Your mitochondria and responses to stress are more connected than you think.
In this episode, Dr. Scott Sherr is back to tell us about why 94% of US adults have mitochondrial dysfunction and how chronic stress and inflammation deplete GABA, your brain’s primary calming neurotransmitter.
We also discuss why methylene blue has exploded from an obscure mitochondrial enhancer to a controversial biohacking trend, how GABA deficiency masquerades as anxiety and depression, and why healing requires shifting from sympathetic dominance to parasympathetic activation.
Dr. Sherr shares his 20 years of clinical experience, demonstrating that within 30 seconds to 2 minutes, he can determine if someone can heal; it all comes down to the state of their nervous system.
Table of Contents
In this podcast, Dr. Sherr and I discuss:
- The fascinating history of methylene blue—why it was proclaimed a “magic bullet” as far back as the late 1800s, its role as the first pharmaceutical, and how it can be synergistically combined with red light
- The supplemental combination some endurance athletes are using—and you can too!—to increase VO2 max by 5-10%
- The shocking stat that 94% of US adults have some form of mitochondrial dysfunction
- The controversy around GABA supplementation in determining if you have a leaky gut and brain
- How sympathetic activation and elevated cortisol destroy your nervous system over time
- The glutamate/GABA conversion and what can block this crucial process
- Why alcoholics and their families tend to be GABA-deficient
- The important impact of nutrient deficiencies and inflammation on GABA production
- Why THC makes some people anxious (yes, it’s linked to GABA!)
- The Santa Claus mushroom compound that mimics GABA
- One simple breath trick that helps calm your nervous system and promotes healing
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Transcript
Ari Whitten: Dr. Sherr, welcome back to the show.
Scott Sherr: It’s great to be back with you, Ari. It’s been a minute.
Ari: It has. I think the last time we saw each other in person, it’s got to be six, seven years ago at this point.
Scott: Oh, yes. Long time. We did a podcast for one of your other podcast channels on methylene blue, maybe about three or four years ago.
Ari: Oh, that’s right.
Scott: I remember you asking me, “Scott, do you think we could do a whole podcast on methylene blue?” He’s like, “That’s not going to take very long.” I’m like, “I promise you it’s going to be fine.” [chuckles] We had a great conversation, I remember, too.
Ari: Yes. Since that time, methylene blue has exploded onto the scene. Actually, before we plan to talk all about GABA in this one, but it might be worth touching on methylene blue a little bit.
Scott: Sure, yes.
Ari: Since it’s become so popular and now somewhat controversial-
Scott: Of course.
Ari: -it’s gone from this very fringe thing that very few people knew about to becoming super popular. Now everybody knows about it, now everybody’s running around with blue tongues. Robert F. Kennedy Jr. is on airplanes with a blue tongue, and now it’s in, I don’t know, the major newspapers around the world.
Scott: The zeitgeist. Yes, that’s how I like to call it.
Has the understanding around Methylene Blue changed?
Ari: Yes, everybody is talking about it now. Also, some people are speaking– I don’t want to say speaking negatively about it or are speaking in a way that is doubtful that it has the benefits that are claimed for it. Just curious what maybe thoughts you want to share on this topic as things have– that the whole landscape has shifted in the last few years.
Scott: Absolutely. When we first started the company, the Troscriptions company, in 2020, we were the only company and the first to come out with a commercial product that had methylene blue in it. Over the 2020 to 2024, there has been a very obvious and a very significant rise in visibility and in interest. Especially in 2024, there were other people talking about it other than me.
In 2023, I was the only person really talking about methylene blue in any kind of context. In 2024, all these other practitioners at all these other conferences I was going to were starting to talk about methylene blue. I’m like, “Oh, there’s something happening here,” as the old song would say. Then in 2025–
Ari: Very quickly, I actually want to mention I did a podcast on it back in 2020.
Scott: Did you?
Ari: Early on the topic of COVID because there was some interesting data coming out that suggested it could be beneficial for that, and it was being used in blood transfusions combined with red light to-
Scott: It was, yes.
Ari: -basically create an antiviral effect to sterilize blood. If you can use methylene blue plus red light in a plastic bag full of blood to kill COVID, there was some interest in that. I was onto that thread, and I did a podcast with another Dr. Scott, what was his last name? I’m spacing on his last name, but I did a podcast on that subject. I know that there were some doctors at that time who were using methylene blue inhalation. I will say, I have you beat on exploring methylene blue. I think I was exploring this a long time before you.
Scott: Sure, yes, it could be.
Ari: I was doing it as a 10-year-old playing with methylene blue with my– this is 31 years ago with my aquariums, because this is a common ingredient that is used to treat fish diseases. I’ve been playing with methylene blue for 30-some years.
Scott: You’re the OG man. Methylene blue itself, just as a quick primer for those, has been around since the 1870s, actually. It was the first drug registered with our nascent FDA in 1897 as a treatment for malaria. As a profound anti-infective, it got the name of a magic bullet because you could give very high doses of methylene blue. You could kill bacteria, fungus, and virus, but you wouldn’t harm the host cell, the human cell, and that was kind of why they call it the magic bullet. In the beginning of the pandemic–
Ari: Isn’t it the first pharmaceutical? Doesn’t it have some unique characters, like it is technically the first synthetic-
Scott: It is, yes.
Ari: -chemical pharmaceutical ever made?
Scott: The first fully synthetic drug made overall is methylene blue. It was made as a synthetic dye for manufacturing. Then they realized that the class of dyes that it belonged to had antimicrobial properties, the thiazine dye property. Yes, it does have that benefit or whatever it is. That’s what it’s known as.
Ari: Then it was used early on for staining tissues and microscopy, right?
