The Peter Attia Drive - #375 - Ketogenic diet, ketosis & hyperbaric oxygen： metabolic therapies for weight loss, cognition, Alzheimer's & more

00:00:00.000 Hey, everyone. Welcome to the Drive podcast. I'm your host, Peter Atiyah. This podcast,

00:00:16.540 my website, and my weekly newsletter all focus on the goal of translating the science of longevity

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00:00:53.200 of the subscription. If you want to learn more about the benefits of our premium membership,

00:00:58.000 head over to peteratiyahmd.com forward slash subscribe. My guest this week is Dom D'Agostino.

00:01:06.500 Dom is a neuroscientist and professor at the forefront of metabolic therapies, including

00:01:11.020 ketogenic strategies, exogenous ketones, and hyperbaric oxygen. In this episode, we discuss

00:01:16.100 nutritional versus supplemental ketosis, clear definitions, thresholds for clinical ketosis,

00:01:21.360 and practical ways to achieve it while keeping protein adequate. Why the early transition into

00:01:26.600 a ketogenic diet can be challenging and how electrolytes and ketone salts can smooth that

00:01:31.180 on-ramp. The growing landscape of exogenous ketones, the salts versus the esters, 1,3-butanediol,

00:01:38.880 taste and insulin effects, and simple effective pairings such as caffeine, MCT, and alpha-GPC.

00:01:46.020 Ketogenic diets as metabolic therapy for cancer, especially glioblastoma, the prospects for

00:01:52.560 ketogenic diets in neurodegenerative diseases, including dementia and Alzheimer's disease

00:01:57.280 specifically, hyperbaric oxygen chambers, Dom's recommended protocols, practical barriers,

00:02:03.020 and the rigor of ongoing trials. When fasting and ketones shine as a situational tool for cognition,

00:02:09.640 workload, travel, and inflammation, and the carnivore diet as a ketogenic variant and what it implies

00:02:16.440 for certain autoimmune and metabolic conditions. So without further delay, please enjoy my conversation

00:02:22.540 with Dom D'Agostino.

00:02:29.100 Hey Dom, thank you for making the trip out to Austin. It's, boy, it has been a long time since

00:02:33.840 we've been in person. I'm afraid to hazard a guess as to when, but I know you and my brother see each

00:02:39.300 other a lot more, and I'm always getting pictures of you visiting him and him visiting you.

00:02:44.020 Yeah, yeah, Paul's amazing. He's a mentor to me, and as you are, through the health,

00:02:48.260 and Paul's like an amazing entrepreneurial mentor and a life mentor in many different ways. So

00:02:52.980 great to see you both. You guys are such uber high achievers in different domains,

00:02:58.140 and I think it's great to see you in person for one thing, but it's great to see both of you thrive

00:03:02.520 in doing what you do.

00:03:04.260 Well, the same can be said for you. Dom, you've been on the podcast a couple of times,

00:03:08.300 but I know that in podcast land, A, we've probably got hundreds of thousands of listeners

00:03:13.380 today that weren't listeners the first and second time you were on the podcast. And frankly,

00:03:18.260 those that were, I think it would be understandable that they've forgotten most of what we've spoken

00:03:22.260 about. And maybe just by way of background, I'll let folks understand how you and I connected.

00:03:27.360 I believe Ken Ford connected us back in 2011-ish, thereabouts. At the time, I was about a year

00:03:35.740 into experimenting with a ketogenic diet, having all sorts of interesting success with it for the

00:03:41.280 most part, once I got over the hump of figuring out how to do it. And I think we must have connected

00:03:45.660 at his institute, and then the rest is kind of history. We then, through our friendship,

00:03:50.900 became very deeply involved in the testing of the earliest generations of various forms of

00:03:57.760 synthetic ketones, a topic we will undoubtedly get to today because it's impossible to imagine how much

00:04:03.540 proliferation there has been of these things that were, I mean, literally, you're sending me like

00:04:08.600 dirty plastic bottles with stuff in my kitchen that I'm experimenting with. And it's like, now look

00:04:12.700 at what you've done. So maybe let's just talk a little bit about how your interest in this space

00:04:17.400 came to be. So even for my recollection, I don't recall, your PhD was in neuroscience,

00:04:22.720 if I'm not mistaken.

00:04:23.740 Yeah. Nutrition. And then at the time, studying nutrition and biology, I started doing a

00:04:29.480 undergraduate thesis project in neuroscience and the neural control of autonomic regulation.

00:04:35.700 So specifically, the brain network, the rostral ventral lateral medulla. So they are the brainstem

00:04:40.520 network that controls respiration. So inspiratory neurons, expiratory neurons, and how they respond

00:04:45.580 to oxygen and CO2. And that led me down the path of oxygen, hypoxia, hyperoxia, hypercapnia,

00:04:53.320 extreme environments, what happens to the brain under oxygen deprivation and nutrient deprivation.

00:04:58.000 At the time, I was interested in alpha-L polylactate because it was in Cytomax, which was something I

00:05:04.240 used because I raced mountain bikes. I was testing some things, lactate, and then I got steered onto

00:05:09.000 the ketogenic diet after getting a fellowship, a postdoctoral fellowship by the Office of Navy

00:05:14.920 Research, which is part of the Department of Defense, to understand the cellular and molecular

00:05:19.980 mechanisms of central nervous system oxygen toxicity, which manifests as seizures. So I was mostly

00:05:26.480 interested in drugs, but then I pivoted and went back to the ketogenic diet because the ketogenic

00:05:31.660 diet works for many different seizure disorders when drugs fail. So I was like, oh, I can get

00:05:37.300 nutrition back. Although I was gravitating towards a tenure track position and everybody told me this

00:05:43.380 is like the dumbest thing to do. You can't get NIH funding with ketogenic. Nobody heard of the ketogenic

00:05:48.200 diet.

00:05:48.480 And what year was this?

00:05:50.120 This was around 2005. I started tinkering with ketones, but 2007, I started writing grants and

00:05:56.700 then I hit on a grant in 2008, postdoctoral grant. I had a weird position from postdoc to something

00:06:02.500 called a research assistant professor, which is like an intermediate position before you get into

00:06:06.600 a tenure track. And the university was just gauging to see my productivity. My postdoctoral grant was very

00:06:11.780 sizable. It was above like an NIH level grant, which I was getting paid full indirects.

00:06:16.360 That came from the military.

00:06:18.300 Yeah. Office of Navy Research is part of the Department of Defense. And then I got good data

00:06:22.220 on hyperbaric atomic force microscopy, very mechanistic research. I also did patch clamp

00:06:28.200 electrophysiology and confocal microscopy. My work was really focused on redox mechanisms and looking at

00:06:36.680 superoxide production under graded levels of oxygen and different metabolites. So in the process of doing

00:06:43.720 all that, I had no interest in cancer, but we had some glioblastoma cells and we threw them into the

00:06:49.080 hyperbaric chamber. And under confocal microscopy, we could see the mitochondria were lighting up and then

00:06:54.880 kind of exploding or disappearing in the cancer cells. And that was kind of unique. And that led me on a side

00:07:01.720 tangent thing to study cancer. But my central thing that I studied was neuroscience. I've been in neuroscience

00:07:08.240 department and mainly focused on that.

00:07:11.500 Let's go back to something you said at the outset, just because folks might not understand why the Navy would be

00:07:16.840 interested in the effects of too much oxygen. When you think of the Navy, you think of being underwater. When you

00:07:23.520 think of being underwater, you think of oxygen deprivation. So what is it about certain types of diving that

00:07:29.000 actually bring about the opposite problem?

00:07:30.900 Good question. So hyperbaric oxygen, you experience that with hyperbaric oxygen therapy. And there's 14

00:07:38.960 different FDA approved applications. In that context, you only go to about a maximum of 2.5 to

00:07:45.620 3 atmospheres of pure oxygen. In the context of military diving, like a Navy SEAL use a closed circuit

00:07:52.180 rebreather because there's no bubbles. So there's a stealth component to that. You're breathing high

00:07:57.120 concentration of oxygen. And at 50 feet of seawater, the potential for oxygen toxicity exists.

00:08:04.260 Explain to folks exactly what that is. How does a rebreather work? What's the concentration of oxygen

00:08:09.280 that they're breathing in?

00:08:10.680 A closed circuit rebreather, for example, like a Drager rebreather, like the original ones,

00:08:15.000 those early rebreathers, and even now it's high concentration, it's essentially 100% oxygen.

00:08:20.760 You're breathing 100% oxygen. So there's no nitrogen. There's 80% nitrogen air we're breathing right

00:08:26.460 now. There's no nitrogen. So you avert the potential for nitrogen narcosis. So nitrogen's

00:08:32.580 not narcotic at one atmosphere, but you get something called the Martini effect. And as you

00:08:36.800 go down lower, nitrogen becomes narcotic. So that's something else that we study. So you're

00:08:41.680 breathing 100% oxygen, and then there's a CO2 scrubber. So you're blowing out the exhaled carbon

00:08:47.500 dioxide is scrubbed out from the breather. And it's a closed circuit. So there is no off-gassing

00:08:54.160 associated with scuba diving or even other types of technical diving where you have some

00:08:59.980 off-gassing.

00:09:00.600 And the reason that they can do that is because you're not wasting gas on the 80% nitrogen. You

00:09:06.760 basically store the CO2 that's coming out once you've scrubbed it. You've got pure O2 coming

00:09:11.660 in. So your volume of air needed is much lower because you're just solving for the oxygen.

00:09:16.600 That's part of it because the oxygen tanks are pretty small with a rebreather. But it's analogous

00:09:21.980 to, we have a couple of ponds on our property. And when I go in the pond and I see bubbles

00:09:27.160 coming across the pond, I know an alligator is coming towards me. When your brother was there,

00:09:31.760 we were looking at the alligators and just getting them to come to us by throwing pebbles in there

00:09:35.880 when they hear something. So if I go to the pond with a weed whacker, I see bubbles coming across.

00:09:40.220 So analogous situation would be a Navy seal coming across a body of water that still, you can clearly

00:09:46.340 see the bubble trail coming to you. So with a closed circuit rebreather, that completely averts

00:09:51.140 that, the bubble trail. And then there's also the noise that the bubbles make. So you don't have

00:09:56.760 that. The problem is if you're wearing a closer and you dive down to a hundred feet of seawater

00:10:01.440 because someone starts shooting at you, or you have to go down deep to put a mine on the bottom

00:10:06.120 of a bridge or something like that, you're going to have a seizure within five minutes. So oxygen is

00:10:10.720 a stimulant. It stimulates a massive amount of glutamate release that activates AMPA receptors,

00:10:17.000 NMDA receptors. It stimulates the neural network in ways. It also sort of deactivates or inhibits

00:10:23.540 an enzyme, glutamic acid decarboxylase, which converts more glutamate to GABA. And there's a big

00:10:29.640 burst in reactive oxygen species. So you have a constellation of things going on in your brain.

00:10:34.240 So I study the negative effects of high oxygen, which kind of has some people who study hyperbaric oxygen

00:10:40.160 a little bit standoffish towards me. But in the context of lower oxygen, hyperbaric oxygen therapy

00:10:45.440 can be very therapeutic. I do want to talk about that. There's a lot I want to ask you about

00:10:49.800 hyperbaric oxygen, but I want to finish the swing on this particular application. When was it clear

00:10:54.920 to the Navy, the problem that you described, which is when we have closed circuit rebreathers with a

00:11:01.420 hundred percent oxygen, we're running into problems with our divers. These problems are dramatic. I mean,

00:11:07.180 if you have a seizure at a hundred feet, you're going to die pretty quickly. So when did they

00:11:11.240 come to realize this? And was this a relatively recent discovery?

00:11:15.460 No, it's not. And my mentor, Dr. J. Dean, our lab is like a museum. So we have all the historic

00:11:20.740 pictures on there. And there's a guy that wrote a book and his name was Fred Baer. He was a French

00:11:26.100 physiologist. He did a lot of seminal studies well over a hundred years ago in the 1800s showing that

00:11:32.020 you could give animals. They call it caisson's disease too. So that could, when you go down in

00:11:37.000 like chambers, when you're building a bridge, you're under high pressure oxygen or high atmospheric

00:11:41.700 effects. So yeah, I would say about 150 years ago, we realized that oxygen was a stimulant. We didn't

00:11:50.560 know why. And then with military diving, then you have the problem of averting oxygen seizures. And

00:11:56.700 there's a number of people in the Navy. Frank Butler comes to mind, Claude Pianidosi, Richard

00:12:02.280 Moon. There's a network at Duke University, which did a lot of the seminal studies. And they established

00:12:08.360 the dive tables for preventing oxygen toxicity seizures, nitrogen narcosis, high pressure nervous

00:12:14.440 syndrome. So these are all things that you have to avert when you're diving, depending on what kind

00:12:18.940 of diving you're doing. Was the Navy coming to you to say, look, we know this is happening. Can you

00:12:23.820 help us push the envelope? Yeah, I kind of went to them or they came to me because I had specialized

00:12:29.120 knowledge, but I wrote grants to really delve into it's unknown why these seizures occur, but it gives

00:12:35.940 us a lot of insight into the brain to understand it from a redox effect, from a neuropharmacology

00:12:40.660 effect. So the grants that I had were literally called investigating the cellular and molecular

00:12:46.880 mechanisms of CNS oxygen toxicity. And they gave me, unlike the NIH, they gave me, I had a lot of tools

00:12:53.740 to play with that were really expensive that we got through what's called a DOD DURUP grant.

00:12:57.980 And that bought chambers and microscopes and electrophysiology equipment. It allowed me to

00:13:03.080 tinker in the lab. And in the process of tinkering, we just had some serendipitous discoveries with the

00:13:09.160 cancer things and then just fundamental effects that happen in cells under high pressure, oxygen,

00:13:15.480 nitrogen, helium, different gases. Very basic. So the Office of Navy Research has a 6.1 program,

00:13:22.040 and that's basic science. And then 6.2, 6.3. And as I progressed in my career, I started working up

00:13:28.740 from a cell-based system to animal models. Then it went to a pig model system. Now, essentially,

00:13:34.520 we're doing the rat studies at Duke with human subjects that get inside a chamber.

00:13:38.700 We get diaphragmatic, we get EEG. We have a line going into their arm that goes to like a mass spec

00:13:44.520 to get blood gases, to do metabolomics. They're working a simulator, a flight simulator. They're exercising.

00:13:50.560 It's water-out immersion, so their body's underwater, but you get the hypovolemic effect

00:13:56.720 of the fluid shift and things like that to simulate that diet. And then we push them

00:14:00.880 to a seizure, believe it or not. So this got approved through an IRB, which is even more

00:14:06.580 amazing than the Cahill study. But we push them to an EEG seizure to where we can see the seizure,

00:14:11.860 and then we decompress. So we look at latency to seizure under ketosis, dietary ketosis or supplemental

00:14:19.280 ketosis or the combination. So those clinical trials, I'm co-investigator on it because it's

00:14:24.760 being done at Duke. They're registered clinical trials on clinicaltrial.gov.

00:14:29.240 And these are being funded by the DOD?

00:14:31.560 Department of Defense has Office of Navy Research. They have the CDMRP, which is

00:14:36.320 Congressionally Directed Medical Research Program, and also NAVSEA. So this is an ONR project that got

00:14:42.220 spun into a NAVSEA project, so Naval Sea Command project. So NAVSEA is more human studies, and then

00:14:50.100 ONR is basic science, and then some human research.

00:14:53.540 I want to come back and talk about a lot of these things, but I feel like we should now get people

00:14:56.920 up to speed on what ketones are. Again, we can sit here and talk about this and take this stuff

00:15:01.520 for granted all day. You obviously threw around the term nutritional ketosis. You've also talked

00:15:05.920 about supplemental ketosis, sometimes referred to as exogenous ketones. Let's start with

00:15:10.780 nutritional ketosis and just give people some definitions of how you achieve it, how much

00:15:16.480 variability there can be in a diet to get there, what the thresholds are, and a little bit about

00:15:21.600 what's happening physiologically. Before I begin, I want to direct people to your early blogs,

00:15:26.220 which I assume are still up, on nutritional ketosis. I'm sure they are somewhere, yeah.

00:15:30.180 On the Delta G, there's one with exogenous ketones. In our study, we kind of did with the ketone

00:15:35.500 salts, which increased your efficiency, oxygen utilization. So nutritional ketosis, take a little

00:15:42.080 bit of a step back. Ketosis, I like to start with fasting. So when you stop eating, you suppress

00:15:47.180 the hormone insulin, you mobilize fatty acids for fuel. The brain's not a good, it can't use the long

00:15:52.760 chain fatty acids that are stored in your adipose tissue. So through beta oxidation of fatty acids in

00:15:57.980 the liver, accelerated beta oxidation in the context of insulin suppression generates these

00:16:04.460 molecules, beta hydroxybutyrate and acetoacetate. And then they spill into circulation and they become

00:16:11.240 largely responsible for preserving brain energy metabolism in the context of energy deprivation

00:16:17.880 or carbohydrate restriction. And the elevation of beta hydroxybutyrate or acetoacetate in the blood,

00:16:24.000 in the urine, or the breath becomes a biomarker for ketosis. So you can achieve ketosis through fasting,

00:16:32.400 through diet, through supplements, or alcoholic ketoacidosis. That's another thing, or diabetic

00:16:38.200 ketoacidosis. And we could talk about that in context. And then you have nutritional ketosis, which

00:16:43.020 is eating carbohydrate restricted ketogenic diet that's primarily high in fat. The original diet was

00:16:49.660 90% fat. Modified versions of the diet are about 60 to 70% fat with higher protein. Now we know,

00:16:56.720 especially in kids, you restrict protein too much, you could stunt their growth and have some issues

00:17:00.960 there. So clinically, a modified version of the ketogenic diet is actually being gravitated more

00:17:07.060 towards even in pediatric epilepsy. So we're learning that protein is really important. And it was

00:17:11.400 underappreciated, I guess, in the early ketogenic diets. In the context of sports, it's extremely

00:17:15.800 important. And we can talk about that. But still, it remains that the ketogenic diet is the most

00:17:21.080 scientifically researched diet that has an objective biomarker that defines the physiological state of

00:17:26.940 being in the diet. And that's beta-hydroxybutyrate above 0.5 millimoles per liter. So that's clinical

00:17:33.340 ketosis. And in the context of ketosis, there are remarkable changes in our metabolic physiology and

00:17:41.140 the neuropharmacology of our brain. And also beta-hydroxybutyrate has very unique effects,

00:17:46.960 epigenetic effects, which is kind of a new buzzword that people are talking about. And my student just

00:17:51.380 finished a project on that. And I think it's pleiotropic. So ketogenic diets have pleiotropic

00:17:56.300 effects. Tell folks what that means. Pleiotropic is kind of like a fancy, somewhat nebulous word

00:18:01.820 that basically means there are multiple mechanisms that are activated biochemically, physiologically,

00:18:09.040 neuropharmacologically that have beneficial effects. And I can go through the explosion of research that

00:18:15.220 has occurred on PubMed and clinicaltrials.gov. But the important thing is that nutritional ketosis,

00:18:22.680 or let's take a step back, the ketogenic diet, some people say the ketogenic diet is not magical.

