[7:02] About Dr. Dominic D’Agostino
[9:25] The Difference Between Ketone Esters and Ketone Salts
[18:08] How Do They Commercialize the Ketones From Their Labs?
[23:55&25:00&27:01] Three Unique Compounds and Others You Can “mix” with Ketones
[29:00] What Occurs on a Physiological Level That Would Allow the Consumption of Branched Chain Amino Acids to Maintain Ketosis or Elevate It?
[37:44] Sun in your Pocket – The Human Charger
[39:17] Four Sigmatic
[41:07] Why Some People Including Dr. Veech Believe Ketone Esters to be Dangerous and That MCT Oil Blocks Beta-Hydroxybutyrate Absorption or Utilization
[47:50] Are There Any Evidence of People Experiencing Medical Issues with Using Ketone Salts or Esters?
[60:05] Why Ephedrine Can Be Safely Used for Fat Loss and Dom’s Own Experience With It
[65:40 & 1:05:41] Can You Combine Glucose with Ketones to Enhance Performance?
[72:15] Why Esters are More Expensive Than Salts? Are There Ways to Make Either More Cost Effective?
[1:12:14] Why are Ketone Esters More Expensive Than Ketone Salts?
[1:28:40] End of Podcast
Ben: Hey, you smart cookie, it’s Ben Greenfield. You better be a smart cookie because we put our propeller hats on in today’s episode with Dominic D’Agostino we get into ketosis. And speaking of ketosis as a nutritional therapy, I’m headed down to Vancouver in March and you should join me. March 3rd through the 5th. I’m speaking at this thing called the NTA Conference. Do you think I should keep you hanging on the edge of your seat wondering what NTA stands for? It’s actually Nutritional Therapy Association, you guessed it. They do therapy practitioner and consultant certifications meaning they teach people how to be nutritionists but it’s not like run of the mill Gatorade Sports Science Institute sponsored by Power Bar and Kellogg Cereal-type of nutrition. Instead, it’s like a really ancestral approach that focuses on nutrient-dense whole foods. If you wanna be a nutritionist this is the cert to get. So not only can you go to that conference, you register at bengreenfieldfitness.com/nta and tell them I sent you or you heard about it on this podcast to get the white glove treatment. I don’t know why I just said white like that. White. I believe that’s how they pronounce it in Europe and their much, much more sophisticated than us over there. So I’m just gonna stick to it. Nutritionaltherapy.com is where you can go though, to learn about their practitioner and consultant certifications but registration closes February 6 for those, so get on it. Nutritionaltherapy.com Check it out.
This podcast is also brought to you by something I had a giant cup of this morning and that is k-i-m-e-r-a k-o-f-f-e-e. In case you did not spell that along with me it is kimerakoffee.com. kimerakoffee.com they put things in their coffee things you won’t find in any other coffee. Alpha GPC that’s choline. That’s a natural choline compound you find in the brain but you also find in things like soy and meat and fish. Helps with memory, mental focus, power output. They put taurine in there same stuff you find in Red Bull. Actually got some taurine last night I was trying like a new sleep supplement. Surprisingly, taurine can help you sleep and also assist in wakefulness when combined with caffeine. It’s really interesting. We talk about that a little bit in today’s episode actually. It’s just an organic acid usually you find in eggs but it can delay cognitive decline from age and fight oxidative stress and a whole bunch of other cool things. L-Thianine which actually also helps to take some of the edge off of the caffeine. And then DMAE which is another choline molecule that you’ll find in things like fish which also interestingly enough promotes red blood cell function. There’s your fun fact for the day. So anyways, we’re full of literation, fun facts and Kimera Koffee. You get ten percent off of any order from Kimera Koffee when you go to k-i-m-e-r-a k-o-f-f-e-e that’s kimerakoffee.com and use code Ben to get ten percent off.
So there you have it, like I mentioned put on your glasses and your white lab coat and your propeller hat because we’re about to get all nerdy. Let’s do it.
In this episode of the Ben Greenfield Fitness Show:
“We understood ketones as an energy metabolite but it would make sense that these energy metabolites even the Kreb Cycle intermediates, the energy metabolites are powerful signaling modules. The receptors and pathways in our body, in our cells that sense that and there’s downstream signaling that are impacted as a result of that. When you take MCT you make the beta hydroxybutyrate mostly and some of these may either convert to the L that resonate in there, but in the large part you produce beta hydroxybutyrate.”
Ben: Hey folks, it’s Ben Greenfield and it was a few months ago that I recorded this pretty controversial interview about ketosis with a guy named Dr. Richard Veech, and in that interview Dr. Veech claimed that the form of ketones that most people take nowadays when they’re using like a ketone supplement, they can actually be quite dangerous and his solution during that podcast was something called ketone salts. And you may have heard of this that they’re extremely expensive, but according to him a far more natural and safe and healthy way to get your body very quickly into ketosis, for anything from like managing medical conditions to improving cognition, to increasing endurance et cetera.
And I actually, after that interview was sent a few bottles of these ketone salts and I tried them at home just taking a few at the kitchen table. For those of you who do the whole ketosis thing if you’re a nerd sitting in your mom’s basement with nothing better to do than to measure your blood ketone values, then what you’ll learn next is pretty intriguing you know, my ketone shot in about 15 minutes from under one to about five. And then I did this again during a race and this time combined it with drinking about 75 grams of pure glucose along with these ketone salts before a Tough Mudder event, and the results were equally as astounding. I had an extremely fast race eating nothing and I actually won that race and proceeded not to eat for another 4 hours or so, and again, every time I measured ketones they were through the roof. But my big question and yours too, might be whether or not these fancy expensive ketone salts are actually far better or safer than what most supplements have in them which ketone esters. And our ketone esters which is what most people use are those actually gonna result in any kind of long term health issues.
Well, I decided to turn to the man himself, a ketosis expert Dr. Dominic D’Agostino to give us his opinion on this issue. And Doms been a guest on the show before, you may have heard of him if you look into things like ketosis for everything from managing neurological disorders to performance enhancement in extreme environments, to holding your breath for longer periods of time. He’s a professor in the Department of Molecular Pharmacology and Physiology at University of South Florida, and that means that wherever he is right now has got to be warmer than the 3 degrees out my front door. And I would imagine he’s in quite balmier conditions than yours truly. But his research is supported by the Office of Naval Research at the Department of Defense. A ton of different private organizations and foundations turn to this dude to really learn what’s going on when it comes to ketosis and he’s no stranger to this podcast, he was a previous guest in an episode called A Deep Dive into Ketosis how Navy Seals, extreme athletes and busy executives can enhance physical and mental performance with the secret weapon of ketone fuel. So I’ll link to that episode along with everything else that Dom and I talk today if you just go to bengreenfieldfitness.com/dom, that’s bengreenfieldfitness.com/d-o-m. So that being said, Dom, welcome to the show, man. Welcome back to the show.
Dr. D’Agostino: Yeah, thanks for having me on, Ben. Appreciate it. You know, I get a lot of great feedback from that original episode that was quite a while ago.
Ben: It was.
Dr. D’Agostino: A lot has happened since then. Thanks for having me on. Yeah, and I can clarify some of these things that you were talking about ketone esters or ketone salts. So what’s actually in the products that are on the market right now are ketone salts and I could delve into exactly what they are. I have chemistry point of view versus ketone ester and get it in to all that.
Ben: Okay, so what’s currently on the market that’s available for people to buy in most cases that’s a ketone salt?
Dr. D’Agostino: Yeah.
Ben: Did I misspeak?
Dr. D’Agostino: I think you described taking a bottle if it was liquid form. It may have been if it was keto force which is a liquid that’s a ketone salt formula, but there’s also ketone…
Ben: No, what I took was exactly what Dr. Veech had talked about and what they sent up to me. You know what, I did misspeak. I think I presented things completely backwards just a couple of seconds ago. It’s the ketone esters that are the ones that are really hard to get your hands on. Super expensive and those were the ones that are the three thousand or thirty thousand dollar bottle depending on who you ask. Yes, the ketone esters are the ones that Dr. Veech sent to me. The ketone salts are the ones that you can find in most products out there. So just a clarification. I’m not a complete idiot, but I did speak wrong there.
