Exogenous Ketones-Claims vs Reality with Brendan Egan, PhD. #194

Trail and Ultra Runners. What is going on? What's happening? Welcome to another episode of the Coupecast. As always, I am your humble host, Coach Jason Koop, and this episode of the podcast is about ketones and their potential for use as an ergogenic aid as well as an adaptive aid in an endurance context. I do not need to tell you that exogenous ketones are all over the endurance space at the moment.

The research lead for HVMN, which is a producer of ketones, lapmancer, was recently on the single track podcast, as well as a few elite ultra runners like Dylan Bowman and Jeff Browning have recently become endorsers of the product. They also sponsor a number of different podcasts in the space, but not mine, because I don't take any sponsorships, and one of the confusing aspects of this relatively new supplement in the arena are the myriad of claims surrounding the purported benefits. You just need to take a quick search on any of the websites from any of these manufacturers and they will lay claim to their products improving anything from metabolic health to cognition, as well as athletic performance, and many of these claims are repeated, regurgitated and amplified by the vast ambassador network that the companies have started to build up. So, with that as a backdrop, on this particular podcast, we are going to take a little bit of a different approach to the format. What we're going to do is we are going to review many of the claims, some of which are going to be taken directly from websites, podcast interviews and social media accounts, and we're going to put these claims through the scrutiny of a scientific lens.

So to lead this charge, I have enlisted the help of Brendan Egan from Dublin City University. Brendan is the head of school for the School of Health and Human Performance. His current research investigates skeletal muscle function and adaptation, with a special interest in the synergy between nutrition and exercise interventions. His research group performs human trials involving both acute and chronic interventions for outcomes around both physical and cognitive performance, recovery and adaptations. They line up perfectly with all of the claims that many of the ketone manufacturers are actually making. I will point the listeners to his great 2022 review paper on ketone use in sport, which is free and open access. A link to that will be in the show notes. Y'all go and check it out. But what makes Brendan really special that I did not know until recording this particular podcast is his ability to weave the practical and mechanistic aspects of many pieces of research together and communicate what they actually mean to the end user.

As we go through this, I want the listeners to remember that we are attempting to put claims and statements into their proper context. So, when applicable, I'll actually read the claim or statement directly and provide a link to it in the show notes. Sometimes those claims need to be generalized and I will point out when they actually are. As I also mentioned previously, many of these claims have been repeated and amplified by the athlete ambassador network, and none of this dialogue is personal. It is just professional. What I want the listeners to come away with is both the discernment of marketing and reality with these products, as well as some realistic use cases based on the current evidence. And finally, stay tuned for the outro of this podcast, well, where I will provide some color commentary on the landscape as a whole. You certainly will not want to miss that.

Okay, with that out of the way, I am getting right out of the way. Here's my conversation with Brendan Egan. Thanks for joining the podcast. To start out with. I appreciate you taking time out of your busy day. You look like you're in your office right now. I want to start out with.

I did do a little bit of background on you as I do with all of my guests and I know sometimes that can be revealing for the guests themselves, because sometimes you don't know how your work gets proliferated out in the space. And even before you jumped on the video call today and I saw you for the first time, the first thing I thought was this person has produced a lot in a short period of time. You're seemingly very young. You and I are probably right around the same age. You're probably a little bit younger than me. Your name came up constantly with a lot of metabolism studies across a wide range of both scenarios athletes, firefighters, athletes of all different types and things and also across different scenarios within what you were actually studying. And I kind of just want to know how did you get into the space and what's kind of allowing you to have such a prolific Pub Med Search right off the gate?

Yeah, Okay, so funny enough, I don't think I'm that prolific, but it's interesting to hear you say that. But not certainly in the last number of years my research group's output has definitely increased. So, yeah, in terms of age, yeah, I'm 40 actually, so but I've been my a group leader, let's say, having my own research group, since 2011 to over 12 years.

I was relatively young when I finished my PhD and did my postdoc and was lucky to get into a faculty position fairly young. So it takes a little bit of time to ramp up, you know, at the start, because in Ireland at least, much of the work is lecturing and teaching and your research is kind of it's important for career development, but you're paid to teach, basically, and so it takes a little bit of time to get all that in order and then begin to sort of ramp up the research side of things.

But I've just been fortunate to have good collaborations, particularly coming out of my postdoc, with Julian Zeerath at the Carolin Institute, and that's where a lot of the molecular work that I would have done came from. And then more recently, you know it's funny, a lot of researchers go down the route that they just focus on one thing and they become kind of known for one thing and I actually have to say I never really that, never really appealed to me and I was much more interested in when talented students or postdocs come along and they've got an interesting question that's related to my area of expertise and we just go out and work on something interesting, if we can get funding, of course. So in some respects you sort of you're complimenting my range within my CV. Other people would say what's this guy working on? Now it seems to be all over the map.

It just depends on your perspective. But, look, what we try to do is work on interesting practical questions and apply the best we can from a scientific design point of view in terms of rigor, and what you'll notice in several of my studies is that when we go to test, you know concepts that are floating around as we promising, or supplements that are thought to be beneficial. Oftentimes we find there are no benefits or no signal out of the noise there, and you know that I would say that that's just due to the fact that we approach these projects with an open mind, like is there a difference here or not? Putting the best methods we can and whatever the data turns out to be? You know that's what it is.

And that's one of the things that also has kind of come out of your work, as far as what I can track from it chronologically is. Something comes up in the marketplace, it starts to enter the popular vernacular and, you know, in people's headspace, as they see, athletes take it on and even a lot of the Olympic sport teams are early adopters with interventions and supplements and things like that. You guys take it, you look at it and you try to like, like, like, pop the hood open and figure out what's going on underneath, either from a mechanistic level and or from a performance level or even a molecular level. And I've always appreciated that back and forth, because from a sports science perspective we want to be on the leading edge, right. We want to kind of be on that very, that very. You know instant that something comes out that might have some degree of efficacy. You want first mover position in that, because six months down the line everybody's going to be using it and you know you've then kind of like lost that, lost that advantage.

So I've appreciated that follow up that you guys have done in your, in your research, and which kind of brings us to the topic today, right, which is ketones is something that's popped up across the, you know, the popular space and a lot of different areas, a lot of different contexts. I was I follow a few of the mixed martial arts nutritionists and it's been a supplement that they've used in a variety of different contexts, from performance, to their weight cuts, to appetite suppression and things like that. Your lab has picked up on this. Was there any sort of genesis with that where you guys were kind of like looking at this and said, okay, we're going to design a number of studies and look at the effect of ketones in an athletic context?

Yeah, and it's exactly the way you describe it. We had been hearing for a couple of years around this idea of these ketones being used across the pond in the UK and you know, as it turned out, when the press reports came out and they were probably only a few years ago that they began to talk about the fact that British cycling may have been using ketones as early as 2012. And, like you know, it's newspaper reports, probably in the Daily Mail. We're not really sure if it's true or not, but certainly when we began this work, it was 2016. And the at the time that we began the work, the, a talented student had come to me Mark Evans was his name and he had the benefit of being able to receive funding for a PhD where the topic wasn't defined, and that's kind of unusual. Now, it is Usually you obtain funding based on a proposed project, whereas he had received a student ship within University College Dublin, where we're based at the time, to just do his PhD with me no defined topic, which is the best thing in the world. It comes to work on an interesting question. So we had had both of us new people who had been working in in the UK, particularly in elite sports who had talked about the fact that you know, basically we knew ketone esters were being used and that was that.

Like I said, that was 2015, 16, when we began that work, and you know you bring up the point about.

You know, we've tried to be at the cutting edge and do things that people are talking about, but we were already a couple of years behind at that point.

Based on what we now know and that does tend to be the case, to be honest is that, with the best will in the world, researchers who are trying to work at the cutting edge are actually a year or two behind what pro teams and pro athletes are doing. So we're doing our best, but you know, there's always a bit of a lag time there and in fact, just again, purely because of the way research and PhDs tend to go, america had to write a really long literature review prior to getting any experimental work done and again that you know that delayed us by even more, although, of course, the review was an excellent piece of work that he put together and yeah, so it just landed literally the combination, the good fortune of a PhD student ship that didn't have a defined topic, a student who was interested in kind of pushing out the boat and us hearing on the ground that these keystone asters were being used and just putting it all together and developing a body work around that.