00:18:27.140 The ketogenic diet does nothing magical. In the context of body composition alterations or fat loss,

00:18:32.640 there's truth to that. However, I say there's a hard stop there. The ketogenic diet is indeed

00:18:37.840 a magical diet in the way that it remarkably changes our physiology. And there's no other diet

00:18:44.560 that exists that can, for example, manage drug-resistant seizures. And it does that

00:18:50.740 because it profoundly changes our fuel system, our physiology, our biochemistry, and our

00:18:56.080 neuropharmacology. Let's talk a little bit about that. You've mentioned it a few times now.

00:19:00.120 So let's help folks understand what's going on here. So this was first identified in kids,

00:19:05.060 and if I'm not mistaken... Adults, actually, if you go back to... Oh, is it adults?

00:19:08.160 Yeah, like the Mayo Clinic in 1920s, because there was no drugs for epilepsy. So...

00:19:12.820 So what gave them the idea... We defaulted.

00:19:14.860 Hey, we've got these people that are experiencing this awful thing. Now,

00:19:18.180 they had EEGs back then, but they really didn't know much.

00:19:21.320 Yeah, yeah. They actually did some really good physiology back in the 1930s, 40s. Underappreciated.

00:19:25.920 Well, we knew that fasting controlled seizures.

00:19:28.880 So that was the first observation.

00:19:30.160 Yeah. I mean, the Gospel of Mark talks about fasting. I mean, it's all over like in the literature.

00:19:34.500 Fasting could control seizures. So a ketogenic diet, by virtue of elevating these ketone bodies,

00:19:39.860 which were showing up in the blood and the urine, and even in the breath,

00:19:43.080 they just understood that these ketone bodies were somehow associated with seizure control.

00:19:47.900 And we did not have anti-seizure drugs back then.

00:19:50.280 And when were these first identified? So you've got Banting and Best identify insulin,

00:19:54.100 or at least isolate insulin in the 1920s.

00:19:56.320 Yes.

00:19:56.760 So that's really the... In my mind, I think of that as kind of the golden era of metabolism.

00:20:00.960 When were ketones first isolated, BHB specifically?

00:20:03.880 Within a decade around that time, with Banting and Best, discovered it in the context of diabetic

00:20:10.260 ketoacidosis, and then worked at the Mayo Clinic by Wilder and a few other people were helping

00:20:16.600 sort of establish the framework for what would be ultimately the first ketogenic diet therapies.

00:20:23.140 And the thing was just eating all fat. And then we realized we got to titrate in the protein to

00:20:27.520 prevent protein malnutrition. And then there was a tiny... In 1921,

00:20:32.660 in a clinical... It was just like a side note on a clinical journal. The first observation or

00:20:39.020 clinical report of a ketogenic diet used in epilepsy and the remarkable effects. And we didn't have

00:20:44.560 anything.

00:20:45.400 They didn't understand why. Mechanistically, I mean.

00:20:47.860 I mean, we could go a hundred years later and we don't fully grasp and understand all the

00:20:53.000 mechanisms involved. And that's why it's such a fruitful, robust area of research right now with

00:20:58.060 drug companies scrambling to mimic. If we had a drug that would mimic the ketogenic diet,

00:21:02.220 it would be a blockbuster drug.

00:21:03.420 Because if I understand correctly, Dom, if you took a hundred patients who are drug resistant,

00:21:09.940 so they're having nonstop seizures despite all the best available pharmacology, my recollection,

00:21:17.020 this could be incorrect and you can update this, is that a ketogenic diet will completely cure one

00:21:22.940 third of them, will cause about a 50% reduction in seizure activity for another third of them,

00:21:28.340 while one third of them will still be unresponsive. Is that still directionally correct?

00:21:32.920 In the context of pediatric epilepsy, about two thirds will be, so it's that high.

00:21:37.760 Two thirds will be?

00:21:38.380 Two thirds will be therapeutically responsive to a ketogenic diet therapy for managing seizures,

00:21:44.520 are highly efficacious for managing seizures. Two thirds of people who have failed drug therapy,

00:21:50.040 we're not just talking about one drug, we're talking about polypharmacy adding multiple drugs,

00:21:53.840 the list goes on.

00:21:54.800 What about adults?

00:21:56.200 So in adults, it's more about closer to post-adolescence, about 30 to 40%. But then it's

00:22:03.600 thought that adherence and compliance with adolescents, with kids, the parents feed usually a ketogenic

00:22:09.300 formula and calculate it out. But there's also something about the pediatric brain that's probably

00:22:13.640 more responsive. And then of that two thirds, about one third have like complete seizure control,

00:22:20.180 95 to 100% seizure control. And then 10 to 15%, and this really interested me when I went to the

00:22:26.300 first conferences back maybe 15 years ago, were super responders, meaning that they could get on

00:22:31.180 a ketogenic diet, follow it for a year or two, transition off and never get seizures again.

00:22:36.640 So they talked about the ketogenic diet being curative. And that was really interesting to me.

00:22:41.280 Of course, the brain is changing as you go through development, but it was shifting brain networks

00:22:47.140 and network stability, suppressing inflammation and changing neurotransmitters in a way that

00:22:52.220 there's the kindling effect with seizures. So seizures beget seizures. So once you have a seizure,

00:22:58.660 you're more likely to have another seizure. So if you control seizures and you do it through a

00:23:02.820 protracted timeframe, it's going to lessen the chance of you. It's going to decrease that

00:23:07.340 kindling effect. So there's something going on there. And we've replicated that just throwing

00:23:11.280 sodium beta-hydroxybutyrate into a hippocampal brain slice preparation under different levels of

00:23:15.940 things that stimulate seizures, like measuring seizures in a slice. With like the orthodromic

00:23:20.280 population, you can stimulate and measure the orthodromic population spike of the neurons like

00:23:25.040 firing back. And then you can decrease the amplitude of that over time and essentially just

00:23:29.780 silence seizures in a slice. And at the same time, you're making that hippocampal brain slice

00:23:35.020 more metabolically resilient. You could throw different agents at it that would be neurodegenerative

00:23:40.680 or hyper-excitable and it will protect it under the context of various neurotoxins. I think that

00:23:46.700 really interested me. So the early observations, and then I was completely unaware of all this

00:23:52.280 literature in my postdoc. And then when I started delving into it, I was like, I have to change the

00:23:56.840 trajectory of my career, but I'm going to do it in an innovative way. I'm going to study the ketogenic

00:24:01.400 diet, but also in parallel or in tandem, or maybe in some cases exclusively, just delve into what is the

00:24:08.280 most efficacious form of exogenous ketone we can use and how can it augment the therapeutic efficacy

00:24:14.320 of a ketogenic diet. There's a lot to unpack here and nobody was doing it at the time.

00:24:19.620 You've obviously experimented a lot with a ketogenic diet yourself. I mean, when did you first

00:24:23.960 try a ketogenic diet? The clinical ketogenic diet where I got the little cardio check meter,

00:24:29.780 which was super expensive at the time, I would say 2009, I started actually checking ketones.

00:24:35.320 I was using the Abbott one. Yeah. Precision extra.

00:24:39.060 I got that later. I don't even think that might've been out yet, but I got that soon after because the

00:24:45.440 cardio check actually did like your HDL and like triglycerides and things. We also had like a lab

00:24:50.800 assay, like an ELISA assay to, you know, we're comparing it to it. Yeah. And then we got the

00:24:55.180 precision extra by Abbott. And then I remember I bought something like $10,000 of strips.

00:25:00.860 I was about to say the strips were five to $10 each. Yeah.

00:25:04.620 At the time. I found, uh, I bought them in bulk and I think.

00:25:08.520 Yeah. You hooked me up at one point and we were able to get them for like $1.50 or something.

00:25:12.780 Yeah. But I was going through three a day.

00:25:14.760 Yeah. Yeah. Yeah. Seriously. Yeah.

00:25:16.080 That price point has come down, but now we have the keto mojo actually aligns more with our assays

00:25:21.120 and it does the glucose ketone index that we can talk about. So I started doing that. And when I started

00:25:26.840 it within, I guess, five years after starting the ketogenic diet, I probably rapidly lost 10 to 15

00:25:31.920 pounds. And then my exercise and my lifts tank too, lost strength on bench press, not so much deadlift

00:25:38.080 and squat, but I saw that, but I didn't really care that much at the time. But I also learned

00:25:42.400 the lesson that protein was really important. I was thinking ketones would be basically save muscle

00:25:48.020 and they have an anti-canabolic effect that we can talk about. But if your protein goes from like

00:25:52.940 250 grams a day to like 70 to 80 grams per day, you're going to lose a lot of muscle.

00:25:58.520 Just don't tell the USDA that or the RDA, they still want you to believe that 0.8 grams per

00:26:04.360 kilogram is all you need.

00:26:06.740 It's very context dependent too. I was kind of in the gym and I was even training with Lane at the

00:26:12.000 time.

00:26:12.060 Don't be totally facetious. I mean, these guys are out to lunch and they just want to cling onto this

00:26:15.520 idea that protein is bad.

00:26:17.120 They're avoiding like work from Donald Lehman and Stu Phillips and guys I think you might've had on the

00:26:22.180 podcast. So yeah, I learned a lot of lessons. I learned that clinical ketogenic diet skyrockets

00:26:28.000 my LDL and ApoB. I've learned how to manage that pharmacologically. I have a mutation for the MPC1L1

00:26:34.080 receptor. So a tiny dose of azetamide brings that down. But most importantly, I realized that titrating

00:26:39.440 the protein in to meet your needs for protein. And if you're an athlete, if you have a high metabolic

00:26:44.320 rate, if you're trying to gain muscle, you do have to leverage protein. And that becomes the key

00:26:50.300 factor. I think the key variable in getting the ketogenic diet to work for you and also tracking

00:26:56.700 your lipids is really important.

00:26:58.620 What do you think of the most common mistakes people make when they're trying to enter nutritional

00:27:03.140 ketosis? What would be the top three or four mistakes that people are making?

00:27:06.860 Not tracking. I mean, people do it. They're just like, oh, I'm just going to eat this or that and

00:27:10.960 not just like, no, you need to like just write it. You don't have to do it every day, day in and day out.

00:27:15.360 But use a good tracking metric. Carbon app is great. I know you've had lean on. I've used that.

00:27:21.740 And there's other apps out there.

00:27:23.620 So tracking because you want people to be able to correlate the blood levels they're seeing with

00:27:28.400 what they're eating?

00:27:29.220 Yeah. So the macronutrient ratios and the composition, but also the total amount of

00:27:34.200 calories, which at the time when I get into this, everybody was said, you know, if you do ketogenic

00:27:38.520 diet, you don't have to track calories. Calories don't matter. I just knew that was BS to begin with

00:27:42.940 because there are some people who can easily overeat on a ketogenic diet. I could sit down

00:27:47.500 with a bag of macadamia nuts and polish the bag off or sour cream or heavy cream or whatever. So

00:27:52.960 it's easy to do. So yeah, track total calories, macronutrients, track your blood ketone levels.

00:27:59.220 You could do urine or breath too.

00:28:01.420 What is the state of the art on urine and breath meters these days?

00:28:04.660 With the breath meter, I do think that's pretty legitimate because breath acetone correlates with

00:28:08.800 seizure control. There was the Biosense device, but they've kind of fallen out of favor. There's

00:28:13.260 a device called KetoAir that's pretty good. It's like the size of a pen. And that actually

00:28:17.320 correlates really well with some of the blood ketone measurements. I do notice that if I'm in

00:28:22.080 a calorie deficit, my blood ketones can be very low, but my breath ketones are high. And I think

00:28:27.900 your ketone production that you're measuring is a consequence of ketone production and ketone utilization.

00:28:33.740 And in the context of an energy deficit, your tissues are sucking up ketones out of your blood

00:28:39.000 fast, but you're blowing off more acetone. So your blood ketones are, and I think you maybe

00:28:44.180 made some observations of that too with different device.

00:28:47.380 Yeah. Also under high exercise, normal exercise, super normal exercise, fasting, et cetera.

00:28:53.700 Yeah.

00:28:54.540 And then urine.

00:28:55.820 People still use it.

00:28:56.980 My view back at the time was I was never going to get better precision than using blood.

00:29:01.720 Yeah. But still the gold standard. And then you have interstitial. So I just switched out. I was

00:29:08.000 wearing a continuous ketone monitor.

00:29:10.080 How many companies make those now?

00:29:11.780 Abbott makes one. I can't use it because they use test flight software and I have an Android. I'm

00:29:16.300 the guy that has the Android. So I can't use that, but I've been involved with the company a little

00:29:20.360 bit and just had some calls with them. I know, I think you have maybe two involved with them.

00:29:25.200 I have no involvement.

00:29:26.000 Oh, okay. Just disclose. I don't get paid by them or anything, but there's a company that's in China.

00:29:30.520 And I think now they have a footprint in the US. They're called CyBio. And I am very impressed

00:29:35.420 with CyBio. So the first week, the ketone measurements are very accurate, but the last

00:29:40.440 week they tend to measure about only half of what you measure in blood.

00:29:45.060 So it's a device.

00:29:46.080 Yes.

00:29:46.260 Is it microneedles or is it a long filament?

00:29:48.300 Looks exactly like a CGM device. Uses essentially the same technology, just a different enzyme.

00:29:54.260 I could swim all day in salt water. I can do stuff on the farm. I don't knock it off.

00:29:59.180 It's probably as reliable as a CGM device is now. It's remarkably reliable. The specificity

00:30:05.240 is good.

00:30:06.160 And it's BHB?

00:30:07.180 It's beta-hydroxybutyrate. Yeah. It's important to acknowledge that it's the D-enantiomer or

00:30:12.200 the R-enantiomer of BHB because there's supplements out there that are racemics. But yeah, I've

00:30:16.260 tested it, pressure tested it, if you will, with high doses of ketones and it performs well.

00:30:21.880 And so there's emerging technologies. So the continuous ketone monitor, continuous lactate

00:30:26.160 monitor, which is, I think it's going to be lactates and oncometabolate.

00:30:29.440 Does anybody have one of those commercially ready yet?

00:30:31.920 Not commercially ready yet. There's programs, but I don't think monetarily, I don't think

00:30:36.900 the companies are motivated to bring it to market. And I think there's some more testing

00:30:40.520 that needs to be done. But for example, my colleagues at the Moffitt Cancer Center, they're

00:30:44.860 like salivating over the opportunity to do glucose ketone and lactate monitoring, especially.

00:30:50.820 We see that tumor burden is tightly correlated with blood lactate levels. So we use lactate

00:30:56.840 monitoring. And if you have an expanding mass of like metastatic cancer, it just correlates

00:31:02.740 very nicely and lactates and oncometabolate that should be measured.

00:31:06.520 So if mistake number one is you're not measuring your actual ketone levels and you're not tracking

00:31:11.500 what you're eating so you can see the association of, hey, when I ate this, it went down. When I

00:31:15.640 ate this, it went up. What are some other mistakes people make with their diet formulation?

00:31:19.600 Is that they typically erring on the side of too much protein, not enough protein? Are

00:31:23.660 they not realizing where carbs are sneaking into their diet? And what kind of guidance

00:31:27.400 do you give people? How many grams of carbs a day do you tell somebody or do you vary that

00:31:31.320 based on their activity level?

00:31:32.900 Yeah. Taking a step back. So I view, unlike many people out there, I view a ketogenic diet

00:31:38.920 as a prescription metabolic therapy. So that's the world that I come from. There's clinical keto

00:31:45.800 and then there's internet keto and which a lot of people are following a low carb diet,

00:31:49.940 which has a plethora of metabolic benefits, just have to be up on your blood work and you have to

00:31:55.680 be very vigilant with tracking your biomarkers. But a clinical ketogenic diet is typically done

00:32:02.080 with consulting or advice or even following the framework. For example, a lot of books out there

00:32:08.560 by Eric Kossoff. If you have cancer, Miriam Kalamian has a guide, ketogenic diet for cancer.

00:32:14.020 Books that are out there that tell you step-by-step on how to do it. And from a practical

00:32:19.780 or logistical point of view, we had a small study we ran with Dr. Allison Hall that looked at people

00:32:25.560 that were just, they didn't have any overt pathology, but they were just take normal people,

00:32:29.880 put them on a low carb ketogenic diet. And the practitioners tell me that if you transition a

00:32:34.560 person over four to six weeks, they adhere to it better and you actually get more favorable

00:32:40.540 health responses. You don't have a lot of funky blood work that come back. It could be the

00:32:46.540 electrolytes. With people that have certain mutations with fatty acid oxidation disorders,

00:32:50.980 even ApoE4 carriers, you'll see their LDL go up and you'll see things like HDL go down

00:32:56.520 and you'll see they start the diet and their triglycerides go up. I've seen that a lot in quite a few

00:33:02.020 people. And I think there's some genetics that need to be unpacked there. In several cases,

00:33:06.200 it was people that were ApoE4 carriers. They're homozygous. I think there's something to unpack

00:33:11.540 there. They just don't metabolize. Their lipid metabolism is a little bit different. So I think

00:33:16.560 it's really important to get blood work, track triglycerides, track HDL, ApoB, LDL, hemoglobin

00:33:22.020 A1C, insulin levels. I think I've seen people's insulins go up, but generally speaking, 90% or 80%

00:33:28.380 or more insulin goes down. But really just to use, there's so many different guides out there. And if

00:33:34.320 you're doing it to manage a clinical condition, you should be working with a registered dietitian

00:33:40.100 that's savvy. And the people I recommend, there's advanced ketogenic therapies and it's a team of

00:33:46.160 people and it's kind of spearheaded by Denise Potter. She's a registered dietitian, came from the

00:33:51.680 world of epilepsy and worked as a conventional registered dietitian and then transitioned to

00:33:57.020 ketogenic and now has a team of a half dozen or more people.

