EPISODE 240

[INTRODUCTION]

[0:00:01] ANNOUNCER: Welcome to the BetterHealthGuy podcast, where we take a deep dive into complex chronic conditions and explore ways to build resilience, improve vitality, and achieve better health. To stay updated on Scott's work, you can sign up for his newsletter in the show notes, where you'll also find ways to support the show and help make more episodes like this one possible. If you find the podcast valuable, please subscribe, rate, or leave a review, as it helps the show reach additional listeners exploring similar questions.

The content of this show is for informational purposes only and is not intended to diagnose, treat, or cure any illness or medical condition. Nothing discussed on this podcast should be considered medical advice. As always, please discuss any health-related decisions with your own personal medical authority. And now, here's Scott, your BetterHealthGuy.

[0:00:57] SCOTT: Welcome to episode 240 of the BetterHealthGuy podcast. If you are searching for answers on your path to better health, I might just be your guy. Today we continue with part two of our discussion on Beyond Mold: Exploring the Continent of the Cell Danger Response with Dr. Andrew Heyman, where we talk more about the Cell Danger Response and CDR1, and then get into CDR2 and CDR3 and continue to learn more about Dr. Heyman's five-phase treatment model.

If you've not had the opportunity to listen to part one of our discussion in episode 239, I urge you to listen to that first as it builds the foundation for our discussion today in part two. We already introduced Dr. Heyman in episode 239, so today we're going to jump right in and learn more about the continent of the Cell Danger Response. So, with that, here's part two of my interview with Dr. Andrew Heyman.

[INTERVIEW]

[0:01:56] SCOTT: So where does Actinobacteria fit into your overall thought process? We know in the Shoemaker realm, we're saying now that based on GENIE specific causation, that 42% is Actinobacteria, 28% endotoxins, only 7% actually mold and mycotoxins. So, do you see that clinically play out? And then where are you working on the Actinobacteria piece? Is it part of both phase one and two in terms of both the external environment and the internal environment or the body that's being impacted by it? And how are you approaching the mitigation of Actinobacteria in your patients?

[0:02:34] DR. HEYMAN: Of course, I was there from the very beginning when we wrote the first papers on Actinos. In fact, I was doing some of the original research behind the scenes to better understand the role of Actinos. There are 6,000 varieties around the world, and they're very hardy. So, they can live in everything from dry environments like the desert to in very watery environments. They are communal in the sense that they like to congregate together in living spaces. They're motile. Actually, move around the house. Actually, develop a pseudopod almost and they pull themselves across surfaces. Because if you get enough of them in one place, they'll start releasing chemical compounds into the environment that call Actinos at a distance.

Whether or not they're a major actor and/or as common as they're promoted to be, I think all that's still to be determined. We hear these terms 42% Actinos, and that was based on GENIE findings. But again, that was based on MAP kinases. And I don't think MAP kinases are all that specific for Actinos, but that's where that came from. This sort of delineation of, "Oh, if you have a couple MAP kinases turned on, it must be Actinos." And gosh, we see 42% of our GENIEs showing that pattern. So, there must be 42% that are suffering from Actino exposure.

Well, I think there's a series of conjectures there. And again, it's more to me the model of living in sort of harmony with our environment. And I think there's some things that we just kind of get right almost by accident, but we don't really know for certain what are we actually treating.

And so, for example, I think one of those is Actinos. We can measure in the environment. You can measure it on the skin. And we say, "Well, the best thing to do is turn on some special air filters and do small particle cleaning." And that's the best way to deal with Actinos and endotoxins, for example. Mold is in a separate category. But whether or not the strategy is actually dealing with what we think is the problem, if you think about what's the benefit of a really good air filter, what's the benefit of small particle cleaning? Well, I think anybody would benefit from that of getting the dust levels down, cleaning up the microbial surface, getting rid of the pathogenic load. All of that would help. But whether or not we know for certain, that's what we're actually dealing with is to me full of conjecture.

The same analysis is for MARCoNS. And that is to say there's a whole body of literature on sort of basically dysbiosis of the nose. And you can imagine there are bugs sitting right below the brain that could be pro-inflammatory, and we end up treating the nose. And that might end up being the right thing to do as well. That again, it's that microbial idea where we're doing things, but are we really treating MARCoNS? Are we treating other things that we're not measuring very well in the nose? But are we just kind of restoring a normal microbial milieu? I think that's more the case.

And so, do I think GENIE says Actinos, and therefore Actinos are bad, and therefore we need to deal with small particle cleaning to get Actino levels down? There's a kind of intellectual connections that I think are a little weak there, but it leads to the right sort of solutions in terms of look for mold, look for microbes, clean up the environment, get the air clean, and people just tend to do better. But I'm not so sure that the bugs that we've assigned blame to are really the problem actors. I think we know mold is, but when it gets into the bacterial side of the equation, it's a little harder to tell.

[0:06:06] SCOTT: So I think with the Actino conversation, many people have gone deeply into the various topical skin preparations, loofah, some things that are actually pretty aggressive. So, have you not found that treating or mitigating Actinobacteria with something topically is necessarily a big needle mover?

[0:06:26] DR. HEYMAN: I think there's an interesting notion that we carry those around and that we can recontaminate environments if we don't have good personal hygiene. But at the end of the day, maybe it's that biblical idea of just being clean and making sure that you bathe regularly and that you're not carrying some of this stuff around. But is it a great insight in that regard?

And I think in this community in particular we need to be careful because people kind of take things to the nth degree. When we say, "Hey, have good personal hygiene,” what do people do? All of a sudden, they're trying to invent the most aggressive personal hygiene regimens they can. The same is true for our living spaces where people go to an extreme and now, all of a sudden, they're living in a bubble, or they're living in a tent, or they're living in the forest, or they never feel like they can leave their home because they feel like everything outside of the home is a threat.

And my experience has been that behavior and that sense of fear of what's on your skin or what's in the outside world is worse than the actual illness itself. It cements the person in CDR. Because they're just re-traumatizing themselves every single day because they live in such fear.

One of the things I try and do is be a little tongue-in-cheek about this stuff that clean your home, clean your skin, clean up your diet, do this stuff, clean up your tissues. You'll probably be okay. But you don't have to go to such an extreme in any one direction to regain resiliency. Our bodies are designed for that. We're supposed to have resilience and resiliency, homeodynamics, allostatic load, whatever term you want to give it. So, we certainly advise people; and I think I have some of the best in the world when it comes to the home. But do we go to the nth degree? No. Do I go to the nth degree with cleaning the skin? No.

Now I'm hearing about people saying, "Oh, there's Actinos in the mouth, there's Actinos in the gut. Oh my God, what are we going to do?" But thank goodness, I've never had to go that far to help people get better. And I've never had a patient who went that far that said, "That was the thing. That was the issue. I had Actinos in my gut. And when I treated it, all of a sudden, the clouds parted and the birds came out and the rainbows were shining." I'd never seen that.

[0:08:41] SCOTT: We'll come back to that. But I similarly have the perspective like you just talked about with MARCoNS. I have not heard of many people that have found that to be the holy grail.

So, we're still in phase one trigger removal. So, I do want to touch briefly on endotoxins, whether it's environmental or potentially endogenously produced endotoxins. What are some of the tools in your toolbox for mitigating or helping the body to remove endotoxins?

[0:09:07] DR. HEYMAN: I think there are two things. One is the idea that I think the data is – in the way I read it, and you certainly can argue with me on this, but I think the data is stronger for the ways in which endotoxemia and lipopolysaccharides trigger an inflammatory response, probably more robust than Actinos. I would also put beta-glucans into that category too where we're beginning to turn on toll-like receptors, basically PAMPs and DAMPs which are these specialized receptors. We're turning on what's called the Dectin pathway, which all have been acknowledged to trigger these incredible inflammatory responses. And that in fact these are some of the most pro-inflammatory compounds that humans ever encounter.

And so, to that end, that's where I think GENIE shines because we can see toll-like receptors turning on. I also think that was only part of the story to say, but a really important one, that endotoxins are in the environment. Where would they come from? Well, not to be too graphic, but they come from poop. And whether or not you're living with animals, or you live on a farm, or there's a leak in a sewer pipe, or there's a septic tank that has an issue, or a sump pump that's not sealed, we can get exposed to these gram-negative bacteria and their production of endotoxins. I think that has been a biggie for me more so than Actinos and a recognition of how pro-inflammatory they are.

But in addition to that, it took me kind of right back to my early days kind of almost like pre-Lyme, pre-mold where I was just more in that anti-aging integrative metabolic mode where all we did was look at the gut and realizing that gram-negatives predominate, the gut can be a huge engine in and of itself of endotoxins.

And one of the most interesting lessons for that for me, because this is what I did, was have you ever seen like you've been watching TV and you see the end of an Ironman where someone's been performing all day and then they just collapse and then they're kind of rushed off to a tent somewhere? Well, why do they collapse? Well, it's interesting. The reason why is because prolonged physical exertion will create, among other things, a huge dysbiosis in the gut. And you get this enormous outpouring of endotoxins as a result. When those endotoxins bind to muscle tissue, you basically see; they interfere with muscle contraction, people become almost feverish, they get really dehydrated, they collapse as a result. They get rushed off to the medical tent, they put in an IV of fluids, they dilute the endotoxins, they have people rest and we start cleaning those up.

So, the notion that endotoxins are a problem for humans in one form or another has actually been around for a while and the gut itself being a major generator of it. So, if I see a GENIE saying endotoxins, I now think external, internal, or both. And in the literature, one of the best ways to clean up gram-negative bacteria very simply is just good probiotics. And that that's been one of the most tried and true in that regard. So, I think a lot of these patients absolutely need to have a step where we're looking at the gut, we're measuring their microbiome, we're measuring their food exposures, we're measuring leakiness, we're measuring zonulin and endotoxin production and the rest.

Now granted, a lot of those tests are okay but not great. But I do think for one reason or another, if you're in this category, you do need to focus on the gut and take it really seriously. But I do that again after getting out of exposure, passing the visual test, clearing up pathogens. Some of my tried and true in that regard. I like things that natural compounds like berberine, and cat's claw, and grapefruit seed extract, and black walnut to really kind of begin to beat up pathogens, including gram-negatives. But you got to take those seriously.

So, I think endotoxins for me in the pantheon is up near mold. And that I think Actinos is a bit of a rabbit hole for people. Yes, small particle cleaning. Yes, good personal hygiene. But do we need to take it to the nth degree where it's the perfect soap, the perfect shampoo, perfect loofah? I'm not so sure that that's really the requirement, honestly.

[0:13:27] SCOTT: And if I'm not mistaken, both Cholestyramine and Colesevelam have some role in binding endotoxins as well, right? So we're already doing that by nature of the fact that we're using those kinds of binders.

So, let's just touch a little bit more on detoxification of these environmental toxicants. I think many people will start with a broad detoxification focus looking at binders and other things, and then maybe really more aggressive heavy metal chelation type things if needed later in the process. So I'm curious, do you start early with metals? Do you work more broadly? And then what are some of your go-to tools for chemicals, pesticides, heavy metals, plastics, all of those different environmental toxicants?

[0:14:10] DR. HEYMAN: One of my favorite subjects. So, for a number of years prior to my mold and Lyme journey, when I entered that clinic in Virginia, it had been essentially a chelation clinic run by an integrative rheumatologist for decades. And so, I stepped into a patient population that was already expecting expertise when it came to detox. And we had a whole area downstairs of; we'd run 30 to 40 IVs a day. EDTA, DMPS, alpha-lipoic, hydrogen peroxide, you name it, we did it. And it was a fascinating immersion. In fact, we were one of the study sites for the big EDTA study for cardiovascular disease. And so, I got a lot of experience of kind of dealing with these things.

With that being said, here's where I was making mistakes. I remember very specifically a patient of mine who I had inherited. And he had been seeing another practitioner at my clinic. And then he came over to me. Not much was done with him prior to that clinically, but he sort of was stated to want heavy metal detox and chelation therapy. And I was happy to do it. So, I remember we set him up to do IV EDTA challenge and then do a 24-hour urine collection as normal. And he did the IV EDTA. And he had a psychotic episode during the administration of the medication.

