Mast Cells and MCAS in complex illness: understanding and treatments

Emily Kate Stephens (0:07): Welcome. I hope that you're all having a reasonable day. This week, I have the pleasure of bringing you an interview that I recorded in person with Dr. Theoharis Theoharides in Florida, where he is now a professor at the Institute for Neuro-Immune Medicine at Nova Southeastern University in Clearwater. He has over 40 years' experience researching mast cells, calling himself the mast cell master. I went to him for an overview of what these cells are responsible for in our body, how they might be contributing to these invisible illnesses, looking at the crossovers, discussing better diagnostics, and considering how we might inhibit their activation, preventing these allergic-like symptoms from taking place, rather than treating it after the fact. I hope that you enjoy it, Dr. Theoharis Theoharides, thank you so much for joining me today.

Theoharis Theoharides (1:58): Perfect. You are probably the only person that just pronounced my name perfectly. I go by Dr. Theo for sure.

Emily Kate Stephens (2:04): Dr. Theo, it is such a pleasure to actually be here meeting you in person. Thank you. Likewise, what a joy! Really, what I would like to focus on today is one of the things that I ask our audience for every week is for feedback and to tell us what they need more information about, and I have had a lot of people asking me about mast cells, mast cell activation syndrome, but for an explanation of what this is, and so of course I came to the mast cell master. I think this is one of those symptoms. Possibly, people are feeling it as a symptom. This mast cell activation in Long Covid that's therefore got more prevalence than it had previously. But I think that it's possibly something that is fairly underrepresented or misunderstood amongst the general population, and I'm not just talking about patients. I'm talking about physicians as well, because I know that you have talked historically about how people approach their physician with a certain condition, and you have the understanding that perhaps that is mast cell activation.

Theoharis Theoharides (3:23): Well, couldn't be a better time to be having this conversation because I was actually invited to write a review on mast cell activation comorbidities and lookalikes, and I'm 90% through. In fact, I'm finishing it up downstairs.

Emily Kate Stephens (3:43): Right.

Theoharis Theoharides (3:44): I'm raising a lot of the issues that I'm sure you have in mind, and many of those in your audience have in mind. So let me start by the fact there are many misnomers. So we talk about allergies, atopic diseases, mast cell activation unspecified, mast cell activation syndrome, conditions with mast cell activation, atopic inflammation, and the list goes on and on. So, the scientific, the medical community has just not gotten it together as of yet to really define what we're talking about, and of course, patients are left scratching their heads as to what do I really have? In a month or so, I'm giving a lecture about mast cell activation in multiple chemical sensitivity syndrome that seems to be just like mast cell activation, and in fact, I think it is. And I'm not suggesting we change the nomenclature necessarily. We don't really have to rediscover the wheel about what is the basis for many of these conditions,

Emily Kate Stephens (4:43): But we need to gain that understanding that they might possibly all have the same basis.

Theoharis Theoharides (4:47): So about 15 years ago, I actually taped an episode out of the blue. I was actually giving a lecture in Copenhagen, and two patients approached me, and they had complex problems along the lines of what we're discussing, so we created an episode which is on YouTube and it's called "My Mystery Symptoms and Mast Cells. So there was no question then, and there's even more no question now that the mast cells are everywhere. So let's start with the fact that they're everywhere, they're in every tissue in the body, especially tissues exposed to the outside, like eyes, nose, mouth, lungs, skin, gut. They're also inside the brain, and in fact, that critical part of the brain that connects the hypothalamus that regulates everything in our body, with a pituitary that releases all the hormones in the body, it's called the median eminence. It's a little stalk connecting the two, has more mast cells per unit volume than our skin. Yet our brain doesn't get allergic reactions. We used to think that the mast cell, which has 1000 secretory granules, can store and release about 100 molecules. As of about a year ago, now we're to 350 molecules that can release, and yet we're still dealing only with histamine and maybe leukotrienes that constrict the bronchi. We're at a loss about how those other molecules are released, when they are released, and to make things even worse, if we were to assume that a mast cell will be triggered by a particular trigger, whatever the trigger might be, the first hormone released under stress, called corticotropin releasing factor in Europe, or corticotropin releasing hormone CRF or CRH in the states resets the reactivity of the mast cells. That means that individuals that might have had some history of allergic-like problems-let's call them that for now-they undergo a major surgery event or car accident. God forbid, someone dies in the family, and now they're allergic to everything. Quote unquote allergic. So we know that the mast cells are not static, and they will respond to pretty much anything. And there's no question from work other colleagues have done that they respond to pathogens. There can be bacteria, there can be fungi, there can be viruses, and not only they stimulate the mast cells, but they themselves reset the reactivity of the mast cells. Hence, people that might have been down with Covid, for instance, now they have all kind of symptoms that are reminiscent of activation of the mast cells.

Emily Kate Stephens (7:39): And I think what's interesting there is in the things that you mentioned is you're not only talking about something that infiltrates the body in a pathogenic way. You also mentioned you said, God forbid, someone dies in the family. So you're talking about psychological impact, the trauma in that sense, and not differentiating that against a physical,

Theoharis Theoharides (8:05): Not at all. Both physical and emotional stress will release those hormones, especially CRF. The difference is that while, for instance, someone who had, let's say, eczema, which is more allergic type, might undergo a mental stressful event, and now they're kind of will be covered with eczema. We've seen hundreds of patients like that. But what we're entering now an era where the triggers are hidden. So if someone, let's say, were sick with Covid or they had mononucleosis at some point, and now we have viral reactivation, and that will trigger the mast cells. And now they might either respond to triggers that had been quiet for a very long time, or new triggers are showing up now.

Emily Kate Stephens (8:51): Does it always tend to be one big trigger, like a Covid, like a virus, or that kind of analogy of a glass of water, and you add a bit more, and you add a bit more. So, can the do the mast cells operate in that way? So you have a virus, and then you have emotional trauma, and then you have something that you were already triggered by. Maybe it's a chemical, maybe it's a cleaning chemical.

