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Director's Report to the National Advisory Council on Drug Abuse - February, 2006

Research Findings - Research on Pharmacotherapies for Drug Abuse

Effects of the Novel Kappa Opioid Receptor Antagonist, JDTic, on Reinstatement and Antidepressant Measures in Rats

The selective kappa opioid receptor antagonist, JDTic, was evaluated in two behavioral models relevant to the development of medications for the prevention of relapse to cocaine abuse. Both stress and depression have been linked to relapse to cocaine abuse in humans, so compounds with anxiolytic and antidepressant effects in animal models may have utility as treatments. JDTic administered orally at doses of 3, 10, and 30 mg/kg was found to dose-dependently block the effects of a footshock stressor to reinstate previously extinguished cocaine self-administration in Long-Evans rats. In contrast, JDTic did not block the effects of a priming injection of cocaine on reinstatement, suggesting that JDTic did not simply interfere with lever-pressing or have sedative effects. In the forced-swim test, JDTic reduced immobility and increased swimming in rats placed in a cylinder of water, which are effects similar to those produced by marketed SSRI antidepressants. It should be noted that JDTic has a long duration of action and was administered at least 23 hours prior to both tests. Kappa opioid receptor antagonism was verified by measuring blockade of kappa opioid receptor agonist-induced diuresis immediately after reinstatement testing; this ensured that relevant pharmacological activity was present at the time of testing. Taken together, the results suggest that JDTic has both anti-stress and antidepressant behavioral activity, which appears to be attributable to long-acting kappa opioid receptor antagonism. These effects may be desirable in a cocaine-relapse prevention treatment medication, and this compound is a promising lead that warrants further evaluation for safety and efficacy. Beardsley P.M., Howard, J.L., Shelton, K.L., and Carroll, F.I. Psychopharmacology 183, pp. 118-126, 2005.

A Randomized Placebo-controlled Trial of Gabapentin for Cocaine Dependence

In laboratory animals, augmentation of GABA neurotransmission results in inhibition of cocaine self-administration and inhibition of reinstatement to cocaine-seeking behaviors. If parallel effects were observed in humans, GABA-ergic medication should be effective both in the abstinence-induction as well as in the relapse-prevention phase of cocaine dependence treatment. Gabapentin is an anticonvulsant medication that increases human brain GABA levels. The safety and efficacy of gabapentin combined with relapse-prevention therapy in the treatment of cocaine-dependent individuals was evaluated. The study involved 129 individuals with cocaine dependence. Of the 99 participants who were randomized into a double-blind trial, 88% were males, 66% were minorities and with an average age of 39 years (range 22-58 years). After 2 weeks of placebo lead-in, participants were randomized to receive either gabapentin 3200mg (1600mg bid) or placebo for 12 weeks, followed by 2 weeks of placebo lead-out. Prior to randomization, participants were stratified into four groups based on the principal route of cocaine use (smokers versus intranasal users) and the level of cocaine use during the 2 weeks of lead-in (high level versus low level). Throughout the 16 week study, participants received weekly individual relapse-prevention therapy. The outcome measures included: days of cocaine use and a binary indicator of abstinence based on urine toxicology test, self-reported cocaine craving and retention in treatment. Forty-nine percent of randomized patients completed 12 weeks of the trial. Retention did not differ by treatment group but cocaine-smokers dropped out of treatment at a significantly faster rate than intranasal users. For the entire sample, odds of cocaine use over the course of the study did not differ between gabapentin- and placebo-treated individuals. There was a significant difference in the odds of cocaine use between high and low-use groups, with the odds in high-use groups decreasing over time and odds in the low-use groups gradually increasing over the course of the study, such that by the end of the study low and high users were similarly likely to use cocaine. In the low-use group, there was a non-significant trend suggesting that gabapentin-treated subjects had more favorable outcome compared to placebo-treated individuals. There was no treatment effect on abstinence rates, craving or other substance use. Gabapentin at 3200mg/day was very well tolerated in this group of cocaine-dependent participants. When combined with weekly individual relapse-prevention therapy, gabapentin 1600mg bid was no more effective than placebo in the treatment of cocaine dependence. When reviewed in conjunction with other published studies, gabapentin and other GABA enhancing anticonvulsant medications may deserve further study as relapse-preventive agents in cocaine-dependent individuals who achieve abstinence early in treatment. Bisaga, A., Aharonovich, E., Garawi, F., Levin, F. R., Rubin, E., Raby, W. N. et al. Drug Alcohol Depend.,E- publication, 2005; A multisite double blind placebo controlled trial of 140 cocaine dependent patients was recently completed (data presented at CPDD 2005 by Eugene Somoza in a symposium entitled "Pharmacotherpy for Cocaine Addiction: An Update From NIDA/DPMC" which showed no effect for gabapentin over placebo in reducing cocaine use.

