Olanzapine Reduces Urge to Smoke and Nicotine Withdrawal Symptoms in Community Smokers

Experimental and Clinical Psychopharmacology Copyright 2008 by the American Psychological Association 2008, Vol. 16, No. 3, 215 222 1064-1297/08/$12.00 DOI: 10.1037/1064-1297.16.3.215 Olanzapine Reduces Urge to Smoke and Nicotine Withdrawal Symptoms in Community Smokers Damaris J. Rohsenow Providence Veterans Affairs Medical Center and Center for Alcohol and Addiction Studies, Brown University Jennifer W. Tidey and Robert Miranda Jr. Center for Alcohol and Addiction Studies, Brown University John E. McGeary, Robert M. Swift, Kent E. Hutchison, Alan D. Sirota, and Peter M. Monti Providence Veterans Affairs Medical Center and Center for Alcohol and Addiction Studies, Brown University Olanzapine (OLAN), an atypical antipsychotic medication with mixed 5-HT2/DA antagonist properties, was predicted to dose-dependently decrease urge to smoke, withdrawal, and cigarette reinforcement in smokers without psychosis. A double-blind placebo-controlled within-subjects cross-over trial investigated the acute effects of OLAN (0, 2.5, and 5.0 mg; counterbalanced order) in 24 community smokers who underwent 10-hr smoking deprivation. Urge to smoke, tobacco withdrawal, and cigarette reinforcement were assessed with cue reactivity and behavioral choice procedures. OLAN (2.5 mg) reduced withdrawal symptoms before and during cue exposure and decreased urge associated with anticipated positive affect from smoking before and during cue exposure; 5.0 mg OLAN decreased withdrawal only when cues were included. OLAN did not affect preference for cigarette puffs versus money, smoke intake, or urge to smoke associated with negative affect relief. The results indicate a potentially beneficial effect of 2.5 mg OLAN on tobacco withdrawal and urge to smoke. Combined 5HT/DA antagonists should be considered for future development of pharmacotherapies for smoking cessation. Keywords: Olanzapine, smoking, cue reactivity, urge to smoke, nicotine withdrawal, atypical antipsychotic Developing effective pharmacotherapies for tobacco addiction is clearly a public health priority. Despite considerable efforts to improve smoking cessation rates, treatment outcomes remain modest (Fiore et al., 2000). Current pharmacotherapies are far from panaceas, given that long-term abstinence rates are only 10% to 35%, even with nicotine replacement (NR), bupropion or varenicline (e.g., Fiore et al., 2000; Gonzales et al., 2006; Rose, 1996). Although the past decade has identified novel pharmacological agents to improve smoking cessation rates, additional research is needed to identify the diversity of medication types that may best suit the needs of each smoker (Henningfield et al., 2005), given that different medications may be more effective for different smokers based on different biobehavioral mechanisms. Interest in the potential for atypical antipsychotics to improve smoking cessation efforts was generated by the observation that these medications reduce tobacco and other drug use among patients with schizophrenia (Drake, Xie, McHugo, & Green, 2000; George, Sernyak, Ziedonis, & Woods, 1995; George et al., 2000; Lee et al., 1998; McEvoy, Freudenreich, Levin, & Rose, 1995; McEvoy et al., 1995; Zimmet, Strous, Burgess, Kohnstamm, & Green, 2000). These effects could be secondary to their beneficial effects on psychiatric symptoms or their ability to reverse brain reward system deficits in patients with schizophrenia (e.g., Green, Zimmet, Strous, & Schildkraut, 1999; Khantzian et al., 1997). Alternatively, the fact that atypical antipsychotic medications reduce drug use in animals (e.g., Meil & Schechter, 1997) suggests that these beneficial ef- Damaris J. Rohsenow, John E. McGeary, Robert M. Swift, Kent E. Hutchison, Alan D. Sirota, and Peter M. Monti, Providence Veterans Affairs Medical Center and Center for Alcohol and Addiction Studies, Brown University; Jennifer W. Tidey and Robert Miranda Jr., Center for Alcohol and Addiction Studies, Brown University. Dr. Hutchison is now at the Department of Psychology, University of New Mexico, Albuquerque, NM. This research was supported in part by a Merit Review Grant from the Office of Research and Development, Medical Research Service; by a Research Career Scientist Award and a Senior Research Career Scientist Award from the Department of Veterans Affairs; and by a