Nicotine & Tobacco Research

Genome-wide association studies have identified associations between variation at rs16969968/rs1051730 in the CHRNA5-A3-B4 gene cluster and smoking related outcomes. Experiments in rodents have described the nicotinic acetylcholine receptors (nAChRs) subunits encoded by this gene cluster and showed a lack of nicotine aversion in nAChRs deficient animal models. We conducted a nicotine challenge and a smoking topography study in humans, hypothesising that: 1. responses to a nicotine challenge would differ according to the rs16969968/rs1051730 genotype and 2. genotype may influence nicotine intake via smoking topography.\n\nWe used linear regressions to examine associations between rs16969968/rs1051730 genotype and subjective (questionnaires) and objective (physiological parameters) responses following acute nicotine exposure in never smokers (hypothesis 1) or cigarette smoking in current smokers (hypothesis 2). There was evidence to suggest nicotine exposure increases blood pressure and heart rate, and negatively affects mood, but insufficient evidence that these effects differ by genotype. Carriers of the minor allele following smoking one cigarette, exhibited reduced cravings (b=-2.46, 95% CI -4.87 to - 0.06, p=0.04) and inhaled less smoke per cigarette (b=-0.24, 95% CI - 0.43 to - 0.06, p=0.01) and per puff (b=-0.18, 95% CI -0.32 to -0.01, p=0.02). These results suggest that we need to carefully consider the translational value of the findings of aversion behaviour in nAChRs rodent models, and that deeper inhalation does not explain the strong association between rs16969968/rs1051730 genotype and objective biomarkers of tobacco exposure.

IntroductionIncreased salience of drug-related cues over non-drug reinforcers can drive drug use and contribute to tobacco use disorder (TUD). An important scientific and clinical goal is to effectively measure this elevated drug-seeking behavior in TUD. However, most TUD assessments rely on self-reported cravings and cigarette consumption, not providing an objective measure of the impact of drug-cues on biasing behavior towards drugs. The probabilistic image choice (PIC) task investigates the choice of viewing drug-related pictures as compared to other salient pictures (e.g., pleasant and unpleasant). This study aimed to develop and validate the PIC task for TUD and evaluate the associations between behavioral choice and tobacco craving, daily cigarette consumption, quit attempts and motivation to quit, and nicotine dependence (the Fagerstrom score). MethodsWe recruited 468 smokers and 121 nonsmokers using the Prolific online platform. Participants performed the PIC task twice (at a one-month interval) and completed other measures relevant to TUD. Resultscompared to nonsmokers, tobacco smokers selected to view significantly more tobacco images and less pleasant (non-drug reinforcer) images, a profile that remained stable at retest. Individual differences in choice of tobacco as compared to pleasant images on the PIC task were associated with craving but not with the other tobacco dependence measures, suggesting that the task may serve as a behavioral proxy measure of drug "wanting" rather than of cumulative nicotine exposure or physical dependence. Conclusionsthese results suggest that the PIC task can be a valuable tool for objectively assessing craving-associated tobacco seeking in TUD. Implications section, which should provide a brief description about what the study adds. Most of the current measures of tobacco use disorder (TUD) rely on self-reports of consumption, dependence and craving and do not take into consideration the role of drug-related cues in driving tobacco seeking. This study shows that the probabilistic image choice (PIC) task provides an objective, reliable proxy measure of tobacco image seeking behavior in cigarette smokers that is linked to craving (desire) for smoking but not to other measures of TUD. Therefore, the PIC task may be a useful complementary tool for the classification, diagnosis, and prognosis of TUD.

