Cannabinoids apparently act on inflammation through mechanisms different from those of agents such as nonsteroidal anti-inflammatory drugs (NSAIDs). As a class, the cannabinoids are generally free from the adverse effects associated with NSAIDs. Their clinical development thus provides a new approach to treatment of diseases characterized by acute and chronic inflammation and fibrosis. A concise survey of the anti-inflammatory actions of the phytocannabinoids Δ9-tetrahydrocannabinol (THC), cannabidiol, cannabichromene, and cannabinol is presented. Mention is also made of the noncannabinoid plant components and pyrolysis products, followed by a discussion of 3 synthetic preparations—Cesamet (nabilone; Meda Pharmaceuticals, Somerset, NJ, USA), Marinol (dronabinol; THC; AbbVie, Inc., North Chicago, IL, USA), and Sativex (Cannabis extract; GW Pharmaceuticals, Cambridge United Kingdom)—that have anti-inflammatory effects. A fourth synthetic cannabinoid, ajulemic acid (AJA; CT-3; Resunab; Corbus Pharmaceuticals, Norwood, MA, USA), is discussed in greater detail because it represents the most recent advance in this area and is currently undergoing 3 phase 2 clinical trials by Corbus Pharmaceuticals. The endogenous cannabinoids, including the closely related lipoamino acids, are then discussed. The review concludes with a presentation of a possible mechanism for the anti-inflammatory and antifibrotic actions of these substances. Thus, several cannabinoids may be considered candidates for development as anti-inflammatory and antifibrotic agents. Of special interest is their possible use for treatment of chronic inflammation, a major unmet medical need.—Zurier, R. B., Burstein, S. H. Cannabinoids, inflammation, and fibrosis.
Preparations derived from Cannabis have been the source of medical therapies since the earliest records on pharmacobotany (1). Many beneficial effects of Cannabis on the human body, including those on “rheumatism” were noted 4000 yr ago in a work reported by Hui-Lin Li called Pen-tsao (2). The term cannabinoid usually refers to compounds that activate the G-protein-coupled cannabinoid receptors 1 and 2 (CB1 and -2). CB1 receptors, located mainly on neurons in the hippocampus and basal ganglia, mediate the psychoactive actions of cannabinoids (3). CB2 receptors are present mainly on tissue and circulating cells of the immune system (4). However, many Cannabiscomponents that do not activate either receptor are sometimes called cannabinoids. Given that the Cannabis plant contains more than 60 cannabinoids and 200–250 noncannabinoid constituents, it follows that the therapeutic benefits of marijuana are related to some combination of these compounds. We review the current knowledge of the mechanisms whereby phytocannabinoids, noncannabinoid plant components, and their pyrolysis products aid in the control of inflammation and fibrosis. We also address the development of synthetic cannabinoids as treatment for patients with diseases characterized by chronic inflammation and subsequent fibrosis. The ability of some cannabinoids to facilitate the resolution of inflammation by stimulating the action of several specialized proresolving mediators (SPMs), an important emerging concept, is also discussed. The roles of endogenous cannabinoids (endocannabinoids) and the closely related lipoamino acids in control of inflammation are also discussed.