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Director's Report to the National Advisory Council on Drug Abuse - September, 2005

Research Findings - Research on Pharmacotherapies for Drug Abuse

Desipramine Treatment for Cocaine Dependence in Buprenorphine- or Methadone-treated Patients: Baseline Urine Results as Predictor of Response

Dr. Tom Kosten and colleagues at Yale University examined the prognostic importance of baseline urines for cocaine in a randomized, placebo-controlled, twelve-week clinical trial in 165 opioid- and cocaine-dependent patients who were treated with desipramine in combination with buprenorphine or methadone. Patients with a cocaine-positive urine at baseline had significantly fewer cocaine-free urines than those with a negative urine at baseline. The group with cocaine-positive urines at baseline showed a treatment effect of desipramine. This effect was significant in patients maintained on buprenorphine, but not on methadone. Kosten, T., Sofuoglu M., Poling J., Gonsai K., and Oliveto, A. Am. J. Addiction, 14(1), pp. 8-17, Jan-Feb 2005.

Immunotherapy for the Treatment of Drug Abuse

Dr. Tom Kosten at Yale and Dr. Michael Owens at University of Arkansas have summarized the present status of preclinical and clinical studies on immunotherapies (using both active and passive immunization) for drugs of abuse. Antibody therapy in the area of drug abuse treatment research is designed primarily to prevent drugs of abuse from entering the central nervous system. Because antibodies remain primarily in the circulatory system, they have no apparent CNS side effects. Antibodies have two immediate clinical applications in drug abuse treatment, to treat drug overdose and reduce relapse. Active immunization with vaccines has been tested preclinically for cocaine, heroin, methamphetamine and nicotine. There have been Phase 2 clinical trials with one cocaine vaccine and three nicotine vaccines in humans. Passive immunization with high affinity monoclonal antibodies has been tested preclinically for cocaine, methamphetamine, nicotine and PCP. The specificity of the antibodies, lack of abuse liability, minimal side effects, and long-lasting protection against drug use offer a major therapeutic benefit over small molecule agonists and antagonists. Immunotherapies could also be used in combination with other antiaddiction medications and enhance behavioral therapies. Kosten, T. and Owens, S.M. Pharmacology and Therapeutics 13, July 2005.

Vaccine Pharmacotherapy for the Treatment of Cocaine Dependence

Dr. Martell and colleagues at Yale University evaluated the safety, immunogenicity and clinical efficacy of a cocaine vaccine (TA-CD) in an open label, fourteen week, dose-escalation study in eighteen cocaine dependent subjects, of which sixteen completed the study. Ten subjects received four-100 microgram injections (totaling 400 micrograms) and eight subjects received five 400 microgram injections (totaling 2000 micrograms). There were no serious adverse events and the vaccine was well tolerated. The 2000 microgram total dose group had a significantly higher antibody titer response as compared to the 400 microgram dose group. The 2000 microgram dose group maintained more cocaine-free urines than those in the 400 microgram dose group. Despite relapse in both groups, most subjects reported an attenuation of cocaine's euphoric effects at the six month follow-up time points (63% in the 400 microgram dose group and 100% in the 2000 microgram dose group). Cocaine specific antibodies persisted at least six months. Martell, B.A., Mitchell, E., Poling, J., Gonsai, K. and Kosten, T.R. Biological Psychiatry, 58(2), pp. 158-164, July 2005.

Methadone Versus Buprenorphine With Contingency Management or Performance Feedback for Cocaine and Opioid Dependence

Although buprenorphine can now be prescribed for opioid agonist maintenance treatment outside of narcotic treatment programs, treatment guidelines for patients with co-occurring cocaine and opioid dependence are not available. Dr. Schottenfeld and other investigators at Yale carried out a 24 week clinical trial in 162 subjects to compare the effects of buprenorphine and methadone and evaluate the efficacy of combining contingency management (CM) with maintenance treatment for patients with a comorbidity of cocaine and opioid dependence. Cocaine and opioid dependent subjects were provided manual-guided counseling and randomly assigned in a double-blind design to receive daily sublingual buprenorphine (12-16 mg) or methadone (65-85 mg po) and to CM or performance feedback. It was found that subjects treated with methadone remained in treatment significantly longer and achieved significantly longer periods of sustained abstinence and a greater proportion of drug-free tests compared with subjects who received buprenorphine. Subjects receiving CM achieved significantly longer periods of abstinence and a greater proportion of drug-free tests during a period of escalating voucher compared with those who received performance feedback, but there were no significant differences between groups in these variables during the entire 24 week study. The conclusion drawn from this study is that methadone may be superior to buprenorphine for maintenance treatment of patients with co-occurring cocaine and opioid dependence. Combining methadone or buprenorphine with CM may improve treatment outcome. Schottenfeld, R.S., Chawarski, M.C., Pakes, J.R., Pantalon, M.V., Carroll, K.M. and Kosten, T.R. American Journal of Psychiatry 162, pp. 340-349, Feb 2005.

