128. Progress Note #13: Long COVID Theories - Low Serotonin to Blame?

Hello everyone, I'm Dr. Darsha, and I'm Dr. Altamash Raja, and welcome to Medicine Redefined. A podcast where we will explore the often overlooked but necessary components of health, what we consider to be the fundamentals. We will investigate topics and practices that can give you and your patients the best chance to optimize a healthy lifestyle. It's time to move the needle forward and put the health back in health care. All right, welcome back everyone to another progress note sitting across from me on the green, Dr. Altamash Raja. First off, man, you had some new travels to BAMF country. How was it? Amazing, as we spoke about offline, I think it was definitely, I think this is the first time I got to visit someplace that's been on the bucket list for quite some time. Anybody who is not familiar, if you just quickly Google it, you'll know why that's the case. And it was absolutely gorgeous. I think three days in, I was just like, I can't wait to come back because you realize quickly as you get there, despite having an agenda and having to have GPT plan for me, that there's just no way as you start talking to people of all the things you have to see. And you know, I went in the beginning of October, so the weather, it wasn't the most cooperative, but I think for the most part is pretty good. And then there are certain places that are just more conducive to visiting in the summertime and just because of the area and the slopes and the avalanche zone and whatnot. So can't wait to go back already. I'm stoked, but yeah, absolutely gorgeous place that I think everybody needs to visit, especially if you're kind of in that nature-esque thing that that turns you on. Did you end up hiking because I know you have a little girl. So what did you like end up doing as far as the area in nature goes? I'd say modified hikes. We, some of the, some places we, it took a stroller to where a stroller was not meant to go. And so I'm surprised that a stroller still made it back in one piece. Like Johnston Canyon is this really cool place where you kind of go down and up in Canyon and you head from waterfalls that you can see. And that was not stroller friendly, but we made it happen anyway. And other places you just kind of just do the baby carrier and stuff. But yeah, yeah, I mean, every place that you go to like Lake Louise, the big one that everybody sees when they Google it, right? That's like this calm water, perfectly blue turquoise water. And they have so many different trails. Like it just depends like you want to take the two kilometer trail or the six kilometer trail or the 12 kilometer trail and they have all these little t times that you can go up to, which is really, really nice. But definitely, definitely we're checking out amazing, definitely adding it to the bucket list. So, you know, awesome. Well, why don't you set us up with today's topic, give us a little introduction on what we're going to be going through. Yeah, this one is going to be a brand new one, right? So we are going to be talking about COVID after several years. And so we touched on it here and there and probably not in the sense that that people are thinking there's going to be nothing political here that we're going to look at the science of it. And not just SARS-CoV-2 virus or COVID-19, the infection, but really a specific disease called long COVID, also referred to as long call COVID. Some people call it post COVID, chronic COVID, post acute sequelae of SARS-CoV-2 is recognized by multiple names. And I think at this point is relatively well recognized by the medical community as a legitimate diagnosis, as legitimate distinct disease or sequelae of COVID-19. So what is it, as a name suggests, this is either prolonged recovery or prolonged symptoms of COVID-19 or people who've had recurrence of multiple COVID-19 infections that just linger on and they haven't quite recovered, haven't been the same after they have recovered from just a standard, you know, the URI type symptoms if you're lucky enough to not have a very severe illness. And the challenge with this specific disease has been for a long time, for people to admit that, hey, this is a real issue, it's because it presents with a wide variety of non-specific symptoms, spanning multiple different organ systems in the body, right? So you have these non-specific constitutional symptoms like malaise, fatigue, you have brain fog, you have mood related stuff, you can have some cardiovascular stuff, you know, in terms of like even congestive heart failure type symptoms or just shortness of breath or decreased, you know, exertional capacity, et cetera, et cetera, you can have vague GI related symptoms. So it's very hard to diagnose. And the other challenge is that there aren't any specific diagnostic tests, right? I mean, we know that if you're positive for COVID-19, you know, you might be positive quite some time or even if you're no longer positive after you've had, you know, clearing