Nicotine dependence is associated with functional variation in FMO3, an enzyme that metabolizes nicotine in the brain.

A common haplotype of the flavin-containing monooxygenase gene FMO3 is associated with aberrant mRNA splicing, a twofold reduction in in vivo nicotine N-oxidation and reduced nicotine dependence. Tobacco remains the largest cause of preventable mortality worldwide. CYP2A6, the primary hepatic nicotine metabolism gene, is robustly associated with cigarette consumption but other enzymes contribute to nicotine metabolism. We determined the effects of common variants in FMO3 on plasma levels of nicotine-N-oxide in 170 European Americans administered deuterated nicotine. The polymorphism rs2266780 (E308G) was associated with N-oxidation of both orally administered and ad libitum smoked nicotine (P⩽3.3 × 10-5 controlling for CYP2A6 genotype). In vitro, the FMO3 G308 variant was not associated with reduced activity, but rs2266780 was strongly associated with aberrant FMO3 mRNA splicing in both liver and brain (P⩽6.5 × 10-9). Surprisingly, in treatment-seeking European American smokers (n=1558) this allele was associated with reduced nicotine dependence, specifically with a longer time to first cigarette (P=9.0 × 10-4), but not with reduced cigarette consumption. As N-oxidation accounts for only a small percentage of hepatic nicotine metabolism we hypothesized that FMO3 genotype affects nicotine metabolism in the brain (unlike CYP2A6, FMO3 is expressed in human brain) or that nicotine-N-oxide itself has pharmacological activity. We demonstrate for the first time nicotine N-oxidation in human brain, mediated by FMO3 and FMO1, and show that nicotine-N-oxide modulates human α4ß2 nicotinic receptor activity in vitro. These results indicate possible mechanisms for associations between FMO3 genotype and smoking behaviors, and suggest nicotine N-oxidation as a novel target to enhance smoking cessation.

Genome-wide association study across European and African American ancestries identifies a SNP in DNMT3B contributing to nicotine dependence.

Cigarette smoking is a leading cause of preventable mortality worldwide. Nicotine dependence, which reduces the likelihood of quitting smoking, is a heritable trait with firmly established associations with sequence variants in nicotine acetylcholine receptor genes and at other loci. To search for additional loci, we conducted a genome-wide association study (GWAS) meta-analysis of nicotine dependence, totaling 38,602 smokers (28,677 Europeans/European Americans and 9925 African Americans) across 15 studies. In this largest-ever GWAS meta-analysis for nicotine dependence and the largest-ever cross-ancestry GWAS meta-analysis for any smoking phenotype, we reconfirmed the well-known CHRNA5-CHRNA3-CHRNB4 genes and further yielded a novel association in the DNA methyltransferase gene DNMT3B. The intronic DNMT3B rs910083-C allele (frequency=44-77%) was associated with increased risk of nicotine dependence at P=3.7 × 10-8 (odds ratio (OR)=1.06 and 95% confidence interval (CI)=1.04-1.07 for severe vs mild dependence). The association was independently confirmed in the UK Biobank (N=48,931) using heavy vs never smoking as a proxy phenotype (P=3.6 × 10-4, OR=1.05, and 95% CI=1.02-1.08). Rs910083-C is also associated with increased risk of squamous cell lung carcinoma in the International Lung Cancer Consortium (N=60,586, meta-analysis P=0.0095, OR=1.05, and 95% CI=1.01-1.09). Moreover, rs910083-C was implicated as a cis-methylation quantitative trait locus (QTL) variant associated with higher DNMT3B methylation in fetal brain (N=166, P=2.3 × 10-26) and a cis-expression QTL variant associated with higher DNMT3B expression in adult cerebellum from the Genotype-Tissue Expression project (N=103, P=3.0 × 10-6) and the independent Brain eQTL Almanac (N=134, P=0.028). This novel DNMT3B cis-acting QTL variant highlights the importance of genetically influenced regulation in brain on the risks of nicotine dependence, heavy smoking and consequent lung cancer.