Anesthesia-Assisted vs Buprenorphine- or Clonidine-assisted Heroin Detoxification and Naltrexone Induction: A Randomized Trial

Rapid opioid detoxification with opioid antagonist induction using general anesthesia has emerged as an expensive, potentially dangerous, unproven approach to treat opioid dependence. To determine how anesthesia-assisted detoxification with rapid antagonist induction for heroin dependence compared with 2 alternative detoxification and antagonist induction methods. A total of 106 treatment-seeking heroin-dependent patients, aged 21 through 50 years, were randomly assigned to 1 of 3 inpatient withdrawal treatments over 72 hours followed by 12 weeks of outpatient naltrexone maintenance with relapse prevention psychotherapy. This randomized trial was conducted between 2000 and 2003 at Columbia University Medical Center's Clinical Research Center. Outpatient treatment occurred at the Columbia University research service for substance use disorders. Patients were included if they had an American Society of Anesthesiologists physical status of I or II, were without major comorbid psychiatric illness, and were not dependent on other drugs or alcohol. Anesthesia-assisted rapid opioid detoxification with naltrexone induction, buprenorphine-assisted rapid opioid detoxification with naltrexone induction, and clonidine-assisted opioid detoxification with delayed naltrexone induction. Withdrawal severity scores on objective and subjective scales; proportions of patients receiving naltrexone, completing inpatient detoxification, and retained in treatment; proportion of opioid-positive urine specimens. Mean withdrawal severities were comparable across the 3 treatments. Compared with clonidine-assisted detoxification, the anesthesia- and buprenorphine-assisted detoxification interventions had significantly greater rates of naltrexone induction (94% anesthesia, 97% buprenorphine, and 21% clonidine), but the groups did not differ in rates of completion of inpatient detoxification. Treatment retention over 12 weeks was not significantly different among groups with 7 of 35 (20%) retained in the anesthesia-assisted group, 9 of 37 (24%) in the buprenorphine-assisted group, and 3 of 34 (9%) in the clonidine-assisted group. Induction with 50 mg of naltrexone significantly reduced the risk of dropping out (odds ratio, 0.28; 95% confidence interval, 0.15-0.51). There were no significant group differences in proportions of opioid-positive urine specimens. The anesthesia procedure was associated with 3 potentially life-threatening adverse events. These data do not support the use of general anesthesia for heroin detoxification and rapid opioid antagonist induction. Collins, E. D., Kleber, H.D., Whittington, R.A. and Heitler, N.E. JAMA, 294, pp. 903-913, 2005.

