Mast Cell Activation Syndrome: The Functional Medicine Approach with Kelly McCann, MD

Content By: Ari Whitten

In this episode, I’m speaking with Kelly McCann, MD, a functional medicine doctor who has lectured all over the world on commonly overlooked causes of chronic illness, such as mold and mycotoxins, Lyme and associated infections, environmental medicine, and, the topic of our podcast, mast cell activation, which, surprisingly, may affect up to 25% of people!

Table of Contents

In this podcast, Dr. McCann and I discuss:

  • The fascinating physiology (and evolutionary history!) of mast cells and why, even though Mast Cell Activation Syndrome (MCAS) is problematic, mast cells are mandatory for proper immune function 
  • The hallmark signs and symptoms of Mast Cell Activation Syndrome, including (but not limited to) allergies, chronic fatigue, and, amazingly, hyper-flexibility 
  • The surprising link between COVID-19, a predisposition for blood clotting, and Mast Cell Activation Syndrome and why some people may have a mast cell reaction while others don’t
  • 2 hidden reasons MCAS might manifest and how to avoid these evasive triggers
  • Dr. McCann’s unique, multilayered approach to treating MCAS, including why the nervous system is such a crucial component of healing…and how a person’s unique personality might help or hinder their progress!
  • Diagnostic criteria for MCAS and the specific approach Dr. McCann and her contemporaries take to recognize and diagnose their patients
  • 3 steps you should take if you suspect you have MCAS, including resources for finding a qualified clinician who can help

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Ari Whitten: Hey, this is Ari. Welcome back to the Energy Blueprint Podcast. With me today is Dr. Kelly McCann, and she is a functional and integrative physician. She lectures regularly all over the world at professional conferences on the subject of Mast Cell Activation Syndrome. She is on the board of directors for two professional organizations. She holds board certifications in integrative medicine and functional medicine. She’s also got a master’s degree in spiritual psychology, and she’s been the host of many previous iterations of the Mast Cell Activation Syndrome Summit, as well as co-host of the Allergy and Asthma Summit.

She’s a wonderful expert on this topic of Mast Cell Activation Syndrome, which affects, as you’ll hear in the podcast, roughly 20% of people. Listen closely to the symptoms. See if maybe this helps explain some of what you have going on, and there’s lots of different interesting areas we delve into here, and some of the root causes of this condition, some of the drivers or the mechanisms behind some of the symptoms, and most importantly, how to get better. Enjoy this interview with Dr. Kelly McCann. Hi, Dr. McCann. Welcome to the show.

Dr. Kelly McCann: Thank you so much for having me, Ari.

Mast Cell Activation Syndrome

Ari: First of all, not everyone is familiar with this term; Mast Cell Activation Syndrome. Can you define exactly what it is and what’s going on in the body that causes this?

Dr. McCann: Absolutely. Let me give you a little bit of information about what mast cells are, first. Mast cells are a normal part of our immune system. They are born related to our white blood cells and our red blood cells. After they’re born, they move to the areas we call of interface between ourselves and the outside world. They line our respiratory tract, our entire gastrointestinal tract. They’re in any of our mucous membranes. They actually have a high affinity for what’s called the perivascular system. They hang out around the blood vessels. They like our nerves. There are some in the brain, in the meninges. Their job is to constantly survey for foreign invaders.

They’re very old. They’ve been around for 500 million years. They’re in humans and vertebrates, as well as many of the invertebrate species. They have been around a lot longer than the rest of our immune systems. They’re the first line of defense for our bodies. When we get an infection, when we get exposed to a toxin, they have a response that happens very, very quickly, where they can release these different packages of information called mediators. The release is often inflammatory or sometimes allergic in nature.

They are filled with hundreds, if not thousands, of different mediators. The packages of mediators that get released vary from person to person, and from organ-to-organ system, and from different tissues. This is their normal job. That’s what they’re supposed to do. What happens in some lucky people who have a genetic susceptibility or whose mast cells decide to become a little bit rogue is they get what’s called Mast Cell Activation Syndrome. When that happens, the mast cells now are starting to perceive things that are not necessarily foreign invaders, like our food, like fragrance, like light or sound, or vibration.

These things can be perceived as foreign and dangerous. Then the mast cells start to release their inflammatory mediators, and we get allergic inflammatory responses in different systems in the body. The definition of Mast Cell Activation Syndrome is actually a clinical definition of multi-system, multi-symptom, inflammatory, allergic, and sometimes growth-related conditions. It’s a mouthful.

The most common symptoms of Mast Cell Activation Syndrome

Ari: Okay, so what are the common symptoms? What would indicate to someone that they actually have Mast Cell Activation Syndrome going on chronically?

