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BackgroundPrior 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.MethodsOne 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.FindingsAnalyses 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.ConclusionThe 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.ImplicationsA 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.

IntroductionIn response to reducing cigarette nicotine content, people who smoke could attempt to compensate by using more cigarettes or by puffing on individual cigarettes with greater intensity. Such behaviors may be especially likely under conditions where normal nicotine content (NNC) cigarettes are not readily accessible. The current within-subject, residential study investigated whether puffing intensity increased with very low nicotine content (VLNC) cigarette use, relative to NNC cigarette use, when no other nicotine products were available.Aims and methodsSixteen adults who smoke daily completed two four-night hotel stays in Charleston, South Carolina (United States) in 2018 during which only NNC or only VLNC cigarettes were accessible. We collected the filters from all smoked cigarettes and measured the deposited solanesol to estimate mouth-level nicotine delivery per cigarette. These estimates were averaged within and across participants, per each 24-h period. We then compared the ratio of participant-smoked VLNC and NNC cigarette mouth-level nicotine with the ratio yielded by cigarette smoking machines (when puffing intensity is constant).ResultsAverage mouth-level nicotine estimates from cigarettes smoked during the hotel stays indicate participants puffed VLNC cigarettes with greater intensity than NNC cigarettes in each respective 24-h period. However, this effect diminished over time (p < .001). Specifically, VLNC puffing intensity was 40.0% (95% CI: 29.9, 53.0) greater than NNC puffing intensity in the first period, and 16.1% (95% CI: 6.9, 26.0) greater in the fourth period.ConclusionAverage puffing intensity per cigarette was elevated with exclusive VLNC cigarette use, but the extent of this effect declined across four days.ImplicationsIn an environment where no other sources of nicotine are available, people who smoke daily may initially attempt to compensate for cigarette nicotine reduction by puffing on individual cigarettes with greater intensity. Ultimately, the compensatory behavior changes required to achieve usual nicotine intake from VLNC cigarettes are drastic and unrealistic. Accordingly, people are unlikely to sustain attempts to compensate for very low cigarette nicotine content.

The introduction of alternative nicotine and tobacco products (such as e-cigarettes, heat-not-burn devices, nicotine pouches) warrants an updated framework from which to conceptualize tobacco use disorder (TUD). The following review provides considerations for TUD within the context of novel products. Historically, the tobacco industry falsely claimed that cigarettes were not addictive or harmful and that those who smoked simply chose to do so. This generated an inaccurate lay perception that smoking is a free or informed choice. Research on nicotine pharmacology demonstrates the powerful addictive potential of nicotine, which is shaped by dose, speed of delivery, and other constituents generated. In addition, non-pharmacologic reinforcers motivate and maintain tobacco use behaviors for both traditional cigarettes and novel products. The negative consequences of combustible tobacco use are well known; however, these outcomes may differ for alternative products. Strategies used for combustible product cessation may be adapted for novel products, and treatment recommendations for TUD should be made within the context of a harm reduction framework wherein alternative product use may be the desired outcome. Providers must therefore be willing to modify their perceptions of products and treatment recommendations accordingly. Better public health outcomes are accomplished through promotion of abstinence from combustible smoking. For those who cannot wean from nicotine entirely, switching to less risky modes of delivery might be a secondary goal, with an eventual aim of stopping use of the alternative product. Implications: Given the advent of novel, alternative tobacco products, tobacco use disorder (TUD) must be conceptualized within a contemporary framework that includes harm reduction and alternative outcomes. The unique contributions of nicotine pharmacology, non-pharmacologic reinforcers, and consequences of use can be used to inform treatments for TUD with the ultimate goal of improving the health of individuals who use tobacco.

A simple approach for analyzing longitudinally measured biomarkers is to calculate summary measures such as the area under the curve (AUC) for each individual and then compare the mean AUC between treatment groups using methods such as t test. This two-step approach is difficult to implement when there are missing data since the AUC cannot be directly calculated for individuals with missing measurements. Simple methods for dealing with missing data include the complete case analysis and imputation. A recent study showed that the estimated mean AUC difference between treatment groups based on the linear mixed model (LMM), rather than on individually calculated AUCs by simple imputation, has negligible bias under random missing assumptions and only small bias when missing is not at random. However, this model assumes the outcome to be normally distributed, which is often violated in biomarker data. In this paper, we propose to use a LMM on log-transformed biomarkers, based on which statistical inference for the ratio, rather than difference, of AUC between treatment groups is provided. The proposed method can not only handle the potential baseline imbalance in a randomized trail but also circumvent the estimation of the nuisance variance parameters in the log-normal model. The proposed model is applied to a recently completed large randomized trial studying the effect of nicotine reduction on biomarker exposure of smokers.