training grant from the National Institute on Alcohol Abuse and Alcoholism (T32 AA07459). Portions of these data were presented at the annual meeting of the Society for Research on Nicotine and Tobacco, Prague, Czech Republic, March 2005, and at the annual meeting of the World Congress of Psychiatric Genetics, Cagliari, Italy, October 2006. The experiment complied with the laws of the United States of America and the ethical principles of the Declaration of Helsinki and of the American Psychological Association. Correspondence concerning this article should be addressed to Damaris J. Rohsenow, PhD, Center for Alcohol and Addiction Studies, Brown University, Box G-S121-5, Providence, RI 02912. E-mail: Damaris_Rohsenow@Brown.edu 215

216 ROHSENOW ET AL. fects are not limited to psychiatric patients, but may directly result from their dopamine D 1 or D 4 antagonist activity (Imperato, Mulas, & DiChiara, 1986; Merea et al., 1987; Self, Burnhart, Lehman, & Nestler, 1996; Van Tol et al., 1991) and/or serotonin antagonist effects (McMillen et al., 1993; Meert, Awouters, Niemegeers, Schellekens, & Janssen, 1991; Myers, Lankford, & Bjork, 1992). Only one published report has examined the effects of olanzapine on smoking-related variables among individuals without a history of a psychotic disorder. In a randomized between-subjects placebo-controlled design, olanzapine (5 mg) significantly reduced cue-elicited craving for cigarettes in the laboratory among nonpsychotic smokers, but did not affect subjective effects of smoking cigarettes, such as stimulation, enjoyment, and wanting more cigarettes (Hutchison et al., 2004). Olanzapine and clozapine (an atypical antipsychotic with similar pharmacological characteristics) have been reported to reduce cue-elicited craving for alcohol and attenuate other substance use (Drake et al., 2000; Green et al., 1999; Hutchison et al., 2001; Lee et al., 1998; Zimmet et al., 2000), as well as block the reinforcing effects of cocaine in rats (Meil & Schecter, 1997), further supporting their potential value. Lower doses (2.5 5.0 mg; Hutchison et al., 2006; Hutchison et al., 2004) appear to be more effective than higher doses (10 15 mg; Guardia et al., 2004) for drinking-related outcomes. Despite initial promise for the use of olanzapine to treat nicotine dependence, the side effect profile seen in doses generally used with psychotic disorders (10 15 mg/day; Olanzapine, 2000), especially weight gain and sedation, tempers enthusiasm for its clinical use for smoking cessation. Therefore, it would be valuable to determine whether lower doses that minimize side effects are associated with significant benefit. Furthermore, an understanding of biobehavioral mechanisms by which smoking interventions exert beneficial effects can suggest directions for future pharmacologic approaches to treating smoking. Even if olanzapine itself is not acceptable to smokers, beneficial effects of olanzapine on smoking variables that are often associated with treatment success could lead to the development of other medications for smoking that have similar mechanisms of action but fewer side effects. The efficacy of medications for smoking can occur in part by their ability to decrease craving and withdrawal during abstinence and in part by their ability to reduce reinforcing effects of smoking when a lapse occurs (Dale et al., 1995; Ferguson, Shiffman, & Gwaltney, 2006; Hurt, Dale, Offord, & Croghan, 1995; Jorenby et al., 1996; Levin et al., 1994; Perkins, Stitzer, & Lerman, 2006). Medications that reduce increases in craving elicited by smoking-related stimuli may prove especially effective in reducing smoking relapse (Hutchison et al., 2004) since intensity of urge to smoke has been found to predict relapse in the natural environment (Shiffman et al., 1997; Shiffman, Paty, Gnys, Kassel, & Hickcox, 1996). No studies among nonpsychotic smokers have assessed the effects of olanzapine on nicotine withdrawal or on the reinforcement value of smoking cigarettes. Effects of a medication on craving may be independent of ability to alter the reinforcement value of smoking to the extent that desire and reinforcement value are independent (Robinson & Berridge, 1993). Since craving is not a necessary aspect of withdrawal (Hughes & Hatsukami, 1998; Hughes, 2007), involves both positive-affective and negative reinforcement components (Tiffany & Drobes, 