Background

Maternal cigarette smoking is an important modifiable risk factor for low birth weight in the US. We investigated the maternal nicotine metabolite ratio (NMR; trans-3'-hydroxycotinine/cotinine) - a genetically-informed biomarker of nicotine clearance - as a moderator of links between prenatal cigarette use and birth weight. We also explored the role of race in these associations.

Methods

Participants were 454 pregnant women (M_age = 25 years; 11% Black) who smoked cigarettes and their 537 infants from the Collaborative Perinatal Project. Cigarettes smoked per day were assessed at each prenatal visit; maternal NMR was assayed from third trimester serum. Birth weight was obtained from medical records. Generalized estimating equations were used to evaluate associations between cigarette smoking, NMR, race, and birth weight.

Results

NMR moderated continuous associations between cigarettes per day over pregnancy and infant birth weight (p = .025). Among women who smoked at moderate levels (<15 cigarettes per day), those with slower NMR showed ~50-100 g decrements in birth weight versus those with faster NMR., while there were no significant associations between NMR and birth weight among women who smoked 15+ cigarettes per day. Although effects of NMR on birthweight were similar for Black and white women, Black women showed significantly slower NMR (p < .001).

Conclusions

This is the first demonstration that the maternal nicotine metabolism phenotype moderates associations between maternal smoking during pregnancy and birth weight. Infants of women with slower nicotine metabolism - including disproportionate representation of Black women - may be at heightened risk for morbidity from maternal smoking.

While smoking is the primary cause of lung cancer, only 11-24% of smokers develop the malignancy over their lifetime. The primary addictive agent in tobacco smoke is nicotine and variation in nicotine metabolism may influence the smoking levels of an individual. Therefore, inter-individual variation in lung cancer risk among smokers may be due in part to differences in the activity of enzymes involved in nicotine metabolism. In most smokers, cytochrome P450 2A6 (CYP2A6)-catalyzed C-oxidation accounts for >75% of nicotine metabolism, and the activity of this enzyme has been shown to correlate with the amount of nicotine and carcinogens drawn from cigarettes. We prospectively evaluated the association of urinary biomarkers of nicotine uptake (total nicotine equivalents [TNE]) and CYP2A6 activity (ratio of urinary total trans-3'-hydroxycotinine to cotinine) with lung cancer risk among 2,309 Multiethnic Cohort Study participants who were current smokers at time of urine collection; 92 cases were diagnosed during a mean follow-up of 9.5 years. We found that higher CYP2A6 activity and TNE was associated with increased lung cancer risk after adjusting for age, sex, race/ethnicity, body mass index, smoking duration, and urinary creatinine (p's = 0.002). The association for CYP2A6 activity remained even after adjusting for self-reported cigarettes per day (CPD) (Hazard Ratio [HR] per unit increase in log-CYP2A6 activity = 1.52; p = 0.005) and after adjusting for TNE (HR = 1.46; p = 0.01). In contrast, the association between TNE and lung cancer risk was of borderline statistical significance when adjusted for CPD (HR = 1.53; p = 0.06) and not statistically significant when further adjusted for CYP2A6 activity (HR = 1.30; p = 0.22). These findings suggest that CYP2A6 activity provides information on lung cancer risk that is not captured by smoking history or a (short-term) biomarker of dose. CYP2A6 activity should be further studied as a risk biomarker for smoking-related lung cancer.

AIMS: To 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. DESIGN: Double-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. SETTING: Two hospital-affiliated clinics (study 1), and two university-affiliated clinics (study 2). PARTICIPANTS: A total of 792 self-identified white treatment-seeking smokers aged ≥18 years smoking ≥10 cigarettes per day over the last year. MEASUREMENTS: Age, gender, Fagerström 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. FINDINGS: Significant 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. CONCLUSIONS: A 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.

