cocaine withdrawal within hours of cessation of dosing but provide no evidence of symptoms persisting beyond 24 hours. Walsh SL, Stoops WW, Moody DE, Lin SW, Bigelow GE, Repeated dosing with oral cocaine in humans: Assessment of direct effects, withdrawal, and pharmacokinetics. Exp Clin Psychopharmacol. 2009; Aug;17(4):205-216.

Association Analysis Between Polymorphisms in the Conserved Dopamine Neurotrophic Factor (CDNF) Gene and Cocaine Dependence

Cocaine-induced neuroplasticity changes in the mesocorticolimbic dopamine systems are thought to be involved in the pathophysiology of cocaine dependence. Since neurotrophic factors have been observed to prevent/reverse and mimic cocaine-induced neurobiological changes in the brain, related genes are plausible candidates for susceptibility to cocaine dependence. The novel conserved dopamine neurotrophic factor protein (CDNF) promotes the survival, growth, and function of dopamine-specific neurons and is expressed in brain regions that undergo cocaine-induced neuroplasticity. In this study, the investigators hypothesized that polymorphisms in the CDNF gene (CDNF/ARMETL1) contribute to increased risk for cocaine dependence. Cocaine dependent individuals (n=351) and unaffected controls (n=257) of African descent were genotyped for four single nucleotide polymorphisms (SNPs) in the CDNF gene (rs11259365, rs7094179, rs7900873, rs2278871). No significant differences were observed in allele, genotype, or haplotype frequencies between cases and controls for any of the tested SNPs. This study suggests that there is no association between variants in the CDNF gene and cocaine dependence. However, additional studies using larger sample sizes, comprehensive SNP coverage, and clinically homogenous populations are necessary before confidently excluding CDNF as a significant genetic risk factor for cocaine dependence. Lohoff FW, Bloch PJ, Ferraro TN, Berrettini WH, Pettinati HM, Dackins CA, O'Brien CP, Kampman KM, Oslin DW. Association analysis between polymorphisms in the conserved dopamine neurotropic factor (CDNF) gene and cocaine dependence. Neuroscience Letters. 2009; 453:199-203.

Comparisons of Subjective, Pharmacokinetic, and Physiological Effects of Marijuana Smoked as Joints and Blunts

Recent increases in marijuana smoking among the young adult population have been accompanied by the popularization of smoking marijuana as blunts instead of as joints. Blunts consist of marijuana wrapped in tobacco leaves, whereas joints consist of marijuana wrapped in cigarette paper. To date, the effects of marijuana smoked as joints and blunts have not been systematically compared. This within-subject, randomized, double-blind, placebo-controlled study sought to directly compare the subjective, physiological, and pharmacokinetic effects of marijuana smoked by these two methods. Marijuana blunt smokers (12 women and 12 men) were recruited and participated in a 6-session outpatient study. Participants were blindfolded and smoked three puffs from either a blunt or a joint containing marijuana with varying Delta(9)-tetrahydrocannabinol (THC) concentrations (0.0, 1.8, and 3.6%). Subjective, physiological (heart rate, blood pressure, and carbon monoxide levels) and pharmacokinetic effects (plasma THC concentration) were monitored before and at specified time points for 3h after smoking. Joints produced greater increases in plasma THC and subjective ratings of marijuana intoxication, strength, and quality compared to blunts, and these effects were more pronounced in women compared to men. However, blunts produced equiva-lent increases in heart rate and higher carbon monoxide levels than joints, despite producing lower levels of plasma THC. These findings demonstrate that smoking marijuana in a tobacco leaf may increase the risks of marijuana use by enhancing carbon monoxide exposure and increasing heart rate compared to joints. Cooper ZD, Haney M. Comparison of subjective, pharmacokinetic, and physiological effects of marijuana smoked as joints and blunts. Drug and Alc Dep. 2009;103:107-113.

