Plasma menthol delivery from a heated tobacco product predicts substitution for menthol cigarettes.

Abstract

Substitution between tobacco products depends on similarity in abuse liability profiles, particularly pharmacologic reinforcement. While nicotine delivery has been extensively characterized in the literature, the contribution of menthol delivery remains poorly understood. This study examined menthol exposure from a heated tobacco product (IQOS) and assessed whether plasma menthol delivery predicts willingness to substitute it for menthol cigarettes. This exploratory analysis used data from a randomized, parallel-group, 14-day clinical trial of adults who smoke menthol cigarettes (N = 22). Participants used their own-brand menthol cigarettes (Week 1), then were randomized to use IQOS with Fresh Menthol (IQOS-M) or Regular/Tobacco (IQOS-T) HeatSticks (Week 2). Plasma nicotine and menthol glucuronide were measured before and after a laboratory-based 10-puff directed use bout. Substitution was assessed via the cross-price elasticity (CPE) of IQOS relative to menthol cigarettes in the Experimental Tobacco Marketplace task. IQOS-M boosted plasma menthol glucuronide levels more than IQOS-T (18.9 versus 0.2ng/mL, p < 0.01), while nicotine delivery did not differ significantly. The CPE of IQOS was greater in the IQOS-M group than in the IQOS-T group (0.8 versus 0.0; p = 0.03), indicating greater substitutability. Menthol glucuronide boosts were positively associated with CPE (τ=0.32, p = 0.03), whereas nicotine boosts were not significantly associated (τ=0.19, p = 0.20). IQOS can deliver high levels of menthol, and menthol delivery predicted willingness to substitute this heated tobacco product for menthol cigarettes. These findings highlight the importance of non-nicotine constituents in shaping abuse liability and have direct implications for the regulation of tobacco products.