Geoff

Bri, it's always really fun to have the magic team here. You and I on the podcast.

Brianna

Dream team.

Geoff

Dream team. So we thought it would be helpful to just have this episode to answer your frequently asked questions. FAQs. Let's knock them out and we'll have this resource for everyone down the line. And of course, if there's new frequently asked questions we'll do another episode. I'll just kick it off and I'll ask the first FAQ question here.

What is H.V.M.N. Ketone and what is it meant to be used for?

Brianna

To start off, H.V.M.N. Ketone contains 25 grams of ketone ester. So one part of the ketone ester is beta-hydroxybutyrate and it's the D iso form, so that means it's exactly the same as beta-hydroxybutyrate which your body would naturally make. And it's bound to a Ketone precursor called 1,3 Butanediol. And so when you consume that, your body can break apart the ester bond, 'cause we eat esters in our food the whole time. And then the two parts can be absorbed into the blood. The beta-hydroxybutyrate is ready to go straight into the bloodstream through the liver, and the butanediol part gets processed a little bit by the liver, really quickly processing it forms D beta-hydroxybutyrate as well. So when you drink H.V.M.N. Ketone you end up with two parts of D beta-hydroxybutyrate for each one part of ketone ester that you're eating. So really like on the highest level we see it providing ketones as a fuel for the body to use. And a lot of the research up until now has focused on how the extra fueling with ketones can affect metabolism during sport and exercise. So right now we're really focused in on how athletes can use ketones to help them improve their endurance and improve their recovery.

Geoff

Yeah. And the super one-sentenced answer that I would answer that FAQ with is that this is a sports/energy drink that doesn't have any sugar, doesn't have any caffeine, but it improves your performance. And it does so by fueling with ketones.

Brianna

Geoff's gonna have to give the one sentence summary for all my answers (laughs).

Geoff

No, no, but I think it is helpful to get that full depth of what kind of working technology's behind our products. I think a lot of sports drinks that you see on the market are often just carbohydrate or really, sugar drinks. Or a remix of some amino acids, a little bit of fat, a lot of sugar, maybe some caffeine or not caffeine. What we have with H.V.M.N. Ketone is just really a paradigm shift in having a fourth macro-nutrient in there that's very, very separate from anything else that exists on the market. So it is helpful to add that color of what it actually is before just saying, "Hey this is a sports energy drink for better athletic performance."

Brianna

So next up, question for you Geoff.

Can non-athletes use the product? I want to use it for fasting, if so is that beneficial? How do I use it for that?

Geoff

Good question. So you're right, a lot of our marketing language is focused on athletic use cases but I wouldn't necessarily consider myself an elite athlete. I work out often but I'm not an elite athlete or a professional athlete. And I like using H.V.M.N. Ketone a lot. And I think that's applicable to almost everyone that wants better performance throughout their day. So if you're a human being that wants to get a little bit more out of the day, I think H.V.M.N. Ketone has a role in your nutritional toolkit, if you will. The way I would use it is, sometimes as a pre-workout fuel for some workouts. Or in lieu of caffeine, or in addition to caffeine, have just as a really nice cognitive boost to start the day. Or right before an important meeting I'll have H.V.M.N. Ketone and get that little bit of a subjective cognitive boost. And I know that you're working on a bit of research that will prove that out, different research collaborators we can maybe talk about later in this podcast.

And then one of my ... Actually the third favorite use case here, it's one, for my workouts, two, for cognitive performance, it's actually really helpful for me when I'm starting a fast, a longer fast, or shifting back into a ketogenic diet. And the reason why it's helpful is, one, you publish a nice paper showing that it reduces ghrelin, the appetite hormones, so it's a very nice, controlled appetite. But, secondarily, it's non-insulinogenic, it doesn't require insulin to go into your cells, which means that the reason why you fast or you go on a ketogenic diet is reduced carb-load, and the pain there is that your body isn't necessarily used to feeling off of ketones or fat just quite yet. So you have energy deficit in your brain, in your body, you feel a bit sluggish, you feel hangry. Ketone ester is a really good bridge to give you that quick boost of energy that's non-carbohydrate, doesn't trigger insulin, gets into your brain and you don't really feel hungry. So when I'm shifting to a ketogenic diet or when I start a longer fast, really, really awesome way to just smoothly get into that, the ketogenic state.

Brianna

Great answer.

Geoff

How about you? Do you use it for non-athletic use cases?

Brianna

I mean, similar to you I would sip it ... No as you said at the very outset, we're still not at the stage where I'm completely swapping out my sparkling water for ketone ester, but on the times when I've gotta focus for a long time and get things done, it's a really great alternative to the third cup of coffee, or some kind of sugary pick me up. It is cool that it's fueling and revitalizing your body in a way that's just really completely different to caffeine or sugar or a bunch of other products that you can get out there.

Geoff

Yeah so hopefully in longer term we prove out in more use cases where this can be thought of as a fourth macro-nutrient that we talk about, as opposed to just the sports performance product, and obviously that's gonna take quite a bit of work from both of us and the broader team, and Oxford and all the other research partners and collaborators from that.

Brianna

But I'm really, really proud of the way that we speak about it and the company and that we focus on the evidence that's already out there and published and peer researched and we work really hard to find the right partners and to facilitate the other research to be done before we get too far ahead of ourselves with talking about how to use it.

Geoff

Absolutely. Alright, the next FAQ.

What's the difference between our ketone ester and other ketone compounds like ketone salts or MCT oils?

Brianna

I love this question. I actually spent a good part of my PhD thesis looking at the difference between different ketone supplements. So giving all types of supplements to different people and studying the results. So first up, let's compare with MCT, so MCT stands for medium chain triglyceride, as it's specifically referring to the carbon chain length of a fat molecule.

Brianna

So, when you eat a medium chain triglyceride, it's very rapidly processed by the body, a little bit differently to typical longer-chained fats. And because it's rapidly processed and you kind of dump this big fat load in on the liver, the body will naturally convert some of that fat load into ketones. But it's kind of an inefficient conversion, so not all of the MCT that you eat gets converted into ketones.