Dr. D’Agostino: (Laughs). Well, I put it under the umbrella yeah, no issue there coz I put it under the umbrella of ketone supplement and it’s easy to get the 2 mixed up. So and you can get an equally expensive ketone salt if you wanted to. So the expense just comes down to how, what kind of ketone salt you wanna make and what kind of ketone ester you wanna make based on your starting materials.
Ben: But in most cases when somebody goes out and they buy one of these newer ketone enhancing supplements they’re purchasing the ketone salt not the ketone ester in most cases?
Dr. D’Agostino: Absolutely, unless you’re getting it as a research chemical which we do. We also make them in-house and I also buy them from a variety of sources, and we test in our lab like about 20 different types of formulas. The individual molecules and formulations of them but yeah, if you’re gonna go out there the commercial products out there that you’re familiar with the marketing is a ketone salts and that essentially you take the beta-hydroxybutyrate molecule, and you can do this with acetoacetate too and you can use that for other purposes, but beta-hydroxybutyrate combined with a monovalent or divalent cation which is a fancy term for electrolyte, a mineral and that could be sodium or potassium that’s your monovalent cation that’ll bind very tightly, ionically bind to beta-hydroxybutyrate and its mono soluble. You can assume it and your ketone levels spike up quick, or calcium, magnesium. You could make a lithium salt with beta-hydroxybutyrate and then if you look at your periodic table, you know, strontium, barium you could make a lot of different types of ketone salt molecules but the ones that are being sold out there are typically sodium, potassium, calcium and magnesium.
Ben: Right, pretty much all of them are just like beta-hydroxybutyrate bound with some kind of a salt.
Dr. D’Agostino: Exactly. Yeah, we use a lithium salt too, acetoacetate for some experiments coz acetoacetate has some unique properties. So a salt does not have to be a sodium and we were just talking about excess sodium load. I had formulations of ketone salts that have no sodium, so it’s just a mineral. I actually tested one with a magnesium and got some blood work and my magnesium was sky high. Maybe not a bad thing, I mean you don’t want it too high but it was an indication that a beta-hydroxybutyrate magnesium salt is actually very bioavailable. And we know, you know people that are ketogenic dieting tend to run on a low on magnesium. You definitely don’t wanna be low if you’re running marathons out there.
Ben: Yeah, sure.
Dr. D’Agostino: That was very informative to me as I test these things and you can also have a salt of an amino acid. So the basic alkaline amino acids would be arginine, glycine and histidine and some people told me they’ve created a creatine salt but I have yet to kinda test that experimentally.
Ben: So in the case of like a creatine salt or an amino acid salt, are you saying that beta-hydroxybutyrate could be bounced to a creatine salt or an amino acid salt, theoretically?
Dr. D’Agostino: Absolutely, you could make an amino acid-balanced mineral salt with beta-hydroxybutyrate. So you’d be delivering the ketone and also some beneficial alkaline amino acid like lysine in particular, it’s something that I add into my amino acid formula and balance out the minerals to supplement your electrolytes.
Ben: That’s kinda cool.
Dr. D’Agostino: So you could definitely do that. And that’s what we do in the lab.
Ben: Now what Dr. Veech was describing when I had him on my show was that to get as much beta-hydroxybutyrate delivered into the body as necessary to get your ketone levels really high or to get yourself into a state of ketosis that the amount of salt should have to have that bound to would be really high. And as you just alluded to the salt would not necessarily need to be sodium per se. You know, you mentioned that you did it with magnesium and your magnesium levels went through the roof, or you could do it with lithium on this amino acid salts or creatine salts, but painting with a broad brush does this just mean that any salt that you bind this stuff to, you have to take copious amounts of, potentially dangerous amounts of?
Dr. D’Agostino: Yeah, he was speaking pretty much strictly about sodium beta-hydroxybutyrate and you could get sodium levels up. Barely high to get into the, you know, 2-3 to 4 millimeter range. That could be putting a stress on your body, conceivably.
Ben: Like how much salt are we talking? Coz like I personally will take, you know if you add up all the sea salt and stuff that I’m taking during the day. On a typically day for me I’m consuming like a lot of times 3-6 grams-ish worth of salt.
Dr. D’Agostino: Yeah, okay. Yeah, when I first started doing this stuff like just testing and binding the sodium beta-hydroxybutyrate from like sigma, for me to get into that 1- 2 millimeter range like bumped up above where I was already at, I was getting about that amount up to ten grams of salt per day and through multiple dosing during the day. So that’s why I realized quickly that the sodium could get you there but the sodium by itself tasted kinda horrible but what all the work was, you know, to bring this to the market you really have to balance out the mineral with potassium and other minerals and also formulate it with ideally with a carrier because when you consume sodium beta-hydroxybutyrate what I noticed and I also noticed this with the mono esters of beta-hydroxybutyrate, your levels shoot up really fast initially and that’s great if you want energy in like 10 minutes. If you’d get on your bike, you drink it and then go and your energy’s kind of there. But it also comes down and basically back to baseline within an hour with the salts and within an hour and a half to two hours with the ketone ester.
Typically, kind of it depends on your dose and how you take and what not. So we started formulating the ketone salts in a balance preparation with sodium potassium, calcium magnesium and formulating it with various MCT-based powders; C8 and C10 powders and showing that if you deliver the ketone salts with the ketogenic fat it delays gastric absorption, and then the ketogenic fats also get broken down to ketones, the beta-hydroxybutyrate and then extends up pharmacokinetic profile. We kind of tested a bunch of different combinations and then figured out which ones were optimal based on the testing that was done, and then different companies kind of got that and marketed that and were continuing to look at all the different forms of ketone salts and also ketone esters we worked with a variety of ketone esters in the lab. And comparing them to figure out which one is most efficacious and which one is most potent.
Ben: I wanna ask you about ketone esters here in just a moment, but when you’re talking about these ketone salts that you’ve developed and kind of like mixed with MCTs et cetera and companies that then take what you’ve developed and use in their product, how does that work, coz I know for example, one that I’ll use is Pruvit and earlier you mentioned Patrick Arnold I know he has one, I think it’s called Keto Kanan. I’ve used that for example, for free-diving before to see if it would increase breath hold. There’s a few other companies now, a lot of them actually popping up that are producing ketones but do folks approach you guys after you’ve kind of like fettered this up out in your lab in like license that from you or how does that actually work from like a commercial standpoint?
Dr. D’Agostino: Yeah, good questions. So I just stay in the lab and do my thing in the lab but we have, our university has a pretty good technology transfer office and a patent and licensing office, and they will basically say, “Hey, what are you doing? Show us what you’re doing,” kind of thing. And as we publish stuff too, they want it out there but typically they want it before you get it published, right, to get a patent out for it. So as we are testing and screening things for the military work I was doing, some of the formulations that we’re testing were kind of standing out as superior against other formulations where we could achieve a level of ketosis that was above and beyond what we could get with even the highest dose of things in isolation when we start formulating them together. And also from not only pharmacokinetic profile wise but also power ability and pound ability that is factored in there.
So our university will kind of just take all the raw data that they can get and they continually ask, and they look to see what other intellectual property is out there related to formulation and things like that. And if it’s kind of something that’s a novel finding, a formulation that’s a novel finding or you could get a composition of matter where you’re creating different types of ketone salts which we’re doing in the lab too. We work with our organic chemistry department to do some things, and Patrick Arnold was really great initially as a small company and an independent kind of chemist that’s kind of way out there and really forward thinking. Patrick was instrumental in helping me kind of develop my research program by developing ketone salts or ketone esters and later ketone salts.
So essentially, we do the research and then we have people in our technology transfer office that looks through all the research to see if anything is patentable, whether it be a new molecule, or formulation, or a novel application of ketones. Ten years ago, the only thing that the ketogenic diet was used for clinically was pediatric epilepsy. And now a big theme of our conference that we’re holding The Metabolic Therapeutics Conference is that the applications are exploding in all these different directions, and you have high-end researchers at Ivy League institutions doing research on exogenous ketones that suppress inflammation to activate epigenetic pathways that confer protection against oxidative stress then maybe can extend longevity. Like Dr. Longale will be speaking about longevity and Dr. Deep Dixit from Yale University will be speaking about Dramatic Inflamazone suppressing effects of exogenous ketones at our meeting. This is all new information that’s just hitting.
