OVERALL - ABSTRACT The US Food and Drug Administration has the authority to regulate tobacco products to protect public health. Regulatory measures that address constituents that contribute to the appeal and addiction of tobacco products are critically needed. The FDA has proposed plans to regulate nicotine concentration in cigarettes and flavors in many tobacco products and needs rigorous scientific evidence to support these plans and defend legal challenges. Currently, important gaps remain in our understanding of how nicotine and flavor additives influence the appeal of and addiction to tobacco products and how these constituents might influence initiation and support harm reduction. Moreover, recent “disruptive innovations” directed at nicotine and flavor additives and introduced by the tobacco industry, have led to new unknowns. To address these gaps in knowledge, the Yale Center for the Study of Tobacco Products (YCSTP) brings together a multidisciplinary team to investigate the effects of different forms and concentrations of nicotine (tobacco-derived, synthetic, freebase/salt), constituents that add cooling (menthol, odorless synthetic coolants), and constituents that add sweetness (humectants, sweeteners) delivered via different routes and products (oral, inhaled, intravenous) on initiation, addiction and harm reduction. Project 1 (Jordt/Addy) will examine if odorless cooling flavors, sweeteners, humectants, and different nicotine stereoisomers impact initiation, nicotine preference, reinforcement, and transitions in use form adolescence to adulthood. Project 2 (Sofuoglu) will determine if thresholds for nicotine reinforcement, discrimination, and subjective reward are altered by nicotine dependence and exposure to sweeteners. Project 3 (Krishnan-Sarin) will examine if odorless synthetic coolants and synthetic nicotine racemic mixtures alter the appeal and addiction potential of nicotine-containing e- cigarettes. Project 4 (Fucito/Bold) will examine the impact of potential regulations of flavors and nicotine concentration in non-combustible tobacco products (nicotine pouches, e-cigarettes) on switching from combustible tobacco products. The YCSTP will be supported by a Measurement and Analytics Core (Morean/Gueorguieva) that will provide and develop psychometrically sound measures and rigorous statistical analyses, a Laboratory Core (Eid/Zimmerman) that will provide chemical analyses of new and existing tobacco products and biological estimates of tobacco/nicotine exposure and health/toxicity biomarkers, a Career Enhancement Core (O’Malley/Kong) that will train fellows and junior faculty in tobacco regulatory science and provide pilot funding, and an Administrative Core (Krishnan-Sarin/O’Malley) that will ensure the generation of rigorous science through scientific, regulatory, and community oversight as well as facilitate intra- and inter- TCORS communications and collaborations. We will build on the methods and findings from our prior ...