Rhonda Patrick: Today I'm joined by Dr. Darren Candow who is a leading researcher in the creatine field and muscle aging. He's published over 140 papers on nutrition and exercise performance, how it affects muscle, muscle health, muscle aging. Darren, I'm super excited to have you here today to have this conversation with you to go deep into the science of creatine.

Darren Candow: Yeah, no, thanks for having me. I'm really excited as well. Absolutely.

Rhonda Patrick: I've read several of your studies. I'm a huge fan. A lot of really important and interesting research to talk about. Uh, maybe we could start where it's most popular. I mean, a lot of people think about creatine as in its role in, in exercise performance. However, there's been a lot of emerging research in other areas. Maybe you could give people just a quick snapshot and yeah, like it's really.

Darren Candow: Evolved over the last 40 years. It's gone from athletes getting bigger, stronger, faster. Now we're looking at potential benefits on bone health, brain health, cardiovascular health, even in children and during pregnancy. So it's evolved. Young male athlete to. Pretty much anybody on the planet is now considering creatine either in their diet or supplementation. So for the next few hours, super excited to talk about all aspects of creatine and the evidence based research behind it.

Rhonda Patrick: Well, let's talk about resistance training and improving performance, muscle health. I mean why, why are people, why is it so popular?

Darren Candow: Well, because it works from a muscle performance perspective. So it really, it basically increases the ability to produce ATP or maintain it during an exercise se. So for example, when you're doing, you know, a squat or leg press or even running, you're doing muscle contractions and phosphocreatine, which is what we're going to be talking about today. From creatine supplementation, it really maintains ATP or adenosine di triphosphate. So if you have more ATP longer you can exercise at a higher capacity, a higher intensity and that delays the utilization of other energy systems that might be a bit slower. So anybody involved in high Explosive anaerobic type of sports weightlifting, high intensity interval training, for example, probably would experience some benefits from creatine supplementation.

Rhonda Patrick: And how is it going to benefit you? Is it going to improve your training volume? Is it going to make you stronger?

Darren Candow: All the above. So it definitely seems to increase training volume. So that's either the load by the reps, by the set or exercise capacity. From a cardiovascular perspective it definitely, if you were to choose one thing, why creatine has been so effective, it's improving muscle strength. You could also encompass that with endurance and power. It also improves lean body mass. So here's a big discrepancy that a lot of the viewers might not know. When we measure lean body mass in the labs, we're, we're technically measuring blood, connective tissue, soft tissue. So we're not directly measuring muscle mass. We need to do a lot more research on that. But in general about 50% of the value of lean body mass, we consider muscle. So it has some small favorable effects. There's been some studies with QCT as well as ultrasound, but you can get an increase in lean body mass, regional muscle thickness, muscle performance. But probably the area that most people don't realize is the recovery aspects. It really seems to have some anti catabolic effects, potentially anti inflammatory effects. And that's interesting because it's from the aerobic community. For the longest time we never thought creatine was for endurance or aerobic type athletes. And the best lines of evidence from a recovery aspect come from long duration aerobic exercise, a marathon, ultramarathon triathlon. It seems to reduce cytokines, so those are markers of inflammation. So there's a whole gamut of mechanisms. There's about 10 what we consider anabolic factors and then there's probably just as many as an anti catabolic effect. So it has a plethora of benefits which I'm sure we'll talk more about in detail today. Yeah.

Rhonda Patrick: So you okay to go back? You just gave total information dump, which is awesome. Let's go back first to the explosive power you were talking about. It seems to really help benefit in that explosive power. Like you're talking about doing, doing a squat.

Darren Candow: Yes.

Rhonda Patrick: Or I don't know, maybe the first few seconds of a interval, something where you're going, you know, using all that power.

Darren Candow: Yeah.

Rhonda Patrick: Is, is it, is creatine benefiting? Benefiting? Is that how it's benefiting, increasing the training volume or is there something else that's happening?

