Partial Nicotine Reduction and E-Cigarette Users' Puffing Behaviors Among Adults Aged 21 to 35 Years: A Randomized Crossover Clinical Trial.

Importance: The advent of salt-based, high-nicotine electronic nicotine delivery systems [e-cigarettes] has contributed to their epidemic use among young people in the US, necessitating the need for policies to address the addictiveness of these products. Objective: To evaluate the effect of partial nicotine reduction on new-generation e-cigarette users' puffing behaviors. Design, Setting, and Participants: This randomized crossover clinical trial was conducted at the Clinical Research Lab for Tobacco Smoking at Florida International University in Miami between April 15, 2022, and October 17, 2023. Using a volunteering sampling method by distributing flyers and advertisements, current e-cigarette users (who preferred 5% nicotine concentration), aged 21 to 35 years, were included. Intervention: In a crossover design, participants completed 2 sessions of the same product (JUUL or NJOY) that differed by nicotine concentration (3% [JUUL] or 2.4% [NJOY] and 5% [JUUL or NJOY]) in random order. In each session, participants vaped up to 60 minutes ad libitum, preceded by 12 hours of nicotine abstinence. Main Outcomes and Measures: The primary outcomes were puffing topography parameters (eg, total session time, puffing time, total puffing number, interpuff interval, total inhaled volume, average puff volume, duration, and flow rate) measured during each session and plasma nicotine measured before and after each session. Results: Among 735 participants who were approached for eligibility, 675 were excluded, and 10 did not complete session 2. Of the 50 remaining current e-cigarette users (mean [SD] age, 23 [3] years; 56% men), 23 (46%) were low nicotine dependent. The median topography parameters were significantly higher during the e-cigarette use sessions with 3% or 2.4% nicotine concentration compared with 5% nicotine concentration for 3 outcomes: puffing time (1.3 minutes [IQR, 0.3-9.4 minutes] vs 1.2 minutes [IQR, 0.2-5.6 minutes]; P = .02), puff duration (2.6 seconds [IQR, 0.8-6.9 seconds] vs 2.4 seconds [IQR, 0.4-6.6 seconds]; P = .02), and total inhaled volume (1990.0 mL [IQR, 279.0-24 400.0 mL] vs 1490.0 mL [IQR, 148.0-14 300.0 mL]; P = .05). The median plasma nicotine boost observed in the 5% nicotine concentration condition (0.0060 mg/L [IQR, 0.0001-0.0249 mg/L]) was significantly higher than that in the 3% or 2.4% session (0.0043 mg/L [IQR, 0.0008-0.0225 mg/L]) (P = .001). Additionally, deeper puffing (increased average puff duration and average puff volume) was observed in participants with higher nicotine dependence (1.42 seconds [95% CI, 1.12-1.80 seconds]; P = .03) and male users (1.38 mL [95% CI, 1.09-1.75 mL]; P = .04) in response to nicotine reduction. Conclusions and Relevance: This randomized crossover clinical trial provides direct evidence that partial nicotine reduction in salt-based e-cigarettes was associated with acute compensatory puffing and the potential for increased exposure to toxicants. However, given the reduced nicotine delivery associated with nicotine reduction, the acute compensatory response observed in this study may not preclude a population benefit due to the marketing of less addictive products. These results suggest that at least for current e-cigarette users, partial nicotine reduction can lead to enhanced exposure to some toxicants in the short term. Trial Registration: ClinicalTrials.gov Identifier: NCT05205382.