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The topic of e-cigarettes is controversial. Opponents focus on e-cigarettes’ risks for young people, while supporters emphasize the potential for e-cigarettes to assist smokers in quitting smoking. Most US health organizations, media coverage, and policymakers have focused primarily on risks to youths. Because of their messaging, much of the public—including most smokers—now consider e-cigarette use as dangerous as or more dangerous than smoking. By contrast, the National Academies of Science, Engineering, and Medicine concluded that e-cigarette use is likely far less hazardous than smoking. Policies intended to reduce adolescent vaping may also reduce adult smokers’ use of e-cigarettes in quit attempts. Because evidence indicates that e-cigarette use can increase the odds of quitting smoking, many scientists, including this essay’s authors, encourage the health community, media, and policymakers to more carefully weigh vaping’s potential to reduce adult smoking-attributable mortality. We review the health risks of e-cigarette use, the likelihood that vaping increases smoking cessation, concerns about youth vaping, and the need to balance valid concerns about risks to youths with the potential benefits of increasing adult smoking cessation.

CYP2A6 activity, phenotyped by the nicotine metabolite ratio (NMR), is a predictor of several smoking behaviors, including cessation and smoking‐related disease risk. The heritability of the NMR is 60–80%, yet weighted genetic risk scores (wGRSs) based on common variants explain only 30–35%. Rare variants (minor allele frequency

The Nicotine Metabolite Ratio (NMR; 3-hydroxycotinine/cotinine), a highly heritable index of nicotine metabolic inactivation by the CYP2A6 enzyme, is associated with numerous smoking behaviors and diseases, as well as unique cessation outcomes. However, the NMR cannot be measured in nonsmokers, former smokers, or intermittent smokers, for example, in evaluating tobacco-related disease risk. Traditional pharmacogenetic groupings based on CYP2A6 * alleles capture a modest portion of NMR variation. We previously created a CYP2A6 weighted genetic risk score (wGRS) for European (EUR)-ancestry populations by incorporating independent signals from genome-wide association studies to capture a larger proportion of NMR variation. However, CYP2A6 genetic architecture is unique to ancestral populations. In this study, we developed and replicated an African-ancestry (AFR) wGRS, which captured 30-35% of the variation in NMR. We demonstrated model robustness against known environmental sources of NMR variation. Furthermore, despite the vast diversity within AFR populations, we showed that the AFR wGRS was consistent between different US geographical regions and unaltered by fine AFR population substructure. The AFR and EUR wGRSs can distinguish slow from normal metabolizers in their respective populations, and were able to reflect unique smoking cessation pharmacotherapy outcomes previously observed for the NMR. Additionally, we evaluated the utility of a cross-ancestry wGRS, and the capacity of EUR, AFR, and cross-ancestry wGRSs to predict the NMR within stratified or admixed AFR-EUR populations. Overall, our findings establish the clinical benefit of applying ancestry-specific wGRSs, demonstrating superiority of the AFR wGRS in AFRs.

Smoking behaviors, including amount smoked, smoking cessation, and tobacco-related diseases, are altered by the rate of nicotine clearance. Nicotine clearance can be estimated using the nicotine metabolite ratio (NMR) (ratio of 3 ' hydroxycotinine/cotinine), but only in current smokers. Advancing the genomics of this highly heritable biomarker of CYP2A6, the main metabolic enzyme for nicotine, will also enable investigation of never and former smokers. We performed the largest genome-wide association study (GWAS) to date of the NMR in European ancestry current smokers (n = 5185), found 1255 genome-wide significant variants, and replicated the chromosome 19 locus. Fine-mapping of chromosome 19 revealed 13 putatively causal variants, with nine of these being highly putatively causal and mapping to CYP2A6, MAP3K10, ADCK4, and CYP2B6. We also identified a putatively causal variant on chromosome 4 mapping to TMPRSS11E and demonstrated an association between TMPRSS11E variation and a UGT2B17 activity phenotype. Together the 14 putatively causal SNPs explained similar to 38% of NMR variation, a substantial increase from the similar to 20 to 30% previously explained. Our additional GWASs of nicotine intake biomarkers showed that cotinine and smoking intensity (cotinine/cigarettes per day (CPD)) shared chromosome 19 and chromosome 4 loci with the NMR, and that cotinine and a more accurate biomarker, cotinine + 3 ' hydroxycotinine, shared a chromosome 15 locus near CHRNA5 with CPD and Pack-Years (i.e., cumulative exposure). Understanding the genetic factors influencing smoking-related traits facilitates epidemiological studies of smoking and disease, as well as assists in optimizing smoking cessation support, which in turn will reduce the enormous personal and societal costs associated with smoking.

Introduction Varenicline is the most efficacious smoking cessation treatment; however, long-term cessation rates tend to be Methods We conducted a genome-wide association study of nausea incidence at 1 week following the initiation of varenicline treatment (corresponding to the target quit date) in 189 cigarette smokers of European ancestry (NCT01314001). Additive genetic models examining the likelihood of experiencing any versus no nausea controlled for population substructure, age, and sex. Variants with minor allele frequencies (MAF)≥10% were considered. Results Fifty-seven (30.2%) out of 189 participants reported nausea. The top variant associated with nausea was rs1568209 (odds ratio [OR] = 2.61 for A vs. G allele; 95% confidence interval [CI] = 1.65,4.15; p = 2.1e-7; MAF = 48.7%), mapping to the SLCO3A1 drug transporter gene on chromosome 15. In the same trial, rs1568209 was not associated with nausea in either the nicotine patch (p = .56; n = 181) or placebo (p = .59; n = 174) arms. In varenicline-treated smokers, the incidence of nausea was higher in females (44.6%; n = 74) versus males (20.9%; n = 115) (p = .001), however there was no evidence of a difference in the influence of rs1568209 on nausea between the sexes (p for sex*genotype interaction = .36). Future studies in larger samples are required to test the robustness of this finding. Conclusions Variation in SLCO3A1 may influence the risk for developing nausea in varenicline-treated smokers, which may alter adherence and cessation. Implications Varenicline-associated nausea reduces adherence and limits cessation success. Previous candidate gene association studies showed genetic factors influence nausea on varenicline. This pilot genome-wide investigation of nausea, the most common side effect associated with varenicline treatment and an important cause of treatment discontinuation, suggests the potential involvement of common variation in the SLCO3A1 drug transporter gene.

Nicotine is inactivated by the polymorphic CYP2A6 enzyme to cotinine and then to 3′hydroxycotinine. The Nicotine Metabolite Ratio (NMR; 3′hydroxycotinine/cotinine) is a heritable nicotine metabolism biomarker, varies with sex and ancestry, and influences smoking cessation and disease risk. We conducted sex-stratified genome-wide association studies of the NMR in European American (EA) and African American (AA) smokers (NCT01314001, NCT00666978). In EA females (n = 389) and males (n = 541), one significant (P CYP2A6 (intronic), for C vs. T: females: beta = 0.67, P = 7.5e−22, 21.8% variation explained; males: beta = 0.75, P = 1.2e−37, 26.1% variation explained). In AA females (n = 503) and males (n = 352), the top variant was found on chromosome 19 but differed by sex (females: rs11878604, CYP2A6 (~ 16 kb 3′), for C vs. T: beta = − 0.71, P = 6.6e−26, 16.2% variation explained; males: rs3865454, CYP2A6 (~ 7 kb 3′), for G vs. T: beta = 0.64, P = 1.9e−19, 18.9% variation explained). In AA females, a significant region was found on chromosome 12 (top variant: rs12425845: P = 5.0e−9, TMEM132C (~ 1 Mb 5′), 6.1% variation explained) which was not significant in AA males. In AA males, significant regions were found on chromosomes 6 (top variant: rs9379805: P = 4.8e−9, SLC17A2 (~ 8 kb 5′), 8.0% variation explained) and 16 (top variant: rs77368288: P = 3.5e−8, ZNF469 (~ 92 kb 5′), 7.1% variation explained) which were not significant in AA females. Further investigation of these associations outside of chromosome 19 is required, as they did not replicate. Understanding how sex and ancestry influence nicotine metabolism genetics may improve personalized approaches for smoking cessation and risk prediction for tobacco-related diseases.

