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10 Mar 2021 Cannabidiol Inhibits SARS-CoV-2 Replication and Promotes the Host Innate Immune Response
Cannabidiol from the cannabis plant has potential to prevent and inhibit SARS-CoV-2 infection
Version 1. bioRxiv. Preprint. 2021 Mar 10.
doi: 10.1101/2021.03.10.432967
10 June 2020 The potential of cannabidiol in the COVID-19 pandemic: a hypothesis letter
Identifying candidate drugs effective in the new coronavirus disease 2019 (Covid‐19) is crucial, pending a vaccine against SARS‐CoV2. We suggest the hypothesis that Cannabidiol (CBD), a non‐psychotropic phytocannabinoid, has the potential to limit the severity and progression of the disease for several reasons: 1) High‐CBD Cannabis Sativa extracts are able to downregulate the expression of the two key receptors for SARS‐CoV2 in several models of human epithelia 2) CBD exerts a wide range of immunomodulatory and anti‐inflammatory effects and it can mitigate the uncontrolled cytokine production featuring Acute Lung Injury 3) Being a PPARγ agonist, it can display a direct antiviral activity 4) PPARγ agonists are regulators of fibroblast/myofibroblast activation and can inhibit the development of pulmonary fibrosis, thus ameliorating lung function in recovered patients. We hope our hypothesis, corroborated by several preclinical evidence, will inspire further targeted studies to test CBD as a support drug against the COVID‐19 pandemic.
Giuseppe Esposito Marcella Pesce Luisa Seguella Walter Sanseverino Jie Lu Chiara Corpetti Giovanni Sarnelli Published on 2020 Jun 10. doi:10.1111/bph.15157
22 May 2020 Fighting the storm: novel anti-TNFa and anti-IL-6 C. sativa lines to tame cytokine storm in COVID-19
Overall, we are the first to show that application of C. sativa extracts profoundly decreases the level of pro-inflammatory cytokines in human 3D tissues. Still, our study has several pitfalls. Here, we used human 3D full-thickness skin model to analyze the effects of cannabis extracts on inflammation and fibrosis. While it would be important to replicate the data in an airway epithelial and alveolar tissue models, our data can be used as a roadmap for the future analysis. Moreover, key fundamental mechanisms of inflammation and fibrosis are similar in various tissues, and key roles of TNFα, IL-6 and other interleukins, chemokines, and MMPS have been well-established in an array of fibroproliferative diseases15. Pending further validation in lung tissue models, our novel extracts need to be studied in a clinical trial aimed to prevent or mitigate COVID-19 pneumonia and ARDS. To do so, the extracts have to be administered early upon positive diagnosis has been made to allow sufficient time for modulation of cytokine levels.
Most importantly, out of 7 selected extracts, only 3 performed best, one had no effects at all, and one exerted effects that may in turn be deleterious, signifying that cannabis is not generic and cultivar selection must be based on thorough pre-clinical studies. Furthermore, the current study was developed to analyze the effects of medical cannabis applications rather than smoking.
In the future, anti-TNFα and anti-IL-6 extracts need to be analyzed for their potential to mitigate inflammation in rheumatoid arthritis, ankylosing spondylitis, and other rheumatologic conditions, especially given the fact that extracts profoundly downregulate the RA pathway and target TNFα and IL-6. Also, the effects of novel extracts also need to be analyzed for their potential to combat ‘inflammaging’ – the inflammatory underpinning of aging and frailty46.
Anna Kovalchuk, Rocio Rodriguez-Juarez, Slava Ilnytskyy, Dongping Li, Bo Wang, Igor Kovalchuk, Olga Kovalchuk Published 2020 May 22. doi:10.21203/rs.3.rs-30927/v1
20 May 2020 Acute inflammation and pathogenesis of SARS-CoV-2 infection: Cannabidiol as a potential anti-inflammatory treatment?