Dr. McCann: Really, the key is in the multi-system, multi-symptom. If somebody just has allergies, they probably don’t have mast cell activation. If they have allergies and gastrointestinal issues, and chronic fatigue, and migraines, and interstitial cystitis and asthma, they may want to start to suspect that there’s an underlying link there between these different conditions or these lists of diagnoses that could be explained by Mast Cell Activation Syndrome.

Many people with long-haul COVID, for example, may have a mast cell activation component to their symptoms because we know that it’s an inflammatory, dysregulated state, for example. Other symptoms that can show up in patients who have mast cell activation, they can have autonomic nervous system problems. They could have blood pressure issues like orthostatic intolerance, or they could have postural orthostatic tachycardic syndrome, otherwise known as POTS, where they stand up and the heart rate shoots up, and they feel very uncomfortable and have to sit down. That’s commonly associated with mast cell activation.

We also can see some associations with endometriosis, for example, or other hormone dysregulated issues. We can see issues with hypermobility. If people are extra flexi-bendy, that they can sometimes have issues with Mast Cell Activation Syndrome. Really, fatigue is a very, very common symptom with mast cell patients. People born–

Ari: Why is that? What is the connection between, because this is an immune component that you’re talking about here, this is a response to foreign non-self stuff, this is part of our body’s immune reaction to it? How does this connect to energy levels in your view?

Dr. McCann: I think it’s multifactorial. I think when the body is inflamed, in general, it’s going to cause that fatigue. When we’re trying to fight something, this is the sickness response that we get, right? When you get the flu, what do you want to do? You want to hibernate. That’s because the body sends itself into sickness, cell danger response, and then we want to rest and recover. I do think that fatigue and energy or lack of energy are very, very common presenting symptoms with Mast Cell Activation Syndrome.

Can COVID cause Mast Cell Activation?

Ari: Okay. In your view, is this a true binary of you have it or you don’t? Is this more like a continuum where different people fall in different places on the spectrum as far as being prone to overactive versus underactive mast cells?

Dr. McCann: I absolutely think it’s a spectrum. I have some patients who can eat like 5 or 10 foods, who feel terrible all the time. Of course, we’re getting them better, so they’re starting to feel much better, but their starting place is extremely sensitive. Maybe they can take a handful of supplements if they’re lucky. All their medications have to be compounded because they react to virtually everything. Those are very severe what I would call hypersensitive mast cell patients.

Then I have people who are fairly robust. They may not have any allergy symptoms at all, but they could have more exercise intolerance and fatigue, and chronic viral issues that don’t even look like a mast cell patient. Everything in between. You don’t have to have every system involved in order to have mast cell activation, but it’s multiple symptoms is really the presentation.

There is thought to be a genetic component. There was some research that was done in Germany, and what the literature shows is that these are not necessarily somatic mutations, not germline mutations. People can have a variety of different presentations. The expectation is that it’s about 17% of the population, so 1 in 6 of the population. I do think with COVID, those statistics have increased, and so it looks like it’s more 25% of the population. Now we’re talking about one in four people have some sort of variation of mast cell activation potentially.

Ari: Explain that last part more elaborate, please. You’re saying with COVID, the prevalence of these gene mutations has increased. How would that be?

Dr. McCann: Because COVID is a very toxic inflammatory condition, whether it’s the spike protein. Reaction to the spike protein from either option can trigger mast cell activation in somebody who may have a predisposition. Maybe they were an allergic kid. Maybe they had asthma or eczema as a kid and they’ve been pretty robustly healthy. They may not know that they’re living in a moldy house or that they had a chronic infection that their immune system has previously kept in check. Now you add a flame of COVID to the person who has this underlying susceptibility and it sparks a fire, and that fire we call a mast cell activation.

Ari: Okay. How do you see the causation of this? How does somebody arrive at a place of overactive mast cells? Is that an accurate way of phrasing it? Can we say that this is overactive mast cells?

Dr. McCann: Yes.

The root causes of Mast Cell Activation Syndrome

Ari: Okay, so how do you see the root causes of this syndrome actually developing?

Dr. McCann: I don’t know if we know exactly what’s happening at a cellular level for the trip to happen. What I can tell you clinically is that it seems to be cumulative and some of the biggest root causes are mold exposure. Mold exposure in the vast majority of my professional colleagues’ experience is one of the primary triggers. We know mold causes oxidative stress, it causes inflammation, it can trigger autoimmune conditions, it can trigger allergy symptoms. I think in some people it’s also triggering mast cell activation syndrome. That’s been one of the biggest drivers in terms of a root cause.