Actions of Delta-9-tetrahydrocannabinol (THC) in Cannabis: Relation to Use, Abuse, Dependence

Cannabis use disorders have been identified as a relevant clinical issue. A subset of cannabis smokers seeks treatment for their cannabis use, yet few succeed in maintaining long-term abstinence. The rewarding and positive reinforcing effects of the primary psychoactive component of smoked cannabis, THC, are mediated by the cannabinoid CB1 receptor; the CB1 receptor has also been shown to mediate cannabis dependence and withdrawal. This paper reviews findings implicating the CB1 receptor in the behavioral effects of exogenous cannabinoids with a focus on cannabinoid dependence and reinforcement, and discusses the prevalence of cannabis use and dependence, cannabinoids and reward, reinforcing effects of cannabinoids, cannabinoid dependence and withdrawal, and the opioidergic contribution to cannabinoid effects. The conclusions are that across species, cannabinoids produce positive affective, rewarding, and reinforcing effects. Upon repeated drug administration, cannabinoid dependence develops marked by a withdrawal syndrome that is induced by either a cannabinoid antagonist or abstinence. The positive effects likely promote use, whereas both the positive and negative effects (dependence and withdrawal) of repeated use contribute to the difficulty that a subset of cannabis users have achieving and maintaining abstinence. Across species, the behavioral effects of cannabis, THC, and synthetic cannabinoids are clearly mediated by the endogenous cannabinoid systems. Cooper ZD, Haney M. Actions of delta-9-tetrahydro-cannabinol in cannabis: relation to use, abuse, dependence. Int. Rev. Psychiatry. 2009; April 1: 21(2):104-112.

The Effect of Olanzapine Pretreatment on Acute Cocaine Toxicity in Mice

Acute cocaine poisoning causes neuroexcitation and can be fatal. The toxic effects of cocaine can be attenuated by antagonists of serotonin, muscarinic cholinergic, and dopamine receptors. Olanzapine, an atypical antipsychotic medication, is an antagonist of these receptors. The objective of this study is to evaluate the efficacy of olanzapine pretreatment for attenuation of acute cocaine toxicity using a mouse model. Eighty male CF-1 mice were randomly assigned to olanzapine (1 mg/kg) or placebo pretreatment. Fifteen minutes later, all animals received 103 mg/kg intraperitoneal cocaine. Overall mortality was 11% for olanzapine-treated animals and 45% for placebo. Olanzapine also appeared to alter the characteristics of seizures due to cocaine. In this model of acute cocaine toxicity, olanza-pine pretreatment attenuated acute cocaine toxicity. Olanzapine should be evaluated further as a po-tential treatment for acute cocaine poisoning. Heard KJ, Cleveland NR, Krier S. The effect of olan-zapine pretreatment on acute cocaine toxicity in mice. Clin Tox (Phila). 2009 Jul;47(6):542-544.

Cue-Induced Dopamine Release Predicts Cocaine Preference: Positron Emission Tomography Studies in Freely Moving Rodents

Positron emission tomography studies in drug-addicted patients have shown that exposure to drug-related cues increases striatal dopamine, which displaces binding of the D(2) ligand, [(11)C]-raclopride. However, it is not known if animals will also show cue-induced displacement of [(11)C]-raclopride binding. In this study, the authors use [(11)C]-raclopride imaging in awake rodents to capture cue-induced changes in dopamine release associated with the conditioned place preference model of drug craving. Ten animals were conditioned to receive cocaine in a contextually distinct environment from where they received saline. Following conditioning, each animal was tested for preference and then received two separate [(11)C]-raclopride scans. For each scan, animals were confined to the cocaine and/or the saline-paired environment for the first 25 min of uptake, after which they were anesthetized and scanned. [(11)C]-raclopride uptake in the saline-paired environment served as a within-animal control for uptake in the cocaine-paired environment. Cocaine produced a significant place preference (p = 0.004) and exposure to the cocaine-paired environment decreased [(11)C]-raclopride binding relative to the saline-paired environment in both the dorsal (20%; p < 0.002) and ventral striatum (22%; p < 0.05). The change in [(11)C]-raclopride binding correlated with preference in the ventral striatum (R(2) = -0.87; p = 0.003). In this region, animals who showed little or no preference exhibited little or no change in [(11)C]-raclopride binding in the cocaine-paired environment. This noninvasive procedure of monitoring neurochemical events in freely moving, behaving animals advances preclinical molecular imaging by interrogating the degree to which animal models reflect the human condition on multiple dimensions, both biological and behavioral. Schiffer WK, Liebling CN, Reiszel C, Hooker JM, Brodie JD, Dewey SL. Cue-induced dopamine release predicts cocaine preference: positron emission tomography studies in freely moving rodents. J Neurosci. 2009 May 13;29(19):6176-6185.

