Addictive Threshold of Nicotine and the Impact of Sweeteners

项目摘要 尼古丁是烟草的主要成瘾成分。FDA正在考虑一项监管策略， 将烟草制品的尼古丁含量降至“不上瘾”的水平，以防止 青少年尝试烟草产品成瘾。实施这一战略将 需要来自一系列临床前和临床研究的强有力的科学支持。然而，我们的工作存在差距， 目前对尼古丁成瘾作用的实际阈值以及该阈值是否存在差异的了解 或与通常添加到吸入烟草产品中的香料一起使用。研究旨在 由于难以通过香烟递送准确剂量的尼古丁， 吸烟或电子烟。此外，将尼古丁的作用与吸入的多种其他化学物质分开， 尼古丁仍然是一个挑战。在纯尼古丁的选择中，静脉（IV）途径是金标准 用于临床前研究，并越来越多地用于临床研究。IV途径近似于吸入 尼古丁的药代动力学，它也产生了加强和主观奖励的效果。中 在一系列的试点研究中，我们改进了IV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 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的基准， 甜味剂对这个阈值的影响。具体而言，我们将1）确定尼古丁阈值剂量， 强化，歧视，和主观奖励的影响，吸烟者（目的1）和2）评估是否 这些阈值剂量随着吸入甜味剂（三氯蔗糖）的变化而变化， IV尼古丁输注（目标2）。对于这两个目的，我们将使用安慰剂对照研究，招募男性 女性吸烟者。对于目标1，在4个测试阶段的每一个中，不同的尼古丁剂量（0.1，0.05， 0.025和0.0125 mg尼古丁/脉冲）将与生理盐水进行强化、尼古丁辨别和 主观效果。与脉冲输注同时，参与者将吸入无味的电子烟， 将允许更接近地匹配吸入烟草使用的感官方面。评估甜味剂的作用 在目标2中，安慰剂对照研究的参与者将有6个测试阶段。每个测试会话将包括 3种尼古丁剂量之一（选自目标1）与盐水，均与或不与甜味剂组合 三氯蔗糖甜味剂和对照溶液将通过电子烟与IV输注同时给药。通过 提供了关于尼古丁成瘾阈值和甜味剂对其影响的新信息， 阈值，这项研究的结果将告知FDA在制定基于科学的基准，以减少 烟草产品的风险。

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.