IntroductionThe FDA announced its intention to issue proposed product standards banning menthol as a characterizing flavor in cigarettes and cigars. The public health benefits of these product standards may be attenuated by the role of plausible substitutes in the marketplace. Therefore, the present study examined the addiction potential of plausible combustible menthol alternatives compared to usual brand menthol cigarettes (UBMC). MethodsEighty adult menthol cigarette smokers completed four visits, smoking their UBMC at the first session and 3 menthol cigarette alternatives in random order at the subsequent visits: 1) a pre-assembled menthol roll-your-own cigarette using menthol pipe tobacco and mentholated cigarette tube (mRYO), 2) a menthol filtered little cigar (mFLC), and 3) a non-menthol cigarette (NMC). Measures of smoking topography, exhaled carbon monoxide (CO), craving and withdrawal, subjective effects, and behavioral economic demand indices were assessed. ResultsCompared to UBMC, menthol cigarette alternatives resulted in similar topography and CO exposure but significantly lower levels of positive subjective experience and behavioral economic demand indices. Among the alternative products, participants reported the highest level of positive subjective experience and higher demand for mRYO, compared with mFLC and NMC. Similarly, participants were significantly more likely to want to try again, purchase, and use the mRYO product regularly compared with mFLC and NMC. Conclusions and RelevancemRYO cigarettes were the most highly rated cigarette alternative among study products, suggesting their potential appeal as a menthol cigarette substitute and needed inclusion of menthol pipe tobacco and cigarette tubes in FDAs proposed ban. What is already known on this topicMenthol cigarettes are associated with increased smoking initiation, higher nicotine dependence, and decreased adult cessation, particularly among vulnerable populations. To address this public health issue, the FDA announced in April 2021 its intention to issue product standards banning menthol as a characterizing flavor in both cigarettes and cigars within a year. However, the public health benefits of these product standards may be attenuated by the role of plausible substitutes available in the marketplace What this study addsIn this randomized cross-over design study that included 80 adult menthol cigarette smokers, each of the alternative products demonstrated the ability to significantly reduce nicotine craving and withdrawal symptoms, but the combination of mentholated pipe tobacco and tubes in a menthol roll-your-own cigarette, resulted in the highest behavioral economic demand and positive subjective experience. How this study may affect policyTo maximize the benefits of a menthol cigarette ban, restrictions should extend to plausible substitutes, particularly menthol pipe tobacco and cigarette tubes.

IntroductionE-cigarette use among youth and young adults remains of public health concern. Pod-based e-cigarettes, including JUUL, significantly changed the e-cigarette landscape in the United States (US). Using an online survey, we aimed to explore the socio-behavioral correlates, predisposing factors, and addictive behaviors among young adult pod-mod users within a University in Maryland, USA. Methods112 eligible college students aged 18-24 years recruited from a University in Maryland who reported using pod-mods were included in this study. Participants were categorized into current/non-current users based on past-30-day use. Descriptive statistics were used to analyze participants responses. ResultsOf the 112 participants with mean age 20.5{+/-}1.2 years, 56.3% were female, 48.2% White, and 40.2% reported past-30-day (current) use of pod-mods. The mean age of first experimentation with pod-mods was 17.8{+/-}1.4 years, while the mean age of regular use was 18.5{+/-}1.4 years, with the majority (67.9%) citing social influence as the reason for initiation. Of current users, 62.2% owned their own devices, and 82.2% predominantly used JUUL and menthol flavor (37.8%). A significant proportion of current users (73.3%) reported buying pods in person, 45.5% of whom were below the age of 21. Among all participants, 67% had had a past serious quit attempt. Among them, 89.3% neither used nicotine replacement therapy nor prescription medications. Finally, current use (adjusted odds ratio (aOR):4.52; 95%CI:1.76,11.64), JUUL use (aOR:2.56; 95%CI:1.08,6.03), and menthol flavor (aOR:6.52; 95%CI:1.38,30.89) were associated with reduced nicotine autonomy, a measure of addiction. ConclusionOur findings provide specific data to inform the development of public health interventions targeted at college youth, including the need for more robust cessation support for pod-mod users.

