The Family Smoking Prevention and Tobacco Control Act 2009 gave FDA authority to limit cigarette nicotine levels. Arguments have been made for mandating a reduction in cigarettes in order to reduce levels of nicotine dependence and therefore increase smoking cessation rates and decrease the overwhelming morbidity and mortality associated with smoking (Benowitz and Henningfield, 1994). Studies have suggested reduced nicotine cigarettes result in decreased nicotine intake (Benowitz et al. 2007; Donny et al., 2015) and decreased nicotine dependence (Donny et al., 2015). However, critical questions remain regarding the abuse-liability of reduced nicotine cigarettes, whether exposure to reduced nicotine cigarettes reduces use in both reduced- and full-nicotine cigarettes, whether reduced-nicotine cigarettes will substitute for full-nicotine cigarettes, and the dose-effects of these potential effects. The addictive effects and abuse liability of reduced nicotine cigarettes, therefore, are not well understood. This double-blind study will systematically determine the abuse liability of reduced-nicotine cigarettes compared to standard full-nicotine cigarettes using a behavioral economics abuse- liability approach. The proposed study in 100 (50 men/women) non-treatment seeking dependent smokers will determine the abuse liability of reduced-nicotine cigarettes compared to full-nicotine cigarettes using a behavioral economics abuse-liability approach. Laboratory determination of cigarette consumption under various response requirements will occur before and after 6 weeks of at-home exposure, with participants randomized to full (15.8 mg nicotine/g tobacco) or varying levels of reduced nicotine cigarettes (5.2, 2.4, and 1.3 mg/g) to determine the role of experience on the abuse-liability of reduced nicotine cigarettes. Abuse liability will be assessed by 2 essential demand metrics: lower demand intensity and increased demand elasticity, as well as other demand metrics and subjective ratings of “liking”. The study will also determine the degree to which reduced-nicotine cigarettes may substitute for full-nicotine cigarettes – testing whether a reduced-nicotine policy would achieve the goal of reducing full-nicotine cigarette consumption. By examining nicotine dose-effects, the study will also determine a nicotine “addictiveness threshold” below which abuse- liability and nicotine dependence decreases. We hypothesize that abuse liability of reduced- and full-nicotine cigarettes will be decreased after 6-weeks exposure to reduced-nicotine, but not full-nicotine cigarettes. We hypothesize that reduced-nicotine cigarettes will substitute for full-nicotine cigarettes both before and after the exposure period, but there will be an increase in the degree of substitutability. Regarding dose effects, we hypothesize that reduced abuse liability will be observed with exposure to 2.4 and 1.3 mg/g relative to 5.2 and 15.8 mg/g cigarettes. We hypothesize that results with demand curve metrics (decreases in intensity of demand and increases in elasticity) will show significant but modest correlations to decreased ratings of “liking.” This study stands to substantially inform tobacco public policy with advanced empirical abuse-liability testing.

NARRATIVE Nicotine addiction is the leading preventable cause of mortality worldwide. The FDA holds the authority to reduce nicotine levels in cigarettes, although the addictive effects and abuse liability of such reduced nicotine cigarettes are not fully understood. The present study will determine the addictiveness and abuse liability of reduced nicotine cigarettes compared to full nicotine cigarettes in order to inform the FDA regarding nicotine reduction policies.