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.

In studies of tobacco toxicology, including comparisons of different tobacco products and exposure to secondhand or thirdhand smoke, exposure assessment using biomarkers is often useful. Some studies have indicated that most of the toxicity of tobacco smoke is due to gas-phase compounds. 3-Ethenylpyridine (3-EP) is a major nicotine pyrolysis product occurring in the gas phase of tobacco smoke. It has been used extensively as an environmental tracer for tobacco smoke. 3-EP would be expected to be a useful tobacco smoke biomarker as well, but nothing has been published about its metabolism and excretion in humans. In this Article we describe a solid-phase microextraction (SPME) GC-MS/MS method for determination of 3-EP in human urine and its application to the determination of 3-EP in the urine of smokers and people exposed to secondhand smoke. We conclude that 3-EP is a promising biomarker that could be useful in studies of tobacco smoke exposure and toxicology. We also point out the paucity of data on 3-EP toxicity and suggest that additional studies are needed.Graphical Abstract

ObjectiveIt is unclear why Black smokers in the United States have elevated risk of some tobacco-related diseases compared to White smokers. One possible causal mechanism is differential intake of tobacco toxicants, but results across studies are inconsistent. Thus, we examined racial differences in biomarkers of toxic volatile organic compounds (VOCs) present in tobacco smoke.MethodWe analyzed baseline data collected from 182 Black and 184 White adult smokers who participated in a randomized clinical trial in 2013-2014 at 10 sites across the United States. We examined differences in urinary levels of ten VOC metabolites, total nicotine equivalents (TNE), and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), controlling for covariates such as cigarettes per day (CPD), as well as differences in VOCs per TNE to assess the extent to which tobacco exposure, and not metabolic factors, accounted for racial differences.ResultsConcentration of metabolites of acrolein, acrylonitrile, ethylene oxide, and methylating agents were significantly higher in Blacks compared to Whites when controlled for covariates. Other than the metabolite of methylating agents, VOCs per TNE did not differ between Blacks and Whites. Concentrations of TNE/CPD and VOCs/CPD were significantly higher in Blacks. Menthol did not contribute to racial differences in VOC levels.ConclusionsFor a given level of CPD, Black smokers likely take in higher levels of acrolein, acrylonitrile, and ethylene oxide than White smokers. Our findings are consistent with Blacks taking in more nicotine and toxicants per cigarette smoked, which may explain their elevated disease risk relative to other racial groups.

BackgroundThe U.S. Food and Drug Administration (FDA) is considering a low-nicotine product standard for cigarettes. The purpose of this qualitative study was to explore participants' experiences after 72 hours of exclusively smoking very low nicotine content (VLNC) cigarettes.MethodsWe conducted a residential study during which participants who smoked cigarettes (N = 16) stayed in a smoking-friendly hotel for 5 days/4 nights. Participants only had access to VLNC cigarettes and were told the cigarettes had 97% less nicotine compared to conventional cigarettes. We conducted individual interviews with participants to assess their initial expectations about VLNC cigarettes, subjective experiences when smoking VLNC cigarettes, opinions regarding a low-nicotine product standard, and predicted use behavior if only VLNC cigarettes were available. Interviews were transcribed verbatim and analyzed using thematic analysis methods.ResultsSeveral participants expected, prior to trying VLNC cigarettes, to compensate for the reduced nicotine levels by smoking more cigarettes but were surprised when they did not increase their smoking. A subset of participants reported experiencing minor withdrawal symptoms, such as irritability and fatigue. Several participants reported feeling less dependent after exclusively smoking VLNC cigarettes. Most participants said they would smoke VLNC cigarettes if they were the only cigarettes available to purchase. Some also said that smoking VLNC cigarettes could help people taper down or quit smoking.ConclusionsHealth communication strategies are needed to inform people who smoke about what to expect from a low-nicotine product standard for cigarettes in order to maximize the public health impact of the policy and increase support.