BACKGROUND: Variation in CYP2A6 activity influences tobacco smoking behaviors and smoking-related health outcomes. Plasma Nicotine Metabolite Ratio (NMR) is a robust phenotypic biomarker of CYP2A6 activity and nicotine clearance. In urine, the NMR has been calculated as a ratio of free trans-3’-hydroxycotinine to free cotinine (NMR(F/F)), total trans-3’-hydroxycotinine to free cotinine (NMR(T/F)), or total trans-3’-hydroxycotinine to total cotinine (NMR(T/T)). We evaluated these three urinary NMR versions relative to plasma NMR and nicotine clearance and elucidated mechanisms of discrepancies among them. METHODS: Baseline plasma and urine biomarker data were available from two smoking cessation clinical trials and one nicotine pharmacokinetic study (total N=768). NMRs were compared using Pearson correlations, linear regressions and ANOVA analyses. UGT2B10 and UGT2B17 were genotyped. RESULTS: Urinary NMR(T/F) was the most highly related to plasma NMR (R(2)=0.70, P urinary NMR(T/F) > NMR(F/F) > NMR(T/T) (R(2)=0.41>0.37>0.35>0.25 respectively). CONCLUSION: Urinary NMR(T/F) followed by NMR(F/F) are the best urinary alternatives to plasma NMR or nicotine clearance. NMR(T/T) has the least utility as it is influenced substantially by variation in cotinine glucuronidation. IMPACT: This work highlighted the variation in urinary NMRs, and identified mechanisms for disparities among them, which facilitates their use in predicting smoking-related outcomes.

OBJECTIVE: Addressing tobacco use among HIV+ smokers is a priority. Lack of knowledge about how HIV+ smokers respond to tobacco use treatments limits our ability to effectively treat this population of smokers. METHOD: Using data from two clinical trials that provided 12 weeks of varenicline and behavioral counseling, one with smokers with HIV (n=89) and one with smokers without HIV (n=179), we used mixed logistic regression modeling to compare point-prevalence abstinence rates and adherence to the initial target quit date (TQD) and Cox regression for repeated outcomes to evaluate lapse and recovery dynamics between the groups. RESULTS: 60% of HIV− smokers refrained from smoking at the TQD while only 33% of HIV+ smokers did (OR=0.32, 95% CI: 0.18-0.56, p

INTRODUCTION: Adherence to pharmacotherapies for tobacco dependence, such as varenicline, is necessary for effective treatment. The relationship between varenicline adherence, determined by commonly used indirect (i.e., self-reported pill counts) and infrequently used direct (i.e., varenicline levels) methods, and abstinence outcomes have not been previously examined, nor has their impact on the outcomes of a genetically randomized clinical trial been assessed. METHODS: At Week 1 following target quit date, self-reported pill count and salivary varenicline levels were obtained from participants (N=376) in a smoking cessation clinical trial (NCT01314001). Point-prevalence abstinence was biochemically-verified by salivary cotinine at Week 1 and by exhaled carbon monoxide at Week 1, end-of-treatment, 6 and 12 months following treatment. Blood nicotine metabolite ratio (NMR) was obtained at baseline. RESULTS: Adherent individuals based on varenicline levels were significantly more likely to be abstinent than non-adherent individuals at Week 1 (odds ratios [ORs] 1.92–3.16, p’s≤ .006), end-of-treatment (OR=2.53, p=.004), and six months following treatment (OR=2.30, p=.03). In contrast, pill counts did not consistently predict abstinence. Including direct measures of adherence enhanced the association between rate of nicotine metabolism (NMR) and end-of-treatment abstinence; normal metabolizers (NMR≥0.31) were significantly more likely than slow metabolizers (NMR

INTRODUCTION:While adherence to medication in smoking cessation clinical trials is strongly associated with clinical outcome, very few studies have evaluated the validity of pill count as a measure of adherence relative to a biological assay, and evaluated a broad range of correlates of adherence. METHODS:In a smoking cessation clinical trial of varenicline, we compared pill counts collected over 4 different time periods to varenicline salivary levels taken after 2weeks of treatment, as well as evaluated predictors of adherence to varenicline. RESULTS:Using a binary measure of adherence based on salivary varenicline levels, adherence was higher among older, white, and more educated participants. Relative to 3, 7, and 14-day pill count, 12-week pill count was the only significant measure able to discriminate adherence as defined by salivary varenicline levels (assessed by area under the receiver operating characteristic curve; AUC=0.59, p=0.004). Seventy-two percent of participants who indicated adherence on 12-week pill count were classified as adherent based on varenicline saliva levels (sensitivity=0.80; specificity=0.40). There was modest variability in the relationship between 12-week pill count and varenicline levels across race and rate of nicotine metabolism. Lastly, General Estimating Equation models demonstrated that longitudinal changes in withdrawal, craving, negative and positive affect, and side effect count and severity were not related to adherence based on salivary varenicline levels. CONCLUSIONS:These results indicate that 12-week pill count was the best, albeit a relatively weak, measure of varenicline adherence; additional factors associated with treatment adherence need to be identified.

BACKGROUND: Adherence to nicotine patches relates to cessation. This is the first study to examine the validity of self-reported nicotine patch adherence relative to saliva cotinine. METHODS: We used data from 198 clinical trial participants who received 11 weeks of nicotine patches, self-reported patch use, had saliva cotinine 1-week after the start of treatment assessed, and were not smoking when saliva was collected (CO≤6). Self-reported patch adherence was defined as: 3-day (before saliva collection), 7-day (before saliva collection), 3-week use (7 days before, and 14 days after, saliva collection), and 11-week use (7 days before, and 10 weeks after, saliva collection). Analyses, including receiver operating characteristic curves, considered differences in nicotine metabolism. Sensitivity, specificity and positive (PPV) and negative predictive value (NPV) assessed optimal cotinine cut-point for adherence. RESULTS: Self-reported 7-day (r=0.13) and 3-week (r=0.13) patch use marginally correlated with week 1 cotinine (p’s=0.08) but not 3-day or 11-week. Significant area under the curve (AUC) values of 0.67 (95%CI: 0.55–0.79) and 0.72 (95%CI: 0.57–0.88) were found using 7-day self-report for the overall sample and for slow metabolizers (p’s

Introduction By improving our understanding of the neurobiological mechanisms underlying addiction, neuroimaging research is helping to identify new targets for personalized treatment interventions. When trying to quit, smokers with larger electrophysiological responses to cigarette-related, compared with pleasant, stimuli (“C > P”) are more likely to relapse than smokers with the opposite brain reactivity profile (“P > C”). Aim and Method The goal was to (1) build a classification algorithm to identify smokers characterized by P > C or C > P neuroaffective profiles and (2) validate the algorithm’s classification outcomes in an independent data set where we assessed both smokers’ electrophysiological responses at baseline and smoking abstinence during a quit attempt. We built the classification algorithm applying discriminant function analysis on the event-related potentials evoked by emotional images in 180 smokers. Results The predictive validity of the classifier showed promise in an independent data set that included new data from 177 smokers interested in quitting; the algorithm classified 111 smokers as P > C and 66 as C > P. The overall abstinence rate was low; 15 individuals (8.5% of the sample) achieved CO-verified 12-month abstinence. Although individuals classified as P > C were nearly 2.5 times more likely to be abstinent than smokers classified as C > P (12 vs. 3, or 11% vs. 4.5%), this result was nonsignificant, preliminary, and in need of confirmation in larger trials. Conclusion These results suggest that psychophysiological techniques have the potential to advance our knowledge of the neurobiological underpinnings of nicotine addiction and improve clinical applications. However, larger sample sizes are necessary to reliably assess the predictive ability of our algorithm. Implications We assessed the clinical relevance of a neuroimaging-based classification algorithm on an independent sample of smokers enrolled in a smoking cessation trial and found those with the tendency to attribute more relevance to rewards than cues were nearly 2.5 times more likely to be abstinent than smokers with the opposite brain reactivity profile (11% vs. 4.5%). Although this result was not statistically significant, it suggests our neuroimaging-based classification algorithm can potentially contribute to the development of new precision medicine interventions aimed at treating substance use disorders. Regardless, these findings are still preliminary and in need of confirmation in larger trials.