Pharmacotherapy for Cannabis Dependence - How Close Are We?

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;23(7):543-553.

Methadone and Buprenorphine Prescribing and Referral Practices in US Prison Systems: Results from a Nationwide Survey

More than 50% of incarcerated individuals have a history of substance use, and over 200,000 individuals with heroin addiction pass through American correctional facilities annually. Opiate replacement therapy (ORT) with methadone or buprenorphine is an effective treatment for opiate dependence and can reduce drug-related disease and recidivism for inmates. Provision of ORT is nevertheless a frequently neglected intervention in the correctional setting. This paper reports a survey of the 50 state Departments of Corrections; Washington, District of Columbia (DC); and Federal Department of Corrections' medical directors or their equivalents about their facilities' ORT prescribing policies and referral programs for inmates leaving prison. The investigators received responses from 51 of 52 prison systems nationwide. Twenty-eight prison systems (55%) offer methadone to inmates in some situations. Methadone use varies widely across states: over 50% of correctional facilities that offer methadone do so exclusively for pregnant women or for chronic pain management. Seven states' prison systems (14%) offer buprenorphine to some inmates. The most common reason cited for not offering ORT was that facilities "prefer drug-free detoxification over providing methadone or buprenorphine." Twenty-three states' prison systems (45%) provide referrals for some inmates to methadone maintenance programs after release, which increased from 8% in 2003; 15 states' prison systems (29%) provide some referrals to community buprenorphine providers. The conclusion is, that despite demonstrated social, medical, and economic benefits of providing ORT to inmates during incarceration and linkage to ORT upon release, many prison systems nationwide still do not offer pharmacological treatment for opiate addiction or referrals for ORT upon release. Nunn A, Zaller N, Dickman S, Trimbur C, Nijhawan A, Rich JD. Drug and Alcohol Dep. 2009; [E-pub ahead of print].

Attitudes Toward Methadone Among Out-of-Treatment Minority Injection Drug Users: Implications for Health Disparities

Injection drug use (IDU) continues to be a significant public health issue in the U.S. and internationally, and there is evidence to suggest that the burden of injection drug use and associated morbidity and mortality falls disproportionately on minority communities. IDU is responsible for a significant portion of new and existing HIV/AIDS cases in many parts of the world. In the U.S., the prevalence of HIV and hepatitis C virus is higher among populations of African-American and Latino injection drug users (IDUs) than among white IDUs. Methadone maintenance therapy (MMT) has been demonstrated to effectively reduce opiate use, HIV risk behaviors and transmission, general mortality and criminal behavior, but opiate-dependent minorities are less likely to access MMT than whites. A better understanding of the obstacles minority IDUs face accessing treatment is needed to engage racial and ethnic disparities in IDU as well as drug-related morbidity and mortality. This study explores knowledge, attitudes and beliefs about methadone among 53 out-of-treatment Latino and African-American IDUs in Providence, RI. The findings suggest that negative perceptions of methadone persist among racial and ethnic minority IDUs in Providence, including beliefs that methadone is detrimental to health and that people should attempt to discontinue methadone treatment. Additional potential obstacles to entering methadone therapy include cost and the difficulty of regularly attending a methadone clinic as well as the belief that an individual on MMT is not abstinent from drugs. The investigators recommend that substance use researchers and treatment professionals should engage minority communities, particularly Latino communities, in order to better understand the treatment needs of a diverse population, develop culturally appropriate MMT programs, and raise awareness of the benefits of MMT. Zaller ND, Bazazi AR, Velazquez L, Rich JD. Attitudes toward methadone among out-of-treatment minority injection drug users: implications for health disparities. Int J Environ Res Public Health. 2009; 6:787-797.