IntroductionWe illustrate the differential impact of common analysis approaches to handling urinary creatinine, a measure for urine dilution, on relationships between race, gender, and biomarkers of exposure measured in spot urine.MethodsIn smokers, spot urine levels of total nicotine equivalents (TNE, sum of total nicotine, total cotinine, and total 3'-hydroxycotinine) and total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) overall and per cigarette were examined. Relationships between race (African Americans [AA] n = 373, Whites n = 758) or gender (males n = 629, females n = 502) and TNE or NNAL were examined using the following approaches to handling creatinine: (1) unadjusted/unstandardized; (2) standardization; (3) adjustment as a covariate. Significance was considered at p < .05.ResultsCreatinine was higher in AA versus Whites (1.19 vs. 0.96 mg/mL; p < .0001) and in males versus females (1.21 vs. 0.84 mg/mL; p < .0001). Independent of how creatinine was handled, TNE was lower among AA than Whites (TNE ratios AA vs. Whites: 0.67-0.84; p's < .05). Unadjusted TNE per cigarette was higher among AA versus Whites (ratio 1.12; p = .0411); however, the relationship flipped with standardization (ratio 0.90; p = .0360) and adjustment (ratio 0.95; p = .3165). Regarding gender, unadjusted TNE was higher among males versus females (ratio 1.13; p = .0063), but the relationship flipped with standardization (ratio 0.79; p < .0001) or adjustment (ratio 0.89; p = .0018). Unadjusted TNE per cigarette did not differ across gender (ratio 0.98; p = .6591), but lower levels were found in males versus females with standardization (ratio 0.68; p < .0001) and adjustment (ratio 0.74; p < .0001). NNAL displayed similar patterns.ConclusionsRelationships between race, gender, and spot urine levels of biomarkers of exposure can vary greatly based on how creatinine is handled in analyses.ImplicationsLack of appropriate methods can lead to discrepancies across reports on variability of urinary biomarkers by race and gender. We recommend that for any analyses of biomarkers of exposure measure in spot urine samples across race, gender, or other population subgroups that differ in urinary creatinine levels, sensitivity analyses comparing the different methods for handling urinary creatinine should be conducted. If methods result in discrepant findings, this should be clearly noted and discussed.

ObjectivesWhen examining the relationship between smoking intensity and toxicant exposure biomarkers in an effort to understand the potential risk for smoking-related disease, individual biomarkers may not be strongly associated with smoking intensity because of the inherent variability in biomarkers. Structural equation modeling (SEM) offers a powerful solution by modeling the relationship between smoking intensity and multiple biomarkers through a latent variable.MethodsBaseline data from a randomized trial (N = 1250) were used to estimate the relationship between smoking intensity and a latent toxicant exposure variable summarizing five volatile organic compound biomarkers. Two variables of smoking intensity were analyzed: the self-report cigarettes smoked per day and total nicotine equivalents in urine. SEM was compared with linear regression with each biomarker analyzed individually or with the sum score of the five biomarkers.ResultsSEM models showed strong relationships between smoking intensity and the latent toxicant exposure variable, and the relationship was stronger than its counterparts in linear regression with each biomarker analyzed separately or with the sum score.ConclusionsSEM is a powerful multivariate statistical method for studying multiple biomarkers assessing the same class of harmful constituents. This method could be used to evaluate exposure from different combusted tobacco products.

BackgroundWe examined the nicotine metabolite ratio's (NMR) relationship with smoking intensity, nicotine dependence, and a broad array of biomarkers of exposure and biological effect in commercial cigarette smokers.MethodsSecondary analysis was conducted on two cross-sectional samples of adult, daily smokers from Wave 1 (2013-2014) of the Population Assessment of Tobacco Use and Health (PATH) Study and baseline data from a 2014-2017 randomized clinical trial. Data were restricted to participants of non-Hispanic, white race. The lowest quartile of NMR (

