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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.

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.

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.

Noncompliance or non-adherence to randomized treatment is a common challenge when interpreting data from randomized clinical trials. The effect of an intervention if all participants were forced to comply with the assigned treatment (i.e., the causal effect) is often of primary scientific interest. For example, in trials of very low nicotine content (VLNC) cigarettes, policymakers are interested in their effect on smoking behavior if their use were to be compelled by regulation. A variety of statistical methods to estimate the causal effect of an intervention have been proposed, but these methods, including inverse probability of compliance weighted (IPCW) estimators, assume that participants' compliance statuses are reported without error. This is an untenable assumption when compliance is based on self-report. Biomarkers (e.g., nicotine levels in the urine) may provide more reliable indicators of compliance but cannot perfectly discriminate between compliers and non-compliers. However, by modeling the distribution of the biomarker as a mixture distribution and writing the probability of compliance as a function of the mixture components, we show how the probability of compliance can be directly estimated from the data even when compliance status is unknown. To estimate the causal effect, we develop a new approach which re-weights participants by the product of their probability of compliance given the observed data and the inverse probability of compliance given confounders. We show that our proposed estimator is consistent and asymptotically normal and show that in some situations the proposed approach is more efficient than standard IPCW estimators. We demonstrate via simulation that the proposed estimator achieves smaller bias and greater efficiency than ad hoc approaches to estimating the causal effect when compliance is measured with error. We apply our method to data from a recently completed randomized trial of VLNC cigarettes.

Introduction Understanding how smokers perceive reduced nicotine content cigarettes will be important if the FDA and global regulatory agencies implement reduced nicotine product standards for cigarettes. Prior research has shown that some smokers incorrectly believe "light" cigarettes are less harmful than regular cigarettes. Similar misunderstandings of health risk could also apply to reduced nicotine cigarettes. To date, most studies of reduced nicotine cigarettes have blinded subjects to the nicotine content. Therefore, little is known about how smokers experience reduced nicotine content cigarettes when they are aware of the reduced content, and how use may be impacted. Methods The present study was a within-subjects experiment with 68 adult daily smokers who smoked two identical very low nicotine content Quest 3 (0.05 mg nicotine yield) cigarettes. Subjects were told that one cigarette contained "average" nicotine content, and the other contained "very low" nicotine content. After smoking each cigarette, subjects completed subjective measures about their smoking experience. Results Subjects rated the "very low" nicotine cigarette as less harmful to their health overall compared to the "average" nicotine cigarette; this effect held true for specific smoking-related diseases. Additionally, they rated the "very low" nicotine cigarette as having less desirable subjective effects than the "average" nicotine cigarette and predicted having greater interest in quitting smoking in the future if only the "very low" nicotine cigarette was available. Conclusions Explicit knowledge of very low nicotine content changes smokers' perceptions of very low nicotine content cigarettes, resulting in reduced predicted harm, subjective ratings and predicted future use. Implications Before a reduced nicotine product standard for cigarettes can be implemented, it is important to understand how product information impacts how smokers think about and experience very low nicotine content cigarettes. Prior research has shown that smokers incorrectly believed light cigarettes were less harmful products. As such, smokers may also misunderstand the health risks associated with smoking very low nicotine content cigarettes. This study highlights the importance of smokers' perceptions of nicotine content in cigarettes on the perceived health risks and the subjective effects of smoking very low nicotine content cigarettes.

INTRODUCTION Product standards reducing the level of nicotine in cigarettes could significantly improve public health by reducing smoking behavior and toxicant exposure. However, relatively little is known about how the regulatory strategy could impact alcohol use, a closely related health behavior that is also a major contributor to morbidity and mortality. The primary objective of this paper is to predict the effect of nicotine reduction on alcohol use, identify priorities for future research, and highlight areas for mitigating any adverse outcomes. METHODS We critically reviewed and integrated literatures examining the effects of very low nicotine content (VLNC) cigarettes on smoking-related outcomes (nicotine exposure, nicotine withdrawal, and smoking as a cue to drink) and, in turn, the effects of those outcomes on alcohol use. RESULTS Current evidence suggests reducing the nicotine content of cigarettes may benefit public health by reducing alcohol use and problematic drinking over time as a consequence of reduced exposure to nicotine and the smoking cues associated with drinking. Nicotine withdrawal could increase risk of drinking, although these effects should be short-lived and could be mitigated by other sources of nicotine. Gender, hazardous drinking, and psychiatric comorbidities are likely to be important moderators of the effects of VLNC cigarettes. CONCLUSIONS It is imperative to broadly assess the public health impact of potential tobacco product regulations by including measures of closely related health behaviors that could be impacted by these interventions. Nicotine reduction in cigarettes may contribute to improved public health through reductions in alcohol use.

Introduction Research has identified at least two positive reinforcement-related effects of nicotine: (a) primary reinforcement and (b) enhancement of reinforcement from concurrently available stimuli. Prior examples of the reinforcement-enhancing effects with rats showed that repeated, intermittent nicotine exposure increased responding for non-nicotine reinforcers, and this effect remained robust over several weeks. However, the effects of continuous nicotine exposure on responding for a non-nicotine reinforcer are unknown, as are the effects of abruptly withdrawing continuous nicotine on behavior maintained by the same reinforcer. Methods Lever pressing for a visual reinforcer under a fixed ratio schedule was assessed while rats were maintained on a chronic, continuous infusion of nicotine (3.16 mg/kg/day; osmotic minipump). The effects of precipitated withdrawal on responding, following 16 days of continuous nicotine exposure, were assessed by pre-session subcutaneous injections of mecamylamine (1.0 mg/kg). Results Continuous nicotine initially increased active responding for the visual reinforcer; however, continued exposure resulted in an attenuation of this effect. Precipitated withdrawal from nicotine resulted in a significant decline in active responding. Conclusions The initial increase in responding for the visual reinforcer with chronic nicotine exposure is consistent with prior research showing that intermittent exposure to nicotine acts as a reinforcement enhancer. However, the attenuation of this enhancement following prolonged nicotine exposure is in contrast with the persistent effects previously reported. Finally, the decrease in visual reinforcers below control levels (nicotine-naive animals) following nicotine withdrawal highlights a potential for affective withdrawal, which may serve as a motive for continued nicotine use.