PROJECT 4 ABSTRACT Cigarette smoking remains the leading cause of preventable disease and death. Thus, better population-based strategies are urgently needed to reduce cigarette smoking and tobacco-related harm. One approach is to improve regulation of cigarettes and other tobacco products, which is a core mission of the U.S. Food and Drug Administration (FDA) under the Tobacco Control Act. Indeed, the FDA has signaled its intention to ban menthol and lower nicotine concentrations in cigarettes to protect public health. The FDA may consider similar product standards that restrict flavors and lower nicotine concentrations in non-combustible products as well. However, scientific data is needed to understand the impact of these regulations. For example, the FDA has approved only tobacco flavored e-cigarettes for marketing so far, in both high and moderate nicotine concentrations, and is still evaluating premarket tobacco product applications for menthol non-combustible products. Although e-cigarettes and pouches may help adults reduce smoking and smoking-related harm, it remains to be determined whether menthol flavor and higher nicotine concentrations in non-combustible products are important for cigarette substitution in adults. To inform tobacco regulatory policies of e-cigs and pouches, we propose to conduct a controlled trial of the effects of non-combustible tobacco product type and constituents on smoking behaviors in adults. Specifically, we will randomize adults who currently smoke cigarettes (N=256) to switch to either e-cigs or pouches for 4-weeks and will also randomly assign participants to four possible regulatory scenarios within product where flavor availability is either menthol and tobacco/unflavored or tobacco/unflavored only, and nicotine concentration is either high (5% e-cig or 6mg pouch) or moderate (2.4% e-cig or 3mg pouch). The design will yield 8 conditions (N=32 participants each). Data from these participants will be used to compare the effects of product type, flavor availability, and nicotine concentration on cigarette smoking behaviors and dependence using validated self-report measures and biomarkers (Aim 1), and to assess the effects of these conditions on e-cig/pouch use behaviors and appeal using validated self-report measures and biomarkers (Aim 2). In addition, we will explore potential interactions between conditions (e.g., flavor availability and nicotine concentration) and participant characteristics (sex, race/ethnicity, menthol cigarette preference, and baseline nicotine dependence level) (Aim 3). Our analyses will provide key information on which individuals may be more likely to switch completely from smoking to non- combustible products and whether certain flavors or nicotine concentrations in these products are important for cigarette substitution and appeal among adults. This project focuses on key FDA priority areas of behavior, addiction, and impact analysis. Our results will provide crucial evidence ...