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Director's Report to the National Advisory Council on Drug Abuse - May, 2003

Research Findings - Treatment Research and Development

Brief Interventions for Smoking Cessation in Alcoholic Smokers

Dr. Rohsenow and colleagues conducted a 2 X 2 randomized controlled trial with alcoholic smokers comparing Motivational Interviewing (MI) to Brief Advice (BA). Treatments were provided in a single session or with two booster sessions 1 week and 4 weeks after the first session. The MI session was approximately 50 minutes and included personalized feedback and setting stage-specific goals. BA was approximately 10 minutes and involved direct brief advice to quit smoking along with assistance in obtaining needed information or help. All participants were given free access to NRT on request. Preliminary results show that more patients were abstinent at 1 month in BA (35%) than in MI (13%) with a trend for more abstinence at 6 months (13% vs. 2%). Neither treatment type affected alcohol or drug use outcomes. BA takes approximately one eighth of the time that MI does yet is significantly more effective in motivating smoking cessation. Providing booster sessions of either treatment results in better long-term quit rates. Rohsenow, D.J., Monti, P.M., Colby, S.M., and Martin, R.A. Alcoholism: Clinical and Experimental Research, 26(12), pp. 1950-1951, December 2002.

Depressive Symptoms and Readiness to Quit Smoking Among Cigarette Smokers in Outpatient Alcohol Treatment

Researchers at Brown Medical School examined whether length of alcohol abstinence and depressive symptoms were related to motivational readiness to consider smoking cessation among patients in alcohol treatment. Participants were adults (N= 253) enrolled in a smoking cessation trial. A significant interaction of days since last drink and depressive symptoms was found. Results showed that a greater number of days since last drink was associated with greater readiness, but only among patients with a low depression score. The findings suggest that alcoholic smokers with low depressive symptoms are more receptive to quitting after sustained alcohol abstinence. Hitsman, B., Abrams, D.B., Shadel, W.G., Niaura, R., Borrelli, B., Emmons, K.M., Brown, R.A., Swift, R.M., Monti, P.M., Tohsenow, D.J., Colby, S.M. Psychology of Addictive Behaviors, 16(3), pp. 264-268, 2002.

Computer and Manual Self-Help Behavioral Strategies for Smoking Reduction: Initial Feasibility and One-Year Follow-Up

Researchers examined the feasibility of two self-help behavioral interventions to reduce and maintain a 50% reduction in smoking among those unable or unwilling to quit, and to evaluate the impact of smoking reduction on subsequent quit attempts. Ninety-three smokers who desired to reduce rather than quit smoking were randomly assigned to either computerized scheduled gradual reduction (CSGR) or to a manual-based selective elimination reduction (SER). Both groups produced significant reductions in smoking (approximately 10 cigarettes per day, during the 7-week treatment phase), which were maintained over one year. The CSGR group reported greater mean percent reductions in smoking from pre- to post-treatment (37% for CSGR, 20% for SER) and a greater percentage of subjects meeting the 50% reduction goal (30% for CSGR, 16% for SER) compared to the SER group. The results of this study lend support to the feasibility of self-help behavioral interventions to produce sustained reductions in smoking rates without apparent negative impact on subsequent quit attempts. Riley, W., Jerome, A., Behar, A., and Weil, J. Nicotine & Tobacco Research, Supplement 2, pp. S183-S188, 2002.

A History of Depression and Smoking Cessation Outcomes Among Women Concerned About Post-Cessation Weight Gain

Drs. Levine, Marcus, and Perkins at the University of Pittsburgh School of Medicine sought to document the prevalence of depression history among weight-concerned women smokers, and evaluate its effect on treatment outcome. They also evaluated the impact of baseline depressive symptoms and cessation-related changes in symptoms. Two hundred and nineteen women were classified as depression history positive (MDD+; 52%) or negative (MDD-) and received a group-based smoking cessation treatment. Findings showed that although MDD+ women were significantly more nicotine dependent, rates of continuous abstinence did not differ between MDD+ and MDD- women. However, MDD+ women were more likely to drop out of treatment prior to quitting. Irrespective of depression history, depressive symptoms were associated with abstinence. Women who reported an increase in depressive symptoms from pre- to post treatment were significantly less likely to be abstinent post treatment, suggesting that depressive symptoms are more predictive of outcome than previous disorder. Levine, M.D., Marcus, M.D., and Perkins, K.A. Nicotine & Tobacco Research, 5(1), pp. 69-76, 2003.

African Americans and Caucasians Have Need for Different Services Ancillary to Treatment

Nancy Petry and colleagues at the University of Connecticut Health Center found several important differences between a cohort of non-Hispanic Caucasians and African Americans seeking outpatient treatment for cocaine problems on the Addiction Severity Index. African Americans had similar years of education but lower incomes than Caucasians. Caucasians were a few years older. Although the groups began first use of drugs and regular use at similar ages (21 and 27 years respectively) Caucasians were more likely to use injection drugs and African Americans were more likely to present with a drug positive urine at intake. In terms of drug related problems, African Americans were more likely to have employment problems but less likely to have family, psychiatric, legal or alcohol problems. These findings suggest the two groups might benefit from tailored treatment approaches to address these needs. For example, African Americans might benefit from treatments with employment as a focus. Petry, N.M. A Comparison of African American and Non-Hispanic Caucasian Cocaine-Abusing Outpatients. Drug and Alcohol Dependence, 69(1), pp. 43-49, 2003.

Drug Avoidance Activities Predict Treatment Outcome

Richard Rawson and colleagues at UCLA Integrated Substance Abuse Programs examined the post-treatment behavior of drug abusers who received either Cognitive Behavioral Therapy (CBT) or Voucher Based reinforcement for clean urines, i.e., Contingency Management (CM) and found that regardless of treatment condition assignment, individuals who reported engaging in Drug Avoidance Activities (DDAs) most frequently had higher levels of abstinence at treatment end and 12 months after treatment. Those exposed to CBT reported engaging in a larger number of DAAs and doing DDAs more frequently. This suggests the importance of engaging frequently in a range of strategies to avoid drugs rather than relying on a single strategy. This study lends support to the idea that one mechanism of action of CBT may be increasing use of coping skills. Farabee, D. Rawson, R. and McCann, M.A. Adoption of Drug Avoidance Activities Among Patients in Contingency Management and Cognitive-behavioral Treatments. Journal of Substance Abuse Treatment, 23(4), pp. 343-350, 2002.

Pregnant Homeless Women More Challenged Upon Treatment Entry

Hendree Jones and colleagues at Johns Hopkins University School of Medicine found a number of important differences when they compared housed and homeless pregnant women at substance abuse treatment entry. Homeless pregnant women reported spending more money on cocaine and alcohol than pregnant women with permanent residences. They experienced three times the number of medical problems, and received only 65% of the social service income of the housed group. Significantly greater rates of psychopathology were observed including greater lifetime rates of anxiety and depression, histories of suicidal thoughts and attempts, and higher lifetime incidence of emotional, physical, and sexual abuse. Homeless pregnant women also left treatment at greater rates. Results suggest treatment programs may need special interventions to treat and engage homeless pregnant women. Tuten, M., Jones, H.E., and Svikis, D.S. Comparing Homeless and Domiciled Pregnant Substance Dependent Women on Psychosocial Characteristics and Treatment Outcomes. Drug and Alcohol Dependence, 69(1), pp. 95-99, 2003.

Concurrent Treatment for Alcohol and Tobacco Dependence: Are Patients Ready to Quit Both?

Drs. Stotts, Schmitz, and Grabowski, at the University of Texas, Houston, examined mechanisms involved in changing both alcohol and tobacco use concurrently using the trans-theoretical model measures of change. One hundred and fifteen alcohol and tobacco dependent outpatients entering a dual- substance dependence program were compared on baseline measures of motivation, self-initiated change activities, and self-efficacy associated with each substance use behavior. Motivation to change each behavior was also examined as a potential predictor of retention in treatment. Results indicated that patients reported high self-efficacy to abstain and lower temptation to use alcohol relative to cigarettes. Change activities were also initiated at higher levels for drinking compared with smoking. An interaction between drinking and smoking motivation for change was found in the prediction of treatment retention; those with higher motivation for changing their alcohol use and lower motivation to quit smoking remained in treatment longer, while those who were higher in motivation for changing both behaviors dropped out the earliest. Overall, participants in this dual-dependence program were more confident and active in changing their alcohol use. Initiating cessation of both behaviors equally and simultaneously may prove difficult for this population. Stotts, A., Schmitz, J., and Grabowski, J. Drug and Alcohol Dependence, 69, pp. 1-7, January 2003.