We used to know that ketones viewed them only as a metabolite that supplied energy and Dr. Veech did some fantastic and spearheaded a lot of work to show that ketones are a superior metabolite and that their ability to generate ATP is greater. The delta G of ATP hydrolysis is greater for ketone molecules and for glucose or beta-hydroxybutyrate. So we understood ketones as an energy metabolite but it would make sense that these energy metabolites even Kreb Cycle intermediates, the energy metabolites are powerful signaling molecules. The receptors and pathways in our body, in our cells that sense that and there’s downstream signaling that are impacted as a result of that. And these are like metabolically independent which means independent of their effects on metabolism. They have very unique signaling properties that are of high interest to the pharmaceutical companies. I know coz they’ve contacted me (chuckles) and they wanted to basically reverse, kind of engineer molecules that work like ketones or specific pathologies. So it’s an emerging field that really started emerging about 4 or 5 years ago. It’s really new science.
Ben: Careful with those pharmaceutical companies, man, they have a lot of money. You might wind up with a garage full of test loads if you’re not careful. (Laughs)
Dr. D’Agostino: Oh (laughs), yes, I know. I’d like to add, one of the pharmaceutical companies that makes the most common anti-epilepsy drug out there is called Keppra and that’s made by UCB Pharmaceuticals, and I went to Belgium about a year or two ago and they held a conference with other ketogenic diet scientists to understand coz they know that the diet makes their drug work better. Like you could use a quarter of the drug and get remarkable seizure control. Or even get completely off the drug. But I think more importantly they’re kinda fishing for understanding mechanistically the anti-convulsion effect of ketones by themselves. So as the science starts to emerge, you’re gonna get more pharmaceutical companies interested in metabolism in general, but also specifically interested in the signaling properties of specific ketones.
Ben: Yeah, it’s really interesting. You’ve got into just a there a little bit ago, some of the things that you mix with ketones to enhance deliverability. I know that for example, you see when you look at the label of a lot of these ketone supplements the addition of MCT, you know usually like an MCT powder. You actually forwarded over to me a study that you did that showed that the blood brain barrier was relatively impermeable to a lot of hydrophilic substances and that would include something like ketones or ketone bodies, and so the transport of ketones across your blood brain barrier if you do want them to be available to brain tissue is dependent on these, I think what you described them as was proton-linked monocarboxylic acid transporters. Meaning that MCT powder could basically act as like shuttle to carry ketone bodies across the blood brain barrier. So if you inject your body, or not inject your body but consume, right some supplement that has a one-two combo of beta-hydroxybutyrate and MCTs, you could potentially increase what’s available to the brain. Now, are there other things though in addition to MCTs that you have found that one could combine ketones with to enhance their deliverability or their efficacy?
Dr. D’Agostino: Yeah, amino acids tend to be pretty, they’re good buffers so they tend to increase the tolerability, and now we’re doing the pharmacokinetics phase to see if they increase sort of extend out the pharmacokinetic profile. How it influences the blood levels. But medium-chained triglycerides are really, they’re awesome because they’re pretty cheap. They’re very ketogenic. If you give MCTs as a [0:25:44.5] ______ and intragastric gavage to a rat, you can achieve the level of ketosis similar to a ketone ester. And we’re really blown away by that. The C8 oil is probably one of a bit more ketogenic maybe about the immediate, the regular C8, C10 is about 80% of what a C8 oil would be, but you could easily get the 5 or 6 milli more with MCTs.
Ben: And then that would be something very similar to like the Brain Octane that Dave Asprey sells.
Dr. D’Agostino: Yup. We’ve tested brain octane and it did really well against the standard MCT oil by Now Nutrition. The Parrillo brand nutrition too, they sell it in like 1 liter bottles was really kind of a star performer in our lab too. And the Parrillo Nutritions is kind of like a small company based in Florida that sells Cap Tri, I think is the name of the oil in 1 liter bottles, so we used that a lot for experiments.
Ben: I’ll link to that in the show notes for people who wanna look it up. So you’ve got like C8-type of versions of the MCT oil. You also mentioned amino acids and I believe that you mentioned branched chain amino acids, Dom. I’m curious why you chose those versus like a fuller spectrum of amino acids like essential amino acids. And the reason I ask that is because I tend to personally during exercise find that essential amino acids seem to give me a little bit more of a boost compared to the BCAA’s, but I’m curious what your take is on that with the EAA’s versus BCAA’s?
Dr. D’Agostino: Yeah, well, branched chain amino acids with leucine kind of the more potent of them. If you take a formula that’s kind of a 2:1:1 ratio of branched-chain amino acids: leucine, isoleucine and valine. The other amino acids would kind of more or less get oxidized but spare the leucines that you can get like similar leucine levels with that. So branched chain amino acids have been known for quite some time to impact anabolic pathways by activating mTOR more or less in a tissue-specific manner in skeletal muscle. And it may also have or some versions of branched chain amino acids perhaps HMB may have anti-catabolic effects. And there’s some evidence that indicate that branched chain amino acid may delay essential key when you send some [0:28:22.8] ______. So I’m kind of a fan of that and also citrulline malate is something that’s in a product that I’d use myself, branched chain amino acids and extend for all formula without any sweeteners or anything in it that I’ve used myself. We’ve actually used it in experiment that we’re doing in the lab even cancer experiments. We find that the ketone salts when it’s combined with branched chain amino acids allows you to continue to maintain ketosis, and a high level of ketosis while you’re delivering.
Ben: And what’s occurring on a physiological level that would allow the consumption of branched chain amino acids to maintain ketosis or elevate it?
Dr. D’Agostino: Well, there’s 2 purely ketogenic amino acids and one is leucine and other is lysine. They have minimal impact glycemic response. So that’s one of the benefits of it and from a performance point of view, I think that they may offer some advantages we haven’t studied that. I’m always a little bit cautious to talk about things that we haven’t directly studied in the lab, but there’s some evidence that suggest that they may be helpful taking intra workout. I’ve taken them for years during fasting and I can tell you that they kind of help you get through periods of fasting and I believe have an anti-catabolic effect, if you are fasting. You talked about also supplementing essential amino acids and I think it is important that you have essential amino acids for repair, muscle-building anabolic properties or whatever. But the meal that you ate, I had venison and liver last night for my meal. It was kind of a heavy meal I think. Your gut and your liver actually store amino acid and throughout probably twenty four hours after you eat especially something like a steak and as long as you have baseline levels of those essential amino acids, they will be available for anabolic properties whereas the relative changes in a leucine are what’s most important for triggering through the anabolic machinery for growth and repair.
Dr. D’Agostino: And you know, you can take leucine and you get above some threshold level and that activates delta muscle protein synthesis but you think, you know if the essential amino acids are not there, how’s it going to rebuild? But really, the meal that you ate the previous day provides availability of those essential amino acids. I tend to couple my workouts or exercise later in the day, so if I kinda go into it fasting I will have a meal within a few hour time frame after. Unless I’m doing an extended fast and there may be some utility and essential aminos but that’s not really been showing experimentally. But I do think that anecdotally from just experimenting with different fasting protocols that branched chain amino acids can have some utility there and a number of people can be blood work and DEXA scans and what not are fasting with or without branched chain and it looks like they kept a couple pounds to lean body mass as they incorporated branched chain amino acids into their fasting which went from 3 days to… 1 guy did like fourteen days (chuckles). I’m inclined to believe that they’re beneficial.
Ben: I have a couple of thoughts on that. The first is that for me what I’ve found is that in a calorically restricted state and frankly dude, I walk around at about a hundred and seventy five pounds and my normal stable way is about a hundred and ninety. So I’m constantly eating about 80% of the calories I actually want to eat to stay lean for things like obstacle course racing, triathlon and some of these other events I compete in where having that mass to power ratio be a little bit more advantageous is a good thing. What I found is that when I’m doing that, typically I am doing a lot of protein restriction and caloric restriction. That’s where I found something like essential amino acids to allow me to maintain muscle more effectively than branched chains because what I did I interviewed Peter Attia and also spoke with him pretty extensively back when I was doing full-blown ketosis for Ironman.
