#375 - Ketogenic diet, ketosis & hyperbaric oxygen: metabolic therapies for weight loss, cognition, Alzheimer's & more | Dom D'Agostino, Ph.D.

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My guest this week is Dom D'Astino. Dom is a neuroscientist and professor at the forefront of metabolic therapies, including ketogenic strategies, exogenous ketones, and hyperbaric oxygen.

In this episode, we discuss nutritional versus supplemental ketosis, clear definitions, thresholds for clinical ketosis, and practical ways to achieve it while keeping protein adequate.

Why the early transition into a ketogenic diet can be challenging and how electrolytes and ketone salts can smooth that on-ramp.

The growing landscape of exogenous ketones, the salts versus the esters, 1,3-butanediol, taste and insulin effects, and simple effective pairings such as caffeine, MCT, and alpha-GPC.

Ketogenic diets as metabolic therapy for cancer, especially glioblastoma. The prospects for ketogenic diets in neurodegenerative diseases, including dementia and Alzheimer's disease specifically.

Hyperbaric oxygen chambers, Dom's recommended protocols, practical barriers, and the rigor of ongoing trials, when fasting and ketones shine as a situational tool for cognition, workload, travel, and inflammation, and the carnivore diet as a ketogenic variant and what it implies for certain autoimmune and metabolic conditions.

So, without further delay, please enjoy my conversation with Dom DeGostino.

Hey, Dom, Thank you for making the trip out to Austin. It's, boy, it has been a long time since we've been in person.

I'm afraid to hazard a guess as to when, but I know you and my brother see each other a lot more. And I'm always getting pictures of you visiting him and him visiting you.
Yeah, yeah. Paul's amazing.

He's a mentor to me, and as you are through the health, and Paul's like an amazing entrepreneurial mentor and a life mentor in many different ways. So great to see you both.

You guys are such uber high achievers in different domains. And I think it's great to see you in person for one thing, but it's great to see both of you thrive in doing what you do.

Well, the same can be said for you.

Dom, you've been on this podcast a couple of times, but I know that in podcast land, A, we've probably got hundreds of thousands of listeners today that weren't listeners the first and second time you were on the podcast.

And frankly, those that were, I think it would be understandable that they've forgotten most of what we've spoken about.

And maybe just by way of background, I'll let folks understand how you and I connected. I believe Ken Ford connected us back in 2011-ish, thereabouts.

At the time, I was about a year into experimenting with a ketogenic diet, having all sorts of interesting success with it for the most part, once I got over the hump of figuring out how to do it.

And I think we must have connected at his institute, and then the rest is kind of history.

We then, through our friendship, became very deeply involved in the testing of the earliest generations of various forms of synthetic ketones, a topic we will undoubtedly get to today because it's impossible to imagine how much proliferation there has been of these things that were, I mean, literally you're sending me like dirty plastic bottles with stuff in my kitchen that I'm experimenting with.

And it's like, now look at what you've done. So maybe let's just talk a little bit about how your interest in this space came to be.

So even for my recollection, I don't recall your PhD was in neuroscience, if I'm not mistaken. Yeah, nutrition.

And then at the time, studying nutrition and biology, I started doing a undergraduate thesis project in neuroscience and the neural control of autonomic regulation.

So specifically the brain network, the rostral ventral lateral medulla. So they are the brainstem network that controls respiration.

So inspiratory neurons, expiratory neurons, and how they respond to oxygen and CO2.

And that led me down the path of oxygen, hypoxia, hyperoxia, hypercapnia, extreme environments, what happens to the brain under oxygen deprivation and nutrient deprivation.

At the time, I was interested in alpha-L polylactate because it was in Cytomax, which was something I use because I race mountain bikes.

I was testing some things, lactate, and then I got steered onto the ketogenic diet after getting a fellowship, a postdoctoral fellowship by the Office of Navy Research, which is part of the Department of Defense, to understand the cellular and molecular mechanisms of central nervous system oxygen toxicity.

which manifests as seizures.

So I was mostly interested in drugs, but then I pivoted and went back to the ketogenic diet because the ketogenic diet works for many different seizure disorders when drugs fail.

So I was like, oh, I can get nutrition back. Although I was gravitating towards a tenure track position and everybody told me this is like the dumbest thing to do.

You can't get NIH funding with ketogenic. Nobody had heard of the ketogenic diet.
And what year was this? This was around 2005. I started tinkering with ketones, but 2007, I started writing grants.

And then I hit on a grant in 2008, postdoctoral grant.

I had a weird position from postdoc to something called a research assistant professor, which is like an intermediate position before you get into a tenure track.

And the university was just gauging to see my productivity. My postdoctoral grant was very sizable.
It was above like an NIH level grant, which I was, and it paid full indirects.

That came from the military. Yeah.
Office of Navy Research is part of the Department of Defense. And then I got good data on hyperbaric atomic force microscopy, very mechanistic research.

I also did patch clamp electrophysiology and and confocal microscopy.

My work was really focused on redox mechanisms and looking at superoxide production under graded levels of oxygen and different metabolites.

So in the process of doing all that, I had no interest in cancer, but we had some glioblastoma cells and we threw them into the hyperbaric chamber.

And under confocal microscopy, we could see the mitochondria were lighting up. and then kind of exploding or disappearing in the cancer cells.
And that was kind of unique.

And that led me on a side tangent thing to study cancer. But my central thing that I studied was neuroscience.
I've been in a neuroscience department and mainly focused on that.

Let's go back to something you said at the outset, just because folks might not understand why the Navy would be interested in the effects of too much oxygen.

When you think of the Navy, you think of being underwater. When you think of being underwater, you think of oxygen deprivation.

So what is it about certain types of diving that actually bring about the opposite problem? Good question. So hyperbaric oxygen, you experience that with hyperbaric oxygen therapy.

And there's 14 different FDA approved applications. In that context, you only go to about a maximum of 2.5 to three atmospheres of pure oxygen.

In the context of military diving, like a Navy SEAL, use a closed-circuit rebreather because there's no bubbles. So there's a stealth component to that.
You're breathing high concentrations of oxygen.

And at 50 feet of seawater, the potential for oxygen toxicity exists. Explain to folks exactly what that is.
How does a rebreather work? What's the concentration of oxygen that they're breathing in?

A closed circuit rebreather, for example, like a Drager rebreather like the original ones, those early rebreathers and even now it's high concentration. It's essentially 100% oxygen.

You're breathing 100% oxygen. So there's no nitrogen.
There's 80% nitrogen in the air we're breathing right now. There's no nitrogen.
So you avert the potential for nitrogen narcosis.

So nitrogen's not narcotic at one atmosphere, but you get something called the martini effect. And as you go down lower, nitrogen becomes narcotic.
So that's something else that we study.

So you're breathing 100% oxygen, and then there's a CO2 scrubber. So you're blowing out, the exhaled carbon dioxide is scrubbed out from the breather.
And that keeps, it's a closed circuit.

So there is no off-gassing associated with scuba diving or even other types of technical diving where you have some off-gassing.

And the reason that they can do that is because you're not wasting gas on the 80% nitrogen. You basically store the CO2 that's coming out once you've scrubbed it.
You've got pure O2 coming in.

So your volume of air needed is much lower because you're just solving for the oxygen. That's part of it because the oxygen tanks are pretty small with a rebreather.

But it's analogous to we have a couple ponds on our property. And when I go in the pond and I see bubbles coming across the pond, I know an alligator is coming towards me.

When your brother was there, we were looking at the alligators and just getting them to come to us by throwing pebbles in there when they hear something.

So if I go to the pond with a weed whacker, I see bubbles coming across.

So analogous situation would be a navy seal coming across a body of water that still, you can clearly see the bubble trail coming to you.

So with a closed circuit rebreather, that completely averts that, the bubble trail. And then there's also the noise that the bubbles make.
So you don't have that.

The problem is if you're wearing a closed circuit and you dive down to 100 feet of seawater because someone starts shooting at you or you have to go down deep to put a mine on the bottom of a bridge or something like that, you're going to have a seizure within five minutes.

So oxygen is a stimulant. It stimulates a massive amount of glutamate release that activates AMPA receptors, NMDA receptors.
It stimulates the neural network. in ways.

It also sort of deactivates or inhibits an enzyme, glutamic acid decarboxylase, which converts more glutamate to GABA. And there's a big burst in reactive oxygen species.

So you have a constellation of things going on in your brain.

So I study the negative effects of high oxygen, which kind of has some people who study hyperbaric oxygen a little bit standoffish towards me.

But in the context of lower oxygen, hyperbaric oxygen therapy can be very therapeutic. I do want to talk about that.

There's a lot I want to ask you about hyperbaric oxygen, but I want to finish the swing on this. particular application.

When was it clear to the Navy the problem that you described, which is when we have closed-circuit rebreathers with 100% oxygen, we're running into problems with our divers.

These problems are dramatic. I mean, if you have a seizure at 100 feet, you're going to die pretty quickly.
So when did they come to realize this? And was this a relatively recent discovery?

No, it's not. And my mentor, Dr.
Jay Dean, our lab is like a museum. So we have all the historic pictures on there.
And there's a guy that wrote a book, and his name was Fred Baer.

He was a French physiologist. He did a lot of seminal studies well over 100 years ago in the 1800s showing that you could give animals, they called it caissons disease too.

So that could be when you go down in like chambers, when you're building a bridge, you're under high pressure oxygen or high atmospheric effects.

So yeah, I would say about 150 years ago, we realized that oxygen was a stimulant. We didn't know why.
And then with military diving, Then you have the problem of averting oxygen seizures.

And there's a number of people in the Navy. Frank Butler comes to mind, Claude Pianadosi, Richard Moon.

There's a network at Duke University which did a lot of the seminal studies and they established the dive tables for preventing oxygen toxicity seizures, nitrogen narcosis, high-pressure nervous syndrome.

So these are all things that you have to avert when you're diving, depending on what kind of diving you're doing. Was the Navy coming to you to say, look, we know this is happening.

Can you help us push the envelope?

Yeah, I kind of went to them, or they came to me because I specialized knowledge, but I wrote grants to really delve into, it's unknown why these seizures occur, but it gives us a lot of insight into the brain to understand it from a redox effect, from a neuropharmacology effect.

So the grants that I had were literally called investigating the cellular and molecular mechanisms of CNS oxygen toxicity. And they gave me...

Unlike the NIH, they gave me, I had a lot of tools to play with that were really expensive that we got through what's called a DOD DURIP grant and that bought chambers and microscopes and electrophysiology equipment.

It allowed me to tinker in the lab.

And in the process of tinkering, we just had some serendipitous discoveries with the cancer things and then just fundamental effects that happen in cells under high pressure oxygen, nitrogen, helium, different gases.

Very basic. So the Office of Navy Research has a 6.1 program and that's basic science and then 6.2, 6.3.

And as I progressed in my career, I started working up from a cell-based system to animal models. Then it went to a pig model system.

Now essentially, we're doing the rat studies at Duke with human subjects that get inside a chamber. We get diaphragmatic.
We get EEG.

We have a line going into their arm that goes to like a mass spec to get blood gases, to do metabolomics. They're working a simulator, a flight simulator.
They're exercising.

It's water out immersion, so their body's underwater, but you get the hypovolemic effect of the fluid shift and things like that to simulate that dive.

And then we push them to a seizure, believe it or not. So this got approved through an IRB, which is even more amazing than the Cahill study.

But we push them to an EEG seizure to where we can see the seizure and then we decompress. So we look at latency to seizure under ketosis, dietary ketosis or supplemental ketosis or the combination.

So those clinical trials, I'm co-investigator on it because it's being done at Duke. They're registered clinical trials on clinicaltrial.gov.
And these are being funded by the DOD?

Department of Defense has Office of Navy Research. They have the CDMRP, which is Congressionally Directed Medical Research Program, and also NAVC.

So this is an ONR project that got spun into a NAV-C project. So Naval Sea Command project.
So NAV-C is more human studies, and an ONR is basic science, and then some human research.

I'm going to come back and talk about a lot of these things, but I feel like we should now get people up to speed on what ketones are.

Again, we can sit here and talk about this and take this stuff for granted all day. You obviously threw around the term nutritional ketosis.

You've also talked about supplemental ketosis, sometimes referred to as exogenous ketones.

Let's start with nutritional ketosis and just give people some definitions of how you achieve it, how much variability there can be in a diet to get there, what the thresholds are, and a little bit about what's happening physiologically.

Before I begin, I want to direct people to your early blogs, which I assume are still up, on nutritional ketosis. I'm sure they are.
Yeah, on the Delta-G, there's one with exogenous ketones.

And our study we kind of did with the ketone salts, which increased your efficiency, oxygen utilization. So nutritional ketosis, let's take a little bit of a step back.

Ketosis, I like to start with fasting. So when you stop eating, you suppress the hormone insulin, you mobilize fatty acids for fuel.

The brain's not a good, it can't use the long-chain fatty acids that are stored in your adipose tissue.

So through beta oxidation of fatty acids in the liver, accelerated beta-oxidation oxidation in the context of insulin suppression generates these molecules, beta-hydroxybutyrate and acetoacetate.

And then they spill into circulation and they become largely responsible for preserving brain energy metabolism in the context of energy deprivation or carbohydrate restriction.

And the elevation of beta-hydroxybutyrate or acetoacetate in the blood, in the urine, or the breath becomes a biomarker for ketosis.

