We use the terminology ketone metabolic therapy, and that's much better because there are many types of ketogenic diets, and for all intents and purposes, you wouldn't want to use the original clinical ketogenic diet anyway. We use highly modified versions, higher in protein, you know, it's got fiber and it's got a certain fatty acid profile, and it's essentially like an engineered, personalized, prescriptive metabolic therapy. It's far different than the original diets used for epilepsy.
All right, Dom. Good to see you, my friend.
Great to see you again, Scott.
So, actually Dom, you were one of our first guests at the formerly known as the Smarter Not Harder podcast. And now, as we are now the Health Optimization Medicine podcast, and I really want to bring you back because you are the premier researcher, the guy that knows more about the world of the ketogenic diet, ketogenic metabolic therapies more than anybody. And I think what was super interesting is that, you know, it became like this fad thing as you and I know, like three or four years ago everything was like keto everything, keto ice cream, keto pizza. And like we know how things will go with fads, they go up and they come back down. But it doesn't mean that the research is any less relevant because it's not as popular, right? And actually we've seen something similar with methylene blue recently at prescriptions where huge spike in 2025 and now it's come back down to earth on some level, but it still doesn't mean that there isn't a significant amount of potential with this particular compound. So, I'm really happy you've been out there on the airwaves, you know, doing your thing and talking. And today what I wanted to do is, like personally, I've been confused with all the types of ketogenic products that have been on the market. You know, there's the beta-hydroxybutyrate, there's acetoacetate, there's the 1,3-butanediol. So, I think maybe in the beginning before we get into, you know, the details and talk about some of the cool things that you're doing in research, maybe kind of define or just give us the lay of the land, Dom. Like, what's happening in the world of ketogenic supplementation? And then, you know, maybe if you want, what we can do as a starting point, we can define what ketone metabolic therapies are. And then from there, let's kind of talk about the lay of the land as it is now.
Yeah, I'm glad you brought up sort of, I guess you're referring to like the Google Analytics... kind of exploded maybe about 10 years ago or something. So, I pay far less attention to the Google Analytics, but my attention is typically paid to PubMed. So, if you look at PubMed, which is peer-reviewed literature on ketogenic diets and ketone supplementation, and if you look on clinicaltrials.gov, which is registered clinical trials doing research on ketogenic diets or ketone supplements, that growth has been exponential and has actually gone up significantly in the last 5 years, like exponentially. But, I think Google Trends have a mind of their own depending upon what influencer is talking about them. From my perspective as a research scientist, yeah, I'm more excited now than ever because the trajectory of ketone research is growing exponentially.
So, we use the term ketone metabolic therapy or ketogenic metabolic therapy to describe a ketogenic diet and different versions of that, but also exogenous ketone supplementation, which there are many forms of that in the form of exogenous electrolyte salts, ketone salts, ketone esters, diols, 1,3-butanediol as a precursor, MCT is considered a ketogenic supplement. And, you know, we've kind of, I'm going on paper, we have like 30 different compounds, right? That are very ketogenic that kind of will be bioactive in some way when they're orally consumed. So, that's a pretty big category that's emerging in sort of the innovative aspect of a ketone. And these things are not mutually exclusive. So, you have ketogenic diets, and then you have ketone supplementation, and things like intermittent fasting, which can produce ketosis. So, these things can be used situationally, you know, in combination or as a stand-alone kind of therapy, right?
Right. I mean, I think certainly there's very much a difference between being in the research world and seeing what's going on versus the popular world of fads. And that's what I can imagine why you have to avoid the word diet is because obviously fat and diet are very much combined in popular culture, right? And there's a significant difference as well when we're talking about, you know, the ketogenic diet versus ketone supplementation, right? And I think that, you know, what's happened a lot over the last several years is that, you know what, you don't have to follow the diet. All you need to be is on the supplements, right? But I think that's a little bit of a not exactly correct idea. So, how do you typically piece that out for people when you say, 'You know what, like, you should be on the ketogenic diet or maybe you should be on supplementation to help ketones.' It very much depends on the person, I would imagine. How do you think about that?
