Search

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.

Racial/ethnic disparities in breast cancer outcomes may be related to quality of care and reflected in emergency department (ED) visits following primary treatment. We examined racial/ethnic variation in ED visits following breast cancer surgery. Using linked data from the California Cancer Registry and California Office of Statewide Health Planning and Development, we identified 151,229 women diagnosed with stage 0-III breast cancer between 2005 and 2013 who received surgical treatment. Differences in odds of having at least one breast cancer-related ED visit within 90 days post-surgery were estimated with logistic regression controlling for clinical and sociodemographic variables. Secondary analyses examined health care-related moderators of disparities. Hispanics and non-Hispanic (NH) Blacks had an increased likelihood of having an ED visit within 90 days of surgery compared to NH Whites [OR = 1.11 (1.04–1.18), p = 0.0016; OR = 1.38 (1.27–1.50), p

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

Background: The opioid crisis has reached epidemic proportions, yet risk of persistent opioid use following curative intent surgery for cancer and factors influencing this risk are not well understood. Methods: We used electronic health record data from 3,901 adult patients who received a prescription for an opioid analgesic related to hysterectomy or large bowel surgery from January 1, 2013, through June 30, 2018. Patients with and without a cancer diagnosis were matched on the basis of demographic, clinical, and procedural variables and compared for persistent opioid use. Results: Cancer diagnosis was associated with greater risk for persistent opioid use after hysterectomy [18.9% vs. 9.6%; adjusted OR (aOR), 2.26; 95% confidence interval (CI), 1.38–3.69; P = 0.001], but not after large bowel surgery (28.3% vs. 24.1%; aOR 1.25; 95% CI, 0.97–1.59; P = 0.09). In the cancer hysterectomy cohort, persistent opioid use was associated with cancer stage (increased rates among those with stage III cancer compared with stage I) and use of neoadjuvant or adjuvant chemotherapy; however, these factors were not associated with persistent opioid use in the large bowel cohort. Conclusions: Patients with cancer may have an increased risk of persistent opioid use following hysterectomy. Impact: Risks and benefits of opioid analgesia for surgical pain among patients with cancer undergoing hysterectomy should be carefully considered.

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

101 Background: Health risks and outcomes among Asian American patients are not adequately understood when Asians are treated as a homogenous ethnic group. This work is the first to explore trends in time to surgical treatment for breast cancer amongst Asian American ethnic subgroups. Methods: We used data from the population-based California Cancer Registry to identify a cohort of females diagnosed with invasive breast cancer between 2012-2017 in California. Time to surgical treatment was defined as the time elapsed between definitive diagnosis of breast cancer and receipt of surgery. Covariates included individual patient sociodemographic, health history, and tumor characteristics. Multivariable logistic regression was used to determine the odds of receiving surgery within 30 and 90 days of breast cancer diagnosis and multivariable Cox proportional hazards regression was used to analyze the likelihood of shorter time to surgery. A Bonferroni corrected alpha level was used to account for multiple racial/ethnic group comparisons. Results: Of 106,441 breast cancer patients, 57% were non-Hispanic white (NHW), 21% were Hispanic, 14% were Asian (4% Filipino; 3% Chinese; 1% each of Asian Indian or Pakistani (AIP), Vietnamese, Japanese, and Korean; 3% other Asian), and 6% were non-Hispanic black (NHB). Compared to NHWs, Hispanics (OR = 0.86, 99.5% CI = 0.82-0.92) and NHBs (OR = 0.82, 99.5% CI = 0.76-0.90) were less likely to receive surgery within 30 days of breast cancer diagnosis, while Chinese (OR = 1.30, 99.5% CI = 1.17-1.45) and AIPs (OR = 1.24, 99.5% CI = 1.04-1.48) were more likely to receive surgery within 30 days. These trends persisted for Hispanic (OR = 0.87, 99.5% CI = 0.79-0.96), NHB (OR = 0.73, 99.5% CI = 0.63-0.85), and Chinese patients (OR = 1.33, 99.5% CI = 1.04-1.71) when analyzing the likelihood of receiving surgery within 90 days of diagnosis. Compared to NHWs, Hispanics (OR = 0.94, 99.5% CI = 0.92-0.97), NHBs (OR = 0.88, 99.5% CI = 0.85-0.91), and Vietnamese (OR = 0.90, 99.5% CI = 0.83-0.98) were less likely to experience shorter time to surgical treatment, while Chinese (OR = 1.15, 99.5% CI = 1.09-1.21) and AIPs (OR = 1.09, 99.5% CI = 1.01-1.18) were more likely to have shorter time to surgery. Conclusions: In this population-based study of the California Cancer Registry, trends in time to surgical treatment for breast cancer were not consistent for patients belonging to different Asian ethnic subgroups. While Chinese and AIP patients tended to receive surgery sooner than NHW patients, Vietnamese patients face a disparity in receiving timely surgical treatment relative to NHW patients. Further research is needed to fully understand and appropriately target disparities in breast cancer treatment for patients of different Asian American ethnic subgroups.

