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Research on tobacco use disorder relies on a combination of self-reported use (e.g., cigarettes per day) and biochemical validation to quantify heaviness of use. However, electronic nicotine delivery system (ENDS) users may be unaware of how much they have vaped per day. The aim of this study was to test the relationship between self-reported heaviness of ENDS/tobacco use and nicotine biomarkers. Young adults (

Introduction The FDA proposed rule-making to reduce nicotine in cigarettes to minimally addictive levels. Research suggests decreasing nicotine levels (i.e. very low nicotine content cigarettes [VLNCs]) produced greater quit attempts, reduced smoking, and reduced exposure to harmful constituents among smokers. The impact of long-term VLNC use among people who co-use cigarettes and cannabis on non-tobacco-specific toxicant and carcinogen exposure has not been investigated. Aims and Methods This study presents secondary analyses of a controlled clinical trial examining switching to VLNC (versus a normal nicotine cigarettes control group [NNCs]) between people who co-use cigarettes and cannabis (n = 174) versus smoked cigarettes (n = 555). Linear mixed-effects models compared changes in smoking behavior, and tobacco-specific (i.e. total nicotine equivalents [TNE], 4-[methylnitrosamino]-1-[3-pyridyl]-1-butanone [NNK; total NNAL]) and non-tobacco-specific (i.e. carbon monoxide (CO), 2-cyanoethylmercapturic acid [CEMA], phenanthrene tetraol [PheT]) toxicant and carcinogen exposure at week 20 (with random intercept for participants). Cannabis use was measured among co-use groups. Results CO was significantly lower only among the cigarette-only group assigned VLNCs (interaction: p = .015). Although both VLNC groups demonstrated decreased CEMA, greater decreases emerged among the cigarette-only group (interaction: p = .016). No significant interactions emerged for TNE, cigarettes per day (CPD), NNAL, and PheT (ps > .05); both VLNC groups decreased in TNE, CPD, and NNAL. Only the cigarette-only group assigned VLNCs demonstrated decreased PheT (p < .001). The VLNC co-use group showed increased cannabis use over time (p = .012; 0.5 more days per week by week 20). Conclusions Those who co-use cannabis and cigarettes may still be at risk for greater exposure to non-tobacco-specific toxicants and carcinogens compared to those who only smoke cigarettes. Implications The present study is the longest longitudinal, prospective comparison study of smoking behavior and exposure to harmful constituents among those who co-use cigarettes and cannabis versus cigarette-only after immediately switching to very low nicotine content cigarettes (VLNC). Those who co-use experienced similar reductions in CPD and tobacco-specific exposure, compared to those who only use cigarettes. However, co-use groups experienced smaller reductions in non-tobacco-specific toxicants and carcinogens compared to the cigarette-only group, potentially because of combustible cannabis use. Additionally, those who co-use and switched to VLNC may be susceptible to slight increases in cannabis use (approximately two more days per year).

Individual participant data meta-analysis is a frequently used method to combine and contrast data from multiple independent studies. Bayesian hierarchical models are increasingly used to appropriately take into account potential heterogeneity between studies. In this paper, we propose a Bayesian hierarchical model for individual participant data generated from the Cigarette Purchase Task (CPT). Data from the CPT details how demand for cigarettes varies as a function of price, which is usually described as an exponential demand curve. As opposed to the conventional random-effects meta-analysis methods, Bayesian hierarchical models are able to estimate both the study-specific and population-level parameters simultaneously without relying on the normality assumptions. We applied the proposed model to a meta-analysis with baseline CPT data from six studies and compared the results from the proposed model and a two-step conventional random-effects meta-analysis approach. We conducted extensive simulation studies to investigate the performance of the proposed approach and discussed the benefits of using the Bayesian hierarchical model for individual participant data meta-analysis of demand curves.

Introduction US FDA issued an advance notice of proposed rulemaking to reduce nicotine in cigarettes. To maximize the benefits of this potential standard, very low nicotine content (VLNC) cigarettes must be communicated in a way that does not result in misperceptions. Aims and Methods Adults (n = 567 who smoke; n = 610 non-smokers) from an online platform were randomized to a control message previously associated with accurate addictiveness perceptions of VLNC cigarettes but health misperceptions or to one of five messages that also included messaging on nicotine morbidity effects or VLNC cigarettes morbidity or mortality effects. p value Results In participants who smoke, perceived lung cancer risk (responses: 1, very little risk to 10, very high risk) if smoked VLNC cigarettes regularly was higher in conditions that communicated mortality effects of VLNC cigarettes compared to the control (7.12–7.18 vs. 5.97, p values < .01). In non-smokers, perceived lung cancer risk was higher in all five message conditions when compared with the control (7.58–8.22 vs. 6.35, p values < .01). Proportion who responded accurately (ie, False) to the statement Cigarettes with 95% less nicotine are safer than cigarettes with normal nicotine levels was higher in conditions describing VLNC morbidity or mortality effects when compared with the control in both participants who smoke (52.04–67.37% vs. 30.85%, p values < .01) and do not smoke (62.50–72.38% vs. 32.00%, p values < .01). Conclusions Messaging on mortality effects of VLNC cigarettes (ie, cigarettes with 95% less nicotine are as deadly as current cigarettes) was associated with more accurate perceptions of the health risks of VLNC cigarettes than the control; however, misperceptions remained in one-third of participants. Implications One approach to communicating a VLNC cigarette standard to the public is to include messaging on the mortality effects of VLNC cigarettes. However, further study and possible refinement of this message condition are recommended since approximately one-third of participants exposed to this message still perceived VLNC cigarettes to be safer than normal nicotine content cigarettes.

Background: The 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.Methods: Data 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.Results: The 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.Conclusion: Biomarker analysis demonstrates a high degree of noncompliance with smoking VLNC cigarettes, indicating that smokers are supplementing these with conventional cigarettes.Impact: We propose a practical approach to assessing compliance with smoking VLNC in clinical trials of nicotine reduction. Cancer Epidemiol Biomarkers Prev; 24(2); 331–5. ©2014 AACR.

