Effects of ketamine on tobacco use disorder - Resubmission

摘要 阿肯色州的吸烟率在全国排名第三（占人口的25%）， 吸烟导致的癌症死亡率（33.5%）。对烟草成瘾更有效的干预措施是 需要，特别是对基于非尼古丁的干预措施的持续需求。例如尼古丁 本身可能会增加术后并发症的风险。尼古丁的强化作用可能是 由于其对烟草能传播的影响，以及烟草能药物的使用 成瘾已经提出。一种谷氨酸N-甲基-D-天冬氨酸（NMDA）受体拮抗剂氯胺酮， 在减少尼古丁自我给药方面显示出临床前功效，与其他NMDA拮抗剂相似。 此外，氯胺酮已显示出减少渴望、戒断症状和使用其他药物的希望。 人类的成瘾药物然而，氯胺酮对烟草使用障碍的影响尚不清楚， 研究其对烟草成瘾的神经心理学基础的影响是必要的。而 氯胺酮对烟草成瘾的影响尚未在人类中进行过测试，有间接证据表明它 减少烟草使用的潜在功效。为了填补这一知识空白，我们已经开始收集初步的 支持氯胺酮在完成香烟实验室测量的吸烟者中的可行性和耐受性的数据 在输注氯胺酮或安慰剂之前和之后24小时的渴望和吸烟潜伏期。推进这一 在一项研究中，我们提出了一项受试者内交叉试验，吸烟者将接受 氯胺酮和活性对照药物以平衡顺序给药，至少间隔2周。在目标1中，我们 测量渴望、烟草戒断和烟草使用行为的变化。在目标2中，我们将确定 氯胺酮对脑功能影响的功能磁共振成像研究安全性、耐受性和 氯胺酮的可接受性将使用生理学、药物作用和副作用测量来评估。这 该提案意义重大，因为它将是第一个将临床前研究转化为新药物疗法的提案 治疗烟瘾这一信息很有价值，因为准确了解氯胺酮如何破坏烟草 成瘾将有助于指导未来氯胺酮的治疗用途或其他药物疗法的开发 具有相似的作用机制。

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.