This was like 3 years ago when I was literally bugged during the race and also in my meals and my diet leading up to the race just doing complete ketosis with zero to extremely low carbohydrates, and he recommended branched chain amino acids. There was a specific brand that he used and I’ll link to the episode that I did with Peter in which we discussed this. And I used the branched chain amino acids right about 8 hours into the event I bonked, right like I ran out of energy, and I also found that I had quite a bit of muscle loss during my training and then repeated that experiment using essential amino acids and I actually found that having a full respect for amino acids and again this is probably coz I wasn’t doing a lot of venison, and liver, and meat, and I was eating a relatively restricted diet from both a caloric and a protein-based standpoint.
I found the essential amino acids and still do find the essential amino acids to be more efficacious from a performance and a muscle-maintenance standpoint than the branched chains. And that’s just kinda my N=1 experience with those. But the other thing and you mentioned this and I had kinda forgotten about this. I don’t talk about this too much on the show these day but, HMB is something that you briefly mentioned a few moments ago as an active metabolite of leucine. And I know that’s been shown in multiple studies to be able to reduce muscle protein breakdown, but I’m not sure if you saw the study last year and it was after the study came out that I started trying this combination especially before hard workouts and a ketotic or fasted state.
The combination of HMB and adenosine triphosphate. This was in the Journal of Strength and Conditioning Research and the results were substantial. They showed that through a twelve-week protocol with a bunch of trained men in a double-blind placebo diet-controlled study, overall strength improved by more than 20% in the group supplementing with HMB and ATP compared to about 5% for the placebo group and they also had enormous changes in lean mass as well, meaning the supplement group increased their lean mass by something like 20 pounds over the 12 weeks compared to about 4 pounds in the placebo group. So it looks like in this case even taking something like leucine in isolation combined with strength training and adequate calories and the addition in this case of ATP, they’re using about 400 milligrams of ATP per day. There was a significant beneficial effect for strength power and lean mass.
Dr. D’Agostino: Yeah, I do think there’s a lot of potential and those I’d like to see the data kinda reproduced in multiple labs so we have kind of an understanding how it works from a resistance training perspective to kind of like a more of a Crossfit workout, to like an endurance workout but I do think that HMB is something in a toll box that I think could be really helpful. Talking with the military and going climbing to high altitude, a lot of proteolytic pathways get kicked on when you get above 14,000 feet and formulating something for prevention or muscle-sparing at altitude, HMB seems to be hitting a lot of the pathways that we think are hyper-activated in a hypoxia environment at altitude.
I talked with a number of researches that studied this and they think where HMB shines would be a situation where the person is putting themselves in kind of an overtrained state. So if you take guys and really like hammer them hard in the gym and put them through a crazy hard workout and give HMB, you’re gonna see an effect. But if you take like the average lifter you know, you may not see an effect. You really have to almost put them into a catabolic state and give a relatively high dose to start seeing an effect. The effect can be significant, I think. But I think it’s context-dependent.
Dr. D’Agostino: But yeah, an interesting effect that you saw and makes me wanna look into it more and incorporate it into a formula instead.
Ben: Yeah, I’m sure you have access to essential amino acids but if you want me to shoot you a bottle over after the call I can send you. I also have some HMB and ATP around in the pantry too so I can shoot some in your way if wanna try it for your next massive dead lifting session.
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Ben: We touched on things we could combine with ketones. We touched on how a ketone salt actually works and how the salt doesn’t necessarily need to be just sodium but could be as you mentioned lithium, or creatine, or an amino acid, or a magnesium salt, but why is it that some people including of course, Dr. Veech in that podcast that I did with him, why is it that some people believe these ketone salts to be dangerous and also, and this is another thing that Dr. Veech mentioned, they also believe that MCT oil which we just talked about as being something that could enhance deliverability across the blood brain barrier, believe that to be able to block beta-hydroxybutyrate absorption or utilization?
Dr. D’Agostino: Yeah, okay, good questions as there’s 2 questions there? So ketone salts have been around for quite some time like even 60s and 70s, so even racemic compounds like 13 butanediol racemic was used back in the 1950’s and through sixties and seventies. Actually, if you talk to some of those investigators who said it did super high concentrations to human and military studies, but getting back to the ketone salts, why they are dangerous? So I think there’s a couple of things that Dr. Veech may be concerned about and I’m sure he probably did research, actually I know he did research coz I think he actually had some patents on sodium beta hydroxybutyrate like a long while back and probably put it on the shelf because he was concerned about the sodium overload.
So I think first and foremost if you’re trying to achieve therapeutic levels of ketosis like for treating clinical conditions, you probably don’t wanna load someone up with sodium beta hydroxybutyrate. I don’t think it’s ideal, right but there are a range of studies and one published in the [0:42:45.4] ______ actually showing that even intravenous of pure sodium racemic beta hydroxybutyrate for a disorder, there’s a number of disorders actually that’s been used to. It’s actually a prescription compound in Europe. One is called MAD it’s called multiple acyl-CoA dehydrogenase deficiency syndrome, and kids that received this were basically kept alive because they’re given massive amounts of sodium DL which is racemic beta hydroxybutyrate, and it’s been used for a wide variety of disorders even glycogen synthesis deficiency disorder. I know type 3 maybe even type 1 and 2 it’s been used. And I have people that actually email me, some parents who have gone through exclusive channels acquired it for their children who have various forms of epilepsy and say it’s been a lifesaver coz they just could not get through child to adhere to a strict ketogenic diet for some reason or another.
So unless he has data to show that scientific publication. For someone to say it’s dangerous, it should be backed up by science, right? As scientists we all have opinions but we need to back up our data with science so unless there’s publications out there that I’m not aware of. There are a number of safety committees for these things. For ketone esters and what not. So I think he may have said that because the ketone esters that he’s developed and put a lot of thought and experiments into, it’s kind of just one agent, right? But our lab is interested in testing you know, many different dozens of different things and testing it against one another. And we have say, ketone salts up to twenty-five grams per kilogram per day in long term feeding studies. And so no kidney, no mark in what we know we do comprehensive metabolic panel and CBC, and we see no indication of liver stress or kidney stress and then we harvest all the organs at the end and do histology, and have never seen anything that would be alarming and there’s nothing in the literature.
Actually, it’s saving the lives of many kids with different disorders and this is actually given very large doses intravenously. And I would say, the science is not there unless he’s aware of something that I’m not aware of but when it comes and not even with sodium. So I think ideally to make it even more safe once you’ve balanced out the mineral preparations. So there may be a conflict of interest there related to patents and accompanying products, and things and I think that could be a factor. But I think Dr. Veech believes in his heart that the R version of beta hydroxybutyrate in the ester form is best and it could be but it is not shaken out experimentally yet, and he may think that the sodium load. You know, we kinda demonized sodium (chuckles) as being a bad thing but that could be a bad thing but it’s not. It just doesn’t show up in the clinical evidence or experimentally.
Ben: And to clarify just a few things for those of you listening in who don’t have white lab coats on the racemic mixture that Dominic just referred to are the racemic salts are what most of these ketone salts are, and all that means is that it includes both the D and the L configurations. So in chemistry a D refers to Dexter which would be like on the right and L, I think is what is that Lavice, Levice something like that on the left? And so, when we look at something that’s in its D or in its L configuration, when we find beta hydroxybutyrate in like its physiological form in the human body in many cases it is in the D form, but a racemic mixture which is what a lot of these ketone salts are, it’s in both its D and it’s L form and so some would theorize that because that’s synthetic or non-native to the human body it might not be as good as the D form. I know that’s one thing that Dr. Veech brought up and the actual form that he developed this ketone ester that he developed is apparently not only not a racemic mixture but more like a non- racemic mixture, and I think to his credit, Dom, I know that when you mentioned that he was experimenting with ketone salts some time ago, I think a few decades ago he was doing research on them, I don’t think he was using a racemic salt. I’m pretty sure he was using like a non- racemic ketone salt. It sounds to me though like what you’re saying is unless you’re seeing bodies in the streets from or disrupted physiology from people using this racemic salts, you’re saying it is in your opinion kind of a non-issue?