Effect of Nicotine Replacement Therapy on Post-cessation Weight Gain and Nutrient Intake: A Randomized Controlled Trial of Postmenopausal Female Smokers

This study of 94 postmenopausal female smokers evaluated the effect of nicotine replacement therapy (NRT) and hormone therapy (HT) on change in weight, energy intake, and physical activity during 2 weeks of smoking abstinence. Women, stratified by current use of HT, were randomized to nicotine or placebo patch. After 2 weeks of abstinence, women on nicotine patch had significantly larger increases in total caloric and fat intake than women on placebo patch and a trend toward larger increases in carbohydrates (total and sweet). Conversely, the nicotine group had less weight gain, 0.47 kg, than the placebo group, 1.02 kg (F=10.31, p=0.002). No effects were observed for hormone therapy. It appears that in short-term smoking abstinence, postmenopausal women on NRT gain less weight than do women on placebo, in spite of consuming more calories. This may be beneficial in the critical first 1-2 weeks of tobacco cessation, especially in light of postmenopausal weight gain. Allen, S.S., Hatsukami, D., Brintnell, D.M. and Bade, T. Effect of Nicotine Replacement Therapy on Post-cessation Weight Gain and Nutrient Intake: A Randomized Controlled Trial of Postmenopausal Female Smokers. Addict. Behav., 30, pp. 1273-1280, 2005.

Utility of Lead-in Period in Cocaine Dependence Pharmacotherapy Trials

The authors examined whether drug use behaviors during a 2-week lead-in for a pharmacotherapy trial were predictive of retention in treatment and of the level of cocaine use during the subsequent 12 weeks of treatment. Fifty cocaine dependent patients were grouped based on: (1) principal route of cocaine administration: intranasal versus smoking, and (2) level of cocaine use during the 2-week lead-in: high versus low. Results indicate that level of cocaine use during the 2-week lead-in was a significant predictor of cocaine use during the subsequent 12 weeks of treatment. Patients with reported higher level of use during the lead-in period were more likely to continue using cocaine during the treatment. Patients who used smoking as their primary route of cocaine use were more likely to drop out early in the treatment. Findings of this study suggest that route and level of cocaine use during lead-in be used as a covariate in models testing treatment effect. Bisaga, A., Aharonovich, E., Garawi, F., Levin, F. R., Rubin, E., Raby, W. N. et al. Utility of Lead-in Period in Cocaine Dependence Pharmacotherapy Trials. Drug Alcohol Depend., 77, pp. 7-11, 2005.

Tobacco Abstinence Symptom Suppression: The Role Played by the Smoking-related Stimuli that are Delivered by Denicotinized Cigarettes

This study was designed to clarify the impact of smoking-related stimuli on tobacco withdrawal, and to explore the duration of their ability to suppress withdrawal in smokers. Three double-blind, within-subjects, Latin square-ordered, 5-day conditions in which participants smoked nicotinized, denicotinized or no cigarettes. Subjective, physiological and performance measures were collected daily and compliance with study conditions was verified objectively. Smoking-related stimuli are sufficient for suppressing some symptoms of tobacco abstinence over a 5-day period [i.e. Questionnaire of Smoking Urges (QSU) factor 1, 'Desire for sweets', 'Hunger' and 'Urges to smoke'], while in this study a combination of nicotine and smoking-related stimuli suppressed other symptoms (i.e. 'Difficulty concentrating', 'Increased eating', 'Restlessness' and 'Impatient'). These results indicate that, while some tobacco abstinence symptoms may be suppressed with nicotine, suppressing others may also require strategies that address the absence of smoking-related stimuli. Buchhalter, A.R., Acosta, M.C., Evans, S.E., Breland, A.B. and Eissenberg, T. Tobacco Abstinence Symptom Suppression: The Role Played by the Smoking-related Stimuli that are Delivered by Denicotinized Cigarettes. Addiction, 100, pp. 550-559, 2005.

