PROJECT SUMMARY The use of electronic nicotine delivery systems (ENDS; e-cigarettes) has reached epidemic levels among young people in the United States (US). ENDS heat and vaporize a nicotine-containing liquid to produce an inhalable aerosol mist. While generally considered less harmful than combustible cigarettes, ENDS use exposes users to dependence-producing nicotine and respiratory and cardiovascular toxicants such as aldehydes. Flavor is a major factor in getting young people to use ENDS, thus limiting flavors to menthol and tobacco for prefilled cartridge ENDS “pod mods” was the first major action taken by the FDA to reduce the spread of ENDS among young people. Menthol flavor, however, can present a potential risk given its increasing popularity among young people in the US, and its puffing and nicotine-enhancing properties. Yet, the extent of menthol’s ability to affect users' experience and puffing patterns, and how these affect dependence, exposure to toxicants, and clinical outcomes continue to be understudied. Such evidence will be critical to the FDA's ability to set further regulatory standards to reduce ENDS potential harm. Our team of experts in tobacco regulatory science will apply clinical and analytical laboratory methods to address this gap in evidence by conducting a 2x2 (pre-post x menthol vs. tobacco flavor) crossover clinical lab study. We will recruit current/past month ENDS users (n=200, 21-35 yrs), who will come to the lab for two sessions and use their ENDS once with menthol and once with tobacco flavors. While we apply standard and well-tested lab models suitable for regulatory-related research, we have supplemented these with cutting-edge puffing robot technology to detect ENDS-associated emissions of toxicants. The proposed studies will answer two key regulatory questions consistent with FDA’s focus on the role of flavor in tobacco products’ addiction and toxicity; 1) compared to tobacco flavor, does menthol carry additional risk by enhancing puffing, abuse liability, and toxicant exposure in ENDS users, and; 2) is this effect more pronounced among high dependence compared to other users. Other outcomes such as harm perception, satisfaction, clinical responses, intention to use or quit, and group comparisons such as according to race, and sex will allow the FDA a comprehensive assessment of the pros and cons of regulating mentholated ENDS for different segments of the society. Such evidence will help advance FDA regulatory policies with the potential to reduce ENDS harm.

PUBLIC HEALTH RELEVANCE As flavor is one of the main drivers of ENDS epidemic among young people in the US, we propose to investigate the potential of menthol, compared to tobacco flavors to enhance users’ experience, puffing behavior, and toxicant exposure. This evidence will be critical to the FDA's ability to set ENDS products' regulatory standards to reduce their potential harm.