Theoharis Theoharides (9:24): No, I agree with you. Eventually, just the glass overflows. It's just that if there is a distinct event, it's easier for a patient to understand it and convey? Let's say to a physician, "Oh, I remember that everything started after that. And as you said, that can be an incident after an incident, eventually leading out.

Emily Kate Stephens (9:44): So it can be those small increments.

Theoharis Theoharides (9:46): In medicine, we always look for triggers because it's easier to say, "Well, there is a trigger, but we don't really look for inhibitors. I mean, my mast cell is on fire; yours may not. So why? It may be that you're exposed to triggers, but there are individuals who've never been exposed to any trigger that I can put my finger to, and yet they respond. So, if we were to look for possible inhibitors in our body, in general, in medicine, we don't have that many inhibitors. We have a couple of molecules that inhibit enzymes that break down proteins, so alpha-2-macroglobulin, alpha-1 antitrypsin, but that's about it. So, and I don't believe nature, you know, God over 300 million years didn't actually endow us with some inhibitors. So, one of our major efforts is to identify why we are not looking for possible inhibitors. Give you an example. We had done a small experiment a long time ago, but it was n equals one. One particular experiment, so we couldn't really publish it. Where we took blood from an individual about 26 years of age, female, working in my lab, with your permission, of course, and blood from an individual that had severe mast cell problems. Okay, and we culture mast cells in the laboratory. So what we did is we removed half of the medium we put in the tube that we culture the mast cells, and in one instance we replaced with a medium from the normal individual, quote unquote normal, and the other with a person with mast cell problems, and then we stimulated the cells with a neuropeptide called substance P. Well, the cells in the medium of the otherwise normal individual fired less, and the ones in the mast cell sort of person fired much more. But there was nothing else; same trigger. So something in the blood of the otherwise normal individual was preventing the stimulation, and in the other instance was actually making the stimulation worse.

Emily Kate Stephens (11:40): So is that suggesting that people that get this mast cell activation or this flood of mast cells, however we want to call it, this kind of reaction are lacking that inhibitor in their body?

Theoharis Theoharides (11:56): That's what I'm implying. That we have to deal with a balance, the triggers, and then the possible lack of innate inhibitors, and I think they're both true, except that until now no one has actually uncovered an innate internal inhibitor of the mast cells, and I've spent my last 40 years looking for one, and I'm still looking. In fact, I have some clues as to what might be possible.

Emily Kate Stephens (12:19): Right.

Theoharis Theoharides (12:20): In nature, there are ways for us to potentially look for such. For instance, lizards have lots of mast cells; they don't get allergic reactions. Same goes for fish. Sharks, where, you know, you don't get allergic reactions; they have lots of mast cells. So obviously, number one, they're doing something there other than succumbing to allergies, which they don't get, or they're prevented from doing that. So I think the science we might get back to this is somewhat misguided in the way we approach solving problems. So number one, we still don't understand the function of the mast cell, other than in this type of reaction that we're talking about, number two, we're not looking for possible inhibitors, and there's no way that science will come up with drugs that block every one of the 350 molecules that are released from the mast cells. That's why we only have antihistamines and maybe a couple of anti-leukotrienes. And

Emily Kate Stephens (13:20): It's actually those molecules that are released from the mast cells that are the problem, rather than the mast cells themselves. Can you talk to me about that process of the way in which the mast cells impact the body, the route that they take?

Theoharis Theoharides (13:37): Depending on the trigger, different things will come out. If you're unlucky and you get into anaphylactic shock, the mast cell will explode like a hand grenade and release pretty much everything. And you know, unless we act quickly, you're doomed. If you're allergic to something specific, like a food or pollen or something, we know what the trigger is. So either you avoid the trigger, or we do what we call immunotherapy. We kind of get your body used to that trigger, and eventually the body says, "Ah, I need to bother anymore.

Emily Kate Stephens (14:08): Is that the sublingual tiny drops?

Theoharis Theoharides (14:09): Yes, yes. But you know, you can't do it 100 different things. You do one, two, three. However, are very important. Then we're left not knowing what triggers. So if I scratch someone's underarm or the back, and all of a sudden, in one minute, I get a red line where I scratch. That means that the mast cells in the skin reacted just to the pressure. And in fact, most of the patients I deal with, they have complex issues that relate to the mast cells, do get that red line, and we call that dermatographia. That's the quickest way to find out that the mast cells in that person's body are ready to fire, and who might not know the triggers. Now, once they release, some molecules are released and destroyed very quickly. Some molecules linger on for a very long time. Some cross into the brain. Some don't cross into the brain, and that's why we have such different symptoms in all individuals, because the molecules released from the mast cell will affect every cell in the body. Back in 2015, or whatever it was, I and colleagues wrote a review in the New England Journal of Medicine, and I was grateful to the journal. I still am because they allowed us to use the title, "Mast Cells, Mastocytosis, and Related Conditions. It was the first time that we started talking about related conditions. Now going back to the misnomers about what we call what. For some reason, my colleagues decided that if you have a telltale history of allergic-like problems, and we give you the only thing we have, antihistamine, so you do a little better, and if only one of the molecules released from the mast cells called tryptase, it's a meat tenderizer, it's a proteolytic enzyme, is high within 48 hours of an episode, then we call it mast cell activation disorder syndrome, MCAS. But it's almost impossible to get a tryptase measure within 48 hours of an episode, unless you have an indwelling catheter. Most hospitals have no clue what tryptase is, and they send it out anyhow. So there's no way to address the patient when they show up at the emergency room if they're going to get a tryptase result a week later from whichever company they send you to. And therefore, I don't understand why everybody is stuck with either wanting to be identified with MCAS mast cell activation syndrome, or have a diagnosis thereof, because the diagnostic codes we use have a different code for mast cell activation unspecified for other mast cell activation disorders. So I can call a patient. You have another mast cell activation disorder, and the treatment approach will be identical to if you had MCAS. So I don't understand what the endgame is and why everybody is saying, "Oh, yeah, you don't have MCAS because you don't have tryptase. And to make things worse, we really don't have a panel of molecules that we can say if you have high X, Y, and Z, you have mast cell activation disorder because these molecules are not necessarily specific for the mast cell. So here's the fallacy: we have tryptase, which is specific for the mast cell, but doesn't help me because, as I already said, most of the time is not high. And even if it is high, we don't have an anti-tryptase. We don't have a way to block tryptase. So we're back to basically trying to inhibit the mast cells from releasing tryptase and histamine and everything else. So that's where the emphasis should be. Now, unfortunately, granting agencies have not paid attention to that at all. They focus more, for good reason, if you wish, to how to just destroy the mast cells in the body, because there are too many in mastocytosis or mast cell leukaemia, which is a horrible problem. But that's only the tip of the iceberg. If we could consider all the other patients have mast cell activation, so

