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 尼古丁是烟草的关键添加成分。 FDA正在考虑一种监管策略的目的 将烟草产品的尼古丁含量降低到“非成瘾性”水平，以防止发展 青年实验烟草产品的成瘾。这种策略的实施将 需要一系列临床前和临床研究的强大科学支持。但是，我们的差距 有关尼古丁添加剂效果的实际阈值以及该阈值品种的当前知识 跨个体或通常添加到掺入烟草产品的口味。旨在进行的研究 解决这些差距被困难通过香烟提供准确剂量的尼古丁的困难。 吸烟或电子烟。此外，将尼古丁的作用与遗传的其他多种化学物质分开 尼古丁仍然是一个挑战。在纯尼古丁选择中，静脉（IV）路线是金标准 用于临床前研究，并且越来越多地用于临床研究。 IV路线近似继承 尼古丁药代动力学的递送，并且还会产生加强和主体奖励作用。在 一系列试验研究，我们完善了静脉注射尼古丁的程序，以更好地模拟粉扑大小的尼古丁。 吸烟或电子烟，并允许评估尼古丁的剂量依赖性对多种 与成瘾有关的结果，包括加强，药物歧视和受试者奖励效应。 使用这种方法，我们建议确定有关尼古丁的额外阈值的基准和 甜味剂对这个阈值的影响。具体而言，我们将确定尼古丁阈值的剂量 吸烟者中的加强，歧视和主题奖励效应（AIM 1）和2） 这些阈值剂量通过遗传的甜味剂（三氯蔗糖）的变化，由电子烟同时发生 静脉输注尼古丁输注（AIM 2）。对于这两个目标，我们将使用一项安慰剂对照研究，将招募男性 和雌性吸烟者。对于AIM 1，在4个测试会话中的每一个中，不同的尼古丁剂量（0.1，0.05， 将比较0.025和0.0125 mg尼古丁/脉搏）与盐水的加固，尼古丁歧视和 主观效果。与脉冲输注同时，参与者将吸入未口味的电子烟，这是 将允许更紧密地匹配继承的烟草使用的感觉方面。评估甜味剂的效果 在AIM 2中，参加安慰剂对照研究的参与者将进行6次测试课程。每个测试会议都将包括 3种尼古丁剂量之一（从AIM 1中选择）与盐水，均与甜味剂结合使用 三氯蔗糖。甜味剂和对照溶液将由同时发生的电子烟和静脉输注。经过 提供有关尼古丁添加阈值以及甜味剂对此的影响的新颖信息 阈值，这项研究的结果将为FDA提供基于科学的基准来减少基于科学的基准 烟草产品的风险。