E202: Dr. Theo Theoharides on mast cells driving dysautonomia and much more - Mast Cell Matters

Check out the original post here with The POTSCAST.

Dr. Theoharides is among the world’s top mast cell researchers and speaks with Dr. Dempsey about his recent article reviewing how mast cells may drive dysautonomia and vice verse.  They also cover a range of topics from mast cells’ diversity to their role in autism, most effective mast cell stabilizers and much more.  This episode is packed with advanced mast cell information.

Dr. Theoharides has a website here and his supplements can be found here.

You can learn more about Dr. Dempsey and her practice here.

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Episode Transcript

[00:00:00] Jill Brook: Hello, fellow mast cell patients and marvelous people who care about mast cell patients. I’m Jill Brook, and today we have another amazing episode of Mast Cell Matters with our incredible guest host, Dr. Tania Dempsey, a world renowned Johns Hopkins trained physician, researcher, and expert in treating MCAS and related disorders. In these episodes, she brings along some of her world renowned expert colleagues to discuss their important work related to MCAS. We are so lucky. Dr. Dempsey, thank you for hosting, and whom did you bring with you today? Dr. Tania Dempsey: Well, I’m honored to introduce Dr. Theoharides. I’ll do a little brief a bio on him, and then we’ll, we’ll go right into lots, lots to talk about today. Dr. Theoharides actually joined Nova Southeastern University in 2022 as professor at the Institute of Neuroimmune Medicine and director of a new center of excellence on Neuroinflammation

[00:01:00] Research at the Clearwater Campus. He has been Professor of Pharmacology at Internal Medicine and Director of Molecular Immunopharmacology and Drug Discovery at Tufts School of Medicine and will remain as Adjunct Professor there. Dr. Theo Hardies received his Bachelor of Art, Master of Science, Master of Philosophy, Doctor of Philosophy, and Doctor of Medicine from Yale University. And was awarded the Winternitz Prize in Pathology. He trained in internal medicine at New England Medical Center. He’s received numerous awards. And he was the first to show that the unique tissue immune cells, mast cells, play a key role in the pathogenesis of Autism Spectrum Disorder, as well as in other conditions that involve neuroinflammation such as Chronic Fatigue Syndrome and Long COVID syndrome. Dr. Theoharides has over 470 publications with

[00:02:00] 41,853 citations, placing him in the world’s top 2% of most cited authors. And he is a top rated expert on mast cells by Expertscape. Dr. Theoharides, thank you so much for being here today. Jill Brook: Thank you so much for being here today. I feel like I’m on Mount Olympus, honestly, hanging out with the gods here. Dr. Theo Theoharides: It’s a real pleasure and it’s so important because the field is moving fast and unfortunately there are many misconceptions that still linger on making both our lives and those of the patients miserable. So let’s see if we can maybe navigate through some of those. Dr. Tania Dempsey: Thank you. Yeah, that’s really, it’s so important. So, you know, maybe we can start just to talk a little bit about your new position where you’re at, what you’re doing there, and then and then we’ll go from there. Yeah. Dr. Theo Theoharides: So, I was at Tufts for like 37 years and I think I gave it my due. And the reason why

[00:03:00] I wanted to move is I was looking for a place that, regardless of how well known or not it may be, can think outside the box, think much more integratively than many of the well known otherwise medical schools, especially in the Massachusetts area, and allow some new initiatives that were very difficult to come about in Boston. So I felt rather than just retiring why don’t I just make a move? And Dr. Nancy Klimas, a good friend and excellent researcher, had been well known to me for her work in Myalgic Encephalomyelitis, Chronic Fatigue Syndrome, but she was also very cognizant of the fact that mast cells seem to be involved in many other complex diseases, so that’s what made the move. It’s been wonderful and in addition, as you know, some of our listeners know, I’ve had a

[00:04:00] company in Sarasota, Florida for 20 years making some dietary supplements, many of them directed towards mast cells, so it was a double blessing because I could be in Sarasota and I could take care of the company and also participate in the upcoming research. So I’m very happy. Dr. Tania Dempsey: Oh, that’s wonderful. Congratulations. So, you just published, actually in November of 23 an article in the AAAI journal I think it’s the Annals of Allergy and Asthma Immunology on mast cells in the autonomic nervous system and potential role in disorders with dysautonomia and neuroinflammation. I’d love to talk about this. This article was fabulous. I would love you to, to cover some of the main points for the, for the audience. Dr. Theo Theoharides: So, probably I’ve been one of the very few people that have been studying mast cells in the brain. I had one mini review cut 30 years ago when no one was thinking of mast cells in the brain, yet I was not the

[00:05:00] first one. There were colleagues from Sweden that published that mast cells surround, for instance, multiple sclerotic plaques. But as I kept on working mast cells, other colleagues published either primary material or reviews of the fact that the mast cells may be involved neuropsychiatric problems, and we’ve been aware of the fact that at least Mastocytosis patients, potentially other Mast Cell Activation Disorder patients, also have sort of mental fatigue, sort of psychosis like symptoms and other such symptoms, and we had to figure out how mast cells may be involved. Now, during the course of my work we were among the first, I dare say, to show that the mast cells regulate the blood brain barrier, number one, and that the first hormone released under stress, corticotropin releasing hormone, or CRH can actually open up the blood brain

[00:06:00] barrier by stimulating mast cells, so we now know that CRH can not only trigger the mast cells directly, but can reset the reactivity so they become more responsive. And we’ve known this in the clinic because many patients, whether they have Mast Cell Activation Disorder or something else, might have a history of allergic like symptoms, and then something horrible happens, you know, car accident, death in the family, major surgery, and now they’re allergic to everything. Quote unquote allergic, because they’re not really true allergies, but let’s just call them allergic for now. And then the journal actually invited me to write something about mast cells in the nervous system, and it was a great opportunity to pull some of this data together. So first of all, I reviewed whatever I could find indicating the mast cells exist in the brain. Where they exist in the brain, and whether they respond to substances

