The Immunopathology of COVID-19 and the Cannabis Paradigm

Abstract

Coronavirus disease-19 caused by the novel RNA betacoronavirus SARS-CoV2 has first emerged in Wuhan, China in December 2019, and since then developed into a worldwide pandemic with >99 million people afflicted and >2.1 million fatal outcomes as of 24th January 2021. SARS-CoV2 targets the lower respiratory tract system leading to pneumonia with fever, cough, and dyspnea. Most patients develop only mild symptoms. However, a certain percentage develop severe symptoms with dyspnea, hypoxia, and lung involvement which can further progress to a critical stage where respiratory support due to respiratory failure is required. Most of the COVID-19 symptoms are related to hyperinflammation as seen in cytokine release syndrome and it is believed that fatalities are due to a COVID-19 related cytokine storm. Treatments with anti-inflammatory or anti-viral drugs are still in clinical trials or could not reduce mortality. This makes it necessary to develop novel anti-inflammatory therapies. Recently, the therapeutic potential of phytocannabinoids, the unique active compounds of the cannabis plant, has been discovered in the area of immunology. Phytocannabinoids are a group of terpenophenolic compounds which biological functions are conveyed by their interactions with the endocannabinoid system in humans. Here, we explore the anti-inflammatory function of cannabinoids in relation to inflammatory events that happen during severe COVID-19 disease, and how cannabinoids might help to prevent the progression from mild to severe disease.

Antimicrobial and Antiviral (SARS-CoV-2) Potential of Cannabinoids and Cannabis sativa: A Comprehensive Review

“…Evidence suggests that the severity and high mortality of COVID-19 are associated with a cytokine storm [ 25 , 148 , 149 ]. Pro-inflammatory cytokines IL-6, IL-8 and TNF-α are responsible for the cytokine storm in COVID-19 patients ( Figure 3 ), leading to impairment of oxygen diffusion, pulmonary fibrosis and eventually multiple organ failure [ 150 , 151 , 152 , 153 ].…”

“…Cannabinoids and terpenes, or essential oils (EO) enriched with these, are well known to confer anti-inflammatory effects in mammals during infectious diseases [ 21 , 22 , 23 ]. So far, 545–550 known compounds, of which about 177 phytocannabinoids, about 200 terpenes and nearly same number of phenolics, have been identified from C. sativa [ 20 , 24 , 25 , 26 ]. Bonini et al reviewed the pharmacological potential of cannabinoids, stating that preclinical and clinical studies of cannabinoid compounds are beneficial for treatment of pain, colitis, spasticity, nausea and vomiting, anorexia, sleep disorders, anxiety, epilepsy, and Alzheimer’s disease [ 24 ].…”

“…However, the antimicrobial activity of cannabinoids, extracts and EOs from C. sativa is not unexpected, as many secondary metabolites of plants exhibit bioactivity against numerous pathogenic bacteria and fungi [ 33 , 34 , 35 ]. There is also fragmentary evidence in the literatures that cannabis compounds have efficacy against some viruses [ 25 , 32 ]. This paper represents a comprehensive review of the antibacterial, antifungal, antiviral, and therapeutic potential for cannabinoids, cannabis extracts and EOs against COVID-19, based on research in old and contemporary articles.…”

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

“…CBD has been shown to stimulate peroxisome-proliferator activated receptors alpha and gamma (PPAR-α and PPAR-γ) to attenuate the pathways leading to proinflammatory cytokine release [ 70 , 73 , 75 , 76 ]. Through their actions at inflammasomes and the transient cation receptor potential channels (TRPs) these non-psychoactive cannabinoids depress the NFκB signaling pathway, decreasing the release of IL-6, IL-1β, IFN-γ and TNF-α in animal and in vitro models [ 77 – 79 ]. Thus, the interest in cannabinoids to diminish the effects of the cytokine storm as a serious manifestation of SARS-CoV-2 infection is pronounced, of late.…”

Contrasting Roles of Ang II and ACEA in the Regulation of IL10 and IL1β Gene Expression in Primary SHR Astroglial Cultures

“…Thus, activation of this receptor may trigger responses that counter-regulate AT1R-mediated potentiation of inflammatory states. This is especially intriguing since leveraging the cannabinoid receptor-mediated anti-inflammatory role has been considered as a therapeutic alternative in several pathological conditions [ 24 ], and more recently in COVID-19-related cytokine storm [ 25 ]. Hence, we investigated the role of both Ang II and the CB1R-specific agonist, Arachidonyl-2′-chloroethylamide (ACEA), in the regulation of inflammatory states in primary astroglial cultures obtained from SHR and Wistar rats.…”