Toxicant Exposures After Switching From Cigarettes to a Pod-Based Electronic Cigarette: A Randomized Clinical Trial

Electronic cigarettes (EC) have been shown to expose users to fewer tobacco-related toxicants compared with combustible cigarettes. The current generation of ECs has rapidly shifted toward pod-based nicotine salt formulation ECs, and more research is needed to understand the impacts of using these EC products among those who smoke.

To determine the short-term effects of switching from cigarettes to a pod-based 5% nicotine EC, compared with a 0% nicotine EC.

This double-blind, parallel-arm, randomized, placebo-controlled trial with follow-up at 6 weeks (randomized phase) and 10 weeks (postrandomized phase) was conducted at a single-site academic medical center in Pennsylvania from April 22, 2022, to December 12, 2023. Participants included adults who smoked more than 4 cigarettes per day (CPD) and expressed interest in switching completely to an EC. Data were analyzed from August 23, 2024, to December 1, 2025.

Participants were allocated 1:1 to the standardized research EC (SREC) with 5% nicotine or 0% nicotine for 6 weeks.

The primary outcome was concentration of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) in urine corrected for creatinine level at 6 weeks. Secondary outcomes included exhaled carbon monoxide (CO), cotinine level, CPD, CO-verified cigarette abstinence, and levels of volatile organic compounds.

A total of 104 participants (52 per group) were randomized, of whom 68 (65.4%) were female, with a mean (SD) age of 50.9 (10.0) years. At 6 weeks, the 5% SREC group did not have significantly lower NNAL levels (mean difference [MD], -116.6 [95% CI, -245.4 to 12.2] pg/mg; P = .08). However, a greater proportion of participants in the 5% SREC group were abstinent from cigarettes (19 of 52 [36.5%] vs 6 of 52 [11.5%]; P = .005), compared with the 0% SREC group. The 5% SREC group had greater cotinine levels (MD, 2367.8 [95% CI, 407.5-4328.2] ng/mg; P = .02); however, there were no differences in CPD (MD, -0.9 [95% CI, -3.9 to 2.1] CPD; P = .55) or exhaled CO levels (MD, -5.1 [95% CI, -12.9 to 2.6] ppm; P = .19) between groups. Levels of cyanoethyl mercapturic acid (CYMA) (MD, -49.0 [95% CI, -90.4 to -7.6] ng/mg; P = .02) and 3-hydroxypropyl mercapturic acid (3HPMA) (MD, -290.8 [95% CI, -514.0 to -67.6] ng/mg; P = .01), biomarkers of acrylonitrile (a carcinogen) and acrolein (a cardiac toxicant) exposure (both of which are respiratory toxicants), were lower in the 5% SREC group compared with the 0% SREC group.

In this randomized clinical trial of adults who smoke, switching from cigarettes to a 5% SREC vs a 0% SREC resulted in reduced exposure to some toxicants delivered by cigarette smoking and an increased rate of smoking cessation. ECs that deliver nicotine like a cigarette may have an important role in reducing the harmful toxicant exposure caused by cigarette smoking.

ClinicalTrials.gov Identifier: NCT03625986.