{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T15:12:44Z","timestamp":1774278764630,"version":"3.50.1"},"posted":{"date-parts":[[2026,3,20]]},"group-title":"Public and Global Health","reference-count":47,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T00:00:00Z","timestamp":1773964800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,20]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>The clinical safety profile of e-cigarette use for smoking reduction remains poorly characterized. This study compared the relative safety and tolerability of nicotine e-cigarette use with non-nicotine e-cigarettes or a non-aerosol cigarette substitute (CS) among adults interested in reducing their smoking.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We conducted a secondary analysis of adverse events (AEs) reported in a 6-month, double-blind RCT involving 520 participants assigned to either e-cigarettes with 0, 8, or 36 mg\/mL nicotine or a CS. AEs were coded using CTCAE V4.0 and assessed for frequency, severity, seriousness and relatedness across groups. Cumulative incidence was calculated over 24 weeks. We estimated risk differences (RDs) and 95% confidence intervals (CIs) for frequently reported AEs (\u22651% of participants overall) comparing e-cigarette vs. CS and nicotine versus non-nicotine e-cigarette groups. Fisher\u2019s exact test, with adjustment for multiple comparisons, was used to assess statistical significance.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Most study-related AEs (those rated as possibly, probably, or definitely related by medical monitor) were mild in severity and none were classified as serious. At 24 weeks, cumulative incidence of first study-related AE was highest in the 36 mg\/mL (37.0%) and 8 mg\/mL (35.2%) e-cigarette groups, followed by 0 mg\/mL (23.4%), and lowest in CS group (2.5%). E-cigarette users experienced significantly greater risks of cough (RD [95%CI]: 8.5% [5.6 \u2013 11.3]), headache (RD [95%CI]: 5.4% [3.3 \u2013 7.6]) and sore throat (RD [95%CI]: 5.4% [3.2 \u2013 7.6]) as compared with the CS group. Cough was also more common in those randomized to nicotine versus non-nicotine e-cigarettes (RD [95%CI]: 8.1% [3.4 \u2013 12.8]).<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>All study products were generally well-tolerated; however, AEs were more common in e-cigarette groups, especially with nicotine. Findings highlight the need to monitor common symptoms such as cough, headache, and sore throat in clinical and regulatory evaluations of e-cigarette safety.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>What is already known on this topic<\/jats:title>\n                  <jats:p>Nicotine e-cigarettes can help people who smoke to quit combustible cigarette use and reduce some cigarette-related toxicant exposures. However, the safety of inhaled nicotine and other constituents such as propylene glycol, vegetable glycerin in e-cigarettes remains unclear.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>What this study adds<\/jats:title>\n                  <jats:p>This study suggests that e-cigarette use is associated with a higher incidence of study-related AEs such as cough, headache, and sore throat, particularly among those using nicotine-containing products. However, overall safety and tolerability profiles were comparable across e-cigarette groups with differing nicotine concentrations.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>How this study might affect research, practice or policy<\/jats:title>\n                  <jats:p>These findings offer methodological guidance for evaluating e-cigarette safety in clinical trials and may inform regulators, clinicians, and public health professionals regarding the tolerability of e-cigarette products varying in nicotine concentration.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.03.18.26348637","type":"posted-content","created":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T02:45:12Z","timestamp":1774061112000},"source":"Crossref","is-referenced-by-count":0,"title":["Safety and tolerability of electronic cigarettes to reduce cigarette smoking: Secondary analysis from a randomized placebo-controlled trial"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0507-8996","authenticated-orcid":false,"given":"Sitasnu","family":"Dahal","sequence":"first","affiliation":[{"name":"Center for Research on Tobacco and Health, Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA 17033, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3520-675X","authenticated-orcid":false,"given":"Soha","family":"Talih","sequence":"additional","affiliation":[{"name":"Mechanical Engineering Department, American University of Beirut, Beirut, Lebanon"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9838-2569","authenticated-orcid":false,"given":"Shari","family":"Hrabovsky","sequence":"additional","affiliation":[{"name":"Ross