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

以大麻为基础的产品通常被公众用来自我管理焦虑症状；然而， 人们正在决定使用哪种类型的产品(例如，CBD，THC)，以及以什么剂量，在 缺乏严谨的经验数据。大麻二酚(CBD)是一种无毒的植物大麻素，已显示出 Promise-基于动物和人类的单剂研究结果-作为一种治疗焦虑和 与压力相关的障碍。这些情况是常见的、致残的，对于这些情况，第一线的药物和 50%的患者心理社会治疗失败。尽管初步证据表明CBD具有抗焦虑作用 特性，剂量依赖的生物学和行为效应还没有在临床上被表征 焦虑的样本。据我们所知，还没有研究比较同一临床中不同剂量的CBD 样本，也没有测量假定的生物目标(例如，内源性大麻素功能)和焦虑 反应性或症状测量。这种有限的知识阻碍了将单剂研究结果转化为 焦虑人群的慢性给药随机临床试验。建议的两个阶段，里程碑驱动 该项目旨在通过促进对这种机制和治疗潜力的了解来解决这一差距。 治疗焦虑的CBD。我们将测试内源性大麻素介导的焦虑反应性在减少焦虑中的因果作用 被诊断为社交焦虑症(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AND水平的剂量依赖性影响 已被证明可调节应激反应的内源性大麻素；主要生物学特征)和 亚急性(4天)剂量研究中对社交压力任务(次要目标)的焦虑反应(即，当 已达到稳定的CBD水平)。目标1将检验CBD增加ANANDIAME的假设 与安慰剂相比，可降低焦虑反应性。目标2将确定哪种剂量(300或900 Mg/d的CBD对双胺和焦虑反应性的影响更大。如果发现CBD优于 安慰剂在提高血浆花生胺水平和降低焦虑反应性方面，R33阶段项目将 尝试复制R61项目的发现(目标1；亚急性剂量研究)，并检查 阿南达胺和焦虑反应与临床改善(即焦虑的减少)有关 症状和损害；目标2)在为期8周的双盲、随机、安慰剂对照试验后 诊断为SAD的受试者的CBD(由R61项目告知的剂量)。次要临床结果将是 功能干扰的改变，以及抑郁和普遍焦虑的共同症状。正性 研究结果将支持一项更大规模的验证性疗效试验，以进一步评估CBD的治疗潜力 焦虑症。无论研究结果如何，都将获得关于CBD在 调节内源性大麻素介导的焦虑结果，这将为未来研究铺平道路 大麻素和焦虑。

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.