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Episode 51: All Things Mast Cell with World-Renowned Clinical Researcher Dr. Theoharides

Kara Fitzgerald, ND
All things Mast Cell with World-Renowned Clinical Researcher Dr. Theoharides

All things Mast Cell with World-Renowned Clinical Researcher Dr. Theoharides

Listen to Episode 51

Summary (full transcript below)

In recent years, mast cell diseases have become a hot topic in functional medicine and Dr. Theoharis Theoharides has been at the forefront of the research on mast cells. He was the first to show that mast cells are involved in a wide range of allergic reactions and inflammatory conditions, including allergies, asthma, eczema, psoriasis, migraines, multiple sclerosis. He’s also investigated mast cells and autism.

What’s more, he’s demonstrated that certain flavonoids inhibit mast cell-driven inflammatory processes, and he’s patented these flavonoids as dietary supplements. In this podcast, Dr. Fitzgerald talks to Dr. Theoharides about our understanding of mast cell’s involvement in disease development, and how clinicians can test for and help treat patients with mast cell disease.

In this podcast, you’ll hear:

  • About the role of mast cells in common conditions (like asthma and atopic dermatitis) and rare conditions (mastocytosis)
  • About mast cell involvement in conditions like fibromyalgia and cancer
  • The criteria for defining mastocytosis and why some of the criteria are problematic
    About tryptase and its usefulness as an indicator of mast cell load
  • The unreliability of certain lab tests (and lab testing companies) in diagnosing mast cell conditions
  • The nuances of testing for mast cell conditions
  • The role of parathyroid hormone in triggering mast cells
  • Possible prophylaxis for migraines
  • How most chronic conditions have mast cell involvement
  • The usefulness, and limitations, of food intolerance testing
  • The dearth of pharmaceutical mast cell blockers, and the lack of progression in antihistamine research and development since the 1940s
  • Why mast cells aren’t always the bad guy
  • Mast cells role in cancer
  • The protective properties of the flavonoid luteolin and its potential beneficial roles in breast cancer
  • The proper dosage for flavonoids (and the dangers of overdosing)
  • Next-step treatments when patients don’t respond to antihistamines
  • When the use of low-dose Naltrexone is appropriate
  • How the dyes used in over-the-counter drugs may trigger reactions that the drugs are designed to
    treat
  • How to diagnose a phenol intolerance
  • How supplements misrepresent their flavonoid content
  • The importance of avoiding antihistamines that contain a decongestant

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Theoharis C. Theoharides, BA, MS, MPhil, PhD, MD, FAAAAI

Dr. Theoharides is Professor of Pharmacology and Internal Medicine, as well as Director of Molecular Immunopharmacology and Drug Discovery, in the Department of Immunology at Tufts University School of Medicine, Boston, MA.

He was born in Thessaloniki, Greece, and graduated with Honors from Anatolia College. He received all his degrees with Honors from Yale University, and was awarded the Dean’s Research Award and the Winternitz Price in Pathology.

He trained in internal medicine at New England Medical Center, which awarded him the Oliver Smith Award “recognizing excellence, compassion and service.” He also received a Certificate in Global Leadership from the Tufts Fletcher School of Law and Diplomacy and a Fellowship at the Harvard Kennedy School of Government. He has been serving as the Clinical Pharmacologist of the Massachusetts Drug Formulary Commission continuously since 1986. In Greece, he served on the Supreme Advisory Health Councils of the Ministries of Health and of Social Welfare, as well as on the Board of Directors of the Institute of Pharmaceutical Research and Technology. He Chaired an International Committee appointed by the Hellenic Ministries of Education and Health for the establishment of an independent medical school in Greece, and he is a member of the International Advisory Committee for the University of Cyprus School of Medicine.

He is a member of 15 academies and scientific societies. He was inducted into the Alpha Omega Alpha National Medical Honor Society and the Rare Diseases Hall of Fame. He has received the Tufts Excellence in Teaching ten times, the Tufts Distinguished Faculty Recognition Award twice, the Tufts Alumni Award for Faculty Excellence, Boston Mayor’s Community Award, and the Dr. George Papanicolau Award, as well as Honorary Doctor of Medicine from Athens University, Honorary Doctor of Sciences from Hellenic-American University., and the 2018 Albert Nelson Marquis Lifetime Achievement Award (Marquis Who is Who). He is “Archon” of the Ecumenical Patriarchate of Constantinople.

He first showed that mast cells, known for causing allergic reactions, are critical for inflammation, especially in the brain, and are involved in a number of inflammatory conditions that worsen by stress such as allergies, asthma, eczema, psoriasis, migraines, multiple sclerosis and most recently autism spectrum disorder. He has also shown that corticotropin-releasing hormone (CRH), neurotensin and substance P, peptides secreted under stress, act together, and with the cytokine IL-33, to trigger mast cells and microglia to secrete inflammatory molecules. These processes are inhibited by the novel flavonoids, luteolin and tetramethoxyluteolin that he has helped formulate in unique dietary supplements and a skin lotion. He has published over 410 scientific papers (JBC, JACI, JPET, NEJM, Nature, PNAS, Science) and 3 textbooks with 30,501 citations (h-factor 86) and he is in the top 5% of authors most cited in pharmacological and immunological journals. He has received 37 patents and trademarks, including three patents covering the use of luteolin in brain inflammation and autism: US 8,268,365 (09/18/12); US 9,050,275 (06/09/15); US 9,176,146 (11/03/15). He is also the President of Theta Biomedical Consulting and Development Co., Inc., of BiomedAdvice, LLC, of Algonot, LLC and of the nonprofit Brain-Gain.org

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Show Notes

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Full Transcript

Dr. Kara Fitzgerald: Hi everybody, welcome to New Frontiers in Functional Medicine where we are interviewing the best minds in functional medicine. Today is no exception. I’m your host, Dr Kara Fitzgerald. Hey, if you are enjoying our podcast, we’ve been doing it for years now, please consider circling over to iTunes for us and leaving a review.

All right, today I am just thrilled, thrilled, thrilled to be interviewing Dr. Theoharides. I’m so sorry, Dr. Theo. I don’t want to mangle your beautiful name, meaning God’s grace. Dr. Theo, we’ve been trying to get him booked on the program now for over a year. He’s a brilliant clinician/scientist. Let me give you his background. We’ll jump right in. He’s professor of pharmacology and internal medicine as well as the director of molecular immunopharmacology and drug discovery in the Department of Immunology at Tufts University School of Medicine in Boston. He was born in Greece and graduated with honors from Anatolia College there. Then he went on to do all his graduate work at Yale University. He’s in the Tufts School of Medicine now where he’s been teaching for some years. He’s just received virtually every award that there is.

It’s actually kind of amazing reading his bio. He’s a beloved teacher at Tufts. He’s in about 15 academies and scientific societies. He has published in over 400 papers, folks, in really top-tier journals, including the New England Journal of Medicine, Nature, Proceedings in the National Academy of Science. He’s published in Science. He’s got a few textbooks under his belt and has many, many patents.

His research, so he was the first to show that mast cells, known for causing allergic reaction or critical for inflammation, especially in the brain and are involved in a number of inflammatory conditions that are worsened by stress such as allergies, asthma, eczema, psoriasis, migraines, multiple sclerosis. Most recently, he’s been looking at autism. He’s also showed the connection that corticotropin releasing hormone, neurotensin substance P are peptides secreted under stress that act together releasing interleukin 33 to trigger mast cell and microglia to secrete inflammatory molecules. He’s gone on to demonstrate these processes are actually inhibited by novel flavonoids, specifically luteolin and tetramethoxyluteolin. He’s formulated dietary supplements and actually holds patents on these products. He’s been making them available to us clinicians as well as the public for some years now.

Today, we’re going to be talking about all things mast cell activation syndrome and then beyond that, histamine-related conditions in general. Dr. Theo, before we jump into the meat of our talk today, I just wanted to ask you, being so firmly entrenched in the hallowed halls of academia and science and doing your graduate work at Yale, which is a pretty conservative university as well as now you’re in Tufts, how did you leap over to studying botanicals, to studying flavonoids?

Dr. Theoharis Theoharides: It’s a great question. It takes me back actually to good work done in 1972-1973. When I was doing, actually, my doctoral work at Yale, which I started before medical school and then I went back to it, I studied basically a drug that we can probably talk a little bit about later, which is called disodium cromoglycate or cromolyn. Of course what’s known as gastrocrome. I was looking at the structure of that. In fact, my first publication ever, before I even graduated was in Science on cromolyn. I looked at the structure of cromolyn. Cromolyn was very difficult to put in solution. It also wasn’t really that good of an inhibitor of mast cells, even though it did inhibit rat mast cells very well. It did not inhibit human mast cells almost at all, to which we can actually return later. I did a computer search using the structure, chemical structure library, and it appeared, if you just imagine cromolyn being a butterfly with two wings. Each of the two wings is 90% similar to flavonoids.

Dr. Kara Fitzgerald: Fascinating.

Dr. Theoharis Theoharides: I started thinking about flavonoids, but of course at that time, as you correctly stated, my professors were very conservative. They didn’t even want to consider thinking about flavonoids. May I remind you, well, not that you should know, but I have two mentors. One was Bill Douglas who was a member of the Royal Academy of Sciences in England. The other was Paul Greengard who got the Nobel prize in physiology and medicine in 2000. In my external examine for my PhD was George Palade, who had just received the Nobel prize. You can imagine the climate at that point. I tucked it away.

I was thinking about it and then came to Tufts and strangely in 1998, I got actually a phone call from the wife of Dr. Middleton. Now you may not know the name, but the classical textbook Allergens and Immunologic Diseases is Elliot Middleton. I was absolutely surprised, because Dr. Middleton had written numerous papers on flavonoids and mast cells. As it turned out, he had just died. His wife said that he had actually left in his will, which absolutely flabbergasted me, that I should actually write a review to finish his work. I was like, “Oh, wow.” Make a long story short, I worked for two years. My review on flavonoids was published in Pharmacological Reviews in 2000 and has received about 7,000 citations just that alone.

From then on, it was nonstop. We can stop there, so we can pick up the rest and I can give you some other stories later.

Dr. Kara Fitzgerald: Yes, it’s extraordinary really. Thank you for sharing that pearl. It’s just, it’s amazing to me how the journey connects. Let’s just jump into mast cell activation syndrome. What is it? Just distinguish it from the growing, it seems, family of histamine associated conditions like allergy and intolerance and all the others.

Dr. Theoharis Theoharides: I think I’ll start by using the title mast cell diseases. Actually, I’m going to be the keynote speaker in Halifax, Canada on the 16th of September. Invited but the Canadian Allergen Clinical Immunology Association and the title is actually mast cell diseases. Now, why do I start with that? Because as you know, mast cells are involved in a number of diseases that we know very well, such as atopic dermatitis, such as rhinitis, such as asthma. Then we have the more rare conditions such as mastocytosis , where by definition you have to have a lot of mast cells clustered in islets of your bone marrow, and their shape rather than being oval or round tends to be spindle shaped. The only known specific molecule associated mast cells, tryptase has to be high.