Yeah, it's a good topic of discussion because I think people that market ketone supplements talk about it as a replacement to diet. And that's not... So, there are definitely overlapping physiological and metabolic similarities with ketones, but a clinical ketogenic diet would involve a level of carbohydrate restriction that significantly shifts your metabolism to fatty acid oxidation and ketone metabolism.
So, that's a big... And when you, if you are on a high-carb diet and you take exogenous ketones, you are shifting metabolism more towards ketone metabolism, but not necessarily fatty acid metabolism. So, although ideally, I mean, my approach, what I do is like a low-carb, if you want to call it, I don't like the term Mediterranean-ish diet, but sort of a higher protein ketogenic diet that has a mix of, you know, vegetables and fruits and things like that. But it's restricted enough in digestible carbohydrates that I maintain like a low level of nutritional ketosis bouncing around 0.5 to 1 mmol later in the day. And then, I, you know, supplement periodically, situationally, when it's beneficial. And also, you know, on some days I won't have the first meal until like noon or two. And if I have a heavy workload in the morning, I tend to be a little bit more lucid and quick with my thinking and everything. So, that's an important sort of consideration. The problem with a ketogenic diet will always be, for many people, the high fat.
It is hard, especially for people who have a high metabolism, to consume that amount of fat. And consuming that amount of fat every day, all day, every day, can produce some abnormalities in blood work that are maybe not perceived as optimal. Although, my metabolism was pretty quick to shift over to fat and ketones. I did have a remarkably elevated LDL cholesterol and apoB. And I think the jury's still out on that, whether that sustained super hyper elevation... I err on the side of caution. And I'm not willing to take a statin, but my genetics are such that I am a hyper absorber. And I do have a mutation in the NPC1L1 transporter in the gut, you know, so a tiny dose of ezetimibe, actually just split it in half, would drop my apoB and LDL in half. And that was like, I thought it was very unique to me, but I talked to other people that have that. Although, my mutation is particularly unique. But, it also lowered my triglycerides a bit. And I don't really have any side effects associated with taking that drug. It works very specifically, very mechanistically. And what I would be concerned about is taking a statin, especially a lipophilic statin that crosses the blood-brain barrier, and decreases cholesterol synthesis in the muscles and in the brain, especially. Because the brain, I mean, cholesterol is amazing, and it does... And then from a neuroscientist perspective, and also if you're exercising, the tissue remodeling associated with skeletal muscle protein synthesis following resistive training has a high requirement for cholesterol. So, you do not want to be globally, you know, inhibiting the synthesis of cholesterol. So, that's like an important... These are things like really not discussed by statin enthusiasts.
Yeah, this is an important point, and maybe we can harp on it for a minute because I mean I was just talking to another patient of mine yesterday, and they're trying to get his LDL below 55. Like, that's the newest of these recommendations. And you know, it sounds like, I mean I worry about this too from a lot of different reasons. I mean, certainly the lipophilic ones are getting to the brain, but you know, what you see in some of the studies too, like, and which is interesting, that statins sometimes can have pleiotropic effects as an anti-inflammatory and be used in anti-cancer protocols as well. So, I guess where I kind of come to here is that it's not a one-size-fits-all. It really depends on the situation, but I do worry about, you know, driving people's LDLs down to 50 and using really high-dose statins to do it for the reason you just mentioned along with its effect on the mitochondria as well.