Scott: Yes, and it still is. In biochemistry class, when I was in college, we would use methylene blue as a stain because it actually stains part of your cell called your mitochondria because it actually concentrates in that part of the cell, and that’s where it does all of its redox. It does its energy capacity, optimization, it does its detox as well.
It’s on the World Health Organization’s list of essential medications still for something called methemoglobinemia, which is when you can’t carry oxygen on your red blood cells, typically from a poisoning, from sodium nitrite poisonings of huffing glue and huffing paint, and things like that. Overdoses can actually cause this. Every emergency room in the country, the US at least, carries methylene blue IV in their emergency rooms.
It’s also an antidote for cyanide poisoning, which I don’t recommend anybody do or get, but cyanide destroys one of the complexes on your mitochondria Complex IV and prevents it from working, but methylene blue can bypass and compensate for that, allowing you to make some energy, even if you don’t have Complex IV, which is like your final complex in the electron transport chain that actually allows you to bind oxygen after that and allow electrons to flow.
It’s got a very storied history. We couldn’t talk about it during COVID, of course, but we had lots of practitioners that were bringing it to people’s homes, combining it with near-infrared light because there is synergy there. High-intensity, near-infrared light, along with high doses of methylene blue, is anti-infective, and this has been well described in the literature as an antiviral, as an antifungal, antibacterial, also being used in cancer this way too. There’s been some studies looking at high doses of methylene blue as a photodynamic photosynthesizer for types of chemotherapy, and for breast cancer specifically, and for using it in combination with near-infrared light. It’s got this really interesting history there and–
Ari: Small point, but isn’t it red rather than near-infrared? I thought it was right around 660, that’s the main–
Scott: Oh, 660 to 680. The classification would be red– [crosstalk]
Ari: That’s red rather than near-infrared.
Scott: Okay, cool. Thank you for the clarification.
Ari: Generally, it’s not that meaningful to differentiate the mechanisms, but in this case, it’s like the absorption of methylene blue is specific– the peak of the absorption is right in that wavelength range.
Scott: Yes, somewhere between 600 and 680, but definitely between 660 and 680 seems to be the sweet spot overall.
Ari: Fascinating. What do you think of– has there been research that’s emerged in recent years that’s coincided with the rise in popularity and the trendiness of methylene blue, or-
Scott: No, actually.
Ari: -is the research still pretty old?
Scott: Most of the research has been around for a while, and there’s a pretty well-respected researcher at the University of Texas, Austin. His name is Francisco Gonzalez-Lima. He’s done a number of different studies. He did one on the combination of methylene blue and red light, specifically for a model of Alzheimer’s in animals, with some significant benefit. He’s done some additional things looking at neurodegenerative disease in general, using methylene blue as the carrier or as the compound, really, that can really physiologically work on mitochondrial function in a way that can compensate for blockages, for oxidative stress, for et cetera, and really have a significant benefit.
What really changed the whole landscape, there was this, definitely, increase in interest over the last five years. We saw this every year, especially in the practitioner space, was when RFK, as you mentioned earlier, was seen on an airplane using methylene blue in his water, and then–
Ari: Was caught with a blue tongue. [chuckles]
Scott: Yes. Then there was also some additional podcasters with very big platforms that were talking about it and using it. As a result of that, the zeitgeist in popular world became gigantic. That’s been great, as you can imagine, in a lot of different ways, but the nuances of how you use it and the dosing is lost on people that don’t really understand the science. The dose response curve thing is probably the most important.
When you have people, the naysayers out there saying that methylene blue is causing a blue brain, for example, or that methylene blue has all these risks for oxidative stress and toxicity and poisoning and things like that, that’s all related to a dose response aspect of how methylene blue can be thought of, because very low doses, 4 milligrams, 8 milligrams, 16, up to even 1 milligram per kilogram orally are very, very safe and have been shown to be safe for years and years and years, but there are nuances–
Ari: Do you turn your pee blue?
Scott: Yes, even at low doses, they turn your pee blue. Even at 4 milligrams or 8 milligrams, most people will have blue urine, but there are people out there, and these are mostly non-clinicians, honestly, Ari, that are coming out and saying these things about methylene blue that you shouldn’t take it for X, Y, and Z, mostly because they’re not looking at the dose response aspect of the nuances of dosing.
The clinical experience that we’ve had over the last five years is pretty dramatic. In the beginning, I was even surprised at people coming to me afterwards and saying, “I’ve tried everything for, fill in the blank, my autoimmune condition, my fibromyalgia, my long COVID,” although that was a little bit later, “And nothing worked except when I started taking a small dose of this and then ramping it up over time.”
Of course, it’s not just about taking one compound. It’s about the whole thing. It’s just in the sense of what are you doing for your diet, your lifestyle, your stress, et cetera. As a way to start working with people very early on and start using low doses and working on mitochondrial function, you can see a very significant benefit very quickly. Then it’s easier for people in a lot of ways to start doing some of the other things that may be harder to do and that have been more challenging.
Then the other thing I know we’ll talk about is the sympathetic versus parasympathetic response and healing. I know you’re a big proponent of this as well, but focusing on relaxing the nervous system has been so essential to how we all have to heal. That’s a big part of things. Of course, if you’re so stressed because your mitochondria don’t work, you can’t just de-stress the system without working on mitochondrial function, too, because that’s why somebody’s in sympathetic dominance. Bringing in methylene blue has been game-changing overall, and it’s been a fun ride this year.
Ari: I want to circle back to what you just said in a minute, but just to wrap up the methylene blue thing, I think part of what’s been brought forward by people like Chris Masterjohn, I would say, him in particular. I know you’re familiar with his take on this subject because we spoke about it on the phone. I think some other people have maybe expressed some similar thoughts, probably pulling from Chris. I think Chris is the main one who dug into the research and came to this first anti– I don’t know if that’s a mischaracterization, but let’s just say he’s not very pro-methylene blue.