Darren Candow: Yeah, in two ways. So it really seems to maximize either the recruitment or the ability of type 2 muscle fibers. And when we talk about aging, unfortunately, those are the ones we're losing as we get older. But it really seems to work in the second, third, and fourth set. So, for example, if you were to do four sets of leg press compared to placebo, you may not notice any difference in the first set because we think we have enough ATP or fossil creatine stores in our muscle. But when it comes to set 2, 3, and 4, that's where creatine really comes to the rescue. The individual or group can do more repetitions, and then over time, they can actually do a greater volume. We think with weeks of training, if you're doing more volume, you can actually get greater physiological adaptations. So when we look at all the meta analysis, when you compare creatine and weight training to creatine, placebo, and weight training, there is a greater increase in lean body mass, muscle size, as well as muscle performance. So creatine, there is something there from a mechanistic standpoint to allow that. And we think muscle fiber recruitment, primarily type 2 muscle fibers, is one of the main reasons.

Rhonda Patrick: Does it affect the recovery time in between sets?

Darren Candow: Excellent question. It does. It really speeds it up. So, on average, if you were to totally wipe out your normal creatine stores, it takes about three to five minutes for your mitochondria to recover that. However, creatine really, really speeds up that recovery, which is great for the average person. They don't have a lot of time to work out. They can't wait around for three to five minutes in between a really intense set. So it really speeds up the recovery. Not only does it speed up the recovery after every set, but in between contractions as well. So over time, the individual could probably have a really intense, great workout in less time total, and get actually more favorable effects.

Rhonda Patrick: And I think what this is really important we're talking about here, I mean, we were talking about squats, you know, these explosive types of power types of training. And this is a really important field because, you know, you often hear about people talking about the loss of muscle mass as we age. You talked about losing type 2 types of muscle fibers more readily than the type 1. So these are the types of muscle fibers involved in that explosive type of power type, you know, exercise. And, you know, people don't think about how power decreases with age, how, you know, strength decreases with age, and how that affects our quality of life, how it affects our physical independence, our fall risk.

Darren Candow: Right, right.

Rhonda Patrick: And so I think just focusing on this Type of training. I mean the creatine is the icing on the cake, right?

Darren Candow: Yeah.

Rhonda Patrick: But just focusing on doing these types of multi joint compound types of lifts, which is something that I, in the past, I would say year, a good year, now a solid year of doing CrossFit type of training where I'm doing strength training, I'm doing resistance training, shrink training and high intensity inner training. That's including, you know, the types of stuff that I'm used to doing biking and rowing, but also adding in, you know, doing, doing some drop sets with, with, you know, front squats with the barbell and things like that.

Darren Candow: It's super important. So this velocity or power train or a variety training, first we got to get people to move and then allowing them to give some type of benefit to their training program. So creatine is probably the one that will be number one when people select it, even probably more than caffeine nowadays from an exercise training. So it should be considered it can have a lot of substantial beneficial effects. And as we get older, after about the fourth decade, unfortunately we start to lose these type 2 muscle fibers. And so exercise has to be foundational and if anything else can be beneficial, protein, creatine, I'm all for it. And I think most people hopefully will be as well. Yeah.

Rhonda Patrick: So the improvements in the muscle strength presumably are coming because you're increasing your training volume. Right. Is that or is there a direct effect on strength?

Darren Candow: Yeah, there's actually a neurophysiological recruitment. So now creatine has been touted as a new neurotransmitter. So this is quite interesting. It actually seems to release a lot of things from a neuromuscular perspective. But the biggest thing is the ability to recruit not only type 1, but these type 2 muscle fibers as well. And then of course, if we're having greater muscle or motor unit recruitment, we can potentially lift longer, heavier and over time get sort of more an increase in strength. The other big thing from a cellular perspective is that creatine causes calcium to come back in a little vesicle in our muscles. If you're taking high school biology or university, this will be your nightmare. But I remember everybody talking about the sarcoplasma reticulum and it's an area that just releases calcium to allow our muscles to contract. And creatine speeds up the uptake of calcium. So some of the evidence out of Europe has shown that it increases relaxation time or the ab of the, the proteins in your muscle to grab hold of each other to Contract. So there's a cellular aspect there explaining why we think we get an increase in muscle performance. I say strength, but endurance and power are all lumped in there as well. So endurance is the ability to perform repetitions to fatigue or power. Move an object as fast as you can, they're all vitally important. But we think strength is overall from a global perspective. Number one, it's probably the main reason a lot of older adults are placed in long term care facilities. If they have a reduction in strength, they can't live independently. So that's why again, resistance training or weight bearing exercise, as you mentioned, CrossFit, whichever it is foundational. I'm from Canada, so shoveling the driveway in the winter counts because anything that's a load against you is really beneficial to the body. I think people underestimate the benefits of moving. And then if anything can be taken in, in this form, creatine, it'd be very, very beneficial.