Probably the second root cause that I see is Bartonella infection. Bartonella is otherwise known as cat scratch fever. It’s related, it’s lumped together with Lyme disease even though they’re not always seen in tandem. We can see Lyme disease without Bartonella and vice versa, but that tends to be a very big trigger. Again, those mast cells, their job is to survey for foreign invaders. They’re seeing these foreign invaders and having that triggered response. I don’t know why exactly it’s happening. I don’t know if we have the details of why that happens, but that’s clinically what myself and my colleagues are seeing.

Ari: This often translates into a loss of immune tolerance where someone stops being able to tolerate lots of other things. Like you described earlier, people being limited with their diet to only a handful or a dozen foods, or something and not being able to tolerate other kinds of foods or various supplements, having very negative reactions to that, presumably because of their immune system being overly reactive to these substances that it should be able to tolerate, but it’s now reacting to them as though they are pathogenic foreign substances.

What’s going on there? Can you take me deeper into understanding why the body loses immune tolerance?

Dr. McCann: Because it’s seeing those as foreign invaders, the mast cells are degranulating and releasing inflammatory mediators. These inflammatory mediators may be histamine, they could be other cytokines or chemokines. The combination of things, as I mentioned, it varies from person to person and tissue to tissue. When we have an increase in our inflammatory mediators, it gets really uncomfortable. When you have an overabundance of histamine, you can have skin reactions, you can have gastrointestinal distress reactions.

For example, if somebody is eating foods that are high in histamine, and they have mast cell activation syndrome, and they may have a histamine intolerance where they don’t have adequate enzymes to break down the histamine, they’re going to feel flushed, they may develop hives, they could get diarrhea, they’re going to have abdominal pain, they could have gas and bloating. Those symptoms are so uncomfortable that they’re not going to want to eat those foods. That’s the loss of tolerance.

There definitely are some things that we can do to help restore that tolerance. It’s multifactorial. Though I think that there are layers. It’s like there are symptoms, there’s causes, there’s triggers, and these are all interweaving together to create that picture that the person is experiencing.

Ari: Got it. Is there any understanding of the underlying physiology of loss of immune tolerance and regaining immune tolerance? What are the needle movers as far as that? When we consume food, for example, I just drank a smoothie here with some matcha green tea powder and some bananas. These are non-self substances.

Dr. McCann: Correct.

Ari: These are not substances that are part of my cells, and yet my immune system can tolerate them and recognizes them as nutrients, as food that’s beneficial for my body. Whereas other people with differently wired immune systems might react to those same substances and the immune system attacks them.

Dr. McCann: Right.

Ari: What is going on with what’s influencing the immune system to behave one way versus another?

Dr. McCann: Well, the body starts to see these allergies– so I’m not an allergist, right? The idea is that mast cells can be triggered by IgE mediated reaction, so true allergy. The allergen, the body makes IgE antibodies to an allergen, they match up, and then that combination of things triggers a receptor on a mast cell, right? Now, if it’s non-IgE mediated, it could be IgG mediated, it could be another cell or another molecule in the immune system combining with that receptor to cause degranulation of the mast cells. Then you get all the symptomatology.

In your mast cells, you’ve got all these mediators, you also have a whole host of receptors on the mast cells as well. There are corticotropin-releasing hormone receptors on the mast cells. Stress can trigger mast cell degranulation if you have extra cortisol running around. If you have different kinds of cytokines and chemokines, IL-6, TNF-alpha, those things also have receptors on the mast cells. Those inflammatory mediators themselves can trigger mast cell degranulation. It’s multifactorial and multilayered physiology that’s happening.

Ari: It’s almost like the biochemical milieu of the body, inflammatory cytokines and perhaps different toxins and psychological stress is creating a hypersensitivity or an overactivity of these mast cells where they’re much more prone to degranulating more easily.

Dr. McCann: Correct.

How to treat Mast Cell Activation Syndrome

Ari: Got it. What do treatments look like? How do we start to reverse this and recover from it?

Dr. McCann: Lots of different ways. Super important to look at the causes, the root cause it is, of course. When we’re talking about helping stabilize those mast cells, we have a variety of different tools in the toolkit. If histamine and allergy is a common presentation for somebody, we can use things like over-the-counter antihistamines. That would be Claritin Zyrtec, Zyzol, Allegra. Those are H1 blockers. We can also use H2 blockers like Pepcid. Which medications and which combination of medications work best for people depends on an individual.

