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 快速向大脑分娩可增强包括尼古丁在内的滥用药物的滥用潜力。如提议 Shihadeh和Eissenberg，“尼古丁通量”或给定电子烟的速率（电子烟） 提供尼古丁是评估其滥用潜力的最关键因素。在此模型中，当电子烟 以高于特定但尚不确定的阈值的速度提供尼古丁，它可能具有很高的滥用潜力，并且 可以启动或维护烟草成瘾。相反，当尼古丁通量最佳时，电子烟可能 在提供足够的尼古丁递送时具有低成瘾的潜力，以帮助吸烟者戒烟 减轻敦促吸烟的冲动。这个提出的“最佳尼古丁通量”概念尚未经验评估 受控人类研究。此外，口味和其他电子烟的用途也可能影响 尼古丁添加作用的递送率。最值得注意的是，Menthol可能会通过 抑制烟碱受体和尼古丁代谢减缓。我们小组的系统研究 其他人则表明，静脉注射（IV）尼古丁输注是量化影响的最佳方法 尼古丁行为和身体影响的递送率。该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），及其减轻吸烟和戒断的潜在有益作用。我们也寻求 要确定是否从精神病转换为非门票香烟，建模禁止精神病香烟， 改变尼古丁递送率对研究结果的影响。为了实现这些目标，我们提出了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 等量的薄荷醇（n = 35）和非胸膜（n = 35）偏爱5个实验性会话的吸烟者， 这将至少相隔24小时。每个会话将包括1个随机分配的输注 盐水或单剂量的尼古丁（每70千克体重1毫克）以4种不同的输注率：0.24，0.24， 0.096、0.048或0.024 µg每千克每秒体重）。费率在尼古丁交付范围内 混合和电子烟所实现的速度，并在我们最近的研究中进行了试验。在研究2中，精神病 - 偏爱吸烟者（n = 38）将被随机分为一系列Menhol或非胸烟吸烟 条件，每个持续2周，使用跨界设计。在每个时期的第2周，3个实验 会议将在三天的三天举行。我们应用程序的结果将有助于FDA建立 尼古丁输送率的标准率最小化电子烟和其他电子的添加剂风险 尼古丁输送系统（末端）。