[00:07:00] that are released by cells of the brain in general, whether they’re neurons, microglia, you know, etc. And then I try to review some of the better well known, quote unquote, because they’re not really well known, disorders where mast cells may participate, such as ME CFS, such as Long COVID, such as Autism, such as Dysautonomia, and even though it wasn’t really a systematic review, at least I created a very long table of the salient papers that were referring to mast cells in that context. And I thought that was very important because we many times talk about mast cells being involved, you know, in neuropsychiatric problems, etc., but we really don’t have the information at our fingertips. That way someone can look at the tables and say, well look, in Autism for instance, there were about 50 papers talking about a very strong association between eczema,

[00:08:00] asthma, and other laryngeal problems. And in spite of the fact that all those papers are listed, my colleagues still don’t believe that mast cells have anything to do with autism. Dr. Tania Dempsey: Right. Dr. Theo Theoharides: Which is really freaking me out because we keep on talking about, you know, medicine we keep on saying has to be you know, data driven, so to speak, or publication driven. Sure. So now we have 50 papers saying that, so why are we still not paying attention to it? So we’re really in medicine, unfortunately, you know, by, I don’t know, by the way we think we ought to play it rather than being evidence based. Dr. Tania Dempsey: Great. Dr. Theo Theoharides: Clearly in some conditions there isn’t enough evidence to call it, like in Dysautonomia, POTS, you know, EDS, the papers were not there. There’s a lot of clinical information, a lot of anecdotal information, but good papers were not there.

[00:09:00] In ME CFS, same thing. There were a lot of smoke, but not a lot of papers. But in Long COVID, there were many papers. And in Autism, as I said, numerous papers. So at some point, I hope that our colleagues will at least use this information to move on. I’m not saying, you know, they should be necessarily convinced, but I just cannot stand the fact that even at this point, folks that I give, and there’s Q& A’s, et cetera, people keep on asking or keep on doubting, and I say, it’s for crying around, does it read? You know, if you don’t read, I cannot convince you. So I thought that by this review, at least it will be easy for colleagues to see where the evidence is, and then kind of decide, you know, on their own. But there were some interesting points in pulling this data together. One point was that whether we call it you know, central nervous system or not, is a lot of evidence that hormones can stimulate the mast cells.

[00:10:00] Not just CRH. For instance, mast cells, we found out, are plentiful around the pineal gland that regulates, you know, diurnal rhythm or circadian rhythm. They’re plentiful around the pituitary gland, which of course releases pretty much all hormones that regulate the body. And they’re particularly plentiful In the hypothalamus, it regulates homeostasis, and in amygdala and hippocampus, they regulate behavior and, of course, memory. And I’m jumping ahead because we just had a paper accepted today with a whole bunch of colleagues from the University of Minnesota where we looked actually at brain samples of children with Autism as compared to normal typical children. All of them had died pretty much by the same, the same way whether it was car accidents or drowning, et cetera, et cetera. We tried to have it as tight as it can be.

[00:11:00] And we showed that in the hippocampus and not in the cortex, not only mast cells were activated and for the first time ever we now have pictures of mast cells from the hippocampus and the amygdala. And not only did they release pro inflammatory molecules, but very importantly, no one knows, you’re the first one to hear this, is they release metalloproteinase 9, MMP9, now why is this important? I usually try to be very simplistic, and it’s a danger to be too simplistic, but I tell sometimes families, think of your brain, in addition to neurons, having spiders, and the spiders make the spiderweb, that’s all the microglia. And the spiderweb is all the skull folding where the nerves crawl and make connections, etc. And the skull folding is made of proteoglycans.

[00:12:00] Very much like the proteoglycans we have in our joints, actually, and, you know, and they go to pieces in arthritis, etc. Somewhat different, but very similar. So MMP9 destroys the, these proteins, these glycoproteins, so they destroy the skull folding. So, what we’re showing is not only their pro inflammatory molecules that will cause inflammation in their own right and stimulate microglia to release their own pro inflammatory molecules, but they release MMP9 that destroys the skull folding. So the synaptic connectivity in those areas is basically gone. Luckily, from clinical evidence, we know that this is not permanent. That, you know, things can, can recover. But now we have very distinct evidence in addition to cytokines that MMP9 is involved. And the reason I’m excited about this is, number one, because it’s new evidence.

[00:13:00] Number two, it’s solid evidence that something happens. It’s not just, oh, you know, it’s just behavior. Something happens that leads to the behavior. And number three, not necessarily that sequence, it was accepted in the journal called Molecular Psychiatry, which is one of the best journals. Dr. Tania Dempsey: That’s wonderful. Dr. Theo Theoharides: So now we have additional targets. Not only we should be blocking the mast cells in the brain, the microglia in the brain, but maybe we’ll come up with blockers of MMP9 action, and there are none right now. Unfortunately, in medicine, we look for targets, you know, all the time. We don’t look for any inhibitors. Think for a second. What inhibitors do we have? We have alpha 2 macroglobulin, alpha 1 antitrypsin, and those are inhibitors of proteases. But that’s all we have. Everybody must have other inhibitors. And in fact, today I finished a small grant that’s going to

[00:14:00] NIH looking for innate inhibitors of mast cells, because when we stimulate mast cells in the laboratory, these are human culture mast cells, so I give them a trigger, it’s an allergic trigger, or a neuropeptide trigger, at any time, 50 percent of the mast cells don’t respond, just don’t. So we separated this in two groups using flow cytometry, and we looked to see if the expression of the receptor is the same, because if the receptor expression was different, of course it would not be firing. It was the same. So now we’re doing proteomic and genomic analysis to find out what is it in these cells that don’t respond. Because we find the difference that we might have actually a potential protein, because eventually it will be a protein, that we can exploit as a way of inhibiting mast cells going forward. Because so far, what do we have to inhibit the mast cells? The

