A recent study shows that cannabidiol, an important active ingredient in the Cannabis-sativa plant, can augment the innate antiviral immune response and prophylactically prime the innate antiviral response of cells – in turn enabling an enhanced response against viruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The research paper is currently available on the bioRxiv* pre-release server while undergoing peer review.

Study: Effect of cannabidiol on apoptosis and cellular interferon and interferon-stimulated gene responses to SARS-CoV-2 ORF8, ORF10 and M genes. Image Credit: Dmytro Tyshchenko/Shutterstock

A current situation with emerging variants of SARS-CoV-2, a causative agent of the ongoing coronavirus disease (COVID-19) pandemic, shows how a multi-faceted approach will ultimately be needed to mitigate the medical, social and health ramifications. economics of this disease.

This means not only finding effective drugs alongside the vaccine options we have, but also harnessing our innate immune systems to more easily fight off infection. This is important because unlike adaptive immunity (mediated by specialized cells of the immune system), all human cells can mount an innate immune response.

Nevertheless, viruses frequently develop functions to disrupt this protective facet of our immunity, which is also a function of several non-structural proteins in the genetic makeup of SARS-CoV-2. Therefore, scientists are very interested in finding ways to protect our innate immune response.

Recent evidence from the medical literature supports the idea that certain constituents of Cannabis-sativa plant (such as cannabidiol) have anti-inflammatory traits, with a possible role as a protective or therapeutic agent in cells facing metabolic distress (such as that associated with viral infection).

Based on this, a research group from the Faculty of Health at the University of Waterloo in Canada hypothesized that SARS-CoV-2 genes are proapoptotic (meaning they can cause cells to disassemble innate immune systems) and that cannabidiol might actually reverse these effects.

Assess markers of apoptosis

In the current study, the researchers aimed to examine the effects of expression of the ORF8 and ORF10 genes, as well as the structural membrane protein of SARS-CoV-2, reported to inhibit responses to type I and III interferons, on apoptosis (ie, programmed cell death) and the expression of interferons and downstream effectors.

In addition to evaluating the effects of expressing these genes alone, they also studied the impact of combining their expression with cannabidiol, a major non-psychotropic phytocannabinoid constituent of Cannabis-sativa.

Immortalized human embryonic kidney cells (HEK293) cells were transfected with a control plasmid (or plasmids expressing ORF8, ORF10, M protein) and tested for apoptosis markers at 24 hours. In addition, the expression of interferon and interferon-stimulated genes at 2 p.m. was also assessed.

Effect of ORF8, ORF10 or M protein expression, with and without CBD treatment, on HEK293 cell count and apoptosis indices. (A) Dose-dependent effects of CBD on the relative number of cells per well 24 h after transfection with a control plasmid (pCMV) or plasmids expressing ORF8, ORF10 or the M protein (n = 3-12). IC50 values ​​for the concentration of CBD in combination with each group are shown. (BD) Dose-response effect of CBD on early apoptosis index in HEK293 cells expressing pCMV or viral genes at 24 h. (EG) Dose-response effect of CBD on late apoptosis index in HEK293 cells transfected with control or viral plasmids. Apoptotic indices were calculated by dividing the relative uptake of the respective marker by the number of cells per well. Apoptosis data were analyzed by 2-way ANOVA with Tukey’s post-hoc test, n=3-9. The differences between the groups are as indicated, *P

Mediating apoptosis in SARS-CoV-2 infected cells

Overall, the results demonstrate a weak ability of HEK293 cells to respond to SARS-CoV-2 genes alone but highlight an enhanced innate antiviral response to these genes in the presence of cannabidiol. In other words, this compound can prime the components of the innate immune system and increase the ability to respond to viral infection without activating the process of apoptosis.

A substantial reduction in cell number, as well as an increase in apoptosis, was found after 24 hours in cells where viral gene expression was combined with cannabidiol treatment, but not in control transfected cells. treated with cannabidiol or in cells expressing viral genes but treated only with vehicle.

Moreover, the finding that cannabidiol regulates the expression of OAS family genes is of particular interest, given the role of these enzymes as potent mediators of the virus-associated apoptosis process.

From clinical use to public health benefits

“Our results demonstrating increased apoptosis in cells treated with cannabidiol and transfected with SARS-CoV-2 viral genes suggest a potential protective effect of cannabidiol upon initial infection,” the study authors state in this bioRxiv paper. “However, it also raises the question of whether it could be harmful in an individual who already had a high viral load,” they add.

Although we are still eagerly awaiting the results of many more registered clinical trials, so far none of them have been terminated prematurely by medical oversight committees, indicating that no significant harm has occurred. been detected.

Therefore, it is possible that cannabidiol may offer prophylaxis against initial viral infection through a pro-apoptotic mechanism that does not lead to widespread cell death in heavily infected patients. Nevertheless, further research will be needed to fully understand the nature of cannabidiol’s effects on SARS-CoV-2 and other viral pathogens.

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be considered conclusive, guide clinical practice/health-related behaviors, or treated as established information.