Even with recently approved vaccines being rolled out in many countries, the virus continues to spread rapidly, heightened by more-transmissible variants such as the B.1.1.7 variant. Rosner and her colleagues say that this highlights the need for alternative approaches, especially among populations with limited access to vaccines. Few therapies to date have been identified as being able to block SARS-CoV-2 replication and viral reproduction.
Through the combination of CBD and 7-OH-CBD, the expression of certain genes within the viral cells were inhibited and changes in gene expression within the lung cells that resulted from the presence of COVID-19 were reversed (4). Thus, CBD and 7-OH-CBD serve in both protective and therapeutic roles. CBD was also found to have the ability to block viral ribonucleic acid (RNA), including the coding for the spike protein, which is the tool the virus uses to enter our cells. “This study highlights CBD, and its active metabolite, 7-OH-CBD, as potential preventative agents and therapeutic treatments for SARS-CoV-2 at early stages of infection,” said Rosner and the team (1).
To analyze 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 infecting them with SARS-CoV-2. Evaluation of the cells 48 hours later expressed CBD had potently inhibited viral replication in the cells. When CBD was assessed to possibly prevent proteolytic cleavage by MPro and PLPro, it was observed that CBD had no effect on the activity of either protease. This revelation led the team to hypothesize that CBD targets host cell processes. Consistent with their hypothesis, RNA sequencing of infected A549-ACE2 cells treated with CBD for 24 hours showed significant suppression of SARS-CoV-2-induced changes in gene expression. CBD was shown to have effectively eliminated viral RNA expression, which included RNA coding for the spike protein. It was also found that both SARS-CoV-2 and CBD triggered significant changes in cellular gene expression, such as the expression of several transcription factors. Further analysis of host cell RNA expressed that the virus-induced changes were almost completely reversed, though rather than the cells returning to a normal cell state, the CBD plus virus-infected cells resembled those treated with CBD alone.
Another critical finding researchers discovered was that CBD had “effectively reversed” the triggering of a hyperinflammatory response, also known as a “cytokine storm” which is brought on by the presence of the virus, restoring cells not to a previral level of inflation, but a state as if the cells had been treated with only CBD. A study completed near the end of 2020 by the Dental College of Georgia (DCG) (Augusta, Georgia) and the Medical College of Georgia (Augusta, Georgia) also had similar findings to the team from the University of Chicago (5). Cytokine storms have been one of the principal causes of death resulting from a COVID-19 infection. CBD was identified in reducing damage in the lungs spurred by cytokine storms caused from COVID-19 by normalizing levels of apelin, a peptide known to reduce inflammation, decreasing physical lung damage associated with adult respiratory distress syndrome (ARDS), and improving oxygen levels. During a COVID-19 infection, these apelin levels were seen to be at very low levels. Rosner and her team stated that “CBD has 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,” (1).
Primarily, the SARS-CoV-2 virus enters host cells through the binding of a surface viral protein—called spike protein— to the human host cell receptor angiotensin-converting enzyme 2 (ACE2). From there, the viral genome is then translated into two large polypeptides that are severed by the viral proteases main protease (MPro) and papain-like protease (PLPro) to produce the proteins necessary for viral replication, assembly, and budding (1).
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Transient receptor potential (TRP) channels are a family of ion channels. They are membrane proteins which consist of channel subunits built of six putative transmembrane-spanning segments (S1-S6) with a pore-forming loop between S5 and S6 which assemble into tetramers to form functional channels (122). TRPs are involved in the signal transduction of numerous chemical and physical stimuli and regulate many neural signaling processes and other physiological functions such as temperature sensation, smell, taste, vision, pressure, or pain perception (123). Thus, they are potentially attractive targets for the therapeutic use of phytocannabinoids in the treatment of sensory, inflammatory or dermatological pathologies (124). Most TRPs can cause channelopathies which are risk factors for many disease states (125).
Regulation of the Immune Response by Phytocannabinoids
Table 1. Cannabinoids receptors.
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IL-H and NP conceptualized the manuscript and established the writing consortium. AP wrote the section about the cannabinoid receptors. MA wrote the section about the anti-inflammatory properties of cannabinoids. HH, TP, and ES contributed to the writing and reviewing process. All authors contributed to the article and approved the submitted version.
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