Essentials: Breathing for Mental & Physical Health & Performance | Dr. Jack Feldman

Andrew Huberman: Welcome to Huberman Lab Essentials, where we revisit past episodes for the most potent and actionable science-based tools for mental health, physical health, and performance.

Andrew Huberman: I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. And now for my conversation with Dr. Jack Feldman.

Andrew Huberman: Thanks for joining me today.

Jack Feldman: Pleasure to be here, Andrew.

Andrew Huberman: You're my go-to source for all things respiration and how the brain and breathing interact. You're the person I call. Why don't we start off by just talking about what's involved in generating breath?

Jack Feldman: So on the mechanical side, which is obvious to everyone, we want to have air flow in, inhale, and we need to have air flow out. And the reason we need to do this is because for body metabolism, we need oxygen, and when oxygen is utilized through the aerobic metabolic process, we produce carbon dioxide.

Jack Feldman: And so we have to get rid of the carbon dioxide that we produce, in particular, because the carbon dioxide affects the acid-base balance of the blood, the pH, and all living cells are very sensitive to what the pH value is. So your body is very interested in regulating that pH. So how do we generate this airflow? We have to expand the lungs, and as the lungs expand, basically, it's like a balloon that you would pull apart.

Jack Feldman: The pressure inside that balloon drops, and air will flow into the balloon. That lowers the pressure in the air sacs, called alveoli, and air will flow in because pressure outside the body is higher than pressure inside the body when you're doing this expansion, when you're inhaling. What produces that? Well, the principal muscle is the diaphragm, which is sitting inside the body just below the lung.

Jack Feldman: And when you want to inhale, you basically contract the diaphragm, and it pulls it down, and as it pulls it down, it's inserting pressure forces on the lung. The lung wants to expand. At the same time, the rib cage is going to rotate up and out and therefore expand the cavity, the thoracic cavity. At the end of inspiration, under normal conditions, when you're at rest, you just relax, and it's like pulling on a spring.

Jack Feldman: You pull down a spring, and you let go, and it relaxes. Where does that activity originate? The region in the brainstem. That's once again this region sort of above the spinal cord, which was critical for generating this rhythm. It's called the Pre-Bötzinger complex.

Jack Feldman: This small site, which contains, in humans, a few thousand neurons, is located on either side and works in tandem. And every breath begins with neurons in this region beginning to be active. And those neurons then connect ultimately to these motor neurons going to the diaphragm and to the external intercostals, causing them to be active and causing this inspiratory effort.

Jack Feldman: When the neurons in the Pre-Bötzinger complex finish their burst of activity, then inspiration stops, and then you begin to exhale because of this passive recall of the lung and rib cage.

Andrew Huberman: Is there anything known about the activation of the diaphragm and the intercostal muscles between the ribs as it relates to nose versus mouth breathing?

Jack Feldman: I don't think we fully have the answer to that. Clearly, there are differences between nasal and mouth breathing. At rest, the tendency is to do nasal breathing because the airflows that are necessary for normal breathing are as easily managed by passing through the nasal cavities. However, when your ventilation needs to increase, like during exercise, you need to move more air.

Jack Feldman: You do that through your mouth because the airways are much larger than, and therefore, you can move much more air. But at the level of the intercostals and the diaphragm, their contraction is almost agnostic to whether or not the nose and mouth are open.

Andrew Huberman: Maybe you could march us through the brain centers that you've discovered and others have worked on as well that control breathing, Pre-Bötzinger, as well as related structures.

Jack Feldman: So when we discovered the pre-Bötzinger, we thought that it was the primary source of all rhythmic respiratory movements, both inspiration and expiration. And then in a series of experiments, we discovered that there was a second oscillator and that oscillator is involved in generating what we call active expiration. That is this active...

Andrew Huberman: They're like a, "Shh!"

Jack Feldman: Yeah...

Jack Feldman: Or when you begin to exercise, you have to go... and actually move that air out.

Andrew Huberman: Yeah.

Jack Feldman: This group of cells, which is silent at rest, suddenly becomes active to drive those muscles, and it appears that it's an independent oscillator in a region around the facial nucleus. When this region was initially identified, we thought it was involved in sensing carbon dioxide.

