The Latest Research on Exogenous Ketones and Other Performance Enhancers [transcript]

Written by Christopher Kelly

April 24, 2019

[0:00:00]

Christopher:    Brianna, thank you so much for hosting me once again in Fran Sancisco. My five-year-old daughter, Ivy, has this delightful thing I refuse to correct. She calls San Francisco, Fran Sancisco.

Brianna:    Oh, dear.

Christopher:    I love it. It's fantastic. She said that we should cancel the trip because it was too foggy.

Brianna:    Too foggy?

Christopher:    Too foggy.

Brianna:    Down in Santa Cruz or too foggy up here in San Francisco?

Christopher:    Yeah, the sea fog rolled in last night and too foggy. That's not a very good reason to not come to San Francisco.

Brianna:    Not if you're not going to be able to drive safely up here. Got to watch out for that fog.

Christopher:    Can you give us an update on your racing and training? For those of you that don't remember the last interview that we did, you were transitioning out of being a world champion rower into the crazy world of triathlon, up out of the frying pan into the fire.

Brianna:    Yeah. I don't know why I thought that it would be easier. I mean, I guess now I don't have to turn up at 7:30 a.m. at a designated place with other people. There'd be like almost an attendance register. It was kind of more like being at school. It was kind of a bit more institutional. Now, I still have 15 hours of training a week to do but I can start at seven or quarter to seven. There's just that little bit more flexibility. I can start from my door. I think it's definitely nice being able to be a bit more in control of your training and modulate it a bit.

    I think I've got the type of personality that's always looking for that little bit more. So, when we last spoke, I was training and racing for some cycling and some running and it was kind of exciting. I was improving a lot on just the training that I was doing. I was doing my own thing. I know a bit about exercise physiology and how to train and that was all going pretty well for me.

    Last season, I did my first half Ironman and in my first ever half Ironman race I qualified for the world championships which were in South Africa. It was an awesome--

Christopher:    Are you going?

Brianna:    No, I went last year.

Christopher:    Oh, shit. I didn't know. I didn't know it was in South Africa.

Brianna:    No, it was awesome. I qualified in Mexico and that was a great trip. And then I had just six months or so to prep for South Africa. It was in Port Elizabeth. I flew into Cape Town which is really beautiful, and I had a chance to have coffee with Tim Noakes which was pretty awesome.

Christopher:    That's amazing.

Brianna:    Yeah. He's been a fantastic source of interesting ideas and interesting discussion and perspective. He's definitely seen and done a lot of interesting things with his career. It was great of him to make time to just meet up with me one on one. And I also met his professor at the University of Cape Town. His name is a. He used to be one of Dr. Noake's or Professor Noake's students and now Dr. Bosch works or is working on a two-hour marathon project independent to our marathon project called Sub-2.

    I had a chance to connect, do some science learning while I was down there and then went from Cape Town over to Port Elizabeth, went on safari for a day, which was great, saw some lions, saw some elephants, and then did the race. It was pretty good. I definitely had a lot to learn. I think competing in a provincial Ironman like one of the smaller races, there's not the depth of field that there is at the world championships because everyone is qualified.

    But it's very cool to be in. There's such a big buzz at the venue and it was pretty inspiring to see so many people of different ages competing. They have the women's race on a Saturday, the men's race on a Sunday so we were able to actually watch the men's elite race and get really up close and personal to those guys as they were doing the run, which was pretty awesome. For myself, I came in the top half of people of my age group. I think I'd have liked to have done a little bit better but I think it was decent result.

Christopher:    How do you decide that though? I always think that it's so arbitrary as we come up with this idea that this is the time I have to meet, this is the position I have--

Brianna:    That varies course to course, right, especially on an Ironman. If you've got wind or something on the bike it's going to slow you down a lot. But I think one of my biggest mistakes that probably everyone listening who competes in triathlon will kind of shake their head at this but I ended up with a drafting penalty. I think I lost -- I think it's five minutes, which is not a small amount of time.

Christopher:    So, how long? Was it deliberate?

Brianna:    No. It was so frustrating because starting off on the bike, there were tons of people everywhere and it was absolutely unavoidable to be drafting. I road ride quite a bit and I road ride in groups quite a bit so I'm pretty comfortable inches away from people's wheels. In the initial part of the race, the road was absolutely full so I was drafting and moving up through the [0:04:07] [Indiscernible] I was like, everyone is drafting. They can't get everyone.

    And then it started to string out and we were on this long straight road and it's quite ten bike lengths. It's really long distance that you're not meant to be within people and it's difficult to judge that. And in any case, it was this one woman who overtook me and then we'd slow down and I was overtaking. I wasn't really paying that much attention but people aren't particularly consistent in triathlon and I feel like I'm quite consistent.

    Anyway, I ended up -- This woman overtook me again and I was moving back up to her and that was when I got pulled up. But it's hard to know whether or not your violation of that rule but that was an easy five minutes that I just gave away. I still did a PR time but, I mean, it was only my second one so it's not like -- It was decent. I enjoyed the experience and the event. It was good.

Christopher:    And you're going to stick with it?

Brianna:    So, right now, I'm training for full Ironman.

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    This weekend, I'm racing a half Ironman. It's sort of like a prep race. For me, it's sort of like a bucket list thing. I really want to see how it feels to compete in that event.

Christopher:    I really want to feel what it's like to completely tank my hormones.

Brianna:    Yeah, well. I think I've got six months of this in me. I started working with Lesley Paterson. I know you've had her on the podcast a number of times and that was definitely a big step on for me from just setting my own training to getting a coach and getting some structure. Now, it feels a bit more, with the rowing training where I go out and all of sessions have got prescribed work and zones. I have the energy for this for short amount of time and I know how to do it from my past.

    The ultimate goal will be to qualify for Kona this time around. That's what I'm really training really hard for. And if I can do that then I'll compete that this year and then maybe move on to a different challenge. I did my first marathon in December as well and I'm enjoying running. Here in Northern California, there's a really great bike racing scene and I'd love to do some stage racing and some time trail. I think I'm pretty good at that.

    I'm not super tactical just yet so I think the time trailing would be a pretty good event for me. We'll see. There's an endless world of possibilities in sport and I'm excited to explore them all but it seems like a good time to be building on the half Ironman, do the full distance, see how I enjoy it. I don't know that I'm going to be a career triathlete. I've done my professional sport. But it's interesting how many successful business people are in triathlon. Mainly, I think it's interesting because they have so much on in the rest of their lives they shoehorn this training around.

Christopher:    Yeah, it's incredible.

Brianna:    It's sort of this -- It's this type A kind of person who is super driven and kind of a bit of a lone wolf maybe and into data. It's interesting for me to get a peek into that kind of character.

Christopher:    I struggled with one sport let alone three.

Brianna:    It's tough trying to balance all three. And back when I was training previously for my half Ironman and setting my own stuff I only swam once a week and I was training maybe twice some days but mainly once. And now, setting on Lesley's program, it's pretty punishing fitting it all in. And you definitely feel like you're compromising your progress in each of the individual sports you could be progressing.

    But swimming now more with Lesley's program and I feel like my swimming has really progressed and doing more stretches cycling and I feel like that's really progressed. I don't feel like I've got that much better at running on this training program but I think I got a lot better at running when I was training for the marathon and running every single day.

