The Hidden Stress Response That's Hijacking Your Brain | Dr. Scott Sherr

About 94% of US adults have metabolic dysfunction. They have the inability to make energy effectively or to detox or to neutralize the stress of making energy until you find yourself into this kind of state where it's very difficult to get out of. And I call it the sympathetic spiral of doom in some ways, right? In general, on average, we have about 70,000 thoughts per day. There's some different estimates out there, about 70,000 thoughts is Is commonly thought as how many thoughts you're having per day. When you're stressed and when you're anxious, they go up to about 120,000 thoughts per day. Okay.

Every time I had that glass of wine, my sleep was affected and my HRV was lower than it should be.

Yeah. Alcohol is probably the worst sleep aid ever invented. Right.

These are way downstream from the primary issue, which is the mitochondropathy that is acquired.

Yes, exactly. So cellular medicine, mitochondrial medicine is the future. And I'm glad we're We're a part of it at this point. It's been fun.

Well, hey everybody, we're going to get right back to the podcast, but I want to share something with you that is very personal. Uh, you know, for decades I've been a practicing neurologist. I've been asking a single question, and what makes a good brain go bad? More importantly, Obviously, what can we do about it? And that question has led me to write my new book, which is called Brain Defenders. It's now available for preorder. And in this book, I'm going to take a hard look at where we are today and offer up some challenges as to where we are today in terms of what we're being told. You know, despite all the attention on targeting proteins, misfolded proteins like beta amyloid for Alzheimer's, we still don't really have any meaningful treatments for diseases like Alzheimer's. And Parkinson's disease per se. And we certainly can treat symptoms, but as it relates to treating the underlying issue, we're falling short. Many of these approaches manage the symptoms at best, but without really addressing what's driving the underlying process. And this science is evolving, but what's really exciting is the emerging research on what I've called the microglia. I didn't call it, but that's what they're called. These are the brain's immune cells. And when they're balanced, they are protecting, they are repairing. Well, when they're dysregulated, and we can talk about why that happens, and we do talk about it in the book, they can drive inflammation and lead to brain degeneration, often long before symptoms appear. And here's the empowering part. These microglial cells are deeply influenced by your day-to-day lifestyle choices, your nutrition, your sleep, your environment. And in the new book, Brain Defenders, I share both the science and provide a practical roadmap that'll help you calm inflammation, support supportive microglia, and really ultimately take control of your brain's destiny. And if you preorder your copy today at braindefenders.com, you can receive some special bonuses like a sneak peek at chapter 1, the full glossary for the book, and curated offers from my favorite brain health products, many of which I've discussed here on the podcast. This is a new way of thinking about brain health. And I truly believe that this book hopefully is going to change everything. I can't wait for you to read it. And I think you're going to be as excited as I am about the information you're about to receive. That said, let's get right back to our podcast. Hello everyone. I'm Dr. David Perlmutter. Welcome again to The Empowering Neurologist. We're going to do today a deep dive into understanding why it is that so many people are feeling just basically stuck. in chronic stress and why they're experiencing a poor ability to recover and basically experiencing declining resilience even when they're doing all of the so-called right things that we all know about. My guest is Dr. Scott Sherr. He's an integrative medicine physician and a leader in health optimization medicine and practice, which is called HOMP. What he brings to us is this powerful framework That connects something we've been talking about quite a bit on the program—that is mitochondrial dysfunction—but he connects it to autonomic imbalance and chronic stress physiology in what he calls the sympathetic spiral of doom. And he's going to unpack that for us. It's it's an interesting moniker, isn't it? This conversation is about understanding why the body ultimately gets locked in defense mode, in fight or flight mode, and how we can do things to deliberately restore. recover and regain our resilience and ultimately regain our ability to experience better mental health and neurological health as well. So let's jump right into our podcast. Dr. Sherr, very nice to see you.

It's great to be here. Thank you for having me, David.

I want to start off and let our viewers know that we're going to be looking at stress and the stress response and sympathetic overload, if you will, through a different kind of lens. And what you've made so clear is that there's this strong, I think, metabolic component that is often overlooked, I think generally overlooked, as playing such a pivotal role in how, you know, our set point of stress, of sympathetic overactivity. Uh, so what does that even mean, that there's a metabolic component?

Well, I appreciate you asking the question. I think it's important that people, you know, have a different concept of what stress can be. Like, obviously we know that stress can happen from, you know, trauma, from relationships, from challenges with our children, with lots of things, our work. But, what can also happen is that we can get significant mitochondrial stress, significant stress cellularly that actually causes a spiral of stress to happen in multiple different ways that you didn't even realize that it was happening until you find yourself into this kind of state where it's very difficult to get out of. And, I call it the sympathetic spiral of doom in some ways, right?

That's a great name, by the way.

Yeah. It sounds ominous, right? And, it can be a top-down or bottom-up thing where you can have stress that comes from outside that causes this, but it's also underappreciated that it happens from the cellular side because I think you probably know these statistics too, David, but about 94% of U.S. adults have metabolic dysfunction. They have the inability to make energy effectively or to detox or to neutralize the stress Of making energy. I always say like we're like a gasoline-powered car. We make ATP, but we also make water, carbon dioxide, reactive oxygen species, and we have to be able to neutralize that stress.

And so what you just said is so important. I mean, all of the downstream consequences of our metabolic dysfunction— cardiovascular disease, neurological disease, all the chronic degenerative conditions, and cancer— are increased in people who are experiencing metabolic dysfunction. And there are only about 6 to 8% of American adults who are metabolically intact.

Yep.

So, right there is a pretty powerful explanation as to why people are having such issues.