Scott: That’s got to an airplane. He’s now agreed that if you fly and you are hypoxic, that methylene blue is something that you could potentially use to help mitigate hypoxic stress. He’s agreed with that.
Methylene Blue and Mitochondrial function
Ari: That’s the distinction that I want to get at is methylene blue in the context of, let’s say, someone who is experiencing some kind of problem, let’s say has some deficit of cellular energy production due to being on an airplane or due to a genetic issue or due to poor health, maybe more broadly chronic fatigue syndrome, let’s say something like that, versus someone who is already healthy. The distinction being maybe methylene blue is genuinely beneficial in the context of a problem state of some kind, but maybe becomes less so or becomes more harmful in the case of somebody who’s already well. What do you think of that general distinction?
Scott: I think I like Chris Masterjohn’s work a lot, and you and I discussed this, as you mentioned. He’s a fantastic biochemist and really great. He did a great thing, maybe about 18 months ago now, on the biochemistry of methylene blue and talked about it in detail. I think the main thing I like to mention here, Ari, is that the statistics are pretty grim.
94% of US adults have some element of mitochondrial dysfunction, and this is really metabolic dysfunction. What is metabolic dysfunction? Metabolic dysfunction is the inability to make energy effectively because you can’t do various things, the inputs into the mitochondria, the mitochondria itself, or the detoxification pathways that are required to deal with the energy that we make on a regular basis.
As a result of that, most people have some element of mitochondrial dysfunction already. If you have chronic fatigue syndrome, if you have a chronic complex medical illness, if you have issues with brain fog and fatigue, these are often mitochondrial issues. What Chris and what Paul Saladino also both will say is that if you don’t have an inherited disorder of mitochondrial function, then you shouldn’t take methylene blue. That’s ridiculous because so many people have some element of mitochondrial dysfunction already. It may not be a complete blockage of one of the complexes, but they can’t make energy from Complex I or from Complex II very well.
As a result of that, downstream on their electron transport chain, they can’t do very little at all to make energy because those first two complexes aren’t working very well. You need I and II to be working, for III and IV to be working most of the time. With methylene blue, you can bypass some of those dysfunctional complexes, maintain or increase energy production, and actually optimize even Complex IV production itself, the actual complex, while you’re doing some of the other work of optimizing your vitamins, minerals, nutrients, et cetera, to work on mitochondrial function.
My first response to that is that it only actually applies to about 6% of US adults overall, maybe a little bit more than that if you think of all the inputs and outputs that are going inside the mitochondria. When it comes to healthier people that are using methylene blue in general, it’s going to be less often that you would need it because you are already pretty well optimized, but even people that are very well optimized are still under significant stress some of the time.
On an airplane, for example, is a good example. You have hypoxic stress on an airplane. Methylene blue can help compensate for that. It can help with detoxification. It works like an antioxidant. It can actually act just like oxygen and be the final electron acceptor in the mitochondria as well, so that you can continue to maintain energy. Anybody that comes to visit me here in Colorado, they all get methylene blue, hopefully, before they even get on the airplane, but definitely when they get off, they get it as well.
Methylene Blue and sports performance
I also work with endurance athletes, and this increased aerobic capacity is very compelling, Ari, it’s very compelling, and I’m going to be starting to work with a couple cycling teams to actually show this, but maintaining a heart rate elevation for longer periods of time, doing aerobic work is something that could be very, very significant. That’s what we’re seeing, at least anecdotally. Now that being said, if you’re well optimized, I don’t think you need methylene blue very often, but I think you could use it some of the time, that kind of thing, when you’re under more stress.
Ari: That’s interesting that you’re exploring the sports performance angle because I was big into methylene blue several years ago, and I remember exploring the research to try to find any studies where they tested it, and I found almost nothing. I was experimenting with it myself to take it, for example, some mornings before I would go surfing or do other forms of exercise, to see if I noticed anything. I can’t say that I ever got a really clear signal, and I found almost nothing in the research. It’s interesting that you’re doing that now, but you’re finding improvements in endurance performance.
Scott: We are seeing it, but I do want to make it make this more quantified. We are working to get some additional data, hopefully, within the next six months to a year, to be able to show. The problem with an old medicine is that nobody really cares about it from a research perspective-
Ari: Or from a financial perspective
Scott: -because there’s no billion-dollar drug at the end of it.
Ari: Right. Yes, which is the state of affairs for most of lifestyle medicine.
Scott: Indeed. It’s end of one kinds of things, but now we have more ways of looking at end of one data, which is good. I’m going to be working with a cycling guy. Actually, he’s up in Wyoming, and we’re going to be testing him and his athletes and doing some pre-posts. I’m excited for it because I’ve gotten a lot of reports of positive, especially with hypoxic training associated with methylene blue use.
Ari: That’s interesting. That makes sense in light of the conversation we were just having.
Scott: Exactly. Brian McKenzie, you probably know, Brian’s a guy that was with Laird Hamilton for many years, XPT. He does a lot of hypoxic training, and he sees points of 5 to 10 increased VO2 max percentage points by using the combination together.
Ari: Is that meaning in an immediate effect of how they measure it when you’re on methylene blue, or is that over a long period of time that you see greater improvements in VO2 max from–
Scott: This is immediate so far. He’ll do hypoxic training, methylene blue onboard, do your VO2 max training then, and that’s when he sees the increase, but as far as looking at long-term, we haven’t looked at that yet.