1991), and can persist long after withdrawal has abated, medication effects on craving may be independent of its ability to attenuate withdrawal. The present study examined the hypothesized dose-dependent effects of olanzapine (0, 2.5, 5.0 mg) on urge to smoke, 1 withdrawal symptoms, and the reinforcement value of smoking in community smokers after 10-hr tobacco abstinence. The first question was whether a lower dose of olanzapine (2.5 mg) would also be effective in reducing urges to smoke, since a lower dose should have fewer side effects while higher doses of olanzapine may produce iatrogenic effects (Hutchison et al., 2006). Second was whether effects of olanzapine would be different across appetitive-based versus negative reinforcement-based urges to smoke since these may involve different neural substrates (Baker, Sherman, & Morse, 1987; Tiffany & Drobes, 1991). Third and fourth were whether olanzapine would affect withdrawal symptoms and a behavioral measure of degree of reinforcement from smoking. Urges to smoke and withdrawal were assessed both before and after cigarette cue exposure because deprivation in the absence of smoking cues reflects a common experience for smokers trying to quit smoking, while exposure to smoking cues mimics a common smoking relapse precipitant (Shiffman, 1982). As has been the case with medications for alcohol dependence (e.g., Rohsenow et al., 2000), a medication that mitigates cue-elicited increases in urge to use or withdrawal could be protective in high-risk situations. Naltrexone was found to decrease cue-elicited increases in nicotine withdrawal, but not abstinence-induced increases in withdrawal or urge to smoke (Rohsenow et al., 2007), while transdermal nicotine has not shown differential effects in urge or withdrawal based on presence or absence of smoking cues (e.g., Tiffany, Cox, & Elash, 2000). Reinforcement from smoking was assessed within a behavioral choice paradigm (choice between cigarette puffs and monetary reinforcement), in which response allocation and smoke intake are used to indicate reinforcing efficacy while latency to smoking indicates anticipated reinforcement from smoking (Herrnstein, 1970; Katz, 1990). This paradigm was intended to model medication effects on the reinforcement value of a lapse during abstinence. Thus, the design allowed for a determination of the dose-response effects of olanzapine on several of the mechanisms by which medications could be beneficial from smoking cessation after a period of tobacco deprivation. 1 We agree with the recommendations of Kozlowski et al. (1989) to use the term urge or desire rather than craving (except when referring to someone else s measure) because urge is less ambiguous and covers a broader continuum of degree of desire to use.

OLANZAPINE DURING SMOKING DEPRIVATION 217 Design Method Participants were administered a single dose of olanzapine (0, 2.5, 5.0 mg) in a double-blind placebo-controlled within-subjects cross-over trial. Sessions were scheduled a week apart, with dose order counterbalanced across participants. Doses were selected based on Hutchison et al. (2004) as most likely to be effective while minimizing sedation. A study with the same repeated-assessment design without medication demonstrated no threat to validity of repeated days of cue reactivity assessment (Miranda, Rohsenow, Monti, Tidey, & Ray, 2008). Participants Smokers recruited from the community (n 24) participated in the study. Participants needed to be at least 18 years old, to have smoked 10 cigarettes per day for the past 6 months, and to be contemplating smoking cessation within 6 months (to increase the relevance of the population; Perkins et al., 2006) but not in the next month (during the study). Exclusionary criteria were (a) contraindicated medical condition or medication; (b) positive urine drug screen; (c) history of schizophrenia spectrum disorder; (d) pregnancy, nursing, or refusal to use reliable birth control method if female; (e) medications that could affect smoking urges/behavior or cue reactivity; (f) weight other than 110 220 lbs (to prevent excessive range in g/kg dose). Power analysis (Cohen, 1988) indicated that at least 20 participants would be needed to detect a medium statistical effect. Procedure Recruitment and screening procedures. Smokers were recruited from an urban community using flyers and radio announcements. A brief telephone