{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T08:05:11Z","timestamp":1784016311501,"version":"3.55.0"},"reference-count":114,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T00:00:00Z","timestamp":1783987200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Understanding the neuropharmacological effects and abuse liability (AL) of electronic nicotine delivery systems (ENDS) is essential for evaluating their potential role in tobacco harm reduction (THR). Nicotine delivered via ENDS engages central nervous system (CNS) pathways involved in reinforcement, craving, and dependence. This research characterized nicotine pharmacokinetics (PK) and AL of Vuse Alto ENDS across multiple nicotine concentrations and flavor and contextualized these findings relative to combustible cigarettes and nicotine replacement therapy (NRT) gum.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Two randomized, open-label, crossover clinical studies were conducted under controlled human-use conditions. Study 1 evaluated eight Vuse Alto ENDS flavors containing 1.5% nicotine, with sequential plasma sampling over 240\u00a0min following product use. Study 2 assessed four Vuse Alto ENDS (1.5%\u20135% nicotine) and incorporated validated subjective effect assessments and PK sampling, alongside participants\u2019 usual brand cigarettes and NRT gum. Adult smokers and dual users were enrolled under strict eligibility criteria to ensure participant safety and data integrity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      All Vuse Alto variants demonstrated rapid systemic nicotine uptake, with PK profiles consistent across flavors, indicating flavor-independent nicotine delivery. Observed C\n                      <jats:sub>max<\/jats:sub>\n                      ranged from 4.27 to 6.04\u00a0ng\/mL, AUC\n                      <jats:sub>0\u201315<\/jats:sub>\n                      from 46.09 to 64.63 ng \u00d7 min\/mL, and AUC\n                      <jats:sub>0\u2013240<\/jats:sub>\n                      from 420 to 509\u00a0ng \u00d7 min\/mL. Higher nicotine concentrations produced proportionally greater C\n                      <jats:sub>max<\/jats:sub>\n                      and AUC values, though all remained lower than those from cigarettes. T\n                      <jats:sub>max<\/jats:sub>\n                      for ENDS were consistently 6\u00a0min, aligning with the rapid onset typical of inhaled nicotine, while NRT gum exhibited delayed absorption (45\u00a0min). Subjective measures including product liking, positive effects, and intent to use again were lower for ENDS compared with cigarettes and generally comparable to NRT gum. Urge-to-smoke decreased within 15\u00a0min for all ENDS variants, similar to NRT gum but less rapidly than cigarettes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Findings demonstrate that Vuse Alto ENDS deliver nicotine more slowly and at lower levels than cigarettes, reflecting a lower AL while maintaining sufficient CNS-relevant nicotine exposure to potentially support transitions away from smoking. Flavor did not materially influence PK or AL outcomes. Collectively, the results indicate an intermediate neuropharmacological profile consistent with reduced dependence potential and support the potential utility of Vuse Alto ENDS within THR strategies.<\/jats:p>\n                    <jats:p>\n                      The clinical studies were registered at\n                      <jats:ext-link>ClinicalTrials.gov<\/jats:ext-link>\n                      ; NCT05239884 and NCT05210699.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1796858","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T07:30:32Z","timestamp":1784014232000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Assessment of nicotine pharmacokinetics and abuse liability in randomized, crossover studies of Vuse Alto electronic nicotine delivery systems"],"prefix":"10.3389","volume":"17","author":[{"given":"Milly N.","family":"Kanobe","sequence":"first","affiliation":[{"name":"RAI Services Company","place":["Winston-Salem, NC, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah A.","family":"Baxter","sequence":"additional","affiliation":[{"name":"RAI Services Company","place":["Winston-Salem, NC, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen","family":"Prevette","sequence":"additional","affiliation":[{"name":"RAI Services Company","place":["Winston-Salem, NC, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Jin","sequence":"additional","affiliation":[{"name":"RAI Services Company","place":["Winston-Salem, NC, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa A.","family":"Tapia","sequence":"additional","affiliation":[{"name":"RAI Services Company","place":["Winston-Salem, NC, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Ayoku","sequence":"additional","affiliation":[{"name":"RAI Services Company","place":["Winston-Salem, NC, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary M.","family":"Dull","sequence":"additional","affiliation":[{"name":"RAI Services Company","place":["Winston-Salem, NC, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrudu","family":"Makena","sequence":"additional","affiliation":[{"name":"RAI Services Company","place":["Winston-Salem, NC, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Mohrmann","sequence":"additional","affiliation":[{"name":"RAI Services Company","place":["Winston-Salem, NC, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian M.","family":"Keyser","sequence":"additional","affiliation":[{"name":"RAI Services Company","place":["Winston-Salem, NC, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan","family":"Gale","sequence":"additional","affiliation":[{"name":"BAT (Investments) Limited, Research and Development","place":["Southampton, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen G.","family":"Jordan","sequence":"additional","affiliation":[{"name":"RAI Services Company","place":["Winston-Salem, NC, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1146\/annurev-publhealth-040617-013849","article-title":"Harm minimization and tobacco control: reframing societal views of nicotine use to rapidly save lives","volume":"39","author":"Abrams","year":"2018","journal-title":"Annu. 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