Brianna

Typically after people have had MCTs they get a small increase in ketones anywhere up to between .3 and .5 millimole of beta hydroxybutyrate. It's quite low.

Geoff

Yeah I believe Richard Veech from the NIH mentioned about 10% of MCTs convert into ketones.

Brianna

Yeah I don't know if anyone's actually done that research study. You would have to kind of label it up. But that said, you can't force your ketone levels higher by taking more, because if you take too much MCT, it can cause explosive GI issues, and we actually tested this quite a bit in the office and we've had a few people having to run to the toilet every half hour or so-

Geoff

And GI is gastrointestinal issues, for folks who don't know the lingo.

Brianna

Yeah, and when I say explosive, that will probably give you a bit of a clue as to what happens. So there's definitely limitations to using MCTs, but you can go and purchase them from a health food store, it's kind of easy to find them cheap. And a lot of people use them as a compliment to their ketogenic diet. They dress their salads in them, they put them in coffee and things like that.

Geoff

Yeah, and just to jump in a little bit on MCTs, I use it every now and then, I was actually on a ketogenic diet, when I cycle into it. And I'll say it's relatively palatable to me, but I've been in the case where I get a little bit aggressive, get a little bit extra too many squirts of MCT oil in the coffee or in my food, and it's like "oomph."

Brianna

I feel like it's probably worse if you have it just neat, or if you have it in a liquid form. I feel like maybe if you have it with some fiber-

Geoff

Yeah it's more palatable on a food.

Brianna

On a food, but then you may not get so much of a ketogenic effect, maybe. Maybe. It would probably affect absorption time and the general state of the liver. So it's unclear to me whether giving it with food would be quite as effectively ketogenic. Maybe, maybe not.

Geoff

Yeah so I think the underlining point for me here is that MCT oil is reasonable as a ketogenic precursor, but it's not really impactful in terms of sustaining elevated ketones to a very significant level.

Brianna

I mean we see they're used quite widely in clinical studies, and the reported levels are typically .3-.4, so that's fairly mild ketosis, and you can achieve that through the diet probably, fairly easily, or with some fasting, again fairly easily. So it's a topper and the biology is there, but it's not really super-charged.

Brianna

So next up we'll talk about ketone salts, these have really exploded in popularity recently because they're quite easy to make. What they are is, you have ketone beta-hydroxybutyrate typically bound with a mineral ion. So again that's typically sodium or potassium or calcium, so if you think of when you go to a restaurant and there's a salt shaker on the table, it's not too dissimilar from that. Table salt is sodium chloride, and what you get in the keto salt package is sodium or potassium ketone. And just kind of nice mental picture, you would never really open up that salt shaker, pop it in a glass of water, and then drink that whole thing. And that's kind of what you're doing with ketone salts. When ever you drink ketone salts you have to consume quite a lot of these mineral ions along with the ketones.

So whilst people who are one a ketogenic diet do tend to have a higher mineral intake, if you're gonna be using these regularly, the general consensus is, that this might be an overly high level of salt consumption and therefore pose a bit of a risk in terms of blood pressure or kidney function. There's debate in the literature about how much salt is the right amount of salt, but I think broadly speaking, to use ketone salts regularly could pose a health risk. There's a number of other small issues. I mean firstly, and probably should have said this at the very top, is that typical blood ketone increase with the ketone salt is a roundabout 1 millimole, that seems to be the typical-

Geoff

On the higher end though, it said.

Brianna

On the higher end, anywhere between 0.6 to 1, I mean one paper from Brendan Eagan's group over in Ireland only have found a 0.4 increase in blood ketones, so it might change a little bit product to product and how much you have, but again similar to MCTs, the bump in ketones that you get with ketone salts is a little bit underwhelming, and part of that is because most ketone salts that you get out there on the market are mixtures of two types of beta-hydroxybutyrate. So in nature there is what's called D beta-hydroxybutyrate, which is the same as our body makes, and there is one that is called L beta-hydroxybutyrate, and I like to describe it as left and right-handed forms of the molecule. They're kind of identical in terms of structure, but they don't overlay on one another, and that affects how the body can use them for energy.

So when you take ketone salt, you're getting a mixture of these two forms and your body can't use half of it, and also your typical blood ketone reader can't detect the L half of it that your body can't use. So, you're consuming these extra ketones that's not quite so useful for the body and that stays elevated for quite a long period of time after you drink it. So, not only are you getting lower levels of ketones, you're consuming this non-physiologic iso form. You're getting quite a high mineral load, and another subsidiary consequence of the mineral load is also risk of gastrointestinal distress, a little similar to MCT. Again, we've had that here, testing out in the office. It's a little bit hit and miss, and personally I've used salts a few times. Sometimes I'll react to it, and other times not. Especially as an athlete you don't really wanna be worried about whether or not you're gonna have to be pooping your pants.

Geoff

Yeah, but I would say on the plus side those ketone salts and MCT oil are much more affordable than ketone ester right now. That's something that we're working really, really hard on. And my personal experience with ketone salts to add some color, I'd say it's pretty similar to your experience, on and off, sometimes I'd have a pretty seamless experience, sometimes a little bit of GI issues. The taste I would say is smoother than H.V.M.N. Ketone, but you have to consume quite a bit of liquid, because you're diluting 12 grams of salt, or 25 grams of salt, and I think of that really as a big packet of powder. So you can't really just shoot it. Like you can shoot H.V.M.N. Ketone. So typically you can flavor it a little bit and it kind of tastes like salty lemonade, but with a lot of salt and a little bit of a weird salt aftertaste with it. So palatability, not as a big bitter punch as a ketone ester, but kind of a weird lingering salty feel to it.

Brianna

They've both got their pros and cons in terms of drinking it and neither of them are super nice to drink. But I've got to say that I guess the feedback from people using ketone salts in the broader market is encouraging, that we're in the right space. If people can get good results and come back and buy more and more and more of these products, then I think that they'll be really impressed when they use the ketone ester and it proves out that we're on the right path.