So you can achieve ketosis through fasting, through diet, through supplements, or alcoholic ketoacidosis. That's another thing, or diabetic ketoacidosis.
And we could talk about that in the context.

And then you have nutritional ketosis, which is eating carbohydrate-restricted ketogenic diet that's primarily high in fat. The original diet was 90% fat.

Modified versions of the diet are about 60% to 70% fat. with higher protein.
Now we know, especially in kids, you restrict protein too much, you could stunt their growth and have some issues there.

So clinically, a modified version of the ketogenic diet is actually being gravitated more towards even in pediatric epilepsy.

So we're learning that protein is really important and it was underappreciated, I guess, in the early ketogenic diets. In the context of sports, it's extremely important, and we can talk about that.

But still, it remains that the ketogenic diet is the most scientifically researched diet that has an objective biomarker that defines the physiological state of being in the diet, and that's a beta-hydroxybutyrate above 0.5 millimoles per liter.

So that's clinical ketosis. And in the context of ketosis, there are remarkable changes in our metabolic physiology and the neuropharmacology of our brain.

And also beta-hydroxybutyrate has very unique effects, epigenetic effects, which is kind of a new buzzword that people are talking about. And my student just finished a project on that.

And I think it's pleiotropic. So ketogenic diets have pleiotropic effects.
Tell folks what that means. Pleiotropic is kind of like a fancy, somewhat nebulous word.

That basically means there are multiple mechanisms that are activated biochemically, physiologically, neuropharmacologically that have beneficial effects.

And I can go through the explosion of research that has occurred on PubMed and clinicaltrials.gov. But the important thing is that nutritional ketosis, or let's take a step back, the ketogenic diet.

Some people say the ketogenic diet is not magical. The ketogenic does nothing magical.
In the context of body composition alterations or fat loss, there's truth to that.

However, I say there's a hard stop there. The ketogenic diet is indeed a magical diet in the way that it remarkably changes our physiology.

And there's no other diet that exists that can, for example, manage drug-resistant seizures.

And it does that because it profoundly changes our fuel system, our physiology, our biochemistry, and our neuropharmacology. Let's talk a little bit about that.
You've mentioned it a few times now.

So let's help folks understand what's going on here. So this was first identified in kids.
And if I'm not mistaken.

Adults, actually, if you go back to the Mayo Clinic in the 1920s, because there was no drugs for epilepsy. So what gave them the idea? Defaulted.

Hey, we've got these people that are experiencing this awful thing. Now, they had EEGs back then, but they really didn't know much.

Yeah. Yeah.
They actually did some really good physiology back in the 1930s, 40s. Underappreciated.
Well, we knew that fasting controlled seizures. So that was the first observation.

Yeah, I mean, the Gospel of Mark talks about, yeah, fasting. I mean, it's all over like in the literature.
Fasting could control seizures.

So a ketogenic diet, by virtue of elevating these ketone bodies, which were showing up in the blood and the urine and even in the breath, they just understood that these ketone bodies were somehow associated with seizure control.

And we did not have anti-seizure drugs back then. And when were these first identified? So you've got Banting and Best identify insulin, or at least isolate insulin in the 1920s.
Yes.

So that's really the, in my mind, I think of that as kind of the golden era of metabolism. When were ketones first isolated, BHB specifically?

Within a decade around that time, with Banting and Best discovered it in the context of diabetic ketoacidosis.

And then work at the Mayo Clinic by Wilder and a few other people were helping sort of establish the framework for what would be ultimately the first ketogenic diet therapies.

And the thing was just eating all fat. And then we realized we got to titrate in the protein to prevent protein malnutrition.

And then there was a tiny, in 1921 in a clinical, it was just like a side note on a clinical journal, the first observation or clinical report of a ketogenic diet used in epilepsy and the remarkable effects.

And we didn't have anything. They didn't understand why.
Mechanistically, I mean. I mean, we could go a hundred years later and we don't fully grasp and understand all the mechanisms involved.

And that's why it's such a fruitful, robust area of research right now with drug companies scrambling to mimic. If we had a drug that would mimic the ketogenic diet, it'd be a blockbuster drug.

Because if I understand correctly, Dom, if you took 100 patients who are drug resistant, so they're having nonstop seizures despite all the best available pharmacology, my recollection, this could be incorrect and you can update this, is that a ketogenic diet will completely cure one-third of them.

will cause about a 50% reduction in seizure activity for another third of them, while one-third of them will still be unresponsive. Is that still directionally correct?

In the context of pediatric epilepsy, about two-thirds will be, so it's that high. Two-thirds will be.

Two-thirds will be therapeutically responsive to acetogenic diet therapy for managing seizures, are highly efficacious for managing seizures.

Two-thirds of people who have failed drug therapy, we're not just talking about one drug. We're talking about polypharmacy, adding multiple drugs.
The list goes on. What about adults?

So, in adults, it's more about closer to post-adolescence, about 30 to 40%.

But then it's thought that adherence and compliance with adolescents, with kids, the parents feed usually a ketogenic formula and calculate it out.

But there's also something about the pediatric brain that's probably more responsive. And then of that two-thirds, about one-third have like complete seizure control, 95 to 100% seizure control.

And then 10 to 15%, and this really interested me when I went to the first conferences back maybe 15 years ago, were super responders, meaning that they could get on a ketogenic diet, follow it for a year or two, transition off, and never get seizures again.

So they talked about the ketogenic diet being curative, and that was really interesting to me.

Of course, the brain is changing as you go through development, but it was shifting brain networks and network stability, suppressing inflammation and changing neurotransmitters in a way that there's the kindling effect with seizures.

So seizures beget seizures. So once you have a seizure, you're more likely to have another seizure.

So if you control seizures and you do it through a protracted time frame, it's going to lessen the chance of you. It's going to decrease that kindling effect.
So there's something going on there.

And we've replicated that just throwing sodium beta-hydroxybutyrate into a hippocampal brain slice preparation under different levels of things that stimulate seizures, like measuring seizures in a slice.

when like the orthodromic population, you can stimulate and measure the orthodromic population spike of the neurons like firing back.

And then you can decrease the amplitude of that over time and essentially just silence seizures in a slice.

And at the same time, you're making that hippocampal brain slice more metabolically resilient.

You could throw different agents at it that would be neurodegenerative or hyperexcitable and it will protect it under the context of various neurotoxins. I think that really interested me.

So the early observations and then I was completely unaware of all this literature in my postdoc.

And then when I started delving into it, I was like, I have to change the trajectory of my career, but I'm going to do it in an innovative way.

I'm going to study the ketogenic diet, but also in parallel or in tandem, or maybe in some cases exclusively, just delve into what is the most efficacious form of exogenous ketone we can use and how can it augment the therapeutic efficacy of a ketogenic diet.

There's a lot to unpack here and nobody was doing it at the time.

You've obviously experimented a lot with a ketogenic diet yourself. I mean, when did you first try a ketogenic diet?

The clinical ketogenic diet where I got the little cardio check meter, which was super expensive at the time i would say 2009 i started actually checking ketones i was using the abbot one yeah precision extra precision i got that later i don't even think that might have been out yet but i got that soon after because the cardio check actually did like your hdl and like triglycerides and things we also had like a lab assay like an elias assay yeah we were comparing it to it yeah and then we got the precision extra by abbot and then i remember i bought something like back then this ten $10,000 thousand of strips.

I was about to say, the strips were $5,000 to $10 each. Yes.
At the time. I found, I bought them in bulk.

Yeah, you hooked me up at one point. And we were able to get them for like $1.50 or something.

I was going through three a day. Yeah.
Yeah, yeah.

That price point has come down, but now we have the Keto Mongeau actually aligns more with our assays and it does the glucose ketone index that we can talk about. So I started doing that.

And when I started it, within, I guess, five years after starting the keto giant diet, diet, I probably rapidly lost 10 to 15 pounds. And then my exercise and my lifts tanked too.

Lost strength on bench press, not so much deadlift and squat, but I saw that. But I didn't really care that much at the time.
But I also learned the lesson that protein was really important.

I was thinking ketones would be basically save muscle. And they have an anti-catabolic effect that we can talk about.

But if your protein goes from like 250 grams a day to like 70 to 80 grams a day, you're going to lose a lot of muscle. Just don't tell the USDA that or the RDA.

They still want you to believe that 0.8 grams per kilogram is all you need. It's very context-dependent too.
I was kind of in the gym and I was even training with Lehman at the time.

It's not really facetious. I mean, these guys are out to lunch and they just want to cling on to this idea that protein is bad.

They're avoiding like work from Donald Lehman and Stu Phillips and guys I think you might have had on the podcast. So, yeah, I learned a lot of lessons.

I learned that clinical ketogenic diet skyrockets my LDL and APOB. I've learned learned how to manage that pharmacologically.
I have a mutation for the MPC1L1 receptor.

So a tiny dose of azetamide brings that down. But most importantly, I realized that titrating the protein in to meet your needs for protein.

And if you're an athlete, if you have a high metabolic rate, if you're trying to gain muscle, you do have to leverage protein.

And that becomes the key factor, I think, the key variable in getting the ketogenic diet to work for you and also tracking your lipids is really important.

What do you think are the most common mistakes people make when they're trying to enter nutritional ketosis? What would be the top three or four mistakes that people are making? Not tracking.

I mean, people do it. They're just like, oh, I'm just going to eat this or that and not try.
It's like, no, you need to like just write it.

You don't have to do it every day, day in and day out, but use a good tracking metric. Carbon app is great.
I know you've had Lean On. I've used that.
And there's other apps out there.

So tracking because you want people to be able to correlate the blood levels they're seeing with what they're eating. Yeah.

So So the macronutrient ratios and the composition, but also the total amount of calories, which at the time when I get into this, everybody was said, you know, if you do a ketogenic diet, you don't have to track calories.

Calories don't matter. I just knew that was BS to begin with because there are some people who can easily overeat on a ketogenic diet.

I could sit down with a bag of macadamia nuts and polish the bag off or sour cream or heavy cream or whatever. So it's easy to do.

So yeah, track total calories, macronutrients, track your blood ketone levels. You could do urine or breath too.
What is the state of the art on urine and breath meters these days?

With the breath meter, I do think that's pretty legitimate because breath acetone correlates with seizure control. There is the biosense device, but they've kind of fallen out of favor.

There's a device called KetoAir that's pretty good. It's like the size of a pen.
And that actually correlates really well with some of the blood ketone measurements.

I do notice that if I'm in a calorie deficit, my blood ketones can be very low, but my breath ketones are high.

And I think your ketone production that you're measuring is a consequence of ketone production and ketone utilization.

And in the context of an energy deficit, your tissues are sucking up ketones out of your blood fast, but you're blowing off more acetone.

So your blood ketones are, and I think you maybe made some observations of that too with different device. Yeah, also under high exercise, normal exercise, super normal exercise, fasting, et cetera.

Yeah.

And then urine. People still use it.
My view back at the time was I was never going to to get better precision than using blood. Yeah.
Blood's still the gold standard. And then you have interstitial.

So I just switched out. I was wearing a continuous ketone monitor.
How many companies make those now? Abbott makes one. I can't use it because they use test flight software and I have an Android.

I'm the guy that has the Android. So I can't use that.
But I've been involved with the company a little bit and just had some calls with them. I know, I think you have maybe two involved with them.

I have no involved. Oh, okay.
Just disclose, I don't get paid by them or anything. But there's a company that's in China, and I think now they have a footprint in the U.S.
They're called SciBio.

And I am very impressed with SciBio. So the first week, the ketone measurements are very accurate, but the last week they tend to measure about only half of what you measure in blood.

So it's a device? Yes. Is it microneedles or is it a long filament? Looks exactly like a CGM device.
Uses essentially the same technology, just a different enzyme. I could swim all day in salt water.

I can do stuff on the farm. I don't knock it off.
It's like probably as reliable as a CGM device is now. It's remarkably reliable.
The specificity is good. And it's BHB? It's betahydroxybutyrate.

Yeah, it's important to acknowledge that it's the D-enantiumer or the R-enantiumer of BHB because there's supplements out there that are racemics.

But yeah, I've tested it, pressure tested it, if you will, with high doses of ketones, and it performs well. And so there's emerging technologies.

So the continuous ketone monitor, continuous lactate monitor, which is, I think it's going to be lactates and oncometabolites. Does anybody have one of those commercially ready yet?

Not commercially ready yet. There's programs, but I don't think monetarily, I don't think the companies are motivated to bring it to market.

And I think there's some more testing that needs to be done.

But for example, my colleagues at the Moffitt Cancer Center, they're like salivating over the opportunity to do glucose, ketone, and lactate monitoring, especially.

We see that tumor burden is tightly correlated with blood lactate levels. So we use lactate monitoring.
And if you have an expanding mass of like metastatic cancer, it just correlates very nicely.

And lactate's an oncometabolite that should be measured.

So if mistake number one is you're not measuring your actual ketone levels and you're not tracking what you're eating so you can see the association of, hey, when I ate this, it went down.

When I ate this, it went up. What are some other mistakes people make with their diet formulation? Is that they typically erring on the side of too much protein, not enough protein?

Are they not realizing where carbs are sneaking into their diet? And what kind of guidance do you give people? How many grams of carbs a day do you tell somebody?

Or do you vary that based on their activity level? Yeah, taking a step back. So I view, unlike many people out there, I view a ketogenic diet as a prescription metabolic therapy.

So that's the world that I come from. There's clinical keto and then there's internet keto.
And which a lot of people are following a low carb diet, which has a plethora of metabolic benefits.