[00:15:00] only drug in the market is Cromolyn, and it’s lousy. It doesn’t inhibit, you know, and when it works in the gut, it does. But if you, you know, you get used to it very quickly, and then you have to increase the dose, and if you increase the dose, you get diarrhea, and you get tachyfetaloxin, doesn’t work anymore. So we really want to have some inhibitors, you know, luteolin, quercetin. You know, are fairly good, we can talk about them later, but they’re not drugs, and our colleagues don’t want to use supplements, they’re looking for drugs. So you know, we have this tremendous disconnect between a drug that is pretty bad, and then supplements that may work, but we really need a better way of administering them so they, you know, reach a high concentration in the body. Alright. Dr. Tania Dempsey: So I have, I have so many questions, but I, but I just want to follow up on this conversation on MMP9. And so do you think that there are, I mean, this is obviously conjecture, but do you think that mast cells in

[00:16:00] other parts of the body are potentially also releasing MMP9? And, and could this be, be, let’s say, a contributory factor to, let’s say, connective tissue issues or other things? I’m trying to extrapolate. Dr. Theo Theoharides: Absolutely yes. I really think I’m jumping ahead. That both MMP9 or other such metalloproteinases, and potentially some of the proteoglycans such as chondroitin sulfate, may be involved actually in EDS. And as you know, even though there aren’t that many publications there is higher incidence of mast cell related problems in EDS patients. And with some colleagues from New York, we’re writing a paper right now. We actually used an IBM database of about, I don’t know, 20 million patients or so. And we searched the database by using terms to see if there is any

[00:17:00] correlation between EDS and mast cells. And in fact there is. There’s no question. The difficulty is that for many years we didn’t have insurance codes. So in the database there are words like, you know, Mast Cell Activation, Mast Cell Cancer, Mast Cell this, Mast Cell that, and it was very hard to separate them out to something that might be just Mast Cell Activation and not necessarily other horrible problems. But even when we did that there’s no question that there’s about four to ten fold higher possibility of a mass cell related problem in EDS patients. So think for a second. You know, EDS or hypermobility patients have obviously connective tissue problems. Now, we published at least twice the chondroitin sulfate, which is found in connective tissue and it’s found in mast cell granules, inhibit mast cells. So maybe that’s a possible innate inhibitor. We don’t know the amount exactly, but let’s

[00:18:00] say that. In EDS patients, maybe in other hypermobility patients, they’re lacking sufficient chondroitin sulfate in their skin. Dermatan sulfate would also inhibit the mast cell, we showed that too. So maybe dermatan sulfate is different in these patients, in which case when the mast cells release, they might not have anything either coming from the mast cells or from the tissue to inhibit them. So, we tried to send an application in to the international, you know, EDS Society, etc., to do biopsies, because if we do biopsies and we show that the proteoglycans in the skin are different or, or lacking, then there might be an explanation why the two occurred together but we didn’t get funded, so this is the thing, you know, we ask the questions, which I think at least they’re decent questions to be answered. You know, if you don’t get the funding, you don’t go anywhere. You know, this, this is the

[00:19:00] real problem with many of these studies. So, anyhow going back to your question now, could you please rephrase the question so I can answer a different part of it? Dr. Tania Dempsey: Okay, so, so I was interested in MMP9 and, and how it may be influencing other tissue and, you know, other places where mast cells are. Dr. Theo Theoharides: Thank you. So, let’s assume now that the mast cells are activated and releasing MMP9. MMP9 will destroy some of the proteoglycans in the tissue anyhow, and those might be the proteoglycans that are inhibitory to the mast cell. So, it could be a double whammy. Number one, the tissue, the connective tissue will change, by virtue of the fact that these molecules are being released, and they might be destroying some innate materials. And I’m absolutely convinced that there is an innate inhibitor of the mast cells because we did the following experiment, but because it was N equal 1, I never published it, but maybe I

[00:20:00] should nevertheless. So here’s what we had done many years ago back at Tufts. So we, we cultured the mast cells, human mast cells, okay, and we decided to take half of the volume, let’s say we have them in one, one milliliter. So we said, let’s remove half of that volume, half a milliliter, and replace it either with serum from otherwise normal individual, and there was someone in my lab basically, a female in the lab, and the other set of cells will add serum from a mastocytosis patient, untreated, about the same age. And now we stimulated them. Well, what happened is the cells that had half a milliliter of the normal female almost did not fire. While the ones with the volume from the mastocytosis patient went off the roof. So either there was something

[00:21:00] innate in the mastocytosis patient triggering the mast cells on top of the trigger we had given or the serum of the normal individual contained something that reduced the firing. And we’ve never looked for such inhibitors. I reached out to the companies that prepare immune IgG for injection, because they throw away the rest of the serum, you know. And I said, let me just get that serum and start using it to see if I can actually get some fraction. They were not interested . So it’s not that we’re not trying, and I’m sure other colleagues are trying in their own ways. That’s why at some point. You know, I felt that NIH should have a request for applications just for mast cell biology. In my 40 years of studying the mast cell, I never got funded for mast cells. It was always either because of psoriasis or eczema or, you know, Autism or MECFS where I was

[00:22:00] invoking that the mast cells are involved, but not for mast cells. And I keep on looking and there’s never been a request for applications for mast cells. Because that’s the only way to force us to then write applications to address the questions that I’ve been saying. Or someone from Silicon Valley or someone else will say, here’s 50 million, did all the studies you can. And in all honesty, if there were such an opportunity, that I would reach out, which is pretty much one of the reasons why I came to Florida, to all the people I know are very interested for basic work on mast cells and say, let’s put our hands together. I mean, I spent two thirds of my time writing grants, with one in ten being funded, you know, so all the rest of the time goes wasted, basically, because you could be, we could be brainstorming like we are doing now, and putting it to the test, rather than just keep on writing, you know, grants. I had a

