Researchers in the United States conducted a study showing that a component of a 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 (COVID-19) pandemic that continues to engulf the world and threaten global public health and the global economy.
Marsha Rosner of the University of Chicago in Illinois and colleagues found that cannabidiol (CBD) and its metabolite 7-OH-CBD potently blocked SARS-CoV-2 replication in lung epithelial cells.
The 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 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 had used CBD, compared to comparable patients who had not used CBD.
“This study highlights CBD and its active metabolite, 7-OH-CBD, as potential preventives and therapeutic treatments for SARS-CoV-2 in early stages of infection,” said Rosner and the team.
A preprinted version of the research paper is available at bioRxiv server, while the article is under peer review.
Rapid spread of SARS-CoV-2 emphasizes 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 resulted in more than 119.5 million infections and caused more than 2.64 million deaths.
Although recently approved vaccines are now being rolled out in many countries, the virus is still spreading rapidly. Rosner and colleagues say this highlights the need for alternative approaches, especially among populations with limited access to vaccines.
However, to date, few therapies have been identified that block SARS-CoV-2 replication and viral production, the researchers write.
More about SARS-CoV-2 and CBD
The SARS-CoV-2 virus enters host cells primarily 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, while limited, some studies have reported that certain cannabinoids have antiviral effects against the hepatitis C virus and other viruses.
In addition, an oral solution of CBD has already been approved by the U.S. Food and Drug Administration for the treatment of epilepsy.
High dose CBD use in patients is significantly correlated with a reduction in COVID-19 positivity. Associations between reported cannabinoid drug use and COVID-19 test results among adults tested at the University of Chicago Medicine (total n = 93,565). P *: p-values of percent positivity of the specified patient population compared to percent positivity of all patients (10% COVID-19 positive among 93,565 patients). Center right: 85 patients took CBD before their COVID test date. Top right: 82 of 85 patients took FDA-approved CBD (Epidiolex®) and were compared to 82 of 93,167 patients (Matched Controls) with a closest neighbor propensity model that scored patients based on their demographics and their recorded diagnoses and medications from the two years prior to their COVID-19 test. P values were calculated using Fisher’s exact test two-tailed.
What did the current investigation entail?
To test the effect of CBD on SARS-CoV-2 replication, the researchers pretreated A549 human lung carcinoma cells expressing ACE-2 (A549-ACE2) with 0-10 μM CBD for 2 hours before being infected with SARS- CoV-2.
Analysis of the cells 48 hours later showed that CBD had potently inhibited viral replication in the cells.
Because CBD is often consumed as part of a diet Cannabis sativa extract, the team investigated whether other cannabinoids could also inhibit SARS-CoV-2 infection, especially those with closely related structures.
Remarkably, CBD was the only agent that potently inhibited viral replication; limited or no antiviral activity was exhibited by the other structurally similar cannabinoids tested.
In addition, the CBD metabolite 7-OH-CBD, the active ingredient in the CBD treatment of epilepsy, also effectively inhibited SARS-CoV-2 replication in the A549-ACE2 cells.
CBD effectively eliminated viral RNA expression
When the researchers assessed whether CBD could prevent proteolytic cleavage by Mpro or PLpro, they found that CBD had no effect on the activity of either protease.
This led the team to hypothesize that CBD targets host cell processes.
In accordance with this hypothesis, RNA sequencing of infected A549-ACE2 cells treated with CBD for 24 hours revealed a significant suppression of SARS-CoV-2 induced changes in gene expression.
The CBD effectively eliminated viral RNA expression, including RNA coding for the spike protein.
Both SARS-CoV-2 and CBD caused significant changes in cellular gene expression, including the expression of various transcription factors.
Further analysis of host cell RNA showed that the virus-induced changes were almost completely reversed, but instead of the cells returning to a normal cell state, the cells infected with CBD + virus resembled those treated with CBD alone.
What About Interferon Signaling?
Since infection with SARS-CoV-2 is known to suppress the interferon signaling pathway, the researchers tested whether CBD can suppress viral infection by introducing this pathway.
Some genes were induced by CBD in both the absence and presence of SARS-CoV-2, including genes encoding interferon receptors and mediators of the interferon signaling pathway.
In addition, CBD effectively reversed the viral induction of cytokines, which during the later stages of infection can cause a lethal hyperinflammatory response, the “cytokine storm.”
“Thus, CBD has the potential not only to act as an antiviral agent in the early stages of infection, but also to protect the host against an overactive immune system in later stages,” said Rosner and the team.
The incidence of SARS-CoV-2 was lower in patients using CBD
Finally, the team assessed the incidence of SARS-CoV-2 infection among 82 patients who had been prescribed CBD prior to SARS-C0V-2 testing and matched patients who had not received CBD.
Interestingly, the incidence of SARS-CoV-2 was only 1.2% among the patients prescribed CBD, compared to 12.2% among the matched patients who had not used CBD.
“The substantial reduction in SARS-CoV-2 infection risk of about an order of magnitude in patients using FDA-approved CBD highlights the potential efficacy 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 to define the role of CBD in preventing and treating early SARS-CoV-2 infection,” they conclude.
*Important announcement
bioRxiv publishes preliminary scientific reports that have not been peer reviewed and therefore should not be considered conclusive, serve clinical practice / health-related behavior, or be treated as established information.