5-HT2A Agonist Psilocybin in the Treatment of Tobacco Use Disorder

我们提出了一个多中心，双盲，随机临床试验的5-HT 2A受体激动剂裸盖菇素， 戒烟。我们之前进行了一项开放标签的试点试验（N = 15），裸盖菇素与认知功能相结合， 行为疗法（CBT）。数据显示，生物学验证的7天点流行率戒烟率为67%， 12个月和2.5年时分别为60%（持续戒烟率：分别为53%和47%）（约翰逊等人， 2014;约翰逊等人，2017年）。我们现在正在进行一项开放标签随机比较疗效试验， psilocybin与尼古丁贴片，两者都与CBT组合。中期结果（N = 44;每组22例）显示， 裸盖菇素12个月时经生物学验证的戒断率：7天点患病率：59% vs 27%; 持续禁欲：36% vs. 9%。尽管有这些有希望的发现，我们还没有进行双盲 裸盖菇素用于戒烟研究此外，以前的裸盖菇素研究样品在很大程度上 社会经济地位较高的白色，部分原因是缺乏参与者补偿和适度的 非营利组织的资助。目前的试验将在三个研究中心解决这些问题， 进行裸盖菇素研究的经验：约翰霍普金斯，伯明翰的亚拉巴马大学（UAB）， 和纽约大学（NYU）。将招募关于民族认同和社会经济地位的不同样本 在每个研究中心进行研究访视并给予补偿。拟议的双盲研究将治疗66名参与者（22名在 每个研究中心），随机接受：1）裸盖菇素;第1阶段20 mg/70 kg，第2阶段30 mg/70 kg， 疗程间隔1周;或2）烟酸;疗程1为250 mg，疗程2为375 mg，疗程间隔1周。 选择烟酸是因为它在以前的两个随机治疗中被用作活性安慰剂。 裸盖菇素的试验（Grob等，2011; Ross等人，2016年），FDA已通知我们，烟酸是他们的首选 裸盖菇素的活性安慰剂CBT将管理两组，并将允许我们测试裸盖菇素的 有效性高于并超越了既定的治疗方法。经生化学证实的7天时点患病率 将在长达12个月的时间内对禁欲情况进行评估。我们假设裸盖菇素（与烟酸相比） 将导致12个月随访时经生物学证实的7天时点戒烟率增加。基于 试点数据，我们将测试治疗反应的认知/心理介质。我们假设裸盖菇素 将与认知控制的改善和对戒断缓解（吸烟）的预期降低相关 目标戒烟日期后1天，这将与12岁时更大的7天时点戒烟率相关， 月随访。虽然迷幻疗法是一种新颖的方法，约翰霍普金斯网站已经进行了 裸盖菇素试验超过700次超过16年，并为人类安全行为设定了标准。 具有适当风险缓解策略的迷幻研究（约翰逊等人，2008年）。这次审判将提供一个 在不同的研究样本中进行严格的疗效测试，并测试相关机制，为创新的吸烟 停止治疗显示出潜在的实质性疗效。

We propose a multi-site, double-blind, randomized clinical trial of the 5-HT2A receptor agonist psilocybin for smoking cessation. We previously conducted an open-label pilot trial (N = 15) of psilocybin paired with cognitive behavior therapy (CBT). Data showed a biologically-verified 7-day point-prevalence abstinence rate of 67% at 12 months and 60% at 2.5 years (continuous abstinence rates: 53% and 47%, respectively) (Johnson et al., 2014; Johnson et al., 2017). We are now conducting an open-label randomized comparative efficacy trial of psilocybin vs. nicotine patch, both in combination with CBT. Interim results (N = 44; 22 per group) show greater biologically-verified abstinence rates at 12 months for psilocybin: 7-day point-prevalence: 59% vs. 27%; continuous abstinence: 36% vs. 9%. Despite these promising findings, we have yet to conduct a double-blind study of psilocybin for smoking cessation. Furthermore, previous psilocybin study samples have been largely White with higher socioeconomic status (SES), partly due to lack of participant compensation and modest funding from non-profit organizations. The current trial will address these issues across three sites with experience in conducting psilocybin research: Johns Hopkins, the University of Alabama at Birmingham (UAB), and New York University (NYU). A diverse sample with regard to ethnoracial identity and SES will be recruited at each site with compensation for study visits. The proposed double-blind study will treat 66 participants (22 at each site), randomized to receive either: 1) psilocybin; 20 mg/70 in session 1 and 30 mg/70 kg in session 2, with sessions 1 week apart; or 2) niacin; 250 mg in session 1 and 375 mg in session 2, with sessions 1 week apart. Niacin was selected because it has been used as an active placebo in two previous randomized therapeutic trials of psilocybin (Grob et al., 2011; Ross et al., 2016), and the FDA has informed us that niacin is their preferred active placebo for psilocybin. CBT will be administered to both groups and will allow us to test psilocybin’s efficacy above and beyond an established treatment approach. Biochemically-confirmed 7-day point-prevalence abstinence will be assessed throughout for up to 12 months. We hypothesize that psilocybin (compared to niacin) will cause increased biologically-confirmed 7-day point-prevalence abstinence at 12-month follow-up. Based on pilot data, we will test cognitive/psychological mediators of treatment response. We hypothesize that psilocybin will be associated with improved cognitive control and decreased anticipation of withdrawal relief (from smoking) 1 day after the target quit date, which will be associated with greater 7-day point-prevalence abstinence at 12- month follow-up. Although psychedelic therapy is a novel approach, the Johns Hopkins site has conducted psilocybin trials with >700 sessions for >16 years, and has set the standard for the safe conduct of human psychedelic research with appropriate risk mitigation strategies (Johnson et al., 2008). This trial will provide a rigorous test of efficacy in a diverse study sample, and test relevant mechanisms, for an innovative smoking cessation treatment showing potential for substantial efficacy.