PROJECT SUMMARY. Black/African Americans (AA) have the highest tobacco-related cancer incidence and mortality rates of any racial/ethnic group. Over 70% of AA smokers smoke menthol as their usual brand, compared to 20% for White smokers. Menthol is the only characterizing flavor allowed in cigarettes under current federal regulations, and menthol use is associated with progression to established cigarette smoking as well as more difficulty quitting. Evidence regarding the effects of electronic nicotine delivery systems (ENDS, i.e., e-cigarettes) suggests these products may be a less harmful alternative to cigarettes. Little work has examined how ENDS uptake affects tobacco use and associated toxicity among AA smokers, particularly those who smoke menthol. Recently, FDA began regulating closed-system devices like JUUL, which have captured over 70% of the ENDS market and contributed to dramatic increases in youth ENDS use. As of early 2020, flavored ENDS cartridges (small, enclosed unit used as part of an ENDS) other than menthol/tobacco are banned in the US. However, to achieve its public health mission, the FDA must balance restricting access to ENDS flavors that appeal to youth with the need for evidence on “whether and how certain flavors may help adult cigarette smokers reduce cigarette use and switch to potentially less harmful products” (FDA, 2018). Understanding the potential of ENDS to reduce the public health burden of combusted tobacco use equitably requires a targeted study to predict how future ENDS flavor regulations will impact AA menthol smokers. The current study will evaluate whether ENDS menthol flavor availability affects measures of tobacco use, biomarkers of cigarette/ENDS exposure, and addiction among AA menthol smokers (N=210) by performing a 3-arm, parallel-group, 6-week clinical trial of ENDS provision with follow-up to 30 days. JUUL devices with compatible cartridges at 5% nicotine, which our team has extensively evaluated, will be provided. Study arms will differ by potential FDA regulations on ENDS flavor availability: 1) the current market where only menthol and tobacco flavored ENDS cartridges are available; 2) a market where only tobacco flavor is available, and 3) a market with only unflavored cartridges. Study visits will occur weekly beginning 1 week prior to randomization with daily tobacco use monitoring throughout and biomarker/self-report data collection at each weekly visit. AA menthol smokers are disproportionately harmed by tobacco products and could experience significant health benefits from increased availability of well-regulated ENDS. Results of this work will help FDA make predictions about the impact on AA menthol smokers of moving from the current regulatory market for cartridge-based ENDS where menthol and tobacco are available, to one where only tobacco or no flavors are available. Answers to these questions will address FDA's priorities in behavior, toxicity, and addiction, and will provide new d...