quote-unquote of infection, you can still have these symptoms. And so it's a clinical diagnosis. It actually reminds me of something called post-concussive syndrome. So these miserable minority that we talk about, these are the people that we see, right? So concussion, everybody's familiar with concussion. And there's a very small subset of population, probably less than 10% of individuals who have these symptoms that persist, right, three months, six months, two years. I've got a very young patient who has just completely taken her life because she's two years in after getting hit by a wave. And the challenge was that, again, because it's a clinical diagnosis, you know, a lot of physicians would say, oh, that's not really a thing and, you know, that's a different debate. But the other interesting thing about this is for a long time, we, and actually still, we don't really know the causes. And we have a poor understanding, although that understanding is developing, right? So some of the proposed theories are that the SARS-CoV-2 particle becomes a reactivated over time, you know, and then it goes into, what's the more, look, look, look, like a suppression almost and become reactivated, so it's these recurrent reactivation times. And then the symptoms will reappear. There's the immune theory where you have these overactive immune cells and they are constantly releasing inflammatory markers. And so you have this prolonged inflammatory state, which, you know, chronic inflammation typically not associated with good outcomes. From the other immune theories, there's also your immune system has created auto-antibodies, right, which are wreaking havoc on the system, right? So it's kind of like an autoimmune type of situation. And then the topic of today's discussion, somewhat of a novel theory, is this serotonin mismatch or serotonin deficit, so to speak, what we're going to talk about. But before we do that, a couple other things. So risk factors wise, you know, folks who've had a severe illness, who've been hospitalized, fever, immune system, comorbidities, underlying health conditions, the non-vaccinated, as they say, this is what the science says, not me, you know, other potential risk factors could be female sex, the elderly population, a high immune response, again, very similar to the things that we were to talk about. And with respect to treatment, there really isn't one, right? So it's just supportive management of symptoms. Although there are several studies that I was able to find, you know, several clinical trials, like the recovered trials, a big one, looking at Paxlovid and its role in long COVID. And there are several other observational studies as well in terms of both symptomatically and different treatments, whether it's exercise and whatnot. So it does look like a lot of people are finally putting a lot of attention into this. And I think, you know, one of the interesting in our world, I don't know if you've seen this in your rehab experience was that we were getting a lot of patients after this, who needed acute and patient rehab, because they just had chronic debility from their COVID types of symptoms. And so we even had like a COVID clinic. When I was in residency, they were building that toward that. And there was actually a COVID, you know, prolonged COVID section and part of the rehab facility that these patients like me, I think we may have allocated four or six beds to that, if I remember correctly. So with that, I am going to hand it over to you and let's chat about this serotonin stuff here. Yeah, absolutely. So just to highlight what you were talking about, right? We did a great job measuring all the different theories. And so the one that we're going to talk about, which has been highlighted as a potential theory in the original, you know, so-called papers talking about long COVID is the dysbiosis theory. So essentially the gut microbiota get altered. And because of that, it wreaks havoc on a lot of different systems. So recently at UPEN, they did some research and it got published in the journal cell. And this was probably maybe a week or two ago, and you know, we're recording this, what, October 19th. So what they are proposing is that this other theory called the theory of viral persistence, right? So obviously, once you have COVID, not all the viral particles go away. And so they measured it in the feces that there were a certain number of remaining particles in the body. And because it was in the feces, obviously means it wasn't the gut. And so what they found was that in long COVID, these viral particles would disrupt the neurotransmitters in the gut, specifically serotonin. And you know, just the back up, what we've talked about multiple times with this podcast is the importance of the gut and how 80 to 90% of the immune system relies on the gut, as well as the gut brain connection. So we know from the vagus nerve, we know from neurotransmitters, dopamine, serotonin, they're primarily in the gut and that can actually affect our mood, which is