Where ketones shine is in the context of if there's a deficit, if there's a metabolic deficit, if there's a brain energy metabolism bottleneck. I view exogenous ketones as a powerful tool to further augment the therapeutic efficacy of a ketogenic diet.
Let's talk about exogenous ketones. So, endogenous ketones, your body naturally produces them, and exogenous ketones are basically things you can drink that provide ketones for your body. And I'm joined by Dr. Dominic D'Agostino. So, if you know, he goes by Dom. He's well known within the ketone world. He's a very well known scientist, researcher. He's a professor at University of South Florida School of Medicine. A lot of his research focuses on metabolic health, on ketones, on ketogenic therapies. He's done a lot of work with the Department of Defense and safety in divers and military and hyperbarics and all this exciting, really fascinating work and how do ketones play into this? Really with a goal of being how to treat medical conditions, how to make things safer for a lot of individuals in a number of different areas. And he knows so much about exogenous ketones, which is why I was really thrilled to have him join us to talk about this. Now, he gets into a lot of detail. He knows so much that he gets into a lot of detail, but we try to cover the overarching parts of what are exogenous ketones, why would you use them, which ones would you use, and of course none of this is advice. This is just sort of his what he knows about it, all the research and all the knowledge. And we hope it's helpful and we hope you enjoy this very thorough discussion on exogenous ketones with Dr. Dom D'Agostino. Dr. Dom D'Agostino, welcome back to Metabolic Mind. It's great to see you again.
Great to be here. Thank you, Bret, for having me.
Oh, my pleasure. It's always a pleasure to talk to you. I mean, you know so much in this field of metabolic health and ketones and metabolic interventions. So, before we jump into the interview, I always like to ask, what is one thing that you think medical science or medical practice gets wrong that you wish were different?
Yeah, I have to say the idea that changing your metabolic physiology can change your brain energy metabolism and also the neuropharmacology of your brain. So, just appreciating that, I mean, that's not a controversial statement. You can look at the literature supports that. For example, a ketogenic diet has neuroprotective anti-seizure effects. So, we should appreciate that and then want to understand fundamentally why that happens so we can apply that to other disease states.
That's very well said. Well, thank you. There's so much we can talk about, but today I really want to drill down on exogenous ketones. So, endogenous ketones, the ketones our body produces, and exogenous ketones, ketones that we can ingest in some form. And it seems like I remember, you know, when exogenous ketones were just started, there was salts and esters and barely any products. And people would come with like little baggies full of white powder that you would be like, "Try this. Check out this ketone." Now, it seems like everybody is promoting their own form of ketone and, you know, podcasts are talking about it and you see commercials about it. So, it seems to have exploded. So, I think we just need to take a step back and say, "What are exogenous ketones? How are they similar or different from endogenous ketones? How can we use them?" So, let's get the ball rolling with that. Just give us your sort of high-level view of what is the basics that we need to know about what exogenous ketones are?
Yeah, and I think people, I mean, listening to the podcast already know what ketosis is, right? And there are different ways to achieve ketosis and different ways to achieve and maintain sustained ketosis. And, you know, at the very we all know about fasting, you know, short-term fasting, long-term fasting, that's not sustainable, right? There's intermittent fasting, that's one way to achieve it. The ketogenic diet, of course, which is the standard of care for drug-refractory epilepsy, over 100 years history. And so there's like at least 10 ways to get into ketosis. So that's two. And then there's ketogenic fats. I'll kind of go down the line. So a ketogenic fat would be a type of a lipid or fat that you consume. In this case, we're talking about medium-chain triglycerides, which are typically from coconut oil or palm kernel oil. And these are typically eight carbon or 10 carbon. We consume them, and some of these on clinicaltrials.gov, if you type in ketone supplement, you get about 150 hits. So it's important to acknowledge that some of those hits of a ketone supplement are actually MCT oil. That's medium-chain triglyceride oil. So these MCT oils are often added to ketogenic diets to further augment and enhance therapeutic ketosis.
The big difference there is what separates them from other fats is just that they are converted in the liver much more quickly to ketones.
Is that correct? Is that a correct statement? Okay. Whereas like saturated fats and other polyunsaturated fatty acids aren't converted sort of that efficiently in the liver.
