Before we get into the weeds ( I am on fire with the puns ), I need to give you a primer on COVID-19 that should help you frame the conversation in the right context. You will need to understand some fundamentals of the COVID-19 disease before you will be able to truly appreciate how cannabis fits into all of this. So in this article we are going to go over a couple of COVID-19 basics. How the virus binds to the cells it infects, why it matters and how that leads to some of the more severe COVID-19 complications. Once you understand this prerequisite information, it will be much easier to understand the new cannabinoid research that we are discussing in part 3 of this series.
Part 2: The COVID side of this story <--- you are here
COVID-19 is caused by a virus called SARS-CoV-2, which stands for “Severe Acute Respiratory Syndrome Coronavirus 2.” Loosely translated, that means “sudden bad lung problems, version 2”. You’ll find medical language is actually quite descriptive that way.
COVID-19 is the disease; SARS-CoV-2 is the virus
Of course, SARS-CoV-2 rolls off the tongue about as well as peanut butter and so henceforth we shall refer to it as the virus. COVID-19 complications can be quite severe and as we all know, in certain cases, deadly. But why is that exactly?—Well, that largely boils down to the fact that the virus attaches itself to, and enters our human cells via the ACE-2 receptor. I know, I know that still doesn’t mean anything. Ok, let me explain. The ACE-2 receptor is really important for our bodies. The receptor sits on the surface of cells that are part of essential organs, like the cardiovascular system, that is to say the heart and blood vessels which span throughout the body. From your lungs to your brain, intestines, kidneys, spleen, etc. you will find ACE-2 in a lot of important places.
ACE-2 , which stands for angiotensin-converting enzyme 2 is part of something called the “renin-angiotensin-aldosterone system (RAAS)”. So why is this important? Well, that system is quite critical. It is a hormone system which regulates blood pressure, electrolyte and fluid balance. This is why, when you suffer from heart problems and high-blood pressure the doctors will often prescribe ACE-2 inhibitor drugs that will interact with this system in order to keep your blood pressure down and your heart pumping. With that in mind, you can imagine that it is probably not good when a virus like “the virus” specifically binds to cells that express the ACE-2 receptor, since those cells are likely to be important. But not only are they important, but they are everywhere in your body.
The most dangerous COVID complications.
We all know COVID can have deadly complications. But there is a lot of debate about how deadly and who is at risk here. I think in most people’s mind the idea exists that COVID is usually mild, but if you are really old or maybe really unhealthy then it can hit you harder.
"The virus" binds to ACE-2 in the body. ACE-2 is in all the important parts of your body.
Unfortunately, the reality isn’t quite that simple and you have no way of knowing whether your disease progression will be mild, life-threatening or long-term debilitating like in the case of “long-COVID”. As you know about the ACE-2 receptor now, you may be able to appreciate why COVID can have deadly complications. Yes, it can hit you harder when you already have chronic, pre-existing metabolic conditions, but there are two major complications that can do some serious damage and even kill you, even if you appear to be otherwise healthy.
The two major COVID-19 complications are :
- blood clots (hypercoagulation/thrombotic events)
- cytokine storm (hyperactivity of inflammatory signals)
Those two are not disconnected from each other, rather they are a consequence of the same problem. The virus infects cells that express ACE-2 receptors. Many of those cells are endothelial cells that line every blood vessel in your body. Ultimately, both complications could be described as a result of endothelial cell dysfunction, because endothelial cells are integral to the mechanisms that regulate both inflammation and coagulation. Those two things are some of the most important features of the immune system that keep us alive on a daily basis. Inflammation is the recruitment of immune cells to the site of an infection or tissue damage, while coagulation is the process in which blood clots are formed. Both of those are very helpful and happen routinely in our body. However, they are tightly regulated and need to happen only in specific situations and only for a limited time. For example, inflammation is good when it fights off a local infection, but if it is not turned off again, then it will destroy the neighboring tissue as collateral damage. Meanwhile coagulation prevents us from bleeding to death when we get a paper cut. But if coagulation is not turned off again after a leak is plugged, well then there is a risk that you form a larger blood clot that may clog a whole blood vessel. This can have devastating consequences, when it blocks the blood flow to something important like your brain or heart muscles, for example. Our cells cannot survive without oxygen for too long so a traveling blood clot constitutes a major hazard. By infecting both endothelial cells and immune cells, the virus fucks with both systems.