Yeah, and the dose is important. You know, the side effects come, you know, when you're pushing, you know, 20, 40, 60 mg of the stuff, but you know, my parents are on, you know, baby doses statins. And in certain contexts, I think it's totally okay because you do have the pleiotropic effects, so if you're not getting the benefits from the LDL lowering, there are other benefits you are deriving from it. And I do think the negative effects are highly dose dependent. I remember my mom took a pretty big dose, and it really made her sick, very much sick. And I think she had to change to another one, but taking a tiny fraction of the original dose. And when I was in... these drugs came out and they gained popularity in the mid-90s and I was doing landscaping and work outside on the farm and worked with a guy that was pretty active and he started using it and it crippled him. Like, he had crippling pain and things like that. And I remember it because I think the original, you know, statins were prescribed at a pretty high dose and I think now we know that that's not a good thing to do.
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Yeah, speaking of, I mean we're on that topic. Have you seen the recent study on Metformin and VO2 max? That was kind of crazy, too. Yeah, the quick and dirty of it is that, you know, Metformin is an anti-diabetic drug that's been around forever, right? But it's also a complex one inhibitor in the mitochondria. So, it actually causes more oxidative load and the goal of this drug, at least on some levels, is to force you to make more mitochondria to keep up, you know, as a result. It also has a, you know, a decreasing blood sugar, but they found that if you were using it with exercise, your VO2 max increases were 50% less than those that were not using Metformin. So, a big deal, right? And I think we always have to remember that there's always going to be like a risk versus benefit and there's always a network effect on this. And even with statins, like we see people's hormones drop to the tank, right? We see their testosterone level go down. We see, you know, some of their other adrenal hormones go down. If you're not compensating for these things, you know, and that's what the main aspect of the study was, like if you're taking Metformin and you're metabolically relatively healthy, you should not be taking Metformin.
Yeah, we studied it in the context of cancer cells. So, my former PhD student Nathan Ward, he has a lab now at the Moffitt Cancer Center, but... we published over 10 years ago and showed that superoxide production was elevated in response to that. So, it functions as a weak mitochondrial toxin. And when you're taking Metformin, your liver is kind of de-energized in a way that doesn't, you know, do the Cori cycle too well. So, if you're making lactate, that lactic acid goes back from muscles to the liver, it's also because you're kind of de-energizing the liver in a way, you're decreasing gluconeogenesis. So, that has the glucose-lowering effect, but it impairs, you know, various aspects of liver function through, you know, increased reactive oxygen species, you know, complex one. And we measured it with dihydroethidium. It was very clear that you can kind of see that with Metformin. And I experienced when I was experimenting with Metformin, I stopped a long time ago, but really intense exercise made me dizzy and kind of like really tanked me.
I saw that with some of my patients as well, you know, when they were using it. I had a couple patients that were on it off-label in the beginning and then I saw how terrible they felt after exercise. I'm like, there's something going on here. So, that signal's been around for a while. I mean, maybe as a quick primer on how the ketones work in the mitochondria would be helpful here because there's obviously multiple different types. Like we talk about oxidative phosphorylation, we talk about the complexes, like the people that are listening on this podcast, we talk about these things, you know, very deep, you know, sort of into the electron transport chain a lot. Like if you're thinking about ketones itself, why are they potentially more efficient than glucose, for example, when we are trying to make energy in the mitochondria?