And body work is a great way to describe it, because since then, you have published several studies as well as reviews on the entire not only your research, but the research across the entirety of the landscape. I'm going to start out this the research part of this by something that you've done the most recently, in fact, two weeks ago as of the time that we're recording this, on August 11th. This is something that just came out, where you looked at acute ketone ingestion without co-ingestion of carbohydrates and its impact on running economy. First off, really well done study, solid methods, thanks. Yeah, I really appreciate the study design here, and that's not easy to do, especially with the nutrition intervention like this, where you're very trying to tightly control what's going on within the blood. Why don't you describe to the users what that study design was, so hopefully they can appreciate how good it is? Yeah, and then what you guys found, specifically with running economy in this type of intervention.

Yeah, so the first thing I do is give a huge amount of credit to Aiden Brady, who's the first author on that. Aiden is a postdoctoral fellow here at DCU, but he's got a really strong interest in endurance sports and he's really good in the lab when it comes to physiological testing, lactate profile, in running economy and so on. So this was right up his alley in terms of his skill set. And then obviously we married the question of these ketone ancestors with that, with his expertise. The premise behind the study was that we had been and many others have been doing studies looking at performance outcomes, and more often than not, the approach that's taken is to combine carbohydrate with ketones and compare that to carbohydrate alone, and the idea there is well, everyone uses carbohydrate. That's the kind of gold standard or the optimum fueling strategy. Let's layer ketones on top of that and see if anything happens.

And it struck us that very few people have actually done the more basic question, which is what actually happens if you just consume ketones alone. And it's out of the roughly 30 or so studies have been done on ketone salts and ketone esters, people that have actually used a ketone alone condition, and we probably. Again, we can if you want to get into all the nitty-gritty around the mechanisms as to why this might be the case. But there has been a suggestion that ketones will be more efficient fuel, for want of a better word. Now, that's entirely dependent on them actually being used as a fuel in the muslin. That's maybe up for debate to a certain extent, but in theory at least. An improvement in efficiency, in other words, a reduction in the amount of oxygen that's needed to run at a given speed or to produce a certain power output, that, in theory, could be a consequence of ketones being used as a fuel. So we want to go right back to basics and, instead of focusing on performance, just focus on this question of essentially what is the metabolic response to exercise, and we used rated exercise in this case. When you compare optimal fueling as cars in the case of ketones I'm sorry kebahydr alone, a combination of the two and then the ketones alone, so that ketones alone condition is probably the novel aspect of this design and it turns out actually to be the kind of headline finding, as I'm sure we'll get to in a second.

So we were interested in primary outcome of being run economy. Again, aden has quite a bit of interest in running economy and its ability to predict performance and endurance athletes, and we employed a graded exercise test. So one of the features is that we use long stage duration, so eight minute stages at different running speeds. So 10km an hour, 11, 12, 13, 14km an hour, so not necessarily very fast paced. But again, we're not dealing with the elite of the elite here. We're dealing with competitive runners training four or more times per week. They had decent 10K times in terms of criteria as well. So they're good club level, maybe national level in Irish terms, but not international or elite in that sense. So, and obviously to measure running economy, they needed to be running below the lactate threshold. So that was the idea as well of the slightly lower running speeds. But essentially across all running speeds what we observed was an improvement in running economy, so essentially less oxygen being used per kilometer per hour of running speed, and that was evident.

Within the ketone only condition there was a, you know, compared to carbohydrate.

The carbohydrate plus ketones are somewhere in between, but not statistically different from either one of the other conditions, and so what we can kind of conclude there is that there's something a little bit different going on in terms of the metabolic response of the run, the oxygen utilization, when you have ketones only on board as opposed to carbohydrates plus, ketones are carbohydrate alone.

And the other thing just to point out is that these were fed at the time. They had had a day of high carbohydrate feeding. The day beforehand they had consumed relatively high amount of carbohydrate that day, so they weren't fast or anything like that which is typically done in studies. So it was a pretty interesting finding, one that we honestly hypothesized would be the case, although we were kind of struck by the fact that it looked like you know pretty much every participant was, because we have the individual data points presented within the paper. They all seem to improve on the ketone only condition, which is a fairly unusual finding to see very consistent findings like that across a test like that. But again, I think it's a testament to Ed and Sam ability in the lab, but also the controls and the study standardization and the protocol that we use as well.

Well, and one of the other reasons that makes this so powerful just from a sheer pragmatic standpoint and I kind of look at this through my coaching lens is that, particularly in the road marathon crowd, running economy has been this king and queen maker of sorts, and people are trying to do everything they can to improve running economy. They're trying to find fast courses and use different types of nutrition interventions, kind of like this one the carbon plate had choose a few years ago led into kind of led into that controversy, and one of the reasons why ketones is such a like a hot topic is because of this potential economic improvement that you get during that you that you might be able to get during submaximal exercise.

and to kind of summarize what you're saying is that you see it when there are only ketones available, but when there are ketones but carbohydrates, that effect is either not nearly as much or not any different as compared to carbohydrate only.

Yeah, and I think there are lots of. I mean, it's one observation, and there are lots of ways that the research could go after this. You know, in one sense, when I say optimal carbohydrate, it's actually not optimum in the sense that we give one gram per minute. But, as you well know, there are people who are doing twice that amount nowadays, maybe not in running necessarily, but certainly in cycling. It's getting up there. So someone could easily come back and argue well, actually you didn't give them enough carbohydrates, so you know they. You know, do another study.

There's always another one, yeah, and then in terms like the implication, which, again, we didn't, we didn't make this. You know we didn't say

this, but it's. I've heard people kind of come back with and kind of they say well, you know, you're not seriously telling us that we should just perform races on ketones alone and we didn't say that yeah.

So we haven't been done. But, like that is, the obvious question is is you know what? What would it look like if someone tried to race on ketones alone? And what we have at the moment, actually, which might be of interest to you and your audience, is we have a study on going at the moment. Where this is the logical extension of this particular study, is that we're running endurance, at least for three hours on a treadmill at a kilometer per hour below lactate threshold, and the idea there is again, it's not a performance test, it's ketones versus carbohydrate and it's simply to see what is the metabolic response here.

What are the GI responses? How do they feel? What's heart rate look like? What does the rate of perceived exertion look like? So we'll see what happens. But I mean the the, the point we kind of made in the paper is that, okay, there's the evidence at the moment in a lot of the shorter duration and the higher intensity types of events. Clearly there's not really an effect there, but maybe, just maybe, in your endurance runners or ultra endurance runners, there could be something there, and so we'll see where the data takes us. But at the moment that's where we're going with it.

I've always felt that when research comes out and Louise Burke's research, research with the whole nail in the coffin and low carbohydrate things several years ago is a really great example of this.

But when ultra marathon represents the, so you're saying there's still a chance whenever we go through these different iterations and it's only a byproduct of it's hard to study because you can't get people in the lab, or you can get many people in the lab to run more than three or four hours. It's just your pool of people that can that can actually complete those trials is actually quite, is kind of quite small, so I always give a little bit of a chuckle to it, okay.

And it's true, we actually what we did before doing this three hour trial. We actually wanted to do an ultra endurance race. We wanted to simulate a race and I don't know enough about adult endurance and someone could think this is pie in the sky. But we were talking about getting people in, because usually in these types of designs you want to do a crossover design where the people act as their own controls and Peter Hesfield's group out of Belgium. They published an ultra endurance study earlier this year using ketones, but it was a parallel group design. In other words, you just had all the runners went out at the same time, some of ketones, some didn't, and it's all.

It's kind of hard to make inferences there around the performance side of things, but Eddyn and I were trying to get together this idea that we would just run people for, like you know, six or eight hours on a track round the circles, and you know we again that was the I usually hear. We eventually talked to a few people like no, no, no, that's not happening. I never hope you have a, maybe put them out in a trail and have to run around a track. That's not really why they do this, yeah.

