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Introduction Patients with lower urinary tract symptoms often report urgency and incontinence episodes which are triggered by environmental scenarios, for example, "latch-key incontinence." To better understand the extent of this phenomenon, and how best to reduce its impact, we tested ways to recreate these situational cues in a controlled environment and obtain cue reactivity measures. Methods We developed a standardized set of urgency cue scenarios from interviews with sufferers of situational urgency urinary incontinence (UUI), personalized urgency, and safe cue sets consisting of photographs of specific locations, and measurements of cue reactivity during computer-based presentation and urodynamic monitoring. Results Common urgency and safe cues were identified for the standardized cue set. Exposure to these standardized cues elicited change in bladder sensation in 7 of 12 participants. Participants created personalized cue sets with photographs depicting their own urgency triggering scenarios; exposure to personalized cue photos elicited change in sensation in 11 of 12 participants. In addition, personalized cues elicited measurable detrusor overactivity and leakage during urodynamic monitoring. Safe cues reduced bladder sensation in five participants. Conclusion We developed a computer-based means of displaying cue photos which elicited cue reactivity from women suffering from situational urgency incontinence. Cue reactivity was increased by personalizing photos of cue scenarios and obtaining physiological measures from urodynamics. We have developed an appropriate way to test cue reactivity in women with situational UUI.

Introduction Cue reactivity (CR) research has reliably demonstrated robust cue-induced responding among smokers exposed to common proximal smoking cues (eg, cigarettes, lighter). More recent work demonstrates that distal stimuli, most notably the actual environments in which smoking previously occurred, can also gain associative control over craving. In the real world, proximal cues always occur within an environment; thus, a more informative test of how cues affect smokers might be to present these two cue types simultaneously. Methods Using a combined-cue counterbalanced CR paradigm, the present study tested the impact of proximal (smoking and neutral) + personal environment (smoking and nonsmoking places) pictorial cues, on smokers' subjective and behavioral CR; as well as the extent to which cue-induced craving predicts immediate subsequent smoking in a within-subjects design. Results As anticipated, the dual smoking cue combination (ProxS + EnvS) led to the greatest cue-induced craving relative to the other three cue combinations (ProxS + EnvN, ProxN + EnvS, and ProxN ± EnvN), ps < .004. Dual smoking cues also led to significantly shorter post-trial latencies to smoke, ps < .01. Overall CR difference score (post-trial craving minus baseline craving) was predictive of subsequent immediate smoking indexed by: post-trial latency to smoke [B = -2.69, SE = 9.02; t(143) = -2.98, p = .003]; total puff volume [B = 2.99, SE = 1.13; t(143) = 2.65, p = .009]; and total number of puffs [B = .053, SE = .027; t(143) = 1.95, p = .05]. Conclusions The implications of these findings for better understanding the impact of cues on smoking behavior and cessation are discussed. Implications This novel cue reactivity study examined smokers' reactivity to combined proximal and distal smoking cues. Exposure to a combination of two smoking cues (proximal and environment) led to the greatest increases in cue-induced craving and smoking behavior compared to all other cue combinations. Further, the overall magnitude of cue-induced craving was found to significantly predict immediate subsequent smoking. This work provides new insight on how exposure to various cues and cue combinations directly affect smokers' craving and actual smoking behavior, as well as the relationship between those two indices of reactivity.

Exercise is presumed to be a potentially helpful smoking cessation adjunct reputed to attenuate the negative effects of deprivation. The present study examined the effectiveness of moderate within-session exercise to reduce 4 key symptoms of smoking deprivation during 3 72-hr nicotine abstinence blocks in both male and female smokers. Forty-nine (25 male, 24 female) sedentary smokers abstained from smoking for 3 consecutive days on 3 separate occasions. At each session, smokers' abstinence-induced craving, cue-induced craving, negative mood, and withdrawal symptom severity were assessed prior to and after either exercise (a.m. exercise, p.m. exercise) or a sedentary control activity (magazine reading). Abstinence-induced craving and negative mood differed as a function of condition, F(2, 385) = 21, p < .0001; and, F(2, 385) = 3.38, p = .03. Planned contrasts revealed no difference between a.m. and p.m. exercise, but exercise overall led to greater pre-post reduction in abstinence-induced craving, t(385) = 6.23, p < .0001, effect size Cohen's d = 0.64; and negative mood, t(385) = 2.25, p = .03, d = 0.23. Overall exercise also led to a larger pre-post reduction in cue-induced craving in response to smoking cues, F(2, 387) = 8.94, p = .0002; and withdrawal severity, F(2, 385) = 3.8, p = .02. Unlike the other 3 measures, p.m. exercise reduced withdrawal severity over control, t(385) = 2.64, p = .009, d = 0.27, whereas a.m. exercise did not. The results support the clinical potential of exercise to assist smokers in managing common and robust negative symptoms experienced during the first 3 days of abstinence. (PsycINFO Database Record