You just have to be up on your blood work and you have to be very vigilant with tracking your biomarkers.

But a clinical ketogenic diet is typically done with consulting or advice or even following the framework. For example, a lot of books out there by Eric Kossoff.

If you have cancer, Miriam Kalamian has a guide, ketogenic diet for cancer. Books that are out there that tell you step by step on how to do it.

And from a practical or logistical point of view, we had a small study we ran with Dr. Allison Hall.

that looked at people that were just, they didn't have any overt pathology, but they were just take normal people, put them on a low-carb ketogenic diet.

And the practitioners tell me that if you transition a person over four to six weeks, they adhere to it better and you actually get more favorable health responses.

You don't have a lot of funky blood work that come back. It could be the electrolytes with people that have certain mutations with fatty acid oxidation disorders, even APO E4 carriers.

you'll see their LDL go up and you'll see things like HDL go down and you'll see they start the diet and their triglycerides go up.

I've seen that a lot in quite a few people and I think there's some genetics that need to be unpacked there. In several cases, it was people that were APOE4 carriers.
They're homozygous.

So I think there's something to unpack there. They just don't metabolize, their lipid metabolism is a little bit different.

So I think it's really important to get blood work, track triglycerides, track HDL, ApoB, LDL, hemoglobin A1C, insulin levels.

I think I've seen people's insulins go up, but generally speaking, 90% or 80% or more insulin goes down. But really just to use, there's so many different guides out there.

And if you're doing it to manage a clinical condition, you should be working with a registered dietitian that's savvy.

And the people I recommend, there's advanced ketogenic therapies and it's a team of people. And it's kind of spearheaded by Denise Potter.

She's a registered dietitian, came from the world of epilepsy. and worked as a conventional registered dietitian and then transitioned to ketogenic and now has a team of a half dozen or more people.

But if someone just says, look, I just want to do this on my own, just like any other diet I might follow, what would be sort of the guidance you'd give them? Yeah, it depends why they want to use it.

Well, I think the most common reason would be weight loss. Yeah, weight loss.
So I would say calories are super important. So just gravitate towards a high-protein ketogenic diet.

And if it's just purely weight loss, I would say high-protein, moderate fat, and then high fiber. So the carbohydrates that you're getting should be just fibrous carbohydrates.

So you can get 50 to even 100 grams of carbs per day if one third of those carbohydrates are fiber. So that excludes all ultra-processed food, even processed food.
Broccoli is about one-third fiber.

So if you go down the list, there's about, I think I have a list of about 30 or 40 forms of carbohydrates that are about one-third, a quarter to one-third fiber. So if you're pulling from that list,

you've got all your leafy vegetables.

You mentioned broccoli. Would carrots be in there? No, no.
Broccoli, cauliflower. Carrots, no, especially if they're cooked, they can be highly glycemic.
But avocado, bell peppers.

Yeah, bell peppers are a little bit too high in sugar. They're at the cutoff point, maybe like a green pepper or something like that.
But generally, things that you'd find in like cucumber.

Cucumber, yes. Asparagus.
Tomatoes. Tomato, no.
Tomato is like a fruit, pretty high in sugar. So these are things that you need to be kind of vigilant.
And there's a lot of go-to guides.

And that's why I think it's important to use like a tracking app. I use it now time to time if I want to make adjustments and be very vivid.

Because one thing I noticed, especially using the Carbon app or other apps, I was like, eh, I'm getting about 3,200 calories per day.

But when I put it into these tracking apps, it's more like 4,000 calories per day. Meaning you think you're at 3,000 calories? I underestimate it.
Yeah, I always, always underestimate it.

Probably because just fat is so calorically dense. So the amount of egg yolks and a lot of fatty fish.
This morning I had like three cans of sardines.

Each can is 20 grams of fat and 15 grams of protein. And that's 20, that's 60 grams of fat just from sardines and extra virgin olive oil.
It adds up. It just seems like, oh, this is like nothing.

This is like less than I would have if I'm eating at home, but it adds up.

And I think that people that are not losing weight or managing whatever they're trying to manage with the ketogenic diet, they need to try at calories.

And simple caloric restriction or creating even like a 10 or 20% energy deficit will be the big lever that's going to cure 90% of what most people are seeking the ketogenic diet for.

So what's the efficacy then? So why do you think a ketogenic diet works?

Do you think it works because under conditions of caloric restriction, it's more satiating than diets that are high in carbohydrates?

Yeah, I mean, just off the top of my head, it's hyper-satiating, especially a high-protein ketogenic diet. It's hypopalatable.

Some people may argue that, but you're not going to overeat a ketogenic diet just because it doesn't have the hyper-palatability of a standard American diet.

And I think it fundamentally is changing metabolic physiology and brain neuropharmacology in a way that decreases appetite regulation.

So with a higher protein diet, you're getting higher GLP-1, you're reversing insulin resistance, you're improving fatty acid oxidation, and I think you're fundamentally weaning your brain off glucose.

Your brain is dependent on glucose with a standard American, and as you're decreasing glucose availability, your brain has a counter-regulatory dysphoric reaction to that.

And as it transitions into ketosis, you could avert a lot of this simply by using ketone electrolytes, the stuff that I gave you, the key to start.

So that's electrolytes, similar blend as element, but bound to beta-hydroxybutyrate. Consume that when you start the diet, and that'll largely mitigate.
Two things. It'll mitigate the electrolytes.

A ketogenic diet has a naturetic effect, which means you dump sodium and a diuretic effect. Let's talk about why those occur.

These are the things that kind of really throw a monkey wrench into some of the clinical trials. They're electrolytes and they get dehydrated.
So it's an important topic.

So when I stop eating carbohydrates and ramp up my fat, by the way, I do want to go back to, sorry, one other point. You keep saying high protein.
Can you define high protein in this context?

Are you talking high by the standards of the RDA? Or are you just saying one gram per pound of body weight? Is that sort of your guidance? I mean, historically, 8% to 10% to 12%

was used with ketogenic diets. So I'm talking about a ketogenic diet that's 20 to 30% protein.
So that's considered high. But that's hard for people, I think, sometimes.

I mean, you can obviously back calculate into that by the calories, but do you find it easier to just say, look, keep your carbs at 50 grams and try to get them from high fiber carbs, get your protein to X grams, and then limit your total calories to whatever, 3,000 with fat filling the rest?

In other words, what is it typically working out to in terms of grams per pound of body weight in protein? Me, for example, would be upwards of

about 220 pounds. So that would be, I know it sounds crazy, but from the average RD registered dietitian, but 220 grams of protein.
So that would be the upper end if I'm very active.

And I mean, today, maybe I won't get that or when I'm traveling. But that amount of protein, I think, is the upper end.
I don't think there's any benefits to go above and beyond that.

At that level of protein, you're not undergoing so much gluconeogenesis that you're making too much glucose that's offsetting the ketone process.

Everybody's a unique metabolic entity, so they're going to have a different response.

But for me personally, especially having eaten four or 500 grams of protein, I'm not exaggerating there when I was in my late teens and 20s, that works for me. That level of protein works for me.

For some people, especially if they're going to jump from 50 grams a day or the RDA recommendations, and you want to do that to ideal body weight. The RDA for you is 80 grams.
Yeah.

Exactly 80 grams. You're 100 kilos.
The RDA recommends you have 80 grams of protein, not 220 grams. Yeah.
At 80 grams, you would not be able to maintain your muscle. No, not in my context.

No, definitely not. The more muscle you have, they just have much higher protein turnover.
So you're breaking down protein, building protein.

That whole cascade is amped up probably several times higher in the context, especially if you're working out and breaking down protein and you have a a fast metabolism.

My recent resting metabolic rate showed it was 34% higher. I'd have to do further studies, but they wanted to redo it.
That's even when adjusted for your lean mass? Yeah, my resting. Yep.

I'm going to redo it in about two weeks. I was also off creatin and some other things.
So I'm reloading on creatine just started. I'm going to redo that again.

But yeah, my lean mass is kind of, I'm pretty heavier. So that's the upper limit.

You can gradually increase your protein, but I've been very vigilant now with my protein, especially after turning 50, that this is important because sarcopenia and the loss of lean body mass is almost considerably higher, as you know, in your 50s.

And there's different reasons for that, but activity is the main mitigator for that.

So if you're providing a stimulus for your body to grow and maintain muscle, you need protein that's double the recommended daily allowance, I think, if you're really going to be proactive about it.

Any other quick do's and don'ts around things like fruit, berries, artificial sweeteners? How do you think about all of those things as they factor into a ketogenic diet?

I tend to like, I guess, carb backload at the end of the day. I eat no carbs all day.
And at dinner, I'll have like a salad or vegetables.

And then in the evening, I have wild blueberries, which have like a third of the sugar of regular raspberries, blueberries, wild ones.

And then I have a keto mousse, which is just cocoa powder, chocolate ketone powder, and some stevia stevia or monk fruit and cinnamon it has no effect on my cgm it actually goes down i've found out what works for me and as long as i am eating fiber if the carbohydrates are delivered with fiber there's really no glycemic counter effect to that no spiking i have a short list of foods so it's basically berries broccoli asparagus dark chocolate.

These are things that I eat every day. Maybe not the asparagus, but broccoli, berries, dark chocolate, and salads.
I'm kind of simple and I keep things pretty simple.

I don't, in the past, I had a desire to have more different kinds of foods. I enjoy that.
I mean, we were traveling in Greece and I'm not going to pass up all the great food when I'm traveling.

I ate as much carbohydrates as whatever they were serving me and I came back six pounds lighter because I'm in and out of the water every day. I'm walking out in the sun.
and things like that.

So actually increasing, tripling or quadrupling my carbohydrate made me lose six pounds when I come back. Did you feel different? I felt great.
Yeah. I'm pretty metabolically flexible.

So I think that's also a consideration that if you really delve to carbohydrate restriction and your body is completely fat adapted and it's like carbohydrates are a foreign substance and glucose spikes, you're going to have a pretty big counterregulatory effect once you start getting bolusing carbohydrates again.

Because you're changing your physiology, you're changing enzymes. So your gut, for one thing, is not going to tolerate that.

Just from like fitness competitors when they diet and then they finish the competition and then they go out and have, you know, like a cheat meal, then they're up all night with gas and bloating.

I mean, I could go through all the different systems, but the GI system takes a big hit, the liver takes a big hit, the glucose hitting the peripheral system can't absorb it.

So your CGM goes off the charts and that can trigger inflammation. That can alter gut microbiome.
It's going to affect your mood. These are wild swings that yo-yo dieters go through.

So if you're low carb, you achieve your goals, like your weight and you want to, and you miss miss carbohydrates, you can slightly just titrate them back in and just do fibrous vegetables.

Just start with that. And some people can't tolerate that.
But fruits, most people who have like an aversion to plants or some immune reaction to them usually can tolerate fruits.

So before we go to the exogenous or synthetic ketones, I want to now ask you about an even more extreme form of diet, which I'm sure you get asked a lot about.

I know I do, and I have no insight clinically, nor do I have any personal experience with it. So let's talk about this carnivore diet.
I realize there are different ways people go about doing this.

There are some versions that are incredibly strict, where you literally are just eating meat and nothing but meat.

And then there are others where you expand that into, well, you can eat other animal products, you can eat eggs, you can have dairy and things like that.

Let's start with just the meat-only version of that diet. First of all, what do you think is happening metabolically? How does one achieve ketosis with just meat?

Because even the fattest serving of meat, even if you were eating just ribeyes, I suppose it's possible that you could get 30% of your calories from protein and 70% from fat.

Does it produce a ketotic state as well, typically? I had a ribeye the other night I think would hit the keto macros because it was a lot of fat.

And I was kind of annoyed because, you know, there was less meat and more fat. I think you can achieve ketosis with a fatty carnivore diet, especially if calories are restricted.

You couldn't do it if it was a New York strip or a filet. You just don't have enough fat in it relative to the protein, right? You could if you were in a caloric deficit.

So if you're in an energy deficit, your insulin is going to get like everything is going to kind of go in the right direction. And that's the issue.

I am a firm believer that carnivore diets can be therapeutic for people who have autoimmune disorders. So that's pretty clear.

There's some people who They could also follow a path and do an elimination diet, but the carnivore diet is the ultimate elimination diet.

So you're meeting your protein requirements, have enough protein to build muscle, steak, and an animal-based protein diet has pretty much all the micronutrients.

I mean, you could argue maybe vitamin C and magnesium, but you do not see vitamin C deficiency in people that are on carnivore diets, surprisingly.

So there's some vitamin C in like liver and stuff too. So if you're eating nose to tail, that's not something you have to worry about.

I've seen magnesium trending low, although we don't have the best magnesium measurements of the blood work, but I've seen magnesium being beneficial for people because magnesium, we get it from chlorophyll.

It's like the central molecule of chlorophyll. And we're not getting any of that really with a QJang diet or very little.
You're getting a lot. I mean, I got a ton.

I had two salads a day when I was on a ketogenic diet. Yeah.
I'm talking pure carnivore. Yeah, I see.
We're talking steak and water, right? Like not even coffee, not even putting pepper on the steak.

There are a group of people who believe that and it's working for them and they have a lot of anecdotal data to support that.

I get an inbox full of people that say, hey, look, I had this condition or that condition. I followed carnivore and here's my blood work.
And I can't argue with that.

Yeah, no, I find that stuff pretty compelling from an elimination diet perspective. And I've certainly met a number of folks who feel that way.
And it's quite binary. It either it works or it doesn't.