Jack Feldman: It was what we call a central chemoreceptor. That is, we want to keep carbon dioxide levels, particularly in the brain, at a relatively stable level because the brain is extraordinarily sensitive to changes in pH. If there's a big shift in carbon dioxide, there'll be a big shift in brain pH, and that'll throw your brain, if I can use the technical term, out of whack.

Andrew Huberman: Mm-hmm.

Jack Feldman: And so you want to regulate that. And the way to regulate something in the brain is to have a sensor in the brain, and others basically identified that the ventral surface of the brainstem, that is, the part of the brainstem that's on this side, was critical for that.

Jack Feldman: And then we identified a structure near the trapezoid nucleus. It was not named in any of these neuroanatomical atlases, so we just picked the name out of the hat, and we called it the retrotrapezoid nucleus.

Jack Feldman: If you go back in an evolutionary sense, and a lot of things that are hard to figure out begin to make sense when you look at the evolution of the nervous system and the control of facial muscles, going back to more primitive creatures, because they had to take things in their mouths for eating, so we call that the face sort of developed. The eyes were there, the mouth is there.

Jack Feldman: These nuclei that contain the motor neurons, a lot of the control systems for them developed in the immediate vicinity. So if you think about the face, there's a lot of subnuclei around there that had various roles at various different times in evolution. And at one point in evolution, the facial muscles were probably very important in moving fluid in and out of the mouth and moving air in and out of the mouth.

Jack Feldman: And so part of that, of these many different subnuclei, now seems to be in mammals to be involved in the control of expiratory muscles. But we have to remember that mammals are very special when it comes to breathing because we're the only class of vertebrates that have a diaphragm.

Jack Feldman: If you look at amphibians and reptiles, they don't have a diaphragm, and the way they breathe is not by actively inspiring and passively expiring. They breathe by actively expiring and passively inspiring because they don't have a powerful inspiratory muscle. And somewhere along the line, the diaphragm developed.

Jack Feldman: The amazing thing about the diaphragm is that it's mechanically extremely efficient. If you look at how oxygen gets from outside the body into the bloodstream, the critical passage is across the membrane in the lungs. It's called the alveolar-capillary membrane.

Jack Feldman: The alveolus is part of the lung, and the blood runs through capillaries, which are the smallest tubes in the circulatory system, and at that point, oxygen can go from the air-filled alveolus into the blood. The key element is the surface area. The bigger the surface area, the more oxygen that can pass through. It's entirely a passive process. There's no magic about making oxygen go in.

Jack Feldman: Now, how do you get a pack, a large surface area in a small chest? Well, you start out with one tube, which is the trachea. The trachea expands. Now you have two tubes, then you have four tubes, and it keeps branching. At some point, at the end of those branches, you put a little sphere, which is an alveolus, and that determines what the surface area is going to be.

Jack Feldman: Now, you then have a mechanical problem. You have this surface area, you have to be able to pull it apart. So imagine you have a little square of elastic membrane. It doesn't take a lot of force to pull it apart, but now, if you increase it by 50 times, you need a lot more force to pull it apart.

Jack Feldman: So amphibians who were breathing, not by compressing the lungs and then just passively expanding it, weren't able to generate a lot of force. So they have relatively few branches. So if you look at the surface area that they pack in their lungs relative to their body size, it's not very impressive.

Jack Feldman: Whereas when you get to mammals, the amount of branching that you have is you have 400 to 500 million alveoli. So you have a membrane inside of you, a third the size of a tennis court, that you actually have to expand every breath, and you do that without exerting much of a...

Jack Feldman: You don't feel it, and that's because you have this amazing muscle, the diaphragm, which, because of its positioning, just by moving two-thirds of an inch down, is able to expand that membrane enough to move air into the lungs. At rest, the volume of air in your lungs is about two and a half liters. When you take a breath, you're taking another 500 milliliters or half a liter. That's the size, maybe of my fist.

Jack Feldman: So, you're increasing the volume by 20%, but you're doing that by pulling on this 70-square-meter membrane. But that's enough to bring enough fresh air into the lung to mix in with the air that's already there that the oxygen levels in your bloodstream goes from a partial pressure of oxygen, which is 40 mmHg to 100 mmHg.