[00:23:00] large grant from NIH rejected just recently. And the main comment from the reviewers was the mast cells have nothing to do with this disease. Well, if we don’t prove that they don’t have it, then we’ll never know if, if they have it, you know? It’s just, you know, if you want basically the answer before the grant, then what’s the point of finding it? Dr. Tania Dempsey: Yeah, so just along those lines of thinking before I ask you other questions about the study and all that, but what do you think will change that this? What do you think is going to be the, the way to get more money for mast cell research? Do you have any thoughts on that? Dr. Theo Theoharides: Well, I’m actually trying to do that, but that’s hard to o. You know, the way it works is you’ve got to reach out to your representatives. Thank you very much. convince them that the mast cell is important, then they have to actually, you know, get it through Congress, and then Congress will basically indicate to NIH, put an RFA together. Unless the people within the NIH, and there is a section of infectious disease and

[00:24:00] allergies, were to think that it’s important to study the mast cell. Give you another example. We submitted a grant for MECFS. That, that, that was rejected for, because mast cells are not involved, as I said, etc. But the institute, which is run by a wonderful you know, scientist, had a series of conferences to bring people together to think outside the box. So these are conferences, okay? Any three of the seven conferences pretty much everybody was talking about mast cells. So I kind of sent a note saying, well, here’s a disconnect. You put the conferences together and half the people were talking about the importance of mast cells, but the study section that you put together had individuals that don’t believe this. So how can you get, how can you fund what is obvious from the discussion? So, it usually takes, you know, two, three years for someone to, you know, create a new study

[00:25:00] section, etc. But the study section members, unfortunately, are not necessarily knowledgeable in these areas. They might be good scientists, don’t get me wrong, and I’ve sat on many of them, but, you know, here’s where it is. So, there’s got to be an RFA somewhere. And, and, and that will stimulate a lot of people to, to send grants because, you know, you look at the history, and if no one is funded for mast cells, then, you know, people, especially younger people say, why bother? I mean, I look at the history, no, there’s no RFA, hardly anything has got funded, so what’s the point? I’m going to waste my, my time. Dr. Tania Dempsey: Right. Dr. Theo Theoharides: So Dr. Tania Dempsey: There will be change. There will be change. You’re gonna… Dr. Theo Theoharides: I, I’m always, I’m always hopeful. Always hopeful. Dr. Tania Dempsey: I love, I love that. So let’s go back a little bit to the, to that paper on the autonomic nervous system. We talk a lot about in, in the mast cell community we talk a lot about POTS and

[00:26:00] Dysautonomias. So I’d love to hear from you how you see that, that link. What is, what is the connection? What’s the pathophysiology? Dr. Theo Theoharides: First of all, now, if we think of Dysautonomia in the kind of stricter sense, you know, we’re talking about, you know, blood pressure, we’re talking about the heart, you know, etc., mast cells line up the carotid arteries. And as you know, if we stimulate the carotid arteries, we inhibit the heart. So that’s one component. Mast cells line up the coronary arteries. If you stimulate the mast cells you constrict the coronaries even though histamine dilates other vessels, but the coronaries are constricted, and that’s where you have Kounis Syndrome, K-O-U-N-I-S, my great compatriot, who basically said, you can have hypersensitivity of the coronary arteries. It will look like a myocardial infarction, but it’s not an MI. Then the two pacemakers in the heart are loaded with mast cells, and we don’t exactly know what will happen when the mast cells

[00:27:00] fire in the heart. Will we stimulate, will we inhibit, will we derail the system? We still don’t know. A paper was published just recently and I was reviewing this in the ground that I’m writing because, and this is a digression for a second, think of the mast cells at least historically in two categories. The mast cells that have only tryptase, which are pretty much every mast cell, including the mucosal mast cells, and then the connective tissue mast cells, they have tryptase and chymase. And that’s how we’ve defined them over the years. However, the mast cells, as you know, have many more molecules, including other enzymes, such as MMP9, such as carboxypeptidase, you know, et cetera. But quite importantly, about five years ago or so this new receptor was identified that is stimulated by positively charged molecules, whether it’s substance B, whether it’s mastoparan, whether it’s positively charged

[00:28:00] drugs, etc. This is becoming a big deal now, because unlike allergic stimulation, this is not allergic stimulation, and we’ll talk about MCAS in a second in this context. So they’ve shown, for instance, just recently, that human skin contains these mast cells, express this receptor, but lungs do not. And heart mast cells do not. So if we can now separate mast cells based on just the expression of this receptor, and then they show it farther than that, they’re actually subclasses of this receptor. And they showed that some mast cells in certain tissues have X, Y, and Z of that receptor and others do not. So we cannot even say that the mast cells are the same even vis a vis receptor expression anymore.

[00:29:00] And even more importantly, a wonderful paper, short but wonderful paper, was published about ten years ago by Dr. Zuberbeer in the Charité Hospital in Berlin. So they purified skin mast cells from either circumcision or breast tissue, but not from cancer. So these are not purified cells from normal individuals. Their reactivity to an allergic trigger varied a hundredfold. So these are, not identical, but normal purified skin mast cells, and whether they looked at the breast tissue or the circumcision tissue, if you see the graph, it goes from zero to to 100 up there, and the dots in between. So every patient is different, and therefore for, that’s why I don’t like using terms like MCAS, and I’ll go into it in a second. They’re so different that I don’t know what to call them.