We never really know what’s going to be most effective for people. Sometimes patients need, two and three times the amount that is regularly prescribed. Oftentimes, we’ll start with something like that. There are leukotriene inhibitors, things like Singulair. Leukotriene is an inflammatory mediator that is commonly released by mast cells. We can do things like aspirin, which are going to block prostaglandins in some patients.

There are lots of different pharmaceuticals that are out there. Some work great, some not so good. There are some more targeted mast cell medications, things like cromolyn. Cromolyn was an old-time medication that was typically used for heartburn type symptoms. It coats the gastrointestinal tract and it provides a barrier between the mast cells in the mucosa and the food that’s going down the GI tract. That can sometimes help patients. There’s a compounded prescription called Ketotifen, which I love a lot, that works really well to help stabilize those mast cells.

Then there’s boatloads and boatloads of different kinds of supplements, things like quercetin, luteolin, Vitamin D even can have some mast cell stabilizing effects. Pycnogenol, quercetin, I mentioned that, turmeric, resveratrol, the list goes on and on. In preparation for my mast cell summit last year, I looked at the literature and there was probably at least 65 different nutraceuticals that can help stabilize mast cell. Oftentimes, we’ll use them in combination.

We can use DAO enzymes to break down histamine in the gastrointestinal tract. We can use different kinds of low histamine probiotics to help stabilize things. A lot of different tools in the toolkit for stabilizing mast cells. Because of the unique presentation of each individual person, we have to find the combination that works for that person. That’s stabilizing mast cell. Then we need to deal with the nervous system, but I can answer that question next.

Ari: Okay. Yes, let’s go there. Stabilizing mast cells is number one, just decrease the amount of mast cell degranulation, bring symptoms down. Then you’re now taking on the next layer of trying to go deeper into the root causes of the physiology that’s driving this.

Dr. McCann: Yes. Actually, before I even go to root causes, I do want to talk about what I think is the role of the interplay between the immune system and the nervous system. What happens when people find that they’re reactive to so many things, is that they become more and more fearful and worried about ongoing reactions. The longer people don’t feel well, the more trauma and upset, and worry they have about the fact that they are not feeling well, the more dysregulated the nervous system gets as well.

We find that in patients who have mast cell activation, they also have limbic system activation. Limbic system is the ancient part of the brain that takes our emotions and turns them into memory. If we don’t deal with the limbic system activation piece of the puzzle for patients with mast cell activation, we don’t get them fully better. I’m not going to get you better on Zyrtec and Pepcid, and a bunch of Quercetin. We really have to help the nervous system find a place of safety because the mast cells and the nervous system now perceive the world as a very dangerous place. Retraining the limbic system is also key to helping people recover. Then the third piece is really–

Ari: Real quick question. Actually, the autonomic nervous system probably ties in. I’ll let you complete before I ask that.

Dr. McCann: Okay. Autonomic nervous system, that’s the part of our body that enables us to digest our food, our heart to pump, our blood pressure to be regulated without us having to think about it, right? It’s also the part of the nervous system that either puts us into fight or flight, or freeze, or can help us be in parasympathetic or rest and digest. Truly, we can’t heal unless we’re in the parasympathetic nervous system. Again, when you feel terrible all the time, you’re usually stuck in the sympathetic overdrive, either fight or flight, or freeze.

A lot of people have not heard about the freeze response and they don’t recognize that that is part of sympathetic overdrive. Fight or flight, we understand we’re running away from the bear or we’re fighting the bear. With freeze, we’re standing still. We’re hoping that the bear ignores us. Usually, this can overwhelm as depression, as fatigue, again, an inability to move forward. Many people who are chronically ill bounce back and forth between fight or flight and freeze, fight or flight and freeze.

The truth is we have to get into parasympathetic in order to heal. Vagus nerve stimulation devices that get us into that parasympathetic rest and digest sense of joy and safety is where we really need to help patients get in order to heal.

Can stress affect the Mast Cells?

Ari: You describe both of those things, the limbic system and the autonomic nervous system, being shifted towards sympathetic overactivation. From the starting point of a person feeling bad first and then going into sympathetic overactivation or limbic system overactivation. I wonder how much is going on in the other direction, meaning especially because you spoke earlier about psychological stress contributing to mast cell overactivity or increased susceptibility for degranulating. How much do you think is explained by personality types that are prone to chronic psychological stress?

For example, in chronic fatigue syndrome, there’s a body of literature, and in clinical burnout syndrome and stress-related exhaustion disorder, there’s a lot of research linking self-critical perfectionism, that personality trait, to a propensity for these conditions. Meaning you can have a type of personality that maybe leads to a chronic level of, baseline level of overactivation of cortisol or other stress hormones. You can have a type of personality that’s more or less prone to chronic psychological stress. I’m just wondering how much you perceive maybe mast cell activation to overlap with personality types who are more oriented in those directions.