why, hopefully, in the future topic, we'll talk about nutrition and how nutrition and the foods you eat can actually affect your mood. But getting back to this, so what they found was that the viral reservoirs, right? So they've been persistently high. And the first thing that they found was that because of that, you would have persistently high levels of type 1 interferons, right? So what does that mean? Type 1 interferons, basically, in the immune system, your immune system's activated. It's essentially fighting against something that may not even be causing something, right? So these viral particles, even though they're at a decreased number, they're not going to have the same effect as you possibly would if you tested COVID positive. But yet, because you have these inflammatory markers and immune markers at such high levels, the body's going to react to that. The second thing they found is that this viral infection altered amino acid uptake. And primarily, they found that it was tryptophan that wasn't able to become, what's the word I'm looking for, not uptake, but an absorbed absorbed is the word I'm looking for. So yeah, so because of that, right? Tryptophan. I like my tablet. I like that one. Yeah, I might use that door, door around here and there, sound scientific. But essentially, tryptophan has different metabolites. One is niacin, right? So vitamin B3, NAD, which we always talk about with the mitochondria, anti-aging, I mean, in this case, probably more mitochondria, and melatonin, which, I mean, I think if people read, I don't know if you saw Dr. Tia's, Peter Tia's, one of his newsletters could talk about melatonin and long term effects and things about how we really don't know how to fix circadian rhythm and hormones, it becomes a big player and not as innocuous as people think it is. But essentially, again, because you're having this post-acute COVID syndrome, you're going to have these metabolites not working properly. All right. Now, third, this is where it gets really interesting, right? This is where we start to put all the theories together. So you mentioned theory of platelets, aggregation, hypercogubility. And so what they found was that there becomes a formation of microbiome, right, as a result of hypercogubility. And because you have reduced serotonin storage, this enhances essentially the turnover serotonin and the degradation products. So you basically get hypercogable states even with a decreased serotonin. And, you know, this is whole complex interaction and has with the malenzyme, MAO, for people who want to understand MAO, I mean, you can go down multiple rabbit holes. I think a good episode to turn to is either part one or part two with will bolster witch. I think we talked a lot about MAO and the role that it has in the gut with him. Now, I was going to say, at some point, do you think it's worth explaining to people what serotonin is? I think we'd presume that the listener is here and know what serotonin is, but perhaps maybe somebody's tuning in and is like, what is exactly serotonin? Sure. Yeah. And we're going to be a little bit better that we know. And we like it to be the happiness molecule. So oftentimes when it comes to anxiety and depression, serotonin is our main target. So people may have heard of lexapro or prozac or zooloth. These are all SSRIs. Selective serotonin re-uptake inhibitors. So essentially, you are not allowing serotonin to get re-uptaked by certain neurons, certain processes. But letting serotonin be in the bloodstream and serotonin, essentially, in that case, is making you happier, right? Because it's the happiness molecule. I'm sure there are multiple major effects as we are, as I'm now learning, too. I mean, as we go through training, we really learn serotonin is just this molecule of the brain. We now know it's in the gut, but we really just look at it from a depression and mood standpoint. But obviously, from this paper about having decreased serotonin due to COVID, talking about all the multi-system abnormalities that people have, it's fair to say that, wow, serotonin has a bigger role than, you know, I even knew before reading this paper. Absolutely. And in terms of the triptophan, part that we talked about, triptophan is actually a precursor to serotonin. And that's where some people will come in, yeah, so triptophan and turkey, since we're Thanksgiving's right around the corner of my favorite holiday. So when we look at the downstream reactions of triptophan, I think there is a one intermediate step, if I'm remembering, and then that'll eventually downstream get down to triptophan. And so, again, happy, positive mood can also make you sleepy in terms of that, right? So, and other, I suppose, adverse effect of high levels of serotonin to kind of relax you in terms of anxiety and stuff that you're talking about. So, yeah, this is a very neat, but, yeah, I guess the question that becomes is, so what are key takeaways? Like, how is this going to matter? Should everybody be taking more SSRIs, right? Or did they talk a