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

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.

e12589 Background: Surgical delays for invasive breast cancer have been increasing over time and are associated with an increased risk of mortality. Black and Hispanic breast cancer patients are more likely to experience surgical delays than white patients; however, surgical delays among Asian ethnic subgroups remain unstudied. Methods: We used data from the population-based California Cancer Registry to identify all females diagnosed with stage I-III invasive breast cancer from 2012-2017. Our main independent variable was patient race/ethnicity, including five Asian ethnic subgroups. Covariates captured tumor, treatment-related, and patient sociodemographic characteristics. We conducted multivariable logistic regression to determine the odds of receiving surgery within 30 and 90 days of diagnosis and multivariable Cox proportional hazards regression to determine the risk of shorter time to surgical treatment. Results: Of 106,441 breast cancer patients, 57.5% were non-Hispanic white (NHW), 20.7% were Hispanic, 5.9% were non-Hispanic black (NHB), and 12.6% were Asian (consisting of 33.7% Filipino, 24.6% Chinese, 8.1% Asian Indian or Pakistani (AIP), 7.7% Japanese, 6.7% Korean, and 19.2% other Asian (OA) patients). Compared to NHWs, Hispanics and NHBs were less likely to receive surgical treatment within 30 and 90 days of diagnosis (Hispanic, 30-day: OR = 0.94, 95% CI = 0.89-0.98; Hispanic, 90-day: 0.89, 0.85-0.92; NHB, 30-day: 0.91, 0.85-0.98; NHB, 90-day: 0.86, 0.80-0.92). However, Chinese and AIP patients were more likely than NHWs to receive surgery within 30 and 90 days of diagnosis (Chinese, 30 day: OR = 1.30, 95% CI = 1.19-1.41; Chinese 90-day: 1.26, 1.08-1.47; AIP 30-day: 1.29, 1.11-1.50; AIP 90-day: 1.34, 1.17-1.53). In addition, Koreans were more likely than NHWs to receive surgery within 90 days of diagnosis (OR = 1.26, 95% CI = 1.08-1.47). Hispanics, NHBs, and OAs were less likely to receive timely treatment compared to NHWs (Hispanic: HR = 0.95, 95% CI = 0.94-0.97; NHB: 0.91, 0.89-0.94; OA: 0.95, 0.92-0.99), while Chinese, AIP, and Korean patients were more likely to receive timely treatment compared to NHWs (Chinese: HR = 1.15, 95% CI = 1.11-1.20; AIP: 1.10, 1.04-1.17; Korean: 1.10, 1.03-1.17). Lastly, patients diagnosed in 2017 were 14% less likely to receive timely treatment than those diagnosed in 2012 (HR: 0.86, 95% CI = 0.84-0.88). Conclusions: In this population-based cohort of female breast cancer patients in California, Hispanics and NHBs continue to experience surgical treatment delays and Asian American minority subgroups experience similar delays compared to NHWs. In addition, increasing delays over time could potentially exacerbate racial/ethnic disparities in breast cancer mortality. Continued work investigating the causes of breast cancer treatment delays among Asian ethnic subgroups is necessary to fully elucidate and target racial/ethnic treatment disparities.

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 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)

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.