blood clots and cytokine storm are the big killers
(#blood clots) Sudden COVID-19 deaths are often caused by blood clots
Blood clots are the first major COVID complication. They have been discovered in autopsies of sudden COVID-related deaths and even in patients with mild symptoms. Autopsies have described multiple blood clots scattered throughout the body. Even a single ill-positioned blood clot can cut off circulation to a vital organ such as your heart or brain and lead to a stroke or heart attack. But in COVID-19 patients it can happen that blood clots spontaneously from throughout the body. So, it is possible to get infected with the virus, only have mild symptoms and then suddenly die of a stroke or heart attack 3 days later. Since 2019 the scientific community has learned a lot about COVID-19 and today it is often regarded as a disorder of blood clotting. Furthermore evidence points to micro-clots being responsible for many of the prolonged impairments that long-COVID patients are suffering from. To counteract this clotting disorder, doctors often use blood thinners, such as Aspirin and Warfarin, for COVID patients. Aspirin, is a non-steroidal anti-inflammatory drug (NSAID) and is mainly used for reducing fever and pain, but it can also be used as a blood thinner when taken in a low-dose of 70 mg to 100 mg per day. At those low-doses Aspirin, or baby Aspirin, can interfere with coagulation and help prevent blood clots from forming in the first place. So it makes sense to take it early as a preventative measure even if your COVID symptoms are mild. Warfarin, which started out as a commercial rat-poison in 1948, was FDA approved in 1954 to treat blood clots and was most famously employed to treat President Eisenhower after a heart attack. Like Aspirin, Warfarin is still in use today for the same purpose and just like Aspirin, Warfarin has a very narrow therapeutic dose range in which it acts as a blood thinner. So getting the dosing right is critical.
Cannabis consumption affects blood thinner dosage
(#blood clots) Cannabis interacts with blood-thinners.
By now, you will know that trying to prevent blood clots is a good thing, especially in the context of COVID-19. However, mixing Aspirin with cannabis consumption is not recommended. Research shows phytocannabinoids can inhibit metabolic enzymes of the liver (cytochrome P450) and thus diminish its ability to metabolize drugs like Aspirin. This will affect the dosing of Aspirin and must be taken into account when trying use Aspirin as a blood-thinner. Beyond this, CBD has some serious interactions with Warfarin as well. Due to Warfarin’s narrow therapeutic window, small changes to its blood-thinning properties can increase your risk for a negative outcome. Lastly, cannabis also interacts with heparin which is an even stronger blood-thinner that is only used in a clinical setting as a sort of nuclear blood thinning option. Cannabis enhances its effects which can be dangerous when it leads to excessive bleeding. So the thing to remember here is. Blood clots are bad. COVID-19 causes blood clots. Blood-thinners can mitigate some clotting risks. However, cannabis interferes with that. So, if you test positive for COVID-19 and your doctor prescribes you blood-thinners. Be sure to let them know that you are a cannabis user.