A Partner's Drug Using Status Impacts Women's Drug Treatment Outcome

Drs. Michelle Tuten and Hendree Jones at Johns Hopkins University School of Medicine examined the role that male sexual partners play in the treatment outcome of drug dependent pregnant women. Pregnant women enrolled in a comprehensive treatment program with drug free or drug using male sexual partners completed a relationship survey and were compared on partner and psychosocial variables. Compared with male drug free partners, male drug using partners had more unemployment and more current legal involvement, less education, were less likely to be supportive of the pregnant woman's recovery efforts and were more likely to give them money to buy drugs. Male drug free partners also had fewer medical, dental, legal, and transportation needs than male drug using partners. Data from treatment retention suggests that women with male drug using partners are retained in a comprehensive treatment for a shorter time than women with male drug free partners. A male partner's drug using status should be considered when treating pregnant drug dependent women. Tuten, M. and Jones, H., Drug and Alcohol Dependence, pp. 1-4, March 2003.

Concurrent Validity of a Brief Self-Report Drug Use Frequency Measure

Dr. O'Farrell of Harvard University, and Drs. Fals-Stewart and Murphy of SUNY Buffalo RIA, developed and tested a self-report measure of the illicit drug use frequency (DUF). Male alcoholic patients in treatment and a community sample of male and female participants without identified drug or alcohol use disorders completed the DUF. All participants also completed the Timeline Followback (TLFB) and consented to collaterals providing information about participants' drug and alcohol use. The DUF showed good concurrent validity, with high correlations between self-reports of drug use on the DUF and TLFB, and between participant and collateral reports of the use and frequency of use of illicit drugs. This study suggests that the Drug Use Frequency measure provides accurate drug use data, relative to other accepted methods of assessing drug use. O'Farrell, T.J., Fals-Stewart, W. and Murphy, M. Addictive Behaviors, 28(2), pp. 327-337, March 2003.

Past Anabolic-Androgenic Steroid Use Among Men Admitted for Substance Abuse Treatment: An Under Recognized Problem?

Dr. Roger Weiss, along with colleagues from McLean Hospital and Harvard University, assessed prior use of anabolic-androgenic steroids (AAS) among 223 male substance abusers admitted for treatment. Participants with likely AAS experience participated in semi-structured interviews that included questions about whether AAS had helped to introduce participants to other drugs. Twenty-nine participants reported prior AAS use, only 4 of which were recorded on physicians' admission evaluations. Significantly more men reported past AAS use whose primary drug of choice was opioids (25%) compared to men reporting primary use of other drugs (5%). Some men with AAS experience also reported buying opioids from the same person who had sold them AAS, that AAS was the first drug they had ever self-administered by injection, and that AAS use was associated with severe aggressiveness. This study highlights the potential association between AAS use and other drug use, particularly opioid dependence. Kanayama, G., Cohane, G.H., Weiss, R.D. and Pope, H.G. Journal of Clinical Psychiatry, 64(2), pp. 156-160, May 2003.

Gender Differences Found with a Novel Cognitive-Behavioral Approach for Treatment-Resistant Drug Dependence

Many opiate-dependent patients continue illicit drug use despite the application of treatments that combine methadone administration, weekly counseling, and contingency reinforcement strategies. Dr. Pollack and colleagues tested a novel cognitive-behavioral treatment (CBT) designed to reduce illicit drug use among patients receiving methadone treatment. The CBT was a modification of a treatment designed to treat benzodiazepine dependence in patients with panic disorder, which was now focused to reduce sensitivity to interoceptive cues associated with drug craving and trained alternative responses to these cues. Twenty-three methadone maintenance patients were randomly assigned to either this novel CBT program or a program of increased counseling, such that the two programs of treatment were equated for therapist contact, assessment time, and contingency-reinforcement strategies. The new program was associated with significantly greater reductions in illicit drug use for women, but not for men measured by percentage of negative urine drug screens. The (CBT) program offered advantages to women who attended the treatment on the order of a very large (d = 1.00) effect size. Contrary to expectations, results indicated that intensified counseling with existing providers tended to offer better outcome than CBT-IC for men in our program (d = 0.89). Pollack, M.H., Penava, S.A., Bolton, E., Worthington III, J.J., Lanka, G., Farach Jr., F.J. and Otto, M.W. Journal of Substance Abuse Treat, 23(4), pp. 335-342, December 2002.

Bupropion Enhances Smoking Cessation in Schizophrenic Smokers

Schizophrenic patients have high rates of cigarette smoking compared with the general population. The investigators compared sustained-release (SR) bupropion with placebo for smoking cessation in patients with schizophrenic disorders. Thirty-two subjects meeting DSM-IV criteria for schizophrenia or schizoaffective disorder and nicotine dependence were randomized to bupropion SR (BUP, 300 mg/day) or placebo (PLA). Outcomes included treatment retention, smoking abstinence rates, expired breath carbon monoxide (CO) levels, psychotic symptoms, and medication side effects. Bupropion significantly increased prevalence smoking abstinence rates compared with placebo. The results suggest that 1) BUP enhances smoking abstinence rates compared with PLA in nicotine-dependent schizophrenic smokers; 2) BUP is well-tolerated and safe for use in these patients; and 3) atypical antipsychotics may enhance smoking cessation outcomes with BUP. George, T.P., Vessicchio, J.C., Termine, A., Bregartner, T.A., Feingold, A., Rounsaville, B.J. and Kosten, T.R. A Placebo Controlled Trial of Bupropion for Smoking Cessation in Schizophrenia, Biol. Psychiatry, 52(1), pp. 53-61, July 1, 2002.

Triple HIV Therapy May Increase the Rate of Methadone Metabolism

There is a belief among methadone patients that triple therapy for HIV reduces methadone potency. This cross-sectional study compared the rate of methadone metabolism (peak-trough blood levels) in two groups of methadone-maintained patients, AIDS patients receiving triple therapy (N = 17), and HIV patients without triple therapy (N = 19). These preliminary findings suggest that triple therapy may increase the rate of methadone metabolism, though further studies are warranted. Akerele, E.O., Levin, F., Nunes, E., Brady, R. and Kleber, H. Effects of HIV Triple Therapy on Methadone Levels, Am. J. Addict.,11(4), pp. 308-314, Fall 2002.

Attrition is a Serious Problem for Naltrexone Maintenance: Previous Methadone Therapy Worsens Outcome

Treatment of opiate dependence with naltrexone has been limited by poor compliance. Behavioral Naltrexone Therapy (BNT) was developed to promote adherence to naltrexone and lifestyle changes supportive of abstinence, by incorporating components from empirically validated treatments, including Network Therapy with a significant other to monitor medication compliance, the Community Reinforcement Approach, and voucher incentives. In an uncontrolled Stage I trial (N = 47), 19% completed the 6-month course of treatment. Retention was especially poor in the sub-sample of patients who were using methadone at baseline (N = 18; 39% completed 1 month, none completed 6 months), and more encouraging among heroin-dependent patients (N = 29; 65% completed 1 month, 31% completed 6 months). Thus, attrition continues to be a serious problem for naltrexone maintenance, although further efforts to develop interventions such as BNT are warranted. Rothenberg, J.L., Sullivan, M.A., Church, S.H., Seracini, A., Collins, E., Kleber, H.D. and Nunes, E.V. Behavioral Naltrexone Therapy. An Integrated Treatment for Opiate Dependence. J. Subst. Abuse Treat., 23(4) pp. 351-360, December 2002.

Naltrexone Increases the Reinforcing Effects of Oral THC

Studies in animals suggest that opioid antagonists block the reinforcing effects of cannabinoids These studies in humans investigated how naltrexone modulates (1) the subjective and physiological effects of oral THC in comparison to methadone, (2) the reinforcing effects of oral THC, and (3) plasma levels of oral THC. Pretreatment with naltrexone significantly increased many of the "positive" subjective effects of oral THC ratings of Good Drug Effect and Capsule Liking. Naltrexone did not alter plasma THC levels. These studies demonstrate that naltrexone increases the subjective effects of oral THC. Thus, oral THC's effects are enhanced rather than antagonized by opioid receptor blockade in heavy marijuana smokers. Haney, M., Bisaga, A. and Foltin, R.W. Interaction Between Naltrexone and Oral THC in Heavy Marijuana Smokers. Psychopharmacology (Berl), 166(1), pp. 77-85, May 2003.