[00:30:00] In other words, someone could be extremely responsive, and another might not be responsive at all. And if it’s not responsive, what do we call them? But they still have the mast cells, they still have the receptors, et cetera. So, one of the questions is could it be that in those individuals where we purify, they purify the mast cells, some have some innate inhibitors and their mast cells don’t respond? I mean, we see it. It’s not just the clinical impression that 30 percent of the people have allergic problems and others do not. Okay. Well, one might say, who knows? They’re exposed to the trigger. There’s that. Here we’re talking about normal individuals that don’t have any allergies. And the mast cells are all over the place. So we have to start thinking of the mast cell just like we say we should have personalized medicine, we should have a personalized approach to the mast cell. And therefore I take, I

[00:31:00] disagree with my colleagues at two different extremes of the spectrum. I disagree with my colleagues like Peter Valen who says that every mast cell activation has to release tryptase. Well, we know that’s not true. I mean, we’ve published it galore, and so have others. So why stick to the tryptase? Well, the answer is because tryptase is uniquely present in mast cells. True. In about 30 percent of mastocytosis patients, tryptase is not even released. In most mast cell activation disorders, tryptase is not released. In fact, in quite a few of the otherwise Mast Cell Activation Syndrome patients, tryptase not released. So, we’ve got to think what to do with this patient. And what, therefore, go to the other spectrum, my good friend Larry Afrin, etc., he thinks that everything is mast cells and everything is MCAS. And we were at a meeting the other day on

[00:32:00] Sunday, we were talking about this. Every mast cell activation does have to be MCAS. And you know there are diagnostic criteria for Mast Cell Activation unspecified and Mast Cell Activation other disorders. So you have diagnostic codes to use and it does not have to be MCAS. So I don’t understand why we kept on sticking on MCAS and then we keep on arguing should tryptase be present or not. Forget the tryptase. Let’s just call it Mast Cell Activation unspecified and forget about the dichotomy of whether tryptase is up or down. At the end of the day, what is important is we get symptoms that are consistent with activation of the mast cells. Now, there are certain molecules that I tend to measure and they happen to be frequent in Mast Cell Activation Disorders. I find interleukin

[00:33:00] 6 in the serum quite high. I find Vascular Endothelial Growth Factor, VGF, quite high. I measure osteopontin, and it’s quite high. Now, someone could argue, well, these are not specific for mast cells. Sure. In that I actually fire back, if a patient doesn’t have any other reason for these to be high, then why not say they come from the mast cells? Sure, if someone has inflammatory bowel disease, you’re not going to worry about IL 6 because it might go up. So that’s why we have to actually make sure that our patients are as well defined as possible and then measure the molecules and try to link them. The difficult part is you cannot do these studies because we cannot get a quote unquote pure population of either MCAS patients or unspecified patients. The closest I came, I had an agreement with Dr. Metcalf, who was until recently the director of

[00:34:00] NIH section on mast cells, to send me 100 mastocytosis patients. And the idea is to measure some of these other molecules, at least in mastocytosis. But both we and Dr. Metcalf and Dr. Escribano, separately from Spain, had published that interleukin 6 is a better indicator of severity of mastocytosis than tryptase. That was published 10 years ago, but my colleagues just don’t pay attention to that. And of course, we haven’t shown that in MCAS or Mast Cell Activation patients, because it’s hard to get these patients. Now there are some companies that do genetic analysis that now have come up with panels that say, you know, Mast Cell Activation panel. It’s not entirely true. All they look for is genes that have been associated with mast cells. So it might be, for instance, histogenic

[00:35:00] carboxylase that makes histamine. Well, if that’s up, sure, it might be making a lot of histamine. They look at diamine oxidase, if that’s low, it’s not breaking down histamine. They look at the Ig receptor, but having too many Ig receptors doesn’t mean you’re going to have problems. In any event, it’s a reasonable approach, because if something is off, it might trigger some of us to say, well, I didn’t think of that, let me now measure it in the blood. I don’t think it’s diagnostic, but it’s useful. So that’s as far as I will say about those panels. And then there’s some assays. And unfortunately, last Sunday, this past Sunday, we were talking about mast cell activation markers. You know, all the discussion was about just urine markers. I wish we had spent more time talking about other markers, not urine markers. So, you know, some people say there is a mast cell assay, basically

[00:36:00] it’s an assay for autoimmunity. About 50 percent of chronic spontaneous urticaria, chronic enzyma, it’s autoimmune. Why? Because these patients have antibodies. against the IgE receptor, but these antibodies, rather than blocking the receptor, they activate it. It’s like what we call gain of function. So if you have those antibodies, you’ll be stimulating the mast cells, but you cannot isolate mast cells to do the test. So what they do in this test, they take basophils, because basophils also have IgE receptors, and if the plasma of the patient stimulates the basophils to release, they call it mast mast cell assay, it’s a basophil assay. But it’s important in chronic problems to make sure that we’re not having such an issue. Because if there is actually a presence of antibodies against the IgE receptor, then one might qualify for immune IgG treatment. Because we don’t have any

[00:37:00] other treatment. So there are ways to think, you know, evidence based, if you wish, how to go forward. But at the end of the day, as I said earlier, we do not have inhibitors of mast cells other than cromolyn, which gets absorbed less than 5 percent from the gut, so. Dr. Tania Dempsey: So, so along these lines, I’m curious about your thoughts. I’ve had this conversation with Dr. Afrin, who’s a colleague of ours, right? So we, we’ve talked, he talks a lot about somatic mutations at the level of the mast cell, potentially causing the production of certain mediators, certain receptors. Do you think that that’s the, the way we need to go in terms of research, in terms of personalizing the approach to mast cell activation? Should we be looking at that? Dr. Theo Theoharides: Dr. Afrin’s colleague from Germany has published a number of papers indicating there are some familial types of