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. Cancer Epidemiol Biomarkers Prev; 24(2); 472–6. ©2014 AACR.

Supplemental Table 1. Mean (SE) of ratio of reduced nicotine cigarette (RNC) divided by baseline usual brand cigarette (UBC) values for cigarettes per day (CPD), carbon monoxide (CO) and cotinine, respectively. For studies that had a control group of UBC, the ratio of UBC during study period divided by baseline UBC values for CPD, CO and cotinine and also the ratio of RNC/baseline UBC divided by the ratio of UBC during study/baseline UBC (Ratio: RNC/UBC).

Supplementary Table 1. Biochemical Measures of Compliance: Data from Individual Subjects

Introduction A nicotine product standard reducing the nicotine content in cigarettes could improve public health by reducing smoking. This study evaluated the potential unintended consequences of a reduced nicotine product standard by examining its effects on (1) smoking behaviors based on drinking history; (2) drinking behavior; and (3) daily associations between smoking and drinking. Methods Adults who smoke daily (n = 752) in the United States were randomly assigned to smoke very low nicotine content (VLNC) cigarettes versus normal nicotine content (NNC; control) cigarettes for 20 weeks. Linear mixed models determined if baseline drinking moderated the effects of VLNC versus NNC cigarettes on Week 20 smoking outcomes. Time-varying effect models estimated the daily association between smoking VLNC cigarettes and drinking outcomes. Results Higher baseline alcohol use (vs no use or lower use) was associated with a smaller effect of VLNC on Week 20 urinary total nicotine equivalents (ps < .05). No additional moderation was supported (ps > .05). In the subsample who drank (n = 415), in the VLNC versus NNC condition, daily alcohol use was significantly reduced from Weeks 17 to 20 and odds of binge drinking were significantly reduced from Weeks 9 to 17. By Week 7, in the VLNC cigarette condition (n = 272), smoking no longer predicted alcohol use but remained associated with binge drinking. Conclusions We did not support negative unintended consequences of a nicotine product standard. Nicotine reduction in cigarettes generally affected smoking behavior for individuals who do not drink or drink light-to-moderate amounts in similar ways. Extended VLNC cigarette use may improve public health by reducing drinking behavior. Implications There was no evidence that a VLNC product standard would result in unintended consequences based on drinking history or when considering alcohol outcomes. Specifically, we found that a very low nicotine standard in cigarettes generally reduces smoking outcomes for those who do not drink and those who drink light-to-moderate amounts. Furthermore, an added public health benefit of a very low nicotine standard for cigarettes could be a reduction in alcohol use and binge drinking over time. Finally, smoking VLNC cigarettes may result in a decoupling of the daily associations between smoking and drinking.

Introduction As the FDA works to determine whether a nicotine reduction policy would benefit public health, one key question is whether to mandate an immediate or gradual reduction in nicotine levels in cigarettes. The aim of this study was to determine whether the effects of gradual versus immediate nicotine reduction on cigarettes per day (CPD), total nicotine equivalents, and subjective responses differed in younger adults versus older adults. Methods Using data from a recent randomized trial conducted in the United States (N = 1250) that switched smokers over a 20-week period to very low nicotine content (VLNC) cigarettes either immediately, gradually (via monthly reductions in nicotine content), or not at all (control condition, normal nicotine content research cigarette), we analyzed the moderating effect of age (age 18–24 or 25+). Results For both age groups, CPD in the immediate condition was significantly lower relative to gradual condition (estimated mean difference of 6.3 CPD in young adults, 5.2 CPD in older adults; p’s < .05). Younger and older adults in the immediate and gradual reduction conditions had lower total nicotine equivalents at Week 20 (all p’s < .05) than those in the control condition; age group did not moderate this effect. Positive subjective responses to cigarettes were lower among young adults relative to older adults in the immediate condition. Conclusions These results indicate that an immediate reduction in nicotine would result in beneficial effects in both young and older adults. Young adults show less positive subjective effects of smoking following switching to VLNC cigarettes relative to older adults. Implications As researchers work to understand how a potential reduced-nicotine product standard for cigarettes may affect public health, one question is whether nicotine should be reduced immediately or gradually. This study demonstrates that both young and older adults who were switched immediately to the lowest content of nicotine smoked fewer CPD and had lower nicotine intake than those in the gradual condition. Furthermore, young adults appear to show lower positive subjective effects following switching to VLNC cigarettes relative to older adults. This is consistent with previous work demonstrating that young people appear to show lower abuse liability for VLNC cigarettes.

Background: Lowering nicotine in cigarettes may reduce smoking prevalences; however, it is not known whether an immediate or gradual reduction in nicotine is the optimal approach for all population groups. Objectives: We examined whether the optimal approach to nicotine reduction depended on the education, gender, or race of people who smoke and whether the optimal approach differentially benefited people who smoke based on their education, gender, or race. Methods: Secondary analysis was conducted on a randomized clinical trial (N = 1250) comparing (1) immediate reduction from 15.5 to 0.4 mg of nicotine per gram of tobacco (mg/g);(2) gradual reduction to 0.4 mg/g;(3) control group with normal nicotine cigarettes(15.5 mg/g). Outcomes included cigarettes per day(CPD), carbon monoxide(CO), total nicotine equivalents(TNE), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides(NNAL), phenanthrene tetraol(PheT), N-Acetyl-S-(2-cyanoethyl)-L-cysteine(CEMA). Data were analyzed as area under the curve(AUC). Results: Results were presented by education (High school [HS] or less n = 505, more than HS n = 745), gender (males n = 701, females n = 549), and race (Black participants n = 373,White participants n = 758). Regardless of education, gender, and race, CPD, CO, TNE, NNAL, PheT, and CEMA were lower in immediate versus gradual nicotine reduction. Comparing immediate versus the control, outcomes were lower for all subgroups; however, the magnitude of the effect for TNE varied by race. Specifically, geometric mean of the AUC of TNE in immediate versus gradual was 49 % lower in Black participants and 61 % lower in White participants (p-value = 0.047). Conclusions: Immediately reducing nicotine in cigarettes has the potential to benefit people who smoke across lower and higher educational attainment, male and female gender, and Black and White race.

