RHR: Understanding the Science of Metabolism and Ketones, with Dr. Latt Mansor

In this episode, we discuss:

• The basics of ketone science and why the brain needs ketones to function, especially in the absence of excess glucose
• An overview of the body’s methods for generating ketones (endogenous ketones) and inducing ketosis
• The problems with using supplemental ketone salts for performance
• How ketone diols operate in the body versus ketone salts and ketone esters
• What various factors affect blood levels of ketones with exogenous ketones
• The biological effects of ketones on anaerobic metabolism
• How exercise affects the metabolism of exogenous ketones and the role of exogenous ketones in exercise recovery
• The optimal use, including dosages and frequency, of exogenous ketones for improving performance and recovery
• How to use exogenous ketone diols for maintaining focus and improving cognitive performance
• Who may benefit from supplementing with ketone diols, and whether there are any contraindications based on diet, lifestyle, or genetics
• The emerging research on ketones for treating traumatic brain injuries and conditions like chronic fatigue

Show notes:

• “14-Day Ketone Supplementation Lowers Glucose and Improves Vascular Function in Obesity: A Randomized Crossover Trial” by Jeremy J. Walsh, Helena Neudorf, and Jonathan P. Little
• “Exogenous Ketones and Lactate as a Potential Therapeutic Intervention for Brain Injury and Neurodegenerative Conditions” by Naomi Elyse Omori, Geoffrey Hubert Woo, and Latt Shahril Mansor
• Watch the HVMN test and measure ketone levels in real time
• Visit hvmn.com/CHRISKRESSER and use the code CHRISKRESSER for 20% off
• Learn more about the Adapt Naturals Core Plus bundle or take our quiz to see which individual products best suit your needs
• If you’d like to ask a question for Chris to answer in a future episode, submit it here
• Follow Chris on Twitter, Instagram, or Facebook
• Get your free LMNT Recharge Sample Pack when you purchase any LMNT product at Kresser.co/lmnt
• Visit Paleovalley.com/Chris and use the code KRESSER15 to get 15% off your order
• Go to ZeroAcre.com/Chris and use the code CHRIS at checkout for free shipping on your first order

Hey, everybody, Chris Kresser here. Welcome to another episode of Revolution Health Radio. I’ve talked a lot over the years about the benefits of nutritional ketosis and ketogenic diets. [I provided] a lot of information about how to get into ketosis through diet [and] all of the different considerations. And we talked a little bit about exogenous ketones, the ketone supplements that you might take to help induce ketosis or raise your level of blood ketones. But there have been a lot of problems with ketone salts and ketone esters, which are the main two types of ketone supplements, over time. Ketone salts often just don’t really move the needle very much. They don’t raise blood ketone levels. And ketone esters have the opposite problem. They can raise them too fast and lead to a big spike, and that can cause nausea, discomfort, and they taste disgusting. I think anyone who’s taken ketone esters knows what I’m talking about.

So I’m really excited to welcome Dr. Latt Mansor as my guest today. He is a global expert in ketosis, and particularly exogenous ketones. He holds a PhD in physiology, anatomy, and genetics from the University of Oxford, where his research focused on the metabolism of type 2 diabetic heart and hypoxia. And we’re going to talk a lot about ketone diols, which are a relatively new form of exogenous ketones that are much easier to take, have a much more optimal form of ketone supplementation because they lead to more stable levels of blood ketones, they don’t taste disgusting, [and] they’re more affordable. And I’m using these myself; I’ve recommended them to patients and the clinicians I train, with really good results.

We’re going to do a deep dive into exogenous ketones, who might want to use them, how to use them effectively, different considerations and use cases, and just how you can get the benefits of this new form of ketones. I hope you enjoy the show. Let’s dive in.

Chris Kresser:  Dr. Latt Mansor, welcome to the show. It’s a pleasure to have you on.

Latt Mansor:  Thank you for having me.

Chris Kresser:  I’ve had over many years, lots of episodes on nutritional ketosis [and] the benefits of it. But I always like to revisit this topic because I think there’s so much new interesting research coming out over the last few years. Now especially, the general public is so much more aware of ketones and ketosis and what some of the applications might be both for people who are trying to improve their performance and recovery as athletes or just trying to be able to think more clearly throughout the day and stay focused, and, of course, for the application of ketosis in a variety of medical conditions like diabetes, neurodegenerative conditions, traumatic brain injury, etc. Why don’t you tell us a little bit about your background, how you got interested in ketosis, and then we can dive in and just do a brief overview [of] some basic terms for people who are less familiar, and then we’ll do a deeper dive into the science of ketones.

Latt Mansor:  Sure, sounds great. I [was] born and bred in Malaysia; I grew up in Malaysia. And then I left the country for the first time and did my undergraduate abroad in the [United Kingdom], in biotechnology [at the] University of Nottingham, and then I moved on and did my master’s also in biotechnology. And this time, it was my first time in the [United States]. I did my master’s [at] Columbia University in New York. Then I thought, “I’m done with research and science. I want to start earning money.” So I got to [looking] for jobs and finally landed a job. It was a tough time; it was 2010, [and] it was recession time. And as an international student at that point, it was very, very tough because you needed a green card and sponsorship and all that stuff. But ultimately, I did land a clinical trial coordinator job with a pharmaceutical company in New Jersey called The Medicines Company. I worked for them for half a year, and then they promoted me to full time and flew me to Munich, Germany, and [I] worked in their German office for a year before I got inspired again by the people within the company to apply for my PhD. This time around, I decided to apply for a PhD in the [United Kingdom] instead of the [United States], because in the [United States], it takes about five, six years. In the [United Kingdom], it takes three years because I already had a master’s [degree]. So that makes a difference. Because usually, people may just move straight in from undergraduate straight to a PhD in the [United States]. That comes with all the fundings, and then the first two years, they’ll make you take some master’s courses and stuff.