Well, here we can pull it out. A call to the listeners here and we'll leave a link to get a hold of you in the show notes if they want to participate in that so. I think you'll be surprised. We're pretty good glottons for punishment over here, and the thing to go back to Louise's point, just on a from a research point.

you are Louise's study from a research point of view. They were flying people in from all around the world to compete in some of those, participate in some of those research studies and that obviously was was funded by the Australian Institute of Sports. So one of the again, one of the reasons why it's sometimes hard to do this type of research in elite athletes is that if you want to take them out of their training programs or if you want to bring them to a certain part of again in Ireland we have a very limited pool of you know, elite, elite athletes so it becomes difficult to do the kinds of studies that you know. A lot of people say why didn't? You do this study? Why did you do?

that study. But I mean it's it's just, it's the net. We're not trying to hide anything, we just can't get them done.

I appreciate that context. I'm sure the listeners will appreciate that context as well. Okay, so there was a little bit in the background, there was a little bit of a, there was a little bit of a ploy for using this most recent study as kind of a lead in. Uh, bernie and I we've been going back and forth a little bit on email in advance of this podcast to discuss how we wanted to kind of orient it. For a long time. Listeners this podcast, you'll recognize that this is the second podcast that I've had about ketones specifically, and the first one I had was with Heal Poffay, who's part of Peter's group that you were mentioning earlier. I'll leave a link in the show notes to that if you want to go listen to it, because we talked about some of his uh research in the area and in order to kind of like differentiate the podcast, what brand and I came up with is this uh, this, this really kind of neat design where we were going to go through the research but we were going to lead into the research through the claims that a lot of the ketone manufacturers are making and you know this sounds like uh, this does sound like a ploy for me to be like salacious and all of this other stuff.

But what I will say is, after being a professional coach for over for over 25 years, nutrition interventions always follow a very regular pattern when they're introduced into the commercial space. And there is and that pattern is, there seems to be some efficacy, either based off of observation or and or mechanistic data. That those observations and those mechanistic data is usually exact, exacerbated or exaggerated by the manufacturers who are trying to sell them, and I don't blame them, they're trying to be. They've got small businesses where you know we're talking about. They've got to, you know, earn a living and things like that. I don't, I don't blame that aspect of it. And then the research comes in, as you mentioned earlier, brendan.

Two years later we start to uncover some of the not the truths and the lies, but just sort of more of the nuance of how some of these interventions work and don't work. Don't work, and there's a great example of that that is actually kind of recently reemerged, and that's with sodium bicarbonate. Um, this is an intervention that we used, you know, maybe 20, 25 years ago. Just put baking soda in a glass, swirl it around. I used it when I was a very mediocre track runner in college and I'd swig it 30 minutes before the race and I thought that I got some sort of performance benefit from it. Turns out we have lots of research that backs that up that you can use it in some circumstances and it can be very effective if you get the dosing right and the intensity is right, and all this other stuff. And now it's come back in another format with Martin's product, and so this is I use that as an example that none of this is new or novel. It's the same pattern that might not exactly repeat, but it at least rhymes.

So what we're going to do is we're going to kind of go through the claims as the manufacturers have either presented them on their website and or in interviews. We're going to play a couple of interviews or social media posts. I'll leave links to all of that in the show notes, so I'm being completely transparent. And then what we're going to do is they're going to throw it over to Brendan to go through what the actual research says about this and where there's maybe a little bit too much of an extension of the claim, and then where there are some actual threads of the truth, all right, we're game for it. Okay, so the first one is a little bit of a lead in to the recent research that you did. That's why we started out with it.

The first claim is that ketones are the preferred energy source and there's permutations of this preferred energy source that have started started to emerge everywhere. Okay, we're directly from HVMN site, which is a ketone manufacturer. They're referring to it as a preferred energy source for the muscles and in fact, I'm going to read the direct quote here. So your body uses ketones as a preferred fuel source, meaning your precious glycogen stores deplete less quickly. The permutations of this kind of exist in other different formats, and I'm going to play a quick clip from a podcast that a lot of the listeners are familiar with, since it's endemic to the ultrording space. This is a single track podcast with Finn Mulansen. This is Lat Manser, who's the research lead at HVMN, describing this concept of a preferred energy source.

Because now we can confidently say that the brain prefers ketones, a failing heart prefers ketones, and ketones have certain signaling properties that may induce anti-inflammatory properties.

Okay, so I'm going to stop it there, because then there's a rest of the dialogue that kind of deviates from this preferred energy source. So if I'm a user out there and I'm a coach and I see something that hey, this is going to be the preferred energy source, I view that as is an athlete's going to take this in and it's going to be first in line to be oxidized in order to create work output. So what does the research actually say about this preferred energy source? Because you have data that says you know what, if you take it in, it's a more economical source of fuel, right, which you could interpret that as quote unquote preferred. What does the rest of the research say about this particular topic?

Yeah, I suppose it's worth tracing where I think the term comes from and then maybe how it could be, how it's been extended or maybe misinterpreted. So if I would say at which point are ketones the preferred energy source, I think that comes from these derivation studies that were done in the 1960s. So what they effectively show is that when people are starved, the you know, obviously ketogenesis is an amplified ketone body concentrations, the bloodstream rise and if you look at fuel utilization in the brain under those conditions, what you see is that effectively, after pretty prolonged starvation period, ketones eventually become the dominant or preferred fuel, let's say within the brain. But I say dominant and preferred there in the same light, because even if ketones are dominant, at that point it's difficult to say that they're preferred. You know, neurons may still prefer glucose, it's just that there's not enough of it around and therefore ketones are making a fairly major contribution. And again, I don't know how much science we want to go into the background here, but the whole ketogenic sorry, ketogenesis response in a period of low carbohydrate availability or fastener starvation, it's a survival mechanism because those ketone bodies do go to the brain and become, you know, as I said, the dominant fuel source after a prolonged period of time. So that to me, is where the background comes from, where people might talk about a preferred fuel source. But again, it may seem like semantics to be talking about which word we're using here, but I think it's important because it does get to the crux of the issue.

There is one other example actually more recently that has become obvious is in that that's an experiment that's been done now in failing hearts. So there's a lot of interest in the therapeutic value of ketone bodies for failing hearts and the idea there is that in a failing heart the contribution of ketones, especially if they're giving exogenously the form of a supplement or an infusion, they can become again a major fuel source within the heart and potentially rescue heart failure in that situation. So there are examples like two fairly extreme examples of where ketones do become a dominant or again, do we say prefer, we say dominant fuel source within those organs. So then in the case of muscle and you know to your point, I'm an athlete I hear they're a preferred fuel source. I should go out and get them because my muscles going to use them that's probably unlikely.

The scenario as best we know at the moment is that back in the 70s and 80s there was a number of studies that were done where they had people fast for various different durations and there were a couple of studies with infusions of ketone bodies as well, and effectively, in those studies what was shown is that the contribution of ketone bodies to substrate or energy provision was around about 10% at the most. So I don't think anyone would say, but at that level that would, that will be a preferred substrate. In fact, what happens is that the more prolonged that a faster or a period of starvation proceeds, the less likely the muscle is to use ketone bodies. And that's, they think that's to do with a kind of auto inhibitory effect of really high ketone body concentrations actually switch off up to take into the muscle the idea that they're being preserved to the brain. So again, an obvious question, that is, what about exogenous ketone supplements? You know, if you provide it as a substrate acutely rather than relying on fasting or starvation, could that impact on fuel utilization?

And again, the early evidence there was from this 2016 paper that's very famous at the stage from cell metabolism by the group out of Oxford and the finding that they had in that study was that ketones when they were ingested as a ketone ester were making a 16 to 18% contribution to energy provision during exercise and that seems a little high to everyone.

Based on the research that we've done in the 70s and 80s and subsequently you know it was it was clear that they were totally open about it in their in their publication.

They said there were some certain estimates and assumptions made in those calculations. When the same group then subsequently went back and measured the ketone body oxidation rate more accurately using a tracer methodologies, it turns out that it's probably somewhere around 5%. And again they're explicit in their paper where they say this is less than we previously found and to explain a couple of reasons why. So if you can pull all of that together, if we're talking about ketone bodies as a substrate during exercise and their utilization by skeleton muscle, you know we're probably thinking that even under relatively high concentrations of ketone bodies within the bloodstream produced by consuming, say, ketone ester, it's still probably only going to be a maximum 10% contribution to energy provision and it's still going to be carbohydrate and fat predominantly. Obviously we know that lactate and amino acids can make small contributions as well, but I think the the idea that it's a preferred or dominant substrate in skeleton muscle during exercise. I don't think that's backed up by anything we have to hand at the moment.

