Exploring the effects of oral nicotine pouch use topography on measured abuse liability and adverse effects - PROJECT ABSTRACT Oral nicotine pouches (ONPs; e.g., Zyn) are small white pouches containing nicotine but no tobacco leaf. Without tobacco leaf, ONPs carry a low toxicant burden that is similar to that of nicotine replacement therapy. To understand ONPs' potential effects on public health, several studies are investigating their appeal and addiction potential (i.e., their abuse liability) and testing whether they can help people quit smoking. However, a critical limitation undercuts the real-world relevance of these studies: none account for how ONPs are actually used, i.e., their use topography. Human laboratory studies evaluating ONPs' abuse liability instruct participants to “park” the ONP between their upper lip and gum and hold it in place for 30-60 minutes. However, emerging observational research suggests that many people use ONPs between their lower lip and gum and frequently move the ONP around their mouth (rather than “parking” it). Because there are anatomical differences in blood flow and saliva distribution between the upper and lower portions of the oral cavity, using the ONP in the lower vs. upper lip could contribute to differences in the measured abuse liability of ONPs. Indeed, our team learned from focus groups with ONP users that using the ONP in the upper lip is associated with perceptions of stronger nicotine delivery and sensory effects, and using the ONP in the lower lip is associated with perceptions of milder but faster nicotine delivery and sensory effects. To bridge the gap between clinical trial methods of evaluating ONPs and how they are used in the real world, we propose a 3-condition randomized crossover study among adult daily cigarette smokers (N=36). Participants will sample ONPs at home for at least 1 week to become familiar with ONPs and try different use topographies, then they will complete 3 clinic visits in a randomized and counterbalanced order: parking an ONP between the upper lip and gum, parking an ONP between the lower lip and gum, or using an ONP ad libitum (i.e., how they typically use an ONP). We will collect objective (i.e., plasma nicotine delivery) and subjective (e.g., craving and withdrawal relief, sensory effects, product appeal) measures of ONP abuse liability and measure adverse effects throughout clinic visits. We hypothesize that using the ONP in the upper lip (vs. lower lip) will lead to greater peak and total plasma nicotine delivery, but slower time to peak plasma nicotine, as well as higher ratings of aversiveness, stronger perceived sensory effects, and greater rates of adverse effects. We also expect that positive product appeal measures (e.g., liking, satisfaction) and demand will be highest in the ad libitum use condition. The results of this study will provide critically important information about how to bridge prior and ongoing human laboratory assessments of ONPs' abuse liability to real-world use behaviors. As ONP sales continue to skyrocket, this timely study's findings will inform ONP interventions and regulations, as well as research on ONP toxicity and health effects, to improve public health.
