Effects of ketamine on tobacco use disorder - Resubmission

摘要 阿肯色州的吸烟流行率在全国排名第三(占总人口的25%)，排名第二。 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，特别是对非尼古丁干预措施的持续需求。例如，尼古丁 其本身可能会增加手术后并发症的风险。尼古丁的强化作用可能是 由于其对谷氨酸能传递的影响，以及谷氨酸能药物在烟草中的使用 上瘾已经被提出了。谷氨酸N-甲基-D-天冬氨酸(NMDA)受体拮抗剂氯胺酮 与其他NMDA拮抗剂类似，在减少尼古丁自身给药方面显示出临床前的有效性。 此外，氯胺酮在减少渴求、戒断症状和使用其他药物方面也显示出了希望 使人上瘾的药物。然而，氯胺酮对烟草使用障碍的影响尚不清楚，而且 有必要调查它对烟草成瘾的神经心理基础的影响。而当 氯胺酮对烟草成瘾的影响尚未在人类身上进行测试，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 数据支持在完成香烟实验室测量的吸烟者中使用氯胺酮的可行性和耐受性 在输注氯胺酮或安慰剂之前和24小时后，渴望和吸烟的潜伏期。为了推进这一进程 我们建议对吸烟者进行一项受试者内交叉试验，他们将接受输注 氯胺酮和一种有效的对照药物处于平衡状态，至少相隔2周。在目标1中，我们将 测量渴望、戒烟和烟草使用行为的变化。在目标2中，我们将确定 应用功能磁共振成像研究氯胺酮对脑功能的影响。安全性、耐受性和 将使用生理、药物效果和副作用措施评估氯胺酮的可接受性。这 这项提案意义重大，因为它将是第一个将临床前研究转化为新的药物疗法的方案 为了戒烟。这一信息很有价值，因为确切地知道氯胺酮是如何破坏烟草的 成瘾将有助于指导未来氯胺酮的治疗用法或其他药物疗法的开发 有着相似的作用机制。

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.