Response to Cocaine, Alone and in Combination with Methylphenidate, in Cocaine Abusers With ADHD

Attention deficit hyperactivity disorder (ADHD) is prevalent in adult cocaine abusers. Yet, it remains to be determined how the response to cocaine differs in cocaine abusers with ADHD compared to cocaine abusers without ADHD. Further, since ADHD is commonly treated with stimulants, such as methylphenidate (MPH), it is important to examine whether MPH maintenance alters the response to cocaine in cocaine abusers with ADHD. Thus, the first phase of this study compared the response to cocaine in adult cocaine abusers with ADHD to those without ADHD. The second phase assessed the effects of oral sustained-release methylphenidate (MPH-SR) maintenance (40 and 60mg) on the response to cocaine only in those with ADHD. Cocaine abusers with ADHD (N=7) and without ADHD (N=7) who were not seeking treatment remained inpatient initially for 1 week, when the effects of cocaine alone were tested (Phase 1). Cocaine abusers with ADHD remained inpatient for an additional 3 weeks, during which the effects of cocaine during oral MPH-SR maintenance were tested (Phase 2). During cocaine fixed dosing sessions, participants received four injections of i.v. cocaine (0, 16 or 48mg/70kg), spaced 14min apart. During cocaine choice sessions, participants had a choice between receiving i.v. cocaine (16 or 48mg/70kg) or two tokens, each exchangeable for US $2. Subjective effects related to ADHD symptoms (e.g. ratings of "Able to Concentrate") were significantly lower in cocaine abusers with ADHD compared to those without ADHD when placebo cocaine was administered. Active cocaine produced similar increases in cardiovascular and positive subjective effects in both groups and there was no difference in cocaine choice between the two groups. These data suggest that the response to cocaine is not different between cocaine abusers with ADHD compared to those without ADHD. When the cocaine abusers with ADHD were maintained on MPH-SR, cardiovascular effects were increased, however, this did not warrant termination of any test session. Maintenance on MPH-SR decreased some of the positive subjective effects of cocaine. Further, maintenance on a high dose of MPH-SR decreased cocaine choice. Thus, oral MPH-SR is safe in combination with repeated cocaine doses and decreases some of the positive and reinforcing effects of cocaine in cocaine abusers with ADHD. Collins, S.L., Levin, F.R., Foltin, R.W., Kleber, H.D. and Evans, S.M. Drug Alcohol Depend. (e-publication ahead of print) October 2005.

Buprenorphine Versus Methadone in the Treatment of Pregnant Opioid-dependent Patients: Effects on the Neonatal Abstinence Syndrome

Buprenorphine may be shown to be an alternate medication to methadone in pregnant women. The purpose of this study was to compare the neonatal abstinence syndrome (NAS) in neonates of methadone and buprenorphine maintained pregnant opioid-dependent women and provide preliminary safety and efficacy data for a larger multi-center trial. In this randomized, double-blind, double-dummy, flexible dosing, parallel-group controlled trial, treatment involved daily administration of either sublingual buprenorphine or oral methadone using flexible dosing of 4-24 mg or 20-100 mg, respectively, Primary outcome measures were number of neonates treated for NAS; amount of opioid agonist medication used to treat NAS; length of neonatal hospitalization; and peak NAS score. Two of 10 buprenorphine-exposed and 5 of 11 methadone-exposed neonates were treated for NAS. Total amount of opioid-agonist medication administered to treat NAS in methadone-exposed neonates was three times greater than for buprenorphine-exposed neonates. Length of hospitalization was shorter for buprenorphine-exposed than for methadone-exposed neonates. Peak NAS total scores did not significantly differ between groups. Results suggest that buprenorphine is not inferior to methadone on outcome measures assessing NAS and maternal and neonatal safety when administered starting in the second trimester of pregnancy. Jones, H.E., Johnson, R.E., Jasinski, D.R., O'Grady, K.E., Chisholm, C.A., Choo, R.E., Crocetti, M., Dudas, R., Harrow, C., Huestis, M.A., Jansson, L.M., Lantz, M., Lester, B.M. and Milio, L. Drug Alcohol Depend. 79(1), pp. 1-10, July 2005.

Fetal Response to Maternal Methadone Administration

This study investigated the effect of methadone on fetal neurobehavioral functions and maternal physiologic indicators. Forty women were evaluated at peak and trough methadone levels. At peak methadone, fetal heart rate was slower, less variable, and displayed fewer accelerations. Fetuses displayed less motor activity and the integration between heart rate and motor activity was attenuated. Maternal heart rate and skin conductance were unchanged, but methadone administration was associated with lower respiratory rate. The conclusions were that maternal methadone administration has significant effects on fetal behavioral functions that are independent of maternal effects. Jansson, L.M., DiPietro, J. and Elko, A. Am. J. Obstetrics and Gynecology 193(3) pp. 611-617, September 2005.