BackgroundThe FDA is considering a mandated reduction in the nicotine content of cigarettes. Clinical trials have been limited by non-study cigarette use (noncompliance), which could mask compensation. The goal of this study was to assess whether compensation occurs when smokers provided with very low nicotine cigarettes cannot access normal nicotine cigarettes.MethodsIn a within-subjects, crossover design, current smokers (n = 16) were confined to a hotel for two 4-night hotel stays during which they were only able to access the research cigarettes provided. The hotel stays offered normal nicotine cigarettes or very low nicotine content (VLNC) cigarettes, in an unblinded design, available for "purchase" via a study bank.ResultsIn the context of complete compliance with the study cigarettes (n = 16), there was not a significant increase during the VLNC condition for cigarettes smoked per day, expired carbon monoxide, or N-acetyl-S-(cyanoethyl)-l-cysteine (cyanoethyl-MA, metabolite of acrylonitrile). There was a significant nicotine × time interaction on urine N-acetyl-S-(3-hydroxypropyl)-l-cysteine (hydroxypropyl-MA, metabolite of acrolein), driven by an increase in the VLNC condition during the first 24 hours. By the end of the VLNC condition, there was no evidence of compensation across any measure of smoking or smoke exposure.ConclusionsAmong current smokers who exclusively used VLNC cigarettes for 4 days, there was no significant compensatory smoking behavior.ImpactThese data, combined with the larger body of work, suggest that a mandated reduction in nicotine content is unlikely to result in an increase in smoking behavior to obtain more nicotine.

BackgroundA mandated reduction in the nicotine content of cigarettes could reduce smoking rate and prevalence. However, one concern is that smokers may compensate by increasing the intensity with which they smoke each cigarette to obtain more nicotine. This study assessed whether smokers engage in compensatory smoking by estimating the mouth-level nicotine intake of low nicotine cigarettes smoked during a clinical trial.MethodsSmokers were randomly assigned to receive cigarettes with one of five nicotine contents for 6 weeks. An additional group received a cigarette with the lowest nicotine content, but an increased tar yield. The obtained mouth-level nicotine intake from discarded cigarette butts for a subset of participants (51-70/group) was estimated using solanesol as described previously. A compensation index was calculated for each group to estimate the proportion of nicotine per cigarette recovered through changes in smoking intensity.ResultsThere was no significant increase in smoking intensity for any of the reduced nicotine cigarettes as measured by the compensation index (an estimated 0.4% of the nicotine lost was recovered in the lowest nicotine group; 95% confidence interval, -0.1 to 1.2). There was a significant decrease in smoking intensity for very low nicotine content cigarettes with increased tar yield.ConclusionsReductions in nicotine content did not result in compensatory changes in how intensively participants smoked research cigarettes.ImpactCombined with data from clinical trials showing a reduction in cigarettes smoked per day, these data suggest that a reduction in nicotine content is unlikely to result in increased smoke exposure.

IntroductionBecause 30% of cigarettes sold in the United States are characterized as menthol cigarettes, it is important to understand how menthol preference may affect the impact of a nicotine reduction policy.MethodsIn a recent trial, non-treatment-seeking smokers were randomly assigned to receive very low nicotine cigarettes (VLNC; 0.4 mg nicotine/g tobacco) or normal nicotine cigarettes (NNC; 15.5 mg/g) for 20 weeks. On the basis of preference, participants received menthol or non-menthol cigarettes. We conducted multivariable regression analyses to examine whether menthol preference moderated the effects of nicotine content on cigarettes per day (CPD), breath carbon monoxide (CO), urinary total nicotine equivalents (TNE), urinary 2-cyanoethylmercapturic acid (CEMA), and abstinence.ResultsAt baseline, menthol smokers (n = 346) reported smoking fewer CPD (14.9 vs. 19.2) and had lower TNE (52.8 vs. 71.6 nmol/mg) and CO (17.7 vs. 20.5 ppm) levels than non-menthol smokers (n = 406; ps < .05). At week 20, significant interactions indicated that menthol smokers had smaller treatment effects than non-menthol smokers for CPD (-6.4 vs. -9.3), TNE (ratio of geometric means, 0.22 vs. 0.10) and CEMA (ratio, 0.56 vs. 0.37; ps < .05), and trended toward a smaller treatment effect for CO (-4.5 vs. -7.3 ppm; p = .06). Odds ratios for abstinence at week 20 were 1.88 (95% confidence interval [CI] = 0.8 to 4.4) for menthol and 9.11 (95% CI = 3.3 to 25.2) for non-menthol VLNC smokers (p = .02) relative to the NNC condition.ConclusionsAlthough menthol smokers experienced reductions in smoking, toxicant exposure, and increases in quitting when using VLNC cigarettes, the magnitude of change was smaller than that observed for non-menthol smokers.ImplicationsResults of this analysis suggest that smokers of menthol cigarettes may respond to a nicotine reduction policy with smaller reductions in smoking rates and toxicant exposure than would smokers of non-menthol cigarettes.

