Randomized placebo controlled trial to determine the biological signature of cannabidiol as a treatment for social anxiety disorder

随机安慰剂对照试验，以确定大麻二酚治疗社交焦虑症的生物特征

• 批准号: 10706609
• 负责人: Esther Marian Blessing
• 金额: $ 58.93万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-19 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10706609
• 关键词: Acute; Address; Adult; Adverse effects; Aftercare; Amygdaloid structure; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Area Under Curve; Behavioral; Biological; Biological Availability; Blood; Brain; Cannabidiol; Cannabis; Chronic; Clinical Trials; Complex; Data; Disease; Dose; Double-Blind Method; Drug Kinetics; Evidence based treatment; Exhibits; Extinction; FDA approved; Face; Formulation; Fright; Functional Magnetic Resonance Imaging; Future; Goals; Guidelines; Hemp; High Prevalence; Hour; Human; Impairment; Laboratories; Laboratory Study; Learning; Legal; Link; Measurement; Measures; Mental disorders; Methods; Mind; Moods; National Center for Complementary and Integrative Health; Natural Compound; Natural Products; Neurobiology; Neuropsychology; Oral; Outcome; Participant; Patients; Performance; Pharmacodynamics; Phase; Phased Innovation Awards; Placebo Control; Placebos; Plants; Plasma; Prefrontal Cortex; Primary Care; Protocols documentation; Quality of life; Reporting; Rest; Rodent; Safety; Self Medication; Social Anxiety Disorder; Speech; Standardization; Stress; Symptoms; Testing; Therapeutic Effect; Trier Social Stress Test; Visual; analog; anxiety treatment; childhood epilepsy; clinical effect; clinically significant; comorbidity; conditioned fear; design; drug candidate; early onset; early onset disorder; early phase clinical trial; efficacy study; efficacy trial; evidence base; health care service utilization; improved; neural; neural circuit; novel; novel therapeutics; phase III trial; phytocannabinoid; pre-clinical; randomized placebo controlled trial; randomized, clinical trials; response; social; social anxiety; symptomatic improvement; therapy development

PROJECT SUMMARY/ABSTRACT Social anxiety disorder (SAD) SAD is a common, early onset disorder that untreated, results in high chronicity, comorbidity, health care utilization, and functional and quality of life impairment. Novel treatments for SAD are needed, as many patients do not access, tolerate or respond to available treatments. Cannabidiol (CBD) is a natural compound from the cannabis plant that lacks the mind-altering effects of THC. With a recent surge in use of unregulated forms of CBD sold online or over the counter, patients are attempting to self-medicate without regulated formulations or evidenced based dose guidelines of CBD for anxiety disorders including SAD, creating an urgent need for rigorous biologically informed study. Together there exist strong preclinical and well-replicated human laboratory evidence for CBD’s acute anxiolytic effects, making it one of the most promising novel drug candidates for the treatment of anxiety, and social anxiety in particular. This proposal aims to build on promising preliminary scientific support for potential engagement with SAD-relevant neural and behavioral targets and clinical effects of CBD to help fill this gap. The goal of these studies is to establish a biological signature of CBD’s putative therapeutic effects in SAD and its link to core SAD symptoms, and to provide clinical effect sizes, safety, and feasibility data to guide a future definitive RCT of CBD for SAD. Our overarching hypothesis is that CBD will improve well-established abnormalities present in fear neurocircuitry and performance stress responding in adults with SAD, and that this SAD target engagement will be associated with symptom improvement. First in the R61, we will study two dose levels of a Phase 3 trial suitable hemp-derived (legal) oral CBD formulation with enhanced bioavailability versus placebo (PBO) in a 3 week double-blind RCT. Participants will undergo a modified Trier Social Stress Test (TSST) at week 2, and a standardized 2-day fear learning and extinction protocol at week 3, with fMRI brain activation accompanying fear extinction recall and fearful faces tasks on the second day. These methods will enable measurement of CBD vs PBO target engagement with three evidence- based targets: 1) Ventromedial prefrontal cortex (vmPFC) activation during fear extinction recall, 2) Amygdala activation in response to fearful faces, and 3) Visual analogue mood scale (VAMS) anxiety rating in response to the TSST speech. The GO criterion for progression from R61 to R33 will be met if target engagement is observed for at least one target, ordered as above, for at least one of the two CBD doses in the absence of clinically significant adverse effects. Next, the R33 will replicate CBD vs PBO R61 target(s) engagement using identical methods and timing of assessment, except with one (optimal) CBD dose vs. PBO continued over 8 weeks to enable association of target engagement with SAD symptom change. A pharmacokinetic study of plasma CBD levels will be completed in both R61 and R33 studies. This study’s objectives are aligned with NCCIH’s PA-20- 218 Natural Product Early Phase Clinical Trial Phased Innovation Award by studying a natural product with strong scientific premise for further testing, CBD, in a disorder commonly seen in primary care, SAD.

