Tobacco Constituents, Flavorants, and Paper Permeability of Factory-Made and Roll-Your-Own Cigarettes on the Australian Market.

INTRODUCTION: Roll-your-own (RYO) tobacco is a popular choice in Australia, with some people who smoke finding these products more attractive than factory-made cigarettes (FMC). Differences in visual and tactile properties and in the feel and taste of the smoke may contribute to this attractiveness. These differences may be driven by variation in tobacco constituents and wrapping paper permeability. However, to date, there has been no comparison of RYO and FMC products on the Australian market. AIMS AND METHODS: Chemical constituents, pH, flavorants, and paper permeability were compared in unburned RYO tobacco and tobacco from FMC. RYO and FMC products from matched brands were compared, as were products from the most popular FMC and RYO brands on the Australian market in 2018. RESULTS: RYO tobacco had higher moisture and humectant content (glycerol and propylene glycol) than FMC tobacco. RYO tobacco also had higher amounts of total and reducing sugars and lower nicotine when comparing the most popular brands. RYO papers were less permeable than FMC papers. Both RYO and FMC tobacco contained many chemicals identified as flavorants, including fourteen with known potential health risks. For most measured constituents and flavorants, RYO tobaccos had more in common with other RYO than FMC, with the commonalities remaining even when matched brands were compared. CONCLUSIONS: Higher levels of moisture, humectants, and sugars in Australian RYO tobacco compared to FMC may be increasing attractiveness of RYO by reducing the harsh taste of the smoke and increasing the moist feel of the tobacco. IMPLICATIONS: While price is the main factor driving the use of RYO tobacco, some people who smoke find these products more attractive. This study has shown that Australian RYO tobacco contains higher amounts of glycerol, propylene glycol, and sugars than FMC. These chemicals may be improving the taste of the tobacco, as well as creating a moist feel that is falsely perceived as indicating that the tobacco is "fresh" and "less chemically." Ironically, it may be that higher amounts of some added chemicals in RYO contribute to false perceptions of a more natural and less harmful product.

Society for Research on Nicotine and Tobacco as an Outgrowth of the 1988 Surgeon General's Report on Nicotine Addiction: Reflections of the Early Presidents.

INTRODUCTION: The Society for Research on Nicotine and Tobacco began in the United States as a scientific organization "to stimulate the generation and dissemination of new knowledge concerning nicotine and tobacco in all its manifestations." Now in its 30th year, the Society is taking on new challenges in tobacco control, nicotine vaping, product regulation, and public policy. AIMS AND METHODS: This Review describes the formative years of the Society from the perspective of researchers who were in leadership positions during that time, documenting how biobehavioral and clinical research in the first 10 years was a continuation of the scientific mission of the 1988 United States Surgeon General's Report on Nicotine Addiction and summarizing organizational innovations during each president's term of office. CONCLUSIONS: The Society's promotion of scientific research served as a catalyst for funding, policy, and regulation, setting the stage for its influence and credibility. IMPLICATIONS: This Commentary provides context and an overview of the scientific research and the organizational innovations that occurred during the early years of the Society for Research on Nicotine and Tobacco using publications and available documentation. The Society was able to thrive because biobehavioral research on nicotine addiction provided the scientific underpinnings for the tobacco control enterprise as a whole. The objective of this Commentary is to describe formative events in the Society's history based on the accomplishments of its early leaders.

Selective Reduction of Socioeconomic Disparities in the Experimental Tobacco Marketplace: Effects of Cigarette and E-cigarette Flavor Restrictions.