And I learned of this because I heard some kind of commotion behind the clinic. And he had ripped the IV out of his arm, went back outside, picked up a rock, and basically had gone into a rage and was banging the rock against car windows and then banging his head against cars. And it was obviously very stressful. I had no idea what was going on. I didn't know much about him, but I'd never really seen that before. And it turned out he had had a history of some of this in the past, but clearly the EDTA had triggered this with him.

In retrospect, the big mistake was that he had Lyme disease and nobody knew it. He probably also had a mold exposure going on at the same time. All of that is to say he was in a big inflammatory state when we administered the EDTA. And that was a big no-no because we started pushing heavy metals around his system, his brain and his body in ways that it just couldn't compensate. And it was very scary and I'll never forget it, but it also was a lesson in terms of order of things.

And so, what I've learned is that in the beginning, you need to really reduce that inflammatory load, binders, cleaning up the home that sort of stuff. Start doing some gentle detox with phospholipids and bile support with bitters such as artichoke and dandelion. Just get stuff moving. And then to me once you pass the visual test and you're in a kind of a safer position, if you want to do a heavy metal challenge, usually that's safer. But you do need to kind of do some prep work where I get very nervous about doing a chelation challenge, for example, in someone who's still really inflamed. Because I've seen firsthand the worst of the worst in that regard. He wasn't the only one, but I started picking up on it over time and I realized that these were the canaries in the coal mine.

And so, what I'll do is, in the beginning, if you look at kind of my original approach of using a binder such as Colesevelam or Cholestyramine, plus a little bit of detox support, once they pass the visual test, then I'll go deeper. I'll use the EnviroBind, which includes the charcoal, and clay, and chlorella, and that sort of thing. But that will be the time or even later where I might consider doing heavy metal work. And I'll add, let's say, oral DMSA or whatever's at my disposal.

I think fulvic and humic acid are okay. But heavy metals are bound so tightly to the tissue, you need a pretty strong chelating agent to get rid of them. Chemicals, not as much. So, phospholipids, chlorella, cracked cell wall chlorella, plus phase two support such as glycine and taurine, glutathione support in general, saunas, those sorts of things are very good for getting rid of chemicals. And I've done a lot of that work in the past. So not that hard to do if you know what you're doing.

I'll also use, let's say, aged garlic extract, which has some heavy metal chelating support, especially out of the liver and kidneys. So aged garlic has been shown to help reduce cadmium in the kidneys. So, there's a variety of natural compounds that I might use and add in if that's a direction that we feel like we need to go with a patient. But I'll do it after they pass the visual test. I'll start with phospholipids, which clear out the cell membranes, but then I can go a layer deeper and grab metals, grab chemicals as we're moving down the path.

[0:19:09] SCOTT: So that's a great segue then talking about the lipids. So, in phase one, you're also supporting the liver and introducing things like glutathione, NAC, phosphatidylcholine, working on neuroinflammation, working on sleep. But let's focus a little bit on lipids. I think we're both big fans of phospholipids for supporting cell membranes. Some think of it potentially as being helpful for toxin removal from the cells and the mitochondrial membranes. We've got other tools like Balance Oil so we don't overdo the omega-3s, which is not uncommon. We have things like C15. We have the SPMs or the resolvins to kind of calm down the macrophages. There's the plasmalogen precursors out there now as well.

So, some people seem to wait to do the phospholipid restoration until kind of the repair and restoration stage at the very end. Others like you seem to consider it more foundational. Some talk about phospholipids as potentially helping to move us out of a Cell Danger Response. So, talk to us a little about why you're such a lover of lipids or a fan of fats.

[0:20:16] DR. HEYMAN: So, a couple of reasons. Number one, in general, as you know, in our island of misfit toys of patient population, many of them tend to be very reactive to things. But it turns out most of these reactions are to proteins or epitopes of proteins that are on compounds that we administer. It turns out the one thing that the body is not really well designed to do to react to are lipids.

And so, if you're trying to get a person moving in the beginning and they're hyperreactive, lipids are generally pretty safe. Again, I feel like I've had the pleasure of working very closely with a number of luminaries in the field and people who had a very specific perspective on things. And you sort of absorb as much as you can and take what feels relevant. So, for a number of years, I worked directly with and taught with Patricia Kane. I invited her to the Anti-Aging Association. We did a lot of team teaching together. And she had her perspective on lipid replacement therapy. And I thought it was very insightful, very valuable.

And it was one of the therapies that I noted in my patients that when we began, there was often a report that they felt better. That didn't happen very often with sort of this multimodal approach, but there was something unique about phospholipid replacement. And it's interesting because there was this tension between the CIRS world and the Kane world, as much as between the CIRS world and the Neil Nathan world.

And if you talk to Patricia Kane, she'll sing the praises of phospholipid replacement and how that's all you need to get these patients better. It'll clear out mycotoxins. It'll clear out heavy metals. It'll clear out debris from old medications that are still sitting in the cell. And she would do this very sophisticated DNA testing out of Europe. She allowed me to start doing that same testing. We'd also do the Kennedy Krieger testing out of Johns Hopkins University looking at lipid composition and sort of what was there. And did we have very long chain fats, or saturated fats, or trans fats, or did we have enough phospholipids in general? Did they need omega-6s or 3s?

I was totally immersed in that world as much as CIRS. And I found it fascinating. We applied the discipline of it as I was taught in a sense where you begin with the orals. And then you do your Kennedy Krieger test and make sure that your levels are above a certain range so that you can start your IV phosphatidylcholine. You don't want to do the reverse of IV first and then oral, that you need to build them up orally. And I saw people really improving to some degree, but what didn't I see? I did not see full resolution.

If you look at the literature on lipid replacement, there is some interesting literature, but it's relatively anecdotal in particular in mitochondria. And as you know, the mitochondria have a double lipid bilayer. The outer is mostly just phosphatidylcholine. The inner components are either phosphatidylinositol, phosphatidylethanolamine, and/or cardiolipins. And so, you need to kind of replace all of them to one degree or another to kind of recharge the mitochondria and to expel toxins.

So, it also turns out if you look at the lipid research in general, it can take a year or longer to turn over cell membrane status throughout the body. So, I start right away. Number one, because when people are reactive, it's one of those few safe things that we can go to. Number two, it's a detoxifying agent on its own. I don't go as far as Patricia Kane in terms of saying it's the only thing you need, but I do think it's very helpful. Number three, it's direct mitochondrial support, that over time we can begin to replace those membranes that are so critical for mitochondrial functioning.

And number four, the process is slow and it takes time. So, I start them from the very beginning. I do not see a reason to wait. People don't react. It's really good as a detox. It charges the mitochondria. It's very supportive for the brain and myelin sheath and other tissues and organs. There's no reason to wait on phospholipid therapy. I don't make the promises that Kane makes, but I do think it's an anchor for patients. And I tell them if you can afford only one supplement throughout this process, it's phospholipids. And I will say that until the cows come home until maybe I find something better. But still to this day, I think phospholipids are critical for getting people better.

[0:24:46] SCOTT: Reducing neuroinflammation with things like RG3, curcumin, BPC, magnesium, omegas, SPMs or resolvins, and then also looking at some of the drivers like blood sugar, for example, is part of what you're also doing in phase one. So, let's talk a little bit about that RG3. It's RG3 with nicotinamide riboside in a nasal spray. So, has that emerged as a top tool in your toolbox? Is it mitigating microglial activation? And how does the nasal spray application differ from the oral Metabolic Elite Synapsin or Synapsin Pro LPT?

[0:25:23] DR. HEYMAN: One of my favorite topics.

[0:25:26] SCOTT: You have a lot of favorite topics.

[0:25:27] DR. HEYMAN: I do.

[0:25:28] SCOTT: I love it.

[0:25:29] DR. HEYMAN: When you do this long enough. I don't know, 15 years ago now, maybe, my group, my research group, clinical group was approached by the School of Pharmacy at Beijing and they had isolated RG3 as an exciting candidate compound for neuroprotection. And their challenge, though, was not so much understanding its action in a petri dish.

So when you look at Chinese ginseng, they're a family of what are called ginsenosides, and these are considered biologically active. And there's different families or lines of ginsenosides, the RB line and the RG line, for example. So there's RB1, RB2, RB3, RB4, and the same is true for the RG line, RG1, RG2, RG3, RG4, all of these derivatives of these active compounds.

The RG line, of course, are the ginsenosides themselves, and RG1 and RG3 in particular were pretty exciting in their ability to reduce neuroinflammation, blunt microglial activation. So, what's a microglial cell? A microglial cell is just a specialized macrophage in the brain. And macrophages are sort of the thugs of the immune system, especially the innate immune system. So, when we do have a trigger or exposure, especially part of the Dectin pathway, we turn on macrophages and they shift into a physicality, what we call a phenotype, where they start overproducing inflammatory compounds and cytokines. This shift is called an M1 macrophage. They become the thug, essentially.

And in the brain, they're microglial cells. We just rename them. But they're just specialized macrophages in the brain. RG3 among other compounds are very strong in their ability to blunt the cytokine production in a microglial cell and particularly strong actually. RG1 also has similar properties too. And to that extent; and not only does it have those sort of anti-microglial properties, but also it turns on the sirtuin pathway, which is part of the repair cycle and anti-aging cycle. It works through a variety of mechanisms and in particular protects the brain in that regard.

So, when the School of Pharmacy called us, they said, "We really are excited about RG3, but we don't know how to administer it clinically." And so, we started working on different formulations that would allow us to deliver RG3 therapeutically. And originally, we came up with a nasal spray. We also felt that by combining it with nicotinamide riboside, in particular as a direct precursor to NAD, made a lot of sense because they would be very complimentary in terms of reducing brain inflammation in particular and encouraging repair from injury, which among other things, I mean, essentially that's what this illness leads to. And so, yeah, I mean, you can recover out of CDR, but you might be left with a brain injury.

So very early on, you want to be thinking about how do I protect the brain? I make a therapeutic decision. I don't put every patient of mine on this stuff because it's a little expensive, comparably speaking. But if they do have a history of a traumatic brain injury, if there's severe cognitive deficits or decline, I at least put it on the table and say, "Are you interested in doing something like what we call Synapsin, which is that combination of RG3 with the NAD precursor."

And you can do it as a nasal spray. So especially if they have cognitive issues in particular, I'll recommend the nasal spray. But now we also have the availability of a chewable. And that chewable is a special matrix where when you chew it, it directly crosses the buccal mucosa and you get very, very high intracellular levels of whatever is put in that chewable matrix. So, we've put RG3 in it, but we've also put testosterone. We've put BPC-157. We've put curcumin. We put things in it that are not easily absorbed by the body. But when we put it in the chewable, you get this lovely systemic effect. We even put VIP in it.

So, remember when I said when we bypass the TRP pathways in the nose, how do we go systemic? Well, we can use this very special chewable. And so, if a person has more generalized fatigue, a post-exertional malaise, we're just trying to reach the mitochondria in general, I'll use a chewable Synapsin. If they have direct cognitive issues, maybe early dementia, Parkinson's, TBI, that sort of thing, or let's say they fully flatline their cortisol curve, particularly opt for the Synapsin nasal spray.

[0:30:00] SCOTT: So phase two, then, of the three phases that are part of CDR1 treatment in your approach is the pathogen reduction phase or clearing out hidden infections. This is where you look at things like vector-borne infections, herpes viruses, SIBO, fungal burdens, biofilms, and really bringing homeostasis back to the microbiome. You say that Lyme and mold are kissing cousins. So, I'm wondering how often do you see Lyme as an issue in your patient population? And then one of the things that was interesting about your approach is many people that look at mold and Lyme talk about addressing mold first. You actually do the opposite and you address Lyme first. So, I'm wondering if you can talk a little bit about why you approach Lyme and co-infections before mold. And how much of an issue this is in your patient population?

