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

研究项目 3：尼古丁输送率及其滥用潜力：薄荷醇的影响

• 批准号: 10242020
• 负责人: Mehmet Sofuoglu
• 金额: $ 52.76万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10242020
• 关键词: Address; Affect; Attenuated; Behavior; Behavioral; Blood Pressure; Body Weight; Brain; Characteristics; Cigarette; Cigarette Smoker; Clinical Research; Cotinine; Crossover Design; Dose; Electronic Nicotine Delivery Systems; Electronic cigarette; Female; Generations; Goals; Heart Rate; Hour; Human; Infusion procedures; Intravenous; Measures; Mediating; Menthol; Metabolism; Methods; Modeling; Nicotine; Nicotine Dependence; Nicotinic Receptors; Outcome; Outcome Study; Patient Self-Report; Pharmaceutical Preparations; Physiological; Plasma; Procedures; Psychological reinforcement; Randomized; Research Project Grants; Risk; Saline; Severities; Sex Differences; Smoke; Smoker; Smoking; Symptoms; Tobacco; Tobacco Dependence; Tobacco use; Withdrawal; Work; addiction; cigarette smoking; cognitive performance; combustible cigarette; drug of abuse; economic value; experimental study; hydroxycotinine; interest; male; nicotine abuse; placebo controlled study; preclinical study; recruit; response; smoking cessation; tobacco products

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).

摘要：项目#3 快速输送到大脑会增加滥用药物（包括尼古丁）的滥用潜力。提出的 由Shihadeh和Kissenberg，“尼古丁通量”，或给定的电子烟（电子烟） 传递尼古丁，是评估其滥用潜力的最关键因素。在这个模型中，当电子烟 以高于某个但未确定的阈值的速率递送尼古丁，它可能具有高滥用潜力， 可能引发或维持烟草成瘾。相反，当尼古丁流量最佳时，电子烟可以 低成瘾性，同时提供足够的尼古丁输送，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”概念尚未得到经验评估， 对照人类研究。此外，香精和其他电子烟成分也可能影响 尼古丁的成瘾作用。最值得注意的是，薄荷醇可能通过以下方式具有这种效果： 抑制烟碱受体和减慢烟碱代谢。我们小组的系统研究， 其他人已经表明静脉内（IV）尼古丁输注是量化 递送率对尼古丁的行为和生理影响。该项目的主要目的是研究 尼古丁输送率对尼古丁滥用潜力的影响（通过积极的主观效应评估， 强化），以及其缓解吸烟欲望和戒断的潜在有益效果。我们还寻求 为了确定从薄荷醇香烟转换到非薄荷醇香烟，模拟对薄荷醇香烟的禁令， 改变尼古丁输送率对研究结果的影响。为了实现这些目标，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）偏好吸烟者进行5次实验， 至少相隔24小时每次治疗将包括1次随机分配的输注， 生理盐水或单剂量尼古丁（每70 kg体重1 mg）以4种不同输注速率递送：0.24， 0.096、0.048或0.024 µg/kg体重/秒）。速率在尼古丁释放的范围内 可燃香烟和电子香烟所达到的吸烟率，并在我们最近的研究中进行了试点。在研究2中，薄荷醇- 喜欢吸烟的人（n=38）将被随机分配到吸薄荷烟或吸非薄荷烟的顺序中 条件下，每个持续2周，使用交叉设计。在每个阶段的第2周， 会议将分三天举行。我们申请的结果将有助于FDA建立 尼古丁输送率的标准，最大限度地减少电子烟和其他电子产品的成瘾风险 尼古丁输送系统（ENDS）。