Search

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.

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.

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.

The available research on switching from normal nicotine to very low nicotine content cigarettes shows minimal evidence of compensatory smoking. Mathematical estimations suggest that substantial compensation after switching to very low nicotine cigarettes would be impossible. It is likely that smokers who are unable to tolerate the extent of proposed nicotine reduction would switch to other sources of nicotine, rather than try to compensate by smoking more very low nicotine content cigarettes more intensely.

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.

The urinary metabolites cyanoethyl mercapturic acid (CEMA) and 3-hydroxypropyl mercapturic acid (3-HPMA) have been widely used as biomarkers of exposure to acrylonitrile and acrolein, respectively, but there are no published data on their consistency over time in the urine of cigarette smokers. We provided, free of charge over a 20 week period, Spectrum NRC600/601 research cigarettes to cigarette smokers in the control arm of a randomized clinical trial of the reduced nicotine cigarette. Urine samples were collected at weeks 4, 8, 12, 16, and 20 and analyzed for CEMA and 3-HPMA, and total nicotine equivalents (TNE) using validated methods. Creatinine-corrected intra-class correlation coefficients for CEMA, 3-HPMA, and TNE were 0.67, 0.46, and 0.68, respectively, indicating good longitudinal consistency for CEMA, while that of 3-HPMA was fair. A strong correlation between CEMA and TNE values was observed. These data support the use of CEMA as a reliable biomarker of tobacco smoke exposure. This is the first report of the longitudinal stability of the biomarkers of acrylonitrile and acrolein exposure in smokers. The data indicate that CEMA, the biomarker of acrylonitrile exposure, is consistent over time in cigarette smokers, supporting its use. While 3-HPMA levels were less stable over time, this biomarker is nevertheless a useful monitor of human acrolein exposure because of its specificity to this toxicant.

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.

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

In the United States, the Food and Drug Administration (FDA) has initiated a public dialogue about reducing the nicotine content of cigarettes. A reduced-nicotine standard could increase withdrawal symptoms among current smokers. We examined the impact of switching smokers to cigarettes that varied in nicotine content on withdrawal symptoms over 6 weeks. A secondary analysis (N = 839) of a 10-site, double-blind clinical trial of nontreatment-seeking smokers was completed. Participants were instructed to smoke study cigarettes, containing 0.4 to 15.8 mg of nicotine/g of tobacco, for 6 weeks and were then abstinent overnight. Using latent growth curves, trajectories of individual withdrawal symptoms were compared between the reduced nicotine content (RNC) conditions and a normal nicotine content (NNC) condition. Path analyses compared symptoms after overnight abstinence. Relative to NNC cigarettes, participants smoking RNC cigarettes had increased anger/irritability/frustration and increased appetite/weight gain during the initial weeks, but the symptoms resolved by Week 6. Individuals who were biochemically verified as adherent with using only the 0.4 mg/g cigarettes had higher sadness levels (Cohen's d = .40) at Week 6 compared with the NNC condition, although symptoms were mild. After a post-Week 6 overnight abstinence challenge, some RNC conditions relative to NNC condition exhibited reduced withdrawal. Individuals who were biochemically confirmed as adherent to the lowest nicotine condition experienced only mild and transient symptom elevations. Thus, a reduced-nicotine standard for cigarettes produced a relatively mild and temporary increase in withdrawal among nontreatment-seeking smokers (ClinicalTrials.gov No. NCT01681875). (PsycINFO Database Record