An NMDA Receptor Antagonist Produces Some Stimulant-like Subjective Effects

This study investigated the discriminative stimulus, subjective (e.g. "Good Drug Effect"), psychomotor performance, and cardiovascular effects (e.g. blood pressure) of oral methamphetamine following acute oral memantine (a non-competitive NMDA antagonist) in humans. Initially, participants were trained to discriminate 10 mg methamphetamine from placebo using a standard two-response procedure (drug versus placebo). Then, the effects of memantine (0, 40 mg) on methamphetamine discrimination were examined across several methamphetamine doses (0, 5, 10, 20 mg) using a novel-response procedure (drug versus placebo versus novel). Following placebo pretreatment, 10 mg methamphetamine produced 99% methamphetamine-appropriate responding and placebo produced 75% placebo-appropriate responding. Following memantine pretreatment, participants responded as if they had been given a novel compound, although memantine did not significantly alter most subjective-effects ratings following methamphetamine. Memantine alone produced "positive" subjective effects and novel drug-appropriate responding. These data indicate that the memantine-methamphetamine combination produced novel discriminative stimulus effects and that memantine produced some stimulant-like subjective effects. Hart, C.L., Haney, M., Foltin, R.W. and Fischman, M.W. Effects of the NMDA Antagonist Memantine on Human Methamphetamine Discrimination. Psychopharmacology (Berl), 164(4), pp. 376-384, December 2002.

Oral Delta (9)-THC Does Not Alter Self-administration of Marijuana

Agonist therapies have been demonstrated to be effective for the treatment of substance use disorders. This study evaluated the influence of oral Delta (9)-THC maintenance on choice to self-administer smoked marijuana. During this 18-day residential study, 12 healthy research volunteers received one of three doses of oral Delta (9)-THC capsules (0, 10, 20 mg q.i.d.) for 3 consecutive days, followed by 3 consecutive days of matching placebo. Each morning, except on days 6, 12, and 18, participants smoked the 'sample' marijuana cigarette (1.8% Delta (9)-THC w/w) and received a $2 voucher. Following the sample, volunteers participated in a four-trial choice procedure during which they had the opportunity to self-administer either the dose of marijuana they sampled that morning or to receive the $2 voucher. Relative to placebo Delta (9)-THC maintenance, participants' choice to self-administer marijuana was not significantly altered by either of the two active Delta (9)-THC maintenance conditions. Some 'positive' subjective drug-effect ratings following the sample marijuana cigarette were reduced. The effects of smoked marijuana on psychomotor task performance were only minimally affected by oral Delta (9)-THC maintenance. The data indicate that participants' choice to self-administer marijuana was unaltered by the oral Delta (9)-THC dosing regimen used in the present investigation. Hart, C.L., Haney, M., Ward, A.S., Fischman, M.W. and Foltin, R.W. Effects of Oral THC Maintenance on Smoked Marijuana Self-Administration. Drug Alcohol Depend., 67(3), pp. 301-309, August 1, 2002.

Cardiovascular and Subjective Effects of Smoked Cocaine Vary as a Function of Menstrual Cycle Phase

Few studies have systematically determined whether the response to cocaine in human females is related to hormonal fluctuations at different phases of the menstrual cycle. The goal of this study was to investigate the responses to repeated doses of smoked cocaine in women during two phases of the menstrual cycle using a within-subject design. Eleven non-treatment seeking female cocaine smokers were administered smoked cocaine during the follicular and mid-luteal phases of the menstrual cycle. The order of menstrual cycle phase was counterbalanced across women and the order of cocaine doses was randomized. During each phase, there were four cocaine administration sessions. During each session, participants could smoke up to six doses of cocaine (either 0, 6, 12, or 25 mg cocaine base, depending on the session) at 14-min intervals. Results obtained showed that the number of cocaine doses administered did not vary between the follicular and luteal phases. After cocaine administration, heart rate and several ratings - such as "good drug effect", "high", "stimulated", and "drug quality ratings" - were increased more during the follicular phase than the luteal phase, although, for some measures, these effects varied based on the cocaine dose. Further, dysphoric mood during the luteal phase was improved after cocaine administration. These results indicate that the cardiovascular and subjective effects of repeated doses of smoked cocaine are complex and vary as a function of menstrual cycle phase and cocaine dose. Evans, S.M., Haney, M. and Foltin, R.W. The Effects of Smoked Cocaine During the Follicular and Luteal Phases of the Menstrual Cycle in Women. Psychopharmacology (Berl), 159(4), pp. 397-406, February 2002.

Maternal Vaccination Against Nicotine Reduces Nicotine Distribution to Fetal Brain in Rats

This study examined whether vaccination of female rats prior to pregnancy would reduce the distribution to fetal brain of a single nicotine dose administered during gestation. Female rats immunized with a nicotine conjugate vaccine received a single dose of nicotine 0.03 mg/kg i.v. on gestational day 16-22. Five minutes later, vaccinated rats had substantially higher bound and lower unbound serum nicotine concentration, and lower brain nicotine concentration than controls. Fetal brain nicotine concentration was reduced by 43% in vaccinated rats, comparable to the reduction in the maternal brain nicotine concentration. The whole fetus nicotine concentration was not altered by vaccination. A similar experiment was performed in which pregnant rats were passively immunized with rabbit nicotine-specific IgG 7 or 21 mg/kg just prior to nicotine dosing. The effects of passive immunization on nicotine distribution in the mother were IgG dose-related and the higher dose reduced nicotine distribution to fetal brain by 60%. These data suggest that vaccine effects on nicotine distribution to serum and brain are similar in pregnant female rats to those previously reported in adult males. Vaccination of female rats prior to pregnancy, or passive immunization during pregnancy, can reduce the exposure of fetal brain to a single dose of maternally administered nicotine. Keyler, D.E., Shoeman, D., LeSage, M.G., Calvin, A.D. and Pentel, P.R. Maternal Vaccination Against Nicotine Reduces Nicotine Distribution to Fetal Brain in Rats. J Pharmacol Exp Ther., February 11, 2003 [epub ahead of print].

Contingent Monetary Reinforcement of Smoking Reductions, With and Without Transdermal Nicotine In Outpatients with Schizophrenia

This study investigated the effects of contingent monetary reinforcement (CM) for smoking reduction, with and without transdermal nicotine, on cigarette smoking in individuals with schizophrenia. Fourteen outpatients participated in each of 3 conditions: (a) CM combined with 21 mg transdermal nicotine, (b) CM combined with placebo patch, and (c) noncontingent reinforcement combined with placebo patch. Each condition lasted 5 days. Carbon monoxide levels were measured 3 times daily, and nicotine withdrawal symptoms were measured once daily in each condition. Results indicated that CM reduced smoking but that 21 mg transdermal nicotine did not enhance that effect. These results offer further evidence supporting the efficacy of CM for reducing smoking among people with schizophrenia, but higher doses of nicotine replacement therapy, or another pharmacotherapy, may be needed to enhance that effect. Tidey, J.W., O'Neill, S.C. and Higgins, S.T. Contingent Monetary Reinforcement of Smoking Reductions, With and Without Transdermal Nicotine, in Outpatients with Schizophrenia. Exp Clin Psychopharmacol., 10(3), pp. 241-247, August 2002.

Acute Effects of "Advance": A Potential Reduced Exposure Product for Smokers

This study examined the acute effects of "Advance", a potential reduced exposure product (PREP) for smokers marketed as a means to reduce exposure to toxic gases and tobacco specific nitrosamines. A Latin square ordered, three condition, laboratory based, crossover design with 20 smokers of light or ultra-light cigarettes (15 or more cigarettes/day) was employed. In each 2.5 hour condition, participants completed an 8-puff smoking bout from their own brand, "Advance", or an unlit cigarette (that is, sham smoking) every 30 minutes for a total of four bouts. Subject rated measures of tobacco/nicotine withdrawal; carbon monoxide (CO), and heart rate; plasma nicotine concentrations. Relative to own brand, "Advance" produced similar withdrawal suppression and heart rate increase, lower CO boost, and higher plasma nicotine concentrations. In conclusion, PREPs for smokers need to be evaluated using a comprehensive strategy that includes empirical examination of acute and long-term effects. Adequate withdrawal suppression and potentially lower concentrations of CO associated with "Advance" use are positive factors, although higher nicotine concentrations do not constitute "reduced exposure". Overall, longer exposure periods are necessary to determine carcinogen delivery. PREP evaluation is complex and should be completed objectively. Breland, A.B., Evans, S.E., Buchhalter, A.R. and Eissenberg, T. Acute Effects of "Advance": A Potential Reduced Exposure Product for Smokers. Tobacco Control, 11(4), pp. 376-378, December 2002.