For many of these people, they're so debilitated on any other form of diet that it's a no-brainer. You're going to stick with that type of restriction.
Yeah. The influencer voice is also amplified.

Joe Rogan, for example, had vitilego. That's an autoimmune disorder.
And I know people who have that saying going on a carnivore diet cured my vitilego. People that are interested in that.

So there's a wide variety of things that it can be therapeutic for. There's a group in Budapest, Hungary called Paleo-Medicina.

And I went to their clinic and they pulled their files and I saw everything from type 1 diabetes to cancer to different neurological disorders. They're showing me blood work longitudinally over time.

Could be cherry-picked the cases, but it was pretty convincing. And they probably have a dozen or more publications, case series and things like that.
But it's a form of a ketogenic diet.

So I think that's important to understand.

Like a carnivore diet is fundamentally, if practiced the way they do with paleomedicina, where you just focus on super fatty cuts, fatty fish, fatty meats, it's a version of a ketogenic diet.

And I think that's why it works. All right, let's go back to now talk about this world of exogenous ketones, these supplemental ketones.

You alluded to them already through the lens of kick-starting a ketogenic diet. But before we talk about application, I want to kind of orient people to the journey you've been on.

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

I will say lately, when I mean lately, I mean only in the past three months, I recently tried a product that I like.

I put it in my coffee in the morning and I believe it is a dieester of 1,3-butanediol.

So it doesn't come with sort of the liver toxicity that I think we should talk about with respect to 1,3-butanediol, which unfortunately seems to be running rampant right now. But it's a white powder.

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

You wouldn't go out of your way to drink it, but it is not horrible the way that most of these synthetic ketones used to taste. So you can just make a shot glass of it, and it's totally reasonable.

Alternatively, it's the creamer in my coffee, and it's fantastic. But let's go way back to the beginning.
Circa 2011,

you had basically only two products you could consume. You had a beta-hydroxybutyrate monoester.
Actually, there were more than that.

There was a ketone salt, which we should talk about, and you had an acetoacetate diester. Is that correct? B-monoester and 1,3-butanediol, acetoacetate diester.
Two acetoacetates on 1,3-butanediol.

So there are two esters. So just explain to people, I mean, unfortunately, we have to get into a little biochemistry here for you to explain the difference between esters and salts.

And so to everybody listening, apologies.

But if you want to understand these things, and you have to if you want to be a consumer of them, because everybody is talking about these things as though they're the same, and they're categorically not the same.

Most people have no idea what they're talking about. And most people who are selling these things are not being transparent about what it is you're buying.
They just call everything a ketone.

Let's do a little bit of biochemistry, Dom. Sure.
Glad to do that.

I think it's maybe even good to step back a little bit because if you go to clinicaltrials.gov and you search ketone supplement, MCT, that's a 8 to 10 carbon fatty acid that can convert to ketone.

So that'll come into the conversation. But one of the original ketogenic substances was 1,3-butanediol.

And I have, I think, compliments of Ken Ford, some of the MIT reports of testing this compound that from the 1960s.

And then there was a report written by people at NASA where they were basically looking at this as a long-duration spaceflight food. 1,3-butanediol, which is an alcohol.
It's a di-alcohol or a glycol.

It is remarkably ketogenic, which means you consume it and you elevate beta-hydroxybutyrate and it's incredibly stable. So hence for long-duration spaceflight.
Also, it preserves food.

In the report, they basically soaked, they put it into some biscuits. And the biscuits were like extremely shelf-stable.
So it's a humectant, which means it keeps food moist.

It's actually grass-approved to be put in sausage casings and things like that. So that existed.
That was 1,3-butanediol. And there were two people who really I'd like to credit, Dr.

Henri Bruninggraber from Case Western and Dr. Richard Veach, the late Dr.
Richard Veach. Oh, he passed away.
A mentor of mine. Yeah, he passed away two or three years ago, I think.
And I remember Dr.

Veech saying, because I was trying to acquire his ketone ester for some studies and I ultimately used the 1,3-butanediol or the monoester of beta-hydroxybutyrate for seizures, but it didn't work.

And I will pivot and talk about that. So you have 1,3-butanediol was the original ketogenic molecule.
And then you have two people who spearheaded ketone esters.

Sorry, just before we leave that, you said 1,3-butanediol elevates beta-hydroxybutyrate. Let's explain how.
Okay, yeah. You can consume 1,3-butanediol, and it's a precursor to beta-hydroxybutyrate.

When you consume it, it goes through the alcohol dehydrogenase pathway and produces, much like alcohol. You can elevate BHB with this precursor, but it needs to be metabolized by the liver.

And when it's metabolized by the liver, the liver does have to work a bit.

If you consume enough to like jack up your ketones to three or five millimolar for two or three weeks, you're going to see your liver enzymes jump up. So I've done that with 13B.

And you have to take a lot of it. You're talking about 150 to 200 milliliters per day for someone like me to be in therapeutic ketosis.
So when you do that, you're also generating an aldehyde.

Let's take a step back here. If I asked you to consume 100 grams of ethanol a day for two weeks, your transaminases would go up.
Yeah. I've done that before.
Yeah. So let's talk about that.

So a standard drink is about 15 grams of ethanol, maybe more, right? Yeah. Yeah.
Called 20. We rounded up 20.
So now I'm asking you to have five alcoholic beverages a day.

And by the way, you could space that out over the course of the day and not even get a buzz. Say five alcoholic beverages a day for two weeks.
You are metabolizing ethanol with alcohol dehydrogenase,

and you're going to create all of the various metabolites.

And the reason your transaminases are elevating is those enzymes are leaking out of hepatocytes because the hepatocytes are injured due to the inflammation that results from that metabolic pathway.

Is that at all analogous to what's happening with a comparable dose of 1,3-butanediol? Yeah, it is. There's a couple of things going on.
You drink alcohol.

You're de-energizing the redox state of the liver, and you're generating acetyl aldehyde, an aldehyde molecule, which aldehyde damages DNA.

It's got oxidative stress issues, baggage that comes with it. You're also generating acetate.
When you drink alcohol, you're generating acetate. And the brain...

Acetate is actually something I looked into. It's a remarkable alternative fuel for the brain.
Maybe a lot of people don't know that, but when you drink alcohol, you're giving your brain acetate.

We can come back to that. It's analogous to 1,3-butanediol is analogous to drinking alcohol.

Instead of generating acetate, you're generating beta-hydroxybutyrate, another alternative fuel for the brain. Do you generate the same amount of aldehyde?

You are generating a beta-hydroxybutyrate aldehyde that is relatively short-lived, but you can overwhelm the ADH enzyme. So if you drink too much of it, you can overwhelm the enzymatic degradation.

And Henri Brunengraber did some seminal studies on this that he shared with me. Some of it's published.
They had a ketogenic dog model that they gave 1,3-butanediol is a hypoglycemic agent.

So it's a hypoglycemic agent because it de-energizes the liver and prevents glycogenolysis and gluconeogenesis because those mechanisms in the liver are highly, highly energy dependent.

So that's analogous to alcoholic ketoacidosis. When you have an alcoholic that's fasting and he overconsumes alcohol, he goes to the ER because he experiences alcoholic ketoacidosis.

You have runaway ketogenesis because you're inhibiting gluconeogenesis. And why can't that patient make enough insulin in response to the beta-hydroxybutyrate to bring the acidosis under control?

Because the liver cannot ⁇ if you increase insulin, that insulin is going to only facilitate glucose disposal. So the main thing is the liver.
The liver is like

the liver doesn't respond to the insulin signal to make less BHB in that situation. And alcoholic ketoacidosis? It does? So why does it in the rest of us?

Like when you and I used to do our ridiculous 10-day fasts. Do you still do those, by the way? I do like a sardine fast.

I'll do like a five-day, yeah, yeah, yeah. Two or three cans of sardines a day.
I get the same benefits and it mitigates a lot of the negative effects. Yeah, yeah, yeah.

When we used to do these 10 and 14-day water-only fasts, our ketones would actually plateau.

And even when George Cahill did the seminal studies of 40-day water-only fasts, their ketones plateaued at seven to 10 days. And a big part of that was that insulin is now keeping them in check.

The reason the ketones aren't going to produce a level of acidosis is that, and that's why, of course, kids primarily with type 1 diabetes can develop ketoacidosis.

They don't have the beta cell capacity to offset that rise in ketones. This case of the alcoholic is very interesting to me.
I actually was never aware of this.

You de-energize the liver so the liver can't undergo gluconeogenesis, some extent glycogenolysis. Then you have the electrolyte balance, you get dehydration.
So it's a constellation of things.

But getting back to 1,3-butanediol, if you consume it and you consume large amounts of it, like some of the early work that was done by, you can overwhelm that enzymatic cascade and you can start generating a lot of these aldehyde intermediates.

And that's maybe not a good thing.

So with 1,3-butanediol, I see two problems I think people should be aware of, especially people maybe that are elderly or using it for cognitive enhancement, is that you get buzzed on it.

I've probably consumed 1,3-butanediol than anybody. We had it in like big 20-liter vials of it.
I used to buy it at Sigma Chemicals. The stuff was dirt cheap.
Yeah.

Experimented with the racemic and then also with the RNA tumor and kind of the same thing. It's great.

And actually, I think it has applications for cancer because it does have a glucose lowering effect.

We mixed it in with a standard diet and gave it to animals with metastatic cancer, and it suppressed cancer growth and put them into ketose. So it has some applications there.

But getting back to the ideal ketone, drinking 1,3-butanediol to elevate BHB is somewhat analogous to drinking alcohol to generate acetate, which is a great molecule.

But it's a very indirect way to do it that comes with toxicity. Yeah.
So what Dr.

Vech and Andre Berninggraber did, and there were some others too involved in the research, Sammy Hasham developed the glycerol beta-hydroxybutyrate ester.

You can take 1,3-butanediol and do a transesterification reaction and add beta-hydroxybutyrate to it, or you can add acetoacetate to the molecule.

And when you consume it, you quickly liberate the ketones. So you get a quick elevation of ketones, beta-hydroxybutyrate or acetoacetate.
And then the 1,3-butanediol then goes to the liver.

And the pharmacokinetics, and we mimicked it exactly in our lab, you have an initial peak, and then like an hour or two later, you have a second peak from the 1,3-butanediol.

It's dose-dependently potentially problematic. And with the 1,3-butanediol, there's two issues would be the potential for liver toxicity in people that do not have healthy livers.

Like my liver is pretty healthy, I think, and it doubled my liver enzymes if I take a large dose for two weeks.

And then the other thing is, if you take a large dose of 1,3-butanediol, the narcotic effect in someone who's frail, who doesn't have good stability, it's going to, in Dr.

Veach's word, it's going to make you drunk stupid because I was trying to acquire some of his ester for something and I was like, well, I'm just going to use 1,3-buty.

And he kind of talked me out of it. The whole reason for developing the monoester was to avert the problem.
So the monoester is beta-hydroxybutyrate with a monoester bond to 1,3-butanediol?

Yeah, 1,3-butanediol that's bounded to beta-hydroxybutyrate. So you could say it either way.

Why is it that you don't experience the same negative issue with that molecule? Is it because you just consume less of it because you're getting the BHB directly? Yeah, you could take half the amount.

The kinetics are a little bit slower too, because you have to hydrolyze the BHB from that in the liver.

And why can't you just consume BHB? Is that not stable enough by itself? Other than an acid? You can. Yeah.
So there's a free acid.

I tinkered with that originally, with the free acid, because you could buy it. And it's super acidic and it's not very stable in solution.

And for a variety of different reasons, although you could put free acid, it needs to be liquid into like an electrolyte formulation.

So we gravitated towards at the time, I was using in my electrophysiology experiments, you can't put a ketone ester in the bath because it needs to be metabolized by the liver.

So you can't put it onto neurons. So you have to use the salt.
So you mimic the pharmacokinetics of what you get with the ester. So we were putting sodium beta-hydroxybutyrate in.

I was thinking, okay, I'll give this to the animals. But then it was like, I was very concerned with the sodium overload.
hypertension, all the negative effects about salt.

But all the negative effects about salt, and your listeners may not know this, but most physiologists kind of do that, study it.

The salt-sensitive people or the problem with salts, and people maybe even think ketone salts, is that when you consume salt, you get hypertension and some people salt-sensitive, but that's specific to sodium chloride.

So sodium bicarb, sodium citrate, sodium betahydroxybutyrate is what I'm talking about. If you consume large doses, gram molecules of that, that doesn't have the same hypertension.

Something about chloride. So sodium chloride.

So you could use potassium chloride instead of sodium chloride for salt but I think that's an important thing to consider because a lot of people shy away from ketone salts because it's sodium but the salt sensitive hypertension that you get is pretty much associated with sodium chloride and I was communicating with Patrick Arnold at the time and we were I was like If I have sodium chloride, but I wanted to get potassium chloride, but I looked, I couldn't buy it from Sigma.

It wasn't in the CAS database and nobody had thought about this. How could nobody have thought about putting ketones on different electrolytes? It just wasn't out there.

So I kind of had the idea of sodium, calcium, potassium, and magnesium, different things that you can combine. So you just needed a positive cation.
Yeah.

And I wanted to balance the sodium with potassium. So that was my original thing.
I was like, I was going to create a ketone soul and just balance the sodium with potassium, but it wasn't possible.

And are those covalently bound or not? I don't know. You don't covalently? Yeah.
I agree. Okay.
So again, just sodium's

trying to get everybody back to high school chemistry.

