Fighting the storm: novel anti- TNFα and anti-IL-6 C. sativa lines to tame cytokine storm in COVID-19

Abstract

The main aspects of severe COVID-19 disease pathogenesis include the increasing hyper-induction of proinflammatory cytokines, also known as ‘cytokine storm’, that precedes acute respiratory distress syndrome (ARDS) and often leads to death. COVID-19 patients often suffer from lung fibrosis, a serious and untreatable condition. There remains no effective treatment for these complications. Out of the cytokines, TNFα and IL-6 play crucial roles in cytokine storm pathogenesis and are likely responsible for the escalation in disease severity. These cytokines also partake in the molecular pathogenesis of fibrosis. Therefore, new approaches are urgently needed that can efficiently and swiftly block TNFα, IL-6, and the inflammatory cytokine cascade in order to curb inflammation and prevent fibrosis, and lead to disease remission.Cannabis sativa has been proposed to modulate gene expression and inflammation and is under investigation for several potential therapeutic applications against autoinflammatory diseases and cancer. Here, we hypothesized that the extracts of our novel C. sativa lines may be used to modulate the expression of pro-inflammatory cytokines and pathways involved in inflammation and fibrosis. To analyze the anti-inflammatory effects of novel C. sativa lines, we used a well-established full thickness human 3D skin artificial EpiDermFTTM tissue model, whereby tissues were exposed to UV to induce inflammation and then treated with extracts of seven new cannabis lines.We noted that out of seven studied extracts of novel C. sativa lines, three (#4, #8 and #14) were the most effective, causing profound and concerted down-regulation of TNFα, IL-6, CCL2, and other cytokines and pathways related to inflammation and fibrosis. Most importantly, one of the tested extracts had no effects at all, and one exerted effects that may be deleterious, signifying that cannabis is not generic and cultivar selection must be based on thorough pre-clinical studies.The observed pronounced inhibition of TNFα and IL-6 is the most important finding, as these molecules are currently considered to be the main actionable targets in COVID-19 cytokine storm and ARDS pathogenesis. Many currently trialed agents, such as anti-TNFα and anti-IL-6 biologics are expensive and cause an arrays of side effects. On the other hand, anti-TNFα and anti-IL-6 cannabis extracts that are generally regarded as safe (GRAS) modalities can be a useful addition to the current anti-inflammatory regimens to treat COVID-19, as well as various rheumatological diseases and conditions, and ‘inflammaging’ - the inflammatory underpinning of aging and frailty.

In Vitro Evaluation of the Activity of Terpenes and Cannabidiol against Human Coronavirus E229

“…In this study, we report the antiviral activity of the NT-VRL-1 terpene formulation and show that that activity was enhanced when it was applied together with CBD, suggesting either a synergetic or additive effect between the terpene formulation and CBD. Several studies have suggested that phytochemicals found in cannabis may be useful as potential anti-inflammatory agents [ 22 , 23 ]. Such activity may be particularly useful for controlling the cytokine storm syndrome and acute respiratory distress syndrome associated with COVID-19.…”

Cross-Sectional Associations Between Lifetime Use of Psychedelic Drugs and Psychometric Measures During the COVID-19 Confinement: A Transcultural Study

“…Some studies have warned about the clinical risks that cannabis users may face, since they could be more exposed to contagion and have specific vulnerabilities in terms of respiratory issues (81). However, other studies have suggested that some compounds of cannabis might be beneficial for the treatment of some COVID-19 symptoms (82)(83)(84)(85)(86). Moreover, other studies reported that cannabis use had positive effects in terms of helping individuals to cope with stressful situations, effects that could partially explain its benefits with regards to chronic disorders (87).…”