The nicotine metabolite ratio (NMR; 3-hydroxycotinine/cotinine) is an index of CYP2A6 activity. CYP2A6 is responsible for nicotine’s metabolic inactivation and variation in the NMR/CYP2A6 is associated with several smoking behaviors. Our aim was to integrate established alleles and novel genome-wide association studies (GWAS) signals to create a weighted genetic risk score (wGRS) for the CYP2A6 gene for European-ancestry populations. The wGRS was compared with a previous CYP2A6 gene scoring approach designed for an alternative phenotype (C2/N2; cotinine-d2/(nicotine-d2 + cotinine-d2)). CYP2A6 genotypes and the NMR were assessed in European-ancestry participants. The wGRS training set included N = 933 smokers recruited to the Pharmacogenetics of Nicotine Addiction and Treatment clinical trial [NCT01314001]. The replication cohort included N = 196 smokers recruited to the Quit 2 Live clinical trial [NCT01836276]. Comparisons between the two CYP2A6 phenotypes and with fractional clearance were made in a laboratory-based pharmacokinetic study (N = 92 participants). In both the training and replication sets, the wGRS, which included seven CYP2A6 variants, explained 33.8% (P < 0.001) of the variance in NMR, providing improved predictive power to the NMR phenotype when compared with other CYP2A6 gene scoring approaches. NMR and C2/N2 were strongly correlated to nicotine clearance (ρ = 0.70 and ρ = 0.79, respectively; P < 0.001), and to one another (ρ = 0.82; P < 0.001); however reduced function genotypes occurred in slow NMR but throughout C2/N2. The wGRS was able to predict smoking quantity and nicotine intake, to discriminate between NMR slow and normal metabolizers (AUC = 0.79; P < 0.001), and to replicate previous NMR-stratified cessation outcomes showing unique treatment outcomes between metabolizer groups. CLINICAL TRIAL REGISTRATIONS: NCT01314001 and NCT01836276.

IMPORTANCE The US Food and Drug Administration (FDA) has announced its intention to reduce the nicotine content in combustible cigarettes but must base regulation on public health benefits. Fast nicotine metabolizers may be at risk for increased smoking following a national nicotine reduction policy. We hypothesized that using reduced nicotine content (RNC) cigarettes would be associated with increases in smoking behaviors and exposure among smokers with a fast—but not slow—nicotine-metabolite ratio (NMR). OBJECTIVES To examine the association of RNC cigarettes with smoking behaviors and biomarkers of exposure and to compare these associations in fast and slow metabolizers of nicotine based on the NMR. DESIGN, SETTING, AND PARTICIPANTS A 35-day, 3-period, within-participant nonrandomized clinical trial was conducted at an academic medical center in Philadelphia, Pennsylvania. A 5-day baseline period using the smokers’ preferred brand of cigarettes was followed by 2 consecutive 15-day periods using free investigational RNC cigarettes. A total of 100 daily, non–treatment-seeking, nonmenthol cigarette smokers (59 fast, 41 slow metabolizers) were recruited from December 24, 2013, to December 2, 2015. Data analysis was performed from December 12, 2016, to January 3, 2018. INTERVENTIONS Two 15-day periods using cigarettes containing 5.2 mg (RNC1) and 1.3 mg (RNC2) of nicotine per gram of tobacco. MAIN OUTCOMES AND MEASURES Smoking behaviors (number of cigarettes per day [CPD], total puff volume) and biomarkers of exposure (carbon monoxide [CO], urine total nicotine equivalents [TNE], and 4-[methylnitrosamino]-1-[3-pyridyl]-1-butanol [NNAL]). RESULTS Smokers (73 [73.0%] men; 74 [74.0%] white; mean [SD] age, 43.02 [12.13] years; mean [SD] CPD, 17.31 [5.72]) consumed 2.62 (95% CI, 1.54–3.70) more CPD during the RNC1 period vs their preferred brand during baseline (P < .001) and approximated baseline CPD during the RNC2 period (mean difference, 0.96 [95% CI, −0.36 to 2.28]; P = .24). Additional outcome measures were lower during both RNC periods vs baseline (total puff volume, mean [95% CI]: RNC1, 537 mL [95% CI, 479–595 mL]; RNC2, 598 mL [95% CI, 547–649 mL] vs baseline, 744 mL [95% CI, 681–806 mL]; TNE, mean [95% CI]: RNC1, 30.9 nmoL/mg creatinine [95% CI, 26.0–36.6 nmoL/mg]; RNC2, 22.8 nmoL/mg creatinine [95% CI, 17.8–29.0 nmoL/mg] vs baseline, 54.6 nmoL/mg creatinine [95% CI, 48.1–62.1 nmoL/mg]; and NNAL, mean [95% CI]: RNC1, 229 pg/mg creatinine [95% CI, 189–277 pg/mg]; RNC2, 190 pg/mg creatinine [95% CI, 157–231 pg/mg] vs baseline, 280 pg/mg creatinine [95% CI, 231–339 pg/mg]; all P < .001). Carbon monoxide measures were similar across study periods (CO boost [SD], RNC1, 4.6 ppm [4.1–5.1 ppm]; RNC2, 4.2 ppm [3.7–4.6 ppm]; and baseline, 4.4 ppm [3.8–4.9 ppm]). The RNC cigarette associations did not differ by NMR. CONCLUSIONS AND RELEVANCE Both RNC cigarettes were associated with decreased puffing and urinary biomarker exposure but not with decreased daily cigarette consumption or CO levels. The NMR did not moderate associations at the nicotine levels tested, suggesting that fast metabolizers may not be at greater risk of increasing use or exposure from these products should the FDA mandate an RNC standard for cigarettes.