That was a brilliant walkthrough. By the way, I didn't expect you to come like kind of be able to merge both history and current, but here's what a lot of people are thinking, a lot of people that are actually using ketones. If I can get 10% extra not extra, but if I can get 10% of my total substrate utilization from something that is not carbohydrate and not fat, isn't that additive meaning I don't have to take in up to two grand, up to two grams per minute? As we mentioned earlier, there's a lot of GI distress that can be associated with that. Those are really high carbohydrate intake rates. If I can somehow offset that with a non competitive fuel source, couldn't that potentially be an advantage? It might not be preferred we can argue about those semantics but couldn't that be a performance advantage?

That's the great question in all of this, because, okay, where do we attack this from? So in our hands. When we saw this improvement in running economy in that recent study let's just assume that the contribution to social utilization was 10% it was a very small contribution that ketones made, but enough to have an effect on oxygen consumption. In that regard, you would say, okay, you're right that 10% is something that could be meaningful to performance, because the percentage improvement in running economy that we saw was around about 3% or 4%, which you mentioned earlier about the carbon fiber shoes.

That's around about the percentage improvement that people are crazy for.

Again, if that 10% contribution to energy provision from ketones has then a meaningful effect on running economy, then you're right that 10% is a good idea. But you also make the point about gastro-testinal upset. So early on there was some concerns about ketones cause and GI upset In our hands as well. We saw one particular study. We saw really bad GI issues. But actually over the last number of years I think the concerns about GI upset have kind of dissipated in relation to ketones, especially the ketone esters. So go back to your point. If I could consume a moderate amount of carbohydrates and a small amount of ketones on top of that but ultimately have the same performance. So again now we're back to the question is is same good enough? So now we're back to the simple math here in terms of finances. Is simple good enough? Are the same good enough if you're spending $60?

an hour. You're saying it's not worse.

So I think that these are all practical questions. These are hard to answer by research, because you're getting down to the questions of what coaches or what athletes would prefer to do. And even if we're not detecting differences within our lab protocols, but people in the field are finding them beneficial or they're for some reason like that they have less GI upset, for example by consuming less carbohydrate, but performance is the same, Then there are many different nuanced considerations to have there in terms of how we recommend them.

Okay. So this leads into another one of the claims, and I'm going to generalize this because a lot of the ketone manufacturers get to this in different vocabularies and I don't want to make it a semantic debate. The use of ketones in an endurance application is glycogen sparing. We just talked about it. If it can be up to it, it makes logical sense, right? If I can either take in the same amount of carbohydrate and then taking ketones on top of that, that means that proportionally, I'm taking in or I'm utilizing or oxidizing 10% less carbohydrate potentially. So what does the research say about that?

That ingestion of ketones during endurance exercise is in fact, glycogen sparing, and I'm going back to the old Tour de France stuff that initially kind of like started all the hype cycle here because that was a big, that was a big component of the dialogue around why the Tour de France riders were actually using it. So what does the research say?

So, again, there's a sound mechanistic basis as to how the provision of ketone bodies would impact on carbohydrate utilization, and that's really what we're talking about here. The mechanism we're talking about is that you can reduce reliance on carbohydrate utilization because of the fact that ketones are there and making a contribution to energy provision. Or you could argue that they may shift the balance towards using a little bit more fat, which is another thing that you see if you dig into the weeds of some of the papers. But it comes back to, I suppose, the question of how often has this been observed? So the mechanistic basis is to do with the way it's, like the Randall cycle, as it's called, where, if you have this extra substrate within the cell, that it actually there's inhibition on glycolysis, particularly at the level of the enzyme phosphofructrokinase. So, again, sound theoretical basis. What happens in practice? Well, there's really only been two studies that have looked at glycogen utilization in muscle during exercise. There's a lot of studies that are, including some of our own, where you see differences in lactate appearance within the bloodstream and that's sometimes inferred to mean that there's been a change in carbohydrate utilization. But there's a couple of assumptions baked into that the probably aren't safe to make, and so what we would say is how many studies have actually looked directly at glycogen?

Well, there's only two. One of them showed that there was sparing let's call it or reduced utilization of muscle glycogen during exercise. The other showed that there was no difference. So both the studies were ketone asters. Both of them are roughly similar designs. One of them was out of the Oxford group from that 2016 paper that I mentioned. The more recent data comes from Peter Haspow's group. The big difference between the two studies was that they use different methods of determining muscle glycogen. So in the 2016 paper, where they saw an effect a reduction in glycogen utilization it was using a staining method, to kind of interact, semi quantitative measure for muscle glycogen. And a Peters group, it was again in the muscle biopsy, but it was whole muscle quantified using direct determination of glycogen. So where do we stand? Effectively, we don't know, is the answer. We see some again. If you take those two studies that measure glycogen directly and then say well, what does the lactate data say? Well, it turns out that's very mixed as well.

So what we would say at the moment is, to sum up, sound theoretical basis, but very mixed results as to whether that is the case or not when it's actually examined directly within exercising muscle which I think is always really interesting when it gets so mixed like that, because then, as you mentioned, you start to dig into what the research design is, and oftentimes what we're finding is is that research design is relatively similar, with exception of how they might actually be measuring the end product of muscle glycogen or maybe even lactate or something like that.

Before we leave this, we've kind of been focusing on the potential for ketones as a real-time argogene decay. It's either going to be glycogen sparing in real time or it's going to be a more economical source of fuel, and their performance is always multifactorial. I mentioned this to our coaches and to our athletes all the time. It's never going to be one thing that unlocks performance. Yet this multifactorial phenomenon is part of the fascination with ketone supplementation.

I can look at this bottle right here. For those of you that are watching the YouTube version. This is just 10 grams, 10 grams or 25 grams, 10 grams of ketones the ketone IQ shot that I can purchase at my grocery store. It's a grocery store right around the street. It costs me four bucks. It's not really that expensive right now but interestingly, underneath the dosing which I couldn't find earlier 10 grams ketone supplements it has four distinct features Energy, focus, athletic performance and appetite control. And this multifactorial approach is amusing that as a lead-in to part of the fascination with it. So what can we say? Since performance is multifactorial, it has to do with fuel utilization, glycogen sparing and things like that. If we kind of alchemize all of these. Somebody's going to run an ultramarathon and use ketone supplementation. What can we say about that performance alchemization Is there a realistic performance benefit that we can expect to glean from use of this particular nutrition intervention?

Well, just to add more context to what you said there, the point I always make about ketone bodies is that they're an incredibly powerful, but not only the better word, but they do so many things to so many organs within the body. And it makes sense because, as I said earlier, the production of ketone bodies is a survival mechanism. They're always been produced, but the high rates of production is a survival mechanism, so it's not surprising the effects all over the body and fairly dramatic effects. So if we weren't studying performance and there wasn't a controversy as such, there's so many interesting avenues for where ketone supplements can be used. Like I said, I touched on things, like I mentioned head failure earlier, but there are things like cognitive function in older adults. There's the whole anti-catabolic effect that we've talked about before. There's glucose lowering effects. There's so much going on, but the controversy is all in performance, of course.

But to go back to your question about the performance alchemy as such, I mean what we've studied a couple of times, and others have as well, is whether there's effects on cognition and various different measures of cognitive performance. Again, I'm not an ultra-endurance or endurance athlete, so I know less about how that would be useful in that context. But one of the stories that we had done was looking at decision making effectively in soccer players having performed a simulated soccer game and what we see here is it was a statistically significant mitigation of decline, as the way we described it so effectively. Decision making got worse as the simulated soccer game went on and that decline was actually prevented in the ketone condition and that's got. Even though it was a very modest effect, it was like the difference between four bad decisions versus two bad decisions over the course of this 75 or 19-minute protocol, but in team sport so I'm bringing it back to my own demand here in team sport, two bad decisions could be a huge impact on performance.