[00:38:00] mutations different than the main one. And of course, we have familial hypertrophic leukemia, which we don’t know what it does, actually, because there’s high tryptase, but tryptase is the alpha tryptase, and the tryptase that we usually measure is the beta tetramer tryptase, and I’m still puzzled because the alpha tryptase, especially the dimer, is inactive, and it’s not even in the mast cell granules, so I have no idea how it is released, it’s inactive, and yet 60, if not more, percent of these patients have mast cell related symptoms. Whether it’s GI, skin, etc. So what on earth is causing the symptoms since we’re talking about inactive tryptase? So it’s a lot to find out, you know, there as well. Now there is evidence, however, that there are epigenetic changes to the mast cell. Now what is epigenetic? We all know, but I’ll repeat it anyhow. So we have our genes, some genes might be dormant. And then all of a sudden,

[00:39:00] something happens and wakes up that gene, so that would be epigenetic. We say that for Autism as well, because 900 genes have been shown to be a little more prevalent in Autistic individuals, but even putting them all together, they don’t cause Autism except in certain cases which are chromosome related, like Rett Syndrome, PTEN, you know, Tuberous Sclerosis, Fragile X, etc. All the other genes, who knows? Now, there have been a number of studies showing that methylation, or lack of methylation of some genes, may change their reactivity up or down, and that has been shown in Autism as well, because about 30 percent of the kids seem to have methylation defects. And what is interesting is, some of the well known molecules, to us at least, seem to have different effects. For instance, stem cell factor is the factor that makes the mast cells grow, at least in the bone marrow, okay? But biopsies of

[00:40:00] mast cells in the skin of cutaneous mastocytosis don’t show that. So something else is driving the mast cells in the skin, and some colleagues have shown that that might be nerve growth factor. And in fact, this is not new. Dr. Moltaccini from Italy who got the Nobel Prize you know, and died a few years ago at the age of 107, had published 50 years ago that NGF actually makes the mast cells grow. You know, we, we, we, we like history, you know, we just don’t think back. We think everything was discovered yesterday. And to give you credit, you know, she was an Italian Jew that was persecuted by, by the, the Nazis and the Mussolini’s, you know, Black Coats, and she did almost all the work that led to the Nobel Prize in a laboratory in a farm. Okay, so that tells you you don’t need millions and millions and millions of dollars to do good work, you know. So anyhow,

[00:41:00] so coming back, so now stem cell factor seems to be stimulating the allergic triggering, but seems to have a different effect on the low affinity receptor for the cationic proteins. NGF different effects as well. So it seems like molecules released in the microenvironment of the mast cell clearly change the reactivity, you know, up or down. Can we actually use these molecules to our advantage? So far, no, because if we give them systemically, they’re going to have all kinds of different effects. But it’s telling us that the reactivity of the mast cell, it’s not just, you know, we’re lighting, you know, a cannon, so to speak, and all of a sudden it explodes. There are many things that can vary that. And by the same token, I’ve been saying for years and years and years, I consider the mast cell a microcosm of

[00:42:00] pharmacology. The mast cell contains pretty much every molecule discovered, except for maybe antibiotics. So if I could tell the mast cell to release something I know, I could probably treat disease without having to give anything. For instance, mast cells contain tons of heparin, but the mast cells are not circulating in the bloodstream. So why do they have heparin? If I would tell the mast cell to release heparin, maybe I wouldn’t need to give an anticlotting agent. Also, mast cells surround solid tumors, especially breast tumor and pancreatic cancer and ovarian cancer. So the mast cell releases histamine, tryptase, MMP9, what will these do? They will disrupt the surrounding area and will allow mast, the tumor cells, to actually grow blood vessels to feed themselves. Mast cells release

[00:43:00] VEGF, Vascular Endothelial Growth Factor, they will make actually new blood vessels. However, if the mast cell would release only tumor necrosis factor maybe we can kill the tumor cells, but I don’t know how to tell the mast cell not to release VEGF and to release TNF, and God knows what other such, you know, molecules, and in the brain it gets much more complicated because the mast cells are very close to nerve endings. And I, yesterday I uploaded a small five minute video for the International Society of the Study of Pain. They asked about 15 investigators to kind of talk about their perspective, and it was all about mast cells and pain. The Journal of Investigative Dermatology, a couple of years ago, had on its cover the mast cells on the skin close to blood vessels and nerve endings. And then a subsequent paper, in addition to one in that journal, showed that this new receptor for positively charged molecules

[00:44:00] is involved actually in pain. So I think that a lot of the clinical impressions of the patients are explainable by what the mast cell can release. Mast cells have about 20 molecules that are pain producing and itch producing. We published one of the first papers that interleukin 31 can cause more itching than histamine. But no laboratory measures interleukin 1 and there’s no blocker for interleukin 1. So we’re stuck with the stupid antihistamines. I’m sorry I’m calling them that, but we’ve known antihistamines since 1948. We don’t have, we don’t have really, so they’re not sedating. So you, you know, you go four times the regular dose and then they become sedating. We really don’t have very good drugs. And considering that, as I said, 30 percent of the people have bona fide allergies, and another 20 percent of other mast cell activation disorders, we could be helping 50 percent of the bloody

[00:45:00] population. Who don’t have anything to be helped with. So I thought that the, the companies, the pharma should be drooling over finding a blocker of mast cells just for the money alone, and where are they? Jill Brook: Well, Dr. Theoharides, you were saying that doctors want drugs, they don’t want supplements. But as a patient, I’m pretty excited about supplements. Can you talk about that? Because it sounds like, like you are the guy who has created some of the best supplements. tools we have in the supplement world. Do you mind covering those? Dr. Theo Theoharides: So first of all, let me tell you that a paper will be published shortly, I’m doing some corrections, where we compared Cromolyn to Luteolin, the Flavonol Luteolin, and we measured release of about 10 different mediators. There was no question Luteolin was beating Cromolyn to the dust, okay? And we did that because, I keep on saying that, but as we all know,