Yeah, so ketones can be an energetic substrate, you know, in the brain and the mitochondria, and when ketones are metabolized to generate ATP, our energy currency, right? They have a unique capability, and this was first shown by, I think, Dr. Richard Veech who published in the heart, and we are assuming this also happens in the brain, and there's like cell-based studies, but he had a very unique model. He had a working heart preparation where he could actually measure the hydraulic efficiency of the heart, like the... In the context of like glucose and insulin, and then without insulin they would give ketones, and essentially showed that the hydraulic efficiency of the heart was remarkably enhanced when it metabolized ketones relative to glucose. And that hydraulic efficiency, Sato was the first author, it was like 1995 they showed this, was primarily due to oxidizing Q. So, you had less leak of the electrons at the level of, you know, complex one and two, the semiquinone site. So, but yeah, by oxidizing Q you have basically tighter electron flow, and so tighter electron flow, yeah, you get the generation of more reduced intermediates to drive the electron transport chain through the TCA cycle and the reduction in superoxide, which is a precursor to more reactive intermediates, so that goes to hydrogen peroxide and then can go to like hydroxyl radical, and then that's very, very damaging to membrane lipids and proteins and nucleic acids. But superoxide in of itself is not super reactive, but it gets broken down to other things. What ketones do, it reduces superoxide production overall, and we see that... I spent my whole post-doctoral fellowship developing ways to measure ROS production using dihydroethidium and many different ROS dyes. That was like, I spent years doing that. So, that was very apparent in cell-based systems and also like brain slices and tissue slices and things like that. So, you're making less superoxide, but it's also enhancing production of endogenous antioxidant mechanisms from, you know, superoxide dismutase, the catalase, to glutathione, things like that. NRF2, like these things are all, and it's doing that through a number of different mechanisms, some of them even epigenetic, we know now through beta-hydroxybutyrylation. So, there's multiple mechanisms through which ketones can be energetically favorable, but also reduce ROS production and endogenous ROS production and also enhance endogenous antioxidant capacity of the cells. And it can vary between tissues, too. So, a lot of what I'm talking about from my experience is the brain, but it happens presumably like in the muscle and other areas. I've not studied muscle, but mostly what we study is the brain. And it does happen in brain cells for sure. And then other investigators have looked at the heart.
Right. And this is direct correlation to some of the research that you were initially doing with the Office of Naval Research and looking at preventing Navy SEALs from having seizures at pressure, right?
Yeah. Yeah, because as you know, like the limitation of hyperbaric oxygen therapy or diving, especially with a closed-circuit rebreather, is central nervous system oxygen toxicity. If you stay down too long, even if you don't get CNS ox tox, if that duration is very long, you start to get pulmonary oxygen toxicity. So, that'll happen even without pressure. I mean, you're in a room with 100% oxygen within like a day or two, you'll get, you know, you'll die of pulmonary oxygen toxicity.
Yes. Yeah. Continuous people on ventilators, we see this all the time, right? So, yeah.
So, these are considerations. Ketones tend to help both situations, but they do, by providing the brain an alternative form of energy from a bioenergetic perspective and also an antioxidant perspective, it's working through that. And also, it's activating systems like glutamic acid decarboxylase, and that converts from glutamate to GABA. So there's a benefit there, and we've shown that in various animal models of the diseases, but the wild type animals, which, you know, animals that don't even have diseases, also you get more glutamate to GABA. So I think that, and then we've studied adenosine and the NLRP3 inflammasome, and there's multiple mechanisms. I thought it would be sort of easy and we'd identify like a single mechanism that was the driver. But it does not, it seems to be very context dependent and in some cases tissue dependent and like situationally sort of different too. But that's metabolism, right? So meta... different hubs throughout the network, and you can kind of hit the network in different ways, and I think of the physiological system as like, you know, our bodies are basically networks and hubs that are more relevant and context dependent than other hubs.
And this is what we talk about all the time, right? At Health Optimization where everything is all networked together. If you move one node in the system, things are going to compensate. There's feedback loops everywhere. This is like the classic is go get TRT. Everything else is going to go down. All your other hormones if the testosterone's going elevated, right? And so your thyroid's going to go crazy. And so it's such an important thing to know and like, you know, you've always seen those diagrams like of the spaghetti looking stuff on the wall that's all the diagrams of everything that's happening for energy metabolism. When you're thinking about exogenous ketones specifically and how to utilize these most effectively, you know, what are like the best use cases here? Like what's the dosing expectations we might have for like certain types of various types of performance like, you know, cardiometabolic. You talked about the heart for example. Stress resilience, mood, like are there particular types of ketones that are better than other ketones for particular situations or how do you think about this, Dom?