INTRODUCTION: Cigarette smoking accounts for >30% of the socioeconomic gap in life expectancy. Flavored restrictions claim to promote equity; however, no previous studies have compared the effect of cigarette and e-cigarette flavor restrictions among individuals who smoke with lower and higher socioeconomic status (SES). AIMS AND METHODS: In a between-group within-subject design, individuals with lower (n = 155) and higher (n = 125) SES completed hypothetical purchasing trials in the experimental tobacco marketplace (ETM). Conditions were presented in a 2 × 2 factorial design (cigarette flavors restricted or unrestricted and e-cigarette flavors restricted or unrestricted) with increasing cigarette prices across trials. RESULTS: Results show (1) SES differences in cigarette, e-cigarette, and NRT purchases under unrestricted policies, with lower SES showing higher cigarette demand and lower e-cigarette and NRT substitution than higher SES, (2) cigarette restrictions decreased cigarette and increased NRT purchases among lower SES, but no significant changes among higher SES, (3) decreased SES differences in cigarette demand under cigarette restrictions, but persistence under e-cigarette restrictions or their combination, (4) persistence of SES differences in e-cigarette purchases when all restrictions were enforced, and (5) waning of SES differences in NRT purchasing under all restrictions. CONCLUSIONS: Flavor restrictions differentially affected individuals based on SES. Within-group comparisons demonstrated restrictions significantly impacted lower SES, but not higher SES. Between-group comparisons showed SES differences in cigarette purchasing decreased under cigarette restrictions, but persisted under e-cigarette-restrictions or their combination. Additionally, SES differences in NRT substitution decreased under flavor restrictions. These findings highlight the utility of the ETM to investigate SES disparities. IMPLICATIONS: With increasing trends of socioeconomic differences in smoking prevalence and cessation rates, smoking-related health disparities are expected to continue to widen. Restricting menthol flavor in cigarettes while enhancing the availability and affordability of NRT have the potential to alleviate SES disparities in tobacco use, therefore, positively impacting health equity. However, this effect may depend on flavor availability in other tobacco products.

Menthol and filter ventilation in cigarettes: prevalence estimates and relationships with harm perception and smoking exposure.

INTRODUCTION: Menthol and filter ventilation (FV) contribute to cigarette appeal. This observational study examines the US prevalence of menthol versus non-menthol cigarette use by FV and how harm perceptions, cigarettes per day and biomarkers of exposure vary. METHODS: Population Assessment of Tobacco and Health Study (2013-2014) was merged with FV levels of cigarettes and restricted to daily smoking adults who had a usual cigarette variety and did not regularly use other tobacco (N=1614). Weighted descriptive statistics identified the prevalence of menthol and non-menthol use by low (0.02%-10.04%), moderate (10.05%-23.40%), high (23.41%-28.12%) and very high FV (28.13%-61.10%). Weighted linear regression was used to examine differences in outcomes by menthol/FV adjusted for potential confounders. RESULTS: The prevalence of a usual brand that was non-menthol, low FV was the lowest at 2.91%. Using non-menthol cigarettes with high and very high FV (≥23.4%) vs low FV (≤10.04%) was associated with a greater likeliness of misperceiving one's cigarette variety to be less harmful than other varieties (p values<0.05). Total nicotine equivalent, biomarker for nicotine exposure, was elevated (p values<0.05) among three non-menthol groups (low, moderate and very high FV) compared with two menthol groups (moderate, very high FV). CONCLUSION: The well-documented harm misperception linked to higher FV is more apparent in those using non-menthol than menthol cigarettes. Increased exposures were observed among some non-menthol cigarette users compared with some menthol cigarette users. These results should by no means delay a menthol ban but rather motivate concerted public health efforts to accompany the menthol ban to maximise smoking cessation.

Furan Metabolites Are Elevated in Users of Various Tobacco Products and Cannabis.

Humans are exposed to furan, a toxicant and possible human carcinogen, through multiple sources including diet and tobacco smoke. The urinary metabolites of furan are derived from the reaction of its toxic metabolite with protein nucleophiles and are biomarkers of exposure and potential harm. An established isotopic dilution liquid-chromatography mass spectrometry method was used to measure these biomarkers in urine from users of e-cigarettes, cannabis, and/or combustible tobacco with/without reduced nicotine levels. Amounts of furan mercapturic acid metabolites were higher in these individuals relative to nonsmokers, indicating that they may be at risk for potential furan-derived toxicities.

