This episode features Leo Galland, MD, who outlines a systems biology approach to understanding and treating post-COVID syndrome.
Dr. Galland created the graphic below to model factors and biological repercussions of long COVID. In the interview, Dr. Galland walks us through each element in the web of long COVID.
During the pandemic, he also created and published two hour-long videos—one for patients and one for providers—containing research and recommendations on addressing long COVID. The information he shares is intended to empower and educate both health care providers and patients.
Download and listen to this episode to learn more about:
- The deficiency that both contributes to and results from long COVID
- Key information about what causes long covid
- How to prevent severe infection and address symptoms
- Downstream effects of viral damage that should be addressed by functional medicine providers
Resources mentioned in this episode:
- Understanding Long Covid: a comprehensive presentation for health professionals
- ACE2 in Immune Resilience, Presentation to American Nutrition Association
- Healing Long Covid, video presentation for patients
James Maskell: This broadcast is brought to you by the Evolution of Medicine’s Practice Accelerator. For more than six years, we’ve helped doctors and health professionals build their own low-overhead, high-technology practice, making it efficient and effective at bringing in patients, educating them consistently, getting the right technology stack and building a strong, sustainable practice. If you want to find out more about the Practice Accelerator, go to goevomed.com/accelerator.
Hello and welcome to the podcast. We have a real treat in store for you today. Dr. Leo Galland, one of the godfathers of functional medicine, the creator of the patient-centered diagnosis, and someone who’s been a leader in the field of understanding gut dysbiosis and viral illness, is coming to share his take on COVID-19 and long COVID. And ultimately, for the last two and a half years, he has been studying every day all of the science that has been coming out as it relates to long COVID. What you’re going to get today is you’re going to understand his model, which he calls the web of long COVID, super critical. He’s going to be talking about the role of the microbiome in COVID, and he’s really going to share the protocols that he’s seen work for what he calls the middle of the web.
I’m not going to share with you what that is. You have to listen in and find out. But I think anyone in our community that’s dealing with long COVID should be seeing a functional medicine doctor and a functional medicine practitioner. There is so much good stuff in here. It’s very clinical, and I think it’s one of the best and most concise podcasts that we’ve been able to create at really understanding all of the parts of science that go into understanding long COVID, where it comes from, how it manifests, how it affects the function of the body, and what we can do about it. Incredible 40 minutes, 50 minutes, enjoy.
So, a warm welcome to the podcast, Dr. Leo Galland. Welcome doc.
Dr. Leo Galland: Great to see you, James.
James Maskell: It’s great to have you here on the show again. The event that we did back in 2014 early on at ABC, still one of my favorite functional forums. And it was no surprise to me to see you actually about a few months ago on Dr. Hyman’s podcast sharing incredible information on long COVID because your discipline, obviously, to learning about the biggest viral issue in our lives is consistent with, obviously, being at the very front end of really trying to understand chronic illness, trying to understand gut dysbiosis, a term that you coined. So, I’m really grateful to have you here on the show to share about your insights to long COVID. I know many practitioners in the community are seeing these patients. They’re trying to do the best they can.
So, I hope today in line with our year of growth, we can really talk about whether or not functional medicine is a good fit for long COVID and how practitioners out in the community can be in service to solving this. So, I guess, let’s just go back to the beginning, right? First viral pandemic of certainly my life, maybe yours as well. What did you decide early on about how you were going to play a part in this issue?
Dr. Leo Galland: Well, in January of 2020, it became clear to me that this new viral infection was going to spread outside China and that patients of mine were going to have a lot of questions about it. At the time, I didn’t really know how it was going to upend everybody’s lives. And so, I thought, well, I really need to understand what’s going on here so I can answer the questions my patients are going to bring to me. And I started reading about the SARS epidemic, which was the precursor of this, and everything that I could learn about coronaviruses. Basically working, studying this every night after I’d finished work on a daily basis. It was pretty fascinating but also stressful.