You can either take this highly, highly acidic BHB molecule and you can covalently bind it through an ester to 1,3-butanediol, or you can say, let's be done with that baggage of the 1,3-butanediol and let's have a non-covalent, an ionic bound to a salt.

And I just need a positive charge to offset the negative charge. So then you were saying, okay, I want to do sodium because I can do a lot with it.

And then tell me where the potassium comes in because you want sodium and potassium, both of them are two positive charges instead of one calcium or one magnesium, which have two positive charges.

Yeah. So the idea is to have monovalent and divalent cations.

You can spread the beta-hydroxybutyrate out to create like a quad salt was the idea back in 2011. So reaching out to Patra, it wasn't in the CAS database.
No one had thought about it.

You couldn't buy it. So we had to make it.
And then we made the calcium and the magnesium. And through time, basically we settled on a ratio of sodium, potassium to calcium similar to element.

So they're kind of ahead of it, but element is sodium chloride. So keto start or from audacious nutrition is sodium beta hydroxybutyrate and the calcium.

And it's got a spread of electrolytes that are similar. So you're giving electrolytes and also giving ketones.
And that's really important when you start a ketogenic diet because you're replenishing.

the electrolytes that you are spilling out more through a naturetic effect, especially the sodium.

And also there's an energetic gap in the brain when you start a ketogenic diet, where you have an energetic need for the increase in ketones.

We should go back to that, Dom, because I think a lot of people have lived that experience and they don't understand why, which is in the early stages of a ketogenic diet, there's little room for error where as glucose levels are going down and ketone levels haven't come up enough to fill the gap, you really feel lousy.

In retrospect, you can work around that, but it's easy to miss it, meaning it's easy easy to miss the mark and therefore suffer that painful transition, which can last weeks in some people.

And therefore, using these exogenous ketones can be a very elegant bridge through it so that you don't experience the negative side effects of the transition. Yeah, the energetic effects.

FGG PET scan, you're going to see like less brain glucose utilization for one thing.

And then you have the contraction of plasma volume because as you lose water and electrolytes so that you might have orthostatic hypotension, you get the brain fog.

And then you have electrolytes, which are literally molecules that are involved in action potentials and keeping membrane potentials in cells.

And all these can be kind of mitigated through ketone salts, have an advantage over the ketone esters. They also have the advantage because the mineral delays gastric absorption.

So when you take a dose of a ketone salt, it does not cause an insulin effect.

If you drink a ketone ester or a large dose of 1,3-butanediol, and I've done this before, and you do an insulin measurement an hour after, you're going to see your insulin levels increase.

How much would you see an increase in you? So the increase seems to be proportional to the differential.

So if you rapidly increase ketones to millimolar, and if you stay under two millimolar, then you don't get the spike in insulin.

But if you consume it and you get above 1.5 to 2 millimolar, at least in me and a few other people that did this, then you see this counterregulatory dump in insulin.

And that would also explain when people drink a large dose of a ketone ester, their glucose levels go down.

And it's a bit of a scary situation because I know people have gotten themselves into the situations that when you drink the ketone ester about two hours later or thereabouts, you can be hypoglycemic and also hypoketotic, which means your ketones come up, you utilize them as fuel, but you've released insulin and that caused peripheral glucose disposal.

And then you get into a point where you're running, for example, and then you tank. And you could trigger a headache as it does with me if you take a large dose.
So there's ways around that.

But you're saying the salt produces that effect much less? The salt does not produce that effect at all for a number of different reasons.

I think the rate of rise of ketones in the bloodstream seemed to be the predictor of if you're going to release insulin, for one thing.

And then there's something about the electrolytes, too, that maybe delays gastric absorption.

And with the salts, you're just not getting that elevation of ketones that's as high and as rapid as you would get with the ketone ester. So in the packet, what's the brand that you brought for me?

Audacious Nutrition Keto Start. Okay.
So in that packet, you're getting about how many grams of electrolytes? About one gram total?

Yeah, total about one gram, like sodium, then calcium, magnesium, potassium. So there's different formulations.
The packets are a little bit smaller, about the size of element now.

You're getting about six to 10 grams of pure beta-hydroxybutyrate minus the electrolytes. So a lot of people that say you're getting this amount of ketones, that also includes the electrolytes.

So you're getting, depending upon which packet you take, six grams or 10 grams of pure beta-hydroxybutyrate and the two different enantiomers. So that's another thing that we could talk about too.

Equal mix of R and D? Yes, a 50-50 ratio of D and the L, an R and S. I guess you could say there's four different ketone molecules.

There's D-betahyroxybutyrate, the L, or the RNS, if you use that nomenclature.

And then you have the acetoacetate, and beta-hydroxybutyrate does need to break down to acetoacetate to be used in the mitochondria.

And then you have acetone, which has some interesting signaling and metabolic effects, surprisingly. So it also correlates really well with seizure control.
I'm not forgetting about acetone.

So in somebody my size, 180 pounds, 10 grams of BHB will will take me to what level for how long? At rest, let's just say I'm not exercising. For me, maybe we could include it in the show notes.

I could show you my CKM, my continuous ketone monitor, and shoots me up for, I guess it's about four hours, one packet, four hours. But you're starting at a high level.
I'm at zero. No.

Well, I would eat carbohydrates to make sure I'm zero to start with. And I did it under, I've done this dozens of times, but it's interesting.

If I'm sitting in my car and driving, I had a road trip and I drank it and i had my ckm on it was elevated for like four to six hours and i was super like hyper focused driving and it was great how elevated like one to two yeah it was about between one and two which i think is an ideal range because you're not stimulating insulin so keto start is d and the l and it was only measuring the d but it's not accounting for the l or acetoacetate or acetone right so it's a 50 50 mixture of d and l but it's only measuring the d and it's still getting between one and two millimoles.

Does that mean you're actually at twice that level? Potentially, yes. What were we doing with our Abbott finger sticks? Measuring D, beta-hydroxybutyrate.

So does that mean every time we were measuring this, we were probably only capturing half what Cahill was capturing, or has everybody always measured half?

No, well, racemic ketones were some of the first ones to come out on the market, and then everybody gravitated to the D, enantomer.

I think we should stop, Dom, and explain to people what the hell we're talking about. I don't think people know what enantomers are.
Okay.

Beta-hydroxybutyrate is produced in the body primarily in the form of D-beta-hydroxybutyrate, which is a form.

The mirror image of D-beta-hydroxybutyrate is L-beta-hydroxybutyrate.

So we say if a beta-hydroxybutyrate supplement is racemic, it has D and it has L in it. But let's go back to what you said a second ago because I want to make sure people understand.

The mirror, it's literally a mirror image. A mirror image, yeah.
So for example, allulose is an enantomer of fructose. Yeah.

If you draw frictose and you hold it in the mirror, what you see is not fructose. It's the reflection of fructose, but that's allulose.
Allulose is not an enantomer. It's an epimer.

It's an epimer. I always thought it was an enantomer.
No, it's an epimer. So it has it, yeah.
It has another flip. Yeah, yeah.
Oh, okay. So it's two flips.

It's similar to an enantiomer, but it's an epimer. I think an important thing to remember is that you have Ringer's lactate, which is also D-L-lactate.
So you could, I mean, maybe analogous.

But why does this matter chemically? I think the point I want to make to people is when you have a D and an L of something, do they behave the same? Yeah. There's a lot of racemic compounds.

So statins, Adderall, ibuprofen. So these are all racemic mixtures of the same molecule.
So racemic beta-hydroxybutyrate, you have the D.

The D-betah hydroxybutyrate gets metabolized like very, very fast. So it gets in your system, your tissues suck it up, you metabolize it.

Your body makes very small amounts of L-beta-hydroxybutyrate with a racimase enzyme. That racimase enzyme is not in the liver, but it's in the tissues.

That's very interesting because I think some tissues are converting D to L to maybe use the L-beta-hydroxybutyrate as a signaling, but I'm just speculating.

But nonetheless, you have D gets metabolized very quickly, and then the L is like a timed release version of beta-hydroxybutyrate. That's how I've always thought about it.

Brianna Stubbs did some nice work looking looking at the D to L, and we've done quite a bit of work on the D and the L and a lot of work with racemic compounds.

So the L will get metabolized three or four times slower and you get about 20% conversion of the L back to D, but it's a very slow process.

The advantage of taking the D to L or the racemic, when you consume a racemic mixture, the ketones elevate and stay elevated quite a bit longer.

I think of the L betahydroxybutyrate as an important signaling molecule because you get higher concentrations of L in the brain.

So if you give someone racemic beta-hydroxybutyrate and then you pull out the heart and you take samples of the brain out, the levels of L-beta-hydroxybutyrate are going to be quite a bit higher.

And is that just because it sticks around longer and therefore crosses the blood-brain barrier or in the case of the brain? It metabolizes slower. So this is important.

We think this is important because the L-beta-hydroxybutyrate probably does not have, definitely does not have the same energetic potential in regards to generating ATP. It does not.

So, no, Veech told me that, and I'm a believer because it gets metabolized much slower.

Right, but if you just take the total metabolism of it, are you saying one mole of one and one mole of the other produce a different amount of ATP? Yeah.

Ultimately, L-beta-hydroxybutyrate will go into acetyl-CoA, but it'll be metabolized more like a fatty acid. The D has a redox shift, and it causes a reductive shift.

Actually, you could have reductive stress. I'm going to come to that in a minute.
But you have the D and the the L. They get metabolized at different rates.

D gets metabolized slower than the L takes about three or four times longer. But the L seems to have...

Sorry, you said D metabolized slower, I think. Oh, I'm sorry.
D metabolized very fast and L metabolized slower. Sorry.
But the L retains signaling effects that D does.

So for example, the NLRP3 inflammasome, so the nature medicine paper in 2015. doesn't seem to be enantiomer specific.
So the D will suppress it.

So that's important because if the L gets elevated in the brain, then it could inhibit neuroinflammation and inflammatory processes. So it's almost like the drug form of BHB.

The epigenetic effects, the signaling effects and the epigenetic effects of the L seem to be present too.

So you have the D that gets burned up quickly for fuel and then the L that kind of hangs around, gets metabolized slower. But then that's hitting the various receptors.

So you have the GPR109A receptor and you have epigenetic effects. You have the NLRP3 inflammasome.
So you have important signaling functions that ketones are attributed to.

And D-beta-hydroxybutyrate has been spent and used as fuel, but the L is hanging around and actually preserving that signaling effect, the positive signaling effect.

The continuous ketone monitor and the Abbott are more measuring D or L? They only measure the D. They do not measure the L.

I've had conversations with them and even though your body makes small amounts of it, it's usually just in the tissue. However, pharmaceutical companies are the ones kind of that have reached out.

As you know, there's quite a bit of patent literature because I was talking about this a while ago. So I think the Buck Institute has like patents on L-betah hydroxybutyrate.

I would say there's probably about three dozen patents on L now because I've kind of probably attributed to me because I'm talking about. the effects.
However, I think Dr.

Veach brought up a good point and he was right in that D-beta hydroxybutyrate is energetically favorable for producing ATP.

But a DL mixture is almost like you get the benefits of the D and then you get the signaling benefits of the L.

And we delivered that with an ester. We delivered that with the ketone diester.
And that gave us remarkable results in seizure control and animal models of cancer. And we also use the DL salts.

So I think the industry is kind of coming full circle. So now you have L enriched formulations with D.

But we've always kind of stuck with the racemic mixtures because I kind of knew that there was fundamentally something interesting about the D and the L, because when I use pure D beta-hydroxybutyrate, it actually trended to make seizures happen faster.

And I didn't know why. Say that again? When we use pure beta-hydroxybutyrate, the D in antimer and with an ester, like the monoester.
This is when you were saying that Veech's initial compound

was your first attempt and it didn't work. Yep, 1,3-butanediol and then the monoester had no effect on seizures.
So my colleague, Dr. Jung Ro said you need to look at acetoacetate.

And when you elevate beta-hydroxybutyrate and acetoacetate in a one-to-one ratio, that creates a redox balance. And I do think that's important.

Also, people have brought to my attention that when you rapidly spike D-beta-hydroxybutyrate, you're causing something called reductive stress.

So you have the production of NADH from NAD, and that's actually depleting NAD. A ketogenic diet will boost your NAD.
You could take NAD supplements.

That's something that we're working on too, because I think a central mechanism in ketogenic diets and supplements is the elevation of NAD. So we're working with NAD compounds.

I can't talk about that because it's through an industry, but there are multiple compounds of stabilized NAD that have interesting and remarkable effects.

And we're going to combine them with various new ketone molecules that we're developing. But NAD is sort of like this hub that is a central player in the benefits of ketogenesis.

What do you make of the fact that there hasn't been any efficacy of NAD supplementation or even NAD precursors? NR and NMN have really not yielded any meaningful or measurable benefits.

The only thing I've ever seen that looked somewhat positive was in the trial that looked at patients with ALS. And you saw a slightly shorter time to ventilator use with an NR

formulation.

But really, we just haven't seen any benefits. And so what do you attribute that to with respect to the NAD story? And what do you think might be missing if indeed there's efficacy there?

I can't say what I'm doing now, but we're running experiments, I think even today. So there's different NAD molecules that are out that are stabilized forms of them that are in clinical trials.

I think phase two and maybe phase three clinical trials. So you think it's a delivery problem? It's a stabilized, you have to stabilize NAD.