Evaluating Acute Effects of Potential Reduced-exposure Products for Smokers: Clinical Laboratory Methodology

The study of smoke constituent exposure, and any resulting harm reduction from a potential reduced-exposure product (PREP), involves preclinical, clinical, and epidemiological research. The purpose of this study was to evaluate a clinical laboratory model for assessing the acute effects of PREPs for smokers. Philip Morris' Accord and R.J. Reynolds' Eclipse were used as examples. Twenty overnight-abstinent smokers (> 15 'light' or 'ultra-light' cigarettes/day) participated in 4 Latin-square ordered, 2.5-hr sessions in which they completed an 8-puff smoking bout every 30 minutes. Sessions were separated by at least 24 hours and differed by product used: own brand, denicotinized tobacco cigarettes, Accord, or Eclipse. Tobacco withdrawal and carbon monoxide (CO) were assessed before and after smoking, heart rate was assessed before and during smoking, and puff volume, duration, and interpuff interval were assessed while subjects smoked. Blood was sampled at the beginning and end of each session. Relative to normal cigarettes, Accord was less effective at suppressing withdrawal and produced minimal CO boost despite the fact that, when using Accord, subjects took bigger and longer puffs. Eclipse suppressed withdrawal fully and increased CO boost by approximately 30%. Own brand, Accord, and Eclipse, but not denicotinized cigarettes, increased plasma nicotine concentration. Taken together, these results suggest that neither Accord nor Eclipse is likely to be an effective reduced-exposure product for smokers and that this clinical laboratory model is valuable. Breland, A.B., Buchhalter, A.R., Evans, S.E. and Eissenberg, T. Evaluating Acute Effects of Potential Reduced-Exposure Products for Smokers: Clinical Laboratory Methodology. Nicotine Tob. Res., 4 Suppl 2, pp. 131-140, 2002.

A Liquid Chromatographic-Electrospray Ionization-tandem Mass Spectrometric Method for Determination of Buprenorphine, its Metabolite, Norbuprenorphine, and a Co-formulant, Naloxone, that is Suitable for In Vivo and In Vitro Metabolism Studies

The authors report the development and validation of a liquid chromatographic-electrospray ionization-tandem mass spectrometric method for determination of the anti-abuse medication, buprenorphine, its primary metabolite, norbuprenorphine, and a proposed co-formulant, naloxone. The method uses deuterated internal standards and a simple liquid-liquid extraction. Mass spectrometry employed selected reaction monitoring of the transitions of m/z 468 to 396 for buprenorphine, 472 to 400 for [2H4]buprenorphine, 414 to 101 for norbuprenorphine, 423 to 110 for [2H9]norbuprenorphine, 328 to 310 for naloxone, and 345 to 327 for its internal standard, [2H3]naltrexone. The method was accurate and precise across the dynamic range of 0.1 to 10 ng/ml. All analytes were stable in human plasma stored at room temperature for up to 24 h and after three freeze-thaw cycles. Reconstituted extracts were stable at -20 degrees C for up to 3 days. In human subjects receiving a sublingual tablet of 8 mg buprenorphine and 2 mg naloxone, buprenorphine and norbuprenorphine were detected for up to 24 h with respective maximum concentrations at 1 and 1.5 h. Maximal concentrations ranged from 2.2 to 2.8 and 1.5 to 2.4 ng/ml for buprenorphine and norbuprenorphine, respectively (i.e., approximately 6 nM). The method detected norbuprenorphine formation in human liver microsomes incubated with 5-82 nM buprenorphine, which encompasses the therapeutic plasma concentration range. When cDNA-expressed P450s were incubated with 21 nM buprenorphine, norbuprenorphine formation was detected for P450s 3A4, as previously described, but also for 3A5, 3A7, and 2C8. Buprenorphine utilization generally exceeded norbuprenorphine formation, suggesting that P450s 2C18, 2C19, 2D6, and 2E1 may also be involved in buprenorphine metabolism to other products. These results suggest this method is suitable for both in vivo and in vitro studies of buprenorphine metabolism to norbuprenorphine. Moody, D.E., Slawson, M.H., Strain, E.C., Laycock, J.D., Spanbauer, A.C. and Foltz, R.L. A Liquid Chromatographic-Electrospray Ionization-tandem Mass Spectrometric Method for Determination of Buprenorphine, Its Metabolite, Norbuprenorphine, and a Co-formulant, Naloxone, that is Suitable for In Vivo and In Vitro Metabolism Studies. Anal Biochem., 306(1), pp. 31-39, July 1, 2002.

An Investigation of Predictors of Nicotine Abstinence in a Smoking Cessation Treatment Study of Smokers with a Past History of Alcohol Dependence

This study examined predictors of nicotine abstinence at 12-week follow-up among 85 smokers with a past history of alcohol dependence enrolled in a smoking cessation trial. Length of alcohol abstinence at time of enrollment and longest previous period of smoking abstinence were significantly associated with smoking status at follow-up. Multiple logistic regression with these variables entered as predictors suggested that longest previous period of smoking abstinence partially mediated the relationship between length of alcohol abstinence at enrollment and smoking status at follow-up. Additional research is warranted to identify predictors of nicotine abstinence and smoking relapse in this population and to understand the factors that mediate the relationship between length of alcohol abstinence at enrollment and smoking outcome. Kalman, D., Tirch, D., Penk, W. and Denison, H. An Investigation of Predictors of Nicotine Abstinence in a Smoking Cessation Treatment Study of Smokers with a Past History of Alcohol Dependence. Psychol Addict Behav., 16(4), pp. 346-349, December 2002.

A Clinical Approach to Integrating Treatment for Adolescent Depression and Substance Abuse

This study provides a preliminary, but empirically derived, clinical treatment algorithm which could be useful as a starting point to help clinicians structure an integrated approach to the treatment of depression in adolescents with SUD. Adolescents with substance use disorders (SUD) commonly suffer from co-occurring major depression (MDD), which impairs psychosocial functioning, contributes to the severity of substance abuse, and interferes with effective engagement in substance treatment. Because the magnitude of the public health impact and the clinical complexity of adolescents with comorbid disorders are so great, it is important to at least begin to derive a more standardized clinical treatment algorithm to guide our approach to integrated treatment from the current empirical base. Riggs, P.D. and Davies, R.D. A Clinical Approach to Integrating Treatment for Adolescent Depression and Substance Abuse. J Am Acad Child Adolesc Psychiatry., 41(10). pp. 1253-1255, October 2002.

A Preliminary Placebo-Controlled Trial of Selegiline Hydrochloride for Smoking Cessation

This study assessed the safety and efficacy of the monoamine oxidase B inhibitor selegiline hydrochloride compared with placebo for smoking cessation in nicotine-dependent cigarette smokers. Forty subjects with DSM-IV nicotine dependence were randomized to: 1) selegiline hydrochloride (5 mg p.o. twice daily) or 2) placebo in an 8-week trial. Outcome measures included smoking cessation rates, treatment retention, and medication side effects. Selegiline hydrochloride increased trial end point (week 8) 7-day point prevalence smoking cessation rates (selegiline hydrochloride, 9/20 [45.0%]; placebo, 3/20 [15.0%], odds ratio = 4.64, 95% CI, 1.02-21.00, p <.05), and smoking cessation rates during the last 4 weeks of the trial (selegiline hydrochloride, 6/20 [30.0%]; placebo, 1/20 [5.0%], odds ratio = 8.14, 95% CI, 0.88-75.48, p =.07) in comparison with placebo. Six-month follow-up 7-day point prevalence smoking cessation rates were reduced compared with trial end point (selegiline hydrochloride, 4/20 [20.0%]; placebo, 1/20 [5.0%], odds ratio = 4.75, 95% CI, 0.48-46.91, p =.18). Treatment retention was similar between drug and placebo groups (p =.13), and selegiline hydrochloride was well tolerated in cigarette smokers. This preliminary study suggests that selegiline (10 mg/day) is safe for use and enhances smoking cessation rates compared with placebo in nicotine-dependent cigarette smokers. George, T.P., Vessicchio, J.C., Termine, A., Jatlow, P.I., Kosten, T.R. and O'Malley, S.S. A Preliminary Placebo-Controlled Trial of Selegiline Hydrochloride for Smoking Cessation. Biol Psychiatry, 53(2), pp. 136-143, January 15, 2002.