Author(s): Peng, Annie R; Swardfager, Walter; Benowitz, Neal L; Ahluwalia, Jasjit S; Lerman, Caryn; Nollen, Nicole L; Tyndale, Rachel F | Abstract: Background and aimsVarenicline effectiveness may be related to the level of adherence, which might be reduced by adverse effects such as nausea. The aim of the study was to test a possible effect of nausea on smoking cessation outcomes mediated by adherence.DesignMediation path analysis.SettingMultiple sites within Canada and the United States.ParticipantsTreatment-seeking smokers receiving varenicline from two smoking cessation clinical trials: Quit2Live (NCT01836276; n = 449) and Pharmacogenetics of Nicotine Addiction Treatment (PNAT) (NCT01314001; n = 421).MeasurementsNausea severity was collected through self-report and adherence was biologically assessed using varenicline concentrations (Quit2Live, plasma sample at week 4; PNAT, saliva sample at week 2). In Quit2Live, the end-points were cotinine-verified abstinence at weeks 4, 12 and 26. In PNAT, the end-points were carbon monoxide-verified abstinence at weeks 2, 12 and 26.FindingsEarly nausea was not directly associated with abstinence [odds ratio (OR) ranging from 0.73-1.28; P ≥ 0.26]. However early nausea was indirectly associated with lower cessation rates at multiple timepoints (ORs ranging from 0.92-0.94; 95% CI between 0.83-0.99) in a relationship mediated by reduced varenicline adherence (assessed by plasma varenicline concentrations) in the primary trial (Quit2Live). This relationship between nausea, adherence and cessation was similar in direction but weaker in effect size (ORs ranging from 0.98-0.99; 95% CI between 0.90-1.03) in a secondary trial (PNAT), where adherence was assessed using salivary varenicline concentrations.ConclusionsThese data suggest that early nausea during varenicline treatment may be indirectly associated with lower likelihood of smoking cessation through reducing varenicline adherence. Differences in robustness between the trials may be due to the different biological matrices (plasma vs. saliva) and/or timing used to assess varenicline adherence. The results of the first study suggest that improved management of early nausea during varenicline treatment may positively impact smoking cessation success through increasing varenicline adherence.

Background Subjective stress is a well-documented predictor of early smoking relapse, yet our understanding of stress and tobacco use is limited by reliance on self-reported measures of stress. We utilized a validated functional neuroimaging paradigm to examine whether stress exposure during early abstinence alters objective measures of brain function. Methods Seventy-five participants underwent blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) during the Montreal Imaging Stress Task (MIST) on two occasions: once during smoking satiety and once following biochemically confirmed 24-hour abstinence (order counterbalanced). The primary outcome measure was brain response during stress (vs. control) blocks of the MIST, assessed using whole-brain analysis corrected for multiple comparisons using clusters determined by Z ≥ 3.1. Results Abstinence (vs. satiety) was associated with significantly increased activation in the left inferior frontal gyrus, a brain region associated with inhibitory control. Abstinence-induced change in brain response to stress was positively associated with change in self-reported stress. Conclusions This study provides objective evidence that the brain response to stress is altered during the first 24 hours of a quit attempt compared to smoking satiety. Implications These results point to the potential value of inoculating smokers with stress management training prior to a quit attempt.

The nicotine metabolite ratio (NMR), a genetically informed biomarker of rate of nicotine metabolism, has been validated as a tool to select the optimal treatment for individual smokers, thereby improving treatment outcomes. This review summarizes the evidence supporting the development of the NMR as a biomarker of individual differences in nicotine metabolism, the relationship between the NMR and smoking behavior, the clinical utility of using the NMR to personalize treatments for smoking cessation, and the potential mechanisms that underlie the relationship between NMR and smoking cessation. We conclude with a call for additional research necessary to determine the ultimate benefits of using the NMR to personalize treatments for smoking cessation. These future directions include measurement and other methodologic considerations, disseminating this approach to at-risk subpopulations, expanding the NMR to evaluate its efficacy in predicting treatment responses to e-cigarettes and other noncigarette forms of nicotine, and implementation science including cost-effectiveness analyses. See all articles in this Special Collection Honoring Paul F. Engstrom, MD, Champion of Cancer Prevention

Background and aims Deficits in cognitive function are observed during nicotine withdrawal and present a challenge to successful smoking cessation. This clinical trial evaluated a cognitive exercise training (CT) program to improve smoking cessation rates. Methods Adult treatment-seeking smokers (n = 213) were randomized to receive nicotine patch therapy and 12 weeks of either computerized CT or computerized relaxation (control) training. Smoking status was biochemically verified at the end of treatment and 6-month follow-up. Results Quit rates did not differ by treatment arm at either time-point, nor were there effects on withdrawal symptoms or smoking urges. Reaction time for emotion recognition and verbal interference tasks showed improvement in the CT group. When including only successful quitters, improvements in recognition memory, verbal interference accuracy, and attention switching error rate were also observed in the CT group, while commission errors on the continuous performance task decreased in the control group. Conclusions Despite modest changes in cognitive performance, these results do not support the efficacy of computerized cognitive training as an adjunctive therapy for smoking cessation.

Background Inherited differences in the rate of metabolism of nicotine, the addictive chemical in tobacco, affect smoking behavior and quitting success. The nicotine metabolite ratio (3′-hydroxycotinine/cotinine) is a reliable measure of nicotine clearance and a well-validated predictive biomarker of response to pharmacotherapy. To clarify the mechanisms underlying these associations, we investigated the neural responses to smoking cues in normal and slow nicotine metabolizers. Methods Treatment-seeking smokers ( N = 69; 30 slow metabolizers and 39 normal metabolizers) completed a visual cue reactivity task during functional magnetic resonance imaging on two separate occasions: once during smoking satiety and once after 24 hours of smoking abstinence. Results In whole-brain analysis, normal (compared with slow) metabolizers exhibited heightened abstinence-induced neural responses to smoking cues in the left caudate, left inferior frontal gyrus, and left frontal pole. These effects were more pronounced when extreme groups of slow and normal metabolizers were examined. Greater activation in the left caudate and left frontal pole was associated with abstinence-induced subjective cravings to smoke. Conclusions Inherited differences in rate of nicotine elimination may drive neural responses to smoking cues during early abstinence, providing a plausible mechanism to explain differences in smoking behaviors and response to cessation treatment. Normal metabolizers may benefit from adjunctive behavioral smoking cessation treatments, such as cue exposure therapy.

INTRODUCTION The decrease in smoking rates in North America has plateaued, underscoring the need for new approaches to treat nicotine dependence. Inter-individual differences in smoking behavior result, in part, from variation in the rate of CYP2A6-mediated nicotine metabolism. A phenotypic measure of CYP2A6 activity is the nicotine metabolite ratio (NMR), the ratio of 3'hydroxycotinine/cotinine. The NMR is associated with smoking cessation. However, the NMR is also associated with genetic (eg, CYP2A6 genotype) and other (eg, sex and ethnicity) factors. Here we aimed to determine if previously identified non-CYP2A6 sources of variation in the NMR mitigated the association between the NMR and short-term abstinence. METHODS The NMR was determined from blood samples collected at intake from daily smokers aged 18-65. Biochemically-verified point prevalence abstinence (exhaled carbon monoxide level ≤ 8 ppm) was measured at 1 week following the target quit date in participants from a smoking cessation clinical trial (NCT01314001). Analyses were restricted to N = 462 blacks and N = 693 whites in the intent-to-treat sample. RESULTS Lower NMR (