And I think that's important to have it stabilized because when you consume it, the liver takes a lot of it.

And if it doesn't, you're not taking enough of it in a stabilized form, the liver is very greedy. Actually, I think it would be good for non-alcoholic fatty liver disease.

So that's another, I think NAD could be important for that. But I think you have to take a dose that gets past the liver into circulation and crosses the blood-brain barrier.

And there's a number of different stabilized versions of NAD that are in development and testing. And some of them we're working on that I think have potential for oxygen toxicity.

So we're working on those now, giving acutely and also chronically in graded doses.

Will there be other applications for a DOM such as the holy grail of giro protection or even just performance enhancement, physical performance enhancement? Yes.

I am convinced that some of the animal literature, I want to replicate it. So I'm not going to believe something until I replicate it.

So I think we have plans to do some exercise studies, oxygen toxicity, brain studies. So I do think that you need to give quite a bit of it in a stabilized form and it needs to get to the muscle.

And for me, I'm very interested in it crossing the blood-brain barrier and getting to the brain.

I also think that these things will be more efficacious in the context of energetic or metabolic stress.

So for someone who's already aged, where your NAD level tanks and goes down in a linear fashion, like with age. NAD goes down, but also in the context of traumatic brain injury or shock.

And these are the things that we study. So I'm not studying NAD as a longevity molecule.

I'm studying in the context of rare disorders to military, like operational stress, extreme environments, things like that.

But you have to do those studies and then you glean insights into that that can then translate into the world of longevity if you're showing mitochondrial enhancement and preservation.

Because as we age and we go through different stress conditions, then it's analogous to some of the things that we study. I know there's a lot of buzz about NAD and a a lot of work going on.

I feel like the buzz over NAD has largely died, actually. I feel like it's sort of underdelivered and most people aren't really talking about it anymore.
Some people say that with keto, right?

But I went to PubMed right before coming here. There's 6,000 peer-reviewed publications on PubMed.
And over the last year, 717 of them.

And there's also 558 registered clinical trials on a ketogenic diet on clinicaltrials.gov. I mean, you could look at CAR T therapy as something like this.
There's like maybe four or five hundred.

Are those spread mostly between cancer, metabolic disease?

I've been on top of this. There's 40 to 50 clinical trials on psychiatric disorders.

So that includes bipolar schizophrenia, major depression, anxiety disorders, anorexia, alcohol use disorders, alcohol withdrawal, traumatic brain injury, autism. Anorexia is quite interesting.

What do you think is the hypothesis there? Well, anorexia is a psychiatric disorder. It's the psychiatric disorder that kills more people.
Yes, it's the highest mortality.

So there was a number of studies. Guido Frank, he's at the University of San Francisco, I believe.
He's an expert in eating disorders, as is my colleague, Dr.

Deanna Rancourt, who kind of has a peripheral interest in this. But Dr.
Guido Frank is running a study. on anorexia, I believe from what I last heard.

I can't talk about it too much, but I think some of the data is very encouraging. There was case reports that combined a ketogenic diet with ketamine, and that put anorexia into remission.

And there's been quite a bit of buzz about that. And for anorexia, typically you steer people away from any kind of dietary restriction.
Yeah, that would be traditional thinking.

Yeah, but the effects of the ketogenic diet on neuropharmacology, on the hedonic response, on stabilizing your mood. and other factors that could play into anorexia seem to be at play.

I was super skeptical because it flies in the face of everything that I know. We have one of the leading experts at the University of South Florida, Deanna Ranquer.

I remember talking to her about it and she was a little bit skeptical, but the data coming out looks very promising and compelling.

So there's continuing emerging data on psychiatric disorders, largely funded by the Bazuki Group. I think exclusively funded by Jen and David Buzuki, their foundation.

And I think they're funding million-dollar studies. Six of them that I know, you have Ohio State University, Stanford, Oxford, Stony Brook, UCSD, UCLA, I think Edinburgh.
There's a study too.

I'm just looking at the different applications. So they're funding many different studies, mostly across severe psychiatric disorders.

And are they doing this with ketogenic diets, ketogenic diets plus supplements, just supplements?

Primarily the ketogenic diet, although having served as a reviewer, because they have study section, in the pipeline of emerging studies that they're funding, I would say quite a few studies will be incorporating exogenous ketone supplementation.

So they see that as an innovative approach and a necessary approach for the feasibility of therapeutic ketosis, because with a psychiatric disorder, it's really difficult to get someone to adhere to a ketogenic diet with bipolar, with schizophrenia.

I mean, it's like a nightmare. If an individual says, look, I totally understand why a ketogenic diet might have efficacy for weight loss.
Could be multiple mechanisms that explain it.

But there are undoubtedly thousands of people listening to us who have no interest in weight loss. They're at an appropriate weight.
They're happy with their weight.

But some of the things you've talked about might have piqued their curiosity with respect to performance. Let's just start with cognitive performance.

Can you get all the same benefits of a person who slaves their way through what I used to do and you do and to varying degrees do, you're on this very, very strict diet.

Can they get virtually all of those benefits through judicious use of ketone supplements? It depends. People don't like that answer.
And it's also very context-dependent.

But I'll say this, that there are benefits that you get from carbohydrate restriction that cannot be replicated with exogenous ketone supplementation.

With that said, exogenous ketone supplementation tends to lower blood glucose independent of carbohydrate restriction.

Is that part of the mechanism that you just described earlier where, look, you ingest enough ketones, you're going to drive insulin enough.

That's going to drive down glucose, which, by the way, would not be the most desirable way to lower glucose. Well, that's what I originally thought.
Actually, I do remember talking with Dr.

Veach about this, and his opinion was that you're enhancing insulin sensitivity and facilitating glucose disposal by virtue of enhancing insulin sensitivity.

But I think it's a combination of different factors. I think consuming exogenous ketones influences the liver in ways that we don't understand.

So the next big project that I want to do is liver metabolomics, giving exogenous ketones, because the liver is a master regulator of metabolism, especially in the the context of everything, really, everything that we study.

So what I think is happening is that it's decreasing gluconeogenesis, decreasing glycogenolysis, and also simultaneously enhancing insulin sensitivity for greater glucose disposal.

However, if ketones get too high, then you have competition. The tissues are basically happy with ketones and they probably decrease glucose.
consumption to some extent.

So an important message that I want to send is that higher ketones are not advantageous and I think potentially very problematic. Define high in that setting.

We've killed quite a bit of animals inadvertently in early studies by putting them into ketoacidosis with different ketone esters.

We've never done that with ketone salts, although we can achieve therapeutic ketosis with ketone salts or MCT.

So high ketosis would be in animals, once we get above six or seven, then they start sort of like hyperventilating, they get sluggish, and sometimes we can't bring them back.

So, that has made me a bit scared about some of the ketone esters. And I think some of them could be in the bucket of a drug, especially if used in pediatric population.
I think that's important.

So, higher ketones, it's like we're not shooting to get our glucose to like seven, eight millimolars. There's very powerful homeostatic mechanisms that maintain glucose under normal conditions.

If we're jacking up our ketones above two,

once you get above two to get the three, four, and five, then you're approaching energy toxicity. So you have a level of ketones in your blood that's producing energy toxicity.

Energy toxicity is defined by an elevation of a metabolite circulating in your blood that is causing a number of things.

One is a counterregulatory reaction, which means it's increasing the release of insulin, the secretion of insulin. And your kidneys have to dispose of that.

And our blood gases and blood pH, blood pH will start to go down. Your blood will become more acidic.
That's not a good thing. And that occurs once you get above two or three millimole?

Above two, pretty much always kind of above two, maybe three.

In the context of supplemental ketosis. So if you're on a ketogenic diet and your glucose is so low, Your levels of ketones may approach three or four

because of the glucose deficiency that you have in your body. So fat oxidation is so high, it's a very elegant and finely tuned response that you have.

And presumably it's happening slowly enough that the redox reaction to balance your pH is happening. You're going to

blow off enough CO2, I assume, in that situation. If you're nutritionally at three or four millimole, I don't remember what my blood gas looked like.
Yeah.

I mean, you have respiratory and renal compensation, and that's not hard at all for you to do.

So if you're consuming large doses of exogenous ketones, this does not apply to the ketone salts because the salt is actually a natural buffer. So that's the ionic bond is a positive and a negative.

When you consume large doses of beta hydroxybutyrate, it's an anion and you're creating an acidic condition that your body needs to mitigate through respiratory and renal compensation.

So I think that can be problematic, especially in people like purchasing maybe ketone esters in elderly population where liver function is not good, they're not very stable, and they're already under metabolically compromised situations.

So that's something I think that people don't think about is energy toxicity in the context of supplemental ketones.

We think energy toxicity in the form of supplemental calories, which is problematic. And in reversing that.
So do you think there's any meaningful application for a BHB monoester these days?

What is the application for that? It's context dependent, but I think these things can be given orally or IV in the context of acute situations.

So I'm in favor of ketone esters and more potent ketone molecules for medical applications, quickly elevating ketones under, for example, status epilepticus, a traumatic brain injury, like blasted.

But I thought you said they didn't work well in epilepsy. Depends.
No, I'm talking about maybe a ketone diester of acetoacetate, which we use. So, okay, so the monoester, yeah.

I'm talking about the original molecule from NIH that was a monoester of BHB. I think they can be formulated.
So this comes to something that's a gap in the literature.

And there's a gap because every company or university with IP wants to study a single molecule in isolation. I think what we need to do is actually formulate things.
And that's what we do.

So every molecule will have pros and cons and caveats.

And you could largely mitigate the problem with ketone esters by simply mixing it with MCT, but you're still going to have the 1,3-butanediol issue.

If you're consuming that over long periods of time, that is something to consider. But you can also have a glycerol triester of beta-hydroxybutyrate or acetoacetate.

We published, the title is like novel ketogenic formula where we had a beta-hydroxybutyrate or a glycerol triester. So we're working with those compounds too.

But I think, yeah, it's very context-dependent.

And the go-to would probably be the electrolyte salts, just because you don't want to, for the average person, if you stay into that sweet spot of one to two millimolar, if you elevate bethydroxybutyrate in the blood, one millimolar, that represents a 10% increase of available energy to the brain.

We know that, roughly speaking. So all these calculations from the AV difference have been done.
So I think that's important. Lactate is also something to consider.

So when you think about the advantages of lactate for alternative brain fuel and ketone as an alternative brain fuel, you know, I had George Brooks on the podcast a while ago and he talked about how you could probably rescue concussion patients if you administered lactate quickly following a concussion.

Would you say the same is likely true for ketones? I think lactate's an incredible molecule. My early studies in 2004 and 2005, I think with lactate.

But the ketones represented a more viable option and also had the anti-seizure effects that we had. Plus, I was inspired by the work of George Cahill and Dr.
Veitsch and Theodore Van Italy.

And then I got steered towards beta hydroxybutyrate. But I think an important message is that formulation is the key.

So you have beta-hydroxybutyrate, you have lactate, you have MCTs cross the blood-brain barrier. So it's a type of fat that actually can cross-brain brain brains.
Do you still use MCTs for anything?

I think MCTs are great. I use a coffee creamer called KetoBrains.
It's like alpha-GPC, MCT, theanine, has a couple. It's a mixture of combinations of things.

But when you combine a ketone salt, with MCT, then you have a formulation that stimulates your own ketone production while you're delivering an exogenous ketone.

And if it's a racemic DL beta-hydroxybutyrate like keto start, then you have a sustained ketone delivery system for half of the day. So you just dose that a couple times.

But also some of the problems that we talked about with fast entry of ketones into the bloodstream with the ketone esters or 1,3-button, if you formulate that with MCT,

which we've published on that, that can mitigate some of the negative effects. So we don't see, you can mitigate the toxicity, at at least in animal models.

You need to appreciate the rate of rise of ketones. Is that's kind of the trigger for some of the counterregulatory effects? More like a dosing issue.

And if you're taking the currently formulated ketone salt that you brought,

you do not have to worry about the electrolyte load.

So if you're consuming three of those a day, that would be three grams of additional electrolytes, which based on what you're also getting in your food, a lot of people would say, gosh, that's too many electrolytes.

But you're not seeing the effect because of the lack of chloride.

I would say for people that have normal physiology, no, kidney, or maybe even with impaired kidney function, because ketocitra is sold.

I think a study just came out with beta-hydroxybutyrate citrate and other electrolytes too for kidney disorders. But generally, no.

So I was concerned that sodium would cause hypertension, but sodium chloride seems to be the major player there. So I would say no, but also do your blood work.
I haven't seen that.

And that was one of the early concerns I had. Actually, it steered me toward developing something other than sodium to potassium and calcium and other things.

So electrolytes are largely benign unless you're above the 10 grams per day kind of issue.

And I think even with sodium, the guidelines are something like five grams of sodium per day, like dietary sodium.

But then something just came out that said that should probably be more like eight to 10. Which guideline? The guidelines right now, I think, cap it at five grams of sodium.

Yeah, and I think a lot of them are recommending, in my mind erroneously, like two to three.

Yeah, yeah, depending on what guideline. But I think maybe the more looser guidelines saying it becomes problematic after five.

Okay, I want to talk about two particular applications with ketogenic diets, one of which you've spoken about a little bit. The other one we've sort of talked about kind of indirectly.

But let's say a word about what you think the future is for ketogenic diets and the treatment of cancer, and then separately for the treatment of dementia, specifically potentially Alzheimer's disease, but any form of dementia.

