Addictive Threshold of Nicotine and the Impact of Sweeteners

尼古丁的成瘾阈值和甜味剂的影响

• 批准号: 10666236
• 负责人: Mehmet Sofuoglu
• 金额: $ 34.82万
• 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 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10666236
• 关键词: Address; Behavior; Benchmarking; Characteristics; Chemicals; Cigarette; Cigarette Smoker; Clinical Research; Clinical Trials; Dependence; Detection; Development; Discrimination; Dose; Drug Kinetics; Electronic cigarette; Female; Human; Individual; Infusion procedures; Inhalation; Intravenous; Intravenous infusion procedures; Knowledge; Metabolism; Methods; Modeling; Nicotine; Outcome; Participant; Physiologic pulse; Pilot Projects; Population; Potassium; Procedures; Psychological reinforcement; Rewards; Risk; Route; Saline; Sampling; Science; Self Administration; Sensory; Series; Smoker; Smoking; Stimulus; Sucrose; Sweetening Agents; Testing; Tobacco; Tobacco Dependence; Tobacco use; Work; Youth; abuse liability; addiction; addiction liability; behavioral pharmacology; behavioral study; cigarette smoking; drug discrimination; electronic liquid; interest; male; nicotine inhalation; nicotine self-administration; novel; placebo controlled study; pre-clinical research; preclinical study; prevent; prototype; recruit; response; sex; tobacco products; young adult

Project Summary Nicotine is the key addictive ingredient of tobacco. The FDA is considering a regulatory strategy aiming to reduce the nicotine content of tobacco products to “non-addictive” levels to prevent the development of addiction among youth experimenting with tobacco products. The implementation of such a strategy would require strong scientific support from a range of preclinical and clinical studies. However, there are gaps in our current knowledge about the actual threshold for nicotine's addictive effects and whether this threshold varies across individuals or with flavors that are commonly added to inhaled tobacco products. Studies aiming to address these gaps are hampered by difficulty in delivering accurate doses of nicotine through cigarette smoking or e-cigarettes. Further, separating nicotine's effects from multiple other chemicals that are inhaled with nicotine remains a challenge. Among pure nicotine options, the intravenous (IV) route is the gold standard for preclinical research and is increasingly used in clinical studies as well. IV route approximates the inhaled delivery for nicotine pharmacokinetics, and it also produces reinforcing and subjective-rewarding effects. In a series of pilot studies, we refined our IV nicotine procedure to better model puff-sized nicotine delivered by smoking cigarettes or e-cigarettes and to allow assessment of nicotine's dose-dependent effect on multiple addiction-related outcomes, including reinforcement, drug discrimination, and subjective-rewarding effects. Using this method, we propose to determine benchmarks regarding the addictive threshold of nicotine and the impact of sweeteners on this threshold. Specifically, we will 1) determine the nicotine threshold dose(s) for reinforcement, discrimination, and subjective-rewarding effects in smokers (Aim 1) and 2) evaluate whether these threshold doses change with inhaled sweetener (sucralose), administered by e-cigarettes concurrent with IV nicotine infusions (Aim 2). For both Aims, we will use a placebo-controlled study that will recruit male and female cigarette smokers. For Aim 1, in each of the 4 test sessions, a different nicotine dose (0.1, 0.05, 0.025, and 0.0125 mg nicotine/pulse) will be compared to saline for reinforcement, nicotine discrimination, and subjective effects. Concurrently with the pulsed infusions, participants will inhale unflavored e-cigarettes, which will allow a closer matching of the sensory aspects of inhaled tobacco use. To assess the effect of sweeteners in Aim 2, participants in a placebo-controlled study will have 6 test sessions. Each Test Session will include one of the 3 nicotine doses (selected from Aim 1) vs. saline, all combined with or without the sweetener sucralose. Sweetener and control solution will be administered by e-cigarettes concurrent with IV infusions. By providing novel information on the addictive threshold of nicotine and the impact of sweeteners on this threshold, the results of this study will inform the FDA in setting science-based benchmarks for reducing the risks from tobacco products.

项目概要 尼古丁是烟草的主要成瘾成分，FDA 正在考虑一项监管策略，旨在 将烟草制品中的尼古丁含量降低至“不会成瘾”的水平，以防止发展成瘾 实施这样的策略将减少青少年尝试烟草产品的成瘾。 需要一系列临床前和临床研究的强有力的科学支持然而，我们的研究还存在差距。 关于尼古丁成瘾作用的实际阈值以及该阈值是否变化的当前知识 跨个人或通常添加到吸入烟草产品中的味道。 由于难以通过香烟提供准确剂量的尼古丁而阻碍了解决这些差距 此外，将尼古丁的作用与吸入的多种其他化学物质分开。 在纯尼古丁选择中，静脉注射 (IV) 途径是金标准。 用于临床前研究，并且也越来越多地用于临床研究，类似于吸入。 尼古丁药代动力学的传递，它还产生强化和主观奖励效应。 通过一系列试点研究，我们改进了静脉注射尼古丁程序，以更好地模拟由 吸烟或电子烟，并允许评估尼古丁对多种吸烟者的剂量依赖性影响 与成瘾相关的结果，包括强化、药物歧视和主观奖励效应。 使用这种方法，我们建议确定有关尼古丁成瘾阈值和尼古丁成瘾阈值的基准。 具体来说，我们将 1) 确定尼古丁阈值剂量。 吸烟者的强化、歧视和主观奖励效应（目标 1）和 2）评估是否 这些阈值剂量随着吸入甜味剂（三氯蔗糖）而变化，同时通过电子烟给药 静脉注射尼古丁（目标 2） 对于这两个目标，我们将使用一项安慰剂对照研究，该研究将招募男性。 对于目标 1，在 4 次测试中，每次使用不同的尼古丁剂量（0.1、0.05、 0.025 和 0.0125 毫克尼古丁/脉冲）将与生理盐水进行比较，以进行强化、尼古丁辨别和 在脉冲输注的同时，参与者将吸入无味的电子烟。 将允许更紧密地匹配吸入烟草使用的感官方面来评估甜味剂的效果。 在目标 2 中，安慰剂对照研究的参与者将进行 6 次测试，每次测试将包括以下内容。 3 种尼古丁剂量中的一种（从目标 1 中选择）与盐水对比，全部与甜味剂结合使用或不与甜味剂结合使用 三氯蔗糖和对照溶液将通过电子烟与静脉输注同时给药。 提供有关尼古丁成瘾阈值以及甜味剂对此影响的新信息 阈值，这项研究的结果将为 FDA 制定基于科学的基准来减少 来自烟草制品的风险。