Emily Kate Stephens (17:51): You have a few people who have that extreme mastocytosis, but you have multiple millions.

Theoharis Theoharides (17:59): At least 10 times, if not more, the patients have mast cell activation, and that's defining mast cell activation, as we pretty much said, because now, as I'm writing this review, you've got other conditions where the mast cells do play a role, but we don't consider them to be, for the time being, the primary pathogenesis of those conditions.

Emily Kate Stephens (18:18): So this is one of the things when I was reading your papers, and you have written 500 papers. So I have not read every single one. I hope

Theoharis Theoharides (18:27): Not,

Emily Kate Stephens (18:27): Because obviously your knowledge is so broad. But when I was focusing in specifically on what I wanted to talk to you about today, I came up with some papers. In 2005, you published a paper looking at mast cells in migraine, and then much more recently, mast cells in 2019, mast cells in fibromyalgia, 2019 mast cells in ME/CFS, 2023 mast cells in autonomic nervous system and dysautonomia, and what I am showing you here by talking about some of those previous papers that you've written, going back 20 years, is so many of these conditions that have possibly been brought to the fore with Long Covid, or are considered to be symptoms of Long Covid, or symptoms of ME/CFS, or other titles that give yet another umbrella term for a collection of underlying symptoms. It, in so many instances, seems to be these same symptoms, this same physical situation that you have in mast cell activation syndrome, or whatever the title is that people are looking for it. So you are suggesting that mast cells play a part in so many of these things.

Theoharis Theoharides (19:57): I'm not the only one that has done that. You know, as you know, Dr. Larry Afrin was a good friend. Has said that as well. I'm just trying to limit myself to the extent that where there is repeated evidence that mast cells or mast cell activation is involved, then I'll make the leap of faith and say yes, they are the problem. There are other instances where mast cell activation might be just something happening at the same time, but not necessarily the beginning and the end of that condition until proven otherwise. And the reason why I'm being a little more cautious in medicine in general, and even within the specialty of allergy, we don't talk about all these other problems. You know, we focus unfortunately on just allergies. So there aren't that many physicians who can think outside the box and say exactly what he said. I mean, there's evidence that there's mast cell activation in migraines, in this and that and the other thing, and therefore we should make physicians aware of the fact so that when patients show up, we know what we're talking about. I just got a desperate email from a lady from Brazil who showed up at a major hospital in Maryland last week, and she had issues like ones we are discussing, and they basically told her it's her mind, and she went out and she had an anaphylactic crisis and almost died. So physicians are just not aware of these issues. Now I understand that in an emergency room we're not likely to deal with a complex disease, but there should be us somewhere out there working collectively to address these problems. Give you an example: in irritable bowel syndrome, we have lots of symptoms that otherwise are found in mast cell activation disorders. So you've got, you know, diarrhoea. Sometimes you might have constipation, mostly diarrhoea. You can have hypertension. You can have headaches. All of these are similar to symptoms that one experiences in mast cell activation disorders in general. So colleagues look for more mast cells in the gut, but it's difficult to biopsy because you don't know where the mast cells will be high in the gut, and most of the times the results are negative because you don't know where to biopsy, a colleague of ours, Dr. Miner, many years ago said that maybe the ileocecal junction is the best place to biopsy. And I wrote actually an editorial years back. It's not the numbers of mast cells; it's the activation of the mast cells. Because you might have 100 mast cells that are quiet, and then you have 10 mast cells that are going crazy, releasing everything. In which case you might never see them, but the mediators will be there. So, for instance, if I suspect that someone has mast cell activation problems, with or without potentially IBS, I will ask them do actually total histamine in the stool. Why? Because if histamine is released outside the body, it will be destroyed within one minute and will end up in the urine as methylhistamine, the breakdown product. If, however, it's released in the gut, it's going to be histamine. They're not going to be broken down. So, if I actually measure total histamine in the stool and it's high, something is happening in the gut, whether I can measure the number of mast cells or not. Just give you an example how one can approach and potentially help you know solve some of those problems because then you would want some interventions that mostly address, let's say, those in the gut. Back when we were talking about mast cells in migraines, yeah. Other than what I mentioned earlier, where the mast cells are in the brain, the meninges, the three membranes that cover the brain, are loaded with mast cells. That's why we thought they're actually involved in migraines. Well, back then, 20 years ago, I was saying it might be actually a molecule called CGRP that is involved. Well, no one paid attention until five years ago, and now we have 10 drugs that are CGRP blockers. Well, why it didn't take us 20 years to do that? And mind you, I had three U.S. And international patents on this, but the university up in Boston thought they were irrelevant, and they never did anything about it, and that's that. So, so it's not even just the science. You get actually to the place where you say, "Well, here it is. Let's do it,' and then they tell you you're crazy. Nothing's going to happen, and then you waste 20 years, and all of a sudden, yes, it works.