ObjectiveTo systematically review and meta-analyse evidence regarding the efficacy of electronic nicotine delivery systems (ENDS) as smoking cessation aids. Data SourcesPubMed, Scopus, Web of Science, PsycINFO, MEDLINE and Cochrane Library were searched up to February-March 2020 (PROSPERO registration CRD42020170692). Study selectionPublished peer-reviewed randomised controlled trials (RCTs) of the efficacy of ENDS for sustained cessation of combustible tobacco smoking and/or nicotine use, compared with no intervention, placebo or nicotine replacement therapy (NRT) by intention-to-treat, with a minimum of four months follow-up. Data ExtractionData were extracted independently into a pre-specified template. Risk of bias was assessed with the Cochrane Collaborations tool and evidence quality rated using GRADE. Data SynthesisFrom 3,973 titles identified, nine RCTs were identified; 330 of 5,445 smokers randomised quit. Smoking cessation did notPublic health consequences differ significantly for randomisation to ENDS versus: no intervention (three studies, random-effects meta-analysis RR 1.95; 95%CI 0.90-4.22); placebo (three studies, 1.61; 0.93-2.78) or NRT (three studies; 1.25; 0.74-2.11). Fixed-effects sensitivity analyses showed significant results for ENDS vs NRT (1.43; 1.10-1.86). Smokers randomised to ENDS were substantially more likely than control to use nicotine at follow-up. Overall evidence quality was low. Considering only studies without potential competing interests further limited evidence but did not materially change conclusions. ConclusionsThere is insufficient evidence that ENDS are efficacious for smoking cessation compared to no intervention, placebo or NRT. Results are promising, particularly for therapeutic use, but vary according to analytic method. ENDS may lead to greater ongoing nicotine exposure than other smoking cessation methods. ImplicationsThis systematic review and meta-analysis consolidates current evidence on the efficacy of ENDS as an aid to sustained smoking and nicotine cessation and considers these findings in the context of potential competing interests. While findings are promising more research - preferably independent of industry funding - is needed to provide robust evidence of the efficacy of ENDS for smoking cessation. Future research should investigate nicotine cessation in addition to smoking cessation.

IntroductionLongitudinal surveys provide data to estimate transition probabilities between cigarette smoking, e-cigarette use, and dual use of both, facilitating projections of future use and the impact of policies. MethodsWe fit a continuous time Markov multi-state model for youth (ages 12-17y) and adults ([&ge;]18y) in Waves 1-4.5 of the Population Assessment of Tobacco and Health (PATH) longitudinal survey and estimated smoking and e-cigarette transition frequencies, including initiation, cessation, and relapse. We validated transition frequency results in a microsimulation model by projecting smoking and e-cigarette use prevalence over time. ResultsThere was more volatility in smoking and e-cigarette use among youth than among adults. For youth never smokers, annual smoking initiation among never/current/former e-cigarette users occurred in 0.4% (95% CI 0.2-0.6%)/8.8% (7.0-10.7%)/3.1% (2.1-4.2%), and current e-cigarette users were more likely to quit e-cigarettes than to initiate smoking (absolute difference in annual probability 46.5%, 38.7-54.2%). For adult current smokers, annual smoking cessation among never/current/former e-cigarette users occurred in 22.6% (20.9-24.3%)/14.5% (11.5-17.4%)/15.1% (12.1-18.2%). For adult current dual users, 14.5% quit smoking and 49.5% quit e-cigarettes annually. For adult former smokers, annual smoking relapse among never/current/former e-cigarette users occurred in 17.7% (15.8-19.6%)/29.3% (23.8-34.7%)/32.8% (27.1-38.6%). Using these transition probabilities in a microsimulation model accurately projected smoking and e-cigarette use prevalence at 12 and 24 months compared to PATH empirical data (root-mean-square error <0.7%). DiscussionPATH Waves 1-4.5 contain sufficient data to generate smoking and e-cigarette use transition frequency estimates for youth and adults in a microsimulation model. E-cigarette use among youth is especially volatile. IMPLICATIONSThis study estimates longitudinal transitions between nine cigarette smoking and e-cigarette use states among both youth and adults. Youth smoking and e-cigarette use was more volatile than that of adults. Smoking initiation, cessation, and relapse differed by e-cigarette use status, but it is not clear that e-cigarette use itself caused these differences. A tobacco and nicotine policy model parametrized with our estimates accurately predicted smoking and e-cigarette use prevalence over two years, enabling future work to project the outcomes and cost-effectiveness of policies targeting smoking and e-cigarette use.

