The Effects of Changes in Cigarette Menthol Content on Acute Nicotine Pharmacology and Smoking Topography.

INTRODUCTION: Menthol influences the appeal and addictiveness of cigarette smoking, however the data regarding menthol's effects on nicotine pharmacokinetics (PK) and smoking topography are inconsistent. This study investigated the impact of different cigarette menthol levels on nicotine pharmacology and smoking topography in current menthol smokers. AIMS AND METHODS: The study was a double-blind, randomized, four-period, crossover study to investigate the effects of smoking cigarettes with varying menthol content (0, 3, 6, and 12 mg menthol) on nicotine PK, smoking topography, and subjective effects in current menthol smokers. Each experimental session consisted of a prescribed use session, followed by 145 min of no smoking and a 1-h ad libitum smoking session. Serial blood samples were collected; smoking topography was recorded using CReSS Lab topography device. RESULTS: There was no significant effect of menthol on nicotine PK after prescribed smoking of cigarettes with varying menthol contents. During ad libitum smoking, there was significantly smaller total puff volume and puff duration in the 12 mg menthol condition compared to other menthol conditions. Subjective and sensory measures indicated significantly higher overall positive ratings for the 3 mg and 6 mg menthol cigarettes compared to the 0 mg menthol cigarette; the 12 mg menthol cigarette was less liked and harsher than the 3 mg condition. CONCLUSIONS: These findings suggest that menthol, at concentrations reflecting the marketplace (3-6 mg), contributes to positive subjective smoking experiences among menthol smokers, but does not have a significant effect on nicotine PK or smoking topography in an acute laboratory setting. IMPLICATIONS: While our data indicate that varying menthol content does not have a significant impact on nicotine's pharmacological effects under acute exposure conditions, these data highlight the contribution of menthol's flavor and sensory effects to product preference and positive smoking experiences, which facilitate repeated experimentation, progression to regular use, and subsequent dependence.

A Method to Amend Cigarettes With Menthol for Use in Research.

INTRODUCTION: Studies have evaluated the role of menthol cigarettes on various addiction-related outcomes; however, the effect of varying menthol content on these outcomes has not been evaluated. We developed a method to amend non-menthol SPECTRUM Research Cigarettes to contain menthol at four different levels. AIMS AND METHODS: SPECTRUM Research Cigarettes, NRC 600 (0.8 mg nicotine; 10 mg tar), were modified to contain target menthol amounts at 3, 6, and 12 mg/cigarette by injecting 25 µL ethanol/triacetin/menthol solutions of varying concentrations (120 mg menthol/mL, 240 mg/mL, and 480 mg/mL) into four distinct locations in the filter and tobacco rod. Menthol content was tested in triplicate in the whole cigarette and in the tobacco rod and filter at 1, 24, 48, and 72 hours for each target menthol level using an extraction solution of quinoline in methyl-tert-butyl ether and measured using gas chromatography with flame ionization detection. RESULTS: Injections into the filter and tobacco rod (12.5 µL each) yielded equal menthol distribution up to 72 hours. However, total menthol content decreased from an average of 90.3% of the target menthol concentration at 1 hour to 80.7% at 72 hours in cigarettes stored individually in glass tubes at room temperature. Analysis of urinary menthol glucuronide confirmed that amended cigarettes used within 24 hours of injection delivered dose-related menthol levels to participants in a clinical laboratory setting. CONCLUSION: This method can be used to modify cigarettes with a range of reliable menthol levels in both filter and tobacco rod for use in laboratory and clinical research. IMPLICATIONS: This study presents a technique for modifying cigarettes with different levels of menthol that can reliably deliver dose-related menthol levels to participants when smoked in a clinical study. The technique can be used to quickly amend cigarettes to examine the independent effects of varying flavor and additive levels on smoking behavior, nicotine pharmacokinetics, mainstream smoke emissions, and other laboratory or clinical research outcomes.

Validation of the Wave 1 and Wave 2 Population Assessment of Tobacco and Health (PATH) Study Indicators of Tobacco Dependence Using Biomarkers of Nicotine Exposure Across Tobacco Products.