Jack Feldman: So we have this amazing mechanical advantage by having a diaphragm.

Andrew Huberman: Do you think that our brains are larger than that of other mammals, in part because of the amount of oxygen that we have been able to bring into our system?

Jack Feldman: I would say a key step in the ability to develop a large brain that has a continuous demand for oxygen is the diaphragm. Without a diaphragm, you're an amphibian.

Andrew Huberman: You know, over the years, whether it be for yoga class or a breathwork thing, or you hear online that we should be breathing with our diaphragm, that rather than lifting our rib cage when we breathe and our chest, it is healthier, in air quotes, or better somehow to have the belly expand when we inhale. I'm not aware of any particular studies that have really examined the direct health benefits of diaphragmatic versus non-diaphragmatic breathing.

Andrew Huberman: But if you don't mind commenting on anything you're aware of as it relates to diaphragmatic versus non-diaphragmatic breathing, that would be, I think, interesting to a number of people.

Jack Feldman: In the context of things like breath practice, I'm a bit agnostic about the effects of some of the different patterns of breathing. Clearly, some are going to work through different mechanisms, and we can talk about that. But at a certain level, for example, whether it's primarily diaphragm or you move your abdomen or not, I am agnostic about it.

Jack Feldman: I think that the changes that breathing induces in emotion and cognition, I have different ideas about what the influence is, and I don't see that primarily as which particular muscles you're choosing, but that just could be my own prejudice.

Andrew Huberman: Could you tell us about physiological sighs? What's known about them, what your particular interest in them is, and what they're good for?

Jack Feldman: It turns out we sigh about every five minutes, and I would encourage anyone who finds that to be an unbelievable fact to lie down in a quiet room and just breathe normally. Just relax, just let go, and just pay attention to your breathing, and you'll find that every couple of minutes, you're... taking a deep breath, and you can't stop it.

Jack Feldman: You know, it just happens. Now, why? Well, we have to go back to the lung again. The lung has these 500 million alveoli, and they're very tiny. They're 200 microns across, so they're really, really tiny. And you can think of them as fluid-filled. They're fluid-lined, and the reason they're fluid-lined has to do with the esoterica of the mechanics of that.

Jack Feldman: It makes it a little easier to stretch them with this fluid line, which is called surfactant. Your alveoli have a tendency to collapse. There's 500 million of them. They're not collapsing at a very high rate, but it's a slow rate that's not trivial. And when an alveolus collapses, it no longer can receive oxygen or take carbon dioxide out. It's sort of taken out of the equation.

Jack Feldman: Now, if you have 500 million of them and you lose 10, no big deal. But if they keep collapsing, you can lose a significant part of the surface area of your lung. Now, a normal breath is not enough to pop them open, but if you take... a deep breath.

Andrew Huberman: Through nose or mouth?

Jack Feldman: Doesn't matter.

Andrew Huberman: Okay.

Jack Feldman: Doesn't matter. But it's just increased that lung volume, because you're just pulling on the lungs, they'll pop open about every five minutes. And so we're doing it every five minutes in order to maintain the health of our lungs.

Jack Feldman: In the early days of mechanical ventilation, which was used to treat polio victims who had weakness of their respiratory muscles, they'd be put in these big steel tubes, and the way they would work is that the pressure outside the body would drop. That would put expansion pressure on the lungs-- Excuse me, on the ribcage.

Jack Feldman: The ribcage would expand, and then the lung would expand, and then the pressure would go back to normal, and the lung and ribcage would go back to normal. But there was a relatively high mortality rate. It was a bit of a mystery, and one solution was to just give bigger breaths. They gave bigger breaths, and the mortality rate dropped. And it wasn't until, I think it was the 50s, where they realized that they didn't have to increase every breath to be big.

Jack Feldman: What they needed to do is, every so often, they'd have one big breath. So you have a couple of minutes of normal breaths, and then one big breath, just mimicking the physiological sighs, and then the mortality rate dropped significantly. And if you see someone on a ventilator in the hospital, if you watch, every couple of minutes, that you see the membrane move up and down, every couple of minutes, there'll be a super breath, and that pops it open.