Males and Females Differ in Response to Opioid Agonist Medications

Few clinical trials include sex as a factor. This analysis explored within-sex differences in response to opioid agonist medications. Males and females randomly assigned to buprenorphine, LAAM, or methadone were compared on opioid use and retention in treatment. Females receiving buprenorphine had less objective drug use than females receiving methadone, while males receiving LAAM had less objective drug use than males receiving buprenorphine. Retention in treatment was longer for both sexes receiving methadone versus LAAM. Within-subject change results indicate that all three medications benefit both sexes. Clinical trials should be designed to examine the impact of sex on outcomes. Jones, H.E., Fitzgerald, H.and Johnson, R.E. Am. J. Addict. 14(3) pp. 223-233, May-June 2005.

Isradipine Decreases the Hemodynamic Response of Cocaine and Methamphetamine: Results From Two Human Laboratory Studies

Massive hypertensive crises relating to cerebrovascular accidents such as strokes or ruptured aneurysms, or cardiovascular dysfunction and toxicity, are an important cause of morbidity and mortality associated with cocaine or methamphetamine use. Experimentally administered, pharmacologically effective doses of cocaine and methamphetamine may serve as a model for studying the effects of these drugs on hemodynamic response and for examining the potential utility of the antihypertensive and dihydropyridine-class calcium channel antagonist isradipine to block these effects. This group examined, in two separate experiments of similar design conducted contemporaneously, the hemodynamic effects of cocaine or methamphetamine in the presence and absence of isradipine. In both experiments (total N = 31), isradipine pretreatment was provided to cocaine- or methamphetamine-dependent male and female subjects before intravenous administration of low and high doses of cocaine (0.325 or 0.650 mg/kg) or methamphetamine (15 or 30 mg), respectively, on separate test days. The results showed that both cocaine and methamphetamine administration produced predicted elevations in blood pressure (with peak response between 1 and 3 min after infusion). Apart from tachycardia, no arrhythmias were reported. Isradipine significantly reduced stimulant-associated increases in all measures of blood pressure except pulse pressure, but tended to enhance the effects of these drugs on heart rate. The conclusions were that clinical studies are needed to determine whether isradipine is therapeutically efficacious in preventing hypertensive crises and the associated cerebrovascular and cardiovascular sequelae in cocaine- or methamphetamine-dependent individuals. As there is no established pharmacotherapy for treating cocaine or methamphetamine dependence, identification of a medication that reduces the harmful medical consequences of these drugs would be scientifically and clinically important. Johnson, B.A., Wells, L.T., Roache, J.D., Wallace, C., Ait-Daoud, N. and Wang, Y. Am. J. Hypertens. 18(6), pp. 813-822, June 2005.

Comparison of Pharmacological Treatments for Opioid-dependent Adolescents: A Randomized Controlled Trial