INTRODUCTION: This study examined the predictive relationships between biomarkers of nicotine exposure and 16-item self-reported level of tobacco dependence (TD) and subsequent tobacco use outcomes. AIMS AND METHODS: The Population Assessment of Tobacco and Health (PATH) Study surveyed adult current established tobacco users who provided urine biospecimens at Wave 1 (September 2013-December 2014) and completed the Wave 2 (October 2014-October 2015) interview (n = 6872). Mutually exclusive user groups at Wave 1 included: Cigarette Only, E-cigarette Only, Cigar Only, Hookah Only, Smokeless Tobacco Only, Cigarette Plus E-cigarette, multiple tobacco product users who smoked cigarettes, and multiple tobacco product users who did not smoke cigarettes. Total Nicotine Equivalents (TNE-2) and TD were measured at Wave 1. Approximate one-year outcomes included frequency/quantity used, quitting, and adding/switching to different tobacco products. RESULTS: For Cigarette Only smokers and multiple tobacco product users who smoked cigarettes, higher TD and TNE-2 were associated with: a tendency to smoke more, smoking more frequently over time, decreased likelihood of switching away from cigarettes, and decreased probability of quitting after one year. For other product user groups, Wave 1 TD and/or TNE-2 were less consistently related to changes in quantity and frequency of product use, or for adding or switching products, but higher TNE-2 was more consistently predictive of decreased probability of quitting. CONCLUSIONS: Self-reported TD and nicotine exposure assess common and independent aspects of dependence in relation to tobacco use behaviors for cigarette smokers. For other product user groups, nicotine exposure is a more consistent predictor of quitting than self-reported TD. IMPLICATIONS: This study suggests that smoking cigarettes leads to the most coherent pattern of associations consistent with a syndrome of TD. Because cigarettes continue to be prevalent and harmful, efforts to decrease their use may be accelerated via conventional means (eg, smoking cessation interventions and treatments), but also perhaps by decreasing their dependence potential. The implications for noncombustible tobacco products are less clear as the stability of tobacco use patterns that include products such as e-cigarettes continue to evolve. TD, nicotine exposure measures, and consumption could be used in studies that attempt to understand and predict product-specific tobacco use behavioral outcomes.

National longitudinal tobacco product cessation rates among US adults from the PATH Study: 2013-2019 (waves 1-5).

OBJECTIVE: To report on longitudinal tobacco product cessation rates, by product type, among adults (ages 18+ years) in the USA between 2013 and 2019. METHODS: The Population Assessment of Tobacco and Health Study, a nationally representative, longitudinal cohort study was used to report on annual and biennial rates of the following three cessation behaviours across 2013-2019: (1) discontinuing tobacco product use (ie, transition from past 30-day use to no past 30-day use), (2) attempting to quit tobacco product use and (3) quitting tobacco product use among those who attempted to quit. Each cessation behaviour was evaluated separately for cigarettes, electronic nicotine delivery systems (ENDS), cigars, hookah and smokeless tobacco. Generalised estimating equations were used to evaluate linear and nonlinear trends in cessation rates across the study period. RESULTS: Between 2013 and 2019, rates of discontinuing cigarette smoking among adults in the USA statistically increased from 16% to 18%, though these were consistently lower than rates of discontinuing use of other tobacco products. Similarly, quit attempt rates and rates of quitting among attempters increased for cigarette smokers. However, rates of discontinuing ENDS use sharply declined across the study period, from 62% to 44%. CONCLUSIONS: Findings show that tobacco product cessation rates have been changing in recent years in the USA alongside the changing tobacco product marketplace and regulatory environment, though rates of discontinuing cigarette smoking remain relatively low. Findings can serve as a benchmark against which future cessation rates can be compared with evaluate the impacts of future tobacco regulatory policies.

Can Increased Locomotor Task Difficulty Differentiate Knee Muscle Forces After Anterior Cruciate Ligament Reconstruction?