[00:46:00] unless our colleagues see something published and well done, they’ll never believe it. So, and it will come out in a very good journal. So hopefully that will change the terrain. I’m not saying one should abandon Cromolyn. So what we did many years ago is something very simple. I looked at the structure of Cromolyn and think of Cromolyn as a butterfly with two wings. And then I ran a computer program, and I said, what molecules that exist in nature looks like that? And what do you know? The flavonoids are like butterfly with one wing. You know, I’m being very simple. But 90 percent similar. So then, we started looking at different flavonoids, because there are about 3, 000 flavonoids in nature. And some of them are bad, some of them are useless, some of them are pretty good. Why do I say that? Let’s say someone, God forbid, has breast cancer. I don’t want to give them soy flavonoids because they’re estrogenic and that will make things worse. So we have to think of the

[00:47:00] flavonoids for what they are. Flavonoids are also polyphenolic. So we have a benzene ring with a hydroxyl group that’s a phenol group. Like pycnogenol has 15 phenolic groups. Quercetin has 5, Luteolin has 4. Why am I saying that? The more hydroxyl groups, the more antioxidant. The fewer hydroxyl groups, the more anti inflammatory and more anti allergic. Therefore you can’t just say I’ll take curcumin, I’ll take pycnogenol, because depending on the structure, the outcome will be different. So that’s number one. Number two, we wanted to show if the flavonoids do in fact inhibit and do they inhibit histamine release? They inhibit other molecules, like cytokines, okay? So we screened a whole bunch of them, and it was quite obvious the Luteolin was the best. And it remains the best. Two reviews, not my reviews, were just published about Luteolin and anti inflammatory reactions, etc.

[00:48:00] But then the problem was, okay, we knew 100 micromolar Luteolin in the laboratory shuts the mast cells down 100%. How do I take that to the human now? See, a human is not one compartment, you know, we’ve got brain, liver, spleen, you know, etc. fat. So we cannot extrapolate. So we said, OK, if we extrapolate, we need about 500 mg. But if you take powder, Luteolin powder, or any flavonoid powder, it doesn’t get absorbed more than 10 percent from the gut. So, we then said, let’s create some liposomes. So if you take any oil, you mix it with powder, you shake it, or you give it energy, you create little spheres, they trap the powder inside, that increases the absorption because it’s lipophilic. So we showed that olive oil was extremely good, but olive oil is expensive, so we want to make it a little cheaper, so we got olive pomace oil, after you

[00:49:00] take, you know, the olive oil from the flesh, you’re left with a pit. If you crush the pit and the leaves, then you get a thicker oil, and it’s cheaper. So we ended up using that, and we created soft gel capsules, so that 50 percent of the content is the oily pomace oil, and the other is the powder that is strapped, and that increases the absorption 3 to 5 times. So that way, you can get a little more and you get the benefit of so called Mediterranean diet if you’re getting some olive oil on top of your diet. Now the difficulty is though, many of our colleagues, including some colleagues that we know very well, say, well I’ll give you 2 grams Quercetin or 2 grams Luteolin. Well if only 10 percent is absorbed, that means 1900 or 1800 or whatever stays in your gut, it shuts down all your bioflora enzymes. So you end up actually with SIBO. Your whole gut goes to pieces. So too much of

[00:50:00] something that will actually accumulate in the gut is not good at all. So we need to use enough to reach a certain level but hopefully not too much to stay in the gut and then you start chasing your tail because your gut is not working properly anymore. Dr. Tania Dempsey: Interesting because when I looked at your products, you know, the, the, the amount of, let’s say, Luteolin or Quercetin seems smaller relative to a lot of other products on the market, right? Dr. Theo Theoharides: Reason why, that’s exactly the reason why. You see it’s so difficult to explain that on a website or to the patient. But many patients look for just the cost and then the amount, or they say 500, three times a day, cost 15, I’ll take it. The other difficulty which is not obvious, that’s why I’m so proud of the company that makes them, you know, Algonot. Number one, it is FDA registered. We get examined and inspected every two years. Hardly any diet supplement does that because it’s

[00:51:00] expensive. We also have a food license from the state of Massachusetts. There’s some companies that just make products in the basement, no one knows what they do. Everything is actually analyzed before it becomes a final product, and when it is final product, and Eurofins, that’s an independent company in California, they give the reports. If the content is off by 15 percent, I don’t release the product. Okay, that’s strict. And finally, the cheapest source of Quercetin, of Luteolin, is actually peanut shells or fava beans, but no one is telling you that, so if you’re allergic to peanuts, you’re doomed, and it’s extremely cheap. The Luteolin from peanut shells, for instance, is 10 times cheaper than if you get it from citrus seeds, okay? Also, why did I mention fava beans? Because about 50 percent of Mediterranean people, as you know have deficiency of the enzyme

[00:52:00] G6PD, and if you eat fava beans, you get Hemolytic Anemia. Who’s going to tell you that? You know, so, I’m trying to make this product as if I I mean, first of all, I take one of the products now for years. I take NeuroProtek for four of those a day for years. And, you know, if it’s any indication, I’m 74 and I still put 10 hours a day, you know, work. So it’s helping. And especially for the families that have children, especially on the spectrum or other children we created the NeuroProtek Low Phenol Liquid, so it’s nine dropper bottle, one dropper full, it’s about equivalent of one capsule, soft gel capsule, and if you squeeze it under the tongue It literally becomes a sublingual, so you can absorb, you know, almost 100 percent if you can keep it under the tongue. And finally, many of our patients have a lot of skin problems, whether it’s eczema, whether it’s, you know, other types of reactions, etc.