AimA previous study showed significantly greater reductions in number of cigarettes smoked and biomarkers of toxicant and carcinogen exposure in smokers assigned to immediate reduction of nicotine in cigarettes to very low levels versus gradually over time or continued smoking of normal nicotine content cigarettes. This study examines the effects of these approaches on selected biomarkers associated with harmful biological effects.DesignThree-arm, randomized controlled trial.SettingTen United States academic institutional sites.ParticipantsDaily smokers uninterested in quitting smoking with a mean age of 45.1 [standard deviation (SD) = 13.4)] years and smoking 17.1 (SD = 8.5) cigarettes/day; 43.9% (549 of 1250) female; 60.6% (758 of 1250) white ethnicity.Interventions(1) Smoking cigarettes where nicotine content was immediately reduced to very low levels (n = 503); (2) smoking cigarettes where nicotine content was gradually reduced, with dose changes occurring monthly (n = 498); and (3) continued smoking with normal nicotine content cigarettes (n = 249).MeasurementsSmokers were assessed at baseline while smoking their usual brand cigarettes, and again at 4, 8, 12, 16 and 20 weeks. Outcomes were areas under the concentration time curve (AUC) for the period of study of biomarkers of inflammation, oxidative stress and hematological parameters.FindingsNo consistent significant differences were observed across groups (Bayes factors showing data to be insensitive), with the only exception being red blood cell size variability, which was observed to be lower in the immediate versus gradual nicotine reduction [mean difference =  -0.11; 95% confidence interval (CI) = -0.18, -0.04, P = 0.004] and normal nicotine control groups (mean difference = - 0.15, 95% CI = -0.23, -0.06, P = 0.001).ConclusionIt remains unclear whether switching to very low nicotine cigarettes leads to a short-term reduction in biomarkers of tobacco-related harm.

Randomized trials seek efficient treatment effect estimation within target populations, yet scientific interest often also centers on subpopulations. Although there are typically too few subjects within each subpopulation to efficiently estimate these subpopulation treatment effects, one can gain precision by borrowing strength across subpopulations, as is the case in a basket trial. While dynamic borrowing has been proposed as an efficient approach to estimating subpopulation treatment effects on primary endpoints, additional efficiency could be gained by leveraging the information found in secondary endpoints. We propose a multisource exchangeability model (MEM) that incorporates secondary endpoints to more efficiently assess subpopulation exchangeability. Across simulation studies, our proposed model almost uniformly reduces the mean squared error when compared to the standard MEM that only considers data from the primary endpoint by gaining efficiency when subpopulations respond similarly to the treatment and reducing the magnitude of bias when the subpopulations are heterogeneous. We illustrate our model's feasibility using data from a recently completed trial of very low nicotine content cigarettes to estimate the effect on abstinence from smoking within three priority subpopulations. Our proposed model led to increases in the effective sample size two to four times greater than under the standard MEM. [ABSTRACT FROM AUTHOR]

The urinary metabolites (Z)-7-[1R,2R,3R,5S)-3,5-dihydroxy-2-[(E,3S)-3-hydroxyoct-1-enyl]cyclopentyl]hept-5-enoic acid (8-iso-PGF2α), an F2-isoprostane and biomarker of oxidative damage, and "prostaglandin E2 metabolite" (PGE-M), a biomarker of inflammation, are elevated in cigarette smokers. However, there is little information in the literature on the longitudinal stability of these widely used biomarkers. In a large clinical trial involving 10 institutional sites, smokers were given, free of charge over a period of 20 weeks, Spectrum NRC600/601 research cigarettes containing 15.5 mg nicotine/g tobacco. All participants were instructed to smoke these cigarettes for the duration of the study. At weeks 4, 8, 12, 16, and 20, first morning urine voids were collected and analyzed for 8-iso-PGF2α and PGE-M using validated liquid chromatography-electrospray ionization-tandem mass spectrometry methods. The mean level of 8-iso-PGF2α at Week 4 was 1.34 ± 1.08 (S.D.) pmol/mg creatinine (N = 226) while that of PGE-M was 73.7 ± 113 (S.D.) pmol/mg creatinine (N = 232). The corresponding levels at Week 20 were 1.35 ± 0.93 (S.D.) pmol/mg creatinine (N = 209) for 8-iso-PGF2α and 74.2 ± 142 (S.D.) pmol/mg creatinine (N = 210) for PGE-M. There was variation in these values in the intervening weeks. The intra-class correlation coefficients (ICC) were 0.51 (95% CI, 0.45, 0.57) and 0.36 (0.30, 0.43), for 8-iso-PGF2α and PGE-M, respectively, indicating fair longitudinal stability for 8-iso-PGF2α and poorer longitudinal stability for PGE-M in cigarette smokers. Males had higher ICC values than females for both 8-iso-PGF2α and PGE-M. These results indicate that, in addition to cigarette smoking, endogenous processes of oxidative damage and inflammation influence the levels of these biomarkers over time among current smokers.