I realized I was beginning to experience crisis adjustment disorder, which was a psychiatric diagnosis. I started dreaming about it, but I also realized that the time to get crisis adjustment disorder is before the crisis, so you can be prepared for it rather than once the crisis strikes. And so, in February of 2020, I began posting on my website, drgalland.com, something that I called The Coronavirus Guide, which was an attempt to explain everything that I was learning. I did it as much to help organize my thoughts as to communicate to other people because I realized this is so complicated and so new that the only way I’m really going to be able to wrap my mind around it fully is if I’m trying to explain it to others.
It became clear by the spring of 2020 that there were people who weren’t recovering, that there was this phenomenon which was called long-haul COVID. And I started looking for research and data that would come out, kind of explaining what was going on. And the early reports were always basically, well, person has persistent symptoms and when the research studies are done, these people have ongoing inflammation in their body. And there were a lot of attempts to compare it to post-viral fatigue syndrome, CFS/ME. But as I followed the research, it became clear to me that there’s something more going on here than previous post-viral fatigue syndromes. That’s part of it. But there are unique aspects to long COVID. And they manifest themselves in different ways actually.
The only prospective study that I’ve seen of CFS, chronic fatigue syndrome, as a post-infectious syndrome, was done in Australia, and they followed the residents of this small city for a year. And they looked at people who got acute mononucleosis, Ross River virus. And what they found was that six months later, roughly 12.5% had not fully recovered. The symptoms that they had were all very uniform—fatigue, brain fog, muscle pain—and it was directly related to how sick they had been with the initial infection. Well, long COVID, there’ve been about 200 symptoms described. People with mild illness can go on to develop severe long COVID, and one pattern is a failure to fully recover.
But another pattern is you seem to fully recover and then you get the symptoms back either weeks or months later, usually following some other event, maybe another viral infection. But then there’s a pattern in which you get a whole new set of symptoms weeks or months after the original, and it’s quite a distinct illness. And then there are people who don’t necessarily just get a symptomatic disease. They actually get something with an ICT code. The rates of diabetes, hypertension, cardiovascular events, neurologic disorders and psychiatric diseases… It roughly doubles in the year after having COVID-19 in some very carefully controlled studies of large populations.
And then of course there’s the research looking at brain MRIs from the UK, which is scary because they took a large database of people who had had brain MRIs before the pandemic and offered them MRIs again once the pandemic was underway. And they divided them into two groups, those who’d gotten COVID-19 and those who hadn’t. And the group that had gotten COVID-19 had changes in their brains that were not seen in the other group. And they very much matched a lot of the cognitive disturbances that have been described in people who’ve had COVID-19. And some of these people weren’t even going around thinking they were sick. So, there really is a unique set of phenomena here.
In the spring of 2021, I began organizing all of the research that I’d seen on long COVID into some presentations. And in June, I posted two presentations online, each of them over an hour long. One was for health professionals called Understanding Long COVID. They’re both available on Vimeo. YouTube hosted one but took it down. And so, I’ve got them both on Vimeo. And the other one is for patients. I’ve gotten really great feedback about the content. Over the past 14 months since posting those, I’ve seen a lot of people with long COVID, not among my patient population. Actually, among the patients that I have been treating who were my patients when they got COVID and who followed my protocols from the onset of COVID until they recovered, the incidence of long COVID has been under 1%. I follow these patients very carefully.
So, I really do think that the principles that I describe do something that’s important from a preventive perspective. It doesn’t matter what their previous risk factors were. The people that have consulted me since who have had long COVID have been ill for varying periods of time, sometimes a year and a half, sometimes with really devastating illness. And so, I’ve tried to… And many of them are people who’d seen my video. So, they followed everything that I said, and they got some degree of benefit. That’s been very common that people get some degree of benefit, but they’re still stuck. And so, I’ve been challenged to look deeper and look further, and I really follow the research on this on a daily basis and have for two and a half years.
