E-cigarette use frequency mediates effects in three randomized controlled trials of reduced nicotine cigarettes with tobacco vs preferred flavor e-cigarettes in high-risk populations in the U.S

Objectives: The U.S. Food and Drug Administration is authorized to implement a nicotine-reducing standard to decrease smoking. Three recent trials found switching to very low nicotine content (VLNC) cigarettes produced the greatest reduction in cigarettes/day and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL, a tobacco-specific carcinogen) among adults from high-risk populations when participants also received preferred- vs tobacco-flavored e-cigarettes. This pooled secondary analysis investigates e-cigarette use frequency as a mechanism driving these effects. Methods: Participants (U.S. adults with affective disorders, adults with opioid use disorder, and reproductive-age females with ≤high-school education) were randomized to 16 weeks of VLNC cigarettes with preferred-flavored e-cigarettes selected from eight options (VLNC+PF; n = 84) or VLNC cigarettes with tobacco-flavored e-cigarettes (VLNC+TF; n = 74) from October 2020–November 2023. General linear models explored whether e-cigarette use frequency (days/week) between Weeks 1–15 mediated effects on Week-16 cigarettes/day and NNAL. Results: Participants were 40.4 (mean) years old (SD = 11.5), 69.0 % female, 81.0 % white, and smoked 17.3 (mean) cigarettes/day (SD = 9.0) at baseline. The VLNC+PF condition reported more e-cigarette use days/week (LSmean[SEM]): 4.3[±0.4]) than the VLNC+TF condition (LSMean[SEM]: 3.4[±0.5]; F[1151] = 3.9, p < .05) across weeks 1–15. More e-cigarette use days/week predicted greater reductions in mean cigarettes/day (β[SE]: −0.32[±0.05)]; F[1106] = 50.5, p < .01) and NNAL (β[SE]: −0.14[±0.04]; F[1,92] = 12.2, p < .01) at Week-16. E-cigarette use frequency fully mediated the effects of condition on cigarettes/day and partially mediated effects on NNAL. Conclusions: Greater frequency of e-cigarette use was a mechanism by which preferred-flavor e-cigarettes led to reductions in smoking and tobacco-toxicant exposure, demonstrating the potential for appealing e-cigarettes to reduce harm among high-risk populations who smoke.