Introduction A mandated reduction in the nicotine content of cigarettes may decrease smoking, but also increase demand for other nicotine products. The present study tested the impact of smoking cigarettes with very low nicotine content and concurrent use of a transdermal nicotine patch. Study design A balanced 2 × 2 factorial randomized clinical trial investigating the impact of cigarette nicotine content (double-blind, very low nicotine content versus normal nicotine content) and use of a transdermal nicotine patch (open label, patch versus no patch). Setting/participants Adult daily smokers (n=240) in the Pittsburgh, PA area. Intervention Participants were provided with research cigarettes and transdermal nicotine patches (if assigned to patch condition) for 7 weeks. Cigarettes were Spectrum brand (National Institute on Drug Abuse) and either 15.8 mg nicotine/g tobacco (normal nicotine content) or 0.4 mg nicotine/g tobacco (very low nicotine content). In the 7th week, participants were monetarily incentivized to abstain from smoking. Main outcome measures Participants reported daily cigarette use throughout the trial and the primary outcome was average number of cigarettes smoked per day (study + nonstudy) during Week 6. Participants were recruited from 2015 to 2017 and data were analyzed between 2017 and 2018. Results Assignment to very low nicotine content cigarettes and assignment to wear a nicotine patch both reduced the number of cigarettes smoked per day during Week 6 (p=0.001 and 0.04, respectively). However, assignment to the patch along with very low nicotine content cigarettes did not significantly reduce cigarette smoking compared with assignment to very low nicotine content cigarettes alone. Conclusions A mandated reduction in the nicotine content of cigarettes is likely to reduce the number of cigarettes smoked per day, but the added benefit of concurrent transdermal nicotine is unclear. Future studies should investigate whether alternative sources of noncombusted tobacco, such as e-cigarettes, enhance the effects of very low nicotine content cigarettes on smoking. Trial registration This study is registered at www.clinicaltrials.gov NCT02301325.

Environments associated with prior drug use provoke craving and drug taking, and set the stage for lapse/relapse. Although the neurobehavioral bases of environment-induced drug taking have been investigated with animal models, the influence of drug-environments on brain function and behavior in clinical populations of substance users is largely unexplored. Adult smokers (n=40) photographed locations personally associated with smoking (personal smoking environments; PSEs) or personal nonsmoking environment (PNEs). Following 24-h abstinence, participants underwent fMRI scanning while viewing PSEs, PNEs, standard smoking and nonsmoking environments, as well as proximal smoking (eg, lit cigarette) and nonsmoking (eg, pencil) cues. Finally, in two separate sessions following 6-h abstinence they viewed either PSEs or PNEs while cue-induced self-reported craving and smoking behavior were assessed. Viewing PSEs increased blood oxygen level-dependent signal in right posterior hippocampus (pHPC; F(2,685)=3.74, p

This cross-sectional study assesses the utility of deep learning for identifying environments and objects associated with smoking., Key Points Question Can a deep learning approach identify environments and environmental features associated with smoking? Findings In this cross-sectional study of 4902 images of daily environments taken by 169 smokers, a deep learning classifier was trained to identify environments associated with smoking (area under the receiver operating characteristic curve, 0.840; accuracy, 76.5%). Results generalized well across participants and geographic locations and indicated specific objects and settings associated with smoking; model predictions were significantly correlated with participant-reported craving when unfamiliar environments were viewed. Meaning The findings suggest that a deep learning approach can be applied to trigger just-in-time adaptive cessation interventions, to optimize a smoker’s environment during a quit attempt, or to study environmental correlates of other behaviors., Importance Environments associated with smoking increase a smoker’s craving to smoke and may provoke lapses during a quit attempt. Identifying smoking risk environments from images of a smoker’s daily life provides a basis for environment-based interventions. Objective To apply a deep learning approach to the clinically relevant identification of smoking environments among settings that smokers encounter in daily life. Design, Setting, and Participants In this cross-sectional study, 4902 images of smoking (n = 2457) and nonsmoking (n = 2445) locations were photographed by 169 smokers from Durham, North Carolina, and Pittsburgh, Pennsylvania, areas from 2010 to 2016. These images were used to develop a probabilistic classifier to predict the location type (smoking or nonsmoking location), thus relating objects and settings in daily environments to established smoking patterns. The classifier combines a deep convolutional neural network with an interpretable logistic regression model and was trained and evaluated via nested cross-validation with participant-wise partitions (ie, out-of-sample prediction). To contextualize model performance, images taken by 25 randomly selected participants were also classified by smoking cessation experts. As secondary validation, craving levels reported by participants when viewing unfamiliar environments were compared with the model’s predictions. Data analysis was performed from September 2017 to May 2018. Main Outcomes and Measures Classifier performance (accuracy and area under the receiver operating characteristic curve [AUC]), comparison with 4 smoking cessation experts, contribution of objects and settings to smoking environment status (standardized model coefficients), and correlation with participant-reported craving. Results Of 169 participants, 106 (62.7%) were from Durham (53 [50.0%] female; mean [SD] age, 41.4 [12.0] years) and 63 (37.3%) were from Pittsburgh (31 [51.7%] female; mean [SD] age, 35.2 [13.8] years). A total of 4902 images were available for analysis, including 3386 from Durham (mean [SD], 31.9 [1.3] images per participant) and 1516 from Pittsburgh (mean [SD], 24.1 [0.5] images per participant). Images were evenly split between the 2 classes, with 2457 smoking images (50.1%) and 2445 nonsmoking images (49.9%). The final model discriminated smoking vs nonsmoking environments with a mean (SD) AUC of 0.840 (0.024) (accuracy [SD], 76.5% [1.6%]). A model trained only with images from Durham participants effectively classified images from Pittsburgh participants (AUC, 0.757; accuracy, 69.2%), and a model trained only with images from Pittsburgh participants effectively classified images from Durham participants (AUC, 0.821; accuracy, 75.0%), suggesting good generalizability between geographic areas. Only 1 expert’s performance was a statistically significant improvement compared with the classifier (α = .05). Median self-reported craving was significantly correlated with model-predicted smoking environment status (ρ = 0.894; P = .003). Conclusions and Relevance In this study, features of daily environments predicted smoking vs nonsmoking status consistently across participants. The findings suggest that a deep learning approach can identify environments associated with smoking, can predict the probability that any image of daily life represents a smoking environment, and can potentially trigger environment-based interventions. This work demonstrates a framework for predicting how daily environments may influence target behaviors or symptoms that may have broad applications in mental and physical health.