Right. And then, we think about, well, mitochondria are these amazing, amazing parts of our cell. When I was in high school, my daughter now is in 9th grade, she learned about the cell. You learn that there's one mitochondria in the cell. But no, you actually have some cells in your body that have thousands of mitochondria per cell. You have others that have very few. In fact, We have only one human cell that does not have mitochondria. It used to. It's the red blood cell, right? But, we have thousands of mitochondria in our ovaries if you're female, eggs have— excuse me, in sperm in male. And then, the brain, heart, liver, musculoskeletal tissue have thousands of mitochondria per cell. And, we have huge amounts of energy demand. We make about 150 pounds of ATP every single day to meet those energy demands. And, if you can't meet those, if you're In that 94%, you have challenges. It's fertility challenges. It's brain fog. It's mental health issues. It's cardiac dysfunction. It's metabolic dysfunction from a perspective of liver detoxification. You can't exercise effectively. And this is just kind of a huge amount of an issue for so many people. And then the question becomes, well, why do so many people have this metabolic dysfunction? And the number of reasons is actually quite large. But the number one reason, as you probably know, David, is insulin resistance. So, people that have high blood sugars for long periods of time, their mitochondria start becoming dysfunctional. And, as a result of this, multiple things happen which I'll talk about in a minute. But so, insulin resistance is number one. Then, you have medications that people take that cause nutrient deficiencies, that cause toxicity directly to the mitochondria. You have toxins in your environment. You have people that are floating around in soups of amazingly terrible food, water, air. If you live in cities, for example, especially in developing countries, I mean, it's crazy, right? Like, go to a city like Beijing in China or a city in India and just like the smog that you're just being— that's coming into your lungs at all times. And, you have infections that do this too. You have things like COVID infections or mold infections or Lyme infections and so many others that are just having significant detrimental effect on the mitochondria itself. And then, as a result of all this stress, the mitochondria stop working as well. And as a result, they can't make as much energy. And then, what happens is that this spiral starts happening where the system, you, your organism tries to start compensating for this mitochondrial stress by putting out more stress hormones to get you to make more energy so that you can compensate for the energy that you're not making. And then, all of a sudden, you're stressed all the time. You're anxious all the time and you don't know why. And this is where that spiral starts in a lot of ways. And we don't think about it because we think about, yes, stressful events can cause this, but it— and stress is a big reason for mitochondrial dysfunction too, but it's not the only one. And these other ones are kind of these bottom-up challenges that many of us are having on a regular basis.

Well, I think this is a really interesting discussion because you are relating mitochondrial dysfunction to this autonomic dysfunction to this overrepresentation of the sympathetic fight-or-flight part of our nervous system.

Right.

And, you know, we could end the podcast right now. You made an incredible point. I mean, obviously, we're going to talk about at the end or soon what we can do about these things. But I think what a relationship that first, you know, this overwhelming number of adults is metabolically compromised, setting the stage for this sympathetic overload that makes them feel chronically stressed and edgy and drained, brain fog, you know, all the things that are so, you know, consistent with this sympathetic overload. So how is this relationship then between mitochondrial dysfunction and the sympathetic nervous system? First of all, how do you actually delineate that? And how do they both kind of, I think, conspire to make this death spiral or downward spiral much worse?

Right. So, what it comes down to is that if you're sympathetically overdriven, if you're living your life in a sympathetic overload, fight or flight, this is the nervous system that we're not supposed to be in all the time, everybody, right? We're supposed to be in sympathetic when we need to, when we have to do something that's stressful, that causes some challenges. I mean, we all get these microevents throughout the day that our sympathetic nervous system should come up for, especially if you're exercising, right? Or, if you're doing something like Getting chased by a lion. I hope nobody else is getting—

Why does everybody always talk about that? Or the saber-toothed cat?

The saber-toothed cat. Like, that's the always— like, that's always the example. Because like classically, from like from our ancient biology, if you watch the National Geographic, it was like either you were being preyed upon or you were just hanging out drinking water from the stream, right? And so for the most part, you were hanging out drinking water, hanging out with your family, you know, like as an animal on the stream and not being preyed upon. But if you look at some of those National Geographic documentaries, what was very interesting, right, is that you see this animal that's being preyed upon by like the saber-toothed tiger or whatever, and then somehow they get away, right? The animal gets away and they have this sort of dump of sympathetic stress, all this stuff that, and all of a sudden they're shaking. And then about 15 to 30 seconds later, they're back to drinking water in the stream. That's not how the modern world is for us, because we have constant stress, constant things that are coming up on our inbox. And then we're always in this sympathetic spiral kind of thing because we're always staying in that sympathetic mode as opposed to being in the parasympathetic mode, which is the other part of our autonomic nervous system that helps us rest, digest, and detoxify and recover. And that's where we need to be more of the time to be able to really do the things that we want to do in life. And, but the challenge is if you're in that sympathetic system, sympathetic activation, you have neurotransmitters like norepinephrine and epinephrine. You have hormones like cortisol that are pumping into the system that are stimulating your mitochondria to try to make more energy because that's what those signals are trying to help you or giving you the signal to do. And then, over time, that energy production capacity is going to go down because you don't have the capacity anymore to make energy at that level. And then, what your mitochondria do is that they start going into this sort of hibernation mode called the cell danger response where instead of making more energy, they actually make less. trying to protect itself from the stress of making so much energy. And then, your system's like, well, I need to make more energy because you're still asking me to make more. And then, it becomes this sort of very difficult spiral to break. And, that's where that sympathetic activation really needs to be addressed along with the mitochondrial dysfunction at the same time. So, even if the dysfunction started off in the mitochondria and you have significant things to address there, you also have to address what's happening on that sympathetic side as well. Because if you don't address that sympathetic activation, no matter what you do in the mitochondria to help somebody, you're not going to see the benefit. And these are people that have tried every supplement, every diet, everything, and nothing ever seems to work for them. It's because they're so stuck in that sympathetic mode. So you have to address that at the same time. And that's the key with all of this is that you have to address them.

So important. I mean, I have a book coming out called Brain Defenders. And the thesis of that book is that mitochondrial dysfunction tends to polarize our brain's immune cells, the microglial cells, from being friend to being foe.

Yes.

That amplifies inflammation in the brain. It ultimately leads to destruction of synapses, and a lot of bad things happen. And really, fundamentally, it's mitochondrial dysfunction, just like you're describing here. And all the inroads to mitochondrial dysfunction are at play as it relates to our microglial cells as well. But what then keeps these mitochondria away from doing their job and the cell shifts to glycolysis Even when you have glucose and you have abundant oxygen, what is it that shifts those, uh, the energy production to that less efficient way of creating ATP?