Emily Kate Stephens (23:57): When you talk about that, you talk about specifically the mast cells in the brain for migraine, and you were talking about doing biopsies of the gut for mast cells for irritable bowel syndrome. Do we know that mast cells are active in that area that is affected? So, if it is headache related, is that normally mast cells within some area of the head, or is it the case that these are always activated in the brain neurologically, and then the symptoms that prevail are actually driven by the neuroinflammation of the mast cells?

Theoharis Theoharides (24:38): Well, it's a difficult question to answer. You're right in a sense. I mean, if we have mast cells in the meninges, we have mast cells in the brain, and we don't have any symptoms. What are they doing? Well, either they're just quiet there because 300 million years ago they had a role to play, now they don't, or the potential triggers for the mast cells in the brain are not there. The mast cells, as I said earlier, basically protect the blood-brain barrier. They kind of literally embrace the blood-brain barrier. So if the mast cells fire, they open up the blood-brain barrier. Now blood-borne substances are going to get into the brain, and the defenders of the brain, the microglia, are going to go crazy trying to fight them. It's going to get now neuroinflammation. So what is it that might trigger the mast cells in that part of the brain, well, high temperature will do it. I mean, young people they get, for instance, you know, sunstroke or very high temperature, the mast cells will fire, and then all of a sudden we'll start having all kind of issues, neuropsychological and other issues, and that's absolutely true. Heat, for instance, and stress, as we said earlier, are the biggest triggers, the most common triggers of mast cell activation disorder, individuals,

Emily Kate Stephens (25:46): Emotional, mental stress, or physical, whatever

Theoharis Theoharides (25:49): Stress. It could be mental stress, it could be physical stress. See, if you have a sunstroke, you can have both emotional and physical stress. The physical is that the heat, basically, the temperature opens up the blood barrier, and all kind of things will get in. Then all of a sudden you have headache. The headache will be a stress, and that exacerbates basically the problem. I guess I'm getting back to the fact that there are three issues in my mind. One is let's recognise that in a number of conditions, complex or otherwise, mast cells are activated. Whatever we call it, they're activated, and therefore the first thing we should do is try to limit the potential triggers and see if we can block the mast cells. That would be the initial address to any such problem until we know otherwise, and we can do that. You can either avoid certain conditions, whether it's pollen, whether it's food, you know, whether it's stressful circumstances. Of course, you might not be able to avoid everything, but at least you will limit it. And in some circumstances, we don't even know where the trigger is. I was lecturing in Australia about eight years ago, and I was stunned by the fact that many people that ate red meat were having actually allergic-like problems. I was never aware of that, and as it turns out, colleagues in Australia and us later uncovered that one, let's call it antigen, a substance called alpha gal, which is found only in pork and beef, can make people allergic. And to make things worse, if you're actually living close to woods where there might be deer and squirrels, then tick can bite the squirrels and the deer, and if they bite you, you might not only get other diseases such as Lyme disease, but they'll carry the alpha gal. Now you become allergic to alpha gal. We didn't know that. Now it's become a major problem. It's called alpha gal syndrome, and it's even worse because most of the dietary supplements, drugs, cosmetics have actually gelatin and other products that come from animal sources, and you wouldn't know it. I've got persons who kind of turn red on their face who used to call that actually mouth allergy, and they were just allergic to alpha gal, which is found in ChapStick or lipstick.

Emily Kate Stephens (28:02): Oh my goodness! I'm allergic to. I can't eat things with gelatin in, but I think it's because I'm allergic to sulphur dioxide. I am reactive, and post Covid, I'm reactive to so many things. There are just so many things. But the problem is identifying, like you just said. So even just in the shells of the capsules, that all of us who have these symptoms start taking all of these multiple supplements, and actually, then you often don't have any idea of all of the various tiny chemicals and components that you're taking. True. So that is an issue, and trying to therefore break down what is the trigger is one of the biggest problems. Because yes, eliminate that trigger when you have that trigger, when you know what that trigger is, but a lot of the time we don't know. Could you just, for our audience, give me a run through of the list of symptoms that you see as a result of some kind of mast cell situation.

Theoharis Theoharides (29:09): Gastrointestinal problems are quite frequent. It might not be frank diarrhoea, but it might be like a bloating kind of pain type of thing that comes especially associated with food, that's one. Itching is not really the most common symptom that we see, even though it might show up. But brain fog is. You know, you cannot concentrate anymore. You start forgetting words, and of course, that all of a sudden it's not in the domain of the allergies, and they don't even believe that's possibly true. I see a lot of flushing of the neck and torso, especially if people are upset, which means that just that circumstance can trigger the mast cells without any particular allergy, etc. So it is the otherwise not directly mast cell-related symptoms that trigger me to think that there might be a problem, because if it's chronic itching, you know we call it chronic spontaneous urticaria, for instance. So we have a name for that. If it's an eczema, we have a name for that, even though we still don't know what an eczema is, because there are many processes being involved. And probably one of the most typical trigger points for me is if we give someone antihistamines and they don't respond. That is telling me that there are other molecules than histamine that are being released from mast cells, which means that the mast cells are activated, because I really believe that it is all the other molecules that are causing the problems, and not necessarily the histamine.

Emily Kate Stephens (30:33): Okay.

Theoharis Theoharides (30:33): Okay. Let's say you know you've got frank, you know, issues, and you get usually we can give as many times as four times recommended dose of an antihistamine. By that time, you start getting sedated, of course. So if I push the concentration four times that, then you're not doing well. Mast cells are activated, and something else is going on, which makes it

Emily Kate Stephens (30:54): Really hard to also eliminate to try and work out what it is because someone takes an antihistamine and thinks, Oh, well, the antihistamines had no effect. So it's not that. It's not that kind of reaction. Well,

Theoharis Theoharides (31:06): Unfortunately, what the allergist would say. Well, it's not an allergy, and they forget that the mast cells can be doing all those other things without necessarily releasing histamine. That's what everybody's stuck to histamine and tryptase being released. And unfortunately, we don't have drugs to block the mast cells, as I said earlier, we've got drugs that kind of kill the mast cells. We call them. We put them into apoptosis, and those are the drugs that block the enzyme, which is basically called tyrosine kinase or c-KIT, which is on the surface of the mast cells, and the stem cell factor, among other factors trigger the mast cell to multiply. So yes, if you have 1000 cells and I bring them down to 10, the symptoms are going to be fewer. But it doesn't inhibit the mast cells. While in mast cell activation disorders, you have normal number of mast cells that just fire like crazy. And in fact, I have some systemic mastocytosis patients that don't have very many symptoms, which is kind of crazy, because you would imagine they'll have lots of symptoms.