and Carol Nese College of Nursing, Penn State University, University Park, PA 16802, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0693-6347","authenticated-orcid":false,"given":"Christopher","family":"Sciamanna","sequence":"additional","affiliation":[{"name":"Department of Medicine, Penn State College of Medicine, Hershey, PA 17033, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-6444-5102","authenticated-orcid":false,"given":"Craig","family":"Livelsberger","sequence":"additional","affiliation":[{"name":"Center for Research on Tobacco and Health, Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA 17033, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2740-5633","authenticated-orcid":false,"given":"Eric","family":"Soule","sequence":"additional","affiliation":[{"name":"Department of Psychology, Virginia Commonwealth University, Richmond, VA 23298, USA"},{"name":"Department of Health Education and Promotion, East Carolina University, Greenville, NC 27858, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3258-252X","authenticated-orcid":false,"given":"Caroline O.","family":"Cobb","sequence":"additional","affiliation":[{"name":"Department of Psychology, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3028-668X","authenticated-orcid":false,"given":"Jessica","family":"Yingst","sequence":"additional","affiliation":[{"name":"Center for Research on Tobacco and Health, Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA 17033, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2296-0726","authenticated-orcid":false,"given":"Jonathan","family":"Foulds","sequence":"additional","affiliation":[{"name":"Center for Research on Tobacco and Health, Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA 17033, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026032307251100000_2026.03.18.26348637v1.1","unstructured":"U.S. Department of Health and Human Services. The Health Consequences of Smoking: 50 Years of Progress. A Report of the Surgeon General. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2014."},{"key":"2026032307251100000_2026.03.18.26348637v1.2","unstructured":"CDC. Cigarette Smoking. Smoking and Tobacco Use. January 6, 2025. Accessed December 14, 2025. https:\/\/www.cdc.gov\/tobacco\/about\/index.html"},{"key":"2026032307251100000_2026.03.18.26348637v1.3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra0809890"},{"key":"2026032307251100000_2026.03.18.26348637v1.4","unstructured":"Panel TU and DG. Treating Tobacco Use and Dependence: 2008 Update. US Department of Health and Human Services; 2008."},{"key":"2026032307251100000_2026.03.18.26348637v1.5","doi-asserted-by":"crossref","unstructured":"Cahill K , Stevens S , Perera R , Lancaster T. Pharmacological interventions for smoking cessation: an overview and network meta analysis - Cahill, K - 2013 | Cochrane Library. Accessed December 14, 2025. https:\/\/www.cochranelibrary.com\/cdsr\/doi\/10.1002\/14651858.CD009329.pub2\/full","DOI":"10.1002\/14651858.CD009329.pub2"},{"key":"2026032307251100000_2026.03.18.26348637v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.drugalcdep.2007.09.005"},{"key":"2026032307251100000_2026.03.18.26348637v1.7","doi-asserted-by":"publisher","DOI":"10.1111\/add.13394"},{"key":"2026032307251100000_2026.03.18.26348637v1.8","doi-asserted-by":"publisher","DOI":"10.1111\/nyas.12977"},{"key":"2026032307251100000_2026.03.18.26348637v1.9","unstructured":"McNeill A , Brose L , Robson D , et al. Nicotine vaping in England: An evidence update including health risks and perceptions, 2022. Published online September 29, 2022. Accessed March 23, 2023. https:\/\/kclpure.kcl.ac.uk\/portal\/en\/publications\/nicotine-vaping-in-england(58869843-3d0c-40e7-a9e9-d92881a2ed22).html"},{"key":"2026032307251100000_2026.03.18.26348637v1.10","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.cd010216.pub10"},{"key":"2026032307251100000_2026.03.18.26348637v1.11","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(21)00022-9"},{"key":"2026032307251100000_2026.03.18.26348637v1.12","doi-asserted-by":"publisher","DOI":"10.1093\/ntr\/ntab247"},{"key":"2026032307251100000_2026.03.18.26348637v1.13","unstructured":"National Academies of Sciences, Engineering, and Medicine. Public Health Consequences of E-Cigarettes. Washington, DC, The National Academies Press, 2018."},{"key":"2026032307251100000_2026.03.18.26348637v1.14","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000001160"},{"key":"2026032307251100000_2026.03.18.26348637v1.15","doi-asserted-by":"publisher","DOI":"10.1111\/add.15675"},{"key":"2026032307251100000_2026.03.18.26348637v1.