Yeah, that's right. And I would go a little bit further that so MCT oil is a saturated fat. So that's important because that can, you know, elevate LDL, and that's another story like coconut oil. And so it is a saturated fat, but unlike long-chain fats, MCT oil goes right to your liver, and the liver does not have the capacity to use ketones as an energy source. It lacks an enzyme succinyl-CoA transferase, so that actually helps, you know, evolutionarily speaking, the liver's not going to be greedy and suck up nutrients like it does everything else, like amino acids and glucose for glycogen. But it spares the ketones, so it produces ketones. Those ketones get into circulation and then via the monocarboxylic acid transporter, the ketones get into the brain. So, similarly, when you consume exogenous ketones, which we can get to, they do go to the liver and they're minimally sort of processed by the liver, excluding another category I'll talk about, and then they get into circulation and then they become super fuels. They become a source of energy for peripheral tissues, for the heart, and for the brain. Skeletal muscle does use some, too. The kidneys and different organs. And so, there are different classes of ketones. So, can we just drink ketones? So, to do that, so the ketone in its simplest form is beta-hydroxybutyric acid. And if we were to consume, and this was like the first thing I looked at. It's just like, well, just buy beta-hydroxybutyric acid. Yeah, try to drink it. It's highly acidic and it's not super bioavailable. And if you were to consume about 10 g of beta-hydroxybutyrate acid, which there are supplements coming on the market that do have acid as a formulation. It needs to be diluted. But if we just consume beta-hydroxybutyric acid, it's quite acidic and a 10-g dose would transiently cause a metabolic acidosis. That would be compensated for in healthy people through respiratory and renal compensation. But if you consume a large amount, and we've seen this in like our animal models, you could have a pretty big anion gap of like, you know, typically it's like 4 to 12. And we've seen it in, you know, 15, 20, approaching diabetic ketoacidosis if you titrate the levels up. So, that may be something that people don't think about. So, from my perspective, it's very important to deliver exogenous ketones in a buffer and also make it more stable. And the next categories that we have, you know, ketogenic diets, MCT oil, ketogenic fats, beta-hydroxybutyrate or acetoacetate, so that's something we're also looking at. And then there's beta-hydroxybutyric acid salts, BHB salts, and acetoacetate salts we could talk about cuz they might have applications for seizures. So, a ketone salt that's sold in the little packets that people are pushing to replace the ketogenic diet. And there's many, and they do have, you know, a lot of emerging science behind them. So, that would be in a category of like bioavailable natural ketones.
And so, another version we hear about is an ester. So, just real briefly, how is an ester different?
Yeah. Okay, so an ester, I think of an ester, a ketone ester, as I actually think of it as a drug, a ketone ester, especially the ones that are commercially available right now. So, a ketone ester is you take a ketone and you combine that to a molecule with an ester bond. So, that could be glycerol, you could put three, like a triglyceride, you could have a triester, you could have glycerol acetoacetate triester, we've been working with that, you can glycerol beta-hydroxybutyrate triester. So, you drink it, the glycerol gets, you know, it gets hydrolyzed off and then the ketones go into circulation. But, one that is potentially problematic is the one that many people are using. It's 1,3-butanediol beta-hydroxybutyrate monoester, which we've used, we've published on that in different studies. And also 1,3-butanediol acetoacetate diester. So, 1,3-butanediol is like a prodrug for ketones and it's a ketone alcohol. It's technically a glycol or dialcohol. So, when you consume 1,3-butanediol, it is also being sold as a ketone ester. It takes up a large portion of the market share right now. And what's interesting to know, and we've done quite a lot of work with it and had positive results with it and negative in some. And we've published a paper, Ben Bikman just published a paper that replicated kind of our results. 1,3-butanediol on a per gram basis, the liver has to work just as hard on a per gram basis as it does with ethanol. So, what does that mean for a person that's consuming 34.4, 30, 34.5 g is the FDA generally recognized as safe level. If they were to consume that in one dose, about 40% of people experience dizziness. And there are no really long-term studies on this. There's a paucity of long-term studies. There's one case report by Dr. Mary Newport. It's actually her husband had Alzheimer's with a beta-hydroxybutyrate monoester. And I think 128-day study that was actually published by the group that makes it and they reported, you know, dizziness, nausea, things like that with consuming this dose. And you do need 34.5 g pretty much per day to keep you in a mild state of ketosis. So, that makes 1,3-butanediol a bit problematic. In our context, we were using it for military operations. You take a shot of this stuff and then before you go diving. And we never envisioned, you know, 15 years ago, we never envisioned that people would be like buying this and using it as a supplement.