So I started my PhD research in cardiovascular disease and diabetes. I looked at metabolism of the type 2 diabetic heart in hypoxia, which is [a] low oxygen environment as a subset of heart attack, no ischemia, where you have lack of blood going into the heart, and hypoxia is one of the subset[s] of that condition. So all in all, I have always been really interested in metabolism [and] physiology, just because [in] my family, my dad’s side has [a] high prevalence of heart attack, and my dad passed away from [a] stroke. He had a heart attack a few years prior. My mom’s side has [a] really high prevalence of obesity and diabetes. So together, you may tell me that that’s not the best genetic combination. So I think that was what got me into learning more about these diseases and learning more about human physiology, in general, and human metabolism, in general. Because only then I realized there are so many things that I could potentially do in my daily life to improve my health and improve my lifestyle.

Chris Kresser:  Great. And I imagine in that research at some point, because you were focused on metabolism, you encountered ketosis and nutritional ketosis and became aware of how that was being used in these different contexts.

Latt Mansor:  Exactly, exactly. In fact, the irony was the first time I heard the term “ketones” even, it was known as just a side product, a byproduct of metabolism, a byproduct of respiration. Where we mainly use glucose and fats for energy generation, or [adenosine triphosphate] (ATP) generation, ketone just happens to be a side product. So that was the first time I heard about ketones. Not until later [did] I [look] more into diabetes and chronic diseases and metabolic inflexibility that ketogenic [diets] have been used to treat epilepsy for more than 100 years now. And then, companies popped up like Virta Health that use ketogenic [diets] to treat diabetes. And then, I started looking into ketones. Then I got hired by HVMN, which is the company I’m working for now, as the research lead. They had a $6 million contract with the [US] Department of Defense looking at the effect of exogenous ketones on cognitive and physical performance in hypoxia.

So that’s where my sort of expertise and my prior knowledge and experience [came] in handy. And basically, that allowed me to look really deep into the area of ketosis, of ketone metabolism, of the difference between endogenous ketones, what they use in [the] ketogenic diet to treat all these different diseases versus exogenous ketones, which is a supplement that you can directly consume to elevate your blood ketone levels in order to boost performance. And that was also a realization of these two different populations. One is the disease population. The other part is the high performance population. Essentially, they are both on the same spectrum. They are both on the human metabolism spectrum. One just [does] it much better than the others, and the other group has some form of dysfunction, whether it’s being caused by genetic factors or environmental factors or lifestyle factors.

Chris Kresser:  Yeah, that’s a great setup, and I think my take on where things are at now, just as a clinician who’s used ketogenic diets and also exogenous ketones with my patients for many years for many different reasons, is [that] I like that concept of a spectrum. There are people, for example, kids with recalcitrant and drug-resistant epilepsy, who have very, very severe, life-altering condition[s] that a very strict ketogenic diet that puts them in deep ketosis can be a game changer for them, can work when nothing else has worked and really change their quality of life. But they have to be very strict, and they often have to be in pretty deep ketosis to get that benefit. Whereas on the other end of the spectrum, you have a weekend warrior athlete, who’s working most of the week, then goes out and does a half marathon or a 5K or something on the weekend. Fundamentally, they’re healthy, but they’re just looking for an additional edge in their performance and a way of enjoying their weekend activities.

Then you have maybe an executive, entrepreneur, someone who relies on really sharp cognitive performance who’s just looking for that additional edge and everything in between. I think now, there’s a greater understanding of how ketones can benefit all of those different use cases or populations, rather than just people with metabolic disease or cognitive or neurodegenerative conditions.

Latt Mansor:  Yeah.

Chris Kresser:  So let’s just back up a little bit here because we probably [have] some people who are less familiar with what a ketone even is in the first place. Then we can talk a little bit about nutritional ketosis. Well, actually, let’s just start with ketones. I’ve heard you say why ketones might be looked at as the fourth macronutrient. We have carbohydrates, protein, and fat, traditionally considered the three macros. And I know you’ve said that ketones may be considered the fourth. So let’s talk about just the basics of ketone science, and we’ll go from there.

Latt Mansor:  Sure. I think a lot of people don’t realize how we are evolutionarily designed to produce ketones as well as metabolize ketones. Our own bodies produce ketones from fats, we break down fats and produce ketones whenever we are in a mode of starvation, or we are in a mode where we have little to no access to our carbohydrate sources, i.e., either blood glucose or our glycogen stores. And when that happens, our brain and our heart, organs, and systems that need to keep going, would run out of [a] source of energy, right? For example, our brain uses primarily sugar most of the time. What happens then if we run out of sugar [because] either we’re going through fasting, or we’re going through a ketogenic diet where we just restrict the access to carbohydrates? That’s when our body knows it needs to break down fat to produce ketones to then deliver to the brain. But then, one might also ask, “Why can’t the brain directly metabolize fats like the rest of the body, like muscle cells or in the liver, where it can use fats and other substrates to build glucose via gluconeogenesis?” The answer lies within the blood–brain barrier, which is a thin layer of epithelial cells that stops bigger molecules [from entering] the brain via blood. And glucose can answer that because it’s a relatively smaller molecule compared to a fatty acid. Because fatty acid has a long carbon chain that inhibits it from going through the blood–brain barrier.

