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

• 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
• 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

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.

摘要