Background and Objective Tobacco and cannabis are frequently used in combination and cannabis co-use may lead to poor tobacco cessation outcomes. Therefore, it is important to explore if cannabis co-use is associated with a reduced likelihood of achieving successful tobacco abstinence among treatment-seeking tobacco smokers. The present study examined whether current cannabis use moderated tobacco cessation outcomes after 12 weeks of pharmacological treatment (varenicline vs. nicotine patch vs. placebo) with adjunctive behavioral counseling. Methods Treatment-seeking tobacco smokers (N = 1,246) were enrolled in an intent-to-treat study, of which 220 were current cannabis users. Individuals were randomly assigned to 12 weeks of placebo (placebo pill plus placebo patch), nicotine patch (active patch plus placebo pill), or varenicline (active pill plus placebo patch), plus behavioral counseling. The primary endpoint was biochemically verified 7-day point prevalence abstinence at the end of treatment. Results Controlling for rate of nicotine metabolism, treatment arm, age, sex, alcohol, and level of nicotine dependence, cannabis users were as successful at achieving biochemically verified 7-day point prevalence abstinence compared to tobacco-only smokers. Conclusions and Scientific Significance Findings suggest that cannabis use does not hinder the ability to quit tobacco smoking. Future tobacco cessation studies should employ prospective, longitudinal designs investigating cannabis co-use over time and at different severity levels. (Am J Addict 2016;XX:1–6)

Introduction: The nicotine–metabolite ratio (NMR) predicts treatment response and is related to treatment side effect severity. Sleep disturbance may be one important side effect, but understanding sleep disturbance effects on smoking cessation is complicated by the fact that nicotine withdrawal also produces sleep disturbance.Aims: To evaluate the effects of withdrawal and treatment side effects on sleep disturbance.Methods: This is a secondary analysis of data from a clinical trial (Lerman et al., 2015) of 1,136 smokers randomised to placebo (n = 363), transdermal nicotine (TN; n = 381), or varenicline (n = 392) and stratified based on NMR (559 slow metabolisers; 577 normal metabolisers). Sleep disturbance was assessed at baseline and at 1-week following the target quit date (TQD). We also examined whether sleep disturbance predicted 7-day point-prevalence abstinence at end-of-treatment (EOT).Results: The varenicline and TN groups exhibited greater increases in sleep disturbance (vs. placebo; treatment × time interaction; p = 0.005), particularly among those who quit smoking at 1-week post-TQD. There was a main effect of NMR (p = 0.04), but no interactions with treatment. TN and varenicline attenuated withdrawal symptoms unrelated to sleep (vs. placebo). Greater baseline sleep disturbance predicted relapse at EOT (p = 0.004).Conclusions: Existing treatments may not mitigate withdrawal-related sleep disturbance and adjunctive treatments that target sleep disturbance may improve abstinence rates.

Background The ability to exert self-control over temptation is a fundamental component of smoking behavior change. Transcranial direct current stimulation (tDCS) of the dorsolateral prefrontal cortex (DLPFC) has been shown to modulate cognitive control circuits. Although prior studies show that stimulation reduces cigarette craving and self-reported smoking, effects on ability to resist smoking have not been investigated directly. Objectives We assessed effects of a single 20-minute session of 1.0 mA anodal stimulation over the left DLPFC with cathodal stimulation over the right supra-orbital area (vs. sham stimulation) on ability to resist smoking in a validated smoking lapse paradigm. Methods Twenty-five participants completed two tDCS sessions (active and sham stimulation) in a within-subject, double-blind, randomized and counterbalanced order with a 2-week washout period. Following overnight abstinence, participants received tDCS in the presence of smoking related cues; they had the option to smoke at any time or receive $1 for every 5 minutes they abstained. After 50 minutes, they participated in a 1 hour ad libitum smoking session. Primary and secondary outcomes were time to first cigarette and cigarette consumption, respectively. Results In multiple regression models, active tDCS (compared to sham) significantly increased latency to smoke (p = 0.02) and decreased the total number of cigarettes smoked (p = 0.014) during the session. Conclusion These findings suggest that acute anodal stimulation over the left DLPFC (with cathodal stimulation over the right supra-orbital area) can improve ability to resist smoking, supporting the therapeutic potential of tDCS for smoking cessation treatment.

Smokers attempting to quit often attribute smoking relapse to negative affect, craving, and other nicotine withdrawal symptoms. In addition, there is evidence that smoking relapse can increase these symptoms, particularly negative affect. To address this issue, we analyzed data from an 11-week smoking cessation clinical trial in which smokers (n = 1,246) were randomized to receive either nicotine replacement therapy (NRT), varenicline, or placebo, combined with behavioral counseling. Using cross-lagged analyses, we examined the temporal bidirectional relationships between self-reported measures of affect, craving, and composite withdrawal symptoms and biochemically verified smoking abstinence. The relative strength of these temporal relationships was examined by comparing the explained variances of the models. The results showed that higher negative affect, craving, and composite withdrawal symptoms increased the likelihood of subsequent smoking relapse, and that smoking relapse led to subsequent increases in these same symptoms. A comparison of the explained variances found symptom predicting subsequent relapse models to be stronger than those where relapse predicted subsequent symptoms. Although the explained variance findings generally support a negative reinforcement conceptualization of nicotine dependence, the bidirectional relationship between symptoms and smoking relapse suggests that struggling with quitting smoking leads to significant negative affect, craving, and other withdrawal symptoms that do not quickly resolve. These findings highlight the importance of addressing specific symptoms within the context of smoking cessation. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

This chapter highlights a transdisciplinary behavioral science research program that merges concepts and tools from the fields of behavioral science and cognitive neuroscience. A series of discoveries by this team converged on the importance of working memory-related brain activity in smoking cessation, culminating in a neuroimaging-based biomarker of smoking relapse. This body of work has enabled identification of cognitive and neural mechanisms as potential therapeutic targets for novel behavior change interventions for tobacco dependence and overeating/obesity. The authors will describe their work bridging these fields, highlighting strategies for promoting transdisciplinary research.

BACKGROUND: Transcranial direct current stimulation (tDCS) has been shown to improve measures of executive cognitive function and reduce cigarette consumption. Studies conducted to date have been small, and the results are mixed. METHODS: This randomized, double-blind, parallel arm clinical trial tested the effects of active anodal tDCS targeted to the left dorsolateral prefrontal cortex (versus sham) on 7-day smoking cessation in 106 treatment-seeking smokers. Participants received three sessions of sham (n = 35), 1mA (n = 35), or 2mA (n = 36) tDCS in the context of a validated smoking lapse paradigm then received brief smoking cessation counseling and completed a monitored quit attempt. The primary outcome was total number of days of abstinence confirmed via exhaled carbon monoxide. RESULTS: During the quit period, there were no effects of dose group on days of abstinence (sham, M (SD): 2.5 days (±2.5); 1mA: 2.5 days (±2.5); 2mA: 2.4 days (±2.3); β = −0.08; p = 0.76) or on change in daily smoking rate (sham, M (SD): −12.6 CPD (±4.8); 1mA: −11.8 CPD (±4.4); 2mA: −11.7 CPD (±5.3); β = 0.42, p = 0.49), nor were there effects of dose group on latency to smoke or number of cigarettes smoked during the smoking lapse paradigm. Side effects of tDCS were generally mild (

Background: The highly genetically variable enzyme CYP2A6 metabolizes nicotine to cotinine (COT) and COT to trans-3′-hydroxycotinine (3HC). The nicotine metabolite ratio (NMR, 3HC/COT) is commonly used as a biomarker of CYP2A6 enzymatic activity, rate of nicotine metabolism, and total nicotine clearance; NMR is associated with numerous smoking phenotypes, including smoking cessation. Our objective was to investigate the impact of different measurement methods, at different sites, on plasma and urinary NMR measures from ad libitum smokers. Methods: Plasma (n = 35) and urine (n = 35) samples were sent to eight different laboratories, which used similar and different methods of COT and 3HC measurements to derive the NMR. We used Bland–Altman analysis to assess agreement, and Pearson correlations to evaluate associations, between NMR measured by different methods. Results: Measures of plasma NMR were in strong agreement between methods according to Bland–Altman analysis (ratios, 0.82–1.16) and were highly correlated (all Pearson r > 0.96, P < 0.0001). Measures of urinary NMR were in relatively weaker agreement (ratios 0.62–1.71) and less strongly correlated (Pearson r values of 0.66–0.98, P < 0.0001) between different methods. Plasma and urinary COT and 3HC concentrations, while weaker than NMR, also showed good agreement in plasma, which was better than that in urine, as was observed for NMR. Conclusions: Plasma is a very reliable biologic source for the determination of NMR, robust to differences in these analytical protocols or assessment site. Impact: Together this indicates a reduced need for differential interpretation of plasma NMR results based on the approach used, allowing for direct comparison of different studies. Cancer Epidemiol Biomarkers Prev; 24(8); 1239–46. ©2015 AACR.