00:34:00.440 But if someone just says, look, I just want to do this on my own, just like any other diet I might

00:34:04.040 follow, what would be sort of the guidance you'd give them?

00:34:06.520 Yeah, it depends why they want to use it.

00:34:08.520 Well, I think the most common reason would be weight loss.

00:34:10.580 Yeah, weight loss. So I would say calories are super important. So just gravitate towards a high

00:34:17.620 protein ketogenic diet. And if it's just purely weight loss, I would say high protein, moderate fat,

00:34:23.940 and then high fiber. So the carbohydrates that you're getting should be just fibrous carbohydrates.

00:34:30.620 So you can get 50 to even a hundred grams of carbs per day if one third of those carbohydrates

00:34:36.200 are fiber. So that excludes all ultra processed food, even processed food. Broccoli is about one

00:34:42.060 third fiber. So if you go down the list, there's about, I think I have a list of about 30 or 40 forms

00:34:47.320 of carbohydrates that are about one third, a quarter to one third fiber. So if you're pulling from that

00:34:52.320 list, you've got all your leafy vegetables. You mentioned broccoli. Would carrots be in there?

00:34:58.380 No, no. Broccoli, cauliflower, carrots. No, especially if they're cooked, they can be highly

00:35:02.540 glycemic, but avocado.

00:35:04.740 Bell peppers.

00:35:05.620 Yeah. Bell peppers are a little bit too high in sugar. They're at the cutoff point,

00:35:09.600 maybe like a green pepper or something like that. But generally things that you'd find in like,

00:35:14.960 you know.

00:35:15.100 Cucumber.

00:35:16.040 Cucumber, yes. Asparagus.

00:35:18.340 Tomato.

00:35:19.060 Tomato, no. Tomato is like a fruit, pretty high in sugar.

00:35:21.560 So these are things that you need to be kind of vigilant. And there's a lot of go-to guides. And

00:35:26.820 that's why I think it's important to use like a tracking app. I use it now time to time if I want

00:35:31.900 to make adjustments and be very, because one thing I noticed, especially using the Carbon app or other

00:35:37.180 apps, I was like, eh, I'm getting about 3,200 calories per day. But when I put it into these

00:35:41.820 tracking apps, it's more like 4,000 calories per day.

00:35:45.360 Meaning you think you're at 3,200?

00:35:46.980 Underestimate it. Yeah. I always, always underestimate it.

00:35:49.700 Probably because just fat is so calorically dense. So the amount of egg yolks and a lot

00:35:55.540 of fatty fish. This morning I had like three cans of sardines. Each can is 20 grams of fat

00:36:00.600 and 15 grams of protein. And that's 20, that's 60 grams of fat just from sardines and extra virgin

00:36:06.260 olive oil. It adds up. It just seems like, oh, this is like nothing. This is like less than I would have

00:36:10.880 if I'm eating at home. But it adds up. And I think that people that are not losing weight or

00:36:16.100 managing whatever they're trying to manage with a ketogenic diet, they need to track calories. And

00:36:20.720 simple caloric restriction or creating even like a 10 or 20% energy deficit will be the big lever

00:36:27.800 that's going to cure 90% of what most people are seeking the ketogenic diet for.

00:36:32.480 So what's the efficacy then? So why do you think a ketogenic diet works? Do you think it works because

00:36:36.820 under conditions of caloric restriction, it's more satiating than diets that are high in carbohydrates?

00:36:42.680 Yeah. I mean, just off the top of my head, it's hypersatiating, especially a high protein

00:36:47.740 ketogenic diet. It's hypopalatable. Some people may argue that, but you're not going to overeat

00:36:53.500 a ketogenic diet just because it doesn't have the hyperpalatability of a standard American diet.

00:36:59.100 And I think it fundamentally is changing metabolic physiology and brain neuropharmacology in a way that

00:37:05.700 decreases appetite regulation. So with a higher protein diet, you're getting higher GLP-1,

00:37:11.120 you're reversing insulin resistance, you're improving fatty acid oxidation. And I think

00:37:17.720 you're fundamentally weaning your brain off glucose. Your brain is dependent on glucose with

00:37:24.280 the standard American. And as you're decreasing glucose availability, your brain has a counter

00:37:28.940 regulatory dysphoric reaction to that. And as it transitioned into ketosis, you could avert a lot

00:37:35.840 of this simply by using ketone electrolytes, the stuff that I gave you, the key to start.

00:37:40.200 So that's electrolytes, similar blend is element, but bound to beta-hydroxybutyrate. Consume that when

00:37:45.540 you start the diet, and that'll largely mitigate two things. It'll mitigate the electrolytes. A ketogenic

00:37:50.820 diet has a natriuretic effect, which means you dump sodium and a diuretic effect.

00:37:55.700 Let's talk about why those occur.

00:37:57.260 These are the things that kind of really throw a monkey wrench into some of the clinical trials.

00:38:02.060 They're electrolytes and they get dehydrated. So it's an important topic.

00:38:05.440 So when I stop eating carbohydrates and ramp up my fat, by the way, I do want to go back to,

00:38:11.040 sorry, one other point. You keep saying high protein. Can you define high protein in this

00:38:14.800 context? Are you talking high by the standards of the RDA, or are you just saying one gram per pound

00:38:21.720 to body weight? Is that sort of your guidance?

00:38:23.920 I mean, historically, eight to 10 to 12% was used with ketogenic diets. So I'm talking about

00:38:30.340 a ketogenic diet that's 20 to 30% protein. So that's considered high.

00:38:36.820 But that's hard for people, I think sometimes. I mean, you can obviously back calculate into that

00:38:40.700 by the calories, but do you find it easier to just say, look, keep your carbs at 50 grams and try to

00:38:46.860 get them from high fiber carbs, get your protein to X grams, and then limit your total calories to

00:38:53.800 whatever, 3,000 with fat filling the rest. In other words, what is it typically working out to

00:38:59.740 in terms of grams per pound of body weight in protein?

00:39:02.640 Me, for example, would be upwards of, I'm about 220 pounds. So that would be, I know it sounds crazy,

00:39:10.820 but from the average RD registered dietitian, but 220 grams of protein. So that would be the upper

00:39:16.580 end if I'm very active. And I mean, today, maybe I won't get that or when I'm traveling,

00:39:21.220 but that amount of protein, I think, is the upper end. I don't think there's any benefits to go above

00:39:26.600 and beyond that.

00:39:27.680 At that level of protein, you're not undergoing so much gluconeogenesis that you're making too much

00:39:32.040 glucose that's offsetting the ketone process?

00:39:35.320 Everybody's a unique metabolic entity, so they're going to have a different response. But for me

00:39:39.420 personally, especially having eaten 400 or 500 grams of protein, I'm not exaggerating there. When I was in my

00:39:45.760 late teens and 20s, that works for me. That level of protein works for me. For some people,

00:39:51.220 especially if they're going to jump from 50 grams a day or the RDA recommendations,

00:39:55.600 and you want to do that to ideal body weight.

00:39:57.980 The RDA for you is 80 grams.

00:40:00.620 Yeah.

00:40:01.420 Exactly 80 grams. You're 100 kilos. The RDA recommends you have 80 grams of protein,

00:40:07.220 not 220 grams.

00:40:08.800 Yeah.

00:40:09.180 At 80 grams, you would not be able to maintain your muscle.

00:40:11.920 No, not in my context. No, definitely not. The more muscle you have, you just have much higher

00:40:18.440 protein turnover. So you're breaking down protein, building protein, that whole cascade is amped up

00:40:24.760 probably several times higher in the content, especially if you're working out and breaking

00:40:29.020 down protein and you have a fast metabolism. My recent resting metabolic rate showed it was 34%

00:40:34.580 higher. I'd have to do further studies, but they wanted to redo it.

00:40:37.840 That's even when adjusted for your lean mass?

00:40:40.480 Yeah. My resting. Yep. I'm going to redo it in about two weeks. I was also off creatine and some

00:40:45.840 other things. I'm reloading on creatine just started. I'm going to redo that again. But yeah,

00:40:50.920 my lean mass is kind of, I'm pretty heavier. So that's the upper limit. You can gradually increase

00:40:56.100 your protein, but I've been very vigilant now with my protein, especially after turning 50,

00:41:02.240 that this is important because sarcopenia and the loss of lean body mass is almost considerably higher,

00:41:09.240 as you know, in your fifties. And there's different reasons for that, but activity is the main mitigator

00:41:14.840 for that. So if you're providing a stimulus for your body to grow and maintain muscle, you need

00:41:20.080 protein that's double the recommended daily allowance, I think, if you're really going to be

00:41:26.400 proactive about it. Any other quick do's and don'ts around things like fruit, berries,

00:41:33.300 artificial sweeteners? How do you think about all of those things as they factor into a ketogenic diet?

00:41:37.920 I tend to like, I guess, carb backload at the end of the day. I eat no carbs all day. And at dinner,

00:41:43.660 I'll have like a salad or vegetables. And then in the evening, I have wild blueberries, which have like

00:41:49.520 a third of the sugar of regular raspberries, blueberries, wild ones. And then I have a keto mousse,

00:41:55.420 which is just cocoa powder, chocolate ketone powder, and some stevia or monk fruit and cinnamon.

00:42:02.500 It has no effect on my CGM. It actually goes down. I've found out what works for me. And as long as I

00:42:08.320 am eating fiber, if the carbohydrates are delivered with fiber, there's really no glycemic counter effect

00:42:15.760 to that. No spiking. I have a short list of foods. So it's basically berries, broccoli, asparagus,

00:42:23.340 dark chocolate. These are things that I eat every day. Maybe not the asparagus, but broccoli, berries,

00:42:29.920 dark chocolate, and salads. I'm kind of simple and I keep things pretty simple. I don't. In the past,

00:42:35.240 I had a desire to have more different kinds of foods. I enjoy that. I mean, we were traveling

00:42:40.240 in Greece and I'm not going to pass up all the great food when I'm traveling. I ate as much

00:42:46.100 carbohydrates as whatever they were serving me. And I came back six pounds lighter because I'm in and out

00:42:51.940 of water every day. I'm walking out in the sun and things like that. So actually increasing,

00:42:56.200 tripling or quadrupling my carbohydrate made me lose six pounds when I come back.

00:43:00.880 Did you feel different?

00:43:01.880 I felt great. Yeah. I'm pretty metabolically flexible. So I think that's also a consideration

00:43:06.320 that if you really delve to carbohydrate restriction and your body is completely fat adapted and it's like

00:43:12.760 carbohydrates are a foreign substance and glucose spikes, you're going to have a pretty big

00:43:18.500 counter-regulatory effect once you start getting bolusine carbohydrates again.

00:43:23.000 Because you're changing your physiology, you're changing. And so your gut for one thing is not

00:43:27.120 going to tolerate that. Just from like fitness competitors when they diet and then they finish

00:43:31.700 the competition and then they go out and have, you know, like a cheat meal, then they're up all night

00:43:36.480 with gas and bloating. I mean, I could go through all the different systems, but the GI system takes a

00:43:40.940 big hit. The liver takes a big hit. The glucose hitting the peripheral system can't absorb it.

00:43:45.980 So your CGM goes off the charts and that can trigger inflammation. That can alter gut microbiome.

00:43:51.400 It's going to affect your mood. These are wild swings that yo-yo dieters go through.

00:43:56.040 So if you're low carb, you achieve your goals, like your weight and you want to, and you miss

00:44:00.100 carbohydrates, you can slightly just titrate them back in and just do fibrous vegetables. Just start

00:44:05.320 with that. And some people can't tolerate that, but fruits, most people who have like an aversion

00:44:10.240 to plants or some immune reaction to them usually can tolerate fruits.

00:44:16.380 So before we go to the exogenous or synthetic ketones, I want to now ask you about an even more

00:44:20.940 extreme form of diet, which I'm sure you get asked a lot about. I know I do, and I have

00:44:24.700 no insight clinically, nor do I have any personal experience with it. So let's talk about this

00:44:28.800 carnivore diet. I realized there are different ways people go about doing this. There are some

00:44:33.020 versions that are incredibly strict where you literally are just eating meat and nothing but

00:44:38.920 meat. And then there are others where you expand that into, well, you can eat other animal products,

00:44:44.800 you can eat eggs, you can have dairy and things like that. Let's start with just the meat only

00:44:49.680 version of that diet. First of all, what do you think is happening metabolically? How does one achieve

00:44:55.800 ketosis with just meat? Because even the fattest serving of meat, even if you were eating

00:45:02.760 just ribeyes, I suppose it's possible that you could get 30% of your calories from protein and 70%

00:45:09.480 from fat. Does it produce a ketotic state as well, typically? I had a ribeye the other night. I think

00:45:14.800 would hit the keto macros because it was a lot of fat, and I was kind of annoyed because, you know,

00:45:19.720 there was less meat and more fat. I think you can achieve ketosis with a fatty carnivore diet,

00:45:26.040 especially if calories are restricted. Couldn't do it if it was a New York strip or a filet. You just

00:45:29.920 don't have enough fat in it relative to the protein, right? You could if you were in a caloric

00:45:34.960 deficit. So if you're in an energy deficit, your insulin is going to get like everything is going

00:45:39.200 to kind of go in the right direction. And that's the issue. I am a firm believer that carnivore diets

00:45:45.120 can be therapeutic for people who have autoimmune disorders. So that's pretty clear. There's some

00:45:51.300 people who they could also follow a path and do an elimination diet, but the carnivore diet is the

00:45:56.680 ultimate elimination diet. So you're meeting your protein requirements, have enough protein to build

00:46:01.700 muscle. Steak and an animal-based protein diet has pretty much all the micronutrients. I mean,

00:46:07.220 you could argue maybe vitamin C and magnesium, but you do not see vitamin C deficiency in people

00:46:13.500 that are on carnivore diets, surprisingly. So there's some vitamin C in like liver and stuff too. So if

00:46:18.740 you're eating nose to tail, that's not something you have to worry about. I've seen magnesium trending low,

00:46:24.340 although we don't have the best magnesium measurements, the blood work for that, but I've

00:46:28.360 seen magnesium being beneficial for people because magnesium, we get it from chlorophyll. It's like

00:46:33.320 the central molecule of chlorophyll. And we're not getting any of that really with a ketogenic diet

00:46:37.800 or very little. You're getting a lot. I mean, I got a ton of, I had two salads a day when I was on a

00:46:42.720 ketogenic diet. Yeah. I'm talking pure carnivore. We're talking steak and water, right? Like not even

00:46:48.220 coffee, not even putting pepper on the steak. There are a group of people who believe that and

00:46:53.540 it's working for them and they have a lot of anecdotal data to support that. I get an inbox

00:46:59.640 full of people that say, Hey, look, I had this condition or that condition. I followed carnivore

00:47:03.600 and here's my blood work. And I can't argue with that. Yeah, no, I find that stuff pretty compelling

00:47:07.840 from an elimination diet perspective. And I've certainly met a number of folks who feel that way

00:47:12.540 and it's quite binary. Either it works or it doesn't. For many of these people, they're so debilitated

00:47:17.200 on any other form of diet that it's a no brainer. You're going to stick with that type of restriction.

00:47:21.900 Yeah. The influencer voice is also amplified. Joe Rogan, for example, had vitiligo. That's an

00:47:27.700 autoimmune disorder. And I know people who have that saying going on a carnivore diet cured my vitiligo

00:47:32.760 people that are interested in that. So there's a wide variety of things that it can be therapeutic

00:47:37.680 for. There's a group in Budapest, Hungary called paleomedicina. And I went to their clinic and they

00:47:42.700 pulled their files and I saw everything from type one diabetes to cancer to different neurological

00:47:47.800 disorders. They're showing me blood work longitudinally over time. Could be cherry pick the cases, but it

00:47:53.340 was pretty convincing. And they probably have a dozen more publications, case series and things

00:47:57.660 like that. But it's a form of a ketogenic diet. So I think that's important to understand. Like a

00:48:01.920 carnivore diet is fundamentally, if practiced the way they do with paleomedicina, where you just focus

00:48:07.260 on super fatty cuts, fatty fish, fatty meats, it's a version of a ketogenic diet. And I think

00:48:12.320 that's why it works. All right. Let's go back to now talk about this world of exogenous ketones,

00:48:18.400 these supplemental ketones. You alluded to them already through the lens of kickstarting a ketogenic

00:48:23.380 diet. But before we talk about application, I want to kind of orient people to the journey you've been

00:48:29.820 on. I was once on that journey with you being a regular consumer of all sorts of these things.

00:48:35.460 I will say lately, when I mean lately, I mean only in the past three months, I recently tried a product

00:48:42.620 that I like. I put it in my coffee in the morning and I believe it is a diester of 1,3-butanediol.

00:48:51.760 So it doesn't come with sort of the liver toxicity that I think we should talk about with respect to

00:48:56.080 1,3-butanediol, which unfortunately seems to be running rampant right now. But it's a white powder.

00:49:01.180 And what blows my mind about it is when you mix it in water and drink it, it's palatable. It's not

00:49:07.640 delicious. You wouldn't go out of your way to drink it, but it is not horrible the way that most of

00:49:13.820 these synthetic ketones used to taste. So you can just make a shot glass of it and it's totally

00:49:18.840 reasonable. Alternatively, it's the creamer in my coffee and it's fantastic. But let's go way back to

00:49:24.800 the beginning. Circa 2011, you had basically only two products you could consume. You had

00:49:33.600 a beta-hydroxybutyrate monoester. Actually, there were more than that. There was a ketone salt,

00:49:39.680 which we should talk about, and you had an acetoacetate diester. Is that correct?

00:49:44.740 B monoester and 1,3-butanediol acetoacetate diester. Two acetoacetates on 1,3-butanediol.

00:49:50.620 So there's a two esters. So just explain to people, I mean, unfortunately, we have to get

00:49:55.000 into a little biochemistry here for you to explain the difference between esters and salts. And so

00:50:00.160 to everybody listening, apologies, but if you want to understand these things and you have to,

00:50:05.600 if you want to be a consumer of them, because everybody is talking about these things as though

00:50:09.780 they're the same and they're categorically not the same. Most people have no idea what they're

00:50:14.860 talking about. And most people who are selling these things are not being transparent about what it is

00:50:19.960 you're buying. They just call everything a ketone. Let's do a little bit of biochemistry, Dom.

