β-Caryophyllene, A Natural Dietary CB2 Receptor Selective Cannabinoid can be a Candidate to Target the Trinity of Infection, Immunity, and Inflammation in COVID-19

Abstract

Coronavirus disease (COVID-19), caused by novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an ongoing pandemic and presents a public health emergency. It has affected millions of people and continues to affect more, despite tremendous social preventive measures. Identifying candidate drugs for the prevention and treatment of COVID-19 is crucial. The pathogenesis and the complications with advanced infection mainly involve an immune-inflammatory cascade. Therefore, therapeutic strategy relies on suppressing infectivity and inflammation, along with immune modulation. One of the most promising therapeutic targets for the modulation of immune-inflammatory responses is the endocannabinoid system, particularly the activation of cannabinoid type 2 receptors (CB2R), a G-protein coupled receptor which mediates the anti-inflammatory properties by modulating numerous signaling pathways. To pharmacologically activate the CB2 receptors, a naturally occurring cannabinoid ligand, beta-caryophyllene (BCP), received attention due to its potent anti-inflammatory, antiviral, and immunomodulatory properties. BCP is recognized as a full selective functional agonist on CB2 receptors and produces therapeutic effects by activating CB2 and the nuclear receptors, peroxisome proliferator-activated receptors (PPARs). BCP is regarded as the first dietary cannabinoid with abundant presence across cannabis and non-cannabis plants, including spices and other edible plants. BCP showed tissue protective properties and favorably modulates numerous signaling pathways and inhibits inflammatory mediators, including cytokines, chemokines, adhesion molecules, prostanoids, and eicosanoids. Based on its pharmacological properties, molecular mechanisms, and the therapeutic potential of BCP as an immunomodulator, anti-inflammatory, organ-protective, and antiviral, we hypothesize that BCP could be a promising therapeutic and/or preventive candidate to target the triad of infection, immunity, and inflammation in COVID-19. In line with numerous studies that proposed the potential of cannabinoids in COVID-19, BCP may be a novel candidate compound for pharmaceutical and nutraceutical development due to its unique functional receptor selectivity, wide availability and accessibility, dietary bioavailability, nonpsychoactivity, and negligible toxicity along with druggable properties, including favorable pharmacokinetic and physicochemical properties. Based on reasonable pharmacological mechanisms and therapeutic properties, we speculate that BCP has potential to be investigated against COVID-19 and will inspire further preclinical and clinical studies.

Enzymatic and Microwave Pretreatments and Supercritical CO2 Extraction for Improving Extraction Efficiency and Quality of Origanum vulgare L. spp. hirtum Extracts

“…Bicyclic sesquiterpene and naturally occurring cannabinoid ligand trans -caryophyllene is a constituent of the volatile profile of oregano with anti-inflammatory, antiviral, immunomodulatory, anticancer, and analgesic activities. Also, a recent study suggests that β -caryophyllene and the plants containing β -caryophyllene as a major constituent may be candidates for developing antiviral and immunomodulatory therapies for coronaviruses [ 62 ]. Its metabolite, caryophyllene oxide, is also attributed with anticancer and analgesic properties.…”

Can SARS-CoV-2 Induce Uterine Vascular Anomalies and Poor Contractile Response?—A Case Report

“…The present study supports the conclusion of a recent meta-analyses where the authors proved that COVID-19 with at least one co-morbidity increases risk of intensive care and mortality [ 25 ]. However, new insights are showing the promising role of different therapies such as modulators of endocannabinoids receptor and alpha-lipoic acid in the management of COVID-19 related inflammation [ 26 , 27 ]. Further studies are required to prove the hypotheses and support the results with clinical, pathological and laboratory evidences.…”

A review of natural products, their effects on SARS-CoV-2 and their utility as lead compounds in the discovery of drugs for the treatment of COVID-19

“…β-Caryophyllene (BCP, Fig. 6 ) is a terpene found in cannabis as well as a number of other plant species, and is a full agonist of CB2 receptors [ 84 ]. BCP also activates peroxisome-proliferator activated receptors alpha and gamma (PPAR-α and PPAR-γ) leading to attenuation of the pathways causing proinflammatory cytokine release [ 84 ].…”

“…6 ) is a terpene found in cannabis as well as a number of other plant species, and is a full agonist of CB2 receptors [ 84 ]. BCP also activates peroxisome-proliferator activated receptors alpha and gamma (PPAR-α and PPAR-γ) leading to attenuation of the pathways causing proinflammatory cytokine release [ 84 ]. Interestingly, BCP also binds SARS-CoV-2 M Pro with a binding free energy of −7.2 kcal/mol, which is comparable to that of glycyrrhizin, −8.1 kcal/mol [ 69 ].…”