Patients' Views on Smoking Cessation and Tobacco Harm Reduction during Drug Treatment

The investigators conducted focus groups and interviews among 78 patients from five Methadone Maintenance Treatment (MMT) sites. Measures included a written survey and open-ended questions on (a) motivation for quitting, (b) what quit methods worked and what didn't work, and (c) interest in smoking reduction and nicotine maintenance as an alternative to complete cessation. Discussions were audiotaped, transcribed, and coded using computer-based qualitative software; inter-observer reliability was 83%. Successful quitters used in general a combination of quit methods such as prayer, nicotine gum, keeping busy, quitting 'one day at a time,' nicotine patches, deep breathing, and avoidance of triggers. Nicotine craving, rather than withdrawal, was cited as the biggest challenge to staying quit. Some current smokers feared quitting smoking would divert them from their goal of quitting illicit drug use or tapering off MMT. Current smokers were interested in smoking reduction as an alternative to quitting; however, those who had tried but failed to reduce smoking preferred complete cessation. Nicotine maintenance was favored by only a few participants with major health problems who did not believe they would be able to quit. Findings suggest combination pharmacotherapy could help patients control withdrawal and acute episodes of craving. Patients have a number of skills from coping with illicit drug dependence that are useful in combating nicotine dependence. Behavioral methods and short-term pharmacotherapy to help patients reduce tobacco exposure should be explored. Richter, K.P., McCool, R.M., Okuyemi, K., Mayo, M.S. and Ahluwalia, J.S. Patient's Views on Smoking Cessation and Tobacco Harm Reduction during Drug Treatment. Nicotine and Tobacco Research, S139-S136, 2002.

African American Smokers Interested In and Eligible for a Smoking Cessation Clinical Trial: Predictors for not Returning for Randomization

The investigators compared 287 enrolled African American smokers who did not return for randomization, to the 500 who returned and were randomized to participate in a clinical trial for smoking cessation in African Americans. Analyses were conducted to identify variables associated with not returning for randomization. Univariate comparisons found the nonrandomized group to be significantly different from those randomized. Logistic regression showed younger age, less readiness to quit, having been proactively recruited, lacking a regular source of health care, believing that they will be smoking in 6 months, less church attendance, and a lower literacy level to be jointly related with not returning for randomization. In conclusion, African American participants who did not return for randomization into a clinical trial were different from those who did. Better understanding of these factors may allow researchers to target recruitment efforts resulting in enhanced accrual in clinical trials and increased efficiency. Ahluwalia, J.S., Richter, K.P., Mayo, M.S., Ahluwalia, H.K., Choi, W.S., Schmelzle, K.H. and Resnicow, K. African American Smokers Interested In and Eligible for a Smoking Cessation Clinical Trial: Predictors for Not Returning for Randomization. Annals of Epidemiology, 12, pp. 206-212, 2002.

Smoking Reduction Practices Among African American Smokers

A survey was conducted of 484 African American smokers classified as occasional, light, moderate, and heavy smokers to examine sociodemography, smoking characteristics, and eight smoking reduction strategies, including intentional limiting of smoking, smoking less than half of a cigarette, setting a daily limit for smoking, changing cigarette brand, reducing number of cigarettes, smoking only on some days, switching to a lighter tar cigarette, and not inhaling deeply. Compared to moderate and heavy smokers, occasional and light smokers were more likely to have engaged in most of these strategies. Smokers who used >/= 4 strategies on average smoked 11 cigarettes per day (cpd), compared to 14 cpd and 18 cpd for those who used 1 to 3 strategies and no strategies respectively (p <.0001). After analyses controlled for age, gender, and education, the number of smoking reduction strategies utilized was a significant predictor of smoking 10 or fewer cigarettes per day. This study provides evidence that African American smokers who engaged in multiple smoking reduction strategies smoked fewer cigarettes per day. Smokers not interested in quitting but willing to reduce their smoking should be encouraged to utilize a variety of smoking reduction strategies. Okuyemi, K.S., Richter, K.P., Ahluwalia, J.S., Mosier, M.C., Nazir, N. and Resnicow, K. Smoking Reduction Practices Among African American Smokers. Nicotine and Tobacco Research, 4 Suppl 2:S167-S173, 2002.

Effects of Smoking Cessation on Reduction of Hormone Profiles and Bone Turnover in Postmenopausal Women

A prospective study was conducted to evaluate the impact of smoking cessation on hormonal concentrations, sex hormone-binding globulin (SHBG) and markers of bone turnover in postmenopausal women. Sixty-six women who were either users or non-users of estrogen replacement therapy (ERT) were randomly assigned, using a weighted randomization scheme, to smoking cessation (SC) or to smoking cessation after 6 weeks of monitoring (wait-list control group, WLC). The study measured hormones [estrone, estradiol, testosterone, parathyroid hormone, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS) and androstenedione] and SHBG, markers of bone turnover [procollagen peptide (PINP), bone alkaline phosphatase (BAP), and osteocalcin (OC), N- and C-terminal collagen cross-links (NTx and CTx)], and cotinine, at baseline and again at 6 weeks in women who reported smoking cessation and in women randomized to the WLC group. Analyses included 20 subjects who quit or significantly reduced their smoking and 18 subjects in the WLC group. After controlling for differences in age and ERT use between groups, we found a significant change in SHBG in the SC vs. the WLC group (-8% vs. +5%, respectively; p = 0.01), and in DHEA (-18% vs. -5%, respectively; p = 0.04), but not in other hormonal concentrations. Authors also noted a significant change in NTx in the SC vs. WLC group (-5% vs. +56%, respectively, p = 0.01), but not in other markers of bone turnover. Percentage changes in SHBG and NTx were correlated with changes in plasma cotinine (r = 0.48; p = 0.004 and r = 0.36; p = 0.04, respectively). Six weeks of smoking abstinence produces reductions in SHBG and NTx. This may partly explain how smoking contributes to osteoporosis in postmenopausal women. Oncken, C., Prestwood, K., Cooney, J.L., Unson, C., Fall, P., Kulldorff, M. and Raisz, L.G., Nicotine Tob. Res., 4(4), pp. 451-458, November 2002.

Effect of Maternal Smoking on Fetal Catecholamine Concentrations at Birth

Catecholamine concentrations in the fetal umbilical artery cord blood from the offspring of smokers were compared to the offspring of nonsmokers. Pregnant women who were self-identified as smokers (>/=10 cigarettes per day throughout pregnancy) or nonsmokers were recruited for study participation. Maternal blood was collected for cotinine concentrations. Umbilical artery cord blood was collected at delivery for arterial pH and catecholamine concentrations. Cord blood was obtained from 51 subjects, including 21 smokers and 30 nonsmokers. Median epinephrine concentrations [304 pg/mL versus 597 pg/mL (Mann-Whitney U = 170; p = 0.006)] and median norepinephrine concentrations [3148 pg/mL versus 6558 pg/mL (Mann-Whitney U = 191; p = 0.006)] were significantly lower in smokers compared with nonsmokers, respectively. After controlling for gestational age, route of delivery, and arterial pH, log-transformed epinephrine concentrations between smokers and nonsmokers were statistically significant (p = 0.03), with a similar trend for log-transformed norepinephrine concentrations (p = 0.07). Analyses of the data using cotinine <20 ng/mL to classify nonsmokers also showed differences in epinephrine concentrations between groups (p = 0.02). These results are consistent with results from animal studies showing that catecholamine concentrations may be affected by prenatal nicotine exposure. Further studies are needed to validate these findings and to examine the specific mechanism by which these differences may arise. Oncken ,C.A., Henry, K.M., Campbell, W.A., Kuhn, C.M., Slotkin, T.A. and Kranzler, H.R. Effect of Maternal Smoking on Fetal Catecholamine Concentrations at Birth. Pediatr Res. 53(1), pp. 119-124, January 2003.