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.

RATIONALE: Reducing nicotine content in cigarettes to ≤ 2.4 mg per g of tobacco [mg/g] reduces smoking behavior and toxicant exposure among adult daily smokers. However, cigarettes with similar nicotine content could support continued experimentation and smoking progression among young adults who smoke infrequently. OBJECTIVES: This study evaluated the threshold for nicotine in cigarettes that produces reactions associated with smoking progression in a sample of young adults who smoke infrequently. METHODS: Young adults (n=87, 18-25 years, 49% female) using tobacco products ≤15 days per month completed three counterbalanced, double-blinded sessions, each measuring Positive and Negative subjective reactions to fixed doses of smoke from investigational cigarettes containing one of three different nicotine contents: normal (NNC; 15.8 mg/g); very low (VLNC; 0.4 mg/g); and intermediate (INC; 2.4 mg/g). In a final session, participants chose one of the cigarettes to self-administer. RESULTS: Post-cigarette breath carbon monoxide was greater for VLNC than for NNC (p

Objectives: When examining the relationship between smoking intensity and toxicant exposure biomarkers, 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. Methods: We used baseline data from a randomized trial (N = 1250) to estimate the relationship between smoking intensity and a latent toxicant exposure variable summarizing 5 volatile organic compound biomarkers. We analyzed 2 variables of smoking intensity: 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 5 biomarkers. Results: SEM 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. Conclusions: SEM 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.

Introduction In 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 Methods Sixteen 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). Results Average 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. Conclusion Average puffing intensity per cigarette was elevated with exclusive VLNC cigarette use, but the extent of this effect declined across four days. Implications In 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 United States Food and Drug Administration has the authority to reduce the nicotine content in cigarettes to minimal or non-addictive levels and could do so immediately or gradually over time. A large clinical trial compared the two approaches. This secondary analysis assesses abstinence and cessation-related outcomes one month after the trial concluded, when participants no longer had access to very low nicotine content (VLNC) research cigarettes. Smokers not interested in quitting (N = 1250) were recruited for the parent trial from 2014 to 2016 across 10 sites throughout the US and randomized to a 20-week study period during which they immediately switched to VLNC cigarettes, gradually transitioned to VLNC cigarettes with five monthly dose reductions, or smoked normal nicotine research cigarettes (control). At the one-month follow-up, both immediate and gradual reduction resulted in greater mean cigarette-free days (4.7 and 4.6 respectively) than the control group (3.2, both p .05). Immediate reduction resulted in fewer mean cigarettes per day (CPD = 10.3) and lower Fagerström Test for Cigarette Dependence (FTCD = 3.7) than the gradual (CPD = 11.7, p = .001; FTCD = 3.8, p = .039) and control (CPD = 13.5, p .001; FTCD = 4.0, p .001) groups. Compared to controls, gradual reduction resulted in reduced CPD (p = .012) but not FTCD (p = .13). Differences in CO-verified 7-day point-prevalence abstinence were not significant. Findings demonstrate that switching to VLNC cigarettes resulted in reduced smoking and nicotine dependence severity that was sustained for at least a month after the VLNC trial period in smokers who were not interested in cessation. The greatest harm reduction endpoints were observed in those who immediately transitioned to VLNC cigarettes.

Background: Cotinine is the most widely used biomarker of tobacco exposure. At similar smoking levels, African Americans have higher serum cotinine than Whites. UGT2B10-catalyzed cotinine glucuronidation impacts these levels, and African Americans often have low UGT2B10 activity due to a high prevalence of a UGT2B10 splice variant (rs2942857). Methods: Two UGT2B10 SNPs (rs6175900 and rs2942857) were genotyped in 289 African Americans and 627 White smokers. Each smoker was assigned a genetic score of 0, 1, or 2 based on the number of variant alleles. Total nicotine equivalents (TNE), the sum of nicotine and six metabolites, and serum cotinine and 3′-hydroxycotinine were quantified. The contribution of UGT2B10 genetic score to cotinine concentration was determined. Results: Serum cotinine was significantly higher in smokers with UGT2B10 genetic scores of 2 versus 0 (327 ng/mL vs. 221 ng/mL; P < 0.001); TNEs were not different. In a linear regression model adjusted for age, gender, cigarettes per day, TNE, race, and CYP2A6 activity, geometric mean cotinine increased 43% between genetic score 2 versus 0 (P < 0.001). A 0.1 increase in the CYP2A6 activity ratio, 3′-hydroxycotinine/cotinine, resulted in a 6% decrease in cotinine. After adjustment for UGT2B10 genotype and the other covariants, there was no significant difference in serum cotinine by race. Conclusions: UGT2B10 genotype is a major contributor to cotinine levels and explains the majority of high serum cotinine in African American smokers. Impact: Cotinine levels in smokers may greatly overestimate tobacco exposure and potentially misinform our understanding of ethnic/racial difference in tobacco-related disease if UGT2B10 genotype is not taken into account.