Modafinil Influences the Pharmacokinetics of Intravenous Cocaine in Healthy Cocaine-Dependent Volunteers

To determine if modafinil, a putative treatment for cocaine dependence, influences the pharmacokinetics of intravenous cocaine in otherwise healthy cocaine-dependent volunteers. Cocaine 20 or 40 mg was administered intravenously on consecutive days over 1 minute at baseline and after modafinil administration at each of two dosages of 400 and 800 mg/day for 7 days. Twelve subjects completed the clinical protocol. Compared with baseline, the cocaine peak plasma concentration was decreased after both the 20 and 40 mg cocaine infusions, but the reduction was only statistically significant after the 40 mg cocaine infusion (p < 0.01 after modafinil 400 mg/day; p < 0.05 after modafinil 800 mg/day). The area under the cocaine plasma concentration-time curve from 0 to 180 minutes (AUC180) was significantly decreased by modafinil administration (p < 0.01 and p < 0.001 for modafinil 400 and 800 mg/day, respectively, for the cocaine 20mg dose; p < 0.001 for the cocaine 40 mg dose at both modafinil levels). There were no significant changes in total AUC, clearance or elimination half-life of cocaine. This study did not find evidence for a harmful pharmacokinetic interaction between modafinil and cocaine. In contrast, long-term administration of modafinil significantly decreased systemic exposure to cocaine during the first 180 minutes following intravenous cocaine administration. Donovan, J.L., DeVane, C.L., Malcolm, R.J., Mojsiak, J., Chiang, C.N., Elkashef, A. et al. Modafinil Influences the Pharmacokinetics of Intravenous Cocaine in Healthy Cocaine-dependent Volunteers. Clin.Pharmacokinet., 44, pp. 753-765, 2005.

Screening and Intervention for Alcohol and Illicit Drug Abuse: A Survey of Internal Medicine Housestaff

This study attempts to determine how internal medicine housestaff screen and intervene for problematic alcohol and illicit drug use, as well as identify factors correlating with favorable practices. A cross-sectional survey was administered to 93 medical housestaff. Of 64 (69%) respondents, 94% reported routinely screening new patients for alcohol or illicit drug use, while only 52% routinely quantified alcohol consumption and 28% routinely used a screening instrument. Housestaff were unfamiliar with national guidelines and felt unprepared to diagnose substance use disorders, particularly prescription drug abuse. Most routinely counseled patients with alcohol (89%) or illicit-drug problems (91%), although only a third of these patients were referred for formal treatment. More thorough screening practices were associated with greater treatment optimism, while favorable referral practices were associated with greater optimism about 12-step program benefit and difficulty with management. These findings suggest areas to be addressed in residency curricula on substance abuse. Gunderson, E.W., Levin, F.R. and Smith, L. Screening and Intervention for Alcohol and Illicit Drug Abuse:A Survey of Internal Medicine Housestaff. J. Addict. Dis., 24, pp. 1-18, 2005.

Dronabinol and Marijuana in HIV+ Marijuana Smokers: Acute Effects on Caloric Intake and Mood

The aim of this study was to compare dronabinol (0, 10, 20, 30 mg p.o.) and marijuana [0.0, 1.8, 2.8, 3.9% Delta(9)-tetrahydrocannabinol (THC)] in two samples of HIV+ marijuana smokers: those with (n=15) and those without (n=15) a clinically significant loss of muscle mass (<90% body cell mass/height), which is one component of AIDS wasting. Mood, physical symptoms, self-selected food intake, cardiovascular data, and cognitive task performance were measured before and repeatedly after dronabinol and marijuana administration in eight 7-h sessions. Marijuana and dronabinol were administered in randomized order using a within-subject, staggered, double-dummy design. As compared to placebo, (1) marijuana (1.8, 2.8, 3.9% THC) and the lower dronabinol doses (10, 20 mg) were well tolerated (e.g., few physical symptoms, significant increases in ratings of "good drug effect") in both groups of participants; the highest dose of dronabinol (30 mg) was poorly tolerated in a subset of participants; (2) marijuana and dronabinol significantly increased caloric intake in the low bioelectrical impedance analysis (BIA) group but not in the normal BIA group; and (3) drug effects on cognitive performance were minor. These data suggest that for experienced marijuana smokers with clinically significant muscle mass loss, both dronabinol (at acute doses at least four to eight times the current recommendation) and marijuana produce substantial and comparable increases in food intake without producing adverse effects. Haney, M., Rabkin, J., Gunderson, E. and Foltin, R.W. Dronabinol and Marijuana in HIV+ Marijuana Smokers: Acute Effects on Caloric Intake and Mood. Psychopharmacology (Berl), Online First, March 19, 2005.