So whenever we are in the state of [a] low-carb, low-food, sort of environment or condition, the brain needs to access some form of substrates in one way or another. And this is where ketones come in. The three main ketone bodies that we produce in our bodies are acetoacetate, acetone, and beta-hydroxybutyrate. And the last one, beta-hydroxybutyrate, or BHB for short, is the main ketone body that is being used for metabolism and also the main ketone body that has been transported in our blood. Whenever people say, “Oh, I measured my blood ketone levels via finger prick, either [with a] Keto-Mojo or Abbott Precision Xtra sort of ketone meter that you can get from Amazon, they are essentially measuring the blood BHB. So that’s where the idea of okay, ketones being the brain preferred fuel, because then with the existence of exogenous ketones, meaning the ketones you didn’t produce yourself in your body, but rather, you can consume directly to increase your blood BHB levels, it allowed us to really examine these organs. When there is presence of glucose, would they still take up ketones? And the answer is most of these organs, the heart for sure, upregulate the uptake of ketones independent of the other substrates, meaning that the other substrates will still carry on to be taken up. But whenever ketones are available, it will always take up ketones, as well.

Chris Kresser:  Does it take them up preferentially? Or does it take them up at similar rates to other substrates?

Latt Mansor:  So it is similar rates, and it’s proportional to the availability of ketones. And what they have seen is that other substrates, if you increase the blood concentration of the substrates, they ultimately reach a plateau because of the saturation of transporters. So [for] glucose, you’ll have glutes, which are glucose transporters, and [for] fatty acids, you have fatty acid transporters. At some point, when you increase the substrate concentration in the blood to a certain extent, these transporters get saturated, and they reach a plateau in the uptake. I don’t know whether it’s because the ketone[s] that they’re providing in these studies are not concentrated enough, are not high enough to reach the plateau, but they have seen a really directly proportional uptake relative to the availability of the ketones, meaning that they still haven’t reached that saturation point or plateau yet. Which is quite interesting.

Chris Kresser:  Okay, so let’s talk a little bit more about [the] methods of generating, inducing ketosis, generating ketones, the two primary being endogenous, like we produce them ourselves, or we get them from a supplement of some kind.

Latt Mansor:  Yeah. So one, let’s talk about [producing ketones] ourselves. And I talked about this earlier a little bit on intermittent fasting and [the] ketogenic diet. So the main condition that you need to be in is to have low carb storage. So you can achieve that via just not eating, i.e., fasting, or via a diet that severely restricts your carbohydrate intake, which is a ketogenic diet. So then, when that happens over time, one day, two [days], three days, especially when you go on a longer fast, you will see a huge increase in your blood ketone levels two to three days in if you are fasting for that long. For [a] ketogenic diet, because you still have some form of intake and some form of calories, it depends, from person to person, obviously, but you may see the increase in your blood ketone levels not as starkly, not as [drastically] as you would if you fast for a long time. So those are endogenous ketones, internal ketones that you make in your liver.

Exogenous ketones, however, are relatively new, I would say in the past 10 years or so. I think the first few types of exogenous ketones that came out were ketone salts and MCT. MCT is medium-chain triglycerides, mainly found in lots of different healthy fats like avocado. I’m not sure avocado has it, but coconut oil, for sure, has MCT. And ketone salts are essentially BHB. Ketone bound with a salt molecule, either sodium, potassium, or magnesium. Now, the problem with these supplements, these two supplements, yes, it does increase your blood BHB to a certain extent. So just for reference, if you are not on [a] ketogenic diet and you’re not producing your own ketones, your blood ketone levels should be around zero to 0.1 millimolar. But if you are nutritionally in nutritional ketosis, the definition is anything above 0.5 millimolar. So what we have seen in studies is that with ketone salts and MCT, it increases your blood BHB up to about 0.7 to maximum, a little bit below one millimolar. And that’s when people started using ketones, exogenous ketones for performance. And [in] a lot of studies that use ketones salt as performance, they didn’t see any increase in performance. And then later on, they found out it’s because of two things. One is that it doesn’t increase your blood BHB to a high enough level, because for performance, the threshold of around 1.52 millimolar. And two, while it is dose-responsive, it is dose-dependent, you can take more in order to increase your blood BHB more. But because it is bound to a salt, you are significantly increasing the amount of salt you’re consuming, which also increases the risk of [gastrointestinal] (GI) issues. So that’s where it became an obstacle for these two supplements to be able to raise your blood ketone levels up to a higher level.

And then in 2017, that was when the first ketone ester entered the market, and our company HVMN brought that into the market for the first time. And that does very well in increasing blood BHB level. It can spike your blood BHB level within half an hour up to 3 to 5 millimolar. What is ketone ester? Ketone ester is essentially BHB bound with butanediol. It’s the bond that binds those two molecules that is called an ester bond. That’s why it’s called ketone ester. But nowadays, you get multiple, that’s just one form of ketone ester; this ketone monoester. Nowadays, you can get ketone diester, you can get C6 bound to butanediol, [and] you can get acetoacetate diester. So [there are] different forms of ketone esters these days, but the main more prevalent ketone ester [on] the market right now is ketone monoester. And then, do you have any questions, Chris?