Dr. D’Agostino: Just based on the medical literature for treating disorders and that’s published in the [0:47:56.8] ______ Journal of Biological Science dating back to like 1957 and you gotta remember, I mean the companies out there selling a lot of this stuff. I looked at some of the financials and amounts that had been sold and it’s like literally millions of doses that had been consumed, and to my knowledge no adverse effects had been seen. And keep in mind like a lot of animal work was done with racemic compounds. Like I have a look through my computer here, like I have a whole file here on just studies done with racemic beta hydroxybutyrate or ketones showing lower oxidative stress, protects animals against hypoxia injury, protects animals against stroke, brain injury, various disorders like MAD and glycogen synthesis disorders. So across the board, you know everything is positive there’s no negative thing. Actually, I’ve contacted some of the researches that did some work through MIT actually and they looked at 13 butanediol which I’ll talk about that a little bit more because that’s actually how we make some of the ketone esters. And there was a lot of intensive work done by AFRL, the Air Force looking at 13 butanediol which basically, splits and makes fifty-fifty beta hydroxybutyrate, and this was given very large doses to mice, rats, pigs, dogs. Dogs were put on a treadmill with this stuff and given 40% of their calories from that and they showed that it could maintain their exercise performance, so it is synthetic. They called it the most promising synthetic fuel for long duration space flight and it served the purpose that it was extremely stable. It was highly energy dense, and actually if you incorporate it into food it was a [0:49:52.2] ______ which kept the food moist but it also protected the food from degradation. The big showstopper was that it tasted really bad. So it tasted pretty much like a ketone ester and 13 butanediol does and that’s what Dr. Veech actually makes his ketone esters from and that’s what we actually have used as a starting material to make our ketone esters too but by itself, 13 butanediol by itself breaks down in the liver. It’s an alcohol, di-alcohol, it breaks down the liver to beta hydroxybutyrate in the racemic form, it breaks down too. So what I’m saying here is that…
Ben: You think that to use 13 butanediol and to market that is like a supplement for people to get into ketosis it’s simply not palatable for the general population or rather like disadvantages?
Dr. D’Agostino: It’s not palatable, and actually if you divulge it (chuckles) to rodents and actually take it yourself and then take like Dr. Veech’s ester or a beta hydroxybutyrate mono ester the pharmacokinetic profile is pretty similar, actually. So what the beta hydroxybutyrate mono ester is that Dr. Veech has is 13 butanediol, the R form with an ester bond that connects the beta hydroxybutyrate to that and we have a di-ester. So we have our molecules 13 butanediol with 2 ketones attached to it acetoacetate. So the 13 butanediol breaks down the beta hydroxybutyrate but then it releases the acetoacetate which has effects on neuroprotection that we’re interested in. But that’s an ester though just to clarify, I talked about a salt being a mono valiant or di-valiant [0:51:34.7] ______ or amino acid in ester. You can have an ethyl ester. You can have a methyl ester. So actually, if you have a methyl beta hydroxybutyrate you’ll get some methanol that you produce. Not a good thing but people are using that, I think (laughs). You could take an alcohol or like glyceride or a glycerol. For example, you could take glycerol and attach 3 beta hydroxybutyrates to it and consume it. So we have various esters like this in the lab and we have 13 butanediol mono esters and di esters and we test them pharmacokinetically and we also test them for different applications, but there’s a variety of esters that could be made too. Not all of them have the same potency and not all of them are very palatable too. So we found the most potent ester that we have in our lab tends to be the most unpalatable. It seems like potency is inversely correlated with palatability (laughs).
Ben: And by the way, just for the record I took the ketone ester that’s very similar with Dr. Veech and I talked about. My wife pokes fun at me coz I eat anything. I’ll suck down anything that people send me supplements and I’ll just drop them straight into my mouth, I don’t really care. But I still, even with my jaded taste buds I didn’t think it tasted that bad it just tastes (inaudible) basically.
Dr. D’Agostino: Yeah, I’ve tried it too. I actually went to Dr. Veech’s lab and tried various versions of it that he had. He was actually working with a girl working on the different flavoring agents and stuff and it’s totally from my perspective, you could totally dilute it out, you know, five, ten and twenty-five percent to put it in a bottle that would make it potent enough to get you in high levels of ketosis, and for me I can tolerate it but for the average I think it’s probably because for like a niche market but people out there are very picky about taste, I mean we’re not normal when it comes to taste like I can drink the stuff straight and it would put most people on the floor like puking coz I mean people have come but the performance maybe the people who are listening to your podcast are a little off the spectrum in terms of what they can tolerate.
But getting back to the issue, yeah, the racemic so there’s not a whole lot not anything to my knowledge to indicate that they would be harmful in any way, but what we want to determine is if they are optimal, right. So that’s why it’s really important to test the various things and pick out 5 or 6 different things that are top performers and then test them all together against one another. That’s the sort of the things that we’re doing now and we test a lot of things. We have absolutely no intellectual property on or anything so we approach it unbiased. Even companies that have their own intellectual property on ketones compounds we test them and buy a stash in here, and I’m equally as interested in all things. But it does throw in when you have someone kind of negatively talking about other ketone products out there and they have patents and company enters a bit of a conflict of interest there, that’s why I’m kind of always careful not to put down any one. I just like to put out science and then people can decide. But if something is dangerous and the science is out there I’d like to see it. I’m pretty much up on the science coz it’s kind of what I do.
And with racemic, keep in my mind that something like ephedrine, most of the pharmaceuticals out there that we use there was one in the history called the phulidumide, I think that impacted babies and this goes way back into the history of pharmacology where it caused developmental effects on the baby with racemic compound. But keep in mind like a large majority of drug out there that we use on a regular basis are sitting next to me right here is a bottle of ephedrine and we do some research on ephedrine for divers all over the network for diving and it’s racemic ephedrine you know, it’s been used for years sudafed is racemic. Ibupofen I believe is racemic. So there’s lots of big drugs out there that are racemic. So being racemic does not make it dangerous. You can’t go back to one molecule of thousands in the history and say, look at that racemic compound it costs. That’s just not scientific.
Ben: I wanna actually ask you in a second about that second part of the question we didn’t address about beta hydroxybutyrate absorption and the presence of MCT all being inhibited. But the ephedrine are you just using that or would folks just be using that as a decongestion, I assume for diving?
Dr. D’Agostino: Ah, yeah, so a lot of divers use it prior to diving on enriched air. My wife is actually in Palau right now doing research on manta rays. I travelled for the last 2 or 3 weeks we both did and I visited my family and they’re all sick and I got the sniffles. So I got like a little something. I haven’t been sick in years, actually but I got the little sniffles now it was like, ah I hope you don’t get it and she’s on the other side of the planet and have to do research under the water and she’s on nitrox which is enriched air and needs to get down there to do research coz she’s funded to do that, and what a lot of divers do is that they load up on sudafed on ephedrine. So Divers Alert Network realized that this was a problem, so our lab actually studied the effects of dosing high levels of ephedrine as in a stimulant to see if it would reduce delay in fetus seizure for CNFN toxicity which manifests itself as a grand malseizure. For that to happen you really have to take a mega dose of it like you have to basically take 5-10 pills for you to get. And I was actually surprised. I thought it would quickly resolve in faster seizures but it does increase your chances but you really have to take a lot of it. So that just came into mind because we have it on my desk here, it’s racemic compound and it reminded me that many of the drugs out there that are commonly used are racemic.
And it’s also important to notice that we have the resunate enzyme, so the L form and various tissues have different levels of this enzyme. And were kinda looking into it but it’s even in the human metabalone project which is in a public website that you can go to, and see that this enzyme, we have the resunate to inter convert D to the L. And that’s important. So they’re saying it’s not the natural form is incorrect because we do have the ability to convert it over to and actually a lot of the percentage of it does. So if you do the biochemistry or the pharmacokinetics and you administer racemic compound and they look at the D and the L form what ends up happening after about twenty-four to forty-eight hours of that. You know, eighty percent of it is the D form and the L form just gets kind of oxydized like a fatty acid which just leads into the [0:59:18.1] ______.