Introduction We previously reported poor associations between salivary varenicline and pill counts, and a substantial overestimation of adherence by pill counts in “Measures and predictors of varenicline adherence in the treatment of nicotine dependence” (Peng et al., 2017). We have since conducted supplementary analyses characterizing, and then excluding, individuals with established inaccurate pill count recall. Methods Based on published varenicline pharmacokinetics (including drug levels, and the long half-life) and our detection limits, conservatively we should be able to detect varenicline in anyone who took at least one pill during the 48 h prior to saliva collection; thus, those reporting 1 or more pills in this time frame but who had undetectable salivary varenicline were deemed to have inaccurate pill count recall. Correlations between pill counts and salivary varenicline, and Receiver Operating Characteristics curve analyses were conducted following exclusion of participants with inaccurate pill count recall. Results Nearly 20% of our participants (N = 67/376) had inaccurate self-reported pill counts. These participants were younger, non-white, lower income, and unmarried (evaluated using chi-square or Mann-Whitney U test). Following exclusion of these individuals, the correlations between salivary varenicline and pill count improved and the area under the curve (AUC) of pill counts for discriminating adherence improved modestly. Conclusion When the 20% of individuals with inaccurate pill count recall were excluded, an improved association between self-reported pill count and salivary varenicline was observed, albeit still weak. A substantial overestimation of adherence by pill counts relative to salivary varenicline is still observed even after exclusion of almost 20% of the group having established inaccurate reporting suggesting that these individuals, with identifiable inaccuracies, were only part of the overestimation of adherence.

Brief abstinence from smoking impairs cognition, particularly executive function, and this has a role in relapse to smoking. This study examined whether working memory-related brain activity predicts subsequent smoking relapse above and beyond standard clinical and behavioral measures. Eighty treatment-seeking smokers completed two functional magnetic resonance imaging sessions (smoking satiety vs 24 h abstinence challenge) during performance of a visual N-back task. Brief counseling and a short-term quit attempt followed. Relapse during the first 7 days was biochemically confirmed by the presence of the nicotine metabolite cotinine. Mean percent blood oxygen level-dependent (BOLD) signal change was extracted from a priori regions of interest: bilateral dorsolateral prefrontal cortex (DLPFC), medial frontal/cingulate gyrus, posterior cingulate cortex (PCC), and ventromedial prefrontal cortex. Signal from these brain regions and additional clinical measures were used to model outcome status, which was then validated with resampling techniques. Relapse to smoking was predicted by increased withdrawal symptoms, decreased left DLPFC and increased PCC BOLD percent signal change (abstinence vs smoking satiety). Receiver operating characteristic analysis demonstrated 81% area under the curve using these predictors, a significant improvement over the model with clinical variables only. The combination of abstinence-induced decreases in left DLPFC activation and reduced suppression of PCC may be a prognostic marker for poor outcome, specifically early smoking relapse.

Background: The ratio of 3′hydroxycotinine to cotinine, or nicotine metabolite ratio (NMR), is strongly associated with CYP2A6 genotype, CYP2A6-mediated nicotine and cotinine metabolism, and nicotine clearance. Higher NMR (faster nicotine clearance) is associated retrospectively with heavier smoking and lower cessation rates. Methods: NMR as a predictive biomarker of cessation outcomes is being investigated (NCT01314001). In addition to strong CYP2A6 genetic influences on NMR, demographic and hormonal factors alter NMR. Here, we analyzed, for the first time together, these sources of variation on NMR in smokers screened for this clinical trial (N = 1,672). Results: Participants (mean age = 45.9) were 65.1% Caucasian, 34.9% African American, and 54.8% male. Mean NMR (SD) was higher in Caucasians versus African Americans [0.41 (0.20) vs. 0.33 (0.21); P < 0.001], and in females versus males [0.41 (0.22) vs. 0.37 (0.20); P < 0.001]. Among females, birth control pill use (N = 17) and hormone replacement therapy (N = 14) were associated with 19.5% (P = 0.09) and 29.3% (P = 0.06) higher mean NMR, respectively, albeit nonsignificantly. BMI was negatively associated with NMR (Rho = −0.14; P < 0.001), whereas alcohol use (Rho = 0.11; P < 0.001) and cigarette consumption (Rho = 0.12; P < 0.001) were positively associated with NMR. NMR was 16% lower in mentholated cigarette users (P < 0.001). When analyzed together in a linear regression model, these predictors (each ≤2%) accounted for Conclusions: Although these factors significantly affected NMR, they contributed little (together Impact: Thus, when using NMR, for example, to prospectively guide smoking cessation therapy, these sources of variation are unlikely to cause NMR misclassification. Cancer Epidemiol Biomarkers Prev; 23(9); 1773–82. ©2014 AACR.

Initial screening of new medications for potential efficacy (i.e., Food and Drug Administration (FDA) early phase 2), such as in aiding smoking cessation, should be efficient in identifying which drugs do, or do not, warrant more extensive (and expensive) clinical testing.This focused review outlines our research on development, evaluation, and validation of an efficient crossover procedure for sensitivity in detecting medication efficacy for smoking cessation. First-line FDA-approved medications of nicotine patch, varenicline, and bupropion were tested as model drugs, in three separate placebo-controlled studies. We also tested specificity of our procedure in identifying a drug that lacks efficacy, using modafinil.This crossover procedure showed sensitivity (increased days of abstinence) during week-long "practice" quit attempts with each of the active cessation medications (positive controls) versus placebo, but not with modafinil (negative control) versus placebo, as hypothesized. Sensitivity to medication efficacy signal was observed only in smokers high in intrinsic quit motivation (i.e., already preparing to quit soon) and not smokers low in intrinsic quit motivation, even if monetarily reinforced for abstinence (i.e., given extrinsic motivation).A crossover procedure requiring less time and fewer subjects than formal trials may provide an efficient strategy for a go/no-go decision whether to advance to subsequent phase 2 randomized clinical trials with a novel drug. Future research is needed to replicate our results and evaluate this procedure with novel compounds, identify factors that may limit its utility, and evaluate its applicability to testing efficacy of compounds for treating other forms of addiction.

Background Dopamine levels in the prefrontal cortex (PFC) are thought to play an important role in cognitive function and nicotine dependence. The catechol-O-methyltransferase (COMT) inhibitor tolcapone, an FDA-approved treatment for Parkinson's disease, increases prefrontal dopamine levels, with cognitive benefits that may vary by COMT genotype. We tested whether tolcapone alters working memory-related brain activity and performance in abstinent smokers. Methods In this double-blind crossover study, 20 smokers completed 8 days of treatment with tolcapone and placebo. In both medication periods, smokers completed blood oxygen level-dependent (BOLD) fMRI scans while performing a working memory N-back task after 24 h of abstinence. Smokers were genotyped prospectively for the COMT val158met polymorphism for exploratory analysis. Results Compared to placebo, tolcapone modestly improved accuracy (p = 0.017) and enhanced suppression of activation in the ventromedial prefrontal cortex (vmPFC) (p = 0.002). There were no effects of medication in other a priori regions of interest (dorsolateral PFC, dorsal cingulate/medial prefrontal cortex, or posterior cingulate cortex). Exploratory analyses suggested that tolcapone led to a decrease in BOLD signal in several regions among smokers with val/val genotypes, but increased or remained unchanged among met allele carriers. Tolcapone did not attenuate craving, mood, or withdrawal symptoms compared to placebo. Conclusions Data from this proof-of-concept study do not provide strong support for further evaluation of COMT inhibitors as smoking cessation aids.