Importance: Oral nicotine pouches (ONPs) are tobacco-leaf-free nicotine products that have experienced a substantial increase in sales in recent years. Objective: To determine how ONP experimentation, initiation, and cessation rates differ by other tobacco product use and sociodemographic characteristics. Design: Nationally representative longitudinal cohort study; data from Waves 7 and 8 (2022-2024) of the Population Assessment of Tobacco and Health (PATH) Study. Setting: US civilian, non-institutionalized population. Participants: Adults in Waves 7 and 8 of PATH. Of 27,800 eligible participants, 24,640 with complete information on the exposure and outcome were included. Exposures: Other tobacco product use (cigarette-only, electronic nicotine delivery system [ENDS]-only, smokeless tobacco [SLT]-only, and multiproduct use) and sociodemographic characteristics (sex, race and ethnicity, age, and educational attainment). Main Outcomes: Hazard rates and ratios of transitioning between never, current, and non-current ONP use, defined by ever and past-30-day use, overall and by exposure group. Rates are estimated in univariable weighted multistate transition models. Results: Among 24,640 participants, 23,555 (96.7%) never used, 802 (2.5%) non-currently used, and 283 (0.8%) currently used ONPs in 2022. From 2022-24, ONP initiation was higher among those using cigarettes only (HR 3.34, 95% CI 1.59-7.02), ENDS only (HR 9.68, 95% CI 2.89-32.5), SLT only (42.4, 95% CI 22.3-80.7), or multiple products (HR 18.4, 95% CI 7.11-47.8) compared to those who did not use these tobacco products. Those who used cigarettes only (HR 3.02, 95% CI 1.24-7.34), ENDS only (HR 2.03, 95% CI 1.11-3.71), or multiple products (HR 2.61, 95% CI 1.12-6.09) discontinued ONPs at higher rates than those using no other products. Men had higher ONP initiation and lower cessation rates than women, adults ages 35+ years had lower initiation rates than those ages 18-24, and non-Hispanic Black participants had higher cessation rates than non-Hispanic White participants. Conclusions and Relevance: Initiation of ONPs was higher among those who used other tobacco products, highlighting the need to investigate whether ONPs replace these products or lead to poly-tobacco use. Higher cessation rates among those using cigarettes only or ENDS only may suggest experimentation rather than sustained use.

Withdrawal StatementThe authors have withdrawn their manuscript owing to an issue, which they were recently alerted to, with GWAS of paternal smoking used here. They hope to update the manuscript with an alternative GWAS as soon as possible. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

IntroductionGraphic warning labels (GWLs) are widely employed to communicate smoking-related health risks; however, their implementation in the US has been held back by concerns about their efficacy. Most GWLs elicit a high level of emotional reaction (ER). The extent to which ER contributes to GWLs efficacy in improving smoking outcomes is a subject of debate. Our recent study showed poorer efficacy of the high-ER GWLs versus the low-ER ones during a month-long naturalistic exposure. Whether GWL effects persist after discontinuing the exposure remains unclear. MethodsWe conducted a secondary analysis to investigate the delayed effects of GWLs on smoking severity in adult smokers. The number of cigarettes smoked per day (CPD) was measured immediately as well as 4 weeks after the end of a month-long exposure to high-ER versus low-ER GWLs. Participants indicated their subjective feeling of being relieved from having to see the GWLs. ResultsWe found a significant reduction in CPD from the immediate to the 4-week post-exposure timepoint. There was no difference in CPD reduction between the high-ER and low-ER groups. Subjective sense of relief from GWL exposure was associated with greater CPD reduction in the high-ER group, but not the low-ER group. ConclusionsOur study suggests lasting impact of GWLs on smoking behavior. The findings may be particularly important to high-arousal GWLs, which appear less effective in reducing smoking during active exposure. ImplicationsWhether GWLs that evoke higher ER are more effective remains inconclusive. We recently showed that high-ER GWLs are less effective than low-ER ones in reducing smoking during continuous exposure. Here, we found evidence of delayed GWL effects such that smoking decreased from immediately to four weeks after the end of GWL exposure. Feeling of relief from GWL exposure was associated greater smoking reduction in the high-ER group. We suggest that continuously exposing smokers to high-ER GWLs that have been well remembered may be unnecessary and counterproductive.

The debate about electronic cigarettes has divided healthcare professionals, policymakers, and communities. Central points of disagreement are whether vaping electronic cigarettes are addictive and whether they produce major pulmonary complications. We developed a novel model of nicotine vapor self-administration in rats and found that rats voluntarily exposed themselves to nicotine vapor to the point of reaching blood nicotine levels that are similar to humans, exhibiting both addiction-like behaviors and cardiopulmonary abnormalities. The smoking cessation drug varenicline decreased electronic cigarette self-administration. These findings confirm the addictive properties and harmful effects of nicotine vapor and identify a potential medication for the treatment of electronic cigarette addiction.\n\nOne Sentence SummaryVaping nicotine-containing electronic cigarettes produces cardiopulmonary abnormalities, nicotine dependence and addiction-like behaviors, which are reduced by the smoking cessation drug varenicline.