Patients Maintained on Methadone or Buprenorphine During Pregnancy Can Have Adequate Pain Control Postpartum

Empirical evidence is needed to guide adequate postpartum pain relief of methadone and buprenorphine stabilized patients. To that end, the objective of this study was to first determine the adequacy of pain control using non-opioid and opioid medication in participants stabilized on buprenorphine or methadone before a vaginal delivery. Secondly the study attempted to compare the amount of non-opioid and opioid medication needed for adequate pain control for buprenorphine- and methadone-maintained patients during the immediate postpartum period. Pain control adequacy and amount of non-opioid and opioid medication needed in buprenorphine- and methadone-maintained patients, over the first five days postpartum, were examined. Pain ratings and number of opioid medication doses decreased over time in both medication groups. While the buprenorphine and methadone groups began with similar mean daily ibuprofen (IB) doses, the buprenorphine group decreased its IB use, while the methadone group increased its IB use. Patients treated daily with either buprenorphine or methadone can have adequate pain control postpartum with opioid medication and IB. Pain control is dependent on the opioid-agonist medication in use at delivery, and must be individualized. Jones HE, O'Grady K, Dahne J, Johnson R, Lemoine L, Milio L, Ordean A, Selby P. Management of acute postpartum pain in patients maintained on methadone or buprenorphine during pregnancy. Am J Drug Alcohol Abuse. 2009; 35(3):151-156.

Variable Buprenorphine Excretion During Pregnancy May Indicate Metabolic Changes Requiring Dose Adjustment During Later Stages of Gestation

Buprenorphine (BUP) is under investigation as a medication therapy for opioid-dependent pregnant women. This study investigated BUP and metabolite disposition in urine from women maintained on BUP during the second and third trimesters of pregnancy and postpartum. Investigators measured BUP, norbuprenorphine (NBUP), buprenorphine glucuronide (BUP-Gluc), and NBUP-Gluc concentrations in 515 urine specimens collected thrice weekly from 9 women during pregnancy and postpartum. They examined ratios of metabolites across trimesters and postpartum to identify possible changes in metabolism during pregnancy. NBUP-Gluc was the primary metabolite identified in urine and exceeded BUP-Gluc concentrations in 99% of specimens. Whereas BUP-Gluc was identified in more specimens than NBUP, NBUP exceeded BUP-Gluc concentrations in 77.9% of specimens that contained both analytes. Among all participants, the mean BUP-Gluc:NBUP-Gluc ratio was significantly higher in the second trimester compared to the third trimester, and there were significant intrasubject differences between trimesters in 71% of participants. In 3 women, the percent daily dose excreted was higher during pregnancy than postpregnancy, consistent with other data indicating increased renal elimination of drugs during pregnancy. These data are the first to evaluate urinary disposition of BUP and metabolites in a cohort of pregnant women. Variable BUP excretion during pregnancy may indicate metabolic changes requiring dose adjustment during later stages of gestation. Kacinko SL, Jones HE, Johnson RE, Choo RE, Concheiro-Guisan M, Huestis MA. Urinary excretion of buprenorphine, norbuprenorphine, buprenorphine-glucuronide and norbuprenorphine-glucuronide in pregnant women receiving buprenorphine maintenance treatment. Clin Chem. 2009; Jun;55(6):1177-1187.