00:50:24.080 Sure. Glad to do that. I think it's maybe even good to step back a little bit because if you go to

00:50:29.200 clinicaltrials.gov and you search ketone supplement MCT, that's a 8 to 10 carbon fatty acid that can

00:50:36.600 convert to ketones. So that'll come into the conversation. But one of the original ketogenic

00:50:41.900 substances was 1,3-butanediol. And I have, I think, compliments of Ken Ford, some of the MIT

00:50:48.500 reports of testing this compound that from the 1960s. And then there was a report written

00:50:55.300 by people at NASA where they were basically looking at this as a long duration spaceflight food.

00:51:01.420 1,3-butanediol, which is an alcohol. It's a di-alcohol or a glycol. It is remarkably ketogenic,

00:51:08.240 which means you consume it and you elevate beta-hydroxybutyrate and it's incredibly stable.

00:51:14.420 So hence for long duration spaceflight. Also it preserves food. In the report, they basically

00:51:20.020 soaked, they put it into some biscuits and the biscuits were like extremely shelf stable. So

00:51:26.220 it's a humectant, which means it keeps food moist. It's actually grass approved to be put in sausage

00:51:32.220 casings and things like that. So that existed, that was 1,3-butanediol. And there was two people

00:51:38.060 who really I'd like to credit, Dr. Henri Brunengrabber from Case Western and Dr. Richard

00:51:44.200 Veitch, the late Dr. Richard Veitch.

00:51:46.000 Oh, he passed away.

00:51:46.840 A mentor of mine. Yeah, he passed away two or three years ago, I think. And I remember Dr.

00:51:51.980 Veitch saying, because I was trying to acquire his ketone ester for some studies and I ultimately

00:51:56.720 used the 1,3-butanediol or the mono ester beta-hydroxybutyrate for seizures, but it didn't

00:52:02.160 work. And I will pivot and talk about that. So you have 1,3-butanediol was the original

00:52:06.480 ketogenic molecule. And then you have two people who spearheaded ketone esters.

00:52:11.800 Sorry, just before we leave that, you said 1,3-butanediol elevates beta-hydroxybutyrate.

00:52:16.720 Let's explain how and why. Okay, yeah. You can consume 1,3-butanediol and it's a precursor

00:52:21.320 to beta-hydroxybutyrate. When you consume it, it goes through the alcohol dehydrogenase pathway

00:52:26.880 and produces much like alcohol. You can elevate BHB with this precursor, but it needs to be metabolized

00:52:35.360 by the liver. And when it's metabolized by the liver, the liver does have to work a bit. If you

00:52:40.780 consume enough to like jack up your ketones to three or five millimolar for two or three weeks,

00:52:46.260 you're going to see your liver enzymes jump up. So I've done that with 1,3-butanediol. And you have

00:52:49.640 to take a lot of it. You're talking about 150 to 200 milliliters per day for someone like me to be

00:52:54.680 in therapeutic ketosis. So when you do that, you're also generating an aldehyde.

00:52:59.860 Let's take a step back here. If I asked you to consume a hundred grams of ethanol a day

00:53:09.160 for two weeks, your transaminases would go up. Yeah. I've done that before.

00:53:15.180 Yeah. So let's talk about that. So a standard drink is about 15 grams of ethanol, maybe more,

00:53:20.960 right? Yeah. Yeah. Call it 20, round up 20. So now I'm asking you to have five alcoholic beverages a

00:53:26.340 day. And by the way, you could space that out over the course of the day and not even get a buzz.

00:53:30.300 Say five alcoholic beverages a day for two weeks, you are metabolizing ethanol with alcohol dehydrogenase

00:53:38.500 and you're going to create all of the various metabolites. And the reason your transaminases

00:53:45.900 are elevating is those enzymes are leaking out of hepatocytes because the hepatocytes are injured

00:53:50.840 due to the inflammation that results from that metabolic pathway. Is that at all analogous to

00:53:56.520 what's happening with a comparable dose of 1,3-butanediol? Yeah, it is. There's a couple

00:54:01.180 of things going on. You drink alcohol, you're de-energizing the redox state of the liver and

00:54:05.980 you're generating acetyl aldehyde, an aldehyde molecule, which aldehyde damages DNA. It's got

00:54:11.660 oxidative stress issues, baggage that comes with it. You're also generating acetate. When you drink

00:54:17.900 alcohol, you're generating acetate. And the brain, acetate is actually something I looked into. It's

00:54:23.440 a remarkable alternative fuel for the brain. Maybe a lot of people don't know that, but when you

00:54:27.480 drink alcohol, you're giving your brain acetate. We can come back to that. It's analogous to

00:54:33.340 1,3-butanediol is analogous to drinking alcohol. Instead of generating acetate, you're generating

00:54:39.160 beta-hydroxybutyrate, another alternative fuel for the brain. Do you generate the same amount of

00:54:44.820 aldehyde? You are generating a beta-hydroxybutyrate

00:54:48.360 aldehyde that is relatively short-lived, but you can overwhelm the ADH enzyme. So if you drink too

00:54:58.060 much of it, you can overwhelm the enzymatic degradation. And Henri Brunengrabber did some

00:55:02.760 seminal studies on this that he shared with me. Some of it's published. They had a ketogenic dog

00:55:07.760 model that they gave 1,3-butanediol as a hypoglycemic agent. So it's a hypoglycemic agent

00:55:13.700 because it de-energizes the liver and prevents glycogenolysis and gluconeogenesis because those

00:55:21.940 mechanisms in the liver are highly, highly energy dependent. So that's analogous to alcoholic

00:55:26.560 ketoacidosis. When you have an alcoholic that's fasting and he over-consumes alcohol, he goes to

00:55:32.220 the ER because he experiences alcoholic ketoacidosis. You have runaway ketogenesis because you're inhibiting

00:55:39.340 gluconeogenesis. And why can't that patient make enough insulin in response to the beta-hydroxybutyrate

00:55:47.020 to bring the acidosis under control? Because the liver cannot, if you increase insulin,

00:55:54.800 that insulin is going to only facilitate glucose disposal. So the main thing is the liver. The

00:56:00.240 liver is like the driver. Oh, you're saying the liver doesn't respond to the insulin signal to make

00:56:04.540 less BHB in that situation? In alcoholic ketoacidosis? It does? So why does it in the rest of us?

00:56:10.640 Like when you and I used to do our ridiculous 10-day fasts, do you still do those by the way?

00:56:15.100 I do like a sardine fast. So protein-sparing fast? I'll do like a five-day, yeah, two or three

00:56:20.580 cans of sardines a day. I get the same benefits and it mitigates a lot of the negative effects.

00:56:24.640 Yeah, yeah, yeah. When we used to do these 10 and 14-day water-only fasts, our ketones would

00:56:29.660 actually plateau. Yeah. And even when George Cahill did the seminal studies of 40-day water-only

00:56:36.280 fasts, their ketones plateaued at seven to 10 days. And a big part of that was that insulin is now

00:56:42.340 keeping them in check. The reason the ketones aren't going to produce a level of acidosis is

00:56:46.940 that, and that's why, of course, kids primarily with type 1 diabetes can develop ketoacidosis.

00:56:53.100 They don't have the beta cell capacity to offset that rise in ketones. This case of the alcoholic is

00:56:59.260 very interesting to me. I actually was never aware of this.

00:57:01.580 You de-energize the liver so the liver can't undergo gluconeogenesis, to some extent glycogenolysis.

00:57:07.440 Then you have the electrolyte balance, you get dehydration. So it's a constellation of things.

00:57:12.080 But getting back to 1,3-butanediol, if you consume it and you consume large amounts of it,

00:57:17.780 like some of the early work that was done by, you can overwhelm that enzymatic cascade and you can

00:57:23.380 start generating a lot of these albohyde intermediates. And that's maybe not a good thing.

00:57:28.820 So with 1,3-butanediol, I see two problems I think people should be aware of, especially

00:57:33.220 people maybe that are elderly or using it for cognitive enhancement, is that you get buzzed

00:57:38.260 on it. I've probably consumed 1,3-butanediol than anybody. We had it in like big 20 liter

00:57:43.160 vials of it.

00:57:44.440 I used to buy it at Sigma Chemicals. The stuff was dirt cheap.

00:57:47.540 Yeah. Experimented with the racemic and then also with the R enantiomer and kind of the same thing.

00:57:52.800 It's great. And actually, I think it has applications for cancer because it does have a glucose lowering

00:57:58.100 effect. We mixed it in with a standard diet and gave it to animals with metastatic cancer and it

00:58:03.720 suppressed cancer growth and put them into ketose. So it has some applications there.

00:58:08.340 But getting back to the ideal ketone, drinking 1,3-butanediol to elevate BHB is somewhat analogous

00:58:14.780 to drinking alcohol to generate acetate, which is a great molecule. I mean...

00:58:18.860 But it's a very indirect way to do it that comes with toxicity.

00:58:21.660 Yeah. So what Dr. Veach and Henri Brunengrabber did, and there was some others too involved in

00:58:26.520 the research, Sammy Hashem developed a glycerol beta-hydroxybutyrate ester. You can take 1,3-butanediol

00:58:32.720 and do a trans-esterification reaction and add beta-hydroxybutyrate to it, or you can add

00:58:37.480 acetoacetate to the molecule. And when you consume it, you quickly liberate the ketones. So you get a

00:58:43.320 quick elevation of ketones, beta-hydroxybutyrate or acetoacetate. And then the 1,3-butanediol then goes to

00:58:49.440 the liver. And the pharmacokinetics, and we mimicked it exactly in our lab, you have an

00:58:54.280 initial peak, and then like an hour or two later, you have a second peak from the 1,3-butanediol.

00:58:59.620 It's dose-dependently potentially problematic. And with the 1,3-butanediol, there's two issues would be

00:59:06.360 the potential for liver toxicity in people that do not have healthy livers. Like my liver is pretty

00:59:12.360 healthy, I think, and it doubled my liver enzymes if I take a large dose for two weeks. And then the

00:59:16.920 other thing is, if you take a large dose of 1,3-butanediol, the narcotic effect in someone

00:59:22.020 who's frail, who doesn't have good stability, it's going to, in Dr. Veach's word, it's going to make

00:59:27.440 you drunk stupid. Because I was trying to acquire some of his ester for something, and I was like,

00:59:32.240 well, I'm just going to use 1,3-butanediol. And he kind of talked me out of it. The whole reason for

00:59:35.800 developing the monoester was to avert the problem.

00:59:38.680 So the monoester is beta-hydroxybutyrate with a monoester bond to 1,3-butanediol?

00:59:45.240 Yeah, 1,3-butanediol. That's, yeah, bounded to beta-hydroxybutyrate. So you could say it either

00:59:50.260 way. Why is it that you don't experience the same negative issue with that molecule? Is it because

00:59:56.460 you just consume less of it because you're getting the BHB directly?

00:59:59.660 Yeah, you could take half the amount. The kinetics are a little bit slower too,

01:00:03.820 because you have to hydrolyze the BHB from that in the liver.

01:00:07.400 And why can't you just consume BHB? Is that not stable enough by itself, other than in a salt?

01:00:12.060 You can. Yeah. So there's a free acid. I tinkered with that originally with the free acid because

01:00:17.620 you could buy it and it's super acidic and it's not very stable in solution. And for a variety of

01:00:23.740 different reasons, although you could put free acid, it needs to be liquid into like an electrolyte

01:00:28.320 formulation. So we gravitated towards, at the time I was using in my electrophysiology experiments,

01:00:35.080 you can't put a ketone ester in the bath because it needs to be metabolized by the liver. So you can't

01:00:40.420 put it onto neurons. So you have to use the salt. So you mimic the pharmacokinetics of what you get

01:00:45.020 with the ester. So we were putting sodium beta-hydroxybutyrate in. I was thinking,

01:00:49.820 okay, I'll give this to the animals. But then it was like, I was very concerned with the sodium

01:00:53.780 overload. Hypertension, all the negative effects about salt. But all the negative effects about

01:00:59.620 salt, and your listeners may not know this, but most physiologists kind of do that study it.

01:01:04.240 The salt-sensitive people or the problem with salts, and people maybe even think ketone salts,

01:01:09.860 is that when you consume salt, you get hypertension in some people, salt-sensitive.

01:01:13.580 But that's specific to sodium chloride. So sodium bicarb, sodium citrate, sodium beta-hydroxybutyrate

01:01:19.560 is what I'm talking about. If you consume large doses, gram molecules of that, that doesn't have

01:01:24.640 the same hypertension. Something about chloride. So sodium chloride. So you could use potassium chloride

01:01:31.220 instead of sodium chloride for salt. But I think that's an important thing to consider

01:01:36.080 because a lot of people shy away from ketone salts because it's sodium. But the salt-sensitive

01:01:42.140 hypertension that you get is pretty much associated with sodium chloride. And I was communicating with

01:01:48.100 Patrick Arnold at the time, and we were, I was like, I have sodium chloride, but I wanted to get

01:01:53.760 potassium chloride. But I looked, I couldn't buy it from Sigma. It wasn't in the CAS database,

01:01:58.120 and nobody had thought about this. How could nobody have thought about putting ketones on

01:02:03.120 different electrolytes? It just wasn't out there. So I kind of had the idea of sodium, calcium,

01:02:07.840 potassium, magnesium, different things that you can combine.

01:02:11.500 So you just needed a positive cation.

01:02:14.760 Yeah. And I wanted to balance the sodium with potassium. So that was my original thing. I was

01:02:19.460 like, I was going to create a ketone sol and just balance the sodium with potassium, but it wasn't

01:02:24.320 there. And are those covalently bound or not? Ionically bound. You don't covalently? Yeah.

01:02:28.040 Ionically bound. Okay. So again, just- Sodium's positive.

01:02:30.460 Trying to get everybody back to high school chemistry. You can either take this highly,

01:02:34.720 highly acidic BHB molecule, and you can covalently bind it through an ester to 1,3-butanediol,

01:02:42.660 or you can say, let's be done with that baggage of the 1,3-butanediol, and let's have

01:02:47.380 a non-covalent, an ionic bound to a salt. And I just need a positive charge to offset the negative

01:02:53.740 charge. So then you were saying, okay, I want to do sodium because I can do a lot with it.

01:02:58.560 And then tell me where the potassium comes in because you want sodium and potassium,

01:03:02.480 both of them are two positive charges instead of one calcium or one magnesium, which have two

01:03:06.800 positive charges? Yeah. So the idea is to have monovalent and divalent cations. You can spread

01:03:12.500 the beta-hydroxybutyrate out to create like a quad salt was the idea back in 2011. So reaching out to

01:03:19.160 Patrick, it wasn't in the cast database. No one had thought about it. You couldn't buy it. So we had to

01:03:23.640 make it. And then we made the calcium and the magnesium. And through time, basically,

01:03:28.620 we settled on a ratio of sodium, potassium to calcium, similar to element. So they're kind

01:03:33.540 of ahead of, but element is sodium chloride. So keto start or from audacious nutrition is sodium

01:03:39.200 beta-hydroxybutyrate and the calcium. And it's got a spread of electrolytes that are similar. So

01:03:44.260 you're giving electrolytes and also giving ketones. And that's really important when you start a

01:03:49.240 ketogenic diet because you're replenishing the electrolytes that you are spilling out more

01:03:55.260 through a natriuretic effect, especially the sodium. And also there's an energetic gap in the

01:04:00.340 brain when you start a ketogenic diet where you have an energetic need for the increase in ketones.

01:04:07.220 We should go back to that, Dom, because I think a lot of people have lived that experience and they

01:04:11.060 don't understand why, which is in the early stages of a ketogenic diet, there's little room for error

01:04:17.640 where as glucose levels are going down and ketone levels haven't come up enough to fill the gap,

01:04:23.600 you really feel lousy. In retrospect, you can work around that, but it's easy to miss it,

01:04:29.500 meaning it's easy to miss the mark and therefore suffer that painful transition, which can last

01:04:34.720 weeks in some people. And therefore using these exogenous ketones can be a very elegant bridge

01:04:39.940 through it so that you don't experience the negative side effects of the transition.

01:04:43.360 Yeah. The energetic effects, FGG PET scan, you're going to see like less brain glucose utilization

01:04:49.320 for one thing. And then you have the contraction of plasma volume because as you lose water and

01:04:54.540 electrolytes so that you might have orthostatic hypotension, you get the brain fog. And then you

01:04:59.880 have electrolytes, which are literally molecules that are involved in action potentials and keeping

01:05:06.060 membrane potentials in cells. And all these can be kind of mitigated through ketone salts,

01:05:11.080 have an advantage over the ketone esters. They also have the advantage because the mineral delays

01:05:17.800 gastric absorption. So when you take a dose of a ketone salt, it does not cause an insulin effect.

01:05:23.940 If you drink a ketone ester or a large dose of 1,3-butanediol, and I've done this before,

01:05:29.560 and you do an insulin measurement an hour after, you're going to see your insulin levels increase.

01:05:35.560 How much would you see an increase in you?

01:05:37.780 So the increase seems to be proportional to the differential. So if you rapidly increase ketones

01:05:44.620 2 millimolar, and if you stay under 2 millimolar, then you don't get the spiking in insulin. But if

01:05:51.540 you consume it and you get above 1.5 to 2 millimolar, at least in me and a few other people that did this,

01:05:58.780 then you see this counter-regulatory dump in insulin. And that would also explain when people

01:06:04.840 drink a large dose of a ketone ester, their glucose levels go down. And it's a bit of a

01:06:09.520 scary situation because I know people have gotten themselves into the situation is that when you

01:06:13.680 drink the ketone ester about two hours later or thereabouts, you can be hypoglycemic and also

01:06:20.340 hypoketotic, which means your ketones come up, you utilize them as fuel, but you've released insulin,

01:06:26.540 and that caused peripheral glucose disposal. And then you get into a point where you're running,

01:06:31.160 for example, and then you tank. And you could trigger a headache, as it does with me,

01:06:35.460 if you take a large dose. So there's ways around that.

01:06:38.740 But you're saying the salt produces that effect much less?

01:06:42.600 The salt does not produce that effect at all for a number of different reasons. I think

01:06:45.920 the rate of rise of ketones in the bloodstream seem to be the predictor of if you're going to

01:06:52.140 release insulin for one thing. And then there's something about the electrolytes too,

01:06:56.260 that maybe delays gastric absorption. And with the salts, you're just not getting that elevation

01:07:01.620 of ketones that's as high and as rapid as you would get with a ketone ester.