Genome-wide meta-analysis reveals common splice site acceptor variant in CHRNA4 associated with nicotine dependence.

We conducted a 1000 Genomes-imputed genome-wide association study (GWAS) meta-analysis for nicotine dependence, defined by the Fagerström Test for Nicotine Dependence in 17 074 ever smokers from five European-ancestry samples. We followed up novel variants in 7469 ever smokers from five independent European-ancestry samples. We identified genome-wide significant association in the alpha-4 nicotinic receptor subunit (CHRNA4) gene on chromosome 20q13: lowest P=8.0 × 10(-9) across all the samples for rs2273500-C (frequency=0.15; odds ratio=1.12 and 95% confidence interval=1.08-1.17 for severe vs mild dependence). rs2273500-C, a splice site acceptor variant resulting in an alternate CHRNA4 transcript predicted to be targeted for nonsense-mediated decay, was associated with decreased CHRNA4 expression in physiologically normal human brains (lowest P=7.3 × 10(-4)). Importantly, rs2273500-C was associated with increased lung cancer risk (N=28 998, odds ratio=1.06 and 95% confidence interval=1.00-1.12), likely through its effect on smoking, as rs2273500-C was no longer associated with lung cancer after adjustment for smoking. Using criteria for smoking behavior that encompass more than the single 'cigarettes per day' item, we identified a common CHRNA4 variant with important regulatory properties that contributes to nicotine dependence and smoking-related consequences.

Five population-based interventions for smoking cessation: a MOST trial.

Little is known about the relative, additive, and interactive effects of different population-based treatments for smoking cessation. The goal of this study was to evaluate the main and interactive effects of five different smoking interventions. Using the multiphase optimization strategy (MOST), 1,034 smokers who entered a Web site for smokers (smokefree.gov) were randomly assigned to the "on" and "off" conditions of five smoking cessation interventions: the National Cancer Institute's (NCI) Web site (www.smokefree.gov vs a "lite" Web site), telephone quitline counseling (vs none), a smoking cessation brochure (vs a lite brochure), motivational e-mail messages (vs none), and mini-lozenge nicotine replacement therapy (NRT vs none). Analyses showed that the NCI Web site and NRT both increased abstinence; however, the former increased abstinence significantly only when it was not used with the e-mail messaging intervention (messaging decreased Web site use). The other interventions showed little evidence of effectiveness. There was evidence that mailed nicotine mini-lozenges and the NCI Web site (www.smokefree.gov) provide benefit as population-based smoking interventions.

Any further progress in smoking cessation treatment?

The release of the US Public Health Service's quantitative review of smoking treatments, Treating Tobacco Use and Dependence (TTUD; Fiore, Bailey, Cohen et al., 2000, AHRQ Publication, USDHHS), is a fitting occasion to revisit a question posed by Shiffman (1993, Journal of Consulting and Clinical Psychology, 61:718-722): has there been any recent progress in smoking cessation treatment? Using TTUD meta-analyses as a rough guide, we present an overview of current elements of clinical treatments (structure, content, and pharmacotherapy) with statistical claims to efficacy. We note characteristics of treatment, or treatment research, that may retard accumulation of critical knowledge, including the hegemony of multi-component treatments and a seeming disinterest in treatment process. Finally, we sketch avenues of potentially generative research that might foster new insights and improved treatments. It is concluded that not much has changed since Shiffman's (1993) review, and that his call for a rededication to basic research is still prudent but largely unanswered.

Strike while the iron is hot: can stepped-care treatments resurrect relapsing smokers?