Ari: My only question with that would be, I would wonder if taking certain antioxidants blunt hormetic signal from exercise. Scott, I know you know what I’m talking about, but for listeners, if you take antioxidant supplements in tandem with doing intense exercise, the very short version of this is there’s a lot of data that indicates that it actually blunts some of the adaptive stimulus, the hormetic stimulus from exercise and actually, to some degree, suppresses or inhibits the adaptations that your body makes to exercise. I know that antioxidant function is complex and it can potentially even act as a prooxidant, but I would wonder if it might get in the way of the adaptations to hypoxia.
Scott: It’s a good question. I think the jury is still out, but my sense of it is that it depends on the type of training you’re doing. If you’re doing more anaerobic work, then I do think that there– I have a question as to whether a methylene blue is a good idea or not, but from an aerobic capacity perspective, I have a sense that it is potentially more beneficial, but we still have to figure this out in overall, but it’s a really good question. All right.
Ari: Very, very interesting stuff. Thank you for indulging me into the methylene-
Scott: Of course.
Ari: -blue discussion.
Scott: Good stuff.
The nervous system and neurotransmitters
Ari: Let’s dive into the nervous system and neurotransmitters. I want to come back to something you said a few minutes ago that was very intriguing to me, you said something to the effect of linking mitochondria to being in a sympathetic to a parasympathetic state. It’s rare that I hear someone directly link the mitochondria to the autonomic nervous system. I have my own model for discussing that, but I’m curious what you’ve come up with or how you’ve put the pieces together on in terms of that link.
Scott: That’s such multifaceted in a way to describe it. There’s so many different angles. I think maybe the best angle in is– I’ve been a clinician for, for a while now. I think I started seeing patients 20 years this year, which is crazy. That was in my second year, I remember, third year of medical school. As a clinician, what I’ve figured out over the years is that within about 30 seconds to 2 minutes, I know if I can help somebody or not from a physical perspective. I work in hyperbaric medicine, I work in something called Health Optimization Medicine, which is a foundational approach to health. It’s a nonprofit.
You’ve interviewed Dr. Ted and me, I think, on this topic in the past as well many moons ago. Dr. Ted’s the founder. What I realized very quickly is that there’s a certain significant subset of people that have such sympathetic dominance. Their fight or flight system is so high that no matter what you do from a diet, from a supplementation perspective, lifestyle– of course, lifestyle corresponds to what I’m about to say and the other things too, but if you don’t focus on that sympathetic dominance, nothing else is going to work.
That could be something as easy as just doing some breath work and learning how to meditate, or it could be as hard as dealing with childhood trauma and sexual abuse and things like that, that might be just their nervous system is just so elevated. This is because one of the hormones that gets elevated all the time when we’re always stressed is a hormone called cortisol. Cortisol is our stress hormone. We need cortisol. That’s what gets us going and running from something that’s trying to chase us and eat us back in paleolithic times, it doesn’t happen much anymore. Maybe an ostrich or something, but they’re probably just trying to scare you away.
In general, cortisol is fantastic, but if it’s elevated for long periods of time, it starts to deteriorate your whole nervous system, your mitochondria gets super, super inflamed and stressed as a result of it, and you also deplete a very important neurotransmitter called gamma aminobutyric acid, or GABA for short. GABA is our primary inhibitory neurotransmitter in our brain. It calms things down as opposed to our excitatory neurotransmitters, one called glutamate, which is our primary excitatory neurotransmitter that nobody knows about. Between glutamate and GABA, that’s 80% of your brain’s neurotransmission actually altogether.
You have your superstar neurotransmitters like norepinephrine, your dopamine, serotonin that everybody knows about, and your norepinephrine, of course, is the one that’s also involved in fight or flight. If your norepinephrine is elevated, your cortisol is elevated, if your cortisol is elevated, your norepinephrine is elevated too.
The key that I found over the years is to really focus on that parasympathetic activation that– especially that GABAergic neurotransmitter system, because so many people out there don’t realize– and clinicians, even myself and others, before I really learned about this, people are walking around are GABA deficient and they don’t know it. They’ll go to their doctor complaining of anxiety, complaining of insomnia, complaining of depression, but really what they are, they’re not serotonin-deficient, they are GABA-deficient actually instead.
Ari: It’s an interesting way of describing it. Basically, this chronic sympathetic dominance leads to a GABA-deficient state?
Scott: It can. Yes, absolutely. Yes, because–
Ari: Sorry, go ahead.
Scott: I was just going to just mention, yes, and so because GABA is trying to relax the nervous system, but you’re not able to make enough to support your system if you’re always in sympathetic overdrive, and so GABA gets depleted very quickly, and it’s always in balance with this other neurotransmitter glutamate. Glutamate is our primary excitatory neurotransmitter, GABA is our primary inhibitory. Glutamate is converted into GABA in the brain, and you need the cofactors vitamin B6 and magnesium to do that.
Ari: This is a very biochemistry-centric view of this. You’ve done this to some extent already, but can we expand this out to how a person lives, how a person behaves as an example in the-
Scott: Of course.
GABA
Ari: -slides that you shared with me on GABA from your presentation, so that I could prep for this interview. One of the interesting studies that you cited was on yoga, how yoga influences the amount of GABA that’s in the brain. This links up with how we behave in both directions, presumably. If we-
Scott: Absolutely.
Ari: -are behaving at the macro level, instead of looking at it in terms of receptors and neurotransmitters and this mechanism and this nutrient is a precursor for that chemical, and these– we have a tendency towards biological or biochemical reductionism where in our current zeitgeist of way of conceptualizing things, most people are running around thinking that chemicals in their brain control them.
There’s a lack of integration with the fact that also one’s behaviors influence those chemicals. It’s like, “Oh, the chemicals are controlling me, so I need to take other chemicals to control those chemicals, so that–” of course, the most famous version of this sort of oversimplified, biological reductionism is the SSRI serotonin deficiency model of depression.