Jack Feldman: So there are these mechanisms for these physiological sighs. So, just like with the collapse of the lungs, where you need a big pressure to pop it open, it's the same thing with the alveoli. You need a bigger pressure, and a normal breath is not enough, so you have to take a big inhale...

Jack Feldman: And what nature has done is, instead of requiring us to remember to do it, it does it automatically, and it does it about every five minutes.

Andrew Huberman: We hear often that people will overdose on drugs of various kinds because they stop breathing. So barbiturates, alcohol combined with barbiturates, are a common cause of death for drug users and contraindications of drugs, and these kinds of things. You hear all the time about celebrities dying because they combined alcohol with barbiturates.

Andrew Huberman: Is there any evidence that the sighs that occur during sleep or during states of deep, deep relaxation and sedation, that sighs recover the brain? Because you could imagine that if these sighs don't happen as a consequence of some drug impacting these brain centers, that could be one cause of basically asphyxiation and death.

Jack Feldman: If you look at the progression of any mammal to a death due to, quote, "natural causes," their breathing slows down, will stop, and then they'll gasp. So we have the phrase "dying gasp." Super large breaths. They're often described as an attempt to auto-resuscitate. That is, you take that super deep breath, and maybe it can kickstart the engine again.

Jack Feldman: We do not know the degree to such things as gasps are really sized, that are particularly large. And so, if you suppress the ability to gasp in an individual who is subject to an overdose, then whereas they might have been able to re-arouse their breathing, if that's prevented, they don't get re-aroused. So that is certainly a possibility.

Andrew Huberman: I'd love to get your thoughts on how breathing interacts with other things in the brain. As we know, when we get stressed, our breathing changes. When we're happy and relaxed, our breathing changes. But also, if we change our breathing, we, in some sense, can adjust our internal state. What is the relationship between brain state and breathing?

Jack Feldman: This is a topic which has really intrigued me over the past decade. I would say before that, I was in my silo, just interested about how the rhythm of breathing is generated, and didn't really pay much attention to this other stuff. For some reason, I got interested in it. I felt maybe I can study this in rodents. So we got this idea that we're going to teach rodents to meditate, and that's laughable.

Jack Feldman: But we said, "But then we can actually study how this happens." So I was able to get a sort of a starter grant, an R21 from NCCIH. That's the National Complementary Medicine Institute.

Andrew Huberman: A wonderful institute, I should mention.

Jack Feldman: Yeah.

Andrew Huberman: Our government puts major tax dollars toward studies of things like meditation, breathwork, supplements, herbs, and acupuncture. This is, I think, not well known, and it's an incredible thing that our government does that, and I think it deserves a nod.

Jack Feldman: I totally agree with you. I think that it's the kind of thing that many of us, including many scientists, think is too woo-woo and unsubstantiated, but we're learning more and more. You know, we used to laugh at neuroimmunology. There are all these things that we're learning that we used to dismiss, and I think there's real nuggets to be learned here. So recently, we had a major breakthrough. We found a protocol by which we can get awake mice to breathe slowly.

Jack Feldman: In other words, whatever their normal breath is, we could slow it down by a factor of 10, and they're fine doing that. We did that 30 minutes a day for four weeks, okay? Like a breath practice. And we had control animals where we did everything the same, except the manipulation we made did not slow down their breathing. We then put them through a standard fear conditioning, which we did with my colleague, Michael Fanselow, who's one of the real gurus of fear.

Jack Feldman: We measured a standard test that put mice in a condition where they're concerned they'll receive a shock, and their response is that they freeze. And the measure of how fearful they are is how long they freeze. The control mice had a freezing time, which was just the same as that of ordinary mice would have. The ones that went through our protocol froze much, much less.

Jack Feldman: The degree to which they showed less freezing was as much as if there was a major manipulation in the amygdala, which is a part of the brain that's important in fear processing.

Andrew Huberman: I'll just pause you for a moment there, because I think that you're talking about a rodent study, but I think the benefits of doing rodent studies are that you can get deep into the mechanism. And for people that might think, "Well, we've known that meditation has these benefits, why do you need to get mechanistic science?" I think that one thing that's important for people to remember is that, first of all, as many people as one might think are meditating out there or doing breathwork, a far, far, far greater number of people are not, right?