The prevalence of heroin and other opioid use has markedly increased among adolescents in the last decade; however, virtually no research has been conducted to identify effective treatments for this population. The objective of this study was to evaluate the relative efficacy of two pharmacotherapies, buprenorphine hydrochloride and clonidine hydrochloride, in the detoxification of opioid-dependent adolescents. A double-blind, double-dummy, parallel-groups randomized controlled trial was conducted in a university-based research clinic from October 2001 to December 2003. Patients were a volunteer sample of 36 adolescents who met DSM-IV criteria for opioid dependence (ages 13-18 years eligible). Participants were randomly assigned to a 28-day, outpatient, medication-assisted withdrawal treatment with either buprenorphine or clonidine. Both medications were provided along with thrice weekly behavioral counseling and incentives contingent on opiate abstinence. Postdetoxification, all participants were offered the opportunity for continued treatment with the opiate antagonist, naltrexone hydrochloride. The main outcome measures were treatment retention, opiate abstinence, and human immunodeficiency virus risk behavior, along with measures of withdrawal and medication effects. The results of the study showed that a significantly greater percentage of adolescents who received buprenorphine were retained in treatment (72%) relative to those who received clonidine (39%) (P<.05). For those in the buprenorphine group, a significantly higher percentage of scheduled urine test results were opiate negative (64% vs 32%; P = .01). Participants in both groups reported relief of withdrawal symptoms and drug-related human immunodeficiency virus risk behavior. Those in the buprenorphine condition generally reported more positive effects of the medication. No evidence of opioid intoxication or psychomotor impairment was observed. Sixty-one percent of participants in the buprenorphine condition and 5% of those in the clonidine group initiated treatment with naltrexone. This study suggests that combining buprenorphine with behavioral interventions is significantly more efficacious in the treatment of opioid-dependent adolescents relative to combining clonidine and behavioral interventions. Marsch, L.A., Bickel, W.K., Badger, G.J., Stothart, M.E., Quesnel, K.J., Stanger, C. and Brooklyn, J. Arch. Gen. Psychiatry, 62(10), pp. 1157-1164, October 2005.

Gender Effects Following Repeated Administration of Cocaine and Alcohol in Humans

Use of cocaine, alcohol, and the two drugs simultaneously is common and the risk of morbidity and mortality associated with these drugs is widely reported. This group carried out a double-blind, placebo-controlled, randomized study examining gender differences in response to administration of these drugs alone and in combination. Current users of cocaine and alcohol (n = 17) who met diagnostic criteria (DSM-IV) for cocaine dependence and alcohol abuse or dependence (not physiologically dependent on alcohol) and who were not seeking treatment for substance use disorders gave voluntary, written, informed consent to participate in three drug administration sessions:1) four doses of intranasal cocaine (1 mg/kg every 30 min) with oral alcohol (1 g/kg following the initial cocaine dose and a second drink at +60 min (120 mg/kg) calculated to maintain a plasma alcohol concentration of approximately 100 mg/dL; 2)four doses of cocaine and alcohol placebo; 3) cocaine placebo and alcohol. Pharmacokinetics were obtained by serial blood sampling, physiological measurements (heart rate and blood pressure) were obtained with automated equipment, and subjective effects were assessed using visual analog scales over 480 min. The results showed that responses to cocaine, alcohol, and cocaine-alcohol were equivalent by gender for most measurements. Women had higher heart rates following alcohol administration (p = .02). Women consistently reported higher ratings for "Feel Good", a measure of overall mental/physical well-being, for all study conditions, reaching statistical significance for cocaine (p = .05) and approaching significance for alcohol administration (p = .1). Women showed equivalent responses to drug administration with the exception of perception of well-being, which was significantly increased for women. These findings may have implications for differential risk for acute and chronic toxicity in women. McCance-Katz, E.F., Hart, C.L., Boyarsky, B., Kosten, T. and Jatlow, P. Subst. Use Misuse 40(4), pp. 511-528, 2005.

Safety and Immunogenicity of a Nicotine Conjugate Vaccine in Current Smokers

Immunotherapy is a novel potential treatment for nicotine addiction. The aim of this study was to assess the safety and immunogenicity of a nicotine conjugate vaccine, NicVAX, and its effects on smoking behavior. Smokers (n = 68) were recruited for a noncessation treatment study and assigned to 1 of 3 doses of the nicotine vaccine (50, 100, or 200 microg) or placebo. They were injected on days 0, 28, 56, and 182 and monitored for a period of 38 weeks. Results showed that the nicotine vaccine was safe and well tolerated. Vaccine immunogenicity was dose-related (P < .001), with the highest dose eliciting antibody concentrations within the anticipated range of efficacy. There was no evidence of compensatory smoking or precipitation of nicotine withdrawal with the nicotine vaccine. The 30-day abstinence rate was significantly different across the 4 doses (P = .02), with the highest rate of abstinence occurring in the 200 microgram group. The nicotine vaccine appears to be a promising medication for tobacco dependence. Hatsukami, D.K., Rennard, S., Jorenby, D., Fiore, M., Koopmeiners, J., de Vos, A. et al. Clin.Pharmacol.Ther., 78, pp. 456-467, 2005.