Rhonda Patrick: You mentioned some of the anti inflammatory effects of creatine, particularly in the context of more endurance type of training. People that are perhaps running marathons or just clocking in a lot of hours of running or cycling per week. Is that so? I think that goes to some respect in the recovery sort of bin. Right. And I'm wondering if that also plays a role in recovering from doing your resistance training, strength training, like on a recovery day. So I mean, do you think it plays a role just broadly in recovery?

Darren Candow: Yeah, it does. Now this is interesting, and I probably would have been the most surprised when we wrote the paper on this, that we don't think traditional weight training, where you're doing a set, you're resting maybe a minute to two, it seems like it's not catabolic or intense enough. Now most people will say, shake their head, say, hey, when I'm in the gym, I'm really putting a lot of effort in. I think from a mechanistic standpoint, when you're doing running or long distance, continuous muscle contractions, it causes this large catabolic effect to the body. So that really heightens the inflammatory response. Weight Training is acute. 10 seconds of work, 3 minutes of rest, 10 seconds of work, 3 minutes of rest, or whichever it is. And we just don't see creatine having a lot of superior effects from a resistance training recovery aspect, probably because the rest intervals for the average person are there. But from a long distance event, you're running hours, you're swimming, whichever it is. The best lines of defense come from triathlon and marathon running where the increase in These markers called cytokines were elevated but creatine sort of attenuated that rise could allow the individual to recover and get back on the, the track or whichever it is quicker. But I've talked to some good colleagues in Canada and it just seems like weight training is, is too intermittent. Now when you mentioned CrossFit, that's different. I'm thinking of the three sets of 10. You move from machine to machine, you rest, you have a CrossFit or something that's really continuous would probably fall in line here of the necessity for creatine. So that would be a very good study to look at the effects of creatine on the recovery aspects of something like high intensity interval training or CrossFit, for example, our military type of training that's really endurance and resistance training. So you just gave me another idea to run with. But it, it's logical. The more intense, the more demanding. I think that's where creatine's anti inflammatory properties would come into play.

Rhonda Patrick: Yeah, so when people hear catabolic or you know, they'll think, they'll think of muscle breakdown. Right. And certainly, you know there's, there's a big component to sarcopenia, inflammation in sarcopenia, which is age related muscle breakdown. Is there, is there a role for creatine in, in preventing the breakdown of muscle?

Darren Candow: There is, it's very mix. So we don't have a lot of data. First off, creatine doesn't directly increase protein synthesis which might be a surprise for a lot of review. Sort of works in a magical other way which we can talk about. But from a muscle breakdown perspective it seems to reduce something called leucine oxidation, primarily in young males. And that's an indicator of whole body breakdown. We've also shown in our lab it reduces three methyl histamine, which is another indicator of whole body breakdown. But nothing is directly shown in the muscle itself. And for some reason females don't experience this. We've looked at it in young and older females we don't see the same effect. The only logical explanation is it could have something to do with progesterone or estrogen, we just don't know that. And from an anti catabolic effect, decreasing some of these tissue repair mechanisms, there's not a lot of research out there, but unfortunately we're not seeing any evidence that creatine increases protein synthesis. So unlike protein, which it does, creatine seems to help increase muscle size in other ways. Satellite cells, growth factors, things like that. But it does decrease protein breakdown Primarily though in males and we still don't know exactly why, but we think estrogen or the other sex hormones might be involved.

Rhonda Patrick: Does creatine have a general anti inflammatory effect in, in both males and females?