In murine models of lung injury, CBD reduced lipopolysaccharide (LPS)-induced acute pulmonary inflammation [41,42]. In rat models of experimental asthma, CBD treatment reduced airway inflammation, as well as levels of serum IL-4, IL-5, IL-13, IL-6 and TNF-α, which are implicated in airway inflammation and fibrosis in asthma [43,44]. Moreover, CBD was able to directly suppress T-cell secretion of IL-1 and IFNγ [45]. In piglets with hypoxic-ischemic lung damage, CBD reduced histologic damage, decreased leukocyte infiltration and modulated IL-1 concentration in bronchoalveolar lavage fluid [46], while in a rat model of sepsis, CBD reversed oxidative stress and reduced mortality [47]. In humans, cannabinoid use prevented induction of pro-inflammatory CD16+ monocytes and production of IP-10, In murine models of lung injury, CBD reduced lipopolysaccharide (LPS)-induced acute pulmonary inflammation [41,42]. In rat models of experimental asthma, CBD treatment reduced airway inflammation, as well as levels of serum IL-4, IL-5, IL-13, IL-6 and TNF-α, which are implicated in airway inflammation and fibrosis in asthma [43,44]. Moreover, CBD was able to directly suppress T-cell secretion of IL-1 and IFNγ [45]. In piglets with hypoxic-ischemic lung damage, CBD reduced histologic damage, decreased leukocyte infiltration and modulated IL-1 concentration in bronchoalveolar lavage fluid [46], while in a rat model of sepsis, CBD reversed oxidative stress and reduced mortality [47]. In humans, cannabinoid use prevented induction of pro-inflammatory CD16+ monocytes and production of IP-10, suggesting anti-inflammatory effects in humans [48]. In another human study, in addition to reduction of pro-inflammatory monocytes, heavy cannabis use was also associated with decreased frequencies of HLA-DR+CD38+ activated CD4 and CD8 T-cells and frequencies of IL-10, IL-12 and TNF-α -producing antigen presenting cells compared to non-cannabis users [49].
Cecilia T. Costiniuk and Mohammad-Ali Jenabian Published online 2020 May 20. doi:10.1016/j.cytogfr.2020.05.008
28 Apr 2020 SARS-CoV2 induced respiratory distress: Can cannabinoids be added to anti-viral therapies to reduce lung inflammation?
Like Δ9-tetrahydrocannabinol (Δ9-THC), the most well-studied cannabinoid, CBD decreased lung inflammation in a murine model of acute lung injury potentially through the inhibition of proinflammatory cytokine production by immune cells and suppressing exuberant immune responses (Ribeiro et al., 2015). CBD can inhibit the production of proinflammatory cytokines like interleukin (IL)-2, IL-6, IL-1α and β, interferon gamma, inducible protein-10, monocyte chemoattractant protein-1, macrophage inflammatory protein-1α, and tumor necrosis factor-α (Nichols and Kaplan, 2020) (Fig. 1 ) that have been associated with SARS-CoV2 induced multi-organ pathology and mortality. In a murine model of chronic asthma, CBD reduced proinflammatory cytokine production, airway inflammation and fibrosis (Vuolo et al., 2019). Moreover, CBD can effectively inhibit the JAK-STAT pathway including the production and action of type I interferons without leading to addiction, alterations in heart rate or blood pressure and adverse effects on the gastrointestinal tract and cognition (Nichols and Kaplan, 2020). In simian immunodeficiency virus (SIV)-infected rhesus macaques (RMs), we reported THC mediated attenuation of IFN stimulated gene expression in the intestine (Kumar et al., 2019). Similar to CBD, chronic THC administration blocked inflammation induced fibrosis in lymph nodes of chronically SIV-infected RMs (Kumar et al., 2019). Unlike THC, CBD has a high margin of safety and is well tolerated pharmacologically even after treatments of up to 1500 mg/day for two weeks in both animals and humans (Nichols and Kaplan, 2020), which suggests its feasibility to reduce SARS-CoV2 induced lung inflammation/pathology and disease severity.
Siddappa N Byrareddy and Mahesh Mohan Published online 2020 Apr 28. doi:10.1016/j.bbi.2020.04.079
17 Apr 2020 In Search of Preventative Strategies: Novel Anti-Inflammatory High-CBD Cannabis Sativa Extracts Modulate ACE2 Expression in COVID-19 Gateway Tissues
The observed down-regulation of ACE2 gene expression by several tested extracts of C. sativa is a novel and crucial finding. Our results lay a foundation for further in-depth analysis of the effects of C. sativa on the molecular etiology and pathogenesis of COVID-19, as well as other viral diseases in which viruses use the ACE2 receptor as a molecular gateway. If further confirmed, select high-CBD cannabis extracts can be used to develop prevention strategies directed at lowering or modulating ACE2 levels in high-risk tissues. ACE2 level modulation is of particular importance since it appears to change throughout disease progression, and some studies show that ACE2 is essential for lung function in animal models of SARS. It would also be important to test the effects of C. sativa lines on other receptors involved in SARS-CoV2 entry, as well as for their anti-inflammatory potential.
Bo Wang, Anna Kovalchuk, Dongping Li, Yaroslav Ilnytskyy, Igor Kovalchuck and Olga Kovalchuck Published online 2020 Apr 19. doi:10.20944/preprints202004.0315.v1