Combustible cigarettes remain the most harmful and addictive tobacco product, and reducing the prevalence of smoking continues to be a critical public health goal. While nicotine is the constituent primarily responsible for addiction to cigarettes, most of the harm associated with smoking comes from byproducts of tobacco combustion. Recently, two different approaches for reducing the harms of smoking have emerged, both of which focus on breaking the link between the addiction to nicotine and the harms caused by smoking. First, the addictive potential of cigarettes could be minimized by requiring a large reduction in the nicotine content of cigarettes. Evidence for a nicotine reduction policy thus far shows that the use of very low nicotine content cigarettes results in a reduction in the number of cigarettes people smoke per day and a reduction in cigarette dependence. Second, emerging alternative nicotine delivery systems (ANDS) like electronic cigarettes may provide sufficient nicotine to act as substitutes for cigarettes while delivering much lower levels of toxicants. Evidence suggests that the emergence of ANDS has increased the percentage of smokers who are able to quit. The present paper will briefly review the evidence for each of these approaches, and consider what contemporary reinforcement and addiction theories can tell us about their likely success. We argue that the most effective endgame approach is one that pursues both nicotine reduction and alternative nicotine delivery systems as complementary.

ObjectiveFoetuses and neonates of women who use tobacco are exposed to nicotine and tobacco-derived carcinogens. We determined the relationship between urine biomarkers of tobacco toxicant exposure postpartum and in the neonates of Alaska Native (AN) women, comparing smokers and smokeless tobacco (ST) users, including iqmik, a homemade ST product.MethodsAN women, including 36 smokers, 9 commercial ST and 16 iqmik users their neonates participated. Urine from the woman at the time of delivery and her neonate's first urine were analysed for cotinine, the major metabolite of nicotine, and 4-(methylnitrosamino)-1-(3) pyridyl-1-butanol (NNAL), a tobacco-specific carcinogen biomarker.ResultsMaternal urine cotinine and neonatal urine cotinine were strongly correlated in all tobacco use groups (r from 0.83 to 0.9, p

ImportanceThe optimal temporal approach for reducing nicotine to minimally or nonaddictive levels in all cigarettes sold in the United States has not been determined.ObjectivesTo determine the effects of immediate vs gradual reduction in nicotine content to very low levels and as compared with usual nicotine level cigarettes on biomarkers of toxicant exposure.Design, setting, and participantsA double-blind, randomized, parallel-design study with 2 weeks of baseline smoking and 20 weeks of intervention was conducted at 10 US sites. A volunteer sample of daily smokers with no intention to quit within 30 days was recruited between July 2014 and September 2016, with the last follow-up completed in March 2017.Interventions(1) Immediate reduction to 0.4 mg of nicotine per gram of tobacco cigarettes; (2) gradual reduction from 15.5 mg to 0.4 mg of nicotine per gram of tobacco cigarettes with 5 monthly dose changes; or (3) maintenance on 15.5 mg of nicotine per gram of tobacco cigarettes.Main outcomes and measuresBetween-group differences in 3 co-primary biomarkers of smoke toxicant exposure: breath carbon monoxide (CO), urine 3-hydroxypropylmercapturic acid (3-HPMA, metabolite of acrolein), and urine phenanthrene tetraol (PheT, indicator of polycyclic aromatic hydrocarbons) calculated as area under the concentration-time curve over the 20 weeks of intervention.ResultsAmong 1250 randomized participants (mean age, 45 years; 549 women [44%]; 958 [77%] completed the trial), significantly lower levels of exposure were observed in the immediate vs gradual reduction group for CO (mean difference, -4.06 parts per million [ppm] [95% CI, -4.89 to -3.23]; P