Despite the withdrawal of CB₁ antagonists, such as rimonabant, from the market and from active clinical development because of concerns about their side effect profiles, research suggests that the endocannabinoid system may play an important role in modulating nicotine's effects. We report the combined results, using a pooled analysis, of three previously unpublished trials assessing rimonabant as a smoking cessation pharmacotherapy conducted between 2002 and 2004. Smokers (n = 2097) motivated to quit were enrolled in three randomized, double-blind, placebo-controlled trials, STRATUS EU, US, and META, which consisted of a 10-week treatment period with either rimonabant 20 mg (n = 789), 5 mg (n = 518; used in only two of the three studies), or placebo (n = 790), in conjunction with brief counseling. The impact of drug on prolonged abstinence and adverse events was examined at 8 weeks (end-of-treatment) and at 48 weeks (available for STRATUS EU and US) after the targeted quit date. Rimonabant 20 mg resulted in significantly higher abstinence at end-of-treatment and at 48 weeks post-targeted quit date compared with placebo, while rimonabant 5 mg and placebo did not differ. Serious AEs did not differ by drug group. The 20 mg rimonabant dose, compared with placebo, produced increased nausea, diarrhea, anxiety symptoms, hyporexia, and vomiting, and decreased headache, constipation, and cough. These results support rimonabant 20 mg as a modestly effective aid for smoking cessation. Although work on CB₁ antagonists such as rimonabant has mostly been stopped because of unacceptable adverse events, these results may inform and spur the development of other endocannabinoids for smoking cessation.

Aims

To 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.

Design

Double-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.

Setting

Two hospital-affiliated clinics (study 1), and two university-affiliated clinics (study 2).

Participants

A total of 792 self-identified white treatment-seeking smokers aged ≥18 years smoking ≥10 cigarettes per day over the last year.

Measurements

Age, gender, Fagerström 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.

Findings

Significant 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.

Conclusions

A 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 aims

With no established standard for assessing tobacco dependence (TD) across tobacco products in surveys, the Population Assessment of Tobacco and Health (PATH) Study provides a unique platform for examining the psychometric properties and validity of multiple indicators of tobacco dependence across a range of tobacco products.

Participants

A U.S. nationally representative sample from the 32,320 adult Wave 1 interviews with analyses focused on 14,287 respondents who were current established users of tobacco products.

Findings

This analysis confirms a single primary latent construct underlying responses to TD indicators for cigarettes, e-cigarettes, cigars, hookah, and smokeless tobacco products. Mutually exclusive past year tobacco-user groups included: cigarette only (n=8689), e-cigarette only (n=437), cigar only (traditional, cigarillo, or filtered) (n=706), hookah only (n=461), smokeless tobacco only (n=971), cigarette plus e-cigarette (n=709), and multiple tobacco product users (n=2314). Differential Item Functioning (DIF) analyses supported use of 16 of the 24 examined TD indicators for comparisons across tobacco users. With cigarette users as a reference (mean=0.0, SD=1.0), we observed a range of TD with hookah (mean=-1.71) and cigar (mean=-1.92) only users being the lowest, and cigarette plus e-cigarette product users being the highest (mean=0.35). Regression models including sociodemographic factors supported concurrent validity with increased product use frequency and TD among cigarette-only (p<0.001), e-cigarette only (p<0.002), cigar (p<0.001), hookah only (p<0.001), and smokeless tobacco users (p<0.001).

Conclusion

The PATH Study Adult Wave 1 Questionnaire provided psychometrically valid measures of TD that enables future regulatory investigations of nicotine dependence across tobacco products.

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

Although the important roles of postquit affect and withdrawal symptoms in the process of smoking cessation have been well established, little is known about the relations between prequit affective trajectories and cessation outcome on the target quit date (TQD). This study examined whether a 16-week course of fluoxetine initiated 8 weeks prequit ("sequential" fluoxetine) improved TQD abstinence relative to placebo through its effects on prequit depressive symptoms, affect (withdrawal-relevant negative affect, general negative affect, and positive affect), and craving to smoke among 206 smokers with elevated depressed symptoms. The moderating effects of gender were also examined. In total, 83 smokers (40%) failed to achieve abstinence on TQD, with no difference between treatment conditions or gender. Overall structural equation models showed that fluoxetine had significant indirect effects on TQD abstinence through changes in prequit withdrawal-relevant negative affect and craving, but not depressive symptoms. However, multigroup analyses revealed gender differences. Sequential fluoxetine reduced prequit depressive symptoms, withdrawal-relevant negative affect, and craving only among women. Reduction in prequit depressive symptoms and craving among women, and withdrawal-relevant negative affect among men was associated with TQD abstinence. Moreover, exploratory analysis showed negative trend-level indirect effects of fluoxetine on TQD abstinence via increased side effects, regardless of gender. This study demonstrated the importance of considering gender when examining treatment efficacy. Identifying ways to further reduce prequit depressive symptoms and craving for women and withdrawal-relevant negative affect for men whereas alleviating side effects may help smokers with elevated depressed symptoms achieve the first smoking cessation milestone.