Passive Immunization with a Nicotine-Specific Monoclonal Antibody Decreases Brain Nicotine Levels But Does Not Precipitate Withdrawal in Nicotine-Dependent Rats

Vaccination against nicotine is under investigation as a treatment for tobacco dependence. Passive immunization with nicotine-specific antibodies represents a complementary strategy to vaccination. A potential adverse effect of passive immunization in nicotine-dependent individuals is that it may lead to a rapid reduction in brain nicotine levels and trigger withdrawal. The goal of this study was to determine if passive immunization with the nicotine-specific monoclonal antibody Nic311 precipitated withdrawal in nicotine-dependent rats as measured by increases in brain reward thresholds and somatic signs. Another cohort of rats was used to measure brain nicotine levels after Nic311 administration. Nic311 30, 80 or 240 mg/kg reduced brain nicotine concentrations by 45, 83 or 92% compared to controls. None of these Nic311 doses precipitated withdrawal measured at intervals up to 72 h following antibody administration. Administration of the nicotinic antagonist mecamylamine precipitated a robust nicotine withdrawal syndrome. Therefore, a substantial, but not complete, acute reduction in brain nicotine levels following passive immunization was not sufficient to precipitate nicotine withdrawal in nicotine-dependent rats. The Nic311 doses used have been shown to attenuate the behavioral effects of nicotine, suggesting that the use of passive immunization to treat nicotine addiction is not likely to precipitate withdrawal. Roiko SA, Harris AC, LeSage MG, Keyler DE, Pentel PR. Passive immunization with a nicotine-specific monoclonal antibody decreases brain nicotine levels but does not precipitate withdrawal in nicotine-dependent rats. Pharmacol Biochem Behav 2009 August;93(2):105-111.

Effect of Rapamycin on Cue-induced Drug Craving in Abstinent Heroin Addicts

The mammalian target of rapamycin is an evolutionarily conserved serine-threonine kinase (mTOR), which controls protein synthesis and catabolism in response to environmental cues. This randomized double-blind clinical trial enrolled 60 abstinent heroin addicts and randomly assigned them to three groups: placebo, 2.5 mg and 5 mg rapamycin. The participants were given the cue-reactivity paradigm with 5 min exposures to neutral and drug-related imagery while craving, anxiety, blood pressure and heart rate pre- and post-exposure were assessed. The investigators found that drug-related cues increased both craving and anxiety of abstinent heroin addicts, and had no effect on blood pressure and heart rate. A single high-dose of rapamycin significantly reduced the craving, but not anxiety induced by drug-related cues. These findings suggested that rapamycin merits outpatient clinical trials as a potential pharmacotherapy for relapse prevention from drug-related cue induced craving. Shi J, Jun W, Zhao LY et al. Effect of rapamycin on cue-induced drug craving in abstinent heroin addicts. Eur J Pharmacol 2009 August 1;615(1-3):108-112.

Do Stimulants Protect Against Psychiatric Disorders in Youth with ADHD? A 10-Year Follow-Up Study

Little is known about the effect of stimulant treatment in youth with attention-deficit/hyperactivity disorder (ADHD) on the subsequent development of comorbid psychiatric disorders. The investigators tested the association between stimulant treatment and the subsequent development of psychiatric comorbidity in a longitudinal sample of patients with ADHD. They conducted a case-control, 10-year prospective follow-up study into young-adult years of youth with ADHD. At baseline, the investigators assessed consecutively referred white male children with (n = 140) and without (n = 120) ADHD, aged 6 to 18 years. At the 10-year follow-up, 112 (80%) and 105 (88%) of the children in the ADHD and control groups, respectively, were reassessed (mean age: 22 years). The association between stimulant treatment in childhood and adolescence and subsequent comorbid disorders and grade retention by using proportional hazards survival models was examined. Of the 112 participants with ADHD, 82 (73%) were previously treated with stimulants. Participants with ADHD who were treated with stimulants were significantly less likely to subsequently develop depressive and anxiety disorders and disruptive behavior and less likely to repeat a grade compared with participants with ADHD who were not treated. The results suggest evidence that stimulant treatment decreases the risk for subsequent comorbid psychiatric disorders and academic failure in youth with ADHD. Biederman J, Monuteaux MC, Spencer T, Wilens TE, Faraone SV. Do stimulants protect against psychiatric disorders in youth with ADHD? A 10-year follow-up study. Pediatrics 2009 July;124(1):71-78.