Emily Kate Stephens (32:06): So that's an instance where you can see that they have the problem, but they're not symptomatic.

Theoharis Theoharides (32:12): Correct. It's a minority, but they're there. So and the only drugs we have to really block the mast cells and every other cell is actually what we call glucocorticoids, like steroids, like cortisone. But you can't give this forever. You know, if someone has anaphylactic shock, I'll cover them. That's when we started using some natural molecules that actually can block the mast cells, at least in the laboratory, 100% Just a matter of getting enough concentration in the body to help make sure the mast cells quieten down over time.

Emily Kate Stephens (32:44): So if we think about something like, and you've also written a paper on this, the role of mast cell activation in asthma and in that sort of breathing difficulty, which has been quite prevalent in the post-Covid condition. Correct. That's a lot of the time addressed using corticosteroids, correct. And I know so many people who have had corticosteroids for various different things in the past five years. They just seem to be a lot of people are developing psoriatic arthritis or these kind of things. You believe that there are natural things that we could absolutely

Theoharis Theoharides (33:22): Yes,

Emily Kate Stephens (33:22): Instead of suppressing the immune system, because that's the other thing that we haven't actually mentioned is that mast cell it is all part of the immune and the endocrine system, and so suppressing things is putting everything.

Theoharis Theoharides (33:38): One of the things I hate about supplements is that they give crazy names that mean nothing. So you see so many supplements that say immune support.

Emily Kate Stephens (33:46): Yeah.

Theoharis Theoharides (33:46): Well, if I have inflammation, I don't want to support the immune system. I don't want to make it worse. I want to regulate the immune system. So all of those supplements, about 80% of the supplements, say immune support, immune this, immune that, and they might be doing the wrong thing altogether. For instance, there is an immune support histamine support supplement that has cumin. Well, cumin has histamine, and cumin triggers the mast cells. So whoever was the idiot that put actually cumin on a histamine, you know, it's beyond me. So people come up with all kind of stuff without any, you know, reasoning to. Well, they don't know the science, and they don't talk to anybody to tell them about the science. I started working on a class of molecules called flavonoids 30 years ago, and there is a review of mine that was published in the journal Pharmacological Reviews, along with Dr. Middleton, who's long past one of his colleagues. This became a classic in pharmacology. It's received about 30,000 citations just that paper alone. There are 3000 flavonoids in nature. Do we know all of them? Of course we don't. So you will see things like bioflavonoids, soy flavonoids, or whatever flavonoids. Recently, I was talking to an unfortunate cancer patient that is actually oestrogen positive. Well, I said, don't even touch soy. Because soy and soy flavonoids are estrogenic, they're going to make your cancer worse. How would you know unless someone tells you that the flavonoid you're getting is from soy? Because they don't tell you the source. Another cheap source is actually peanut shells, and they don't tell you that. So if you're allergic to peanuts and you get those flavonoids, you're going to have a reaction. And no one is regulating these things, so over the years we came down to a couple of flavonoids that seem to be pretty good. One is quercetin, which I guess you know, and the other is luteolin. They're 98% similar structure-wise. Very similar. The problem is that they're not absorbed more than 10% from the gut. So my colleagues will say, "Well, I give you two grammes a day. Eventually, something will be absorbed. What happens is, you absorb 10%, 200 milligrammes. You're left with 1800 milligrammes in the gut. You shut down your gut bioflora, and now you get SIBO, small intestinal overgrowth, and now you start chasing your tail because you don't absorb your vitamins. You can't absorb, you know, a whole bunch of other things. Okay, so too much of some things are not necessarily good. So that's why we mixed it up with olive oil, because any time you have oil and powder and you give it energy, you shake it up, so to speak, you create little spheres called liposomes, and you trap the solid inside. That way, you absorb about five times more from the gut than if you were to take powder alone.

Emily Kate Stephens (36:19): And that just enables the gut to hold it and absorb it better.

Theoharis Theoharides (36:23): Correct, and so we created a number of those. One is called PureLut, which is only luteolin. One is called NeuroProtek, that allows it to get into the brain, for instance, for people that have all kind of problems. And to the extent that the trigger might have been a pathogen like a virus or fungi, mould, etc. We created BrainGain that had actually berberine in it that is also antibacterial. So we're trying, since we don't have drugs, to make combinations that are 98% pure, pharmaceutical grade, that they're actually backed with a lot of science, and try to address different types of mast cell activation disorders within reason until we come up with a better way to do that.

Emily Kate Stephens (37:08): So explain to me, please, what the effect, the impact the luteolin has. Have you found an inhibitor? Is it just boosting your system in a different way?

Theoharis Theoharides (37:19): Luteolin inhibits the mast cells, no question about it. In the laboratory, 100% Just that we need to translate that to our body, and our body is not a test tube. We kind of extrapolate, if you wish. Yeah. Luteolin and other flavonoids are lipid soluble. So if someone is very obese, a lot will go into the fat, and it will never reach the areas where you're supposed to go. If someone has, let's say, irritable bowel syndrome, you might not be absorbing it, so it might not be absorbed. It's not available in any way to inject it, for instance, because it's not a drug. So we'll be struggling to make actually a nasal spray. So might get in the brain through the olfactory nerve that communicates our brain with the outside world.