Background

Prior work established a measure of tobacco dependence (TD) among adults that can be used to compare TD across different tobacco products. We extend this approach to develop a common, cross-product metric for TD among youth.

Methods

One thousand one hundred and forty-eight youth aged 12-17 who used a tobacco product in the past 30 days were identified from 13 651 youth respondents in Wave 1 of the Population Assessment of Tobacco and Health (PATH) Study.

Findings

Analyses confirmed a single primary latent construct underlying responses to TD indicators for all mutually exclusive tobacco product user groups. Differential Item Functioning analyses supported the use of 8 of 10 TD indicators for comparisons across groups. With TD levels anchored at 0.0 (standard deviation [SD] = 1.0) among cigarette only (n = 265) use group, mean TD scores were more than a full SD lower for e-cigarette only (n = 150) use group (mean = -1.09; SD = 0.64). Other single product use group (cigar, hookah, pipe, or smokeless; n = 262) on average had lower TD (mean = -0.60; SD = 0.84), and the group with the use of multiple tobacco products (n = 471) experienced similar levels of TD (mean = 0.14; SD = 0.78) as the cigarette only use group. Concurrent validity was established with product use frequency among all user groups. A subset of five TD items comprised a common metric permitting comparisons between youth and adults.

Conclusion

The PATH Study Youth Wave 1 Interview provided psychometrically valid measures of TD that enable future regulatory investigations of TD across tobacco products and comparisons between youth and adult tobacco product use group.

Implications

A measure of tobacco dependence (TD) has been established previously among adults to compare TD across tobacco products. This study established the validity of a similar, cross-product measure of TD among youth. Findings suggest a single latent TD construct underlying this measure, concurrent validity of the scale with product use frequency across different types of tobacco users, and a subset of common items that can be used to compare TD between youth and adults who use tobacco.

Introduction

We examined the relationship between current tobacco use and functionally important respiratory symptoms.

Methods

Longitudinal cohort study of 16 295 US adults without COPD in Waves 2-3 (W2-3, 2014-2016) of the Population Assessment of Tobacco and Health Study. Exposure-Ten mutually exclusive categories of tobacco use including single product, multiple product, former, and never use (reference). Outcome-Seven questions assessing wheezing/cough were summed to create a respiratory symptom index; cutoffs of ≥2 and ≥3 were associated with functional limitations and poorer health. Multivariable regressions examined both cutoffs cross-sectionally and change over approximately 12 months, adjusting for confounders.

Results

All tobacco use categories featuring cigarettes (>2/3's of users) were associated with higher risk (vs. never users) for functionally important respiratory symptoms at W2, for example, at symptom severity ≥ 3, risk ratio for exclusive cigarette use was 2.34 [95% CI, 1.92, 2.85] and for worsening symptoms at W3 was 2.80 [2.08, 3.76]. There was largely no increased symptom risk for exclusive use of cigars, smokeless tobacco, hookah, or e-cigarettes (adjustment for pack-years and marijuana attenuated the cross-sectional e-cigarette association from 1.53(95% CI 0.98, 2.40) to 1.05 (0.67, 1.63); RRs for these products were also significantly lower compared to exclusive use of cigarettes. The longitudinal e-cigarette-respiratory symptom association was sensitive to the respiratory index cutoff level; exclusive e-cigarette use was associated with worsening symptoms at an index cutoff ≥ 2 (RR = 1.63 [1.02, 2.59]) and with symptom improvement at an index cutoff of ≥ 3 (RR = 1.64 [1.04, 2.58]).

Conclusions

Past and current cigarette smoking drove functionally important respiratory symptoms, while exclusive use of other tobacco products was largely not associated. However, the relationship between e-cigarette use and symptoms was sensitive to adjustment for pack-years and symptom severity.

Implications

How noncigarette tobacco products affect respiratory symptoms is not clear; some studies implicate e-cigarettes. We examined functionally important respiratory symptoms (wheezing/nighttime cough) among US adults without COPD. The majority of adult tobacco users smoke cigarettes and have higher risk of respiratory symptoms and worsening of symptoms, regardless of other products used with them. Exclusive use of other tobacco products (e-cigarettes, cigars, smokeless, hookah) was largely not associated with functionally important respiratory symptoms and risks associated with their use was significantly lower than for cigarettes. The association for e-cigarettes was greatly attenuated by adjustment for cigarette pack-years and sensitive to how symptoms were defined.