Geoff

Yeah that's a good way to put it, I think we're, fairly agnostic, and fairly data-science driven folks here, so I think we try to look at the data, look at the subjective experience that we have, obviously benchmark that towards folks that are doing this infield testing, both from professional athletes or consumers. All the polished peer reviewed research. And I think there is potentially a role for all of these compounds. MCT oil, ketone salts and variants of ketone salts, ketone esters.

Brianna

I think that you just hit on a really important point that I didn't cover, and really gets back to the core of what you're saying is that there is just the most evidence around the ketone ester in terms of efficacy and benefits right now. There's a number of positive results come out from Oxford, but also other labs have found that the ketone can help with endurance, and can help with really profoundly shift metabolism, and there just isn't the data there yet for ketone salts. So watch the space and hopefully because they're so broadly available, more studies will be done and give us more of a definitive answer.

Geoff

Just get a more fuller picture.

Brianna

Yeah.

Geoff

Yeah. I mean I think the studies that have been done on ketone salts have been pretty objectively underwhelming in the sense of null or negative effects, but that's not to say that there aren't applications that ketone salts could be useful for. I think we've seen pretty reasonable data on both ester and salts for lowering blood sugar. So again I think there potentially could be applications for salts, MCTs that will be more fleshed out as more research is done, but I think we're really proud of standing on the shoulders of giants from Kieran Clarke at Oxford, Richard Veech at NIH, who have invented the ketone ester and we're taking it and then bringing it to the world here.

Brianna

We haven't really covered this yet, but it leads on kind of nicely.

Why is H.V.M.N. Ketone so expensive?

Geoff

One way to think about it, is to think about it in terms of where it came from. So back in the early 2000s there was a DARPA program called "Metabolic Dominance" and Doctor Joe Bielitzki who is the program manager in DARPA who is actually on podcasts, well we'll link that podcast, so that's an interesting conversation, wanted to essentially make U.S. war fighters the most metabolically efficient on the battlefield. Think multi-day physically and cognitively demanding missions. And one of the research areas that he put 10 million dollars behind was exogenous ketones, specifically ketone esters. And that program was led by Professor Kieran Clarke at Oxford, where you did your PhD work at, and Richard Veech at the NIH and they're really two giants of the field in ketone metabolism. Some of their works published in the early 90s around some of the key facts on ketones being more efficient than glucose per unit oxygen came out of ... That's really why we've decided and why ketones are a super-food were written by these two academics, and now our close collaborators has we're bringing ketones and H.V.M.N. to the market.

So during that program, equivalent dose of ketone ester that you now can get for around $30, would have been thousands and thousands of dollars. Just traditional synthesis techniques would have been thousand dollars a gram. So think $25,000 per drink of ketone ester. So in that lens, we've brought down the cost of manufacturing down two orders of magnitude. And a little bit behind the curtain on how that was done, was that, in a traditional synthesized technique, you would really be purifying petroleum or crude oil, and that's a typical method to find right carbon length molecules, and then you build on top of that. But with the current process for H.V.M.N. ketone today, we genetically engineered E. Coli to front sugar, so you get sugar, you get some fancy E. Coli, you get the precursors of ketone ester pumped out, and then you glue them together through another bacterial process, and boom, you have ketone esters. So a lot more natural, I would say, a lot more biological a very cleaner method of production, and that obviously has been a lot more efficient that allows us to bring down the cost of goods. And in the future we want to bring that down even further. This was literally the first time, metric ton of ketone ester production was ever done. I know that when you were doing your PhD work, it was-

Brianna

By the liter.

Geoff

By the liter or-

Brianna

In a bucket.

Geoff

Or in buckets and you had 200 ml was all you could have for experiments, and now we have thousands of liters of this end-production. So as we continue to scale volume it's gonna make that cost cover go down. So the theoretical yield is, because inputs are sugar, can get closer to the cost of sugar, and that's our goal.

Brianna

I have a great story from before I did my PhD, it was one of the earliest times I was working on the ketone ester, and I was doing a kinetic study, so watching ketones go up and down in the blood. I was by myself in the research office, and I was using a syringe to measure out volume of ketone ester and it was a little jar, little bit like the same kind of size that our nootropics are in, so a small little jar of ketone ester, and I knocked over this jar that was like 3/4 of ketone ester and I spilled it all down myself.

Brianna

I was covered in this smelly, horrible, slightly viscous, undiluted, unflavored ketone ester, and then I didn't want to tell my boss at the time that I had spilled ... Because I didn't know how much money's worth of ester I'd spilled, so I went back to the cupboard and I took a little bit off the top of all of the other jars that were in there so it didn't look like I'd just binned a jar down myself. I think it's okay to come clean now. We have enough of it now.

Geoff

Yeah, we have enough of it now. So it's somewhat expensive today, but we think it's worth it, people are breaking, again, their personal records using it for all sorts of applications, and hopefully we get that price down even further and pass those savings along to you guys.

Brianna

Well the way that I like to look at it is, I can be in Ironman triathlons, or long-course triathlon, typically I'm gonna be spending several hundred dollars on entry fee, gonna be spending money every week to go swimming, perhaps spending money on a coach, or on special nutrition to do my training. Spending money on flights to get to the events on any build-up events. So really, by the time that you get to that start line, you're probably committed around $1000, maybe more for some people. I mean if you buy a bike, that's thousands of dollars on top of that. So really you've already made a really big investment in your performance, not only in money, but also in time, and so for that day, it's kind of really, really worth it to use it a couple times in training, and then use it on those really big days. And for me, I've used it when I'm racing, and I wouldn't race without it, let's just say. It's always part of my ritual when I do those big important races now, and I think it's worth it.

Geoff

I think that's a good way to think about it just in terms of time and money invested over the training block for a big event. It's like, "Okay if you really want to optimize for your performance that day," it seems like a no brainer to me as well. The recent event that I did was the San Francisco half marathon, and I was ketoned up, absolutely. Let's move on to the next question.

Can it work for weight loss? Can it work for weight management and body composition?