Filter ventilation in cigarettes has been associated with alterations in smoking topography in order to compensate for the lower nicotine yields. Subjective effects of cigarettes include sensations, which can be affected by how a person smokes a cigarette. We look at smoking topography as a mediator in the relationship between filter ventilation levels and subjective effects.Smoking topography and subjective effects data come from the baseline usual cigarette brand laboratory visits of participants (N = 607) in a randomized clinical trial on reduced nicotine cigarettes. Conditional process analysis was done using PROCESS macro version 3.5 in SPSS.There was a positive indirect effect of ventilation on satisfaction through total puff volume (0.004, 95% CI: 0.002, 0.007]) as well as ventilation on satisfaction through puff count then total puff volume, sequentially (0.001, 95% CI: [0.000, 0.003]). There was a positive indirect effect of ventilation on enjoyment through puff count for individuals less than 43 years of age (0.01, 95% CI: [0.002, 0.013]). There was a positive indirect effect of ventilation on enjoyment through total puff volume for individuals who smoke less than 14.33 cigarettes per day (0.009, 95% CI: [0.004, 0.015]).We found preliminary evidence that topography measures (puff count and total puff volume), mediate the relationship between filter ventilation and specific subjective effects of smoking (satisfaction and enjoyment). Age and cigarettes smoked per day moderated these relationships. These results could have implications regarding filter ventilation restrictions and smokers' perceptions of using such cigarettes.

The reinforcing characteristics of e-cigarettes could moderate the impact of reducing cigarette nicotine content. In this study, people who smoke daily were recruited from North Carolina and Pennsylvania (US) in 2018 and 2019. Within a randomized 2 × 2 × 2 factorial design, participants received investigational cigarettes and an e-cigarette for 12 weeks. Cigarette nicotine content was very low (0.4 mg/g of tobacco; VLNC) or normal (15.8 mg/g; NNC). E-liquids were 0.3% ("low") or 1.8% ("moderate") freebase nicotine, and available in tobacco flavors or tobacco, fruit, dessert and mint flavors. Study recruitment concluded before reaching the planned sample size (N = 480). Fifty participants were randomized and 32 completed the study. We found that randomization to VLNC, relative to NNC cigarettes, reduced self-reported cigarettes per day (CPD; mean difference: -12.96; 95% CI: -21.51, -4.41; p = 0.005); whereas e-liquid nicotine content and flavor availability did not have significant effects. The effect of cigarette nicotine content was larger in the moderate vs. low nicotine e-liquid groups and in the all flavors versus tobacco flavors e-liquid groups; tests of the interaction between e-liquid characteristics and cigarette nicotine content were not significant. Biomarkers of smoke exposure at Week 12 did not differ across conditions, which may reflect variability in adherence to only using VLNC cigarettes. In conclusion this study offers preliminary evidence that the extent to which cigarette nicotine reduction decreases smoking may depend on the reinforcing characteristics of alternative products, including the available nicotine contents and flavors of e-cigarettes.

Although overall health in the United States (US) has improved dramatically during the past century, long-standing health inequities, particularly the unequal and unjust burden of tobacco-related disease and death among racialized populations, persist. A considerable gap exists in our understanding of how commercial tobacco product regulations and policies cause and/or exacerbate race-based health inequities among Black/African American (B/AA) and Indigenous American people. The purpose of this paper is to 1) describe how existing US commercial tobacco regulatory policies may contribute to structural racism and undermine the full benefits of tobacco prevention and control efforts among B/AA and Indigenous American groups; and 2) initiate a call to action for researchers and regulators of tobacco products to examine policies using an equity lens. These actions are imperative if empirically-informed regulation of commercial tobacco products is to address health equity.

OBJECTIVE: The US Food and Drug Administration recently announced its intention to pursue a federal ban on menthol cigarettes. This qualitative study assessed reactions to a potential menthol cigarette ban among people who smoke menthol cigarettes. METHODS: As part of a laboratory study examining menthol flavor regulations, we conducted follow-up interviews with participants who smoke menthol cigarettes (N=35). We explored the following topics: (1) menthol cigarette risk perceptions; (2) knowledge, attitudes, and perceptions of menthol cigarette regulations; and (3) anticipated behavior if menthol cigarettes were banned. Interviews were audio-recorded, transcribed verbatim, double-coded, and analyzed using reflexive thematic analysis. RESULTS: Many participants thought menthol cigarettes carried more health risks than non-menthol cigarettes. Some participants said regulators wanted to ban menthol cigarettes because they appeal to youth. Others thought a ban would be good for public health because fewer people, particularly youth, would smoke. Several voiced skepticism about banning only menthol cigarettes rather than all cigarettes. Most said they would use other products, including electronic cigarettes or non-menthol cigarettes, but many also thought a menthol ban could motivate them or others to quit smoking. CONCLUSIONS: Banning menthol cigarettes could lead some people who smoke menthol cigarettes to switch to potentially less harmful products, like e-cigarettes, or quit smoking, which would likely benefit public health; however, others may simply transition to non-menthol cigarettes. As regulators move forward with banning menthol cigarettes, communication campaigns explaining the public health benefits, potentially focusing on the benefits for youth, should be part of the policy implementation plan.

Background In May 2018, the Secretariat for the World Health Organization Framework Convention on Tobacco Control convened a meeting to discuss the potential for reducing the addictiveness of tobacco products. A central focus was to review research findings on the behavioral effects of reducing the addictiveness of cigarettes. Methods This manuscript reports the results of a review of the behavioral science literature, updated through April 2021, with special attention to both the potential benefits and unintended consequences of reducing nicotine in cigarettes. Results Available evidence suggests that reducing nicotine content in cigarettes to very low levels could benefit public health in three primary ways, by 1) decreasing uptake of regular smoking, 2) decreasing the amount people smoke, and 3) increasing the likelihood of smoking cessation. Current evidence also suggests that reducing nicotine in cigarettes may produce similar benefits across many important subpopulations of people who smoke, including those with psychiatric comorbidities, those who use other substances, those with low socioeconomic status, young people, people who smoke infrequently and people who prefer menthol cigarettes. Cigarette nicotine reduction could also lead to some undesirable outcomes, such as experiencing withdrawal, product manipulation, an illicit market, and harm misperceptions; strategies that may mitigate each are discussed. Conclusion Overall, behavioral research suggests product standards that limit the nicotine content of combusted tobacco products could render cigarettes and similar products less addictive. The availability of legal, non-combusted products that effectively substitute for cigarettes and the dissemination of public health campaigns that clarify misperceptions about the relationship between nicotine, tobacco and disease may facilitate the extent to which a nicotine reduction policy reduces smoking.