Our research program sort of got spearheaded by looking at ketone esters because they were like sort of the most potent ketogenic agents. So, I just went right to the top, you know? So, the first one was a beta-hydroxybutyrate monoester, and that did not have anti-seizure effects. Although the NIH and Oxford had studied it for exercise performance and seemed to be a signal there, although that's kind of debatable. I think there's a performance enhancement under certain environmental conditions and under stressor conditions like if you're really sleep-deprived, hypoxic, or hyperoxic.
Specifically with the esters, you mean?
Yeah, with the esters. I think they do have certain use applications, especially for military and extreme environments. Absolutely. Although the beta-hydroxybutyrate monoester did not prevent seizures, so we sort of developed with the late Patrick Arnold, we developed a 1,3-butanediol diester with acetoacetate, and it, you know, it generates in the blood a beta-hydroxybutyrate and acetoacetate, which was really important for preventing seizures. And some of the reasons for that is that it maintains a redox balance. If you get a big dose of BHB, that can cause reductive stress. Kind of. But the ratio of acetoacetate to beta-hydroxybutyrate would kind of mimic that which was found in the diet. So, that was like something that was interesting. And then the acetoacetate spontaneously decarboxylates to acetone. And acetone sort of had interesting effects on the receptors and has like sub-narcotic levels of acetone seems to dampen hyperexcitability. Like, you know, there's a lot more to unpack there, but, you know, it's just different ketogenic agents.
You know, different. But what we didn't know at the time, but we did a study with rats where we fed them 1,3-butanediol and the esters that were derived from 1,3-butanediol, and if we give them high doses chronically, we saw some liver abnormalities and see some abnormalities maybe in the blood work too a little bit. In histology, you start to see sinusoidal dilation and you start to see like fat droplets and you start to see pre-necrotic effects like in the liver that were concerning to me. And also with the human randomized controlled studies that just came out in the last few years, the maximum dose of 1,3-butanediol is 34 g I think, and when subjects consume that, 40% of them got dizzy. And these were healthy robust subjects. Imagine giving that dose, which is not really that high, to subjects that are like, you know, older or that have cognitive... So, 1,3-butanediol is an alcohol. It's a diol alcohol technically. It has to go through alcohol dehydrogenase and aldehyde dehydrogenase and it kicks off a BHB aldehyde. It's short-lived, but if you take a lot of it, then it can stick around and aldehydes are not good to have.
Yeah. Those rat studies that you're talking about when you had the elevated liver enzymes in them, was it a dose that would be relevant to humans at all or was it something, I mean you talked about how long they were taking it as well. Maybe those would be helpful because I know there's a lot of controversy here, so.
The dose with the 1,3-butanediol specifically would be a dose that would keep a human at 2 millimolar ketones throughout the duration of the day. So, for me, like someone like me, that's like 100 ml per day. But that's what I need to be in like therapeutic ketosis just to keep that 1 to 2 to 3. And that's 1,3-butanediol. And now the beta-hydroxybutyrate monoester is technically 1,3-butanediol esterified to BHB. It's 51% molar concentration, 51% chemically 1,3-butanediol. So, when you take that, you are delivering 1,3-butanediol, too. And I think the take-home message is that these molecules have been around since the 50s and 60s. Like 1,3-butanediol, you know? And now there are definitely new molecules that are equally or more potent that have no toxicity. So, you know, we've inadvertently killed quite a few animals with these agents just trying to figure out how to dose them when we first got them. And that would create a lot of confusion and sort of, you know, pain on our end to do that, to really titrate the dosages down. But when we're working with like the glycerol triester of acetylated glycerol triester or various ketone salts, the racemic salts seem to be, you know, very, especially when you combine them with MCT. And then we have a whole catalog of different agents. We never get any toxicity in ketogenic agents that are not 1,3-butanediol or 1,3-butanediol associated molecules. They have their place and I think, you know, they were a big part of our original research, but now we like to pivot away towards molecules that don't have any long-term toxicity or, you know, with chronic use. Also, 1,3-butanediol because it is an alcohol, it can create dependency and also withdrawal symptoms when you're taking it and you get off of it. So, solid evidence, you know, with that, too.