So, that's a really good point though. So, you're talking about the salts, the esters, and then the sort of precursor esters. And those are the ones that are most available probably right now, but also potentially most problematic cuz this leads to, like you said, a paucity of long-term research on these. So, let's step back again and say, well, what are people using them for and what do we know? So, we see them marketed for, you know, weight loss. We see them marketed for brain cognition. We see them marketed for physical performance. What do you see as sort of the most proven clinical benefits of the exogenous ketones?
I still have the stance, broadly speaking, I still have the stance. In our studies, we use them independent of the ketogenic diet. And for example, we did studies yesterday. We're doing them today, too, in the lab, where we acutely administer them and within 30 to 60 minutes, animals are put inside a hyperbaric chamber and at five atmospheres of oxygen, it causes a very powerful tonic-clonic, you know, grand mal seizure. And if you're in a state of high ketosis, independent of following a ketogenic diet, this can delay seizures from 200% to up to 600%. And that, in our experience and from all the research published, the anti-seizure neuroprotective effect is above any anticonvulsant drug that we know of. So, an exogenous ketone, I always thought that, you know, getting into this before metabolic psychiatry and everything, why are people not using this for seizures? So, the research that was being funded was the war fighter dominance program by DARPA. And there was some compelling data to show that ketone esters could enhance exercise performance. Not much, but it tends to enhance exercise performance not so much in healthier people, but in older people. The new research is showing that. It is sort of less robust than we thought it would, and I tend not to talk about performance stuff. I talk more about the therapeutic effects. But where ketones shine is in the context of if there's a deficit, if there's a metabolic deficit, if there's a brain energy metabolism bottleneck, I view exogenous ketones as a powerful tool to further augment the therapeutic efficacy of a ketogenic diet. So, in the context of 95% of most applications, the diet is really going to do the big lifting. And then through precision, personalized, prescriptive diets for the individual cuz everybody is a unique metabolic entity, we can then titrate the level of ketosis by having them drink a fruity drink, you know, that tastes good or a chocolate drink or whatever that has the ketones in it and ideally not 1,3-butanediol or a 1,3-butanediol-based ester, and then adjust the diet from there.
I'm glad you brought up the diet. So, let's talk about the diet for a second. So, you know, when you're on a ketogenic diet, you're producing ketones and you are frequently improving your metabolic health by, you know, reducing your carbohydrates and getting into the fat burning mode, and it changes your metabolic switch. So, you're really doing both, producing ketones, improving your metabolic health. If you just drink ketones and are eating a high-carb diet, you're getting ketones, but does the ketone itself do anything for your metabolic health, or are you now completely missing that part?
Yeah. So, the people that sell ketones will say, "It is definitely improving your metabolic health. Consuming exogenous ketones does have beneficial effects. It's very context-dependent, but it's also dependent upon, you know, the state of the individual." And as we age, like these things probably have, you know, a better effect. Then there's also the different types of ketones. If your beta-hydroxybutyrate, D-beta-hydroxybutyrate levels are off the charts, that is, I used to think that that was where you wanted to be, but our research was basically, you know, showing that more ketones are not better, and maybe could it actually induce like a manic state because, you know, I've had my ketones up high. I've experimented with like every, probably taken more exogenous ketones than anybody. And they do have subjective effects, and they have effects on objective biomarkers. And I think that if your ketone levels are high and your glucose levels are normal, that represents a potential energy toxicity. And if your ketone levels get high, that can cause reductive stress. And reductive stress over time is not good. And that's kind of why you want to balance the...
Yeah, I mean, it presents us a scenario that like has really never existed in natural evolution, in natural state for forever to have high glucose, high insulin potentially, and high ketones all at the same time. So, it sounds like you're saying it could trigger things like a manic episode. Are there other things that worry you about that combination, though? Eating a high-carb diet, having metabolic dysfunction, high insulin, and taking exogenous ketones?