Even with that, there are conditions where we don’t know what to call them. For instance, in interstitial cystitis which is otherwise called bladder pain syndrome, we have bladder mastocytosis. In fact, we have almost identical conditions to what was in the bone marrow, but in these patients tryptase is not high and the bone marrow is not involved. Yet, the bladder is involved. In Europe, bladder mastocytosis, one of the criteria for calling someone having interstitial cystitis. In the United States, my colleagues don’t use it because they don’t want to biopsy the detrusor muscle in fear that they might actually perforate.

Then we have conditions where we suspect mast cells are involved such as myalgic encephalomyelitis, chronic fatigue syndrome, such as fibromyalgia. Then we have conditions such as cancer where around solid tumors, we have collection of mast cells as well. Technically all of these involve mast cells to one degree or another.

The strange thing is, and that’s where the word in the tear muscle activation is very confusing to everybody, including myself, because you can have therefore either a normal number of mast cells or high number of mast cells. We call it a master load. At the end of the day, you could have a lot of mast cells, but if they’re not actually stimulated by anything, then probably nothing’s going to happen. In fact, what we call indolent systemic mastocytosis, so these individuals do have high tryptase in their serum, they do have actually positive bone marrow biopsy, but they live actually, have a normal lifespan. Their only problem is that have a lot of symptoms derived from mast cells.

Some years back, Dr. Jim Aiken, who was in Michigan then he went to Harvard then he’s back in Michigan, and Peter Valent from Austria decided to call a condition mast cell activation if in fact the mast cells seemed to have been activated, and we’ll talk about the word activation in a second, without necessarily however, having either atopic dermatitis or asthma or bladder mastocytosis or cancer. You see where I’m going?

Dr. Kara Fitzgerald: Yeah, yeah.

Dr. Theoharis Theoharides: In other words, you exclude all those conditions. You’re left with patients that have all the telltale signs of mast cell activation, but we don’t know what to call them. Then they made the diagnosis even more complicated, because they said you could either have mastocytosis, mast cell activation or you could have mast cell activation without mastocytosis. In other words, you could have systemic mastocytosis, but if you don’t have symptoms, you live your life, so to speak, and you have a pathologic diagnosis. If you have symptoms, you have mast cell activation. Therefore, mast cell activation is mostly a description, even though it became an entity. As I said, you can have mastocytosis with mast cell activation, without mast cell activation.

Now, having said all of that, the real problem was how they defined it. Now it’s getting worse. The definition had four criteria. You have all the symptoms, meaning you’re flush, you have itching, you might have headaches, some diarrhea, everything that is associated with basically mast cell activation. If you take some of the drugs that we have to use, such as anti-histamines such as antileukotrienes, steroids, if you do better, that’s the second criteria.

The third criteria was that during an episode and within a window four hours of the episode, serum tryptase should be elevated, which I think is absolutely useless, because I’ve never had a patient who can manage to have serum drawn during an episode and sent, actually for measurement of tryptase. There are only a few labs in the United States that do that, so clearly hardly any patient will qualify unless you happen to be in the hospital at that time.

The fourth criteria, which was a little more useful, was measuring breakdown product of histamine and prostaglandin. The breakdown product of histamine would be methylhistamine or methylimidazole acetic acid, which is abbreviated MIAA or the breakdown product of prostaglandin D2, which is 17 beta-prostaglandin F2-alpha. The urine has to be 24 hours. It has to be kept cold and sent to the lab cold. I had numerous patients where the urine actually came to room temperature, and it was useless. The only lab that does that, that I trust and even Harvard sends it there is actually the Mayo Clinic where Dr. Butterfield is.

Now, for some reason, even though as I said, there will be a whole day workshop on September 7th at NIH, sponsored by NIH, specifically I am, about 15 colleagues including actually, Dr. Jamaican, and Peter Valent, who’s the first author and whole bunch of others, wrote this letter, which now impressed, if you go to PubMed, you will see it, where they basically tried to do two things. One thing is I think legit. The other thing is actually a disaster.

The legit part is that they’re pointing to the fact that everybody now is flooded by patients that come in. They say, “I have mast cell activation syndrome.” In fact, I have called in bona fide allergists who beg me not to send anybody, because their practice is collapsing. They cannot recoup through insurance and takes much longer. They don’t know what to do, etc.

Dr. Kara Fitzgerald: Yes, yes.

Dr. Theoharis Theoharides: They’re paying attention to the fact that we have to be a little more cautious about who really has this syndrome, so far so good. Then they drop the fourth criterium, which was actually the urinary metabolites. Dr. Butterfield had published a very good paper, I’m sorry that he’s actually one of the 15 authors of this letter, where he had shown, he took actually both tryptase in the serum as well as methylhistamine and PGF2 alpha, and he actually said that the combination of methylhistamine and PGF2 alpha was the best possible way of selecting these patients. Through all of those, the prostaglandin metabolite was the best, not tryptase, not histamine or methylhistamine.

Having said that, now we’re stuck that hardly anybody will qualify as MCAS going forward, which is sad because the mastocytosis society had tried very hard and MCAS is included in the insurance, basically a jargon so you can actually have tests covered. Now in addition, which is really what worries me most, and I’ve been saying this, is that even though tryptase is the only specific molecule for mast cells we know, what good does it do if number one, it’s not elevated in most patients with MCAS, and in addition, we’ve no idea what it does and we have no way to block it. My take was, and this is what I will be saying at this conference as well, “Sure, tryptase is specific, but at the end of the day, if a patient does not have any other serious problem like inflammatory bowel disease or Lupus or something like this, if any mediator that can come from the mast cells is high. that’s good enough for me.” I don’t care about tryptase.

In fact, I wrote a letter to their letter. We’ll see if it’s accepted for publication. I reminded my colleagues that I had published about 10 years ago and then two years later, Dr. Metcalfe who’s been in charge of the mast cell biologist section at NIH, and then Dr. Escribano just two years ago from Spain that interleukin-6 levels in the serum of patients with mastocytosis actually track with disease severity …

Dr. Kara Fitzgerald: Oh, really?

Dr. Theoharis Theoharides: … and prognosis better than tryptase. I reminded them that we all published, three different people, different cohorts of patients, and yet no one is talking about it. Having said all of that, and I gave you an earful, I don’t know which way the field will go. As far as I’m concerned, if someone has the symptoms that are an admission of mast cell activation, I will treat them as such, unless there’s another reason why. Now you can either ask me a few questions or I can go into what would be the reasons why if you want.

Dr. Kara Fitzgerald: Well, that was just a really remarkable introduction. You’ve already covered some of the labs. Let me just say that interleukin … I just want to … Let me just flesh out some of the lab pieces and then we’ll jump back into the presentation and what else we might be looking for, because I think that’s incredibly important. I just want to underscore some of what you’ve said. For instance, we can easily get interleukin-6 at a standard reference lab like Quest or LabCorp.

Dr. Theoharis Theoharides: Correct.

Dr. Kara Fitzgerald: That would be a great marker for us to consider tracking.

Dr. Theoharis Theoharides: Correct.

Dr. Kara Fitzgerald: You said that that tracks with tryptase, however, which …

Dr. Theoharis Theoharides: No, no, no, no. I said he tracked with severity of disease while tryptase does not.

Dr. Kara Fitzgerald: Okay. Oh, excuse me. Thank you for that. I really …

Dr. Theoharis Theoharides: I consider tryptase an indicator of mast cell load. If someone has mastocytosis and they have a lot of mast cells, there will be a lot of tryptase, of course.

Dr. Kara Fitzgerald: Well, and I haven’t seen … I’ve measured tryptase plenty of times in my exploration around this. I think I’ve seen one nudging towards positive once, but everything else is clearly negative. That four-hour window, as you pointed out, is impossible.

Dr. Theoharis Theoharides: It is. Before we go onto the measurements, as you know another colleague who actually is from Dr. Metcalfe’s laboratory at NIH, a year ago, published a paper in the Journal of Nature, and now he calls a new entity, which is actually high tryptase that he calls it tryptasemia.

Dr. Kara Fitzgerald: Interesting.

Dr. Theoharis Theoharides: I don’t know if you’ve heard about it.

Dr. Kara Fitzgerald: I haven’t. That’s fascinating.

Dr. Theoharis Theoharides: That is actually even more confusing, because number one, the levels that he considers high enough for him to call a patient having tryptasemia are below the cut off point.

Dr. Kara Fitzgerald: Oh, isn’t that interesting.

Dr. Theoharis Theoharides: In other words, 14 or about 14 is the cut off point. Most of these patients hovered about 10 to 12, yet he called that a new entity, even though it’s below. If it’s below, then why don’t we call them MCAS patients, tryptasemic patients, you know?

Dr. Kara Fitzgerald: Right.

Dr. Theoharis Theoharides: The only difference is that in his studies and the study was very good, those patients with tryptasemia, even though, as I said, it’s below the cut off point, were familial. For some reason, they were tracking the same families, which makes it a little more interesting.

Dr. Kara Fitzgerald: Yes, that’s fasc- …

Dr. Theoharis Theoharides: I just wanted to mention that that’s out there, so if you hear it, don’t get confused. It’s not MCAS. It’s something else.

Dr. Kara Fitzgerald: It is. Well, we might be seeing that in practice though. I have seen a couple of patients nudging up in that direction. By and large, I’ve found the test to be entirely useless.

Dr. Theoharis Theoharides: I agree. I agree.

Dr. Kara Fitzgerald: We can get N-methylhistamine. We can get 17 beta-prostaglandin alpha. Given the fact that they have to be maintained cold, the patient obviously has to be really correctly educated, and I’m thinking that it’s probably best for us, the clinicians to mail it cold to Mayo rather than giving it to Quest where it might be improperly handled.

Dr. Theoharis Theoharides: I don’t trust Quest for the urine metabolites, to be honest.

Dr. Kara Fitzgerald: Okay. All right, so we want to send it directly to Mayo and pack it as they tell us.

Dr. Theoharis Theoharides: By the way, what I’ve done recently, and I’ve done that more, as you probably know, I see a lot of patients in Greece, in Cyprus. By the way, if any of my colleagues, our colleagues or any of your patients, want to have a really nice vacation and get everything done, they can come to Cyprus for 10 days and have a gorgeous vacation.

Dr. Kara Fitzgerald: Oh, my gosh.

Dr. Theoharis Theoharides: We’ll get all the labs on day one. By day 10, they’ll have all the results back. We’ll tell them what to do.

Dr. Kara Fitzgerald: Well, I think I’ve just developed MCAS myself.

Dr. Theoharis Theoharides: Come join me. I’ll be there in the first two weeks of October.

Dr. Kara Fitzgerald: That’s wonderful. That sounds like a great vacation.