Andrew Huberman: I mean, the majority of people don't take any time to do dedicated breathwork or meditate. So whatever can incentivize people would be wonderful. But the other thing is that it's never really been clear to me just how much meditation is required for a real effect, meaning a practical effect. People say 30 minutes a day, 20 minutes a day, once a week, or twice a week, same thing with breathwork.

Andrew Huberman: Finding minimum or effective thresholds for changing neural circuitry is what I think is the holy grail of all these practices. And that's only going to be determined by the sorts of mechanistic studies that you described.

Jack Feldman: One of the issues, I think, for a lot of people is that there's a placebo effect. That is, in humans, they can respond to something, even though the mechanism has nothing to do with what the intervention is. And so, it's easy to say that the meditative response has a big component, which is a placebo effect.

Jack Feldman: My mice don't believe in the placebo effect, and so if we could show there's a bona fide effect in mice, it is convincing in ways that no matter how many human experiments you did, the control for the placebo effect is extremely difficult in humans. In mice, it's a non-issue. So I think that in and of itself would be an enormous message to send.

Andrew Huberman: Excellent, and indeed a better point. A 30-minute-a-day meditation in these mice, if I understand correctly, the meditation, we don't know what they're thinking about-

Jack Feldman: It was breath practice.

Andrew Huberman: Right, so it's breath practice.

Jack Feldman: Right.

Andrew Huberman: Presumably, they're not thinking about their third eye center, lotus position, levitation, whatever it is. They're not instructed as to what to do, and if they were, they probably wouldn't do it anyway. So, 30 minutes a day in which breathing is deliberately slowed or is slowed relative to their normal patterns of breathing. Got it. So the fear centers are altered in some way that creates a shorter fear response to a foot shock.

Jack Feldman: Right.

Andrew Huberman: What are some other examples that you are aware of from work in your laboratory or work in other laboratories, for that matter, about interactions between breathing and brain state or emotional state?

Jack Feldman: I want people to understand that when we're talking about breathing affecting emotional or cognitive state, it's not simply coming from pre-Bötzinger. There are several other sites. I need to sort of go through that. One is olfaction. So when you're breathing, normal breathing, you're inhaling and exhaling.

Jack Feldman: This is creating signals coming from the nasal mucosa that is going back into the olfactory bulb, that's respiratory modulated. And the olfactory bulb has a profound influence and projections through many parts of the brain. So there's a signal arising from this rhythmic moving of air in and out of the nose that's going into the brain that has contained in it a respiratory modulation.

Jack Feldman: Another potential source is the vagus nerve. The vagus nerve is a major nerve which is containing afferents from all of the viscera.

Andrew Huberman: Afferents just being signals, too.

Jack Feldman: A signal.

Andrew Huberman: Yeah.

Jack Feldman: Signals from the viscera. It also has signals coming from the brain stem down, which are called efferents, but it's getting major signals from the lung, from the gut, and this is going up into the brain stem. So it's there. There are very powerful receptors in the lung. They're responding to the expansion and relaxation of the lung.

Jack Feldman: And so, if you record from the vagus nerve, you'll see that there's a huge respiratory modulation due to the mechanical changes in the lung. Now, why that is of interest is that for some forms of refractory depression, electrical stimulation of the vagus nerve can provide tremendous relief.

Jack Feldman: Why this is the case still remains to be determined, but it's clear that signals in the vagus nerve, at least the artificial signals in the vagus nerve, can have a positive effect on reducing depression. So, it's not a leap to think that under normal circumstances, that that rhythm coming in from the vagus nerve is playing a role in normal processing. Okay, let me continue. Carbon dioxide and oxygen levels.

Jack Feldman: Now, under normal circumstances, your oxygen levels are fine, and unless you go to altitude, they don't really change very much. But your CO2 levels can change quite a bit with even a relatively small change in your overall breathing. That's going to change your pH level.

Jack Feldman: I have a colleague, Alicia Meuret, who is working with patients who are anxious, and many of them hyperventilate, and as a result of that hyperventilation, their carbon dioxide levels are low.

Jack Feldman: She has developed a therapeutic treatment where she trains these people to breathe slower to restore their CO2 levels back to normal, and she gets relief in their anxiety.

