1. A Placebo-Controlled Trial of Selegiline Hydrochloride for Smoking Cessation Tony P. George, M.D., Jennifer Vessicchio, M.S.W., Angelo Termine, B.S., Peter Jatlow, M.D., Thomas Kosten, M.D. and Stephanie S. O’Malley, Ph.D. Center for Nicotine and Tobacco Use Research at Yale (CENTURY), Department of Psychiatry, Yale University School of Medicine New Haven, Connecticut USA 06519 tony.george@yale.edu Supported by NIDA (P50-DA-13334)

3. Introduction Cigarette smoking rates in the general population are ~23%, and those who continue to smoke have had multiple quit attempt failures [CDC, 2003] In spite of nicotine replacement therapies and Bupropion SR (Zyban ® ), there is a strong need to develop better pharmacological treatments for nicotine dependence. Monoamine oxidase B (MAO-B) preferentially metabolizes dopamine, which is an important neurotransmitter in the biology of nicotine dependence. Selegiline hydrochloride (L-Deprenyl ® ) is a MAO-B inhibitor that increases synaptic levels of dopamine. In addition, an unidentified component of tobacco smoke (not nicotine) inhibits MAO-A and B isoforms [Fowler et al., 1996].

4. [Fowler et al., 1996. Nature. 379: 733-736] Inhibition of MAO-B by Cigarette Smoking [Fowler et al., 1996. Nature. 379: 733-736]

5. Study Aims To determine if selegiline (10 mg/day) enhances smoking cessation rates compared to placebo in refractory cigarette smokers. To determine the safety and tolerability of selegiline in cigarette smokers. To determine if the presence of depressive at the beginning of treatment alters smoking cessation outcomes with selegiline.

6. Study Methodology Potential cigarette smoking subjects were recruited from the community through newspaper advertisements and word of mouth. Smoked at least 20 cigarettes/day, with a CO level >10 ppm, plasma cotinine > 150 ng/ml and FTND score > 5 (see Table 1). Excluded if they met DSM-IV criteria for an Axis I psychiatric disorder and/or alcohol or illicit drug abuse and dependence disorder (besides nicotine or caffeine). Subjects with a past history of major depression or current depression were included but could not be prescribed antidepressant drugs. Subjects were randomized to selegiline hydrochloride (SEL; 5 mg po bid) or matching placebo, which was begun during Week 1 of the study, for a total of 8 weeks. The quit date was set at the beginning of Week 3. Study medications were tapered during Week 9 of the study. All subjects participated in weekly individual therapy for the 8-week trial which emphasized motivational enhancement and relapse- prevention therapies, derived from AHCPR (2000) Guidelines.

7. Selegiline Smoking Cessation Study Design Quit Date (Week 3) SEL (taper to 5 mg qd x 7 days), then d/c Weekly Individual Therapy (AHCPR) Week 1 (start meds; SEL 5 mg qd) Week 9 Week 2 Maintain at 5 mg po bid x 7 weeks Week 4Week 8 6-Month Follow-up

8. Table 1: Demographic and Baseline Clinical Characteristics of Cigarette Smokers Prescribed Selegiline Hydrochloride versus Placebo (n=40) Selegiline (n=20) Placebo (n=20) Age: 49.7±7.0 48.3±10.3 Sex: 8M/12F 7M/13F Race: 15W/5B 15W/3B/2O Education (years): 13.5 ± 1.6 14.4±3.2 Cigarettes/Day: 23.0±10.0 22.4±8.1 Smoking Pack-Years a : 38.2­+22.1 32.9+16.2 Previous Quit Attempts: 9.4±21.7 4.7±2.7 Baseline CO Level (ppm): 21.7±7.3 22.6±9.9 FTND Score: 6.6±1.4 6.6±1.8 Plasma Cotinine (ng/ml) 294±99 241±84 Urine Cotinine (ng/ml): 1705±772 1673±770 Motivation to Quit (0-4): 3.7±0.8 3.8±0.6 History of MDD: 3/20 (15.0%) 7/20 (35.0%) BDI Score: 7.4±5.9 8.4±7.3 _______________________________________________________________ _______ _ W=white B=black O=other race CO=Carbon Monoxide FTND=Fagerstrom Test for Nicotine Dependence MDD = Major Depressive Disorder BDI=Beck Depression Inventory a Smoking Pack-Years were calculated as average daily smoking multiplied by number of years smoking. p>0.05, all comparisons George, T.P. et al (2003). Biological Psychiatry. 53: 136-143.

9. Selegiline versus Placebo: Treatment Retention Log Rank Test   = 2.27, df =1, p=0.13

10. Selegiline versus Placebo: Abstinence Outcomes George, T.P. et al. (2003)

11. Table 2: Number (Percentage) of Cigarette Smoking Subjects Reporting Adverse Events Prescribed Selegiline Hydrochloride and Placebo During the Trial (n=40) Adverse Event: Selegiline (n=20) Placebo (n=20) Headache: 8 (40) 9 (45) Anorexia: 3 (15) 2 (10) Constipation: 5 (25) 3 (15) Nausea/Vomiting: 5 (25) 4 (20) Difficulty Falling Asleep: 4 (20) 6 (30) Frequent Night Awakenings: 6 (30) 4 (20) Early Morning Awakenings: 4 (20) 5 (25) Memory Problems: 6 (30) 5 (25) Anxiety/Agitation: 7 (35) 8 (40) Psychotic Symptoms: 0 (0) 1 (5) Dyskinesias: 0 (0) 0 (0) p>0.05, all comparisons George, T.P. et al. (2003)

12. Depressed (Beck Score >10) versus Not Depressed at Baseline: Smoking Abstinence * * Wald Statistic=1049, df=1, p<0.01

13. Conclusions Selegiline hydrochloride (10 mg/day) significantly enhanced smoking cessation rates compared to placebo in nicotine-dependent cigarette smokers. SEL is well-tolerated and safe for use in these patients. Current depression (Beck Score>10) at trial baseline is a negative predictor of smoking cessation outcomes with selegiline. These preliminary results support the safety and efficacy of an MAO-B inhibitor for smoking cessation.

14. Future Studies Replication of these findings in a larger placebo- controlled, single-site Phase II trial [NIH grant 1R01-DA- 15757-01A1; PI: Tony P. George, M.D., 3/1/04-2/29/08, Priority Score 126 from NIDA-E IRG].Replication of these findings in a larger placebo- controlled, single-site Phase II trial [NIH grant 1R01-DA- 15757-01A1; PI: Tony P. George, M.D., 3/1/04-2/29/08, Priority Score 126 from NIDA-E IRG]. Special populations – heavy drinkers, women, adolescents.Special populations – heavy drinkers, women, adolescents. Pre-clinical studies (self-admnistration, place preference, neurochemical studies to evaluate alternative mechanisms of action to MAO-B inhibition?).Pre-clinical studies (self-admnistration, place preference, neurochemical studies to evaluate alternative mechanisms of action to MAO-B inhibition?). Human laboratory studies to evaluate the clinical mechanism of action of selegiline, and other selective MAO-B inhibitors as they become available (e.g. labazemide).Human laboratory studies to evaluate the clinical mechanism of action of selegiline, and other selective MAO-B inhibitors as they become available (e.g. labazemide).