Dr. Theoharis Theoharides: The reason I mentioned it is because what I’m about to say, I did actually there. I collected both 24 from Cyprus. We sent it actually to a lab in Germany, which is very good for measurements. We collected both 24-hour urine as well as first morning urine.

Dr. Kara Fitzgerald: Okay.

Dr. Theoharis Theoharides: Unless someone has nocturia, the results were about the same.

Dr. Kara Fitzgerald: Oh, interesting.

Dr. Theoharis Theoharides: That makes it much easier for a patient. Roughly the first morning urine collection about eight hours worth of urine during the night. We got the same results. Now, looking at your questions, I just wanted to mention I never measure histamine in plasma. Histamine is degraded within one minute in the blood. Unless with basophils, which are very similar to mast cells secreting, I never use it. As you know, there’s what is called a basophil activation tests.

Dr. Kara Fitzgerald: Yes.

Dr. Theoharis Theoharides: Some laboratories call it, actually most properly anti IgE receptor test. I only do that if I suspect autoimmune eczema. Atopic dermatitis, 50% of it is allergic, 50 is not. If I worry about it, then I may actually do that. When you ask whole blood histamine, you say about 70% upper limit improves the sensitivity of the test. I never measure histamine. IgE, I always do. Many patients have very high IgE. That does not mean that that will have mast cell activation, but that’s, for me, a telltale sign to look for other reasons that they might have problems. As you know, that in mastocytosis and in mast cell activation patients, the incidence of allergies is about the same as in the general population. It is all the other triggers that actually trigger the mast cells in both mastocytosis and mast cell activation.

Dr. Kara Fitzgerald: Oh, interesting, so you can see two separate conditions that are both …

Dr. Theoharis Theoharides: Correct.

Dr. Kara Fitzgerald: … mediated by histamine and similar cytokines.

Dr. Theoharis Theoharides: Correct. The only difference is that the systemic mastocytosis patients, they can have this 15-times higher chance of having an anaphylactic reaction to wasp stings, to hymenoptera stings. That is different than the general population. For some reason, only for hymenoptera stings not anything else.

Dr. Kara Fitzgerald: That is fascinating.

Dr. Theoharis Theoharides: Now, when I actually am presented with a patient that has especially headaches and diarrhea as well, there are a few things that I absolutely want to measure. One is parathyroid hormone. We and others published almost 20 years ago that PTH is a very strong trigger of mast cells. I want to make sure, especially if you know someone’s calcium is a little high or in the urine or in the blood, then I want to make sure that I’m not missing that. Also, there are benign VIPomas. They release vasoactive intestinal peptide. If a patient has a lot of diarrhea and I cannot figure out what is going on, I will measure VIP. Both LabCorp and Quest could measure those.

Dr. Kara Fitzgerald: Would you say that those are common underlying causes?

Dr. Theoharis Theoharides: No, they’re not.

Dr. Kara Fitzgerald: Okay, so those are the outliers.

Dr. Theoharis Theoharides: Right, but if I’ve been tracking mediators for instance, and I don’t know what on earth is going on and antihistamines don’t seem to be helping very much, then at least I want to make sure that I’m not missing something that might be correctable. Also, if someone has a lot of headaches and all of these patients are miserable because of the headaches and migraines, I will measure the molecule called CGRP, calcitonin gene related peptide. Not only is it a very strong trigger of mast cells, but as of a few months ago, there is now a CGRP receptor antagonist for prophylaxis of migraines.

Dr. Kara Fitzgerald: Oh, interesting.

Dr. Theoharis Theoharides: Finally, if someone has a lot of edema and many patients actually do have edema, I will measure both bradykinin and D-dimer. Bradykinin because again, it’s a trigger of mast cells. It’s associated with edema. We also have bradykinin receptor antagonist. In Europe, D-dimer, which routinely we measure if we suspect sepsis clotting, whatever. In Europe D-dimer is one of the well established indices of edema.

Dr. Kara Fitzgerald: Oh, interesting. Okay.

Dr. Theoharis Theoharides: I went a little off topic here …

Dr. Kara Fitzgerald: But that’s …

Dr. Theoharis Theoharides: Lets get back on track.

Dr. Kara Fitzgerald: Yeah, that’s actually great. We will have the transcript folks. It’s there available to you in the show notes, so that you can comb through this and pull out some of these pearls for laboratory assessments. It’s extremely useful. Now, if I heard you correctly in your introduction, it seems to me that many, if not most, chronic conditions that we’re seeing in clinic can have mast cell involvement. Would you say that’s true?

Dr. Theoharis Theoharides: Absolutely, yes.

Dr. Kara Fitzgerald: Okay. Now what do we do about it?

Dr. Theoharis Theoharides: We’re jumping a little bit ahead.

Dr. Kara Fitzgerald: I know we are, sorry.

Dr. Theoharis Theoharides: Don’t worry about it. I know I’m cognizant off the time too, actually.

Dr. Kara Fitzgerald: Well, well, okay. Yeah. Let me … Actually, before… I don’t want to jump into treatment. I guess what I want to say is in terms of our diagnosis, so a patient comes to me with cardiovascular disease. I’m going to be thinking, putting it in my chart down in the assessment or in my differential. I’m thinking about mast cell involvement, but like what … I guess, so we know it’s involved in everything. We will move onto discussing treatment. That’s incredibly important, because I know that you’ve got a lot of pearls to offer us there. In terms of the standout mast cell conditions, can we just again go through when am I going to be, as opposed to being perhaps secondarily involved in the pathogenesis. I mean, what are my priority conditions for patients coming to me?

Dr. Theoharis Theoharides: Oh, I hear you, and I’m about to answer, but why did you bring a cardiovascular patient as an example?

Dr. Kara Fitzgerald: Well, I guess the reason that I did is because as you gave your elegant introduction to mast cell involvement, and I think also just having looked at some of the papers, it seems like it’s a potential. It’s the potential pathogenic piece.

Dr. Theoharis Theoharides: You’re right. I just thought you might have a particular question in mind, because I can actually address the cardiovascular disease patient. First let me say, I’m starting so pedantic that I apologize. If I see anybody, especially children, but adults with black circles under their eyes, unless they haven’t slept for a week, that’s a telltale sign they have an allergic, a sort of diathesis. Let’s call it that. You can call them moonshiners, whatever you want to call them. I don’t think I’ve missed any patient in 30 years that literally didn’t have that. Now in addition, I will scratch every one of those patients under the underarm with my nail to see if I can elicit a Darier’s sign or dermatographia. Most of these patients, they have the dark circles, will actually respond. That alone indicates that the mast cells in the skin responds to pressure, which has nothing to do with allergies. Those patients are likely to have, mast cell activation of some sort. By definition, the mast cells are activated by pressure.

Then I will start chasing those down. Whether the presenting … If they came in with a cardiovascular problem, but in the history they tell you, “Well, I get bitten by a mosquito, and I get a huge swelling, I get diarrhea. I scratch like crazy every now and again, etc.” All of those are telltale signs of something is happening. I will do obviously the Ig levels. They might be important for treatment, which I will come to. I will definitely do a RAST test for at least 10 antigens. I will cover obviously casein, gluten. I always cover alpha-gal, which is important in meat, as you know.

Dr. Kara Fitzgerald: Oh, yes. Absolutely, yes.

Dr. Theoharis Theoharides: We didn’t used to do that. Now we do. Of course, I’ll cover some pollens depending on what the patient says. I will definitely cover at least a five fungi, molds of some sort.

Dr. Kara Fitzgerald: What do you think? I mean, area specific for the various molds?

Dr. Theoharis Theoharides: I would say area specific. Some molds are actually common in pretty much every house to some extent, so I’ll cover those. We’ve got, I mean, I can send you the list if you want.

Dr. Kara Fitzgerald: Yeah, we can put it in the show notes.

Dr. Theoharis Theoharides: Sure. By the way, the journal Clinical Therapeutics, which is online so anybody can actually download for free, last June, the issue actually it was about mold and immunity. I think I sent you the PDFs.

Dr. Kara Fitzgerald: Yes, yep. We have that. I have that. Thanks.

Dr. Theoharis Theoharides: By the way, if any of our colleagues want to download anything, you can actually give them my site. It’s a little corny name, but it’s mastcellmaster.com. All my presentations and publications and what have you are there that can be downloaded from there.

Dr. Kara Fitzgerald: Perfect. Yep, we will absolutely list that. Go ahead.

Dr. Theoharis Theoharides: Going back to the … I’ll cover some fungi. In my experience, about 80% of the people that have problems, turn out to be negative on RAST. Then I will at least do a food intolerance test even though many of our colleagues don’t believe in the food intolerance. I’ll tell you why they don’t believe it. I find it’s actually very useful with two caveats. The two caveats, one is that most laboratories measure IgG4. I like to measure IgG1 and and IgG4. I’ve sent actually blood to three different labs from the same patient. The results were very different. The one that measures IgG1 and IgG4, ended up giving me the fewer sensitivities, which I believe were actually closer to the truth. I’ve nothing to do with this lab and that may be more. One is called Pinner test, P-I-N-N-E-R, in New York. They will send basically a kit. You basically stick your finger just like doing sugar testing. You sending it back to them. They send you the result.

Dr. Kara Fitzgerald: That’s great to know that. Yes, I agree with you that IgG1 and IgG4 is it.

Dr. Theoharis Theoharides: Right, and now I tend to measure total IgG1 and IgG4 as well if I really suspect.

Dr. Kara Fitzgerald: Oh, you do?

Dr. Theoharis Theoharides: Yes.

Dr. Kara Fitzgerald: Okay.

Dr. Theoharis Theoharides: The second caveat is that if someone eats for three, four days or longer, the food substance you suspect, it turns out to be false positive. I’ve seen it numerous times. I ask patients not to eat most of the things I suspect for about three days before giving blood for a food intolerance test. If you had an egg everyday, it will turn out to be positive. Now in children, this becomes a little difficult because you don’t want to starve a child. I usually tell families the most innocuous substances that are hardly ever see any sensitivity would be rice and chicken. You can feed a child rice and chicken for three days and do all the rest, so to speak.

Dr. Kara Fitzgerald: Now, wouldn’t the reference range control for exposures?

Dr. Theoharis Theoharides: Well, it depends what you mean by control. Many labs will give you a horizontal line that goes from green to red. Others will give you three pluses. It varies. Others will give you numbers. Usually the numbers are below 20. In those lab tests that they give you the numbers, I almost don’t pay attention to them. If something comes out of 140, then I start worrying about it. Officially, the academies don’t believe in the food intolerance test.

Dr. Kara Fitzgerald: Right.

Dr. Theoharis Theoharides: I understand.

Dr. Kara Fitzgerald: Tell me why. I mean I know that they don’t, but …

Dr. Theoharis Theoharides: They don’t because number one, no one has done really good testing and shown the results, to be honest. Second, because most of the labs measure IgG4 and it turns out to be positive to everything under the sun. It’s almost not believable. I guess that.

