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.

公众通常使用大麻产品来自我管理焦虑症状;然而， 人们正在决定使用什么类型的产品（例如，CBD，THC），以及在什么剂量下， 缺乏严格的经验数据。大麻二酚（CBD）是一种非麻醉性植物大麻素， 承诺-基于动物和人类单剂量的发现-作为一种自然的治疗焦虑和 与压力有关的疾病这些疾病是常见的，致残的，并且对于这些疾病，一线药物和 心理社会治疗失败的患者占50%。尽管初步证据表明CBD具有抗焦虑作用， 由于其性质，剂量依赖性生物学和行为学效应尚未在临床上表征。 焦虑的样本据我们所知，没有研究在相同的临床试验中比较不同的CBD剂量。 样品，也没有推定的生物靶标（例如，内源性大麻素功能）与焦虑 反应性或症状测量。这种有限的知识阻碍了将单次给药结果转化为 在焦虑人群中进行的慢性给药随机临床试验。拟议的两阶段，里程碑驱动 该项目旨在通过推进有关机制和治疗潜力的知识来解决这一差距 CBD治疗焦虑症我们将测试内源性大麻素介导的焦虑反应性在减少 诊断为社交焦虑障碍（SAD）的患者的临床症状和损害。R61阶段 该项目将评估CBD对血浆中花生四烯酸水平的剂量依赖性影响（ 内源性大麻素已被证明可调节应激反应;主要生物学特征）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，当 已达到稳定的CBD水平）。目的1将检验CBD增加大麻素的假设。 水平和降低焦虑反应相比，安慰剂。目标2将决定剂量（300或900 mg/d）的CBD对花生四烯酸和焦虑反应性产生更大的影响。如果发现CBD优于上级 安慰剂提高血浆花生四烯酸水平和降低焦虑反应，R33阶段项目将 试图复制R61项目的结果（目标1;亚急性剂量研究），并检查 大麻素和焦虑反应与临床改善相关（即，减少焦虑 症状和损害;目的2）在一项为期8周的双盲、随机、安慰剂对照试验后， 诊断为SAD的受试者中的CBD（R61项目告知的剂量）。次要临床结局将是 功能性干扰的变化，以及抑郁和焦虑的共同发生症状。积极 研究结果将支持一项更大规模的确证性疗效试验，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在以下方面作用的重要信息： 调节内源性大麻素介导的焦虑结果，这将为未来的研究铺平道路。 大麻素和焦虑