Christopher:    That's great.

Brianna:    Yeah. I run a 3:15 marathon. It's not too bad, the first one. Well, 3:14, under that, kind of qualified for Boston, maybe I'll train for that next.

Christopher:    Wow, blimey. Listen to her. Maybe I'll train for that next.

Brianna:    Well, I mean, I've qualified so maybe I'll just see if I can go faster.

Christopher:    So, do you take the ketone ester when you're doing a triathlon?

Brianna:    Yes. I tend to take it in transition one because sometimes there're kind of like buzzy feeling that it gives me when you're also getting in cold water and there's a lot going on. I don't know. Swimming is a bit of a weird alien environment more so in the open water than in a pool. It's not sort of -- There's just a lot going on and so I don't want to be too zippy in the water. I just want to be quite tranquil.

    And I feel like the swim, especially in a half Ironman, it's 35 minutes, and a full Ironman, it's about an hour. It's very different than cycling and running so I don't feel like metabolically I'm -- At that stage in the race, you don't need to take on any extra fuel. So, I take it on the start of the bike for the half Ironman where I feel like it kind of gets me through that first couple of hours of the bike in much better shape than otherwise.

Christopher:    Okay. You better tell us your exact dosing regime because people are going to be asking.

Brianna:    I take one bottle just because it's much easier just to take the one serving rather than measuring out more or less. But I also would take it with carbs on the bike as well. So, I'll have electrolytes and a little bit of carbohydrate in the bottle and try and take on fuel every sort of 45 minutes or so. I'm definitely not running at -- I do a lot of fasted training. Lots of my training, three days a week maybe, I'll train in the morning after an overnight fast. I would say that I'm still pretty metabolically flexible. But in the race I'm trying to make sure that I drip some carbs during that time.

Christopher:    Yeah, all the energy from all the sources.

Brianna:    Yeah. Well, you need it when you're going to go for ten hours on an Ironman.

Christopher:    Do you find it hard to fuel at that level when you're used to -- I'm sure you don't eat a lot of stuff when you're going out for a--

Brianna:    No, no. But I think in a way that means that when I do fuel even just 50% better I feel freaking awesome. I don't really do shots or anything like that and I prefer bars and real food. Especially when you're doing long distance triathtlon, it's not ever so intense that you're going to -- It's a cumulative intensity. It's not like you're doing sprints or anything like that. So, you've kind of got the breath and the feeling in my body that I can eat a bar and digest it or eat like a PB and J, little sandwich or something. You can have some real food, not something like that, banana, whatever you can carry with you.

    I prefer to eat that than I would just drink energy drinks. With the half Ironman, when I get to the run I switch on to the gels. Just to get me through that last little bit, kind of if I need a bit more instant energy source.

Christopher:    I envy you that. On the mountain bike, I think I'd die if I try to eat anything. It's just like--

Brianna:    But you guys, that's like sprint and then stopping. You can't -- Triathlon is much more like rowing in that it's just how much wattage can you put out for the set period of time. So, you just have to set and produce the power on the bike and drip it in. You don't need to sprint to get ahead of anyone.

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Christopher:    And so what other applications are there for the ketone esters? It's been a while since we spoke. Who's been using it and what for?

Brianna:    I mean, in terms of sport, we've been working with football teams, American football teams. We've been working with elite cyclists. A number of teams from the Tour de France are using it. It's been really cool to see not only the teams buying it but a number of the individual athletes coming to us and buy it as well. We're excited to see that market continue to grow. We supplied a few basketball teams and a few -- A lot of people in the elite level sports are early adoptors and just trying out some baseball players, some fighting, from fighting sports as well.

Christopher:    Okay. And what are the fighters and the American football players? Are they more interested in the ketone as an energy substrate or are they interested in the neuroprotective properties possibly?

Brianna:    Yeah. I mean, there's different ways you could look at it. Some people are using it more for the steady energy feeling and cognitive boost that they feel like they have. In a way, that's supported by some of the preliminary data. So, Brendan Egan published a paper looking at decision making, higher order cognitive functions after ketone ester drinks. They're seeing improvements there. That's consistent with what we've seen with our research that we've done with the military. The more complicated the task gets, the more likely that you are to see a difference with ketone ester once you put a stressor in there.

    There's definitely some signal there that the decision making cognitive function may be improved in that kind of setting. To me, it would be quite interesting to compare to caffeine or another stimulant.

Christopher:    Right. Something where you feel something. An active placebo, they call that.

Brianna:    I suppose in most cases they're comparing it to carbs and glucose. I mean, that's something at the very least. I think people are interested in thinking clearer but then also, as you alluded to, there's the neuroprotective component and I think the more people get into the basic science there and look at all the animal work that's been done the more people believe it. But we're still not there with having like a really robust human studies to support that.

    It just makes total sense when you look at, like I said, the animal work where there are lesion parts of the brain or makes part of the brain hypoxic and then look at brain ATP levels with and without extra ketones and on top of that there's this huge rescue of brain ATP levels when ketones are also present. And so the basic mechanism that goes with hypoxic or traumatic injury as you get the insult itself causes tissue damage and harm. And then you have secondary phases of injury where there's hyper excitability, oxidative stress and hypoglucose metabolism. In that time, the parts of the brain get energy starved and ketones can rescue that. It's what a number of these studies have shown.

Christopher:    Why is it that it seems to be glucose metabolism that gets impaired and then you can still use lactate and ketones and other things?

Brianna:    I mean, part of it could be insulin sensitivity like breakdown of the insulin signaling in the brain that's going to affect glucose uptake. But also it could be--

Christopher:    Is that relevant though? If the cell is screaming out for energy, is insulin really going have any say in that? I don't--

Brianna:    But, I mean, people call Alzheimer's disease, which is again compromised brain energy metabolism, they call that type III diabetes. There's a high incidence of it in people where there's insulin insensitivity as well. I mean, I think at this stage, we can't rule out there's something happens to the insulin signaling pathway that compromises that action. And that would explain why it's just glucose. Or another potential point of regulation would be pyruvate dehydrogenase and sort of actually affecting in them as well. I think at this stage maybe we know a little bit about it but I think it's maybe still being--

Christopher:    An area.

Brianna:    Yeah.

Christopher:    Can you talk about some of the research you've done with the military? Is any of that published?

Brianna:    It's not published yet so we're just working on extending that into another research effort with them but we certainly plan to write up our findings and people can actually find this online. I can talk about this. This is public. We were awarded some funds from the US military to look at ketones and hypoxia. We would give people ketone drinks, turn down the oxygen and make them solve cognitive puzzles. Again, as I mentioned before, we found similar results in that higher order cognitive tasks were sort of ketones were protective against the hypoxia induced decline in cognitive performance.

Christopher:    What would induce hypoxia in the real world application?

Brianna:    Well, I mean, in the military, they're doing even missions at altitude. They're being dropped or the recent problems with some of the air systems in some of the planes. So, there's a few things. Diving as well. There's a number of extreme environment settings. For me, I've looked at hypoxia as a tool to stress the brain and allow us to tease out subtle differences that might be difficult to measure otherwise.