Chris Kresser:  No, no, go ahead. I’ll circle back. I’ve got several questions. But you finish the exogenous ketones, and then we’ll have plenty to chat about.

Latt Mansor:  Sounds good. Sounds good. And then that was 2017. And then a few years down the road, a lot of cyclists started taking ketone esters, including those in [the] Tour de France, and it was out in the news and everything, and people were questioning should this be allowed. Because essentially, it is a macronutrient. It is not a drug, it’s not a stimulant, [and] it doesn’t directly increase or decrease your sort of physiology, the main processes like anabolic steroids would or performance-enhancing drugs would. It’s just taking glucose. That’s just a source of ATP generation, right? And more studies then came out that looked at ketone esters, some of which showed no improvement in performance. And of course, there’s that discrepancy in the protocols that they use, right? How do you use it? Do you use it fed? Do you use it fasted? Do you use it half an hour before? Do you use it two hours before? And then do you top it up? Do you want to make sure, all that stuff, all that difference in protocol obviously makes a difference. But then one paper came out, McCarthy et al., that showed that because you are spiking your blood BHB to such a high level, you are essentially decreasing the pH of your blood, which means it is increasing the acidity of your blood. And as a result, you are upregulating all your cardiorespiratory stress biomarkers. You’re increasing your heart rate, you’re increasing your breathing rate, because your body is trying to expel as much carbon dioxide as possible in order to neutralize your blood pH levels. And, as a result, these athletes, these cyclists did not get any performance gain. They didn’t do worse, it wasn’t detrimental, but they did have a much higher rate of perceived exertion. Meaning that you’re working out as hard or you’re feeling that subjectively you’re working out as hard, but you’re not getting any benefit. So clearly, you don’t want that.

And two years ago, HVMN decided to come out with Ketone-IQ, which is our latest current flagship product, that is essentially butanediol. Chirally pure (R)-1,3-butanediol. So when I said earlier ketone ester is BHB bound with butanediol, we basically took half of it and made it a drink. And the reason why we evolved our ketone ester product into this, are three reasons, right? One is [that] ketone ester tastes really, really bitter, and it was really hard to flavor. In fact, [for] our $6 million contract with the military, one of the tasks is to improve the flavor. And we worked with Monell Research Center, which is a sensory research institution, who are experts in flavoring and masking flavors and all of that. They’ve done everything they could. They put artificial sweeteners, natural sweeteners, dairy, coat this, coat that, [and] it didn’t do anything. It was really bitter.

Chris Kresser:  I can attest to that personally and with patients. I had people vomit, people have just extreme reactions to both the esters and the salt. So I think this is a very worthwhile innovation and necessary to get it to make it accessible to the mainstream, because most people are just not going to tolerate the taste of ketone esters.

Latt Mansor:  And in fact, [in] some of the studies, it has negative results, just because half of the people were puking their lungs out. So I mean, how can you expect these athletes to perform well if they’re puking their lungs out? And also having diarrhea from the salts or whatever. So taste, [and] price. It was about $40 per 25 grams of ketone ester versus $10 per 25 grams of Ketone-IQ. So that’s a huge difference there. And thirdly, obviously, the physiological change, the pharmacological aspect of ketone ester versus Ketone-IQ, as well. Ketone-IQ does raise your blood ketone levels significantly, but because butanediol goes through your liver and gets converted into BHB and gets released slowly into your blood, you don’t spike your blood BHB in the same manner as ketone ester, and therefore, you are avoiding that acidification of blood. And therefore, you’re also avoiding all those increases in cardiorespiratory stress biomarkers. And because it is being modulated and monitored by the liver, the liver also gets signals from the rest of your body to really make sure that, if you’re in a state of abundance, where you have enough substrates, the release will be kept. And if you don’t, then the release will increase that sort of way, which is a great gatekeeping mechanism that we realize with Ketone-IQ.

Now, [I’ll] give you one simple example when I talk about this. So three of us, Geoff, Michael, and myself—Geoff and Michael are the cofounders of the company. We were on a podcast to introduce Ketone-IQ when we first launched it. And all three of us had three different doses of Ketone-IQ. One of us took one dose, which is 10 grams, the other took two doses, 20 grams, and the third one took three doses. All of us had above 1 millimolar blood ketone levels after in the middle of our podcast. But I believe it was Geoff. Geoff was fasting that day, and he had a much higher blood ketone level as a baseline. So he probably started around 0.8, and this video is up on our YouTube [channel], as well. I’m sure you can find it. It’s on [the] HVMN podcast.

Chris Kresser:  That sounds entertaining to watch that.

Latt Mansor:  Yeah, we basically took a shot on camera, recorded our blood ketone levels live, and showed it to our camera. And even at a higher level when Geoff started at a higher level, it capped at 2.3, 2.4, I believe. And that’s the same as what we’ve seen in our internal pharmacokinetic study, where when we increase the dose up to 1 gram per kilogram of body weight, so imagine if you’re a 70-kilogram person, you are having seven shots of Ketone-IQ in one go. [I] do not recommend that because that is not our recommended dose. But we had to do that for our pharmacokinetics study for safety and tolerability. We saw a plateauing around 2.5 millimolar, which is great because then we know that your body can actually limit and [make] sure that your blood ketone level doesn’t go way too high. Because what I tell people about metabolism is that it’s not about piling on something that is good. Just because something is good doesn’t mean more is better. Metabolism is all about optimal range. You have to have the optimal pH range; you have to have your optimal temperature range. You can’t be too cold, you can’t be too hot, otherwise, you know your body is going through something wrong.