To give context to that, I think, initially when we launched the product we got a lot of comparisons to Kim Kardashians ketogenic diet. Is this gonna melt fat off your body? Can you elucidate that, and unpack that question?

Brianna

At the end of the day, no one's ever done a formal weight loss study with it, so I'm really, really interested to see that be done, because you mentioned earlier we have seen taking ketones, ketone ester drinks, can decrease hunger and also the hunger hormone ghrelin. So there's something there that suggests that maybe there will be an effect on body fat composition, and certainly when people follow the ketogenic diet, they tend to see maintenance of lean mass and loss of fat mass, and part of that could be because the ketones themselves help you to hold on to muscle while at the same time you're using fat. But that said, I think that the headline here is that drinking ketones does not equate to naturally producing ketones from fat. So if you're on the ketogenic diet, you get to a point where you're releasing a lot of fat from your fat tissue, belly fat, and then that's being converted into ketones by the liver. So if you have ketones in your blood, if you're in a state of ketosis, that is because you've been ketogenic, so generated ketones from your fat. So, the ketogenic diet does melt fat off you. But if you drink human ketone, or any exogenous ketone product, then you put ketones in your blood that have not come from your fat. So it's not directly fat melting in the same way that being on the ketogenic diet and being in a state of ketogenic ketosis is, and actually it may even, for a short time, stall fat burning, because ketones naturally inhibit fat release from fat tissue.

Geoff

Just like any other source of calories, right?

Brianna

Exactly, like carbohydrate that spikes insulin and that decreases fat release.

Geoff

Yeah, and protein.

Brianna

Yeah all of these things put a handbrake on your body's natural fat burning. So it's definitely not weight loss in a bottle, but there may well be an application to help people maintain a calorie deficit as part of either a ketogenic, or a non-ketogenic diet. I think one of the key things there is to be consuming fewer calories and whatever diet it is that helps you do that, and any supplements that help you do that, then that's great.

Geoff

I think that's a good way to put it. I think of the ketogenic diet as a reasonable weight management, weight loss strategy for people, but I think there's also an important component of calories in, calories out. And our ketone ester drink has calories, this is an energy substrate, this is something that gives your body energy. So if you're just maintaining the same amount of calories of a standard diet of a bunch of pizza, donuts, whatever, and you just throw ketone esters on top, probably you're not gonna lose weight. Because if you're already gaining weight, you're over caloric and adding more calories, this is not a magic calorie destroyer thing. I mean that's just thermodynamics. But the possible mechanism is that, because ketone esters are very satiating and reduce ghrelin, perhaps you can actually reduce your appetite, reduce overall caloric load through-

Brianna

It may just be easier to stick to the diet, right?

Geoff

Right, and you could probably therefore reduce calories from processed foods, or foods that are obesogenic, and from that mechanism potentially lead to weight management and weight loss.

Brianna

Seems like a good trade right? Like a good trade-out? A couple of hundred calories from sugar for a couple hundred calories from ketones.

Geoff

Yeah this ain't some magic drink that's gonna melt fat off your body, but with the right expectation and understanding and the use cases, there might be some application there.

Brianna

So next question.

Why is H.V.M.N. Ketone good for recovery after exercise?

Geoff

You're the physiologist here, but I can answer that question too. Folks from Oxford and the collaboratives there looked at ketone esters with protein, and with carbohydrate drinks after workouts and compared that to placebo drinks, and a couple of the key results there were improved muscle resynthesis rates, and improved glycogen resynthesis rates. So muscle protein resynthesis, obviously when you're doing a lot of workouts, you're breaking that muscle tissue. If you can repair muscle faster that's obviously good for recovery. I would say to underline the glycogen resynthesis point, little bit of a mixed result. I'll let you dive into the nuances there, but there is some signal that the human body will regenerate and replenish glycogen faster and again, glycogen is the storage form of glucose. You don't store blood sugar floating around ambiently, having too much blood sugar is bad for you, very inflammatory. Our body stores that in the form of glycogen. Mainly, primarily in your liver, but also in muscle tissue. Ketone esters have some evidence of showing that it helps that process of creating glycogen. I would say some other interesting effects of exercise recovery is the anti-inflammatory properties of ketone esters. Of course, after exercise there's gonna be some damage, some wear and tear, so inflammation, and ketones have been shown broadly to be quite powerful anti-inflammatory. I'll toss the ball over to you.

Brianna

I think you covered most of it. I think it's through effects on muscle proteins. So we haven't actually measured ... In order to measure muscle protein resynthesis, you'd need to do a fancy isotope tracer study, but what was done in this study, was they took a little muscle biopsy and they looked for activity enzymes that are involved with muscle protein synthesis. It seems like maybe I'm a bit overly, heavily caveating this, but activity in the pathway doesn't always equal M-synthesis. So just to be 100% transparent, they've measured activity in an upstream pathway called mTOR and they found that that was more strong with ketone esters added in. To clarify the glycogen results, so we have one study that showed improved resynthesis, one study that didn't show any effect, so it's kind of 1:1. I would say that I think that the methodology of the study that showed the positive effect was quite what we call supra-physiological, so above setting that you see in everyday life, so we were, we the royal we, were infusing ketones direct ... No I'm sorry, infusing glucose directly into the bloodstream, and giving ketones as well the second study had glucose and carbs in a drink. So I guess what it suggests is that you really needs to have lots of carbohydrate to get more glycogen-

Geoff

With the presence of ketones as well. Yeah.

Brianna

With ketones, yeah. And then I guess some people would say that with optimal carbohydrate fueling you're gonna get there in the end anyway, so it depends on how much time you've got to recover back to back. But I really do think that the-

Geoff

The muscle protein result is-

Brianna

I think that's real, because we also see if you take ketones before you exercise, then you actually have fewer branch chain amino acids free within the muscle, so it indicates actually breaking down less protein during exercise then also boosting the pathways associated with resynthesis after exercise, so that's certainly interesting. And then I think the reason that a lot of our athletes and teams use ketosis recovery is this inflammation piece, and we're actually looking at this ourselves, hopefully there'll be more research there as well, because ketones can kind of dampen down that inflammatory response that might make you sore or might make you fatigued. So I think that's probably a bigger component than we can say from the data right now, but let's keep an eye out for that. I think that's gonna be a big area for future evidence emerging.