Heterogeneity of Harmful Constituent Profiles in Smokeless Tobacco Products from Five African Countries.

Addictive, toxic, and carcinogenic constituents present in smokeless tobacco (SLT) products are responsible for the harmful effects associated with SLT use. There are limited data on levels of such constituents in SLT products used in Africa, a region with high prevalence of SLT use and the associated morbidity and mortality. Manufactured and custom-made SLT products were purchased from five African countries (South Africa, Uganda, Mauritania, Nigeria, and Zambia) using a standard approach for sample collection, labeling, and storage. Moisture content, pH, total and unprotonated (biologically available) nicotine, five tobacco-specific N-nitrosamines (TSNA), 10 polycyclic aromatic hydrocarbons (PAH), five metals and metalloids (As, Cd, Cr, Ni, and Pb), nitrate, and nitrite were analyzed. A total of 54 samples representing 15 varieties of manufactured SLT products and 13 varieties of custom-made SLT products were purchased and analyzed. In all samples, the total nicotine ranged from 1.6 to 20.5 mg/g product and unprotonated nicotine accounted for 5.3-99.6% of the total nicotine content. The sum of all five TSNA ranged from 1.6 to 100 µg/g product, with significant within-country variations observed across both the manufactured and custom-made varieties. Significant variations were also found for PAH, metals and metalloids, nitrates, and nitrites. This is the most comprehensive report on the chemical profiling of products from African countries. This is also the first study illustrating the variability of harmful constituents within the same types and brands of African SLT. Our findings emphasize the need for consumer education and interventions to reduce SLT use in Africa. The data reported here can be useful to regulators in considering measures to prevent the occurrence of high levels of known toxicants and carcinogens in manufactured products.

Increased Levels of the Acrolein Metabolite 3-Hydroxypropyl Mercapturic Acid in the Urine of e-Cigarette Users.

Carcinogen and toxicant uptake by e-cigarette users have not been fully evaluated. In the study reported here, we recruited 30 e-cigarette users, 63 nonsmokers, and 33 cigarette smokers who gave monthly urine samples over a period of 4-6 months. Their product use status was confirmed by measurements of exhaled CO, urinary total nicotine equivalents, cyanoethyl mercapturic acid (CEMA), and total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol. Urinary biomarkers of exposure to the carcinogens acrolein (3-hydroxypropyl mercapturic acid, 3-HPMA), benzene (S-phenyl mercapturic acid, SPMA), acrylonitrile (CEMA), and a combination of crotonaldehyde, methyl vinyl ketone, and methacrolein (3-hydroxy-1-methylpropyl mercapturic acid, HMPMA) were quantified at each visit. Data from subject visits with CEMA > 27 pmol/mL were excluded from the statistical analysis of the results because of possible unreported exposures to volatile combustion products such as secondhand cigarette smoke or marijuana smoke exposure; this left 22 e-cigarette users with 4 or more monthly visits and all 63 nonsmokers. Geometric mean levels of 3-HPMA (1249 versus 679.3 pmol/mL urine) were significantly higher (P = 0.003) in e-cigarette users than in nonsmokers, whereas levels of SPMA, CEMA, and HMPMA did not differ between these two groups. All analytes were significantly higher in cigarette smokers than in either e-cigarette users or nonsmokers. The results of this unique multimonth longitudinal study demonstrate consistent significantly higher uptake of the carcinogen acrolein in e-cigarette users versus nonsmokers, presenting a warning signal regarding e-cigarette use.

Manipulation of Menthol and Nicotine Content in Cigarettes: Effects on Smoking Behavior and Toxicant Exposure in Women Menthol Smokers.