And it’s the same here with ketone levels. [With] blood ketone levels, you want to be within that Goldilocks zone. So what with ketone ester, because half of it is BHB, it goes directly into your blood, and that is what spikes your blood BHB up. And when it is not regulated by any organs like the liver, it is very dose-dependent. So if you have three 25-gram bottles of those ketone ester[s], you will go up to 6, 7 millimolar. And we have seen that with our military project because we are using weight match dosing. So some of these guys are huge, right? So they’ll have 50, 60 grams of ketone esters, and they’ll feel ill afterward. They just genuinely feel unwell when you have that high of a blood ketone level. It’s the same thing and you can do that with any other substrates. If you overdose yourself with sugar, you will feel sick, right? If you have too much sugar, you will literally feel sick.

Chris Kresser:  Even water, right?

Latt Mansor:  Yeah. Even water.

Chris Kresser:  Too much water. Yeah, so I want to just review a little bit here because I think as we talk, I wanted to focus mostly on exogenous ketones because I’ve done a lot of podcasts on ketogenic diets and the benefits and how to optimize and different ranges of ketosis, etc. But we haven’t really done a deeper dive into the different types of exogenous ketones, how to use them, [and] what the considerations are. So just to summarize, with ketone salts, you have a pretty low peak. So they just don’t move the needle very much, in other words. And that was one of the main problems there. With ketone esters, [it] is the opposite problem. You had this huge spike; if you’re imagining a graph, you’ve got just a straight up line on the left, as it goes up, and then it just falls off really quickly. And you can have side effects on both parts of that journey going up and going down, right?

Latt Mansor:  Exactly.

A new form of supplemental ketones, ketone diols, have proven to be more stable in the bloodstream and easier to take than ketone salts and ketone esters. Global ketosis expert Dr. Latt Mansor joins Chris to reveal the biology behind ketone diols and why they have become the preferred exogenic option. #chriskresser #metabolism #ketones

Chris Kresser:  So if those are the sort of two bookends of the curves on the chart, then you have ketone diols, which kind of strike a middle ground there, where you have a slower rise in ketone levels, [and] then you have a peak, you just said, of around two to 2.5. So you don’t skyrocket into a range that could make you feel uncomfortable. But you also have a more extended persistent curve, meaning you’re staying in that optimal level of ketones for longer because you have a slower build, and then a slower decline in blood ketone levels. Is that accurate?

Latt Mansor:  That is absolutely accurate. And in the internal study that we did, as well, we all had to fast overnight, and we took it, and we had to prick ourselves every hour for six hours. So we got seven bricks because you get t equals zero as well as one prick. So we ran our fingers almost to prick ourselves. And we saw that even at six hours, if you’re at rest, you are getting your blood ketone levels above 1 millimolar still after six hours, which is something that we have not seen with ketone esters, as the drop is quite significant. Because you’ve sort of spiked it up, and then your body uses it really quickly, and then it goes back down.

Chris Kresser:  Yeah, yeah, that’s really interesting. And I’ll share some of my personal experience with Ketone-IQ toward the end. But I can say that I definitely can feel this difference because I’ve tried all the different methods of exogenous ketones, and I’ve also tried and still cycle through [a] ketogenic diet. So I’m familiar with how endogenous ketosis feels. But I want to talk a little bit more about the various factors that affect blood levels of ketones with exogenous ketones. You mentioned one of them, which is whether you’re in a fed or fasted state. So you’re going back to your experiment with the co-founders. If you’re in a fasted state, and you take 10 grams of exogenous ketones, you’re going to end up with a different blood level than if you take it right after a meal. So what are some of the other factors that might impact how ketones affect your blood level?

Latt Mansor:  Yeah, and this is a very interesting question, as well. So what we have received in terms of people reporting that when, oh, actually, in some studies, as well, whenever they have a fed demographic. These participants or athletes were fed before they were given ketone esters, [and] their blood ketone levels seemed to be a little bit lower compared to when they’re fasted. What we have seen in our Ketone-IQ study that we just completed with the University of North Georgia (it is under review right now with the Frontiers [in] Physiology journal), we did not see any difference if you’re fasted or if you’re fed, when it comes to blood ketone levels. I don’t know if that has something to do with butanol going through a liver versus half of ketone ester is BHB that goes directly into the blood. I don’t quite know what the mechanism is. I don’t think we do as a scientific community. But we have seen really interesting results with [uracil-DNA glycosylase preform] (UNG1) now that I’m talking about it. It’s the first anaerobic exercise trial that has ever been done. Because whenever we talk about ketones, exogenous ketones, people think of endurance exercise, people think of cyclists, people think of triathletes. But for the first time, we decided to do a true anaerobic test, which uses the Wingate anaerobic test. We asked these participants to go on five bouts of sprints on a stationary bike at 7.5 percent of body weight as resistance. And they have to go as hard as they can, and we measure the peak power, the average power, the velocity, as well as their fatigue levels. All of those parameters improved. They improved their peak power, they improved their average power, they improved their velocity, and they decreased their fatigue, as they go toward the last bout of their anaerobic test, which is super interesting. We didn’t really expect that to be that significant because we know that in an aerobic exercise, glycolysis and glucose, or dependency on glucose is still very much dominant and really, the preferred pathway of metabolism when it comes to that sort of exercise.