Geoff

Yeah and I think one thing to additionally add was that, ketone esters when use it as a pre-fuel actually spare glycogen and spare or reduce the damage of muscle protein breakdown. So while not necessarily directly related to recovery in this case here, but if you have ketone esters before intense exercise, you're gonna be less damaged, or less depleted so you can therefore recover faster.

Brianna

I guess if you're gonna be doing multiple efforts in a day, I know some of my cycling races that I do, I'll do a 40 minute race at 10 a.m. and then another one at like 1 p.m. and it's if you wanna be stacking up these back to back efforts in fairly quick succession, then not only breaking down less glycogen, but also the chance of boosting all these resynthesis processes would be beneficial.

Geoff

Okay, next question.

Is the ketone ester helpful for diseases? For example, Alzheimer's & diabetes.

Brianna

I'm gonna start off this answer by saying that neither Geoff or I are clinicians, we interpret the literature, and we need to do more, or we, the royal we again, their needs to be more clinical studies looking at how ketogenic diet and exogenous ketones can be used for clinical diseases. So at this stage there is no massive drug trials sponsored, pharma-grade study that's looked at, even for the ketogenic diet, a lot of these studies are in pilot stages.

Geoff

Right, we're not giving medical advice, we're not doctors, consult your doctor and get properly briefed before you take any of this advice.

Brianna

Don't ever completely swap out treatment for diet or ketone drinks. But that said, there is a very big body of animal evidence, and increasing amounts of evidence from small studies of humans that indicate that the state of ketosis could be beneficial for a number of diseases. You outlined a few there in the question, so first up say Alzheimer's disease, well we know that before you get any symptoms of Alzheimer's disease, your brain glucose metabolism is a little bit compromised, so the brain kind of starts to get starved of energy, and actually it's unclear whether that's the chicken or egg problem in the development of the protein mis-folding that characterizes Alzheimer's disease. And so a working hypothesis is, that if you can re-up the brain's energy using another fuel, in this case ketones, because it's the only other thing that the brain can use then you might-

Geoff

Probably can use lactate and other things but-

Brianna

True, okay I appreciate you calling me out there.

Geoff

But the ketones are a dominant-

Brianna

Ketones are a good fuel. So if you can re-up the brain's energy using ketones, then you may mitigate some of the downstream problems. Or maybe even in some cases, reverse. So there's quite a few papers that have used medium chain triglycerides in Alzheimer's disease, and I've seen some promising results there. There's also one published case study that used the ketone acid that's in H.V.M.N. Ketone for a six month single case study of Alzheimer's disease, and there are already positive results there as well. So certainly some good signal that this could be an area to watch out for.

Geoff

Yeah that's the Mary Newport paper right?

Brianna

Mm-hmm (affirmative) published in 2015.

Geoff

So just google "Mary Newport Alzheimer's Ketone Ester"-

Brianna

She's a great resource, and she's a big advocate for coconut oil and using ketones to treat Alzheimer's disease, so I would recommend people looking her up if they're interested to find out more there. Then to move on, you mentioned diabetes, so we know again, that low-carbohydrate diets can be very helpful for people treating diabetes. For example we have here in San Francisco Virta Health, not only offering a service but also publishing the results of people that go through their program, reducing carbohydrate intake and losing lots of weight, and managing their hemoglobin A1c, which is a measure of how bad your diabetes is, managing their blood sugars and getting off their medications. So certainly a good signal that ketosis is interesting there. But that's because probably mainly because they're reducing the carbohydrate intake in their diet. But that said, it's a pretty consistent fact across different types of exogenous ketones, that when you raise ketones in the blood, then your blood sugar drops in response. And I like to think about this as like, most of our body's have a fairly well functioning thermostat, where we want to have the right amount of fuel in the blood. So with diabetes the thermostat's ability to correct for sugar is compromised either through insulin insensitivity, or lack of insulin production. But when you've got ketones, the body's like, "Oh we've got this energy we need from ketones, so we can release less sugar."

Geoff

That's a good analogy, I like that.

Brianna

We really think that the liver releasing sugar at a high level is a big part of the problem in diabetes, not just the consumption of carbohydrate in the diet. And so when you drink ketones, you're telling the liver, "Hey you don't need to release quite as much sugar, we've got this energy already in the system from ketones." And so pretty consistently, we see a fairly meaningful drop in blood sugar after people drink ketone esters, I mean-

Geoff

Yeah, I mean we've done this finger stick study many, many times on people and I see 10, 15, 20% drops I mean-

Brianna

Well yesterday we dropped someone from 5.2 millimoles to 3.9 millimoles in just under an hour right, so that's pretty cool.

Geoff

Yeah, and that's for folks that aren't working in metric, that's around 20-25 mg a deciliter. Which is massive.

Brianna

So it's pretty exciting, and actually this is not just what Geoff and I have seen out in the wild, but there's a public paper published from the University of British-Columbia where they gave ketone ester prior to an oral glucose tolerance test, which is where you consume a sugar drink with 75 grams of neat sugar in. So they saw that the area under the curve, so the amount of sugar that appeared in the blood afterwards was lower, so showing that the ketones actually helped to modulate the response to sugar, so we don't look at ketone ester as a straight-up kind of swap out for the ketogenic diet, because obviously restricting carbohydrate has global effects on the body, but certainly it has some interesting implications for blood glucose control we're interested to see.

And the thing is with diabetes is, not only the blood sugar control being an issue, diabetics have higher rates of Alzheimer's disease, and heart disease and a number of other things that may be actually positively impacted by ketones. Often we focus in on the blood sugar as the problem, but I think these other comorbidities are massive also, and there's a real potential for ketones there. So, talked about Alzheimer's, we've talked about diabetes, we're really interested in traumatic brain injury, especially with our work through the military and again, there's a really good body of animal research there showing that either putting animals on a ketogenic diet beforehand, or injecting them with ketones after an injury can maintain brain energy levels, and decrease the lesion size, so the damaged area size, for animals given an impact injury. So we're really interested to see what we can do to further that research. Also, we're very interested for potential ketones in some forms of cancer. Not all forms but Doctor Dom D'Agostino's lab over in Florida has done some work with their ketone ester, and looked at tumor size being reduced with ketone ester-

Geoff

This is animal models?