Severe, Demyelinating Leukoencephalopathy in AIDS Patients on Antiretroviral Therapy

Dr. Grant and his team at the University of California, San Diego used clinical and neuroimaging findings to test a hypotheses regarding the pathogenesis for a severe form of demyelinating HIV-associated leukoencephalopathy in AIDS patients who fail highly active antiretroviral therapy (HAART). Each patients entered into the study had a detailed neuromedical, neuropsychological, neuroimaging and post-mortem neuropathological examination. Immunocytochemical and PCR analyses were performed to determine brain HIV levels and to exclude other viruses. Seven recent autopsy cases of leukoencephalopathy in antiretroviral-experienced patients with AIDS were identified. Clinically, all were severely immunosuppressed, six (86%) had poorly controlled HIV replication despite combination antiretroviral therapy, and five (71%) had HIV-associated dementia. Neuropathologically, all seven had intense perivascular infiltration by HIV-gp41 immunoreactive monocytes/macrophages and lymphocytes, widespread myelin loss, axonal injury, microgliosis and astrogliosis. The extent of damage exceeds that described prior to the use of HAART. Brain tissue demonstrated high levels of HIV RNA but evidence of other pathogens, such as JC virus, Epstein-Barr virus, cytomegalovirus, human herpes virus type-8, and herpes simplex virus types 1 and 2, was absent. Comparison of the stages of pathology suggests a temporal sequence of events. In this model, white matter damage begins with perivascular infiltration by HIV-infected monocytes, which may occur as a consequence of antiretroviral-associated immune restoration. Intense infiltration by immune cells injures brain endothelial cells and is followed by myelin loss, axonal damage, and finally, astrogliosis. Taken together, the findings provide evidence for the emergence of a severe form of HIV-associated leukoencephalopathy. This condition warrants further study and increased vigilance among those who provide care for HIV-infected individuals. Langford, T.D., Letendre, S.L., Marcotte, T.D., Ellis, R.J., McCutchan, J.A., Grant, I., Mallory, M.E., Hansen, L.A., Archibald, S., Jernigan, T., Masliah, E. and the HNRC Group. Severe, Demyelinating Leukoencephalopathy in AIDS Patients on Antiretroviral Therapy. AIDS, 16(7), pp. 1019-1029, 2002.

Expression of Stromal Cell-Derived Factor 1a Protein in HIV Encephalitis

Dr. Grant and colleagues during further investigation of encephalopathy, analyzed the patterns of stromal cell-derived factor 1 (SDF-1) expression in brains from HIV-positive patients. Evidence suggested that in neuronal cells, SDF-1 might play a role in neuroprotection and neurite extension in response to HIV infection. In all cases analyzed, SDF-1 immunoreactivity was primarily present in astroglial cells. Patients with HIV encephalitis (HIVE) showed intense somato-dendritic neuronal SDF-1 immunoreactivity, while HIVE negative patients with neurodegeneration had a significant decrease in neuronal SDF-1 immunoreactivity. Neuronal cells treated with SDF-1 displayed increased neurite outgrowth. Similarly, neurons treated with HIV-Tat, which induced SDF-1 expression, also showed neurite outgrowth. Tat-mediated neurite outgrowth was blocked by anti-SDF-1 antibody. These results suggest that SDF-1 may play a role in the neuronal response to HIV in the brains of AIDS patients. Langford, D., Sanders, V.J., Mallory, M., Kaul, M., and Masliah, E. Expression of Stromal Cell-Derived Factor 1a Protein in HIV Encephalitis. Journal of Neuroimmunology, 127, pp. 115-126, 2002.

The Functional Impact of HIV-Associated Neuropsychological Impairment in Spanish-Speaking Adults: A Pilot Study

Among English-speaking adults, HIV-associated neuropsychological (NP) impairments have been associated with problems in everyday functioning, including the ability to function at work and drive an automobile. Latinos account for a disproportionate number of HIV/AIDS cases nationwide, and a significant segment of this population is primarily Spanish speaking. This research team had previously developed an assessment that evaluates English-speakers on a variety of instrumental activities of daily living. In this pilot study, Spanish-language translations of the functional battery to investigate the cultural relevance of such measures were used. Additionally, the relationships between NP status and ability to perform important, everyday tasks in HIV-infected Spanish-speakers was explored. Sixteen HIV-infected monolingual Spanish-speaking adults received comprehensive, Spanish language NP testing and functional assessments included the following domains: Medication Management, Cooking, Finances, Shopping, and Restaurant Scenario. Results revealed that most of the functional tasks appeared culturally relevant and appropriate with minor modifications. NP-impaired participants were significantly more functionally impaired compared to NP-normals (88% vs. 13%, p < .01). Performances on the functional assessment and the NP battery were also related to indicators of real world functioning, including employment status and quality of life. These results, though preliminary, suggest that Spanish language functional assessments are potentially valid tools for detecting everyday functioning deficits associated with NP impairments in HIV-infected Spanish-speakers. Rivera Mindt, M., Cherner M., Marcotte, T.D., Moore, D.J., Bentley, H., Esquivel, M.M., Lopez, Y., Grant, I., Heaton, R.K., and the HNRC Group. The Functional Impact of HIV-Associated Neuropsychological Impairment in Spanish-Speaking Adults: A Pilot Study. Journal of Clinical and Experimental Neuropsychology, 25(1), pp. 122-132, 2003.

Decision Making by Methamphetamine-Dependent Subjects Is Associated with Error-Rate-Independent Decrease in Prefrontal and Parietal Activation

Dr. Martin Paulus and colleagues at the University of California, San Diego used fMRI to investigate how success or failure influences subsequent decision-making. Results from a previous investigation, in which methamphetamine-dependent subjects (MD) adopted a more consistent win-stay/lose-shift response pattern than normal comparison subjects (NC), implied that MD are more influenced by success. This study examined whether varying the degree of success and the degree of predictability differentially affected MD's decision making. Fourteen MD individuals were compared with 14 NC individuals while performing the two-choice prediction task at three success rates and the two-choice response task. Win-stay/lose-shift consistent responses by MD subjects relative to NC subjects were independent of success rate. Whereas NC showed success-related patterns of neural activation in the orbitofrontal, dorsolateral prefrontal, and parietal cortex, brain activation in MD was highest when the outcome was most unpredictable. Irrespective of success, MD showed less task-related activation in orbitofrontal cortex (Brodmann's area [BA] 10), dorsolateral prefrontal cortex (BA 9), anterior cingulate (BA 32), and parietal cortex (BA 7). These results are consistent with the hypothesis that MD decision-making is characterized by more rigid stimulus-response relationships, which may be due to a shift from processing "success" toward processing the degree of stimulus "predictability." Paulus, M.P., Hozack, N., Frank, L., Brown, G.G. and Schuckit, M.A. Biological Psychiatry 53(1), pp. 65-74, January 2003.

Early-Onset Cannabis Use and Cognitive Deficits: What Is the Nature of the Association?

Dr. Harrison Pope and colleagues at McLean Hospital investigated whether individuals who initiate cannabis use at an early age might be more vulnerable to lasting neuropsychological deficits than individuals who begin use later in life. After 28 days of monitored abstinence from cannabis, 122 long-term heavy cannabis users and 87 comparison subjects with minimal cannabis exposure were given a battery of neuropsychological tests. Comparison of early onset cannabis users with late-onset users and with controls was controlled for age, sex, ethnicity, and attributes of family of origin. The 69 early-onset users (who began smoking before age 17) differed significantly from both the 53 late onset users (who began smoking at age 17 or later) and from the 87 controls on several measures, most notably verbal IQ (VIQ). Few differences were found between late-onset users and controls on the test battery. After controlling for VIQ, virtually all differences between early-onset users and controls on test measures ceased to be significant. Although early-onset cannabis users exhibit poorer cognitive performance than late-onset users or control subjects, especially in VIQ, the difference may reflect (1) innate differences between groups in cognitive ability, antedating first cannabis use; (2) an actual neurotoxic effect of cannabis on the developing brain; or (3) poorer learning of conventional cognitive skills by young cannabis users who have eschewed academics and diverged from the mainstream culture. Pope, Jr., H.G, Gruber, A.J., Hudson, J.I., Cohane, G., Huestis, M.A., and Yurgelun-Todd, D. Drug and Alcohol Dependence 699(3), pp. 303-310, April 2003.