Intermittent Marijuana Use is Associated with Improved Retention in Naltrexone Treatment for Opiate-Dependence

Naltrexone is a theoretically promising alternative to agonist substitution treatment for opioid dependence, but its effectiveness has been severely limited by poor adherence. This study examined, in an independent sample, a previously observed association between moderate cannabis use and improved retention in naltrexone treatment. Opioid dependent patients (N = 63), admitted for inpatient detoxification and induction onto oral naltrexone, and randomized into a six-month trial of intensive behavioral therapy (Behavioral Naltrexone Therapy) versus a control behavioral therapy (Compliance Enhancement), were classified into three levels of cannabis use during treatment based on biweekly urine toxicology: abstinent (0% cannabis positive urine samples); intermittent use (1% to 79% cannabis positive samples); and consistent use (80% or greater cannabis positive samples). Intermittent cannabis users showed superior retention in naltrexone treatment (median days retained = 133; mean=112.8, SE=17.5), compared to abstinent (median=35; mean=47.3, SE=9.2) or consistent users (median=35; mean=68.3, SE=14.1) (log rank=12.2, df=2, p=.002). The effect remained significant in a Cox model after adjustment for baseline level of heroin use and during treatment level of cocaine use. Intermittent cannabis use was also associated with greater adherence to naltrexone pill-taking. Treatment interacted with cannabis use level, such that intensive behavioral therapy appeared to moderate the adverse prognosis in the consistent cannabis use group. The association between moderate cannabis use and improved retention on naltrexone treatment was replicated. Experimental studies are needed to directly test the hypothesis that cannabinoid agonists exert a beneficial pharmacological effect on naltrexone maintenance and to understand the mechanism. Raby WN, Carpenter KM, Rothenberg J et al. Intermittent marijuana use is associated with improved retention in naltrexone treatment for opiate-dependence. Am J Addict 2009 July;18(4):301-308.

Nicotine Withdrawal and Craving in Adolescents: Effects of Sex and Hormonal Contraceptive Use

While sex differences in the nicotine withdrawal (NW) symptoms and craving (NC) have been extensively described in adult cigarette smokers, few studies have investigated these phenomena in adolescents. The investigators evaluated the effect of gender and hormonal contraception (HC) on NW and NC during the first 14 days of cessation in adolescent smokers using data from a randomized, placebo-controlled, double-blind trial of the transdermal nicotine replacement therapy for smoking cessation. Analyses showed similar levels of NW severity in males and females, regardless of HC use. However, significantly higher NC was observed in females compared to males, (2.22+/-0.12 vs. 1.65+/-1.14; p=0.003). Further, females not using HC reported the highest level of NC (2.38+/-0.16) followed by females using HC (2.08+/-0.25) and males (1.71+/-0.16; p=0.007). The current findings suggest that adolescent females experience similar NW severity to males, but have stronger NC. Further, the use of hormonal contraceptives may impact the severity of craving. Addressing these different symptoms in adolescents may be useful in increasing smoking cessation rates in this special population of smokers. Dickmann PJ, Mooney ME, Allen SS, Hanson K, Hatsukami DK. Nicotine withdrawal and craving in adolescents: effects of sex and hormonal contraceptive use. Addict Behav 2009 June;34(6-7):620-623.