Brianna

This is animal models still. And then also potentially go back to what we were talking about in terms of protein and recovery, ketones could spare muscle wasting that often occurs during cancers, called cancer cachexia. So that's another area that's really interesting as well. Is there anything that you'd like me to talk about that I've not talked about? I mean we've heard of people using it for a number of different things, Parkinson's disease for example.

Geoff

Or COPD right? I think again, how do the ketones work in the system? I think all the use cases, or mechanism that you describe seem sensible but if there's anything that's-

Brianna

Inflammation is gone.

Geoff

Effect of inflammation, like COPD, we've seen anecdotes, we had a conversation with Russell Winwood on a previous podcast who was a COPD patient and he sees material expansion in his ability to breath with ketone ester.

Brianna

He's done blood work as well, so it changes his inflammatory markers in his blood work.

Geoff

His CRP.

Brianna

Exactly.

Geoff

His C-reactive protein actually goes down.

Brianna

So, that goes down a lot. So there's a published case report, I think it's using a ketone salt in Crohn's disease, and that person had fewer exacerbations as well. We haven't even talked about epilepsy, which is the original reason that the ketogenic diet was developed.

Geoff

Right.

Brianna

So there's a number of different areas. Again I'm glad that you sort of highlighted the inflammation story there, and that really is very, very broad, and there is a number of conditions, even mood disorders, that have a very big neuro-inflammatory component. This isn't to do with, energy production in the brain, this is just to do with inflammation in the brain, and again there's some interesting animal models there, two or three papers have shown that ketones can reduce neuro-inflammation, and then affect the behavior of the animals in these models as well.

Geoff

Yeah, and that reminds me of one of my favorite peptides, brain drive neurotrophic factor. And there's been some early work showing that exercise induced ketosis, elevates BDNF, and that by extension-

Brianna

I did not think that they inject ketones as well, so as one part of that, it's a really nice series of experiments. So they start off with exercise and then they move on to injection of ketones as well and then-

Geoff

So direct injection of ketones, directly-

Brianna

Increases BDNF, yeah.

Geoff

Oh, okay.

Brianna

So BDNF, for those of you at home, that's Brain Derived Neurotrophic Factor, and it's really important for maintaining brain health and formation of connections between neurons and neurogenesis.

Geoff

Yeah invaluable from a neurotrophic perspective, it also potentially used from a therapeutic perspective, with folks-

Brianna

Was perturbed in various schizophrenia or-

Geoff

Neurological conditions, yeah I mean-

Brianna

Lots of areas that we're interested in that, to go back to the caveat at the start, a lot of these things are very, very early stage, and really need some good quality small trials, move into bigger trials before we can definitively say.

Geoff

Yeah, a lot of work to be done before any actual claims can be made. But I think talking about the research and highlighting the research streams is always helpful to encourage discussion and analysis here.

Brianna

Alright, next question.

Why does H.V.M.N. Ketone taste like it does and what can we mix it with to make it taste better?

Geoff

Yeah, I don't think it tastes that bad, so I can sip on it. Sip on it like a fine whisky, I mean it's definitely not a soft drink. But to answer the question a little bit more seriously, it's definitely a bitter drink, it's bitter because of the ester bond in the ketone ester. So as Bri was describing in earlier answer, there's an ester bond connecting the ketone BHB with butanediol and a lot of the most fragrant, flavorful chemicals, like fruit flavors, vegetable flavors, they're all esters, so this particular ester is just a very potent bitter flavor. So it's not because there's weird additives or weird processing mechanism, it's literally the form of ester molecule structure that is causing the taste. But I don't think it tastes too bad. I think that there's probably an adaptation process towards it where you just get more used to drinking ketone esters, but a lot of people also start mixing it with things. I've personally experimented quite a bit, and I know a lot of people in our community have experimented with H.V.M.N. Ketone with different drinks and different concoctions. I was just talking to Amy yesterday, and she was saying that mixing with sparkling water, like La Croix tastes really good. I've mixed it with matcha green tea, or cold brew coffee, with a little bit of milk, and that seems to mellow out a lot of the bitterness. Or that bitterness is merged with the coffee bitterness. So it's no longer surprising. I haven't mixed it with fruit juices, that could be an interesting experiment if people have tried it-

Brianna

A lot of people have done that.

Geoff

That would be interesting to hear the feedback there. Have you played around with mixing around?

Brianna

I tend to just shot it before I go out on my long runs and stuff.

Geoff

Yeah you do utilitarian.

Brianna

Yeah, I don't mind if it doesn't taste good. And it tastes an awful lot better than it used to.

Geoff

So I would say, "Hey it tastes like it works." I don't think it tastes that bad, people that have written about it or blogged about it, come on, this is some really cool technology, it works. Handle the bitterness for a few seconds.

Brianna

And we're working on it.

Geoff

And we're working on it. Okay next question.

Why not just eat more carbs as a fuel source instead of adding a ketone ester?

What's the difference here, what's the specialness? There's 120 calories in ketone ester, why not just eat another 120 calories of glucose?

Brianna

Well I guess really, the headline here is, it's probably not practical or possible for athletes to consume optimal carbohydrate. Even the most elite athletes, so let's look at Eliud Kipchoge recently in Berlin, he was re-feeding every bottle station, and that's probably as close as it gets in terms of drip-feeding the body carbohydrates to ensure a steady optimal delivery, consistently the whole time during power exercise. Most of us out there in the real world don't do that. We'll have something to eat before we go out, or we'll have a goo pack every hour, or we'll forget, or whatever. So there's problems in maintaining a constant carbohydrate delivery. It's not practical to be like, "Oh well I'll just eat another 120 calories of carbs." Not only because of the practical reasons, but also, quite a lot of people have GI issues with high amounts of carbohydrates. So it's very difficult when working on new technologies but it's not super straightforward with what's available to get more carbohydrates into your body through the gut. There's different types of glucose uptake, or carbohydrate uptake transporters in the gut and they get saturated at certain concentrations, and past that concentration, anything is just gonna sit in your gut, and if it sits in your gut then it's gonna cause water to roll back in to your gut and that can cause issues.