Background Understanding the mechanisms behind exerting self-control may reveal why health behaviors are resistant to change. Activity in the right inferior frontal gyrus (rIFG) plays a role in self-control processes and may be modulated using transcranial direct current stimulation (tDCS). Objective In this early phase behavioral research study, we investigated whether anodal stimulation over the rIFG with cathodal stimulation over the left IFG (versus sham) reduced chocolate consumption. Methods Twenty-three healthy females (ages 18–35) completed two tDCS sessions (2.0 mA vs. sham; order counterbalanced) in a within-subject, double-blind, randomized design with a 4-week washout. Participants were self-reported “chocolate cravers” and restrained eaters. Self-report assessments on disinhibited eating were completed at intake. Delay discounting and inhibitory control were assessed at the remaining visits. During stimulation, participants completed an inhibitory control training task (chocolate go/no-go task) and were randomized to the chocolate no-go condition (inhibit all responses to chocolate cues) or the control condition (inhibit responses to chocolate cues on half the trials). Following stimulation, participants completed a 15-min chocolate “taste test” with chocolate rating forms. Afterwards, staff measured the remaining chocolate to determine total consumption. Results Contrary to our hypotheses, active tDCS significantly increased chocolate consumption vs. sham (mean = 43.2 vs. 32.2, p=0.005) in both task conditions, but had no effect on chocolate ratings (ps > 0.05). Higher delay discounting and self-reported disinhibited eating predicted greater consumption (ps Conclusions The results suggest widespread activation of the prefrontal cortex may reduce the ability to resist chocolate. Our data highlights important methodological considerations for conducting tDCS studies to target health behaviors.

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.

Background: Impulsivity is a core deficit in attention deficit hyperactivity disorder (ADHD). Transcranial direct current stimulation (tDCS) of the dorsolateral prefrontal cortex (DLPFC) has been shown to modulate cognitive control circuits and could enhance DLPFC activity, leading to improved impulse control in ADHD. Objective: Hypothesis: We predicted 2.0 mA anodal stimulation (tDCS) versus sham stimulation applied over the left DLPFC would improve Conners Continuous Performance Task (CPT) scores. Our secondary hypothesis predicted that stop signal task (SST) reaction time (SSRT) would decrease with tDCS (versus sham). Methods: Thirty-seven participants completed two periods of three tDCS (or sham) sessions two weeks apart in a within-subject, double-blind, counterbalanced order. Participants performed a fractal N-back training task concurrent with tDCS (or sham) stimulation. Participants completed the CPT and SST at the beginning of treatment (baseline), at the end of the treatment, and at a 3-day post-stimulation follow-up. Results: There was a significant stimulation condition by session interaction for CPT false positive scores (χ2 = 15.44, p 0.05). There was no significant stimulation condition by session interaction effect on CPT true positive errors or response time (ps > 0.05). No significant change in SSRT performance was observed (p > 0.05). Conclusion: These findings suggest that stimulation of the left DLPFC with tDCS can improve impulsivity symptoms in ADHD, supporting the therapeutic potential for tDCS in adult ADHD patients.

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.

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.

