Pharmacokinetic and abuse liability assessment of tobacco-flavored and menthol-flavored pod-based electronic nicotine delivery systems with 5% and 3% nicotine concentrations relative to combustible cigarettes

BACKGROUND: Nicotine pharmacokinetics (PK) and subjective effects influence the abuse liability of electronic nicotine delivery systems (ENDS). This two-arm randomized crossover pharmacokinetic study assessed nicotine delivery from and subjective responses to four JUUL2 ENDS products (Virginia Tobacco and Fresh Menthol flavors [5% and 3% nicotine concentrations]) compared to combustible cigarettes and NJOY Ace (Classic Tobacco and Menthol flavors; 5% nicotine) among adult dual users. METHODS: Adults who smoked cigarettes daily and concurrently used ENDS (dual users) were assigned to one of two study arms based on whether they smoked nonmentholated cigarettes (Tobacco Arm [N = 30]) or mentholated cigarettes (Menthol Arm [N = 30]). On four consecutive study days participants first used each assigned product in a controlled use session (10 standardized 3-second puffs), and then, after ≥ 4 h of nicotine abstinence, in a 5-minute ad libitum use session. RESULTS: In both study arms and use conditions, peak nicotine delivery and total nicotine exposure from study ENDS products either did not statistically significantly differ from or was significantly lower than that of combustible cigarettes; time to maximum nicotine concentration did not significantly differ. All study ENDS products were rated as substantially less reinforcing than cigarettes, but similarly effective at reducing urge-to-smoke. CONCLUSIONS: The abuse liability profiles of all menthol-flavored and tobacco-flavored ENDS evaluated in this study were lower than cigarettes. The 5% nicotine ENDS products generally delivered comparable peak levels of nicotine and alleviated cravings for cigarettes to a similar extent as participants' usual brand cigarettes, suggesting they can be effective substitutes for cigarettes. CLINICAL TRIAL NUMBER: ISRCTN29801527 on October 25, 2024.