Introduction: Environments associated with smoking may promote lapse and relapse in smokers attempting to quit. Here we examined the effects of exposure to visual smoking environment cues on smoking urge and the ability to resist smoking, as measured with a delay-to-smoking task in which monetary contingencies are provided for resisting smoking. Methods: Adult daily smokers (n = 22) completed two experimental sessions, each following 6 h smoking abstinence. Sessions differed only in the type of cue participants were exposed to (smoking environments vs. nonsmoking environments). Participants completed subjective ratings of smoking urge, withdrawal and other reactions (i.e. craving, affect). Behavioral outcomes on the delay-to-smoking task included latency to first cigarette, number of cigarettes smoked and average number of puffs per cigarette. Results: Across cue exposure sessions, 64% of participants initiated smoking (no effect of condition was observed). However, exposure to smoking environments as compared to the nonsmoking environments resulted in greater craving, faster initiation of smoking, and more smoked cigarettes. Greater craving was associated with a shorter time to initiate smoking, but this effect did not differ across sessions. In contrast, withdrawal was more strongly associated with number of cigarettes smoked during smoking environment sessions. Conclusion: Together, these results suggest smoking environments increase smoking urge and promote smoking behavior. Further research is necessary to examine the specific and interactive effects of smoking-related environments on real-world smoking lapse and relapse.

Smoking behavior may be more persistent among those who expect that smoking will relieve negative affect (NA). Assessing smoking expectancies temporally close to mood situations could enhance the predictive value of that assessment. Dependent smokers (n = 71; 43 male, 28 female) participated in five laboratory sessions, each involving mood induction. The NA relief scale of the Smoking Consequences Questionnaire-Adult (SCQ-A), a very common measure of smoking expectancies during hypothetical situations, was assessed during initial screening. The SCQ-A was compared with a modified acute version administered each session, in which items asked about immediate expectancy for NA relief by smoking "right now" (termed Immediate Negative Affect Relief, or INAR). Actual NA relief due to smoking was measured each session by change on the NA scale of the Diener & Emmons Mood Form. The five sessions (counterbalanced) involved three different negative mood tasks, the negative mood condition of overnight smoking abstinence, and neutral mood (control). Generalized estimating equations showed that temporal proximity to the mood situation slightly enhanced the ability of expectancy to predict actual change in NA due to smoking, as the interaction with condition was significant for the INAR but marginal for the SCQ-A. However, the acute INAR predicted NA relief due to smoking only after overnight smoking abstinence and not during the other specific mood induction conditions, contrary to expectations, while the SCQ-A was not significant during any of the individual conditions. In sum, assessment of expectancy for NA relief may be of limited use in predicting actual NA relief from smoking during a current mood situation, aside from NA due to overnight abstinence.

INTRODUCTION Acute smoking behavior (i.e., puff topography) and subjective responses during the ad lib smoking of a single cigarette in the laboratory may provide useful measures of smoking reinforcement and reward, respectively. However, the reliability of such measures is not clear, leaving uncertain the utility of a single assessment of smoking behavior as an individual difference measure. METHODS Dependent smokers (N = 94) smoked normally prior to each of 4 laboratory sessions during which they were instructed to smoke 1 cigarette of their preferred brand in ad libitum and unblinded fashion and then rate it for subjective effects. Puff topography (puff number, total volume, and maximum volume) was assessed via portable Clinical Research Support System device. Subjective reward and perception were assessed by visual analog scales of "liking" and "how strong," respectively. The reliability of puff topography and subjective measures was determined across days by intra-class correlations (ICCs). Differences due to sex and nicotine dependence (high and low Fagerstrom Test for Nicotine Dependence score) were also examined. RESULTS Reliability was highly significant for each measure. ICCs were .70 for total puff volume, .60 for maximum puff volume, .73 for puff number, .64 for liking, and .78 for how strong. Reliability generally did not differ by sex or dependence, but absolute values for total volume and maximum puff volume were greater in men and in high dependent smokers. Liking was also greater in high dependent smokers. CONCLUSIONS Puff topography and subjective measures during the ad lib smoking of a single cigarette are highly reliable. Smoking responses during a single ad lib smoking session may be useful in identifying stable individual differences in smoking reinforcement and reward.

Negative mood increases smoking reinforcement and may do so to a greater degree in smokers vulnerable to negative mood dysregulation.Adult smokers (N = 71) without current depression were randomly assigned to one of two smoking conditions (nicotine or denic cigarettes, presented blind) maintained across all sessions. Subjects completed one neutral mood session and four negative mood induction sessions. Negative mood inductions included one each of the following: 1) overnight smoking abstinence, 2) challenging computer task, 3) public speech preparation, 4) watching negative mood slides. In each session, subjects took 4 puffs on their assigned cigarette, rated it for "liking" (reward), and then smoked those cigarettes ad libitum (reinforcement) during continued mood induction. Affect was assessed intermittently before and after smoking. Differences in responses were examined as functions of self-reported history of major depression and levels of distress tolerance and anxiety sensitivity.Smoking reinforcement, but not reward or negative affect relief, was greater in all sessions in those with a history of depression and greater after overnight abstinence in those with lower distress tolerance. Reward and affect relief, but not reinforcement, were greater during speech preparation among those high in anxiety sensitivity.Low distress tolerance may enhance acute smoking reinforcement due to abstinence, while depression history may broadly increase acute smoking reinforcement regardless of mood. Neither smoking reward nor affect help explain these individual differences in smoking reinforcement.

Smokers are highly reactive to smoking-related cues that are directly linked, or most proximal, to actual smoking behavior (e.g., lit cigarettes). However, over the course of smoking, proximal cues may not be the only stimuli to become strongly associated with smoking. Distal cues, such as the environments in which smoking occurs (e.g., bar) might also gain associative properties and come to evoke robust reactivity from smokers. To test this, a pilot study was first conducted to develop standard pictorial stimuli of smoking and nonsmoking environments, all of which were completely devoid of proximal smoking cues. A comparison set of smoking and nonsmoking proximal cues was then created. Using the 12 total pictorial cues developed, 62 adult smokers participated in a cue-reactivity study during which they viewed and rated pictorial smoking and nonsmoking environment and proximal cues. Results demonstrate that, similar to proximal cues, environments associated with smoking can alone function as stimuli capable of evoking strong subjective reactivity from smokers. This work supports a broader conceptualization of drug-related cues in cue-based research and treatment development that includes proximal and distal cues as distinct categories. (PsycINFO Database Record (c) 2008 APA, all rights reserved).