01:07:07.720 So in the packet, what's the brand that you brought for me?

01:07:10.640 Audacious Nutrition and KetoStart.

01:07:12.520 Okay. So in that packet, you're getting about how many grams of electrolytes, about one gram total?

01:07:18.900 Yeah, a total about one gram, like sodium, then calcium, magnesium, potassium. So there's

01:07:25.620 different formulations. The packets are a little bit smaller about the size of element now. You're

01:07:30.240 getting about six to 10 grams of pure beta-hydroxybutyrate minus the electrolytes. So a lot

01:07:37.160 of people that say you're getting this amount of ketones, that also includes the electrolytes. So

01:07:41.960 you're getting, depending upon which packet you take, six grams or 10 grams of pure

01:07:46.820 beta-hydroxybutyrate in the two different enantiomers. So that's another thing that we

01:07:52.260 could talk about too.

01:07:53.520 Equal mix of R&D?

01:07:54.860 Yes. A 50-50 ratio of D and the L and R&S. I guess you could say there's four different

01:08:01.680 ketone molecules. There's D-beta-hydroxybutyrate, the L or the R&S, if you use that nomenclature.

01:08:08.280 And then you have the acetoacetate. And beta-hydroxybutyrate does need to break down to

01:08:12.340 acetoacetate to be used in the mitochondria. And then you have acetone, which has some interesting

01:08:17.380 signaling and metabolic effects, surprisingly. So it also correlates really well with seizure

01:08:22.820 control. I'm not forgetting about acetone.

01:08:25.280 So in somebody my size, 180 pounds, 10 grams of BHB will take me to what level for how long?

01:08:32.300 At rest. Let's just say I'm not exercising.

01:08:34.720 For me, maybe we can include it in the show notes. I could show you my CKM, my continuous

01:08:39.600 ketone monitor, and shoots me up for, I guess it's about four hours. One packet, four hours.

01:08:46.600 But you're starting at a high level. I'm at zero.

01:08:48.600 No. Well, I would eat carbohydrates to make sure I'm zero to start with.

01:08:52.820 And I did it under, I've done this dozens of times, but it's interesting. If I'm sitting

01:08:57.420 in my car and driving, I had a road trip and I drank it and had my CKM on, it was elevated

01:09:02.380 for like four to six hours. And I was super hyper-focused driving and it was great.

01:09:07.760 How elevated? Like one to two?

01:09:09.600 Yeah. It was about between one and two, which I think is an ideal range because you're not

01:09:14.440 stimulating insulin. So keto start is D and the L, and it was only measuring the D,

01:09:20.340 but it's not accounting for the L or acetoacetate or acetone, right? So it's a 50-50 mixture of D

01:09:27.520 and L, but it's only measuring the D and it's still getting between one and two millimolar.

01:09:31.860 Does that mean you're actually at twice that level?

01:09:34.560 Potentially, yeah.

01:09:35.100 What were we doing with our Abbott finger sticks?

01:09:37.440 Measuring D, beta-hydroxybutyrate.

01:09:39.240 So does that mean every time we were measuring this, we were probably only capturing half

01:09:44.340 what Cahill was capturing or has everybody always measured half?

01:09:48.120 No. Well, racemic ketones were some of the first ones to come out on the market and then

01:09:52.800 everybody gravitated to the D enantomer.

01:09:55.420 I think we should stop, Dom, and explain to people what the hell we're talking about.

01:09:58.640 I don't think people know what enantomers are.

01:10:00.520 Okay. Beta-hydroxybutyrate is produced in the body primarily in the form of D-beta-hydroxybutyrate,

01:10:08.440 which is a form, the mirror image of D-beta-hydroxybutyrate is L-beta-hydroxybutyrate.

01:10:16.440 So we say if a beta-hydroxybutyrate supplement is racemic, it has D and it has L in it.

01:10:24.480 But let's go back to what you said a second ago because I want to make sure people understand.

01:10:27.400 The mirror, it's literally a mirror image.

01:10:30.320 A mirror image, yeah.

01:10:31.040 So for example, allulose is an enantomer of fructose.

01:10:34.380 Yeah.

01:10:34.660 If you draw fructose and you hold it in the mirror, what you see is not fructose.

01:10:40.120 It's the reflection of fructose, but that's allulose.

01:10:43.500 Allulose is not an enantomer.

01:10:45.560 Oh, it's not?

01:10:45.760 It's an epimer.

01:10:47.120 Oh.

01:10:47.360 It's an epimer.

01:10:48.040 I always thought it was an enantomer.

01:10:49.340 No, it's an epimer.

01:10:50.320 So it has it, yeah.

01:10:51.020 It has another flip.

01:10:52.000 Yeah, yeah.

01:10:52.940 Oh, okay.

01:10:53.620 So it's two flips.

01:10:54.380 It's similar to an enantomer, but it's an epimer.

01:10:57.000 I think an important thing to remember is that you have ringer's lactate, which is also DL

01:11:01.220 lactate.

01:11:01.760 So you could, I mean, maybe analogous.

01:11:02.940 But why does this matter chemically?

01:11:04.400 I think the point I want to make to people is when you have a D and an L of something,

01:11:08.900 do they behave the same?

01:11:10.360 Yeah.

01:11:10.740 There's a lot of racemic compounds.

01:11:12.700 So statins, Adderall, ibuprofen.

01:11:15.720 So these are all racemic mixtures of the same molecule.

01:11:19.380 So racemic beta-hydroxybutyrate, you have the D.

01:11:22.260 The D beta-hydroxybutyrate gets metabolized like very, very fast.

01:11:26.620 So it gets in your system, your tissues suck it up, you metabolize it.

01:11:31.220 Your body makes very small amounts of L-beta-hydroxybutyrate with a racemase enzyme.

01:11:36.120 That racemase enzyme is not in the liver, but it's in the tissues.

01:11:40.140 That's very interesting because I think some tissues are converting D to L to maybe use the

01:11:45.720 L-beta-hydroxybutyrate as a signaling, but I'm just speculating.

01:11:48.720 But nonetheless, you have D gets metabolized very quickly, and then the L is like a timed

01:11:54.260 release version of beta-hydroxybutyrate.

01:11:56.500 That's how I've always thought about it.

01:11:58.280 Brianna Stubbs did some nice work looking at the D to L, and we've done quite a bit of

01:12:02.140 work on the D and the L and a lot of work with racemic compounds.

01:12:05.280 So the L will get metabolized three or four times slower, and you get about 20% conversion

01:12:12.180 of the L back to D, but it's a very slow process.

01:12:15.460 The advantage of taking the D to L or the racemic, when you consume a racemic mixture,

01:12:21.140 the ketones elevate and stay elevated quite a bit longer.

01:12:24.840 I think of the L-beta-hydroxybutyrate as an important signaling molecule because you get

01:12:29.920 higher concentrations of L in the brain.

01:12:32.920 So if you give someone racemic beta-hydroxybutyrate and then you pull out the heart and you take

01:12:38.480 samples of the brain out, the levels of L-beta-hydroxybutyrate are going to be quite a bit higher.

01:12:43.240 And is that just because it sticks around longer and therefore crosses the blood-brain

01:12:47.060 barrier or in the case of the brain?

01:12:49.060 It metabolizes slower.

01:12:50.780 So this is important.

01:12:52.200 We think this is important because the L-beta-hydroxybutyrate probably does not have, definitely does not have

01:12:58.020 the same energetic potential in regards to generating ATP.

01:13:01.980 It does not.

01:13:02.820 So no, Veach told me that, and I'm a believer because it gets metabolized much slower.

01:13:06.840 Right.

01:13:07.020 But if you just take the total metabolism of it, are you saying one mole of one and one

01:13:12.140 mole of the other produce a different amount of ATP?

01:13:14.600 Yeah.

01:13:15.000 Ultimately, L-beta-hydroxybutyrate will go into acetyl-CoA, but it'll be metabolized more

01:13:19.840 like a fatty acid.

01:13:21.100 The D has a redox shift and it causes a reductive shift.

01:13:24.900 Actually, you could have reductive stress.

01:13:27.580 I'm going to come to that in a minute.

01:13:28.920 But you have the D and the L. They get metabolized at different rates.

01:13:32.320 D gets metabolized slower than the L.

01:13:34.700 It takes about three or four times longer, but the L seems to have...

01:13:39.160 Sorry, you said D metabolized slower, I think.

01:13:41.440 Oh, I'm sorry.

01:13:42.000 D metabolized very fast and L metabolized slower.

01:13:44.360 Sorry.

01:13:44.800 But the L retains signaling effects that D does.

01:13:48.080 So for example, the NLRP3 inflammasome, so that Nature Medicine paper in 2015, doesn't

01:13:54.620 seem to be enantiomer specific.

01:13:56.620 So the D will suppress it.

01:13:58.700 So that's important because if the L gets elevated in the brain, then it could inhibit neuroinflammation.

01:14:04.540 And inflammatory processes.

01:14:06.080 So it's almost like the drug form of BHB.

01:14:08.920 The epigenetic effects, the signaling effects and the epigenetic effects of the L seem to

01:14:15.540 be present too.

01:14:17.560 So you have the D that gets burned up quickly for fuel and then the L that kind of hangs

01:14:22.960 around, gets metabolized slower.

01:14:25.080 But then that's hitting the various receptors.

01:14:27.360 So you have the GPR109A receptor and you have epigenetic effects.

01:14:31.860 You have the NLRP3 inflammasome.

01:14:33.640 So you have important signaling functions that ketones are attributed to and D beta hydroxybutyrate

01:14:39.780 has been spent and used as fuel, but the L is hanging around and actually preserving

01:14:45.380 that signaling effect, the positive signaling effect.

01:14:48.360 The continuous ketone monitor and the Abbott are more measuring D or L.

01:14:52.380 They only measure the D.

01:14:54.560 They do not measure the L.

01:14:55.720 I've had conversations with them and even though your body makes small amounts of it,

01:14:59.680 it's usually just in the tissue.

01:15:01.640 However, pharmaceutical companies are the ones kind of that have reached out.

01:15:06.660 As you know, there's quite a bit of patent literature because I was talking about this

01:15:10.680 a while ago.

01:15:11.820 So I think the Buck Institute has like patents on L beta hydroxybutyrate.

01:15:15.820 I would say there's probably about three dozen patents on L now because I've kind of probably

01:15:21.040 attributed to me because I'm talking about the effects.

01:15:24.180 However, I think Dr. Veach brought up a good point and he was right in that D beta hydroxybutyrate

01:15:28.800 is energetically favorable for producing ATP, but a D-L mixture is almost like you get the

01:15:35.400 benefits of the D and then you get the signaling benefits of the L. And we delivered that with

01:15:41.960 an ester. We delivered that with the ketone diester and that gave us remarkable results

01:15:47.300 in seizure control and animal models of cancer.

01:15:51.440 And we also use the D-L salts.

01:15:53.800 So I think the industry is kind of coming full circle.

01:15:56.420 So now you have L enriched formulations with D, but we've always kind of stuck with the

01:16:02.040 racemic mixtures because I kind of knew that there was fundamentally something interesting

01:16:06.740 about the D and the L because when I use pure D beta hydroxybutyrate, it actually trended

01:16:12.840 to make seizures happen faster.

01:16:14.560 And I didn't know why.

01:16:16.120 Say that again.

01:16:17.040 When we use pure beta hydroxybutyrate, the D enantiomer and with an ester like the monoester.

01:16:23.180 This is when you were saying that Veach's initial compound was your first attempt and it didn't

01:16:29.560 work.

01:16:29.900 Yep.

01:16:30.040 1,3-butanediol and then the monoester had no effect on seizures.

01:16:34.040 So my colleague, Dr. Jung Rho said, you need to look at acetoacetate.

01:16:39.120 And when you elevate beta hydroxybutyrate and acetoacetate in a one-to-one ratio, that creates

01:16:43.900 a redox balance.

01:16:45.100 And I do think that's important.

01:16:46.660 Also, people have brought to my attention that when you rapidly spike D beta hydroxybutyrate,

01:16:51.480 you're causing something called reductive stress.

01:16:53.480 So you have the production of NADH from NAD, and that's actually depleting NAD.

01:17:00.540 A ketogenic diet will boost your NAD.

01:17:02.640 You could take NAD supplements.

01:17:04.680 That's something that we're working on too, because I think a central mechanism in ketogenic

01:17:09.600 diets and supplements is the elevation of NAD.

01:17:12.600 So we're working with NAD compounds.

01:17:15.260 I can't talk about that because it's through an industry, but there are multiple compounds

01:17:18.900 of stabilized NAD that have interesting and remarkable effects, and we're going to combine

01:17:24.660 them with various new ketone molecules that we're developing.

01:17:28.640 But NAD is sort of like this hub that is a central player in the benefits of ketogenesis.

01:17:35.180 What do you make of the fact that there hasn't been any efficacy of NAD supplementation or even

01:17:40.140 NAD precursors?

01:17:42.000 NR and NMN have really not yielded any meaningful or measurable benefits.

01:17:46.740 It's the only thing I've ever seen that looked somewhat positive was in the trial that looked

01:17:50.960 at patients with ALS, and you saw a slightly shorter time to ventilator use with an NR formulation.

01:17:58.460 I'm aware of that thought, yeah.

01:17:59.320 But really, we just haven't seen any benefits.

01:18:01.340 And so what do you attribute that to with respect to the NAD story, and what do you think

01:18:04.760 might be missing if indeed there's efficacy there?

01:18:07.180 I can't say what I'm doing now, but we're running experiments, I think even today.

01:18:10.900 So there's different NAD molecules that are out, that are stabilized forms of them that

01:18:16.200 are in clinical trials.

01:18:17.500 I think phase two and maybe phase three clinical trials.

01:18:20.940 So you think it's a delivery problem?

01:18:22.360 It's a stabilized, you have to stabilize NAD.

01:18:25.440 And I think that's important to have it stabilized because when you consume it, the liver takes

01:18:29.880 a lot of it.

01:18:31.180 And if it doesn't, you're not taking enough of it in a stabilized form, the liver is very

01:18:36.440 greedy.

01:18:36.880 Actually, I think it'd be good for non-alcoholic fatty liver disease.

01:18:40.160 So that's another, I think NAD could be important for that.

01:18:43.540 But I think you have to take a dose that gets past the liver into circulation and crosses

01:18:48.700 the blood-brain barrier.

01:18:50.000 And there's a number of different stabilized versions of NAD that are in development and

01:18:55.060 testing, and some of them we're working on, that I think have potential for oxygen toxicity.

01:19:00.100 So we're working on those now, giving acutely and also chronically in graded doses.

01:19:04.760 Will there be other applications for it, Dom?

01:19:06.280 Such as the holy grail of Giro protection, or even just performance enhancement, physical

01:19:10.700 performance enhancement?

01:19:12.100 Yes.

01:19:12.940 I am convinced that some of the animal literature, I want to replicate it.

01:19:16.880 So I'm not going to believe something until I replicate it.

01:19:19.000 So I think we have plans to do some exercise studies, oxygen toxicity brain studies.

01:19:24.600 So I do think that you need to give quite a bit of it in a stabilized form, and it needs

01:19:28.940 to get to the muscle.

01:19:30.340 And for me, I'm very interested in crossing the blood-brain barrier and getting to the brain.

01:19:34.680 I also think that these things will be more efficacious in the context of energetic metabolic

01:19:42.320 stress.

01:19:43.280 So for someone who's already aged, where your NAD level tanks and goes down in a linear

01:19:48.560 fashion, like with age, NAD goes down, but also in the context of traumatic brain injury

01:19:53.940 or shock.

01:19:55.620 And these are the things that we study.

01:19:56.960 So I'm not studying NAD as a longevity molecule.

01:20:01.560 I'm studying in the context of rare disorders to military, like operational stress, extreme

01:20:08.600 environments, things like that.

01:20:10.720 But you have to do those studies, and then you glean insights into that that can then translate

01:20:16.960 into the world of longevity if you're showing mitochondrial enhancement and preservation.

01:20:21.800 Because as we age and we go through different stress conditions, then it's analogous to some

01:20:26.720 of the things that we study.

01:20:27.900 I know there's a lot of buzz about NAD and a lot of work going on.

01:20:30.920 I feel like the buzz over NAD has largely died, actually.

01:20:33.900 I feel like it's sort of under-delivered, and most people aren't really talking about

01:20:37.180 it anymore.

01:20:37.860 Some people say that with keto, right?

01:20:39.800 But I went to PubMed right before coming here.

01:20:42.080 There's 6,000 peer-reviewed publications on PubMed.

01:20:44.680 And over the last year, 717 of them.

01:20:48.720 And there's also 558 registered clinical trials on a ketogenic diet on clinicaltrials.gov.

01:20:56.000 I mean, you could look at CAR-T therapy as something like this.

01:20:58.700 There's like maybe 400 or 500.

01:21:00.460 Are those spread mostly between cancer, metabolic disease?

01:21:05.200 I've been on top of this.

01:21:06.200 There's 40 to 50 clinical trials on psychiatric disorders.

01:21:09.540 So that includes bipolar, schizophrenia, major depression, anxiety disorders, anorexia,

01:21:17.280 alcohol use disorders, alcohol withdrawal, traumatic brain injury, autism.

01:21:22.420 Anorexia is quite interesting.

01:21:23.780 What do you think is the hypothesis there?

01:21:26.000 Well, anorexia is a psychiatric disorder.

01:21:28.800 It's the psychiatric disorder that kills more people.

01:21:30.920 Yes, it's the highest mortality.

01:21:32.860 So there was a number of studies.

01:21:35.420 Guido Frank, he's at University of San Francisco,

01:21:39.300 I believe he's an expert in eating disorders, as is my colleague, Dr. Deanna Rancourt,

01:21:45.220 who kind of has a peripheral interest in this.

01:21:47.280 But Dr. Guido Frank is running a study on anorexia.

01:21:51.120 I believe from what I last heard, I can't talk about it too much,

01:21:54.360 but I think some of the data is very encouraging.

01:21:56.200 There was case reports that combined a ketogenic diet with ketamine.

01:22:02.720 And that put anorexia into remission.

01:22:05.800 And there's been quite a bit of buzz about that.

01:22:07.760 And for anorexia, typically you steer people away from any kind of dietary restriction.