[0:30:47] DR. HEYMAN: I find that you have to deal with a pathogen burden as part of this issue. And I think it's because you get sort of this internal whole body dysbiosis that I think when we treated the nose, we dealt with one body compartment, but the other, of course, big one is the gut. We could extend it to the skin and maybe others as well. And maybe that's why having the revelation of just really good personal hygiene driven by the idea of Actinos has helped people in the same way that treating the nose for "MARCoNS" has been helpful.

But I do think, and maybe this is my old school way of looking at the world, that you get candida overgrowth, you can get maybe some parasites, you can have reactivated viruses, all of which I think are part and parcel. SIBO is a really good example. I mean, how many patients of mine have I seen with SIBO in this category where there's lack of peristalsis in the gut, the bacteria now moving up into the small intestines, and now we got to deal with using some antimicrobial support for that. But in general, I do try and pay attention to this issue. And we also know candida will release beta glucans into the system just like we worry about external fungal forms like mold creating exposure to beta-glucans.

So, I do pay attention to this stuff. I don't overdo it, but most of my patients are going to be doing the cat's claw, berberine, grapefruit seed extract, plus the black walnut, and artemisinin and the rest to try and reduce that burden that's likely there. Do I go even further into CDR1 measuring viruses? Unless they're really sick and they have sort of temperature instability and other things that sound viral, I don't do a lot of testing there. But remember when I gate at the end, like they're emerging from CDR2 and I'm reassessing, that's when I might do a viral test as part of my T helper panel to see whether or not they have an activated Epstein-Barr. Again, usually viruses disappear if you get all that other precursor stuff right. So, I kind of wait until the end for the viruses.

COVID. COVID, my goodness, what a black hole that is. All I can say, if you kind of listen to a lot of other contemporaries of mine dealing with that issue, many of them are basically saying the same thing, that if you have kind of long COVID, you're likely in a pro-inflammatory state and you need to figure out whether or not COVID is still present and then somehow deal with that. Or is it just that essentially said differently, are you in CDR? And I think a lot of these patients are basically in CDR.

Now, there is some literature to show COVID can still hang out in the gut, for example, and maybe we need to get rid of that. But I haven't seen anyone with a really tried and true protocol to deal with spike protein and residual COVID. But if you look at kind of the gestalt, they're all saying the same thing. Get rid of the mold, fix the gut, balance the hormones, get out of exposure, detoxify the patient, and somehow the long COVID magically gets better. But at an individual level, different experts have a different order of doing things or a different way of measuring them. But in general, we're all kind of in the same category. But I do think the bugs matter and you need to beat them up.

[0:34:03] SCOTT: So let's talk a little bit about the sinubiome. I want to talk about how much does treating MARCoNS matter in your clinical experience? Do you look at mitoribosomes on GENIE before starting treatment for MARCoNS? How much do polycyclic ethers or palytoxins matter? Could it be that we're unknowingly treating many different types of bacteria, including Actinobacteria, which some people see in the sinuses as well? Maybe even fungi when we're using things like EDTA and silver, for example? Should we be looking at tools like the SinusKEY from MicroGenDx to look more broadly at some of those microbial burdens? Is the link to low MSH specific to MARCoNS, or could it be an indication of a sinu-dysbiosis? And could it be that MARCoNS has become such a focus in mold illness because we haven't been looking beyond it?

[0:35:01] DR. HEYMAN: So, I feel like that's where I've landed. And maybe it's just because I've seen what feels like a billion MARCoNS patients and kind of watching who gets better, what gets better when we pursue MARCoNS. And so just to kind of frame it, the idea generally was that MARCoNS releases certain compounds that would interfere with the effects of VIP therapy. And in particular, kind of the CIRS thinking was we retrofitted that to say somehow palytoxins or polycyclic ethers would impair mitoribosomes and suppress ribosome function. And by virtue of that, VIP would not be as effective if MARCoNS is present because you wouldn't see restoration of mitochondrial activity. So that VIP effectiveness was dependent on either eradicating MARCoNS and/or at least suppressing it with ongoing treatment.

A couple things with that. If you really dig into the literature on MARCoNS, it turns out it's very mixed. Some of it actually says its presence is protective against other pathogens. A lot of it will say we're not so sure we see polycyclic ethers and palytoxins produced by MARCoNS. And by virtue of that, it's sort of like HLA. It was this mythic figure that was established within the CIRS world and it became a pillar of what had to be done in terms of getting people better.

The question then is if you committed yourself to treating the nose, were you really dealing with MARCoNS itself and was that a driver of success? Or were we inadvertently maybe treating a dysbiosis that was appearing in the nasal passages that was amenable to that treatment? And should we not necessarily fixate on MARCoNS?

I haven't seen in my own patient population a direct relationship between the presence of MARCoNS and suppression of mitoribosomes. It's kind of all over the map in that regard. So I'm not convinced that that relationship itself is real. But if you look at more broadly just the sinus literature, and it moves from kind of traditional presence of pathogens that ENTs focus on to dysbiosis, that's where it becomes really interesting. Because in fact, just like a dysbiosis in the gut, if you have dysbiosis in the nose, you can be in a pro-inflammatory state, releasing toxic compounds that make their way into the brain.

So, I think as a community, at least in the CIRS world, we got some of it right by saying, "Hey, we need to deal with the nose." But what are we dealing with? There are some companies like SinusKEY that I think do a better job at looking at the landscape of what's in the nose and maybe what we need to be treating. But I sort of feel like it's what we do with the gut. We dump in probiotics and prebiotics and maybe some antimicrobials and glutamine and other things. We hope we get it right. I think the nose is sort of similar in that it probably was right to treat the nose.

What are we treating? I'm not so sure we know for certain, quite frankly. And I don't want to waste too much time kind of having this prolonged scientific discussion about MARCoNS. But again, if you look at the literature, sort of like the HLA, it's not exactly what the brochure says. And so I think it's a little lower in my list of importance, but dealing with the nose, I think is important. And I do think you can get maybe fungal elements in the nose too. And there's that ENT out of Georgia who does a lot of this stuff.

[0:38:37] SCOTT: Donald Dennis. Yeah.

[0:38:38] DR. HEYMAN: Yeah. And I've seen some patients really get better with his approach. There's something with the nose that I think is important. But what we're doing there, I feel like we're still using some blunt instruments.

[0:38:52] SCOTT: So, that's a good lead-in to the next question. I want to make sure to hit all the controversies. So. where does fungal colonization fit into your model? Is it primarily about yeast? Can aspergillus or other environmental molds colonize the sinuses or the GI tract in some people? Is there ever a case for using antifungals in this population? Do you have concerns about azoles? Is the risk not worth the potential benefits? We have the whole conversation about the voltage-dependent anion channels and negatively potentially impacting mitochondria, but I understand that's not the only material that has that potential. Or are you maybe already addressing much of the fungal colonization with the broad-spectrum sinus therapeutics like we talked about and some of the other herbal antimicrobials that you're generally using in your patients anyway?

[0:39:45] DR. HEYMAN: Yeah. So, another great area, interesting area, and I would say where I'm at now is; and what you're talking about is the other model that's out there that somehow fungal elements can low-grade colonize different body compartments and tissues. And very controversial. Very, very controversial. Maybe the most controversial out of everything we've talked about so far. Less so in the nose itself but much more so in the lungs and gut, for example. And is the way out of this therefore sort of treating this illness as if it was sort of a fungal colonization that needed to be dealt with. And the standard would be itraconazole, which among the azoles has proven itself to be the most effective at ridding the body of florid fungal infections, let alone potentially chronic and low-grade. I think there's very little support in the literature for this idea of itraconazole for low-grade fungal colonization.

With that being said, potentially, if we find it in the nasal passages, it's probably something worth dealing with. I hedge my bets by using natural antifungals as opposed to itraconazole because I do have some concern about its impact on the liver in particular. And plus, these patients are already compromised in terms of their detox pathways. And I give liver support from day one. I use a product called Liver Matrix, which is just basically a glandular of the liver. And I get nervous about adding in oral systemic itraconazole, for example.

Now, have I landed where the CIRS world lands, which is to say, does itraconazole impact the VDAC receptor? And in turn, does it push the cell more into the pyruvate pathway, which in turn we should see changes in the brain? Well, when you look at the literature on that, it turns out just the opposite is true, that in fact itraconazole in particular has a positive benefit for the VDAC receptor, not an antagonist benefit.

And interestingly, if the great concern was ultimately the impact on the brain, there's actually a body of literature that shows itraconazole is in fact protective for the brain. Now, is that really the kind of med I want to reach for in this population? No, I don't. I just feel like it's too strong. It has too much of a negative impact on certain detox pathways in the liver in particular. And can we get liver toxicity when people are already compromised? So, I'm very ginger around the notion of itraconazole.

Would I be somewhat liberal about it in terms of putting into a nasal spray? I think I'm more liberal with that if we see something in the nose. But am I fully bought into a big gun to reduce mold in the body. I can't bring myself to agree with the idea of it based on the research. I can't bring myself to agree with it based on its potential impact. But do I make some dispensation for it because I'm already giving some natural antifungals? Yeah, I give some attention to it. But I haven't reached for an oral itraconazole prescription in a long time, but I won't go as far as saying it's as noxious to the VDAC receptor in NeuroQuants as let's say the CIRS model is.

[0:43:00] SCOTT: So, before we move on to phase three of part of your CDR1 stage focus of treatment, I want to touch a little bit on parasites. Some practitioners think that every ailment is caused by a parasite and are doing all kinds of parasite cleanses. Other brilliant practitioners think parasites are uncommon and don't focus on them at all. Could be that they're uncommon because the testing is so poor. I think I heard in a conversation earlier today that a top researcher in this realm suggested that at best the tests might catch 8% of what actually could be present. So, I'm curious, do you test for them? Do you parasite cleanse in everyone? Do you find that it matters if you do test? What's helpful in that exploration? And are you more commonly then using also herbs and natural tools or pharmaceutical antiparasitics?

[0:43:54] DR. HEYMAN: Yeah. So, I'm old enough to have been immersed in the Klinghardt world for a long time as well. And as another luminary who was ahead of his time, as you know, spending time with him, he's very focused on parasites and having quite sophisticated combination prescription regimens for parasites. I went down that road for a long time and also administered the Alinias of the world and more so, and never really saw a huge benefit. But will I go so far as to say no one ever sort of deals with this? And I would say, no, I think we are limited by testing.

There's that company, ParaWellness, that does the testing. I think they're probably the best in the country when it comes to parasite testing. I've been using them for years.

[0:44:48] SCOTT: Dr. Raphael d'Angelo.

[0:44:50] DR. HEYMAN: Correct. But most of the time it comes back entamoeba, it comes back blastocystis. I'm not convinced those are really terrible parasites or ones that are even kind of clinically relevant. With that being said, I think everybody, especially if you just eat sushi, probably deserve some level of parasite cleanse. And so, I do put people on standard, a two month regimen of sort of a natural antimicrobial and a natural antiparasitic. And so that's sort of my nod to the notion that everybody probably deserves some black walnut, some artemisinin, some oregano oil, some cat's claw and berberine as sort of an antimicrobial approach. And I think that it takes at least two months to do that.

Now, am I going to go even further in terms of sort of that almost Lyme notion of really digging into bugs and going after biofilm? No, I don't go that far. But I do think people sort of need a cleanup of candida, maybe clean up a little parasites. Usually two months is about enough if you use strong agents and strong dosing for that two months. And people get some die off, but usually they're already on binder support. They have phospholipids. We worked on their drainage mechanisms. They have glutathione on board. So, they're not dying off so much that it's bad. But I have patients who do have die off.

Now, do I know what bug I'm killing? Nah, not really. I mean, there's so many that are probably out there that we're carrying around. But again, I think this just kind of gets into that dysbiotic model that it's worth just giving a nod and then sort of moving on. If I do sort of that retesting and there's still CDR1, we might go back and say, "Do I need to do a deeper dive? Did I miss something?" But rarely, no. Usually that's enough to get people moving on.

