Researchers in the United States conducted a study showing that a compound from the cannabis plant inhibited infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in human lung cells.
SARS-CoV-2 is the agent responsible for the 2019 coronavirus disease pandemic (COVID-19) that continues to sweep the globe, posing a threat to global public health and the world economy.
Marsha Rosner of the University of Chicago, Illinois, and colleagues found that cannabidiol (CBD) and its metabolite 7-OH-CBD potently blocked the replication of SARS-CoV-2 in the epithelial cells of the lung.
CBD inhibited viral gene expression and reversed many of the virus’s effects on host gene transcription.
The compound also induced the expression of interferons – cell signaling proteins that are produced by host cells as an early response to viral invasion.
In addition, the incidence of SARS-CoV-2 infection was up to an order of magnitude lower in a cohort of patients who were taking CBD, compared with compatible patients who were not taking CBD.
“This study highlights CBD and its active metabolite, 7-OH-CBD, as potential preventive agents and therapeutic treatments for SARS-CoV-2 in the early stages of the infection,” says Rosner and the team.
A pre-printed version of the research article is available at bioRxiv* server, while the article is submitted to peer review.
The rapid spread of SARS-CoV-2 highlights the need for new treatments
Since the COVID-19 outbreak began in Wuhan, China in late December 2019, the rapid spread of SARS-CoV-2 has led to more than 119.5 million infections and caused more than 2.64 million deaths .
Although recently approved vaccines are being launched in many countries, the virus is still spreading rapidly. Rosner and colleagues say this highlights the need for alternative approaches, particularly among populations with limited access to vaccines.
However, “so far, few therapies have been identified that block SARS-CoV-2 replication and viral production,” write the researchers.
More about SARS-CoV-2 and CBD
The SARS-CoV-2 virus enters the host cells mainly through the binding of a viral surface protein called spike to the angiotensin-converting enzyme 2 (ACE2) of the human host cell receptor.
The viral genome is then translated into two large polypeptides that are cleaved by the viral proteases MPro and PLPro to produce the proteins necessary for viral replication, assembly and budding.
Rosner and colleagues say that, although limited, some studies have reported that certain cannabinoids have antiviral effects against the hepatitis C virus and other viruses.
In addition, an oral CBD solution has already been approved by the U.S. Food and Drug Administration for the treatment of epilepsy.
The use of high doses of CBD in patients is significantly correlated with a reduction in the positivity of COVID-19. Associations between the reported use of cannabinoid drugs and the results of the COVID-19 test among adults tested at the University of Chicago Medicine (total n = 93,565). P *: p values of the percentage of positivity of the specified patient population compared to the percentage of positivity of all patients (10% positive COVID-19 among 93,565 patients). Middle right: 85 patients took CBD before the date of the COVID test. Upper right: 82 of 85 patients took FDA-approved CBD (Epidiolex®) and were compared to 82 of 93,167 patients (combined controls) with a propensity score model of the nearest neighbor that scored patients according to their demographics and their diagnoses and medications recorded from the two years prior to the COVID-19 test. P values were calculated using the bilateral Fisher’s exact test.
What did the current study involve?
To test the effect of CBD on SARS-CoV-2 replication, the researchers pretreated human lung carcinoma A549 cells that express ACE-2 (A549-ACE2) with 0-10μM CBD for 2 hours before infecting it them with SARS-CoV-2.
Analysis of the cells 48 hours later showed that CBD potently inhibited viral replication in the cells.
Since CBD is often consumed as part of a Cannabis sativa extract, the team investigated whether other cannabinoids could also inhibit SARS-CoV-2 infection, especially those with closely related structures.
Notably, the only agent that potently inhibited viral replication was CBD; limited or no antiviral activity was exhibited by the other structurally similar cannabinoids tested.
In addition, the metabolite 7-OH-CBD of CBD, the active ingredient in the treatment of epilepsy with CBD, also effectively inhibited the replication of SARS-CoV-2 in A549-ACE2 cells.
CBD effectively eliminated viral RNA expression
When the researchers evaluated whether CBD can prevent proteolytic cleavage by Mpro or PLpro, they found that CBD had no effect on the activity of any of the proteases.
This led the team to raise the hypothesis that CBD is targeting host cell processes.
Consistent with this hypothesis, RNA sequencing of infected A549-ACE2 cells treated with CBD for 24 hours revealed significant suppression of SARS-CoV-2-induced changes in gene expression.
CBD effectively eliminated viral RNA expression, including RNA encoding for the spike protein.
Both SARS-CoV-2 and CBD triggered significant changes in cellular gene expression, including the expression of various transcription factors.
Further analysis of the host cell’s RNA showed that the changes induced by the virus were almost completely reversed, but instead of the cells returning to the normal state of the cell, cells infected with the CBD + virus resembled those treated with CBD alone.
What about interferon signaling?
Since SARS-CoV-2 infection is known to suppress the interferon signaling pathway, the researchers tested whether CBD could suppress viral infection by introducing this pathway.
Some genes have been induced by CBD in the absence and presence of SARS-CoV-2, including genes that encode interferon receptors and mediators of the interferon signaling pathway.
In addition, CBD has effectively reversed viral cytokine induction that can trigger a deadly hyperinflammatory response called a “cytokine storm” during the final stages of infection.
“Thus, CBD has the potential not only to act as an antiviral agent in the early stages of the infection, but also to protect the host against a hyperactive immune system in later stages,” says Rosner and the team.
The incidence of SARS-CoV-2 was lower in patients taking CBD
Finally, the team assessed the incidence of SARS-CoV-2 infection among 82 patients who had received CBD prior to the SARS-C0V-2 test and paired patients who had not received CBD.
Surprisingly, the incidence of SARS-CoV-2 was only 1.2% among patients prescribed with CBD, compared with 12.2% among compatible patients who were not taking CBD.
“The substantial reduction in the risk of SARS-CoV-2 infection of approximately an order of magnitude in patients taking FDA-approved CBD highlights the potential effectiveness of this drug in combating SARS-CoV2 infection,” said Rosner and colleagues.
“We advocate carefully designed placebo-controlled clinical trials with known concentrations and highly characterized formulations in order to define the role of CBD in the prevention and treatment of early SARS-CoV-2 infection,” they conclude.
* Important news
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and therefore should not be considered conclusive, guide clinical practice / health-related behavior or treated as established information.