Smoking cue-reactivity studies have consistently demonstrated heightened self-report craving, as well as moderate autonomic reactivity, among smokers exposed to salient drug-related cues. However, significantly fewer studies have examined whether exposure to smoking cues affects smokers' actual smoking, or examined the predictive relationship between cue-induced craving and smoking behavior. Using our well-tested pictorial cues in a cue-reactivity paradigm, we investigated the impact of smoking-related cues relative to neutral cues on subjective craving and smoking behavior (assessed via CReSS; Plowshare Technologies, Baltimore, MD) measures of latency to smoke, puff volume, and number of puffs). Further, we examined the predictive value of cue-induced craving on subsequent smoking behavior. Sixty nondeprived daily smokers completed 2 experimental sessions involving exposure to either smoking-related or neutral pictorial cues. Following initial exposure to cues, smokers rated their craving and were then allowed to smoke freely if they chose to during a subsequent 6-min cue exposure period. Result showed that exposure to smoking cues relative to neutral predicted significantly greater craving and increases in smoking behavior. Likewise, the magnitude of the difference in cue-induced craving when exposed to smoking cues relative to neutral cues (i.e., the cue-reactivity effect) was highly predictive of shorter latency to smoke, as well as increased number of puffs and puff volume.

Animal research has shown that the environments, or contexts, in which drug use occurs can play a key role in how animals respond to drug-related cues. Less is known about the role of environmental contexts in human drug-dependence research. Traditionally, cue-based studies and treatments focus on conditioned cues most proximal to drug administration (e.g., lit cigarettes, pictorial stimuli of drug paraphernalia). However, there is reason to believe that more distal cues, such as the environments in which drugs were previously used, might similarly gain associative control over human responding. This article describes a body of systematic research aimed at identifying and studying the impact of environmental contexts on smokers' cue reactivity in the laboratory. Overall, results of this program of research demonstrate that exposure to environments associated with smoking, but completely devoid of proximal smoking cues, can function as conditioned stimuli capable of evoking strong subjective responding from abstinent smokers. Furthermore, more robust reactivity can be achieved if environmental context cues are personalized using novel techniques described in this article.

Compared to men, the smoking behavior of women may be less responsive to nicotine and more responsive to nonpharmacological factors, perhaps including verbal information (e.g., dose instructions).This study compared the influence of the presence vs absence of dose instructions on the subjective and reinforcing effects of nicotine via cigarette smoking in men and women.Subjects (n=120) abstained overnight from smoking and were randomly assigned to one of four groups. Half of the subjects received nicotine cigarettes (Quest 1, yield of 0.6 mg), and the other half received denicotinized cigarettes ("denic"; Quest 3, yield of 0.05 mg). Furthermore, half of each subsample was accurately instructed they were receiving a "normal nicotine" or a "no nicotine" cigarette, while the other half received no instructions. Subjects completed baseline measures of craving and mood (positive and negative affect), took two puffs from the cigarette after receiving dose instructions or no instructions, and then rated the cigarette's "reward" value (liking, satisfying) and other characteristics. They also repeated the craving and mood measures. Subjects then smoked more of that same brand ad libitum over the next 30 min to measure reinforcement (puff number and latency to first puff).Overall, nicotine increased reward, other cigarette ratings, and positive affect, but did not affect craving or smoking behavior. However, results varied by sex. Dose instructions enhanced the effects of nicotine on smoking reward and reinforcement in women, while instructions tended to dampen or even reverse these effects of nicotine in men (i.e., interaction of sex x nicotine x instructions).In women but not in men, the influence of nicotine on smoking reward and reinforcement is enhanced by accurate verbal information about the cigarette's nicotine dose. These results are consistent with the notion that the smoking behavior of women, relative to men, may be more responsive to nonpharmacological factors.

Effects of substance use are typically assumed to be related to pharmacological actions. However, beliefs about the drug content of a substance may strongly influence subjective and reinforcing responses to that substance(i.e., "placebo" effects). We examined the subjective and reinforcing effects of a nasal spray containing no nicotine as a function of instructions about the nicotine content of the spray (Told Nicotine vs. Told No Nicotine). Smokers (n = 49) not interested in quitting smoking abstained overnight prior to a single session in which they were randomly assigned to one of three groups, involving one of the two instructional sets or a group that got no spray. Following dose instructions, subjects in the two spray groups were administered one set of four sprays from the spray bottle and then rated them intermittently on items related to "reward" (e.g., "liking", amount they would pay for more) and other effects. At the same time points, they also rated mood, craving, and withdrawal, and had heart rate and blood pressure measured. Reinforcement was then determined by the number of ad libitum sprays they self-administered during a 20-min period. The no-spray group simply rested quietly during the session, while measures were assessed at the same time points as subjects in the other two groups. Those in the Told Nicotine group reported greater spray ratings of "how much nicotine," "liking," "satisfying," "buzz/head rush," and "similar to smoking" compared with the Told No Nicotine group. Craving decreased more for those Told Nicotine versus those Told No Nicotine, but also decreased more for those Told No Nicotine compared with the no spray group. There were no significant differences in amount they would pay for more sprays, withdrawal, mood, cardiovascular responses, or in spray self-administration. These results show that instructions about the nicotine content of a novel delivery device (nasal spray) can influence self-reported spray ratings and reduce craving but are limited with respect to effects on other measures of drug response.