And one of the things that I struggled a little bit with is that I've tried these ketone supplements in my own sport, which is Gala Games. It's a football a former football we play here in Ireland. It's like soccer with your hands, basically, and it's very hard for me to say whether the performance benefit. But it could come back to the things like is the ratio of perceived exertion less? Is there ability to concentrate better? These are the types of things that would matter in a team sport. Now, how that would affect ultra performance. For example, maybe there's some better pacing strategy.

And this is one of the things we speculated way back when, when these first came out, was like could pacing strategies be impacted? Could alertness or attention be improved, you know again, going across different terrain and domains and so on. And equally then, could that rate in a perceived exertion or could the elevation and heart rate, could these types of things be sort of attenuated, the rises attenuated over time? Yeah, and here it doesn't all have to be to do with utilization of ketone bodies by the muscle, but at the same time, across all those domains that I've mentioned there, there's not a huge amount of evidence that those are dramatically affected. You know, if there's anything going on, it's very subtle and it's not consistent across studies. And again, you know, three or four years ago I would have been saying we've won a handful of studies, but as we you know, a recent review that we published at the end of last year there's got to be 30 different studies now at this stage. And again, that's still very mixed in terms of all those outcomes.

Yeah, it's just very weak right. It's very weak and very mixed, and I'll point the listeners to a piece of research that we actually reviewed for our research newsletter from Heal Poffee and Peter Hussball's group. They looked at this in an ultramarathon situation where they gave people exogenous ketones kind of throughout an ultra and it was a lot. It was a $500, $400, $500 intervention at the end of the day I mean could you imagine it's a 100 kilometer race?

So it's taken people 10, 12, like 15 hours to complete it and the amount of supplement that they're having to use is actually a lot. And we actually totaled that up in our research paper and they found the same thing that you mentioned, where there was a prevention of the cognitive decline based on very simple stoop tests and things like that. However, going back to the mechanistic part of it, as you mentioned, from the onset the groups were not isocaloric and in fact the ketone group was taking in about 30% more calories than the other group. So half of you would say, well, we don't care. Right, the ketone use kind of catalyzed, to a certain extent, greater energy intake during the race.

It's potato potato. Whether the total energy intake is causing the mitigation of cognitive decline and or the ketone specifically are causing the mitigation of the cognitive decline, you don't care, as long as there is a mitigation of it. I totally get that rationale, but I'm like you. I kind of want to know the mechanism behind it. So I'll encourage the listeners to leave a link in the show notes to check out that particular paper and then, if they're so inclined, they can check out our interpretation of that.

Okay, we're going to leave the performance side just to move the dialogue along and go into another one of the fascinating areas that has started to emerge, and that is is that ingestion of ketones can somehow amplify the adaptive response, and we know that there's a whole host of response that we're trying to get from the training process. That's the ultimate goal of training. Kind of doesn't matter how hard the workout is or how good the workout is. It matters how much you respond to it, and there's any number of different interventions that you can use to attempt to try to amplify the training response. People have tried to use cold therapy, right Even hot therapy sauna therapy and things like that to amplify nutrition interventions.

It is a golden goose to try to chase around because you're getting more for the same work. You go do the same workout from one day to the next and you get more out of the day that you did it with whatever you know intervention that you decided to use, and there have been. There's been one particular claim that I'm going to bring up, and this is from the Delta G site, so that we make sure that we're, you know, picking on the different ketone companies equally, equally here, and that's it, and that's that it increases your endogenous EPO levels.

And so I'm going to read this directly from the site to make sure I don't get it, make sure that I get it correct, and I'll leave a link in the show notes to where this particular claim is. It is in that that and the claim is specifically, increased endogenous EPO levels by 23%. Delta G ingestion has been shown to increase post-exercise erythropoietin concentrations, revealing a new avenue for orally-ingestible ketone monoesters to potentially alter hemoglobin mass. Link to study here, and they have the study and I'll put that in the show notes as well. This has been something that has kind of come up time and time again, where anytime you mention EPO response and since most people associate it with a banned substance, their friggin light bulbs go off and go. Oh my god, this is something that I've got to chase around. So what says the research about this particular claim that ingestion of ketone esters in a workout kind of context can somehow amplify the EPO response?

Yeah, so that was a really nice piece of work actually done by the guys out at the University of Bath, james Baths and Javier Gonzalez, and it was a study protocol where they had them exercise and then in the post-exercise period they fed them traditional carbohydrate protein types of dolescene, so 0.4 grams per kg of body mass of protein and 0.8 grams per kg of body mass of carbohydrate and fed this on the hour for three, four hours as part of the recovery process. So that type of design where you've got an exercise bout and you've got this kind of protein carbohydrate feeding as recovery, that's been used many times. We've even done a study ourselves a different protein source as well, but what they did differently was to add ketones to the feeding on the hour for two or three of the hours that followed and then they tracked EPO concentrations thereafter. Now, if you look at the design, it strikes me as probably a design that there's a couple more papers to come out of, because the types of measures that are being done it's likely there will be things like muscle glycogen or performance and different things after a short recovery period, but this rapid communication, as it was called when it came out, was to show that, as you described there, which is accurate, is that the endogenous concentrations of EPO were elevated in that post-exercise period.

Now, how far you extend that claim is, I suppose, what's in question here. So the crux of your question there really is does this translate into something down the line? And the answer is that study has to be done because what we would see is those concentrations would not be, they're not too dissimilar to what would be founded out with altitude training, for example. But if they're only there for two to four hours, is that going to ultimately translate into a similar response, that is, going to altitude? That's the question that remains to be determined.

But it's promising and, to be honest, an awful lot of research is done in this style, where researchers do an acute study, they make an interest in observation and the question becomes will this, will this turn into a training effect? And in best practice, whether it's this group of researchers or whether it's another, they will follow that up with a training study where they basically repeat this strategy over and over again and see if there's a difference after four weeks, 12 weeks, whatever the case may be. The one bit of extra colour to add, of course, is that and I'm sure you've seen this is that several and maybe I don't know if you'll talk about this when you was on your podcast, but they subsequently have now published a study Peter's group, so completely independent to the acute study where they show that in their three week overtraining study model that they've used before, that when they look at Marcus Van Duganis' and arresting EPO levels that they see this improvement. There would be kind of a logical extension of what was observed in the acute study.

Yeah, we talked about that in the podcast.

Yeah, and there are again. There are some concerns in that group in that study again about the fact that there was no angiogenesis in the control group. And so was there a true angiogenesis being driven by ketone bodies or was it just the fact that the ketone condition was better able to adapt independent of ketone bodies because that particular group consumed more calories? Again, a bit like what you were talking about in the ultra-engeared scenario as well. So again, it's two studies of. You know it's very hard to put a number on how many studies you would need to see before you'd be confident of this effect. I think the preliminary evidence is quite interesting there in terms of what that might look like. But you know how long. If all you were getting was like a little four-hour window after every training session of this elevated EPO, how many training sessions would that take before it would manifest as a meaningful difference? So that's a big question, I think.

Well, and that's what I come down to with this particular claim, and because you know we have a lot of experience using altitude interventions to get this exact same response and hopefully show up in an improvement in hemoglobin mass amongst improvements and other markers.

But let's be real here. Hemoglobin mass is kind of like the thing that you're shooting for with an altitude intervention. And the one thing that we've learned from this and I just happen to have Oliver Gerard on my podcast talk about this very recently is it takes a lot of altitude exposure to actually achieve that effect. Like 20 hours a day for four weeks, like that's a lot. And whenever I see these acute responses in erythropotent concentrations I come back to is it enough for long enough to produce a reasonable adaptation? And we have a lot of studies to show that.

When it's not not even just the altitude studies go to pressurizing an airplane, you're at sea level you go into a pressurized airplane, you're going to get an EPO response, but you don't see athletes flying around in airplanes in order to get an altitude intervention right. It's illogical because the stimulus is not enough and it's not four long enough, and I use that as kind of a cheeky example to go. Okay, I understand that we're seeing this. I'm not nobody's doubting that we're actually seeing this as a physiological response to a nutrition intervention. Is it actually meaningful? At the end of the day and personally, just based on my observation and experience, the meaning really draws out from how long does that exposure happen for and to what degree does it actually?

happen for and you'd have to be taking ketones all day and training all day in order to make a difference.

