Psilocybin and Affective Function in Chronic Lower Back Pain and Depression

项目总结/摘要 这项R33申请提出了一项机制性临床试验，测试裸盖菇素对情感障碍的影响。 慢性腰痛和抑郁症共病患者的慢性疼痛机制（CLBP+D）。CLBP 是全球残疾的首要原因，并且与抑郁症高度共病。CLBP+D患者面临a 分散和有限的治疗方案，不足以解决他们的疼痛和抑郁症状。 因此，CLBP治疗指南要求从单一的结果集中于疼痛强度， 来治疗情感功能。积极和消极的影响，痛苦灾难化， 积极的情感性疼痛抑制是良好表征的，可改变的，生物介导的机制， 我们建议在CLBP+D患者的这项研究中靶向慢性疼痛。裸盖菇素，一个经典的（5-HT 2A 受体介导的）致幻剂，是一种有前途的非阿片类药物候选人，用于治疗CLBP+D， 并持久改善健康个体、重度抑郁症患者的情感功能， 患有危及生命的癌症诊断的患者。我们的目标是测试裸盖菇素是否会使患有 CLBP+D通过持久改善积极影响，消极影响和痛苦灾难化，并增加 积极情感抑制疼痛的能力。拟议的研究解决了一个重要的未满足的需求，因为它将是 首先，据我们所知，测试裸盖菇素靶向疼痛相关情感功能的能力， 慢性疼痛我们提出了一项双盲、随机、对照试验， 给予裸盖菇素（25 mg绝对剂量; n=20）至活性对照（哌甲酯40 mg绝对剂量; n=20） 在CLBP+D患者中。裸盖菇素或哌醋甲酯将在实验室给药一次， 密切监督和支持性监测。主要结果将是积极和消极的影响（目标1）， 疼痛灾难化（Aim 2）和积极情感性疼痛抑制（Aim 3）。生态瞬时评估 将被用来评估假设，即汇总的正面和负面影响的瞬间报告， 疼痛恶化将在治疗后1周从基线改善， 裸盖菇素和哌甲酯的对比定量感官测试将用于评估 假设积极的情感疼痛抑制将从基线到治疗后1周增加到更大 裸盖菇素与哌醋甲酯条件下患者的程度。结果的持久性将是 在次要分析中，在给药后1个月进行检测。通过测试裸盖菇素对情感的影响， 在CLBP+D功能，我们将开发关键数据，将提供机械洞察的效用 psilocybin作为一种止痛药。这些数据将建立在我们广泛的初步调查结果的基础上， 支持裸盖菇素对重度抑郁症的疗效，并为未来的关键疗效试验铺平道路 对于裸盖菇素作为CLBP+D患者的主要治疗。

PROJECT SUMMARY/ABSTRACT This R33 application proposes a mechanistic clinical trial testing the effects of psilocybin on affective mechanisms of chronic pain in patients with comorbid chronic low back pain and depression (CLBP+D). CLBP is the top cause of disability worldwide, and is highly comorbid with depression. Patients with CLBP+D face a fragmented and limited set of treatment options that insufficiently address their pain and depression symptoms. As such, CLBP treatment guidelines call for a shift away from a sole outcome focus on pain intensity and toward treatments that enhance affective function. Positive and negative affect, pain catastrophizing, and positive affective pain inhibition are well-characterized, modifiable, biologically-mediated mechanisms of chronic pain that we propose to target in this study of patients with CLBP+D. Psilocybin, a classic (5-HT2A receptor-mediated) psychedelic, is a promising non-opioid candidate for the treatment of CLBP+D that reliably and durably improves affective function in healthy individuals, patients with major depressive disorder, and patients with a life-threatening cancer diagnosis. We aim to test whether psilocybin will benefit patients with CLBP+D by durably improving positive affect, negative affect, and pain catastrophizing, and augmenting the ability of positive affect to inhibit pain. The proposed study addresses an important unmet need, as it will be the first, to our knowledge, to test the ability of psilocybin to target pain-related affective function in patients with chronic pain. We propose a double-blind, randomized, controlled trial comparing the administration of high- dose psilocybin (25mg absolute dose; n=20) to an active control (methylphenidate 40mg absolute dose; n=20) among patients with CLBP+D. Psilocybin or methylphenidate will be administered once in the laboratory under close supervision and supportive monitoring. Primary outcomes will be positive and negative affect (Aim 1), pain catastrophizing (Aim 2), and positive affective pain inhibition (Aim 3). Ecological momentary assessment will be used to evaluate the hypotheses that aggregated momentary reports of positive and negative affect and pain catastrophizing will improve from baseline to 1-week post-session to a greater extent in patients in the psilocybin versus the methylphenidate condition. Quantitative sensory testing will be used to evaluate the hypothesis that positive affective pain inhibition will increase from baseline to 1-week post-session to a greater extent in patients in the psilocybin versus the methylphenidate condition. The durability of outcomes will be tested at 1-month post-administration in secondary analyses. By testing the effects of psilocybin on affective function in CLBP+D, we will develop critical data that will provide mechanistic insight into the utility of psilocybin as a pain management medicine. These data will build off our extensive preliminary findings in support of psilocybin’s efficacy for major depressive disorder, and pave the way for future pivotal efficacy trials for psilocybin as a primary treatment for patients with CLBP+D.