COVID-19: CBD right from the start? Newer research data

Summary: CBD has been shown to down-regulate ACE2Rs and TMPRSS2Rs, both of which facilitate the inoculation of SARS-CoV-2. CBD has also been shown to inhibit the progression of the infection in the early stages by activating the of interferon pathway, thereby leading to degradation of viral RNA, down-regulation of inflammatory cytokine production and a favorable outcome of the disease.

The ACE2 and TMPRSS2 receptors are used by the SARS-CoV-2 to initiate its entry into the epithelial cell (inoculation phase). Both of these receptors are down-regulated by CBD, and thus CBD can be considered as a useful protector, not only against SARS-CoV-2, but also SARS-CoV and H1N1.

Once the cell is infected, a mechanism by which SARS-CoV-2 bypasses our primary (innate) immune response is the suppression of the biochemical pathway of interferons I and III, which determine the intensity of the initial defense reaction to the virus, on which early clearance the organism from the invader depends. Inhibition of interferons, in combination with induced production of inflammatory cytokines (mainly IL-6 and IL-2β) produce an inappropriate immune response characterized by a “cytokine storm” ending in acute respiratory distress syndrome (ARDS) and possibly secondary hemophagocytic lymphocytosis (sHLH) and prolonged COVID-19.

CBD seems to have a double therapeutic role here: It enhances the production of interferons I and III, resulting in the immediate degradation of the circulating RNA of the virus, and the rapid clearance from the virus. Humans have genes that are activated by CBD, such as those that produce interferon β and γ receptors (INF-βR, INF-γR), as well as interferon signaling mediators, such as STAT1 and STAT2. The presence of the virus does not inhibit these activations. Besides, CBD activates other genes too, such as OAS1, only in the presence of the virus. This gene is normally stimulated by interferon and results in the destruction of viral RNA through the production of the lytic enzyme RNA-ase L. In other words, in the latter case, CBD mimics the action of interferon. Therefore, in the very early phase of the infection, CBD may significantly reduce the viral load, thus making it easier for the primary (innate) immune response to clear the virus; in this manner, the infection ends early, with minimal symptoms, and the probability to evolve into an uncontrollable cytokine storm is drastically reduced. By the same token, severe clinical conditions like ARDS, sHLH and prolonged COVID-19 become highly unprobable.

In April 2020, before the vaccine era, I published online a short review article on the potential benefits of cannabis in COVID-19 (https://dr-papastavrou.medium.com/covid19-cannabis-ethics-44d3ad98da63), which, based on the abovementioned more recent data needs to be partially revised. In this article, I recommended avoiding CBD administration during the first five days of the infection, in order not to interrupt the momentum of the primary immune response; this was based on the general idea that CBD is immunosuppressive. I also proposed starting CBD in moderate doses after day 5, aiming to mitigate a cytokine storm that might have started. Today, based on more recent research, I advocate administering CBD right from the start. The clinical results I had with the previous regimen were not bad at all, but I think they would be even better under the newer concept, namely that CBD protects the epithelium and boosts the innate immune response.

Needless to say, there is urgent need for proper clinical studies in order to prove these speculative thoughts in practice, and to determine the ideal dosage. My prediction is that the dosage should be high, because our aim is the pharmacological action of CBD and not a delicate regulation of the endocannabinoid system that needs dosage discovery.

Selected Bibliography

1. Otto Haller, Georg Kochs, Friedemann Weber (2006): The interferon response circuit: induction and suppression by pathogenic viruses. Virology Jan 5; 344 (1): 119–30, doi: 10.1016 / j.virol.2005.09.024.
2. Daniel Blanco-Melo et al (2020): Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19: Cell May 28; 181 (5): 1036–1045, doi: 10.1016 / j.cell.2020.04 .026
3. Aias-Theodoros Papastavrou (2020): COVID-19 & cannabis: Medium.com
4. Puja Mehta et al (2020): COVID-19: Consider cytokine storm syndromes and immunosuppression. The Lancet, Volume 395 (10229): 1033–1034, doi: 10.1016 / S0140–6736 (20) 30628–0
5. Khodadadi, H. et al. (2020): Cannabidiol modulates cytokine storm in acute respiratory distress syndrome induced by simulated viral infection using synthetic RNA. Cannabis cannabinoid Res. 5 (3), 197–201, doi: 10.1089 / can.2020.0043
6. Wang, B. et al. (2020). In search of preventative strategies: Novel high-CBD cannabis sativa extracts modulate ACE2 expression in COVID-19 gateway tissues. Aging 12 (22), 22425–22444. doi: 10.18632 / aging.202225
7. Veronica Mollica, Alessandro Rizzo, and Francesco Massari (2020): The pivotal role of TMPRSS2 in coronavirus disease 2019 and prostate cancer. Future Oncol. (published online), doi: 10.2217/fon-2020–0571