Subjective and reinforcing effects of smoking a cigarette were examined within a 2 x 2 modified balanced-placebo design, which manipulated instructions about nicotine content (i.e., told regular nicotine vs. told low nicotine) and actual nicotine dose (given a regular nicotine brand vs. a denicotinized brand). Most ratings of the nicotine content and reward value of cigarettes were higher for those told regular nicotine versus told low nicotine, and for those given regular nicotine versus given low nicotine. Nicotine and instructions did not affect craving, withdrawal, or smoke-reinforced responding, but instructions affected the number of puffs earned for those given low nicotine (i.e., placebo effect). Thus, verbal information (instructions) can influence some responses to smoking consistent with the presence of placebo and antiplacebo effects.

Nicotine has many acute subjective, physiological, and behavioral effects in humans, some of which may explain why nicotine produces dependence. Individual differences in the magnitude of these effects (i.e., nicotine sensitivity) are of interest to many researchers, such as those examining vulnerability to dependence and processes related to chronic tolerance. However, such characterization of individual differences depends on the consistency of the observed responses, and the consistency of acute effects of nicotine in humans has not been studied systematically. We examined the consistency of the acute effects of the same dose of nicotine administered by nasal spray across multiple drug administration trials, within as well as between sessions. Subjective (i.e., self-reported effects), cardiovascular, and performance measures were assessed following each of four dosing trials of nicotine (20 microg/kg) on three sessions and of placebo on one session. For those measures in which the main effect of nicotine vs. placebo was significant, intraclass correlations were calculated for different sets of trials across different numbers of sessions. Our objective was to determine whether the consistency of responses declined when those responses were based on smaller numbers of trials or sessions, in an effort to guide future research in this area. Results indicated that the consistency of nicotine effects is generally high, even across trials within just one session. Additional research is needed to determine the generalizability of these findings to other methods of nicotine administration, including smoking, and to clarify the extent to which this consistency reflects characteristic consistency of the pharmacological actions of nicotine per se vs. consistency of nonspecific responses to the drug administration procedure.

Nicotine intake is a necessary but insufficient factor in maintaining tobacco smoking behavior, and nonpharmacological factors associated with smoking play a key role. Some of these factors may influence smoking behavior by eliciting placebo effects, or responses related specifically to the belief that one is consuming a drug. Greater knowledge of placebo effects of smoking would improve our understanding of factors that maintain smoking behavior, thereby aiding efforts to develop treatments to counter the influence of these factors. In addition, better understanding of placebo effects from other means of nicotine intake could help determine mechanisms of the therapeutic actions of nicotine replacement therapy, perhaps enhancing its efficacy in smoking cessation. Placebo effects of smoking or other nicotine intake have received little research attention. In this review, we first discuss common terms and methods of placebo research, especially the balanced-placebo design. We then examine the limited research directly assessing placebo effects of smoking and other nicotine intake, namely studies that manipulated instructions to subjects about the drug content of an ingested substance. Finally, we examine other studies relevant to gauging the likely magnitude of placebo smoking effects. In an effort to encourage more research on these placebo effects, we pay substantial attention to future directions. Among recommendations are testing the utility of the balanced-placebo design and other rigorously controlled designs, and including multiple measures of placebo effects in addition to self-report. Future research also should explore the moderating influences of the environmental context and of individual difference factors on placebo effects of smoking and other nicotine intake.

Aims To evaluate the efficacy of cue-exposure addiction treatment and review modern animal learning research to generate recommendations for substantially enhancing the effectiveness of this treatment. Design Meta-analysis of cue-exposure addiction treatment outcome studies (N = 9), review of animal extinction research and theory, and evaluation of whether major principles from this literature are addressed adequately in cue-exposure treatments. Findings The meta-analytical review showed that there is no consistent evidence for the efficacy of cue-exposure treatment as currently implemented. Moreover, procedures derived from the animal learning literature that should maximize the potential of extinction training are rarely used in cue-exposure treatments. Conclusions Given what is known from animal extinction theory and research about extinguishing learned behavior, it is not surprising that cue-exposure treatments so often fail. This paper reviews current animal research regarding the most salient threats to the development and maintenance of extinction, and suggests several major procedures for increasing the efficacy of cue-exposure addiction treatment.

Many addiction theories assume that craving plays a central role in the acquisition and maintenance of drug dependence. For example, craving is often depicted as the subjective experience of the motivational state directly responsible for all drinking in the alcoholic. Craving has two prominent features that must be explained by any viable model of craving. First, craving tends to be highly situationally specific, readily triggered by stimuli previously associated with drug use. Secondly, craving can persist well beyond the cessation of drinking in an alcoholic. Conventional theories typically address craving's cue specificity and persistence by invoking concepts of classical conditioning. These theories fall into two classes: those that emphasize withdrawal and those that focus on the positive-incentive properties of drugs. Both types of theories assume that craving processes are represented by the concomitant activation of craving report, drug-seeking and drug use, and specific patterns of autonomic responses. However, research fails to find more than modest relationships across these putative manifestations of craving. The cognitive processing model, described in this paper, offers a different view of craving's form and function and proposes that drug use can operate independently of the processes controlling craving. According to this model, addictive drug use is regulated by automatic cognitive processes, while craving represents the activation of non-automatic processes. These non-automatic processes are activated to either aid in completing interrupted drug use or block automatic drug-use sequences. From this perspective, craving is neither irrelevant nor central to the alcoholic's drug use, but rather serves as a cognitive marker of processes that, only in some instance, may be associated with alcohol seeking and use. The research and treatment implications of this model's assumptions regarding drug use and craving processes are discussed.