Dr. Kara Fitzgerald: Okay, okay.

Dr. Theoharis Theoharides: I think it will, eventually they will move away, especially as we’re learning more and more about IgG1 and IgG4. Clearly, the mast cells can be activated through an IgG receptor as well, not just the IgE in addition to all the other 100 different triggers that we got.

Dr. Kara Fitzgerald: Yes. So I just want to clarify a few things for myself and for the listeners.

Dr. Theoharis Theoharides: Sure.

Dr. Kara Fitzgerald: You’ll see the allergic bias in many of the mast cell activation patients, but it’s not necessarily a significant player. One of the ways that you actually distinguish that IgE involvement is less significant, if I heard you right, is by just doing the skin test and seeing if you can locally activate mast cells by basically, you said, just scratching.

Dr. Theoharis Theoharides: You can do the skin test, but as you know, pretty much if the RAST turns out to be positive, the skin will be positive. In fact many colleagues, for good reason, want to do the skin to absolutely document there is actually an allergy. Most of the patients that are MCAS, in these patients and many of the other categories that we mentioned are not positive. That’s why many of our colleagues, the allergist, will send them away and say, “You’re not allergic.” What are you? That’s where we end up talking about activation. Then we got stuck with the tryptase.

Coming back to your patients, if someone has telltale signs over and beyond the presenting disease, let’s say that you might have a possible diagnosis, whether it’s cardiovascular disease or pituitary tumor or whatever, I will follow the mast cell activation in whatever way I can. We covered some of those. Now if someone’s presentation is even more suspected, for instance, both I and other colleagues have published that one can have a presentation of a myocardial infarction because of activation of mast cells in the coronaries.

Dr. Kara Fitzgerald: Fascinating.

Dr. Theoharis Theoharides: Okay. That’s well documented. If it appears that someone had what might have been a myocardial infarction, but it happened because he was stung by a bee or because he ate something and clearly that will become, the mast cells will come way up at the top of my list now. Even though the presentation was as an MI, for instance. If someone comes up with an explosive diarrhea and they don’t have C-diff or something else, I will definitely think of mast cells or VIPoma or, which I wanted to cover anyhow, I need to screen for carcinoid syndrome.

Dr. Kara Fitzgerald: Okay.

Dr. Theoharis Theoharides: As you remember, carcinoid syndrome is due to enterochromaffin cells, which are very much like mast cells, but the release primarily serotonin. That’s associated with enlargement of the right heart, because serotonin is broken down in the lungs, so nothing happens to the left heart. You get flushing, tremendous flushing, migraine headaches, but you don’t get as much scratching. That’s the differentiation. There, we measure chromogranin A in the blood. That, if you have chromogranin A that is high in that list, I usually do if I suspected three measurements over six months, because you can be episodic and we might miss it. If you do find it high, then you have to send 24 hour urine or maybe first morning urine for methylimidazole acetic acid. Now, it’s 5-hydroxyindoleacetic acid. The two are confused. MIAA is for histamine. 5-Hydroxylinoleacetic acid, 5-HIAA, is for serotonin. If those turn out to be high, then you’ve got to do actually an MRI of at least the abdomen to try to locate where the tumor might be.

One thing to keep in mind is if anybody’s on histamine two receptor antagonist like Famotidine or Ranitidine, especially Ranitidine, chromogranin A gives you a false positive. I will stop any H2 inhibitor for at least three, four days before looking for chromogranin A.

Dr. Kara Fitzgerald: Okay.

Dr. Theoharis Theoharides: Okay, you take me back.

Dr. Kara Fitzgerald: Okay. All right. Well, let’s talk about … Let’s just talk about … Well, first of all, would you say, I mean, you’ve been studying mast cells for decades now. Would you say that there’s a collective rise in the incidents of mast cell associated conditions happening?

Dr. Theoharis Theoharides: Yes, I think there are three factors. One factor is that we always focused on just histamine. What is surprising to me, also being a pharmacologist, is that even though histamine, the first antihistamines were developed in 1947 or so, we really haven’t done any much better in terms of antihistamines. We still don’t have good mast cell blockers. We’ll talk about those when we talk about treatment. As science moved forward and now we know that there are cytokines released, chemokines are released, peptides are released, etc, we’re becoming more and more aware that we might be able to pick up mast cell activation through those.

For instance, I think I might have made an enemy of a good friend. Dr. Marcus Maurer, Charite Hospital in Berlin, because his colleagues, his boss actually primarily. Three years ago they wrote a very large review in experimental dermatology on the reactivity of skin mast cells. They’re very good scientist, okay?

Dr. Kara Fitzgerald: Mm-hmm (affirmative).

Dr. Theoharis Theoharides: The journal asked me to write an editorial. The title of the editorial, which was a little offensive I guess, was “Are We Missing the Forest for the Trees?” The reason I said that was twofold. Number one, they were using mast cells from skin from circumcisions, because it’s very difficult to get actually skin from anywhere else unless you get it from mastectomies. Then you worry that the cells in the area of the mastectomy might have been affected by the cancer anyhow. Problem number one is that they reported themselves that among about 250 such, let’s call them subjects, from which they took the skin, reactivity to just IgM antigen just to that trigger varied as much as 200%. Therefore, we really don’t know, even in normal individuals why some mast cells fire more than others, even to just IgE, let alone all the other triggers.

The most worrisome part for me was that, at least in my 30 years of experience, I’ve never seen anybody unless they fell into poison ivy to have actually skin problems on their testicles or their penis. I’ve seen many patients with horrible eczema, but not there. They might have had eczema on their buttocks but not there. That means to me that those mast cells might not be responding necessarily as the rest of the scheme.

Dr. Kara Fitzgerald: Right.

Dr. Theoharis Theoharides: Then we know for sure in mice, if I take skin from the back of the mouse as compared to their abdomen, they respond very differently. All the mast cells are not the same, which of course is not surprising. At the end of the day, how we actually assess, as we started talking earlier, the mast cell reactivity should be the most important thing moving forward. That’s what I really want to stress during this upcoming workshop. We’re just stuck for years now on tryptase. We’re missing basically the forest for the trees. The mast cells are being activated, and as you said earlier in your kind introduction, we were the first to show the corticotropin releasing hormone released under stress will stimulate the mast cells, but they will not degranulate. For instance, borrelia from Lyme will stimulate the mast cells, but only cytokines are released. There are at least three papers or mycotoxins stimulating the mast cells, but only cytokines have been released. No degranulation. No tryptase release.

We published a paper last year in PNAS showing that if we use the peptide substance P together with interleukin-33, which is called an alarmin, we go from 10 units of TNF being released to 10,000 units. Yesterday, when another paper accepted in PNAS, there’s an embargo, so I can’t say very much about it, but the same results are with interleukin-1. Therefore, the mast cells can participate in inflammatory processes by releasing absolutely impressive amounts of both TNF and IL-1 beta. Again, as I said earlier, if there’s no other underlying condition that would explain why those are high, I will say they’re coming from the mast cells.

Dr. Kara Fitzgerald: That’s fascinating. I mean, because those are just fundamental cytokines, interleukin-1 beta, ILS-6, tumor necrosis factor that participate in most initiating steps of inflammation.

Dr. Theoharis Theoharides: What is amazing, many of the papers where you see, microphages were activated or released pertain to interleukin-1. You’ll see two-fold increase, threefold increase. Here I’m talking 10,000-fold increase from the mast cells, that no one suspected.

Dr. Kara Fitzgerald: That’s astonishing.

Dr. Theoharis Theoharides: It is. What really bothers me as we submitted an application to follow up on the results that were just accepted in PNAS to NIH, and the comments I’ve got back were not really science. One comment was mast cells don’t participate in psoriasis. Another comment was mast cells cannot possibly release IL-1. These are not scientific comments from the body that should be funding work. They should be saying, “Well, if your preliminary results show that, let them prove it.” Well now, it will be published in PNAS, but in the meantime, I didn’t get any grants.

Dr. Kara Fitzgerald: That’s remark- … That’s too bad. It’s really, I mean, it’s remarkable what you’re uncovering, the breadth and depth of mast cell involvement in a variety of pathology. It’s just mind blowing. Circling back to thinking about Lyme disease and mycotoxicity and the fact that they’re only releasing cytokines as opposed to turning on histamine and other chemo-, compounds involved in the classic mast cell cascade.

Dr. Theoharis Theoharides: Allergic reaction.

Dr. Kara Fitzgerald: I mean, what do you have to say about that in terms of treatment? Are you going to be approaching … You treat the underlying mycotoxicity and you address the Lyme disease. In terms of treating the, what appears to be sort of a mass cell activation process secondarily to the infection, are you still thinking about the same overall approach that you take for mast cell activation in general?

Dr. Theoharis Theoharides: I do. Let me just jump in a little bit here. I’ll enter it in two ways. One is that especially for diseases where there might be other organs that we have not thought about involved. Let’s talk about the brain for a second. One of the reasons why I got so excited originally about mast cell activation, because in the definition of the syndrome, it included for the first time, also neurologic complaint. I’m quoting. We were the first, well, among the first, was Dr. Borje Uvnas at Karolinska who published when I was a student, and then we published papers on brain mast cells. The hypothalamus and the median eminence that connects the hypothalamus to the pituitary has as many mast cells as our skin

Dr. Kara Fitzgerald: Wow.

Dr. Theoharis Theoharides: Yet they do not have Ig receptors. Obviously, they respond to other things.

Dr. Kara Fitzgerald: Yes.

Dr. Theoharis Theoharides: We also showed, this was also published a year ago in PNAS that histamine and tryptase and interleukin-one and TNF coming from mast cells and altering how we did that, activates human cultured microglia, which as we know are the defenders of the brain, because the brain doesn’t have T-cells and B-cells and what have you. I really believe that in diseases such as Lyme, where there’s a lot of neurological complaints, of chronic fatigue and obviously myalgic encephalomyelitis as it’s called now, post-Lyme syndrome, etc, the mast cells are activated. They then activate the microglia and cause a local inflammatory process that literally, excuse the expression, screws up the homeostasis of the body, because that’s where it is.

If you now take it a little bit as an extension, hypothalamus or the limbic system talks to the amygdala and the amygdala is what I really think happens in autistic patients or ADHD patients. In fact, now we’re doing some experiments on exactly that. We showed, I’m jumping as an aside, we collected through NIH, samples from children that died from car accidents, drowning, whatever that either were otherwise neurotypical or they had autism. We analyzed with quantitative PCR, the presence of one micro RNA. Again, some of you might not remember, but the micro RNAs can regulate messenger RNA in the cytoplasm. One micro RNA is particularly proinflammatory. We’re showing that it was very high in the amygdala and not in the cortex of these children. Then we showed that when the mast cells are activated and they activate microglia, that micro RNA goes up as well. We’re linking all of this now through molecules that we never thought about such as micro RNAs.