Ben: Yeah, that’s really interesting and ephedrine by the way, was something back when I was a body builder it was like the way to burn fat fast and of course, the alkaloids in it will cause a ton of issues with heart attack, and stroke, and seizures, and death, and I believe mostly the ephedrine supplements, if I’m not mistaken are now permanently banned in the US but it’s pretty synergistic for fat loss like especially when you combine it with caffeine. I know the old like the body building go to for just getting shredded was ephedrine, caffeine and aspirin as kind of like the 3 ways to lose fat extremely quickly and possibly wind up seizing next to the bench press bench but still a pretty potent fat [1:00:06.3] ______.
Dr. D’Agostino: (laughs) Yeah, I think you needed a really high dose of that. Actually, I think ephedrine has a pretty good safety profile if you’ll look at who’s the obese this study done, I think given up to a hundred milligrams per day with the caffeine and I think it might have been like a fifty-two week study, so it has a pretty good safety profile. The problem with ephedrine is, ephedrine hydrochloride is that you can make amphetamines kind of easy from it, so and even sudafed you can make amphetamines kind of easy. So I actually had to get a decongestant that I gave to my wife just to make sure she had the best decongestant. And they do sell sudafed but you have to go to the pharmacy and then they look at your driver’s license then they give you a small amount, and it’s pretty expensive and everything. I still think it is one of the best decongestants out there but it’s sold.
I don’t think you can get ephedrine hydrochloride, I mean we have it in the lab coz we do research and stuff we have bottles of it, but I don’t think you can get, you probably can try to get anything overseas but it’s hard to come by. But as you said it was a very powerful fat-burner especially when combined with caffeine. You must be able to get it because several people have taken it and showing me their ketone numbers and what ephedrine and caffeine do is it mobilizes fatty acids from adipose which travel to the liver and kinda further stimulates beta oxidation of fatty acids in the liver so their ketones tend to shoot up. And it might facilitate some glycogen depletion too in the liver but you generally see almost a doubling of ketone levels in guys that are kind of training taking that and if they keep all variables kind of equal, it stimulates the metabolism in a way that can bump up your ketone levels.
Ben: Got it.
Dr. D’Agostino: To a potential benefit of it.
Ben: Yeah, that’s interesting. The doses I think, were like about twenty to fifty milligrams and you do that like 3 times a day with ephedrine but as you’ve alluded to, yes super makes speed out if it, too if you wanted to. So there’s that advantage, kids.
Dr. D’Agostino: I used that in college, I think. I never took more than twenty-five milligrams than I would. Whenever I took it, I would always make sure that I work out that day. I would never take it and not work out and I always took 1 pill back when it was legal.
Ben: Oh, if you take it and you don’t work out, yeah, you’re bouncing off the walls. Yeah, so what about this issue that Veech brought up about the inhibition of beta hydroxybutyrate to be absorbed or utilized when taken with MCT. It seems a fly in the face or what you were saying earlier about MCTs enhancing delivery across the blood brain barrier.
Dr. D’Agostino: Yeah, I would like to see that publication if that’s available but I don’t think that’s the case. I kinda know what he’s alluding to. I mean, it’s kind of theoretically saying that, if you were to take medium chains triglyceride oil, there’s sort of a rate limitation of how these things get used in metabolic pathways, and you may be restricting to some extent the utilization and the oxidation of exogenous ketones of the ketone ester if you were to take MCT oil. But when you take MCT you make the beta hydroxybutyrate mostly, and some of it may interconvert to the L if the racemic is there, but in most part you produce the beta hydroxybutyrate. So I don’t know of any evidence to my knowledge and I’m pretty up on the publications that taking medium chains triglyceride oil would in any way shape or form be dangerous or block beta hydroxybutyrate. I mean, theoretically, you know, actually to finish, I can go back actually to look at our global metabolomic data and maybe look at the various pathways and metaboloids coming off of that pathways to see if that’s the case. I’m sitting on a whole bunch of data right now and I can kinda go back and look at that but I don’t think he used like citing any actual research. I think it’s more like…
Ben: So it’s basically okay to use like MCT oils and ketones together and the MCT isn’t gonna like keep you from burning the ketones basically.
Dr. D’Agostino: Absolutely, I actually think it’s optimal to do that and you know, I think MCTs may be a little bit threatening to people out there with synthetic ketone products like ketone esters or even ketone salts, but MCTs in our hands are really awesome like in rodents, you can get ketone levels that are really high with medium chain triglycerides. If you can tolerate them, you know, they’re fantastic. I know of a few people contacted me if they even take a teaspoon. They’ll have like explosive diarrhea but I encourage them to take a half a teaspoon and try to build their levels up. I think I did a whole MCT experiment after doing it for weeks to a couple of months, I could target like a hundred and fifty milliliters a day of it and I was staying in pretty strong ketosis just from MCTs alone when I really started getting into this and I didn’t have ketone esters yet. So yeah, I am 2 thumbs up for MCTs, I think they’re great and I think they can even further enhance the delivery and bioavaibility of the ketone salts that are out there when they formulate together.
Ben: For glycolytic performance, like I did in that obstacle course race, have you ever tried combining the use of ketones with just straight up glucose or sugar?
Dr. D’Agostino: You know, I get that question a lot and I see no contradiction there. We’ve actually done quite a bit of work to show that glucose utilization is increased when with ketone supplementation and we think that the combination of things going on, maybe an enhancement of insulin sensitivity. I know Dr. Veech has written several reviews stating that ketones can enhance influence sensitivity in glucose utilization. So I think the 2 together can be great. Most people out there are not gonna be following ketogenic diet or maybe they shouldn’t unless they have some underlying disorder, but I do think it is good to go keto every once in a while whether you do it through carb restriction or intermittent fasting or whatever, but I think what may work optimally is take some kind of slow carb together some lower glycemic carb, or maybe in some cases a fast carb, and combine it with ketones and deliver it into work out depending on the type of workout you’re doing. Most people that I know are not exercising more than like an hour and a half to two hours. So in those cases you don’t need any really intro work out nutrition.
Ben: And the amount of glucose that I took and found to be incredibly efficacious, we’re not talking about 4 gel packs an hour or what I would’ve used to have been doing during like an Ironman Triathlon. We’ll that’s what I did do was every fifteen minutes slamming a gel pack to get up to four hundred calorie an hour of like fructose and maltodextrone. This was seventy-five grams of glucose which is a relatively low amount of sugar taken essentially as the ketones and has the only form of glucose. The only thing going into my body calorically or supplement-,wise for the entire race and really the entire next 6 hours so we’re not talking about like mainlining sugar into the body as much as possibly boosting the effects of the use of ketones with a little bit of glucose. And I found it to be like rocket fuel, honestly.
Dr. D’Agostino: Yeah, I think we need to do some testing of ketones alone and then ketones and glucose together. And I know several people with ketone products want to do those studies, and we’d love to do them in our lab and I know we did a lot of hiking the last couple of weeks about 4 hours into a hike, I drank a ketone salt product, I think it was a Pruvit product, and I took and I ate a chocolate bar. I was kind of off my ketogenic diet when I was part of my trip. Maybe about twenty-five grams of carbs of sugar but it was dark chocolate, so it wasn’t full on sugar and I was fine, and we had hiked a lot already but the last 2 or 3 hours I was heading back and I was super buzzed. I haven’t had any kind of sugar in a while and that combination seem to be pretty synergetic just take from my energy, you know.
Ben: Yeah, the MCTs tend to slow the rate. Whether it’s glucose or fructose sugar molecules, there’s a pretty big stabilization in blood sugar when either of those are included with MCTs. I’m actually working right now with a company called Bariatrics which does a lot of work with diabetics et cetera. I’m trying to develop a bar right now that is a combination of something that would be like ketosis-friendly but also be something acceptable that you could use for a long hike or a bike ride, or something like that. And we’re actually using some pretty trace amounts of raw honey in it and finding that ketone levels stay pretty stabilized, and that blood glucose really doesn’t tend to fluctuate at all with that type of approach. So I think that in some cases people shy away from sugar too much when in fact it can be a pretty cool addition to an MCT or a ketotic-based approach especially for performance.