[0:46:43] SCOTT: So that's the four phenotypes, which we'll get to in just a little bit. So, phase three of three in this CDR1 stage is healing the gut, rebuilding nutrition, looking at the mucosa of the gut, probiotics, potentially, bovine immunoglobulins. Interested in what role bovine immunoglobulins are playing? Is that in part to help with the mitigation of the lipopolysaccharides? And then building on that heal the gut focus, so many people today have no or little bifidobacteria and a far from robust microbiome with very limited diversity. What magical tools have you found are most effective for microbiome restoration?

[0:47:26] DR. HEYMAN: So, I guess kind of like bugs, right? I mean, the whole Candida story is very state of the art 1970s alternative medicine, right? And I think kind of the gut and gut health is too in that regard. And I don't think there's really anything new under the sun. And I think we're also limited by the reliability of the testing. If you look at stool testing, for example, just for microbiome, you're probably only grabbing maybe the lower third of the colon in terms of the window that you're evaluating. And even there, it's a little kind of unreliable.

There are companies like Jona that have entered the market. They're using AI. They're trying to develop more sophisticated measurement tools that are more scientifically validated to measure the microbiome reliably. BiomeFx, I think, is another good company. GI-MAP is okay. But we're still sort of looking at the Mariana Trench when it comes to measuring the gut, in a sense. It's almost like trying to measure the brain in that regard.

And with that being said, I think everybody deserves a sweep when it comes to both measurement and treatment. And I do two things. I'll look at a food panel and I think they're getting better. And then I'll do a microbiome and kind of gut health panel as well. And I'll do two things. One, I want to look at the diversity and amount of microbiome. And then I'll also look at other kind of markers of health, whether it's lipopolysaccharides, or zonulin, or inflammatory compounds like EPX and the rest. And I want to get a sense of kind of what's going on in the gut. I acknowledge that a lot of this is sort of just pointing in the direction of GI health. But we got to start kind of somewhere.

Where do I think things are really important? Now, I work with a whole team of dietitians and all we ever talk about is GI health. This is sort of what they're fixated on. And many of them just get back to if they're going to do one thing it's a good fiber, it's a good soluble fiber. Soluble fiber actually fixes a lot of stuff. And we tend to overlook it in terms of its general health that we want to reach for some of the fancier compounds. But foundationally, you got to have a lot of fiber. Every outcome study demonstrates the same thing, right? Good fiber is a good, healthy gut. Prebiotics as well, I think, make some difference in that regard.

And then the problem really comes in in choosing probiotics. And as you know, there are fads within that too. Which strains do we choose? More recently, I'm sure you've been embroiled in the Akkermansia phase, but it was a really kind of big marketing push. And there were a number of celebrities tied to that in particular. Now, the GI test kits are measuring Akkermansia levels. But as you know, I mean, Akkermansia is really expensive as its own probiotic. And so is it really the silver bullet?

[0:50:08] SCOTT: And levels that are too high can actually be detrimental.

[0:50:11] DR. HEYMAN: Be detrimental, yeah, especially to the brain and neurodegenerative diseases. Sort of like the MTHFR story, I never fully kind of bought into the Akkermansia story as well, because I think diversity matters more than any individual marker. The markers themselves are a little unreliable. But I do like fiber. I do like immunoglobulins. The only issue with some of them is they're bovine-derived. And if the gut is sort of an engine of inflammation, I don't think you can argue with the literature on immunoglobulin therapy, but the choice matters in terms of the source or type.

Now, interestingly, if you look at like Ortho Molecular's product, their SBI Protect, they actually have some literature to show that it mitigates dairy sensitivities. And we also have access to an avian egg albumin immunoglobulin. And so that one also doesn't trigger people the same way that, let's say, bovine sources do or original colostrum. But I do think there is a lot of validity in immunoglobulin therapy. I think that, interestingly, even though if you look at the literature on glutamine sealing up the gut lining, it's not terribly strong, but it's okay, even though it's been kind of touted as sort of the it compound for leaky gut. I also buy into the Patricia Kane idea of butyrate and calcium. Butyrate as really something that is extraordinarily potent for recharging the digestive tract.

I'm not so sure that I have any real interesting stuff. Although, I would say one of the most interesting for me still that sometimes gets overlooked are Ohhira's probiotics. Because they're almost in their own way a mixture. They stand in between a prebiotic and a real probiotic that, in fact, they nourish and help grow resident bacteria that's unique to you. And there's some really interesting imaging studies to show that, that it allows your fingerprint to flourish. But the problem with that is that you have to take a fair amount for it to work.

But I've seen patients with Crohn's disease and ulcerative colitis do really well on high-dose Ohhira plus immunoglobulins and some of these other things. And I do think, again, it's one of the blind spots in a traditional CIRS model that you've got to pay attention to the gut. You got to do something to help people reduce their endotoxin burden, seal up the gut lining, change their diet. I don't think there's a one size fits all diet. I really am sort of allergic to that notion. I think different people have different food needs on top of restoring normal microbiome support.

It is my final step before we transition to CDR2, which houses mitochondria. And if you look at the literature between the microbiome and the mitochondria, you kind of have to get the microbiome right first because otherwise you're still going to have a really impaired mitochondrial function. And so myself and I, I've talked to other colleagues about this, that we feel really strongly do something for the gut before you do something for the mitochondria.

[0:53:15] SCOTT: My last couple of questions before we move on to CDR2. I want to talk a little bit about your use of EMDR and limbic retraining in CDR1. We know that these are also sending safety signals. Potentially, we know the focus of safety signals is more pronounced in CDR3. So, is your protocol overlaying safety signals into every stage of the CDR? And is there any risk of sending an all clear or safety signal when the fire is still raging, essentially telling the body it's safe when it may not be?

[0:53:51] DR. HEYMAN: I think where it really shines is in that hyperreactive mast cell patient. And to sort of they're so reactive, the body's in such an alarm state that we're looking for anything we can to reduce that reactivity. And that would include, of course, traditional things like ketotifen cromolyn, maybe microdosing GLP-1s.

But one of the other tricks is going through the parasympathetic route. And that is to say, toning up the autonomic nervous system. So whether that's through EMDR and limbic training or going through autonomic with vagal nerve stimulators or that sort of thing, I'll tell you from day one, I have a lot of my patients begin to track their HRV. And now sometimes their HRV is fine and it's not something we need to touch. Sometimes it's low, but they're not reporting a lot of perceived self-stress. So we don't necessarily need to touch it.

But if they're in dire straits, they're overwhelmed, they can't take anything. And I'm doing, let's say, low-dose VIP, low-dose GLPs, mast cell stuff, I'll often add in some kind of limbic retraining from the very beginning. EMDR being pretty tried and true. Also, if you've never heard of it, there's a home device that replicates EMDR called Bi-Tapp. And so, you can use Bi-Tapp as a way of sort of – if you don't have access to a practitioner, you don't want to spend all that money on ongoing therapy, you can at least try Bi-Tapp and see if you can reset that limbic response.

[0:55:16] SCOTT: So, I think because we see or what seems to me see more people these days with hypermobility, Ehlers-Danlos, CCI, those kinds of things. From your perspective, are those purely genetic or can they be reversed with proper treatment? How often are you seeing hypermobility, EDS in your patient population? And what's the connection between the issue being in the tissues and high levels of MMP9?

[0:55:42] DR. HEYMAN: Yeah. So, my experience has been if you're truly hypermobile, whether EDS is sort of one version of that, my experience has been it's not acquired, it's genetic. And these patients tend to be sicker, harder to treat, higher levels of inflammation.

I know of a clinic, for example, down in New Orleans, I think at like University of Louisiana or somewhere, or New Orleans, that is now more so focusing on connective tissue issues and the inflammatory states that go along with it. With that being said, I've not seen anyone really come up with what is the therapeutic strategy if you are gumby. And I haven't seen your high dose vitamin C or collagen-based therapies do all that much in this patient population. But the idea is that the connective tissue, the coiling of the connective tissue is just generally looser. And by virtue of that, the cells that traffic in the peripheral connective tissue that release MMP9 and TGF-β1, like Th17 cells, on average, the person will have higher levels of systemic inflammation because the cells are not as trapped in the coiling. But does that really change what we do? Until I see a therapeutic strategy that's specific to connective tissue, which, honestly, I haven't seen anything work very well, we just tend to know we need to work harder to reduce their inflammation that certain dosing needs to be higher in this population.

I'm very aware of the subject. I know there's been a lot of discussion of that relationship between dysautonomias and the connective tissue issues and mast cell activation, sort of the holy trinity of this illness, where people are reactive, they're inflamed, they're loosey-goosey. There's something in that kind of the POTS, EDS, mast cell triad that we've seen people talk about. But I myself haven't seen how that really dictates any change in treatment. But so far in the connective tissue world, all that I've seen is that it's more pro-inflammatory, but I haven't seen anything that's really specific. And do I see people's connective tissue tighten up after proper therapy? I haven't. Maybe people have some kind of special magical berry dust from the Amazon that does, but I haven't.

[0:58:04] SCOTT: So, let's talk then about gates. So, within CDR1, we have phase one, silencing the alarm or trigger removal, where you want to confirm the environment is safe, biotoxin markers improving, symptoms are no longer tied to their location, they're passing the VCS. We then have phase two, clear the hidden infections or pathogen reduction, where you want to see ideally a negative MARCoNS test, control of known infections, managing any reactions. You then have phase three, healing the gut and rebuilding nutrition, where you want to see improved permeability markers, having addressed food stress, rebuilding the microbiome. So are you primarily looking at these gates to move from CDR1 focus to CDR2 focus, or are the specific gates within the three phases in CDR1 gates that have to be cleared to move from phase one to phase two to phase three?

[0:58:57] DR. HEYMAN: The latter. I'd like to see those gates improving so that I know. Because as you say, if I can't measure extracellular ATP as the first alarm, then what choice do I have? So, we sort of do a little hand waving with respect to we know it's an inflammatory phenotype and we know what those exposures are that typically drive that inflammation. So, we tend to pick the categories that are often present.

Now, sometimes I'll do testing and their gut's okay or their food panel's not that bad, or if I do a microbiome test and I don't see a lot of candida or other stuff. So sometimes there's just nothing to do, but I at least have the discipline of kind of looking in the buckets. And my hope is that as we see them gate through visual tests, clearance of mycotoxins, improve gut function, so on and so forth, and they're feeling better and doing better, that's when I know it's time to move on to CDR2, and that's where we'll do full metabolic profiling and then mitochondrial testing.

There is no one single marker. I wish there was. But there's no one single marker that says, Okay, you graduate from CDR1 and now you're going to CDR2." It's rather just kind of do your due diligence, make sure you don't overlook the big drivers. If they're doing better, feeling better, they're out of exposure, then it's okay to move on to CDR2.

[1:00:13] SCOTT: So let's graduate now from CDR1 to CDR2, what you call the rebuild. The fire is out, hopefully. The construction crew arrives to clear the debris and repair the damage. The construction crew might be surprising to some of us. It includes things like TGF beta 1, VEGF, proliferative physiology, which we talked a little bit about, a shift to the M2 macrophage or that repair-focused inflammatory resolution state. We have hypometabolism, aerobic glycolysis. We might have post-exertional malaise. We might have more anxiety, histamine issues, adrenal fatigue, and other common characteristics of CDR2. This is where phase four of your model comes in in this CDR2 stage. That is the metabolic efficiency and autonomic restoration or rebuilding the engines. We talked earlier about this is where we might still see elevations of GDF15 and FGF21 as well and hopefully see normalization as we move out of CDR2.

So, we talked a little bit about viruses, viral mitigation as part of CDR1. You talked about measuring things like the CD3, CD4, and NK cells to see if they're depleted. So, can you talk a little bit about the focus on viral mitigation? Is that both part of CDR1 and CDR2? Talk a little bit about how you're fortifying or modulating, not necessarily boosting, but fortifying or modulating the immune system to address these reactivated viruses that may be more persistence factors than initiating triggers?

[1:01:52] DR. HEYMAN: Yeah, great question. So, I actually leave that to after completing CDR2 as part of the ready-to-heal gate for CDR3. And so that's my double down on if you get all the other stuff right. And again, it follows the COVID model. When you look at what are people doing for long COVID, they say, get out of the mold, treat your other infections, heal your gut, and then see if your long COVID improves sort of thing.