Dr. Kara Fitzgerald: Fascinating.

Dr. Theoharis Theoharides: I think that we will be finding a lot more.

Going back to the conditions, if I could block the mast cells and/or block the microglia as well, I will block them. Now many times students and other colleagues tell me, “Well my god, if the mast cell is useful for something …” I’m sure it’s got some useful functions. For instance, mast cell is actually involved in wound healing. We can talk about this if we have time later. What happens? I give them the reply, which it’s a little corny reply. You recall back in the ’30s psychotic patients who were put in asylums. Some of you may remember One Flew Over the Cuckoo’s Nest where there’s a lobectomy on someone. Well, during the ’40s, one physician from New York experimented with various drugs for the potential that might be anticancer agents. He was astute enough to realize that they were not anticancerous, but they were very sedating. That’s how basically anti-psychotic drugs were discovered. We still have the same blessed antipsychotic drugs pretty much. The antiepileptic in neuroleptics.

Do we know how the neuroleptics work? We still don’t really know. They might be blocking dopamine receptors, but maybe not. The patients are so much better that we don’t really worry about them. That’s the approach I will take. Let me block the mast cells, help the patients. If at the end of the day we find out in the process that maybe there could be a better way of blocking the mast cells, then I’ll take it.

To give you another example, mast cells are found around solid tumors. They’re 10 times as many mast cells around the breast cancer, for instance. However, the mast cells in the breast cancer do not degranulate. What the cancer cells to do, which is absolutely fascinating to me, is they release molecules that they block the mast cell from degranulating, in which case, tryptase, histamine, whatever have you were destroyed. They block the mast cell from releasing tumor necrosis factor. They selectively stimulate the mast cell to release vascular endothelial growth factor that makes, of course, new blood vessels and the cancer can actually feed itself and metastasize.

Dr. Kara Fitzgerald: Isn’t that remarkable. It would be interesting to actually study the mechanism by which …

Dr. Theoharis Theoharides: That’s exactly it. If I could actually turn the mast cell to do what I wanted, what we want it to do, we will have a little microcosm of pharmacology. We wouldn’t need to use as many drugs.

Dr. Kara Fitzgerald: That’s fascinating.

Dr. Theoharis Theoharides: I don’t necessarily see the mast cell as only a bad guy. I just don’t know how to unleash its good properties.

Dr. Kara Fitzgerald: Right. Well, and it’s interesting. I mean, you’ve been studying them arguably longer than pretty much anybody else as this carefully, really under the microscope. If you’re seeing how it’s influence in the pathology of so many different conditions versus the benefits of mass cells, it’s just, it’s…

Dr. Theoharis Theoharides: You may know that there’s been a few reports recently, fairly convincing that the mast cell has existed for 500 million years.

Dr. Kara Fitzgerald: Wow.

Dr. Theoharis Theoharides: Jellyfish have mast cells. Obviously, they don’t get allergic reactions. These are in fish, octopi have mast cells. We really, I and some colleagues believe that the mast cell serve the function of various, what turned out to be later developed systems, like hormonal, immune, neural system, etc. the mast cell contains all of our biogenic amines, pretty much every peptide has been discovered. We published recently, it even releases IL-33, interleukin-33. Back then, maybe the mast cell was functioning in various capacities to allow these organisms to sense danger and respond to danger. As we develop our other organs, mast cell became not important anymore, and only the tip of the iceberg, which is the bad asterisk of the mast cell has been recognized.

Dr. Kara Fitzgerald: Right, right. It’s really remarkable work. Again, I can see how we would, I mean, you can have that presentation of maybe classic mast cell activation with flushing and hives and diarrhea and etc., etc., and IgE may or may not be present. There’s that classic picture. Then, especially with the neurological piece that you’re outlining now, it’s involvement in neuroborreliosis and autism. I don’t want to go down this path, but I’m sure that you could talk … Well, I do want to go down the path, but I also want to spend some time on, I want to get to what we do about it. In Alzheimer’s and cognitive decline and all these neurodegenerative conditions.

Dr. Theoharis Theoharides: I agree. I agree.

Dr. Kara Fitzgerald: We see microglia are activated in all sorts of conditions. It’s our mast cells participating in the up regulation of…

Dr. Theoharis Theoharides: You’re absolutely right. I teach a graduate course, that is called Advances and Failures in Drug Discovery. I go over about 10 cases over the last 20 years where both the scientific and the financial community were drooling over the discovery and everything failed miserably. The most recent such failure is Alzheimer’s. For 15 years companies have been after amyloid plaques and your beta amyloids and tau proteins. They spend probably close to $2 billion. The last, I mean the kiss of death, was two articles in New England Journal of Medicine about four months ago were yet another study failed. Now everybody talking the same thing that we think is happening in the coronaries, that the plaques might be there, but to the inflammation against the plaques is what causes the problem and not the plaque itself.

Dr. Peter Libby, who’s director of cardiology at the Brigham and Women’s Hospital at Harvard in Boston, wrote many years ago. If someone had has not seen it, look up Scientific American about 12 years ago. The title is called “The Fire Within.” He was among the first to say that even though we have or might have cholesterol plaque, the cholesterol plaque is like cement. It doesn’t break off. It might, of course, occlude eventually your coronaries, but the body tries to get rid of the cholesterol plaque and creates a loose inflammatory plaque against it. It’s the loose inflammatory plaque that breaks often caused the infarct. You’re likely to die from the inflammation. Of course, if you close off your arteries and you have inflammation it is even worse. Many, many times you don’t.

We published a number of papers and reviews that you can have, of course, myocardial infraction due to just coronary constriction without any cholesterol plaque. The mast cells play an absolutely important role in that. In animals, we could not actually make the animals die. I can put the mice into a stress mobilizer. I can cause actually coronary constriction. If I use the same thing in mice that are ApoE deficient, so they develop actually a little coronary plaque, they actually just die in my hands when I stress them.

Dr. Kara Fitzgerald: Wow.

Dr. Theoharis Theoharides: If I do the same thing in mice that genetically do not have any mast cells, nothing happens. The animals survive. The mast cells do participate, and the triggers there obviously are different. They’re not allergic triggers. It’s whatever cholesterol is doing to the rest of the immune cells that are coming into the area, anyhow.

Dr. Kara Fitzgerald: That’s fascinating. The trigger, so I asked you about triggers early. The triggers are myriad.

Dr. Theoharis Theoharides: Yes they are.

Dr. Kara Fitzgerald: They’re extensive.

Dr. Theoharis Theoharides: They are.

Dr. Kara Fitzgerald: And not related to antigenic material necessarily.

Dr. Theoharis Theoharides: Not at all, not at all.

Dr. Kara Fitzgerald: That’s fascinating.

Dr. Theoharis Theoharides: As you said, mold, mycotoxins, viruses, malaria stimulates the mast cells. We published a paper on these years back. Then, of course, you have numerous drugs. You have internal peptides, substance P, bradykinin, we talked about those. You’ve got cytokines such as interleukin-33. The list goes on.

Dr. Kara Fitzgerald: Yeah, it goes on. Yes. What you mentioned earlier, PTH, you mentioned CPRP, etc. I mean just, it seems just…..

Dr. Theoharis Theoharides: By the way, one of the things that I also measure if I have a patient with cancer that also has allergic type of problems, there’s a compound, a molecule called adrenomedullin. Adrenomedullin is released from cancer cells and stimulates the mast cells. Measuring adrenomedullin might actually be something useful in patients that might have both your cancer as well as allergic-like problems.

Dr. Kara Fitzgerald: Gosh, that’s fascinating.

Dr. Theoharis Theoharides: That might be a different story altogether.

Dr. Kara Fitzgerald: Well, I want to get over to talking about treatment now. I’m entering into this conversation with you thinking, I mean, especially since you’re designing a bunch of really safe and smart interventions, but it’s like most of our patients probably need to be on some degree of mast cell stabilizing interventions.

Dr. Theoharis Theoharides: I agree with you.

Dr. Kara Fitzgerald: Well, that’s what you’re saying.

Dr. Theoharis Theoharides: I tried with a large company that makes like “energy bars” to convince them that it would be worth putting a flavonoid there. It will be so useful for so many people. They just couldn’t quite see the importance of it.

Dr. Kara Fitzgerald: I mean, I remember years ago reading about luteolin as protective against breast cancer, like years before I heard about it.

Dr. Theoharis Theoharides: That’s absolutely true. In fact, they’re even more papers now. The combination of flavonoids, which I will talk about in the second visit with the mast cells, might even be better for reasons that I will explain.

Dr. Kara Fitzgerald: Okay, so let’s get there. Mast cell involvement, and mast cells probably play a role in most of the conditions we’re seeing, so we know that. The person who presents with the itchy, flushed, the classic picture. Let’s talk about how we want to treat them.

Dr. Theoharis Theoharides: Okay, so there’s no question that we will try at least antihistamines. There are three points I want to make with that. One is that many patients cannot tolerate some antihistamines, some can tolerate others. I would not give up until I’ve tried at least three that suit the patient. Point number two is that some antihistamines are much better than others over and beyond where the patients can tolerate it. For instance, my favorite one is hydroxyzine or Atarax.

Dr. Kara Fitzgerald: Yeah, that’s right.

Dr. Theoharis Theoharides: Even though I will qualify it, as I will do for some other antihistamines. First of all, it’s a much better or more potent antihistamine than anything else in the market. Just to give you a little historical perspective since you kindly asked me about flavonoids earlier. I was a consultant for the European company, UCB almost 20 years ago, where they basically gave me every chemical they had on our shelves. They said, “Can you select something that might be a good antihistamine?” What do you know? I selected citirizine. I did not know what citirizine was. If you give someone hydroxyzine, it’s broken down in the liver to citirizine, which is Zyrtec.

Dr. Kara Fitzgerald: Oh, interesting.

Dr. Theoharis Theoharides: I wish I had money to buy stock in Pfizer at that time. Now why am I saying this? Because in certain cases we needed antihistamines to get into the brain. The non-sedating antihistamines are because they don’t enter the brain. Hydroxyzine does. If I have someone who cannot sleep at night, who’s very anxious person, because hydroxyzine is a little calming as well, or if someone who might be getting up in the middle of the night, even though they fall asleep, hydroxyzine puts you in a deep, refreshing sleep. Even though it might make you groggy the next day, if you take it every day for about three, four days, the sedation goes away. Unlike Benadryl will sedate you every day no matter what.

Dr. Kara Fitzgerald: Right.

Dr. Theoharis Theoharides: Now, in addition, what is different with Benadryl is that most unfortunately Benadryl’s in the market, unless you get the clear caps, have red color. Most patients will respond to the color. I don’t understand how anybody who is interested in treating people with allergies would put color into anything. I will avoid it. It’s very difficult. Every time I go to a drugstore, I try to find gel caps. Most of the time I cannot find them. That’s about those two.

