Research Project 3 : Nicotine Delivery Rate and Its Abuse Potential: Impact of Menthol

摘要：项目#3 快速进入大脑会增加包括尼古丁在内的滥用药物的滥用可能性。如建议的 Shihadeh和Eissenberg提出的“尼古丁流量”，即一支特定的电子烟(电子烟) 提供尼古丁，是评估其滥用潜力的最关键因素。在这个模型中，当一支电子烟 提供尼古丁的速率高于某个特定但尚未确定的阈值它可能具有很高的滥用潜力 可能引发或维持烟草成瘾。相比之下，当尼古丁流量最佳时，电子烟可能会 低成瘾潜力，同时提供足够的尼古丁输送，通过以下方式帮助吸烟者戒烟 缓解吸烟的冲动。这一提出的“最佳尼古丁流量”概念尚未在#年进行实证评估。 受控的人体研究。此外，香精和其他电子烟成分也可能影响电子烟的 尼古丁成瘾效应的递送率。最值得注意的是，薄荷醇可能通过 抑制尼古丁受体和减缓尼古丁代谢。我们小组的系统研究和 其他人则表明，静脉注射尼古丁是量化尼古丁影响的最佳方法。 尼古丁的行为和生理效应的递送率。这个项目的主要目的是检查 尼古丁递送率对尼古丁滥用潜力的影响(通过积极的主观影响和 强化)，以及其缓解吸烟冲动和戒烟的潜在有益效果。我们还在寻求 为了确定是否从薄荷醇香烟转向非薄荷醇香烟，模拟禁止薄荷醇香烟， 改变尼古丁递送率对研究结果的影响。为了达到这些目标，我们建议2 安慰剂对照研究将招募男性和女性尼古丁依赖吸烟者。研究1将招募 相同数量的薄荷醇(n=35)和非薄荷醇(n=35)更喜欢吸烟者进行5次实验， 这将至少相隔24小时。每次会议将包括一次随机分配的输液，将是 生理盐水或单剂量尼古丁(每70公斤体重1毫克)以4种不同的输液速率输送：0.24， 每公斤体重每秒0.096、0.048或0.024微克)。价格在尼古丁递送的范围内 可燃香烟和电子烟所达到的比率，并在我们最近的研究中进行了试点。在研究2中，薄荷醇- 偏爱吸烟者(n=38)将被随机分为薄荷醇或非薄荷醇香烟吸烟组 条件，每次持续2周，使用交叉设计。在每个周期的第二周，3名实验者 会议将分别在3天内举行。我们申请的结果将有助于FDA建立 将电子烟和其他电子烟的成瘾风险降至最低的尼古丁递送率标准 尼古丁输送系统(完)。

Abstract: Project #3 Rapid delivery to the brain enhances the abuse potential of drugs of abuse, including nicotine. As proposed by Shihadeh and Eissenberg, “nicotine flux”, or the rate at which a given electronic cigarette (e-cigarette) delivers nicotine, is the most critical factor for evaluating its abuse potential. In this model, when an e-cigarette delivers nicotine at rates above a certain, yet undetermined, threshold it can have high abuse potential and may initiate or maintain tobacco addiction. In contrast, when the nicotine flux is optimal, that e-cigarette may have low addiction potential while providing sufficient nicotine delivery to help smokers quit smoking by alleviating urges to smoke. This proposed “optimal nicotine flux” concept has yet to be empirically assessed in controlled human studies. In addition, flavors and other e-cigarettes ingredients may also affect the impact of delivery rate on the addictive effects of nicotine. Most notably, menthol may have such an effect through inhibition of nicotinic receptors and slowing of nicotine metabolism. Systematic studies from our group and others have shown that intravenous (IV) nicotine infusion is an optimal approach for quantifying the influence of delivery rate on nicotine's behavioral and physiological effects. The primary aim of this project is to examine the impact of nicotine delivery rate on nicotine's abuse potential (assessed by positive subjective effects and reinforcement), and its potentially beneficial effects of alleviating smoking urges and withdrawal. We also seek to determine if switching from menthol to non-menthol cigarettes, modeling a ban on menthol cigarettes, changes the impact of nicotine delivery rate on the study outcomes. To reach these goals, we propose 2 placebo-controlled studies that will recruit male and female nicotine dependent smokers. Study 1 will recruit equal numbers of menthol (n=35) and non-menthol (n=35) preferring smokers for 5 experimental sessions, which will be at least 24 hours apart. Each session will include 1 randomly assigned infusion that will be either saline or a single dose of nicotine (1 mg per 70 kg body weight) delivered at 4 different infusion rates: 0.24, 0.096, 0.048 or 0.024 µg per kg body weight per second). The rates are within the range of nicotine delivery rates achieved by combustible and e-cigarettes and have been piloted in our recent study. In Study 2, menthol- preferring smokers (n=38) will be randomized to a sequence of menthol or non-menthol cigarette smoking conditions, each lasting for 2 weeks, using a crossover design. During week 2 of each period, 3 experimental sessions will be held on 3 separate days. The results from our application will help the FDA in establishing standards for nicotine delivery rates that minimize the addictive risks of e-cigarettes and other electronic nicotine delivery systems (ENDS).