Phytocannabinoids—Evaluation of their therapeutic role in neuroinflammation

Abstract

Neuroinflammation can be caused by disease, aging, infection, brain injury, toxicity, or stress. It is a contributory factor in the neuropathology of serious conditions that include multiple sclerosis (MS), Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), and autoimmune encephalomyelitis (EAE). The neuroinflammatory response involves the activation of microglia, astrocytes, the endothelial cells of the blood-brain barrier, and peripherally-derived immune cells. The endocannabinoid system is composed of the natural cannabinoids, anandamide and 2-arachidonoyl glycerol (2-AG), enzymes regulating their synthesis/catabolism, and the cannabinoid CB1 and CB2 receptors. It regulates multiple systems in the body including inflammation and endocannabinoid system dysregulation is involved in numerous inflammatory conditions. The Cannabis sativa plant produces over 100 phytocannabinoids, some of which interact with the endocannabinoid system. The major phytocannabinoids are delta-9-tetrahydrocannabinol (delta-9-THC), cannabidiol (CBD), and cannabigerol (CBG). Compelling evidence is emerging that many phytocannabinoids have anti-inflammatory and antioxidant properties. Phytocannabinoids including delta-9-THC, CBD, and CBG bind to a wide variety of targets in the endocannabinoid and/or other systems, which probably accounts for their diversity of effects in non-clinical and clinical studies. The benefits of certain phytocannabinoids have been proven by regulatory approval for medical use of CBD (Epidiolex®), chemically synthesized delta-9-THC (Marinol® and Syndros®) and 1:1 delta-9-THC/CBD (Sativex®). Furthermore, the widely recognized therapeutic properties of Cannabis have been a key driver in legalizing the medical use of Cannabis in 38 USA states. In this review, the potential of phytocannabinoids as effective treatments in neuroinflammatory disorders is discussed based on a critical evaluation of the non-clinical and clinical evidence. We focused on delta-9-THC, CBD, and CBG because they are the most abundant phytocannabinoids in Cannabis sativa and a substantial body of scientific data exists to describe their respective pharmacological mechanisms.