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjmed.2023.04.014"},{"key":"2026032307251100000_2026.03.18.26348637v1.17","doi-asserted-by":"publisher","DOI":"10.1186\/s13643-024-02572-7"},{"key":"2026032307251100000_2026.03.18.26348637v1.18","doi-asserted-by":"publisher","DOI":"10.1136\/tobaccocontrol-2015-052822"},{"key":"2026032307251100000_2026.03.18.26348637v1.19","doi-asserted-by":"publisher","DOI":"10.1111\/dar.13674"},{"key":"2026032307251100000_2026.03.18.26348637v1.20","unstructured":"FDA. Premarket Tobacco Product Applications. March 27, 2024. Accessed December 15, 2025. https:\/\/www.fda.gov\/tobacco-products\/market-and-distribute-tobacco-product\/premarket-tobacco-product-applications"},{"key":"2026032307251100000_2026.03.18.26348637v1.21","doi-asserted-by":"publisher","DOI":"10.1177\/2050312118777953"},{"key":"2026032307251100000_2026.03.18.26348637v1.22","doi-asserted-by":"crossref","unstructured":"Lindson N , Theodoulou A , Ord\u00f3\u00f1ez-Mena JM , et al. Pharmacological and electronic cigarette interventions for smoking cessation in adults: component network meta analyses - Lindson, N - 2023 | Cochrane Library. Accessed December 15, 2025. https:\/\/www.cochranelibrary.com\/cdsr\/doi\/10.1002\/14651858.CD015226.pub2\/full","DOI":"10.1002\/14651858.CD015226.pub2"},{"key":"2026032307251100000_2026.03.18.26348637v1.23","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsat.2012.01.004"},{"key":"2026032307251100000_2026.03.18.26348637v1.24","doi-asserted-by":"publisher","DOI":"10.1093\/ntr\/ntq215"},{"key":"2026032307251100000_2026.03.18.26348637v1.25","doi-asserted-by":"publisher","DOI":"10.1111\/add.12319"},{"key":"2026032307251100000_2026.03.18.26348637v1.26","unstructured":"FDA. E-Cigarettes, \u201cVapes\u201d and Other Electronic Nicotine Delivery Systems (ENDS) Authorized by the FDA. Published online September 18, 2025. Accessed December 15, 2025. https:\/\/www.fda.gov\/tobacco-products\/market-and-distribute-tobacco-product\/e-cigarettes-vapes-and-other-electronic-nicotine-delivery-systems-ends-authorized-fda"},{"key":"2026032307251100000_2026.03.18.26348637v1.27","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.l5275"},{"key":"2026032307251100000_2026.03.18.26348637v1.28","doi-asserted-by":"publisher","DOI":"10.2139\/ssrn.5122926"},{"key":"2026032307251100000_2026.03.18.26348637v1.29","doi-asserted-by":"publisher","DOI":"10.1037\/pha0000140"},{"key":"2026032307251100000_2026.03.18.26348637v1.30","doi-asserted-by":"publisher","DOI":"10.1186\/s12889-016-2792-8"},{"key":"2026032307251100000_2026.03.18.26348637v1.31","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2024-098005"},{"key":"2026032307251100000_2026.03.18.26348637v1.32","doi-asserted-by":"publisher","DOI":"10.1016\/S2468-2667(25)00101-X"},{"key":"2026032307251100000_2026.03.18.26348637v1.33","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0066317"},{"key":"2026032307251100000_2026.03.18.26348637v1.34","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1808779"},{"key":"2026032307251100000_2026.03.18.26348637v1.35","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2020.26324"},{"key":"2026032307251100000_2026.03.18.26348637v1.36","doi-asserted-by":"publisher","DOI":"10.1186\/s12889-016-3236-1"},{"key":"2026032307251100000_2026.03.18.26348637v1.37","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrestox.7b00116"},{"key":"2026032307251100000_2026.03.18.26348637v1.38","doi-asserted-by":"publisher","DOI":"10.1016\/j.toxlet.2025.111739"},{"key":"2026032307251100000_2026.03.18.26348637v1.39","doi-asserted-by":"publisher","DOI":"10.1007\/s11739-022-03161-z"},{"key":"2026032307251100000_2026.03.18.26348637v1.40","doi-asserted-by":"publisher","DOI":"10.1136\/tc.2009.031567"},{"key":"2026032307251100000_2026.03.18.26348637v1.41","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2018.5937"},{"key":"2026032307251100000_2026.03.18.26348637v1.42","doi-asserted-by":"publisher","DOI":"10.1080\/17425255.2022.2058930"},{"key":"2026032307251100000_2026.03.18.26348637v1.43","doi-asserted-by":"publisher","DOI":"10.1111\/add.15628"},{"key":"2026032307251100000_2026.03.18.26348637v1.44","doi-asserted-by":"publisher","DOI":"10.3122\/jabfm.2019.04.180384"},{"key":"2026032307251100000_2026.03.18.26348637v1.45","doi-asserted-by":"publisher","DOI":"10.1016\/j.jdent.2025.105910"},{"key":"2026032307251100000_2026.03.18.26348637v1.46","doi-asserted-by":"publisher","DOI":"10.2147\/JMDH.S319727"},{"key":"2026032307251100000_2026.03.18.26348637v1.47","doi-asserted-by":"publisher","DOI":"10.1093\/ntr\/ntag038"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.03.18.26348637","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T14:25:25Z","timestamp":1774275925000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.64898\/2026.03.18.26348637"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,20]]},"references-count":47,"URL":"https:\/\/doi.org\/10.64898\/2026.03.18.26348637","relation":{},"subject":[],"published":{"date-parts":[[2026,3,20]]},"subtype":"preprint"}}