The same is true, I think, for just kind of persistent viruses in general, that if we're successful in CDR1 and CDR2, and remember, CDR2 includes both mitochondrial restoration and broader just metabolic restoration. My hope is by that point, because we've gone through all these other phases and all these other treatments in sequence, that by the time you get to the end of CDR2 and you're ready to gate to CDR3, that's when I check to see if these viruses are still reactivated and I look at the T helper cell stance. My hope is that they're already quiet again. Because the immune system has really come back online, we're able to re-suppress those DNA viruses. We look at the T helper cell line and make sure that all that's intact. So, I wait until after I build the blocks and restore mitochondrial function.

[1:03:07] SCOTT: I think that many of us would hear the term aerobic glycolysis, or the Warburg Effect, or hypometabolism and think that that's a bad thing. But that metabolic state that results potentially in lower energy production also is where we're repairing or rebuilding. You talked earlier about how that's where we're maybe using more sugar than oxygen. We're producing less ATP. You talked about it as proliferative physiology or repair. So how should we view that? Does hypometabolism primarily happen in CDR2? And then we think of it as a good thing because we're moving past the threat. Do we still have hypometabolism in CDR1 as well? And is CDR2 good for repair, but bad for how we feel?

[1:03:54] DR. HEYMAN: My sense of it is that the aerobic glycolysis is happening probably pretty early in the process, that once we establish a pro-inflammatory state and there's destruction to tissue, at some point we see a transition to the M2 macrophages, which phenotypically are not microglial activation or the thugs, but in fact they're the cleanup crew, and that we also see some cells already switching into aerobic glycolysis. So, I'm not so; at that mosaicism of some cells are still fighting in CDR1, but others are already transitioning.

But by definition, on average, CDR2 is defined by the fact that we're in aerobic glycolysis. And the trade-off is exactly as you say, we feel worse. But in fact, the body is marshalling resources for repair. And what we want to do is fuel the repair process. And that means we want to stoke the metabolism, give the substrates and nutrients and hormones and peptides that are needed for the mitochondria on up to physiology to do what needs to be done to rebuild the house.

[1:04:55] SCOTT: So, let's then talk about some of that rebuilding being the mitochondrial support tools. You talk about things like CoQ10, NAD or precursors, carnitine, B2, alpha-lipoic acid, maybe ribose. But if we introduce these tools too early, they could potentially backfire if we're still in CDR1, essentially turning up the danger signal that the mitochondria are sending out with that creation of the extracellular ATP. So, what role do things like SS31, or urolithin A, or methylene blue play in how you're working to support the mitochondria? And do the mitochondria shift from their protective danger signal mode, their battleship mode to less of a threat response and more of a health supporting response in CDR2, even more so by CDR3? And can we get a sense for the state of the mitochondria, meaning energy production or battleship with mitochondrial testing like the MeScreen or the MitoMe?

[1:05:58] DR. HEYMAN: So, the way I think about it is that if we do our due diligence and you've graduated from CDR1 and you've removed the threats as much as you can, what you're left with are mitochondria that probably need their own support. And by virtue of that, for many years, this was a black box for us clinically. And that is to say, what are mitochondria doing and how do we measure them? There's a lot of sort of adjacent testing. And we can infer based on lactic acid, or acylcarnitines, or other things, or doing urinary amino acid testing to try and get a sense of where's the mitochondria at.

And we were also pretty limited, state of the art sort of old school natural medicine was alpha lipoic, and CoQ10, and carnitine, and these sorts of things. And for a long time in the natural community, we have been talking about the mitochondria, but our understanding of it was limited. And I think our treatments were pretty limited.

But again, if you look at where the big boys are doing mitochondrial research, they're using things like the Seahorse assay, which is a direct functional test of the mitochondria. And what they do is they basically isolate mitochondria and then they give different medications or compounds and they stress the mitochondria in different directions. They can measure, therefore, the degree to which the mitochondria are functioning normally or not. What's their upper limit of energy production? What's their reserve? Is there proton leak out of the cell membrane? What's the cardiolipin status? Are they overproducing reactive oxygen species? What's the physical network? Because we know the number and size can change based on the threat level.

So now finally, we can measure all of that. And a lot of it was hidden behind the veil of the university setting and research groups, but it's finally broken free. And one of the reasons for that is because MeScreen developed a sampling technology that allowed people to measure blood tissue at a distance that was stable and to get it to the lab. Under regular circumstances, you'd actually have to go to a research facility, donate your blood directly to run a Seahorse assay. Now we can instead prick your finger, dab it to a card, it stabilizes, and they can run the Seahorse assay. That was the breakthrough. That's the IP essentially of MeScreen.

The MitoMe is a separate but related way of testing the mitochondria where we look at citrate synthase activity. Basically, the electron transport chain. And we can tell sort of numbers of mitochondria, which is all very complementary to the MeScreen. When you put the two tests together, you have a very complete window into do you have the right number and type of mitochondria and what are the mitochondria doing.

And by virtue of that, it's a real breakthrough now. Because if we sort of all agree even based on the idea of GENIE that at the end of the day this is a mitochondrial disorder, the one thing we haven't really been measuring is the mitochondria. Everything has been sort of around that idea. But now, finally, we can do a direct measurement. The problem with this is that the way in which the mitochondria become disordered and how we analyze that is actually quite complicated. And the analytical tools to analyze that needs to be very sophisticated with respect to the way in which the mitochondria are dysfunctional and/or compensating for kind of the clinical state.

So, by virtue of that, just by running a MeScreen or a MitoMe gives you sort of raw data. But to interpret that in a sophisticated way and to know what to do takes a little bit of horsepower. It took me about two years to figure all that out. And I built that into these algorithms then that allow me to take the deep dive and to understand exactly where things are impaired in the mitochondria and where to intervene.

When I was talking to the research scientist from MeScreen just a couple months ago, and I'd been in touch with them over the years, but we had a prolonged conversation recently. And they asked me, they said; I was talking to them about sort of what their test report shows and how we interpret things. And they asked me if I was a mitochondrial researcher. And I said, "No, I'm sort of adjacent to that. I've done some transcriptomics. I'm very aware of sort of the mitochondrial literature and very aware of Seahorse and spend years sort of trying to figure all this out. But no, I'm not a bench scientist." And they said, "You're kind of one of the first physicians we've talked to that really gets this." And I said, "Well, I think it's unbelievably important as a central feature of what we're dealing with. And I really want to understand it first before I kind of make any clinical recommendations." But it took me a long time to figure that piece out.

And so by virtue of that, what they try to do is take the raw data from Seahorse and then translate that into these scales. So, they say you know mitochondrial energy, zero to 100, or mitochondrial efficiency, zero to 100. So, they reinterpret their findings from kind of raw data into what they think is a clinically useful report. I wish they'd give me the raw data, but they said we can't share that with you. We're just going to continue to give you the report.

I had to retrofit what their report was saying back into what the raw data likely says. And so by virtue of that, pattern matters. When you see different patterns on a MeScreen, for example, it means the mitochondria in different states. There's at least seven patterns that I've identified in MeScreen that are repeatable.

[1:11:08] SCOTT: Please don't call them phenotypes.

[1:11:13] DR. HEYMAN: But let's just call them patterns. But those patterns matter in terms of what we do. And so, as we organize the patterns and we pair that with a MitoMe, for example, I can get very specific in terms of where I think your mitochondrial function is at. And that dictates what we do. Because the other challenge is not just what do we do with these reports, but in both of them, and particularly in MeScreen, it'll make a few recommendations around urolithin A, or CoQ10, or other things. I actually find their recommendations aren't all that great and they're not all that precise.

And that really represents the state of affairs for practitioners where we've been presented with a long list of what are considered mitochondrial support tools. SS31, methylene blue, MOTS-c, carnitine, riboflavin, exogenous ketones. The list goes on and on and on. But how do we organize them in a way that makes sense for where the mitochondria for you are at? How do we personalize that? That's what took me two years.

So, what I found is there's about 30 different mitochondrial treatments on the market right now that are sort of worth exploring, worth recommending. There's an even greater set that includes things that I don't think are worthwhile. But inside that, you've already mentioned several of them and some are kind of the big movers. But what's interesting to me is that if you can map where the mitochondria are functioning, not only does that dictate treatment, but it also means that sometimes we're actually choosing things that will interfere with mitochondrial functioning. That there are certain situations where you don't want to do a MOTS-c or you don't want to do a methylene blue because the pathway is already blocked for some reason or it's already full of electrons. And you don't need to support it with a methylene blue. In fact, that might make things worse. Therefore, they're not all equal.

What practitioners do is they sort of hear urolithin A is great and then they think, "Okay, every mitochondrial patient, I'm going to recommend urolithin A too," sort of thing. And sometimes that can be the exact wrong thing to do. Again, it took me about two years to figure all this out and I built this into an automated platform. So, what I do is I take the MeScreen and I take a MitoMe and I run that data through my platform and then it produces a personalized assessment and plan for the patient. It's very rarefied air. But I find that if this is what stands at the center of this illness, we got to get this right. We all need to speak the language of the mitochondria. We need to understand what this testing means. And this is the way out of the mess that I think a lot of patients are still in.

We can detox them until the cows come home. And everybody's good at that stuff. Everybody's getting good at MCAS. Everybody's good at giving out binders. But where's the black box? It's the mitochondria. And very few people are good at this. And this then sets the person up for CDR3, which is the ride home. This doesn't take you home. This just helps rebuild the engine.

[1:14:07] SCOTT: So a couple of quick questions before we get on to CDR3. So, in CDR2, that's where we may also see more hyper reactivity to things like food and light. You talked about mast cell activation and histamine issues, potentially also related to that mitochondrial strain. That's a focus of CDR2 where we need to offload the triggers and have more all clear signals. Do you find value in things like low histamine diets? You mentioned ketotifen and cromolyn are mast cell stabilizers and antihistamines a key. Part of your approach while you're also then working to remove the nails in the foot that are driving the mast cell issues?

[1:14:45] DR. HEYMAN: Yeah, my philosophy is that we all didn't wake up one day with a mast cell problem. That instead, we still get right back to that very first statement that you had, which is load over reserve. And when we overload the system and we lose reserve, that's when we go into a hyperreactive mode. And that actually has been well-defined in the literature in a sense, especially mitochondrial literature. And it's just part of that defense mechanism. So, my hope is that as we take you through CDR1 and we offload you, and then in CDR2, we start rebuilding you, that reactivity of the mast cells start to improve. And that's what I typically see.

Now, we can begin to drip in the Cromolyns, and Ketotifens, and general antihistamines, and other things that we might find that help modulate mast cell activity. But the real goal is to improve resiliency so the mitochondria are just not in that alarm state. And I do think one of the breakthroughs for me has been if you can measure the mitochondria directly and give them the things they need and give the body what it needs, we start to see a resolution of that hyper reactivity. Because otherwise you're just trying to blunt that response by as much cromolyn as you can get your hands on but it doesn't really fix the underlying problem.

[1:15:55] SCOTT: One of the other things that you work on in this phase four, you're working on hormones, endocrine restoration with things like looking at cortisol regulation, thyroid, sex hormones, and vitamin D. What are the patterns that you commonly see in patients? Is this where you might see low antidiuretic hormone, low testosterone? Is this where the body is essentially guarding our reserves because the tank is low? What are some of the tools in the toolbox that you use for increasing hydration status, optimizing water balance?

In the CIRS realm, I saw kind of hit or miss with people with desmopressin causing issues, not necessarily helping. Can electrolytes potentially be a good tool in that realm? Other things for hydration status. And would you ever introduce endocrine support like sex hormones, adrenals, thyroid, when the patient is still in CDR1 or do you wait until CDR2?

[1:16:50] DR. HEYMAN: Yeah. So parallel to my weirdo world of Lyme and mold, for a decade, I was the Director of Academic Affairs for the American Academy of Anti-Aging Medicine. We were the largest global training organization on longevity therapy, hormone replacement, peptides, sort of all the things that you just kind of mentioned. And I was responsible for not only getting CME for every event, but also overseeing every lecture, every speaker, every slide. Vetting it for its science and evidence base. Was it free of commercial mention?