BACKGROUND: The purpose of this study was to determine the effects of smoking and other outcomes of assigning cigarettes with reduced nicotine and/or no menthol to female menthol smokers. AIMS AND METHODS: Nontreatment-seeking female menthol smokers (N = 263) participated in a randomized controlled trial in which levels of menthol and nicotine in cigarettes were manipulated using experimental cigarettes. After a baseline period, participants were assigned to the following conditions for 6 weeks: (1) their own brand of cigarette (conventional nicotine with menthol), (2) a conventional nicotine cigarette with no menthol, (3) a cigarette with reduced nicotine (RNC) with menthol, or (4) a RNC cigarette and no menthol. Participants then returned to using their own brand and were followed for another 6 weeks. Outcomes included cigarettes smoked, biomarkers of exposure, and dependence measures. RESULTS: Results indicated that, after an initial increase, rates of smoking of all three experimental cigarettes were at or below baseline rates of smoking of one's own brand. Levels of biomarkers also decreased during the experimental phase but rebounded somewhat after participants resumed smoking their own brand. There was evidence that the overall amount of smoking decreased similarly among women who switched to non-menthol and/or RNC cigarettes. CONCLUSIONS: These results suggest that no detrimental effect will occur in nicotine or toxicant exposure levels with a ban on characterizing menthol and/or a product standard on nicotine content in cigarettes. IMPLICATIONS: The implication of this work is that there would be no risk to women menthol smokers associated with regulations restricting nicotine and eliminating menthol in cigarettes.

Indicators of Tobacco Dependence Among Youth: Findings From Wave 1 (2013-2014) of the Population Assessment of Tobacco and Health Study.

BACKGROUND: Prior work established a measure of tobacco dependence (TD) among adults that can be used to compare TD across different tobacco products. We extend this approach to develop a common, cross-product metric for TD among youth. METHODS: One thousand one hundred and forty-eight youth aged 12-17 who used a tobacco product in the past 30 days were identified from 13 651 youth respondents in Wave 1 of the Population Assessment of Tobacco and Health (PATH) Study. FINDINGS: Analyses confirmed a single primary latent construct underlying responses to TD indicators for all mutually exclusive tobacco product user groups. Differential Item Functioning analyses supported the use of 8 of 10 TD indicators for comparisons across groups. With TD levels anchored at 0.0 (standard deviation [SD] = 1.0) among cigarette only (n = 265) use group, mean TD scores were more than a full SD lower for e-cigarette only (n = 150) use group (mean = -1.09; SD = 0.64). Other single product use group (cigar, hookah, pipe, or smokeless; n = 262) on average had lower TD (mean = -0.60; SD = 0.84), and the group with the use of multiple tobacco products (n = 471) experienced similar levels of TD (mean = 0.14; SD = 0.78) as the cigarette only use group. Concurrent validity was established with product use frequency among all user groups. A subset of five TD items comprised a common metric permitting comparisons between youth and adults. CONCLUSION: The PATH Study Youth Wave 1 Interview provided psychometrically valid measures of TD that enable future regulatory investigations of TD across tobacco products and comparisons between youth and adult tobacco product use group. IMPLICATIONS: A measure of tobacco dependence (TD) has been established previously among adults to compare TD across tobacco products. This study established the validity of a similar, cross-product measure of TD among youth. Findings suggest a single latent TD construct underlying this measure, concurrent validity of the scale with product use frequency across different types of tobacco users, and a subset of common items that can be used to compare TD between youth and adults who use tobacco.

Risk perceptions and continued smoking as a function of cigarette filter ventilation level among US youth and young adults who smoke.

