Effects of ketamine on tobacco use disorder - Resubmission

氯胺酮对烟草使用障碍的影响 - 重新提交

基本信息

批准号：
10625289
负责人：
Merideth A. Addicott
金额：
$ 19.63万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10625289
关键词：
Abstinence Affect Alcohols Animal Model Arkansas Behavior Behavioral Brain Cause of Death Chronic Cross-Over Trials Cues Data Development Dopamine Drug Controls Drug usage Ecological momentary assessment Effectiveness Functional Magnetic Resonance Imaging Future Glutamates Homeostasis Hour Human Individual Infusion procedures Intervention Investigation Ketamine Knowledge Malignant Neoplasms Measures Mental Depression Moods N-Methyl-D-Aspartate Receptors N-Methylaspartate Neuropsychology Nicotine Opioid Participant Pathway interactions Patient Self-Report Pharmaceutical Preparations Pharmacotherapy Physiological Effects of Drugs Placebos Population Process Psychological reinforcement Research Rest Rewards Risk Safety Smoke Smoker Smoking Substance Use Disorder Synapses Synaptic plasticity System Testing Therapeutic Uses Time Tobacco Tobacco Dependence Tobacco Use Disorder Tobacco use Translating United States Withdrawal Withdrawal Symptom active control addiction antagonist brain pathway cigarette craving cigarette smoke cigarette smoking cocaine use comorbidity craving cue reactivity design disability drug craving drug of abuse drug seeking behavior effective intervention improved mortality neuroimaging nicotine self-administration novel pre-clinical research preclinical efficacy public health relevance receptor reduce tobacco use side effect smoking cessation smoking cue smoking prevalence substance use transmission process

项目摘要

ABSTRACT Arkansas ranks third in the nation for cigarette smoking prevalence (25% of the population) and ranks second for smoking-attributed cancer mortality (33.5% mortality). More effective interventions for tobacco addiction are needed, and there is an ongoing need for non-nicotine based interventions in particular. For example, nicotine itself may potentially increase the risk of post-surgical complications. The reinforcing effects of nicotine may be due to its effects on glutamatergic transmission, and the use of glutamatergic medications for tobacco addiction has been proposed. A glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, ketamine, has shown preclinical efficacy in reducing nicotine self-administration, similar to other NMDA antagonists. Furthermore, ketamine has shown promise in reducing craving, withdrawal symptoms, and use of other addictive drugs in humans. However, ketamine’s effects on tobacco use disorder are not yet known and an investigation of its impact on the neuropsychological substrates of tobacco addiction is warranted. While the effects of ketamine on tobacco addiction have not been tested in humans, there is indirect evidence of its potential efficacy to reduce tobacco use. To fill this gap in knowledge, we have begun collecting preliminary data supporting the feasibility and tolerability of ketamine in smokers who complete lab measures of cigarette craving and smoking latency before, and 24 hours after, an infusion of ketamine or placebo. To advance this line of research, we propose a within-subject, cross-over trial of smokers who will receive an infusion of ketamine and an active control drug in counter-balanced order, at least 2 weeks apart. In Aim 1, we will measure changes in craving, tobacco withdrawal, and tobacco use behavior. In Aim 2, we will determine the effects of ketamine on brain function using functional magnetic resonance imaging. The safety, tolerability, and acceptability of ketamine will be assessed using physiological, drug effect, and side-effect measures. This proposal is significant because it will be the first to translate preclinical research on a novel pharmacotherapy for tobacco addiction. This information is valuable because knowing precisely how ketamine disrupts tobacco addiction will help guide future therapeutic use of ketamine or the development of other pharmacotherapies with similar mechanisms of action.

抽象的阿肯色州的吸烟率（占人口的25％）排名全美，排名第二用于吸烟的癌症死亡率（33.5％死亡率）。对烟草成瘾的更有效干预措施是需要，并且尤其是基于非凝聚力的干预措施的需求持续不断。例如，尼古丁本身可能会增加手术后并发症的风险。尼古丁的增强作用可能是由于其对谷氨酸能传播的影响以及使用谷氨酸能药物对烟草的使用已经提出了成瘾。谷氨酸N-甲基-D-天冬氨酸（NMDA）受体拮抗剂氯胺酮具有显示出与其他NMDA拮抗剂相似的临床前效率。此外，氯胺酮在减少渴望，戒断符号和使用其他方面表现出了希望人类中的加性药物。但是，氯胺酮对烟草使用障碍的影响尚不清楚，这是有必要对其对烟草成瘾的神经心理底物的影响进行调查。而氯胺酮对烟草成瘾的影响尚未在人类中进行测试，有间接证据表明它潜在的效率来减少烟草使用。为了填补知识的差距，我们已经开始收集初步支持氯胺酮在吸烟者中的可行性和耐受性的数据渴望和吸烟潜伏期之前，以及在氯胺酮或安慰剂输注后24小时。推进这一点研究线，我们提出了一项受吸烟者的受试者内部，交叉试验氯胺酮和一种以平衡顺序的活跃控制药物，相距至少2周。在AIM 1中，我们将测量渴望，烟草戒断和烟草使用行为的变化。在AIM 2中，我们将确定氯胺酮使用功能磁共振成像对脑功能的影响。安全性，耐受性和氯胺酮的可接受性将使用物理，药物作用和副作用措施进行评估。这提案很重要，因为它将第一个翻译有关新药物疗法的临床前研究的研究用于烟草成瘾。这些信息很有价值，因为精确地知道氯胺酮如何破坏烟草成瘾将有助于指导氯胺酮的未来热使用或其他药物治疗的开发具有类似的作用机理。