    When we conceived the exercise studies in Oxford that we were looking for changes in performance with ketones, we wanted to use exercise as a metabolic stressor that makes energy scarce or changes the balance between energy supply and demand in a way that mimics disease in some case.

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    There's a mismatch between supply and demand. And then we can see how ketones are affecting that. And so similar here, rather than exercises like a physical stress, in order to stress the brain, we're turning down the oxygen that makes it harder for the brain to operate and so we see cognitive performance in a number of domains tailing off. And if we mitigate that by ketones then we're doing something whether that's providing the extra substrate or sparing, accurately decreasing oxidative stress or any number of things that could be actually helping with that cognitive performance.

Christopher:    Talk about the one hour cycling record.

Brianna:    Yes. So, that was one of my favorite things that we worked on in the last year. It's kind of a roundabout story. I was studying in Oxford and one of our team members who's helping run the experiments was a cycling coach. And then he gets back in touch with me recently and he's still coaching cycling not researching ketones anymore. He's like, "I am coaching this athlete who is trying to break the one-hour Velodrome world record."

    That record is somewhat legendary. Bradley Wiggins has gone after it, very decorated British Olympic cyclist. Back in the early days of when the record was conceived there were all these innovations around the bike positioning. The guy who -- I'm going to get it wrong. I want to say it was Greg Lemond who made his bike out of washing machine parts. There was a lot of--

Christopher:    I know you mean the flying Scotsman, don't you?

Brianna:    Yes, that's it. Is it correct, Lemond? No?

Christopher:    No, it's not. I'll look his name up. That's a really interesting movie that I've watched.

Brianna:    You're going to need to be more specific than that. Cycling. Chris has put flying Scotsman and then it says the train.

Christopher:    Graham Graeme Obree, of course, the flying Scotsman.

Brianna:    Yeah. We're looking at pictures of him. You can see that super aggressive arrow position and he was very innovative. It's a really storied record, a very cool record.

Christopher:    That's right. And then I think the, if I remember correctly, the UCI changed the rules in 2014. Jens Voigt got the record.

Brianna:    Shut up legs.

Christopher:    Shut up legs. And that was in his final retirement year, right? And then a bunch of other cyclists came along and bettered it. But, yeah, that was why the UCI, they kind of relaxed the rules because it's been silly for a long time. You couldn't even have a heart monitor or a power meter or anything and then in 2014 they changed the rules again and then everybody--

Brianna:    Recently, as you say, because the rules changed, more people have been going after this record and breaking it. And so Victoria is sort of similar to me in that she did her PhD at Oxford. She's a Math PhD, super intelligent, just sort of mind where numbers are like colors to her. She's Italian as well. She could talk about it all very romantic and how you feel about maths.

    That's how she ended up connected with the guy who I used to work with and he was coaching her. She's started cycling at Oxford. She wasn't like a lifelong athlete but she was just very, very talented and was sort of in the process of trying to break into the international team, trying to break into professional teams. And as part of that training on the track to break the one-hour record.

    It was kind of a unique opportunity because she had so much data on herself and could really see what was moving the needle for her and her coach who I'd worked with was like it'd be really interesting to try ketones. It's interesting because if you take a step back an hour it's not going to be completely limited by glycogen.

    Even if you're going quite intensely, it's going to be on the borderline of whether or not you need to be taking on substrate for that. But what we do know about ketone ester sparing glycogen and lowering lactate in the short term that's all kind of interesting for an event like this. And then to link in what we were just talking about, the potential kind of focus element, cognitive element was actually something that Victoria said she felt the most.

    I mean, we work with her titrating up and down her doses and we were looking at her power numbers with the ketones. We were working on her with trying it out in different settings. She was like, "I've just got to try. I'm going to do the same session but I'm going to do it without ketones because I'm not pretty sure if this is helping me or not." And she did the session and then the next morning I woke up and there's a message. She was like, "Absolutely it makes a difference. I really notice the difference in not having had it."

    I was surprised because, pleasantly surprised, that she really noticed that much of a difference with and without. But she would say that she'd be on the track focusing on the black line because you want to be as near into the center of the track as possible taking the tightest line. And she said you're just in that position really on the edge of what's possible, really uncomfortable arrow position for an hour and that mental component was really important to her.

Christopher:    Yeah. And, of course, you mentioned Tim Noakes. If you subscribe to his central governor model of fatigue then it's not an all or nothing thing. Your brain senses an energy crisis. It's not going to wait until you run out of glycogen before it asks you to slow. In fact, one of his PhD students has shown this in the lab that cyclists go slower from the first pedal stroke when you put them in a hot laboratory.

Brianna:    Yeah, sure. There's so many interesting experiments about how the mind affects the output of the body. I don't know whether it's building on the same study that you just mentioned but there's one where letting people sit having cold water in their mouth reduces the perception of effort improved performance. They didn't even have to drink it. It's very interesting.

Christopher:    And it's the same with the carbohydrate solutions, right?

Brianna:    Water in your mouth.

Christopher:    They've done mouth wash. It's like it's been shown to be effective too.

Brianna:    So, Victoria was training with the ketone ester, really going on well with it. She's going to do the attempt in Aguascalientes in Mexico. Or she was. This all happened in the past, happened in August last year.

[0:20:05]

    She goes up there. She's at altitude as well. It's interesting the choice of location for these attempt because there's a tradeoff between air resistance and oxygen. Aguascalientes is not that high. It's sort of medium high but the air resistance is that much less that you go -- This velodrome has been the site of a number of attempts. It's fast velodrome.

Christopher:    Even the audience participation makes a difference. So, you want the air warmer, less resistance, but not so warm that it affects the cooling of the athletes. They get people in at the exact right time and like, "Okay, cheer it more." Warm up the temperature just a little bit.

Brianna:    If you want to make it an event, like you just suggested, and have people watch or have press, the UCI charge a fee. She was just doing it on her own on the velodrome, no one watching other than her partner and some small amount of media. But she gets out there and she starts off an attempt. So, a little like you said, actually. A lot of it was we were on hold because it was like when is the air pressure going to be correct because there were storms coming and she only had the velodrome for certain window of time.

    Everyone was sort of on the edge of their seats waiting for the attempt to be given the green light. And so she took a window and started the attempt and she got 45 minutes in and stopped. And we were following her. Yeah, 45 minutes. It is not an insignificant amount into the one-hour attempt.

Christopher:    I'd say you got significant [0:21:19] [Indiscernible].

Brianna:    Yeah. So, I mean, that was from our end. We were just hoping that she was okay and she just said to us that she wasn't feeling it and she went back the next day. This is the second time that this has happened. One other person has made an attempt. I don't know whether that other person got all the way through or whether he stopped early. But she goes one day, takes ketones and we think that ketones helped with recovery. And then into the next day, makes the attempt and we're there looking at her lap times popping up.

    If she gets to the 45-minute point where she stopped the day before and she just starts speeding up and it's just like, okay. So, yeah, she broke the record by a matter of meters but it was very cool to have supported her with that. And also just I'm sure that ketone helped but she, obviously, put in so much work and was mentally very tough as well. We're not going to own all of that. She did a lot of work. It was great validation to see that she could use it and that she felt like it helped her. Maybe it did make a bit of a difference.

Christopher:    Yeah, absolutely. Paul Larsen, when he talked about high intensity interval training on the podcast recently, he talked about HIIT being one piece of the performance puzzle.