Jack Feldman: So CO2 levels, which are not going to affect brain function on a breath-by-breath level, although it does fluctuate breath by breath, but sort of as a continuous background, can change, and if it's changed chronically, we know that highly elevated levels of CO2 can produce panic attacks.

Jack Feldman: Your body is so sensitive, the control of breathing, like how much you breathe per minute, is determined in a very sensitive way by the CO2 level. So even a small change in your CO2 will have a significant effect on your ventilation. So this is another thing that not only changes your ventilation but affects your brain state.

Jack Feldman: Now, another thing, how breathing practice can affect your emotional state is simply the descending command. Because breathing practice involves volitional control of your breathing, and therefore, there's a signal that's originating somewhere in your motor cortex. Of course, that's going to go down to pre-Bötzinger, but it's also going to send off collaterals to other places.

Jack Feldman: Those collaterals could obviously influence your emotional state. So we have quite a few different potential sources, none of them that are exclusive.

Andrew Huberman: What are some of the other features of our brain and body, be it blinking or eye movements or ability to encode sounds, or any features of the way that we function, move, and perceive things that are coordinated with breathing in some interesting way?

Jack Feldman: Almost everything. So we have, for example, on the autonomic side, we have respiratory sinus arrhythmia. That is, during expiration, the heart slows down. Your pupils oscillate with the respiratory cycle, your fear response. Let's take something like depression.

Jack Feldman: You can envision depression as activity sort of going around in a circuit. And because it's continuous, in the nervous system, as signals keep repeating, they tend to get stronger, and they can get so strong you can't break them. And, I mean, all of us get depressed at some point, but if it's not continuous, it's not long-lasting, we're able to break it. Well, there are extreme measures to break it. We could do electroconvulsive shock.

Jack Feldman: We shock the whole brain. That's disrupting activity in the whole brain, and when the circuit starts to get back together again, it's been disruptive. And we know that the brain, when signals get disrupted a little bit, we can weaken the connections. And weakening the connections, if it's set in the circuit involved in depression, we may get some relief. And electroconvulsive shock does work for relieving many kinds of depression.

Jack Feldman: Focal deep-brain stimulation does the same thing, but more localized, or transcranial stimulation. You're disrupting a network, and while it's getting back together, it may weaken some of the connections.

Jack Feldman: If breathing is playing some role in this circuit, and now, instead of doing like a one-second shock, I do 30 minutes of disruption by doing slow breathing or other breathing practice, those circuits begin to break down a little bit, and I get some relief. And if I continue to do it before the circuit can then build back up again, I gradually can wear that circuit down.

Jack Feldman: I sort of liken this... I tell people it's like walking around on a dirt path. You build a rut. The rut gets so deep you can't get out of it, and what breathing is doing is sort of filling in the rut bit by bit, to the point that you can climb out of that rut. And that is because the breathing signal is playing some role in this way the circuit works, and then when you disrupt it, the circuit gets a little thrown off-kilter.

Jack Feldman: And as you know, when circuits get thrown off, the nervous system tries to adjust in some way or another. And it turns out, at least for breathing, for some evolutionary reason or just by happenstance, it seems to improve our emotional function and our cognitive function. And we're very fortunate that that's the case.

Andrew Huberman: What do you do with all this knowledge in terms of a breathing practice?

Jack Feldman: I find I get tremendous benefit by relatively short periods, between 5 and maybe 20 minutes, of doing box breathing. It's very simple to do. I'm now trying this Tummo because I'm just curious and exploring it, because it may be acting through a different way, and I want to see if I respond differently.

Jack Feldman: I have friends and colleagues who are into particular styles like Wim Hof, and I think what he's doing is great in getting people who are interested.

Jack Feldman: I think the notion is that I would like to see more people exploring this, and to some degree, as you point out, 30 minutes a day, some of the breath patterns that some of these stars, like Wim Hof, are a little intimidating to newbies. And so I would like to see something very simple. What I tell my friends is, "Look, just try it, 5 or 10 minutes. See if you feel better. Do it for a few days. If you don't like it, stop it. It doesn't cost anything."