Introduction: E-cigarettes are the second most commonly used nicotine product in the United States after cigarettes. Their role in smoking cessation remains debated. Further research is needed to clarify their potential impact on quitting combustible cigarette use. Methods: We analyzed data from adults aged 18 and older who participated in Wave 4 (12/2016-01/2018), Wave 5 (12/2018-11/2019), and Wave 7 (01/2022-04/2023) of the Population Assessment of Tobacco and Health Study. We employed a causal forest to estimate the associations between Wave 5 e-cigarette use and past 12-month cigarette smoking abstinence at Wave 7. Eligible participants had smoked at least 100 cigarettes in their lifetime at Wave 4, currently smoked cigarettes some days or every day at both Waves 4 and 5, completed follow-up at Wave 7, and had a substantial estimated probability of either vaping or not vaping at Wave 5. Analyses adjusted for 26 Wave 4 covariates, including demographic characteristics, tobacco use history, and other relevant factors. Results: Compared with no vaping, vaping on 1-5 days was associated with a 2.4 percentage-point lower probability of cessation (95% CI: -7.7 to 2.9), whereas vaping on 6-29 days and daily vaping were associated with increases of 7.5 percentage points (95% CI: -0.4 to 15.5) and 12.5 percentage points (95% CI: 6.2 to 18.7), respectively. Conclusions: The association between vaping and smoking cessation varied by vaping frequency. Compared with non-vaping, infrequent vaping was not significantly associated with subsequent cigarette abstinence, whereas more frequent vaping was associated with a greater likelihood of abstinence. Daily vaping showed the strongest positive association.

Prenatal and early life exposure to cigarette smoke (CS) have repeatedly been shown to induce stable, long-term changes in DNA methylation (DNAm) in offspring. It has been hypothesized that these changes might be functionally related to the known outcomes of prenatal and early life CS exposure, which include impaired lung development, altered lung function and increased risk of asthma and wheeze. However, to date, few studies have examined DNAm changes induced by prenatal CS in tissues of the lung, and even fewer have attempted to examine the specific influences of prenatal versus early postnatal exposures. Here, we have established a mouse model of CS exposure which isolates the effects of prenatal and early postnatal CS exposures in early life. We have used this model to measure the effects of prenatal and/or postnatal CS exposures on lung function and immune cell infiltration as well as DNAm and expression of Cyp1a1, a candidate gene previously observed to demonstrate DNAm differences upon CS exposure in humans. Our study revealed that exposure to CS prenatally and in the early postnatal period cause long-lasting differences in offspring lung function, gene expression and lung Cyp1a1 DNAm, which wane over time but are reestablished upon re-exposure to CS in adulthood. This study creates a testable mouse model which can be used to investigate the effects of prenatal and early postnatal CS exposures and will contribute to the design of intervention strategies to mediate these detrimental effects.

