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（悲伤）SAD是一种常见的早期发作障碍，未经治疗，导致慢性高， 合并症，医疗保健利用以及生活和生活质量障碍。悲伤的新治疗方法是 需要，因为许多患者无法进入，容忍或对可用治疗做出反应。大麻二醇（CBD）是 大麻植物的天然化合物缺乏THC的思维影响。随着最近的激增 使用不受监管的CBD在线出售或在柜台上出售的CBD，患者试图自我治疗而没有 受监管的公式或基于证据的CBD剂量指南，包括SAD，包括SAD，创建 迫切需要严格的生物学知情研究。在一起存在很强的临床前且重复的 人类实验室证据证明了CBD的急性抗焦虑作用，使其成为最有前途的新型药物之一 候选人的动画治疗，尤其是社交动画。该提议旨在建立诺言 初步的科学支持，以潜在的与悲伤的神经和行为目标和行为靶标的参与以及 CBD的临床影响有助于填补这一空白。这些研究的目的是建立CBD的生物学签名 SAD及其与核心SAD符号的联系中的假定治疗作用，并提供临床效果大小，安全性， 以及可行性数据，以指导CBD的未来确定性RCT。我们的总体假设是CBD将 改善了恐惧神经记录和表现压力的良好正常的反应 患有悲伤的成年人，这种悲伤的目标参与将与症状改善有关。首先 R61，我们将研究3阶段试验的两个剂量水平，适用于大麻衍生的（合法）口服CBD公式 在3周的双盲RCT中增强了生物利用度与安慰剂（PBO）。参与者将经历 在第2周修改了Trier社会压力测试（TSST），以及标准化的2天恐惧学习和扩展 第3周的协议，fMRI大脑激活涉及恐惧延伸召回和恐惧面孔的任务 第二天。这些方法将通过三个证据来衡量CBD与PBO目标参与度 - 基于目标：1）在恐惧延伸期间激活腹前额叶皮层（VMPFC），2）杏仁核 响应可怕面孔的激活，以及3）视觉模拟情绪量表（VAMS）动画评级。 TSST演讲。如果观察到目标参与，将满足从R61到R33进展的GO标准 至少一个目标，如上上述，在没有临床上的两个CBD剂量中，至少有一个目标 严重的不利影响。接下来，R33将使用相同的CBD与PBO R61目标进行复制 评估的方法和时间安排，除了一种（最佳）CBD剂量与PBO持续8周 使目标参与与悲伤的符号更改相关联。血浆CBD的药代动力学研究 R61和R33研究将完成水平。这项研究的目标与NCCIH的PA-20-- 218天然产品通过研究自然产品的早期临床试验裁定创新奖 在初级保健中常见的疾病中，CBD的强大科学前提是可悲的。