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

Background: Cotinine, a nicotine metabolite, is a biomarker of tobacco, nicotine, and carcinogen exposure. However, a given cotinine level may not represent the same tobacco exposure; for example, African-Americans have higher cotinine levels than Caucasians after controlling for exposure. Methods: Cotinine levels are determined by the amount of cotinine formation and the rate of cotinine removal, which are both mediated by the enzyme CYP2A6. Because CYP2A6 activity differs by sex (estrogen induces CYP2A6) and genotype, their effect on cotinine formation and removal was measured in nonsmoking Caucasians (Study 1, n = 181) infused with labeled nicotine and cotinine. The findings were then extended to ad libitum smokers (Study 2, n = 163). Results: Study 1: Reduced CYP2A6 activity altered cotinine formation less than cotinine removal resulting in ratios of formation to removal of 1.31 and 1.12 in CYP2A6 reduced and normal metabolizers (P = 0.01), or 1.39 and 1.12 in males and females (P = 0.001), suggesting an overestimation of tobacco exposure in slower metabolizers. Study 2: Cotinine again overestimated tobacco and carcinogen exposure by 25% or more in CYP2A6 reduced metabolizers (≈2-fold between some genotypes) and in males. Conclusions: In people with slower relative to faster CYP2A6 activity, cotinine accumulates resulting in substantial differences in cotinine levels for a given tobacco exposure. Impact: Cotinine levels may be misleading when comparing those with differing CYP2A6 genotypes within a race, between races with differing frequencies of CYP2A6 gene variants (i.e., African-Americans have higher frequencies of reduced function variants contributing to their higher cotinine levels), or between the sexes. Cancer Epidemiol Biomarkers Prev; 22(4); 708–18. ©2013 AACR.

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.

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.

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.

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

OBJECTIVE To review the current state of the science in medication development for nicotine dependence and to identify important areas for future research. METHODS The National Cancer Institute and the National Institute on Drug Abuse convened a conference focused on translational approaches to the development, evaluation, and delivery of medications for the treatment of tobacco dependence. RESULTS Future research directions include investigations of the efficacy of novel compounds and new applications for existing medications; pharmacogenetic trials of nicotine dependence treatments; and studies of the molecular, neural, and behavioral mechanisms of action of efficacious medications. CONCLUSIONS Medication development for the treatment of tobacco dependence remains a scientific and public health priority.

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.

Varenicline may aid smoking cessation by attenuating smoking behavior and reward. We compared the effects of varenicline versus placebo on smoking behavior and reward, assessed both prospectively and retrospectively, and related these effects to subsequent success in a brief simulated quit attempt with medication.Smokers (n = 124) with high or low interest in quitting smoking participated in a double-blind crossover study of varenicline versus placebo effects on smoking behavior and reward. In each of two phases, subjects received a week of medication run-up with varenicline (0.5 mg, b.i.d.) or placebo while continuing to smoke, followed the next week by an attempt to quit while on medication. At the end of each run-up week, subjects completed retrospective measures of smoking reward (liking) and number of cigarettes over the prior 24 hrs, and they provided an expired air carbon monoxide (CO) measure. They then completed a prospective session in which they ad lib smoked and rated the rewarding effects of one of their preferred cigarettes while blind to brand.Varenicline decreased smoking reward significantly in the prospective assessment, but only marginally in the retrospective assessment. Varenicline did not alter smoking behavior prospectively, but did reduce CO and retrospective report of smoking amount. None of these effects of varenicline predicted subsequent days of abstinence due to varenicline.During medication run-up, varenicline decreases acute smoking reward and may attenuate smoking behavior, but these effects do not appear to directly predict varenicline's influence on smoking abstinence in a short-term test.

The ability to quit smoking is heritable, yet few genetic studies have investigated prospective smoking cessation. We conducted a systems-based genetic association analysis in a sample of 472 treatment-seeking smokers of European ancestry after 8 weeks of transdermal nicotine therapy for smoking cessation. The genotyping panel included 169 single-nucleotide polymorphisms (SNPs) in 7 nicotinic acetylcholine receptor subunit genes and 4 genes in the endogenous cholinergic system. The primary outcome was smoking cessation (biochemically confirmed) at the end of treatment. SNPs clustered in the choline acetyltransferase (ChAT) gene were individually identified as nominally significant, and a 5-SNP haplotype (block 6) in ChAT was found to be significantly associated with quitting success. Single SNPs in ChAT haplotype block 2 were also associated with pretreatment levels of nicotine dependence in this cohort. To replicate associations of SNPs in haplotype blocks 2 and 6 of ChAT with nicotine dependence in a non-treatment-seeking cohort, we used data from an independent community-based sample of 629 smokers representing 200 families of European ancestry. Significant SNP and haplotype associations were identified for multiple measures of nicotine dependence. Although the effect sizes in both cohorts are modest, converging data across cohorts and phenotypes suggest that ChAT may be involved in nicotine dependence and ability to quit smoking. Additional sequencing and characterization of ChAT may reveal functional variants that contribute to nicotine dependence and smoking cessation.