I had a front row view for years on what was the most advanced thinking with respect to hormone replacement, and longevity treatments, and all the associated fancy therapies in that regard. It was an extraordinary learning opportunity for me. I feel very privileged to have led that organization for as many years as I did. It brought me around the world. I spoke in just about every continent. I joke that there's a reason why I have so much gray hair and also have millions of miles on flights. I loved it. And I felt like it was really important for me to live in that world too because there's so many interesting things that are going on outside of our world of mold and Lyme.

And sometimes you can't sort of bend the two together. There's a reason why some docs, all they want to do is sort of hand out hormones and peptides and Botox, and they don't want to deal with a really sick population. But I think in the sick population of the mold and Lyme and MCAS and COVID world, there's a lot of navel gazing where we don't look up and around to see what's going on in other lineages. And that there's a lot of interesting things that we could potentially borrow from.

And sort of the notion that it's okay to say, well, VIP is one peptide among many. We don't need to just hang our hat on one peptide. There's all sorts of interesting peptides that are out there that have incredible clinical benefit. We should be open to those ideas too. We find a lot of that narrative in the anti-aging world in ways that I don't see in sort of the mold and Lyme world per se. And I think those worlds are starting to adopt what we've been doing for years in the anti-aging community in that regard.

And so I tend to be open to these notions because I've seen them work in different situations and I have a really big toolbox in that regard. And so to that end, as we sort of look at the metabolic layer, where I see the derangements are people that basically, if you kind of generally stress the system and they've been in what we call metaflammation, we see a system that's in distress.

What does that mean kind of descriptively? Well, if you follow just the stress literature in general and the physiological psychology literature, again, the systems we don't need go quiet. So you don't need to reproduce and you don't need to digest. And we typically see a flattening of the cortisol curve. So, we want to remain hyper vigilant so your body doesn't know when to sleep. So, it just kind of stays active. And all of that is adaptive to the fact that if you see the tiger, you got to fight the tiger. And it's not time to go make love under the tree and eat a sandwich and drink some wine.

[1:20:03] SCOTT: Or detox.

[1:20:05] DR. HEYMAN: Or detox. Exactly. That detox, and rest and repair, and digestion, and reproduction, and all of that happens on the parasympathetic side. And so, again, I think we're missing things if we don't really pay attention to that. That's where you mentioned glucose and its impact on the brain. Well, I'm a big fan of measuring fasting insulin, and glucose, and A1C, and in addition to a full thyroid panel, and looking at cortisol curves, and reproductive hormones, and nutrients, and certainly modulators like vitamin D and other things that are more part and parcel to, let's say, a standard anti-aging workup, that really is just about kind of metabolism.

So I think when you pair that with a mitochondrial approach, that's where you get your best rebuilding. And what do the androgens do? testosterone helps to rebuild, growth hormone helps to rebuild, thyroid helps to rebuild. You don't want a lot of the catabolic hormones around like cortisol and insulin and the rest because they're just continuing to tear down tissue.

So to me, just as much as you need to be good at the mitochondria, what's more available to practitioners just being good with metabolism and the rest, that you need to be good at hormones, and nutrients, and that kind of core philosophy as much as mitochondrial health. And that's what CDR2 is for me. I'm rebuilding the house and giving back the things the person needs to be in better balance, metabolically speaking. That's where I'll measure ADH and osmolality.

What's weird is sometimes I don't think people realize that in the classic kind of CIRS model, we don't just measure ADH. Usually it needs to be a below normal ADH plus an elevated osmolality. The cutoff that Ritchie and I had used was 294 for elevated osmolality. Just because ADH is low on its own doesn't mean the person is having a water balance issue. But if you have discordance between a low ADH and a high osmolality, then there's imbalance.

There, I do two things. One, I do get them on electrolytes. And two, that's when find the short dance of desmopressin every other night works. And people do see a benefit. But if you do it too early in the process, where they're still inflamed, they're still in CDR1, you haven't done some of that other basic work, doing ADH and desmopressin doesn't really work. You really need to clear the decks to resend the signal to that. Because what you're doing is you're trying to send the signal to the brain to reset that water balance status. So the kidneys resorb water and the person remains hydrated. But I do that as part of my hormonal workup. Because ADH to me is just another hormone in that regard.

[1:22:31] SCOTT: So last couple of questions on CDR2 before we move into CDR3 and then wrap up. So how does high oxidative stress or reactive oxygen species impact our ability to move from CDR2 to CDR3 or move through the gate that we'll talk about momentarily?

[1:22:48] DR. HEYMAN: Great question. So, I can get this really brief. So, basically in the MeScreen, I can directly measure reactive oxygen species that are coming out of the mitochondria. And therefore, I know if there's too much exhaust and fumes that they're working too hard. So that's where antioxidants, lipids, urolithin A really shine. So that will become part of my mitochondrial approach if I see a high ROS. I measure it directly from the mitochondria.

[1:23:15] SCOTT: So, another piece of phase four is autonomic rehabilitation, looking at the nervous system, tonification of the parasympathetic, calming the sympathetic to support healing. You explore things like resonance breathing, HRV, which we touched on, graded exercise, vagal toning. Talk to us about your top tools for autonomic rehabilitation and why we can't heal in a sympathetic dominant state. And then how often do you find that your patients are type A personalities?

[1:23:47] DR. HEYMAN: So, what's the most available way of measuring autonomic balance? I think the tried and true, of course, is heart rate variability. And that's been around for a long time. It's nothing new, but I think it's still a subject that hasn't really had its day yet, especially even in our community.

The seminal group that's done the most work, of course, is HeartMath. And they've been around a long time. There's nothing new in terms of the literature and heart rate variability. But very simply, it's the timing of beats between the heart rate. And it turns out the more relaxed you are, the more you're in parasympathetic dominance, the more variability between heartbeats. And that's measured in milliseconds. On the other hand, if there's a background of stress that's kind of buried in the nervous system, not only does the heart rate start to speed up, but the variability reduces between beats. So actually the beat to beat becomes more predictable in terms of timing.

So, here's the interesting thing. And this is where I think people even miss those that have sort of explored heart rate variability. On the surface, yes, it's a measure of stress. And what's nice about it is sort of a measure in the moment that we can do some interventions, especially in the heart math sort of verbiage coherence training, which is a certain kind of breath work, but it's more tied to other internal machinations to ensure that we restore tone in the parasympathetic nervous system.

But interestingly, heart rate variability itself is really just a proxy measure for systemic inflammation. That's all it is. And so if you're in sympathetic dominance, where you have loss of heart rate variability, by definition, you're triggering higher levels of tissue CRP. In fact, that is the proxy measure why loss of heart rate variability has been tied to so many chronic illnesses, because it means the person's in a pro-inflammatory state. And so it's the double whammy of sort of the mental stress that they might be under, but also the tissue level stress that they're under. And so it means there's a background of inflammation at the tissue that we haven't really dealt with.

But one way to shift. And this is why Naviaux said it's the undiscovered country, because how do you shift an inflammatory state in an individual? One way to contact that is parasympathetic tone. And so that's the whole point of getting out of CDR1 and helping to rebuild in CDR2 is ensuring that the parasympathetic tone is elevated. We don't have sympathetic dominance, which really means you're not in a pro-inflammatory state, which means you're out of CDR1.

This is why stress on its own at the molecular level is a CDR1 problem, because it's a pro-inflammatory state. And that's all over the literature. But people don't fully appreciate that. So we contact the immune system through the nervous system by doing these self-regulatory exercises to improve heart rate variability. Low heart rate variability is somewhere between the teens and 20s. A better heart rate variability is sort of in the upper 30s and 40s.

[1:26:29] SCOTT: Oh, good. I was 43 last night. So that's great.

[1:26:31] DR. HEYMAN: Well, there you go. You're A+ in your heart rate variability.

[1:26:37] SCOTT: Any comment on how often your patients are not type A personalities?

[1:26:43] DR. HEYMAN: I don't know if it's so much type A, but the problem is that the condition of this illness is so stressful, they all end up pretty much in low heart rate variability. I would say probably 20% of them have preserved heart rate variability despite being ill. Most of them have some kind of deficiency that they need to kind of work on. Now, do I have to take them all the way back to mommy issues, and EMDR, and kind of post-trauma states? Not all of them. But some of them just need some stress resiliency.

One of the things that we're doing at Beyond Mold is we're partnering with a group that specifically identifies itself with being experts in the subject. And so we're going to have a broad stated relationship with the; they're called the Same Here Organization. And you can look them up online, it's samehere.org. And essentially, they're integrative psychiatrists who a number of years ago wanted to highlight the fact that unlike medicine, where we try and categorize people as depressed, not depressed, anxious, not anxious, and then we give drugs if you sort of "fall into that category". But then in fact stress and emotional issues operate on a scale. And that we all deal with these things.

Kind of that Same Here idea. And they not only did an awareness campaign, but they've created group related interventions. So they go into different environments like schools, and hospitals, and work organizations and they do stress resiliency training. But they also have a network through telemedicine so that you can access experts who help bring you through that process of dealing with it. And they have an app where you do a self-reported scale and then it helps you define on the continuum how stressed are you and then what should you do about it. And they are equally read in on all the things that we could bring to bear on resiliency and stress, which is to say everything from mind-body work, to EMDR, and DNRS, and low-dose naltrexone, and all the things, right? They're really good at all of it.

So, we're pairing with them to say look we know this population is uniquely stressed. And that, yes, I can recommend certain things, but I want you to have access to their entire suite of resources. So that's coming in terms of a big partnership. And it's really important to me to say we're incredibly competent when it comes to helping people manage their mind-body connection.

[1:29:01] SCOTT: So now we're leaving CDR2. We're looking at the gates here. You want to see normalization of GDF15, FGF21, normalization of MMP-9, a near normal TGF-β1, VEGF restoration, still passing the VCS, hormonal restoration, an HRV that's signaling that we have some capacity in the nervous system. You also have what you call the ready to heal gate. So we need to have also addressed the environment, mitigated the microbes, normalized inflammation, decrease those danger mitokine signals from the mitochondria, restore the hormones, fluid balance before we get into phase five as part of CDR3.

You've said here that TGF-β1 is the most important marker to watch. TGF-β1, a big conversation. We touched on it some, but it seems like with the change in methodology in the past few years with the labs that do it in part that it also seems like people's levels are higher in the COVID era than before. So curious if you're still using the same ranges we always used in CIRS. If that range has now changed. Are we seeing higher numbers than what we saw historically? And what tools lead the pack for mitigating TGF-β1 beyond addressing those factors that triggered the elevation? You also alluded earlier to the fact that we may not want to artificially push it down because it may actually be part of the healing process?

[1:30:27] DR. HEYMAN: Yeah. So great question. And I would say TGF-β1 is a nice signal with respect to is the body still kind of proactively healing? And so in the CIRS model, it says, "Gosh, if you get to basically the end, you go through all basically 10 steps." And then you get to your 11th step of treatment, which is TGF-β1, it's still high, use losartan and you suppress it.

My feeling is if it hasn't come down after all the other work that you've done, then it means maybe you've missed something. And that's why it can be kind of a vital sign as part of the readiness to heal component. With that being said, the assay changed and the range changed as well. So, it wasn't just a change in range. It was actually they went from a one-step assay to a two-step assay.

By virtue of that, since the range has expanded, I don't think it's fair to just apply the old range to the new marker. It's a new marker, and it's done differently. Where do I land with that? The range is now 2,000-plus to 22,000, essentially, where it was the normal range prior to was zero to basically 2,800.

What I do is kind of a rule of thumb. I'd like to see the TGF-β1 at least less than half normal. And so, to me, it's around 10,000 or so. For example, if they're 4,000 or 5,000, that's really low. So, the first quartile, second quartile. So as long as I can get people into the second quartile, I'm okay with their TGF-β1. That's been my rule of thumb.