Dr. McCann: I don’t know of any literature that has linked those, Ari, but I absolutely see this in the patients. I think that we can talk about genetics, but my beef with conventional medicine is that we only deal with the physical body. Even in my discussion so far, I’ve only talked about the physical body, right? We’re talking about the immune system and the nervous system. The truth is our minds and our bodies, even our spirit, our being are totally connected. Who we are as people, how we talk to ourselves, what we believe about ourselves absolutely plays a role.

That is part of the healing journey too. I can’t ignore that if I’m actually going to get somebody 100%. Maybe we get 40% to 50% better doing simply biological mast cell stabilizing treatments, and then we’ll get a few more percentage points improvement. Maybe we get to 70% or even 80% improvement. If we don’t deal with the psychology, with the personality traits, with the way people are and how they perceive themselves in the world, if we don’t deal with that, we won’t get them 100%.

Let me tell you a story. I have a mold and mast cell patient. When he first came in, he was probably 15, 20 pounds underweight. He looked gaunt, gray. He had scabs all over his head because he was so malnourished and so inflamed. We worked really hard to get him better. He had to move out and remediate, and get rid of all of his belongings. There was a lot of steps, lots of supplements and IVs. Eventually, he got to the point where now he’s running 7 to 10 miles a day. He’s doing two and three-hour yoga classes. He feels great. He looks great. He’s gone back to work.

Then it started raining in Southern California. His job site was a flat roof building, and there was mold in the building. Then he got mold exposed also in his apartment and he got sick again. He got to the point where he was so sensitive, he would not be able to go into buildings because any building that had any sort of chemical, any mold exposure, he was terrified. He was living in a tent in his backyard and he was miserable.

I finally said to him, I’m like, “Look, you know what? We did all the physical stuff and we got you almost all the way better, but we never addressed the mental, emotional, spiritual side of why you got sick in the first place. That’s where we need to go.” Since addressing that, he’s now 80%, 90% better and really making huge strides at not only becoming a healthier person physically, but becoming a full and happy human being who has joy in his life, who has purpose in his life.

Can exercise help recovering from Mast Cell Activation Syndromee

Ari: Yes, beautiful. Debating which direction we should go from here. I’m curious, have you stumbled across any research on exercise or are you personally aware from your experience with patients of the role in exercise or lack of exercise in creating a propensity for Mast Cell Activation Syndrome, or the role of doing exercise and recovering from it?

Dr. McCann: I haven’t. I do find that most patients who have mast cell have difficulty exercising because heat often triggers mast cell degranulation. Sometimes sweating triggers it too. It’s another thing that people often become limited by– Oftentimes, they’ll develop some–

Ari: Can you repeat that one more time? You cut out there for a sec. I just want to make sure we got it.

Dr. McCann: Oftentimes when people have Mast Cell Activation Syndrome, they also have a lot of fatigue. They may have exercise intolerance. We’re really working with that energy envelope and trying to make sure that they are not overdoing it, causing flares in their symptomatology. Exercise is tough for some people. It gets layered in much later than my patient that I was just sharing about. He didn’t start out being able to run 7 to 10 miles. He could barely come into the office. That it definitely took, I don’t know, two or three years for him to get to that point. It was a slow, steady, incremental thing. I don’t know of a lot of literature looking at exercise in mast cell activation. That’s a good question.

Ari: One of the things that comes to mind for me, my background being in exercise physiology, is there are adaptations that take place with exercise that, there’s many, and it depends on the types of exercise that you do, but it’s not just limited to muscles growing stronger or the cardiovascular system making adaptations to grow a bigger ventricle or something like that.

Some of the adaptations are more biochemical in nature and the autonomic nervous system is involved. The inflammatory cytokines are involved. Cellular defense capacities are involved. The immune system is heavily involved. There’s a paradoxical or counterintuitive nature to this, because as you said, exercise can also be a trigger. I would bet that the adaptations induced by exercise are also protective against things that are triggers for it.

In other words, it’s inducing adaptations that increase the buffering capacity and probably help stabilize mast cells and make them less prone to degranulation from a number of triggers, as long as presumably one does the exercise regimen in a way that doesn’t create more triggers in the first place. Meaning you do a dose that’s appropriate for that individual at that point in time.

Dr. McCann: Yes, it’s a great point. I will make sure that I include more incremental exercise to help build resilience in treatment plans. Thanks for that, Ari. Some of the things that we may want to talk about, and I’ll let you guide this, but I also think that there’s an interesting relationship between mast cell and clotting, and hypercoagulability. I don’t know if you want to go there next as a possibility.