Effects of Cigarette Reduction on Cardiovascular Risk Factors and Subjective Measures

This study, conducted at the University of Minnesota, randomized smokers interested in significantly reducing cigarette use but not quitting to either start 12 weeks of smoking reduction immediately (n = 102), assisted by nicotine replacement therapy, or to a 6-week wait list (n = 49). Those starting smoking reduction were required to reduce smoking by 25% for 2 weeks, 50% for 2 weeks, and 75% during the final 2 weeks. After 6 weeks, the subjects were asked to maintain a 50% reduction or quit. Nicotine gum and, if necessary, nicotine patch were used to achieve reduction goals. The wait list group (n = 49) smoked ad libitum for 6 weeks and then reduced smoking as previously described. Cardiovascular biomarkers (eg, WBC count, cholesterol concentrations, BP, heart rate) were assessed at several time points after enrollment. During ad libitum smoking, cardiovascular biomarkers remained relatively stable with correlation coefficients across the various time measurements, ranging from 0.44 to 1.00 (p < 0.01 for all measures). Among successful nonabstinent reducers (64 of 151 subjects), significant improvements were found in many biomarkers (eg, hemoglobin, hematocrit, RBC and WBC counts, lipids, BP, heart rate, respiratory symptoms, all p < 0.0167). These results show the availability of reliable and dose-sensitive biomarkers and that reduction in smoking can lead to significant but only modest changes in cardiovascular risk factors in healthy smokers. It is not known whether the reductions in cardiovascular risk factors observed after smoking reduction are also associated with reduced disease risk. Additional research is necessary to address this issue. Hatsukami, D.K., Kotlyar, M., Allen, S., Jensen, J., Li, S., Le, C. et al. Chest, 128, pp. 2528-2537, 2005.

Treatment of Methadone-maintained Patients With Adult ADHD: Double-blind Comparison of Methylphenidate, Bupropion and Placebo

The purpose of this double-blind, three-arm, 12-week trial was to compare the efficacy of sustained-release methylphenidate or sustained-release bupropion to placebo in treating adult attention deficit hyperactivity disorder (ADHD) symptoms. The randomized sample consisted of 98 methadone-maintained patients who were predominately male (57%) and 40% Caucasian, 40% Hispanic and 20% African American. All participants met DSM-IV criteria for adult ADHD, with 53% meeting DSM-IV criteria for cocaine dependence/abuse. In addition to medication and treatment as usual at a methadone program, individuals received weekly individual cognitive behavioral treatment. Other than current employment status, there were no significant demographic differences across the three treatment groups. Seventy percent completed the 12-week trial. There were no differences in retention rate based on treatment group. A reduction in ADHD symptoms using the adult ADHD rating scale was observed in all three groups, but there were no significant differences in outcome between treatments. The placebo response rate was high, with 46% of the placebo group self-reporting substantial improvement in their ADHD symptoms (>30% reduction in adult ADHD rating scale). Using other ADHD outcome measures, the placebo response and medication response rates were substantially lower. There was no evidence of misuse of medication or worsening of cocaine use among those randomized to methylphenidate. Taken together, sustained-release methylphenidate or sustained-release bupropion did not provide a clear advantage over placebo in reducing ADHD symptoms or additional cocaine use in methadone-maintained patients. Levin, F.R., Evans, S.M., Brooks, D.J., Kalbag, A.S., Garawi, F. and Nunes, E.V. Drug Alcohol Depend (E-publication ahead of print) 2005.