little bit about whether, you know, modulating serotonin is a potential treatment? Did they discuss that at all? So, I believe I would have to look at this, that there was another study where they actually looked at bringing back the normal serotonin levels in mice and that their memories have improved. So, we also know through this study that there's a hippocampal link from serotonin in the gut. And so, when we talk about brain fog, when we talk about memory loss in post-COVID syndrome, long COVID, these are the theories that they're throwing out there. And then the last thing that I, you know, that's in this discussion of this paper that I didn't even realize is that the vagus nerve, which we talked about is just in a recent episode with Jody Patel, how important it is in the parasympathetic role of calming us down and being able to regulate our fatigue patterns. That's actually the vagus nerve actually responds to peripheral serotonin. And so, that's another finding that they found was that the vagus nerve kind of gets out of whack. And so, it could be a big cause as to why people have this tired, almost fibromyalgia like symptoms in long COVID. But the study itself doesn't go through much of what we can do to help it. I think that's obviously going to be next steps as people look into these theories and really look into the serotonin pathways to say, yeah, doesn't make sense to give these people an SSRI. But then I almost think about on the flip side is that if we take a patient and say, hey, you have one COVID, let's give you SSRI. These are used for depression. How much of a cognitive, you know, what are we communicating to them, right? You know, oftentimes when you're trying to use something off label, the patients tend to just see that medication for its intended use, which is depression. And a lot of times as providers, we have to say, well, no, we're not using that for this case. We're using it. We're going to repurpose it for your long COVID. But it's interesting. I don't truly know where they're going to go with this. Yeah. Not to mention the adverse effects, right? Every single SSRI is notorious for waking, right, that'll cause depression. There is low libido, right, erectile dysfunction, things of that nature is something that are very, very prominent. So depending on the gender of the person and what they're dealing with, there are a lot of adverse effects that are unwanted. And so that can cause a lot of problems. You know, I thought, I'm interesting. I find it interesting that you didn't go to the side because if we, you referenced the discussion with Dr. Will Bolshevik, you know, back then and his proposition here would be when he'd add more fiber, right? So we need to address that gut dysbiosis, particularly. You know, there was another paper that actually came across published in Nature earlier this year. I believe it was a march. And I think the first author is Davis, Hannah Davis, right? And so they, this is a really awesome outline as well in terms of the mechanism and some of the recommendations. And on the bottom of that, they have a really cool table that they talk about the different potential symptoms and, you know, they talk about all those multi symptoms that you have. But when you come to gastrointestinal symptoms, they actually recommend probiotics as a treatment. There's a pilot study that, that showed that it resolved the GI symptoms and some of the other symptoms, although not all of them, specifically. And they even talk about the specific, specific bacteria that were found to be at higher levels. In this study, they talked about it's called, oh, my God. Rumnokaka, skinis and vectoris, vulgatus. I'm surprised I got that. And then lower levels. I'm throwing stuff right there. Yeah. Yeah. Yeah. Fecalibacterium. Proscent. Yeah. I will link that because it is open access for people to check out. But this is what's really cool about this is, again, they go system by system approach. They have some really cool figures in terms of the five main theories in terms of mechanism of the action. And then also, you know, initial infection and the hazard ratio for some critical illnesses like PE and cardiac arrest. And then when it comes to long COVID, this autonomia and ME and things of that nature. So I thought this was really cool and a general overview. I would recommend people to start with this one. So you get a deeper understanding of what it is that we're actually talking about. And then you can dive deeper into the serotonin of one if that is of interest for you. So yeah, I mean, ultimately, really, really cool. I don't think this was anything new or surprising to us. But you know, it's always nice when there's a little bit of confirmation bias, right? So again, most recent get Dr. Jody Patel, the first time certainly she was on, we had talked about the gut brain connection quite a bit and how we tend to address that healthy gut equals healthy brain, right? Again, I don't know if you mentioned this, but this, the 90% number of some house sticks