Ari: Please, yes, tell me about it. I don’t know anything about it, so educate me.

Dr. McCann: Okay, hypercoagulability is the fancy medical term. We also call it clotting. The body is a beautiful balance. We want to be able to clot when we cut ourselves and we want that clot to be dissolved. The fancy term for dissolving a clot is called fibrinolysis. We want the clot to dissolve or be lysed when the healing has happened. Again, COVID really brought this whole idea of clotting to the forefront because so many people who had COVID issues often died of microclots, and there was really not a lot of great understanding as to why. It turns out that [inaudible 00:37:13] triggers the clotting cascade. When you cut–

Ari: Say that one more time, you cut briefly there. What triggers the clotting cascade?

Dr. McCann: Inflammation. Inflammation triggers the clotting cascade to occur in people who have a propensity to make clots. I’ve been recently looking at this in greater detail in my patient population. Now, I have a functional medicine practice. I have a lot of mast cell patients, but not everybody is a mast cell patient. Some people have cancer, some people have autoimmune conditions, I have a variety of different patients. Some have Lyme disease, and I’ve been doing genetic testing looking for clotting disorders in patients. I have found that probably 85%, 90% of my patients have some sort of genetic predisposition for clotting. That’s huge.

Now, statistically, it looks like it should be more like 20% in the population. Of course, we just said that mast cell activation is 17% to 20%. Maybe there’s some weird overlap there. If we think about clotting and energy, oxygen delivery, nutrient delivery, if you have sludgy blood, right? You can’t really carry oxygen or nutrients to the tissues very efficiently as somebody who doesn’t have sludgy blood, right? That’s my very official medical term, sludge. Sludgy blood, or sticky blood, right?

I do think that there’s a relationship between this increased inflammatory response that people are having, whether it’s mast cell activation or exposures to environmental toxicants that can be leading to a sticky, sludgy blood situation that would potentially manifest in different impacts in their health. Oxygen carrying capacity, nutrient delivery to tissues. That’s important to know about.

Ari: Okay, so the hypercoagulability you think predisposes to mast cell overactivity.

Dr. McCann: No, I’m not saying that. I’m not saying that. I’m saying that genetic predisposition to clotting sets somebody up to have more problems with an inflammatory response, whether they have mast cell activation or not.

Ari: They’re going to get more severe symptoms from mast cell activation.

Dr. McCann: Correct.

Ari: Okay.

Dr. McCann: Correct. Say somebody just gets COVID and they have an underlying predisposition for clotting. They may not shift into mast cell activation, but now they have an inflammatory response because of COVID or the flu, or whatever, and now they have sticky blood. They may have a harder time recovering. They may have more significant symptoms of not just hypoxia, like inability to get oxygen to the lungs, but inability to get that oxygen to the tissues because of something in terms of health and energy would be important to know about.

Ari: Is there something on the practical level, like dealing with patients who have that once you’ve identified, okay, you’ve got a genetic predisposition to blood clotting and hypercoagulability. Therefore, in this situation of you’ve got mast cell activation syndrome and you have this genetic predisposition to clotting, we’re going to use anticlotting. We’re going to put you on fish oil or we’re going to put you on medication to thin the blood or something like that. What do you do on a practical level in that situation?

Dr. McCann: There are specific kinds of enzymes. We call them fibrinolytic enzymes. You probably have heard of them, things like nattokinase or lumbrokinase. Those are probably the best things for this sticky blood situation. Whether somebody just has the genetic predisposition or they have markers that show me that they’re actually making more fibrin, which is the building block of a clot, and having difficulty breaking that fibrin down. There are biomarkers that we can look at in blood work that will help guide my choices.

If they have the genetic predisposition but no evidence of current hypercoagulability, I’ll probably put them on nattokinase. If they have obvious signs of sticky blood or biomarkers that are elevated, then I’ll put them on lumbrokinase. In particular, I like a product called Boluoke. It’s interesting that some people have– There was a recent article written about long-haul COVID and using as a foundation, nattokinase, bromelain, and curcumin for treatment of long-haul COVID. Well, those are mast cell treatments and coagulation treatments as a patient.

Ari: Yes, I saw that study that you’re referring to. There’s a protocol, I think, that several physicians are now promoting for that, where it’s the protocol of those compounds that you just mentioned that seems to have a lot of efficacy in those long-COVID patients. Are there–

Dr. McCann: This is why [inaudible 00:43:37] [laughs].

Ari: What’s that?