Dr. D’Agostino: Yeah.
Ben: So it’s an interesting combination in terms of sugar remaining stable over time from a blood standpoint. You know, there was one study I looked into in the development of this and what they did was a fat spread that they enriched with medium chain, I think in this case it was a triacylglycerol and then they added some sugars to that and found that the sugars were completely stabilized. So this is all super interesting stuff.
Dr. D’Agostino: I’m not a big…
Ben: Go ahead.
Dr. D’Agostino: Oh yeah, I was gonna say as a “keto guy”, as people think I am, which I am I mean that’s kind of the cornerstone of my research but don’t believe in demonizing sugar. I think the problem is the excess consumption of sugar, obviously and that I’ve been perfectly fine. I see my nieces and nephews they’re like sugar-holics and they’re burning it up like crazy. You know, when we’re younger we can do that, but as we age there’s sort of an age-dependent decrease in our ability to use carbohydrates has an age to it. The excess sugar. And most of the people that are concerned with it are kinda athletes already and there are people who don’t have to be concerned necessarily with sugar because they’re burning it real fast, like you, but at the same time I have seen the benefits of guys that burn sugar really, really well and have no over metabolic problems transition to burning fat and ketones and doing remarkably well.
Dr. D’Agostino: So they didn’t have any pre-existing problem that was overly noticeable even from blood work but they did remarkably well. And I think as an athlete you have metabolic currency with your mitochondrial health and everything that you transition very nicely into a high fat using diet and quickly get your ketone levels up or start using fat for fuel very efficiently.
Ben: Right and the case with my kids, they get home and we only have a rice cake with honey and almond butter on it which is essentially like a little bit of a carb bomb with some nut butters and then they’re out making snow forts for 2 hours in 3 degrees and I’m not concerned at all about their blood sugar levels.
So, one other question that I wanted to ask you was expense, right, like we talked about like you know, I’ve heard Dave Asprey for example, say on his podcast that when he used ketone esters the cost of them was approximately thirty thousand dollars for a serving and I’ve certainly when the ketone esters have been sent my way by some of the folks associated with Dr. Veech, I was informed that they were incredibly expensive to make, so they wanted to ensure that when I use them I tested and didn’t just kinda pop them like candy but instead I was pretty cognizant of their expense. Why is it that the ester would be so much more freaking expensive than a ketone salt?
Dr. D’Agostino: Yeah, I mean thirty thousand dollars per serving I think someone made a lot of money of (chuckles) Dave Asprey. I’ll sell him some ketone esters for that. So, yeah they are expensive because it’s more of an economy of scale thing, right? So I needed like a little rotor rod device, like a little treadmill device that rat and mice run on and then automatically senses when they fall off, then we can look at exercise performance and not too many people make that device and it was like twelve thousand dollars. I could go buy a really nice used car for that amount. But there’s not a whole lot of people making ketone esters and I can tell you that the precursors are relatively inexpensive if there is an art, there’s a science and an art to doing the transesterification to make ketone esters whether it be glycerol, beta hydroxybutyrate triester or a 13 butanediol monoester, diester or whatever. Each one has kind of several nuances into developing that synthetic pathway and you need a committed organic chemist running the facility pretty much non-stop to be able to make it in the kind of amounts that are needed. So it’s just not cost effective for a company to do it and once you make it, then you have to do some testing on it to ensure the potency and the purity that you don’t have left over stuff in it like methanol or other things, so therein lies kind of the problem. It’s an economy of scale thing. It can be scaled up to be probably as cheap as I would say ten dollars per liter, I think when it’s maximally scaled up.
I think Dave Asprey or someone from his camp mentioned that there was formaldehyde in some of the, they’re testing some of the ketone esters or ketone salts rather. So I can tell you that the way ketone salts are made like in Patrick Arnold’s lab, and the way they’re made here and even the way they should be made in China is that combining beta hydroxybutyrate to these monovalant or deviant cations is relatively simple chemistry and then no way throughout this synthetic process should you be forming formaldehyde at least with even the cheap precursors that are available. I don’t know, I haven’t seen the data on that. I know a lot of people have emailed me about that. Is there formaldehyde and you know, we have some pretty good detailed chemistry analysis of at least the stuff that the companies are using like Pruvit and Patrick Arnold, and Keto Sports, and there’s no way through the synthesis of these things to be making formaldehyde. Maybe in some clandestine labs in Asia or something he got a source from but there’s formaldehydes on any of the products out there based on synthetic chemistry. But they’re expensive, I think just to answer your question because it needs to be scaled up, I mean we’re making in our organic chemistry but in little small batches and we’re making the R enantiomer and the racemic. It’s much more expensive to make the R enantiomer, but if you scale it up in the right way, it could actually be dirt cheap (chuckles) and that’s what’s kind of, some people may call it heartbreaking because these compounds really do have the potential. They have high therapeutic value for a wide range of disorders.
At the core, we’re talking just one of those like, what caused transported deficiency syndrome and I’m really networked with that organization. These kids they just can’t transport glucose across their blood brain barrier and ketones can literally be a life saver for some of them and there’s a wide variety of inborn errors in metabolism that would be highly responsive to therapeutic ketosis in the form of a ketone ester. But these rare disorders really don’t get enough attention and investors behind making it but when you look at it on a grand scale, we also know that their very significant performance, advantages, cognitive and physical performance advantages, to get from synthetic ketones and therein lies probably the opportunity for savvy investors, forward thinking investors to say, hey, the science behind this basically sells itself. So it really would be good technology to invest and I gotta say the ketone salt products on the market they’re about one-third to half as potent as the ketone esters would be, and you know maybe we don’t want some of the other ketone esters that would be too potent and too tasty because you could technically drink too much and get into ketoacidosis. Not so much with the ketone mineral salts because you try out some GI issues and come out the other end before you reach toward the blood levels. That would be dangerous. But with the ketone ester I can tell you from the safety studies that we’ve done you, you can do inter gastric divulging of a rodent and then you can slowly push them into ketosis.
So for a human you would have to drink about seven hundred to a thousand milliliters of the pure undiluted form to really get to the point where you’d be in trouble and that would be very expensive and it would be horrible to anything. So any form of ketone ester that’s like gonna be on the market, it’s gonna be at least a twenty-five percent dilution which means like twenty-five percent of it is the ketone ester and only after that does it, you know, it becomes palatable. But typically, if you see ketone esters hitting the market in liquid form, that’ll probably a five to ten, maybe the super concentrated form will be like twenty-five percent ketone esters and it’ll be heavily flavored and then you got to drink a ton of that stuff to where it’s stretching your stomach to start reaching ketoacidosis.
Ben: Yeah, and to put that in context, I mean ketoacidosis we’re talking about more than twenty millimolar in most cases for something that classify as ketoacidosis. In twenty days of fasting a lot of times will get you up to around ten. I mean to just not eat anything into a water-based fast, so you would have to take copious amounts. Aside from, I don’t know if you saw this…
Dr. D’Agostino: You would throw up (laughs).
Ben: This anecdote, that paper. I think it was published in the Diabetic Medicine Journal and there were several cases in which folks using MDMA or ecstasy combined with the excessive movements of rave dancing actually enter into a ketoacidotic state. So apparently, if you use ecstasy you might be able to get there faster. So if nothing works out for you by listening in to this podcast and you don’t wanna try the ketone esters or the ketone salts, it appears that you could just pop some E and go to rave for a while and potentially just get all of the benefits with none of this confusion. So there you have it.
Dr. D’Agostino: Interesting you mentioned that, I just met with my lab folks which are students from all different backgrounds and stuff we’re telling kind of our stories about things like that, and I know MDMA can be a metabolic stimulant and if you’re around people who had been taking it, you know you get real thirsty, right and you start kinda heating up and one of the main side effects of too much MDMA is that you start like basically overheating. Yeah, that doesn’t surprise me and it kinda makes sense. Any kind metabolic stimulant will mobilize fat from adipose and it will start making ketones and that’s what you see if you give a stimulant like even caffeine and ephedrine are good examples.