Jack Feldman: And invariably, they find that it's helpful. I will often interrupt my day to take 5 or 10 minutes, like if I find that I'm lagging. I think there's some pretty good data that your performance after lunch declines. And so very often, what I'll do after lunch is take 5 or 10 minutes and just sort of breath practice.

Andrew Huberman: And lately, what does that breath practice look like?

Jack Feldman: It's just box breathing for 5 or 10 minutes.

Andrew Huberman: So five seconds inhale, five-second hold, five-second exhale, five-second hold.

Jack Feldman: Yeah. And sometimes I'll do doubles. I'll do 10 seconds just because I get bored. I feel like doing it. And it's very helpful.

Andrew Huberman: Now, you're one of the few colleagues I have who openly admits to exploring supplementation. I'm a longtime supplement fan. I think there's power in compounds, both prescription, non-prescription, natural, and synthesized. I don't use these haphazardly, but I think there's certainly power in them.

Andrew Huberman: And one of the places where you and I converge in terms of our interest in the nervous system and supplementation is vis-à-vis magnesium. Now, I've talked endlessly on the podcast and elsewhere about magnesium for the sake of sleep and improving transitions to sleep, and so forth. But you have a somewhat different interest in magnesium, as it relates to cognitive function and the durability of cognitive function.

Andrew Huberman: Would you mind just sharing with us a little bit about what that interest is, where it stems from? And because it's the Huberman Lab podcast, and we often talk about supplementation, what you do with that information?

Jack Feldman: Okay. So I need to disclose that I am a scientific advisor to a company called Neurocentria, which my graduate student, Guosong Liu, is CEO. So, that said, I can give you some background. Guosong, although when he was in my lab, worked on breathing, had a deep interest in learning and memory. And when he left my lab, he went to work for it with a renowned learning and memory guy at Stanford, Dick Tsien.

Jack Feldman: And when he finished there, he was hired by Susumu Tonegawa at MIT.

Andrew Huberman: Who also knows a thing or two about memory. I'm teasing. Susumu has a Nobel for his work on immunoglobulins, but then is a world-class memory researcher.

Jack Feldman: Yeah, and more.

Andrew Huberman: He's many things.

Jack Feldman: And Guosong, a very curious, very bright guy. And he was interested in how signals between neurons get strengthened, which is called long-term potentiation, or LTP.

Jack Feldman: And one of the questions that arose was, if I have inputs to a neuron and I get LTP, is the LTP bigger if the signal is bigger or the noise is less? So we can imagine that when we're listening to something, if it's louder, we can hear it better, or if there's less noise, we can hear it better. And he wanted to investigate this.

Jack Feldman: So he did this in tissue culture of hippocampal neurons, and what he found was that if he lowered the background activity in all of the neurons, that the LTP he elicited got stronger. And the way he did that was increasing the level of magnesium in the bathing solution.

Jack Feldman: So, he played around with the magnesium, and he found out that when the magnesium was elevated, there was more LTP. All right, that's an observation in a tissue culture.

Andrew Huberman: Right. And I should just mention that more LTP essentially translates to more neuroplasticity, more rewiring of connections, in essence.

Jack Feldman: Okay. So he tested this in mice, and basically, he offered them a... He had control mice, which got a normal diet, and one that was enriched with magnesium. And the ones that lived enriched with magnesium had higher cognitive function, lived longer, everything you'd want in some magic pill, those mice did that, excuse me, rats.

Jack Feldman: The problem was that you couldn't imagine taking this into humans because most magnesium salts don't passively get from the gut into the bloodstream, into the brain. They pass via what's called a transporter. A transporter is something in a membrane that grabs a magnesium molecule or atom and pulls it into the other side.

Jack Feldman: So if you imagine you have magnesium in your gut, you have transporters that pull the magnesium in the gut into the bloodstream. Well, if you had taken normal magnesium supplement that you can buy at the pharmacy, it doesn't cross the gut very easily. And if you would take enough of it to get it in your bloodstream, you start getting diarrhea. So it's not a good way to go.

Andrew Huberman: Well, it is a good way to go.

Jack Feldman: Oh.

Andrew Huberman: Sorry, couldn't help myself.