01:22:14.220 Yeah, that would be traditional thinking.

01:22:15.520 Yeah, but the effects of the ketogenic diet on neuropharmacology, on the hedonic response,

01:22:22.260 on stabilizing your mood, and other factors that could play into anorexia seem to be at play.

01:22:28.520 I was super skeptical because it flies in the face of everything that I know.

01:22:31.940 We have one of the leading experts at University of South Florida, Deanna Rancourt.

01:22:35.400 I remember talking to her about it, and she was a little bit skeptical,

01:22:38.000 but the data coming out and looks very promising and compelling.

01:22:42.820 So there's continuing emerging data on psychiatric disorders largely funded by the Buzuki Group.

01:22:49.160 I think exclusively funded by Jan and David Buzuki, their foundation.

01:22:53.800 And I think they're funding million-dollar studies.

01:22:56.340 Six of them that I know, you have Ohio State University, Stanford, Oxford,

01:23:02.180 Stony Brook, UCSD, UCLA, I think Edinburgh, there's a study too.

01:23:07.580 I'm just looking at the different applications.

01:23:09.600 So they're funding many different studies, mostly across severe psychiatric disorders.

01:23:15.360 And are they doing this with ketogenic diets, ketogenic diets plus supplements, just supplements?

01:23:20.780 Primarily the ketogenic diet, although having served as a reviewer,

01:23:26.080 because they have study section, in the pipeline of emerging studies that they're funding,

01:23:30.400 I would say quite a few studies will be incorporating exogenous ketone supplementation.

01:23:36.300 So they see that as an innovative approach and a necessary approach for the feasibility of therapeutic

01:23:42.080 ketosis, because with a psychiatric disorder, it's really difficult to get someone to adhere

01:23:47.200 to a ketogenic diet with bipolar, with schizophrenia.

01:23:51.240 I mean, it's like a nightmare.

01:23:52.920 If an individual says, look, I totally understand why a ketogenic diet might have efficacy for weight

01:23:57.640 loss, could be multiple mechanisms that explain it.

01:24:00.400 But there are undoubtedly thousands of people listening to us who have no interest in weight loss.

01:24:05.780 They're at an appropriate weight.

01:24:06.840 They're happy with their weight.

01:24:07.620 But some of the things you've talked about might have piqued their curiosity with respect to performance.

01:24:12.340 Let's just start with cognitive performance.

01:24:14.300 Can you get all the same benefits of a person who slaves their way through what I used to do

01:24:21.260 and you do and to varying degrees do?

01:24:23.560 You're on this very, very strict diet.

01:24:25.780 Can they get virtually all of those benefits through judicious use of ketone supplements?

01:24:31.940 It depends.

01:24:32.580 People don't like that answer.

01:24:33.580 And it's also very context dependent.

01:24:35.360 But I'll say this, that there are benefits that you get from carbohydrate restriction that

01:24:40.380 cannot be replicated with exogenous ketone supplementation.

01:24:43.960 With that said, exogenous ketone supplementation tends to lower blood glucose independent of carbohydrate

01:24:50.060 restriction.

01:24:51.320 Is that part of the mechanism that you just described earlier where, look, you ingest enough

01:24:54.420 ketones, you're going to drive insulin enough.

01:24:56.060 That's going to drive down glucose, which, by the way, would not be the most desirable way

01:24:59.320 to lower glucose.

01:25:00.420 Well, that's what I originally thought.

01:25:02.220 Actually, I do remember talking with Dr. Veach about this and his opinion was that you're enhancing

01:25:07.040 insulin sensitivity and facilitating glucose disposal by virtue of enhancing insulin sensitivity.

01:25:13.420 But I think it's a combination of different factors.

01:25:15.660 I think consuming exogenous ketones influences the liver in ways that we don't understand.

01:25:22.040 So the next big project that I want to do is liver metabolomics, giving exogenous ketones,

01:25:26.820 because the liver is a master regulator of metabolism, especially in the context of everything,

01:25:31.600 really, everything that we study.

01:25:33.120 So what I think is happening is that it's decreasing gluconeogenesis, decreasing glycogenolysis, and

01:25:39.000 also simultaneously enhancing insulin sensitivity for greater glucose disposal.

01:25:44.620 However, if ketones get too high, then you have competition.

01:25:48.960 The tissues are basically happy with ketones, and they probably decrease glucose consumption

01:25:54.740 to some extent.

01:25:56.080 So an important message that I want to send is that higher ketones are not advantageous,

01:26:02.780 and I think potentially very problematic.

01:26:05.500 Define high in that setting.

01:26:07.040 We've killed quite a bit of animals.

01:26:09.040 Inadvertently, in early studies, by putting them into ketoacidosis with different ketone

01:26:14.840 esters.

01:26:15.280 We've never done that with ketone salts, although we can achieve therapeutic ketosis with ketone

01:26:19.940 salts or MCT.

01:26:21.240 So high ketosis would be in animals, once we get above six or seven, then they start sort

01:26:27.080 of like hyperventilating.

01:26:28.420 They get sluggish, and sometimes we can't bring them back.

01:26:31.060 So that has made me a bit scared about some of the ketone esters, and I think some of them

01:26:37.200 could be in the bucket of a drug, especially if used in pediatric population.

01:26:42.280 I think that's important.

01:26:43.840 So higher ketones, it's like we're not shooting to get our glucose to like seven,

01:26:48.800 eight millimolars.

01:26:49.820 There's very powerful homeostatic mechanisms that maintain glucose under normal conditions.

01:26:54.380 If we're jacking up our ketones above two, once you get above two to get the three, four,

01:27:00.900 and five, then you're approaching energy toxicity.

01:27:04.720 So you have a level of ketones in your blood that's producing energy toxicity.

01:27:09.600 Energy toxicity is defined by an elevation of a metabolite circulating in your blood that

01:27:16.340 is causing a number of things.

01:27:18.500 One is a counter-regulatory reaction, which means it's increasing the release of insulin.

01:27:23.820 The secretion of insulin.

01:27:25.560 And your kidneys have to dispose of that.

01:27:28.720 And our blood gases and blood pH, blood pH will start to go down.

01:27:33.540 Your blood will become more acidic.

01:27:35.220 That's not a good thing.

01:27:36.760 And that occurs once you get above two or three millimol?

01:27:39.540 Above two.

01:27:40.640 Pretty much always kind of above two, maybe three.

01:27:44.980 In the context of supplemental ketosis.

01:27:46.980 So if you're on a ketogenic diet and your glucose is so low,

01:27:50.420 your levels of ketones may approach three or four because of the glucose deficiency that

01:27:57.680 you have in your body.

01:27:58.640 So fat oxidation is so high, it's a very elegant and finely tuned response that you have.

01:28:05.320 And presumably it's happening slowly enough that the redox reaction to balance your pH is

01:28:12.640 happening.

01:28:13.300 You're going to blow off enough CO2, I assume, in that situation.

01:28:16.600 If you're nutritionally at three or four millimole, I don't remember what my blood gas looked

01:28:21.160 like.

01:28:21.800 Yeah.

01:28:22.060 I mean, you have respiratory and renal compensation.

01:28:24.140 Yeah.

01:28:24.240 And that's not hard at all for you to do.

01:28:26.180 So if you're consuming large doses of exogenous ketones, this is not applied to the ketone salts

01:28:32.280 because the salt is actually a natural buffer.

01:28:34.340 So that's the ionic bond is a positive and a negative.

01:28:37.920 When you consume large doses of beta-hydroxybutyrate, it's an anion and you're creating an acidic condition

01:28:44.560 that your body needs to mitigate through respiratory and renal compensation.

01:28:48.780 So I think that can be problematic, especially in people like purchasing maybe ketone esters

01:28:53.020 in elderly population where liver function is not good, they're not very stable, and they're

01:28:58.320 already under metabolically compromised situations.

01:29:01.120 So that's something I think that people don't think about is energy toxicity in the context

01:29:07.680 of supplemental ketones.

01:29:09.340 We think of energy toxicity in the form of supplemental calories, which is problematic

01:29:13.420 and in reversing that.

01:29:15.100 So do you think there's any meaningful application for a BHB monoester these days?

01:29:19.160 What is the application for that?

01:29:20.680 It's context dependent, but I think these things can be given orally or IV in the context of acute

01:29:27.360 situations.

01:29:27.920 So I'm in favor of ketone esters and more potent ketone molecules for medical applications,

01:29:34.180 quickly elevating ketones under, for example, status epilepticus, a traumatic brain injury,

01:29:39.560 like a blast injury.

01:29:40.660 But I thought you said they didn't work well in epilepsy.

01:29:43.760 Depends.

01:29:44.200 No, I'm talking about maybe a ketone diester of acetoacetate, which we use.

01:29:48.220 So, okay.

01:29:48.780 So the monoester.

01:29:49.700 Yeah.

01:29:49.880 I'm talking about the original molecule from NIH that was a monoester of BHB.

01:29:56.720 I think they can be formulated.

01:29:58.580 So this comes to something that's a gap in the literature.

01:30:01.400 And there's a gap because every company or university with IP wants to study a single

01:30:06.840 molecule in isolation.

01:30:07.900 I think what we need to do is actually formulate things.

01:30:12.120 And that's what we do.

01:30:13.680 So every molecule will have pros and cons and caveats.

01:30:18.000 And you could largely mitigate the problem with ketone esters by simply mixing it with

01:30:24.180 MCT.

01:30:25.100 But you're still going to have the 1,3-butanediol issue.

01:30:27.820 If you're consuming that over long periods of time, that is something to consider.

01:30:32.460 But you can also have a glycerol triester of beta-hydroxybutyrate or acetoacetate.

01:30:37.340 We published, the title is like Novel Ketogenic Formula, where we had a beta-hydroxybutyrate

01:30:42.200 or a glycerol triester.

01:30:44.520 So we're working with those compounds too.

01:30:46.720 But I think, yeah, it's very context-dependent.

01:30:49.520 And the go-to would probably be the electrolyte salts just because you don't want to, for the

01:30:54.440 average person, if you stay into that sweet spot of 1 to 2 millimolar, if you elevate

01:30:59.540 beta-hydroxybutyrate in the blood, 1 millimolar, that represents a 10% increase of available

01:31:05.800 energy to the brain.

01:31:07.220 We know that, roughly speaking.

01:31:08.520 So all these calculations from the AV difference have been done.

01:31:11.480 So I think that's important.

01:31:12.940 Lactate is also something to consider.

01:31:15.700 So when you think about the advantages of lactate for alternative brain fuel and ketone

01:31:21.900 as alternative brain fuel, you know, I had George Brooks on the podcast a while ago, and

01:31:25.200 he talked about how you could probably rescue concussion patients if you administered

01:31:29.240 lactate quickly following a concussion.

01:31:31.720 Would you say the same is likely true for ketones?

01:31:34.660 I think lactate's an incredible molecule.

01:31:36.880 My early studies in 2004 and 2005, I think, was lactate.

01:31:40.840 But the ketones represented a more viable option and also had the anti-seizure effects that

01:31:46.840 we had.

01:31:47.380 Plus, I was inspired by the work of George Cahill and Dr. Veach and Theodore Van Italy.

01:31:54.240 And then I got steered towards beta-hydroxybutyrate.

01:31:56.720 But I think an important message is that formulation is the key.

01:32:02.120 So you have beta-hydroxybutyrate, you have lactate, you have MCTs cross the blood-brain

01:32:07.620 barrier.

01:32:08.180 So it's a type of fat that actually can cross the blood-brain barrier.

01:32:10.300 Do you still use MCTs for anything?

01:32:11.700 I think MCTs are great.

01:32:13.000 I use a coffee creamer called KetoBrain.

01:32:15.260 It's like alpha-GPC, MCT, theanine.

01:32:18.820 It's a mixture of combinations of things.

01:32:21.180 But when you combine a ketone salt with MCT, then you have a formulation that stimulates

01:32:27.820 your own ketone production while you're delivering an exogenous ketone.

01:32:31.960 And if it's a racemic DL-beta-hydroxybutyrate like KetoStart, then you have a sustained ketone

01:32:37.960 delivery system for half of the day.

01:32:40.080 So you just dose that a couple of times.

01:32:41.620 But also, some of the problems that we talked about with fast entry of ketones into the

01:32:47.780 bloodstream with the ketone esters or 1,3-beta can, if you formulate that with MCT, which

01:32:53.240 we've published on that, that can mitigate some of the negative effects.

01:32:57.540 So we don't see, you can mitigate the toxicity, at least in animal models.

01:33:01.440 You need to appreciate the rate of rise of ketones is that's kind of the trigger for some

01:33:06.880 of the counter-regulatory effects, more like a dosing issue.

01:33:09.780 And if you're taking the currently formulated ketone salt that you brought, you do not have

01:33:15.620 to worry about the electrolyte load.

01:33:16.920 So if you're consuming three of those a day, that would be three grams of additional electrolytes,

01:33:21.900 which based on what you're also getting in your food, a lot of people would say, gosh,

01:33:25.200 that's too many electrolytes.

01:33:26.440 But you're not seeing the effect because of the lack of chloride?

01:33:30.260 I would say for people that have normal physiology, no kidney, or maybe even with impaired kidney

01:33:36.040 function because KetoCitra is sold.

01:33:38.640 I think a study just came out with beta-hydroxybutyrate citrate and other electrolytes too for kidney

01:33:43.840 disorders, but generally no.

01:33:45.940 So I was concerned that sodium would cause hypertension, but sodium chloride seems to be the major player

01:33:53.100 there.

01:33:53.600 So I would say no, but also do your blood work.

01:33:57.940 I haven't seen that, and that was one of the early concerns I had.

01:34:01.840 Actually, it steered me toward developing something other than sodium to potassium and

01:34:07.420 calcium and other.

01:34:08.620 So electrolytes are largely benign unless you're above the 10 grams per day kind of issue.

01:34:15.060 And I think even with sodium, the guidelines are something like five grams of sodium per day,

01:34:20.560 like dietary sodium.

01:34:21.760 But then something just came out that said that should probably be more like eight to 10.

01:34:27.080 Which guideline?

01:34:27.980 The guidelines right now, I think, cap it at five grams of sodium.

01:34:32.260 Yeah.

01:34:32.420 And I think a lot of them are recommending, in my mind erroneously, like two to three.

01:34:36.480 Yeah.

01:34:36.900 Yeah.

01:34:37.080 Depending on what guideline.

01:34:38.080 But I think maybe the more looser guidelines saying it becomes problematic after five.

01:34:43.260 Okay.

01:34:43.480 I want to talk about two particular applications with ketogenic diets, one of which you've spoken

01:34:48.200 about a little bit.

01:34:48.780 The other one we've sort of talked about kind of indirectly.

01:34:51.560 But let's say a word about what you think the future is for ketogenic diets and the treatment

01:34:56.540 of cancer and then separately for the treatment of dementia, specifically potentially Alzheimer's

01:35:01.040 disease, but any form of dementia.

01:35:02.340 We had a review come out with 49 authors and the title was ketone metabolic therapy framework

01:35:10.360 for glioblastoma.

01:35:11.480 So that includes basic science researchers, a number of oncologists at major cancer centers

01:35:17.820 and stuff.

01:35:18.060 So the gist of that, I think it's really important to focus on cancers where the standard of care

01:35:24.000 doesn't work.

01:35:24.700 So advanced metastatic cancer, obviously pancreatic and glioblastoma, but glioblastoma has always

01:35:29.600 been sort of the heart of what we're studying.

01:35:32.080 And I think the idea is to make metabolic therapy part of the standard of care.

01:35:37.400 So the general gist with that review and the senior author, Dr. Thomas Seyfried, and I know

01:35:43.400 you've had him on the podcast, Tomas Durak, he was the primary author.

01:35:48.500 In that review, it creates a framework.

01:35:51.820 There's so much in that review.

01:35:53.000 It ended up, it was like 200 pages carved down to like 50 pages with about a thousand references,

01:35:57.780 making it super concise explanation.

01:36:00.220 So the gist of that for ketone metabolic therapy for cancer management, specifically glioblastoma,

01:36:05.900 but we think similar reviews can be written for other types of cancers that are specifically,

01:36:11.380 that are highly glycolytic and have the Warburg effect.

01:36:13.920 So really hot on an FDG PET scan.

01:36:16.520 So above 2.5 SUVs, like on a PET scan, would define it as hyperglycolytic.

01:36:21.840 Achieve and maintain a glucose ketone index of 1 to 4.

01:36:27.720 So that's the millimolar concentration of glucose over ketones.

01:36:31.560 So if your glucose was 4, which is relatively normal, and your ketone levels were 1.

01:36:38.120 You're at the entry of that zone.

01:36:39.440 Where I'm at now.

01:36:40.440 So that gives me a GKI of 4.

01:36:42.860 Standard American diet produces of like a GKI of 50, 40 or 50.

01:36:46.620 So simply the guidelines are 1 to 2, but I think that's too strict.

01:36:51.160 Achieving a glucose ketone index of 1 to 4 is the basis of the therapy.

01:36:56.820 And that sets the stage for other modalities to work.

01:36:59.940 For example, you could have, you want to then target glucose and glutamine with various drugs.

01:37:06.200 If we're going to talk about anti-glycolytic drugs, metformin.

01:37:09.800 We've done quite a bit of research with metformin, and I think that's a great molecule.

01:37:14.700 Could be a synergizer.

01:37:15.940 I also think of that as a redox, and I'll come to that.

01:37:18.820 Let me ask a point-blank question, Dom.

01:37:21.300 Glioblastoma carries with it a mortality rate of 100%.

01:37:24.500 So it's been said that any patient who survives a glioblastoma has been misdiagnosed.

01:37:29.360 They didn't have glioblastoma.

01:37:31.220 It's one of the cancers that really gives cancer a bad name.

01:37:34.940 Is there any evidence that any form of ketogenic diet, even at a one-to-one ratio of glucose to

01:37:40.980 ketone, is going to produce a durable remission in a patient with a GBM?

01:37:45.800 No, it's not going to cure it.

01:37:46.860 So we're talking about the standard of care does nothing.

01:37:50.540 We're talking about...

01:37:51.580 Life extension.

01:37:52.180 Yeah, we're talking about doubling survival, tripling, and then as we learn more.

01:37:58.080 So the ketone metabolic therapy framework for GBM is like the first document in a series

01:38:04.560 of documents that will ultimately be...

01:38:08.720 Version number three will be using AI platforms to decode the genetics.