Current text-only cigarette warning labels (long-term, loss-framed messages) may not motivate positive changes in smoking behavior. The current project was a cross-sectional study examining the effects of tailored cigarette warnings on perceived message effectiveness (PME) in adult smokers (n = 512) conducted using Amazon Mechanical Turk (M-Turk) in January–February 2020. Participants were an average age of 40.7 (SD = 11.6), with the majority of the sample being female (62.2%) and White (88.9%). Participants reported smoking an average of 14.6 cigarettes/day (SD = 9.2) with an average FTND score of 4.6 (SD = 2.2). Participants were asked to complete a tobacco use history questionnaire, and mixed gambles and delay discounting tasks before random assignment to one of five message groups. The groups were based on a 2 (gain versus loss framing) ×2 (short-term versus long-term framing) between-subject design, a fifth group served as the control group. All experimental messages reported higher PME scores than the control (p values &lt, 0.001, Cohen’s d = 1.88–2.48). Participants with shallower delayed reward discounting and lower loss aversion rates reported higher total PME scores, p values &lt, 0.05. Our findings also suggest that loss aversion rates vary widely among smokers and that individuals are more responsive to messages congruent with their behavioral economic profile. Specifically, smokers who viewed messages congruent with their loss aversion and delay discounting rates reported higher PME scores than those who viewed incongruent messages (p = 0.04, Cohen’s d = 0.24). These preliminary findings suggest that anti-smoking campaigns may best impact smokers by tailoring messages based on individual loss aversion and delay discounting rates versus a one-size-fits-all approach.

Introduction The US Food and Drug Administration is considering implementing a reduced-nicotine standard for cigarettes. Given the high rate of smoking among people with serious mental illness (SMI), it is important to examine the responses of these smokers to very low nicotine content (VLNC) cigarettes. Methods This trial compared the effects of VLNC (0.4 mg nicotine/g tobacco) and normal nicotine content cigarettes (15.8 mg/g) over a 6-week period in non-treatment-seeking smokers with schizophrenia, schizoaffective disorder, or bipolar disorder (n = 58). Linear regression was used to examine the effects of cigarette condition on cigarettes per day, subjective responses, nicotine and tobacco toxicant exposure, craving, withdrawal symptoms, and psychiatric symptoms. Results At week 6, participants in the VLNC condition smoked fewer cigarettes per day, had lower breath carbon monoxide levels, lower craving scores, and rated their study cigarettes lower in satisfaction, reward, enjoyment, and craving reduction than those in the normal nicotine content condition (ps < .05). Week 6 psychiatric and extrapyramidal symptoms did not differ by condition, except for scores on a measure of parkinsonism, which were lower in the VLNC condition (p < .05). There were no differences across conditions on total nicotine exposure, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol, withdrawal symptoms, or responses to abstinence. Conclusions These results suggest that a reduced-nicotine standard for cigarettes would reduce smoking among smokers with SMI. However, the lack of effect on total nicotine exposure indicates VLNC noncompliance, suggesting that smokers with SMI may respond to a reduced-nicotine standard by substituting alternative forms of nicotine. Implications Results from this trial suggest that a reduced-nicotine standard for cigarettes would reduce smoking rates and smoke exposure in smokers with SMI, without increasing psychiatric symptoms. However, noncompliance with VLNC cigarettes was observed, suggesting that these smokers might respond to a reduced-nicotine standard by substituting alternative forms of nicotine.

Recent evidence from randomized clinical trials (RCTs) of very low nicotine content (VLNC) cigarettes indicates that smokers randomized to VLNC cigarettes had significantly lower cigarette use, dependence, and biomarkers of exposure than smokers randomized to normal nicotine content control cigarettes. In these trials, a substantial number of participants did not adhere to their randomized treatment assignment, i.e., they used commercial cigarettes not provided by the trial in place of or in addition to the VLNC cigarettes provided by the trial. As with most RCTs, the analysis of these trials followed the intention-to-treat principle, where participants are analyzed according to their randomized treatment assignment regardless of adherence. Alternately, the analysis of an RCT could focus on the estimation and testing of the causal effect of the intervention, which is the treatment effect if all subjects were to adhere to their randomized treatment assignment. In this commentary, we compare these two approaches, highlighting the important role of causal estimation and inference for evaluating the regulatory effect of a nicotine standard for cigarettes. Additionally, we review the results of the secondary analyses of randomized trials of VLNC cigarettes using causal inference methodology to account for non-adherence to the assigned treatment and discuss the implications for a nicotine standard for cigarettes.

Background A recent clinical trial showed that an immediate transition to very low nicotine content (VLNC) cigarettes, compared with a gradual transition, produced greater reductions in smoking behavior, smoke exposure, and dependence. However, there was less compliance with the instruction to smoke only VLNC cigarettes in the immediate versus gradual reduction condition. The goal of this study was to test whether nicotine reduction method alters subjective ratings of VLNC cigarettes, and whether subjective ratings mediate effects of nicotine reduction method on smoking behavior, smoke exposure, dependence, and compliance. Methods This is a secondary analysis of a randomized trial conducted across 10 sites in the United States. Smokers (n = 1250) were randomized to either a control condition, or to have the nicotine content of their cigarettes reduced immediately or gradually to 0.04 mg nicotine/g of tobacco during a 20-week study period. Participants completed the modified Cigarette Evaluation Questionnaire (mCEQ). Results After Week 20, the immediate reduction group scored significantly lower than the gradual reduction group on multiple subscales of the mCEQ (ps < .001). The Satisfaction subscale of the mCEQ mediated the impact of nicotine reduction method on smoke exposure, smoking behavior, dependence, compliance, and abstinence. Other subscales also mediated a subset of these outcomes. Conclusions An immediate reduction in nicotine content resulted in lower product satisfaction than a gradual reduction, suggesting that immediate reduction further reduces cigarette reward value. This study will provide the Food and Drug Administration with information about the impact of nicotine reduction method on cigarette reward value. Implications These data suggest that an immediate reduction in nicotine content will result in greater reductions in cigarette satisfaction than a gradual reduction, and this reduction in satisfaction is related to changes in smoking behavior and dependence.