Recent research has identified that the environments in which smoking has previously occurred can alone, in the absence of any explicit smoking stimuli (e.g., cigarettes, lighters), serve as cues that induce robust craving to smoke. The goal of the present study was to determine if people can similarly function as smoking and nonsmoking cues capable of directly affecting smokers' cue-induced craving.Smokers (N = 72) borrowed cameras to take photos of the people in their lives around whom they do and do not smoke ("personal" smoking and nonsmoking people, PS and PN, respectively). Self-report and physiological cue reactivity to those photos were compared with smokers' reactivity to photos of people unknown to them ("standard" smoking and nonsmoking people, SS and SN, respectively).Results suggest that the people around whom smokers regularly smoke (PS) can alone function as cues capable of eliciting patterns of reactivity similar to that evoked by proximal and environment smoking cues, namely, increased craving to smoke, negative affect, and excitement. In contrast, the people around whom smokers do not smoke become associated with not smoking (PN) and serve a potential protective function by reducing craving and increasing calm.This novel investigation and its results have implications for promoting smoking cessation by developing strategies to manage a smoker's social environment.

The association between smokers' cue-induced craving and subsequent ability to initiate abstinence is unclear. Dependent smokers (N = 158) completed a single cue-reactivity session prior to participating in a larger within-subjects study, which independently examined predictors of initiating quitting during 5 days each on nicotine versus placebo patch. In the larger study, all smokers used nicotine and placebo patch (double blind) for 1 week each following a preceding week of ad lib smoking, in a 2 × 2 cross-over design. Generalized estimating equation (GEE) models determined the predictive ability of cue-induced craving (cue reactivity) on subsequent success at initiating a quit attempt (at least 24 hr quit) for each patch condition. Smokers who exhibited greater craving during exposure to smoking cues had significantly greater odds of successfully initiating abstinence during either quit attempt week (i.e., the nicotine or placebo patch week). This relationship was not statistically significant for self-reported craving in response to neutral cues. However, a greater smoking-neutral cue difference score for cue-induced craving was also a significant predictor of successfully initiating abstinence, but only among those not monetarily reinforced. Implications of these seemingly counterintuitive findings are discussed.

INTRODUCTION Negative mood situations often increase smoking behavior and reward, effects that may be greater among women and smokers low in tolerance for distress. METHODS Adult dependent smokers (N = 164; 86 men, 78 women) first completed measures of distress tolerance via self-report and by mirror-tracing and breath-holding tasks. They then participated in 2 virtually identical laboratory sessions, involving induction of negative versus neutral mood (control) via pictorial slides and music. They rated negative affect (NA) before and during mood induction and smoked their preferred brand ad libitum during the last 14 min of mood induction. Our aim was to examine mood effects on NA, smoking reward ("liking"), and smoking intake (puff volume and number) as a function of sex and distress tolerance. RESULTS Negative mood induction increased NA, as planned, and smoking reward and intake compared with neutral mood. Increases in NA and puff volume due to negative mood were greater in women compared with men, as hypothesized, but no main effects of the self-report or behavioral distress tolerance measures were seen in responses to mood induction. However, unexpectedly, lower self-reported distress tolerance was associated with greater smoking intake due to negative (but not neutral) mood in men and generally due to neutral (but not negative) mood in women. CONCLUSIONS Negative mood may increase smoking intake more in women compared with men. Yet, low distress tolerance may enhance smoking intake due to negative versus neutral mood differentially between women and men, suggesting that sex and distress tolerance may interact to influence smoking responses to negative mood.

Negative mood situations increase craving to smoke, even in the absence of any tobacco deprivation (e.g. “stressors”). Individual differences in effects of negative mood situations on craving have received relatively little attention but may include variability between men and women. Across two separate within-subjects studies, we examined sex differences in craving (via the QSU-brief) as functions of brief smoking abstinence (versus satiation; Study 1) and acute induction of negative mood (versus neutral mood; Study 2). Subjective ratings of negative affect (via the Mood Form) were also assessed. In Study 1, we compared the effects of overnight (> 12 h) abstinence versus non-abstinence on craving and affect in adult male (n = 63) and female (n = 42) smokers. In Study 2, these responses to negative versus neutral mood induction (via pictorial slides and music) were examined in male (n = 85) and female (n = 78) satiated smokers. Results from each study were similar in showing that craving during the abstinence and negative mood induction conditions was greater in women than men, as hypothesized, although the sex difference in craving due to abstinence was only marginal after controlling for dependence. Craving was strongly associated with negative affect in both studies. These results suggest that very acute negative mood situations (e.g. just a few minutes in Study 2), and perhaps overnight abstinence, may increase craving to smoke to a greater extent in women relative to men.

Social learning theory considers self-efficacy as a causal factor in behavior change. However, in line with behavioral theory, recent clinical research suggests that self-efficacy ratings may reflect, rather than cause, behavior change. To test these two disparate views, self-efficacy was related to actual smoking abstinence on the next day (i.e. self-efficacy causes change), and abstinence status over one day was tested as a predictor of rated self-efficacy for being quit the next day (i.e. reflects change). All data were from two very similar cross-over studies evaluating the short-term effects of both placebo versus medication, nicotine patch (n=209) or varenicline (n=123), on smoking abstinence during week-long practice quit attempts. Placebo versus active medication periods were separated by an ad lib smoking washout, and analyses controlled for prior day's abstinence or self-efficacy values. Results were very consistent between studies in showing essentially bi-directional associations: daily self-efficacy predicted next day's abstinence, and current day's abstinence status predicted self-efficacy for not smoking the next day. However, secondary factors differentially predicted abstinence and, to a lesser extent, self-efficacy between these two medication studies. These data provide some support for both social learning and behavioral theories of smoking behavior change, although self-efficacy may only briefly predict subsequent short periods of abstinence as assessed in these studies. Nonetheless, because self-efficacy has long been assumed to cause behavior change, including smoking cessation, the notion of self-efficacy as a reflection of recent smoking behavior change in these studies warrants greater attention in clinical research on smoking cessation treatment.