The main way that it's happening here is this, the buildup of reactive oxygen species, the buildup of oxidative stress in the mitochondria itself. And when that happens, it can get to a certain point where the mitochondria can't survive if they continue to have that kind of oxidative load. So they have to shift away from oxidative phosphorylation to try to protect itself to try to protect the mitochondria from going into mitophagy by going into the place where they actually kill themselves off because they can't survive any longer. And so, in essence, for those that are listening, this is really what we're talking about with inflammation. When inflammation gets so significant where it gets to a certain level, then the mitochondria can't tolerate that kind of stress and have to go into a hibernation mode to try to protect themselves.

So fair to say that what you're describing is the body entering a state of stress response with upregulation of the stress-related neurotransmitters and cortisol, etc., even in the absence perhaps of a psychological stress in your life, uh, you know, uh, whatever that might be. You know, your child is sick or you lost your job, whatever that might be. Those are normally what we think of are the inroads to the stress response, or in ancient times, I guess it was being chased by the saber-tooth, whatever.

Right, right.

But what you're saying is that we can activate these responses by being metabolically compromised.

Exactly. So you don't have to have an external stressor from something that you would typically see as a stressor to have this whole response actually go through this whole process that we've just been describing.

And so that's in a very real way. If these things add up like straws on the camel's back, the situational stress, as it were, coupled to the effects of metabolism being dysfunctional, and so we'll call it the metabolic stress. Sometimes I guess it might seem a little bit easier to deal with the metabolic issues. I mean, they're right there before us and you can do great things for your metabolism as opposed to the fact that you're locked into this very stressful job for the next decade. So that at least there are some straws that you can offload from the camel's back if you look at the metabolic inroads.

Yeah, it's really kind of a very individual way to think about it. But in general, you do want to approach it on both ends. You want to approach it on supporting the mitochondria and also supporting the stress response. Because if you— I mean, I've had a lot of patients over the years like this. I'm sure you too as well, David, where there's no amount of supplements you give them if they're so clamped down, if they're so locked into that stress response, even if it wasn't the initial reason for the whole process. And so, what I find on the stress response that can be very, very helpful is leveraging the GABA system specifically. GABA is our primary inhibitory neurotransmitter in the brain. It's the one that puts the brakes on firing. And so, if you can find a way to support mitochondrial function and at the same time work on the GABA system, I found that to be the one-two combination to be super, super helpful. And, over the long term, we really want to find If there's an external stressor that's caused this, of course, you want to address that. If there's internal things that are going on in the mitochondria, we have to address those. Is it infection? Is it because they have significant nutrient deficiencies? Is it because they have toxicities and other reasons, or they've had exposures for long periods of time to toxins that they have mercury poisoning or they have lead or other kinds of things like that? These are huge.

Or even medication.

Yes. Yeah. I mean, I've seen a number of people over the years that have You know, been Floxed, right? That's what they call it. The ciprofloxacin, those drugs specifically, I've had a lot of patients over the years have significant mitochondrial dysfunction. So the key really is to understand when you're looking at this is that you can do a lot to support mitochondrial function.

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You can do things very quickly. To help them. And then long-term, you can optimize vitamins, minerals, nutrients, and cofactors to significantly improve the capacity of the mitochondria to work better. Short-term, I use a lot of different modalities, different kinds of ways of intervening.

Let's get to those, but let me go back to GABA for a moment. Yeah. Because I think you probably piqued some interest when you mentioned that.

Yeah.

Because there's a popularity of GABA supplements. Yes. And I think that's not where you're going with this, is it?

No, that's important, right? So GABA itself is too big of a molecule to get across into the brain, into the blood-brain barrier.

So the idea of taking GABA orally is not necessarily the solution of the GABA issue that you're describing.

Right. Now, there are other ways to modulate the GABA system, which can be important, right? So we know that the precursors to GABA are glutamine, an amino acid that's also the primary fuel of your small intestine. And then the precursor to to GABA in the brain is a neurotransmitter called glutamate. And so, there should be always a balance between glutamate, which is a primary excitatory neurotransmitter, and GABA, which is your primary inhibitory neurotransmitter. Most people don't know about these 2 neurotransmitters. In fact, which is interesting because actually those 2 neurotransmitters are about 80% of your brain's neurotransmission. Your norepinephrine, your dopamine, your serotonin, these are your superstar neurotransmitters, but they're not the primary drivers of what's going on. And, when you're GABA deficient, Hmm. When you don't have enough GABA around, you have more insomnia, you have more tremors, you have more depression, you have more anxiety. I mean, you and I, I think both grew up or were trained that people with depression, for example, had serotonin deficiencies. But, we now know that it's not exactly the case at all. People with depression—

More than not exactly the case.

Yeah, yeah. It's not the case at all, right?

Depression, here we are a classic inflammation-induced mitochondriopathy as well, right?

Yeah, yeah. And then, There's GABA deficiencies also associated with depression as well. And so, there aren't a lot of studies that show serotonin is at all involved, as we know now. But GABA deficiency actually is associated with depression. It's associated with insomnia, anxiety. And so, if you optimize the GABA system, you can see these things improve very quickly. And so, but the key again, as you mentioned, now, will GABA supplements work for you? They will if you have a leaky gut, if you have a leaky brain. And so, if you find that GABA supplements are working for you, It's oftentimes because you have a leaky gut that needs to be addressed. And I've had patients where they're taking GABA supplements, they're working well for them, and then all of a sudden, we optimize their gut and their GABA supplements stop working. So, I use other things that work on the GABA system. Certainly, you don't want to be using alcohol. Alcohol does work on GABA as probably many of you know that are listening, but GABA binds very tightly to the GABA receptor and then unbinds very tightly and causes tolerance, withdrawal, dependence just like benzodiazepines and And sleep drugs. And so, I use natural compounds mostly because what I love to try to do here, David, is give people the experience of what it feels like to calm down their nervous system. Because once you get the experience of how it feels to calm down, then you can get there again with meditation, with breathwork, with yoga, with other things. But, if you don't know where there is, it can be difficult. And so, I use things like kava, which is really well tolerated at low doses. CBD, CBG, some of these non-psychoactive cannabinoids. I use a really cool compound called nicotinyl GABA, vitamin B3 attached to a GABA, because the B3 does have a transporter that gets it through the brain. And then, GABA comes along with it and you have a little bit of GABA in the brain, a little bit of B3. And, another one called agarin, which is from the Amanita mushroom, the Amanita muscaria, which is a psychedelic mushroom famous for Santa Claus and things, but it also—

It is the classic mushroom that when people draw, paint mushrooms, that's what they see.