BACKGROUND: While evidence demonstrates that the industry's marketing of cigarettes with higher filter ventilation (FV) misleads adults about their health risks, there is no research on the relationships between FV, risk perceptions and smoking trajectories among youth (ages 12-17) and young adults (ages 18-24). METHODS: Data on FV levels of major US cigarette brands/sub-brands were merged with the Population Assessment of Tobacco and Health Study to examine whether FV level in cigarettes used by wave 1 youth/young adults (n=1970) predicted continued smoking at waves 2-4, and whether those relationships were mediated by perceived risk of their cigarette brand. FV was modelled based on tertiles (0.2%-11.8%, low; 11.9%-23.2%, moderate; 23.3%-61.1%, high) to predict daily smoking, past 30-day smoking and change in number of days smoking at successive waves. RESULTS: The odds of perceiving one's brand as less harmful than other cigarette brands was 2.21 times higher in the high versus low FV group (p=0.0146). Relationships between FV and smoking outcomes at successive waves were non-significant (all p>0.05). CONCLUSION: Youth and young adults who use higher FV cigarettes perceived their brand as less harmful compared with other brands. However, level of FV was not associated with continued smoking.

Practical guidance on modeling choices for the virtual twins method.

Individuals can vary drastically in their response to the same treatment, and this heterogeneity has driven the push for more personalized medicine. Accurate and interpretable methods to identify subgroups that respond to the treatment differently from the population average are necessary to achieving this goal. The Virtual Twins (VT) method is a highly cited and implemented method for subgroup identification because of its intuitive framework. However, since its initial publication, many researchers still rely heavily on the authors' initial modeling suggestions without examining newer and more powerful alternatives. This leaves much of the potential of the method untapped. We comprehensively evaluate the performance of VT with different combinations of methods in each of its component steps, under a collection of linear and nonlinear problem settings. Our simulations show that the method choice for Step 1 of VT, in which dense models with high predictive performance are fit for the potential outcomes, is highly influential in the overall accuracy of the method, and Superlearner is a promising choice. We illustrate our findings by using VT to identify subgroups with heterogeneous treatment effects in a randomized, double-blind trial of very low nicotine content cigarettes.

Increased acrolein-DNA adducts in buccal brushings of e-cigarette users.

DNA adducts are central in the mechanism of carcinogenesis by genotoxic agents. We compared levels of a DNA adduct of acrolein, a genotoxic carcinogen found in e-cigarette vapor, in oral cell DNA of e-cigarette users and non-users of any tobacco or nicotine product. e-Cigarette users and non-users visited our clinic once monthly for 6 months, and oral brushings and urine samples were collected. For this study, we analyzed oral cell DNA adducts from three monthly visits in e-cigarette users and non-users as confirmed by urinary cyanoethyl mercapturic acid and total nicotine equivalents. DNA was isolated from the oral brushings and analyzed by a validated liquid chromatography-nanoelectrospray ionization-high resolution tandem mass spectrometry method for the acrolein DNA adduct 8R/S-3-(2'-deoxyribos-1'-yl)-5,6,7,8-tetrahydro-8-hydroxypyrimido[1,2-a]purine-10-(3H)-one (γ-OH-Acr-dGuo). The median value of this DNA adduct in the e-cigarette users was 179 fmol/µmol dGuo (range 5.0 - 793 fmol/µmol dGuo) while that for non-users was 21.0 fmol/µmol dGuo (range 5.0 - 539 fmol/µmol dGuo), P = 0.001. These results demonstrate for the first time that e-cigarette users have elevated levels of a carcinogen-DNA adduct in their oral cells.

Dynamic borrowing in the presence of treatment effect heterogeneity.

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.

Quantitation of DNA Adducts Resulting from Acrolein Exposure and Lipid Peroxidation in Oral Cells of Cigarette Smokers from Three Racial/Ethnic Groups with Differing Risks for Lung Cancer.

