R01DA053316

Evaluation of Cannabidiol for Reduction of Brain Neuroinflammation

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 on 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.

The General Hospital Corporation

TO SUPPORT BASIC AND CLINICAL NEUROSCIENCE, BIOMEDICAL, BEHAVIORAL AND SOCIAL SCIENCE, EPIDEMIOLOGIC, HEALTH SERVICES AND HEALTH DISPARITY RESEARCH. TO DEVELOP NEW KNOWLEDGE AND APPROACHES RELATED TO THE PREVENTION, DIAGNOSIS, TREATMENT, ETIOLOGY, AND CONSEQUENCES OF DRUG ABUSE AND ADDICTION, INCLUDING HIV/AIDS. TO SUPPORT RESEARCH TRAINING AND RESEARCH SCIENTIST DEVELOPMENT. TO SUPPORT DISSEMINATION OF RESEARCH FINDINGS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) LEGISLATION IS INTENDED TO EXPAND AND IMPROVE THE SBIR PROGRAMS TO EMPHASIZE AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF TECHNOLOGY DEVELOPED THROUGH FEDERAL SBIR RESEARCH AND DEVELOPMENT, INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN THE SBIR PROGRAM. THE LEGISLATION INTENDS THAT THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.279 - Drug Abuse and Addiction Research Programs

National Institute on Drug Abuse (NIDA) [HHS - NIH]

Charlestown, Massachusetts 02129 United States

Single Zip Code

Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp Clinical Trial Optional) (PA-20-272)

Amendment Since initial award the total obligations have increased 422% from $753,349 to $3,931,875.