Is the dosing super high for that, too, as far as how much you're taking or you're not really sure at this point?
Same dose as ethanol. So, actually a little bit lower. You get the withdrawal and the chronic. But it would be equivalent to like three shots per day. Three 30 ml shots a day someone my size, you know, 100 kg.
And now 30 ml shots of 1,3-butanediol you're talking about, right? Is it common, I just don't understand, I maybe I just don't know. Is it common for people to be using that much on a regular basis, do you think, at this point or is it not that common overall when people are using these?
You know, the shots, I think they're... Well, the shots that I was taking, I don't know, I'd have to figure out the dosages, like 10 to 30 ml. I think, you know, one product is 30 ml, I think maybe in one shot or whatever. The point is like the amount that's needed to produce a level of ketones that's therapeutic is the amount that actually causes liver stress, but also over time, and we're talking like months, used every day chronically. That's the issue there. Yeah, with that said, I think some of these molecules work really well in formulations, right? So we saw that toxicity, animals died, they become ketoacidosis. So what we did, and actually Chilla, my wife, published a paper where we just simply took the ester and mixed it at 50% MCT with the ester, and that worked. Everything that I'm talking about here is in context of the acute administration. You're still getting that toxicity associated with it, and that concerns me. So if you are going to use like 1,3-butanediol or the ketone esters, think about formulations, and we've done some nice work with ketone salt and ketone ester formulations for seizures. And then also when you deliver an exogenous ketone, whether it's an ester or salt with MCT, which is a ketogenic fat, that significantly delays gastric absorption. The MCT generates endogenously, like your own ketones, and then MCT can cross the blood-brain barrier and be used as fuel. So these MCTs, you're also slowing the digestion and you're also slowing the metabolism of 1,3-butanediol in a way that doesn't produce as much of that BHB aldehyde and stress the liver. So I think it's sort of a formulation issue.
However, you know, there's things that are available, things in the pipeline. Like if for everyday use, you want to use a BHB electrolyte. So I think that would be... However, for use applications, you might want to use the esters, and you can formulate it in the ways to make it more so.
So you have then of BHB, right?
Right. Right. Right. Yeah.
Market share has really focused on D-beta-hydroxybutyrate because our body makes mostly that. Although, if you're on a ketogenic diet and you were to take out somebody's heart, 30% of that is L-BHB, believe it or not. So, there's a metabolic pathway that's producing the L. And L-BHB delivered as a supplement produces a cardiac output that's five times higher than the D. So, this was published in the Journal of the American Heart Association and also in the American Heart Association journal called Circulation. And we don't know why, but it decreased peripheral vascular resistance. And there's some speculation that it could be nitric oxide.
The endothelium gets relaxed with BHB, with the L-BHB, just because when you consume the L-BHB it's resistant to ketolysis, so it stays circulating more, so it's hitting all the different...
Ketone signaling, and that could be the GPR109A receptor, could be adenosine. Like our adenosine signal is really high in our metabolomics. We have not published that yet. So, adenosine is sort of, you know, ATP, adenosine triphosphate. If adenosine is simply part of normal metabolic processes...
...and it builds up during the day. And the most important thing to remember is in regard to adenosine is that it is a very potent vasodilator.
You give adenosine, you could like if you give someone a shot of adenosine, I think they just die. Like they're just like...
Well, it depends on the shot. We actually we use it we use it therapeutically for somebody in supraventricular tachycardia because it...
Yeah. Because it it blocks. Yes. Yeah.
My point is that it's very potent and it's a potent vasodilator. And when you're in ketosis, when you deliver an exogenous ketone, the adenosine levels go up quite high and that could maybe give a little bit of the sedating effect, especially with the esters that are a little bit higher. Some people get a little bit sleepy.
Maybe the dizziness as well that you mentioned too. Maybe, I don't know.