And what I have learned over the past year is: Number one, the principles I had described in June of 2021 have all held fast and held true. There’s just nothing there that was really off the mark. But as the science has looked at this in a deeper and a broader way, the priorities have shifted, and the emphasis has changed. And back in the early part of this year—January, February 2022—I was trying to understand, “How are all these different parts connected?” Because they’re very complicated. And what would make them simple enough that you can really understand them. I’m just going to digress for a moment. One of the huge problems with COVID-19 and long COVID is the way the presses handled this. I mean, it’s really… People are traumatized. They are panicked at the idea of long COVID.
James Maskell: Absolutely.
Dr. Leo Galland: And all they’re being told over and over again is, “Well, we don’t really know what’s causing it, and there’s no real treatment.” And I’ve had some of the patients that are consoling me have been to places that are doing research, and they’re doing great research that I really respect and that I’m following. And universally they are told when they go there, “Well, we’re not treating anybody based on this research. We’re just treating symptoms.” Now when I happen to mention this to a patient of mine, she said, “Well, what else is new?” Because that is the way that conventional medicine operates.
James Maskell: Well, I want to ask you about that because obviously in April 2020, we had Dr. Ari Vojdani on one of our sessions, and he sort of predicted at that moment who would get a bad case of COVID and who wouldn’t based on factors that he understood. That ended up being true all the way through with very little change. You have yourself saying things at the beginning, the world works out and then you see that you are in by and large right. Contrast that to the world and medicine where it was changing every day, and, “What should we do?” Early intervention, the vaccine, the setup. I guess, what is it about the systems biology, functional medicine approach that allows the people in our community, that facilitates the people in our community to kind of get it 90% right from the beginning, predictively?
Dr. Leo Galland: It has to do with a way of understanding and approaching illness and patients. And it’s something that I had described at the first functional medicine symposium, 1993, which I call patient-centered diagnosis. Conventional medicine looks to name diseases. You name a disease, you describe a disease, and then you have a treatment for a disease. And whatever they say about in medical school, “Well, you treat the patient not the disease.” You’re not given any tools in medical school to treat patients. You’re only given tools to treat diseases. So, conventional medicine, when it comes to long COVID, they’re still trying to decide, “Well, what is long COVID? What kind of ICD code are we going to give it, and how are we going to distinguish it from something else?”
Functional medicine is basically a physiologically-based approach to understanding the underpinnings of illness. Going back to the root causes when you can, and looking at it from the perspective of systems biology and how the body functions. This should be the basis for all medicine, frankly. In trying to apply that way of thinking to long COVID, I came up with this visual scheme that I had mentioned, which I call the web of long COVID. It’s a little bit different from the functional medicine matrix or some of the things that I presented on patient-centered diagnosis in the past. It’s very specific for COVID, and it looks like a spider web. It’s not perfect, but it’s the best visual that I could come up with as a didactic tool.
At the center of that spider web, there are two rings, each of which plays a role in creating all of the strands of the web. The central ring is deficiency of an enzyme called ACE2. ACE2 is the gateway by which the virus enters most cells. It is also a vitally important enzyme, and it really balances out the renin-angiotensin system. It has effects on every organ in the body, and it is damaged by viral cell entry and by the inflammation it provokes. And ACE2 deficiency is at the core of almost all the complications of acute COVID-19 and plays an important role in many of the manifestations of long COVID.
James Maskell: Can I ask you then, would that be a deficiency that had built up ahead of time and then the patient gets the virus and then they go down, or would it happen during the infection itself?
Dr. Leo Galland: Well, both things happen actually. The people that get the sickest from COVID-19 are generally those who already have impairment and imbalance in the renin-angiotensin system, which is characterized by a relative ACE2 deficit. However, the infection itself can damage ACE2. And even after the infection, the antibodies that develop to the spike protein can cause what’s called an anti-idiotypic response, creating autoantibodies that damage ACE2. At every stage, pre, during and post, there can be something that’s attacking ACE2. When I realized in March of 2020, when the research came out showing that ACE2 was the entryway for the virus into cells. And, of course, my first thought was, “Okay, well how do we block that?”
But then, when I looked at it more, I realized we don’t want to block this enzyme because this is the victim, not the culprit. And so, I started developing protocols to enhance ACE2 activity. And I think those are the protocols that have really helped to prevent long COVID.