Emily Kate Stephens (38:04): If we could get it into our blood,

Theoharis Theoharides (38:06): Yeah,

Emily Kate Stephens (38:07): Would that?

Theoharis Theoharides (38:08): Well, it will be much more effective. Absolutely,

Emily Kate Stephens (38:11): Yes. So this is a legal standpoint?

Theoharis Theoharides (38:13): Absolutely, you're not allowed to inject things that are not classified as drugs.

Emily Kate Stephens (38:17): Correct. But what flips it over to being something?

Theoharis Theoharides (38:21): Well, companies are not interested because there's no patent covering this. They're natural molecules. So, so unless you create something that is similar to, let's say, luteolin, has

Emily Kate Stephens (38:32): A chemical version.

Theoharis Theoharides (38:34): But that will take another 10 years before we can actually get in the market because that's the going rate. So, what we're trying to do is combine molecules. Not only luteolin has to be absorbed, but it's broken down in the liver as it should be. That's what the liver does. Quercetin is broken down a little faster because of its structure. So we combine luteolin and quercetin to use quercetin for its own actions as little as a decoy to allow the luteolin to stay longer, and because of its structure, it gets into the brain as well.

Emily Kate Stephens (39:04): And does the quercetin inhibit the mast cell?

Theoharis Theoharides (39:06): It will inhibit it as well. Just about a month ago, we published a paper where we compared basically four different flavonoids, trying to get to even better flavonoids. And in fact, we came up with even better, which is called tetramethoxyluteolin. But when you try to order this as powder from anyone out there, it's $10,000 per kilogramme. That will make it excruciatingly expensive for anybody to buy in the market. So unless someone is interested in making that available in large quantities to drop the price down, it's almost meaningless to talk about it. However, if we were to make a skin lotion for people that have, let's say, eczema or chronic itching, etc. You don't need that much of this flavonoid because now you're putting it directly in the skin. It doesn't have to be absorbed. The problem is with all the flavonoids are yellow. So you basically paint someone over. So, but tetramethoxyluteolin does not have colour, and therefore we created a cream that's called GentleDerm, that has 1% tetramethoxyluteolin. It works very well with good publications, and one can use it on the skin.

Emily Kate Stephens (40:18): Does that only work topically on the skin, or does it absorb into the body?

Theoharis Theoharides (40:26): We've been using it for anybody because it's very hydrating. It's totally hypoallergenic, except you don't put in your eyes. You can put it on your skin anywhere, whether you have actually any lesions or not.

Emily Kate Stephens (40:38): But could that help?

Theoharis Theoharides (40:39): Yes,

Emily Kate Stephens (40:40): With IBS potentially

Theoharis Theoharides (40:43): Could. So what we're trying to say basically is, if you combine, let's say, PureLut, luteolin, or NeuroProtek, as quercetin and luteolin, with a GentleDerm, now you get it from two sources. You're going to get as much as you can, and then your skin area here is amazing. It's the biggest source, you know, of space on your body, basically, eventually you will absorb some of the methoxyluteolin, and we also published a paper within the year where we compared head to head the only drug that is known to be a mast cell blocker, although it's a miserably low inhibitor, called cromolyn. So cromolyn is available; a lot of people use it as a mast cell blocker, but both we and others have shown it's a very very weak blocker of human mast cells. It worked very well in rats, and that's telling you we cannot use the animal necessarily as a surrogate for humans. So we pre-incubated human culture mast cells with either luteolin or cromolyn, 10 minutes same concentration, stimulated by two different triggers, luteolin was by far better than cromolyn. Cromolyn is a drug, and people use it. Luteolin is not a drug, but they don't, you know, they don't feel like using it.

Emily Kate Stephens (41:52): So, yeah, 10 years is basically what you're saying. You'd need to turn luteolin into something into

Theoharis Theoharides (41:59): A drug, and it wouldn't be luteolin. It will have to be a new molecule that might be much better. So, in fact, we're doing a lot of science here, a lot of work, using both cultured microglia and cultured mast cells in a different setting now, rather than isolated mast cells.

Emily Kate Stephens (42:16): When you say cultured, what does that mean? Okay, so that means taken from humans originally, and then

Theoharis Theoharides (42:21): Correct. So, what we do is we obtain blood either from normal individuals or individuals who might have it might be chronic fatigue, it might be Parkinson's, it might be whatever, and then out of the blood cells we grow out what are called pluripotent stem cells, and then if you add the right growth factors, you can trigger the cells to go in different directions. So we can grow mast cells, we can grow microglia, we can grow neurons, and we're not the first ones to do that. But until now, pretty much everybody was using isolated cultured cells. It's a mast cell, and we give it a trigger, and then we can measure what comes out, and then we can try to block it. However, the mast cells don't live in isolation. In the skin, they have fibroblasts, they have endothelial cells. In the gut, you've got the gut mucosa. In the brain, you've got the microglia, the neurons. So what we're now creating is what are called human organoids on a chip. So we basically have a self-contained incubator, and then in the plate we have a central well where we put neurons. Let's say in the case of autism or chronic fatigue or Long Covid, and then we have satellite wells, and we put the mast cells or the microglial or endothelial cells, and we can either trigger them separately, we can do them all together, with different triggers to find out what is the worst scenario possible that would do the most damage to the neurons. So now we might have a surrogate for what might be, let's say, autism or might be Parkinsonism, etc. And now we can use that surrogate to start screening natural molecules or repurposing drugs to find out what can either prevent it or reverse it after the fact. That will get us within a couple of years enough, I think, novel molecules to start doing clinical trials, but it's still natural molecules unless we repurpose drugs. But so far, there are no repurposed drugs that can do that. The unfortunate thing is, as I'm sure you can gather, is no one's supporting this kind of research. I've been doing studies funded by the National Institutes of Health, and no one ever had a request for applications just to study the biology of the mast cell. I always got funded either through eczema, through psoriasis, or some other source, trying to convince them. And this brings us to what we started the conversation with. I put an application in a couple of times, both to the Department of Defense and the NIH, on the role of mast cells in Covid. Lots of evidence, as we've been discussing, that they might be involved. The answer from those critiquing the application was, "What the hell do the mast cells have to do with Long Covid? Well, if I knew, I wouldn't be applying a lot. You know, it's like the chicken and the egg all the time. So, and that's why some God bless them entrepreneurs have actually been using money from dot-com companies, you know, out in Silicon Valley to say, "Here's the money. Just show me what you can do, kind of thing. But usually, these are new companies that are being developed rather than giving to people like us, because it takes at least two cycles with granting agencies before something gets funded. So two cycles means two years. So it takes you half a year to write it, two years to wait. At that time, we've lost thousands of patients who are suffering out there. That's not how science should be working. We should be able to say, look, we don't understand what ME/CFS is, we don't understand what Long Covid is. Here's a billion dollars. Collect the 10 best people in the world, just like they did with not that we should have done it with the Manhattan projects. Put them together and figure it out.