Changes in knee mechanics following anterior cruciate ligament (ACL) reconstruction are known to be magnified during more difficult locomotor tasks, such as when descending stairs. However, it is unclear if increased task difficulty could distinguish differences in forces generated by the muscles surrounding the knee. This study examined how knee muscle forces differ between individuals with ACL reconstruction with different graft types (hamstring tendon and patellar tendon autograft) and "healthy" controls when performing tasks with increasing difficulty. Dynamic simulations were used to identify knee muscle forces in 15 participants when walking overground and descending stairs. The analysis was restricted to the stance phase (foot contact through toe-off), yielding 162 separate simulations of locomotion in increasing difficulty: overground walking, step-to-floor stair descent, and step-to-step stair descent. Results indicated that knee muscle forces were significantly reduced after ACL reconstruction, and stair descent tasks better discriminated changes in the quadriceps and gastrocnemii muscle forces in the reconstructed knees. Changes in quadriceps forces after a patellar tendon graft and changes in gastrocnemii forces after a hamstring tendon graft were only revealed during stair descent. These results emphasize the importance of incorporating sufficiently difficult tasks to detect residual deficits in muscle forces after ACL reconstruction.

Nicotine Content and Physical Properties of Large Cigars and Cigarillos in the United States.

Introduction: Cigars are combusted tobacco products consisting of filler, binder, and wrapper, which are derived from tobacco. Despite the abundance of literature on the composition of traditional combusted cigarettes, research is limited on the physical and chemical properties of cigars. Therefore, research on cigar properties may be useful to better understand their health impact. Methods: In this study, twenty large cigar and cigarillo products were characterized for physical properties (ie, weight, length, and diameter), filler nicotine content, and tobacco pH. Tobacco pH was used to calculate free nicotine content, free nicotine concentration, and percent free nicotine for all cigars using the Henderson-Hasselbach equation. An additional analysis was performed on a second batch of two large cigar and two cigarillo brands to determine within-brand consistency. All analyses were performed in triplicate. Results: The initial analysis of the twenty cigars showed that cigars exhibited wide variation in product size and nicotine content, although tobacco pH was similar across cigars. Furthermore, in the two large cigar and cigarillo brands analyzed a second time, there was considerable within-brand variance in nicotine content and concentration between the first and second analyses. Conclusions: While only a small sample of commercially-available cigars was analyzed, our data suggest there is wide variability in nicotine content and some physical properties in the domestic cigar market. The data may help to inform potential future regulatory decisions related to these products. Implications: This study reveals some of the challenges to experimental cigar research and illustrates the need to characterize cigar products (eg, nicotine and tobacco content) before use in clinical studies. Additional studies and characterization of the physical and chemical properties of cigars may be useful to further understand these products' toxicity, abuse potential, and public health impact.

Dependence symptoms and cessation intentions among US adult daily cigarette, cigar, and e-cigarette users, 2012-2013.

BACKGROUND: Cigar and e-cigarette use is becoming increasingly common among US tobacco users and the Food and Drug Administration recently asserted regulatory jurisdiction over these products, among others, in May 2016. Research on tobacco dependence among users of these products is limited, however. We therefore examined several symptoms of dependence and cessation intentions among adult cigarette, cigar, and/or e-cigarette users in a nationally representative sample. METHODS: We used nationally representative data from more than 60,000 participants in the US National Adult Tobacco Survey (NATS) from 2012 to 2013 to analyze dependence symptoms and cessation intentions for users of cigarettes, cigars, and/or e-cigarettes but not other tobacco products. RESULTS: Among daily tobacco users, dual cigarette and cigar users on average smoked more cigarettes per day (17.3, 95 % CI = 16.1, 18.6 vs. 15.8, 95 % CI = 15.4, 16.2), had shorter times to first tobacco use after waking (21.4 min, 95 % CI = 16.6, 24.9 vs. 25.9 min, 95 % CI = 25.3, 26.5), and were more likely to report withdrawal and craving symptoms than exclusive cigarette smokers. Dual cigarette and e-cigarette users were more likely than exclusive cigarette smokers to report withdrawal and craving symptoms and cessation intentions. Exclusive cigar and e-cigarette users were less likely to report withdrawal and craving symptoms than users of other products, but even so, more than a third of exclusive cigar (38.8 %, 95 % CI = 27.4 %, 51.6 %) and e-cigarette (46.1 %, 95 % CI = 35.1 %, 57.4 %) users reported experiencing a strong craving for a tobacco product in the past 30 days. CONCLUSIONS: Dual cigarette and cigar users show evidence of greater dependence symptoms and dual cigarette and e-cigarette users show evidence of greater dependence symptoms and cessation intentions compared with exclusive cigarette smokers. A sizeable number of users of all of the tobacco products report dependence symptoms such as craving for tobacco.