Reinforcing Effects of Oral Delta(9)-THC in Male Marijuana Smokers in a Laboratory Choice Procedure

Oral Delta-9-tetrahydrocannabinol (Delta(9)-THC; Marinol) is medically available for the treatment of nausea associated with cancer chemotherapy and for wasting syndromes related to HIV/AIDS. Little is known about its reinforcing effects. This study was conducted to characterize the reinforcing effects of oral Delta(9)-THC in experienced marijuana smokers under controlled laboratory conditions. Ten healthy male marijuana users completed this 17-day residential study. On days 2, 6, 10, and 14, at 0900 h, participants received a "sample" oral dose of Delta(9)-THC (0, 10, 20 mg) and an alternative reinforcer, a $2 voucher (redeemable for cash at study's end). Over the next 3 days, they had 11 opportunities to self-administer either the sampled dose of Delta(9)-THC or to receive a $2 voucher. Participants chose active Delta(9)-THC (10 and 20 mg) more often than placebo (< two selections vs approximately four selections, respectively). However, they chose active Delta(9)-THC on less than 50% of choice opportunities. Both active Delta(9)-THC doses produced significant increases in "positive" subjective effects, impaired psychomotor performance, and increased heart rate, relative to the placebo conditions. These data indicate that oral Delta(9)-THC may have modest abuse liability in experienced marijuana smokers. Hart, C.L., Haney, M., Vosburg, S.K., Comer, S.D. and Foltin, R.W. Reinforcing Effects of Oral Delta(9)-THC in Male Marijuana Smokers in a Laboratory Choice Procedure. Psychopharmacology (Berl), Online First, April 14, 2005.

Reducing Harm Caused by Tobacco: Research Findings from the University of Minnesota

Researchers from the University of Minnesota Transdisciplinary Tobacco Use Research Center have spent the past 5 years exploring ways to evaluate exposure to tobacco toxins in smokers and nonsmokers and reduce the associated health risks. This article discusses research into the health effects associated with smokers reducing the number of cigarettes they consume and using lower-tar cigarettes, modified tobacco products, and smokeless tobacco. Researchers found little, if any, benefit to products that promise less exposure to cancer-causing tobacco toxins. Hecht, S. and Hatsukami, D. Reducing Harm Caused by Tobacco. Research Findings from the University of Minnesota. Minn. Med., 88, pp. 40-43, 2005.

Co-morbidity of Smoking in Patients with Psychiatric and Substance Use Disorders

This article reviews cigarette smoking in patients with psychiatric disorders (PD) and substance use disorders (SUD). Rates of smoking are approximately 23% in the U.S. population but approximately two- to four-fold higher in patients with PD and SUD. Many remaining smokers have had repeated smoking cessation failures, possibly due to the presence of co-morbid PD and SUDs. There is modest, evidence-based support for effective treatment interventions for nicotine addiction in PD and SUD. Further research is needed to increase our understanding of nicotine addiction in PD and SUD and develop more effective treatment interventions. Kalman, D., Morissette, S.B. and George, T.P. Co-morbidity of Smoking in Patients with Psychiatric and Substance Use Disorders. Am.J.Addict., 14, pp. 106-123, 2005.

Inhibition of CYP2D6 Activity by Bupropion

The purpose of this study was to assess the effect of bupropion on cytochrome P450 2D6 (CYP2D6) activity. Twenty-one subjects completed this repeated-measures study in which dextromethorphan (30-mg oral dose) was administered to smokers at baseline and after 17 days of treatment with either bupropion sustained-release (150 mg twice daily) or matching placebo. Subjects quit smoking 3 days before the second dextromethorphan administration. To assess CYP2D6 activity, urinary dextromethorphan/dextrorphan metabolic ratios were calculated after an 8-hour urine collection. Thirteen subjects received bupropion, and 8 received placebo. In those receiving active medication, the dextromethorphan/dextrorphan ratio increased significantly at the second assessment relative to the first (0.012 +/- 0.012 vs. 0.418 +/- 0.302; P < 0.0004). No such change was observed in those randomized to placebo (0.009 +/- 0.010 vs. 0.017 +/- 0.015; P = NS). At baseline, all subjects were phenotypically extensive CYP2D6 metabolizers (metabolic ratio <0.3); after treatment, 6 of 13 subjects receiving bupropion, but none of those receiving placebo, had metabolic ratios consistent with poor CYP2D6 metabolizers. Bupropion is therefore a potent inhibitor of CYP2D6 activity, and care should be exercised when initiating or discontinuing bupropion use in patients taking drugs metabolized by CYP2D6. Kotlyar, M., Brauer, L.H., Tracy, T.S., Hatsukami, D.K., Harris, J., Bronars, C.A. et al. Inhibition of CYP2D6 Activity by Bupropion. J. Clin. Psychopharmacol., 25, pp. 226-229, 2005.