What Came First, Major Depression or Substance Use Disorder? Clinical Characteristics and Substance Use Comparing Teens in a Treatment Cohort

This study utilized data on a treatment cohort from a randomized clinical trial that recruited adolescents with co-occurring major depression and substance use disorder (N=126). The purpose of this study was to compare adolescents for whom the onset of depression was first versus those for whom the onset of substance use disorder was first or in the same year as depression. Intake clinical evaluations were abstracted to yield common stressors that included childhood abuse, early loss or death, exposure to violence, and attachment problems. Tobacco, alcohol, and cannabis initiation and dependence were compared for the depression first and substance use disorder first groups, and within those groups by gender. Among the substances studied, only cannabis dependence was significantly more prevalent among those with depression first. Comparisons suggest some differences in the developmental path toward comorbid depression and substance use disorders, but remarkable similarity in measures of dependence and severity. Although small samples limited statistical significance, observed differences suggest possible avenues for prevention or intervention. Libby, A M., Orton, H.D., Stover, S.K. and Riggs, P.D. Addict Behav, 30, pp. 1649-1662, 2005.

Smoking Policies in U.S. Outpatient Drug Treatment Facilities

Most drug treatment patients smoke cigarettes, and some facilities are beginning to help patients quit. Facility smoking policies can help or hinder this effort. The present study describes smoking policies in outpatient drug treatment. It is a secondary analysis of a survey on smoking cessation treatment in outpatient methadone maintenance facilities in the United States. One clinic leader (a medical director, head nurse, or clinic director) from each of the 697 U.S. facilities was invited to participate in the study. Main outcome measures included whether clinics had a written smoking policy as well as the types of indoor and outdoor policies in place for patients and staff. A total of 408 (59%) of U.S. clinics responded. Most clinics (73%) had a written smoking policy for patients, and more (82%) had written policies for staff. Over 90% banned indoor smoking by staff and patients. Few totally banned outdoor smoking. Approximately half in some way restricted where patients (48%) and staff (55%) smoke outdoors. Compared with clinics that did not treat nicotine dependence, significantly more clinics that treated nicotine dependence had written policies on smoking and restricted outdoor smoking for patients and staff. Likewise, many public clinics and those affiliated with hospitals had outdoor smoking restrictions for patients and staff. Drug treatment facilities routinely ban alcohol use and drug dealing on their grounds. Only 1 in 10 ban smoking. Outpatient facilities should restrict or ban outdoor tobacco use in order to remain consistent with their mission and avoid sabotaging clinic efforts to treat, and patient and staff efforts to stop, smoking. Richter, K.P., Choi, W.S. and Alford, D.P. Nicotine Tob Res, 7, pp. 475-480, 2005.

Cigarette Smoking Among Marijuana Users in the United States

The vast majority of drug users smoke cigarettes. Most use marijuana and no other illicit drug. Adult responses to the 1997 NHSDA (n = 16,661) were analyzed to explore relationships between marijuana use and cigarette smoking. Multivariate analyses controlled for other illicit drug use and other potential covariates. Nearly three-quarters of current marijuana users (74%) smoked cigarettes. Compared to nonusers, the adjusted odds of being a smoker were 5.43 for current marijuana users, 3.58 for past year marijuana users, and 2.02 for former marijuana users. Odds for cigarette smoking among current poly-drug users, compared to nonusers, were 2.3 to 1. Level of cigarette smoking was directly associated with frequency of marijuana use. Nationwide, an estimated 7 million adults smoke both substances and are at increased risk for respiratory illnesses and mortality. Cigarette smoking is a major co-morbidity of marijuana use and smoking cessation should be addressed among marijuana users in addition to their other illicit drug involvement. Richter, K. P., Kaur, H., Resnicow, K., Nazir, N., Mosier, M. C. and Ahluwalia, J.S. Subst Abuse, 25, pp. 35-43, 2005.