But it also has neuroprotective effects, and adenosine, there's a book this thick written by Dr. Susan Amet on adenosine, and she's a friend and colleague of mine, and it's just the adenosine receptors and metabolism is a very interesting area. But I think importantly, like if your ketones are elevated by virtue of fasting, diet, or supplementation, adenosine and adenosine signaling is going to be higher. That's going to cause vasodilation and that could increase brain blood flow and blood flow to peripheral tissues. So I think there's a strong rationale for ketone supplementation for recovery. So enhancing that blood flow to peripheral tissues, to your brain, and just overall enhance that, and we've seen that in our wound healing model. I mean there's plenty of publications out there. Like 20 or 30% increase in brain blood flow with acute administration of ketogenic agents. So that's something not quite talked about, but you have, you know, American Heart Association journals have published. And when you... it seems to be... you could give D-BHB and L-BHB, but D-BHB gets burned up as energy quickly, and that's a good thing, and the L-BHB stays in circulation longer and may convey or endow like the system with more of this vasodilation effect, this reduction in peripheral vascular resistance. And I think that's really important to me. We have not done the elegant studies to show that. We just showed the effect like with a Doppler blood flow measurement, but we have not mechanistically dissected that, and I don't think anyone has. But I'm aware of a few publications that should be out soon.
This actually brings up an interesting point of the dovetailing of you and I many years ago, which is hyperbaric oxygen therapy, right? Because when you and I talked about traumatic brain injury and hyperbaric oxygen therapy, you started talking about this vasodilatory effect, which potentially could be very helpful in the post-concussion optimization of, you know, getting them better, right? And I know you've been very involved in hyperbaric medicine for many years in your lab. And how do you think about the combination of hyperbaric therapy and ketones in general in various ways?
Yeah, I do think there's a synergy there with hyperbaric oxygen and ketone therapy. I mean, that was what got us funded, is that ketosis prevents oxygen toxicity seizures. But I was studying the negative effects of hyperbaric oxygen really...
Right? [laughter] Yeah. And but by doing those studies, basically, you realize, 'Oh, okay. So, hyperbaric oxygen is very therapeutic for like, you know, 14 different FDA-approved applications.' Then there's these emerging applications that are actually more interesting. That is just ongoing research on that, like traumatic brain injury, PTSD, recovery, and things like that. And then with ketones, the ketones are sort of mitigating that potential oxidative stress issue that you get with like too much hyperbaric oxygen, right? And it's also, you know, our brains' capacity to function is limited by two things: oxygen and substrate for energy, glucose or ketones. So, with hyperbaric oxygen, by reoxygenating the brain and also giving ketones at the same time, that's a stimulant that happens, you know, in the context of when you're in a hyperbaric chamber, but then you get that pulse of oxygen and also reactive oxygen species to some extent. But just the cycling of oxygen can actually have long-term effects, too, and activate genes and other adaptive mechanisms that we call. But I think that the benefits that you can derive from hyperbaric oxygen therapy can be augmented if you're giving an alternative fuel that can further enhance cell metabolism and energy before, during, and after. And I think in all contexts, but I think from our perspective and from a military operational perspective, it makes high concentrations of oxygen more tolerable and also safer, and it makes the war fighter more resilient. And that can be achieved, you know, with fasting. Well, that's what they fasted rats, and that, you know, caught my attention, and it was like, oh, there was a number of... and then, you know, then the diet had a great track record for seizures, and the Office of Naval Research didn't want to really fund ketogenic diet studies, so they said, well, try to investigate, you know, the diet in a pill. So, I was like reluctantly, I was like, okay, I'll try it. That seems like a big tall order, but through testing a number of different compounds, we, you know, settled on the ones that work, and I think we're kind of just scratching the surface, and it's a very nascent field, even though we've been at it for, you know, like 20 years. I think there's just many different molecules. We don't know the dosage, timing, and scheduling, and then there's very different use applications. We just know that ketone, it's almost like creatine. When creatine came out, the data was pretty compelling, and in 1995 in my exercise science, we had to write, you know, about three ergogenic aids, and I wrote about creatine, and it failed because there was like... the professor was like, 'I've never even heard of this.' You know, there's no...