James Maskell: Let’s get into those protocols in a minute. What’s the other thing in the middle of the web?
Dr. Leo Galland: Surrounding that is mitochondrial distress. When ACE2 takes a hit, the mitochondria in those tissues also take a hit. And then, of course, the inflammation that occurs in the oxidative stress damage both ACE2 and mitochondria separately. It’s kind of snowball effect. And mitochondria are important for cell functioning at so many levels. We think about them in terms of the brain and the muscles. So, fatigue and neurologic problems may involve mitochondrial dysfunction. They’re really essential for the way the immune system functions.
And, interestingly, the reparative anti-inflammatory arms of the immune system are especially dependent on mitochondrial function and oxidative phosphorylation to work. When the immune system is in attack mode, it actually relies more on aerobic glycolysis, the Warburg Effect, like cancer cells. So, mitochondria are pivotal for the regulation of immune function.
James Maskell: So, then those two things are centrally determining the factor. And what’s on the edge of the web?
Dr. Leo Galland: Okay, well, there are these strands that go out because the only spider web I could find on Google had eight strands, I had eight strands. Maybe I would’ve liked nine or 10, but I think eight does it. Okay, so, the first one is inflammation of the vascular endothelium, endotheliitis. It’s been very well studied. It’s a really important manifestation of acute COVID-19. And there are a number of studies indicating that this persists after recovery from acute COVID. The next one over is microthrombosis. We know that blood clotting increases with COVID-19. There’s been a lot of work showing that microthrombosis occur in the post-COVID state. And in fact, endotheliitis and microthrombosis reinforce one another.
They create a kind of a dyad because it’s the endothelium that generates the impulse for microthromboses. The microthromboses then further damage the endothelial. That’s a kind of feed forward loop that’s going on there. One of the characteristics about the thromboses that occur with COVID-19 is… These are not normal thrombi. Because of the inflammation and the involvement of neutrophils, these thrombi involve what are called NETs, neutrophil extracellular traps, and they play an important role in the pathology of acute COVID. They also seem to play a role in the microthromboses following COVID-19, which is why they’re so sticky and hard to deal with, and you can’t just use aspirin to deal with them.
Those are two complicated areas. For example, we take endotheliitis; the hit that is taken by ACE2 and the viral entry into the endothelium. That helps to create endotheliitis. But also, the spike protein itself has a high affinity for heparin or heparin sulfate, which is part of the glycocalyx that coats all cells. So, the spike protein can directly damage the endothelial glycocalyx. In fact, the first step in viral attachment is the binding of the spike protein to heparin sulfate on the cell surface. That’s why I created a heparin nasal spray to use as a decoy for preventing infection because of the high affinity of the spike protein for heparins. And there are researchers at the University of Mississippi and in Australia are conducting clinical trials with that concept.
Now, okay, so, we have those two strands. A third strand that I found to be really important is mass cell activation. And there are some clinicians, in particular, and researchers who have really focused on mass cell activation as being critical for the pathology of acute COVID and long COVID. I found it to be very important for those patients who are not responding the way I would expect them to respond to the treatment protocols that are aimed at ACE2 and mitochondria and dealing with microthromboses and endotheliitis, and especially people who have paradoxical reactions seem to be hypersensitive to things that should really be helping them. Virtually all of those people have gotten into a state of mass cell activation from which they cannot back down.
There’s a whole literature on the role of mass cell activation in chronic illness, and it is important here. And there are specific treatments that can be useful there. The fourth spoke in the web is what I refer to as monocyte polarization. It’s actually monocyte and macrophage polarization, but that didn’t fit in the diagram. So, my interest in monocyte polarization or my awareness of it started with the work of Bruce Patterson and his group. Patterson’s gotten a lot of attention for the work that he’s been doing with long COVID, who basically determined that one of the phenomena that they were measuring was the maintenance of monocytes in the circulation where they became senescent and consequently their response pattern changed.