This is the point. So, like if we played out a best case scenario. Let's just say that at the elite level, tiny increments in outcomes are beneficial. We're looking for a percentage difference, your tiny percentages? Well, let's just say you undertook this intervention for a year and after a year you finally saw a difference, but you're going to have spent basically $100 after every single training session that you've done for a year.

It's going to be really expensive intervention that spectators have. That actually is just to touch on that point. It is one of the core issues with this field is that most practitioners and coaches would be slow to embrace or to recommend that an intervention that costs that amount of money Okay, in pro sports, pro cycling, maybe they just think let's take a chance on this because a very small percentage benefit is worth the risk of the cost. But until the ketone esters, let's say, come down in price, until the potency of other alternative forms of exogenous ketones improves, like it's cost is just a huge barrier to any of the things we're talking about here.

I agree. And just to tease the last topic that we're going to go over, we're going to go over the different forms and some of the ways that this cost is actually coming down, more from an origin story perspective.

But we're going to stay on the adaptive response bandwagon. Because the next one is another hot topic. It has to do with mTOR, everybody's favorite signaling molecule. Recently Get mTOR from a host of different interventions.

But another claim is that acute ketone ingestion is going to improve muscle protein synthesis after using it during a workout. Once again, really sexy thing to grab. Hey, I've got you know, I'm going to increase my human clover mass and I'm going to have bigger, stronger muscles after the same workout. I mean, once again, I would take that as well. I'm going to read the claim directly just so that I get it right, and I'll also leave a link to where the users can find it in the show notes so they can kind of like read it for themselves and the link study. So everybody's operating in full transparency here. So the claim itself is Delta G has been shown to increase protein synthesis and tissue regeneration when taken with a recovery protocol. I'm emphasizing the last part deliberately, because I know that's where the conversation is going to go. Link to study here. We're going to link the study in the show notes. What say you, brendan, about this recovery protocol and increases in protein generation.

Yeah, so the tissue generation piece that obviously can't be backed up because that hasn't been studied, but it's what the implication of? A bit like we talked about the acute EPO response. Maybe that leads to human global mass and angiogenesis down the line. In theory, if you get repeated stimulation of protein synthesis, you would get tissue growth. That's actually the premise behind all of the high protein feeding type stuff that's done around resistance training and so on. This is a really interesting topic. It's actually the one I'm most interested in is just we've never been able to do the studies.

When we were writing our big review in 2017, the initial piece of work and we looked at some of the again, the work that had been done in ketone bodies in the 80s had been around anti-carabolic effects and things like surgery or disuse models. There had been one particular study that was just an infusion of beta-hydroxybutyrate that did stimulate a protein synthesis by about 10% over the course of six hours. This was in the 80s. Shreen airs group were behind it. The magnitude of that change is very similar to what we've seen with, say, high protein feed. In theory, if we just take that, this is now, as I said, ketone infusion many years ago, but in principle, protein synthesis could be improved with the cute increase in ketone body concentrations.

Fast forward then to the study that you're referring to. There again, it's from Peter's group From 2017, if I'm not mistaken, van Dorn is the first author. What they've done in that, as you said, the recovery protocol, is very similar to what was mentioned in the paper, where they saw this improvement in EPO. It's a glycogen-repeating exercise, by the way that's called it followed by carbohydrate-protein feeding, with or without ketone, the exogenous ketone monowestrum, in this case. Mtor, actually has not changed in that particular study, but the downstream markers, the downstream markers, the anabolic signaling markers from MTOR, are actually increased in the ketone condition. In that particular study, they haven't directly measured protein synthesis, but they've measured markers that are fairly tightly correlated with increases in protein synthesis.

It's not a major stretch to suggest that there could have been an increase in protein synthesis when we think about, as I said, that infusion study from many years ago. I think things are coalescing there. It's a nice job of some cell work as well, where they show a similar principle in that study. My take on that is that, yeah, like I said, the tissue regeneration that remains to be seen, but in principle again in theory between the mechanisms around how ketone bodies could be anti-catabolic or they could be pro-anabolic, let's say, or anabolic. There's probably something in that that requires more research. You have the conclusion of most of what we'll say it requires more research. I think that one is one of the more promising directions. Actually, like I said, it's the one If someone said to me you can do any ketone study you want right now. That's actually where I go with this type of research, because I think that's where the strongest mechanistic data is. Again, it would be a really interesting application if that was the case.

Yeah, I have come to the same conclusion as well. Is that there's any promise? It's not acutely. It's as a recovery aid, essentially, or an adaptive aid, as some of the research has suggested.

I suppose the other thing just to bring up at that point is the course. Peter's group, Peter Haslund's group, has also done the work on sleep as well. Again, it's one-off study so far, but if I was an endurance athlete who trains in the evening and the cocktail there seems to be ketones after exercise, ketones before bed. I don't know everything is wrong.

It's a great business model because you get it before, during and after right.

Yeah, someone's going to come down after it.

It sounds like that was an endorsement, but I know it's a great business model because you get ingestion before, during and after. I don't claim to know what their profit margins are, but it's an expensive product. As we mentioned that that cost of production will come down.

But, like I said, there's some of a ball-jolting aside. I think there's some merit in there to extend the claim out to be tissue regeneration. I don't think that's the case right now.

Okay, perfect, okay, we're going to move on to the last topic and try to sort through some of the confusion around the different forms that are starting to emerge. I want to use this as both like a window into the present, but then also maybe a potential window into the future, because this is not a static proposition, right? I mean, nutrition science changes daily. We've we're just talking about encapsulating sodium bicarbonate, which I used 25 years ago, almost 30 years ago now, 30 years ago encapsulating it in a hydrogel, you know. And so the food science changes and this is an area that has changed recently and I imagine will kind of continue to change.

And the way I want to set this up is with my personal experience. So when Ketone's first came on the market, I bought a bottle of HVMN and on the front of it one of the features that the company was pointing out is that it would put you into quote rapid and deep ketosis. And I have a chemistry background. So the way that I translate that chemistry background is that the ketones will enter my bloodstream quickly on the rapid side.

And to a great extent meaning the way that the ketones show up in my blood. That curve will be quite steep, rapid and deep. Fast forward to today, and the same company has produced another format, another delivery mechanism, essentially of ketones, that has a slightly different spin on it, where the and I'm going to stylize the way that they've described it to a certain extent, so some people might take a little bit of an exception to this description to to, where the appearance of ketones within the bloodstream doesn't have as steep of a curve and it lasts for a little bit longer. So you're going from a short steep curve to like a longer, to a longer flat one. They've engineered the product, so to speak, to achieve this result, or the product that has been engineered has achieved this result, I guess is a good way to put it.

I'm going to play a clip from Instagram, from the HVM and CEO, ceo and co-founder, michael Brandt, kind of describing this process, and then I want to put the process, I want to put this morphing of the different forms kind of with a science lens on it and why we're starting to see this and what the kind of the biological effect might be. So let's let this clip play for just a little bit and then, brandon, I want to get your kind of like response to

it.

Track with the United States Department of Defense Special Operations Command, looking at ketones specifically, and here's what we've learned. You already know that elite military operators, professional athletes, entrepreneurs and people from all walks of life are using ketones as a super fuel to level up and hit their goals. So what's the most effective way to get ketones? The state of the art of ketone delivery is something called a dial. The pure dial that we've put into ketone IQ converts nearly 100% into blood ketones. The dial turns into blood ketones at a speed, duration and magnitude that are optimal for physically and cognitively demanding missions. You may have also heard of something called ketone esters, which are diluted forms of the dial. The pure dial is what you really want. Ketone esters are chemical bonds between the dial and other less effective molecules. These other molecules cause performance drawbacks and digestion issues.

Ketone IQ is our second iteration in the HVMN ketone product line. Our first version was actually an ester. Through our contract with the Department of Defense, we identified that the dial has the ideal performance characteristics for physically and cognitively demanding tasks. Because of the scale that we've reached with ketone IQ, we've been able to bring down the cost per gram to less than one third. Any of the esters on the market, despite the fact that the esters are diluted versions of the dial in combination with less effective ingredients. So not only is ketone IQ the Ferrari of ketones, we figured out a way to do it at a lower cost than any of the less effective options. So there you have it. Our mission at HVMN with ketone IQ is to make ketones universally accessible, so that anyone in the world can have them and fuel you towards whatever your goals are in life.