INTRODUCTION: The current study pilot tested the effect of a single, brief exposure to nicotine education messages on beliefs about nicotine, nicotine-replacement therapy (NRT), e-cigarettes, and cigarettes with reduced nicotine content (RNC). METHODS: Five hundred twenty-one U.S. adults (aged ≥18 years) on Amazon Mechanical Turk completed a 15-minute survey in 2018. After completing items on sociodemographics, literacy, and cancer risk behaviors, participants were randomized in a 2:1:1 ratio to one of three conditions: nicotine education (n=263), sun safety education (attention control, n=128), or no message control (n=130). All participants completed items regarding nicotine, NRT, e-cigarette, and RNC cigarette beliefs, as well as norms about nicotine use, behavioral control regarding cigarette/tobacco use, and intention to use cigarettes, NRT, e-cigarettes, and RNC cigarettes in the next 12 months. Analyses were conducted in 2019. RESULTS: Following exposure, nicotine education participants reported fewer false beliefs about nicotine (p

Author(s): Hatsukami, Dorothy K; Luo, Xianghua; Heskin, Alisa K; Tang, Mei Kuen; Carmella, Steven G; Jensen, Joni; Robinson, Jason D; Vandrey, Ryan; Drobes, David J; Strasser, Andrew A; al'Absi, Mustafa; Leischow, Scott; Cinciripini, Paul M; Koopmeiners, Joseph; Ikuemonisan, Joshua; Benowitz, Neal L; Donny, Eric C; Hecht, Stephen S | Abstract: 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)n=n13.4)] years and smoking 17.1 (SDn=n8.5) 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 (nn=n503); (2) smoking cigarettes where nicotine content was gradually reduced, with dose changes occurring monthly (nn=n498); and (3) continued smoking with normal nicotine content cigarettes (nn=n249).MeasurementsSmokers were assessed at baseline while smoking their usual brand cigarettes, and again at 4, 8, 12, 16 and 20nweeks. 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 differencen=nn-0.11; 95% confidence interval (CI)n=n-0.18, -0.04, Pn=n0.004] and normal nicotine control groups (mean differencen=n-n0.15, 95% CIn=n-0.23, -0.06, Pn=n0.001).ConclusionIt remains unclear whether switching to very low nicotine cigarettes leads to a short-term reduction in biomarkers of tobacco-related harm.

IntroductionResearch is needed to determine the impact of marketing on perceptions and use of reduced nicotine content (RNC) cigarettes, particularly as US regulators have permitted the sale of an RNC cigarette modified risk tobacco product (MRTP) that seeks further authorisation to advertise using modified risk claims. This study examined the effects of two advertising elements (product name and disclaimer content) on perceptions of an RNC cigarette MRTP.MethodsAdult participants (n=807, 28.7% smokers, 58.2% male, 74.2% non-Latinx white) completed an online MTurk survey. Participants were randomised to view one of six RNC cigarette advertisements, using a 2×3 between-subject factorial design to manipulate product name (‘Moonlight’ vs ‘Moonrise’) and disclaimer content (industry-proposed: ‘Nicotine is addictive. Less nicotine does NOT mean a safer cigarette’ vs focused: ‘Less nicotine does NOT mean a safer cigarette’ vs no content), then completed recall and product perception questionnaires.ResultsAll participants who viewed the industry-proposed disclaimer (vs no content) perceived greater addiction risk (p’sConclusionsDisclaimer content may effectively inform consumers about addiction risk of a new RNC cigarette MRTP, and further inform non-smokers about health risks. This element, however, had little effect on perceived health risks among smokers, among whom the Moonlight product name was associated with health risk misperceptions similar to the banned ‘light’ descriptor.

Background: We conducted a psychometric analysis of an adapted secondhand smoke (SHS) questionnaire by testing the three-component structure of the original scale that measures SHS exposure in home, work and social environments. Methods: The 15-item questionnaire was administered to 839 daily smokers participating in a multi-site randomized controlled trial. Following parallel analysis, we conducted a confirmatory factor analysis specifying a three-factor structure. Cronbach’s alphas and fit indices were calculated to assess internal consistency. Criterion validity was assessed by comparing the Social environments subscale to the Brief Wisconsin Inventory of Smoking Dependence Motives Social/Environmental Goads subscale. Predicative validity of the questionnaire was assessed using linear regressions and tobacco biomarkers of harm, NNAL, expired carbon monoxide and total cotinine. Results: Five items did not load onto any factor and were dropped, resulting in a 10-item questionnaire. The Cronbach’s alphas were (0.86), (0.77) and (0.67) for the Work, Social, and Home subscales, respectively. The WISDM subscale was moderately correlated with scores on the Social subscale (r = 0.57, p &lt, 0.001). The questionnaire demonstrated predictive validity of smoke exposure above individual’s own reported use as measured by cigarettes smoked per day. Conclusions: Three constructs emerged, results indicate that a shortened 10-item scale could be used in future studies.

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.

Background The 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. Methods We 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. Results Several 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. Conclusions Health 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.

