Project Summary/Abstract Smokeless tobacco (SLT) exposes users to a variety of carcinogenic toxicants, yet nearly 6 million people in the US use SLT despite health risks. SLT contains and delivers nicotine, a psychostimulant, that causes dependence and hinders cessation efforts despite the observation that 45% of SLT users report interest in SLT reduction/cessation. A novel, orally administered nicotine pouch marketed as “tobacco-free” recently has become available for purchase in the US. Though the nicotine contained in these pouches is tobacco-derived, the absence of tobacco leaf suggests less exposure to tobacco toxicants when compared to SLT. Therefore, these pouches may provide an innovative tobacco cessation/reduced harm option for SLT users. However, there are no objective data (i.e., not industry-sponsored) regarding the effects of these orally administered nicotine pouches. The current study has two aims. Aim 1 will use clinical laboratory assessments to determine the acute effects of three different doses of a novel, orally administered nicotine pouch in SLT users using a within subjects, Latin-square order design. Participants will come to the Center for the Study of Tobacco Products to complete four sessions that include an own brand SLT positive control and three ON nicotine pouch conditions (2, 4, and 8 mg). Outcomes include plasma nicotine concentration and multiple subjective measures. Aim 2 will investigate the feasibility of the oral nicotine pouch as an SLT substitute. Using a within- subject design, 50 SLT-using participants interested in reducing their SLT use will complete three, five-day conditions during which they will use either their own brand SLT (as a positive control), the most effective nicotine-delivering pouch from Aim 1, or the least effective pouch from Aim 1 (as a negative control). Product use and subjective effects will be recorded multiple times/day. The primary hypotheses are that: 1) In Aim 1, plasma nicotine concentration will increase as oral nicotine pouch dose increases, such that the 8 mg nicotine pouch will approach own brand SLT and 2) In Aim 2, the most effective nicotine pouch will substitute completely for own brand SLT and will be adopted exclusively for one week by the majority of participants. Results will address factors influencing SLT initiation, use, dependence and cessation and may inform clinicians and policymakers, as well as future research examining SLT cessation options. Furthermore, this application describes a comprehensive training plan that will advance the applicant’s expertise in the areas of clinical behavioral pharmacology, clinical epidemiology, drug policy, and psychopharmacology, and will also provide the applicant with the opportunity to learn new techniques and methodologies used in the translation of clinical lab research into clinical trials, as well as new experimental and statistical techniques used in clinical trial research. The proposed training will be invaluable...