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.