Novel approaches to understanding the role of cannabinoids and inflammation in anxiety

项目摘要 大麻的使用不仅在增加，而且越来越受欢迎，作为一种“标签外”的附加疗法 难治性焦虑。然而，矛盾的是，尽管数据表明大麻，特别是∆9- 横截面和纵向数据表明，四氢大麻酚(THC)会急剧增加焦虑 长期吸食大麻与降低焦虑症风险之间的联系。迫切需要研究来 了解大麻对这些结果的影响。鉴于大量证据表明大麻具有抗- 炎症性质和进一步的证据表明炎症在病因中起着关键作用 对于焦虑症，我们认为大麻的抗炎特性与其抗焦虑有关。 效果。重要的是，以前的工作没有考虑到精神药物和抗炎作用 大麻是不同的大麻素类化合物的复合作用，它们的药理和作用各不相同。 具体地说，大麻中的一种非精神分裂成分大麻二酚(CBD)(不会产生兴奋作用)是 被认为具有缓解焦虑的特性，并可能减轻四氢大麻酚的一些有害影响 (THC)。此外，包括我们自己在内的初步数据表明，THC和CBD对 与焦虑相关的过程，如对炎症标志物和应激反应的影响。关键的是，有 THC和CBD的数量和比例存在巨大差异，可在商业上获得并在以下州广泛使用 科罗拉多州。因此，CBD/THC的比值可能在抗焦虑和抗焦虑中起着关键作用。 不同品系的大麻的炎症效应，这反过来可能对1) 对焦虑的影响和2)旨在减少危害的大麻监管政策。 为了解决对大麻素影响的理解上的差距，我们建议测试 认为大麻的抗焦虑作用和抗炎特性随时间变化的假设 CBD/THC比率的作用，以及这些影响可能会对混合数据链接有所启发 大麻的使用和焦虑。我们提出了一项独特的观察性研究，使用了现实世界中的大麻 目前可供科罗拉多州居民使用的菌株，其CBD和THC比率各不相同。我们测试的效果是 根据不同的CBD/THC比率选择的特定大麻菌株[即高CBD菌株 (CBD/-THC)、1：1(THC/CBD)菌株和一种典型的基于THC的菌株THC/-CBD)]对焦虑和 炎症，期待CBD大麻会减轻焦虑，减轻外周炎症反应 (包括有和没有体外免疫挑战的细胞因子水平)，以及行为和生物学 在4周的观察过程中对应激诱导的反应。预计拟议的 研究将产生关于哪些大麻菌株对焦虑产生最有害影响的信息 和炎症，并为与大麻使用和监管有关的个人和政策决策提供信息。

Project Summary Marijuana use is not only increasing, but gaining traction for use as an “off-label” add-on therapy for treatment-resistant anxiety. Paradoxically, however, while data suggest that marijuana, in particular ∆9- tetrahydrocannabinol (THC), increases anxiety acutely, cross sectional and longitudinal data suggest possible links between chronic marijuana use and lower risk for anxiety disorders. Research is critically needed to understand the effects of marijuana these outcomes. In light of considerable evidence that marijuana has anti- inflammatory properties and, further evidence suggesting that inflammation plays a pivotal role in the etiology of anxiety disorders, we propose that the anti-inflammatory properties of marijuana are linked with its anxiolytic effects. Importantly, prior work has not considered that the psychotropic and anti-inflammatory effects of marijuana are the compound action of different cannabinoids, which vary in their pharmacology and effects. Specifically, cannabidiol (CBD), a non-psychotomimetic component of marijuana (doesn’t produce a “high”), is thought to have anxiolytic properties and may mitigate some of the harmful effects of tetrahydrocannabinol (THC). Further, preliminary data, including our own, suggest that THC and CBD render differential effects on anxiety-related processes, such as effects on inflammatory markers and stress response. Critically, there is huge diversity in the amounts and ratio of THC and CBD commercially available and widely used in states like Colorado. Therefore, the ratio of CBD to THC may have a pivotal impact on the anxiolytic and anti- inflammatory effects of various strains of marijuana, which in turn may have important implications for 1) effects on anxiety and 2) marijuana regulation policies aimed at harm reduction. In order to address this gap in understanding of the effects of cannabinoids, we propose to test the hypothesis that the anxiolytic effects and anti-inflammatory properties of marijuana vary as a function of the ratio of CBD to THC, and that these effects may shed light on the mixed data linking cannabis use and anxiety. We propose a unique observational study that employs real-world marijuana strains currently available to Colorado residents that vary in their CBD to THC ratios. We test the effects of specific strains of marijuana selected based on their differing CBD to THC ratios [i.e. a high CBD strain (+CBD/-THC), a 1:1 (+THC/+CBD) strain, and a typical THC-based strain +THC/-CBD)] on anxiety and inflammation, expecting that +CBD marijuana will mitigate anxiety, peripheral inflammatory responses (including cytokine levels with and without an ex-vivo immune challenge), and behavioral and biological responses to stress induction over the course of 4 weeks of observation. It is expected that the proposed research will generate information about which marijuana strains produce the most harmful effects on anxiety and inflammation and inform personal and policy decisions related to marijuana use and regulation.