01:38:13.920 In an RCT, when you place full standard of care versus full standard of care plus ketogenic

01:38:19.680 therapy, what is the difference in median survival?

01:38:22.560 Yeah, those studies are ongoing now.

01:38:24.580 Jethro Hugh at UCLA just published a study at UCLA.

01:38:28.180 She's showing, you know, improved metrics of survival and increased quality of life and

01:38:32.600 different...

01:38:33.360 And I didn't get a chance to...

01:38:34.420 It just came out.

01:38:35.160 A paper just came out.

01:38:35.980 So that research is ongoing.

01:38:38.060 I'd say there's at least a half dozen clinical trials in progress now, and there's problems

01:38:45.040 associated with those clinical trials that I could get into that prevents us from getting

01:38:49.280 to the question.

01:38:50.480 So the way to do the clinical trial, which has not been done yet, is to achieve and maintain

01:38:56.040 a glucose ketone index of one to four.

01:38:59.360 That has never been done.

01:39:00.800 So you want to do that, and then that is not alone.

01:39:04.080 So what I'm talking about here is an adjuvant to the standard of care.

01:39:06.900 So achieve a GKI of one to four, maintain that, and then you go and aggressively target

01:39:13.380 glucose and glutamine.

01:39:14.840 So you could target glucose with lunitamine.

01:39:17.740 It's a hexokinase inhibitor, 3-bromopyruvate, 2-deoxyglucose.

01:39:22.420 You can use an SGLT2 inhibitor.

01:39:24.640 You can use...

01:39:25.360 I mean, we have about two dozen different drugs that you could use and off-the-shelf

01:39:30.020 kind of things like SGLT2.

01:39:31.380 And then you want to target glutamine because you could take glucose out of cell media and

01:39:37.460 put in glutamine and maintain cancer cells in glutamine without glucose.

01:39:41.220 But it's hard to imagine you're ever going to get glucose to less than 40% of the brain's

01:39:45.880 fuel, which would be a big achievement.

01:39:47.980 If you did all of those tricks, you ramped up ketones, you took glucose down peripherally

01:39:54.320 to 2.5, even 3 millimole.

01:39:57.200 So if you have a glucose to ketone index of 1.1 and they're both sitting at 3 millimole,

01:40:01.860 then you're doing all those therapies.

01:40:03.400 The neurons are still getting 40% to 50% of their energy from glucose.

01:40:06.560 I know.

01:40:06.880 So it's like...

01:40:07.240 But the idea then is to use something like lunitamine, like inhibit hexokinase 2.

01:40:12.340 There are enzymes, glycolytic enzymes that are upregulated.

01:40:16.300 There are transporters that are upregulated.

01:40:18.100 And if you create an energy crisis in GBM cells that's great enough, then you trigger autophagy

01:40:25.360 and then you trigger cell death because there's an incredible glycolytic energetic demand in

01:40:31.900 glioblastoma cells.

01:40:33.440 And if that demand is not met, then that triggers cell death pathways.

01:40:37.560 But to make inroads into that and create that energetic crisis, you have to decrease glucose

01:40:42.880 availability, decrease circulating insulin, which decreases growth factors like IGF-1 and

01:40:49.400 a whole host of other mTOR and other growth factors, and then aggressively target pharmacologically

01:40:54.380 circulating glucose and glycolytic enzymes.

01:40:57.480 And then you have to aggressively target glutamine elysis, circulating glutamine, and also drugs

01:41:04.200 that inhibit glutamine metabolism in the cancer cells.

01:41:07.860 So you could target glutaminase.

01:41:09.660 So there's a drug, Don, that Dr. Seyfried uses, and I have not used it.

01:41:14.660 I've talked to some patients that use it.

01:41:16.100 It does cause some GI stress.

01:41:17.600 That's a pretty big heavy hitter.

01:41:19.420 But you have a number of different things.

01:41:22.040 Sodium phenylbutyrate, glycerol phenylbutyrate, which is actually an HDAC inhibitor.

01:41:27.400 It will bind up glutamine, and then you pee some of it out.

01:41:30.740 There's EGCG.

01:41:32.700 There's curcumin.

01:41:35.040 Quercetin has glutamine, glutaminase-inhibiting properties.

01:41:38.060 But again, none of this has been demonstrated clinically.

01:41:40.640 This is all kind of anecdotal, meaning we don't have evidence in a clinical trial that

01:41:45.120 this works.

01:41:45.680 We're sort of extracting mechanistically from what we think these things do.

01:41:49.160 No RCTs.

01:41:50.100 So there's cell data, there's animal data.

01:41:52.700 What's the holdup?

01:41:53.500 I interviewed Tom seven years ago, and we had this exact same conversation.

01:41:58.500 Why do you think, especially for these cancers that are basically just killing machines, people

01:42:04.960 are dead within a year of diagnosis.

01:42:07.220 Why is it so hard to do these trials?

01:42:09.220 I understand your frustration.

01:42:10.360 Yeah, I'm super frustrated.

01:42:11.540 That's what motivates me.

01:42:12.920 I would encourage people to read that framework of the ketone.

01:42:15.920 And then it's really important to access the supplementary information, which gives all

01:42:20.600 the different drugs and everything.

01:42:21.980 Oncologists are not going to read that, right?

01:42:23.740 So the people that are on the front lines that are taking care of these patients.

01:42:27.280 Some of them are authors, so they've read it.

01:42:28.900 But again, what they want and what they need is a clinical trial that says this stack of

01:42:33.260 interventions is going to double median survival.

01:42:37.040 So if someone came along and said, look, we're going to do all the things, we're going to rub

01:42:40.600 curcumin on people's testicles and do all the things that are anecdotally supposed to help.

01:42:45.520 And it takes median survival from 11 months to 27 months.

01:42:50.020 Wow, that's huge.

01:42:51.340 Oh, and by the way, it's going to reduce the burden of seizures and it's going to reduce

01:42:54.520 the catastrophic debilitating side effects of this tumor and its therapy.

01:42:59.260 I mean, it's going to become the standard of care, but the trial has to be done.

01:43:03.180 The trial has to be done.

01:43:04.980 It can't be these sort of one-off, kludgy, like off-in-the-corner little nonsense trials

01:43:10.580 that aren't getting attention.

01:43:11.860 So why is that?

01:43:13.300 So we have to ask the question, who's going to fund this clinical trial?

01:43:17.860 So they have the policymakers and the people at the foundations, people at the federal

01:43:22.040 government, the NIH, the DOD, they have to be convinced that this is going to work.

01:43:27.640 We're talking about something way beyond the ketogenic diet here.

01:43:30.120 We're talking about a very comprehensive, calculated, metabolic-based intervention that

01:43:35.760 targets diet, glycolytic drugs, anti-glutamine drugs, and then there's a redox component too.

01:43:41.680 So it's synergized with different drugs.

01:43:44.020 So that could be hyperbaric oxygen therapy, but radiation and chemo kill cancer cells through

01:43:50.060 oxidative stress.

01:43:51.680 And then another thing too, so where the money is actually, or the interest is going now

01:43:56.400 is that the focus has been using ketone metabolic therapy as an adjuvant for Moffitt Institute

01:44:04.240 CAR-T therapy for lymphoma.

01:44:05.880 So they have that project, but just working on some grants for ketone metabolic therapy

01:44:10.560 and it's strictly, they're focused on beta-hydroxybutyrate because that correlates with the adaptive immune

01:44:16.680 response that will augment checkpoint inhibitors, specifically PD-1 inhibitors and CTLA for

01:44:23.400 checkpoint inhibitors.

01:44:24.900 And also the ketogenic diet, it can expand the CAR-T cells because of that observation.

01:44:29.660 And that correlated with beta-hydroxybutyrate seemed to be involved with CAR-T cell expansion.

01:44:34.300 That became of interest.

01:44:36.700 So right now the funding agencies are kind of focused on augmenting the standard of care

01:44:41.520 because we already use the standard of care.

01:44:43.340 But to run a clinical trial with dietary therapies involved, you have to have oncologists who are

01:44:49.400 savvy and knowledgeable about ketogenic diets.

01:44:51.960 You have to have an RD team.

01:44:53.560 The inclusion exclusion criteria are really important.

01:44:57.160 The heterogeneity of many people with brain tumors.

01:45:00.440 I mean, that's something to consider.

01:45:02.000 Also, when you have a patient with a glioblastoma, the pharmaceutical companies are scrambling

01:45:07.060 to get their drug into that patient.

01:45:09.600 So they are paying a lot of money to the major institutes to conduct the research.

01:45:15.200 Is GBM the wrong model then?

01:45:16.940 Because you need a win.

01:45:17.980 Yeah.

01:45:18.320 You got to demonstrate a win.

01:45:19.300 Should the first one be pancreatic adeno?

01:45:21.340 You have far more patients.

01:45:23.220 Life expectancy is a little bit longer, but it's equally fatal, meaning metastatic or advanced

01:45:27.900 pancreatic cancer is uniformly fatal.

01:45:30.080 Should we be using that as a model where, of course, look, all cancers are heterogeneous,

01:45:34.680 but it might be that GBM is even more so.

01:45:37.160 And it's also heavily impacted by the radiation.

01:45:39.920 Like the radiation then completely changes it.

01:45:42.260 Virtually all of these patients are going to need radiation, which makes it even more

01:45:45.860 difficult.

01:45:46.460 So anyway, look, I don't want to offer advice from the peanut gallery because I'm in the peanut

01:45:50.960 gallery for a reason on this, but that might be something worth considering.

01:45:53.960 Let's talk about Alzheimer's disease, equally devastating, much longer tail, but in my mind

01:46:00.300 seems somewhat easier to address through metabolic therapies because at least in the subset of

01:46:05.740 those patients for whom an energetic crisis is at the core, and I don't think that that's

01:46:10.480 all cases.

01:46:11.240 I think that's also a very heterogeneous disease, but at least one subset of these people are

01:46:15.420 probably in an energetic crisis.

01:46:17.340 What do we know about the current research and what's the current state of affairs for using

01:46:22.320 ketogenic therapies?

01:46:23.100 You're familiar with the Alzheimer's drugs.

01:46:25.260 There's been not a whole lot of movement there.

01:46:28.080 We have the antibodies.

01:46:29.660 You go to antibody therapy, you're talking 50K at least, hundreds of thousands of dollars.

01:46:35.340 You have the potential for side effects like cerebral hemorrhage, and they move the needle

01:46:39.340 maybe for prevention.

01:46:41.820 A hallmark characteristic of Alzheimer's disease is glucose hypometabolism.

01:46:46.160 So that is actually being part of the criteria for evaluating.

01:46:49.420 My thoughts are that in communicating with hundreds of people with Alzheimer's and communicating

01:46:54.920 with people that do dietary therapies is that there's a subset of people with Alzheimer's

01:46:59.860 disease or let's just call it dementia because Alzheimer's is still a pretty fuzzy diagnosis.

01:47:06.480 Clinically, we have the PET scans to look at amyloid and then there's PTAL and other things.

01:47:12.020 I think it's better to put it under the umbrella of mild cognitive impairment.

01:47:17.100 I think it's important to focus on that and advance Alzheimer's disease.

01:47:20.060 A ubiquitous characteristic is glucose hypometabolism.

01:47:22.980 I've always been under the impression that the accumulation of amyloid and TAL are a consequence,

01:47:30.080 are downstream epiphenomenon of inflammation, neuroinflammation.

01:47:35.740 There's, of course, huge, I think there's like 50 different genes that can cause Alzheimer's

01:47:40.180 disease.

01:47:40.520 So if we're talking about APOE4 carrier, that's like, I don't know, 80% likely to get advanced

01:47:46.300 Alzheimer's or early onset.

01:47:48.000 If you have two copies.

01:47:48.840 Yeah, if you have like two copies or even one copy.

01:47:50.140 Yeah, maybe even a bit less than that.

01:47:51.520 If you have two copies, you are destined to have it.

01:47:54.400 There are a handful of genes in which you are destined to get it.

01:47:57.180 Unfortunately, at this point, PSCN1, PSCN2, APP.

01:48:00.780 If you do nothing.

01:48:01.760 But again, I mean, 25% of the population are heterozygous for APOE4.

01:48:07.880 Their risk is twofold higher.

01:48:09.860 I don't think anyone would consider that destiny.

01:48:12.240 Yeah, your genes are not your destiny.

01:48:13.500 I don't want to make that sort of assumption, but puts you at greater risk for sure.

01:48:17.440 So just taking a step back, I think inflammation is the major driver.

01:48:23.160 And that wasn't even on my radar probably the last time we talked or maybe 10 years ago.

01:48:26.820 But I do think that systemic inflammation leads to neuroinflammation.

01:48:31.360 And we know that if we take mice and inject LPS, we can rapidly cause amyloid progression.

01:48:38.340 Those studies have been done.

01:48:39.860 So metabolic-based therapies, ketogenic therapies, diet, these things not only change metabolic

01:48:47.360 physiology and brain energy metabolism, but they reduce systemic inflammation.

01:48:52.400 And I don't know if you measure your inflammatory markers like HSCRP.

01:48:56.420 Mine is even non-detectable.

01:48:59.240 I'll even do things like work out really hard.

01:49:01.380 It only was elevated when I lived in an undersea environment and was breathing hypercapnic under

01:49:06.120 a lot of stress.

01:49:07.000 But I think the advantage of ketogenic metabolic therapies for Alzheimer's disease is really

01:49:12.500 hinging upon suppressing inflammation, improving glucose metabolism, and elevating ketones to

01:49:19.100 increase symptomatically brain energy metabolism.

01:49:22.780 Of those, would you say that the latter is the most important, that it's the alternative

01:49:28.340 fuel source that is the most important?

01:49:30.520 Let's go back to, I haven't paid any attention to this, what's happening in clinical trials?

01:49:34.100 This is a much easier thing to test.

01:49:36.200 Has someone done the experiment where you take people in the earliest stages of dementia or

01:49:42.320 in modest stages of MCI, mild cognitive impairment, who are progressing towards dementia, and you

01:49:48.580 randomize them to standard of care versus the exact same standard of care plus a KD?

01:49:54.480 Has that experiment been done cleanly in a randomized fashion?

01:49:57.800 Those experiments, like many things, are ongoing.

01:50:00.380 You have the acute effects.

01:50:01.940 So I think what we can say that acutely, if we elevate ketones in the context of a cognitive

01:50:06.760 deficit, we can improve cognition under a battery of different exams.

01:50:12.280 But the question that investigators are after is that if you do an amyloid PET scan at baseline

01:50:20.880 and two years, five years, 10 years, that is of the highest interest because amyloid is

01:50:27.120 basically, that's the prerequisite for having Alzheimer's disease.

01:50:30.100 So those studies are ongoing and I'm connected with some investigators that are doing it and

01:50:34.540 some that have done more acute studies.

01:50:36.080 And the feedback is that I think there's a subset of people, most people respond favorably, but

01:50:42.760 there's also a subset of people that are hyper-responders.

01:50:45.800 And with Alzheimer's disease, there's like vascular dementia.

01:50:48.980 It could be a blood flow problem.

01:50:50.360 It could be excess glutamate problem.

01:50:52.120 It could be a number of different things that are amenable to being reversed or mitigated through

01:50:58.340 ketone metabolic therapies.

01:50:59.820 So patient selection is going to matter.

01:51:01.460 Yeah, I think it's going to be huge.

01:51:02.500 And I don't think they've done this yet, is that inclusion criteria should be patients

01:51:07.060 that present with remarkable glucose hypometabolism.

01:51:11.260 So I think that's really an important key.

01:51:14.260 There's people who have brains that are chock full of amyloid, are completely sharp, and are

01:51:19.260 completely normal.

01:51:20.520 The amyloid hypothesis has a lot of baggage with it.

01:51:23.860 So I think tau, amyloid and tau.

01:51:26.160 We have p-tau that we can look at, but there's other things in the pipeline.

01:51:29.400 I think the P75 receptor agonist or amplifier looks pretty promising.

01:51:34.840 Those studies are ongoing.

01:51:36.280 And then for prevention, I think some of these things, the antibodies, do have applications,

01:51:42.120 but they also come with a lot of baggage with not only the cost and accessibility, but cerebral

01:51:46.320 hemorrhage, something they have to consider.

01:51:48.440 So the low-hanging fruit would be dietary, or more likely with this population, a ketone

01:51:55.880 metabolic therapy intervention that could be a ketogenic formula that could also have

01:52:02.460 a number of different cofactors and other things.

01:52:05.000 There's lactate.

01:52:06.200 There's creatine monohydrate.

01:52:08.540 There's alpha-ketoglutarate.

01:52:10.540 And this is the problem with funding agencies.

01:52:12.120 They don't want to fund a formula.

01:52:13.640 There's some work done with MCT.

01:52:16.220 Sam Henderson published in 2008 when the molecule was AC-1202.

01:52:20.860 But if you look at the patent, it was just caprylic triglyceride.

01:52:23.840 And actually improved mini-mental status exam.

01:52:26.800 And Dr. Mary Newport saw that and gave her husband coconut oil and MCT oil.

01:52:31.640 And he improved.

01:52:32.500 And a case report with Dr. Veach being one of the co-authors on that was published.

01:52:36.880 Just a ketogenic intervention.

01:52:38.480 And they followed.

01:52:39.260 That was the longest case report for years.

01:52:41.080 And followed his progression and stabilization.

01:52:43.640 He ended up succumbing to the disease.

01:52:45.720 But she got many more years with him through ketogenic intervention.

01:52:49.920 So I think we have to think about putting together a comprehensive metabolic-based formula.

01:52:56.500 And Dale Bredesen has been spearheading some things and looking at more of a comprehensive

01:53:00.260 approach.

01:53:01.320 Dr. Stephen Cunane has been working on MCTs and other ketogenic agents for Alzheimer's.

01:53:06.660 Also did a dual PET scan where you do a glucose ketone PET scan.

01:53:09.980 And showed and published that as we age, our capacity to use glucose decreases over time.

01:53:16.260 But that does not happen with ketones.

01:53:18.240 Our brain's ability to use ketones over time is preserved.

01:53:21.560 So that's an important distinction.

01:53:23.500 And a good foundational framework for the rationale for doing ketone metabolic therapy.

01:53:29.300 But I think you'll probably have more benefit by thinking about it as a comprehensive metabolic

01:53:35.200 therapy where you can target different things.

01:53:37.480 And I think there's a number of different molecules like alpha-GPC.