Monocytes basically do three things. They attack, they repair and they patrol. There was a shift in the monocyte population—or there appeared to be—in terms of the patrolling monocytes, and they were sending up inflammatory signals. Now, the attacking monocytes happen to be the ones that enter into tissues. They circulate for about a day, then they enter into tissues, where they become macrophages. And macrophages also exist in more than one state. They have complex, all of these cells—not mass cells, mass cells are very primitive—but monocytes and macrophages have pretty complex life cycles, and they have a repertoire of activities. The macrophage response pattern is altered also.
And it’s altered in a direction that not only creates certain types of inflammation but also suppresses T cell function. So, what I discovered, as I was looking into the research on macrophages and monocytes, was that ACE2 has a pretty—indirectly and directly—has a pretty significant impact on the monocyte life cycle. And I do believe that the measures that restore ACE2 can in fact help to restore balance in the monocyte, macrophage response patterns. Now, the next strand in the web is the occurrence of autoantibodies. From a functional medicine perspective, I think this is actually the hardest to deal with because once autoantibodies start to occur and they’re actually producing damage, it’s not necessarily easy to turn them off.
COVID-19 is associated with a very high rate of autoantibody production, more than other viruses. And many of these are actually functional autoantibodies that attack vital cellular functions, ACE2 included. Five percent of people with mild to moderate COVID-19 will develop antibodies to ACE2, autoantibodies. And they are functional. They interfere with ACE2 activity. If you’re sick or if you’re hospitalized, it can be 80%, maybe, the frequency. There are other autoantibodies to receptors, cellular receptors called G protein-coupled receptors, which regulate about at least 50% of biological functions. Many of these only become activated when there’s inflammation. This is an area that’s expanding. There’ll be a lot more research being done on this.
James Maskell: Well, actually back at the conference that we did at Jeff Bland’s PLMI conference that Ari Vojdani and Elroy Vojdani, who did actual presentations, I think, just specifically on this part of the web that you are defining, and how the autoantibody process kicks off from COVID, and it’s potential for that. There’s some good information we’ve already shared earlier this year on that particular—
Dr. Leo Galland: Okay, great. Great. Now the next strand is T cell impairment. There is a lot of evidence of different types of T cell dysfunction associated with COVID-19. It starts right at the beginning because this virus can actually invade T lymphocytes. And lymphopenia, in fact, is one of the bad prognostic factors with acute COVID-19. It may be related to direct viral invasion. And that’s not ACE2 dependent. That uses another molecule for entry. There are many different types of T cells dysfunction that have been described in long COVID. And, of course, T cells control B cells. So, the T cell dysfunction, I’m sure, has something to do with the autoantibody formation.
It used to be thought that T cells control monocytes and macrophages. It actually turns out that the monocytes and macrophages control the T cells and direct them. So, I’m sure that dysfunction in the innate immune system contributes to the T cell dysfunction that we see. But there are other aspects to the T cell dysfunction, which is the next strand of the web, which is viral persistence. T cell dysfunction enables viral persistence, but persistent antigenic stimulation also can create abnormalities in T cell function. And, in particular, it causes an impairment in the activity of a type of T cell called a T effector memory cell. T effector memory cells are CD8+ cells.
They’re cytotoxic, so they’re cytotoxic lymphocytes. But they have a memory for the antigen that they’re going to destroy. And they’re very important in clearing viral infections and in response to vaccines, for that matter. And really interesting study from Northwestern University by Koralnik and his group showed looking at people with what they called neuro-PASC, that is people with long COVID who had neurologic manifestations, including chronic fatigue. And they found in particular in that group impairment of T effector memory cell function. And said that this is really consistent with chronic infection or antigenic stimulation. So, I’ve looked into ways of trying to improve that.
Actually, this brings us to the last strand in the web, which is gut microbial dysbiosis. Because the gut microbiome actually has a pretty profound effect on cytotoxic lymphocytes and especially the T effector memory cells. So, it’s been speculated since the beginning of the pandemic that there was gut bacterial dysbiosis contributing to COVID-19. And it took about six or eight months before there were actual articles. Every time I would check something, there’s always somebody speculating, somebody speculating. I don’t care about speculation. I like data. It became clear that people who had been hospitalized with COVID-19 compared to other conditions had a pattern of abnormality involving the gut microbiome that actually is not that different from what’s been described in CFS/ME.
