A randomized controlled trial of reduced nicotine cigarettes and e-cigarettes among dual users

SUMMARY Cigarette smoking remains the leading cause of preventable morbidity and mortality in the US. Use of multiple tobacco products is becoming increasingly prevalent, with dual use of e-cigarettes and cigarettes representing the most common combination. Though e-cigarettes are not without risk, completely switching from cigarettes to

e-cigarettes likely reduces risk for tobacco-related harm. However, the vast majority of established dual users maintain long-term smoking and the majority, who use e-cigarettes non-daily, are at an even greater risk for prolonged smoking than exclusive cigarette smokers. The Food and Drug Administration Center for Tobacco

Products (FDA CTP) has announced plans to implement a nicotine-limiting product standard, capping the nicotine in cigarettes at a minimally or non-addictive level. Randomized controlled trials (RCTs) demonstrate that exclusive smokers respond to very low nicotine content (VLNC) cigarettes with reductions in smoking, demand,

and dependence. However, nicotine reduction RCTs to date have excluded regular e-cigarette users and therefore it remains unclear how a nicotine-limiting standard for cigarettes would affect smoking among dual users. Given the potential substitutability of e-cigarettes for cigarettes, reducing the nicotine in cigarettes could

promote a transition to exclusive e-cigarette use among dual users unable to completely quit nicotine, but only if sufficiently appealing e-cigarettes remain available. E-cigarettes containing 5% nicotine-salt solution are currently most popular in the US but policy makers have proposed restricting e-cigarettes to ≤2% nicotine to curb

youth e-cigarette use. Prior laboratory studies indicate that higher vs lower nicotine e-cigarettes serve as better substitutes for cigarettes among adult dual users. As such, a restriction on e-cigarette nicotine concentration could undermine the potential for e-cigarettes to substitute for cigarettes and diminish the benefits of a nicotine-

limiting standard for cigarettes among dual users. We propose a 12-week double-blind 2 cigarette level (Normal Nicotine vs Very Low Nicotine) x 2 e-cigarette level (High Nicotine vs Low Nicotine) between-subjects factorial trial to investigate how a nicotine-limiting standard for cigarettes affects adult dual users and whether these

effects are impacted by constraints on e-cigarette nicotine concentration. Outcome measures include cigarettes per day, cigarette dependence, and toxicant exposure. The research is highly relevant to FDA CTP domains of Addiction and Behavior because it will test whether reducing the nicotine content of cigarettes reduces smoking

and dependence, and whether these effects are moderated by the availability of high vs low nicotine e-cigarettes. It also addresses the Health Effects domain by assessing toxicant exposure. It is innovative because it is, to our knowledge, the first RCT of a nicotine-limiting standard among the growing population of US adults who use

multiple tobacco products. Finally, it is programmatic as it builds upon a decade of nicotine reduction research that we have conducted. Overall, this trial has the potential to provide FDA CTP with evidence on an understudied population important to its regulatory responsibilities.