01:53:41.540 But no one does anything with formulations.

01:53:44.320 They're pretty much always doing.

01:53:46.040 A funding agency is not going to fund it.

01:53:47.120 And what do you think is the state of the art with alpha-GPC just in general for normal

01:53:50.600 cognitive enhancement?

01:53:52.100 It's hard because I always take it with something else.

01:53:54.380 But I've used it by itself and it kind of gave me a headache when I took it.

01:53:58.780 And I didn't really notice.

01:54:00.300 I think it has the ability to be beneficial in the context of cognitive deficit, like many

01:54:06.280 things.

01:54:06.600 And I do think that ketones are everything that we study is in the context of environmental

01:54:11.180 stress or some kind of deficit.

01:54:14.020 And that's where ketones shine.

01:54:15.320 And they just tend to work.

01:54:17.240 But just speaking personally, I think they give you an extra boost because they're a source

01:54:21.620 of energy.

01:54:22.000 What do you think they're best taken with?

01:54:24.460 Alpha-GPC.

01:54:25.580 I think it works good with caffeine.

01:54:28.500 So alpha-GPC, MCT, and caffeine, and maybe theanine too has a little bit of a GABAergic

01:54:35.640 effect.

01:54:36.360 That describes a product called KetoBrain.

01:54:38.260 So that's a pretty good product that is kind of a staple product for me.

01:54:42.940 I ran out of it.

01:54:43.740 I kind of miss it.

01:54:44.440 So it reminds me I have to go buy that.

01:54:46.560 But what I sip on, I put that into my coffee.

01:54:48.920 When I'm working on grants or giving lectures, I just need long periods of cognitive.

01:54:53.540 But I think alpha-GPC, because maybe a little bit makes me a little bit too hyper-focused

01:54:57.440 and a little too stimulated.

01:54:58.720 And I think it maybe can affect my sleep.

01:55:01.000 I use that situationally just as I use fasting now.

01:55:04.600 So I use fasting very situationally.

01:55:07.040 And that's what I recommend to people.

01:55:08.740 It shouldn't be your default.

01:55:09.880 It shouldn't be fasting every day.

01:55:11.380 Because I think the more you do it, the easier it gets.

01:55:13.980 But I think you can actually maybe derive more benefits situationally if you have an

01:55:18.980 inflammation event.

01:55:20.040 Like there's a person, two people that reached out to me that has shingles or herpes simplex

01:55:24.260 flare-up, and then they fast then.

01:55:25.700 And then it works for that.

01:55:27.000 Or they have a GI, some kind of GI issue.

01:55:30.040 Or if they're traveling.

01:55:31.300 Or for me, when I'm just bogged down with a lot of paperwork, grant reviews, writing grants

01:55:36.280 or something, I'll fast for half of the day or more of the day.

01:55:38.960 And I'm just sharper, you know, and just using situationally.

01:55:42.060 All right.

01:55:42.260 Let's talk a little bit about hyperbaric oxygen.

01:55:44.500 Now, you mentioned and alluded to the fact that there are a handful of FDA indications

01:55:48.160 for them.

01:55:48.900 To me, the two most apparent would be treatment of the bends and obviously for burn patients.

01:55:53.380 So it dramatically aids with wound healing.

01:55:56.480 But there are many things that are conspicuously absent from any FDA approval.

01:56:00.420 There's no FDA approval for TBI.

01:56:03.060 There's no FDA approval for concussion.

01:56:06.280 There's no FDA approval for anything giro-protective.

01:56:10.700 And yet, I've always said, every time I've gone back, and I maybe do this every two years,

01:56:15.460 I go back and look at the data around concussion and TBI.

01:56:18.940 It depends how you look at the data.

01:56:20.600 There could be a case for it.

01:56:22.260 Patients are always asking me about hyperbaric oxygen.

01:56:24.460 It's truly one of the things I get asked about the most.

01:56:26.480 And I generally tell patients, it's not worth the cost.

01:56:29.480 It's not worth the hassle.

01:56:30.500 It's not worth the inconvenience.

01:56:32.100 Outside of the approved FDA indications, the only thing,

01:56:36.280 I would suggest going against the FDA recommendation is,

01:56:39.960 if I were to have a concussion, if one of my kids had a concussion,

01:56:43.080 I would probably say the downside of hyperbaric oxygen is low enough.

01:56:48.420 I think the potential upside is there.

01:56:49.860 I think it's worth the risk.

01:56:51.460 First of all, do you agree with that statement?

01:56:53.120 If not, modify it.

01:56:54.600 In the context of an acute concussion or a brain injury.

01:56:58.980 Let's start with the concussion and then, yeah, talk brain injury after.

01:57:01.940 In the context of acute, within the first 48 to 72 hours, I think hyperbaric oxygen can be

01:57:08.540 remarkably effective for kids and for younger population and probably effective for adults,

01:57:14.480 if early.

01:57:15.220 What protocol would you recommend in that situation?

01:57:18.440 Well, if it's a penetrating traumatic brain injury as, okay, okay.

01:57:23.000 Yeah, blunt, blunt.

01:57:23.660 We're not military.

01:57:24.460 Yeah, okay.

01:57:24.960 Yeah.

01:57:25.620 I would go with like standard protocol, like two atmospheres of oxygen, 60 to 90 minutes,

01:57:30.920 five days a week, minimum, maybe three days a week, 40 dives over that period of time,

01:57:36.820 I think could be potentially.

01:57:39.080 That's a lot.

01:57:39.980 Beneficial.

01:57:40.600 Yeah.

01:57:40.840 That's a hell of a lot.

01:57:42.820 You're talking two months.

01:57:44.280 Yeah.

01:57:44.860 40 sessions.

01:57:45.820 That's like the most.

01:57:47.200 And you can understand why I don't recommend people do this.

01:57:50.500 That's a job.

01:57:51.380 You just basically decided you're not working for a month because if you got to drive 30

01:57:55.480 minutes each way and you're going to spend 90 minutes in it, that's two and a half hours,

01:58:00.520 five days a week for six weeks.

01:58:04.400 That's just an insane, it's an insane commitment.

01:58:08.080 There better be some reasonable evidence for it.

01:58:10.140 Again, I'm on the fence on this particular indication, but I can't make that much time

01:58:15.120 to do anything in my life.

01:58:16.940 I know.

01:58:17.720 I mean, there's some gyms that have the soft chambers and I think we're gravitating.

01:58:22.280 There's a little more buzz about it with people biohacking.

01:58:25.300 How far can you get in a soft chamber?

01:58:26.680 Yeah, about 1.3 atmospheres.

01:58:29.320 So that would be maybe a good place to start.

01:58:31.260 If you have a mild concussion or you want to do more of a mild hyperbaric oxygen protocol,

01:58:35.620 1.3, three times per week for two weeks or something.

01:58:39.840 And I'm just speculating, but I know these people that run the hyperbaric chambers, I

01:58:44.200 got to go in for minimum 20 sessions, 40 sessions.

01:58:47.040 We want to get in for 40.

01:58:48.100 So I've been a reviewer on a variety of different publications, systematic reviews and things

01:58:53.740 like that and been on top of this field.

01:58:55.360 And there's some data that will be coming out from two different groups that suggested

01:59:00.780 that if you had a traumatic brain injury, even years ago, hyperbaric oxygen increased

01:59:06.560 cognitive function and pretty much all metrics of cognitive after that.

01:59:11.580 This protocol, I believe, was 40 to 60 sessions, 1.5 to 2 atmospheres of hyperbaric.

01:59:19.100 There's also, by me, we have this community called the Villages, and there's a clinic there

01:59:26.300 called the Aviv Clinic.

01:59:27.880 They're not interested in publishing or anything, but they've treated like tens of thousands of

01:59:31.560 patients, like at least 10,000 patients.

01:59:33.900 They have convincing data from what I'm told from people that have worked with them, and

01:59:38.560 I've talked to the director that they have remarkable increase in cognitive function from

01:59:43.980 elderly people there.

01:59:45.980 They don't have TBI, but they have improved cognitive function across different, and also

01:59:50.640 just cardiometabolic biomarkers are improving over time, like glucose control.

01:59:55.320 I'm a little bit skeptical on that, but I do see in our animals, sometimes they just go

01:59:58.600 hypoglycemic when we pull them out.

02:00:00.480 The glucose control could be because they're not eating in the chamber for spending 10 hours

02:00:04.100 a week in a chamber not eating.

02:00:05.380 And oxygen increases metabolic activity too, so especially if you're hyper.

02:00:09.840 But yeah, there's a problem with the studies that have been done.

02:00:13.980 Because the DOD funded a study where they did hyperbaric oxygen, and the control was hyperbaric

02:00:20.660 air.

02:00:21.620 So hyperbaric oxygen is 100% oxygen, you know, an increase to hyperbaric air.

02:00:24.680 Yeah, so you're still getting hyperbaric exposure to 20% oxygen.

02:00:27.460 Yeah, so the control was just hyperbaric pressure, and then both groups got benefits.

02:00:32.820 There's a lot of muddy waters.

02:00:34.280 So the DOD wants to put a nail in this coffin, so they actually funded my university, University

02:00:40.140 of South Florida.

02:00:40.640 We have six beautiful chambers in a facility that's run by the neurosurgery and neuroscience

02:00:45.880 department.

02:00:46.860 And my friend, Dr. Joe Duturi runs the facility there, which is putting a nail in this coffin.

02:00:52.240 So they have subjects with PTSD and also subjects with brain injury, but it's more of a PTSD

02:00:57.860 trial.

02:00:58.920 And they have a sham.

02:01:01.140 The sham is that they pulse the pressure during the initial compression to make you think like

02:01:06.520 you're undergoing pressure, but keep it at one atmosphere.

02:01:09.360 And at the end, with the decompress, they pulse it so you feel a little bit.

02:01:12.640 But why PTSD as opposed to TBI?

02:01:15.000 Well, it's brain injury PTSD.

02:01:17.340 So it's just answering that question, because PTSD is such a huge problem, for one thing,

02:01:21.980 as is brain injuries.

02:01:23.400 But they kind of across the board, they're treating.

02:01:25.880 These chambers, six chambers, are active from morning till night.

02:01:29.040 So it's a $30 million project that has all the right controls, all the people involved,

02:01:34.920 and multiple institutes are sort of collaborating.

02:01:38.460 But the central location is...

02:01:39.380 It's enrolling?

02:01:40.020 Yeah, it's ongoing.

02:01:41.240 And when does it read out?

02:01:42.740 It will be done...

02:01:44.260 I think some preliminary data should be coming out within the next year.

02:01:48.220 And if people do get a benefit from it, and they're in the sham group, or if they're

02:01:53.080 in the hyperbaric group, they're going to give them access to that.

02:01:55.100 They're going to cross it over.

02:01:55.780 Yeah.

02:01:55.920 So if it's going to become like a treatment center, I was not actively involved in the

02:02:00.140 initiation of that, maybe because I studied the negative effects of hyperbaric, but I've

02:02:03.340 been like peripherally involved of it.

02:02:05.000 And I saw...

02:02:05.620 I've been inspired by the work that they're doing and the level of scientific rigor that

02:02:10.220 they're using to approach this question of the potential neuroregenerative and cognitive,

02:02:17.780 even mental health effects of hyperbaric oxygen, which have been reported anecdotally,

02:02:22.440 but have not been systematically studied in this rigorous way.

02:02:26.460 So that project is ongoing right now.

02:02:29.160 In addition to that, I've reviewed some papers that will be coming out and some work that has

02:02:32.680 been done to suggest that if you had traumatic brain injury years ago and you go into chambers

02:02:37.820 and you use a rigorous method, the only thing is they did not have a sham control.

02:02:43.220 They did not have a control.

02:02:43.940 So it's hard to do a control, but they've figured out a way to do it at USF and they

02:02:48.820 have a person that comes in to question the person and figure out if they're lying or not

02:02:54.380 about the control.

02:02:55.280 Like, did you experience it?

02:02:56.540 And basically all the subjects that are getting the sham have no idea if they got sham or treatment.

02:03:01.660 No experiment, no protocol.

02:03:04.160 That's going to be great to see.

02:03:05.020 Have never done that before.

02:03:06.000 And just the sheer amount of people that are going to be treated.

02:03:08.980 It's all veterans?

02:03:09.920 Yeah.

02:03:10.140 Well, that's great to hear.

02:03:11.820 Dom, this has been really interesting.

02:03:14.120 I mean, to me, there have been a lot of things that unfortunately haven't changed fast enough

02:03:18.060 since we last spoke, namely around our insights around cancer and Alzheimer's disease, largely

02:03:23.780 due to a lack of clinical trials.

02:03:26.920 But the unbelievable change in exogenous and supplemental ketones, it's exploded.

02:03:32.200 You've been leading the charge in that.

02:03:33.960 It gives someone like me a lot of hope.

02:03:35.780 I mean, I've long ago given up on the discipline of a ketogenic diet.

02:03:39.380 Although I achieved remarkable benefit from it, but something just changed when my daughter

02:03:44.520 was old enough and I just wanted to start eating everything and that hasn't vanished.

02:03:48.560 I'm on the seafood diet.

02:03:50.380 That is S-E-E food diet.

02:03:53.000 And you're not managing epilepsy or anything like that.

02:03:55.320 You got benefits of it.

02:03:56.460 I know at the time, I distinctly remember going to the gym with you and the amount of

02:04:00.540 volume that you would do or just riding the bike and just swimming and yeah, it was crazy.

02:04:05.240 And you've really piqued my curiosity about these exogenous ketones.

02:04:08.880 And in addition to that one that I've just started putting into my coffee, I think I'm

02:04:12.180 going to really give some of these salts a try, especially given what you've said about

02:04:16.380 I'd always felt that, well, I need to be somewhat mindful of electrolyte load beyond what I already

02:04:21.100 consume.

02:04:21.940 And also, although we didn't talk about it, I know you and I have spoken about it just before,

02:04:25.900 which was you don't have the same GI consequences that used to exist with the ketone salts, which

02:04:30.820 largely limited their consumption. So tell me and tell everybody again, the brand that you're

02:04:35.840 suggesting I give a try to that you brought.

02:04:38.040 Keto Start by Audacious Nutrition.

02:04:40.020 You buy it directly from them?

02:04:41.020 Yeah, you can get it right on the, I think, yeah, it's on Amazon. So, I mean, that's what I use.

02:04:44.660 And it's kind of evolved out of, it was essentially the molecules that we originally studied and

02:04:50.400 stuck with even after looking at all the different keto masters.

02:04:53.360 And you're not financially involved in this company?

02:04:55.100 No.

02:04:55.520 Your wife advises them though?

02:04:56.680 Yes. Yep. I'm on the sideline. So I don't sell anything. So I don't have any companies. I don't

02:05:01.280 sell anything. I do advise for companies and we talked about CGM. So I'm an advisor for Levels Health.

02:05:06.420 I'm an advisor for MedSci, M-E-T-P-Y-S. So it's essentially an app and a program for metabolic

02:05:13.320 psychiatry and advise a little bit for RxSugar, which sold allulose. So I should disclose those

02:05:19.960 things. I don't think we talked about allulose too much.

02:05:22.380 Got to say something for next time.

02:05:23.440 Yeah. So I don't have any brands or selling anything, but I do have Keto Nutrition. So

02:05:27.680 that's my informational website. And I think the big thing that I'm involved in is the

02:05:32.900 Metabolic Link Podcast. That's our podcast that we want to have you on, of course, and

02:05:37.520 the Metabolic Health Initiative, which is an ACCME accredited medical education platform.

02:05:43.300 So that platform is associated with a podcast, but we have educational information where we

02:05:49.260 have doctors, neuroscientists, cardiologists, oncologists, doctors that treat metabolic

02:05:54.920 disorders give lectures on this. And so you can get medical education and learn about ketogenic.

02:06:01.080 It's got to meet the ACCME bar of standards. So that's Metabolic Health Initiative and also the

02:06:07.620 Metabolic Link Podcast and also the Metabolic Health Summit, which we've had many people that have been on

02:06:13.220 your podcast, have spoken at the summit. That was in Clearwater, Florida. So we're regrouping and figuring

02:06:18.740 out what the future of that's going to be, but there's no really experience that you can mimic than an

02:06:24.940 in-person event. And you can network with people and we have basic science, clinical science, and also

02:06:31.140 a big focus of it too is having patients talk and then talk about the implementation strategies

02:06:36.840 with what we're talking about here.

02:06:38.560 We'll stick all of that in the show notes so that everybody can find you. And you're also just

02:06:43.780 arguably the single most generous person with this time I've ever met. I know that you personally take

02:06:48.940 so much time to respond to strangers who are contacting you. And that is, I suppose, the burden

02:06:54.120 and responsibility of being one of the most knowledgeable people on this planet when it comes to this type of

02:06:58.220 therapy. So on behalf of all those people, thank you. And thank you for coming all the way out here.

02:07:02.760 I know how busy you are.

02:07:03.760 Thanks for having me. It's been my pleasure. Thank you.

02:07:05.940 Thank you for listening to this week's episode of The Drive. Head over to

02:07:10.820 peteratiyamd.com forward slash show notes. If you want to dig deeper into this episode,

02:07:17.620 you can also find me on YouTube, Instagram, and Twitter, all with the handle peteratiyamd.

02:07:23.200 You can also leave us review on Apple podcasts or whatever podcast player you use. This podcast is for

02:07:30.060 general informational purposes only and does not constitute the practice of medicine, nursing,

02:07:34.420 or other professional healthcare services, including the giving of medical advice. No

02:07:39.360 doctor patient relationship is formed. The use of this information and the materials linked to this

02:07:45.040 podcast is at the user's own risk. The content on this podcast is not intended to be a substitute for

02:07:50.980 professional medical advice, diagnosis, or treatment. Users should not disregard or delay in

02:07:56.300 obtaining medical advice from any medical condition they have, and they should seek the assistance of

02:08:01.420 their healthcare professionals for any such conditions. Finally, I take all conflicts of

02:08:06.360 interest very seriously. For all of my disclosures and the companies I invest in or advise, please visit

02:08:12.520 peteratiyamd.com forward slash about where I keep an up-to-date and active list of all disclosures.

The Peter Attia Drive - December 08, 2025

#375 - Ketogenic diet, ketosis & hyperbaric oxygen： metabolic therapies for weight loss, cognition, Alzheimer's & more ｜ Dom D'Agostino, Ph.D.

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