[00:53:00] Now you might ask, why don’t you use Luteolin in skin lotion? Well, Luteolin is yellow and so is Quercetin, so you can’t. But, we isolated Methoxyluteolin. So instead of four hydroxyl groups, you have four methyl groups, no color, because the color is due to the number of hydroxyl groups you have. So this skin lotion called GentleDerm, it’s entirely hypoallergenic, it’s got alloy extract, olive leaf extract, oregano extract, and then the Tetramethoxyluteolin, and there are two publications that it’s quite useful, especially in eczema. So you can apply it, and you can apply it anywhere. And, now there’s one report that Luteolin is actually particularly helpful in Rosacea as well. So, there might be other reasons why it might be useful, and there’s no downside to it at all. Except you don’t put it in open wounds, but you wouldn’t put anything in open wounds anyhow, so. Dr. Tania Dempsey: I have one question about,

[00:54:00] well, we’re about to finish up, but I have a question about Luteolin and you mentioned about the bioavailability and the absorption. Can we, can you talk a little bit about the penetration into the central nervous system? Dr. Theo Theoharides: Yes. Yes. So, there are publications showing that both Quercetin and Luteolin can get into the brain, but the more hydroxyl groups you have, the less likely you will cross the blood brain barrier. So Luteolin has one fewer hydroxyl group, so it will get in. We’ve also done studies where we labeled Luteolin and then we did whole animal, basically visualizing whole animal. And we can see basically the Luteolin because Luteolin is autofluorescent. We can see the fluorescence in the brain. And we did another study where we actually extracted the brains of rats to which we had given Luteolin. We published that. And we used basically HPLC to show if

[00:55:00] Luteolin is present in the brain, it does get in the brain. How much? I don’t know. But I’ve been begging for the last five years, companies or individuals to help me out because I’d like to make a nasal spray. Because, as you know, we communicate with the brain through the olfactory tract, so anything in the nose will get into the brain. The, the problem is that the FDA considers any nasal spray a drug. So if I were to put Luteolin or Methoxyluteolin for that matter, I cannot actually call it a supplement anymore. So, I was about to give up and now what I’ve decided to do, but I’m not quite there yet, is to take one known molecule that exists as a nasal spray and add the Luteolin, and we’re not going to call the Luteolin, we’ll call the Luteolin excipient if you wish, rather than an active ingredient. So it will be basically a nasal

[00:56:00] spray that exists in the market, but it will be plus let’s call it X whatever, and we will have the benefit of the Luteolin being there, but it’s not going to be called a drug. So now I’m trying to find a company to allow me to do that with them. So there’s still hope. Dr. Tania Dempsey: Such amazing stuff. Dr. Theoharides, we can talk for hours. If you would come back, we’d love to do a part two. There’s so many other questions and other things that I wanted to discuss with you, but I’m so appreciative of your time. How can the audience find you? Do you have a website or social media? Dr. Theo Theoharides: So first of all, my website has the corny name www. mastcellmaster. com. It’s been there for 40 years. However, by the end of January, there will be a drtheoharides. com, where I’m bringing the crystals down.

[00:57:00] So a lot of the Q& A over the years, I’m answering them. I’ve selected only salient papers that we’ll put in there. So it will be much easier for, especially patients to navigate it because the other side has just a lot of information. So hopefully this will be a little easier. You know, I don’t see patients anymore, as you know, although I consult with some colleagues, etc. So it, it’s difficult when, you know, I get, I get about 10 emails a week, and it’s difficult to answer because I don’t know what to do. In other words, I cannot refer them to except very few people and, and, some of the people that I might be able to refer them to, with all due respect, they’re very expensive as well. I’m not criticizing, you know, what the cost is, everybody calculates the cost, but, you know, when I was seeing patients, I would charge them 100 for an hour, you know, most of my colleagues would be 3, 000 for an hour, so, and they cannot afford it. So what I do is sometimes,

[00:58:00] you know, I’ll just call them and say, look, this is off the record, so to speak, but you can do X, Y, and Z, and most likely 60 percent of your symptoms will be, you know, lessened within, within a few months. So, the bottom line, just to leave with just a take home message, number one, I believe we should stop talking about Mast Cell Activation Syndrome. And talk about Mast Cell Activation Disorders, and include all of them there. Number two, we need a very good history, because if there are certain parts of the history that indicate autoimmunity, we should address them. Number three, many of these supplements, especially the liposomal supplements, like the ones, you know, by Algonot, could be very helpful, but it takes weeks to months to work. And lastly, there is some good evidence that vitamin D3, especially 2, 000 to 5, 000 units a day, has anti allergic effect. So what do we have to do to add

[00:59:00] that? And if there are some individuals who cannot tolerate any of that, there is now two papers that Berberine, which I use a lot for people that have been exposed to mold, etc., can also block mast cells. So we might have some choices for those individuals who just cannot tolerate anything. And lastly, duration is much more important than amount. I’d rather we give a little bit and increase it over time to the extent tolerated, then try to give a lot, and then lose the patients because they’re not tolerated. So, I tell them all, just start with a tenth, if need be, of whatever you can tolerate, and every day just increase it a little bit, until you get to a point where you get whatever benefit you can get, and you don’t get any symptoms, and you’ve got to be patient. But after all, many of these patients have gone through 10 years of searching, so being patient for a few months shouldn’t make that much of a… Dr. Tania Dempsey: Excellent advice. I couldn’t agree more.

[01:00:00] Absolutely. Dr. Theo Theoharides: The company site, of course, is www. algonot. com, and we’ve got a wonderful person, you know, answering the phone, and we’ll spend half an hour talking to the patient and calming them down and taking, you know, everything in. And most of the time I will answer, you know, if someone has a complicated problem, I’ll answer them. And I’ll just say, look, you know, I’m not giving you medical advice, but here are some pointers. Jill Brook: Well, Dr. Dempsey, Dr. Theoharides, this has been amazing. I hope we can do a part two soon. You two just have so much incredible information. We thank you for your work. Dr. Theoharides, we thank you for not retiring yet. Dr. Theo Theoharides: I’m talking to you ladies, scientists, I’ll never retire. Jill Brook: Oh, good, good, good. Oh, you’re just amazing. Just a million thanks. And hey listeners, that’s all for today, but thank you for joining us. May your health be good to you, and please join us again soon.