in my mind where that much is actually made in the gut. Is that, did somebody mention that or am I making that up? No, that's 90% like near transmission of the gut, you know, yeah, yeah, yeah. So yeah, you got to mention that and also actually, if I think of it, very recently actually had a discussion with, I think a psychologist in reference to a patient. Have you, not to get too far, Jack, have you heard of something called gene side testing? Gene side testing site gene site, yeah, I think so this is a, yeah, talk about so precision nutrition 101, right? So when I was in medical school, this something really cool, when I was in medical school, I remember during my psychiatry clerkships, my, the psychologist that I was rotating with had communicated with the patient that they are genetic testing that we can do that helps us figure out which specific SSRIs, antibiotics, antidepressants, the patients are going to respond really well to, right? Because we know we all all have these unique snips and with SSRIs, we, I mean, we got like 20 different ones. So sometimes it's trial and error. Okay, likes are pretty to work after four or six weeks, we switched to pro-Zach, then we switched to, you know, something else and maybe we'll go to the locks and et cetera. And they had mentioned that. And when I started working last year, I realized one of my partners was doing this. So we get this genetic testing and, and we evaluate and so I started doing this because of course, you can use a lot of these medications and, you know, I treat pain and chronic pain and it's hard to dissociate pain and anxiety as we talked about before. And so I've actually started doing it quite a few of my patients. And it's, it's really, now that is it out of pocket or insurance covered in that? I've had great luck with insurance covering it. I have yet to have a patient who has to pay out of pocket. So that's actually very cool. There are other companies that do it again. This is just the company that we use in my practice. But yeah, it's really neat because it's just a simple cheek swab and they'll give you all this information in terms of which agents are going to be, so it'll give you just simple green, yellow red are going to be, if that person going to be more responsive to a certain agent. So I think that's pretty cool to, again, a little out of the scope of this discussion right here. But I thought it was a good thing to bring to your attention something you can check out for next year. Yeah, for sure. That's just super cool stuff. And I'm just glad, like you said, that we can finally put a little bit of data behind maybe what we're seeing. You mentioned post can cause a syndrome and, you know, in our clinic and our program, we're definitely not allowed to write that in our notes. So we're always told that, you know, it's not really a thing, you know, a lot of, yeah, and a lot of the providers also say the same thing about long COVID, you know, and that the sense is like, there's no, it's not a true syndrome, right? In the sense that we don't have a constellation of symptoms that everybody shows. But yet, I mean, you look at these research papers and it even says it in the discussion, you know, like there's highly heterogeneous, everywhere we all know that whoever gets long COVID, they're going to deal with it different. But I think a lot of providers like to chalk it up to, it might just be self-manifestation, just going through COVID. And who knows? Right. But I think that's what we like as lifestyle somewhat of a functional medicine approach to things is regardless of, you know, right or wrong, black or white, people feel a certain way because of their constitution, because of something in their body, because of their mentality, and that all affects one another. So I just hope, I like my biggest wish is that people keep that in mind, right? Is that there's still is something underlying, even if it is self-manifested. Totally. Well, man, I think this was another great one. I certainly educational for me. This was a topic that I had heard a lot about, but again, suffocally, because it doesn't affect me or I haven't been treating this population, I didn't care to read too much about it. So cool information, nonetheless, hopefully somebody's listening to this can get some insight and maybe start investigating some of this stuff. If you are interested or you know somebody who is suffering from this, please feel free to send this podcast to them and certainly share the resources, you know, if we can educate somebody, maybe we can help somebody improve their quality of life. So yeah, yeah, this would be something awesome for those suffering with long COVID to bring up to their doctors and just bring the research to them, because I'm sure not a lot of doctors are actually hearing about this and these mechanisms. So you might just make a light bulb go off for some providers, you know. Alright, man. Another great one of the books. Catch you next time. 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