RationaleThe ability of nicotine to suppress body weight is cited as a factor impacting smoking initiation and the failure to quit. Self-administered nicotine in male rats suppresses weight independent of food intake, suggesting that nicotine increases energy expenditure.ObjectiveThe current experiment evaluated the impact of self-administered nicotine on metabolism in rats using indirect calorimetry and body composition analysis.MethodsAdult male rats with ad libitum access to powdered standard rodent chow self-administered intravenous infusions of nicotine (60 μg/kg/infusion or saline control) in daily 1-h sessions in the last hour of the light cycle. Indirect calorimetry measured respiratory exchange ratio (RER), energy expenditure, motor activity, and food and water consumption for 22.5 h between select self-administration sessions.ResultsSelf-administered nicotine suppressed weight gain and reduced the percent of body fat without altering the percent of lean mass, as measured by Echo MRI. Nicotine reduced RER, indicating increased fat utilization; this effect was observed prior to weight suppression. Moreover, nicotine intake did not affect motor activity or energy expenditure. Daily food intake was not altered by nicotine self-administration; however, a trend in suppression of meal size, a transient suppression of water intake, and an increase in meal frequency was observed.ConclusionThese data provide evidence that self-administered nicotine suppresses body weight via increased fat metabolism, independent of significant changes in feeding, activity, or energy expenditure.

BackgroundThe Food and Drug Administration can reduce the nicotine content in cigarettes to very low levels. This potential regulatory action is hypothesised to improve public health by reducing smoking, but may have unintended consequences related to weight gain.MethodsWeight gain was evaluated from a double-blind, parallel, randomised clinical trial of 839 participants assigned to smoke 1 of 6 investigational cigarettes with nicotine content ranging from 0.4 to 15.8 mg/g or their own usual brand for 6 weeks. Additional analyses evaluated weight gain in the lowest nicotine content cigarette groups (0.4 and 0.4 mg/g, high tar) to examine the effect of study product in compliant participants as assessed by urinary biomarkers. Differences in outcomes due to gender were also explored.FindingsThere were no significant differences in weight gain when comparing the reduced nicotine conditions with the 15.8 mg/g control group across all treatment groups and weeks. However, weight gain at week 6 was negatively correlated with nicotine exposure in the 2 lowest nicotine content cigarette conditions. Within the 2 lowest nicotine content cigarette conditions, male and female smokers biochemically verified to be compliant on study product gained significantly more weight than non-compliant smokers and control groups.ConclusionsThe effect of random assignment to investigational cigarettes with reduced nicotine on weight gain was likely obscured by non-compliance with study product. Men and women who were compliant in the lowest nicotine content cigarette conditions gained 1.2 kg over 6 weeks, indicating weight gain is a likely consequence of reduced exposure to nicotine.Trial registration numberNCT01681875, Post-results.

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%.

Objectives:Research using very low nicotine content (VLNC) cigarettes has shown that participants underreport use of non-study cigarettes. Biomarkers of nicotine exposure could be used to verify compliance with VLNC cigarettes. This study aimed to characterize biomarkers of exposure when participants exclusively use VLNC cigarettes. Methods:23 participants stayed in a hotel that permitted smoking for 5 days and 4 nights. They were provided 2 packs of VLNC cigarettes each day (0.4 mg of nicotine/g of tobacco; Spectrum cigarettes) and did not have access to other tobacco products. 24-hour urine samples were collected to assess exposure to nicotine and anatabine. Results:After 4 days of exclusive use, the geometric means for urinary total cotinine, total nicotine equivalents (TNE), and anatabine were 1.13 nmol/ml (92% reduction), 3.17 nmol/ml (94% reduction) and 0.0031 nmol/ml (93% reduction). The population estimates of the 95th percentile of cotinine, TNE, and anatabine levels were 2.69, 6.41, and 0.0099 nmol/ml, respectively. Conclusions:Study participants exclusively smoking 0.4 mg/g Spectrum cigarettes are unlikely to have biomarker values above these levels. The data presented here will be valuable to researchers conducting research on use of VLNC cigarettes.