Jack Feldman: Well said. So he worked with this brilliant chemist, Fei Mao, and Fei looked at a whole range of magnesium compounds, and he found that magnesium threonate was much more effective in crossing the gut-blood barrier.

Jack Feldman: Now, they didn't realize at the time, but threonate is a metabolite of vitamin C, and there's a lot of threonate in your body. So magnesium threonate would appear to be safe, and maybe a part of the role, or now, they believe it's part of the role of the threonate, is that it supercharges the transporter to get the magnesium in. And remember, you need a transporter at the gut into the brain and into cells.

Jack Feldman: They did a study in humans. They hired a company to do a test. It was a hands-off test. It's one of these companies that gets hired by the big pharma to do their tests for them. And they got patients who were diagnosed as mild cognitive decline. These are people who had a cognitive disorder, which was age-inappropriate.

Jack Feldman: And the metric that they use for determining how far off they were is Spearman's g factor, which is a generalized measure of intelligence that most psychologists accept.

Jack Feldman: And the biological age of the subjects was, I think, 51, and the cognitive age was 61, based on Spearman's g test. Oh, I should say, the Spearman g factor starts at a particular level in the population at age 20 and declines about 1% a year. So, sorry to say, we're not 20-year-olds anymore.

Jack Feldman: But when you get a number from that, you can put it on the curve and see whether it's about your age or not. These people were about 10 years older, according to that metric. And long story short, after three months... This is a placebo-controlled, double-blind study. The people who were in the placebo arm improved two years, which is common for human studies because of the placebo effect.

Jack Feldman: The people who got the compound improved eight years on average, and some improved more than eight years. They didn't do any further diagnosis as to what caused the mild cognitive decline, but it was extraordinarily impressive.

Andrew Huberman: So it moved their cognition closer to their biological age.

Jack Feldman: Biological age.

Andrew Huberman: Do you recall what the dose is of magnesium threonate?

Jack Feldman: It's in the paper, and it's basically what they have in the compound, which is sold commercially.

Andrew Huberman: Mm-hmm.

Jack Feldman: So the compound, which is sold commercially, is handled by a nutraceutical wholesaler who sells it to the retailers, and they make whatever formulation they want. But it's a dosage which, to my understanding, is rarely tolerable. I take half a dose.

Jack Feldman: The reason I take half a dose is that I had my blood magnesium measured, and it was low-normal for my age. I took half a dose, and it became high-normal. And I feel comfortable staying in the normal range. But a lot of people are taking the full dose.

Jack Feldman: At my age, I'm not looking to get smarter. I'm looking to decline more slowly. And it's hard for me to tell you whether or not it's effective or not.

Jack Feldman: When I've recommended it to my friends, academics who are not by nature skeptical, if not cynical, and I insist that they try it, they usually don't report a major change in their cognitive function, although sometimes they do report, "Well, I feel a little bit more alert, and my physical movements are better," but many of them report they sleep better.

Andrew Huberman: Yeah, and that makes sense. I think there's good evidence that threonate can accelerate the transition into sleep and maybe even access to deeper modes of sleep. But that's very interesting, because until you and I had the discussion about threonate, I wasn't aware of the cognitive-enhancing effects.

Andrew Huberman: But the story makes sense from a mechanistic perspective, and it brings it around to a bigger and more important statement, which is that I so appreciate your attention to mechanism. I guess this stems from your early training as a physicist and the desire to get numbers and to really parse things at a fine level. We've covered a lot today. I know there's much more that we could cover.

Andrew Huberman: I'm going to insist on a part two at some point. But I really want to speak on behalf of a huge number of people and just thank you, not just for your time and energy and attention to detail and accuracy and clarity around this topic today, but also, what I should have said at the beginning, which is that you really are a pioneer in this field of studying respiration and the mechanisms underlying respiration with modern tools now for many decades.

Andrew Huberman: I really want to extend a sincere thanks. It means a lot to me, and I know to the audience of this podcast, that someone with your depth and rigor in this area is both a scientist and a practitioner, and that you would share this with us. So thank you.

Jack Feldman: I appreciate the opportunity, and I would be delighted to come back at any time.

Andrew Huberman: Wonderful. We will absolutely do it. Thanks again, Jack.

Jack Feldman: Bye now.