PROJECT SUMMARY E-cigarettes (EC) are an effective harm reduction strategy in adult combustible cigarette smokers who exclusively switch to EC, yet African American (AA) have been slower to adopt EC and are underrepresented in EC research, contributing to an almost complete lack of knowledge about EC as a harm reduction strategy for a group experiencing the highest risk of tobacco-related morbidity and mortality. Relatively little is known about 4th generation nicotine salt-based pod systems (NSPS), which are the leading class of EC. NSPS EC contain high nicotine concentrations with rapid nicotine delivery that facilitates exclusive switching. Our pilot data provide strong preliminary evidence of EC as a harm reduction strategy for AA smokers but there is an urgent need to conduct a fully powered trial with longer follow-up. Moreover, to enhance EC as a harm reduction strategy, there is a critical need for interventions to support exclusive switching in dual cig-EC users who try but initially fail. No such interventions exist. A recent open label study found that varenicline (VAR) helped dual users eliminate cigarette use but this has strategy not been tested in an RCT. Failure to intervene with dual users is a missed opportunity among a group who comprises the largest proportion of EC users (> 50%) and is already motivated to reduce their harm from smoking. The objectives of this application are to 1) compare short- and long-term harm reduction and abuse liability potential (i.e., withdrawal, craving, dependence) of a NSPS EC in AA exclusive EC, dual cig-EC, and exclusive cig users, 2) characterize factors that predict who switches fully, partially, or not at all, and 3) examine if harm reduction can be further enhanced by treating dual users with VAR to eliminate cigarette smoking. Objectives will be accomplished by conducting a 6-week open- label trial of a NSPS EC and counseling to facilitate a complete switch to EC in AA cigarette smokers (n=500) who are not interested in quitting all nicotine products but are interested in switching to EC. We enhance harm reduction potential and capitalize on a missed opportunity by offering dual users additional support to make a complete switch. At six weeks, those who are dual users (n= ~221) will receive an additional 12 weeks of the NSPS EC, ongoing counseling to make a complete switch, and be randomized to receive 12 weeks of VAR or placebo (PBO) to support quitting combustible cigarettes. Follow-up will continue for one-year, providing, to our knowledge, the first evidence on the long-term harm reduction potential of NSPC EC. The current study is the first to examine the short- and long-term harm reduction potential of NSPS EC in a priority population and the first to examine pharmacological support for dual cig-EC users in making a complete switch to EC. Findings have the potential to support EC as a harm reduction strategy among a disparate group that arguably stands to benefit from it the most, co...