Characterization of Effects of Mean Arterial Blood Pressure Induced by Cocaine and Cocaine Methiodide on BOLD Signals in Rat Brain

Dr. F. Luo and colleagues at the Medical College of Wisconsin used functional magnetic resonance imaging (fMRI) in rats to determine whether cocaine analogue that does not pass the blood-brain barrier (cocaine methiodide, CM) can produce a global increase in blood oxygenation level-dependent (BOLD) contrast. Cocaine methiodide is a quaternary derivative of cocaine that shares the same cardiovascular effects of cocaine, but does not penetrate the blood-brain barrier (BBB). Both CM (with doses of 2.5 and 7.5 mg/kg) and cocaine (with doses of 1.25 and 5.0 mg/kg) induced a robust increase 30-80% in mean arterial blood pressure (MABP). In contrast, CM only produced scattered, weak, and transient BOLD signals in a few voxels of the rat brain. Furthermore the CM-induced BOLD signals were not dose-dependent. In contrast, the administration of cocaine induced dose-dependent biphasic BOLD signals that were consistent with pharmacologically induced cerebral vascular constriction and neuronal activity in the mesolimbic systems of the rat brain. These results confirm that the BOLD-weighted fMRI method can be extended to map drug-induced neuronal activity, and that the potential confounding factors of MABP changes have little effect on the interpretation of drug-induced BOLD signal changes. Luo, F., Wu, G., Li, Z., and Li, S.J. Magnetic Resonance in Medicine 49(2), pp. 264-270, May 2003.

Central Beta-Adrenergic Modulation of Cognitive Flexibility

Dr. David Beversdorf and colleagues at Ohio State University investigated whether noradrenergic modulation of cognitive flexibility in normal humans is a centrally or peripherally mediated phenomenon. Prior research had shown that administration of propranolol (beta-adrenergic antagonist) but not ephedrine (beta-adrenergic agonist) lead to better performance on a task requiring cognitive flexibility, the anagram task. However, these drugs have both peripheral and central beta-adrenergic effects. In the present study the effects of propranolol (peripheral and central beta-blocker) were compared to nadolol (peripheral beta-blocker) and placebo on anagram task performance. Solution latency scores for each subject were compared across the drug conditions. Anagram solution latency scores after propranolol were significantly lower than after nadolol. This suggests a centrally mediated modulatory influence of the noradrenergic system on cognitive flexibility. Beversdorf, D.Q.,White, D.M., Chever, D.C., Hughes, J.D., and Bornstein, R.A. Neuroreport, 139(18), pp. 2505-2507, December 2002.

Loss of Striatal Vesicular Monoamine Transporter Protein (VMAT2) in Human Cocaine Users

Dr. Karley Little at the University of Michigan investigated whether cocaine use leads to damage to dopamine nerve terminals. Vesicular monoamine transporter (VMAT2) protein in the striatum was used as an indirect marker of the integrity of dopamine terminals. Post-mortem striatal samples from human cocaine users retrieved at autopsy were compared to striatal samples from age-, sex-, and postmortem interval-matched comparison subjects. Immunoblot assays were performed by using a highly specific VMAT2 antibody, striatal radioligand binding to VMAT2 was assessed with dihydrotetrabenazine ([(3)H]DTBZ), and dopamine levels were determined employing high-performance liquid chromatography. Interviews with family members and friends were used to obtain information regarding drug use and potential psychiatry dysfunction. Cocaine users displayed a marked reduction in VMAT2 immunoreactivity as well as reduced [(3)H]DTBZ binding and dopamine levels. It did not appear that the reduction in VMAT2 immunoreactivity was related to ethanol use, but dopamine levels were lower in subjects with only ethanol diagnoses. Subjects who may have had co-morbid mood disorders displayed a trend towards greater loss of VMAT2 immunoreactivity. These results indicate that human cocaine users lose VMAT2 protein, which might reflect damage to striatal dopamine fibers. These neuronal changes could play a role in causing disordered mood and motivational processes in more severely dependent patients. Little, K.Y., Krolewski, D.M., Zhang, L., and Cassin, B.J. American J Psychiatry, 160(1), pp. 47-55, January, 2003.

The Orbitofrontal Cortex in Methamphetamine Addiction: Involvement in Fear

Dr. Rita Goldstein and colleagues at Brookhaven National Laboratory examined whether cerebral metabolism measured with PET in the orbitofrontal gyrus in methamphetamine abusers was related to personality measures of inhibitory control. Tellegen's Multidimensional Personality Questionnaire (MPQ) harm avoidance (fear) scale and the constraint superfactor were used as the personality measures of inhibitory control. Cerebral rate of glucose metabolism in the orbitofrontal gyrus was measured at rest in 14 recently abstinent methamphetamine-dependent subjects and 22 comparison subjects. Higher MPQ scores were associated with higher relative orbitofrontal gyrus metabolism in the methamphetamine-dependent subjects. There was a tendency towards a negative association for the comparison subjects. These results suggest that stable personality predispositions related to inhibitory control are associated with basal activity in the orbitofrontal cortex. These findings further implicate this region in the core characteristics of drug addiction. Goldstein, R.Z., Volkow, N.D., Chang, L., Wang, G.J., Fowler, J.S., Depue, R.A., and Gur, R.C. NeuroReport 13(17), pp. 2253-2257, December 2002.

Brain Dopamine Associated with Eating Behaviors in Humans

Dr. Nora Volkow and colleagues at the Brookhaven National Laboratory and SUNY Stony Brook investigated the role of the neurotransmitter, dopamine, in food motivation. Ten healthy, nonobese subjects were administered the Dutch Eating Behavior Questionnaire (DEBQ) to measure attitudes toward food (i.e., Restraint, Emotionality, and Externality). These subjects were also scanned (using positron emission tomography) during neutral stimulation (baseline) and during food stimulation. Results revealed that a different pattern of correlations between dopamine (DA) measures and Restraint and Emotionality factors of the DEBQ. Restraint was correlated with DA changes with food stimulation (higher restraint, greater responsivity); emotionality was negatively correlated with baseline D2 receptors (higher emotionality, lower D2 receptors; whereas externality was not correlated. The correlations were significant in the dorsal striatum but not in the ventral striatum. These results indicate that DA in the dorsal striatum is involved with the restraint and emotionality components regulating eating behaviors, and further, these two dimensions reflect different neurobiologic processes. Volkow, N.D., Wang, G.J., Maynard, L., Jayne, M., Fowler, J.S., Zhu, W., Logan, J., Gatley, S.J., Ding, Y.S., Wong, C., and Pappas, N. Brain Dopamine is Associated with Eating Behaviors in Humans. International Journal of Eating Disorders, 33, pp. 136-142, 2003.

Methylphenidate's Cardiovascular Effects Associated with Increased Dopamine in Brain and Epinephrine in Plasma

Dr. Nora Volkow and colleagues evaluated the cardiovascular effects of methylphenidate to assess the role of dopamine (DA) in their mediation. This association was evaluated in humans using positron emission tomography and [11C]raclopride, a DA D2 receptor radioligand that competes with endogenous DA for occupancy of the D2 receptors, to assess changes in brain DA after different doses of intravenous methylphenidate in 14 healthy subjects. Cardiovascular (blood pressure and heart rate) and catecholamine (plasma epinephrine and norepinephrine) were measured to assess their relationship to methylphenidate-induced changes in brain DA. Results revealed that methylphenidate administration significantly increased heart rate, systolic and diastolic blood pressure, and epinephrine concentration in plasma. The blood pressure increases were significantly correlated with methylphenidate-induced increases of DA in striatum and of plasma epinephrine levels. Additionally, methylphenidate-induced DA increases in striatum were correlated with increases of epinephrine in plasma. For those subjects that did not show an increased DA response to methylphenidate, no changes in blood pressure or plasma epinephrine were observed. These results are consistent with the hypothesis that methylphenidate-induced increases in blood pressure are due, in part, to its central dopaminergic effects. They also suggest that methylphenidate's pressor effects may be mediated, in part, by DA-induced increases in peripheral epinephrine. Volkow, N.D., Wang, G.J., Fowler, J.S., Molina, P.E., Logan, J., Gatley, S.J., Gifford, Ding, Y.S., A., Wong, C., Pappas, N., Zhu, W., and Swanson, J.M. Cardiovascular Effects of Methylphenidate in Humans are Associated with Increases of Dopamine in Brain and of Epinephrine in Plasma. Psychopharmacology, 166, pp. 264-270, 2003.