That whole story is, I think, just worth exploring here, because we had essentially– I don’t know, was it 30 years or maybe more than 30 years of generations of hundreds of millions or billions of people being indoctrinated into this idea that basically depression is a neurochemical imbalance in the brain. That’s the “cause” of depression. It’s essentially like a serotonin deficiency. What it boils down to is that’s really what they were saying.
It’s you have too little serotonin, therefore, you need to take these drugs that increase the amount of serotonin in your brain, these specific serotonin re-uptake inhibitors and decades of the public being indoctrinated with this idea, God knows how many billions of dollars in sales of these serotonin-related antidepressants.
Then just recently, I think it was two years ago, a year ago, something like that, there was a big review paper that basically came out and said there really isn’t any evidence to support the serotonin deficiency model of depression, which is itself– I almost want to do five hours of discussion just on that phenomenon alone, the fact that-
Scott: Amazing. That can happen. Yes.
Ari: -what we think of as “evidence-based medicine” and we build this whole mountain of knowledge and claims and drugs and this whole industry around this claim, and then, oh, decades later, yes, it turns out there wasn’t really any evidence to support that. Not to mention the fact that even if serotonin were mechanistically related to depression, it would still be wrong to claim that the cause of depression is this deficiency of serotonin and that the way to correct it is with a drug that increases serotonin in the brain.
That would still be a horrifically reductionistic and oversimplistic way of conceptualizing this problem, which again just– and I could go all day on this subject, so I won’t. I just want to link this back to the fact that most people really are stuck in this idea that chemicals in their brain are controlling them and have a really, I would say, a deficiency in understanding of how their actions and their behaviors are influencing those chemicals.
Scott: It’s well said, all right, overall. The review paper that came out a couple years ago was a bombshell overall, where, as you mentioned, billions of people getting treated with serotonergic drugs with a lack of serotonin deficiency. Serotonin deficiency is not what causes depression. That whole hypothesis has been debunked. Many other things like that have been debunked over the years too after the– [crosstalk]
Ari: The Alzheimer’s amyloid plaques thing too.
Scott: Exactly. That’s what I was thinking. I love the perspective you take here because I think it’s super important. In fact, I was talking to a patient of mine yesterday who loves to look at all of his lab work and then throw it into ChatGPT for all the things that he needs to do to fix it. What I’ve been having him do over the last couple of weeks and months and longer is slowly, like, what if he didn’t take any supplements? Would it be okay? What if you didn’t actually change your diet and just ate what you felt intuitively to do? Would you be okay?
This is where you’re going, is that the things that we’re doing from a lifestyle perspective, the things that we do every day, we don’t realize what we’re doing oftentimes. He doesn’t realize it. He doesn’t. Until I tell him, “Let’s talk about this for a minute. Do we really need to look at every single marker today? Is this going to change anything?”
The answer I keep telling him, and I this is something that’s very common, is we need to focus on the basics. You are always stressed. You have this stress level that’s up here all the time. Your capacity is significantly diminished to be able to understand that’s where you are because that’s where you always are. Things like yoga, for example, like you mentioned, things like breathwork, where relaxing breathwork, increasing your exhales, even exercise, to some degree, can help reset your nervous system in a way to help you downregulate that nervous system, downregulate that sympathetic overdrive. The consequence of that sympathetic overdrive is really what I was describing biochemically.
From a lifestyle perspective, the hustle culture, the never-sleep culture, the sleep-until-we’re-dead thing, the sleep-is-for-quitters thing, which is the shirt that I used to wear in medical school when I was there with my friends. That kind of culture is what’s really depleting us. One of the neurotransmitters that’s really becomes an issue is this GABA neurotransmitter system that, as a result of the stress and the lifestyle and the diet and the things that we’re following, gets significantly impacted overall. Then we’re stuck in this sympathetic dominant state.
These states of one of them, often the one I like to think about for people that’s very common, used to be more common when we were younger, is MSG syndrome, which is, you go to a Chinese restaurant and you have sweetened food with monosodium glutamate. Glutamate, again, is a excitatory neurotransmitter. You go home, you’re irritable, you have headaches, you can’t sleep. This is an “acute glutamate toxicity”, but this is how people feel all the time. Their feeling is that this is the neurotransmitter imbalance that they have because of the lifestyle and because of the relationships and everything else that’s going on. There are simple things that we can do to really start modulating this in a more optimal way.
Ari: What do you think are some of the key nutritional aspects of this story? Do you think GABA deficiency ties into how people are eating as well?
Scott: Absolutely, yes. Our small intestines, specifically, the primary fuel of our small intestine is an amino acid called glutamine. Glutamine is also the precursor to this other amino acid called glutamate that I was mentioning earlier. Then glutamate gets converted into GABA. The issue is that so many of us are walking around with a gut that’s leaky. It doesn’t have the capacity to keep things in it and allow us things into the body. As you well know, that can be inflammatory, be that to our immune system, cause inflammation.
Then also, when our gut is leaky, the blood-brain barrier also becomes leaky as well. What I find is that if you have a leaky gut and a leaky brain, which often happens in correspondence with each other, you are not going to feel very good. You need more glutamine, for example, to try to heal your gut. Not enough is going to get to your brain to actually get converted over to GABA as well. That’s a very common one that I see.
Often what people will do here is, and this is diagnostic, interestingly enough, from a clinical perspective, is that if you take GABA supplements, like, “Oh, I need to relax. I’m going to take GABA.” GABA is too big of a molecule to get across into the blood-brain barrier through the brain typically. If you take GABA and you feel more relaxed, it’s almost diagnostic that that barrier is not doing what it’s supposed to do. That correlates, of course, to having a leaky gut as well.