BackgroundThe Food and Drug Administration can set standards that reduce the nicotine content of cigarettes.MethodsWe conducted a double-blind, parallel, randomized clinical trial between June 2013 and July 2014 at 10 sites. Eligibility criteria included an age of 18 years or older, smoking of five or more cigarettes per day, and no current interest in quitting smoking. Participants were randomly assigned to smoke for 6 weeks either their usual brand of cigarettes or one of six types of investigational cigarettes, provided free. The investigational cigarettes had nicotine content ranging from 15.8 mg per gram of tobacco (typical of commercial brands) to 0.4 mg per gram. The primary outcome was the number of cigarettes smoked per day during week 6.ResultsA total of 840 participants underwent randomization, and 780 completed the 6-week study. During week 6, the average number of cigarettes smoked per day was lower for participants randomly assigned to cigarettes containing 2.4, 1.3, or 0.4 mg of nicotine per gram of tobacco (16.5, 16.3, and 14.9 cigarettes, respectively) than for participants randomly assigned to their usual brand or to cigarettes containing 15.8 mg per gram (22.2 and 21.3 cigarettes, respectively; P

Reducing the addictiveness of cigarettes by reducing their nicotine content can potentially have a profound impact on public health. Two different approaches to nicotine reduction have been proposed: gradual and immediate. To determine if either of these approaches results in significant compensatory smoking behavior, which might lead to safety concerns, we performed a secondary analysis of data from studies that have utilized these two approaches. The number of cigarettes smoked per day, carbon monoxide exposure, and cotinine levels in plasma or urine were assessed while participants smoked reduced nicotine content cigarettes and compared with when they smoked their usual brand cigarettes. The results showed that in general, these two approaches led to minimal compensatory smoking and reduced levels of cotinine over the course of the experimental period, suggesting that neither of these approaches poses a major safety concern.

BackgroundThe reduction of the nicotine content of cigarettes to nonaddicting levels is a potential federal regulatory intervention to reduce the prevalence of cigarette smoking and related disease. Many clinical trials on the effects and safety of nicotine reduction are ongoing. An important methodologic concern is noncompliance with reduced nicotine content cigarettes in the context of freely available conventional cigarettes. We propose two approaches using biomarkers to estimate noncompliance in smokers of very low nicotine content (VLNC) cigarettes in a clinical trial.MethodsData from 50 subjects in a study of gradual nicotine reduction were analyzed. Using plasma cotinine concentrations measured at baseline and while smoking VLNC cigarettes, we compared within-subject ratios of plasma cotinine comparing usual brand to VLNC in relation to nicotine content of these cigarettes. In another approach, we used nicotine pharmacokinetic data to estimate absolute plasma cotinine/cigarettes per day (CPD) threshold values for compliance based on the nicotine content of VLNC.ResultsThe two approaches showed concordance, indicating at least 60% noncompliance with smoking VLNC. In a sensitivity analysis assuming extreme compensation and extreme values for nicotine metabolic parameters, noncompliance was still at least 40%, much higher than self-reported noncompliance.ConclusionBiomarker analysis demonstrates a high degree of noncompliance with smoking VLNC cigarettes, indicating that smokers are supplementing these with conventional cigarettes.ImpactWe propose a practical approach to assessing compliance with smoking VLNC in clinical trials of nicotine reduction.

IntroductionBoth the Tobacco Control Act in the U.S. and Article 9 of the Framework Convention on Tobacco Control enable governments to directly address the addictiveness of combustible tobacco by reducing nicotine through product standards. Although nicotine may have some harmful effects, the detrimental health effects of smoked tobacco are primarily due to non-nicotine constituents. Hence, the health effects of nicotine reduction would likely be determined by changes in behavior that result in changes in smoke exposure.MethodsHerein, we review the current evidence on nicotine reduction and discuss some of the challenges in establishing the empirical basis for regulatory decisions.ResultsTo date, research suggests that very low nicotine content cigarettes produce a desirable set of outcomes, including reduced exposure to nicotine, reduced smoking, and reduced dependence, without significant safety concerns. However, much is still unknown, including the effects of gradual versus abrupt changes in nicotine content, effects in vulnerable populations, and impact on youth.DiscussionA coordinated effort must be made to provide the best possible scientific basis for regulatory decisions. The outcome of this effort may provide the foundation for a novel approach to tobacco control that dramatically reduces the devastating health consequences of smoked tobacco.