Am I right? I don't know. Am I wrong? Maybe. But no one can tell me otherwise because they don't know either. Anyone who says, "I know what the real range should be for TGF-β1," they don't because the assay changed. And so by virtue of that, you read the clinical picture, you look at other markers, you look at a TGF-β1. If it's like 6,000, 7,000, I'm good, especially if their MMP-9 is still low, and their CRP is low, and they're passing the visual test, and their home is good, and they're feeling better. I mean, you can't just look at one marker. But yes, you can use it as kind of a vital sign. Because look, if it's 25,000, then you know there's still work to be done. Or maybe the body's still healing and it's still in that repair mode.

[1:32:47] SCOTT: So now we're getting into CDR3, which is moving back in. Inflammation has been mitigated. Repair is complete. Debris is cleared. There's rhythm and restoration. Now we're working on all clear safety signals, the all clear to move back in and moving back in. We don't mean the home. We're talking about the body, right? And moving through that process, handing back the keys is another way that you refer to this, where we're free from being locked out of our own health and wellness.

Phase five is resolution and salugenesis. So, the focus of treatment in CDR3 is about safety signals, all clear signals to complete the healing cycle. There's also some neuroendocrine support, parasympathetic activation, and tissue restoration as part of the treatment focus of phase five. You've said that the body requires safety and sanctuary to heal. You can't just remove the things and detox. You need to purposefully send those signals. When you give the right signals at the right time, people resolve. I know that Dr. Naviaux has talked also about using things like the limbic and vagal work to support moving out of a Cell Danger Response. So, talk to us a little bit about some of the key safety signals that you might be using in your treatment focus during this stage.

[1:34:05] DR. HEYMAN: So, there's several. And I'm a traditionalist in the sense that I'll look at an MSH and a VIP. And if they're low, that's one part. I look at HRV. That's another. I'll look at self-reported stress. So, I use validated scales for stress. But also, I want to make sure that they're in CDR3 and not in CDR1 and not in CDR2.

You talked briefly about the four phenotypes. So basically, phenotype A. So, let's say they're through CDR2. And I'm wondering, are you ready for CDR3? We pause and we do a panel to kind of recategorize them. And I'll do some inflammatory markers. I'll do CDR2 markers, which is GDF15, FGF, T helper cell panel, maybe viruses, because I want to see whether or not the mitochondria is still under stress. And/or do we see a suppressed immune system. So that's B and C.

Phenotype B would be mitochondrial stress, but no suppressed immune system. C is mitochondrial stress and a suppressed immune system. So, I know there's still some cleanup to do. If all of that's normal, we're in phenotype D, which is CDR3. That is to say they're ready to heal. And so, I'll look at MSH, VIP, HRV, get a sense of kind of just how stressed they are in general. And that opens up the opportunity for us to do some different kind of work.

I find that VIP is wonderful. So, at this point, this is when I find KPV shines because it helps to raise MSH. I think if it's not done under these circumstances, it doesn't work very well. In addition to that, this is when we kind of go deep into the stress resiliency side, and that is to say do we need autonomic nerve stimulator? Do we need to do more HRV work? Do we need to do a little more emotional tone work?

But the other thing that often gets overlooked, and this is where I like some of these online programs, and this is where you had mentioned the research paper that I published, the nervous system heals in community. And this is all out of like Dr. Porges' work and others to say we are primed from the moment we're born to resonate with someone close to us. That as infants, we align our nervous system with the person holding us and we tune in to their heart rate, their breathing, the way we're held, their emotional tone. And that we can train the immune system based on that interactivity.

It's why, for example, when I published that most recent work on the Cell Danger Response, how did I treat people, I treated them in groups. I took six to nine patients at a time, we met together, we went through the journey of healing as a group, that we could see ourselves in the other, and we knew that we weren't alone. There's something tremendously powerful in this illness to remove the isolation and to put people in community. There's something magical about that. And I am more and more convinced that the traditional medical model of me just talking to a patient is not the right model. That maybe a more powerful model is to take groups of people through the treatment process together.

One of the things I realized early on, because I'd done a lot of group work in the past and was convinced that it would apply well. What I also realized is that inadvertently, I was pulling up my skirt because everyone in the group could see whether or not other people were getting better. If everybody was failing, as I took people through the process, guess what would happen? The word would spread. Heyman doesn't help anybody.

On the other hand, if people could see in someone else improvement, passing the visual test, getting out of bed, doing better, getting back to work, getting a family, getting pregnant, all the things we want out of this process, it reinforced the notion, "If they can heal, I can heal." And the resonance that was occurring within the group was incredibly profound. And I think that was part of the healing process that we often overlook as part of the journey.

I think the Facebook groups are great. I think doing Q&A is great. I think these kinds of podcasts are great to let people know at a distance they're not alone. But there's nothing like people actually in the middle of this thing working with other patients going through the process. It's very vulnerable, but it's very powerful.

[1:38:34] SCOTT: So, some of the key safety signals then here are VIP, MSH, oxytocin, I believe is another, low-dose naltrexone you've talked about as well. Did I understand correctly that once they get to CDR3, that the administration of KPV is changing MSH levels? And are there any other tools that are shifting MSH levels? I know we early on went down the path of people trying Melanotan and getting all kinds of spots and black freckles and other things. Isn't a great idea. Any other tools in the increasing MSH toolbox?

[1:39:06] DR. HEYMAN: So, if you think about it, the problem with a low MSH begins and ends in the brain because that's where it’s produced, in the anterior hypothalamus. And basically, the portal circulation needs to be effective. And so in that regard, we get into products like BPC, RG3, potentially Cerebrolysin, if you could get your hands on it, Selank, Semax, Dihexa, Lion's Mane, whatever you can do to heal the brain is what's going to get your MSH levels up. That's why we're doing new NeuroQuant studies, because I want to make certain that people's brains are healed at the end of this thing. And that to me is the key of where you're going to see MSH levels rise.

I can tell you the promise of MSH was never fulfilled. And that is to say, if you talk to Dr. Shoemaker, we often, even though GENIE resolves, even though we see people kind of clinically improve, we still don't see a lot of MSH coming up. And I think it's because we haven't fully resolved the brain-related issues.

Now, where does that come from? Is it because we skipped over the mitochondria? Is it because we still have something in CDR1 that we haven't dealt with? Is it because we haven't fully dealt with the emotional trauma and stress, which we know damage the brain? There's all sorts of reasons why I think MSH hasn't come up. But think of it first and foremost as one more vital sign of rest and repair and the brain. And through that lens, it opens up the discussion of maybe some other treatments and therapies.

[1:40:42] SCOTT: Is this also the place in your overall approach where we might start thinking about introducing some of those GADD34 agonists as safety signals? What are some of the tools in the toolbox to agonize GADD34?

[1:40:57] DR. HEYMAN: If they're hyperreactive in MCAS, I might do microdosing GLP-1s in the beginning. Otherwise, I think they live very well in CDR2. So that's the point where we're trying to stoke metabolism and help people lose some weight because oftentimes there's weight gain associated with this. And so GLP-1s work on that level. But also, they help with neuroinflammation. They, of course, help with insulin sensitivity. They stoke metabolism on their own. And that's where I think they really shine.

So, this notion of "they don't work in CIRS", they do work. But like everything else, positioning of the treatment matters. I think if you expect someone who's still under exposure, still inflamed, failing the visual test to use a GLP1 and lose a bunch of weight, it's probably not going to work. But if you're out of the fire and you're now in CDR2, it's a really nice tool because of its anti-inflammatory benefits, its restorative qualities, its brain healing properties, and yes, it helps stoke metabolism. GLP-1s and the fact that at a higher level, it sends the signal that GADD34 can be promoted.

In addition to that, the quercetin, the forskolin. There's a variety of things that I can use now for GADD34. But hopefully, usually by the time I'm in CDR3, GDF and FGF have resolved, that I don't need that. But maybe because I'm using a lot of GLP-1s anyway. Maybe I'd already addressed the GADD34 as a result.

But I do think GLP-1s have a role to play in the sequencing of this. And that what's interesting to me is when I use GLP-1s, especially hopefully at the right time, patients go, "Oh, my gosh. My brain cleared up. I have a bunch more energy. I feel a lot better. There's something about it helping me turn a corner. It wasn't just about weight loss. My quality of life is better." And that's where I think GLP1 is kind of one more anchor for us in that regard.

[1:42:51] SCOTT: You also mentioned earlier in the GADD34 agonist realm, genistein, which I think is another one that maybe we don't use as much as we could potentially. Low HRV can be a clue as we talked about that autonomic flexibility is not there or the body's capacity to access a safety state may be impaired.

So, you've talked about tools like TruVaga and SONA. You mentioned Bi-Tapp earlier in the conversation. So TruVaga and SONA more for calming the nervous system, working with the vagus nerve. Is there a tool in that realm that's really stood out both from a patient compliance perspective, but also tolerance and effectiveness?

[1:43:28] DR. HEYMAN: Well, I think you kind of mentioned them, and that is to say how do we contact the vagus nerve? We can do that. I like the idea of using heart rate variability because the model is teaching people how to improve coherence, and that means improving their mind-body skills. We can cheat a little bit by using these direct vagal nerve stimulators like TruVaga and SONA. And there's others on the market too. And you clip them to an ear, they connect to the neck, and they send a signal right to the vagal nerve to improve parasympathetic tone.

But I think you rob people of an opportunity to build their emotional resiliency if all you're doing is sending an electrical signal. Now I think they have to work in tandem. The issue behind all of this though, and this is almost very Jungian, is the notion that if there's buried trauma that has to be addressed. And goodness knows there's a lot of it out there in this patient population. You need to go to that deeper layer of EMDR and Bi-Tapp, maybe professional counseling to help people directly deal with these issues that are preventing them from fully healing. I am absolutely more and more convinced.

And again, that's why I'm bringing in same here, but also just raising it as a vital sign in this patient population that, like Neil, I take it very seriously. And as you would say, it's an opportunity for us to more fully heal. That's the whole point of this illness, is that it sort of demands that sort of attention to detail, including the emotional landscape.

[1:45:03] SCOTT: CDR3 is also where we're restoring oxidative phosphorylation. It's where we're shifting away from that reliance on aerobic glycolysis and CDR2, back toward mitochondrial oxidative phosphorylation. We're then able to create ATP more efficiently. In CDR3 as well, and this is probably one of the last topics that we'll touch on here and then we'll start wrapping up, but you talk about CDR3 being where we might see a slip into autoimmunity. So does that mean that we don't commonly see autoimmunity presenting in CDR1 or 2? Does that mean that we want to look at immune modulatory tools like maybe low-dose naltrexone, or Moducare, or black seed oil, maybe low-dose immunotherapy, maybe the mold low-dose immunotherapy, those types of things? Or does that potentially mean that if we have autoimmunity in CDR3 that we missed the trigger that was driving the immune dysregulation that we called autoimmunity?

[1:46:01] DR. HEYMAN: Yeah, and I think that that's probably more consistent even with the HLA model, that exposures can trip people into autoimmunity, but it's not a one-hit hypothesis. Interestingly, even in the conventional literature, when there's loss of barriers and boundary in the body, when the gut is leaky, when vessels are leaky, when the blood-brain barrier is leaky, that also helps to predispose to autoimmunity because you're getting noxious compounds into body compartments where they shouldn't be.

And so, my sense is that, I should have mentioned, you can include ANA as part of your readiness to heal gate, that that should be part of that workup. In addition to MMP9 and other inflammatory compounds, you can throw in at least an ANA and see whether or not there's some autoimmune component. But if you go back to the functional medicine model of how does a dyed-in-the-wool functional practitioner deal with autoimmunity? Well, what do they do? They clean up the bugs. They detox people. They change their diet. They fix the microbiome. They fix stress. I mean, they're going to do all the same things.

Now, in terms of, as you mentioned, a few interesting compounds to help bridge the innate and adaptive immune response and help restore normal adaptive immune tone, one of my favorites is Moducare, which is a plant sterolin extract. It's been around a long time. It comes in a very defined 100 to 1 ratio of sterols to sterolins. It was developed by the Germans many years ago for rheumatoid arthritis, but it's really good in all sorts of other related conditions as well. And it basically improves T regulatory cell function. So, it raises Treg activity. And that's profound in sort of what it's doing in that regard.