Yes, yes.

It's pretty poisonous.

It is poisonous.

Fly agaric. Yeah,

it is. But this particular compound, um, called agarin, is not poisonous, and it's a long-acting GABA agonist binding to where GABA binds on the receptor. So it's, uh, it's, it's like, it's called an orthosteric ligand. So it binds exactly where GABA would bind. Um, and you can combine that with other things like magnolia bark and others. But I, I really find that if you can give people the experience of calming down their nervous system, then they know how it feels to do some of the harder work of optimizing their stress in other ways if it's coming from an external perspective. Now, if it's internal, like if it's a mitochondrial stress, then if you give them the experience of calming down their nervous system before working on their mitochondria, that can be a problem because they don't have enough mitochondrial support to be able to tolerate their nervous system to be downregulated. So then they feel less stressed, but then they feel washed out. They don't have any energy. They can't move and they can't think. think, and this becomes sort of reactively anxiety-inducing actually. So, that's why it's so important to understand that the combination of GABAergic tone in combination with mitochondrial support can be so effective if used in a very intentional way.

Before we get to wearables and monitoring things like HRV, how might a person know without any metricizing of their Parasympathetic versus sympathetic. How might we know that we're in sympathetic overdrive?

So it can be challenging for some people because if you've been in this state for a long period of time, it can be your baseline. But some of the main things to think about here will be how easy is it for you to calm down? How is it easy for you to take a break? Can you, can you come off your computer for a little while and feel like you can just, you can kind of come into like a more relaxed state relatively quickly, or does it take a long time to get you there? Does it take like 2 weeks of vacation before you feel like you can calm down, or can you calm down with, you know, 5 minutes of breathwork, right?

What does it mean calm down?

Yes. And that's important, right? And so can you feel like your brain is not intrusively telling you to do things every minute of every day? And this is difficult because if you're Type A, you may feel like you always got to be on, on, on. But even Type A people have to calm down and have to relax. And so it's almost like the way to think about it is this. In general, on average, we have about 70,000 thoughts per day. There's some different estimates out there. About 70,000 thoughts is commonly thought as how many thoughts you're having per day. When you're stressed and when you're anxious, they go up to about 120,000 thoughts per day. Okay? And so if you are one of those people that feels like their mind is just incessantly going, even if they're calm, There's very likely a portion of you that's still sympathetically dominant. Okay. If you have a hard time falling asleep at night because your mind won't stop thinking, right? If you have a hard time exercising or you have a hard time recovering from exercise because—

Recovery.

Yeah, because recovery is a big part of here. Like, because if you're not recovering, if you're not making gains at the gym, like if you think you're building, if you think you're exercising, you don't make your gains when you're exercising. You make your gains when you're recovering. So if you don't recover as well as you used to, If you're shorter with your friends, with your family, with your kids, you're, for example, your daughter comes in and says she wants a banana and you say, and you yell at her, like, why did you just do that? Right? And like, these are some of the things that, like, I'm a parent too. I know you are. Like, you know, like sometimes you're like, why did I just do that as a parent? Absolutely. It's because you are not in a state where you're responsive, you're reactive. And that is more in that sympathetic balance. So recovery is a big one. How easy is it for your mind to calm down and relax? And so, but I think like, as, as I think about, as we're talking, probably recovery is the biggest place. Like, are you recovering as well as you used to from exercise, from travel, from poor nights of sleep? We're all going to have those.

And so what is your resilience like? In other words?

Yeah. Your resilience. Yeah.

So I touched on this heart rate variability, which is, I think people are becoming more and more familiar with it because you're getting those results from your Oura Ring. Or from your Whoop or Fitbit, Apple Watch. I guess that they all include that now.

Yeah.

So tell us what HRV is, what it's showing us, and then how it plays into perhaps a useful tool for you, uh, to help people with their sympathetic overload.

Yeah. So what I love about HRV, and I'll explain it in a minute, it gives you this sense of the dynamic balance between your sympathetic and parasympathetic nervous systems. So what we all want Optimally is to be able to flip into sympathetic mode when we need it and then flip out of it as fast as we don't need it anymore. The great example of this is exercise. Once you finish exercise, you want to be able to flip out of that sympathetic activation while you were exercising to get into parasympathetic as fast as possible so you actually can recover as fast as possible. Okay? The worst thing that a lot of us do, go directly from exercise into our work, into our meetings, into the cold plunge. Like, these are things that are increasing our sympathetic activation when we need to be parasympathetic to really recover. Now, and what HRV can do, HRV is the measurement of your beat-to-beat variability of your heart rate. Now, most people know that your heart rate's supposed to be regular, right? And, if you listen to it with a stethoscope, it sounds regular for most people unless you have an arrhythmia. But, there is beat-to-beat variability in the millisecond versions or amounts between each beat of your heart. And, we can measure that, and that's what we call heart rate variability. The more variability you have, the more of a balance that you have between your sympathetic and your parasympathetic nervous system. The less variability you have, the less of a balance that you have, and the more you have likely in the sympathetic overdrive scenario. It's a little bit paradoxical. You might think it would be the opposite where more variability—

It's showing resilience and flexibility.

Yes.

And, being able to adapt very small changes as opposed to being stuck and, uh, you know, first order. So I, you know, I think that people are really getting that more and more, right? So people are wearing the Oura Rings and the Whoops, etc., and learning about this. And do you think this is valuable that people have this intel?

I absolutely think it's valuable, but I also think that there's also an anxiety component that can happen with a lot of these wearables as well. So, It depends on the person. I think getting some data to getting a sense of a baseline for you can be very helpful. But, the worst thing you want to do is compare your HRV and others to your friends and family and coworkers. Or your wife. Or your wife, yes. Thank God my wife doesn't wear an Oura Ring. I'm sure hers would be fantastic.