The Effect of Cannabis Compared with Alcohol on Driving

The prevalence of both alcohol and cannabis use and the high morbidity associated with motor vehicle crashes has lead to a plethora of research on the link between the two. Drunk drivers are involved in 25% of motor vehicle fatalities, and many accidents involve drivers who test positive for cannabis. Cannabis and alcohol acutely impair several driving-related skills in a dose-related fashion, but the effects of cannabis vary more between individuals than they do with alcohol because of tolerance, differences in smoking technique, and different absorptions of Delta(9)-tetrahydrocannabinol (THC), the active ingredient in marijuana. Detrimental effects of cannabis use vary in a dose-related fashion, and are more pronounced with highly automatic driving functions than with more complex tasks that require conscious control, whereas alcohol produces an opposite pattern of impairment. Because of both this and an increased awareness that they are impaired, marijuana smokers tend to compensate effectively while driving by utilizing a variety of behavioral strategies. Combining marijuana with alcohol eliminates the ability to use such strategies effectively, however, and results in impairment even at doses which would be insignificant were they of either drug alone. Epidemiological studies have been inconclusive regarding whether cannabis use causes an increased risk of accidents; in contrast, unanimity exists that alcohol use increases crash risk. Furthermore, the risk from driving under the influence of both alcohol and cannabis is greater than the risk of driving under the influence of either alone. Future research should focus on resolving contradictions posed by previous studies, and patients who smoke cannabis should be counseled to wait several hours before driving, and avoid combining the two drugs. Sewell RA, Poling J, Sofuoglu M. The effect of cannabis compared with alcohol on driving. Am J Addict 2009 May;18(3):185-193.

Neurotransmission-Related Genetic Polymorphisms, Negative Affectivity Traits, and Gender Predict Tobacco Abstinence Symptoms Across 44 Days With and Without Nicotine Patch

Genetic and personality trait moderators of tobacco abstinence-symptom trajectories were assessed in a highly controlled study. Based on evidence suggesting their importance in stress reactivity and smoking, moderators studied were serotonin transporter gene (5-HTTLPR) and dopamine D2 receptor gene (DRD2) polymorphisms and personality traits related to negative affect (NA). Smokers were randomly assigned to quit smoking with nicotine or placebo patches. Financial incentives resulted in 80% verified abstinence across the 44-day study. Individuals with 1 or 2 short alleles of 5-HTTLPR (S carriers) experienced larger increases in NA symptoms than did those without a short allele. Nicotine replacement therapy (NRT) alleviated anxiety only in S carriers. NRT reduced NA to a greater extent in DRD2 A1 carriers than in A2A2 individuals during the 1st 2 weeks of treatment (when on the 21-mg patch); however, A1 carriers experienced a renewal of NA symptoms when switched to the 7-mg patch and when off the patch, while A2A2 individuals continued to benefit from NRT. The results suggest that the effects of genotype and treatment may vary across different durations of abstinence, treatment doses, and genotypes. Gilbert DG, Zuo Y, Rabinovich NE, Riise H, Needham R, Huggenvik JI. Neurotransmission-related genetic polymorphisms, negative affectivity traits, and gender predict tobacco abstinence symptoms across 44 days with and without nicotine patch. J Abnorm Psychol 2009 May;118(2):322-334.

Multi-Center Trial of Baclofen for Abstinence Initiation in Severe Cocaine-Dependent Individuals

Baclofen is a GABA(B) receptor agonist that in preclinical and early pilot clinical trials has shown promise for the treatment of cocaine dependence. The purpose of this multi-site, double-blind study, was to compare the safety and efficacy of baclofen (60 mg/day) vs placebo in an 8-week treatment of individuals with severe cocaine dependence. The primary outcome measure was subjects' self-reported cocaine use substantiated by urine benzoylecgonine (BE). Analysis of the data did not show a significant difference between the groups treated with baclofen and placebo. The current results do not support a role for 60 mg baclofen in treating cocaine dependence in the population studied. The contrast of this result to earlier, preclinical and human pilot data with baclofen may reflect the trial's focus on severe cocaine-dependent users, and/or the need for a higher baclofen dose. Baclofen's potential as a relapse prevention agent was not tested by the current design, but may be a useful target for future studies. Kahn R, Biswas K, Childress AR, Shoptaw S, Fudala PJ, Gorgon L, Montoya I, Collins J, McSherry F, Li SH, Chiang N, Alathari H, Watson D, Liberto J, Beresford T, Stock C, Wallace C, Gruber V, Elkashef A. Drug Alcohol Depend. 2009 Jul 1;103(1-2):59-64. E-pub 2009 May 2.


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