Brianna:    For sure.

Christopher:    It's not silver bullet anything.

Brianna:    No, no. I think she had to get a lot of things right. And when you're an athlete and reflecting on like my own time, it's like you just want to stock up as many of the things like in your plus points as possible. You want to have good nutrition, good hydration, the right equipment, the right sleep the night before. I think you're a great advocate for looking at a system kind of holistically.

Christopher:    Exactly. Systems approach.

Brianna:    Yeah. So, it was good to be part of that.

Christopher:    Talk about some of the potential therapeutic applications of the ketone esters? Has anyone been looking at that in neurodegenerative disease or anything else like that?

Brianna:    Yes. So, we have a number of researchers that are in touch with us looking to use ketone esters for various clinical things and the applications are very wide ranging from genetic disorders of glycogen metabolism, for example, looking at if ketones can bypass that defect due to alcohol withdrawal and if ketones could help to mitigate the [0:23:22] [Indiscernible] or negative symptoms of withdrawal.

    And again, the logic there is a little like what we were talking about with TBI where the brain in an alcoholic becomes sort of somewhat dependent on energy from ethanol and acetone because you're drinking alcohol a lot and then you remove that to go cold turkey and the brain is energy starved. They've actually shown that a ketogenic diet can help in that case. It's something that's very interesting.

Christopher:    And there's no mechanism involving GABA.

Brianna:    Potentially. I mean, yeah, you've hit the nail in the head. There's potentially a role there as well, GABA or oxidative stress or DNA damage, a number of things. But this is very exploratory. I mean, I think there's a group looking to use the ketone esters in humans for that but it'd be interesting to do the experiment of ketone ester and ketone salts in animals as well just so we could get a bit more insight into the mechanism.

Christopher:    So, this is really just getting started, people writing grants, that type of thing?

Brianna:    Yeah. And I hear a lot from different people. A lot of people in exercise physiology as well, people running training studies and starting to get some end results in there that are really, really promising showing that ketones can help mitigate overreaching and things like that. It's really promising. I think we're getting to a point where we understand that metabolism and substrate provision is central to a number of disease processes and that ketones and some of those processes can be helpful. I'm trying to think if there's anything else that's sort of--

Christopher:    Nothing in Alzheimer's or Parkinson's?

Brianna:    We are working on Alzheimer's as well. We've been speaking to Dr. Stephen Cunnane up in Sherbrooke, Canada and hopefully having a project on the way with him to look at -- He recently published a paper using MCTs and looking at feeding MCTs three times a day and they maintain blood ketone levels around about 0.6. It was definitely under one. Maybe it was 0.8.

Christopher:    And that's not in the carbohydrate restricted diet?

[0:25:01]

Brianna:    Not in a carbohydrate restricted diet. Supplemental MCTs. And his specialty is using FDG-PET for glucose and also PET for ketone metabolism. So, he's got this labeled metabolites, can inject them into people and then look at where, how much is being metabolized in the brain. And so he really pioneered the studies that showed that glucose metabolism starts to decline even before you have symptoms of Alzheimer's in people.

    It could be five years before you actually have symptoms and diagnosed and your brain glucose metabolism is falling. But then with his more recent work he showed that ketone metabolism doesn't fall in these people or ketone metabolic capacity remains the same. And then if you supplement with ketones you can mitigate some of that energy deficit that's coming through the slow decline of glucose metabolism.

    And so his studies with MCTs are really promising. They did six months of three drinks a day and they looked at not only metabolism of glucose and of ketones but also cognition as well and they saw that changes in cognitive function correlated really nicely with blood ketone levels and ketone metabolism.

Christopher:    Wait. You said three drinks a day?

Brianna:    Yeah. I think it was 30 grams of MCT a day, something like that.

Christopher:    Okay. So, do you know what blood level of BHB?

Brianna:    Yeah, 0.6 to 0.8.

Christopher:    So, really not much.

Brianna:    Not much.

Christopher:    So, what would be the advantage of using the ester over the MCT oil?

Brianna:    We see from his results that we're getting, I can't remember at the top of my head, don't quote me on this, I believe they rescued 25% of the energy deficit. They partially rescued the brain energy deficit with that level of ketosis and so the logic is that by having greater levels of ketones that will more completely rescue the energy deficit by providing more substrate.

Christopher:    Right. And so with the ester, you can raise blood BHB to whatever you want. You can't really do that with the oil.

Brianna:    Yeah, or with salts at this stage. I think this will be a really interesting study because we don't know whether there is like an upper limit to, if you care in providing more ketones, is the benefit going to continue to accrue linearly or is there going to be no difference between having people at 0.6 and two? This will be interesting. Our hypothesis is that greater ketones is greater substrate provision and, therefore, greater brain energy rescue. We'll see if that's borne out in the results.

    And then another big thing that we'll be working on is just seeing if this is a practical and tolerable intervention for people because I don't know how of your listeners will have tried the ketone ester but I know you have and I have myself and you kind of--

Christopher:    I've only tried Uncle Frank's special blend. I have not done the legit thing.

Brianna:    You haven't tried it?

Christopher:    No, no. It's a little bit out of my price range, I should say.

Brianna:    No. I mean, it's out of most people's price range. As a business, that's something that we're working on.

Christopher:    Yeah, I get it. I mean, you put a lot of money, I mean, decades of research went into this product and I think people like me will benefit later on once the price -- I hope the price will come down. You would have thought so.

Brianna:    Yeah. There's a clear road map to do that with scale, if we multiply our order size, our manufacturer size by ten then the cost comes down by half, for example. You can work out or something like that with scale. And we hope to be able to do that soon. It's just a practical problem. We may need the [0:28:00] [Indiscernible] to do that.

Christopher:    Right. Do you know if anyone's looking at it as -- how can I put this -- a nootropic perhaps? Just a normal person, can you improve cognitive function with the ester even without disease?

Brianna:    Well, I think a number of our community are using it for mental boost. We actually have a big institutional customer that are concierge coaches for executives so they're looking for the mental edge in and around their job and these people they travel a lot, transmeridian travel, and dealing with jet lag and whatnot. Some of the feedback we'd been getting from them is that this has been a really useful part of their tool kit to help people function cognitively in situations where they might otherwise be so tired and frazzled.

    Yes, I mean, the short answer is that a lot of people associate the feeling of ketosis with that mental clarity and focus and the anecdotal feedback that we get from people is that people experience that with the ester. I would say it's been one of my questions that I would love to see answered is why some people really, really do feel it and experience it. I know I feel it myself and other people don't.

    Whether that's to do with metabolic flexibility or age or habitual diet or -- I would love it if I gave it to everyone and I was 100% sure. I'm 100% sure when I give it to anyone it's going to raise that ketone levels. I can put my hand on the bible, I will stake my life on I give you a drink of ketone ester and your blood ketone levels will go up by some measure of one to two to three millimoles depending on how much I give you.

    But the subjective thing, which actually is more important in terms of getting it out there more and making people want to implement it in their lives, that's a little more hit and miss. I'd say like seven out of ten people feel something. I'd love to know why those other three don't.

Christopher:    And so MCT, the transporter.

Brianna:    Yeah. Maybe it's MCT isoform as well.