Yeah, I hear you.

So, the way you use the data is when you do different things in your life, You create a sleep routine, for example. You start wearing eye protection at night before you go to bed instead of looking at the screen in front of you right before you go to bed. See what happens to your HRV. See what happens to your sleep. That's the best way to use them, not as absolute values but as relative ones depending on the various things that you do. And, that's what I tell my patients all the time. It's like your HRV might be trash. That's okay, but that's okay for now. Let's see how you Let's look at your trend over time and let's look at various interventions that we do. Let's, I mean, the biggest one is sleep, obviously, David, right? So if you get somebody sleeping better, getting a better sleep routine, optimizing their sleep, their stress levels, their mitochondria as well are going to significantly improve.

Hey, we're going to get right back to the podcast, but I do have an important message. You know, for decades we've been told that our genes are basically our destiny as it relates to health and that everything's locked in place predicting even our future brain health. But Let's be clear, your DNA isn't a verdict, it's a roadmap. And I'm talking to you today about 3x4 Genetics. I actually described them in the new book, Brain Defenders. And this is a company that helps you understand your genetics, what you've inherited, and I think more importantly, how your daily choices can influence how those genes are actually expressed. In other words, how you can control your own genetic expression. And you know, that matters for your health and it really matters for brain health, including things like memory and mood and cognitive resilience. You may carry genetic markers associated with cognitive decline, like as we've talked about APOE4, but possession doesn't equal expression. Your lifestyle, your nutrition and metabolic health, all the things that we talk about here on the podcast can powerfully influence which genes are turned on and which stay quiet. The 3x4 Genetics Test looks at how your genes impact brain function. at a cellular level, and which then through the 3x4 Health Journey, which they provide you, guides you through a clear and a science-backed program focused on inflammation, methylation, oxidation, oxidative stress, things that we routinely discuss here on the podcast that are the key drivers of basically what makes a good brain go bad. And we have spoken with the team at 3x4 Genetics. And they were able to get a special offer for our podcast community. So head on over to 3x4genetics.com/drperlmutter and get that special offer and start really your personalized brain health journey today. Let's get your genes working for you and let's get back to the podcast. Well, again, getting the metrics on that, I think is really valuable. And I don't wear an Oura Ring all the time, I do wear these days a little bit more. And, you know, I think it's great intel. That's the reason I cut back and basically abandoned alcohol. I used to have, you know, a glass of wine a couple of times a week thinking that the literature said that was the way to go. But I found that every time I had that glass of wine, my sleep was affected and my HRV was lower than it should be.

Yeah, alcohol is probably the worst sleep aid ever invented, right? The problem with alcohol is it binds to that GABA receptor so quickly. And then, it unbinds in a couple hours and then you get this sort of glutamate overload. And, that's why you get headaches and one of the reasons why you get liver stuff too, but it's not going to be your friend for sleep. And, the best way to know this for people is to see it, right? Or, if you have a late meal, for example, like a big meal right before you go to bed, your sleep's going to not be very optimized there too. Totally, right. So, yeah, HRV is a great measure of this sympathetic-parasympathetic balance. And then, as you get more plugged in, like, oh, this is what caused my HRV to tank. This is what caused my HRV to improve. And then, you can kind of start bringing those things more into your daily regimens as a result of that.

I found a real benefit to HRV using— there's a device called Apollo made by Dave Rabin.

I know Dave.

Yeah. I was very impressed with the change in my HRV in a couple of days. It was pretty remarkable.

Yeah. I've had really good experiences with Apollo as well. And, one of the biggest ones I found over the years, it's now been a while, is It's just getting people with better eye protection in the evenings, right?

Interesting.

If you just get them off their screens and wear blue light blockers, either even yellow lenses or orange lenses are ideal, I've seen people's deep sleep and HRV go up dramatically just with that too. Because melatonin production, which is important for helping us with our circadian rhythms and maintaining and helping us fall asleep as well, if you suppress that right before you go to bed, it's also going to affect your HRV. And so, I found that using Just that can be very, very helpful. And, the other big thing that I found to be super helpful is just having people go to bed at the same time every night. So, having a very good sleep routine. But, the balance of this autonomic nervous system is not just before you go to bed. I think it's what you're talking about too with the Apollo. It's throughout your entire day. If you're stressed the entire day, even if you have a great sleep routine, it's not going to compensate for it. You still have a debt of that whole day Were you in that sympathetic mode?

And it's so incredibly common these days. You know, I, I think one of the simplest things people can do is turn the TV off and just unengage the news. I mean, if you want to, you know, it's not a saber-toothed animal, but it is a constant threat. One of the news stations always flashes alert, alert. Another is breaking news. Uh, you know, you want to light up your sympathetic nervous system and keep yourself, keep your mitochondria threatened. That's to me, that's the way to do it. You know, I think it's reasonable to be informed. But to have that stuff going on in the background while you're trying to relax and enjoy life doesn't make any sense. I learned about something called Nowatch, or maybe it's Nowatch.

Okay.

And this is— it's actually a watch that is measuring HRV, pulse rate, et cetera. But I think designed more, at least in terms of their algorithms, to look more at recoverability. And, I think it's clear that the recoverability part based on what you said before is really very important.

You mean, so bringing yourself back into parasympathetic as fast as possible after being—

After exercise, after you do whatever.

And then, there's really good data here that the faster you can get into parasympathetic after exercise, especially the bigger gains you're going to make with less work you actually did in the gym actually. Well,

interesting because one of the things that's common amongst the hackers is cold plunging right after a vigorous exercise.

You don't want to—

with the idea of limiting the production of inflammatory cytokines, and that would be then good for you. And that would be arguing against what you're talking about, wouldn't it be?

Yeah, I think it absolutely does. I think it would for a number of different reasons. The first one being, if you're going into a cold plunge after exercise, you're mitigating the benefits of the inflammatory cascades that are required for your health.

What did you just say? Limiting the benefits of the inflammatory cascade? You got to unpack that. That's great.