Dr. Kara Fitzgerald: Well, one of the things I observed clinically with hydroxyzine versus Benadryl was that people who were really dependent on Benadryl tend to get depressed. I mean, I think there’s the nonspecific binding, which didn’t seem as significant with hydroxyzine is that …

Dr. Theoharis Theoharides: You’re absolutely right, even though there’s another provisor by hydroxyzine. What happens is, and I wrote tutorials about this, is histamine is very important in the brain. It’s a neurotransmitter. It’s very important for learning as well as for memory. I hate when colleagues give 150 milligrams Benadryl, the people will end up having dementia, even temporary because of that.

Dr. Kara Fitzgerald: Yeah, that’s right.

Dr. Theoharis Theoharides: We really cannot go overboard. In some patients, especially elderly patients, you might not need to reach 150 milligrams. I usually try to stay below 50 milligrams if can. Although you know, if someone is having an anaphylactic reaction, you’ll push whatever you can, because you need to at the time.

Dr. Kara Fitzgerald: Yes, so you think low-dose antihistamines actually will preserve the brain?

Dr. Theoharis Theoharides: Yes.

Dr. Kara Fitzgerald: Okay, so it’s safe?

Dr. Theoharis Theoharides: That’s why I try not to go, as I said, more than 100 at maximum.

Dr. Kara Fitzgerald: All right, that’s a pearl.

Dr. Theoharis Theoharides: If either a child or a patient has a history of seizures or active seizures, then I worry about all the antihistamines. I try not to go more than 50, because they could make the propensity for seizures worse. Now, the two antihistamines, other than hydroxyzine that I like a lot are not available in the United States. They are available everywhere else in the world. Any compounding pharmacy with a prescription will do that.

One is, and I’m sure you’ve heard of, Ketotifen or Ketotifen, however you want to pronounce it. Now that has been called as a mast cell stabilizer. It’s not really a mast cell stabilizer. It’s just a very good antihistamine. The reason why it’s been called a mast cell stabilizers, because there were two publications where they showed using human conjunctiva mast cells that it might actually block the mast cells. From then on, everybody has been calling it a mast cell stabilizer, even though by mouth it’s not available in the United States. It is available as eye drops for allergic conjunctivitis. Sometimes for children, I might actually use that and let them swallow it rather than giving them cromolyn, which I’ll talk about in a second.

The other one is called Rupatadine, R-U-P-A-T-A-D-I-N-E. It goes by the trade name of Rupafin, R-U-P-A-F-I-N. The reason why I like it is number one, it is very strong anti-eosinophilic. If someone has eosinophilic esophagitis or gastroenteritis, I’ll use that. Very good. Second, it is also anti platelet-activating factor. We don’t really talk about PAF very much, even though I think it’s a very important molecule in the allergic kind of problems we’re dealing with.

Dr. Kara Fitzgerald: Yep.

Dr. Theoharis Theoharides: Unfortunately, it’s broken down within about 15 seconds, so no lab can measure it. We actually showed and published two papers that Rupatadine also blocks human mast cells at about 40% or so, which is as much as you get with cromolyn, by the way. If one can get that compounded, for some patients that might be just as wonderful.

Dr. Kara Fitzgerald: Yeah, that’s great. For your eosinophilic esophagitis and gastritis patients, it sounds great.

Dr. Theoharis Theoharides: Now let’s say we covered the antihistamines and the patient continues to have itching and little twitching of the lungs and what have you. I will consider actually Singulair, the antileukotriene, even though it’s primarily given for asthma. Clearly for asthma, it’s very important. I’ve seen patients actually do respond positively to Singular. Before giving up, it’s 10 milligrams, I’ll give it a try. The only downside of Singular is about 15% of patients have reported nightmares, so keep that in mind. If that doesn’t work, and if someone has a lot of diarrhea, I will consider cromolyn. Now why do I say diarrhea? Because cromolyn is absorbed from the intestine in less than 4%, so it’s not likely to get into the rest of the body. If now histamine is released in the gut, histamine will get into the circulation. You might get some systemic benefits even though cromolyn doesn’t get absorbed.

Dr. Kara Fitzgerald: That’s fascinating. Would you consider cromolyn for something like IBD?

Dr. Theoharis Theoharides: I would even though I believe it doesn’t have that much diarrhea. I will tell you what I would consider for IBD in a second. I might consider it for IBS.

Dr. Kara Fitzgerald: IBS, diarrhea. Yep.

Dr. Theoharis Theoharides: Right.

Dr. Kara Fitzgerald: Okay.

Dr. Theoharis Theoharides: Now there are three problems with cromolyn. One, in the United States is a clear solution. The company doesn’t tell you how on earth they made a clear solution, because it doesn’t go into water. I’ll tell you what I end up doing. In the rest of the world, it comes as capsules with powder. The directions, god knows why, is to put it in boiling water. If you boil, actually cromolyn is gone, so I don’t understand what they’re doing.

Two years ago, I actually had a contest with my graduate students, because I was absolutely puzzled. How on earth does this company in the United States put it into clear solution. One of my bright graduate students who graduated last year ended up solving the problem. We put 100 milligrams cromolyn, which is exactly how much it is in the United States. I don’t know if you’ve seen them. They’re sort of longitudinal, clear tubes, plastic tubes. You basically break the tube open and there’s a clear solution in it. It condensed 100 milligrams. We put 100 milligrams into either water or normal saline. We just put a probe sonicator for five seconds. It went into the solution. It’s still on my shelf in solution. It did not come out of solution. The company would not tell you that.

In any event, many patients will just drink this even though you’re supposed to put it in water and then drink it for better absorption. Having said that, here are the problems. About 10% to 50% of the people get explosive diarrhea. I had a wonderful young lady in her early 20s who was given cromolyn by my colleague at Harvard. She lost about 20 pounds in two weeks. I kept on saying it’s the cromolyn. They wouldn’t believe me. She stopped the cromolyn and was fine.

Dr. Kara Fitzgerald: Oh, fascinating.

Dr. Theoharis Theoharides: For some patients, don’t get me wrong, if it works, it’s wonderful, but in some patients it doesn’t. About 5% of the people get alopecia, they’ll lose their hair. That’s something to worry about. The most typical thing is you get what is called tachyphylaxis. The body gets used to the drug quickly. We usually start with 100 milligrams twice a day. Before you know it, in six months it’s 400 milligrams four times a day and it’s filthy expensive. Just keep that in mind.

Now, before, and we will talk about the flavonoids last. If that doesn’t work and if someone has absolutely crazy itching, and we don’t know what it is, if nothing works, I will try either one or both. There are some reports that low dose naltrexone may work. Naltrexone, as you recall, it’s basically an opioid antagonist. It’s like narcaine that we use for opioid overdoses. It’s been known now as low dose naltrexone, LDN. People know it as LDN. For some reason, I’ve seen it actually work. I don’t know why. It’s counterintuitive, because when we do skin test, morphine is a positive control, because you will cause mast cells to degranulate. Unless these patients have endorphins or enkephalins, something stimulating them, it doesn’t make sense that naltrexone will work, but it seems to do so. I’ll give it at least a month or so if nothing works.

Finally, especially if patients have elevated IgE and even without elevated IgE, I will use Xolair, X-O-L-A-I-R. Xolair is a neutralizing antibody for IgE. It’s injectable. One shot on each arm every month. I’ll get it for about three months. What is amazing is that it not only improves allergic asthma, because it’s approved for asthma and chronic urticaria, but seems to work in activation of mast cells by other triggers.

Dr. Kara Fitzgerald: Fascinating.

Dr. Theoharis Theoharides: Dr. Maurer that I mentioned earlier, published a paper that even pressure urticaria seems to be helped.

Dr. Kara Fitzgerald: Oh, fascinating.

Dr. Theoharis Theoharides: We don’t know why, but it may be, which will be an important point that it will make in a second, that if you reduce mast cell activation, you raise the bar and that other triggers find it a little harder to trigger their mast cells, however, that happens. Now, having said that, we have a lot of evidence that even subclinical whatever “subclinical” means, levels of triggers might be more important than a major trigger for the mast cells. In other words, if someone is exposed to a little mycotoxins and gets bitten by a tick as well, those might be actually worse than getting stung by bees type of thing. It seems like the combination of triggers unlocks the mast cell. Now instead of having only the Ig receptor now it’s crowded on the surface with 100 different receptors. I’m being a little silly here, but I’ve seen a lot of people who were exposed to a number of things and from then on their life changed. They’re allergic to life, so to speak.

Dr. Kara Fitzgerald: Yes, yes, yes.

Dr. Theoharis Theoharides: I worry about the small triggers as much as a major trigger.

Dr. Kara Fitzgerald: Well, and I think the triggers can be so varied. I mean, as you were just talking about it again, I was thinking, you know, what about metals or what about some of the pesticides?

Dr. Theoharis Theoharides: Correct, correct.

Dr. Kara Fitzgerald: We could go on and on, unfortunately.

Dr. Theoharis Theoharides: For instance, your absolutely right. Aluminum triggers mast cells. Mercury triggers mast cells. There are reports that glyphosate triggers mast cells, and atrazine, which is another herbicide also triggers mast cells. We really have to worry. One of the things that really bothers me as well, many drugs contain, actually, as you know, dyes in order to indicate the strength of the pill, to make it easy. Those dyes are actually very bothersome. In some of the preservatives that are used, actually in addition to preservatives, like in Chinese food, monosodium glutamate or what have you, can also trigger mast cells.

Dr. Kara Fitzgerald: Certainly, a piece of the journey with your patients is cleaning up their lifestyles as much as you can.

Dr. Theoharis Theoharides: Correct. At least until they do better. Once they do better either the patients will disappear and I don’t hear from them again, because as you know, we mostly hear from patients that have problems or they’re going to call back and said, “Oh I had a horrible problem.” I said, “Well, what happened?” “Well, I ate chili last night.” That kind of thing. They’ll feel so well. Then they’ll go back to either their old lifestyle or they might actually take a break, if you wish, and then they’ll see that they’re not really entirely out of it, and they just have to be careful.

Now, since we spoke about mold and mycotoxins, and I really think they’re major triggers, at least the three things I do with since there’s no way to really … I mean I’m not likely to give them antifungals, unless they really have serious disease. I know there are a lot of colleagues and I put them on are studying [inadudible]-B for years. I don’t really like that because the whole GI system will fall apart. I’ll come back to that with the flavonoids as well. I will consider puttIng them on caprylic acid, anywhere from 400 to 600 milligrams. There’s not really a downside to that. Some people don’t like it, but overall I think it’s pretty safe. I will consider also berberine sulfate is both antifungal and antibacterial, probably about the same dose. I might consider a drop or two under the tongue of oregano oil, which is not only very good antioxidant, but it’s all a type of anti-bacterial antifungal. Children, of course, cannot tolerate because of the very strong smell.