ImportanceThe tobacco industry exploits legislative loopholes by introducing products with novel constituents, sensory features, and/or branding to bypass flavor restrictions and maintain appeal, particularly among young populations. Post Californias 2022 flavor ban, leading oral nicotine pouch (ONP) brand (ZYN) started marketing two new "unflavored" products, Classic and Original, but it is unknown if they differed from pre-ban products marketed as "flavor-ban approved" (Chill and Smooth) in their chemical composition, sensory characteristics and human appeal. MethodsNicotine, menthol, and synthetic coolants, WS-3 and WS-23, were quantified using gas chromatography-mass spectrometry. Menthol receptors (TRPM8 and TRPA1) activity was measured by calcium-microfluorimetry to assess cooling-and irritation-potential. ONP sensory attributes and appeal were assessed in young-adults (21-25Yr old) after 5-minute standardized use in a double-blind, randomized remote trial. Results"Chill" and "Classic" ONPs contained WS-3 exclusively (0.24{+/-}0.02 mg/pouch), with consistent levels across nicotine strengths; "Smooth" and "Original" contained neither menthol nor WS-3. Extracts of "Chill" and "Classic" robustly activated the cold/menthol TRPM8-receptor with similar potency and efficacy, while weakly activating the sensory irritant TRPA1 receptor. Human participants rated "Chill" and "Classic" as having stronger cooling sensations (p<0.05), while "Classic" was rated as more minty flavored when compared to unflavored "Smooth" and "Original" (p<0.005) ONPs. Conclusions and RelevancePre- and post-ban ONPs showed similar chemical, sensory, and appeal profiles based on WS-3 presence. By using concept names and sensory cues to disguise flavors, industry exploits regulatory loopholes to sustain marketing of banned products. What is already known on this topicOral nicotine pouches (ONPs) have gained popularity among young adults, and manufacturers have introduced products and marketed as "ban-compliant" with concept names and sensory additives that may mimic flavors despite flavor bans. What this study addsChemical, receptor, and sensory analyses of pre- and post-ban ZYN ONPs showed both contained the synthetic coolant WS-3, producing flavor-like cooling sensations even without menthol or other flavor compounds. How this study might affect research, practice, or policyFindings indicate that post-ban ONPs retain the same sensory and chemical properties as pre-ban products, highlighting enforcement challenges when odorless sensory additives and branding strategies allow products to retain flavor-like effects despite legislative restrictions.

Introduction: Monitoring transitions in cigarette and electronic nicotine vapor product (ENVP) use is important for understanding how marketplace and regulatory changes have affected product use patterns, but information from national surveys is often delayed by several years. Methods: The Rutgers Omnibus Study is a quarterly serial, rapid-response, web-based convenience survey. Using a Markov multistate transition model, we estimated transition rates and one-year transition probabilities between never, non-current, ENVP-only, cigarette-only, and dual use among 5,292 adults aged 18-45 who participated in at least two of Waves 1-16 (February 2022-February 2026), as well as overall transition hazard ratios by sex, age group, and race & ethnicity in a multivariable model. Results: About 40% of individuals using cigarettes (39.5%; 95% CI: 36.9-42.0) or ENVP (40.1%; 95% CI: 36.4-43.7), and 60% of those using both products (60.8%; 95% CI: 58.3-63.2) were predicted to remain in those states after one year. Female participants began using cigarettes from never use (adjusted hazard ratio [aHR] 0.44; 95% CI: 0.29-0.66) or non-current use (aHR 0.65; 95% CI: 0.48-0.88) at lower rates than male participants. Participants aged 35-45 years initiated ENVP-only use from non-current use (aHR 0.34; 95% CI: 0.23-0.51) at a lower rate than those aged 18-34 years. Compared to non-Hispanic White participants, non-Hispanic Black participants initiated ENVP-only use from never use at a higher rate (aHR 4.39; 95% CI: 2.09-9.25). Conclusion: Rapid response surveys can provide important preliminary information on tobacco use transition patterns while we wait for the slower release of nationally representative survey data.

Evidence from observational studies suggested that smokers are at increased risk of coronavirus disease 2019 (COVID-19). We aimed to assess the causal effect of smoking on risk for COVID-19 susceptibility and severity using two-sample Mendelian randomization method. Smoking-associated variants were selected as instrument variables from two largest genetic studies. The latest summary data of COVID-19 that shared on Jan 18, 2021 by the COVID-19 Host Genetics Initiative was used. The present Mendelian randomization study provided genetic evidence that smoking was a causal risk factor for COVID-19 susceptibility and severity. In addition, there may be a dose-effect relationship between smoking and COVID-19 severity.