The efficacies of 2 group counseling step-up treatments for smoking cessation, cognitive-behavioral/skill training therapy (CBT) and motivational interviewing/supportive (MIS) therapy, were compared with brief intervention (BI) treatment in a sample of 677 smokers. Differential efficacy of the 2 step-up treatments was also tested in smokers at low and high risk for relapse (no smoking vs. any smoking during the first postquit week. respectively). All participants received 8 weeks of nicotine patch therapy. BI consisted of 3 brief individual cessation counseling sessions; CBT and MIS participants received BI treatment and 6 group counseling sessions. Neither CBT nor MIS treatment improved long-term abstinence rates relative to BI. Limited support was found for the hypothesis that high-risk smokers would benefit more from MIS than CBT. Other hypotheses were not supported.

Gender and racial/ethnic differences in tobacco-dependence treatment: a commentary and research recommendations.

The preparation of the Public Health Service Report, Treating Tobacco Use and Dependence, brought to light a substantial gap in the smoking cessation literature; there is little or no research evidence regarding the success of formal tobacco-dependence treatment specific to gender or racial/ethnic status. Of the 192 articles included in the meta-analyses of the evidence-based PHS Report, none included results based on racial/ethnic group and only four reported results by gender. This commentary identifies tobacco use as a problem that crosses gender and racial/ethnic boundaries, reviews reasons that the different genders or racial/ethnic groups might require different tobacco-dependence treatments, provides suggestive evidence that both gender and racial/ethnic status influence tobacco-dependence treatment efficacy, and recommends changes and directions for future clinical research that will address gender and racial/ethnicity effects.

Smoking withdrawal dynamics in unaided quitters.

Considerable research shows that withdrawal severity is inconsistently related to smoking cessation outcomes. This may result from measurement problems or failure to scrutinize important dimensions of the withdrawal experience. Two recent studies demonstrated that withdrawal elevation and variations in the time course of withdrawal were related to relapse in smokers treated with the nicotine patch (T. M. Piasecki, M. C. Fiore, & T. B. Baker, 1998). This article reports a conceptual replication and extension of those findings in unaided quitters. Evidence for temporal heterogeneity was found across different types of withdrawal symptoms. Patterns or slopes of affect and urge reports over time predicted smoking status at follow-up, as did mean elevation in withdrawal symptoms. These results suggest that affect and urge withdrawal symptoms make independent contributions to relapse and that relapse is related to both symptom severity and trajectory.

Development and validation of the Wisconsin Smoking Withdrawal Scale.

The accurate assessment of nicotine withdrawal is important theoretically and clinically. A 28-item scale, the Wisconsin Smoking Withdrawal Scale, was developed that contains 7 reliable subscales tapping the major symptom elements of the nicotine withdrawal syndrome. Coefficients alpha for the subscales range from .75 to .93. This scale is sensitive to smoking withdrawal, is predictive of smoking cessation outcomes, and yields data that conform to a 7-factor structure. The 7 scales predicted intratreatment smoking, chi2(7, N = 163) = 15.19, p = .034. Moreover, the questionnaire is sufficiently brief so that it can be used in both clinical and research contexts.

Gender differences in smoking cessation.

Gender differences in smoking quit rates are frequently reported and are the subject of much speculation. This study examined the generalizability of gender differences in abstinence across study sites, treatments, and time of relapse, as well as potential mediators and moderators of gender effects. Participants were smokers who participated in 3 randomized clinical trials of the nicotine patch (N = 632). Men had higher cessation rates than women at all follow-ups. The impact of gender on abstinence was unaffected by controlling for study site, treatment, or time of relapse. There was little evidence for mediation or moderation of this relation by any of a host of predictor variables. The magnitude and consistency of the gender differential, coupled with an inability to account for it, highlights a compelling need for additional research specifically aimed at elucidating the relation between gender and abstinence.

Manipulating smoking motivation: impact on an electrophysiological index of approach motivation.