It's difficult to overload on carbohydrate in a way that isn't net-bad for you. So in that kind of setting, adding ketones is a good way to get extra energy into the body that is not going through any of the same pathways, it's a complementary pathway. If you then add ketones in on top of optimal or near-optimal carbohydrates, then if you're staging in this ... If you're not able to refuel every 20 minutes like Kipchoge, well you've got the ketones present in your blood, your body will burn the ketones in preference to the carbohydrates. So it's almost like a hybrid car, though at some intensities it's able to burn electricity and then it switches seamlessly to gas. So with the ketone, when it's there and it's present you'll burn the ketone, and then when it runs out you've got the carbohydrates left over that were spared by the ketones being present to just sort of transition into burning that. So it really helps with partitioning out the available resources over this long duration activity. That's probably the neatest way to describe it, I don't know if you have anything else to add in there. I think maybe also say that ketones themselves being a very oxygen efficient fuel source, so it's gonna do good things for efficiency in theory while your exercising, and reducing lactate levels as well. All of these things are gonna help you get through, so long as you can continue working at the same output. So I think a lot of people wonder about, if ketones, if you want to be doing glycolysis, burning carbs whether than burning ketones, but from everything that we've seen so far the workout is never compromised. It's always the same, or it may be even a little better the longer that the event gets. So I kind of look at it as a tap, and if you're going to be flowing 100 units of water through the tap, so long as the tap can continue flowing at 100 units per minute, then that's great-

Geoff

With a little side tap of ketones.

Brianna

Yeah you would take 20 units of that off. And you're not completely shutting off carbohydrate burning, ketones are accounting for about 14%. Your fuel oxidation at an intensity of around 70%, so I would just say from everything that we've seen, it will be interesting to see more very basic mechanistic studies done to look at how these fuels interact. But from what we've seen, the higher intensity you go, you can still burn carbohydrates and having ketones sort of spares the carbohydrates for later on. It's a completely novel physiological state. Not having ketones present, and having ample carbohydrates and also having undergone keto adaptation, or fat adaptation to the diet to get yourself into ketosis. So some people are like, "Oh well you lose your sprint power when you go keto." But that's because you've, over many, many days, trained your body to burn fat, and you've almost got gunk in the pipes that you burn carbohydrate. So instead of being able to flow 100 units through your tap, you're down at like 80 already before the outset.

Geoff

Right but the ketone ester eliminates that problem.

Brianna

But the ketone ester means that your tap capacity is still 100, you've still got all of those.

Geoff

Because you don't have to keto adapt to use ketones.

Brianna

No you've still got all of those enzymes and everything that you need to do a high-intensity exercise. So more research should be done here, but it looks like having every single fuel source available to the body is only gonna help maximize performance.

Geoff

Yeah I think one way to unpack this even further for folks who don't have a physiology background is that when people talking about glucose being fat adapted, or running on carbs, it's never black or white, it's always a mix of fuels, and so when you're saying, "Oh you primarily run on fat." That's like 70-80% fat on the high end, and running on sugar, it's again like 50-40, 50, 60, 70% sugar, it's not black or white, and I think ketones just adds a third fuel source, and I think the phrase "fuel partitioning" is a really good phrase. It allows your body to partition it's mix of fuel more optimally.

Brianna

Yeah I guess you can think of it as like a ship and you're gonna go and sail across the ocean, staging out, your gonna eat first, then you're gonna eat from your rations of the things that are gonna go bad first and then you're gonna eat the dry biscuit and the stuff that's gonna keep for when you've been on the voyage for several days. So it's like you're looking at the resources available to your body to complete the work required, and then staging that out over the effort.

Geoff

Yeah and we just give you third one that doesn't exist there normally. You can't eat it through carbs, you can't eat it through fat bombs, if you fast to get ketones then you don't have any carbs left, so this is a novel physiology. So to answer it more succinctly, you just unlock a new physiological state, where you have carbs and ketones at high levels at the same time, which doesn't occur in nature. Where if you wanna have availability of ketones you've gotta be in a ketogenic diet or fasted down, very low glycogen and availability of fat and ketone burning, or the opposite way around you have a lot, a lot of carbs and very little ketone and fat adaptation going on.

Brianna

Well I think that was a good answer. Hopefully people will find that useful, so the next question, and it's a little similar to one we had a little earlier, so maybe we can answer this kind of quickly.

Can I use H.V.M.N. Ketone with a keto diet?

Geoff

So you can use it with any diet, just to clarify. So in all the athletic studies that were done at Oxford these were done in athletes that were eating a standard mixed diet, and using ketone esters acutely to increase performance. So, to expand the question a little bit, you don't need to be a keto athlete to use ketone esters to get better performance. But how to use it with a keto diet? So I answered this a little bit in terms of, this is a really great tool to help you transition into a ketogenic diet or a fasted state. Again, when you start on a normal diet, you have a lot of enzymes more optimized towards glucose burning or carb burning, and as you shift into a fat burning state, or a state of ketosis, a lot of this molecular machinery needs to readapt itself a little bit, so swap out enzymes, up regulate certain things, down regulate certain things. And in that transition period, your overall energy might be a little bit low, so you might feel a little sluggish, a little tired, ketone esters are a really big infusion of ketone energy, really, really, quickly. I think one thing that's kind of interesting to note is that I don't think it's been studied formally, but anecdotally, as we've been testing it out on ourselves, and folks, that people that are keto adapted seem to feel, subjectively, the effects of ketone esters in their head more. And I know we've been talking about this, that we hypothesize that it's because you have increased mono carboxylate transporters, not MCT oils, but these transporters-

Brianna

Confusing.

