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

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

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.

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.

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.

Introduction

Both the Tobacco Control Act in the U.S. and Article 9 of the Framework Convention on Tobacco Control enable governments to directly address the addictiveness of combustible tobacco by reducing nicotine through product standards. Although nicotine may have some harmful effects, the detrimental health effects of smoked tobacco are primarily due to non-nicotine constituents. Hence, the health effects of nicotine reduction would likely be determined by changes in behavior that result in changes in smoke exposure.

Methods

Herein, we review the current evidence on nicotine reduction and discuss some of the challenges in establishing the empirical basis for regulatory decisions.

Results

To date, research suggests that very low nicotine content cigarettes produce a desirable set of outcomes, including reduced exposure to nicotine, reduced smoking, and reduced dependence, without significant safety concerns. However, much is still unknown, including the effects of gradual versus abrupt changes in nicotine content, effects in vulnerable populations, and impact on youth.

Discussion

A coordinated effort must be made to provide the best possible scientific basis for regulatory decisions. The outcome of this effort may provide the foundation for a novel approach to tobacco control that dramatically reduces the devastating health consequences of smoked tobacco.

Cigarette smoking remains highly prevalent in the U.S. and contributes significantly to cardiovascular disease (CVD). Tobacco control policies, including product regulation, can reduce smoking-related harm. One approach being considered in the U.S. is for the FDA to set a low nicotine standard for cigarettes. Such a standard could result in multiple beneficial outcomes including reduced cardiovascular toxicity related to nicotine, reduced smoking intensity in current smokers, increased cessation rates, decreased development of smoking dependence in youth, and decreased passive smoke exposure. Consequently, CVD risk in the U.S. could be dramatically improved by nicotine reduction in cigarettes. Possible pathways linking nicotine reduction in cigarettes to decreased CVD risk are discussed, while potential unintended consequences that could offset expected gains are also presented. Gaps in the literature, including limited data on CVD biomarkers and long-term CVD outcomes following the use of very low nicotine cigarettes, are discussed to highlight areas for new research.

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.

Rationale

The ability of nicotine to suppress body weight is cited as a factor impacting smoking initiation and the failure to quit. Self-administered nicotine in male rats suppresses weight independent of food intake, suggesting that nicotine increases energy expenditure.

Objective

The current experiment evaluated the impact of self-administered nicotine on metabolism in rats using indirect calorimetry and body composition analysis.

Methods

Adult male rats with ad libitum access to powdered standard rodent chow self-administered intravenous infusions of nicotine (60 μg/kg/infusion or saline control) in daily 1-h sessions in the last hour of the light cycle. Indirect calorimetry measured respiratory exchange ratio (RER), energy expenditure, motor activity, and food and water consumption for 22.5 h between select self-administration sessions.

Results

Self-administered nicotine suppressed weight gain and reduced the percent of body fat without altering the percent of lean mass, as measured by Echo MRI. Nicotine reduced RER, indicating increased fat utilization; this effect was observed prior to weight suppression. Moreover, nicotine intake did not affect motor activity or energy expenditure. Daily food intake was not altered by nicotine self-administration; however, a trend in suppression of meal size, a transient suppression of water intake, and an increase in meal frequency was observed.

Conclusion

These data provide evidence that self-administered nicotine suppresses body weight via increased fat metabolism, independent of significant changes in feeding, activity, or energy expenditure.

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