Yeah. So, I mean, when we exercise, we cause inflammation. We cause sheer stress to our muscles that makes them remodel themselves into a way that makes them stronger. You need the inflammatory response. We need inflammation. Inflammation is not— acute inflammation is a good thing. This is what our bodies are programmed to have. They're not programmed to have chronic inflammation. And when you have chronic stress, you have chronic inflammation. You have chronic mitochondrial dysfunction, You have chronic inflammation. But exercise, short bursts of stress are supposed to cause an inflammatory reaction. And then, the body comes out stronger. It releases hormones like growth hormone. It increases GABA as well. And, because of having these inflammatory mediators on board, okay? But, going into a cold plunge right afterwards is going to mitigate that inflammatory cascade and actually decrease your capacity to remodel and to build stronger those muscles, let alone what you're talking about as well, David, which is that stress response as well that you're maintaining by going into a cold plunge and throwing out those stress hormones by going into 32 degrees or something like that.

Or even lower. Yeah. I mean, if it's salted, for example. I'm getting ready for a trip where the water I think is going to be a lot colder than that. And, I don't know, may or may not do it. But, having said that, I think for our viewers, what you just described is going to be really important because, you know, there's this idea that after vigorous exercise, you're training for a long-distance run or whatever, you jump into an ice bath, and you're negating the fact that in what you just described, the upside of these inflammatory mediators, in particular interleukin-6, which is the signal to make— to activate AMP kinase.

Yep.

Which you need for insulin functionality and for fat oxidation, etc. So That's going to be a very good point. Now, let's get back to the idea of the central role of mitochondria in this entire cascade. And I think one of the handy tools that I've used over many, many years— gee whiz, dating back probably 30 years— is hyperbaric oxygen.

Mm-hmm.

And I know you've been involved in that. I mean, if you want the mitochondria to be involved, in oxidative phosphorylation, making the energy from oxygen. It would seem that hyperbaric oxygen might have a role here in accentuating or enhancing rather how mitochondria can do their job. So, I know you looked at that. What can you tell us?

So, what I can tell you here is that when you're bringing in hyperbaric oxygen therapy, it could be a fantastic tool. It's been well understood to increase mitochondrial biogenesis. So, new mitochondria, new blood vessels, release stem cells to help heal tissues that's been injured, address inflammation. The key though is to make sure it's sequenced appropriately and also dosed appropriately because what happens with hyperbaric oxygen therapy is you're flooding the body with a lot more oxygen. That's good if you have the capacity to utilize that oxygen to make energy. Do you have optimized levels of vitamins, minerals, nutrients, the machinery that's required to make energy from oxygen? And also, Do you have the capacity to neutralize the reactive oxygen stress that's going to happen when you bring in all that oxygen as well? So, for me, the way I think about this typically is that if I'm going to use hyperbaric oxygen therapy when somebody's more under significant mitochondrial stress and this sympathetic activation, I'm going to use mild amounts of pressure just to get the body more oxygen in there because there are relative hypoxic areas in the body, especially when you have a lot of inflammation that can be very helpful. But, in general, I tend to wait about 3 months or so after optimizing mitochondrial function, looking at optimizing vitamins, minerals, nutrients, and cofactors, antioxidant status, helping with the sympathetic activation, and then you bring in hyperbaric oxygen therapy, it could be a fantastic tool because you're doing all the things that I just described. You're bringing more oxygen in circulation. You're creating this stimulus where you're— with hyperbaric oxygen therapy, you're actually causing an increase in reactive oxygen species, which drives those changes that I just described actually. So, some reactive oxygen species are good and that's good but only if you have the capacity to tolerate that. And then, you don't if you're in this sympathetic spiral where you're already flipped into glycolysis and the cell danger response and you don't make energy effectively. So, what I found really helpful over the years is to wait to use hyperbaric therapy. So, not using it right away. This has gotten me in trouble in the hyperbaric world. I once was going to give a lecture that said, please don't put them in the chamber. And, that's because there's a sequencing that I found to be very, very helpful here, which is if you optimize foundational biomarkers, optimize biology, lifestyle, stress first, or at least get it started, and then start using hyperbaric therapy to be this accelerator of healing. So, can it accelerate your healing from toxic exposure? Absolutely. Can it accelerate your healing from an infection? Absolutely. From medication damage to your mitochondria? I've seen hyperbaric therapy work really wonders here. But, I've also seen it not work as well if you use it too soon at too deep of a pressure because it does cause its own oxidative load. And so—

And, I would tell you that over the years, I'm always one to say if some is good, more is better, right? And, that's not the case with hyperbarics. We would be increasing the FiO2 or the concentration of oxygen in the air that people are breathing. Actually, we used 100% FiO2.

Sure.

As well as pressure, being careful to monitor the dive tables very carefully. But, I think what Dr. Shai Efrati at the Aviv Clinic in Central Florida has proven or demonstrated, and based first on animal work and then his work in humans, is that it's the change, it's the delta of the amount of oxygen that you're delivering that really is what activates this pathway, this hypoxia-inducible 1-alpha pathway that then leads to the vasoactive, or rather the increased growth of blood vessels and more blood supply, which is obviously going to be helpful for mitochondrial function along with the other mitochondrial-targeted ideas like exercise, time-restricted eating, making sure we're sleeping enough, things like coenzyme Q10 and urolithin A. Are you a fan of urolithin?

Yeah, I've been starting to use it more. I've been using it in combination a lot with with this compound called methylene blue. I don't know if you.

Yeah, I was gonna. Let's get to methylene blue then.

Yeah. So I mean, it's one of those compounds that I've used a lot in mitochondrial support because it's a redox cycler, meaning that at low doses it enhances energy capacity, and it also works as a detoxifier, like an antioxidant directly. So what's nice about it is it's more like an electric car. It comes in; it doesn't have any waste or exhaust. A lot of things that you bring into the system that bring in more energy. Make more ATP, but you also make more reactive oxygen species along the way that antioxidants need to clean up. With methylene blue, what's nice about it, low doses around 8 to about 25 milligrams or so I found are great at giving that initial support to the mitochondria without causing a lot of stress. And, that's really the key. You want to bring in— so, if you just bring in antioxidants, for example, and you clean up the reactive oxygen species like with glutathione, for example, that's great, But, if you don't have any capacity to make energy, you're still not going to feel very good. And so, that's why it's nice to have something that's also enhancing energy at the same time. And so, I use a lot of methylene blue in detox protocols, for example, where people are using sauna or they're using binders and things like that where they feel washed out because they're going through the detox process. But, you add methylene blue to it and all of a sudden they have enough energy that they actually feel great when they get out of the sauna.