As many as one-half of smokers relapse in the first week following a quit attempt, and subjective reports of cognitive deficits in early abstinence are associated with increased relapse risk. This study examined whether objective cognitive performance after three days of abstinence predicts smoking resumption in a 7-day simulated quit attempt. Sixty-seven treatment-seeking smokers received either varenicline or placebo (randomized double-blind) for 21 days. Following medication run-up (days 1-10), there was a 3-day mandatory (biochemically confirmed) abstinence period (days 11-13) during which working memory (Letter-N-Back Task) and sustained attention (Continuous Performance Task) were assessed (day 13). Participants were then exposed to a scheduled smoking lapse and instructed to try to remain abstinent for the next 7 days (days 15-21). Poorer cognitive performance (slower correct reaction time on Letter-N-Back task) during abstinence predicted more rapid smoking resumption among those receiving placebo (p=.038) but not among those receiving varenicline. These data lend further support for the growing recognition that cognitive deficits involving working memory are a core symptom of nicotine withdrawal and a potential target for the development of pharmacological and behavioral treatments.

INTRODUCTION The time of day in which craving, withdrawal, and other tobacco abstinence symptoms are assessed may moderate the influences of abstinence or medication on those symptoms. METHODS Participants were 209 smokers participating in a 4-week crossover study assessing symptoms due to smoking versus abstinence and while using nicotine (21 mg) versus placebo patch when abstinent. None was trying to quit permanently during the study. Abstinence was verified daily by a carbon monoxide level of less than 5 ppm. Participants completed craving (two measures), total withdrawal, and positive affect (PA) and negative affect forms three times per day: in the morning, upon arrival at the clinic in the afternoon, and in the evening. All comparisons of the effects of time of day, abstinence, and nicotine patch treatment were within subjects. RESULTS Results showed a main effect of time of day on all measures while smoking, wherein PA was higher and the other four measures lower, during afternoon versus morning or evening ratings. Time of day interacted with abstinence on both craving measures, but not the other measures, such that abstinence increased craving less in the morning versus the other times. Time of day also interacted with nicotine (vs. placebo) patch effects in alleviating negative mood to a greater degree during evening versus morning or afternoon ratings. DISCUSSION The data suggest that, compared with traditional single assessments of symptoms at midday, assessments at several times of the day may reveal greater overall levels of symptoms and perhaps greater effects of abstinence and nicotine replacement on select abstinence symptoms.

The val allele of the catechol-O-methyltransferase (COMT) val158met polymorphism has been linked with nicotine dependence and with cognitive performance in healthy volunteers. We tested the hypothesis that the val allele is a risk factor for altered brain function and cognition during nicotine abstinence as compared with the normal smoking state. Chronic smokers (n = 33) were genotyped prospectively for the COMT polymorphism for balanced selection of met/met, val/met and val/val groups. A visual N-back working memory task was performed during two separate blood oxygen level-dependent (BOLD) functional magnetic resonance imaging sessions in counterbalanced order: (1) smoking as usual, and (2)≥14 h confirmed abstinence. Significant genotype by session interactions were observed for BOLD signal in right dorsolateral prefrontal cortex (DLPFC; (P = 0.0005), left DLPFC (P = 0.02) and dorsal cingulate/medial prefrontal cortex (P = 0.01) as well as for task reaction time (P = 0.03). Smokers with val/val genotypes were more sensitive to the abstinence challenge than carriers of the met allele, with the greatest effects on BOLD signal and performance speed at the highest working memory load. These data suggest a novel brain–behavior mechanism that may underlie the increased susceptibility to nicotine dependence and smoking relapse associated with the COMT val allele. Exploration of the effects of COMT inhibitors as a possible smoking cessation aid in this group may be warranted.

