Summary: A randomized, placebo-controlled trial reveals that switching to pod-based salt-nicotine electronic cigarettes significantly boosts the odds of quitting traditional smoking while dramatically reducing exposure to harmful, tobacco-related toxins.
The clinical trial demonstrated that daily smokers who transitioned to a 5% nicotine e-cigarette were three times more likely to quit smoking within six weeks compared to those using an identical, nicotine-free placebo device. This study provides vital, real-world data for public health officials seeking safer, non-combustible alternatives for smokers who have failed to quit using traditional medications.
Key Facts
- Three-Fold Quitting Edge: At the end of the six-week study, 36.5% of participants in the 5% nicotine group had completely stopped smoking cigarettes, compared to just 11.5% in the zero-nicotine placebo group—a behavioral divergence that remained stable through a 10-week follow-up.
- Carcinogen Reduction: Both cohorts experienced a distinct drop in several tobacco-related toxicants, specifically NNAL, a potent, lung-selective carcinogen derived exclusively from the tobacco leaf. The 5% nicotine group achieved the most substantial drops in chemical exposure.
- The Power of Salt-Nicotine: Unlike older, less efficient vapor designs, modern pod-based systems utilize a specialized nicotine salt formulation. This chemistry delivers nicotine into the bloodstream more smoothly and efficiently, mimicking cigarette-level delivery to actively suppress withdrawal symptoms and intense cravings.
- A U.S. Clinical Trial First: To the authors’ knowledge, this project represents the first randomized, double-blind, placebo-controlled trial conducted in the United States to evaluate the chemical and behavioral effects of switching completely from combustible cigarettes to pod-based salt-nicotine devices.
- Combustion vs. Substance: The research reinforces a foundational public health concept: while nicotine is the highly addictive component of tobacco, it is not the primary cause of smoking-related cancers and cardiovascular disease. Instead, the toxic byproducts generated by burning tobacco leaf are the primary drivers of disease.
Source: Penn State
Cigarette smoking is the leading preventable cause of death in the United States, even as rates of cigarette smoking have fallen to an all-time low of approximately 10% in 2024. Some studies suggest that electronic cigarettes (e-cigarettes), help people quit smoking and expose them to fewer harmful chemicals — but products have changed rapidly, and it’s unclear whether these benefits still hold true.
A new study led by researchers from Penn State College of Medicine found that switching to a pod-based salt-nicotine e-cigarette — one of the most popular types of e-cigarettes on the market — could improve the odds of quitting cigarette smoking while meaningfully lowering exposure to harmful chemicals.
The study, published today (May 19) in JAMA Network Open, found that daily smokers who started using a nicotine e-cigarette were three times more likely to quit smoking within six weeks compared to those who used an identical-looking e-cigarette containing no nicotine. They also had lower levels of several tobacco-related toxicants in their body.
“For people who smoke and haven’t been able to quit using approved medications, this research suggests that switching to a nicotine e-cigarette is associated with real reductions in harmful toxicant exposures and does support smoking cessation,” said Jessica Yingst, associate professor of public health sciences and lead author on the paper.
“That’s a meaningful finding for public health.”
The researchers said that, to their knowledge, this is the first randomized placebo-controlled trial conducted in the United States to measure the effects of switching completely from cigarettes to pod-based salt-nicotine e-cigarettes.
Nicotine, while addictive, isn’t the primary cause of smoking-related cancers and heart disease. Rather, burning tobacco yields byproducts that can be harmful to health. Since quitting smoking long-term is difficult, health officials have long sought off-ramps to move people away from traditional combustible cigarettes — the most commonly used tobacco product — to less harmful products.
Previous studies in the field have suggested that e-cigarettes could expose people to fewer tobacco-related toxicants and serve as a less harmful alternative for those who have been unable to quit cigarette smoking through other means, Yingst said.
In the current study, the researchers wanted to know the short-term effects on toxicant exposure, cigarette smoking patterns and health when adults who smoke daily switch over to a pod-based salt-nicotine electronic cigarette. These pod-based devices use a nicotine salt formulation, which delivers nicotine more smoothly and efficiently compared to older e-cigarette designs.
The researchers enrolled 104 people who smoked more than four cigarettes a day and who expressed interest in switching completely from cigarettes to an e-cigarette. Participants were randomly assigned to use either a 5% nicotine e-cigarette or an identical device with zero nicotine — 52 per group. Neither the researchers nor the participants knew which group the participants were assigned to.
Participants were instructed to switch completely from cigarettes to the e-cigarette and were followed for six weeks, with an additional check-in at 10 weeks. The no-nicotine e-cigarette acted as the placebo, providing vapor and allowing participants the familiar hand-to-mouth motion of smoking without the nicotine.
Researchers measured biomarkers signaling the presence of toxicants associated with tobacco use in the participants’ urine and breath at the beginning of the study, at three weeks and at six weeks to understand if and how tobacco-related harms change over the course of the study.
The primary outcome measure for the study was NNAL — a marker for a potent lung carcinogen that only comes from the tobacco leaf. Yingst explained that this measure can help researchers understand cigarette exposure, as the presence of NNAL in the body can be an indicator that a person has smoked.
The researchers also measured blood pressure, lung function and heart rate variability and assessed cigarette use as well as cigarette craving and withdrawal symptoms through questionnaires.
