PROJECT SUMMARY/ABSTRACT The prevalence of adolescent nicotine vaping is rising more rapidly than any prior known drug. In some areas of the US, over one third of high school seniors vape nicotine regularly. This rapid rise in popularity of electronic nicotine delivery devices (ENDS, “e-cigarettes”, vapes) has reversed five decades of denormalizing youth tobacco use, putting adolescents at high risk for nicotine dependence, tobacco smoking, other drug use, and direct negative health effects of vapor exposure. While sensible regulation raising the purchasing age and eliminating sweet and mint flavors should curb new uptake of adolescent nicotine vaping among never smokers, these policies are causing many to seek vaping cessation treatment. There are an estimated one million adolescents in the US with an addiction to vaped nicotine. No treatment trials for vaping cessation have been published to date to our knowledge. Effective interventions are critical to aid the estimated one million US adolescents now with addiction to vaped nicotine to quit vaping and not start smoking. Varenicline, the most effective known smoking cessation medication, has been well tolerated and associated with significantly higher tobacco abstinence rates and faster time to abstinence in secondary outcomes in two recent small randomized controlled trials in adolescent smokers. In a recent series in our group, varenicline together with text vaping cessation support has been associated with 65% (34 of 52 patients) prolonged vaping abstinence rates (at 3-9 months follow up) in non-smoking adolescents who are dependent on vaped nicotine, while nicotine replacement therapy has been associated with approximately 21% abstinence rates to date in this population. In the current study, we propose to test whether varenicline, the most effective treatment known for nicotine addiction, helps nicotine dependent adolescents to quit vaping nicotine. To do so, we will enroll 300 adolescents, aged 16 - 20, who vape, are nicotine dependent, do not smoke, and want to quit. Adolescents will be recruited through high schools, colleges, and the community in Greater Boston, and those eligible will be enrolled into a double-blind, placebo-controlled, parallel group, intent-to-treat trial of varenicline up to 1 mg bid for 12 weeks added to an active behavioral control intervention involving 12 weeks of text messaging and group behavioral support specifically designed for teen vaping cessation. Medication adherence and trial retention, challenges in prior adolescent smoking cessation trials, will be incentivized and supported with the innovative AiCure smartphone application for remotely directly observed dosing and collection of daily vaping and other data. This proposal is responsive to urgent and growing requests for vaping cessation treatment for adolescents from patients, their families, and schools. Positive results will define an effective treatment that can be used in this rapidly moving epid...