Bupropion may aid tobacco abstinence by quickly relieving symptoms of nicotine withdrawal, perhaps including impaired cognitive performance. We examined whether bupropion would attenuate abstinence-induced cognitive deficits on the first day of a brief quit attempt, when smokers are most likely to relapse.Smokers (N=24) with high quit interest were recruited for within-subjects cross-over test of bupropion vs placebo on ability to abstain during separate short-term practice quit smoking attempts. After introduction to working memory (N-back) and sustained attention (continuous performance task; CPT) tasks during the pre-quit smoking baseline, performance on these tasks was assessed after abstaining overnight (CO10 ppm) on the first day of each quit attempt, while on bupropion and on placebo.Compared to placebo, bupropion after abstinence improved correct response times for working memory (p=.01 for medication by memory load interaction) and for one measure of sustained attention (numbers, but not letters; p.05).Bupropion may attenuate some features of impaired cognitive performance due to withdrawal on the first day of a quit attempt. Future studies could examine whether this effect of bupropion contributes to its efficacy for longer-term smoking cessation.

Anti-smoking public service announcements (PSAs) often include smoking-related cues; however, visual drug cues can trigger acute cravings that may impede cognitive processing of the anti-smoking message. This experiment evaluated effects of smoking cues in PSAs on smoking urges, immediate smoking behavior, and persuasion measures in daily smokers.Three-hundred and eighteen non-treatment seeking smokers completed a single laboratory session during which they viewed sets of PSAs differentiated by presence of smoking cues (central to the PSA's argument, peripheral, or no cues) and argument strength (high versus low). After viewing the PSAs, participants completed self-report measures of smoking urges, attitudes toward quitting, self-efficacy, and intentions to quit smoking. Smoking behavior was recorded during a 1-h ad libitum smoking period immediately following PSA viewing and assessment.There was a significant positive effect of argument strength on attitudes toward quitting smoking (p=0.012). There were no main effects of smoking cues or smoking cue by argument strength interactions on any of the outcome measures.Visual smoking cues in PSAs do not increase urges to smoke, nor is there evidence that the inclusion of such cues impedes the recall or persuasive effects of anti-smoking arguments.

Author(s): David, Sean P; Strong, David R; Leventhal, Adam M; Lancaster, Molly A; McGeary, John E; Munafo, Marcus R; Bergen, Andrew W; Swan, Gary E; Benowitz, Neal L; Tyndale, Rachel F; Conti, David V; Brown, Richard A; Lerman, Caryn; Niaura, Raymond | Abstract: AimsTo evaluate the associations of treatment and an additive genetic efficacy score (AGES) based on dopamine functional polymorphisms with time to first smoking lapse and point prevalence abstinence at end of treatment among participants enrolled into two randomized clinical trials of smoking cessation therapies.DesignDouble-blind pharmacogenetic efficacy trials randomizing participants to active or placebo bupropion. Study 1 also randomized participants to cognitive-behavioral smoking cessation treatment (CBT) or this treatment with CBT for depression. Study 2 provided standardized behavioural support.SettingTwo hospital-affiliated clinics (study 1), and two university-affiliated clinics (study 2).ParticipantsA total of 792 self-identified white treatment-seeking smokers aged ≥18 years smoking ≥10 cigarettes per day over the last year.MeasurementsAge, gender, Fagerstrom Test for Nicotine Dependence, dopamine pathway genotypes (rs1800497 [ANKK1 E713K], rs4680 [COMT V158M], DRD4 exon 3 variable number of tandem repeats polymorphism [DRD4 VNTR], SLC6A3,3' VNTR) analyzed both separately and as part of an AGES, time to first lapse and point prevalence abstinence at end of treatment.FindingsSignificant associations of the AGES (hazard ratio [HR] = 1.10, 95% confidence interval [CI] = 1.06-1.14, P = 0.009) and of the DRD4 VNTR (HR = 1.29, 95% CI = 1.17-1.41, P = 0.0073) were observed with time to first lapse. A significant AGES by pharmacotherapy interaction was observed (β standard error = -0.18 [0.07], P = 0.016), such that AGES predicted risk for time to first lapse only for individuals randomized to placebo.ConclusionsA score based on functional polymorphisms relating to dopamine pathways appears to predict lapse to smoking following a quit attempt, and the association is mitigated in smokers using bupropion.

Addiction to nicotine and the ability to quit smoking are influenced by genetic factors. We used functional genomic approaches (chromatin immunoprecipitation (ChIP) and whole-genome sequencing) to identify cAMP response element-binding protein (CREB) targets following chronic nicotine administration and withdrawal (WD) in rodents. We found that chronic nicotine and WD differentially modulate CREB binding to the gene for neuregulin 3 (NRG3). Quantitative analysis of saline, nicotine and nicotine WD in two biological replicates corroborate this finding, with NRG3 increases in both mRNA and protein following WD from chronic nicotine treatment. To translate these data for human relevance, single-nucleotide polymorphisms (SNPs) across NRG3 were examined for association with prospective smoking cessation among smokers of European ancestry treated with transdermal nicotine in two independent cohorts. Individual SNP and haplotype analysis support the association of NRG3 SNPs and smoking cessation success. NRG3 is a neural-enriched member of the epidermal growth factor family, and a specific ligand for the receptor tyrosine kinase ErbB4, which is also upregulated following nicotine treatment and WD. Mice with significantly reduced levels of NRG3 or pharmacological inhibition of ErbB4 show similar reductions in anxiety following nicotine WD compared with control animals, suggesting a role for NRG3 in nicotine dependence. Although the function of the SNP in NRG3 in humans is not known, these data suggest that Nrg3/ErbB4 signaling may be an important factor in nicotine dependence.

Background and aim It is important to find economical methods in early Phase 2 studies to screen drugs potentially useful to aid smoking cessation. A method has been developed that detects efficacy of varenicline and nicotine patch. This study aimed to evaluate whether the method would detect the efficacy of bupropion and identify correctly the lack of efficacy of modafinil. Design Using a within-subject double cross-over design, smokers attempted to quit during each treatment, with bupropion (150 mg b.i.d.), modafinil [100 mg twice daily (b.i.d.)] or placebo (double-blind, counterbalanced order). In each of three medication periods, all smoked with no drug on week 1 (baseline or washout), began dose run-up on week 2, and tried to quit every day during week 3. Setting A university research center in the United States. Participants Forty-five adult smokers high in quit interest. Measurements Abstinence was verified daily each quit week by self-report of no smoking over the prior 24 hours and carbon monoxide (CO) < 5 parts per million. Findings Compared with placebo, bupropion did (F(1,44) = 6.98, P = 0.01), but modafinil did not (F(1,44) = 0.29, P = 0.60), increase the number of abstinent days. Also, bupropion (versus placebo) significantly increased the number of those able to maintain continuous abstinence on all 5 days throughout the quit week (11 versus four), Z = 2.11, P

One way to enhance therapeutic development is through the identification and development of evaluative tools such as biomarkers. This review focuses on putative diagnostic, pharmacodynamic, and predictive biomarkers for smoking cessation. These types of biomarkers may be used to more accurately diagnose a disease, personalize treatment, identify novel targets for drug discovery, and enhance the efficiency of drug development. Promising biomarkers are presented across a range of approaches including metabolism, genetics, and neuroimaging. A preclinical viewpoint is also offered, as are analytical considerations and a regulatory perspective summarizing a pathway toward biomarker qualification.

Nicotine withdrawal is associated with subtle working memory deficits that predict subsequent relapse. We examined the neural substrates underlying these processes in treatment-seeking smokers, and explored the moderating influence of age on abstinence-induced alterations in brain activity and performance. Sixty-three smokers participated in two blood oxygen level-dependent (BOLD) functional magnetic resonance imaging scans while performing a visual N-back task on two separate occasions: smoking as usual and after 24 hours of biochemically confirmed abstinence (order counterbalanced). Abstinence (versus smoking) led to reduced accuracy, slower median correct response time and reduced BOLD signal change in the three a priori regions of interest: medial frontal/cingulate gyrus and right and left dorsolateral prefrontal cortex. Significant age × session effects were found for BOLD signal change in all three regions, as well as for withdrawal and craving; for all measures, abstinence effects were attenuated in smokers aged ≥50 years compared with those

Possessing an apolipoprotein E (APOE) ɛ4 allele, advanced age and smoking are risk factors for Alzheimer's disease and cognitive decline. Deficits in cognitive function also increase risk for smoking relapse. Data from 917 adult smokers of European ancestry were pooled across three randomized trials of smoking cessation. We examined whether smokers who carry at least one ɛ4 allele (n=252) have more difficulty quitting smoking compared with noncarriers (n=665), and whether age moderated this association. The genotype by age interaction was significant for 7-day point-prevalence abstinence rates (P=0.04) and time to 7-day failure (P=0.03). Among smokers over age 60, ɛ4 carriers were less likely to quit (odds ratio=0.27, P=0.018) and relapsed more quickly (hazard ratio=3.38, P=0.001) compared with noncarriers. The genotype association with relapse was nonsignificant among younger smokers. An increased understanding of the underlying pathophysiological mechanisms of this association could facilitate the development of targeted therapies for smokers with increased risk for cognitive decline.