Okay, there's a lot to unpack there and I'm going to disregard the super fuel and the Ferrari analogy and all those other things, but to put a synopsis on it, the ester version is either bad or not effective, and the new dial version that was a byproduct of all of this big military contract and things like that is more effective for physically and cognitively demanding tasks, and you can hear a little bit of the dialogue that I was trying to fumble through earlier, where the curve of how the ketones actually appear in the blood is actually altered by altering the chemical composition of what you are actually ingesting. I don't know where to start with this, so I'm going to let you take the floor without any sort of preface on this one.

Yeah, I agree a lot to unpack and I guess if I'm going off on a tangent you know pull me back in here. But Tangents are encouraged as it's good.

Yeah, the. I think the place to start is to describe the esters and the so-called dial, just so that kind of background information is known. So throughout what we've spoken about today, it has almost successfully been us talking about the studies that have used ketone esters, and there's a whole. There are several other exogenous ketone supplements ketone salts, mcts, butane dial, which is what we're going to talk about here now. I think it's probably not worth getting into all the details there, but just so listeners know that the you know pretty much everything we've been talking about is a ketone ester up to this point. And when we say the ketone ester, what we mean is ketone body. In the most cases, b-dialogist butyrate is terrified, so joined to the butane dial molecule, and so that's where the ester word comes from. It's because you've got two molecules that are joined together. The reason we just don't ingest ketone bodies themselves is because they're generally in their free form, their low pH, their acidic. They can't really be ingested in that way. And this is again research going back to the 70s I think it was when the first time esters were described, and they were used at that time for infusion, so for parental nutrition more than anything else. But these esters were effectively a means to be able to elevate ketone body concentrations without ingesting the free ketone body itself. So the butane dial molecule is interesting because, as described in the video, it does increase ketone body concentrations. So the way I try to get people to think about ketone esters is that it's a molecule that has two other molecules bound. It's terrified together. When it goes into the body there's enzymes called esterases that break down that bond. There is a certain amount of the rise in ketone body concentrations come from the butane dial that's present there. That goes to the liver. There's a complex metabolic pathway that eventually produces more BHB, and so the two things combined are better than either one alone. So when we talk about ketone esters, the reason and you mentioned this about you know rapid and so on, like that is kind of the thinking behind why the ketone esters have their prominence that they do is that they do increase ketone body concentrations rapidly and they do so in a fairly reproducible, dose dependent manner. So you can actually titrate the level of concentration or the concentration of ketone bodies in the bloodstream fairly well just by, you know, dosing per milligram or, sorry, on a gram basis or per kg of body mass.

So, with all of that said, then the question becomes like why, all of a sudden, are a company suggesting that this ketone ester, which everyone's been using, has been used in most research studies?

Why removing the ketone body and just providing pure butane dial?

Why all of a sudden would that be as they use it within the video there? Why would it be optimal for physical and cognitive functions or challenges? It's something that's hard to make sense of because of the two studies that have been done with pure butane dial and performance. These don't have shown any benefit. So these were studies that were done around about, I think, if they're not, both dated 2019, that's, 2019, 2020, and both of these studies effectively showed no benefit. And in fact, in both studies they talked about GI upset, about wusiness and so on, because effectively, sometimes the butane dial, the effect on metabolism, can be to have a kind of alcohol like effect. It's often something in the papers that often say narcotic like effect or alcohol like effect.

So in that video where they kept referring to dial, dial dial, effectively that's the butane dial molecule. So it's not a new molecule as such, it's just and it's kind of alluded to in the video that it's the other half. It's one half of the ketone ester, and so to say it's better than ketone esters alone, I can't see why that would be the case. And then the other implication within the video is that it's the pure dial that you want. You don't want the BHB, because that is I forget what the exact wording was but it's basically a bad thing. And again, I'm not really sure how you can reconcile that claim with any of the evidence that's there at the moment, because, yes, you can't consume the free BHB in the way that it would be in the form of an ester, but I don't think that that's the same as saying that if you consume it it's the bad thing and the butane dial is the only thing that you need. That just that doesn't tally with what we know so far about the molecules.

And so just to backtrack a little bit, for those of you that get lost in the chemistry lesson which, once again, I have a chemistry background and I still get lost in the chemistry lesson the dial format is what you are actually seeing in the new ketone IQ product. They changed the name of it as well. Versus the ester, the pure ester form is the first generation of the HVMN product. What's in Delta G? Because that's the Oxford.

The context here is that HVMN had licensed the sale of the ketone mono ester. So most of the time when you hear refer to the ketone mono ester, it's referring to this beta hydroxybutyrate butane dial ester. So it's those two molecules that I mentioned. So HVMN originally licensed that for sale in the US and subsequently that actually I mean I don't know what the ins and outs of all these agreements are, but it's now being sold under the Delta G name.

It's the same molecule same ketone mono ester, but essentially it's now being sold by the Oxford group and their spin out directly. So HVMN no longer sell it and instead now they sell this this ketone IQ, which is, you rightly say, is the debutant dial molecule itself.

So I don't want to get you to speculate because we don't know the business kind of ins and outs and things like that.

But if the dial form is less effective, what would be the rationale to promote this? And this product is being promoted heavily? Let's not like make two, you know. Let's not like beat around the bush with that. They're dumping a lot of money into promoting this product across every single platform that you can think of podcasts, social media, you know. You kind of like sponsoring athletes or a number of different ultra marathon athletes that will be recognizable to the audience, that have taken sponsorships for this particular company. If it's not as well studied and potentially less effective, then the original version. Why the change to the second? One other than I can get it in my sprouts for four bucks.

Yeah, I mean they do make the fair point is that it is cheaper and, like you know, it is cheaper than the ester. So the argument might be well, if it's, you know, if it's less effective, let's say increasing concentrations, why not take more? And so you will ultimately pay less but you'll get the same concentration. I don't know if they ever say that, but I mean that's maybe the logic you'd use. But the problem, the problem, to be honest, is that if you consume this is personal experience as well if you consume a lot of uterine dial, like it's a fairly woozy feeling, you know it's.

I wouldn't say it's the equivalent of being drunk, but there's a bit of a buzz and again, a lot of people talk about it. I mean there's. I sometimes wonder if it's like the feel good factor we used to. We used to talk about supplements. You know back when, when contamination supplements was fairly rife, you know, back in the 90s and early 90s, before all the testing came in there was it was well known the companies used to put in a, you know, a hit of caffeine, or it could be a Sardine or whatever there's a so called a FedDrucker?

Yeah, so I think I think I'm not saying that that's what what history of men are doing here but I think when people are consuming something like the Keto-mol-Q, the putine dial molecule, you do get a pretty buzzed effect.

So, like the one of the companies we haven't mentioned that are in the space as well, as Keto made and so they also sell a version of the Keto Monoester, but they also have a range of products that they call hard ketones, which is effectively butane dial styled in the context of an alcohol free buzz, you know.

And again, like it's the dosing, if you, once you go above 10 to 15 grams is a single dose, in my experience and again people have let try here in my house there is a bit of a buzz that you feel. So maybe it's the feel good factor, but certainly from a from a performance point of view of the, as I said, the couple of the studies that have been done on butane dial, it's obvious that it's difficult to get ketone body concentrations up to a level that we think would be beneficial during exercise without the downside effects of GI discomfort, wosiness and so on. And so you know, unless, unless they bring some of those you know some studies to the table where they show performance benefits. It's. I don't know how much longer they can continue to talk about it as a performance.

Well, and you just touched on one of the things that I kind of really want to wrap up with is that it appears to be that if there is a performance benefit, these are.

This is my emphasis that I'm putting on it that if there is a performance benefit, it's a really tight window to thread. From a biochemical standpoint. You have to get the blood concentration of the, you have to get ketone blood concentration in a fairly narrow range, and you can see that emerge in the research. Where they're, where they're setting up the research protocols to be in a very narrow, narrow range, realizing that below they're probably not seeing an effect and then above it might actually kind of be a negative effect. Whenever that's the case in the real world, that's hard to pull off because you don't have well, first off, you normally don't even have the measurement tools right. Just think about, I mean, how problematic it is to use a continuous glucose monitor which is really common.