Dr. McCann: This is why. This is the explanation as to why those specific nutraceuticals are helpful.

Can long-COVID be connected to Mast Cell Activation?

Ari: What do you think is going on in long-COVID? I know you mentioned the spike protein earlier, and you were also very cautious in your language around the different ways that people can get lots of spike protein in their body. What’s your best guess? I haven’t really kept up with the latest literature and thinking on the physiology of long-COVID, but what do you think is going on there?

Dr. McCann: My sense is that it is often a Mast Cell Activation Syndrome that gets triggered and can be all the things that we’ve been talking about so far today. I will share with you, up until recently, I had one long-COVID patient. I had no deaths amongst my patients. I had no hospitalizations amongst my patients because we were doing all the things. We were treating the mold, we were treating the Lyme, we were treating all the root causes, and then using preventative treatments, using aggressive outpatient therapies to help keep people safe.

Now I have more long-haul COVID patients because people are coming into the practice, and I do think it’s a combination of these sorts of ideas. They could have been, like I mentioned, in a moldy house and previously healthy, and tolerating the mold that was there. They could have had a chronic infection like Lyme disease, but they didn’t know it until you add that inflammatory event of COVID, and it just flips switch and now they can’t recover of the immune system bomb that just went off in their bodies.

Testing for and diagnosing Mast Cell Activation Syndrome

Ari: Yes, very interesting. Are there any other more medical aspects that people should be aware of when it comes to Mast Cell Activation Syndrome? Any other aspects to this that affect a subset of people or are important to test for and to address?

Dr. McCann: Let’s see. I can talk a little bit about testing to get a diagnosis. Does that sound like you–

Ari: Yes. Absolutely.

Dr. McCann: There are two camps with the diagnosis of mast cell activation. One camp, my colleagues and I call Consensus 1. These are going to be your conventional allergists and immunologists. They have a very strict criteria. There’s one marker called tryptase. Tryptase is a rough measure of the amount of mast cells that people have in the body. Their diagnostic criteria is you have to have a baseline tryptase that gets elevated a certain percentage when you have a flair. If you don’t make those criteria, then you don’t have mast cell activation.

Very rigid, narrow definition that excludes a lot of different patients who might not have tryptase or might not be able to capture the difference between a flair and normal that is any degree different for a lot of these patients. I am in the Consensus 2 camp along with Dr. Larry Afrin, Dr. Theo Theoharides, Dr. Tana Dempsey, et cetera. There’s a whole host of my colleagues, and we wrote a Consensus 2 paper. I was one of many different other [laughs] co-authors on this paper that outlined the criteria that’s much broader that really takes into clinical experience and clinical presentation to meet that diagnostic criteria.

In addition to the clinical criteria, there are also laboratory values that we can look at beyond tryptase, including histamine levels, heparin levels, Leukotriene E4, Prostaglandin D2. These markers give us a rough idea as to what the activity of those mast cells are. Again, I told you that there are hundreds, if not thousands of mediators, and we can test for half a dozen. The likelihood of getting a positive test can be pretty low for people.

Ari: What you’re saying is we know everything there is to know about it, and we can test for everything perfectly?

Dr. McCann: Spot on. Exactly. We love getting laboratory values and having that definitive diagnosis. For some patients, that’s really necessary. I vacillate back and forth between, okay, let’s do some more diagnostic workup, and then let’s not worry about it because it’s ridiculously expensive and we might miss the mark on a regular basis. I do think it’s important for patients out there if they do suspect that maybe mast cell is a component. You want to make sure that you’re going to find somebody who is more consensus to you, who’s going to listen to you, who’s going to have more tools in their toolkit, who’s going to look at root causes, and not dismiss you and gaslight you.

Ari: Yes, it’s always important, I think, with most things these days. What does the differential diagnosis look like in terms of let’s say someone comes in complaining of these types of symptoms that you’re talking about, you might suggest doing those types of tests to determine, okay, it’s Mast Cell Activation Syndrome, or it’s this, this, or this.

Ari: What’s the this, this, or this in the case of this scenario?

Dr. McCann: Well, one, you could have mastocytosis, which is pretty rare. Mastocytosis is an overabundance of mast cells that’s actually a form of cancer and it’s probably 1 in 10,000 epidemiologically. Really, really rare, but possible.

Ari: 1 in 10,000 cases of this type of symptoms, or it’s 1 in 10,000 cancers?