Electronic cigarettes and nicotine clinical pharmacology.

OBJECTIVE: To review the available literature evaluating electronic cigarette (e-cigarette) nicotine clinical pharmacology in order to understand the potential impact of e-cigarettes on individual users, nicotine dependence and public health. METHODS: Literature searches were conducted between 1 October 2012 and 30 September 2013 using key terms in five electronic databases. Studies were included in the review if they were in English and publicly available; non-clinical studies, conference abstracts and studies exclusively measuring nicotine content in e-cigarette cartridges were excluded from the review. RESULTS: Nicotine yields from automated smoking machines suggest that e-cigarettes deliver less nicotine per puff than traditional cigarettes, and clinical studies indicate that e-cigarettes deliver only modest nicotine concentrations to the inexperienced e-cigarette user. However, current e-cigarette smokers are able to achieve systemic nicotine and/or cotinine concentrations similar to those produced from traditional cigarettes. Therefore, user experience is critically important for nicotine exposure, and may contribute to the products' ability to support and maintain nicotine dependence. CONCLUSIONS: Knowledge about e-cigarette nicotine pharmacology remains limited. Because a user's e-cigarette experience may significantly impact nicotine delivery, future nicotine pharmacokinetic and pharmacodynamic studies should be conducted in experienced users to accurately assess the products' impact on public health.

Examining the role of menthol cigarettes in progression to established smoking among youth.

BACKGROUND: Menthol, a flavoring compound added to cigarettes, makes cigarettes more appealing to youth and inexperienced smokers and increases cigarettes' abuse liability. However, limited studies are available on menthol's role in smoking progression. METHODS: To assess the association between menthol in cigarettes and progression to established smoking, we used five waves of data from the Evaluation of Public Education Campaign on Teen Tobacco Cohort Study, a nationally representative longitudinal survey of U.S. youth conducted as part of "The Real Cost" evaluation. We used discrete time survival analysis to model the occurrence of two event outcomes-progression to established, current smoking and progression to established, frequent smoking-using a logit model with a menthol use indicator as the key explanatory variable. Based on this framework, we estimated the effect of prior menthol use on the odds of smoking progression. RESULTS: In the progression to established, current smoking model, prior menthol use was significantly associated with progression [adjusted odds ratio (aOR) = 1.80, p < .05, confidence interval (CI) = (1.03-3.16)]. While results were in a similar direction for the model of progression to established, frequent smoking, the association between prior menthol use and this progression model did not reach significance [aOR = 1.56, CI = (0.80-3.03)]. CONCLUSION: The results suggest a relationship between using menthol cigarettes and progression from experimental to established, current smoking among youth. This study adds to a growing literature base that supports that menthol cigarettes, compared to nonmenthol cigarettes, put youth at increased risk for regular cigarette use.

Use Behaviors, Dependence, and Nicotine Exposure Associated with Ad Libitum Cigar Smoking.

