Project 2: Informing oral nicotine pouch regulations to promote public health

项目概要-项目2 从历史上看，烟草业操纵尼古丁的浓度和形式，以提供一系列无烟烟草产品。 烟草（ST）产品，以吸引新用户和老用户。被业界称为“毕业” 计划，他们为新用户提供了低尼古丁浓度和低游离碱的“入门产品” 尼古丁和“成熟”的尼古丁浓度较高的用户，主要是在游离碱形式，以维持 依赖他们现在遵循相同的剧本口服尼古丁袋（ONP），操纵 尼古丁的浓度和形式的尺寸，最近已经开始操纵异构体 通过使用合成尼古丁来生产组合物。虽然ONP可能是一种危害较小的替代品， 对于完全转换的吸烟者和ST使用者，年轻新使用者中ONP摄取的潜在风险是 关于俄亥俄州州立大学烟草管制科学中心的总体综合主题 “翻转脚本”：使用行业的尼古丁剧本最大限度地提高公共健康。正如 烟草业操纵尼古丁制造吸引年轻人的ONP，并提供证据 通过项目2（P2），我们认为FDA可以规范ONP中的尼古丁尺寸，使其 对新用户没有吸引力，同时仍然为吸烟者和ST用户提供危害较小但有吸引力和令人满意的 替代. P2将告知将ONP定位为公共卫生利益而不是威胁的法规， 确定最能支持转换为ONP的尼古丁特征，并评估相应的尼古丁水平。 成年吸烟者和ST使用者口腔微生物组的变化。在第1阶段，使用双盲、交叉- 在设计中，将专门吸烟者（n=80）和ST使用者（n=80）随机分配至高尼古丁或低尼古丁组 浓度，然后参加5个常用品牌的单一产品实验室使用会议和4个ONP （随机顺序），其范围为游离碱级分（低，高）和异构体（外消旋，> 99%S-尼古丁）。成果 包括血浆尼古丁药代动力学、主观效应和行为经济需求指数。在 第二阶段，相同的参与者，经过1周的常规品牌控制期，将取代随机分配的 ONP为他们通常的品牌为4周。研究结果包括使用行为，包括完全转换， 通过生态瞬时评估和生化确认（新烟草碱和假木贼碱）测量，计数 未使用的ONP，主观影响，行为经济需求指数和口腔微生物组评估。P2 是重要的和创新的，因为它使用了严格控制的实验室程序和随意， 自然使用商业烟草产品来评估尼古丁浓度、形式和异构体如何影响 ONP的成瘾潜力和健康影响。这是第一次研究尼古丁的组合尺寸 目的是促进从香烟和ST转向ONP，而不增加青年的吸收。P2 解决了FDA的优先领域成瘾，产品成分和设计，毒性，行为和健康 影响，并将告知ONP尼古丁法规，旨在促进既定吸烟者的完全转换 ST用户。

PROJECT SUMMARY – PROJECT 2 Historically, the tobacco industry manipulated nicotine concentration and form to offer a range of smokeless tobacco (ST) products to appeal to both new and established users. Termed by the industry as the “graduation” program, they provided new users with “starter products” with low nicotine concentration and low freebase nicotine and “mature” users with higher concentrations of nicotine, mainly in the freebase form, to maintain dependence. They are now following the same playbook for oral nicotine pouches (ONPs), manipulating the nicotine dimensions of concentration and form, and more recently have begun manipulating isomer composition through the use of synthetic nicotine. While ONPs may have promise as a less harmful alternative for smokers and ST users who completely switch, the potential risk for ONP uptake among young new users is concerning. The overall integrative theme of The Ohio State University Tobacco Center for Regulatory Science is: “Flipping the Script”: Using the Industry's Nicotine Playbook to Maximize Public Health. Just as the tobacco industry manipulates nicotine to create ONPs that appeal to young people, with the evidence produced by Project 2 (P2), we posit that the FDA can regulate the nicotine dimensions in ONPs, making them unappealing to new users while still providing smokers and ST users a less harmful but appealing and satisfying alternative. P2 will inform regulations that position ONPs as a public health benefit rather than a threat by identifying the characteristics of nicotine that best support switching to ONPs and evaluating corresponding changes to the oral microbiome among adult smokers and ST users. In Phase 1, using a double-blind, cross- over design, exclusive smokers (n=80) and ST users (n=80) will be randomized to high or low nicotine concentration, and then engage in 5 single-product laboratory use sessions of their usual brand and 4 ONPs (random order) that range in freebase fraction (low, high) and isomer (racemic, >99% S-nicotine). Outcomes include plasma nicotine pharmacokinetics, subjective effects, and behavioral economic demand indicies. In Phase 2, the same participants, after a 1-week usual brand control period, will substitute a randomly assigned ONP for their usual brand for 4 weeks. Study outcomes include use behaviors, including complete switching, measured via ecological momentary assessment and biochemically confirmed (anatabine and anabasine), count of unused ONPs, subjective effects, behavioral economic demand indices, and oral microbiome assessment. P2 is significant and innovative because it uses a mix of tightly controlled in-lab procedures and ad libitum, naturalistic use of commercial tobacco products to assess how nicotine concentration, form, and isomer affect the addiction potential and health effects of ONPs. This is the first study of the combined nicotine dimensions with the intent of facilitating switching from cigarettes and ST to ONPs without increasing youth uptake. P2 addresses the FDA priority areas of Addiction, Product Composition & Design, Toxicity, Behavior, and Health Effects, and will inform ONP nicotine regulations designed to foster complete switching for established smokers and ST users.