Christopher:    We're used to using lactate, right? This was you that pointed this out to me the first time many moons ago.

Brianna:    Yeah. I mean, lactate is interesting in that it uses the same transporter as ketones, the monocarboxylate transporter. You can't use the acronym MCTs.

Christopher:    MCT is overloaded, right.

[0:30:00]

Brianna:    So, Tommy and I, we're just working on our review together and one of the changes, because he'd been talking about MCTs, medium-chain triglycerides, and MCTs, monocarboxylate transporters, and I was like, "Look, we have to call MCTs medium chain fatty acids, MCFA or something." We changed one of the acronyms so that it was not confusing because it's a bit, I think, people in space get a bit confused.

Christopher:    Talk about lactate.

Brianna:    Yes. I mean, it's something that I'm personally interested in. As we mentioned, we've been working more and more with the military and they are really, really interested in TBI prevention because as a part of the call of duty of many of these operators they're either being exposed to explosions, that's not quite what I was going to say, but blast kind of injuries or, for example, in parachute school, they'll be learning the parachute jump and there's always the real risk that they could have a blow in the head and end up with concussion.

    It's something that some of the operators that we've worked with personally, some of them have had multiple concussions and it really affects their quality of life now. And I'm really pleased to be able to say that it seems like the American DOD is focusing more and more attention on soldier resilience and actually looking after the people that they have and protecting the investment they've made on those people versus just trying to have a conveyor belt coming through.

    This is kind of a hot topic, what could we do to mitigate TBI. And, obviously, we've discussed ketones as one potential solution there. But if we look at the principles as to why ketones are working, their substrate sort of potentially triggering BDNF release and some of the other effects of these altering metabolism. Actually, lactate does a number of the same things.

    There's a number of clinical trials of lactate in intensive care showing improved outcomes with lactate infusion because if you look at the structure of the molecules, lactate and BHB are not all that different. I think they're just one carbon different. I mean, they're both organic acids and they're both short cutting in a number of the kind of regulated processes of metabolism whether it's insulin mediated uptake or the different regulated steps of glycolysis and then fatty acids as well. They're kind of regulated on a number of levels before the mitochondria where it's ketones and lactate being smaller and less regulated. They're quite already substrate that can be available in times of kind of energetic crisis that bypass them at the steps that get shut down.

    And so, yeah, it was interesting. I saw a review by Professor George Brooks who is actually just around the corner from us here. We're in San Francisco. He is at UC Berkeley. I read this review. It was really, really long and a lot of brain work and then I ended up going to meet with Professor Brooks and just spent the whole afternoon geeking out about the potential for synergy between the two, ways that they might compete maybe, as we were just talking about monocarboxylate transporters. But ketones and lactate use the same transporter, so will that be good or is that going to be bad? Is there a difference in--

Christopher:    Are they going to compete potentially?

Brianna:    Maybe. Potentially. But maybe not also because they have different affinities for the transporter. It's very interesting because you and I were talking before about how both lactate and ketones are kind of little bit outlawed in metabolism. There's actually a paper that calls ketone metabolism as ugly duckling. I think that that's definitely true of ketones. But it's also kind of true for lactate.

    As an athlete, I mean, I had a more sophisticated understanding that most of the other athletes on the British rowing team, but we always would measure lactate and also after really intense workout so we'd been trying to clear lactate and we'll get your lactate levels down. Lactate for an athlete is this super villainized thing where it's like I have high lactate and that's what makes me fatigue and that's what makes me sore. But actually, in reality, it's not the case.

Christopher:    Right. It's the protons, what done it.

Brianna:    Yes. But also if you read this review by Brooks, he says that there's no clear evidence that when you produce lactate, that there's an associated proton produce. So, the proton production and the lactate -- Often lactate is produce they associate but there's no clear evidence that [0:33:52] [Indiscernible] proton producing pathway. Which is interesting to me because there's so many things I just assumed were given.

Christopher:    Yeah. To go back to Paul Larsen again, that's one of the things he defines with his high intensity interval training is blood accumulation of lactate. But in the Brook paper you sent me, that was something that I didn't know was actually there's a continuous production of lactate. So, it's really just--

Brianna:    At rest even.

Christopher:    Yeah. So, it's another really interesting story. Malcolm Kendrick talked about this, that humans have a terrible habit of turning up at the scene of a crime and then accusing the thing that they find at the scene of the crime as being the perpetrator of the crime.

Brianna:    It's like cholesterol, right?

Christopher:    Exactly. So, that's Malcolm Kendrick's context, this cholesterol. And again, we've done it with lactate or lactic acid.

Brianna:    But it's very interesting because if you read this review that I'm sure will link to in the show notes, the historical context is the very earliest exercise physiology experiment or very earliest muscle physiology experiment, is looking at lactate, would take like a hind limb of, I think it was a frog, stimulate it until it was fatigued and they measured the lactate and they were like, "This is it." That colors everything that has happened since then. There's very, very--

Christopher:    Just entirely anaerobic.

[0:35:00]

Brianna:    It's just so interesting to me that the precedent is set by this grandfather of physiology and they set how people think about these things and then it's very difficult to subsequently change that because it's taken as a given that lactate causes fatigue.

Christopher:    Right. Very fixed mindset.

Brianna:    Yeah, very fixed mindset. Personally, their products, sports drink products that contain small amounts of lactate, and that's kind of something that I find interesting too, they actually have one research study where they gave this sports drink that had lactate in it, lactate, fructose, glucose, so it's multiple transportable carbohydrate forms, and it was very elegant experiment because they labeled the glucose, the fructose and the lactate.

    The people came back three times and, when the glucose was labeled, when the fructose was labeled, when the lactate was labeled, and then they had a control where they just had, was it just glucose, but they saw that actually adding in lactate improved and increased the oxidation of both glucose and fructose. Not sure whether that's to do with gut transport.

    So, lactate was increasing carbohydrate usage and being oxidized itself very, very rapidly and they saw an improvement in -- It was a shorter time trial. But they did a performance test and there was some improvement. And I was surprised when I saw this paper that there wasn't more done on this. But then sometimes things just like fall by the wayside with science. Maybe there's a real effect but we'd need more studies. But it's certainly interesting to me from a performance point of view if we buy into the idea that really what we want to do with performance nutrition is provide the body with a choice of substrate, not really shut down too many substrate, provide the appropriate substrate for the exercise that's being undertaken.

    So, yeah, that would be interesting. But then also kind of lactate in terms of brain injury as well. It's tremendously interesting. Professor Brooks is funded by groups that are interested in TBI protection and head injury protection. So, I mean, for me, I think really a great end outcome would be that there is some kind of drink or product that people could have on the sideline. You're a soccer mom and you go watch your kid play and they take a hit. There's something that you can do that's actually actively going to help them in the short term, protect them.

    It doesn't need to be go to hospital and have infusions of ketones or lactate. If we know it's going to move the needle a little bit I think that it would be great to see these things being more accessible and being more understood.

Christopher:    First responder kit.

Brianna:    Yeah.

Christopher:    What about Cytomax? Isn't that exactly what you just described?