Yeah, you're 30 years too early there, Dom.
Muscle and Fitness and a couple, it was like Muscle Mag, and they were talking about it, and I was a little bit overenthusiastic, but now we have like a thousand randomized controlled trials, right? On creatine.
I see ketones as sort of, there's a parallel there. I think ketones will explode and be the next creatine. It's already gaining traction, but I do think we need to have a high bar on the rigor of the science. So, there's a lot of research being done that's driven by industry, and I don't think the dosage, timing, and scheduling... and I think that could involve a whole research project that we're working on is actually like pulling the data to figure out, you know, were the right tests done, were the dosing regimens right? And I think there's a lot that we need to get right for the foundation of understanding this before we start applying this to like big federally funded research projects, and I think that's going to save a lot of time, effort, and taxpayer dollars.
Do that, and yeah, and I'm really excited to lead, you know, kind of leading a group to do that.
In the initial stages of planning it, but that's a big project that I'm working on.
I look forward to the controversy that you will bring, bringing that such... because...
A little controversial, yeah.
Yeah, I mean, and that's okay, like, because you're coming from the research side, from the rigor of looking at all the data, and that's really what matters the most. I think, you know, for me, as you know, Dom, always it's the clinical application, right? And then that's what, you know, what you've been working on so hard is like you have been doing animal studies on, you know, with ketogenic diets for long times, and now it's about, and it has been for a while, like how does this actually work in humans? Like what are we seeing in humans? And there's only so much you can know from an animal model. And I remember just going back a little bit, you were talking about the adenosine system and blood vascular dilation, and we're talking about wound healing, and like we'd love to do a study where we did a combination of hyperbaric oxygen with, you know, exogenous ketones for healing diabetic foot ulcers, but it's very difficult to get this stuff approved and done because again, there's a lot of money that's involved. But looking at this mechanistically and the things that you've been doing has just been transformative, you know, for my practice, right? Because as somebody that's involved in hyperbaric medicine, I use ketones when somebody has a concussion. I use ketones when somebody comes with an acute injury. I also use other things, too, but it's for all the reasons you just mentioned along with the actual other part of it where, you know, there's something about recovery here that I wanted to kind of go into, right? Where like you mentioned recovery a little bit with ketones, and there was a study that you were a part of not too long ago talking about exercise and ketones specifically. Maybe we can go into that because there was a lot of thought, at least in like the fad time of ketones, that everybody needed to be taking ketones to perform better from an exercise perspective. You mentioned the esters maybe under certain duress overall. You could, you know, you can talk about that again if you want. But maybe talk about that study a little bit and what you guys found. Maybe that was underwhelming and maybe more compelling than people realize.
Yeah, well we've done numerous studies and I can give like the punchline and the take-home messages from different ones. And I think, you know, ketone salts and ketone esters and probably MCT too, but we haven't studied that. But exogenous ketones elevating, you know, blood levels to 1 millimolar, actually getting a little bit higher, creates like a little bit of an acidic load, I think, and the body has to, you know, there's renal and respiratory compensations and so...
I don't... higher's not better. I've been higher before and gotten to situations where I could just tell you higher's not better. If you're achieving a 1 millimolar, that's a significant amount of energy like for your cells and your brain to use. And so like 1 to 2 is pretty significant. And then also the level that you're measuring is not taking into account ketone utilization. So athletes, they're dumping a lot of ketones into their tissues.
That 1 millimolar is almost like spilling over and surplus reserve, right?
Your tissues are quickly sucking it up. So the level in your blood is, you know, ketone production, ketone utilization, or ketone consumption if it's exogenous. And that gets taken up far faster in someone who's like an athlete, even at rest, right? So...