BackgroundFactors influencing cessation include biopsychosocial characteristics, treatments and responses to treatment. The first cessation trial designed to assess cessation disparities between African American and White cigarette smokers demonstrated that socioeconomic, treatment, psychosocial and smoking characteristics explained cessation disparities. Ongoing translational efforts in precision cessation treatment grounded in genetically informed biomarkers have identified cessation differences by genotype, metabolism, ancestry and treatment. MethodsIn planned analyses, we evaluated six smoking-related measures, demographic and socioeconomic covariates, and prospective abstinence (7-day point prevalence at 12 weeks with bupropion, nicotine replacement and counseling treatments). We assessed concurrent and predictive validity in two covariate models differing by inclusion of Office of Management and Budget (OMB) race/ethnicity or genomic ancestry. ResultsWe studied Pharmacogenetic Study participants (N=456, mean age 49.5 years, 41.5% female, 7.4% African American, 9.4% Multiracial, 6.5% Other, and 6.7% Hispanic). Cigarettes per day (OR=0.95, P<.001), Fagerstrom score (OR=0.89, P<=.014), Time-To-First-Cigarette (OR=0.75, P<=.005) and predicted urinary nicotine metabolite ratio (OR=0.57, P<=.039) were associated with abstinence. OMB African American race (ORs from 0.31 and 0.35, p-values<=.007) and African genomic ancestry (ORs from 0.21 and 0.26, p-values<=.004) were associated in all abstinence models. ConclusionsFour smoking-related measures exhibited association with abstinence, including predicted nicotine metabolism based on a novel genomic model. African genomic ancestry was independently associated with reduced abstinence. Treatment research that includes social, psychological, treatment and biological factors is needed to reduce cessation disparities. ImplicationsO_LIThis is the first application of a statistical learning model of the urinary nicotine metabolite ratio to cessation. Results are concordant with biochemical and genetic models of the plasma nicotine metabolite ratio in multiethnic samples. C_LIO_LIThe urinary ratio exhibits the largest standardized effect size of four smoking-related measures associated with cessation (time-to-first cigarette, total Fagerstrom score and cigarettes per day were the others). C_LIO_LIThe social construct of African American race and genomic African ancestry are significant covariates in all cessation models. C_LIO_LIResults point to social and biological mechanisms requiring investigation in larger samples to understand and reduce cessation health disparities. C_LI

Cigarette smoking remains the leading preventable cause of disease and death. Nicotine is the primary reinforcing ingredient in cigarettes sustaining addiction. Cotinine is the major metabolite of nicotine that produces a myriad of neurobehavioral effects. Cotinine supported self-administration and rats with a history of intravenous self-administration of cotinine exhibited relapse-like drug-seeking behavior, suggesting cotinine may also be reinforcing. To date, a potential contribution of cotinine to nicotine reinforcement remains unknown. Nicotine metabolism is mainly catalyzed by hepatic CYP2B1 enzyme in the rat and methoxsalen is a potent CYP2B1 inhibitor. The study tested the hypothesis that methoxsalen inbibits nicotine metabolism and self-administration, and that cotinine replacement attenuates the inhibitory effects of methoxsalen. Acute methoxsalen decreased plasma cotinine levels and increased nicotine levels following subcutaneous nicotine injection. Repeated methoxsalen reduced the acquisition of nicotine self-administration, leading to fewer nicotine infusions, disruption of lever differentiation, smaller total nicotine intake, and lower plasma cotinine levels. On the other hand, methoxsalen did not alter nicotine self-administration during the maintenance phase despite great reduction of plasma cotinine levels. Cotinine replacement by mixing cotinine with nicotine for self-administration dose-dependently increased plasma cotinine levels, counteracted effects of methoxsalen, and enhanced the acquisition of self-administration. Neither basal nor nicotine-induced locomotor activity was altered by methoxsalen. These results indicate that methoxsalen depressed cotinine formation from nicotine and the acquisition of nicotine self-administration, and that replacement of plasma cotinine attenuated the inhibitory effects of methoxsalen, suggesting that cotinine may contribute to the development of nicotine reinforcement.

IntroductionSmoking contributes a huge burden on public health; thus, identifying risk factors for smoking remains an important area of research. This study adds to the wealth of existing literature by utilising repeated smoking measures collected in a UK sample of young adults to (a) examine differences between longitudinal smoking behaviours, (b) investigate their association with many risk factors, and c) consider how these associations may change over time. MethodsThis study uses longitudinal latent class analysis and 12 repeated measures to derive patterns of smoking in the Avon Longitudinal Study of Parents and Children. The association of these patterns with 402 risk factor measures collected from 0-28 years is then investigated. The selected risk factors include familial and peer factors, lifestyle and sociodemographic factors, mental health, parenthood, adverse childhood experiences and trauma. ResultsFive different latent classes of smoking were derived and referred to as non-smoking, short-term smoking, occasional smoking, early-onset smoking, and late-onset smoking. These showed differences in age of onset, frequency, and cessation. Other substance use, and parental and peer substance use, showed the strongest association with smoking patterns. More risk factors were associated with early-onset than late-onset smoking. Many risk factors of regular smoking did not show the same associations with occasional smoking. Fewer measures differentiated late-onset from short-term smoking. Some associations varied depending on the time of measurement or smoking pattern in question. ConclusionsFindings from this study may be used to identify groups of people most vulnerable to more harmful smoking patterns despite being exposed to strong tobacco prevention efforts. This could also help better tailor smoking interventions and improve tobacco control policies.