The Multiethnic Cohort Study has demonstrated that the risk for lung cancer in cigarette smokers among three ethnic groups is highest in Native Hawaiians, intermediate in Whites, and lowest in Japanese Americans. We hypothesized that differences in levels of DNA adducts in oral cells of cigarette smokers would be related to these differing risks of lung cancer. Therefore, we used liquid chromatography-nanoelectrospray ionization-high resolution tandem mass spectrometry to quantify the acrolein-DNA adduct (8R/S)-3-(2'-deoxyribos-1'-yl)-5,6,7,8-tetrahydro-8-hydroxypyrimido[1,2-a]purine-10(3H)-one (γ-OH-Acr-dGuo, 1) and the lipid peroxidation-related DNA adduct 1,N6-etheno-dAdo (εdAdo, 2) in DNA obtained by oral rinse from 101 Native Hawaiians, 101 Whites, and 79 Japanese Americans. Levels of urinary biomarkers of nicotine, acrolein, acrylonitrile, and a mixture of crotonaldehyde, methyl vinyl ketone, and methacrolein were also quantified. Whites had significantly higher levels of γ-OH-Acr-dGuo than Japanese Americans and Native Hawaiians after adjusting for age and sex. There was no significant difference in levels of this DNA adduct between Japanese Americans and Native Hawaiians, which is not consistent with the high lung cancer risk of Native Hawaiians. Levels of εdAdo were modestly higher in Whites and Native Hawaiians than in Japanese Americans. The lower level of DNA adducts in the oral cells of Japanese American cigarette smokers than Whites is consistent with their lower risk for lung cancer. The higher levels of εdAdo, but not γ-OH-Acr-dGuo, in Native Hawaiian versus Japanese American cigarette smokers suggest that lipid peroxidation and related processes may be involved in their high risk for lung cancer, but further studies are required.

A Bayesian hierarchical model for individual participant data meta-analysis of demand curves.

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.

Effect of restricting menthol flavored cigarettes or E-cigarettes on smoking behavior in menthol smokers.

Bans of menthol characterizing flavor in tobacco products have been enacted in some localities and proposed in the United States for cigarettes. To gather data regarding how restrictions for menthol in cigarettes and e-cigarettes may affect current menthol cigarette smokers, 37 African American menthol smokers participated in a pilot study in which they were asked to abstain (n = 18) or not abstain from menthol cigarettes (n = 19) for 8-weeks. All participants received menthol flavored e-cigarettes for 4 weeks and tobacco flavored e-cigarettes for 4 weeks in random order. Number of cigarettes smoked per day (estimated mean ratio [EMR] = 0.31; 95% CI: 0.13, 0.72) and exhaled CO concentrations (EMR = 0.61; 95% CI: 0.43, 0.88) were lower in the menthol cigarette abstainer group compared to the menthol cigarette non-abstainer group. Those in the menthol cigarette abstainer group reported higher scores on motivation to quit (p = 0.03) and perceived effectiveness of quitting skills (p = 0.02). There were no substantial effects seen in amount smoked or exhaled CO based on flavor of e-cigarettes provided. Higher e-cigarette use (based on reported puffs per day) was reported in the menthol cigarette abstainer (vs. non-abstainer) group (p < 0.01) and also during the 4-week period when provided with menthol (vs. tobacco) e-cigarettes (p < 0.01). These data suggest that the potential of e-cigarettes to reduce tobacco related harm may be enhanced if combined with a ban on menthol flavor in combustible cigarettes. Larger studies are needed to determine the effect of limiting menthol in e-cigarettes on smoking behavior among current menthol smokers.

Preliminary evidence on cigarette nicotine reduction with concurrent access to an e-cigarette: Manipulating cigarette nicotine content, e-liquid nicotine content, and e-liquid flavor availability.

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.

Smoking abstinence and cessation-related outcomes one month after an immediate versus gradual reduction in nicotine content of cigarettes.

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.

Regulatory Approaches and Implementation of Minimally Addictive Combusted Products.