But then there was a study… The most recent study looked prospectively at how this related to who develops long COVID. And there are some unique features there, I think. But it really reinforced what had previously been discovered: That people with COVID-19, whether or not they have GI symptoms, develop a loss of diversity of the gut microbiome. They’re more susceptible to fungal overgrowth. Anti-inflammatory species that are generally considered protective, like Bifidobacterium, are diminished. One of the reasons that the Bifidobacterium diminished is there’s a marked decrease in butyrate production. And butyrate is a major food for Bifidobacterium.
One of the reasons for the decrease in butyrate synthesis is the loss of butyrate producing bacteria, in particular, a keystone species called Faecalibacterium prausnitzii, which I had spoken about last summer. In addition to that, there’s an overgrowth of kind of inflammatory and undesirable species. Uniquely, in the group that’s going to develop long COVID, there’s an organism called Ruminococcus gnavus, that overgrows. Now, Ruminococci are interesting organisms because they can destroy the mucus layer, which is protective, and increase intestinal permeability. They also produce a metabolite called isoamylamine, which is neurotoxic. Studies in animals have shown that amylamine increases age-related cognitive decline.
Now, one of the big descriptions of the cognitive functions that are impaired with COVID is this is like people are aging, like they’re getting Alzheimer’s, and there’s an increased risk of Alzheimer’s. So, what’s the role of Ruminococcus overgrowth? Not just the loss of butyrate and the loss of diversity, but these specific bacteria in generating a metabolite that actually accelerates age-related cognitive decline. Above and beyond, with all of the impairments that occur directly in the brain, with loss of blood flow to the brain, and disturbances that have been demonstrated by different researchers.
Now, of course, the presentations that you and I have done together were all about the gut microbiome several years ago, and that’s been a major area of interest of mine. It turns out that the gut microbiome actually plays a really important role in long COVID. And it seems to do it in two or three, in a few different ways. And one of the things that may make it a particular target is that ACE2, going back to the beginning, ACE2 has a very special role in the GI tract. It is a chaperone for the transport of large neutral amino acids into the body. ACE2 deficiency produces tryptophan deficiency. Loss of tryptophan not only alters neurotransmitters, it also messes up the indolamine pathways in the gut and the kynurenine pathway and results in a loss of proteins called beta defensins, which are really important for regulating the microbiome.
So, there’s a direct link between ACE2 deficit and microbial dysbiosis in COVID-19. And maybe some of the other problems that occur due to interference with the tryptophan/indolamine pathways. The gut microbiome, as I mentioned previously, also does influence the development of cytotoxic lymphocytes. A lot of the research that supports this has been done in patients with cancer, people who are being treated for cancer with immune checkpoint inhibitors. The whole idea is to enhance the activity of their T effector memory cells, in particular, but other cytotoxic lymphocytes. So, researchers have looked at, “Well, how do we enhance that?” And it’s been very clear that the gut microbiome has an impact on how well these checkpoint inhibitor therapies work.
James Maskell: That’s really interesting doc. So, can I ask you? So, now, you see these ACE strands, you’ve got these things in the middle. The protocols that you were starting to recommend and recommending, was that for mitochondria and ACE2? Or was it mitochondria, ACE2 and then whatever strands were showing up in the individual patient?
Dr. Leo Galland: Right. Well, I start with ACE2 and mitochondria. One reason is that trying to deal directly with some of these other strands, sometimes it gets a little stressful, especially if you’re going to deal with viral persistence. Or how do you balance T cells immunity? You want it just right. So, I think that restoring ACE2 function and enhancing mitochondrial function, those are foundational.
James Maskell: And what is some of your favorite things that you use for that in your protocols?