Chris Kresser:  Yeah, that’s really, really interesting and kind of flies in the face of conventional wisdom when it comes to anaerobic training. Was there speculation on what the mechanism was there?

Latt Mansor:  Yeah, I think we sort of concluded that the speculation could be something to do with signaling in the brain. Essentially, some form of [an] analgesic effect, similar to that of caffeine where you just feel less pain when you’re pushing through. Because [with] anaerobic exercise, essentially, the goal is to go as hard as you can, but as a result, it’s almost inevitable to have high buildup of lactic acid and the burn, and that muscle fatigue while you are in a hypoxic state. So we know the effect of ketones in hypoxia. That has been shown again and again to be very beneficial. But most of the time, it’s not that acute of a setting. It’s more of a hypoxic adaptation or mitigation of cognitive decline in hypoxia versus this anaerobic sort of setting. So I think it’s more to do with the brain and perception, and being in the zone versus purely energetics play here.

Chris Kresser:  What about exercise? If someone has recently exercised, how will that affect the metabolism of exogenous ketones? So someone who takes Ketone-IQ prior to a workout versus someone who takes it during a workout or after a workout. Is there any significant difference there?

Latt Mansor:  I would say if you are at rest, your blood ketone levels would obviously stay up longer compared to when you work out. As to whether you take it before, during, or after, I think if you take it before or during, you will probably see your blood ketone levels drop a little bit quicker. Whereas if you use it after, I personally haven’t seen any sort of measurement of blood ketone levels when people take it after exercise. One study that got really popular by Hespel’s group in Belgium looked at recovery. They looked at exogenous ketones and recovery when cyclists were given proteins, carbs, and ketones after exercise, 30 minutes after exercise and 30 minutes before bed. Unfortunately, I don’t think they measured blood ketone levels after because they’re like what’s the point? But what they did measure is the effect of the recovery or the outcomes of the compounding effect. Because three weeks after utilizing that nutritional protocol, they have seen an improvement of 15 percent increase in power output in the group with carbs, proteins, and ketones.

Chris Kresser:  Yeah, that’s amazing. And I mean, it’s probably the most significant benefit I’ve noticed is in both performance and recovery in long mountain bike rides, or when I’m backcountry skiing or even lifting weights, more anaerobic exercise in addition to cognitive benefits. But I want to explore a few different use cases and get some ideas from you on best practices for these different use cases, both in terms of frequency of dosing and overall dosing. I’m not asking you to give medical advice, but more just sort of scenarios here. So, since we’re on the topic of athletes and improving performance and recovery, take somebody who’s either a competitive athlete or someone who’s exercising fairly hard, whether it be running or mountain biking, weightlifting, etc. Is there sort of an optimal use that you would suggest or that has emerged in studies or in the work with the military, pre-workout and post-workout? How do you use it during recovery days? That sort of thing.

Latt Mansor:  Obviously, like you said, I’m not giving medical advice, but I can certainly share what all these studies are pointing toward, right? So we have our FAQ on HVMN.com, as well, if you want to search what’s the best use case for athletic performance, what’s the best use case for recovery, it’s also all there. It’s all based on all these existing studies. So when you talk about pre-workout and using it for performance, we recommend taking half an hour before, and then if your workout is longer than two hours, top up every 90 minutes into the workout, right? So in that sense, in terms of dosing, we generally recommend one dose whenever you take it, which is 10 grams. But most of our athletes, because all these studies are weight matched, they use between 0.3 to 0.5 grams per kilogram of body weight, which comes out [to] roughly around 20, 30 grams, so about two to three doses every time they take it. So our athletes, if you’re using it for performance, you might want to start with having two shots of 20 grams or 70 mils from the big bottle. If you’re taking the shots, then it’s two shots half an hour before you start exercise. And then 90 minutes into the exercise, top up another two, and then top up every 90 minutes thereafter.

In terms of recovery, like I said, the study that I mentioned earlier. You can take a half an hour after together with whatever post-workout recovery drink that you’re taking, your protein shake and all that. I don’t recommend mixing it into a protein drink. I don’t know. Some people might [like] it. I don’t. I like to take my shot and then wash it [down] with my protein shake. Some people like to take it right before bed, as well. I’ve [gotten] quite mixed messages around that. I personally like to take it right before bed. But some people find that they get too energetic or their brain is still too much awake if they take ketones before bed. So I think that really varies between people.

Chris Kresser:  Yeah, yeah. And that’s true in almost every case, in my experience, with these kinds, with supplements in general, ketones definitely. Even [with] endogenous ketosis, of course, there’s huge variation of how likely people are to produce ketones in response to the same [stimuli]. You can have two people following an identical diet, and you’ll see different ketone production in each of them based on a whole bunch of different factors that we don’t need to go into. And it could even vary from day to day, based on what’s going on, how all of those factors are varying.

I know from my own experience with this product and people who I’ve recommended it to, and patients and stuff, you mentioned you to just take the shot. Some people like to sip on it throughout the day. Given that even if you take the shot, the curve is fairly spread out, what would be the sort of half-life? If you were to take a 10-gram shot, how long would you expect that, for your blood ketone levels to stay elevated?