Ari: Meaning, you’re saying that GABA can reach the brain directly in the context of gut permeability.
Scott: Yes, exactly. If there’s gut permeability, there’s often blood-brain barrier permeability. Then that permeability is going to allow GABA, which is too big of a molecule typically, to get into the blood and get into the brain to get across. I’ve talked to clinicians for years about this as a diagnostic signal that the brain barrier is not doing what it’s supposed to do, that it’s leaking, and then that the gut is leaky as well.
It’s just another diagnostic way of understanding that somebody typically has a leaky gut. That’s where you need to address. You need to address the leaky gut and the gut inflammation. Even inflammation in general, Ari, is also going to be an issue because inflammation also has an effect on the enzyme that converts that glutamate to GABA in the brain. Vitamin mineral deficiencies, magnesium and B6, and things like that, as I mentioned.
Inflammation is also going to do it in general as well. It’s that conversion that’s really important and that balance between that glutamate and the GABA. Nutritionally, where I’m usually going here is actually looking at data if I can, or symptomatically, if somebody’s coming in with GI-related symptoms, that’s where you approach first before going the neurotransmitter route oftentimes. Focus on the gut is a common way to do things in clinical practices.
Ari: Are there any other nutritional factors that come to mind here?
Scott: The main ones, I think I’ve described here, but when it comes down to sympathetic activation, this is going to deplete lots of different things over time, because if you’re sympathetically overactive, you’re going to deplete your vitamins, your antioxidants, your minerals. It’s very easy for me, looking at a panel, for example, to know when somebody’s sympathetically on overdrive with clinical information too. When I talk about GABA deficiency with patients, it’s a clinical diagnosis for the most part.
You can look at data, it can help correspond to what’s going on. If they’re anxious all the time, if they’re depressed, oftentimes, if they can’t sleep, this is often correlated to GABA deficiency because we know that one of the main roles of GABA itself is to be like a waylay station. It’s a gate. It’s called the sensory gate, where it prevents us from getting overwhelmed by thoughts and information. If you don’t have enough GABA around, we get overwhelmed by thoughts and information. On average, do you know how many thoughts we have on average per day, Ari, as a guess?
Ari: Me or the typical person?
Scott: Typical person. Average human, typical thoughts per day.
Ari: Might be a difference.
Scott: Yes. It’s not unique thoughts.
Ari: Let’s say 300,000.
Scott: That’s quite an estimate. On average, the average human has about 70,000 thoughts per day.
Ari: 300,000 for me.
Scott: That’s a lot for you. If you’re anxious, if you’re stressed, or you’re depressed, you can get up to it.
Ari: I’m under book deadlines. Too much work to do, lots to think about.
Scott: Exactly. Then if you’re one of the two people– [crosstalk]
Ari: That’s why when I’m sitting at the dinner table and my wife’s like, “Hey, where are you? Snap out of it. You’re zoning off. You’re in your own little mental world.” I’m like, “I’ve got stuff to think about. Just relax.”
Scott: That’s hysterical. What GABA does is help calm down the thought generator. Don’t believe everything you think, everybody, if you’re thinking 120,000 different thoughts, or it doesn’t have to be different thoughts, but 120,000 thoughts a day. GABA helps calm all that down. If you’re one of those people, as am I sometimes, just like you, your mind just keeps going and going and going. You’re trying to go to bed, but your mind just won’t shut off. It’s the GABA system that’s typically involved in that.
Supporting it with the vitamins, minerals, and nutrients that it needs can be very, very helpful in this case with the dietary factors, with the lifestyle factors, of course, that are thrown on there. Then sometimes supplementation as well, that’s going to modulate the GABA system in comprehensive ways that affects it so that you can get an immediate effect while you’re doing some of the harder work of changing your diet and changing your lifestyle, working on your stress and your breathwork, and going to a yoga class or whatever it might be, and getting your gut all healed up, which can take time.
Ari: I want to touch on two things that you mentioned here. One is GABA absorption into the brain. It’s been probably, I don’t know, three or four years since I last looked into that research. Maybe this has changed since I looked into this, but what I recall is that there was some controversy around whether GABA can be absorbed directly into the brain or not, and that there was speculation on another potential mechanism, which was absorption via the vagus nerve, uptake from the vagus nerve in the gut, and that the GABA is actually traveling up the vagus nerve into the brain. Has there been any further research in this, and any more knowledge that’s updating what the consensus view is?
Scott: Right now, what we think is that GABA doesn’t travel on the vagus nerve, but what can happen is, in the gut, you have certain bacteria like Lactobacillus and Bifidobacterium specifically that make GABA in the gut. That causes vagal signaling via acetylcholine, via the neurotransmitter itself that the vagus nerve runs on, which is acetylcholine. That causes signaling cascades in the brain that help potentially with the conversion of more glutamate to GABA and increase GABA signaling. It’s not a direct pathway that way.
Then, as far as whether GABA can get into the brain or not, there’s still very little evidence that GABA itself as a molecule can get across into the brain. There is the signaling from the gut for sure, but that’s the main additional pathway other than GABA being converted from glutamate in the brain itself.
Ari: Does it need to get into the brain itself if it can essentially act on the brain via the gut, via the vagus nerve?
Scott: The answer is yes, because it does need additional signaling in the brain. The gut is not going to be enough for just signaling in the gut by the vagus nerve to enhance the GABA system as much as it needs to be overall modulated. It definitely helps a lot. Having a good and optimized GI system can be very, very helpful here.
There are some formulations that may get into the gut. If it’s a nano liposomal, so extremely small fat globule that can potentially get across. There’s also the potential you can actually make it with a vitamin B6 attached. It’s called vitamin B3. Nicotinyl GABA, vitamin B3 attached to a GABA molecule, and that can get across the blood-brain barrier. You can use vitamin B3 because the B3 has a transporter. It gets across, and then it hydrolyzes the B3 and GABA. You have increases in vitamin B3, increase in GABA in the brain as well.