Pictorial representations of specific environments related to smoking can evoke robust craving to smoke, even in the absence of any proximal cues to smoke (e.g., cigarettes, lighters). To evaluate the salience of smoking environment cues, we developed a novel procedure for bringing smokers' real world smoking and nonsmoking environments into the laboratory to compare them with standard (i.e., not personalized) environments within a cue-reactivity paradigm. Seventy-two smokers used digital cameras to take pictures of the environments in which they do and do not smoke. They then completed a cue-reactivity session during which they viewed and rated pictures of smoking and nonsmoking environments, half personal and half standard, all devoid of proximal smoking cues. As hypothesized, personal environments led to a significantly larger smoking-nonsmoking difference in craving, compared with the standard environments. Personalization also enhanced stimuli vividness, relevance, positive affect, and excitement, as well as heart rate changes from baseline. Implications of these findings for exposure-based research and treatment for addiction, as well as other psychological disorders, are discussed.

Background Smoking acutely relieves negative affect (NA) due to smoking abstinence but may not relieve NA from other sources, such as stressors. Methods Dependent smokers ( n = 104) randomly assigned to one of three smoking conditions (nicotine or denicotinized cigarettes, or no smoking) completed four negative mood induction procedures (one per session): 1) overnight smoking abstinence, 2) challenging computer task, 3) public speech preparation, and 4) watching negative mood slides. A fifth session involved a neutral mood control. The two smoking groups took four puffs on their assigned cigarette and then smoked those same cigarettes ad libitum during continued mood induction. All subjects rated their level of NA and positive affect on several measures (Mood Form, Positive and Negative Affect Scale, Stress-Arousal Checklist, and State-Trait Anxiety Inventory-state). They also rated craving and withdrawal. Results Negative affect relief from smoking depended on the NA source (i.e., mood induction procedure) and the affect measure. Smoking robustly relieved NA due to abstinence on all four measures but only modestly relieved NA due to the other sources and typically on only some measures. Smoking's effects on positive affect and withdrawal were similar to effects on NA, but relief of craving depended less on NA source. Smoking reinforcement only partly matched the pattern of NA relief. Few responses differed between the nicotine and denicotinized smoking groups. Conclusions Acute NA relief from smoking depends on the situation and the affect measure used but may not depend on nicotine intake. These results challenge the common assumption that smoking, and nicotine in particular, broadly alleviates NA.

We recently showed effects of nicotine dose and nicotine expectancy on some responses to cigarette smoking, with generally no influence of induced mood on these effects. The present study extended this line of research to Nicotrol nasal spray, to determine whether formulation (spray vs. smoking) alters responses.Smokers abstained overnight before each of two virtually identical sessions, involving negative or positive mood induction. They were randomized to one of five groups, four comprising the 2 x 2 balanced placebo design, varying actual and expected dose of nicotine in the nasal spray, and the fifth group a no-spray control. Dependent measures included self-reported affect, craving, withdrawal, and spray ratings of "liking" and "how much nicotine." Analyses were limited to those whose nicotine expectancies were manipulated successfully (N = 48).The following results matched those from our smoking study: expecting nicotine increased liking; expected, but not actual, nicotine dose increased dose perception; neither actual nor expected nicotine dose had much influence on affect or withdrawal; and mood had no influence on these effects. However, both actual and expected nicotine dose decreased craving in response to spray, contrary to our prior study with smoking.Formulation made little difference in some effects of nicotine and expectancies, but other effects differed by formulation. Some of these findings, particularly for craving reduction, may have implications for enhancing the acute therapeutic effects of nasal spray and, perhaps, other medications in smokers trying to maintain abstinence after quitting.

Negative mood increases smoking reinforcement and risk of relapse. We explored associations of gene variants in the dopamine, opioid, and serotonin pathways with smoking reward ('liking') and reinforcement (latency to first puff and total puffs) as a function of negative mood and expected versus actual nicotine content of the cigarette. Smokers of European ancestry (n=72) were randomized to one of four groups in a 2x2 balanced placebo design, corresponding with manipulation of actual (0.6 vs. 0.05 mg) and expected (told nicotine and told denicotinized) nicotine 'dose' in cigarettes during each of two sessions (negative vs. positive mood induction). Following mood induction and expectancy instructions, they sampled and rated the assigned cigarette, and then smoked additional cigarettes ad lib during continued mood induction. The increase in smoking amount owing to negative mood was associated with: dopamine D2 receptor (DRD2) C957T (CCTT or CT), SLC6A3 (presence of 9 repeatabsence of 9), and among those given a nicotine cigarette, DRD4 (presence of 7 repeatabsence of 7) and DRD2/ANKK1 TaqIA (TT or CTCC). SLC6A3, and DRD2/ANKK1 TaqIA were also associated with smoking reward and smoking latency. OPRM1 (AAAG or GG) was associated with smoking reward, but SLC6A4 variable number tandem repeat was unrelated to any of these measures. These results warrant replication but provide the first evidence for genetic associations with the acute increase in smoking reward and reinforcement owing to negative mood.

Acute responses to smoking are influenced by nicotine and by nonpharmacological factors such as nicotine dose expectancy and sensory effects of smoke inhalation. Because negative mood increases smoking reinforcement, the authors examined whether these effects may be altered by mood context. Smokers (n = 200) participated in 2 sessions, negative or positive mood induction, and were randomized to 1 of 5 groups. Four groups comprised the 2 × 2 balanced placebo design, varying actual (0.6 mg vs. 0.05 mg yield) and expected nicotine dose (expected nicotine vs. denicotinized [denic]) of cigarettes. A fifth group was a no-smoking control. Smoking, versus not smoking, attenuated negative affect, as well as withdrawal and craving. Negative mood increased smoking reinforcement. However, neither actual nor expected nicotine dose had much influence on these responses; even those smokers receiving and expecting a denic cigarette reported attenuated negative affect. A follow-up comparison suggested that the sensory effects of smoke inhalation, but not the simple motor effects of smoking behavior, were responsible. Thus, sensory effects of smoke inhalation had a greater influence on relieving negative affect than actual or expected nicotine intake.