screening interview was followed (with separate consent) by an in-person medical screening and laboratory tests prior to obtaining written informed consent for the study. Medication administration. Olanzapine and placebo tablets were placed in opaque gelatin capsules with 50 mg of riboflavin powder filler. Placebo tablets were unlabeled 160 mg tablets of acetaminophen because the bitterness made them credible if tasted (matching placebos were no longer manufactured). Medication was dispensed doubleblind. Participants were told to take the medication at 10 p.m., approximately 10 hours prior to scheduled laboratory sessions. Overnight dosing and taxicab transport were used to minimize potential harm from sedation. Olanzapine concentrations peak within six hours after a single oral dose, with an elimination half-life of about 30 hr ( Olanzapine, 2000). Tobacco deprivation. Participants were instructed to smoke their last cigarette at 10 p.m. to provide 10 hr deprivation by the start of assessment. Compliance assessment. Urine was screened for riboflavin each assessment day to ensure medication compliance per Del Boca, Kranzler, Brown, and Korner (1996). Exhaled carbon monoxide (CO) was collected each day to verify overnight abstinence from smoking (CO 10 ppm). Both criteria needed to be met prior to assessing the participant. Overview of laboratory procedures. Procedures started each day after an 8 a.m. arrival (all times were shifted an hour later for some participants to accommodate schedules). On the first day, participants completed individual difference measures and received medication with instructions. On the subsequent three visits, participants completed the 30-min cue reactivity procedure followed by the 2.5 hr cigarette choice procedure. The choice procedures always followed the cue procedure to ensure deprivation prior to cue reactivity assessment and because knowledge that smoking can occur immediately after cue exposure increases reactivity (Droungas, Ehrman, Childress, & O Brien, 1995). Cigarette cue reactivity procedures. Participants were seated at a table with a computer beside a one-way mirror in a well-ventilated room. A tray with two inverted opaque covers was placed before the participant. Under each cover was an open pack of the participant s preferred brand of cigarettes with one cigarette out of pack, a lighter and an ashtray. After the initial instruction period, all instructions were presented via audiotape. Participants were asked to relax for four minutes and then were exposed to two 4-min trials of smoking cues. Participants were asked to lift the first cover and look at the smoking cues for two minutes, then to pick up the cigarette, light it without putting it in their mouths by holding it downward, hold it in one hand in a comfortable manner without smoking it, and look at it for two minutes. Participants extinguished the cigarette, completed self-report measures, then replaced the cover. Participants repeated the procedures with the second set of cues. This procedure was repeated to determine whether medication effects would increase upon a second exposure to cues as was found for naltrexone s effects on alcohol cue reactivity (Monti et al., 1999; Rohsenow et al., 2000). Measures were completed after each 4-min trial (relaxation and cues). At the end of the cue reactivity procedures was a 5-min supervised break. Cigarette choice procedures. During the 2.5-hr cigarette choice procedure, participants had 20 opportunities to choose between smoking two cigarette puffs versus monetary reinforcement (10 cents per choice). Pilot work determined the monetary amount that would result in approximately 50% smoking choices among unmedicated smokers deprived of tobacco overnight. Participants could make choices at any time except during the 120-s after a previous choice was made, but were required to remain in the laboratory for the 2.5 hr procedure regardless of choice allocation or timing. Choices were registered on a computer keyboard interfaced with a laptop computer. When cigarette puffs were chosen, participants immediately smoked through a cigarette holder connected via flexible tubing to a volumetric low-pressure transducer connected to a desktop computer [Clinical Research Support System (CReSS), Plowshare Technologies, Baltimore], which signaled participants to stop puffing when the puff volume reached 50 ml.