We had a review come out with 49 authors, and the title was Ketone Metabolic Therapy Framework for Glioblastoma.

So that includes basic science researchers, a number of oncologists at major cancer centers and stuff.

So the gist of that, I think it's really important to focus on cancers where the standard care doesn't work.

So advanced metastatic cancer, obviously pancreatic and glioblastoma, but glioblastoma has always been sort of the heart of what we're studying.

And I think the idea is to make metabolic therapy part of the standard of care. So the general gist with that review and the senior author of Dr.

Thomas Sayfried, and I know you've had him on the podcast, Tomas Durak, or Durai, he was the primary author. In that review, it creates a framework.
There's so much in that review.

It ended up, it was like 200 pages carved down to like 50 pages with about a thousand references, making it super concise explanation.

So the gist of that for ketone metabolic therapy for cancer management, specifically glioblastoma, but we think similar reviews can be written for other types of cancers that are specifically, that are highly glycolytic and have the Warburg effect.

So really hot on an FGG PET scan. So above 2.5 SUVs, like on a PET scan, would define it as hyperglycolytic.
Achieve and maintain a glucose-ketone index of 1 to 4.

So that's the millimolar concentration of of glucose over ketones. So if your glucose was four,

which is relatively normal, and your ketone levels were one, you're at the entry of that zone. Where I'm at now, so that gives me a GKI of four.

Standard American diet produces of like a GKI of 50, 40 or 50. So simply the guidelines are one to two, but I think that's too strict.
Achieving a glucose ketone index of one to four

is the basis of the therapy and that sets the stage for other modalities to work. For example, you could have, you want to then target glucose and glutamine with various drugs.

If we're going to talk about anti-glycolytic drugs, metformin, we've done quite a bit of research with metformin and I think that's a great molecule. Could be a synergizer.

I also think of that as a redox and I'll come to that. Let me ask a point-blank question, Dom.
Glioblastoma carries with it a mortality rate of 100%.

So it's been said that any patient who survives a glioblastoma has been misdiagnosed. They didn't have have glioblastoma.
It's one of the cancers that really gives cancer a bad name.

Is there any evidence that any form of ketogenic diet, even at a one-to-one ratio of glucose to ketone, is going to produce a durable remission in a patient with a GBM? No, it's not going to cure it.

So we're talking about the standard of care does nothing. We're talking about...
Life extension. Yeah, we're talking about...
doubling survival, tripling, and then as we learn more.

So the ketone metabolic therapy framework for GBM is like the first document in a series of documents that will ultimately be version number three will be using AI platforms to like decode the genetics.

In an RCT, when you place full standard of care versus full standard of care plus ketogenic therapy, what is the difference in median survival? Yeah, those studies are ongoing now.

Jethro Hugh at UCLA just published a study at UCLA.

It's just showing, you know, improve metrics of survival and increased quality of life and different, and I didn't get a chance to just came out, a paper just came out. So that research is ongoing.

I'd say there's at least a half dozen clinical trials in progress now. And there's problems associated with those clinical trials that I could get into that prevents us from getting to the question.

So the way to like do the clinical trial, which has not been done yet, is to achieve and maintain a glucose ketone index of one to four. That has never never been done.
So you want to do that.

And then that is not alone. So what I'm talking about here is an adjuvant to the standard of care.

So achieve a GKI of one to four, maintain that, and then you go and aggressively target glucose and glutamine. So you could target glucose with lonidamine.

It's a hexokinase inhibitor, three bromopyruvate, two deoxyglucose. You can use an SGLT2 inhibitor.

You can use, I mean, we have about two dozen different drugs that you could use and off-the-shelf kind of things like SGLT2.

And then you want to target glutamine because you could take glucose out of cell media and put in glutamine and maintain cancer cells in glutamine without glucose.

But it's hard to imagine you're ever going to get glucose to less than 40% of the brain's fuel, which would be a big achievement.

If you did all of those tricks, you ramped up ketones, you took glucose down peripherally to 2.5, even 3 millimole.

So if you have a glucose to ketone index of 1.1 and they're both sitting at 3 millimole and you're doing all those therapies, the neurons are still getting 40 to 50% of their energy from glucose.

I know. So it's like, but the idea then is to use like something like lonidamine, like inhibit hexokinase 2.
There are enzymes, glycolytic enzymes that are upregulated.

There are transporters that are upregulated.

And if you create an energy crisis in GBM cells that's great enough, then you trigger autophagy and then you trigger cell death because there's an incredible glycolytic energetic demand in glioblastoma cells.

And if that demand is not met, then that triggers cell death pathways.

But to make inroads into that and create that energetic crisis, you have to decrease glucose availability, decrease circulating insulin, which decreases growth factors like IgF-1 and a whole host of other mTOR and other growth factors.

and then aggressively target pharmacologically circulating glucose and glycolytic enzymes.

And then you have to aggressively target glutamine olysis, circulating glutamine, and also drugs that inhibit glutamine metabolism in the cancer cells. So you could target glutaminase.

So there's a drug, Dawn, that Dr. Seferd uses, and I have not used it.
I've talked to some patients that use it. It does cause some GI stress.
That's a pretty big heavy hitter, but you have...

a number of different things, sodium phenylbutyrate, glycerol phenylbutyrate, which is actually an HDAC inhibitor. It will bind up glutamine and then you pee some of it out.
There's EGCG,

there's curcumin, quercetin has glutamine, glutaminase inhibiting property. Again, none of this has been demonstrated clinically.
This is all kind of anecdotal.

Meaning, we don't have evidence in a clinical trial that this works. We're sort of extracting mechanistically from what we think these things do.
No RCTs. So there's cell data, there's animal data.

What's the holdup? I interviewed Tom seven years ago, and we had this exact same conversation.

Why do you think, especially for these cancers that are basically just killing machines, people are dead within a year of diagnosis? Why is it so hard to do these trials?

I understand your frustration. Yeah, I'm super frustrated, and that's what motivates me.
I would encourage people to read that framework of the ketone.

And then it's really important to access the supplementary information, which gives all the different drugs and everything. Oncologists are not going to read that, right?

So the people that are on the front lines that are taking care of these patients. Some of them are authors, so they have read it.

But again, what they want and what they need is a clinical trial that says this stack of interventions is going to double median survival.

So if someone came along and said, look, we're going to do all the things, we're going to rub curcumin on people's testicles and do all the things that are anecdotally supposed to help, and it takes median survival from 11 months to 27 months.

Wow. That's huge.
Oh, and by the way, it's going to reduce the burden of seizures and it's going to reduce the catastrophic, debilitating side effects of this tumor and its therapy.

I mean, it's going to become the standard of care, but the trial has to be done. The trial has to be done.

It can't be these sort of one-off kludgey, like off-in-the-corner little nonsense trials that aren't getting attention. So why is that?

So we have to ask the question, who's going to fund this clinical trial?

So they have the policymakers and the people at the foundations, people at the federal government, the NIH, the DOD, they have to be convinced that this is going to work.

We're talking about something way beyond the ketogenic diet here.

We're talking about a very comprehensive, calculated, metabolic-based intervention that targets diet, glycolytic drugs, anti-glutamine drugs, and then there's a redox component too.

So it's synergized with different drugs. So that could be hyperbaric oxygen therapy, but radiation and chemo kill cancer cells through oxidative stress.
And then

another thing too, so where the money is actually or the interest is going now is that the focus has been using ketone metabolic therapy as an adjuvant for Moffat Institute CAR T therapy for lymphoma.

So they have that project, but just working on some grants for ketone metabolic therapy.

And it's strictly their focus on beta-hydroxybutyrate because that correlates with the adaptive immune response that will augment checkpoint inhibitors, specifically PD-1 inhibitors and CTLA for checkpoint inhibitors.

And also the ketogenic diet, it can expand the CAR T cells.

Because of that observation and that correlated with beta-hydroxybutyrate seemed to be involved with CAR T cell expansion, that became of interest.

So right now, the funding agencies are kind of focused on augmenting the standard of care because we already use the standard of care.

But to run a clinical trial with dietary therapies involved, you have to have oncologists who are savvy and knowledgeable about ketogenic diets. You have to have an RD team.

The inclusion-exclusion criteria are really important. The heterogeneity of many people with brain tumors, I mean, that's something to consider.

Also, when you have a patient with a glioblastoma, the pharmaceutical companies are scrambling to get their drug into that patient.

So they are paying a lot of money to the major institutes to conduct the research. Is GBM the wrong model then? Because you need a win.
Yeah. You've got to demonstrate a win.

Should the first one be pancreatic adeno? You have far more patients.

Life expectancy is a little bit longer, but it's equally fatal, meaning metastatic or advanced pancreatic cancer is uniformly fatal.

Should we be using that as a model where, of course, look, all cancers are heterogeneous, but it might be that GBM is even more so. And it's also heavily impacted by the radiation.

Like the radiation then completely changes it. Virtually all of these patients are going to need radiation, which makes it even more difficult.

So anyway, look, I don't want to offer advice from the Peanut Gallery because I'm in the Peanut Gallery for a reason on this, but that might be something worth considering.

Let's talk about Alzheimer's disease.

Equally devastating, much longer tail, but in my my mind, seems somewhat easier to address through metabolic therapies because at least in the subset of those patients for whom an energetic crisis is at the core, and I don't think that that's all cases.

I think that's also a very heterogeneous disease. But at least one subset of these people are probably in an energetic crisis.

What do we know about the current research and what's the current state of affairs for using ketogenic therapies? You're familiar with the Alzheimer's drugs.

There's been not a whole lot of movement there. We have the antibodies.
If you go to to antibody therapy, you're talking 50K at least, hundreds of thousands of dollars.

You have the potential for side effects like cerebral hemorrhage. And they move the needle maybe for prevention.
A hallmark characteristic of Alzheimer's disease is glucose hypometabolism.

So that is actually being part of the criteria for evaluating.

My thoughts are that in communicating with hundreds of people with Alzheimer's and communicating with people that do dietary therapies is that there's a subset of people with Alzheimer's disease, or let's just call it dementia, because Alzheimer's is still a pretty fuzzy diagnosis.

Clinically, we have the PET scans to look at amyloid, and then there's P-Tau and other things. I think it's better to put it under the umbrella of mild cognitive impairment.

I think it's important to focus on that and advance Alzheimer's disease. A ubiquitous characteristic is glucose hypometabolism.

I've always been under the impression that the accumulation of amyloid and tau are a consequence, our downstream epiphenomenon of inflammation, neuroinflammation.

There's, of course, huge, I think there's like 50 different genes that can cause Alzheimer's disease.

So if we're talking about APOE4 carrier, that's like, I don't know, 80% likely to get advanced Alzheimer's or early onset. If you have two copies.
If you have like two copies or even one copy.

Yeah, maybe even a bit less than that. If you have two copies, you are destined to have it.
There are a handful of genes in which you are destined to get it.

Unfortunately, at this point, PSE and one PSE and strong APP. If you do nothing.
But again, I mean, 25% of the population are heterozygous for APOE4. Their risk is twofold higher.

I don't think anyone would consider that destiny. Yeah, your genes are not your destiny.
I don't want to make that sort of assumption, but it puts you at greater risk for sure.

So just taking a step back, I think inflammation is the major driver. And that wasn't even on my radar probably the last time we talked or maybe 10 years ago.

But I do think that systemic inflammation leads leads to neuroinflammation. And we know that if we take mice and inject LPS, we can rapidly cause amyloid progression.
Those studies have been done.

So metabolic-based therapies, ketogenic therapies, diet, these things not only change metabolic physiology and brain energy metabolism, but they reduce systemic inflammation.

And I don't know if you measure your inflammatory markers like HSCRP. Mine is even non-detectable.
I'll even do things like work out really hard.

It always was elevated when I lived in an undersea environment and was breathing hypercapnic under a lot of stress.

But I think the advantage of ketogenic metabolic therapies for Alzheimer's disease is really hinging upon suppressing inflammation, improving glucose metabolism, and elevating ketones to increase symptomatically brain energy metabolism.

Of those, would you say that the latter is the most important, that it's the alternative fuel source that is the most important.

Let's go back to, I haven't paid any attention to this, what's happening in clinical trials? This is a much easier thing to test.

Has someone done the experiment where you take people in the earliest stages of dementia or in modest stages of MCI, mild cognitive impairment, who are progressing towards dementia, and you randomize them to standard of care versus the exact same standard of care plus a KD?

Has that experiment been done cleanly in a randomized fashion? Those experiments, like many things, are ongoing. You have the acute effects.

So I think what we can say that acutely, if we elevate ketones in the context of a cognitive deficit, we can improve cognition under a battery of different exams.

But the question that investigators are after is that if you do an amyloid PET scan at baseline in two years, five years, 10 years, that is of the highest interest because amyloid is basically that's the prerequisite for having Alzheimer's disease.

So those studies are ongoing and I'm connected with some investigators that are doing it and some that have done more acute studies. And the feedback is that I think there's a subset of people.

Most people respond favorably, but there's also a subset of people that are hyper-responders. And with Alzheimer's disease, there's like vascular dementia.
It could be a blood flow problem.

It could be excess glutamate problem. It could be.
a number of different things that are amenable to being reversed or mitigated through ketone metabolic therapies.

So patient selection is going to matter. Yeah, I think it's going to be huge.

And I don't think they've done this yet is that inclusion criteria should be patients that present with remarkable glucose hypometabolism. So I think that's really an important key.

There's people who have brains that are chock full of amyloid, are completely sharp and are completely normal. The amyloid hypothesis has a lot of baggage with it.
So I think tal, amyloid and tal.