Background The clinical safety profile of e-cigarette use for smoking reduction remains poorly characterized. This study compared the relative safety and tolerability of nicotine e-cigarette use with non-nicotine e-cigarettes or a non-aerosol cigarette substitute (CS) among adults interested in reducing their smoking. Methods We conducted a secondary analysis of adverse events (AEs) reported in a 6-month, double-blind RCT involving 520 participants assigned to either e-cigarettes with 0, 8, or 36 mg/mL nicotine or a CS. AEs were coded using CTCAE V4.0 and assessed for frequency, severity, seriousness and relatedness across groups. Cumulative incidence was calculated over 24 weeks. We estimated risk differences (RDs) and 95% confidence intervals (CIs) for frequently reported AEs (>=1% of participants overall) comparing e-cigarette vs. CS and nicotine versus non-nicotine e-cigarette groups. Fisher's exact test, with adjustment for multiple comparisons, was used to assess statistical significance. Results Most study-related AEs (those rated as possibly, probably, or definitely related by medical monitor) were mild in severity and none were classified as serious. At 24 weeks, cumulative incidence of first study-related AE was highest in the 36 mg/mL (37.0%) and 8 mg/mL (35.2%) e-cigarette groups, followed by 0 mg/mL (23.4%), and lowest in CS group (2.5%). E-cigarette users experienced significantly greater risks of cough (RD [95%CI]: 8.5% [5.6-11.3]), headache (RD [95%CI]: 5.4% [3.3-7.6]) and sore throat (RD [95%CI]: 5.4% [3.2-7.6]) as compared with the CS group. Cough was also more common in those randomized to nicotine versus non-nicotine e-cigarettes (RD [95%CI]: 8.1% [3.4-12.8]). Conclusion All study products were generally well-tolerated; however, AEs were more common in e-cigarette groups, especially with nicotine. Findings highlight the need to monitor common symptoms such as cough, headache, and sore throat in clinical and regulatory evaluations of e-cigarette safety.

Objective Existing genetic studies of nicotine consumption have largely focused on cigarette smoking. Different modes of nicotine use have varying use patterns and user characteristics that may reflect distinct environmental and genetic influences. This study aims to identify the shared and specific genetic risks for five nicotine use modes. Methods We performed a common variant multi-ancestral genome-wide association study (cross-ancestry N = 304,213) of five types of nicotine use in the All of Us Research Program: lifetime use of electronic nicotine (e-nicotine) products, cigars, tobacco in a hookah, smokeless tobacco, or at least 100 cigarettes. Results Nicotine users, regardless of mode, were more likely to be male and of younger age (except for cigarette use), and all modes of use were positively associated with tobacco use disorder diagnoses. GWAS meta-analyses of cigarette, e-nicotine, cigar, and smokeless tobacco use identified 87, 4, 1, and 1 genome-wide risk loci, respectively (none for hookah), including previously identified genes (e.g., CHRNA4 for cigarettes). Cigarette, e-nicotine, and smokeless tobacco use showed strong genetic correlations (rg=0.82-0.92), while cigar and hookah use were strongly genetically correlated (rg=0.87). Cross-trait correlations diverged: cigarette, e-nicotine, and smokeless tobacco use showed the strongest positive correlations with psychiatric disorders, negative urgency, and neuroticism, whereas cigar and hookah use showed null-to-weak correlations with psychiatric disorders but positive correlations with sensation-seeking and openness. Conclusions Our findings reveal important phenotypic and genetic distinctions across modes of nicotine use, particularly in relation to personality traits such as impulsivity and to socioeconomic context.