Dr. Leo Galland: Okay. Well, when it comes to ACE2, there’s several influences, and some of them are things that we’re already doing and people have been doing since day one of COVID or even before. Diet has an impact on ACE2. And the kind of diet that most favorably impacts ACE2 also most favorably impacts the gut microbiome and actually decreases the growth and activity of Ruminococci. It is a high-fiber, high-polyphenol plant-based diet—it doesn’t have to be exclusively vegan. But that particular kind of diet has been shown in the setting of acute COVID to decrease the risk of severe infection by 70%, in a very well-done cohort study that came out of Johns Hopkins, which I mentioned in, I think, both of the Vimeo videos.
So, now, I do have patients who have been following that kind of diet and still got long COVID, so this is not the answer to everything, but it is the beginning of it. And I think the polyphenols are especially important. And then vitamin D: One of the effects of vitamin D, very well studied, is to enhance ACE2 activity, and it’s been pretty clear that vitamin D deficiency is a risk factor for severe COVID. Sometimes high doses are needed. Curcumin has actually been shown in clinical trial to improve the outcome of acute COVID. It has numerous anti-inflammatory effects. In animal studies, it’s been shown to increase cellular ACE2 activity and so has resveratrol. And resveratrol and curcumin do this in ways… There are no clinical trials looking at these for COVID. There are a lot of clinical trials of curcumin and resveratrol for various clinical diseases pre-COVID.
One of the things about the effects that the relationship between these two and ACE2 is that not only do they improve ACE2 activity, they do it in settings that are clinically relevant for humans. That is ACE2 can prevent aortic aneurysm. Resveratrol can prevent aortic aneurysm. These are really important for vascular health. There are indirect effects of other supplements that I think are important, in particular, fish oils, omega-3s, EPA and DHA.
Omega-3 consumption raises the levels of a group of peptide regulators called apelins. Now, one of the effects of apelins is to increase ACE2 activity. And apelins have really… When you look at the clinical effects of administering apelins, they’re virtually the same as the effects of administering ACE2 or it’s metabolites like angiotensin (1-7). Human clinical trial of omega-3s in elderly men with heart disease and heart failure, omega-3s increase apelin production. And CBD, by the way, also increases apelin production.
James Maskell: Interesting.
Dr. Leo Galland: There was one very fascinating study in which… It was an animal, it was an in vitro study—they haven’t done the in vivo work—where apelins totally reversed the type of damage that was caused by the entrance of a SARS-CoV pseudovirus into the cell culture. And they used CBD to do it. They administered CBD to the cell culture. Because of the effects of oxidative stress on ACE2, there are two other supplements that have a significant impact. See what oxidative stress does… Oxidative stress activates an enzyme called TNF-alpha-converting enzyme or TACE, also known by another name ADAM17. That is what’s called a shed ACE.
It cleaves ACE2 and causes the extracellular domain of ACE2—ACE2 is transmembrane—to be shed, and it goes into the circulation where it loses about 99% of its activity, not all of it, but it’s much less active when it’s circulating in plasma. Antioxidants inhibit TACE activity and activation. And so, they can save it. The two that have been shown to do it in laboratory models are N-acetyl cysteine (NAC) and alpha-lipoic acid. And so, I will frequently use alpha-lipoic acid at a dose of about 600 to 900 milligrams a day and NAC, in conjunction with curcumin and resveratrol to try and deal with enhancing ACE2.
James Maskell: That’s amazing. Well, doc, look, I really want to say I appreciate you sharing so much of your knowledge here for our practitioner community. I guess I just want to take a step back for a moment just to ask you about the state of play of medicine. You mentioned there earlier that all of these big, storied institutions are just treating symptoms, and you’ve laid out treating the center of the web protocol and, obviously, had a lot of success with that. This is the year of growth here at the Evolution of Medicine. We were just sort of thinking that this is a topic that’s not going away, it’s only just got started. Our community knows a lot about things like the gut microbiome, thanks to you and your work and many others.
And I guess I’m just wondering whether you can speak to the need for the functional medicine operating system and could, in the same way that maybe long COVID has led to more of a social acceptance that short-term viral illness can become long-term dysfunction, can some of the protocols that you’re sharing, if we were to get really good at it, to take functional medicine further forward into the front of medicine as opposed to in the fringes and in the background?
