Evaluation of Cannabidiol for Reduction of Brain Neuroinflammation

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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.