That’s another way to get GABA in there. You can use things that are called GABA-mimetics, things that work on the GABA receptor where GABA would bind. The one that we use is something called agarin, which is from a psychedelic mushroom called the Amanita muscaria mushroom. It’s the Santa Claus mushroom.
Ari: Yes, this was interesting. Actually, before we dig into that, I want to come back to one other question on something you said earlier. Let me remind myself what it was. Oh, glutamate. Glutamine is the precursor for both glutamate and GABA.
Scott: It goes in that cycle. It starts with glutamine, and then it gets converted into glutamate, and the from glutamate, it gets converted into GABA. Yes.
Ari: What would make sense to me, given that they both share this precursor molecule of glutamine, and you talked about the gut barrier integrity element of this, but what also logically, I would think, would influence this is a person’s behaviors and whether they are, let’s say, already in more of a sympathetic state versus a parasympathetic state. Whether they are spending their day really working hard in a very stimulated state, being super active, using their mind without a lot of rest versus if they live a more leisurely lifestyle.
Does more of that precursor glutamine essentially get directed towards glutamate because that’s what’s needed, and maybe there’s less leftover of GABA, essentially, as the body’s way of basically just facilitating the way that a person lives? That’s what’s needed in that person. It would make sense to take more of the glutamine, make it into glutamate rather than GABA.
Scott: Yes. I think the feedback loops are interesting, right? In the sense of it depends if the body is very good and the brain is very good at shunting to where it needs to go. If you need more glutamate because that’s what you’re doing, you’re going to also have less GABA available as a result. Then you’ll feel like you’re still wound up and can’t relax because of that feedback loop as well, that’s been modulated in the way that you’ve done your lifestyle in a way that’s allowing it to happen that way, right?
Most of us, especially a type A person, are going to be more glutamate-dominant than GABA-dominant. It’s very uncommon to be GABA-dominant. GABA deficiency actually is something that runs in families. If you have alcoholics in your family, alcohol binds to the GABA receptor, and it’s going to increase the amount of GABA that binds to the receptor, increase the affinity.
Alcoholic families tend to have people that have either issues with their enzymes and conversion, but they tend to be more GABA-deficient. When they take alcohol, they feel normal, right? This is when they’re actually balancing that ratio more between their glutamate and GABA. We know alcohol is not good for us for a lot of different reasons. It binds very tightly to the GABA receptor. It increases the amount of GABA to bind. Then, as a result of that, it makes the GABA receptor do various things to try to compensate, leading to things like withdrawal, potentially if you stop it too quickly, tolerance, and dependence.
In some people, they only feel normal when they drink alcohol or they work on the GABA side of things because they’re GABA-deficient all the time, and they’re anxious all the time, and they’re overstressed all the time. This is something that they’ve probably learned behavior over time in some people, too, but there’s also a familial, there’s also something that can be inherited in this side, as well, interestingly enough.
Santa Claus mushroom
Ari: Yes. Fascinating. Let’s go back to the Santa Claus mushroom now, Amanita muscaria. Your company is the first I’ve heard of anybody using any extract from that mushroom. You said it was called agarin, and agarin works as a GABA agonist. Is that correct?
Scott: Yes. It binds exactly where GABA would bind on the receptor of the GABA receptor. GABA has– it’s called a pentameric structure. It’s not a big deal, but it just has all these different sites on it where things can bind. Either it can bind where GABA would bind, or it can bind to these other sites. If it binds to these other sites, it can either increase the affinity for GABA to bind or it can decrease the affinity, but more likely it’s going to increase.
Things like alcohol and benzodiazepines, kava, CBD, CBG, these are all binding to these, what are called allosteric or separate sites, and increasing binding affinity for GABA to bind. The problem with things like benzos and alcohol, barbiturates, sleep medications like Ambien, Lunesta, and other things, they bind so tightly to the GABA receptor that they deplete GABA very quickly and they make the GABA system remodel itself in a way that makes it over the long-term as mentioned with alcohol tolerance, dependence, and withdrawal, right?
Your plants, things like kava, your cannabinoids that are non-psychoactive like CBD, CBG, CBN, by the way, THC is the opposite. THC binds and decreases the affinity for GABA to bind, and that’s why people that take THC often will get anxious, actually, because it’s more of that glutamate overload compared to the GABA that can’t bind.
Agarn is directly binding to where GABA would bind. What we do at our company, at Troscriptions, is we combine something that binds to where GABA would bind, and then we have an allosteric or a separate thing that binds on another side of the GABA receptor together. That combination is allowing more GABA affinity without causing GABA deficiency because it has a GABA-mimetic, something that works just like GABA as well. Less of a risk of having things like tolerance and issues over time, taking it, because even kava, over time, can cause this with people. People can get addicted or a tolerance to kava as well, for example.
Ari: Interesting. What else is in the supplement that you sell? It’s agarin and–
Scott: We have two that are based on a GABAergic neuro transverse system. We have one that’s called Tro Calm. This is for anxiousness, for stress, for tension. I find it’s really great in a pinch. After a day like today, where I’ve been on calls all day, like taking a little bit of that just–
Ari: I’m stressing you out. Is that what you’re trying to say?
Scott: No, this has been great, man, but it’s been a long day of calls. This is my least stressful call all day, actually. I enjoy this podcast. You’re great as well, Ari, at always keeping people comfortable. Your questions are awesome always. What it does it just downregulates your nervous system just a little bit to take the edge off. Then you can take a bigger dose of it, if you want it, even take the edge off even more, if you like more significant anxiousness.