218 ROHSENOW ET AL. When monetary reinforcement was chosen, the amount was added to a running total paid in cash at the end of the session. The total number of choices made for each option, time remaining in the session, and time remaining during the intertrial intervals were continuously displayed on a computer monitor facing the participant. Breath CO levels were measured immediately before and after the choice period. Domains of Assessment and Measures Individual difference measures. Demographic and smoking history questionnaires and the Fagerström Test for Nicotine Dependence (FTND; Heatherton, Kozlowski, Frecker, & Fagerström, 1991) were completed. Cigarette cue reactivity measures. The Minnesota Nicotine Withdrawal Scale (MNWS; Hughes & Hatsukami, 1986), excluding insomnia (not appropriate for current state) and desire/craving (based on Hughes & Hatsukami, 1986; Hughes, 2007; and to allow assessment of the effects on withdrawal independent of effects on craving), was administered with instructions to refer to how participants felt right now. The six symptoms were rated on 5-point Likert scales of severity. The 10-item brief Smoking Urge Questionnaire (BQSU; Cox, Tiffany, & Christen, 2001) was administered to assess urge to smoke right now on 7-point Likert scales. The two reliable and valid factors of the BQSU, (a) positive affect based or appetitive urge and (b) negative-reinforcement based urge (anticipation of relief from negative affect), represent different underlying neural pathways (Baker et al., 1987). These instruments were administered following relaxation and each cue exposure trial. Cigarette choice measures. Number of choices for cigarette puffs and latency to first puff choice (in msec) were recorded. A CO monitor (Smokerlyzer, Bedfont Scientific Ltd.) assessed CO boost (difference score) across the cigarette choice procedure. Medication side effects. On arrival on each assessment day, an interviewer administered a side effects checklist in which 17 expected side effects (e.g., drowsiness, very low energy, dizziness) were rated on 4-point anchored scales from 0 none to 4 severe and any other side effects were noted. Data Analysis Plan Preliminary analyses. Variables were checked for assumptions of normality. CO boost and latency to first choice of a cigarette puff needed to be log-transformed to correct skewness (untransformed means are reported). Measures repeated across cue exposure trials were checked for collinearity. Sample sizes did not permit order to also be added as a factor along with dose. Order effects were tested by analyzing effects of testing day (collapsed across dose) on resting values of cue-elicited variables and on choice task variables using a 3-group (day) repeated measures analysis of variance (ANOVA) and for cue-elicited variables using 2 3 cue trial (resting trial and mean of two smoking cue trials) by day repeated measures ANOVAs. Analyses of hypotheses. Effects of the medication on unelicited measures (measures following the resting trial prior to any cue exposure) and on cigarette choice variables were analyzed using a 3-group (medication conditions) repeated measures analysis of variance (ANOVA) for each variable. Univariate rather than multivariate analyses were used because of interest in the effects of each measure rather than on the linear combination of measures. Effects of medication on cue-elicited self-report responses were investigated using 2 3 cue trial (resting trial and mean of two smoking cue trials) by olanzapine dose (0, 2.5, 5.0 mg) repeated measures ANOVA. Significant effects were followed up with planned comparisons (Neuman-Keuls) between doses. The two smoking cue trials were combined to simplify analyses because of their collinearity as noted below. Difference scores double error variance, so were not used for cue reactivity. Using analysis of covariance to investigate effects of cues while covarying the baseline value is not valid when a medication can affect the resting value. Analyses were conducted using the two BQSU factors separately, as medication could have a separate effect on positive or appetitive urge as opposed to negative-reinforcement urge pathways. Expected side effects on medicated days were compared to those reported on the placebo day using frequency counts. Statistical effect sizes for ANOVAs are reported using Cohen s f (Cohen, 1988), with f.25 being small, f of.25 to.39 being medium, and f.40 being large. Results Participant Characteristics Participants were 67% male, 54% married or cohabiting, 83% Caucasian, 13% Black, and 4% Hispanic, and 37.5% were employed. Their mean age was 42.1 12.7 [SD] years; mean cigarettes per day was 21.5 5.2 (range 10 30); mean length of daily smoking was 24.4 13.8 years (range 5 30); and mean FTND score was 6.3 1.4 (range 4 9). Preliminary Analyses Dependent measures of cue reactivity were collinear between the two smoking cue trials on all three days: mean r.92 for BQSU total score (range.87 to.95), mean r.90 for MNWS (range.88 to.94), ps.001. Participants mean CO level on arrival was 22.5 11 ppm on the nondeprived DAY1 and was M 7.7 2.3 ppm on the three deprived days, indicating considerable deprivation. The time between taking the medication (self-report) and starting the assessment on the three medicated days was M 11.3 hr 0.9 hr (range 10.0 14.0 h). No effects for day of testing (order) were found for cue-elicited variables, choice variables, or resting trial variables except for resting trial values of BQSU factor 1, F(2, 44) 3.39, p.05. BQSU factor 1 was higher on the first day (M 5.62 1.33) than the third day (M 4.82 1.97) (a decrease of 13%).

