While everyone is trying to forget about and move on from Covid-19, science is finally figuring it out. That is, new research unveiled mechanisms that the virus uses to induce damaging inflammation. Described within three studies is an unusual aspect of fatal Covid infection that might rewire endocannabinoid function.
The endocannabinoid system is a complex array of fatty acid messengers, known as endocannabinoids, and the receptors that they trigger. Viral infections flip special enzymes that metabolize endocannabinoids, dysregulating and throwing them off balance. And while this author developed a hypothesis last year, a piece of the puzzle was misplaced at the time.
Unusual viral infection discovered
At the beginning of 2022, a critical study was released explaining how spike proteins from Sars-Cov2 lodge themselves into certain cells for up to 15 months. Originally, though, the research was released as a preprint last year. (1) Subsequently, researchers from Boston Children’s Hospital, Yale, and elsewhere explored whether or not vaccine immunity causes the same type of long-term infection. It doesn’t. A pair of studies were released on discoveries regarding inflammation caused by Covid-19. (2, 3)
The latter studies described how one type of special cell, CD16+, induces major inflammation once it’s infected by the virus. (3) Damaging antibodies were also released by the infected cells. (2) Less important to the researchers, it seems, is a connection between the cell, endocannabinoid metabolism, and inflammation. In summary, Covid likely leads to major inflammatory assault and damage by degrading endocannabinoid function.
The fact that spike proteins can lodge into these cells was a topic of Long Covid (PASC) in this author’s earlier review. Moreover, that review focused on autoantibodies elicited from ER Stress as the cause of enzyme switching and ECS dysfunction. (4) As it turns out from the latter pair of studies, though, CD16+ — along with another immune cell — produces autoantibodies after viral infection. And again, these cells do not contain a known receptor binding domain that Sars-Cov2 can port. (2, 3)
Inflammasome and the endocannabidiome
True, all three studies on Covid-19 infection of CD16+ failed to mention the endocannabinoid system. (1-3) With that said, the three studies indirectly support the idea that Covid rewires the ECS. (5-10) It should therefore be viable to investigate a never-before analyzed treatment for Covid. And studies on CBGa and CBD might help support the viability of that treatment, (11, 12) which is to protect an often neglected endocannabinoid. (13, 14)
Researchers noted how specific inflammatory markers are induced once CD16+ cells become infected with the virus. (2, 3) Endocannabinoids are, however, known in the literature as major regulators of at least one inflammatory agent mentioned, NLRP3. (15) CB2 receptor agonists will especially regulate this inflammasome. (16, 17)
The relationship between endocannabinoids and viral infection continues. Deleterious effects imposed on endocannabinoid metabolism are further characteristic of that marriage. If ECS function becomes heavily depleted after a viral infection — due to an enzymatic shift in the body (7) — inflammasomes will go without regulation. (15) From here, damage can eventually overtake the body as cells die a fiery death known as pyroptosis. (2, 3)
Inflammation, what is it good for!
The most recent of the three studies identified the purpose of inflammation. Inflammasomes produce cytokines that can kill off the virus. (3) For this reason, inhibiting endocannabinoid degradation and any inflammation must be done so delicately.
Balancing endocannabinoid function to prevent lethal inflammation, whether that is from Covid infection, (4) trauma, (12) or otherwise (11, 18), appears to take incredible caution and care. Conversely, blocking the wrong endocannabinoids can help the virus thrive.
Research continues with a possible treatment left unexplored
Science appears to finally have more answers on Covid-19 inflammation — but progress has been promised for the past two years now. In contrast, the benefits of MAG-l inhibitors have either gone unpublished or remain a mystery. From elsewhere in the literature, damage after the newly documented cells becomes infected with a virus is likely tied to endocannabinoid function and tone. (10, 19, 20)
As the severity of the virus slowly wanes next to its increasing transmissibility, ibuprofen has become accepted as a treatment for mild Covid. Unbeknownst to many doctors is how profens protect anandamide from inflammatory assault. Unfortunately, ibuprofen does not prevent 2-AG metabolism. (21, 22) Yet, 2-AG is critical for good endocannabinoid function and likely important to protect during Covid-19 infection. (8, 9)
This author would like to hypothesize that neurological deficits caused by Covid infection are in part connected to a lack of 2-AG protection. (18, 19) To remedy this, inhibitors of MAG-l, an enzyme that degrades 2-AG, can be explored as improved Covid treatments. CBGa, a precursor cannabinoid, inhibits MAG-l. During in vitro research, CBGa blocked viral entry into cells. (11) As a treatment for Covid, though, MAG-l inhibitors — including CBGa — require good clinical evaluation to be accepted.
In an email, three researchers from Havard Medical School who collaborated on one of the recent studies (2) were contacted for comment. Professor Judy Lieberman is an expert on biochemical sciences, molecular medicine, and pediatrics from Boston Children’s Hospital. Lieberman, one of three email recipients, responded to explain that she has no insight into the relationship. Currently, the connection between Covid-19 infection of Fcγ domains and the ECS solely belongs to my hypothesis herein.
Let us know in the comments if you think the researchers should either forget about Covid or try to understand how it affects endocannabinoid function.
Show your work
Sars-cov2 binds to Fcγ domains, including CD64 ( FcγRI), CD32 (FcγRII), and CD16+ (FcγRIII) independent of ACE2, neuropilin-1, or TMPRSS2. (1-3)
Vaccines do not infect the same Fcγ domains. (2)
CD16+ induces PLA2 dependent on ERK mediation (23)
Phospholipases, including PLA2, are major agents in endocannabinoid synthesis (6, 24)
Covid infection of FcγR domains induces inflammasomes, including NLPR3, and the chemokine, CXCLC10. (15-17)
CB2 receptor signalling attenuates NLPR3 and CXCLC10. (25)
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