Geoff

That transfer ketones into the cell, so it kind of makes sense. So I'd love to hear if that's consistent with folks out there listening, if you are keto adapted, do you feel the effects of ketone ester more?

Brianna

At the end of the say, if you are on a ketogenic diet, the one thing that you do not want to do is consume carbohydrates to spike your blood glucose and insulin. That will derail you out of the ketogenic state. If you need a pick you up of energy that's rapid acting, that's not glucose, then ketones are a good alternative. But, and again the caveat, it's not 100% clear, as I did say, in the temporarily slowed down fat release, like how that will work out, but it's definitely a glucose free ... It's keto compliant.

Geoff

100% keto compliant, yeah. Great, next question.

What are the weirdest things you've heard people using ketone ester for?

Brianna

Well we've got a big time fan of ours who has chronic fatigue, so ME and she uses it as part of when she's having tough days, and she really finds that the ... And she's very experimental, so she'll use it along with hyperbaric oxygen, and sometimes she gets in touch and she's been doing all sorts of crazy stacks with the ketone ester which I always think is fun to hear about. I mean I guess for me, some of the stories of some of the athletes that use it, it's always kind of inspiring, like another friend of mine did a 12 hour long endurance race, and he averaged 40 kph for 12 hours on a bike.

Geoff

On bike? Wow.

Brianna

Yeah and he used ketones there and he said it was really great. Someone else who did the Leadville 100, super long running race I think.

Geoff

A triathlon? 100 miler?

Brianna

It's really cool hearing people use ketones like that.

Geoff

Yeah I remember someone trying to do an extended fast with ketone esters, like three or five days, just drinking ketone ester, that's something I've wanted to do, I haven't gotten around to doing that.

Brianna

I know someone that uses it for jet lag. One of our investors, he always messages me after he's been traveling and he's like, "Used the ketone ester, flown over to Europe." But he's also super experimental and he wears blue blocking glasses for the week before he flies to get into alternative circadian rhythms and then he also uses ketone ester. So some fun bio hacks going on there as well.

Geoff

Yeah I think people are also experimenting with sleep, using that right before sleep, if that helps them sleep better. Yeah, I think a lot of different applications. I think another interesting experiment, people have been using it for free-dive breath holding.

Brianna

Yeah.

Geoff

That gives an interesting use case. So if you guys have interesting use cases and applications I'd love to hear them. It's always fun to see how people are using our product.

Brianna

Some people are like, "It worked for me for this!" And I'm like, "I have no idea how." I just can't even work this out. It's kind of a fun problem to try and unpick. But it's definitely a testament to the crazy things that people put their bodies through, but also how every body is a little different and definitely a range of experiences with human ketones.

Geoff

So we've got a last couple questions here in this FAQ episode. How is H.V.M.N. pursuing additional research on our ketone ester.

Brianna

You know I think, hopefully people can tell from the tone of this whole episode that there's a lot of questions still to answer, and we're really excited to be custodians of the ketone esters as tool for research. So we have our own effort that we're working on with the U.S. military, and we're interested in how ketones could help with brain function, especially in extreme environments. There is a number of other little studies being run with the military that we're helping to support. I'm really interested to see the, and hear the feedback from people tested it in the field. I'm really proud of those efforts. Also, just looking to find really, really top quality researchers in the basic science fields and in the clinical fields, who are interested, who approach us, and are interested in running case studies or clinical trials with H.V.M.N. Ketones. So we're working hard to support the research community in these studies where we can.

Geoff

And hopefully we'll have some exciting announcements related to our research efforts soon. I know that you've been hard at work leading a lot of our efforts here. So I'm excited to see these seeds bloom here.

Brianna

Okay and I think we're getting to the end now, so nice one to wrap up.

What was the hardest thing about bringing ketone esters to market, and what are the current struggles that we're working on here at H.V.M.N.?

Geoff

It's been a beast of a project, so I think we've hinted at it throughout the conversation, but we've really stood on top of the shoulders of giants. You know your advisor, your research advisor, Professor Kieran Clarke at Oxford, Doctor Veech at the NIH, really kicked this off in the early 2000s in the terms of getting the basic science, the basic synthesis, the basic safety and efficacy data proven out. And my last conversation with Kieran, just taking it through FDA grasp took her four years of research and work. So there's just been so many hours and months and years of work with her, the broader team. PhD students, research students have come through the lab and gone off to do other things. It's been a massive community effort behind bringing a ketone ester from a concept and an idea to a real molecule, to something that's been tested in animals, to something that's been tested in humans. It's been something brought through safety standards, that's brought through efficacy studies, and now something that's commercially available. So I think that's a lot of responsibility for us to have the right word around it, being proper custodians and responsible custodians and bring this product to more and more people. I think the current struggle or excitement is, "How do we make this more available to everyone?" I think is the underlining, undergirding principle here. How do we democratize access to what we think could be a fourth macro-nutrient? And the ways that we think about it is, of course, cost, form factors in palatability, can we make it taste better or just more interesting form factors? And just like I was hinting at, hopefully announcing additional research results and research streams, hopefully we'll make announcements around cost, form factors, and in taste soon as well.

Brianna

It's kind of cool to see how much everyone here has got their heads down and working to communicate, educate and also just make the best products that we can, and stay true to the corporate supports of the company.

Geoff

Yeah, so those are all of our questions for the day. It's always fun to chat with you Bri, that's fun. I think these are my favorite episodes, because we talk about a lot of this tuff offline, it's fun to expose some of that thinking and nuance to how we make decisions on things.

Brianna

It's funny because I feel like we go to 90% of the detail that we would go into offline, and then sometimes we've got to pare it back and make sure that the folks at home can follow us. It would be interesting to hear whether this is the kind of conversation that you like, or whether you want more detail, or whether you want us to keep it simple.

Geoff

Of course. Send us additional questions if we didn't answer your FAQ, we'll be very much more than happy to have part two of this FAQ of H.V.M.N. Ketone. So until then, thanks so much.