OLANZAPINE DURING SMOKING DEPRIVATION 219 Effects on Severity of Tobacco Withdrawal Effect of medication on the resting trial MNWS score was significant, F(2, 46) 4.20, p.02, f.44. MNWS scores were significant lower at the 2.5 mg dose, but not the 5.0 mg dose (0 mg: 4.96 3.90; 2.5 mg: 3.58 3.28; 5.0 mg: 3.83 3.88; see Figure 1). The cue trial by medication analysis of the MNWS score showed a marginal effect for cue trial, F(1, 22) 3.32, p.08, f.39, and a significant effect for medication, F(2, 44) 3.84, p.03, f.42, with no significant interaction, f.17. Across trials, both active doses of OLAN significantly reduced MNWS score relative to placebo (0 mg: 5.14 4.00; 2.5 mg: 4.07 3.87; 5.0 mg: 4.21 3.97; see Figure 1). MNWS scores tended to be higher after smoking cues (M 4.72 4.17) than in the resting trial (M 4.22 3.73). Effects on Smoking Urge Factors The medication effect on resting trial BQSU factor 1 was significant, F(2, 46) 4.06, p.03, f.40. OLAN (2.5 mg) significantly reduced BQSU factor 1 scores (M 4.56 2.00; p.05) relative to those in the placebo condition (M 5.38 1.54; See Figure 2). The cue trial by medication analysis of BQSU factor 1 found significant effects for cue trial, F(1, 22) 5.07, p.04, f.48, and for medication, F(2, 44) 3.16, p.05, f.37, but no significant interaction effect, f.17. Collapsed across medication conditions, factor 1 was higher in the smoking cue trials (M 5.52 1.57) than in the Relax trial without cues (M 5.17 1.74). Collapsed across cue conditions, 2.5 mg OLAN reduced factor 1 scores relative to the placebo condition (0 mg: M 5.73 1.44; 2.5 mg: M 4.95 1.84; 5.0 mg: M 5.35 1.69; see Figure 2). Figure 2. Means for the Positive Urge Factor of the Questionnaire of Smoking Urges by medication condition and cue trial (relaxation trial and mean of the smoking cue trials). Bars show standard errors, and significantly different means within trial types are indicated by different letters. For BQSU factor 2, the medication main and interaction effects were not significant (medication f.22, interaction f.17). The effects of cue trial were significant, F(1, 22) 7.54, p.02, f.58, with higher scores after the smoking cue trials (M 3.47 1.65) than after the relaxation trial (M 3.21 1.64). Effects on Choices for Cigarette Puffs Effects of medication on percentage of choices for cigarette puffs, CO boost, and latency to first choice of a cigarette puff were nonsignificant with close to zero effect size. A mean of 58.6 34.3% choices were made for cigarette puffs (0 mg: 57.4%; 2.5 mg: 58.8%; 5.0 mg: 59.7%). CO boost was M 8.39 9.06 ppm. The first puff was chosen a mean of 12.77 30.94 min into the procedure (0 mg: 12.14 31.34; 2.5 mg: 10.70 26.26; 5.0 mg: 15.48 35.21 min). Side Effects Figure 1. Mean nicotine withdrawal (MNWS) by medication condition and cue trial (relaxation trial and mean of the smoking cue trials). Bars show standard errors, and significantly different means within trial types are indicated by different letters. For only two side effects was the effect more frequently reported in medication conditions than in the placebo condition. Drowsiness was reported by 12 people in the 5 mg condition compared to nine people each in the 2.5 and 0 mg conditions. All reports were rated mild except for a moderate rating for three people during the placebo and 2.5 mg days, and one person during the 5 mg day, and a rating of severe for one person on the 2.5 and 5 mg days. Low energy was reported by 11 people in the 5 mg condition, nine people in the 2.5 mg condition and seven people in the placebo condition. All these ratings were mild except for moderate ratings by six people on the 5 mg day and two people on the 2.5 mg day.