We have PTAL that we can look at, but there's other things in the pipeline. I think the the P75 receptor agonist or amplifier looks pretty promising.
Those studies are ongoing.

And then for prevention, I think some of these things, the antibodies, do have applications, but they also come with a lot of baggage with not only the cost and accessibility, but cerebral hemorrhage, something they have to consider.

So the low-hanging fruit would be dietary or more likely with this population, a ketone metabolic therapy intervention that could be a ketogenic formula that could also have a number of different cofactors and other things.

There's lactate, there's creatine monohydrate, there's alpha-ketoglutarate. And this is the problem with funding agencies.
They don't want to fund a formula. There's some work done with MCT.

Sam Henderson published in 2008 when the molecule was AC1202. But if you look at the patent, it was just caprylic triglyceride.
and actually improved mini-mental status exam. And Dr.

Mary Newport saw that and gave her husband coconut coconut oil and MCT oil and he improved and a case report with Dr. Veitsch being one of the co-authors on that was published.

Just a ketogenic intervention and they followed, that was the longest case report for years, followed his progression and stabilization.

He ended up succumbing to the disease, but she got many more years with him through ketogenic intervention. So I think we have to think about putting together a comprehensive metabolic-based formula.

And Dale Bredeson has been spearheading some things and looking at more of a comprehensive approach. Dr.
Stephen Kuhn has been working on MCTs and other ketogenic agents for Alzheimer's.

Also did a dual PET scan where you do a glucose-ketone PET scan and showed and published that as we age, our capacity to use glucose decreases over time, but that does not happen with ketones.

Our brain's ability to use ketones over time is preserved. So that's an important distinction and a good foundational framework for the rationale for doing ketone metabolic therapy.

But I think think you'll probably have more benefit by thinking about it as a comprehensive metabolic therapy where you can target different things.

And I think there's a number of different molecules like alpha GPC, but no one does anything with formulations. They're pretty much always doing a funding agency is not going to be available.

And what do you think is the state of the art with alpha GPC, just in general, for normal cognitive enhancement? It's hard because I always take it with something else, but I've used it by itself.

And it kind of gave me a headache when I took it. And I didn't really notice.
I think it has the ability to be beneficial in the context of cognitive deficit, like many things.

And I do think that ketones are everything that we study is in the context of environmental stress or some kind of deficit. And that's where ketones shine and they just tend to work.

But just speaking personally, I think they give you an extra boost because they're a source of energy. What do you think they're best taken with? Alpha GPC.
I think it works good with caffeine.

So alpha GPC, MCT, and caffeine, and maybe theanine too has a little bit of a GABAergic effect. That describes a product called KetoBrain.

So that's a pretty good product that is kind of a staple product for me. I ran out of it.
I kind of miss it. So I'm going to, it reminds me I have to go buy that.
But it's what I sip on.

I put that into my coffee when I'm working on grants or giving lectures. I just need long periods of cognitive.

But I think alpha GPC cause maybe a little bit makes me a little bit too hyper-focused and a little too stimulated. And I think it maybe can affect my sleep.

I use that situationally, just as I use fasting now. So I use fasting very situationally.
And that's what I recommend to people. It shouldn't be your default.

It shouldn't be fasting every day because I think the more you do it, the easier it gets. But I think you can actually maybe derive more benefits situationally if you have.
an inflammation event.

Like there's a person, two people that reached out to me that has shingles or herpes simplex flare up and then they fast then and then it works for that or they have a GI, some kind of GI issue.

Or if they're traveling, or for me, when I'm just bogged down with a lot of paperwork, grant reviews, writing grants or something, I'll fast for half of the day or more of the day.

And I'm just sharper, you know, just using situationally. All right.
Let's talk a little bit about hyperbaric oxygen.

Now, you mentioned and alluded to the fact that there are a handful of FDA indications for them. To me, the two most apparent would be treatment of the Benz and obviously for burned patients.

So it dramatically aids with wound healing. But there are many things that are conspicuously absent from any FDA approval.
There's no FDA approval for TBI. There's no FDA approval for concussion.

There's no FDA approval for anything girro-protective.

And yet, I've always said, every time I've gone back, and I maybe do this every two years, I go back and look at the data around concussion and TBI. It depends how you look at the data.

There could be a case for it. Patients are always asking me about hyperbaric oxygen.
It's truly one of the things I get asked about the most. And I generally tell patients, it's not worth the cost.

It's not worth the hassle, it's not worth the inconvenience.

Outside of the approved FDA indications, the only thing I would suggest going against the FDA recommendation is if I were to have a concussion, if one of my kids had a concussion, I would probably say the downside of hyperbaric oxygen is low enough.

I think the potential upside is there. I think it's worth the risk.
First of all, do you agree with that statement? If not, modify it. In the context of acute concussion or a brain injury?

Let's start with the concussion and then, yeah, talk brain injury after.

In the context of acute within the first 48 to 72 hours, I think hyperbaric oxygen can be remarkably effective for kids and for younger population and probably effective for adults, if early.

What protocol would you recommend in that situation? Well, if it's a penetrating traumatic brain injury, as

a blood, blood. We're not military.
Yeah, okay. Yeah.

I would go with like standard protocol, like two atmospheres of oxygen, 60 to 90 minutes, five days a week, minimum, maybe three days a week, 40 dives over that period of time, I think could be potentially

beneficial. Yeah.
That's a hell of a lot. You're talking two months.
Yeah, 40 sessions. That's like the most.
And you can understand why I don't recommend people do this. That's a job.

You just basically decided you're not working for a month because if you got to drive 30 minutes each way and you're going to spend 90 minutes in it, that's two and a half hours, five days a week for six weeks.

That's just an insane, it's an insane commitment. There better be some reasonable evidence for it.

Again, I'm on the fence on this particular indication, but I can't make that much time to do anything in my life. I know.

I mean, there are some gyms that have the soft chambers, and I think we're gravitating. There's a little more buzz about it with people biohacking.
How far can you get in a soft chamber?

Yeah, about 1.3 atmospheres. So that would be maybe a good place to start.

If you have a mild concussion or you want to do more of a mild hyperbaric oxygen protocol, 1.3, three times per week for two weeks or something.

And I'm just speculating, but I just, I know these people that run the hyperbaric chambers, I got to go in for minimum 20 sessions, 40 sessions. We want to get in for 40.

So I've been a reviewer on a variety of different publications, systematic reviews and things like that, and been on top of this field.

And there's some data that will be coming out from two different groups that suggested that if you had a traumatic brain injury even years ago hyperbaric oxygen increased cognitive function and pretty much all metrics of cognitive after that this protocol i believe was 40 to 60 sessions 1.5 to two atmospheres of hyperbaric There's also, by me, we have this community called the Villages, and there's a clinic there called the Aviv Clinic.

They're not interested in publishing or anything, but they've they've treated like tens of thousands of patients, like at least 10,000 patients.

They have convincing data from what I'm told from people that have worked with them and I've talked to the director that they have remarkable increase in cognitive function from elderly people there.

They don't have TBI, but they have improved cognitive function across different. And also just cardiometabolic biomarkers are improving over time, like glucose control.

I'm a little bit skeptical on that, but I do see in our animals, sometimes they just go hypoglycemic when we pull them out.

The glucose control could be because they're not eating in the chamber for spending 10 hours a week in a chamber not eating. And oxygen increases metabolic activity too.
So especially if you're hype.

But yeah, there's a problem with the studies that have been done because

the DOD funded a study where they did hyperbaric oxygen and the control was hyperbaric air. So hyperbaric oxygen is 100% oxygen.
You know, it increases.

So you're still getting hyperbaric exposure to 20% oxygen. Yeah, so the control was just hyperbaric pressure And then both groups got benefits.
There's a lot of muddy waters.

So the DOD wants to put a nail in this coffin. So they actually funded my university, University of South Florida.

We have six beautiful chambers in a facility that's run by the neurosurgery and neuroscience department. And my friend Dr.
Joe Duturi runs the facility. there, which is putting a nail in this coffin.

So they have subjects with PTSD and also subjects with brain injury, but it's more of a PTSD trial. And they have a sham.

The sham is that they pulse the pressure during the initial compression to make you think like you're undergoing pressure, but keep it at one atmosphere.

And at the end with the decompress, they pulse it so you feel a little bit... But why PTSD as opposed to TBI? Well, it's brain injury, PTSD.

So it's just answering that question because PTSD is such a huge problem for one thing, as is brain injuries.

But they kind of across the board, they're treating these chambers, six chambers are active from morning till night.

So it's a $30 million project that has all the right controls, all the people involved, and multiple institutes are sort of collaborating, but the central location

is. Yeah, it's ongoing.
And when does it read out? It will be done. I think some preliminary data should be coming out within the next year.

And if people do get a benefit from it and they're in the sham group, or if they're in the hyperbaric group, they're going to give them access to that. Cross it over.
Yeah.

So it's going to become like a treatment center.

I was not actively involved in the initiation of that, maybe because I study the negative effects of hyperbaric, but I've been like peripherally involved of it.

And I saw, I've been inspired by the work that they're doing and the level of scientific rigor that they're using to approach this question of the potential neuro-regenerative and cognitive, even mental health effects of hyperbaric oxygen, which have been reported anecdotally, but have not been systematically studied in this rigorous way.

So that project is ongoing right now.

In addition to that, I've reviewed some papers that will be coming out and some work that has been done to suggest that if you had traumatic brain injury years ago and you go into chambers and you use a rigorous method, the only thing is they did not have a sham control.

They did not have a control. So it's hard to do a control, but they've figured out a way to do it at USF.
And they have a person that comes in to question the person.

and figure out if they're lying or not about the control. Like, did you experience it? And basically all the subjects that are getting the sham have no idea if they got a sham or treatment.

No experiment, no protocol. That's going to be great to see.
Never done that before. And just the sheer amount of people that are going to be treated.
It's all veterans. Yeah.

Well, that's great to hear it. Dom, this has been really interesting.

I mean, to me, there have been a lot of things that unfortunately haven't changed fast enough since we last spoke, namely around our insights around cancer and Alzheimer's disease, largely due to a lack of clinical trials.

But the unbelievable change in exogenous and supplemental ketones, it's exploded. You've been leading the charge in that.
It gives someone like me a lot of hope.

I mean, I've long ago given up on the discipline of a ketogenic diet, although I achieved remarkable benefit from it.

But something just changed when my daughter was old enough and I just wanted to start eating everything. And that hasn't vanished.
I'm on the seafood diet, that is S-E-E food diet.

And you're not managing epilepsy or anything like that. Yeah, you got benefits of it.

And you know, at the time, I distinctly remember going to the gym with you and the amount of volume that you would do or just riding the bike and just swimming. And

it was crazy. You've really piqued my curiosity about these exogenous ketones.

And in addition to that one that I've just started putting into my coffee, I think I'm going to really give some of these salts a try, especially given what you've said about I'd always felt that, well, I need to be somewhat mindful of electrolyte load beyond what I already consume.

And also, although we didn't talk about it, I know you and I have spoken about it just before, which was you don't have the same GI consequences that used to exist with the ketone salts, which largely limited their consumption.

So tell me and tell everybody again the brand that you're suggesting I give a try to that you brought. Keto Start by Audacious Nutrition.
You buy directly from them. Is it on Amazon?

I think, yeah, it's on Amazon. So, I mean, that's what I use.

And it's kind of evolved out of, it was essentially the molecules that we originally studied and stuck with, even after looking at all the different things.

So you're not financially involved in this company. No.
Your wife advises them, though? Yes. Yep.
I'm on the sideline. So I don't sell anything.
So I don't have any companies. I don't sell anything.

I do advise for companies. And we talked about CGM.
So I'm an advisor for Levels Health. I'm an advisor for MedSci, M-E-T-P-Y-S.

So it's essentially an app and a program for metabolic psychiatry and advise a little bit for Arx Sugar, which sold allulose. So I disclose those things.

I don't think we talked about allulose too much. I've got to say something for next time.
Yeah. So I don't have any.
brands are selling anything, but I do have Keto Nutrition.

So that's my informational website. And I think the big thing that I'm involved in is the Metabolic Link Podcast.

That's our podcast that we want to have you on, of course, and the Metabolic Health Initiative, which is an ACCME accredited medical education platform.

So that platform has, is associated with a podcast, but we have educational information.

where we have doctors, neuroscientists, cardiologists, oncologists, doctors that treat metabolic disorders give lectures on this. And so you can get medical education and learn about ketogenic.

It's got to meet the ACCME bar of standards.

So that's Metabolic Health Initiative and also the Metabolic Link podcast and also the Metabolic Health Summit, which we've had many of the people that have been on your podcast have spoken at the summit.

And that was in Clearwater, Florida. So we're regrouping and figuring out what the future of that's going to be, but there's no really experience that you can mimic than an in-person event.

And you can network with people and we have basic science, clinical clinical science, and also a big focus of it too is having patients talk and then talk about the implementation strategies with what we're talking about here.

We'll stick all of that in the show notes so that everybody can find you. And you're also just arguably the single most generous person with this time I've ever met.

I know that you personally take so much time to respond to strangers who are contacting you.

And that is, I suppose, the burden and responsibility of being one of the most knowledgeable people on this planet when it comes to this type of therapy. So on behalf of all those people, thank you.

And thank you for coming all the way out here. I know how busy you are.
Thanks for having me. It's been my pleasure.
Thank you.

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