Low-dose naltrexone has some similar properties, but basically what it does is it reduces temporarily endorphins in the brain. And as they come back two or three hours later, that means that we activate MHC Class II cells that then in turn raise T regulatory cell function. So, LDN also has been studied, in fact, originally in autoimmune conditions too. I'm actually starting a course with the Same Here company or organization on low-dose naltrexone at George Washington University because LDN has been shown to be so important in mental health issues but also autoimmune issues. So that course I'm launching soon at GW just on LDN and sort of how to use it and why it's so important.

Oxytocin, I love as well. Turns out feeling safe in the world actually helps to reduce autoimmunity too. Oxytocin sort of makes sense. LDI as your kind of low-dose exposure therapy, whether you do sublingual or injections can also help too. And then there's a few peptides, so TB500, and in particular, TA1. Unfortunately, TA1 was kind of removed from the market, but it was maybe one of the strongest bridge builders between the innate and the adaptive side of the immune system.

And I love TA1, especially in this illness. But unfortunately, we don't necessarily have direct access to it anymore. Although, of course, you can get it on the gray market. But there's a bunch of these that I really like. But what's interesting is that Moducare has maybe more human clinical studies than almost any other natural compound. There are dozens and dozens and dozens of high quality human studies on Moducare. Interestingly, it's not in people's toolkit. And I don't know why, but it just has been kind of overlooked as maybe kind of a one-off. But in fact, from an evidence-based perspective, it's really good. And the other would be SPMs, right? Because what are you doing with SPMs? You're essentially turning off autoimmune drive by stimulating macrophages and telling the immune system to start healing.

[1:49:23] SCOTT: The other thing that you explore in CDR3 is rebuilding, building reserves, strengthening robustness, fortifying the system with a number of tools. You talk about graded exercise, fasting, hot and cold therapy, intermittent hypoxia, supporting NRF2, supporting the mitochondria, cellular health, working on vagal tone, sleep, and the limbic system. So, are these things that we primarily then start to focus on in CDR3, or are these sprinkled through all of the stages and phases of your recovery model?

[1:49:55] DR. HEYMAN: My concern is that; so when I think about all those therapies, they really shine when a person is relatively healthy, but when they want to maximize their engine. Think of them as kind of an untrained athlete. And if you get people sort of in a very prescriptive way, moving, breathing, resting, kind of exerting themselves purposely, we can build the engine. But the problem is if the engine is already compromised, if they're "overtrained", which would be sort of CDR1, CDR2, you don't want to do those therapies because they're too debilitated.

And so fasting can worsen mitochondrial reserve in a sense if it's done too early in the process. Exercise can easily overwhelm the person if they have post-exertional malaise. Once they start getting into CDR3, then we have them do kind of the rebuilding piece. As if I'm taking an untrained athlete and building an athlete. And that is to say graded walking, for example. I have patients start with keeping their heart rate in zone two, which is basically 120 to 130 beats per minute. And we have them do 10 or 15 minutes at a time and then they build up to 45 minutes several days a week. There's a lot of literature to show that's a sweet spot for invigorating the immune system. It doesn't position people for cardiovascular benefit, but it does position people for repair and sort of immune tonification and fat loss. And so there's that.

And then, of course, we work on intermittent fasting, caloric restriction. Because at that point, we can use that as sort of a mitogen to improve resiliency and reserve. We're getting into the more classical anti-aging and longevity mode, but I reserve those things until they're really ready. If you do them too soon, I think you just get into trouble. Because these things, what are they meant to do? They're meant to restrict or push the body in a certain direction and then stop it and let it heal.

Exercise and rest. Caloric restriction and rest. Hot and cold and rest. But if you're already overwhelmed, and you're overtrained, and you're pro-inflamed, and you're in mold, and whatever, it's not the time to do that stuff. The body doesn't have the reserve to go into that repair cycle. You got to build it up first then you're in CDR3, and you can consider doing those resiliency and restorative practices. And that's where I think the world of anti-aging really shines because that's its home base is taking someone who's been okay in terms of their health and turning them into an animal, right? I mean, that's where we're really good.

[1:52:32] SCOTT: So the last component of this resolution and repair is the genomic piece with VIP. Wondering is that a common needle mover at this stage in the process? Are there other peptides that you're using or excited about? Where does PACAP come into this conversation and into our toolbox and hopefully the not too distant future?

[1:52:52] DR. HEYMAN: Yeah. So, I was writing about PACAP a while ago. And it's actually the stronger version of VIP, but it's on a non-compound list. So, there's no way to get access to it therapeutically, although it is sort of VIP on steroids in that regard. Not only does it bind to VIP receptors, but it also binds to other receptors. It has more potent neurogenesis characteristics to it, more potent anti-inflammatory characteristics. It's the big boy when it comes to that sort of lineage of neuroendocrine response.

We've got access to VIP, which is fine. Maybe one day PACAP will translate. It's been used in small clinical trials actually to induce migraines and other things. But if we ever got access to low-dose PACAP, that potentially is a game changer for us. But right now, we don't have access to it. But thank goodness, some of those peptides that were in the kind of no-go list were just liberated again. So, BPC-157, Semax, Selank, Dihexa. There's a bunch of these now that are available to us that weren't before.

And I think especially if CDR3 is a lot of it is immune regulation and brain healing, that's where these things shine. I wish we had access, as I mentioned before, to Cerebrolysin. We don't. But we have enough now in the portfolio once again, where we can start reaching for the KPVs, BPCs of the world, and really begin to accelerate brain healing in particular. I think that's where a lot of this game is going.

[1:54:16] SCOTT: How can people learn more about the work that you're doing at Beyond Mold? If they're resonating with this conversation, how can they work with you and your team?

[1:54:24] DR. HEYMAN: So very simply, I'm very education first. That's a real love and passion of mine. So, if you just go to our Beyond Mold website, there's a lot of material that's posted that you can read about a lot of these aspects. We continued to post in-depth monographs and scientific treatments of different aspects of this. We have a clinical primer. We've got all sorts of other related material that we'll be releasing into the wild over the coming months that will be posted on Beyond Mold.

In about a year, I'll be coming out with a book that will summarize all of this in great detail. It's been a labor of love. And I'm happy to announce that a number of chapters are actually written with Neil Nathan. So, we're kind of blending the best of all these worlds into one place.

We also, through Beyond Mold, if you feel like you really need some help, we've tried to create a model that is both high access, but also easy to navigate, but low cost. And that is to say, we brought the world's experts together to bring this model to this patient population. And we have a variety of ways of working with people that does not break the bank. And so we've purposely lowered the financial barrier to entry to ensure that people get the kinds of support information and tools they need to heal.

We have several different ways of doing that. For example, we have a messaging program where, for just 99 bucks a month, you can have access to basically as many messages as you need within reason to my entire clinical team. And that's on the home side and health side. So we have people at the ready to answer those sorts of questions as you navigate this process in general. You can have individual appointments with me and my colleagues. I'm not charging that much for any given appointment. It's kind of a first come, first serve. The bar is very low in that regard.

We're also restarting our group model. So, if patients are interested in participating in new groups that we're restarting, those are coming soon as well. Groups are interesting in that you meet with six or seven other patients, two hours at a time, seven sessions in a year. It's 14 hours of contact time as we bring you through the process together in community.

In addition to that, yes, we're very education heavy. So, we have lots of written material. There's all sorts of video content that we've been producing. There's no lack of ways that we're trying to kind of reach people and help them better understand where am I at and where do I need to go. And I'm very happy and thrilled that we have the team in place that we do at Beyond Mold to help people recover from this illness in a thoughtful way.

We have a big research agenda as well in the background. So we're collecting a lot of data. We're really figuring out what's working, what's not working as we stage people through the process. As you know, as an academic, I'm very passionate about we need to collect data and publish. It doesn't matter unless we show that this works. And so by virtue of kind of expanding our platform and reaching more people, we're able to do that at scale.

I would also say that what's unique about us too is that we have a 50-state telemedicine platform. So whatever state you live in, you can get access to medications, you can get access to lab testing, and we're expanding that. So if you need anything from a binder, to methylene blue, to low-dose naltrexone, to VIP, you can just log into our website and get whatever you need. If you want certain lab panels, you can log in and order whatever you need that you don't need to be gated necessarily through an office visit or a practitioner.

And so, telemedicine is really opening up, for example, our ability to deliver if people just need a medication or need a lab, or we offer the resources to go through an entire experience with us. So, we want to be that place where you can get the kind of resources that are required and meet people where they're at. You want a GLP1, you'll be able to come to our website and get it. You don't need to have some kind of prolonged experience. Or if you want that with us, we can give that to you.

[1:58:31] SCOTT: Or some PACAP, or some Klotho, or something.

[1:58:34] DR. HEYMAN: Whatever, you know.

[1:58:37] SCOTT: My last question is the same for every guest. And that is, what are some of the key things you do on a daily basis in support of your own health?

[1:58:44] DR. HEYMAN: I'll tell you what I do, and I'll tell you what I don't do very well. So, I'm lucky in the sense that, as some of you might know, I now live in New Zealand and that means I have access to everything kind of clean and healthy and hearty. And that means clean air, clean water, clean food. Everything here is nutrient-rich and nutrient-dense. It is obvious that the food supply here is very different than what we get in the States.

In fact, my wife and I had to get used to the fact that we would buy vegetables and they would turn in about three days here. And everybody would laugh and say, "Well, that's normal." Because we go to the market pretty frequently to get the things we need. We don't necessarily go every day, but you need to go every few days or so or stuff turns bad. We were used to buying stuff once a week or once every two weeks and it would still be good. Well, here, if you don't eat it right away, it turns. It's amazing to me that the difference in that regard.

So, we purposely made a choice about wanting to have a healthy lifestyle that was outside as much as inside. So, she and I are very physically active. I take that part of my life very seriously. Not only do I like to work out on a regular basis, but I do my walking. So, I get on my treadmill and I wear my monitor and I make sure I keep my heart rate in a certain zone for at least 45 minutes or so. And I'll do a little bit interval stuff. I like high intensity training. So, I'll do some of that as well. But I also like wildlife photography, and kayaking, and other things that kind of just keep me outside.

So, moving is very important to me. Eating healthy food is very important to me. What is elusive? Sleep. I'm a terrible sleeper. Some of my best ideas come in the middle of the night. My wife hates it because I'm up and I'm typing on my phone. I'm typing notes to myself where I'm developing things. And I'm like, "Oh, I made another connection." And even last night I was thinking about our podcast and I was sort of excited and I couldn't sleep. And she's like, "Andy, you're still up." I'm like, "I know. I need to get some rest. It's a big deal. It's going to be a long podcast." but it is elusive. And if I don't take things like high-dose melatonin and other stuff, I have a very hard time sleeping. And I think it's one of the worst habits I have that I can't turn my brain off.

We all struggle with stuff in that regard. But I know that if I can keep moving and breathing and eating okay and keep a healthy mindset, that goes a long way. But sleep is elusive. And I know how important that is, is a vital sign. It is what it is. We all have our challenges.

[2:01:09] SCOTT: We do. We do. Dr. Heyman, this was such an incredible conversation. I love how you've taken the concept and the theory of the Cell Danger Response and made it something that has clinical application. Your passion for helping your patients, for helping people is so clear and so appreciated. I really resonate with the model that you put together. I'm excited to continue to learn more about your model, learn more from you. I really want to honor you for your work and just really thank you for making a difference. So, thank you so much, Dr. Heyman.

[2:01:40] DR. HEYMAN: Thank you for having me.

[2:01:43] ANNOUNCER: Thank you for listening to today's episode of the BetterHealthGuy podcast. You can learn more about today's guest, including relevant links and resources in the show notes. This podcast may provide community discounts and occasionally share links from affiliate partners. You can find this and other episodes on YouTube, Spotify, Apple Podcasts, Amazon Music, iHeart, and more. To learn more about Scott's personal journey to better health, visit BetterHealthGuy.com. Join us next time on the BetterHealthGuy podcast.

[END]