Dr. McCann: 1 in 10,000 people is how frequent that exists. For example, I have one patient with mastocytosis in my practice, and I’ve diagnosed him because I knew about mast cell activation. We happened to check a bunch of markers and his tryptase level was 80. Normal is less than 12, and so repeated that a couple of times and sent him off to the oncologist, and there you have it. All of his symptoms were very similar to mast cell activation, so that’s one possibility. Very rare. There are some genetic elevated tryptase, so it’s called alpha hyperemia, which again, pretty rare.

Most people who have Mast Cell Activation come in with a laundry list of other diagnosis. They might have migraine headaches, endometriosis, interstitial cystitis, they might have fibromyalgia, they might have ME/CFS, they might have, irritable bowel symptoms, they might have SIBO, they might have an autoimmune condition, any neurologic degenerative disorder, they could have some dementia or brain fog, they can have Lyme disease, they can have, toxic mold exposure, and there could be a mast cell component in any number of those things.

It’s really on the part of the clinician to have that suspicion that, “Hey, you’ve got all these things and all these different systems of the body. Maybe there’s something that’s underlying all those things.”

The next step

Ari: What would you say is the most important thing that people should do if they suspect that they have this going on based on the symptoms that you’ve described and based on everything we’ve talked about? What should be step one, “Okay, this sounds like me, what do I do now?”

Dr. McCann: A couple of things. We can boil it down into really simple things. We want to deal with the symptoms and we want to look for root causes. Then of course, you want to find somebody to partner with to help you through all this because it’s not a straight path by any stretch of the imagination. In terms of looking at the symptoms, you could start with some basic antihistamines. You could start to think about what are things that are triggering me? What could be making me feel worse? Avoiding the things that are triggering you and trying some of the over-the-counter stuff that’s really simple.

You could try some of the supplements. Then you bring that information to the provider and say, “Okay, well this worked and this didn’t, and this worked and maybe I got like 10% better with this.” Sometimes that’s what we’re looking for is we’re looking for, are you a little bit better? Actually, the first thing that we look for is, did that make you feel worse? Okay. If it made you feel worse, stop. If you don’t notice anything, great. We’ll keep [inaudible 00:54:13] benefit. Fantastic, we’ll stay on that. If you don’t see a benefit, then we let it go too, because obviously, we want things that are helpful.

Then in terms of looking at root causes, since mold is a big one, does your house smell moldy? Have you had a water leak? You have to go down that pathway and think about the possibility that mold in your home or in your office space that you were exposed to could have set things off. Then looking for a provider, that may be a little bit trickier, but there are a couple of professional organizations that I’m affiliated with that would be a good place to start.

One of them is the International Society for Environmentally Acquired Illness, You can look for a practitioner through that organization. There’s also an organization called the American Academy of Environmental Medicine, so that’s They’ve been around since 1965. The original practitioners who founded AAEM were often allergists, ENT doctors who were taking care of patients, and they were like the grandfathers of functional medicine.

They called themselves environmental medicine doctors. They dealt with a lot of patients with chemical sensitivity. They have a lot of tools in their toolkit to help modulate the immune system to calm people down. Those are some great organizations that might have resources and practitioners for patients.

Ari: Wonderful. Any final words you want to leave people with and let people know where they can get in touch with you, work with you, or follow your work, wherever you want to send them?

Dr. McCann: Okay. I think the most important thing to take away from this is that there is hope, and there are lots of tools and resources to get people better. I never accept that this is your diagnosis, therefore, this is your life. We just need to find the right keys to unlock the locks that have gotten triggered and are not working, not functioning optimally. It’s going to be a journey and you’re going to have to participate. If you’re willing to do the work, you are absolutely going to get better. That’s the most important thing.

Then in terms of working with me, I do have a clinic in Southern California. I’m accepting patients. You can find me at I do see patients from other states, but they do have to come to California based on where I’m licensed and do follow-ups. I’m also on Instagram @drkellymccann and Facebook. I have recently co-hosted a Mast Cell Activation Summit with Beth O’Hara. You can find more information on my personal website. That’s

Ari: Thank you so much, Dr. McCann, for coming on the show, and I look forward to speaking with you again.

Dr. McCann: Thank you so much for having me, Ari.

Show Notes

00:00 – Intro
00:45 – Guest intro
02:02 – Mast Cell Activation Syndrome
05:21 – The most common symptoms of Mast Cell Activation Syndrome
08:20 – Can COVID cause Mast Cell Activation?
11:57 – The root causes of Mast Cell Activation Syndrome
19:50 – How to treat Mast Cell Activation Syndrome
27:00 – Can stress affect the Mast Cells?
32:29 –  Can Exercise help recovering from Mast Cell Activation Syndrome
46:19 – Testing for and diagnosing Mast Cell Activation Syndrome
53:03 – The next step


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