A chief goal of this research was to determine whether stimuli and events known to enhance smoking motivation also influence a physiological variable with the potential to index approach motivation. Asymmetry of electroencephalographic (EEG) activity across the frontal regions of the 2 hemispheres (left minus right hemisphere activation) was used to index approach motivation. In theory, if EEG asymmetry sensitively indexes approach dispositions, it should be influenced by manipulations known to affect smoking motivation, that is, exposure to smoking cues and tobacco deprivation. Seventy-two smokers participated in this research and were selectively exposed to a smoking-anticipation condition (cigarettes plus expectation of imminent smoking) following either 24 hr of tobacco withdrawal or ad libitum smoking. Results indicated that EEG asymmetry was increased by smoking anticipation and that smoking itself reduced EEG asymmetry. Results also suggested that smoking anticipation increased overall (bihemispheric) EEG activation. Results were interpreted in terms of major theories of drug motivation.

Gender differences in response to nicotine replacement therapy: objective and subjective indexes of tobacco withdrawal.

K. A. Perkins (1996) recently proposed that nicotine reinforcement controls smoking to a greater degree among men than women and that consequently, nicotine replacement therapy (NRT) during smoking cessation should benefit men more than women. The authors tested this hypothesis. Polysomnographic measures of sleep and self-report indexes of tobacco withdrawal were collected pre- and postcessation from an active nicotine patch group and a placebo patch group in a randomized, double-blind clinical trial (N = 34). Objective sleep parameters supported Perkins's hypothesis and indicated that among women, NRT may be less effective at suppressing certain withdrawal responses compared with men and may produce some iatrogenic effects. Valid and reliable self-report measures of withdrawal did not reveal gender differences in response to NRT.

A controlled trial of sustained-release bupropion, a nicotine patch, or both for smoking cessation.

BACKGROUND AND METHODS: Use of nicotine-replacement therapies and the antidepressant bupropion helps people stop smoking. We conducted a double-blind, placebo-controlled comparison of sustained-release bupropion (244 subjects), a nicotine patch (244 subjects), bupropion and a nicotine patch (245 subjects), and placebo (160 subjects) for smoking cessation. Smokers with clinical depression were excluded. Treatment consisted of nine weeks of bupropion (150 mg a day for the first three days, and then 150 mg twice daily) or placebo, as well as eight weeks of nicotine-patch therapy (21 mg per day during weeks 2 through 7, 14 mg per day during week 8, and 7 mg per day during week 9) or placebo. The target day for quitting smoking was usually day 8. RESULTS: The abstinence rates at 12 months were 15.6 percent in the placebo group, as compared with 16.4 percent in the nicotine-patch group, 30.3 percent in the bupropion group (P<0.001), and 35.5 percent in the group given bupropion and the nicotine patch (P<0.001). By week 7, subjects in the placebo group had gained an average of 2.1 kg, as compared with a gain of 1.6 kg in the nicotine-patch group, a gain of 1.7 kg in the bupropion group, and a gain of 1.1 kg in the combined-treatment group (P<0.05). Weight gain at seven weeks was significantly less in the combined-treatment group than in the bupropion group and the placebo group (P<0.05 for both comparisons). A total of 311 subjects (34.8 percent) discontinued one or both medications. Seventy-nine subjects stopped treatment because of adverse events: 6 in the placebo group (3.8 percent), 16 in the nicotine-patch group (6.6 percent), 29 in the bupropion group (11.9 percent), and 28 in the combined-treatment group (11.4 percent). The most common adverse events were insomnia and headache. CONCLUSIONS: Treatment with sustained-release bupropion alone or in combination with a nicotine patch resulted in significantly higher long-term rates of smoking cessation than use of either the nicotine patch alone or placebo. Abstinence rates were higher with combination therapy than with bupropion alone, but the difference was not statistically significant.

The Agency for Health Care Policy and Research Smoking Cessation Clinical Practice Guideline. Findings and implications for psychologists.

Smoking is the leading cause of preventable morbidity and mortality in the United States, and the health benefits of quitting smoking are substantial. Nevertheless, over 25% of American adults (48 million individuals) continue to smoke, and the vast majority of quit attempts are unsuccessful. The Agency for Health Care Policy and Research recently addressed the smoking problem by conducting a 2-year research project that was published as the Smoking Cessation Clinical Practice Guideline (Fiore et al., 1996). This article reviews methods, analyses, and results from the Guideline project, and highlights major Guideline recommendations. Guideline findings and recommendations are discussed with respect to their implications for psychology.