Dr. Leo Galland: I really don’t see any other discipline aside from functional medicine that’s going to be able to advance the clinical science of long COVID. There are people who are really great experts in different strands of the web. But you’re an expert here, you’re not an expert there. And there’s hardly… I really haven’t seen anything, even if it pretends to be comprehensive, that looks at this problem with the same scope and perspective that functional medicine can bring to it. So, I think there’s a huge need for this. I would love to see a textbook in which each of these strands is explored.
James Maskell: Absolutely. Well, I wonder about that generally because I thought, even during COVID and the response to COVID, you’ve got virologists who have an idea, you’ve got epidemiologists, you’ve got economists, you’ve got a range of people. I guess I found myself, as an economist, someone who thinks in tradeoffs and that kind of understanding, that ultimately, when you’re dealing with a pandemic, obviously, you need to understand the virology and the epidemiology. I guess I want to talk to, I guess, the power of generalism because it seems like what you’ve concluded there is that there’s a power of generalism in understanding all of these different strands to be able to treat patients effectively.
But it seems like even a step further back, there’s a need for generalism because had we had more of an integrated approach to COVID, perhaps a lot of people who died of COVID wouldn’t need to die of COVID. Perhaps the strategies that we use, like lockdowns, could have been used a little bit differently to try and avoid some of the psychosocial and economic damage from COVID. I guess I was trying to pull two things together here, which is the power of generalism as opposed to just being in the very detailed weeds on one particular topic.
Dr. Leo Galland: Well, Osler said… Osler was the guy that founded Johns Hopkins School of Medicine. He said, “Beware of anyone who enters medicine as a specialist.” Okay? In other words, people specialize. You get into an area, and you find I’m really good with this, this is what really works, this is what I care about. You should be following your passions. There will be areas of special interest, but the basic perspective has to be not only whole person, it has to be community wide. And all of these areas of special knowledge need to be put to the service of the big picture. And you need people who are able to look at the big picture and cooperate with others and are not just into staking out their little piece of territory, says, “Oh, I discovered this, and this is where the truth lies.”
James Maskell: Absolutely. Well, look, I really appreciate the time here, and it reminds me of just how important I think it is that we have communities of practitioners getting together, sharing what they’re learning. I know you’ve done an incredible job of sharing, and we’ll link to both the picture of the web that you just shared amazingly here today and then also those Vimeo videos because I know there’s probably a lot of doctors out there that wish they had a complete way of communicating what patients could do about long COVID or really understanding it for themselves. So, thank you so much for sharing and thanks for your dedication to understanding this. Like you said, two and a half years being in the literature every day, do you finally feel like you’ve got your head around it, or do you think there’s still more to learn?
Dr. Leo Galland: Oh, there’s definitely more to learn. There’s certain areas that the work on T cells and autoantibodies that’s going to explode. What has been exploding this past few months has really been the work on viral persistence. So, there’s more and more that’s going to keep coming out, but I do think that I have a concept of how all these parts relate to one another. And so far, that diagram of the web seems to work. I’m sticking with it.
James Maskell: Absolutely. Well, at the end of the web is, as you said at the beginning, sort of the organ damage. And, ultimately, I think functional medicine is well-positioned to understand, when organs and systems are damaged, how do we bring them back to full function? And that’s not a discipline that is in conventional care and an idea whose time has come. So, doc, thanks so much for all of your leadership and vision here. This has been the Evolution of Medicine podcast. We’ve been speaking with Dr. Leo Galland about long COVID, the state of the research, some of his protocols, and I trust that this has been valuable wherever you’ve been listening from. Thanks so much for tuning in, and we’ll see you next time.
Thanks for listening to the evolution of medicine podcast. Please share this with colleagues who need to hear it. Thanks so much to our sponsors, the Lifestyle Matrix Resource Center. This podcast is really possible because of them. Please visit goevomed.com/lmrc to find out more about their clinical tools like the group visit toolkit. That’s goevomed.com/lmrc. Thanks so much for listening and we’ll see you next time.
Click here to download this podcast
music provided by intomusic.co