Effect of Product Characteristics on the Abuse Liability of Nicotine Pouches - PROJECT SUMMARY There is a growing sector of modern tobacco-free oral nicotine pouches (NPs) that are federally regulated as non-medicinal nicotine/tobacco products. While NPs employ marketing approaches that may attract current tobacco users, such as marketing themes connoting minimal harm, information on the long-term health effects of NPs is lacking. NPs may appeal to young adults because they are available in similar product characteristics (e.g., nicotine concentration, protonated nicotine) that many young people prefer to use in e-cigarettes. In addition, NPs may be of particular interest to young adult e-cigarette users because these products can be used discreetly where vaping is not allowed, which may translate into an increased likelihood of becoming dual users of e-cigarettes and NPs. Indeed, approximately 15% young adults who used EC in the past 30 days were past 30-day NP users. Manufacturers of modern NPs use acid additives to lower pH, which changes nicotine from a free-base to a protonated nicotine, resulting in improved appeal and sensory experience and higher abuse liability. Thus, nicotine concentration and pH in modern NPs should be focal targets for regulatory policies. Evidence is also lacking on mechanisms mediating differences in product appeal and abuse liability of NPs across products varying in nicotine concentration and pH level. The scientific objective of this research plan is to assess the effect of variation in nicotine concentration in NPs and its interaction effect with pH level on three proximal outcomes of relevance to FDA regulation: (1) sensory attributes, (2) product appeal, and (3) abuse liability among young adult dual users of NPs and e-cigarettes. This innovative project proposes to conduct double-blind within-subject randomized clinical trials in which participants (N≈156 [Aim 1 N = 72; Aim 2 N = 84]) will administer NPs varied by nicotine concentration (e.g., 4 vs 2 mg) and pH (e.g., ≥9 vs ≤8, ≥1 point difference) across two flavors (e.g., mint, fruit) to achieve the project aims: to evaluate the effects of nicotine concentration, pH, and flavor on subjective product appeal and sensory attributes of NPs (Aim 1); to assess the effects of nicotine concentration and its interplay with pH on abuse liability of NPs (Aim 2); to estimate the extent to which sensory attribute mediates the pH-moderated effect of nicotine concentration on product appeal and abuse liability (Aim 3). The findings of this proposed research will provide the FDA with new evidence necessary to inform regulatory restrictions on product characteristics and constituents of NPs, which may put young adults at risk of using a novel class of oral nicotine products. A career development plan that complements the research plan builds on the applicant’s background in behavioral epidemiology and quantitative analytic skills, which outlines new training in three areas: (1) clinical trial experiments testing the effects of exposure to tobacco products on behavioral responses (e.g., abuse liability), (2) product characteristics and constituents of emerging oral nicotine products, and (3) within-subject data and causal mediation analyses. The combined research and training plan will prepare the candidate as an independent investigator with expertise in tobacco regulatory science.