A molecular basis for the anti-inflammatory and anti-fibrosis properties of cannabidiol

Cannabidiol (CBD) is considered a non-psychoactive, antioxidant, and anti-inflammatory compound derived from the Cannabis sativa plant. There are various reports on the versatile function of CBD, including ameliorating chronic inflammation and fibrosis formation in several tissue types. However, only a hand full of studies have proposed or provided a molecular justification for the beneficial properties of this Phyto-compound. This review focused on the anti-inflammation and anti-fibrotic effects of CBD based on modulating the associated chemokines/cytokines and receptor-mediated pathways. We also highlighted the regulatory impact of CBD on reactive oxygen species (ROS) producing-NADPH oxidase (Nox), and ROS scavenging-superoxide dismutase (SOD) enzymes. Although CBD has a low affinity to Cannabinoid receptors 1 and 2 (CB₁ and CB₂ ), we reported on the activation of these receptors by other CBD analogs, and CBD on non-CBD receptors. CBD downregulates pro-inflammatory and pro-fibrotic chemokines/cytokines by acting as direct or indirect agonists of Adenosine A_2A /equilibrative nucleoside transporter receptors, Peroxisome proliferator-activated receptor gamma, and Transient receptor potential vanilloid receptors or channels, and as an antagonist of GPR55 receptors. CBD also caused the reduction and enhancement of the ROS producing, Nox and ROS-scavenging, SOD enzyme activities, respectively. This review thus recommends the continued study of CBD's molecular mechanism in treating established and emerging inflammatory and fibrosis-related diseases.