The serotonin pathway has been implicated in nicotine dependence and may influence smoking cessation. Therefore, 792 cigarette smokers from the Patch in Practice trial were genotyped for the tryptophan hydroxylase (TPH1 A779C), serotonin transporter (SLC6A4 5-HTTLPR), and 5-HT1A (HTR1A C-1019G) polymorphisms. Cox regression analysis did not demonstrate significant effects of any of the three genotypes on relapse to smoking: TPH1 (Reference AA; AC: hazard ratio (HR) 0.99, 95% confidence interval (CI) 0.78, 1.24, p = 0.90; CC: HR 0.93, 95% CI 0.73, 1.18, p = 0.55); 5-HTTLPR (Reference LL; SL: HR 1.01, 95% CI 0.85, 1.20, p = 0.90; SS: HR 1.13, 95% CI 0.91, 1.39, p = 0.27); HTR1A (Reference CC; CG: HR 1.04, 95% CI 0.86, 1.25, p = 0.70; GG: HR 1.01, 95% CI 0.82, 1.24, p = 0.93). Moreover, pooled analyses of data from all three extant pharmacogenetic NRT trials (N = 1398) found no significant effect of 5-HTTLPR genotype on continuous abstinence at 12-week (Reference LL; SL: odds ratio (OR) = 1.25, 95% CI 0.89, 1.74, p = 0.19; SS: OR = 1.31, 95% CI 0.86, 1.98, p = 0.21) or 26-week follow-up (Reference LL; SL: OR = 0.93, 95% CI 0.64, 1.33, p = 0.68; SS: OR = 1.00, 95% CI 0.63, 1.58, p = 1.00). These data do not support a statistically or clinically significant moderating effect of these specific 5-HT pathway genetic variants on smoking cessation. However, the possibility remains that other variants in these or other 5-HT genes may influence NRT efficacy for smoking cessation in treatment seeking smokers. © 2008 Elsevier Ireland Ltd. All rights reserved.

Greater sensitivity to early exposure to tobacco smoking may predict higher risk of becoming nicotine dependent. The most common measure of this sensitivity is the retrospective self-report Early Smoking Experiences (ESE) questionnaire. We examined the relationship between responses to the retrospective ESE and prospectively assessed sensitivity to nicotine via nasal spray in young adult nonsmokers (N = 58) with modest lifetime smoking experience (>0 but < or =10 lifetime uses). Nicotine spray (0 vs 10 microg/kg) was used due to ethical and practical concerns with administering tobacco smoke to nonsmokers. Responses to cigarette smoking on the retrospective ESE items of pleasant, unpleasant, nausea, relaxed, dizzy, and buzzed were compared with prospectively assessed nicotine spray effects (NSE) on the same responses. ESE responses were also compared with subjective spray ratings of nicotine reward (e.g., "liking") and perception (e.g., "feel the effects"), cardiovascular activity, and nicotine reinforcement via a nicotine spray choice procedure. Results showed that the retrospective ESE items of dizzy and buzzed were each associated with greater prospective NSE dizzy and buzzed responses to nasal spray nicotine. However, the other four ESE items were unrelated to the corresponding NSE items. Responses to some ESE items were also related to prospective nicotine spray reward and perception, but no ESE item was related to the cardiovascular or reinforcing effects of nicotine spray. These findings show that two of six retrospective ESE items, dizzy and buzzed, predicted the same prospectively assessed responses to acute nicotine via spray in young adult nonsmokers and may reflect a stable and reliable response to nicotine intake.

Although the efficacy of pharmacotherapy for tobacco dependence has been previously demonstrated, there is substantial variability among individuals in treatment response. We performed a systems-based candidate gene study of 1295 single nucleotide polymorphisms (SNPs) in 58 genes within the neuronal nicotinic receptor and dopamine systems to investigate their role in smoking cessation in a bupropion placebo-controlled randomized clinical trial. Putative functional variants were supplemented with tagSNPs within each gene. We used global tests of main effects and treatment interactions, adjusting the P-values for multiple correlated tests. An SNP (rs2072661) in the 3′ UTR region of the β2 nicotinic acetylcholine receptor subunit (CHRNB2) has an impact on abstinence rates at the end of treatment (adjusted P = 0.01) and after a 6-month follow-up period (adjusted P = 0.0002). This latter P-value is also significant with adjustment for the number of genes tested. Independent of treatment at 6-month follow-up, individuals carrying the minor allele have substantially decreased the odds of quitting (OR = 0.31; 95% CI 0.18-0.55). Effect of estimates indicate that the treatment is more effective for individuals with the wild-type (OR = 2.14, 95% CI 1.20-3.81) compared with individuals carrying the minor allele (OR = 0.83, 95% CI 0.32-2.19), although this difference is only suggestive (P = 0.10). Furthermore, this SNP demonstrated a role in the time to relapse (P = 0.0002) and an impact on withdrawal symptoms at target quit date (TQD) (P = 0.0009). Overall, while our results indicate strong evidence for CHRNB2 in ability to quit smoking, these results require replication in an independent sample. © 2008 The Author(s).

