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.

项目摘要/摘要 社交焦虑症(SAD)是一种常见的早发性障碍，未经治疗，导致高度慢性化， 合并症、卫生保健利用、功能和生活质量受损。治疗SAD的新疗法是 由于许多患者不能获得、不能耐受或不能对现有治疗作出反应，这是必要的。大麻二酚(CBD)是一种 从大麻植物中提取的天然化合物，缺乏THC的精神改变作用。随着最近的激增， 使用在线或柜台出售的不受监管的CBD形式，患者正试图在没有 CBD治疗焦虑症的规范配方或证据剂量指南，包括SAD，创建 迫切需要严格的生物学知情研究。共同存在着强大的临床前和良好的复制 CBD急性抗焦虑作用的人体实验室证据，使其成为最有前途的新药之一 考生用于治疗焦虑，尤其是社交焦虑。这项提议的目的是建立在前景看好的基础上 可能与SAD相关的神经和行为目标接触的初步科学支持 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的生物学特征 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， 和可行性数据，以指导未来针对SAD的CBD最终RCT。我们的首要假设是，CBD将 改善在恐惧神经回路和表现应激反应中存在的公认异常 成年人患有SAD，这种SAD目标参与将与症状改善相关。先入 R61，我们将研究适用于大麻衍生(合法)口服CBD配方的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，生物利用度更高。参赛者将接受 第2周的改良Trier社会应激测验(TSST)和标准化的2日恐惧学习和消退 方案在第3周，在恐惧消退回忆和恐惧面孔任务的同时进行fMRI大脑激活 第二天。这些方法将能够测量CBD与PBO目标参与度，并提供三个证据- 基础靶点：1)在恐惧消退回忆中激活腹内侧前额叶皮质(VmPFC)；2)杏仁核 对恐惧面孔的反应，以及3)视觉模拟心境量表(VAMS)对以下反应的焦虑评级 台海科技大学的演讲。如果观察到目标交战，将满足从R61到R33的GO标准 至少一个靶点，如上所述，用于两种CBD剂量中的至少一种，在没有临床应用的情况下 严重的不良反应。接下来，R33将使用相同的方法复制CBD与PBO R61目标(S)接洽 评估的方法和时间，除非CBD与PBO的一个(最佳)剂量持续超过8周 实现目标参与度与SAD症状变化的关联。血浆CBD的药代动力学研究 将在R61和R33两个研究中完成等级。这项研究的目标与NCCIH的PA-20- 218天然产物早期临床试验阶段性创新奖 进一步检测的强有力的科学前提，CBD，在初级保健中常见的疾病，SAD。