There is a need to identify medications to aid in smoking cessation. Reducing withdrawal-related cognitive deficits represents a pharmacological target for new pharmacotherapies. Endogenous acetylcholine levels, which are modulated by acetylcholinesterase inhibitors (AChEIs), play an important role in smoking behavior and cognition. This pilot feasibility study tested whether an AChEI, donepezil, enhanced cognitive performance among healthy smokers.Eighteen non-treatment seeking daily smokers (6 female) received either donepezil (5 mg q.d) or placebo (double-blind; 2:1 allocation ratio) for 4 weeks. Smoking rate, side effects, and neurocognitive measures of working memory (Letter-N-back) and sustained attention (Penn Continuous Performance Task) were assessed weekly.For the working memory task, there was a significant group×load×time interaction (p=0.03) indicating that the donepezil group demonstrated an increase in true positives from baseline to week 4 at the highest working memory load (3-back). The placebo group showed no change in accuracy. For the sustained attention task, there was a marginal effect in the same direction for discriminability, or d', p=0.08. There were no significant effects on reaction time during either task. There was also a reduction in cigarettes per day in the placebo group, but not the donepezil group.AChEIs, such as donepezil, may have pro-cognitive effects among healthy smokers while they continue to smoke as usual. Given the association between cognitive deficits and relapse, AChEIs should be explored as potential therapeutics for smoking cessation.

INTRODUCTION This study examines the impact of smoking cues employed in antismoking advertisements on former smokers. Previous findings indicate that visual smoking cues in antismoking advertisements with weak antismoking arguments can elicit smoking urges in smokers and undermine message effectiveness. This study extends these observations to former smokers asking whether smoking cues in antismoking advertisements influence former smokers' self-efficacy, attitudes, and intention to refrain from smoking, along with smoking urges and perceived message effectiveness. METHODS The study was a mixed 2 (smoking cues; present vs. absent) × 2 (argument strength [AS]; high vs. low) design where smoking cue was a between-subject factor and AS was a within-subject factor. Potential participants recruited via online ads were screened in a phone interview for their eligibility. A total of 105 former smokers (aged 21-65) participated in the study, which was conducted in a laboratory setting. Repeated measure ANOVA and MANOVA were used for the analyses. RESULTS The results showed that the presence of smoking cues in antismoking ads undermines former smokers' behavioral self-efficacy, attitude, and intention about smoking abstinence, which increased as AS for the ads increased. Former smokers' reports of smoking urge were not affected by smoking cues or AS. However, consistent with previous findings for smokers, the presence of cues weakened perceived message effectiveness of antismoking ads rated by former smokers. CONCLUSIONS The effect of smoking cues on former smokers' self-efficacy, attitude, and intention to refrain from smoking is problematic. Inclusion of smoking cues in antismoking ads should be undertaken only when accompanied by strong arguments.

Nicotine metabolism and genetic variation have an impact on nicotine addiction and smoking abstinence; however, further research is required. The nicotine metabolite ratio (NMR) is a robust biomarker of nicotine metabolism used to categorize slow and normal nicotine metabolizers (lower 25th quartile cut off). In two randomized clinical trials of smoking abstinence treatments, we conducted NMR-stratified analyses on smoking abstinence across 13 regions coding for nicotinic acetylcholine receptors and proteins involved in the dopamine reward system. Gene×NMR interaction P-values were adjusted for multiple correlated tests, and we used a Bonferroni-corrected α-level of 0.004 to determine system-wide significance. Three single-nucleotide polymorphisms in DRD1 (rs11746641, rs2168631, and rs11749035) had significant interactions (0.001≤adjusted P-values≤0.004) with increased odds of abstinence within slow metabolizers (odds ratios=3.1-3.5, 95% confidence interval 1.7-6.7). Our findings support the role of DRD1 in nicotine dependence, and identify genetic and nicotine metabolism profiles that may interact to impact nicotine dependence. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.

This study investigated psychological mechanisms underlying the effect of narrative health communication on behavioral intention. Specifically, the study examined how exemplification in news about successful smoking cessation affects recipients' narrative engagement, thereby changing their intention to quit smoking. Nationally representative samples of U.S. adult smokers participated in 2 experiments. The results from the 2 experiments consistently showed that smokers reading a news article with an exemplar experienced greater narrative engagement compared to those reading an article without an exemplar. Those who reported more engagement were in turn more likely to report greater smoking cessation intentions.

Many smokers attempt to quit smoking but few are successful in the long term. The heritability of nicotine addiction and smoking relapse have been documented, and research is focused on identifying specific genetic influences on the ability to quit smoking and response to specific medications. Research in genetically modified cell lines and mice has identified nicotine acetylcholine receptor subtypes that mediate the pharmacological and behavioral effects of nicotine sensitivity and withdrawal. Human genetic association studies have identified single nucleotide polymorphisms (SNPs) in genes encoding nicotine acetylcholine receptor subunits and nicotine metabolizing enzymes that influence smoking cessation phenotypes. There is initial promising evidence for a role in smoking cessation for SNPs in the β2 and α5/α3/β4 nAChR subunit genes; however, effects are small and not consistently replicated. There are reproducible and clinically significant associations of genotypic and phenotypic measures of CYP2A6 enzyme activity and nicotine metabolic rate with smoking cessation as well as response to nicotine replacement therapies and bupropion. Prospective clinical trials to identify associations of genetic variants and gene-gene interactions on smoking cessation are needed to generate the evidence base for both medication development and targeted therapy approaches based on genotype.

Anti-smoking public service announcements (PSAs) often use persuasive arguments to attempt to influence attitudes about smoking. The persuasiveness of a PSA has previously been associated with factors that influence the cognitive processing of its message. Genetic factors that influence cognitive processing might thus affect individuals' responses to the persuasive arguments presented in PSAs. In the current study, we examined polymorphisms in the genes encoding brain-derived neurotrophic factor (BDNF Val66Met) and catechol-O-methyltransferase (COMT Val158Met), which affect cognitive processing in the prefrontal cortex, to identify genetic factors associated with self-reported outcomes of message processing, perceived effectiveness, and quitting intentions among smokers viewing PSAs. 120 smokers viewed sets of 4 PSAs which varied with respect to features of argument strength and message sensation value. We observed significant associations of BDNF genotype with central processing, narrative processing, perceived effectiveness of the anti-smoking PSAs, and participant quitting intentions; the BDNF Met allele was associated with lower scores on all these measures. Central processing acted as a mediator of the association of genotype with quitting intentions and perceived effectiveness. There was a significant interaction of COMT genotype by argument strength in the model of narrative processing, such that individuals homozygous for the COMT Val allele reported higher narrative processing in the high argument strength condition, but not in the low argument strength condition. To our knowledge, this is the first study to identify genetic factors associated with cognitive processing of anti-smoking public service announcements.

