Evaluation of Cannabidiol for Reduction of Brain Neuroinflammation

在美国，数以百万计的人患有慢性疼痛和共病抑郁症， 令人衰弱和难以管理的条件。缺乏安全有效的药物的一个原因 针对这些疾病的治疗方法是我们对可行靶点的有限了解。临床前疼痛模型显示 小胶质细胞和星形胶质细胞在疼痛和抑郁的建立和/或维持中起关键作用 行为。此外，慢性下腰痛(CLBP)患者表现出“疼痛相关”和 与抑郁症相关的胶质标志物18 kDa转运蛋白(TSPO)水平升高，表明 疼痛和抑郁症状可能由神经炎性机制介导/维持 在这项建议中，我们将研究大麻二酚(CBD)是否具有中枢和外周活性 大麻植物中的非毒性化合物，对慢性下腰痛患者具有抗神经炎作用 患有轻度到中度的抑郁症。在动物中，CBD通过一种途径诱导镇痛和抗抑郁作用。 一种复杂的药理作用，包括对大麻素受体的刺激和对大麻素前体的抑制 神经胶质细胞中的炎症途径。这些临床前研究和我们的观察将神经炎症 对于cLBP中疼痛和共病的抑郁症状，表明CBD可以同时减轻疼痛和抑郁- 慢性下腰痛患者的相关神经炎。除了发挥可能的抗神经炎作用外， 对精神病患者的研究表明，CBD可能会使纹状体功能减退正常化，这是我们的 该研究小组最近还利用功能磁共振成像技术发现慢性下腰痛患者的抑郁与其有关 (功能磁共振成像)。由于其作为纹状体生理学的所谓作用，我们因此假设 CBD的作用机制可能是减轻纹状体功能障碍。 我们将进行一项随机、双盲、双臂的机械性试验，以评估CBD(n= 40)和安慰剂(n=40)治疗轻中度抑郁的慢性LBP患者，使用整合正电子技术 发射断层扫描/磁共振成像(PET/MRI)扫描。使用集成的PET/MRI将 允许我们同时评估神经炎症(使用第二代放射性配体[11C]PBR28 TSPO)和纹状体功能(使用货币激励延迟任务，这是一个经过验证的fMRI任务，探测 对奖励和损失的行为和神经反应)。在我们的机械试验中，我们将使用Epidiolex®，一种 FDA批准的产品，含有已知和恒定剂量的纯化CBD。我们已经派了一名现役人员 IND用[11C]PBR28 PET/MRI测试Epidiolex®在cLBP中的作用，初步数据支持我们的 假设。通过研究CBD的神经和神经免疫反应，这项研究将推动我们的 了解这种药物的作用机制，并帮助我们了解哪些情况可能有益 从它的使用中获得最大的好处。更广泛地说，我们的研究将测试调节神经炎症是否可行，以及 治疗疼痛和抑郁的前景看好的方法。

Millions of individuals in the United States suffer from chronic pain and co-morbid depression, conditions that are debilitating and complex to manage. A reason for the scarcity of safe and efficacious therapies for these conditions is our limited knowledge of viable targets. Preclinical models of pain have shown that microglia and astrocytes play a key role in the establishment and/or maintenance of pain and depressive behaviors. Additionally, patients with chronic low back pain (cLBP) demonstrate “pain-related” and “depression-related” elevated levels of the glial marker 18kDa translocator protein (TSPO), suggesting that pain and depressive symptoms may be mediated / maintained by neuroinflammatory mechanisms In this proposal, we will study whether cannabidiol (CBD), the primary centrally and peripherally active non-intoxicating compound in the cannabis plant, exerts anti-neuroinflammatory effects in patients with cLBP with mild-to-moderate depression. In animals, CBD induces analgesic and antidepressant effects, via a complex pharmacology that includes the stimulation of cannabinoid receptors and the inhibition of pro- inflammatory pathways in glial cells. These preclinical studies, and our observations linking neuroinflammation to pain and comorbid depressive symptoms in cLBP, indicate that CBD may reduce both pain- and depression- related neuroinflammation in cLBP patients. In addition to exerting possible anti-neuroinflammatory effects, studies in psychiatric patients suggest that CBD might normalize striatal hypofunction, an alteration that our group has also recently linked to depression in cLBP patients using functional magnetic resonance imaging (fMRI). Because of its purported effects as striatal physiology, we thus hypothesize that a secondary mechanism of action of CBD may be to reduce striatal dysfunction. We will conduct a randomized, double-blind, 2-arm mechanistic trial to assess the effects of CBD (n = 40) and placebo (n = 40) in patients with cLBP with mild-to-moderate depression, using integrated positron emission tomography / magnetic resonance imaging (PET/MRI) scans. The use of integrated PET/MRI will allow us to simultaneously evaluate neuroinflammation (using [11C]PBR28, a second-generation radioligand for TSPO) and striatal function (using the Monetary Incentive Delay task, a validated fMRI task that probes behavioral and neural responses to rewards and losses). In our mechanistic trial, we will use EPIDIOLEX®, an FDA-approved product that contains a known and constant dose of purified CBD. We already hold an active IND to test the effects of EPIDIOLEX® in cLBP with [11C]PBR28 PET/MRI, and preliminary data support our hypotheses. By studying the neural and neuroimmune responses to CBD, this study will advance our knowledge about the mechanisms of action of this drug, and help us understand which conditions might benefit the most from its use. More broadly, our study will test whether modulating neuroinflammation is feasible and a promising therapeutic approach for pain and depression.