 

Brianna:    Cytomax is the product that has lactate in it. Professor Brooks was saying that a number of cycling teams used it and it was very popular back in the day but it's an interesting business story in that the company that made Cytomax was also making Muscle Milk and then someone bought Cytomax and Muscle Milk because they wanted Muscle Milk and then didn't really care about Cytomax. So, Cytomax is kind of a bit of side show to Muscle Milk and it hasn't been developed.

Christopher:    Yeah. Back in the day, I was joking with Julie, "I'm back on the Cytomax. Lactate is back in fashion, baby."

Brianna:    Well, I mean, it would be interesting if we could be fashionable again. I think Cytomax doesn't have all that much in it so they don't -- There's a proprietary blend so, of course, you don't know how much.

Christopher:    You don't know how much.

Brianna:    You don't know much lactate you're getting on their label. So, we know from the science paper how much was in the solution that they tested but whether or not that's still, especially given that Cytomax has changed owner, whether or not that's still what's in Cytomax is another thing altogether. It would be interesting to test that out.

Christopher:    And from a sports science perspective, do you know if anyone ever went beyond just mechanistic stuff with L-lactate? Did they look at, I don't know what kind of performance measure you would look at, probably something horrible like times to exhaustion that we don't care about? Does anyone look at anything like that where something where it's closer to what we actually care about rather than just some mechanistic thing?

Brianna:    So, the paper that I was just referring to where they did the labeling, they did also the do the time -- I think it's either time to exhaustion or fixed time trial. But there's only one paper. So, still more work to be done there. I think I believe that they maybe also had some animal studies as well but it just seemed like it was in its infancy and there was a promising result and then nobody looked at it again.

Christopher:    Was it a mouse on a stationary bicycle doing the Wingate test?

Brianna:    There were humans involved at some point. There was humans involved at some point.

Christopher:    There's also some overlap with ketones in that it's L-lactate that we're talking about.

Brianna:    Yeah. So, there's isoform specificity with lactate. I mean, I was reading this review and I got really -- I enjoyed netting about it because it was just so similar, all of the same issues between lactate and ketones, isoform specificity, the transporters all being the same, the way that they're feeding into metabolism and it was very interesting to me how similar they were. I think it's potentially something they could synergize really well in the future.

Christopher:    And do you know if D-lactate has any role in metabolism?

Brianna:    It's definitely, there's more evidence that suggests that D-lactate is harmful than there is l-beta hydroxybutyrate being harmful.

Christopher:    I can connect the dots for our listeners as well. I recently discovered -- So, there was this big hoo-ha with D-lactate free probiotics and is the gut making too much D-lactate and you can measure it on a urinary organic acid test. They measure the D form. It turns out, and I know this from this Jason Hawrelak. His research has shown there's really only a problem in people with surgically shortened bowels.

[0:40:01]

    That's the only place you'll find evidence that D-lactate is a neurotoxin. If anyone listening and has seen anything else that we should look at then I would love to see that.

Brianna:    Both with, again, ketones and lactate, so butyrate being a very important fatty acid that the gut produces and lactate being an important for fermentation product of the gut microbiome, I think not only are these things going to be affecting metabolism in the body but potentially also shifting the gut microbiome in somewhat ways as well. I mean, so many unanswered questions here that we got to unpack.

Christopher:    Yeah. You're reminding me that we were talking about roseburia and some of these other butyrate producing bacteria and how important the butyrate is for the colonic cells.

Brianna:    There's a really interesting review about the role of butyrate in gut health and metabolism and they also talk about the potential for supplementing that with exogenous ketones and, interestingly enough, they've patented that combination. I know you and I were talking about how patenting kind of put--

Christopher:    Patent hell.

Brianna:    It closes out the doors for other people. But there's clearly some interesting value in the idea. Otherwise, they wouldn't have gone to the effort of getting a patent on it. I don't know. The more I read about the gut microbiome the more I think it's going to be pretty difficult to affect really meaningful and lasting changes and really work out what we want for everyone. But clearly you can do it with a ketogenic diet and the gut is super important.

Christopher:    Right. So, I should probably say something about the patents. My problem with patents is -- So, what we've seen in software is this situation where people end up holding a gun to each other's head. It's like this triad. We've got everybody's pointing a gun at somebody else.

Brianna:    Like the NAD space, right? Elysium and Chromadax. That's really bad.

Christopher:    It's terrible. So, what happened to software? So, okay, you infringe my stupid one click ordering patent but, oh, you also infringed my patent so, okay, we'll just call it quits. I'm holding one patent, you're holding one patent. And so these big players they end up being people like IBM and Apple, these huge companies, Intel, and then what happens is the little guys get squeezed out because they don't have any patents and they don't have the financial capability to defend any of them.

Brianna:    Yeah. I think that's more it, right? You could take out a patent but that in itself costs money. But then if someone infringes on it you have to have the money to defend it and if you're defending against IBM, their pockets are going to be much deeper than yours.

Christopher:    Good luck with that. So, it ends up it thwarts innovation because the little guys are pushed out.

Brianna:    But also I think if you didn't have it then you could be a little guy and then the big guy could just take it, anyway. I don't think there's an easy solution here. I mean, have you got a solution?

Christopher:    Well, you just make it totally open.

Brianna:    So, anyone can just take anything from anyone?

Christopher:    Yeah. That's how software worked in the beginning. Richard Stallman has written some, given some really interesting lectures on this. He's the president of the Free Software Foundation. And that's how it worked. It was like recipes. If you turned up at someone's house for dinner and you said, "I really like that casserole, can you give me the recipe?" They would just write it down on a piece of paper and give it to you.

Brianna:    Yeah. I don't know though. I feel like, especially coming from the science academic background, if you put blood, sweat and tears into developing something, a scientist doesn't necessarily have the skills of an e-commerce company or marketing company. I, as a scientist, could try and sell things myself but there's always going to be someone better. How would I get credit for my invention or have an incentive to invent?

Christopher:    Right. So, there's two things that's important not to conflate. There's like freedom as in speech and then there's freedom as in how much you charge for the thing. You think about it, android and to a certain extent Apple are running flavors of units and it's built on open source software, which is free as in speech, and free as in beer. But they've still managed to commercialize those products. Red Hat Linux has built on Linux which is free as in speech and free as in beer. It can be done but, yeah, it's tricky. And you guys have got enough to worry about so I do worry about that too.

Brianna:    Yeah. I think it's an interesting layer to having come from just doing the research trying to layer on top of regulatory and marketing and IP. There's so much to it and you really need experts from every field to advise you and to make the right decisions.

Christopher:    Yeah. And I'm absolutely not a patent lawyer. So, who knows?

Brianna:    And software is very different to nutrition.

Christopher:    Yeah, it's true. Talk about the GI symptoms paper.

Brianna:    Yeah. I was just telling Chris before we came on that this morning I had a paper accepted into the International Journal of Sports Nutrition and Medicine. I might have got the title of the journal there wrong but it's something along those lines.

Christopher:    Who cites it? Elaine makes fantastic show notes that you can find over at nourishbalancethrive.com/podcast where if you poke around inside of your podcast app that you'll find the show notes and all the citations will be there.

Brianna:    Yeah. So, this paper, imagine by the time the podcast goes live, hopefully the paper, the abstract or something will be live. But for me, this paper was a culmination of an awful lot of conversations that I'd had with people that were using the ketone ester. And also I think we might have discussed on a previous podcast there was a paper that came out that looked at acetoacetate esters in cyclists and they showed that people had a lot of GI symptoms after the acetoacetate ester.