Profiles in discouragement: two studies of variability in the time course of smoking withdrawal symptoms.

Research has suggested that the time course of the smoking withdrawal syndrome is fairly invariant across smokers and that smoking withdrawal symptoms are weakly related to relapse. Withdrawal data from 2 clinical trials of the nicotine patch were analyzed to evaluate these characterizations. In both studies, patients were clustered according to the shapes of their withdrawal profiles across 8 weeks of treatment. In each study, 3 clusters with distinct temporal patterns of withdrawal symptomatology emerged. Clusters included both abstinent and lapsing patients, and patch dose was unrelated to cluster membership. Patients with "atypical" patterns of smoking withdrawal (e.g., late symptomatic elevations) were more likely to relapse than patients who showed a gradual elimination of withdrawal. Withdrawal shape, duration, and severity all contributed significantly to the prediction of relapse. Measures of negative affect closely tracked withdrawal symptoms over time within clusters. Topics for future smoking withdrawal research are discussed.

Transdermal nicotine replacement for hospitalized patients: a randomized clinical trial.

BACKGROUND: This study was undertaken to assess the safety and efficacy of a treatment involving brief counseling and the nicotine patch among hospital inpatients and to identify variables associated with long-term smoking cessation following hospitalization. METHODS: One hundred eighty-five patients were randomly assigned to one of three smoking cessation interventions: (1) A Minimal Care (MC) condition, consisting of a brief physician-delivered motivational message to stop smoking, (2) a Counseling + Active Nicotine Patch (CAP) condition in which patients received the motivational message, a 6-week supply of nicotine patches, and extended bedside and telephone counseling, and (3) a Counseling + Placebo Patch (CPP) condition identical to the CAP condition except the supplied patches contained no nicotine. RESULTS: At 6-month follow-up, abstinence rates for the three treatments were 4.9, 6.5, and 9.7% for the MC, CPP, and CAP treatments, respectively. These differences were not statistically significant. Patients admitted for respiratory disease were more likely to quit than patients with any other diagnosis. The nicotine patch was well tolerated by hospital inpatients. CONCLUSIONS: The initiation of nicotine patch therapy during hospitalization appears to be safe when used among patients carrying a wide range of diagnoses. Our study provided no evidence of the superiority of nicotine patches versus placebo, but this does not preclude the possibility that future research using larger samples might detect differences between patch groups. Hospital interventions for smoking cessation may be most effective among patients hospitalized for a smoking-related illness such as respiratory disease.

Does over-the-counter nicotine replacement therapy improve smokers' life expectancy?

OBJECTIVE: To determine the public health benefits of making nicotine replacement therapy available without prescription, in terms of number of quitters and life expectancy. DESIGN: A decision-analytic model was developed to compare the policy of over-the-counter (OTC) availability of nicotine replacement therapy with that of prescription ([symbol: see text]) availability for the adult smoking population in the United States. MAIN OUTCOME MEASURES: Long-term (six-month) quit rates, life expectancy, and smoking attributable mortality (SAM) rates. RESULTS: OTC availability of nicotine replacement therapy would result in 91,151 additional successful quitters over a six-month period, and a cumulative total of approximately 1.7 million additional quitters over 25 years. All-cause SAM would decrease by 348 deaths per year and 2940 deaths per year at six months and five years, respectively. Relative to [symbol: see text] nicotine replacement therapy availability, OTC availability would result in an average gain in life expectancy across the entire adult smoking population of 0.196 years per smoker. In sensitivity analyses, the benefits of OTC availability were evident across a wide range of changes in baseline parameters. CONCLUSIONS: Compared with [symbol: see text] availability of nicotine replacement therapy, OTC availability would result in more successful quitters, fewer smoking-attributable deaths, and increased life expectancy for current smokers.