Emily Kate Stephens (45:52): But isn't that the thing? Looking at something like the mast cells in this way actually enables us to start looking at multiple of these conditions together, still keeping them as separate conditions, and therefore, in terms of the funding or in terms of the potential pharmacological interventions that could be developed by big pharma, which is when it comes down to it, what people are interested in making money from these things that they can develop. If you're grouping in not just a million ME/CFS patients, but you're grouping in 8 million of these people, 4 million of these people, and you're pulling everyone together and saying, "But if we research this, you're absolutely right,

Theoharis Theoharides (46:37): And I wish that would be the way to go. But the more complicated things get, the less likely it is that anybody will fund them because they want a clear condition with a silver bullet type of thing, which doesn't work. In all honesty, there is some truth to the difficulty as well. I don't mean to bad mouth here, my colleagues, because it's very difficult to do a clinical study when you have so many different symptoms, we tend to say, "I'd like as virgin, excuse the expression, population as possible, because you've got to decide what your primary objective is, and every time you have a secondary objective, there's something called the Bonferroni principle in statistics. You've got to double the number of patients and keeps on going. So if someone shows up with 10 different quote unquote comorbidities, it's impossible to do a clinical study, and then you end up basically doing a study of n equals one. If I can actually make one patient do better, maybe there will be enough to trigger the next patient.

Emily Kate Stephens (47:38): Except for perhaps they're not comorbidities. Perhaps they are from the research done. Perhaps they are all from the same root, and it's a matter of getting back to understanding.

Theoharis Theoharides (47:51): That's why some of my lectures in the paper that I'm putting out now, you know, I've got a daisy, and the daisies, the centre of the daisy is the mast cell, and the first set of petals are the ones we absolutely know mast cells are involved in.

Emily Kate Stephens (48:04): Tell me.

Theoharis Theoharides (48:04): Yeah. So you know we know asthma, allergy, eczema, etc. Then I've got another set of petals who we suspect very strongly the mast cells are involved. You know it might be irritable bowel diseases, it might be multiple chemical sensitivity, it might be sick home syndrome, which is mould, etc. And then you got another set of petals where we're talking about Long Covid, chronic fatigue, fibromyalgia, where the evidence is there. It's kind of telling us, yes, go that direction, but no one is really kind of going that direction.

Emily Kate Stephens (48:34): And I think that one of the problems with many of those conditions that you've mentioned is that you've possibly started with something that is triggered by a mast cell activation or something like that, but because it has then been impacting the body for that length of time, particularly if you're looking at ME/CFS patients who have been sick for a long, long time, you then look at the degradation on organs or on certain parts of the body of having that symptom for X number of years. So if you've got palpitations for that length of time, what does that actually do to your body?

Theoharis Theoharides (49:14): What I usually tell patients, and we saw patients before I came here with my colleagues, is we might not necessarily put all the eggs in one basket. So I'm saying, look, let's assume that this is mast cell activation disorder in general. What can we do to help you? From what do we know? Regardless of any laboratories, because the laboratories will end up basically at square one anyhow. So I'll give someone, let's say, a month with what I think is the best approach to calm the mast cells, let them come back in a month or two and see if how many of those got better and what is kind of left. That's one approach

Emily Kate Stephens (49:51): With this concept of open exploration in medicine, and not necessarily keeping it within that very medical. Or what people term to be medical box, because you're also talking about natural products. You're talking about more holistic approach as well. Who out there is doing what you consider to be really exciting research currently, or coming up with ideas that really might move things for the things we're talking about?

Theoharis Theoharides (50:20): I dare say no one.

Emily Kate Stephens (50:22): Really?

Theoharis Theoharides (50:22): Yeah, because there are some good companies that have developed very important drugs for severe mastocytosis. I said aggressive mastocytosis, etc. We thank them enormously for that, but no one is addressing everything else. And the people that used to do or were very interested in mast cell-related work. Are retiring already have retired? We're talking about you know Butterfield. We're talking about Metcalfe at NIH. We're talking Schwartz in Virginia. Mariana Castells at Harvard just moved out, and there's no one coming in, because it continues to be not only a shifting field, but a field that is not really helpful. I remember talking to a colleague in Michigan who was seeing a lot of patients, and he said my practice was about to collapse because these patients, for good reason, require about two hours at least per visit, and I don't get reimbursed for more than half an hour. So how can I actually keep on going? So unless there is an institution that can support such clinicians in the research, we're not going to go anywhere. And now we're facing, as you know, with the fact that research establishments are shut down. NIH stopped giving money. The indirect cost that kept institutions going from 60% is down to 15%. Columbia was just told they shut down $300 million because they were using DEI. We don't know where to go. They're firing 75,000 of you know VA research employees. So we're going to lose a whole generation of science, and you know, for better or worse, other people are going to go you know ahead of us, but there's nobody else. There was a wonderful colleague, Marcus Maurer, in the Charité hospital in Berlin, and he died while he was hiking, you know, in Italy about a year ago. And we lost one of the best people we ever had. So I'm just worried that not going to be you know a lot of people, if any, researching.