(#cytokine storm) Cytokine Storm, The Dissonant Choir
The second major COVID complication is called “cytokine storm,” and is a result of improper overactivation of the immune system. The cells of the adaptive and innate immune system are tightly regulated and communicate with each other using signaling molecules called cytokines. These specialized molecules allow your immune system to mount and orchestrate the correct response for any given pathogen. Unfortunately, the virus can infect both endothelial cells and immune cells and cause them to send out the wrong signals at full volume. Imagine a gospel choir where every member is singing a different song at the same time and at the top of their lungs. It would be chaotic and dissonant. Even worse, an active immune response left unchecked can damage surrounding tissues. Your body’s ability to regulate or stop an immune response is just as crucial as mounting it in the first place but this requires working communication between the cells. The cytokine storm disrupts that communication, and as a consequence you get massive, uncontrolled inflammation. Where this can get super dangerous and life-threatening is when it occurs in the lung. The infected lung epithelial cells send out this storm of signals that recruit immune cells. This leads to swelling. Swelling happens when the white blood cells exit the blood vessels at the site of infection which makes the blood vessels leaky and fluids collect in the tissue. In the lung this is particularly dangerous because this is where oxygen is supposed to diffuse from the air into your blood. But that type of oxygen diffusion can only happen across very short distances. If there is too much inflammation then there is a lot of swelling and the oxygen won’t be able to cross the added distance. So if you are suffering from COVID-19 and you're experiencing a cytokine storm then your “sudden, bad lung problems” might end with you drowning in the fluids rapidly accumulating in your lungs.
Cannabis can calm cytokine storm in some cell types and make it worse in others
(#cytokine storm) Cannabis is immunosuppressive, can it help?
You may have heard that cannabis has immunosuppressive effects, as it acts on the body via the endogenous cannabinoid signaling system (ECS). This endocannabinoid system is known as a gatekeeper for homeostasis, a self-regulating mechanism by which biological systems return activated cells back to their resting, steady-state. In theory returning cells back to a resting state should help mitigate something like a cytokine storm. But when it comes to cytokine storm there are two players we need to consider. There are the lung epithelial cells that massively contribute to the hyperactive inflammation and then there are the white blood cells themselves that amplify the signals and ultimately effect the tissue damage.So is it wise to use cannabis to treat cytokine storm ? Well, that is a definite maybe. I say maybe, because as is so often the case, we don’t have enough conclusive data in humans yet. There is data to support the idea that cannabidiol (CBD) could indeed calm the cytokine storm in hyperactive epithelial cells. Some of the most recent cannabinoid research that made the splash on social media supports this. However, this seems to only apply to the endothelial cells as the study released in Nature goes on to show that the opposite was observed in white blood cells called macrophages. As previously mentioned, the white blood cells which infiltrated the lung play a major role in the immune response and represent the second component of the cytokine storm story. COVID 19 patients suffering from severe pneumonia often exhibit macrophage activation syndrome (MAS). So, if cannabis indeed makes that MAS worse, then that could be bad. But I am saying “if'' here because we simply do not have enough information to draw any definitive conclusions yet. We need clinical data above all to be able to decide whether or not cannabinoids can or should be used to treat patients with cytokine storm.
Cannabis interferes with vaccines
Cannabis has immunosuppressive properties. Think about that word for a second: “immunosuppressive”. Cannabis can suppress immune responses. At times that can be a really good thing. After all, if an immune response goes on for too long it can hurt quite a bit. You may have a lot of inflammation and swelling and if the inflammation isn’t stopped after a while it will damage your tissue. That would be a really good time for an immunosuppressive agent. But you know what would be a bad time for an immunosuppressive ? When you are taking a vaccine ! At its core the idea of a vaccine is that you show your immune system a “sample/blueprint” of an infectious disease in order to activate your immune system so it can start making neutralizing antibodies against the vaccine target and exponentially build up a pool of memory cells. So when you encounter the real virus you already have antibodies and memory cells and that jumpstarts your immune response and helps clear the infection faster. But if you take an immunosuppressant alongside a vaccine, well then that is like showing your immune system the “wanted poster” of a virus but also telling it. “Bruh, chill. Nothing to see here. You don’t need to remember that. Just relax dude.” Just based on that thought alone you can appreciate that it might be a good idea to take a break from cannabis leading up to and in the days following a vaccination. You’re going to need to give your immune system a couple of days to build some immunity. But if we go beyond this thought experiment into the realm of actual experiments then there is data that shows that THC downregulates TH1-type immune responses via cannabinoid receptor 1 blockade. This is a problem, because we also know that the COVID-19 vaccines like the BioNtech/Pfizer vaccine require TH1-type immune responses in order to provide host protection. In other words, THC containing cannabis can interfere with COVID-19 vaccines. We have another article dedicated to cannabis and vaccines: Should you take a cannabis tolerance break for the COVID vaccine?