The 2014 Surgeon General's Report on smoking and health concluded that changing cigarette designs have caused an increase in lung adenocarcinomas, implicating cigarette filter ventilation that lowers smoking machine tar yields. The Food and Drug Administration (FDA) now has the authority to regulate cigarette design if doing so would improve public health. To support a potential regulatory action, two weight-of-evidence reviews were applied for causally relating filter ventilation to lung adenocarcinoma. Published scientific literature (3284 citations) and internal tobacco company documents contributed to causation analysis evidence blocks and the identification of research gaps. Filter ventilation was adopted in the mid-1960s and was initially equated with making a cigarette safer. Since then, lung adenocarcinoma rates paradoxically increased relative to other lung cancer subtypes. Filter ventilation 1) alters tobacco combustion, increasing smoke toxicants; 2) allows for elasticity of use so that smokers inhale more smoke to maintain their nicotine intake; and 3) causes a false perception of lower health risk from "lighter" smoke. Seemingly not supportive of a causal relationship is that human exposure biomarker studies indicate no reduction in exposure, but these do not measure exposure in the lung or utilize known biomarkers of harm. Altered puffing and inhalation may make smoke available to lung cells prone to adenocarcinomas. The analysis strongly suggests that filter ventilation has contributed to the rise in lung adenocarcinomas among smokers. Thus, the FDA should consider regulating its use, up to and including a ban. Herein, we propose a research agenda to support such an effort.

Early life adversity (ELA) is associated with earlier initiation and maintenance of tobacco smoking and with a greater risk of subsequent relapse. There is growing evidence that appetite hormones, including peptide YY (PYY), which modulates craving and satiety responses, play a role in stress and addiction processes. This study employed a quasi‐experimental design to examine the association between ELA and circulating PYY stress responses in smokers and nonsmokers (N = 152, ages 19–73 years) to examine the effects of nicotine addiction. Smokers initiated a quit attempt as part of the study and were classified as either abstinent smokers or relapsed smokers based on their nicotine use during the follow‐up period. PYY levels were measured at five timepoints during three lab sessions and compared between nonsmokers and the two smoking groups (abstainers, relapsers): while smokers were using nicotine ad libitum, 24 h after smokers initiated a quit attempt, and 4 weeks after smokers initiated a quit attempt. Multivariate analyses showed the main effects of time on PYY, which decreased over time within each session. The main effects of ELA during the first (ad libitum smoking) and second (24‐h post‐cessation for smokers) sessions indicated that experiencing ELA was associated with lower PYY. No systematic effect of nicotine addiction or relapse was observed in this study. These findings suggest that adults with higher ELA may experience lower PYY. Additional research is needed to further explore the role of PYY in stress and addiction processes. [ABSTRACT FROM AUTHOR]

Background: The adequacy of biomarkers of potential harm (BOPH) for assessing tobacco products was explored based on their ability to distinguish tobacco use from non-use, change with cessation, and to show biological gradient. Methods: The sample included individuals with biomarker data in wave 1 of the Population Assessment of Tobacco Health study who never used tobacco, currently smoke cigarettes exclusively, used to smoke cigarettes exclusively (quit in past 12 months), currently use smokeless tobacco exclusively, and currently use e-cigarettes exclusively. We compared BOPH levels between groups and assessed the relationships between log-transformed biomarkers of exposure [BOE; total nicotine equivalents including seven nicotine metabolites (TNE-7), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanonol (NNAL), N-acetyl-S-(2-cyanoethyl)-L-cysteine, 1-hydroxypyrene, cadmium, and serum cotinine (SCOT)], and BOPH [high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), fibrinogen, soluble intercellular adhesion molecule-1 (sICAM-1), and 8-isoprostane]. Results: Among people who smoke, both sICAM-1 and 8-isoprostane distinguished smoking from non-use and were associated with all six BOE. Among people who use smokeless tobacco, 8-isoprostane was associated with TNE-7 and NNAL whereas hs-CRP was associated with SCOT. Among people who use e-cigarettes, no associations between BOPH and BOE were observed. Conclusions: Both sICAM-1 and 8-isoprostane may be useful for assessing the use or changes in use of some tobacco products. Studies examining their predictive validity could further strengthen our understanding of these two biomarkers. [ABSTRACT FROM AUTHOR]

The reduced nicotine content cigarette and the emergence of non-combusted nicotine products like e-cigarettes should be viewed not as alternatives but as complementary components of regulatory interventions that could virtually end combusted tobacco use.