Latt Mansor:  Ten grams is quite low. So some people, maybe if you’re at rest, it will probably stay around three, four hours. Some people start to peak around two, and then they start dropping at three, four hours. But if you’re taking two doses, then it’s probably going to be a little bit higher. And I think one thing that you pointed out, a good point is that because the curve is quite smooth and slow anyway, it’s very slow and steady even at a higher dose. So whenever we run studies, or I’m talking to researchers—because if you drink a lot at the same time, obviously, [as] with any product, it’s going to have some form of side effects. So if they are taking more than four doses because of their weight, while they wait, and they have to match it, I usually recommend they divide that into two boluses. So take 20 grams half an hour before [you] work out, 20 grams right immediately before you work out, and then just hop up to 2 grams every 90 minutes.

Chris Kresser:  Well, if you’re doing an extended workout?

Latt Mansor:  Yeah, if you’re doing an extended workout, yeah.

Chris Kresser:  Yeah. And then let’s talk about someone who, let’s say, they’re not working out really intensely. They exercise, but maybe they’re looking more for a cognitive benefit or just maintaining focus. What would you suggest there in terms of how they use it?

Latt Mansor:  Some people like to take one shot, just 10 grams in the morning before they start work. Some people do it instead of coffee; some people do it stacking with coffee. There is no right or wrong here. There is no contraindication when you stack it with coffee. What I tell people is that coffee or caffeine is a stimulant. It increases your blood pressure, your heart rate, and it blocks your adenosine receptors to make you not feel tired or fatigued. And it may even increase your energy consumption, right? Your brain energy demand.

Ketones, on the other hand, is the fuel that meets the demand. So, in a way, it’s quite synergistic. But at the same time, some people, like myself, can’t drink too much coffee because [we] get jittery and anxious. So instead, I just use Ketone-IQ. And that works perfectly fine for me because I still get the alertness, [and] I get the focus without the jittery feeling.

Chris Kresser:  Yeah, one of my favorites, I do okay with coffee in the morning. If I drink it past 11 [a.m.], I don’t sleep. But I will often use some ketones. I’ll take a shot in the early afternoon after lunch because that tends to be the lowest energy point for me or at least mental focus. And I find that if I do that, it’s easy for me to just jump back in and stay focused, which is amazing. Because the only other things that seemed to have that impact were things that do have some level of caffeine. It might have been less caffeine than coffee, but still, I’m just so sensitive to caffeine that even small amounts in the afternoon would interfere with my sleep. So it’s been pretty amazing to have a different way of achieving a fairly similar effect. I mean, it’s slightly different, but in some ways better because it doesn’t come with those jitters, and it’s a more relaxed focus, I guess is the way I would describe it.

Latt Mansor:  Exactly. Yeah, that’s exactly how we say it. It’s relaxed; it’s subtle. And a lot of people got confused, right? Because we have been so conditioned with coffee. It’s like whenever we talk about energy and alertness, we think of coffee. So they’re like, how can you use the word[s] relax and energy at the same time? They get really confused. And that’s exactly how I describe it. It’s a subtle, relaxed focus. So you don’t need to jump off the wall kind of energy.

Chris Kresser:  Yeah, it doesn’t come with the anxiety that coffee can produce or any kind of caffeine.

Latt Mansor:  And in terms of sleep quality, as well, I think that’s a great point because a lot of people would want to avoid coffee closer to bedtime or even past afternoon. And ketones don’t have the same effect as coffee. So that’s why people like to use [a] ketone ester pick-me-up sort of after lunch.

Chris Kresser:  Yeah. I think you already addressed this, I believe, but I just want to clarify because I know people will wonder about this. Are there any contraindications, so things that would preclude somebody from taking ketone diols? And are there any dietary things that should be avoided concurrently? So [is there] anything that could counteract the effect, essentially, or interfere with the absorption?

Latt Mansor:  So I’ll answer the last question first. No, there isn’t anything. That’s the beauty of it because it’s a direct ketone that you consume. So even with food, with ketone diol, unlike ketone ester, we have seen there’s no diminishing effect on your blood ketone levels.

Chris Kresser:  And how about, let me ask one follow-up question on that, too. How about nutrients or supplements? [Are there] any minerals, vitamins, [or] anything else that anyone should be aware of taking concurrently? If someone wanted to combine it with electrolytes, for example, could they do that?

Latt Mansor:  That’s absolutely fine. I mean, it’s much better. I would rather you take Ketone-IQ and then combine it with electrolyte, than just take ketone salt. Because a lot of people are like oh wow, why don’t I just take ketone salt? Because it’s ketones and electrolyte, but then they’re bound. So you can’t have high enough ketone levels without overdosing yourself with the salts. So that’s a great suggestion. And I don’t know of any supplements or any form of products or food products that have [a] diminishing effect or detrimental effect or contraindication effect to Ketone-IQ.

Chris Kresser:  Great.

Latt Mansor:  Because ultimately, it is not a drug; it is not a pharmacological invention. It’s sugar. It’s fats, right? We can pretty much take sugar and fats with anything. That’s how I would see it. It’s just a substrate. And the first question was, are there people who shouldn’t be taking Ketone-IQ and all that? And I think the wonders of ketone is that, because we are evolved and designed to create and metabolize ketones, and this, even though it’s in the form of butane diol, your body will create BHB from it. And BHB is BHB is BHB. It’s the same molecule, and that’s what your body recognizes, and that’s what your body will use it as. So it will be the same BHB that you produce yourself as you would consume.

