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.

项目摘要 尼古丁是烟草的主要成瘾成分。FDA正在考虑一项旨在 将烟草产品中的尼古丁含量降低到不会让人上瘾的水平，以防止患上 青少年对烟草产品的上瘾。这一战略的实施将 需要一系列临床前和临床研究的强有力的科学支持。然而，我们在这方面还存在一些空白 目前关于尼古丁成瘾效应的实际阈值以及该阈值是否变化的知识 在各个个体之间，或者带有通常添加到吸入烟草产品中的味道。研究的目标是 解决这些差距的障碍是通过香烟传递准确剂量的尼古丁的困难 吸烟或电子烟。此外，将尼古丁的影响与吸入的多种其他化学物质分开 尼古丁仍然是一个挑战。在纯尼古丁选择中，静脉注射(IV)是黄金标准 用于临床前研究，并越来越多地用于临床研究。静脉注射的路线与吸入的 对于尼古丁的药代动力学，它也产生了强化和主观奖励的效果。在一个 一系列的试点研究，我们改进了我们的静脉注射尼古丁程序，以更好地模拟泡芙大小的尼古丁通过 吸烟或电子烟，并允许评估尼古丁对多种疾病的剂量依赖效应 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，我们建议确定关于尼古丁成瘾阈值和 甜味剂对这一门槛的影响。具体来说，我们将1)确定尼古丁的阈值剂量(S) 吸烟者的强化、歧视和主观奖励效应(目标1)和2)评估 这些阈值剂量随吸入甜味剂(三氯蔗糖)而变化，同时使用电子烟 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，招募男性 以及女性吸烟者。对于目标1，在4个测试会话的每一个中，不同的尼古丁剂量(0.1，0.05， 0.025毫克和0.0125毫克尼古丁/脉搏)将与生理盐水进行比较，以增强、区分尼古丁和 主观效果。在脉冲输液的同时，参与者将吸入无味电子烟，这 将使吸入性烟草使用的感官方面更接近匹配。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。每个测试会话将包括 三种尼古丁剂量中的一种(选自Aim 1)与生理盐水，均加或不加甜味剂 三氯蔗糖。甜味剂和对照溶液将在静脉注射的同时通过电子烟给予。通过 提供尼古丁成瘾阈值的新信息以及甜味剂对此的影响 门槛，这项研究的结果将告知FDA制定以科学为基础的基准，以减少 烟草产品带来的风险。