Effects of Tiagabine in Combination With Intravenous Nicotine in Overnight Abstinent Smokers

Preclinical studies suggest that medications enhancing the brain gamma amino butyric acid (GABA) system attenuate the rewarding effects of stimulants including nicotine. These preclinical studies have not been followed up in systematic human studies. This study was conducted to examine the effects of a GABAergic medication, tiagabine, on acute physiological and subjective effects of intravenous (i.v.) nicotine and on tobacco withdrawal symptoms in overnight abstinent smokers. The proposed mechanism of action for tiagabine is selective inhibition of GABA transporter type I, which leads to increases in synaptic GABA levels. Eight male and four female smokers participated in a double-blind, placebo-controlled, crossover study. In each of three experimental sessions, participants were treated orally with a single 4- or 8-mg dose of tiagabine or placebo. Two hours following the medication treatment, participants received i.v. saline, followed 30 min later by 1.5 mg/70 kg i.v. nicotine. Tiagabine treatment did not affect the heart rate or blood pressure changes induced by nicotine. There was a significant treatment effect for the subjective responses to nicotine, such that tiagabine, compared to placebo, attenuated the ratings of "good effects" and "drug liking." Tiagabine treatment at 8 mg attenuated the craving for cigarettes and enhanced the cognitive performance in the Classical Stroop Tests, compared to placebo or 4 mg tiagabine condition. These results suggest that the GABA enhancing medication tiagabine may reduce the rewarding effects of nicotine and improve cognitive performance in abstinent smokers. The utility of GABA medications for smoking cessation needs to be examined further in controlled clinical trials. Sofuoglu, M., Mouratidis, M., Yoo, S., Culligan, K. and Kosten, T. Psychopharmacology (Berl), 181, pp. 504-510, 2005.

Tiagabine Affects the Subjective Responses to Cocaine in Humans

In preclinical studies, medications which increase the synaptic GABA levels have been shown to block cocaine reinforcement. In this study, the interaction between a GABA enhancing medication, tiagabine, and cocaine in cocaine users was examined. A total of 7 subjects, 5 male and 2 female cocaine users had 2 experimental sessions. Before each session, subjects received either two oral doses of 4 mg of tiagabine or placebo. Starting 2 h after the second dose of medication treatment, subjects received an injection of saline followed by 2 escalating cocaine doses (0.15 and 0.3 mg/kg) intravenously. Tiagabine treatment did not affect the cocaine-induced blood pressure and heart rate changes but attenuated the subjective ratings of "stimulated" and "crave cocaine" in response to cocaine administration. These results suggest that tiagabine treatment attenuates some of the subjective effects of cocaine without affecting its cardiovascular effects. GABA medications, including tiagabine, are currently being evaluated in controlled clinical trials for the treatment of cocaine dependence. Sofuoglu, M., Poling, J., Mitchell, E. and Kosten, T. R. Pharmacol. Biochem. Behav., (e-publication ahead of print) December 2005.

Applicability of the Fagerstrom Test for Nicotine Dependence in Smokers With Schizophrenia

Up to 90% of individuals with schizophrenia smoke cigarettes, and many show signs of heavy dependence. Although the severity of nicotine dependence is often measured by the six-item Fagerstrom Test for Nicotine Dependence (FTND), this measure, in its current form, may not be as appropriate in this population--or in others whose smoking is regulated by others--as in the general population due to differences in smoking patterns, living arrangements, and daily routines. These factors may produce an underestimate of nicotine dependence, which may have clinical implications for successful medical detoxification if the FTND scores are used to guide the dosage of nicotine replacement medication. Data indicate poor internal consistency reliability (alpha=.4581) and a factor pattern lacking simple structure (i.e., two nonmeaningful factors/components with substantial cross loadings) when administered to smokers with schizophrenia. Specific examples of problematic items and how these may contribute to an underestimate of tobacco dependence severity are discussed, as well as ways to modify the FTND to be more appropriate for this population. Steinberg, M.L., Williams, J.M., Steinberg, H.R., Krejci, J.A. and Ziedonis, D.M. Addict.Behav., 30, pp. 49-59, 2005.


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