Emily Kate Stephens (52:21): So we got to take the initiative across in Europe for now and see if we can start.

Theoharis Theoharides (52:27): Whoever can, there are good groups in Europe, and one was started by actually Marcus Maurer. There's very little research is being done on this field that I know of, from what I read at least, and the genetics are not going to help us because this is not really a genetic problem. I mean, there might be a familial problem, like with hypertryptasemia, for instance, which is a you know genetic kind of problem. And the other issue is that if we get stuck with tryptase, a paper was published a year ago, and then Mariana Castells wrote an editorial about it. They looked at about 110 patients. They had high tryptase, no diagnosis, just high tryptase. And then they looked at the diagnosis. 20 to 30 percent of them had hypertryptasemia, so not mast cell disorder, not mast cell activation, anything else. 30 percent of them had chronic kidney disease. For crying out loud, with no idea. I have no idea what tryptase does in chronic kidney disease, and the remaining were severe aggressive mastocytosis or mast cell leukaemia. So, from those 150 patients that had tryptase, very few had actually mast cell activation. You know, if any problems, which just kind of takes us back to the fact: we need better markers of mast cell activation,

Emily Kate Stephens (53:42): Which that filters out to so many of the conditions that we have mentioned today, is that understanding in terms of having that marker or having these one things that identify them as a specific condition.

Theoharis Theoharides (53:58): Well, a major reason why I moved from Boston here, I was a professor of medicine at Tufts for 35 years, and I was at Yale University for 15 years before that. Is because this institute, you know, run by Nancy Klimas, thinks outside the box. So not only we're doing integrative approach, and the science that is not integrative is solid. So we're not cutting corners. If someone needs a drug, they're going to get a drug. But at the same time, we're looking what else we can give. But it allows basically the research, so they're supporting this type of research we're talking about, and we're applying for this, and they have a very good track record of doing pilot clinical trials. So my hope is, as it has been, I mean, right now we're just starting a new clinical trial for Long Covid with a product that I helped develop. The company is called Algonot. They made the other products as well. It's called ViralProtek, and it's got four natural ingredients. Each ingredient independently blocking a different target of the coronavirus. So one blocks the binding to the ACE receptor. One blocks the serine protease that actually cleaves that to allow that to go in. The third molecule blocks the polymerases that allow the virus to proliferate, and the fourth one blocks toll-like receptor four that allows the production of the cytokines. Well, as you know, in medicine, the more targets we get, the more likely that we will get actually a response.

Emily Kate Stephens (55:19): Yeah.

Theoharis Theoharides (55:19): So we're doing this study now in Long Covid patients is going to start in a month or so, and that's the beauty. We can actually do the study because they have access to the patients.

Emily Kate Stephens (55:28): So who stands out in terms of the research? It's the team here that you work with at NSU, essentially.

Theoharis Theoharides (55:36): Yeah, it's the team. We can brainstorm together. We can think clinically and basic science, and we feel that we can actually turn the basic science into clinical trial quickly, because otherwise it's almost meaningless. We're going to take forever. And maybe to finish with an example of where things can go wrong, at Tufts I used to teach a course, advances and failures in drug discovery. So I will pick up 10 topics over the last 50 years where both the scientific community and the Wall Street were drooling over something, and it failed miserably. Give you an example. Until now, we've been saying that Alzheimer's due to beta amyloid plaques. Well, millions of dollars have been spent in clinical trials, and they all turn out zero. And what is absolutely incredible to me is that the only drug that came out of Boston, Biogen, you know, was the company, on a clinical scale of one to 15, the benefit was 0.45. So with a benefit where the best would have been 15, if we had benefit, half a point on this scale was only the benefit, and yet it was approved by the FDA, and it cost about $100,000 a year, and it still doesn't work. And 10 to 15% of those get edoema in the brain, so that's how desperate we are. And now my colleagues that were behind beta amyloid plaque forever at MIT and Harvard, now are saying it's inflammation against the amyloid plaques, and for some reason, some people develop more inflammation than others because 30% of the people that die of old age have bad amyloid plaques and never get inflammation. But we use the word inflammation indiscriminately: eczema, inflammation in your skin, asthma is inflammation in your lungs, multiple sclerosis inflammation in your brain, but they're not the same. So we should be more careful about what we are identifying, which takes us back to the research we're doing, where we have actually the central well with the neurons and the satellite cells. Once we stimulate them, we can pluck out basically the cells and do RNA sequencing and find out which specific molecule was actually activated? Even though I had no idea where and how to measure it, then we can say, okay, let's measure it, and then we'll go back to the patients and see if we can pick that up. In which case, we'll have an objective diagnosis much earlier on, which also were missing in many of these conditions. So, I know I gave you an earful here, but you know I'm passionate about this, and I'm passionate for exactly the reason we started the conversation. We just ignore these patients with multiple problems because we don't know how to deal with them, and they're difficult patients in quotation because they're well read. They ask questions we don't know the answers, and it's easier to say it's only your mind.

Emily Kate Stephens (58:27): So fabulous to meet the man in person. I have linked a lot of information about him and about mast cells in the show notes. So please do go and look there, and please feedback. Let me know what you thought of the conversation. Let me know what you'd like to explore further. Let me know if there are other things that you would like me to try and include in those show notes in future. And as ever, please do like, rate, subscribe, and send me all your feedback. I wish you a great week. Thank you for listening to Make Visible. Please do like, follow, or subscribe to listen to our next episode, where we'll be uncovering more insights into complex chronic illness. This was brought to you by the team at Visible, a group of scientists and engineers whose lives have been affected by energy-limiting health conditions. We're building wearable technology that's helping 100,000 people measure and manage their complex chronic illness. To find out more about what we're working on and how Visible could help you, visit our website at makevisible.com.

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