Dr. Kara Fitzgerald: It is.

Dr. Theoharis Theoharides: Adults might.

Dr. Kara Fitzgerald: But why are you administering it sublingually, out of curiosity, in just a couple drops?” Is that what you said? On the tongue or under?

Dr. Theoharis Theoharides: Yes. Under rather than how?

Dr. Kara Fitzgerald: Well, I mean, sometimes I’ll give oil of oregano in capsules or I’ll actually …

Dr. Theoharis Theoharides: Under the tongue, it’s like an injection. That’s why we give things sublingual or suppository.

Dr. Kara Fitzgerald: Yes, right. To get it into circulation.

Dr. Theoharis Theoharides: Correct. It’s very difficult to absorb, of course not the oil. The oil is okay. No, I would give them a capsule as well. It’s just that I find sometimes it works better.

Dr. Kara Fitzgerald: Interesting. That’s just fascinating. I haven’t done that. That’s what …

Dr. Theoharis Theoharides: Try it and you can tell me.

Dr. Kara Fitzgerald: I will.

Dr. Theoharis Theoharides: Before we finish, because I want to say something about skin and skin lotions, remind me of the oregano oil towards the end.

Dr. Kara Fitzgerald: Okay, okay. I’ll make a note.

Dr. Theoharis Theoharides: Now having said all of that, we’ve published a number of papers comparing, let’s say cromolyn, which is the only known mast cell blocker, if you wish, to flavonoids. In addition to what I said about cromolyn, cromolyn inhibits histamine release and tryptase release about 30%, okay? It’s not a very good … In rats, it might inhibit as much as 100%, but for some reason not in humans. But it does not inhibit any of the cytokines and chemokines. Therefore if we suspect those, cromolyn’s not going to do very much.

Dr. Kara Fitzgerald: Anything, right.

Dr. Theoharis Theoharides: We published two papers, one in the Journal of Allergy Clinical Immunology and the other Journal of Pharmacology Experimental Therapeutics comparing cromolyn to luteolin and to methoxyl luteolin. Let me get you the result, then I’ll compare those flavonoids in second. Clearly luteolin was better inhibitor than cromolyn, both antihistamine and tryptase, and it blocked cytokines and chemokines, methoxyl luteolin was even better.

Dr. Kara Fitzgerald: Wow.

Dr. Theoharis Theoharides: Having said that, let me go back to the flavonoids. The flavonoids are basically three benzene rings. They have hydroxyl groups attached to them. Whenever we have a hydroxyl group attached to a benzene ring, we call that a phenolic compound. The reason I’m starting with that is about 15% or so of the general population and as many as 30% of the people that we’ve been talking about have phenol intolerance. I will ask patients or the families if someone gets hyper when they eat chocolate, strawberries, berries, grape seeds, that means they’re phenol intolerant. Therefore, I worry how much flavonoids of any kind that I would give them.

One reason to find out, of course, is to do genetic analysis, which I ask for pretty much every one of the patients we’re dealing with, because I ask for diamine oxidase. If they don’t have enough diamine oxidase, then we can give them a supplement to decrease histamine in the gut. In fact, I’m sure you know, there’s a wonderful site called Healing Histamine. It used to be called a Low Histamine Chef by Yasmina that gives you all kinds of good recipes and tips about foods with histamine. In case our colleagues, ripe tomatoes, ripe avocado is loaded with histamine. Cheese, of course, especially smoked cheeses, nectarines, peanuts, pretty much all the spices have lots of histamine, so be careful.

Now, going back to the enzymes, a COMT, catecholamine-ortho methyltransferase basically metabolize pretty much all the biogenic amines including histamine. Then there’s some additional enzymes for histamine. It’s so easy now to do a general analysis for those enzymes, because as you know, now we categorize patients in slow metabolizers or fast metabolizers. If any patient is on two or more drugs, especially psychotropic drugs, I will do all the CYP-3 enzymes. Those are the ones that break down pretty much everything as you know.

Now, coming back to the phenolics. None of you should have to remember the structures, but for instance, pycnogenol, which is very plentiful in grapes, has 15 phenolic groups. Quercetin has five. Luteolin has four. Methoxyl luteolin has none, because basically methoxyl luteolin has four methyl groups in place of the four hydroxyl groups that luteolin has. If you’re looking at phenolin intolerance, luteolin will be the least likely to cause a problem as compared to the others.

Dr. Kara Fitzgerald: Right.

Dr. Theoharis Theoharides: However, when you lose the hydroxyl groups, you lose antioxidant activity. Methoxylluteolin is not an antioxidant, but it’s a better mast cells blocker and anti-inflammatory. This takes me now to the combination. Since we always have problems with free radicals and we want actually antioxidant activity, what do we do? Either I give patients glutathione, which you can give it either by mouth or you can inject it, which probably is the best antioxidant or I might give them some SAMe, S-Adenosyl-L-Methionine, which is also an antioxidant or I will combine flavonoids if they’re not phenol intolerant. Which flavonoids will I combine? There’s a lot of history with quercetin, which has five phenolic groups. I will combine quercetin with luteolin. In fact, pretty much every product that I helped develop has quercetin and luteolin in various ratios. I’ll explain why.

The problem is that many colleagues will give very high amount of flavonoids. I know very good colleagues who will give two grams a day, let’s say, quercetin. Some give, actually quercetin citrate. That’s even an additional problem. Let me explain why. For instance, Twinlabs has a quercetin citrate, and it’s a number of quercetin molecules. I’ll bring up one more in a second. There’s a quercetin ascorbate as well.

Dr. Kara Fitzgerald: Yes.

Dr. Theoharis Theoharides: Number one, I never give more than one gram a day, flavonoids of any combination for two reasons. Number one, if you actually … The flavonoids are absorbed less than 10% from the gut. Let’s say we prescribed three grams a day quercetin. What will happen is it will basically stay in the gut primarily. It will shut down every enzyme in your gut. You’re literally destroying your bioflora or the microbiota, if you wish. On the one hand, we’ll be giving probiotics. On the other, we’re basically killing all the enzymes. We’re basically just shooting ourselves in the foot.

Dr. Kara Fitzgerald: Well, why is it killing the enzymes? What enzymes are you talking about? The menthyl transferases and stuff? Which……

Dr. Theoharis Theoharides: The first round of enzymes on anything that we absorb is in the gut. Then it goes into the liver. Many of the vitamins have to be actually metabolized before we absorb them. I don’t want to affect gut enzymes. One of my colleagues here, David Greenblatt has published many papers that even juice from citrus, whether it’s oranges or grapefruit or whatever, inhibits basically the gut enzymes and then it causes problems.

Dr. Kara Fitzgerald: Okay.

Dr. Theoharis Theoharides: I would rather give smaller amounts and increase the absorption rather than giving high amount, hoping that that will do it. Moreover, if, let’s say, most of what we give, let’s say we give three grams a day and 10% is absorbed, so 300 milligrams or whatever, that will also inhibit liver enzymes. Now that will be a problem, because first of all, as you recall from years back, the problem with cimetidine, Tagamet, okay?

Dr. Kara Fitzgerald: Yes, mm-hmm (affirmative).

Dr. Theoharis Theoharides: In males, it will cause gynecomastia and reversible impotence. Same thing will happen with high dosages of flavonoids, exactly the same thing. They block the liver enzymes. Any younger girls, you might screw up, again excuse the expression, their period or their cycle. I prefer to give lower amounts and increase the absorption for a longer period of time than high dosages for short period of time for the reasons I mentioned.

Dr. Kara Fitzgerald: That’s interesting.

Dr. Theoharis Theoharides: This is why in all the supplements we created, we mix them up with olive seed extract. Olive seed extract, if you take the olive oil, you’re left with a pit, basically. If you crush the pit, you get a little thicker oil. In Europe, that’s used for salad dressing. It’s nothing exotic. It’s 10 times cheaper than olive oil. I actually import olive seed oil from Greece to Long Island, New York. What happens is if you mix a powder with any oil, basically, and you give it energy, let’s say you shake it or your centrifuge it or you sonicate it, you create basically lyposomes. The oil becomes little lipid spheres. It traps the powder inside. We increase the absorption about three to five fold that way.

Dr. Kara Fitzgerald: Wow.

Dr. Theoharis Theoharides: This way …

Dr. Kara Fitzgerald: You’ve demonstrated that? You’ve demonstrated that?

Dr. Theoharis Theoharides: Oh, yeah. We’ve published that in animals, not in humans. It’s well known that that’s what happens.

Dr. Kara Fitzgerald: Yeah, okay.

Dr. Theoharis Theoharides: Basically, I prefer to have … For instance, one of the products that’s called fibroprotect, and we called it that because I give it a lot of fibromyalgia, chronic fatigue patients, contains, actually about 200 milligrams of luteolin and quercetin. That way, if you mentioned, let’s say you have about 500 milligrams total, but you absorb about 50% of that, that’s 250 milligrams. If you give one gram, not only are you actually screwing up your gut, but you will absorb less than 10%. You’re basically the same amount, but you’re having problems. You see where I’m going?

Dr. Kara Fitzgerald: Yes.

Dr. Theoharis Theoharides: From the cancer field, not from us, there are many publications that if you give quercetin and luteolin together, you get better activity. That’s why I combine the two. Now two things that I also want to stress with flavonoids, it’s the cheapest source or quercetin and luteolin, because luteolin comes, basically, from the same source, because it’s only one hydroxyl group different is actually peanut shells. However, as you know, unfortunately dietary supplements are not regulated. There’s no indication of the purity or the source. Most of the cheaper sources would be about 80% pure. If one of your patients has peanut allergy and they get it from peanut source, they’ll have a reaction, and you’ll never know it.

Dr. Kara Fitzgerald: Yes.

Dr. Theoharis Theoharides: The second cheapest source is fava beans. As you recall, about 15% of Mediterranean extraction people, Greeks, Italians, Jews, North Africans, whatever, lack G6PD. If you eat fava beans and you lack G6PD, you’re going to get hemolytic anemia. Who’s going to tell you if all of a sudden your (inaudible) drops that this might be because of the supplement you’re taking?

Dr. Kara Fitzgerald: Right.

Dr. Theoharis Theoharides: Now coming to the luteolin. Ever since we’ve been publishing on luteolin, now there’s all kinds of formulations on the internet. Just before, our getting on the air, I Googled just luteolin supplements. Eight supplements came up. Not the supplement that I helped develop, interestingly enough, but some of those have only quercitrin and no luteolin. Most of them have lutein. Lutein or lutein is not luteolin. Lutein is actually a very different molecule. The structure’s entirely different. It’s actually a carotinoid. It’s a very good antioxidant, but it’s not a flavonoid. Yet, by searching, half of them that came up had lutein and no luteolin.

Dr. Kara Fitzgerald: Interesting. Yeah, that’s fascinating.

