Endocannabinoid System Engagement and Clinical Symptom Change with Cannabidiol for Social Anxiety Disorder

大麻二酚治疗社交焦虑症的内源性大麻素系统参与和临床症状变化

• 批准号: 10552048
• 负责人: MURRAY B. STEIN
• 金额: $ 54.81万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-18 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10552048
• 关键词: Acute; Address; Animals; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Attenuated; Behavioral; Biological; Brain region; Cannabidiol; Cannabinoids; Cannabis; Chronic; Clinical; Data; Decision Making; Diagnosis; Dose; Double-Blind Method; Drug Kinetics; Emotional; Endocannabinoids; Enzymes; Exposure to; Face; Fright; Goals; Human; Impairment; Individual; Knowledge; Laboratories; Measures; Mediating; Negative Finding; Outcome; Outcome Study; Patients; Persons; Phase; Placebos; Plasma; Population; Primary Care; Property; Randomized; Randomized, Controlled Trials; Role; Safety; Sampling; Self Management; Signal Transduction; Social Anxiety Disorder; Standardization; Stimulus; Stress; Symptoms; Testing; Therapeutic; Translations; anandamide; anxiety management; anxiety reduction; anxiety symptoms; anxious; associated symptom; biobehavior; biological adaptation to stress; cannabinoid treatment; community setting; confirmatory trial; depressive symptoms; endogenous cannabinoid system; evidence base; experimental study; fatty acid amide hydrolase; human subject; improved; neural; pharmacologic; phytocannabinoid; pre-clinical; psychosocial; randomized placebo controlled trial; randomized, clinical trials; recruit; response; social anxiety; social stress; social stressor; stress related disorder; symptom self management; treatment response; virtual

Cannabis-based products are commonly used by the public to self-manage symptoms of anxiety; however, people are making decisions about what type of product to use (e.g., CBD, THC), and in what doses, in the absence of rigorous empirical data. Cannabidiol (CBD) is a non-intoxicating phytocannabinoid that has shown promise – based on animal and single dose findings in humans – as a natural therapeutic for anxiety and stress-related disorders. These conditions are common, disabling, and for which first-line pharmacological and psychosocial treatments fail 50% of patients. Although initial evidence suggests that CBD has anxiolytic properties, the dose-dependent biological and behavioral effects have not been characterized in clinically anxious samples. No studies, to our knowledge, have compared different CBD doses within the same clinical sample, nor have putative biological targets (e.g., endocannabinoid function) been measured alongside anxiety reactivity or symptom measures. This limited knowledge has impeded the translation of single dose findings to chronic dosing randomized clinical trials in anxiety populations. The proposed two-phase, milestone-driven project intends to address this gap by advancing knowledge about the mechanisms and therapeutic potential of CBD for anxiety. We will test the causal role of endocannabinoid-mediated anxiety reactivity in reducing clinical symptoms and impairment in patients diagnosed with social anxiety disorder (SAD). The R61 phase project will evaluate the dose-dependent effects of CBD on blood plasma levels of anandamide (an endogenous cannabinoid that has been shown to regulate stress responses; primary biological signature) and anxiety reactivity to a social stress task (secondary target) in a sub-acute (4-day) dosing study (i.e., when steady state CBD levels have been reached). Aim 1 will test the hypothesis that CBD increases anandamide levels and decreases anxiety reactivity compared to placebo. Aim 2 will determine which dose (300 or 900 mg/d) of CBD produces a greater effect on anandamide and anxiety reactivity. If CBD is found to be superior to placebo in elevating plasma anandamide levels and reducing anxiety reactivity, the R33 phase project will attempt to replicate the R61 project findings (Aim 1; sub-acute dosing study) and examine whether changes in anandamide and anxiety responses are associated with clinical improvement (i.e., reduction in anxiety symptoms and impairment; Aim 2) following an 8-week double-blind, randomized, placebo-controlled trial of CBD (dose informed by the R61 project) in subjects diagnosed with SAD. Secondary clinical outcomes will be change in functional interference, and co-occurring symptoms of depression and general anxiety. Positive findings will support a larger confirmatory efficacy trial to further evaluate the therapeutic potential of CBD for anxiety disorders. Regardless of study outcomes, important information will be gained about the role of CBD in modulating endocannabinoid-mediated anxiety outcomes, which will pave the way for future research on cannabinoids and anxiety.

公众通常将基于大麻的产品用于自我管理的焦虑症状；然而， 人们正在决定要使用哪种类型的产品（例如，CBD，THC），以及剂量，在 缺乏严格的经验数据。大麻二酚（CBD）是一种无毒性的植物大麻素，已显示 承诺 - 基于人类的动物和单剂量发现 - 作为动画和 与压力有关的疾病。这些条件是常见的，残疾的，并且是一线药物和 社会心理治疗失败了50％的患者。尽管最初的证据表明CBD具有抗焦虑 特性，剂量依赖性生物学和行为效应尚未在临床上表征 焦虑的样品。据我们所知，没有研究比较了同一临床中的不同CBD剂量 样本，也没有指定的生物学靶标（例如，内源性大麻素功能）与焦虑一起测量 反应性或症状测量。这种有限的知识阻碍了单剂量发现的翻译 在焦虑群中进行的慢性剂量随机临床试验。提出的两相，里程碑驱动的 项目打算通过提高有关机制和治疗潜力的知识来解决这一差距 CBD的动画。我们将测试内源性大麻素介导的动画反应性在降低的因果作用 诊断患有社交焦虑症（SAD）的患者的临床症状和障碍。 R61阶段 项目将评估CBD对血浆血浆水平的剂量依赖性作用（一个 内源性大麻素已显示可调节应力反应；一级生物学签名）和 在亚急性（4天）给药研究中对社会压力任务（次要目标）的焦虑反应性（即 稳态CBD水平已达到）。 AIM 1将检验CBD增加anandamide的假设 与安慰剂相比，水平和降低动画反应性。 AIM 2将确定哪种剂量（300或900 CBD的mg/d）对肛门胺和焦虑反应产生更大的影响。如果发现CBD优于 安慰剂在升高血浆仙人掌水平并降低焦虑反应性方面，R33相项目将 尝试复制R61项目发现（AIM 1；亚急性给药研究），并检查是否发生变化 anandamide和焦虑反应与临床改善有关（即减轻焦虑症 症状和障碍；目标2）进行为期8周的双盲，随机，安慰剂对照试验 CBD（R61项目告知剂量）在受试者诊断性诊断中。次要临床结果将是 功能干扰的变化以及抑郁和一般动画的同时出现的症状。积极的 调查结果将支持更大的确认效率试验，以进一步评估CBD的治疗潜力 焦虑症。无论研究结果如何，都将获得有关CBD的作用的重要信息 调节内源性大麻素介导的动画结果，这将为未来的研究铺平道路 大麻素和动画。