They've been using that for years in a diabetic population and it still has yet to proven its worth in an endurance application beyond very limited kind of situations. So I look at that very narrow threading of the needle, so to speak, from a pragmatic standpoint that the intervention that you have to apply has to be so precise for a maybe, for a big maybe, a big maybe performance benefit and the potential for a negative part of it if you screw the intervention up. I kind of like, even if the maybe were true and I knew what it was it's 2% right, I'd trip over myself, I'd do a backflip for a 2% performance improvement. I mean you'd get that all day. But if I have to like completely convolut the situation around it in order to get it, and if I know I screw it up it's going to go negative 2%, I kind of take that value proposition on face and go, man, I'm going to leave this alone let's just go train.

I think you put that externally. I don't have anything to add on that, on just on the specifics there, except the just frame, the other side of things, which I don't have in my introduction. If you have mentioned that, I work in practice as well, so, like most of the time with athletes, they're so focused on supplements that they're missing the. You know the forest and the trees in the sense that the other stuff around you know energy, balance and the right amount of macros and protein for recovery and protein and breakfast you know all of these, we've probably got nine or 10 more different what you might call like core features that you would want an athlete to do.

And yes, you say it's really the needle on this extra very specific niche concentration of blood healing bodies. You know it's a very difficult thing to do. So, yeah, like you say, go and train or, you know, go and get your other nutrition in line.

Yeah, well, I think that's where we're going to park it. Man, this has been awesome. I don't know how I'll start like wrap this up. You have a once again. We didn't know each other before this podcast. You have a brilliant way of weaving the narrative together in a way that is informative and logical, and also unbiased and pragmatic, so that the listeners can actually see through it. You know, neither of us have anything to sell. You work with athletes, you work in the research lab and I've always appreciated people's perspective on it. So thank you very much. I hope that we get some additional subjects into your to be designed research studies. If they do want to participate or just learn more about you, brendan, where can they find you and get a hold of you and harass you for?

more info. Yeah, papers are on research guide. If people search my name and the easiest thing is probably to search my name online, because I don't know if you came across the fact that I don't have a social media account, so it's not that way.

But certainly, if you search my name and open city university, you'll either find that my research guide or my own personal page, and just I'm happy. If people want to drop me emails and chat about key tones and performance or any other aspect of performance, I'm happy to do so. And you look, hopefully I enjoyed this very much, so Maybe in a couple of years time we'll come back and revise what we got right, what we got wrong.

I'll tell you. I'll tell you what I'm always up for, that I don't always get it right. I've gotten it wrong plenty of times in my coaching career, that's for sure. People point that out to me on a daily basis. But if you do have, if you have any research that's catalyzed from all the you know, crazy ultra runners and listening to this podcast, then you, then you, then you owe me another, then you owe me another, another showing here, so I'll take you up on the offer Very good. Very good.

All right folks. There you have it. There you go. Much thanks to Brendan for coming on the podcast today. I told y'all during the intro that he is a fantastic communicator and he certainly lived up to that promise throughout the course of this podcast. Thank you, thank you. Thank you, brendan, for coming on and enlightening all of us, and I hope we get to bring you back on the podcast soon. I also promised during the intro of this podcast to provide some color commentary on the space as a whole, and we are going to get into that right now.

This next little section are. It contains my opinions and my opinions alone, not not the opinions of the guests or any of our other coaches that I work with or anybody else but me, the host. So if you have an issue with them, come at me directly. I certainly don't mind it. Keep that in mind as I am walking through this. I want to get down to brass tacks, for do I recommend ketones? And also down to brass tacks on the marketing side of it, both of which we touched on during the course of this podcast.

First off, from ketone use as an ergogenic aid. This is a big no for me, and the reason it is a big no kind of falls along two tracks. First track is the performance track and within that first track there's two different prongs. I don't think that the that the research indicates right now that there is a performance benefit for using ketones within an endurance context. The second part of that is, even if there was a benefit and let's just say it's 2%, roughly 2%, as we talked about during various points during the podcast even if it was 2%, there still is the potential that you can screw it up, and that potential is actually quite high because there are ketones in various formats. They flat, they affect the blood biochemistry and blood ketone levels to certain extents and even have been purportively manufactured to affect blood ketone ketone chemistry differently.

Because of this second nature, because it's hard to actually achieve the intervention in the first place even if the performance benefit were true, I would probably still say no, because that is a very narrow thread to actually pull off when you're talking about a real athlete and the real world with a real situation. Just think about it. You can try this all in training that you want, but once you get out into a race, you have different food stuffs in your system and all these other things are going on, it's going to be really hard to hit that optimal level of blood ketones that is purported to produce some type of benefit. So even if you could do it, it would still be a no for me, just simply from a pragmatic standpoint. Pulling it off, I think, is difficult and also rife to actually have the potential to make you worse, and as a coach, I want to make people better, not make people worse. My first kind of ethos is do no harm. Going back to the Hippocratic oath Not that I'm a doctor or anything like that, but certainly from a coaching perspective, I want to put athletes in a situation where they're better, not worse, from the interventions that I'm giving. So that's a big no for me. Second part is on the adaptive process, and here, sure, maybe I don't think there's enough research to indicate that there is an additional adaptive benefit. We're going to improve heb and global mass, we're going to improve muscle protein synthesis or anything like that. Based on the current literature that is out there, however, there's likely no negative associated with that type of intervention. So if you want to go after it, go ahead and go after it, but I am not putting it not even near to the top of my list of things to do from a recovery or an adaptive standpoint, I would still rather have athletes focus on adequate calorie intake intake, adequate protein intake, adequate carbohydrate intake, adequate sleep all of which we've talked about in previous versions of this particular podcast.

Now we get into the sticky marketing side of things and let me just be frank with everybody. The marketing coming out of the Keto manufacturers is disingenuous at best and flat out lot buying at most, and we touched on a lot of that throughout the course of this podcast. But whenever I see marketing that takes pieces of research and extends that research into claims that are no longer valid or don't have the right context wrapped around them, that's disingenuous. And here's why it's disingenuous Is that there are people within the walls of all those companies that should know better. They should know the research, they should know the context that's wrapped around the research, and somebody should be an adult in the room and look at some of these claims and say you know what? We are not telling this story in an authentic manner. This is not genuine marketing, because we are distorting the research in some way, shape or form in order to have a reported benefit with our particular supplement.

Now, let me just take a personal example with this, because I could do this type of marketing within my own coaching, within my own coaching practice. I just happened to coach several people who have won the Western States 100. I coached Casey, I coached Casey Lichtig, I coached Ryan Sands, I coached Timothy Olson, who won Western States twice, and I coached Steph Howell. It would be a huge feather in my cap for me to say that I coach for Western States winners, and that is true. I coach four of them. However, it would be a disingenuous statement because the entire story is I only coached one of them, casey Lichtig, when she was actually running. The other three I just happened to coach later on in their coaching careers.

If I made that statement I coach for Western States 100 winners I hope that the community would roast me just in the way that I'm roasting a lot of these companies, because that would be a disingenuous way to present what I have done with my coaching career in order to advance, in order to market it. It's something that I could easily do, but if you look at all of the marketing that I've ever put out, you won't see anything related to any type of claim like that. In fact, I tried to steer clear of taking credit for any of my athlete results, even when I am working with them, during the time of which I have had a lot. So when you see these disingenuous marketing claims, it should be a big red flag for you to run, not walk, 180 degrees in the opposite direction, and that is something that I certainly would do as a coach and as a practitioner in this area, not only with these types of supplements, but other ones that have run afoul with this in the past.

That is my spiel on the marketing side. I hope you guys stay safe out there and you examine a lot of these claims critically and not take them wholeheartedly from the influencer crowd, who tend to just repeat and amplify a lot of the messaging that is coming out of the companies in the first place. I hope you guys do take all of that to heart. I do appreciate everybody listening and, in particular, everybody listening through this extremely lengthy outro. If you like this podcast, please share it with your friends and share it with your training partners. If you thought it was interesting, you can share it with a ketone influencer and then ask them what they think. That should be quite fun. In any case, you guys, that is it for today and, as always, we will see you out on the trails.