INTRODUCTION: A joint meeting was held by the World Health Organization (WHO) and the Convention Secretariat of the WHO Framework Convention on Tobacco Control to examine the potential effects of a regulatory policy to reduce nicotine in cigarettes to minimally addictive levels. This paper reviews the feasibility of and approaches to implementing a nicotine product standard. METHODS: Prior WHO reports on this topic were consulted and a systematic review of the scientific literature was conducted. The paper was reviewed by the participants at the aforementioned meeting and their feedback was incorporated. RESULTS: The nicotine dose most likely to consistently reduce smoking behavior and dependence is ≤0.4 mg nicotine/g tobacco. An immediate rather than a gradual nicotine reduction approach appears to be more beneficial. Smokers are likely to seek nicotine from alternate sources (e.g., nicotine replacement therapies, e-cigarettes) or potentially, the illegal market. As such, the availability of alternative products, as well as strong policies against illegal markets, can potentially mitigate unintended consequences. An effectively reduced nicotine regulation must be imbedded in a comprehensive and strong tobacco control program that includes public education and surveillance. Barriers and challenges to implementing a nicotine product standard exist, particularly in low-capacity countries. CONCLUSIONS: Not all countries will have the capacity to implement a regulation to reduce nicotine in cigarettes (and preferably other combusted tobacco products) to minimally addictive levels. However, for the countries that choose to implement it, such a policy could potentially dramatically reduce the burden of tobacco use. IMPLICATIONS FOR TOBACCO REGULATORY SCIENCE: Article 9 of the Framework Convention on Tobacco Control provides signatory governments the authority to implement a product standard for reducing nicotine in tobacco products to minimally addictive levels. This product standard has the potential to result in a dramatic reduction in cigarette and other combusted tobacco use and therefore, smoking-caused mortality and morbidity. This article describes the growing scientific evidence to support nicotine regulation in cigarettes, potential regulatory approaches and describes the infrastructure and tobacco control policies needed to implement a reduced nicotine product standard.

Effect on Tobacco Use and Subjective Measures of Including E-cigarettes in a Simulated Ban of Menthol in Combustible Cigarettes.

INTRODUCTION: Bans of menthol characterizing flavor in tobacco products have been proposed; however, there is limited data regarding the impact on current menthol cigarette smokers of including e-cigarettes in such bans. METHODS: In this six-week pilot study, 47 menthol smokers were randomized to receive all tobacco products from an experimental marketplace simulating either no menthol ban, a menthol ban for cigarettes but not e-cigarettes, or a ban for both ("total menthol ban"). RESULTS: At the first visit, all but one participant selected cigarettes with e-cigarettes selected by 38%, 69%, and 40% of participants in the no ban, menthol cigarette ban, and total menthol ban groups, respectively. Over the study period, the total menthol ban group smoked more than the menthol cigarette ban group (estimated mean ratio [EMR] in cigarettes per day = 1.38; 95% CI: 1.1, 1.75; p = .006). Compared to the no ban condition, the menthol cigarette ban group smoked slightly fewer (EMR = 0.87; 95% CI: .68, 1.11) and the total menthol ban group smoked slightly more (EMR = 1.20; 95% CI: 1.00, 1.45) although neither difference reached statistical significance. In both menthol ban conditions, ratings were lower (vs. no ban) on several measures of craving and cigarette effects and liking. CONCLUSIONS: Menthol bans that include e-cigarettes may result in different patterns of tobacco use than if only combustible cigarettes are included, although e-cigarettes were not extensively used in any group. Larger studies are needed to determine policies most likely to provide the largest public health benefit. IMPLICATIONS: Bans of menthol characterizing flavor have been proposed, however, the effects on menthol cigarette smokers of including e-cigarettes in such bans are not clear. This study found that smokers randomized to a simulated ban on menthol in both cigarettes and e-cigarettes smoked more cigarettes per day over the 6-week study period than those randomized to a simulated ban on menthol in only cigarettes suggesting that smoking patterns among current menthol smokers differ depending on which products are included in a menthol ban. Larger studies are needed to determine the policies most likely to provide the largest public health benefit.