If you take a normal person on even a mild ketogenic diet running about 1 or 2 millimolar and keeps all variables the same and starts getting some pretty moderate to high dosing of ephedrine in caffeine, I’ve seen the blood work it like spikes right up and stays there. It can double their ketone levels and it’s a good and it’s a pretty dramatic demonstration of you kind of the fat burning effect or the fat mobilizing effect and of course, once you start using it you’ll get that effect and then that’ll attenuate over time but I would say use it for 2-3 weeks and then get off of it for like 2-3 weeks and then use it again. It kinda works better if you don’t use it all the time but I’ve seen enough data to indicate you have stimulants like MDMA and other compounds can be ketogenic in that way. We’re also interested in amino acids that may enhance the liver civility of ketogenesis, and taurine is an amino acid that can more or less help your liver make more ketones. I was thinking of an idea throwing it out there for scientists that would jump on it of developing compounds that stimulate their specific enzymes in the liver. Enzymes involved in ketogenesis. So if we could stimulate the enzymes involved in ketogenesis, we can drive our own ketone production, anyways. And I think there’s opportunities out there to do that that people probably could start looking into. But there’s an indication that taurine given 2 grams 3 or 4 times a day can increase your body’s ability to make ketones.
Ben: That’s interesting, yeah, 2 grams is a relatively high dose. I don’t know how much is in of course, Red Bull but I know that’s what most of the energy-enhancing effects of Red Bull are attributed to is the taurine, yeah.
Dr. D’Agostino: And the caffeine.
Ben: Yeah, well interestingly one of the most well-known usages for taurine back in the day, speaking of the devil was that ephedrine and the cramping and some of the potential muscle seizing caused by ephedrine you could reverse that with taurine. So it seems to pair it quite well with central nervous systems stimulants as well to kind of like knock some of the edge off of the caffeine or the CNS stimulant, but that’s really interesting that it could potentially be used as something to go along with for example, ketones and MCT.
Dr. D’Agostino: Yeah, boosting your own body’s ability to make ketones. Going back to when I was doing my post- [1:24:01.9] ______ up in Ohio, there was a guy in emergency medicine and he was like all about taurine and I started looking, I didn’t know much about it at all at that time but I delve into the literature and I was like, wow, this stuff is remarkable. Maybe it’s just not known because there’s not a whole lot of money to be made from it or the way to patent it, whatever but yeah, it seems to have a lot of applications, especially applications like brain injury and things like that and just maintaining osmotic gradiance neurons for neurons to do that under certain conditions. I think it has a range of utility and it’s pretty cheap.
Ben: Yeah, it’s particularly interesting yeah, and mostly benefits, of course for physical performance what they found is with aerobic exercise particularly that cyclist who get taurine just have a time trial performance that goes through the roof without an increase in rating of perceived exertion. And I know also it can interact with the leydig cells so I think I’ve also in addition to kinda like researching how to create like more of a good fat-based energy bar. I’ve been looking into a good testosterone supplement and one of the things I’m looking into is taurine just because of its interaction with the leydig cells and also its ability to reduce some oxidative stress particularly in the nether regions. So perhaps a discussion for another day as we’ve been going for a while and I should let you go soon. I should probably go have lunch and also take a pee soon because I had an enormous cup of tea before we started. I’m on this 3.
Dr. D’Agostino: Gotta make time to do that.
Ben: I know, I’m on this 3-month, it’s almost like a 3-month detox protocol where I’m drinking copious amounts each day of licorice, marshmallow and the slippery elm bark and it coats your stomach and makes you feel amazing, but it also means I’m drinking about as twice as much fluid as I’m used to. So regardless that we covered a lot of material today and I took copious notes. So for those of you listening in, all the notes are at bengreenfieldfitness.com/dom, that’s bengreendfieldfitness.com/d-o-m. If you wanna hop over there I’ll link to the previous episodes with Dominic. That interview with Peter Attia I mentioned. My own article and writings about my experience with ketosis and the use of some of these ketone salts and ketone esters. I’ll even imbed a relatively entertaining video where I snap chatted my use of ketone esters during that Tough Mudder event I alluded to and I’ll put plenty more in there as well. Just go to bengreenfieldfitness.com/dom for that. And of course I’ll also put a link to the original interview I did with Dr. Richard Veech about the ketone esters.
So Dom, thanks for coming on the show and sharing all these stuff with us man. You’re a wealth of knowledge.
Dr. D’Agostino: Yeah, thank for having me.
Dr. D’Agostino: Yeah, we have such a far reach and I think your listeners are really a group of interesting people coz many of them would email me too about questions and you always have an erudite group of listeners out there, kind of another stuff just from listening to your podcast. So I appreciate you’re giving me the platform to speak and I wish you all the best.
Dr. D’Agostino: And I’m here anytime you wanna discuss anything.
Ben: Thanks man and I have to add erudite to my vernacular more often. I’ve forgotten about that word. It’s a good one. Alright, for those of you listening in. Thanks for listening. And until next time. I’m Ben Greenfield along with Dr. Dominic D’Agostino signing out frombengreenfieldfitness.com. Have a healthy week.
A few months ago, I recorded a highly controversial ketosis interview with Dr. Richard Veech, in which Dr. Veech claimed that the form of ketones most people take to get into ketosis (ketone salts) are actually quite dangerous.
Dr. Veech’s solution was something called “ketone esters“, which are extremely expensive, but, according to him, a far more natural, safe and healthy way to quickly get the body into ketosis – for anything from managing medical conditions, to improving cognition, to increasing endurance and beyond.
In the video below, I actually experimented with these spendy ketone esters myself and, as you can see, the results were astounding…
After shooting this video, I took another bottle of ketone esters to a Tough Mudder event and recorded a crazy video on Snapchat during which I elevated both blood glucose by drinking 75 grams of pure glucose and elevated blood ketones by drinking a bottle of the ketone esters, and the results were equally as astounding, resulting in one of the fastest races of my life.
But the question remains: are these fancy, expensive ketone esters actually far better than ketone salts? Are ketone salts, which is what most people use, actually going to result in long term health issues?
In today’s podcast, I bring on ketosis expert Dr. Dominic D’Agostino to get his opinion. Dominic is an Associate Professor in the Department of Molecular Pharmacology and Physiology at the University of South Florida Morsani College of Medicine. He is also a Visiting Senior Research Scientist at the Institute for Human and Machine Cognition (IHMC). His laboratory develops and tests nutritional strategies and metabolic-based supplements for neurological disorders, cancer inflammation and performance enhancement in extreme environments. His research is supported by the Office of Naval Research (ONR), Department of Defense (DoD), private organizations and foundations.
He’s also no stranger to this podcast, having been a previous guest in the episode “A Deep Dive Into Ketosis: How Navy Seals, Extreme Athletes & Busy Executives Can Enhance Physical and Mental Performance With The Secret Weapon of Ketone Fuel“.
During today’s discussion, you’ll discover:
-The difference between a ketone salt and a ketone ester…[9:25]
-Three unique compounds you can “mix” with ketones to enhance deliverability, and the important difference between BCAAs and EAA’s…[23:55]
Why is it that some people, including Dr. Veech, believe ketone esters to be dangerous and MCT oil to block BHB absorption…[41:05 & 62:40]
-What Dominic has found by testing both ketone salts and ketone esters in his lab…[44:30]
-If there is actually any evidence of people experiencing medical issues with the use of ketone salts or esters…[47:50]
-The safety of using ephedrine for fat loss, and Dom’s own experience with ephedrine…[60:05]
-Whether you can combine glucose with ketones to enhance performance…[65:40]
-Why the esters so much more expensive than the salts, and whether there are ways to make either that actually are cost effective…[72:15]
-And much more!
Resources from this episode:
-My article and review of common ketone salt supplements such as Pruvit and KetoCaNa called “How To Get Into Ketosis”
–Is It Possible To Be Extremely Active and Eat A Low Carbohydrate Diet? (my interview with Peter Attia)