Dr. Theoharis Theoharides: We just have to be very careful. My take would be if you’re going to give anything to your patients, find out the source and the purity and the amount that they really have and how they analyzed it. If they’re impure, they’re more likely to cause problems than not.

Dr. Kara Fitzgerald: Well, what do you think of PEA? Do you think there’s a place for it?

Dr. Theoharis Theoharides: Okay. Now it’s a different question. I actually like PEA. The gentleman, the colleague who actually discovered it, is a very good scientists in Italy. I have high respect for him. I don’t know why he’d gotten involved with this product adding luteolin where there is really no luteolin there. Nevertheless, now palmitoylethanolamide has been published for a number of years. In Italy, they sell a product, actually the call it Normast, N-O-R-M-A-S-T that is only palmitoylethanolamide. The problem is as follows, if you just buy palmitoylethanolamide from anybody else in the market, it’s not going to do anything at all. They actually have a patented formula. They actually microcrystallize it. The publications they have indicate that the microcrystallized palmitoylethanolamide is much better than the powder that you can buy. Judging from the publications, which is what I usually try to do, I think the microcrystallized palmitoylethanolamide is a good product, and you can add it on.

Dr. Kara Fitzgerald: But you can’t get it in the states, I would imagine if it’s…

Dr. Theoharis Theoharides: Well, now they sell it. They sell it as a powder. If you look …. If you go onto Amazon, they sell palmitoylethanolamide as a powder. For some reason, again, I don’t know how they get away with it, they say it helps with reducing pain. They don’t talk about mast cells. In fact, the publications they have are about pain not about mast cells. I have never tested it on mast cells. There’s only one publication in mouse mast cells that seems to be inhibiting a little bit. In all honesty, I do not know what it does to the mast cells, even though they call it Normast, obviously for the mast cells in Italy. That’s all I can say.

Dr. Kara Fitzgerald: Let me just ask you, I know we’re coming to the end here and this has been so information dense.

Dr. Theoharis Theoharides: Thank you.

Dr. Kara Fitzgerald: I know it’s been great. You outlined your histamine approach and using Xolair also. You outlined the pharmaco approach first. Are you starting with pharmacotherapy before you’re moving onto the flavonoids?

Dr. Theoharis Theoharides: No. That’s a good point. I will definitely start with an antihistamine, because that will be also diagnostic for us. If they do better, that will tell us something is going on. I use it for both reasons. Then I will put them on flavonoids. My obvious preference would be a combination, of course, again luteolin. As I said, I start low. I think time is more important than high dose. I’ll start them, let’s say, with one capsule to two capsules. By the end of a month, I’ll go to two capsules in the morning and two night and give it about three months. Not an antihistamine. It will, basically, calm the mast cells down.

Now I was not aware of, and I’ll give credit to one of my patients from five years ago we kept on assisting and then these clinical therapeutic journal had a special issue not this past June, the previous June about Vitamin D. I now give at least 2,000 units of Vitamin D3 to everybody. It has very strong antiallergic effects.

Dr. Kara Fitzgerald: Yes, okay.

Dr. Theoharis Theoharides: What is amazing, which surprised me is even in Greece and Cyprus, there is a lot of sunshine. We have about 40% of people actually having Vitamin D3 deficiency. Just to remind everybody, in the skin we have pro-Vitamin D. Sun turns it into Vitamin D. Then it has to go through the liver and the kidneys to add two hydroxy groups. The active Vitamin D3 is 1,25 dihydroxyvitamin D. I actually ask in the labs, two things if I suspect especially, also, either bone problems, etc. I will ask for Vitamin D3 and write out 1,25 hydroxyvitamin D3. Otherwise, most labs will give you Vitamin D, which is one hydroxy, because it’s more stable, which is again, it’s a good reflection, but I would like to know the bottom line, so to speak.

Dr. Kara Fitzgerald: If it’s activated. Right, right.

Dr. Theoharis Theoharides: Correct.

Dr. Kara Fitzgerald: Let me just ask you about the histamine diagnostic test. I mean, are you, anytime you, regardless of the triggering factors, any mast cell associated condition you’re concerned about, you’re going to use that histamine/antihistamine test with?

Dr. Theoharis Theoharides: You mean, giving the antihistamine?

Dr. Kara Fitzgerald: Yes, right. To see how they respond.

Dr. Theoharis Theoharides: I would, because especially if they have itching. My god, 50% of the itching should go away.

Dr. Kara Fitzgerald: Yes, yes. For instance, Lyme triggered, mold triggered, maybe chemical triggered, just any …

Dr. Theoharis Theoharides: No matter what the trigger, I will use some antihistamine. As I said, I’ll go through at least three before I give up, just in case I’m missing something.

Dr. Kara Fitzgerald: Okay, okay. I just wanted to make sure I nailed that down, because I think that’s a really important pearl on how we can start to tease out who’s got mast cell related pathology …

Dr. Theoharis Theoharides: Correct.

Dr. Kara Fitzgerald: … or at least that is significant enough that you have to really get it in there.

Dr. Theoharis Theoharides: Thank you. I don’t start with antihistamines with D. D stands for decongestant as you know. The decongestant used to … In these days is psuudoephedrine. The reason why I start with just pure antihistamine, let’s say, as I said, most commonly I will start with the gel caps of Benadryl, because we know it so well. The pseudoephedrine could trigger, actually, the muscles as well, which is the D.

Dr. Kara Fitzgerald: Oh, interesting.

Dr. Theoharis Theoharides: Which we give for allergic rhinitis. Unless I absolutely need it, I try to avoid it.

Dr. Kara Fitzgerald: Okay, okay. Now are there any other interventions? I know we’ve got to wrap up.

Dr. Theoharis Theoharides: That’s okay. That’s okay.

Dr. Kara Fitzgerald: Any other final interventions that you want to measure, that you want to mention in your …

Dr. Theoharis Theoharides: Yeah, if you find out through the RAST test or through the food intolerance test that someone has actually bona fide intolerances, I will recommend, I don’t do it myself, but I will recommend desensitization whether it’s by injection or sublingual. That’s absolutely true. In fact, I found that when people are desensitized, many times headaches go away, diarrhea doesn’t go away very often, but other symptoms might. Of course, as I said earlier, if we find out that PTH is high, your bradykinin is high or whatever, then there might be additional interventions.

Now, one condition that I want to mention that is not very common, but I happen to have a couple of patients at the end of the day. It’s conditions that have different names now, unfortunately they hijack medicine, hijack the name. They’re called autoinflammatory syndromes. Sometimes they’re called cyropyrin or Mediterranean episodic fever. The reason I’m mentioning this is because this notoriously have very high interleukin-1 beta. We can measure it. The reason I’m mentioning it is one of the presentations is itching. Of course there’s low fever, low grade fever. You know you can have low grade fever with Lyme. You can have it with other conditions, so it’s very confusing.

If other things fail and in a suspect, especially there is repetitive high, low, I mean, low grade fever, I will measure an IL-1 beta. The reason why that would be important is because there are treatments on file on beta. There are three different treatments in the market. There is an antagonist to the molecule. There is a soluble receptor, etc. As long are there are ways that we can treat a disease, I don’t want to be something that might be treatable some other way.

Dr. Kara Fitzgerald: Yep. I got it. Well this is …

Dr. Theoharis Theoharides: Are there any questions from the audience or they’re not allowed to ask?

Dr. Kara Fitzgerald: No, they’re … This is the audience … This is prerecorded and then we’re going to release it.

Dr. Theoharis Theoharides: Oh, prerecorded. Okay, I apologize.

Dr. Kara Fitzgerald: That’s okay. We will, I’m sure that we’re going to get questions. I’ll just reach out to you with those.

Dr. Theoharis Theoharides: Yeah, what I was going to say was that if you want to send me questions, I’ll be happy to …

Dr. Kara Fitzgerald: Oh, perfect.

Dr. Theoharis Theoharides: … either reply to the questions or we can get on Skype and I can just give you the answers if I have any answer.

Dr. Kara Fitzgerald: Oh, that fabulous Dr. Theo. Okay, so if you want us to include your contact information in the show notes, we will absolutely do that.

Dr. Theoharis Theoharides: Yeah. One last thing I’d like to mention not that I expect help, actually, from our colleagues, but as of this July 1st, I have zero funding for research on mast cells anymore. It’s really horrible and desperate. The university created a very easy site for me. I’d just like to mention it, because it might not be our colleagues that might be able to donate, but maybe some patients might be willing to donate. Once you go into the site and you donate, basically you get immediately within seconds, a letter from the vice president basically thanking you. It’s tax deductible. Anything from $1 to whatever.

Dr. Kara Fitzgerald: Oh, that’s fabulous. We will include that website, but you can go ahead and give me the URL. What is it?

Dr. Theoharis Theoharides: It’s basically … The important thing is it’s all lowercase. It has to be lowercase. It’s very easy, giving.tufts.edu/theoharides. All lowercase, so giving.tufts.edu/theoharides, all lowercase.

Dr. Kara Fitzgerald: Okay, easy. We’ll include that in the show notes. We will include links to your supplement companies. I just, I really appreciate the care that you’ve taken in your product design and all the background you’ve given me today on …

Dr. Theoharis Theoharides: One thing I wanted to mention, and I know we’re just about to finish here, you have to go is even though FDA does not regulate supplements, if you export any supplements, and you voluntarily asked the FDA to check them, that there were made in a good manufacturing practice facility, that the dose, the source and the purity is what you have, what they say you have, they give you a certificate. It’s called Certificate of Free Sale. All these products have this certificates. They’re renewable every two years. I can send you, actually, one of these to look at. It basically says Department of Health and Human Services FDA. It’s got a red ribbon on it, etc. Literally, these supplements have raised the bar. That’s what we should be doing for our patients, I believe.

Dr. Kara Fitzgerald: Yes, I think that’s all. That’s all reasonable. Well, I’ve learned a lot today.

Dr. Theoharis Theoharides: Thank you.

Dr. Kara Fitzgerald: Thank you for taking me on this tour and everybody with you,

Dr. Theoharis Theoharides: Thank you very much. I’m sorry you had to wait so long.

Dr. Kara Fitzgerald: Well, it was worth the wait.

Dr. Theoharis Theoharides: Okay, all right. Say hello to everybody for me.

Dr. Kara Fitzgerald:   And that wraps up another amazing conversation with a great mind in functional medicine. I am so glad you could join me. None of this would be possible, through the years, without our generous, wonderful sponsors, including Integrative Therapeutics, Metagenics, and Biotics. These are companies that I trust, and I use with my patients, every single day.

Visit them at IntegativePro.com, BioticsResearch.com, and Metagenics.com. Please tell them that I sent you and thank them for making New Frontiers in Functional Medicine possible.

And one more thing? Leave a review and a thumbs-up on iTunes, Spotify, or Soundcloud or wherever you’re hearing my voice. These kinds of comments will promote New Frontiers in Functional Medicine getting the word on functional medicine out there to greater community. And for that, I thank you.

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