This study explored whether functional genetic variants previously associated with nicotine dependence are associated with regional cerebral blood flow (rCBF) changes during nicotine abstinence (compared to satiety; smoking as usual). Thirteen smokers participating in a prior arterial spin labeled (ASL) perfusion MRI study were scanned on two occasions (after >12 h abstinence vs. satiety), and were genotyped for variants in the dopamine D2 receptor ( DRD2 -141 Ins/DelC; DRD2 C957T); a dopamine metabolizing enzyme ( COMT val 158 met), and the mu opioid receptor ( OPRM1 A118G). Significantly greater CBF increases were found in regions previously linked with cigarette cravings among carriers of the DelC variant of DRD2- 141 and among the COMT val/val group. Smokers with TT genotypes for the DRD2 C957T exhibited less change in rCBF in abstinence relative to satiety, compared to those with CC or CT genotypes. Finally, smokers with OPRM1 AA genotypes showed significant increases in CBF in regions associated previously with cigarette cravings. While preliminary, these results suggest a neural mechanism through which these genetic variants may be linked with nicotine dependence, and provide further support for increased biological vulnerability in these subgroups of smokers.

Smokers tend to increase their cigarette consumption during angry states. We sought to determine whether increases in post-quit anger symptoms predict relapse among smokers who had received 8-weeks of smoking cessation treatment (21 mg nicotine patch + smoking cessation counseling). The 15-item state anger assessment [from Spielberger, C., 1999. STAXI-2: the state trait anger expression inventory professional manual, Odessa, FL] was administered at pre-treatment (2 weeks before the target quit date; TQD) and 1 week after the TQD. Abstinence at 8-weeks post-quit was biochemically verified using carbon monoxide. Smokers who reported increases in pre- to post-quit state anger levels ( n = 117) were significantly more likely to relapse by 8-weeks after treatment as compared to smokers whose anger did not change or decreased after quitting ( n = 130) (OR = 1.06; CI = 1.01–1.10; p = 0.01). Furthermore, smokers with increased post-quit anger relapsed almost twice as quickly than those who did not have an increase in post-quit anger symptoms (HR = 1.98; CI: 1.32–2.96; p = 0.001). These data suggest that anger may be an important withdrawal symptom that influences liability to relapse. Future studies are needed to evaluate treatment strategies that effectively help smokers reduce and manage post-quit anger.

We examined whether a pretreatment phenotypic marker of nicotine metabolism rate (NMR) predicts successful smoking cessation with bupropion. Smokers (N = 414) were tested for pretreatment NMR, based on the ratio of 3′-hydroxycotinine/cotinine derived during smoking, before entering a placebo-controlled randomized trial of bupropion plus counseling. At the end of the 10-week treatment phase, slow metabolizers (1st NMR quartile) had equivalent quit rates with placebo or bupropion (32%). Fast metabolizers (4th NMR quartile) had low quit rates with placebo (10%), and these were enhanced significantly by bupropion (34%). Smokers in the 2nd quartile (placebo: 25%, bupropion: 30%) and the 3rd quartile (placebo: 20%, bupropion: 30%) did not benefit significantly from bupropion. At the 6-month follow-up, the relationship between the NMR and quitting remained similar, but was no longer statistically significant. A pretreatment assessment of NMR may identify smokers who are most and least likely to benefit from treatment with bupropion for smoking cessation. Clinical Pharmacology & Therapeutics (2008); 84, 3, 320–325 doi:10.1038/clpt.2008.57

In a placebo-controlled bupropion smoking cessation trial, we examined blind integrity, the link between blind integrity and quit rates, and whether side effects and changes in nicotine withdrawal symptoms or mood were mechanisms through which blind integrity is threatened. At a 12-month follow-up, 498 participants indicated whether they thought they received bupropion, placebo, or were not sure. Potential mediators of treatment effects on treatment arm guess (i.e., side effects, withdrawal, and mood) were measured during treatment, and 7-day point prevalence cessation was assessed at the end of treatment (EOT) and at 6 and 12 months after quit date. Overall, 55% of participants guessed their randomization correctly. Compared to guessing not sure, participants who guessed they were taking bupropion were more than twice as likely to have been randomized to bupropion. Similarly, participants who guessed placebo were twice as likely to have been randomized to placebo. Treatment arm guess was associated with quit rates. Including treatment arm guess with actual treatment arm in models of quit rates significantly reduced the odds ratio for bupropion efficacy at the EOT and at 6 and 12 months after quit date. There was no evidence for mediation. In bupropion smoking cessation trials, blind failure may occur and participant guess about treatment arm assignment is associated with quit rates.