Spontaneous Smoking Cessation During Pregnancy Among Ethnic Minority Women: A Preliminary Investigation

This study examined the postpartum relapse rates and characteristics of pregnant women who stopped smoking without professional intervention. Baseline characteristics of women who spontaneously quit were compared to women who continued to smoke. Women who spontaneously quit were also randomized to a psychotherapy relapse prevention treatment, or to usual care. The sample was ethnically diverse, containing 141 low-income women who were predominantly Hispanic, 23% (n=33) of whom spontaneously quit smoking. The variables that significantly differentiated between "spontaneous quitters" and ongoing smokers were entered into a regression analysis, which revealed that higher self-confidence, smoking fewer cigarettes per day, and younger age accounted for 25% of the variance in spontaneous cessation. Adding the psychotherapy intervention conferred no additional protection against relapse in this subgroup of spontaneous quitters. The six-month abstinence rate of 36% is similar to that found in Caucasian and higher-income populations. These results extend research with pregnant smokers to a new population and may have implications for healthcare providers and policy makers. Morasco, B.J., Dornelas, E.A., Fischer, E.H., Oncken, C. and Lando, H.A. Spontaneous Smoking Cessation During Pregnancy Among Ethnic Minority Women: A Preliminary Investigation. Addict. Behav. In Press, Corrected Proof Available Online May 24, 2005.

Reinstatement of Morphine-Conditioned Reward is Blocked by Memantine

Protection of abstinent individuals from relapse is the main goal of drug dependence treatment. Relapse is frequently precipitated by exposure to small doses of the drug of abuse or exposure to the environment that was previously associated with the drug. Mice exposed to morphine (10 mg/kg) in a unique test-box environment display a conditioned place preference for this environment. Such preference can be extinguished by subsequent pairing of physiological saline administration with the same environment. Once extinguished, the original place preference can be reinstated after a priming dose (1-2.5 mg/kg) of morphine is given. However, mice treated with 7.5 (but not 3.75) mg/kg of memantine (the glutamate/NMDA receptor antagonist) during the extinction phase were insensitive to morphine's ability to reinstate the place preference 2 days after extinction conditionings. Effect of memantine was also observed when priming dose of morphine was given 21 days after extinction conditionings. In contrast, morphine's ability to reinstate conditioned response was not affected by treatment with 10 mg/kg of chlordiazepoxide, 0.5 mg/kg of LSD-25, or 1 mg/kg of morphine given during extinction conditionings. A separate experiment demonstrated that memantine (7.5 mg/kg) treatment did not affect learning. The authors show for the first time that memantine treatment during extinction conditionings may abolish the ability of drug-related cues to evoke reinstatement, suggesting that this NMDA receptor antagonist can be useful in preventing relapse in opioid dependent individuals. Popik, P., Wrobel, M. and Bisaga, A. Reinstatement of Morphine-Conditioned Reward is Blocked by Memantine. Neuropsychopharmacology, Advance Online Publication, May 1, 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. The investigators analyzed adult responses to the 1997 NHSDA (n = 16,661) 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. Cigarette Smoking Among Marijuana Users in the United States. Subst.Abus., 25, pp. 35-43, 2005.

An Evaluation of the Reinforcing Effects of Memantine in Cocaine-dependent Humans

The purpose of this double-blind, outpatient study was to evaluate the reinforcing and subjective effects of the uncompetitive N-methyl-d-aspartate (NMDA) antagonist memantine in cocaine-dependent humans. Eight participants (two females, six males) completed this study which consisted of three blocks of seven sessions; each block tested a different dose of memantine. During the first two sessions of each block, participants "sampled" the memantine capsule (10, 20, or 30mg) and the placebo capsule that were available for the next five sessions. During the five subsequent sessions, participants had an opportunity to self-administer either the active or placebo capsule. Memantine was not reinforcing and subjective-effects ratings were not altered as a function of dose. Results suggest that these doses of memantine do not have abuse liability in cocaine-dependent individuals. Vosburg, S.K., Hart, C.L., Haney, M. and Foltin, R.W. An Evaluation of the Reinforcing Effects of Memantine in Cocaine-dependent Humans. Drug Alcohol Depend., 79, pp. 257-260, 2005.