And, how are you giving methylene blue?

Yeah, typically orally. So, oral methylene blue, typically somewhere between 8 to 25 milligrams. There are a number of different ways to take it. There's liquids out there, which I don't typically recommend because liquids are kind of all over the map when it comes to quality and when it comes to potency. The problem with methylene blue is it's not a natural compound. It doesn't come from nature. And so, it's made in the lab and it can be contaminated with heavy metals like lead, Mercury, cadmium, and arsenic, and things like that. So you have to be really careful where you source it from. And liquids themselves typically not as potent as they say on the label. And then also they get everywhere. Liquids are just messy in general. So I use I use a troche form. It's called a buckle troche. But these troches can be swallowed as well. And and I find them to be very helpful because one of the first things that I want to do with patients, and David, I think you can understand this. Like I want to give give them enough energy. Without enough stress on the system so they actually are ready to start doing some of the harder work of changing some of the patterns that have gotten them where they are, right?

Yeah. And yet, the go-to is just drink more coffee.

Right. And the unfortunate thing about caffeine is that you're basically borrowing energy from later, right? And then, you're going to get a crash later as well and everything that goes along with that, especially if your mitochondria are already under stress. And so, what methylene blue can do, what I like, is that it doesn't give you that stimulating effect because it also has the detoxifying antioxidant effect at the same time. And then, very low doses are very well tolerated. If you start off at very high doses around 1 milligram per kilogram, you start off at 40, 50, 70 milligrams of methylene blue, you're probably not going to feel very good when you first take it if you have a lot of mitochondrial stress that are ongoing. Because what happens at the higher doses is you get to be more of an anti-infective. I use it that way. It can be used as— it was actually the first antimicrobial prescribed ever was methylene blue back in 1897, 1897, for malaria a long time ago. And, it was used as the primary antimicrobial through World War II because it's such a fantastic antimicrobial, antifungal, antiviral, antibacterial, still used now as a prophylactic for urinary tract infections as well. But, those higher doses cause more stress on the system because they increase the amount of hydrogen peroxide that are produced by our cells to kill bugs. Whereas, the lower doses do not do this and cause just the ability to compensate for electron transport chain issues, for redox issues on both sides of the mitochondria, as I mentioned. And, Complex I, Complex II, the first complexes on mitochondria are almost always affected when you have mitochondrial dysfunction. And, that's where we have a lot of problems taking the electrons from our food which is why we eat food, proteins and, excuse me, carbohydrates and fats to bring into our mitochondria those electrons to make energy. And if those complexes aren't working very well, you're not making energy very effectively. And this whole cycle may have started that way, right? I mean, you may have had a medication that destroyed complex 1 or made it dysfunctional. And then you had all these compensatory mechanisms. So that's why I use methylene blue and find it so helpful.

Well, you know, as far as medications targeting complex 1, I think the biggest issues in our modern world that target complex 1 are things like glyphosate.

Yes.

And, uh, rotenone and paraquat. And yeah, I've had this discussion with Dr. Ray Dorsey in the context of, um, Parkinson's disease. And, you know, if you want to target complex 1 and end up with a mitochondrial dysfunction, that's what you do. You get exposed to these things. And that's, you know, when you drive down the street and see people with tanks on their backs spraying your neighbor's yard, uh, with things that are mitochondrial toxins. It's a little bit concerning. But what we were talking about just for our viewers is called methylene blue. And it's— you would agree it's certainly trendy right now. And it's one of those things that may take hold. And, you know, we're going to certainly watch the science. I do talk about it in Brain Defenders a little bit because, hey, it's out there. We need to know about it. Yeah. Let's go to the gut for a moment and talk about how issues with gut dysbiosis, gut bacteria, ultimately can play out in terms of activating sympathetic response?

So when it comes down to it is that your gut is the outside environment. Your gut is the outside world. And what your, your immune system is trying to do— 80% of your immune system is in your gut— is trying to protect you from the outside world. And your gut is sort of like the— it's the place where everything either ends or begins. Either it comes out The other end, or it gets into the system. And the hope is that you get things into the body that are, that are required to get in there. And the hope is that the things that aren't supposed to get in there leave, right? And so the interesting thing about the gut, it's only one cell thick. It has a mucus layer on the outside of it that helps protect you. But in the end, that's all there is. It's like one cell and the rest of the world.

I got to tell you a story. You're probably wondering why I'm smiling. Yeah. And I was writing a book called Brain Maker, which was about Good book. And I said, isn't it fascinating that the lining of the gut is one cell thick from the esophagus to the anus? That's what I dictated. But what was transcribed was, isn't it amazing it's one cell thick from a soft kiss to the anus? I thought, I'm on the floor laughing, and my wife rushes in. She said, you all right? I said, you got to read that. Anyway, and I thought for a moment, I'm going to just leave this. And send it on and see what happens. And then I thought, you know, there's an infinitesimal but not zero chance that that would end up in the book. Right. And then years later, I thought, I thought, you know, it probably wouldn't have been the worst thing. I mean, obviously it was a typo, but it would have been really popular. But anyway, so you said you triggered that memory for me, but go ahead. I'm listening.

No, I love that. It's, uh, it could have been like one of your Easter eggs that you put in your books, David, you know, like they did in the video games. You have like the thing that like the secret, the secret room, the secret, the secret place, the secret buttons you press on your remote, you could have had the soft kiss.

The bonus.