It has vitamin B3 attached to GABA, that nicotinoyl GABA, kava, CBD, and CBG. It’s been in a troche form, which is a buckle or dissolvable lozenge in the mouth. You can take a quarter of it, a half, a full, depending on what you need. That really does have a fantastic way of just taking the edge off, quieting down your mind, and just making you feel like you’re more in your body, right? That’s a big thing, being back in your body after being so mentally driven for so many of us is like, it’s just so much more relaxing. That’s what it’s great for.
Then we have something called Tro Zzz, which has the agarin in there along with something called Honokiol or Honokiol, which is from Magnolia bark, and that is also working on the GABA system. Combined together, really great for sleep, also have a little bit of 5HTP, a little bit of melatonin, not much. CBD and CBN, both working on the endo-canabinoid system, but also the GABA system, too, along with something called cordycepin, from another great mushroom called the Cordyceps mushroom, the zombie mushroom, the one that takes over insects, and famous for The Last of Us show on HBO right now. Low doses of cordycepin, the active ingredient, actually increase deep sleep and work just like a neurotransmitter called adenosine.
Ari: That’s the thing that you would put cordycepin into a sleep supplement because, normally, that would be more in energy formulas or adaptogens.
Scott: Cordyceps. Cordyceps, the mushroom, is more of an adaptogen used in the mornings. Cordycepin, this active ingredient, only about 0.03% of the mushroom, so a very small amount, is an adenosine agonist that increases deep sleep. You can modulate in other ways and block adenosine in the brain and use it with caffeine, for example, to get fancy and use it for exercise. It’s a fantastic deep sleep inducer. This adenosine is a neurotransmitter that builds up in our body as the day goes on, as we make more energy as a byproduct of energy metabolism, of ATP, as you know, Ari, and then it makes us feel sleepy at night.
Ari: The extract you’re using is a pure cordycepin as opposed to a Cordyceps sinensis with a higher concentration of cordycepin? It’s just pure cordycepin. Wow, that’s interesting.
Scott: Pure. Then we actually have another product called Tro Mune, which is pure cordycepin at higher strength, because cordycepin as a single ingredient is also a fantastic anti-inflammatory. It works on multiple inflammatory pathways, and it’s also an immune system modulator. It’s an antiviral. It’s even being studied as an anti-cancer because one of our base pairs in our DNA is called adenine, and adenosine is its precursor, and then it can get inside fast-replicating RNA and stopper replications.
It’s great for viral infections and maybe even cancer or two, it’s being studied there. We use it as a standalone formula. It’s one that I use on a regular basis, especially when I travel overall, because I find it to be really a great way to not get sick going to conferences all the time.
Troscriptions
Ari: Good stuff. Dr. Sherr, I guess two last things to wrap up, because I know we only have a couple of minutes here. One is let people know where they can follow you, where they can learn more or buy those supplements that you just spoke about, the Troscriptions. The other thing is leave people with maybe two or three key takeaways of how they can start to take action to get control of their autonomic nervous system if they are in that chronically stressed, chronically sympathetic overdrive state.
Scott: For sure. The company is called Troscriptions, and you can find us at troscriptions.com on the web, on Instagram. I also have my own personal Instagram, @drscottsherr, you can check out Tro Calm, Tro Zzz, so for anxiety relief, for sleep, and Tro Mune, if you’re interested in immune system optimization, many of us are. Then also, of course, our methylene blue-containing products, Just Blue and Blue Cannatine, so you can check those out.
I do a lot of education on all these topics, and I’ve talked to Ari a couple of times about some, and so you can check out more information. Our blog has tons of information as well on all of these topics. I write or I edit every single blog that goes out. This hits home to me, Ari, as far as trying to really work on sympathetic overdrive. If you have tons of companies, you have tons of kids, and I have both.
I mentioned it earlier, but find ways to get back into your body or get out of your head, whatever really is good for you. Sometimes that’s rolling on the floor with a puppy, that’s a great one, or rolling on the floor with your kids, or going outside and walking in nature, or this learning that you can just modulate your breath in a very easy way just to increase your exhales to start feeling like your nervous system comes down.
You don’t have to measure everything. You don’t have to take every supplement in the world, even our stuff. There’s lots of great ways to learn how to downregulate your nervous system. When you do that, you will start healing. You will heal better, you will recover better, you will build more muscles. If you want to be huge, like Ari, not me, but like Ari, you need to have a synthetic nervous system that comes offline so that you can build muscle and protein synthesis. It’s really important.
Find ways. Everybody’s going to be different, but get off your screens, typically. Find a way to take away from the hustle-bustle and find ways that really serve you to relax. For me, that’s playing with my kids, that’s going in my infrared sauna, which I love, that’s meditation, that’s breathwork, and that’s just going outside for two minutes between calls and taking off my shirt and just getting some sun. That’ll do it sometimes. Sometimes that’s all the time that we have.
Ari: Does the hospital allow you to do that? If your patients walk by and see you outside the hospital with your shirt off, does anybody get weirded out?
Scott: I’ve probably gotten fired for it at some point, but thankfully, that’s behind me. Now, I just go back in my backyard, and I’m good.
Ari: Dr. Sherr, it’s always a pleasure chatting with you. It was great to catch up with you, and I look forward to the next conversation.
Scott: Thank you, Ari. I really appreciate your time. It’s been fun.
Show Notes
00:00 – Intro
00:44 – guest intro – Dr. Scott Sherr
04:03 – Has the understanding around Methylene Blue changed?
15:20 – Methylene Blue and Mitochondrial function
19:03 – Methylene Blue and sports performance
23:11 – The nervous system and neurotransmitters
28:24 – GABA
49:00 – Santa Claus mushroom
55:11 – Troscriptions
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