Aims To examine person-specific urge-to-smoke trajectories during the first 7 days of abstinence and the relationship of trajectory parameters to continuous abstinence, demographics, medication and smoking history. Design Hierarchical linear modeling was used to model person-specific trajectories for urge-to-smoke. Setting Two university-based smoking cessation trials. Participants Treatment-seeking smokers in a clinical trial of transdermal nicotine (n = 275) versus nicotine spray (n = 239) and of bupropion (n = 223) versus placebo (n = 198). Measurements Self-reported urge-to-smoke for 7 days after the planned quit date, and 7-day point prevalence and continuous abstinence at end of treatment (EOT) and 6 months. Findings Urge-to-smoke trajectory parameters (average level, slope, curvature and volatility) varied substantially among individuals, had modest intercorrelations and predicted continuous and point prevalence abstinence at EOT and at 6 months. Higher trajectory level, slope and volatility were all significantly (P ≤ 0.001) associated with a reduced likelihood of abstinence at EOT (odds ratios 0.44–0.75) and at 6-month follow-up (odds ratios from 0.63 to 0.78), controlling for demographic, medication and smoking use variables. Conclusion Higher urge-to-smoke trajectory parameters of level, slope and volatility (measured over 7 days) predict continuous and 7-day point prevalence at EOT and 6 months. Although there were some associations of trajectory parameters with demographics and smoking history, the associations of trajectory parameters with relapse were relatively uninfluenced by demographics and smoking history.

We conducted gender-stratified analyses on a systems-based candidate gene study of 53 regions involved in nicotinic response and the brain-reward pathway in two randomized clinical trials of smoking cessation treatments (placebo, bupropion, transdermal and nasal spray nicotine replacement therapy). We adjusted P-values for multiple correlated tests, and used a Bonferroni-corrected α-level of 5 × 10(-4) to determine system-wide significance. Four single-nucleotide polymorphisms (rs12021667, rs12027267, rs6702335, rs12039988; r20.98) in erythrocyte membrane protein band 4.1 (EPB41) had a significant male-specific marginal association with smoking abstinence (odds ratio (OR) = 0.5; 95% confidence interval (CI): 0.3-0.6) at end of treatment (adjusted P6 × 10(-5)). rs806365 in cannabinoid receptor 1 (CNR1) had a significant male-specific gene-treatment interaction at 6-month follow-up (adjusted P = 3.9 × 10(-5)); within males using nasal spray, rs806365 was associated with a decrease in odds of abstinence (OR = 0.04; 95% CI: 0.01-0.2). While the role of CNR1 in substance abuse has been well studied, we report EPB41 for the first time in the nicotine literature.

Prior evidence suggests that varenicline, an effective smoking cessation treatment, may relieve negative affective signs of nicotine withdrawal. We examined varenicline effects on emotional processing in 25 abstinent smokers after 13 days of varenicline and placebo using a within-subject cross-over design. Blood oxygen level dependent (BOLD) functional magnetic resonance imaging was acquired while subjects completed a face emotion identification task. Results showed a significant drug effect, characterized by decreased BOLD signal in dorsal anterior cingulate/medial frontal cortex, occipital cortex and thalamus. Increased BOLD signal was observed in the middle temporal gyrus. Varenicline improved correct response time; however, neither BOLD signal nor performance effects were moderated by emotion type. An exploratory region of interest analysis suggests that varenicline reduced amygdala activity independent of emotional valence. Taken together, these results suggest that observed drug effects on brain activity do not reflect affective changes but rather enhanced early processing of perceptual features of facial stimuli.

This summary outlines the evidence base for using a genetically informed biomarker to tailor smoking cessation treatment. This marker represents the rate of CYP2A6-mediated nicotine clearance, and is measured using the ratio of the nicotine metabolites derived from nicotine from smoking (3'hydroxycotinine [3HC]/cotinine), referred to as the nicotine metabolite ratio or NMR. The NMR has been associated retrospectively with the ability to quit smoking and differential response to nicotine dependence therapy in multiple independent clinical trials. We first examined the NMR in an open label trial of transdermal nicotine patch versus nicotine nasal spray. In the patch condition, slow metabolizers (the lowest quartile of the NMR) had significantly higher quit rates than normal metabolizers (2nd to 4th quartiles of the NMR) at the end of 8 weeks of treatment and at 6-month follow up, even after controlling for baseline cigarettes per day and level of nicotine dependence. No such relationship was observed among smokers who received nicotine nasal spray, presumably because they titrated their dose of treatment (and nicotine) based on their CYP2A6-mediated level of nicotine metabolism. Importantly, this relationship of pretreatment NMR (based on smoking) to quit rates with nicotine patch has been validated in an independent trial. Further, a double-blind trial of bupropion versus placebo established a significant NMR-by-treatment interaction; specifically, slow nicotine metabolizers had high quit rates on placebo, which were not enhanced further by the non-nicotine medication bupropion. In contrast, normal nicotine metabolizers performed poorly on placebo, but well on bupropion. Thus, convergent evidence across multiple independent clinical trials supports an association of the NMR with smoking cessation and response to treatments for nicotine dependence. These effects are significant beyond the effects of standard pretreatment clinical measures (e.g., baseline smoking rate, level of nicotine dependence). These data suggest that slow nicotine metabolizers respond well to placebo/behavioral counseling alone and benefit substantially from transdermal nicotine patch, whereas normal nicotine metabolizers achieve little benefit from behavioral counseling alone or nicotine patch, but respond well to non-nicotine medications. To translate these findings to clinical practice, we are initiating a large prospective stratified pharmacogenomic trial that will evaluate the use of the NMR to optimize treatments for nicotine dependence. Citation Information: Cancer Prev Res 2010;3(12 Suppl):PL01-06.

Brief procedures for evaluating medication efficacy may reveal which candidate drugs warrant further testing in clinical trials and which do not. We previously carried out a study of smoking abstinence, involving the nicotine patch, and established the sensitivity of our procedure. In this study, we sought to cross-validate our earlier work by comparing short-term smoking abstinence due to varenicline (relative to placebo) in smokers with high intrinsic quit interest (n = 57) and those with low intrinsic quit interest (n = 67). All the subjects were randomly assigned to either abstinence reinforcement ($12/day) or no reinforcement. In a crossover design, all the subjects participated in two 3-week phases: ad libitum smoking (week 1), dose run-up of varenicline (1.0 mg b.i.d.) or placebo (week 2), and quit attempt on medication verified daily by carbon monoxide

Executive Summary The evidence against tobacco use is clear, incontrovertible, and convincing; so is the need for urgent and immediate action to stem the global tide of tobacco-related death and suffering and to improve public health. The American Association for Cancer Research makes an unequivocal call to all who are concerned about public health to take the following immediate steps:Increase the investment in tobacco-related research, commensurate with the enormous toll that tobacco use takes on human health, to provide the scientific evidence to drive the development of effective policies and treatments necessary to dramatically reduce tobacco use and attendant disease.Develop new evidence-based strategies to more effectively prevent the initiation of tobacco use, especially for youth and young adults.Promote the further development of evidence-based treatments for tobacco cessation, including individualized therapies, and ensure coverage of and access to evidence-based behavioral and pharmacological treatments.Develop evidence-based strategies for more effective public communication to prevent, reduce, and eliminate tobacco use and to guide health policies and clinical practice.Develop effective, evidence-based policies to reduce disparities across the tobacco continuum among social groups and developed and developing nations.Implement to the fullest extent existing evidence-based, systems-wide tobacco control programs to prevent initiation and foster cessation. Adapt and implement appropriate approaches to reduce the growing burden of tobacco use in the developing world.Enhance and coordinate surveillance efforts, both in the United States and globally, to monitor tobacco products, tobacco use, and tobacco-related disease, including tobacco use in oncology clinical trials.Establish a comprehensive, science-based regulatory framework to evaluate tobacco products and manufacturers' claims.Promote research that addresses the following: the potential harms of current and new tobacco products; the impact of altering the levels of addictive components in tobacco products; the identification of risk and risk-reduction measures for current and former tobacco users; enhanced early detection methods for tobacco-related cancers; and effective treatments against tobacco-related cancers tailored to the unique effects of tobacco on cancer.Pursue domestic and international economic policies that support tobacco control.Urge the United States to ratify the World Health Organization Framework Convention on Tobacco Control. Foster global scientific efforts to support the Framework.Work together with stakeholders worldwide, including federal agencies, to develop and implement effective tobacco control strategies and to deter counter-tobacco control efforts by the tobacco industry. Only such concerted global actions by scientists, policymakers, and advocates together can prevent the invidious impact of tobacco, the use of which is cutting wide swathes of death and disease around the world. Cancer Res; 70(9); 3419–30. ©2010 AACR.