Introduction: Participant noncompliance, in which participants do not follow their assigned treatment protocol, has long complicated the interpretation of randomized clinical trials. No gold standard has been identified for detecting noncompliance, but in some trials participants’ biomarkers can provide objective information that suggests exposure to non-study treatments. However, existing methods are limited to retrospectively detecting noncompliance at a single time point based on a single biomarker measurement. We propose a novel method that can leverage participants’ full biomarker history to detect noncompliance across multiple time points. Conditional on longitudinal biomarker data, our method can estimate the probability of compliance at (1) a single time point of the trial, (2) all time points, and (3) a future time point. Methods: Across time points, we model the biomarker as a mixture density with (latent) components corresponding to longitudinal patterns of compliance. To estimate the mixture density, we fit mixed effects models for both compliance and the biomarker. We use the mixture density to derive compliance probabilities that condition on the longitudinal biomarker data. We evaluate our compliance probabilities by simulation and apply them to a trial in which current smokers were asked to only smoke low nicotine study cigarettes (Center for the Evaluation of Nicotine in Cigarettes Project 1 Study 2). In the simulation, we investigated three different effects of compliance on the biomarker, as well as the effect of misspecification of the covariance structures. We compared probability estimators (1) and (2) to those that ignore the longitudinal correlation in the data according to area under the receiver operating characteristic curve. We evaluated estimator (3) by plotting its calibration lines. For Center for the Evaluation of Nicotine in Cigarettes Project 1 Study 2, we compared estimators (1) and (3) to a probability estimator of compliance at the last time point that ignores the longitudinal correlation. Results: In the simulation, for both compliance at the last time point and at all time points, conditioning on the longitudinal biomarker data uniformly raised area under the receiver operating characteristic curve across all three compliance effect scenarios. The gains in area under the receiver operating characteristic curve were smaller under misspecification. The calibration lines for the prediction of compliance closely followed 45°, though with additional variability under misspecification. For compliance at the last time point of Center for the Evaluation of Nicotine in Cigarettes Project 1 Study 2, conditioning on participants’ full biomarker history boosted area under the receiver operating characteristic curve by three percentage points. The prediction probabilities somewhat accurately approximated the non-longitudinal compliance probabilities. Discussion: Compared to existing methods that only use a single biomarker measurement, our method can account for the longitudinal correlation in the biomarker and compliance to more accurately identify noncompliant participants. Our method can also use participants’ biomarker history to predict compliance at a future time point.

Smoking cigarettes with substantially lower nicotine than conventional cigarettes prior to a quit attempt may reduce the reinforcing effects of smoking, which could facilitate smoking cessation through extinction learning. This paper describes the development of a smoking cessation intervention designed to optimize extinction processes using reduced nicotine cigarettes, as well as the design and methods for an ongoing randomized controlled trial (RCT) to evaluate this intervention. Qualitative methods and pilot testing were conducted to develop the novel facilitated extinction (FE) intervention, with a key focus on maximizing opportunities for extinction learning during a five-week pre-quit period. The primary aims of the RCT are to test the effects of the FE intervention versus a standard (cognitive-behavioral) intervention, while also comparing two nicotine reduction schedules for providing very low nicotine content (VLNC) cigarettes. The efficacy of the intervention is currently being evaluated with treatment-seeking smokers (n = 208) randomly assigned to one of four conditions crossing FE versus standard intervention with immediate versus gradual transition to VLNC cigarettes.

Despite notable progress in recent decades, cigarette smoke persists as a leading cause of premature death and preventable disease. To weaken the link between nicotine reinforcement and the toxicity associated with combusted tobacco, the United States Food and Drug Administration is considering a product standard targeting cigarette nicotine content. In this review, we summarize research assessing the potential impacts of reducing nicotine in cigarettes. Evidence to date suggests cigarette smoking, toxicant exposure and dependence would decline following substantial reductions in nicotine content. However, reduced nicotine content may not eliminate smoking entirely. Regulatory efforts that shape the nicotine and tobacco marketplace should consider that non-nicotine reinforcing factors and decision-making biases can contribute to the value of smoking. The impact of reducing nicotine in cigarettes will likely depend on the alternative nicotine products available to current smokers. This article is part of the special issue on ‘Contemporary Advances in Nicotine Neuropharmacology’.

Summary A number of statistical approaches have been proposed for incorporating supplemental information in randomized clinical trials. Existing methods often compare the marginal treatment effects to evaluate the degree of consistency between sources. Dissimilar marginal treatment effects would either lead to increased bias or down-weighting of the supplemental data. This represents a limitation in the presence of treatment effect heterogeneity, in which case the marginal treatment effect may differ between the sources solely due to differences between the study populations. We introduce the concept of covariate-adjusted exchangeability, in which differences in the marginal treatment effect can be explained by differences in the distributions of the effect modifiers. The potential outcomes framework is used to conceptualize covariate-adjusted and marginal exchangeability. We utilize a linear model and the existing multisource exchangeability models framework to facilitate borrowing when marginal treatment effects are dissimilar but covariate-adjusted exchangeability holds. We investigate the operating characteristics of our method using simulations. We also illustrate our method using data from two clinical trials of very low nicotine content cigarettes. Our method has the ability to incorporate supplemental information in a wider variety of situations than when only marginal exchangeability is considered.

BackgroundThe US Food and Drug Administration recently issued an advanced notice of proposed rule-making for reducing the nicotine content in cigarettes to a minimally addictive level. Very little is known about whether use of very low nicotine content (VLNC) cigarettes affects support for a nicotine reduction policy.ObjectiveThis study examined the effects of using VLNC versus usual brand (UB) cigarettes on support for a nicotine reduction policy and determined whether participant characteristics and responses to VLNC cigarettes were associated with policy support.MethodsParticipants from a cigarette trial who were assigned to either 0.4 mg nicotine/g tobacco research cigarettes or their UB for 6 weeks were asked about their support for the policy. χ2 tests were used to compare support for the policy between cigarette conditions and logistic regression analyses were conducted to assess covariates associated with policy support.FindingsPolicy support did not differ by condition. After 6 weeks of using VLNC cigarettes, 50% of participants supported the policy, 26% opposed and 24% responded ‘Don’t Know’. Support was higher among those adherent to smoking only VLNC cigarettes (65%) compared with those who were non-adherent (44%). Older participants and those interested in quitting had increased odds of support. Cigarette satisfaction, perceived harm and perceived nicotine content were not significantly associated with support.ConclusionsSmoking VLNC cigarettes did not affect support for a nicotine reduction policy. Understanding predictors of policy support and opposition will help public health officials to maximise the public health acceptance and impact of this policy (ClinicalTrials.gov Identifier: NCT01681875 Post-Results).

