Comparing brain absorption and lung deposition of nicotine salts and free-base e-cigarettes: insights from [11C]nicotine PET imaging

Nicotine salt-based (NSB) e-liquids have transformed the electronic cigarette (EC) market and are associated with greater nicotine delivery, appeal, and abuse liability compared with free base nicotine (FBN). However, the effects of nicotine protonation on deposition and absorption throughout the respiratory tract and brain are poorly understood. We compared the effects of nicotine protonation on puffing behavior, subjective effects, and distribution of inhaled nicotine across the respiratory tract and brain using a single-blinded, randomized crossover study with PET/CT imagining conducted from March 2022 to June 2023. Participants were a convenience sample of 20 adult exclusive EC users aged 21-50 years old, recruited from Winston-Salem, North Carolina, and surrounding areas. Participants inhaled a single puff of radiolabeled [¹¹C]nicotine formulated as either NSB (100% protonated) or FBN (0% protonated) e-liquid using a standardized EC device. E-liquids were identical except for nicotine form. Nicotine uptake was assessed using dynamic PET/CT imaging and quantified using standardized uptake values (SUVs) and percentage of total absorbed dose per kilogram of tissue (%TAD/kg). Puff topography and subjective effects were also measured. Among 20 participants (M = 33.0 [7.6] years), NSB e-liquids resulted in significantly greater nicotine uptake in the lower respiratory tract, including bronchi and lungs (SUV increases of 101-109%), whereas FBN e-liquids showed greater uptake in the upper respiratory tract, including the oral cavity, throat, and trachea (SUV increases of 40-202%). Analyses of %TAD/kg confirmed these findings, with NSB associated with 78-112% greater lower airway deposition and FBN with 80-108% greater upper airway deposition across imaging sequences. No significant differences were observed in brain nicotine uptake, puffing topography, or subjective effects between nicotine forms. Nicotine protonation alters the deposition of inhaled nicotine, shifting exposure from the upper to the lower respiratory tract with no significant differences in brain nicotine accumulation. These findings underscore that nicotine form may influence site-specific respiratory exposure to EC aerosol constituents, with potential implications for long-term health risks.