[0:44:58]

    

    So, people were coming to me concerned about side effects of ketone drinks. I have been working with these drinks now for like eight, nine years and given them to tons of people that rest and that exercise and if I'd been making people every time I gave them a drink I wouldn't have carried on. I don't want to inflict pain on people. I'm not a nasty person. I'm a nice person.

    It didn't feel right as a scientist to just be like, "Trust me. You'll probably be all right. Almost certain you'll be all right." I wanted to have something more concrete. I was looking back at all the data I have for my PhD and actually every time I'd give someone a drink in all of my years of studies, I'd been asking them about their symptoms at every time point that I sample their bloods.

    I have this huge data set. Actually, I probably should have come to you, Chris, and you could have done some better analysis on it for me but I have this huge data set of ketone levels versus symptoms and the symptoms were broken down into upper, lower and systemic symptoms. And within upper GI symptoms it was like bloating, nausea, I can't remember what the other one was, vomiting. Nobody have that.

    And then lower GI would be like abdominal pain, diarrhea, flatulence. And then systemic was headache, dizziness. We had a lot of granular detail about exactly what symptoms people were getting. But then also about the severity of those symptoms. And it really was frustrating me that people would report in papers like 50% of people had a headache because it doesn't tell you about when the headache happened, how severe it was or any of those details. They're kind of important.

    So, when people look at these things, it's like, it's one out of eight. But then if you just report very simply it's like, headache. It doesn't tell you that it was not particularly severe. So, what I was trying to do was to present my data in a way that captured a little bit more of that detail so that the time course and the severity and the type of symptoms.

    In the paper, we talk a little bit about the differences between esters and salt. Again, those of us in the community that have used all of these compounds know that if you take too much ketone salt or MCT that you might get diarrhea because it's salty, it gives you GI distress. But that's like--

Christopher:    Which is true of anything. You drink too much olive oil, you make yourself run to the bathroom. Too much vitamin C will do it.

Brianna:    Yeah, for sure. Nasty. But the esters don't tend to have sort of same effect. The esters, it might be more like you might have a bit of a headache or you're feel a little bit dizzy or something like that but didn't get that so much with the salt. So, what we're trying to tease out is which symptoms happen with which compound and do they change with dose? And then the final study that I included was an exercise study.

    This hopefully is going to vindicate a lot of people that kind of criticize these compounds because it was a three-hour exercise protocol and people were taking either ketone drink or a carb drink every hour during the exercise and with both drinks the symptoms just slowly increase over time. People just felt worse and was no difference where the people had ketones or carbs.

    For me, I think it's really a very kind of boring paper because it's like not much happens. For me, it's pretty boring but I'm really pleased that there's finally like a formal source for people to go and look at and be like, okay, this is the chance of symptoms with these different drinks. Because I think athletes want to know will my peak likelihood of having symptoms is about X amount after the drink so I'm just going to make sure that I account for that in when I'm taking it or the difference again between making the choice between salts and esters other than just the BHB level. If I'm going to take salts, it's maybe a bit more likely than I'm going to end up with diarrhea and the chance of that is higher when I'm exercising anyways so do I really want to do that? Maybe, maybe not.

    I think, for me, it's just sort of satisfying to see that data which I knew myself formally presented so that people can refer to it and that I can refer to it in conversations.

Christopher:    Was this motivated in anyway by the trouble that Louise Burke had with her pharmacokinetics.

Brianna:    The acetoacetate paper, yeah. I mean, that--

Christopher:    What did she do? She ordered a research chemical from the internet and then just loaded up some--

Brianna:    She ordered a researcher [0:48:57] [Indiscernible] chemical from Dom and Dom gave it to her, Dom D'Agostino gave it to her. I think they were on a bit of time pressure so they ran the study without having done all of the pharmacokinetics that they needed.

Christopher:    Or any of the pharmacokinetics.

Brianna:    Yeah. I'm looking forward to being on a panel with Louise Burke at the ACSM, American College of Sports Medicine meeting in about a month or so times. I don't want to get too personal. But if she tries to talk too much on the ketone ester then I think I would love to hear her answer as to how she got her ethics committee to agree to giving people a compound that had never before been formally studied in humans. I'd love to hear how she did that.

Christopher:    Maybe she intoxicated them with some research chemical.

Brianna:    Yeah, maybe. Maybe she gave it to them beforehand although if they've done that then I don't think they would have given it to the athletes.

Christopher:    I am, of course, joking. Talk about nutritional ketoacidosis during incremental exercise in healthy athletes.

Brianna:    You got through that very quickly. That is another research paper that's just been published out of the University of Oxford. So, a couple of my colleagues that I worked on with the modern research. I think, actually, I'm a participant in the study. I think I'm one of the data points.

Christopher:    That's cool.

Brianna:    Before I left Oxford, they were doing the study.

[0:50:00]

    And again, I think it's just -- There's so much work to do characterizing these molecules so looking at the effects of ketones on acid-base balance and on sort of step test, how it affects -- If you're a regular athlete and you do a step test, you're looking for your ventilatory threshold and your lactate threshold and those are measures that you're using to determine if your training is working.

    And so what we show, what the researchers show in this paper is that taking ketone shifts the ventilatory threshold and their lactate threshold. It's changing those numbers in ways that maybe beneficial. But definitely would confound your conventional interpretation of your step test results. Another thing which I think is kind of interesting about that paper is that people always worry that ketones are going to scrub off top end power.

    Again, we've got quite a substantial level of ketosis here and no difference in top end power. I think that's good to see as well. But really, the paper is kind of going into detail about how the relationship between ketones as an organic acid and lactate as an organic acid and maybe the needing to compensate for that acid load with changes to ventilatory threshold and how all of these very fundamental exercise physiology principles will come into play and together. It's a nice little study.

Christopher:    There was one other study I wanted to talk about, finally, which was beta-hydroxybutyrate and inflammation. There was that early paper that I saw cited a lot on the inflammasome. That was kind of -- Maybe talk about that original paper first because it was kind of--

Brianna:    2013 and I think Dom, I don't know whether he is an author on it but he collaborated with [0:51:35] [Indiscernible]. I think they're in Harvard. I love this story. Basically, everyone's been thinking that BHP interacts with the inflammasome and inhibits inflammation. There was this original paper, I think it was published in Nature or Science. It was published in a high impact [0:51:50] [Indiscernible] journal. And then recently there's been more and more animal studies and in vitro studies that have shown that if you apply ketones to the system, that there is reduced NLRP3 inflammasome activation.

    I kind of feel like the community was starting to take that as a given. So now we have ketone esters and we can raise BHB acutely and look at inflammation, what's going to happen. Completely the opposite to what people expected. We actually saw that adding ketone ester in, if you then trigger an immune response, the inflammatory response is greater.

    Now, I think that the way that they presented their results is maybe a little, maybe not quite how I would have done it. They presented in the title of the paper was that oral ketone ester acutely increased NLRP3 activation in human monocytes. What actually they did was people either had placebo drink or ketone drink and they had a blood sample before and a blood sample 30 minutes after the drinks.

