Cannabidiol inhibits SARS-CoV-2 replication through induction of the host ER stress and innate immune responses

DISCUSSION

Our results suggest that CBD and its metabolite 7-OH-CBD can block SARS-CoV-2 infection at early and even later stages of infection. The mechanism appears to be mediated in part by activation of the IRE1α RNase and interferon pathways. In addition to these cell-based findings, pre-clinical studies show that CBD treatment reduced viral titers in the lungs and nasal turbinates of SARS-CoV-2-infected mice. Finally, analysis of a national sample of patients with active records of 100 mg/ml CBD consumption at the time of COVID testing revealed an association with substantially fewer SARS-CoV-2 positive test results. This negative association was robust to many sensitivity analyses, including changes in the matching and outcomes models, and merits further research into the potential of CBD to combat SARS-CoV-2 infection, such as validation in other large, multi-site electronic health record datasets or prospective experimental designs.

One mechanism contributing to the antiviral activity of CBD is the induction of the interferon pathway both directly and indirectly following activation of the host immune response to the viral pathogen. In fact, interferons have been tested clinically as potential treatments for COVID-19 (30). When hyperactivated by severe ER stress, IRE1α’s RNase activity leads to the endonucleolytic decay of many ER-localized mRNAs (RIDD) and subsequent activation of RIG-I and interferons (18). Although SARS-CoV-2 induces the kinase activity of IRE1α, it does not activate its RNase activity as monitored by XBP1 splicing. Thus, the RNase activity of IRE1α induced by CBD can potentially account both for the degradation of viral RNA and the induction of interferons by the RNA fragments. Further investigation will be required to determine whether both anti-viral effects of CBD are linked to the ER stress response. Importantly, CBD also suppresses cytokine activation in response to viral infection, reducing the likelihood of immune cell recruitment and subsequent cytokine storms within the lungs and other affected tissues. These results complement previous findings suggesting that CBD suppresses cytokine production in recruited immune cells such as macrophages (31). Thus, CBD has to the potential not only to act as an antiviral agent at early stages of infection, but also to protect the host against an overactive immune system at later stages.

CBD has a number of advantages as a potential preventative agent against SARS-CoV-2. CBD as a food additive with THC content less than 0.3% is widely available without restricted access. With proper formulation, quality control and delivery, CBD could be used prophylactically in contrast to recent anti-viral drugs. Multiple means of CBD ingestion are possible, including potential for inhalation and nasal delivery. CBD blocks viral replication after entry into cells and, thus, is likely to be effective against viral variants with mutant spike proteins. Unlike drugs such as remdesivir or antiviral antibodies, CBD administration does not require injection in hospital settings. Finally, CBD is associated with only minor side effects (32).

However, several issues require close examination before CBD can be considered further or even explored as a therapeutic lead for COVID-19 (12). Although many CBD and CBD-containing products are available on the market, they vary vastly in quality, CBD content, and their pharmacokinetic properties after oral administration, which are mostly unknown. CBD is quite hydrophobic and forms large micellar structures that are trapped and broken down in the liver, thereby limiting the amount of drug available to other tissues after oral administration. Inactive carriers and formulation adjuvants have a significant impact on clinically obtainable concentrations. As CBD is widely sold as a preparation in an edible oil, we analyzed flavored commercial hemp oils and found a CBD content of only 0.30% in a representative sample (fig. S22). The purity of CBD and the chemical composition of the materials labelled as CBD are also important, especially in light of our findings suggesting that other cannabinoids such as THC might act to counter CBD antiviral efficacy. This essentially eliminates the feasibility of marijuana serving as an effective source of antiviral CBD, in addition to issues related to its legal status. Finally, other means of CBD administration such as vaping and smoking raise additional concerns about potential lung damage.

Future studies to explore the optimal means of CBD delivery to patients along with clinical trials will be needed to further evaluate the promise of CBD as a therapeutic to block SARS-CoV-2 infection. Our animal studies provide pre-clinical support for evaluation of CBD as an anti-SARS-CoV-2 therapeutic agent in clinical trials. We advocate carefully designed placebo-controlled clinical trials with known concentrations and highly-characterized formulations in order to define CBD’s role in preventing and treating early SARS-CoV-2 infection. The necessary human in vivo concentration and optimal route and formulation remain to be defined. We strongly caution against the temptation to take CBD in presently available formulations including edibles, inhalants or topicals as a preventative or treatment therapy at this time, especially without the knowledge of a rigorous randomized clinical trial with this natural product