The Integration of Tobacco Dependence Treatment and Tobacco-free Standards into Residential Addictions Treatment in New Jersey

New Jersey was the first state to implement a licensure standard for all residential addiction treatment programs to assess and treat tobacco dependence in the context of entirely tobacco-free facilities (including grounds). A program evaluation of the first year of the policy (2001-2002) assessed the impact on programs, clients, and staff. At 1-year follow-up, all 30 residential programs surveyed provided some tobacco dependence treatment and 50% had tobacco-free grounds. Eighty-five percent of the programs accepted the state's offer to provide free NRT, reaching more than 2,326 clients. Seventy-seven percent of all clients were smokers, and 65% of the smokers reported they wanted to stop or cut down tobacco use. Forty-one percent of the smokers reported that they did not use any tobacco during their entire residential stay. There was no increase in irregular discharges, or reduction in proportion of smokers among those entering residential treatment, compared with prior years. Licensure standards regulation can be an effective mechanism for increasing the quantity and quality of tobacco dependence treatment in residential addictions programs. Williams, J.M., Foulds, J., Dwyer, M., Order-Connors, B., Springer, M., Gadde, P. et al. The Integration of Tobacco Dependence Treatment and Tobacco-free Standards into Residential Addictions Treatment in New Jersey. J. Subst. Abuse Treat., 28, pp. 331-340, 2005.

Increased Nicotine and Cotinine Levels in Smokers with Schizophrenia and Schizoaffective Disorder is Not a Metabolic Effect

It has been hypothesized that smokers with schizophrenia take in more nicotine per cigarette than smokers without this disorder. This study examines this phenomenon by comparing the serum nicotine and cotinine levels in smokers with either schizophrenia or schizoaffective disorder compared to control smokers without mental illness. Serum cotinine and nicotine levels of smokers with schizophrenia or schizoaffective disorder were 1.3 times higher than control smokers (cotinine 291 versus 227 ng/mL; p=0.0115; nicotine 28 versus 21 ng/mL; p<0.001) despite smoking a similar number of cigarettes per day. Similar serum 3'-hydroxycotinine (3HC) to cotinine ratios in both groups indicate that this difference was not due to differences in the rate of metabolism of nicotine or cotinine. By examining serum nicotine and 3HC/cotinine ratios in addition to cotinine, this study expands upon previous research that relied on cotinine as an indirect indicator for nicotine intake. Our data support the hypothesis that the increased serum nicotine and cotinine levels observed are attributable to an increased nicotine intake per cigarette in smokers with schizophrenia as compared to those without mental illness. Williams, J.M., Ziedonis, D.M., Abanyie, F., Steinberg, M.L., Foulds, J. and Benowitz, N.L. Increased Nicotine and Cotinine Levels in Smokers with Schizophrenia and Schizoaffective Disorder is Not a Metabolic Effect. Schizophr. Res, In Press, Corrected Proof Available Online, June 14, 2005.

Assessing Missing Data Assumptions in Longitudinal Studies: An Example Using A Smoking Cessation Trial

Due to the chaotic nature of the clinical disorder, longitudinal data analysis in substance abuse research is plagued by missing values. To obtain an unbiased estimation on intervention effects, different longitudinal modeling strategies require various assumptions on the patterns and mechanisms of missing data. By defining missingness as intermittent missingness (occasional omission) and dropout (premature withdrawal), this article demonstrates statistical ways for assessing missing data assumptions using evidence from a clinical trial. Within the framework of multiple imputation, intermittent missing data are imputed first so that dropouts can be isolated and treated specifically. A computational tool called "pattern reduction resampling" is proposed to simplify missing data methods when the number of intra-subject repeated measures is large. To test whether missingness patterns are nondifferential across treatment conditions, a formal testing approach treats indicators of missingness as a special type of repeated measures (e.g., 0: intermittent missing, 1: observed, and 2: dropout missing). After reviewing the idea of ignorability for missing data and of classifying missingness mechanisms into subcategories, the article provides an example for assessing common assumptions on missingness mechanisms and how these assumptions affect model selection for significance testing. A carbon monoxide longitudinal data set in a smoking cessation study is used for illustration. Yang, X. and Shoptaw, S. Assessing Missing Data Assumptions in Longitudinal Studies: An Example Using a Smoking Cessation Trial. Drug Alcohol Depend., 77, pp. 213-225, 2005.


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