OBJECTIVES: To examine factors important to cigar smoking and subsequent nicotine exposure, we evaluated the impact of cigar type, cigarette smoking history, and inhalation behaviors on nicotine dependence, smoking topography, and biomarkers of exposure in current exclusive cigar smokers. METHODS: Adult, exclusive cigar smokers (N = 77) were recruited based on cigar type, cigarette smoking history, and self-reported inhalation behaviors. Participants smoked their own brand product ad libitum for up to one hour; dependence symptoms, smoking topography, and biomarkers of exposure were assessed. RESULTS: Cigar smokers showed low levels of dependence. Cigar smoking alleviated withdrawal and craving symptoms, increased plasma nicotine concentration, and increased exhaled CO. Multiple regression analyses indicate that inhalation behaviors were associated with increased dependence and greater reductions in withdrawal symptoms upon cigar smoking. Large cigar smokers smoked longer and smoked more tobacco than small cigar and cigarillo smokers. Furthermore, large cigar smokers and self-reported inhalers were exposed to more nicotine than small cigar smokers and non-inhalers. CONCLUSIONS: Our study suggests that cigar type and smoking behaviors affect dependence and nicotine exposure upon cigar smoking. These findings provide additional insight into the substantial risks associated with cigar smoking.

Point of Sale Scanner Data for Rapid Surveillance of the E-cigarette Market.

OBJECTIVES: Describe e-cigarette sales trends and market share from U.S. convenience stores and mass market retailers. METHODS: We used Nielsen Scantrack to calculate U.S. e-cigarette sales market share from convenience and mass market channels during the 4-week period ending 1/19/13 through the period ending 12/19/15. Internet searches were used to supplement Nielsen product information. RESULTS: From 2013 to 2015, rechargeable e-cigarette brands VUSE and MarkTen experienced the largest growth in Nielsen channels. E-liquid and tank type brands Vapin Plus and Haus experienced growth although their Nielsen market share is small compared to other brands. Sales of brands with high labeled nicotine content (according to packaging or website) increased. Fruit-flavored sales increased rapidly in Nielsen, yet still represent a minority of market share in these channels. DISCUSSION: Market-leading e-cigarette brands changed substantially in Nielsen channels from 2013 to 2015. Brand leaders in these channels are now owned by tobacco companies. Changes in labelled nicotine content and fruit-flavored products and product types suggest that as e-cigarette use increases, convenience store and mass market channels are offering new products to meet consumer preferences; however, Nielsen channels do not represent the entire e-cigarette marketplace.

Mouth Level Exposure and Similarity to Machine-smoked Constituent Yields.

OBJECTIVES: The goal of this review was to evaluate which standard machine-smoking regimen may be most appropriate to inform tobacco product regulation based on the fraction of cigarette smoke yields that best represents the range of human smoke exposures. METHODS: We searched PubMed and Web of Science to identify peer-reviewed studies that reported percentages of smokers who smoked more or less like a particular machine-smoking regimen based on human mouth level exposure (MLE) tobacco constituent yields. RESULTS: Three studies met our inclusion criteria and were reviewed. Studies found that Canadian Intense (CI) yields were equal to or greater than 86% to 97% of smokers' nicotine and tar MLE yields. CONCLUSIONS: MLE yields indicate that a small percentage of individuals (less than 14%) are exposed to nicotine and tar yields equal to or greater than those measured by the CI regimen. Whereas no machine-smoking regimen reflects human puffing behavior with complete accuracy, based on MLE data, CI constituent yields constitute the best representation of exposure that encompasses the majority of smokers, and may be the most informative for regulatory purposes.

The influence of task complexity on knee joint kinetics following ACL reconstruction.