Equipped with the knowledge of this article you can now safely move on to part 3 of this series. Where I will discuss the new cannabinoid research that made such a splash in the media during the last couple of weeks.
- Damkier, Per et al. “Interaction between warfarin and cannabis.” Basic & clinical pharmacology & toxicology vol. 124,1 (2019): 28-31. doi:10.1111/bcpt.13152 https://pubmed.ncbi.nlm.nih.gov/30326170/
- MGH News and Public Affairs "COVID-19 and Blood Clots". Harvard Medical School campus resource. Sep. 9 2020 https://hms.harvard.edu/news/covid-19-blood-clots
- Daher, Jalil. “Endothelial dysfunction and COVID-19 (Review).”Biomedical reportsvol. 15,6 (2021): 102. doi:10.3892/br.2021.1478 https://pubmed.ncbi.nlm.nih.gov/34667599/
- Hojyo, Shintaro et al. “How COVID-19 induces cytokine storm with high mortality.”Inflammation and regeneration vol. 40 37. 1 Oct. 2020, doi:10.1186/s41232-020-00146-3 https://pubmed.ncbi.nlm.nih.gov/33014208/
- Hamming, I et al. “Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis.” The Journal of pathologyvol. 203,2 (2004): 631-7. doi:10.1002/path.1570 https://pubmed.ncbi.nlm.nih.gov/15141377/
- Miranda, Kathryn et al. “Cannabinoid Receptor 1 Blockade Attenuates Obesity and Adipose Tissue Type 1 Inflammation Through miR-30e-5p Regulation of Delta-Like-4 in Macrophages and Consequently Downregulation of Th1 Cells.” Frontiers in immunology vol. 10 1049. 10 May. 2019, doi:10.3389/fimmu.2019.01049 https://pubmed.ncbi.nlm.nih.gov/31134094/
- Anil, Seegehalli M et al. “Cannabis compounds exhibit anti-inflammatory activity in vitro in COVID-19-related inflammation in lung epithelial cells and pro-inflammatory activity in macrophages.” Scientific reports vol. 11,1 1462. 14 Jan. 2021, doi:10.1038/s41598-021-81049-2 https://pubmed.ncbi.nlm.nih.gov/33446817/
- Wauters, Els et al. “Discriminating mild from critical COVID-19 by innate and adaptive immune single-cell profiling of bronchoalveolar lavages.” Cell research vol. 31,3 (2021): 272-290. doi:10.1038/s41422-020-00455-9 https://pubmed.ncbi.nlm.nih.gov/33473155/
- Nelson, Kathryn M et al. “The Essential Medicinal Chemistry of Cannabidiol (CBD).”Journal of medicinal chemistry vol. 63,21 (2020): 12137-12155. doi:10.1021/acs.jmedchem.0c00724 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666069/
- Sido, Jessica M et al. “Marijuana-derived Δ-9-tetrahydrocannabinol suppresses Th1/Th17 cell-mediated delayed-type hypersensitivity through microRNA regulation.” Journal of molecular medicine (Berlin, Germany) vol. 94,9 (2016): 1039-51. doi:10.1007/s00109-016-1404-5 https://pubmed.ncbi.nlm.nih.gov/27038180/
- Sahin, Ugur et al. “COVID-19 vaccine BNT162b1 elicits human antibody and TH1 T cell responses.”Nature vol. 586,7830 (2020): 594-599. doi:10.1038/s41586-020-2814-7 https://pubmed.ncbi.nlm.nih.gov/32998157/