项目概要/摘要 社交焦虑症 (SAD) SAD 是一种常见的早发性疾病，未经治疗会导致高度慢性化， 合并症、医疗保健利用以及功能和生活质量损害。 SAD 的新疗法是 是必需的，因为许多患者无法获得、耐受现有治疗或对现有治疗有反应。大麻二酚（CBD）是一种 来自大麻植物的天然化合物，缺乏四氢大麻酚（THC）的改变思维作用。随着近期的激增 使用在线或非处方销售的不受监管的 CBD 形式，患者试图在没有药物的情况下进行自我治疗 针对焦虑症（包括 SAD）的 CBD 监管配方或基于证据的剂量指南，创建 迫切需要严格的生物学研究。同时存在强大的临床前和良好的复制性 人体实验室证据表明 CBD 具有急性抗焦虑作用，使其成为最有前途的新药之一 治疗焦虑症，尤其是社交焦虑症的候选人。该提案旨在以有希望的基础为基础 与 SAD 相关的神经和行为目标的潜在参与的初步科学支持，以及 CBD 的临床效果有助于填补这一空白。这些研究的目标是建立 CBD 的生物特征 SAD 的假定治疗效果及其与核心 SAD 症状的联系，并提供临床效果大小、安全性、 以及可行性数据，以指导未来 CBD 治疗 SAD 的最终随机对照试验。我们的总体假设是 CBD 将 改善恐惧神经回路中存在的既定异常和表现压力反应 患有 SAD 的成年人，并且这种 SAD 目标参与将与症状改善相关。首先在 R61，我们将研究适合大麻衍生（合法）口服 CBD 制剂的 3 期试验的两个剂量水平 在为期 3 周的双盲随机对照试验中，与安慰剂 (PBO) 相比，生物利用度有所提高。参与者将接受 第 2 周修改后的特里尔社会压力测试 (TSST)，以及标准化的 2 天恐惧学习和消退 第 3 周的方案，fMRI 大脑激活伴随着恐惧消退回忆和恐惧面孔任务 第二天。这些方法将能够通过三个证据来衡量 CBD 与 PBO 的目标参与度： 基于目标：1) 恐惧消退回忆期间腹内侧前额皮质 (vmPFC) 激活，2) 杏仁核 3) 视觉模拟情绪量表 (VAMS) 焦虑评级 TSST 演讲。如果观察到目标参与度，则将满足从 R61 进展到 R33 的 GO 标准 对于至少一个目标，如上订购，在没有临床试验的情况下，对于两种 CBD 剂量中的至少一种 显着的不利影响。接下来，R33 将使用相同的方法复制 CBD 与 PBO R61 的目标交战 评估的方法和时间，除了一种（最佳）CBD 剂量与 PBO 持续超过 8 周以 使目标参与度与 SAD 症状变化相关联。血浆 CBD 的药代动力学研究 水平将在 R61 和 R33 研究中完成。本研究的目标与 NCCIH 的 PA-20- 一致 218 天然产品早期临床试验阶段性创新奖，通过研究天然产品 进一步测试 CBD 的强有力的科学前提是初级保健中常见的 SAD 疾病。