BACKGROUND: Previous research indicates that subjects with anterior cruciate ligament reconstruction exhibit abnormal knee joint movement patterns during functional activities like walking. While the sagittal plane mechanics have been studied extensively, less is known about the secondary planes, specifically with regard to more demanding tasks. This study explored the influence of task complexity on functional joint mechanics in the context of graft-specific surgeries. METHODS: In 25 participants (10 hamstring tendon graft, 6 patellar tendon graft, 9 matched controls), three-dimensional joint torques were calculated using a standard inverse dynamics approach during level walking and stair descent. The stair descent task was separated into two functionally different sub-tasks-step-to-floor and step-to-step. The differences in external knee moment profiles were compared between groups; paired differences between the reconstructed and non-reconstructed knees were also assessed. FINDINGS: The reconstructed knees, irrespective of graft type, typically exhibited significantly lower peak knee flexion moments compared to control knees during stair descent, with the differences more pronounced in the step-to-step task. Frontal plane adduction torque deficits were graft specific and limited to the hamstring tendon knees during the step-to-step task. Internal rotation torque deficits were also primarily limited to the hamstring tendon graft group during stair descent. Collectively, these results suggest that task complexity was a primary driver of differences in joint mechanics between anterior cruciate ligament reconstructed individuals and controls, and such differences were more pronounced in individuals with hamstring tendon grafts. INTERPRETATION: The mechanical environment experienced in the cartilage during repetitive, cyclical tasks such as walking and other activities of daily living has been argued to contribute to the development of degenerative changes to the joint and ultimately osteoarthritis. Given the task-specific and graft-specific differences in joint mechanics detected in this study, care should be taken during the rehabilitation process to mitigate these changes.

Cigarette smoking cessation attempts among current US smokers who also use smokeless tobacco.

INTRODUCTION: Concurrent use of cigarettes and smokeless tobacco is common, but little is known regarding the association of smokeless tobacco use with cigarette smoking cessation. Dual users may have lower cigarette consumption levels, which may also play a role in smoking cessation. METHODS: The 2010-2011 Tobacco Use Supplement to the Current Population Survey included 26,760 current cigarette smokers, of which 675 concurrently used smokeless tobacco. We compared characteristics of the most recent cigarette smoking quit attempt of the past year between dual users and exclusive smokers, using multivariate regression. RESULTS: Dual users (45%) were more likely than exclusive smokers (37%) to have made a cigarette smoking quit attempt during the previous year (p<0.01), even after adjusting for demographic differences and cigarette dependence levels (ORadj 1.33, 95% CI 1.15-1.53). Half (48%) of dual users who made a quit attempt tried to quit "by switching to smokeless tobacco". However, once in a quit attempt, dual users relapsed more quickly than exclusive smokers (Cox regression HRadj 1.13, 95% CI 1.02-1.26). There was no difference in 30-day abstinence rates on the most recent quit attempt (ORadj 1.09, 95% CI 0.88-1.37). For both groups, the best predictor of past 30-day abstinence was cigarette consumption level. CONCLUSIONS: Current cigarette smokers who also use smokeless tobacco are more likely to have tried to quit, but relapse more quickly than exclusive smokers, and are not more likely to have attained 30day smoking cessation. Prospective studies at the population level are needed.

Symptoms of tobacco dependence among middle and high school tobacco users: results from the 2012 National Youth Tobacco Survey.

BACKGROUND: A growing body of evidence suggests that tobacco dependence symptoms can occur soon after smoking onset and with low levels of use. However, limited data are available nationally and among non-cigarette tobacco users. PURPOSE: To examine the prevalence and determinants of tobacco dependence symptoms among adolescent tobacco users in the 2012 National Youth Tobacco Survey, a nationally representative, school-based survey of U.S. middle and high school students. METHODS: Multivariate logistic regression was used to identify independent predictors of dependence symptoms among current users (i.e., past 30-day use) of cigarettes, cigars, or smokeless tobacco. Analyses were conducted in 2013 using SAS-callable SUDAAN, version 11 to account for the complex survey design. RESULTS: Prevalence of tobacco dependence symptoms ranged from 20.8% (95% CI=18.6, 23.1) of current tobacco users reporting wanting to use tobacco within 30 minutes of waking to 41.9% (95% CI=39.3, 44.5) reporting recent strong cravings. Reporting of dependence symptoms was most consistently associated with polytobacco use, higher frequency of use, earlier initiation age, and female gender. A 2-4-fold increase in the odds of symptom reporting was found in adolescents using tobacco products on as few as 3-5 days compared to those who only used it for 1-2 of the past 30 days. CONCLUSIONS: A substantial proportion of U.S. adolescent tobacco users, including those with low levels of use, report symptoms of tobacco dependence. These findings demonstrate the need for full implementation of evidence-based strategies to prevent both experimentation and progression to regular tobacco use among youth.