Investigational tobacco products, specifically variable nicotine content research cigarettes (SPECTRUM), are available through the National Institute of Drug Abuse Drug Supply Program. Randomized controlled trials using research cigarettes are intended to support tobacco regulatory science research. The current paper provides an in-depth look into managing research cigarettes for two multi-site clinical trials and the design of a computer-based Cigarette Management System (CMS). The paper provides guidance intended for any investigator using similar products on the operating procedures under Good Clinical Practice standards and describes features of the CMS. The CMS and procedures described have been field tested for the past three years and have dispensed over 160,000 cigarette packs to participants. The CMS can accommodate a range of practical issues with real-world study implementation making it a robust application that is scalable to any study.

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

Introduction Reducing the level of nicotine in cigarettes is a regulatory strategy that has the potential to greatly improve public health. If nicotine levels are reduced in all commercially available cigarettes, current smokers might find it easier to quit and young people might be less likely to become dependent. However, it is not yet known whether age moderates subjective or behavioral responses to low-nicotine cigarettes. Methods Recently, a large, multisite randomized clinical trial was conducted to compare the effects of cigarettes differing in nicotine content (either usual-brand or research cigarettes containing 15.8, 5.2, 2.4, 1.3, or 0.4 mg nicotine/g tobacco) across 6 weeks of exposure. In this secondary analysis, we tested whether age moderated smokers' subjective (measures of psychological reward, smoking satisfaction) and behavioral (cigarettes smoked per day, smoking topography, and nicotine exposure) responses to cigarettes varying in nicotine content after 2 and 6 weeks of use, while controlling for baseline dependence and demographic factors. Results Results indicated that younger adults (age 18-24) who smoked cigarettes with 2.4-0.4 mg/g nicotine reported significantly less smoking satisfaction and psychological reward, and smoked fewer cigarettes per day, than older adults (25+ years) after 2 weeks of use. No differences in topography were observed at either time point. After 6 weeks of use, differences had diminished on all measures. Conclusions The reduced positive effects of reduced-nicotine content cigarettes in young adults suggests that this regulatory policy may reduce smoking reinforcement in this vulnerable population. Implications As the FDA considers reducing the level of nicotine in cigarettes to make them less addictive, understanding the potential impact of this policy on young people is of crucial importance. We found that young adults had significantly lower positive subjective effects to very-low nicotine content (VLNC) cigarettes and smoked fewer VLNC cigarettes than older adults after 2 weeks of use, indicating that this policy may reduce smoking reinforcement more quickly in young adults. These data add to the growing body of evidence on the potential for this policy to positively affect public health.

BackgroundReducing cigarette nicotine content may reduce smoking. Studies suggest that smokers believe that nicotine plays a role in smoking-related morbidity. This may lead smokers to assume that reduced nicotine means reduced risk, and attenuate potential positive effects on smoking behaviour.MethodsData came from a multisite randomised trial in which smokers were assigned to use cigarettes varying in nicotine content for 6 weeks. We evaluated associations between perceived and actual nicotine content with perceived health risks using linear regression, and associations between perceived nicotine content and perceived health risks with smoking outcomes using linear and logistic regression.FindingsPerceived—not actual—nicotine content was associated with perceived health risks; compared with those perceiving very low nicotine, individuals who perceived low (β=0.72, 95% CI 0.26 to 1.17), moderate (β=1.02, 95% CI 0.51 to 1.53) or high/very high nicotine (β=1.66, 95% CI 0.87 to 2.44) perceived greater health risks. Nevertheless, individuals perceiving low (OR=0.48, 95% CI 0.32 to 0.71) or moderate nicotine (OR=0.42, 95% CI 0.27 to 0.66) were less likely than those perceiving very low nicotine to report that they would quit within 1 year if only investigational cigarettes were available. Lower perceived risk of developing other cancers and heart disease was also associated with fewer cigarettes/day at week 6.ConclusionsAlthough the perception of reduced nicotine is associated with a reduction in perceived harm, it may not attenuate the anticipated beneficial effects on smoking behaviour. These findings have implications for potential product standards targeting nicotine and highlight the need to clarify the persistent harms of reduced nicotine combusted tobacco products.

Background: Tobacco exposure is often quantified by serum or saliva concentrations of the primary nicotine metabolite, cotinine. However, average cotinine concentrations are higher in African Americans (AA) compared with Whites with similar smoking levels. Cotinine is metabolized by UGT2B10 and CYP2A6, and low UGT2B10 activity is common in AA, due to the prevalence of a UGT2B10 splice variant. Methods: UGT2B10 activity was phenotyped in 1,446 smokers (34% AA) by measuring the percentage of cotinine excreted as a glucuronide. Urinary total nicotine equivalents (TNE), the sum of nicotine and 6 metabolites, were determined to quantify smoking dose, and cotinine and 3′-hydroxycotinine were quantified in saliva (study 1) or serum (study 2). Results: Ninety-seven smokers (78% AA) were null for UGT2B10 activity, and the saliva and serum cotinine levels, after adjustment for TNE and cigarettes per day (CPD), were 68% and 48% higher in these smokers compared with nonnull smokers (P < 0.001). After adjustment for TNE and CPD, salivary cotinine was 35% higher, and serum cotinine 24% higher in AA versus White smokers, but with additional adjustment for UGT2B10 activity, there were no significant differences in saliva and serum cotinine concentrations between these two groups. Conclusions: UGT2B10 activity significantly influences plasma cotinine levels, and higher cotinine concentrations in AA versus White smokers (after adjustment for smoking dose) result from lower levels of UGT2B10-catalyzed cotinine glucuronidation by AA. Impact: UGT2B10 activity or genotype should be considered when using cotinine as a tobacco exposure biomarker, particularly in populations such as AA with high frequencies of UGT2B10 nonfunctional variants. Cancer Epidemiol Biomarkers Prev; 26(7); 1093–9. ©2017 AACR.