In January 2022, related researchers from the University of Chicago and other units published a paper entitled “Cannabidiol inhibits SARS-CoV-2 replication through induction of the host ER stress and innate immune responses” in “Science Advances” (IF: 14.1). A research paper describing CBD as a potential preventive agent and related mechanisms for early SARS-CoV-2 infection.
Highlights of the research
- Cannabidiol (CBD) inhibits SARS-CoV-2 infection in cells and mice
- CBD inhibits viral gene expression during viral entry and reverses many of the effects of SARS-CoV-2 on host gene transcription
- CBD inhibits SARS-CoV-2 replication in part by upregulating host IRE1αRNase endoplasmic reticulum (ER) stress response and interferon signaling pathways
- Patients taking CBD medication were significantly negatively correlated with positive SARS-CoV-2 test
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the culprit behind the 2019 novel coronavirus pneumonia (COVID-19), an epidemic that continues to cause widespread morbidity and mortality worldwide. Despite the recent availability of vaccines, the rapid spread of SARS-CoV-2 underscores the need for alternative treatments, especially for populations with limited access to vaccines. To date, few treatments have been discovered that prevent SARS-CoV-2 from replicating and producing the virus.
A potential modulator of host stress and antiviral inflammatory responses is cannabidiol (CBD), a member of the cannabinoid class of natural products produced from cannabis. Cannabis refers to the cannabis plant or material derived from it that contains 0.3% or less of the psychoactive drug tetrahydrocannabinol (THC) and typically has relatively high CBD content. THC works by binding to cannabinoid receptors, and CBD enhances this interaction. Despite numerous studies and many unsubstantiated claims on CBD-containing products, the biological role of CBD itself is unclear.
The researchers first tested the effect of CBD on SARS-CoV-2 replication by pretreating A549 humans expressing the exogenous human ACE-2 receptor (A549-ACE2) with 0-10 μM CBD prior to infection with SARS-CoV The expression of viral spike protein (S) and viral titers in the cells were monitored after 2 hours in lung cancer cells and 48 hours later. It was found that CBD can effectively inhibit viral replication (including three SARS-CoV-2 variants) under non-toxic conditions, and quantitative NMR (qNMR) verified that the CBD used was more than 97% pure and the content of similar cannabinoids not higher than 1.0%. Furthermore, the CBD metabolite 7-OH-CBD has antiviral activity, while cannabinoids other than CBD, including THC, have limited or no inhibitory effect on SARS-CoV-2 infection.
The researchers further explored that CBD had little effect on virus entry, and was very effective in inhibiting the expression of the SARS-CoV-2 spike protein in host cells in the early stage after virus entry. CBD inhibits viral gene expression after viral entry and reverses many of the effects of SARS-CoV-2 on host gene transcription, preventing viral protein translation and associated cellular changes. Mechanistically, CBD induces endoplasmic reticulum (ER) stress response and IRE1α activity to inhibit SARS-CoV-2 replication, in addition, CBD promotes host cell interferon response and inhibits viral induction of cytokines.
Several drugs, including cationic amphiphiles, can block SARS-CoV-2 replication in cultured cells, but not in vivo. The researchers then validated in female K18-hACE2 mice and found that CBD treatment significantly inhibited SARS-CoV-2 replication in mice, establishing CBD as an antiviral agent for SARS-CoV-2 in the early stages of infection preclinical efficacy.
Given the large number of individuals taking high-purity CBD preparations, the researchers finally examined whether CBD prescriptions or medication records used were associated with signs of SARS-CoV-2 infection. It was found that CBD (100 mg/ml oral solution per medical record) was significantly negatively associated with a positive SARS-CoV-2 test in a matched group of human patients from the National COVID Cohort Collaboration.
Taken together, the results of this study suggest that CBD and its metabolite 7-OH-CBD can inhabit SARS-CoV-2 infection in the early and even late stages of infection. This mechanism appears to be mediated in part through activation of the IRE1αRNase and interferon pathways. This study provides preclinical support for the evaluation of CBD as an anti-SARS-CoV-2 therapeutic in clinical trials.