BackgroundThe FDA recently acquired regulatory authority over tobacco products, leading to renewed interest in whether reducing the nicotine content of cigarettes would reduce tobacco dependence in the United States. Given the association between depressive symptoms and cigarette smoking, it is important to consider whether smokers with elevated depressive symptoms experience unique benefits or negative consequences of nicotine reduction.MethodsIn this secondary analysis of a randomized clinical trial that examined the effects of cigarettes varying in nicotine content over a 6-week period in non-treatment-seeking smokers, we used linear regression to examine whether baseline depressive symptom severity (scores on the Center for Epidemiologic Studies Depression Scale [CES-D]) moderated the effects of reduced-nicotine content (RNC) cigarettes, relative to normal-nicotine content (NNC) cigarettes, on smoking rates, depressive symptom severity, and related subjective and physiological measures.ResultsOf the 717 participants included in this analysis, 109 (15.2%) had CES-D scores ≥ 16, indicative of possible clinical depression. Relative to NNC cigarettes, RNC cigarettes reduced smoking rates, nicotine dependence, and cigarette craving, and these effects were not significantly moderated by baseline CES-D score. A significant interaction between baseline CES-D score and cigarette condition on week 6 CES-D score was observed (p < .05); among those with CES-D scores ≥ 16 at baseline, those assigned to RNC cigarettes had lower week 6 CES-D scores than those assigned to NNC cigarettes. Among those in the lowest nicotine content conditions, biochemically confirmed compliance with the RNC cigarettes was associated with an increase in CES-D score for those with baseline CES-D scores < 16 and no change in CES-D score for those with baseline CES-D scores ≥ 16.ConclusionsThese findings provide initial evidence that a reduced-nicotine standard for cigarettes may reduce smoking, without worsening depressive symptoms, among smokers with elevated depressive symptoms.ImplicationsThis secondary analysis of a recent clinical trial examined whether depressive symptom severity moderated the effects of reduced-nicotine cigarettes on smoking and depressive symptoms. Results indicate that, regardless of baseline depressive symptoms, participants randomized to reduced-nicotine cigarettes had lower smoking rates, nicotine intake, nicotine dependence, and craving at week 6 post-randomization than those assigned to normal-nicotine cigarettes. In participants with higher baseline depressive symptoms, those assigned to reduced-nicotine cigarettes had lower week 6 depressive symptoms than those assigned to normal-nicotine cigarettes. These results suggest that a nicotine reduction policy could have beneficial effects for smokers, regardless of depressive symptom severity.

Background and aimsClinical trials on the impact and safety of reduced nicotine content cigarettes (RNCs) are ongoing, and an important methodological concern is participant compliance with smoking only RNCs. Our aims were to measure non-compliance biochemically with urine cotinine (COT) and total nicotine equivalents (TNEs), compare with self-reported non-compliance and identify associated covariates.DesignSecondary analysis of a double-blind, parallel, randomized clinical trial.SettingResearch centers from the United States, enrolling participants from June 2013 to July 2014.ParticipantsVolunteer sample of 242 participants (55% Caucasian), average age of 41.2 years, smoking at least five cigarettes per day (CPD).InterventionSmoking very low nicotine cigarettes (VLNCs; 0.4 mg nicotine/g tobacco) for 6 weeks.MeasurementsThe primary outcome was biochemically verified non-compliance, measured as thresholds of COT/CPD and TNE/CPD ratios, considering changes in nicotine content from conventional levels to VLNCs, and as an absolute threshold of week 6 TNEs. Self-reported non-compliance was measured via daily phone calls. Key predictors included age, sex, race, menthol preference, nicotine metabolite ratio, time to first cigarette, dependence, CPD, TNEs, tar level and cigarette evaluation.FindingsEstimates of non-compliance with smoking the VLNCs exclusively include: the biochemical ratios (both 78%), the week 6 TNE threshold (76%) and self-report (39%). Of the key covariates, age, dependence and cigarette evaluations of satisfaction were significant; for age, younger participants more likely to be non-compliant [P = 0.01; odds ratio (OR) = 0.98, 95% confidence interval (CI) = 0.96-0.99]. Dependence was associated significantly with self-reported non-compliance (P = 0.01; OR = 1.28, 95% CI = 1.06-1.55). Cigarette evaluations of satisfaction were associated significantly with non-compliance (P = 0.001; OR = 0.71, 95% CI = 0.61-0.82).ConclusionsAmong smokers volunteering to smoke only very low nicotine cigarettes for 6 weeks, non-compliance was common and biochemical assessments detected more cases of non-compliance than self-report. Despite high levels of non-compliance, smokers reduced their intake of nicotine by an average of 60%.