Yeah, there you go. Yeah. So, what it comes down to is that if your gut is not doing what it's supposed to do, it's not keeping things out of your system, if it's leaking things in, your body goes into inflammatory states. And again, it basically upregulates your immune system in ways that causes dysfunction all over the place. And we know this very well now. The science is pretty well established. And then there's also, from a direct GABA signaling perspective, just to give a sense there, there are certain types of bacteria that signal our vagus nerve to enhance our GABA signaling in our brain. Bifidobacterium lactobacillus, for example. These are some of the most common commensals, the most common organisms that are in our gut already that signal our vagus nerve to calm down our brain. So, if you don't have these commensals in there, you're not going to be able to vagal— the vagus nerve is not going to be signaling very well. And so, it's a very interesting sort of tripartite axis, right? You have your gut, you have the gut lining, you have your bacteria, you have our immune system, you have our brain. It's all kind of happening and it's all talking to each other. And, you have all these things called interkingdom crosstalk as well where you have bacteria talking to our human cells, you have human cells talking to the bacteria. So, it's this very amazing— Yeah. It does.

Yeah. And it's relatively new information. I mean, the whole gut-brain connection, you know, years ago when I talked about it, people thought I had a screw loose. I probably did and probably still do, but at least now it's entered the common parlance, right?

Yeah. Yeah. And so it plays a big role in your stress response if your gut is not optimized. And because number one, you can't digest your food if you're always in sympathetic, by the way, right? If you're not getting enough blood flow, To your gut, when you're in sympathetic, you're not going to digest your food well. So this becomes its own problem over time. Number one. So one thing that I try to remind myself to do is like sit down while I eat. You know,

very important point. So that when you're in sympathetic response, you're shuttling blood away from the gut to your muscles so you can again run away from the saber tooth tiger.

Yeah, yeah, yeah.

And and that doesn't make for good digestion. I mean, here you are putting food through. Through a gut that's almost ischemic, that, well, just not getting optimal blood flow.

Right, exactly. And so that's, that's a big thing too. So there's multiple things that are happening here, right? There, you can look at it from a gut-centric perspective, or you can look at it from like what's happening systemically. But in the end, it's all the same, because if your gut's inflamed, if your gut's not working very well, it's going to cause issues systemically. And if your system's not working well, you have like, you're sympathetically activated, your gut's not going to work very well. But the common denominator where I work with a lot of my patients first is often the gut because that's the place where you can make a lot of headway very quickly. Because if you can seal up somebody's gut and make it so that it's not leaking things outside to the rest of the body, then all of a sudden, well, those GABA supplements stop working as I mentioned earlier, but all of a sudden, all the inflammation that brain, that leaky blood-brain barrier, those microglial activations that you were describing earlier, David, that all starts calming down. And then, you start feeling better. This is when you've written books on this. Like, you're— you work on your microbiome and depression gets better. You know, you work on the microbiome and all of a sudden your anxiety is better. Like, why? It's because all this is related.

Well, last topic. Uh, first let me just say this has been some really interesting stuff, but I want to ask you about psychedelics. And sure, is there a place for what you're talking about in terms of recalibrating the tone between sympathetic versus parasympathetic? Is there a place for psychedelic intervention?

I absolutely would have said no 10 years ago, and I think many of us would because we just didn't understand what was possible. And I think now we know that using psychedelics, especially the legal ones for now that are available, can be transformative, especially in that sympathetic dominance spiral aspect of this spiral that we've been talking about. Because if you can break that spiral from the sympathetic side, You can see massive changes in how people are able to show up in their life. And, the biggest aspects of that sort of top-down, the stress that's coming from outside are from trauma, are from severe traumatic events like from a death in the family or even as a traumatic hospitalization can do this as well. And, if you can address some of that stress and trauma, psychedelics seem to be a great way to do this in the right settings. And, I've seen this. I've seen people that have had very difficult times for long periods of time recover from PTSD in 3 treatments with a psychedelic medicine. And so, it's a new world out there. And, if you can look at this as how can we downregulate the stress response now but then also recalibrate for the long term by the neuroplasticity aspect of things too because as you rewire the brain, you rewire your stress response. You rewire your capacity to be resilient, and you rewire your mitochondria as well. And we are seeing this now with some of the psychedelics out there, that it's obviously affecting neurochemistry, and that's obviously affecting mitochondrial function too. So I think it's a very exciting—

Directly affecting neuroplasticity and synapse formation. And, uh, you know, I mean, that's, that's now being demonstrated certainly in, in the animal, and I think pretty much inferred in the human. Yeah, I would tell our viewers, uh, if you're interested in this topic, I just I did a podcast recording with Dr. Will VanderWeer, and it's the entire podcast dedicated to understanding the therapeutic aspects of psychedelic intervention in the appropriate set and setting with the appropriate guidance, which I think was the take-home message from the entire podcast.

Yeah, Will's a friend here.

Thank you so much. What incredible information. Do you feel like things are really converging? All these Seemingly disparate ideas that we've had over the years are converging on mitochondrial dysfunction. It's interesting, isn't it?

100%. I think that's kind of the age that we're in now, David, is that it's mitochondrial medicine. If you can focus and start there, everything else will get better or easier. It doesn't mean you have to start off with the more challenging things, even the sympathetic activation sometimes, right? You can just focus on supporting mitochondrial function because that is the common denominator for everything we've been describing today. If you focus and you work on mitochondrial function, everything else is going to get easier. And, as a clinician, it's been transformative to my practice is because if you start there instead of starting in other locations, you just see dramatic changes much faster in your patients.

Yeah. So, upstream of then the very downstream clinical manifestations of cognitive dysfunction, of agitation, anxiety, all the things that You know, depression, gastrointestinal issues. These are way downstream from the primary issue, which is the mitochondropathy that is acquired.

Yes, exactly. So cellular medicine, mitochondrial medicine is the future, and I'm glad we're, we're a part of it at this point. It's been fun.

Super. Thanks for spending time with us today.

Thanks so much for having me, David. I really appreciate having me.

Bye for now. Well, what did we learn today in our time with Dr. Sherr? We learned that chronic stress isn't a personal failure and shouldn't be stigmatized. It's a physiology that is basically stuck in defense mode. So thanks to Dr. Share for laying out this really clear and innovative idea, a science-based path towards recovery, resilience, and what he calls a parasympathetic edge. So if this episode changed the way you think about stress, your performance and brain health, then share it with somebody who needs to hear it. Until next time, remember that your nervous system is Listening to every signal that you choose to send it. So make these signals of safety, recovery, love, and adaptation. I'm Dr. David Perlmutter here on The Empowering Neurologist. We will be back soon. Bye for now.