Substance Abuse-Related P300 Differences in Response to an Implicit Memory Task

Dr. N. Ceballos and colleagues at the University of Oklahoma examined the P300 component of the event-related potential as an electrophysiological index of cognitive efficiency in alcoholics and controls. They predicted that, if alcohol-related impairment in cognitive efficiency was due to inability to ignore irrelevant stimuli, alcoholics would experience less negative priming than normal controls. They used a negative priming paradigm in which sets of novel shapes were presented: two overlapping green and red shapes on the left and a single white shape on the right. Participants were instructed to ignore the red shape, but to determine whether the green shape was the same as or different from the white shape. On primed trials, previously red (to be ignored; i.e., irrelevant) shapes became green (relevant) shapes in a second component of the task. Participants who were capable of ignoring irrelevant stimuli were expected to experience more difficulty in the primed condition. Both amplitude and latency were measured in response to each trial condition. Controls exhibited increased P300 amplitude and latency in response to negatively primed trials whereas alcoholics did not demonstrate this pattern. These findings were consistent with the prediction of alcohol-related cognitive inefficiency. Ceballos, N.A., Nixon, S.J. and Tivis, R. Progress In Neuropsychopharmacology & Biological Psychiatry 27(1), pp. 157-164, May 2003.

The Multi-Source Interference Task: Validation Study with fMRI in Individual Subjects

Dr. G. Bush and colleagues at the Massachusetts General Hospital used BOLD fMRI in normal human subjects to test a novel cognitive task designed to reliably and robustly activate the dorsal Anterior Cingulate (dACC). Existing tasks used to probe dACC function, such as the classic Stroop Task, require group-averaging techniques to obtain significant dACC activation in functional neuroimaging studies. Development of a task that can be used to discern dACC activation within individuals will improve imaging studies of neuropsychiatric disorders. By combining aspects of tasks that involve cognitive interference (Stroop, Eriksen and Simon) with factors known to increase dACC activity, the Multi-Source Interference Task (MSIT) was developed that was expected to maximally tax dACC function. FMRI responses and performance data were compared between interference and control trials in 8 normal subjects. Significant dACC activation was observed in all eight individuals and in the group-averaged fMRI data. In addition to dACC activation, group data also showed activation of other regions including dorsolateral prefrontal, pre-motor, and parietal cortices, connected to the dACC. The MSIT's reaction time interference effect (overall mean 312+/-61 ms) was up to 10 times greater than that of its component predecessors and temporally stable over hundreds of trials. The robustness, reliability and stability of the neuroimaging and performance data should make the MSIT a useful task with which to study normal human cognition and psychiatric pathophysiology. Bush, G., Shin, L.M., Holmes, J., Rosen, B.R., and Vogt, B.A. Molecular Psychiatry, 8(1), pp. 60-70 2003.

Simultaneous EEG and fMRI of the Alpha Rhythm

Dr. R. Goldman and colleagues at the University of California, Los Angeles used a combination of fMRI and EEG to determine the source of alpha rhythms in normal humans. The alpha rhythm in the EEG is 8-12 Hz activity present when a subject is awake with eyes closed. Simultaneous EEG and fMRI were used to make maps of regions whose MRI signal changed reliably with modulation in posterior alpha activity in 11 normal subjects as they rested with eyes closed. Increased alpha power was correlated with decreased MRI signal in multiple regions of occipital, superior temporal, inferior frontal, and cingulate cortex, and with increased signal in the thalamus and insula. These results are consistent with animal experiments and point to the alpha rhythm as an index of cortical inactivity that may be generated in part by the thalamus. These results also may have important implications for interpretation of resting baseline in fMRI studies. Goldman, R.I., Stern, J.M., Engel, J., and Cohen, M.S. NeuroReport, 13(18), pp. 2487-2492, December 2002.

Hallucinogen Persisting Perception Disorder: What Do We Know After 50 Years?

Drs. John Halpern and Harrison Pope at McLean Hospital reviewed the literature between 1955 and 2001 on 'Flashbacks' following use of hallucinogenic drugs. Flashbacks have been reported for decades; they are recognized in DSM-IV as 'Hallucinogen Persisting Perception Disorder (Flashbacks)', or HPPD. The review analyzed 20 quantitative studies between 1955 and 2001. Many of these studies were performed before operational criteria for HPPD were published in DSM-III-R, so they are difficult to interpret in the light of current diagnostic criteria. Overall, (1) the term 'flashbacks' is defined in so many ways that it is essentially valueless; (2) most studies provide too little information to judge how many cases could meet DSM-IV criteria for HPPD; and consequently (3) information about risk factors for HPPD, possible etiologic mechanisms, and potential treatment modalities must be interpreted with great caution. HPPD appears to be a genuine but uncommon disorder, sometimes persisting for months or years after hallucinogen use. It is reported most commonly after illicit LSD use, but less commonly with LSD administered in research or treatment settings, or with use of other types of hallucinogens. There are case reports, but no randomized controlled trials, of successful treatment with neuroleptics, anticonvulsants, benzodiazepines, and clonidine. Although it may be difficult to collect large samples of HPPD cases, further studies are critically needed to augment the meager data presently available regarding the prevalence, etiology, and treatment of HPPD. Halpern, J. and Pope, Jr., H.G. Drug and Alcohol Dependence 69(2), pp. 109-119, March 2003.

Progress in Developing D3 Dopamine Receptor Ligands as Potential Therapeutic Agents for Neurological and Neuropsychiatric Disorders

Drs. R. Luedtke and R. Mach of Wake Forest University reviewed recent advances in the biochemistry and pharmacology of the D3 receptor from the molecular to the behavioral level and medicinal chemistry approaches toward developing D3-selective ligands. Evidence was presented showing an alteration in D3 receptor function as playing an important role in the etiology of a variety of CNS disorders, including schizophrenia, Parkinson's disease, and substance abuse. Also discussed were the recent developments in attempting to map the ligand-binding domains of the D2 and D3 receptors. Luedtke, R.R. and Mach, R.H. Pharmaceutical Design 9(8), pp. 643-671, 2003.

Haplotypes at the OPRM1 Locus are Associated with Susceptibility to Substance Dependence in European Americans

Drs. Gelernter, Kranzler and associates at Yale and University of Connecticut compared eight single nucleotide polymorphisms (SNPs) for the gene encoding the _-opioid receptor (OPRM1) in two groups of Americans of European and African heritage. There was a significantly greater frequency in the European American group diagnosed with "alcohol+opioid" dependence compared to a matched group for the -2044A allele (-2044C/A mutation). This suggests this allele may play a role in the physiology of substance abuse for this group. There were no differences in frequency for this or any other allele between the African American patients and comparison group. Also, there were significant differences in frequencies of the alleles studied between the two heritage groups. If the mutation confers susceptibility it is apparently diagnosis- and population-specific. Luo, X., Kranzler H.R., Zhao H., and Gelernter, J. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, published online April 10, 2003.

Electrical Response of Retinal Blue Cones May be a Neurobiological Marker to Dopamine Function in Cocaine-Dependent Patients

Using the observation that dopamine in the retina plays an important role in electroretinogram (ERG) amplitudes, Alec Roy and colleagues assessed cone response to blue light in abstinent cocaine-dependent patients and compared this response to concentrations of homovanillic acid (HVA; metabolite of dopamine) in the cerebrospinal fluid (CSF). There was significantly less HVA in the CSF of patients whose ERG amplitude was less than 0.5 μV. This cut-off is considerably below amplitudes of controls (~1.0 μV) and determined in previous work to divide the cocaine patients in approximately two equal groups. Further supporting the grouped data, there was a significant correlation (r = .57; p < .05) between the CSF HVA concentrations and blue cone amplitude. These results suggest that the non-invasive measure of an ERG of cones to blue flash are a neurobiological marker of dopaminergic function in abstinent cocaine patients. Roy A., Roy M., Berman J., Gonzalez B. Psychiatry Research, 117, pp. 191-195, 2003.

Cocaine Abusers Have an Over-Expression of α-synuclein in Dopamine Neurons

Mash and colleagues at the University of Miami assessed post-mortem brains of chronic cocaine abusers who died a sudden death. In particular, increases of α-synuclein protein and mRNA levels were found in the substantia nigra (SN) and ventral tegmental area (VTA) but not the hippocampus. Also of interest, there was no elevation in the SN and less elevation in the VTA in the subset of cocaine abusers who exhibited excited delirium (who exhibit bizarre and violent behavior just prior to death). There was no increase in α-synuclein. It is speculated that over-expression of α-synuclein may occur as a protective response to changes in dopamine turnover and oxidative stress resulting from cocaine abuse. Mash, D.C., Ouyang, Q., Pblo, J., Basile, M., Izenwasser, S., Liberman, A., and Perrin, R. The Journal of Neuroscience, 23(7), pp. 2564-2571, April 1, 2003.


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