The only thing that I want people to know is that when you drink Ketone-IQ, about an hour after, you will see a slight drop in blood glucose. So if you are someone with a tendency to be in hypoglycemia, you might want to be a little bit careful and just make sure you check your blood glucose levels. Either you have a continuous glucose monitor or whatnot, just to make sure you don’t get into that hypoglycemic state where you will get chills and [will not feel well]. And if you do feel that, you will know that it is because of the hypoglycemic effect.

Chris Kresser:  Great. And then lastly, I know this is a huge topic, so we’re only going to be able to scratch the surface. But what is the research? How much research is there so far on ketone diols in disease states, whether that’s metabolic disease like type 2 diabetes or traumatic brain injury or anything that?

Latt Mansor:  That’s a great question. So, as far as diabetes [goes], there is already a study, even though we’ve only been out for a year and a half, there is already a published study using Ketone-IQ to lower blood glucose, published by Dr. Jonathan Little, from [the] University of British Columbia in Canada. And this goes back to what I was talking about, the glucose-lowering effect. And a lot of people, even though they see their blood glucose level drop 50 points, up to 50 points, they don’t feel hypoglycemic. They feel quite energetic, on the contrary, because the ketone is essentially being their main source of energy for the brain.

And for [traumatic brain injury], we are actually in the middle of applying for additional grants with the military because the military population has [a] very high risk of traumatic brain injury. So we are actually compiling a bunch of literature around exogenous and endogenous ketones related to brain injury in both animals and human work. So it’s looking very, very promising. In fact, last year, we published a review paper, myself, Geoff, and our scientific writer, Naomi, in Frontiers in Physiology. We looked at [the] potential use of lactate and ketones in treating traumatic brain injury and, as an extension, neurodegenerative diseases, because they both share a lot of hallmarks of metabolic dysfunction as far as glucose metabolism goes, as far as deficit in energy goes. Because in traumatic brain injury, you get a deficit in energy, and you get a hypermetabolism of glucose in the beginning. Forty-eight hours after you have an injury, the brain upregulates glucose metabolism. Some may say it’s being upregulated because we need the energy to deal with the damage, and some say that the glucose is being shoved into the pentose phosphate pathway to create [nicotinamide adenine dinucleotide phosphate] (NADPH), which will then help with the mitigation and recovery of the injury. But then afterward, they get hypometabolism. So they get a deficit and energy. And this is where ketone could potentially come in and really sits right in between that, the lack of energy and glucose metabolism to normal function.

Chris Kresser:  Yeah, fascinating. That might be a future episode, looking more in depth about how to use it in disease states. But yeah, thank you, Latt, for joining me and sharing all this. It’s really fascinating. I’m a big advocate of nutritional interventions that are safe and effective and easy to implement. So I’m always on the lookout myself for things like that. And not just any intervention, not just nutritional, things that have a pleiotropic effect that can, [to] put in layperson’s terms, [be] the rising tide that lifts all boats. The things that you can do almost regardless of what the problem is, they will help, and they can help in multiple different ways. And of course, that’s true of exercise, it’s true of a good diet, it’s true of maximizing your nutrient intake, and I found it to be true of ketones, as well. And the challenge has always been as we’ve discussed that there, if you’re not following a strict ketogenic diet because either you don’t want to or it’s contraindicated, or you want more carbohydrates in your diet for any number of reasons, there has not been an easy way to benefit from ketones because of the problems with ketone salts just not really raising ketone levels enough or ketone esters, which are arguably even worse because they raise them too fast and all the side effects associated with that. So ketone diols have really been a game changer for me and for my patients. I use Ketone-IQ every day, sometimes less, sometimes more, depending on what I’m doing. And it’s one of the few things that has just become a staple, something that I do every day along with electrolytes. I mentioned electrolytes; those are big for me, too, living in probably one of the driest places in the [United States] and at altitude. Both ketones and electrolytes have been game changers for me and my daily routine.

So for all the listeners, if you want to give Ketone-IQ a try yourself, you can go to HVMN.com/ChrisKresser, and they’re very generously offering 20 percent off for all of the Revolution Health Radio listeners. And there [are] two options there. One is the shots, and these are 10 grams. Just chug it back like Latt said he likes to do. And there you go. And then the other is the Ketone-IQ bottle, and those are 10 servings of 10 grams each. So it’s 100 grams in the bottle. And that’s just a different way of getting the benefit. If you’re going to be out and about, or you know you’re doing a really hard, long workout that day, that might be a better option than carrying 10 different shot bottles with you, for example. So it just depends on what your preferred use case is. I would encourage people to experiment and see what they like to do best, because there’s no one-size-fits-all approach. Latt, thank you again for joining us. I really appreciate it. And where can people learn more about your work?

Latt Mansor:  They can find me at LattMansor on all social media. And I also host the HVMN podcast that they can find on all podcast platforms as well as YouTube. And just a little bit of [a] teaser for your audience, as well, as we are talking about a potential episode on just therapeutics. Right now, there are quite a few researchers who are trying to look at myalgic encephalitis or chronic fatigue syndrome using Ketone-IQ. And we’ve got [a] patient who [has] been using it regularly, and her biomarkers have improved significantly. So I just connected her based in Canada with the doctor I spoke to based in Australia. So it could be an international collaboration to look at fatigue levels. And we are applying for a grant with [the] European Space Agency to use Ketone-IQ for radiation protection for astronauts, as well. So there you go.

Chris Kresser:  Very exciting. Yeah, we’ll have you back in a little while and talk about that research. And everybody, thanks for listening. Keep sending your questions to ChrisKresser.com/PodcastQuestion. We’ll see you next time.

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