Primate and rodent models show that peroxisome proliferator-activated receptor-alpha (PPAR-α) ligands, including fibrate medications, reduce nicotine reinforcement, reward, and related effects. We tested fenofibrate, the most common U.S. Food and Drug Administration-approved fibrate for lipid control versus placebo for initial evidence of efficacy in smoking cessation using a validated cross-over procedure for early Phase 2 evaluations.Adult dependent smokers (N = 38) in this 4-week within-subjects study were those already intending to try to quit in the next 2 months. All smoked ad libitum during weeks 1 (baseline) and 3 (washout) and began fenofibrate (160 mg/d; dosing approved for lipid control) or placebo near the end of weeks 1 and 3. Following each 4-day dose run-up, they were then instructed to try to quit for 4 days (Tuesday-Friday) during weeks 2 and 4, with the order of medication conditions counter-balanced and administered double-blind. Abstinence was verified daily in each 4-day quit period by self-report of no smoking in the prior 24 hours and carbon monoxide5 ppm. Secondary measures of acute smoking reinforcement and cue reactivity prior to quitting, and smoking reduction when trying to quit, were also assessed.No differences between fenofibrate versus placebo were found on days quit (means ± SEM of 1.8±0.3 vs. 1.9±0.3, respectively). Similarly, there were no differences in any of the secondary measures (all P.20).Although higher dosing or other proliferator-activated receptor-alpha agonists may show efficacy, this study indicates that fenofibrate does not aid ability to stop smoking during a brief practice quit period in dependent smokers high in current quit interest.

Research has demonstrated that a lapse in cigarette abstinence often leads smokers to fully relapse (i.e., return to daily smoking). However, patterns of smoking resumption beyond the point at which relapse occurs have not been examined in systematic follow-up studies. Daily cigarette intake data for 108 female adult smokers who participated in a smoking cessation trial were recorded at several points during the 365 days following the participants' quit date. SAS Proc Traj, a group-based mixture modeling procedure, was used to determine cigarette-use trajectories over time (i.e., patterns of smoking resumption). Over the 365 days, 27% of the sample maintained abstinence. Among the 73% who relapsed, four distinct trajectories emerged: low-level users (8% of the overall sample), moderate users (17%), slow-returners (15%), and quick-returners (33%). A few individual characteristics differentiated these groups. Overall, the findings illustrate that, after relapsing, smokers do not follow a unitary course of smoking resumption; rather, they exhibit more variable resumption patterns than previously assumed.

Two notions strongly held by many smokers are that negative mood increases smoking behavior and that this increase is due to the ability of smoking to alleviate negative affect. This study used a modified mood induction procedure to examine both the impact of smoking on induced mood, as well as the effect of induced mood on actual smoking behavior. Forty-eight smokers were randomly assigned to a smoking or a water-drinking comparison group. Each participant attended 3 sessions during which 1 of 3 mood states (positive, negative, or neutral) was induced. Contrary to expectation, smoking did not attenuate negative affect. However, negative mood induction subsequently quickened latency to smoke and increased number of puffs consumed ad lib.

Little is known about the processes that underlie changes in smoking that occur between the first use of a cigarette, subsequent regular use and eventual addictive use. At present, assessments of those critical processes are poorly developed and not strongly informed by contemporary models of drug dependence. The preceding three papers in this special issue address explicitly how modern drug-dependence theories describe the emergence of drug dependence and the implications of those theories for assessment. The papers covered three domains of theories: negative reinforcement, positive reinforcement, and cognitive and social learning. In this paper, we summarize these reviews and extract general themes and issues that emerge across all the articles. These include: (1) the importance of learning processes; (2) limitations of self-report measures; (3) the view of dependence as a process and not a state; (4) the conception of dependence on a continuum in contrast to the conventional perspective of tobacco dependence as a natural category; (5) the ontological status of the dependence concept; (6) limitations of backward extrapolations from adult assessments; (7) the possibility of multiple dimensions or forms of dependence; and (8) the value of a transdisciplinary approach when studying the emergence of tobacco dependence.

Rationale: Associative tolerance to the analgesic effects of morphine is most pronounced when morphine is paired with a distinctive context at a long inter-dose interval (IDI). In contrast, morphine administered at a short IDI promotes the development of non-associative tolerance and disrupts the acquisition of associative tolerance. The impact of IDI on the development of associative tolerance to opioids other than morphine has not been investigated previously. Objectives: This research examined associative and non-associative tolerance to the analgesic effects of fentanyl in rats. Cross tolerance for these two forms of tolerance with morphine (mu- receptor agonist) and U50,488H (kappa-receptor agonist) analgesia was also investigated. Methods: Animals were given eight fentanyl injections (0.10 mg/kg) paired or unpaired with a distinctive context at either a 3-h (short) or 96-h (long) IDI. Subjects were then tested for tolerance in the distinctive context using the tail-flick procedure and dose–response curve methodology. Results: At the short IDI, animals developed non-associative tolerance to fentanyl that was receptor specific, i.e., cross tolerant with morphine analgesia but not with U50,488H analgesia. At the long IDI, fentanyl-tested animals displayed tolerance that appeared to be controlled primarily by associative processes. This associative form of tolerance was also receptor specific, displaying cross tolerance with morphine but not with U50,488H. Conclusions: The impact of IDI on the development of non- associative and associative fentanyl tolerance is consistent with findings obtained with morphine showing that conditions conducive to the development of non-associative tolerance disrupt the acquisition of associative tolerance. The cross-tolerance data, however, did not parallel previous research examining the cross-tolerance profiles of associative and non-associative morphine tolerance.