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.

项目总结/摘要 社交焦虑障碍（SAD）是一种常见的、早期发作的疾病，未经治疗，导致高慢性化， 合并症，医疗保健利用，功能和生活质量损害。SAD的新疗法是 这是必要的，因为许多患者无法获得、耐受或对现有治疗作出反应。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， 使用不受管制的形式的CBD在网上或柜台出售，患者试图自我克制， CBD用于焦虑症（包括SAD）的受管制制剂或基于证据的剂量指南， 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 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 治疗焦虑症的候选人，特别是社交焦虑症。该提案旨在建立在有希望的基础上， 初步的科学支持与SAD相关的神经和行为目标的潜在参与， CBD的临床效果，以帮助填补这一空白。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， 和可行性数据，以指导未来CBD治疗SAD的确定性RCT。我们的总体假设是，CBD将 改善存在于恐惧神经回路和表现压力反应中已确立的异常， 成年SAD患者，并且这种SAD目标参与将与症状改善相关。第一 R61，我们将研究两种剂量水平的3期试验合适的大麻衍生的（法律的）口服CBD制剂， 在一项为期3周的双盲随机对照试验中，与安慰剂（PBO）相比，生物利用度增强。参加者将接受 在第2周进行改良的特里尔社会压力测试（TSST），并进行标准化的2天恐惧学习和消退 在第3周的方案中，fMRI大脑激活伴随着恐惧消退回忆和恐惧面孔任务。 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）在恐惧消退回忆期间腹内侧前额叶皮层（vmPFC）激活，2）杏仁核 3）视觉模拟情绪量表（VAMS）焦虑等级， TSST演讲如果观察到靶点接合，则符合从R61进展至R33的GO标准 对于至少一个目标，如上所述，对于两个CBD剂量中的至少一个，在临床上不存在 严重的不良影响。接下来，R33将使用相同的方法复制CBD与PBO R61靶标的接合。 评估的方法和时间，除了一个（最佳）CBD剂量与PBO持续超过8周， 使目标参与与SAD症状变化相关联。血浆CBD的药代动力学研究 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创新奖通过研究天然产品与 进一步测试的强有力的科学前提，CBD，在初级保健中常见的疾病，SAD。