At the end of six weeks, 69 participants completed the study — 35 in the 5%-nicotine group and 34 in the 0%-nicotine group. The drop-out rate is typical for a smoking cessation study, Yingst said since people tend to drop out of studies if they try to quit smoking and aren’t successful.
Overall, both groups experienced lower exposure to toxicants — including those that contribute to respiratory and cardiovascular disease, specifically NNAL — at the end of the study compared to baseline.
While the presence of NNAL at all indicated that participants still smoked cigarettes, the lower levels suggest that the e-cigarettes assisted in cutting back on their normal smoking levels, with the 5%-nicotine group experiencing greater reductions in exposure. However, the difference between the groups fell just short of statistical significance after controlling for key baseline variables.
The researchers also found that switching to a nicotine-containing e-cigarette is associated with a greater likelihood of quitting smoking. At the end of the six-week study period, 36.5% of the 5%-nicotine group stopped smoking entirely compared to 11.5% in the no-nicotine group, a gap that held up at the 10-week follow-up point.
Yingst explained that this finding corresponds with the lower level of NNAL found in the 5%-nicotine group, which suggests that fewer people in that cohort continued to smoke during the study and were exposed to fewer tobacco-related toxicants. Those who used the 5%-nicotine device also experienced less withdrawal and fewer cravings, which may have also helped them stay off cigarettes.
“The way nicotine is delivered matters,” Yingst said. “The nicotine e-cigarette provides a similar level of nicotine as a cigarette, satisfying cravings and making the switch easier, but their overall toxic chemical exposure dropped substantially.”
The no-nicotine group, in contrast, weren’t getting any nicotine replacement, which may have made it harder to stop smoking completely, Yingst said.
Penn State is a designated Tobacco Centers for Regulatory Science (TCORS) site by the U.S. Federal Drug Administration (FDA) and National Institutes of Health. Under the current TCORS grant, the team at the Penn State Center for Research on Tobacco and Health are conducting a similar study to evaluate whether the use of oral nicotine pouches can reduce tobacco-related harms among those who currently smoke cigarettes.
The principal investigator of the study was Jonathan Foulds, professor of public health sciences and of psychiatry and behavioral health. Other Penn State College of Medicine authors on the paper include Sophia Allen, assistant professor of public health sciences; Zachary Bitzer, assistant professor of public health sciences; Junjia Zhu, associate professor of public health sciences; Christopher Sciamanna, professor of medicine and of public health sciences; Nicolle Krebs, research project manager; Candace Bordner, research project manager; Neil Trushin, senior research associate; Craig Livelsberger, human research technologist; Vicki Peters, research technologist; Allison Salkin, research technologist; Lisa Reinhart, research technologist; Courtney Zimmerman, research technologist; Sitasnu Dahal, postdoctoral scholar; Laraib Mazhar, predoctoral scholar; and Kavitha Hassan; research technologist.
Funding: Funding from the National Institutes on Drug Abuse, the National Center for Advancing Translational Sciences, the National Cancer Institute and the FDA supported this work.
Key Questions Answered:
A: It comes down to a strategy called harm reduction. While quitting all products entirely is the ultimate goal, traditional smoking is notoriously difficult to overcome. This trial proves that switching to a pod-based nicotine e-cigarette causes an individual’s overall exposure to severe, cancer-causing tobacco chemicals to drop substantially. By removing the element of burning tobacco, smokers get an immediate off-ramp from the primary drivers of lung cancer and heart disease.
A: The zero-nicotine e-cigarettes functioned as a placebo, perfectly mimicking the look, vapor, and hand-to-mouth motion of traditional smoking. However, because they lacked the active compound, participants received zero biological nicotine replacement. Without that physical satisfaction, coping with unmitigated withdrawal symptoms and severe cravings proved too difficult for the vast majority of smokers.
A: The secret lies in the chemical engineering of the fluid. Older e-cigarette generations often struggled to deliver nicotine efficiently, leaving users unsatisfied and prone to picking cigarettes back up. Modern pod-based devices utilize a smooth nicotine salt formulation that satisfies biological cravings faster and more efficiently, making the psychological switch away from combustible tobacco vastly easier.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this nicotine and addiction research news
Author: Christine Yu
Source: Penn State
Contact: Christine Yu – Penn State
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Toxicant Exposures After Switching From Cigarettes to a Pod-Based Electronic Cigarette” by Jessica M. Yingst, Nicolle M. Krebs, Sitasnu Dahal, Sophia I. Allen, Craig Livelsberger, Vicki Peters, Allison Salkin, Candace Bordner, Laraib Mazhar, Lisa Reinhart, Neil Trushin, Courtney Zimmerman, Kavitha Hassan, Zachary Bitzer, Christopher Sciamanna, Junjia Zhu, and Jonathan Foulds. JAMA Network Open
DOI:10.1001/jamanetworkopen.2026.13292
Abstract
Toxicant Exposures After Switching From Cigarettes to a Pod-Based Electronic Cigarette
Importance
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.
Objective
To determine the short-term effects of switching from cigarettes to a pod-based 5% nicotine EC, compared with a 0% nicotine EC.
Design, Setting, and Participants
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.
Interventions
Participants were allocated 1:1 to the standardized research EC (SREC) with 5% nicotine or 0% nicotine for 6 weeks.
Main Outcomes and Measures
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.
Results
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.
Conclusions and Relevance
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.
Trial Registration
ClinicalTrials.gov Identifier: NCT03625986