    When they took the blood samples, they split the blood samples in half and one half was just left as is and the other half LPS was applied to. So, LPS is a bacterial toxin that profoundly stimulates inflammation. And so in the un-stimulated samples, ketones or no, there's no extra inflammation. So, I feel like the presentation of the data was that ketones increased activation just as is in kind of a basal state. But actually, that's not what we saw.

    If there's no bacteria present, it's not going to -- Ketones themselves were not inflammatory by themselves. However, when you needed an immune response or when you pop in those bacterial toxins and you want that to be an immune response, there was greater activation of parts of DNA immune system such as caspase 1 and there was increased IL1 beta secretion and increased IL6 secretion as well with ketosis, with the ketone drinks.

    And that's, again, counter to what people might have expected. But actually in line with one other paper that came out last year which, you'll love this, I don't know how they got ethics to do this, they infused people with LPS which is a bacterial toxin. It was done in Denmark. I don't know how they got there.

Christopher:    So, they induced sepsis.

Brianna:    Yeah. They induced sepsis and infused ketones in a crossover design, either LPS by itself or LPS plus ketones. They also saw an increased IL1 beta response as well. So, maybe ketones are there are actually boosting the immune response. So, the presentation of the paper was that ketones actually activated inflammation but I think that they didn't lean super heavily on the fact that might be what you want in bacterial toxin infection lens. It's interesting because it goes counter to all of the animal work that's been done to date. We really need to tease into the context of this, see whether the time [0:54:28] [Indiscernible], you get that one sampling time point 30 minutes after the drink. There's a number of things.

    And also, in that experiment, their control was just water, calorie free. And so if you're providing substrate to the cells in forms of ketones versus an overnight fast, maybe the difference in substrate availability could have affected immune cell activation. It might just be the cells where you have the ketone drink had more energy because you'd have the ketone drink and that's why there was an augmented response. And also interestingly, and I know Tommy and I have a number of interesting discussions about this, there was a really small increase in insulin after the ketone drink.

[0:55:03]

    Now, I always like to keep this in context. Normally, the increase that you see is sort of like from three milliunits per liter to six milliunits per liter. It's doubling. But in context, if you eat a carb rich meal, your insulin will go up like 40 or 50 milliunits per liter. It's really, really small increase in insulin. But then nonetheless an insulin is another factor that can activate the immune response.

    So, without controlling that, they didn't have an insulin increase with the placebo drink. Again, it's like, for me, I would need to see whether substrate made a difference, whether insulin made a difference before I could say whether actually that ketones themselves are boosting the inflammatory response.

Christopher:    I think Tommy also pointed out that it was a very small study with very badly done statistics.

Brianna:    Tommy is really great at statistics.

Christopher:    He has this thing. I don't want to speak for him too much but, yeah, I did understand one of the problems he pointed out. The distribution was clearly not normal and they reported the mean and the standard deviation with error bars. You could just look at it. You don't need to be a statistician to understand that if Bill Gates walks into a crowded room then on average everybody is a millionaire. It was that exact problem but in a published paper.

Brianna:    Yeah. I mean, that's a way with science. I think they did a good job because they do present all of their individual data. You can actually see--

Christopher:    You could see it. You could see it was not a normal distribution.

Brianna:    But, yeah, some of the statistics wasn't quite appropriate. Tommy says that you should always use nonparametric statistics because like that's correct no matter whether it's normally distributed or not. I mean, I'm definitely not a statistics wiz so I'm not going to criticize anyone else's statistics.

Christopher:    I've definitely made that mistake as well, actually. One of our clients pointed out. I made it in the blood chemistry calculator where some of our scores like the five-year wellness score, for example, is also not normally distributed. Or the toxicity score is not normally distributed by reported the mean and the standard deviations, so I need to fix that too. I'll definitely [0:56:51] [Indiscernible] too.

Brianna:    Yeah. Tommy helped me with the stats for this GI paper that just came out. He knows what he's talking about and I think -- I mean, it just really highlights that presentation and interpretation really can color how that is then received by the public and you can't expect everyone to be as good as Tommy at statistics and you can't expect everyone to read the statistical methods thoroughly enough to really understand.

    I think analysis and then presentation of that data, because I think with the inflammation paper there's a line in the methods that's like IL1 beta is not reported for un-stimulated samples because it was undetectable. But that's the only time in the paper that they really mention or highlight at all that just taking ketones really didn't do anything into inflammation. Because that's like a non-result, not that interesting.

    But for me, I think, in order to put people's mind at rest, it's actually kind of important to say, "Look, drinking ketones isn't inflammatory because when you take these un-stimulated samples where there's no bacterial toxin added, there's no immune response." So, I think it just really highlights not only is there a sort of right or wrong way to do things statistically but you can also just from you choose to focus on when you write the paper, really color the interpretation of that kind of thing.

Christopher:    Does that not make you sad that you need a statistician to tell you whether you got something or not? You do your experiment and then you give the data to somebody else and they tell you whether you've got something or not.

Brianna:    I'd rather it was that way. In a way, that would be like a great way to do science because then that avoids the investigator either doing stats badly or picking and choosing what analysis they could actually focus on. I think actually having an independent statistician do the analysis might be good for all experiments.

Christopher:    What I'm driving at though is like you know, as soon as you see the data, okay, we got something here. You don't need to do some clever statistics to know whether you got an effect or not.

Brianna:    Not in every case.

Christopher:    Okay.

Brianna:    Sometimes it looks like it's really different but there's such big variability. It looks like the means are kind of similar but there's that much variability that it's not statistically different. I think it's a good check and balance and got checked on. I think on the flipside, I agree with you that people like [0:58:54] [Indiscernible] and do stats badly and will say something significant when it's small and clinically insignificant. I mean, I think there's just two sides to that argument. It's still a bit like the patent thing. It's a necessary evil, probably could be done better, but without it then until we have a better solution we got to stick with it.

Christopher:    Cool. Well, I want to be respectful of your time. You got a heart stopping three minutes. In three minutes, you're going to have to tell us all about the ketone monoester, where we can find it online, where we can find you online, some of the content that you're producing, you're doing a podcast, you're doing other written material, tell us about it.

Brianna:    Sure. If you're interested in just following what I'm up to, I'm on Twitter @BriannaStubbs. If you're interested to follow what the HVMN is up to, we're at @HVMN. We're also on Instagram as well. Our website is hvmn.com. You can go on there and you can buy the ketone ester but also we've put loads and loads of effort into some really great blog series about the ketogenic diet and athletic training and all of those things as well.

    We have our own podcast, as you just said. It's the HVMN podcast. You can get that on Apple. We're also on YouTube as well if you want to see my pretty face chatting away. Anything else I should mention? Yeah, we're just really keen to hear from people in the community and interested in the same stuff as us. So, reach out and we'll definitely get back to you.

Christopher:    Thank you very much. I very much appreciate you. I hope that I can catch up with you again.

Brianna:    Of course. It's always a pleasure.

Christopher:    I hope that people felt like I sufficiently wrung as much information out of you as physically possible in an hour. You've got so much in there. It's kind of hard.

Brianna:    We could talk for hours. You as well.

Christopher:    Thank you, Brianna. I really appreciate it.

Brianna:    Thanks, Chris.

Christopher:    Cheers.

[1:00:28]    End of Audio

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