220 ROHSENOW ET AL. Discussion A single low dose (2.5 mg) of olanzapine reduced deprivation-induced nicotine withdrawal and urges associated with anticipated positive affect from smoking in smokers interested in but not actively trying to quit smoking. A higher dose of OLAN (5.0 mg) reduced withdrawal symptoms but not smoking urges. The finding that the low dose is effective is notable because higher doses of olanzapine tend to cause sedation and considerable weight gain ( Olanzapine, 2000), whereas results of this study suggest that 2.5 mg olanzapine produces little sedation (same number of people reported drowsiness and almost as many people reported low energy on placebo as on 2.5 mg olanzapine). While a higher dose would be unlikely to be of direct clinical use due to sedation and weight gain, the low dose could possibly be used clinically without excessive side effects. Thus, since reducing urges to smoke or withdrawal can mediate the effects of medication on success with smoking cessation (Ferguson et al., 2006), the results of this study suggest that 2.5 mg of olanzapine could potentially help smokers to quit smoking by making a lapse less likely to occur without inducing clinically significant side effects. Even if olanzapine per se would not be an acceptable medication, the results suggest that medications with combined 5HT/DA antagonist effects should be considered for future development work for use with smoking cessation. When new medications of this class are developed with fewer or less intense side effects, these could be investigated as a smoking pharmacotherapy. Olanzapine 2.5 mg affected urge and withdrawal whether or not smoking cues were present. This suggests neither a differential benefit nor lack of benefit when smokers are presented with a situation similar to ones that often provoke smoking relapse. This finding is consistent with effects of NRT (e.g., Tiffany et al., 2000), but in contrast to the effect of naltrexone, which only reduced cue-elicited withdrawal, not urges or withdrawal in the absence of cues (Rohsenow et al., 2007), suggesting naltrexone s potential benefit would occur only in high-risk situations. Olanzapine did not affect reinforcement obtained from smoking after 10 hr of deprivation as indicated by number of choices made for cigarette puffs versus small amounts of cash or smoke intake (CO boost), or anticipated reinforcement as indicated by latency to first cigarette puff choice. This result is consistent with a previous report that olanzapine does not reduce self-reported enjoyment or stimulation from smoking (Hutchison et al., 2004). This was not due to any floor or ceiling effect since on average about 60% of choices were made for puffs, but percentage of choices for puffs was virtually identical across dosing conditions. This suggests that this type of medication may not protect against the reinforcement obtained from a lapse to smoking. While enrolling participants not actively trying to quit smoking could have reduced our ability to detect effects on smoking reinforcement in this study (Perkins et al., 2006), ethical considerations precluded our offering cigarette puffs to abstainers or smokers actively trying to quit. This is only the second study to investigate the effects of olanzapine on smoking-related variables among smokers without psychosis. The results of the two studies are consistent in showing a benefit of olanzapine on subjective effects of abstinence (Hutchison et al., 2004). Both studies used tightly controlled laboratory models to investigate olanzapine s effects. The main difference between the results of these studies is that the previous study found significant effects on cue-elicited urge at the 5 mg dose and did not study the 2.5 mg dose (Hutchison et al., 2004), while in the present trial the 2.5 dose was found to be more effective than the 5 mg dose. Furthermore, we found that effects on urge were limited to urge associated with positive affect. Limitations of this study include a sample size too small to study moderator variables, exclusion of smokers currently in a cessation attempt for necessary reasons, and only acute medication exposure. A larger study could allow analyses by moderators and follow up promising genetic moderators of olanzapine s effects found by McGeary et al. (2006). Providing several weeks of medication could allow side effects to attenuate, increase effects on smoking-related variables, or produce diminished results or results in the direction opposite from acute effects as has sometimes been seen with dopamine antagonists. The measure of smoking reinforcement was not designed to separate the reinforcing effects of nicotine per se from the reinforcing effects of non-nicotine aspects of smoking, but given the lack of any effect size for olanzapine on this measure it is not necessary to disentangle these two components of smoking reinforcement in a study of olanzapine s effects. Conclusions Combined 5HT/DA antagonists should be considered for future development of pharmacotherapies for smoking cessation. While olanzapine per se may or may not be useful due to its side effects, newer medications using these pathways may be of value in reducing nicotine withdrawal and urge to smoke. 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