Darren Candow: It does in young and older individuals. But here's an important distinction. The more stressed the body is, it seems to come to the rescue more. So if you're a young individual, adequate sleep, proper nutrition, you're probably not going to notice any anti inflammatory effects. It's when the body is under times of extensive exercise or trauma, hypoxia, I'm sure we'll talk about the brain and sleep deprivation. So whenever the body is more stressed or under more attack, that's when creatine seems to come to the rescue.

Rhonda Patrick: And getting circling back to people that are supplementing with creatine and it improves their training volume, improves their strength. Why do people have to supplement with creatine?

Darren Candow: Well, they don't actually. So a little bit of clarity. So we naturally are producing creatine in two main areas, in the liver and in the brain. And on average we're producing about 1 to 2 grams. Then we're also consuming in the diet anywhere between one to three grams or none. So a vegan is not getting any dietary creatine. Those that are on a carnivore diet might be all the way up to about 3 grams. And we excrete through the urine a product called creatinine, about 2. So when you do the math, we're in a net surplus anywhere between one to two grams a day. And we know it's not essential because vegans can live a long, healthy, successful life, but we consider it conditionally essential because when we see all the evidence, I think there's over a thousand peer review papers, when we take in a little bit more, there is some substantial beneficial effects across the whole board, not just muscle. We're now looking at bone, brain and the immune system, you know, so from.

Rhonda Patrick: From a perspective of a vegan who is not getting a, any almost amount of dietary creatine, they're relying on their liver to make it. What, what's going on in their brain. You mentioned the brain makes creatine.

Darren Candow: Yeah, it's very interesting. So on average vegans have substantially less muscle creatine compared to an omnivore carnivore diet. But an elegant study out of Brazil about four years ago, they use sort of an MRI for the brain and they showed that vegans and omnivores had the same amount of brain creatine Store. So that's really substantiating that the brain makes its own creatine. It probably makes enough for the non stressed individual. But during times of metabolic stress, the question is, will vegans or omnivores need more? And it's likely that that's true. Yeah.

Rhonda Patrick: During development, is the developing brain making its own creatine like it is?

Darren Candow: Yep. Just like our liver is making its own creatine, it's using. And it's probably at an accelerated rate for brain development, cognitive development. Again, our brain is. But it uses 20% of our daily energy. And of course, during development, that's when it's very, very precious as well. Yeah.

Rhonda Patrick: So creatine is mostly found in animal foods, meats, poultry, fish.

Darren Candow: Yes.

Rhonda Patrick: None in plants at all.

Darren Candow: Trace amounts. You'd have to eat the entire orchard of whatever plant you're thinking. And same with milk. You'd have to drink all the milk from a Jersey cow to get any significant amounts. So that's why it's unrealistic.

Rhonda Patrick: So, so if we're having, if we're producing between, you know, one to two grams at best.

Darren Candow: At best, at best, yeah.

Rhonda Patrick: Just in, in our liver. Correct. And that presumably then is being transported to muscle.

Darren Candow: That's the hope. 95%. We can't forget about the bone and brain are the main areas. Yep.

Rhonda Patrick: Okay. And then if, let's say, let's say you're getting. I think I was reading some NHANES study where on average people get younger adults, not older adults get anywhere between 1 to 2 grams a day from their diet.

Darren Candow: Right.

Rhonda Patrick: But older adults are getting on that lower end even, not even necessarily at, even at one gram. So. So older adults are getting even, even less. Yes, but then, you know, is there, is there, is there more to be consumed by the muscle or does it get spread around?

Darren Candow: Yeah, that's an excellent question. So the thought is, as we get older, we have reduced fossil creatine stores in our body. So they might need. The Hope is about 95% is housed in our skeletal muscle. But now with the emergence of research, the rest is in bone and brain specifically. So the hope is if we take in more, our muscles will be full, which is great. But now hopefully we're going to have some trickling into our bone, which is even just as important. And I think most people would argue from the neck up. That's really important from a global perspective with all the neurological diseases, depression, anxiety. So I'm one of the big proponents of taking a lot more than probably what's recommended based on the evidence based research to sort of disperse throughout the whole body, not just skeletal muscle.

Rhonda Patrick: Well, let's, let's talk a little bit about that. So in some of these let's, you know, the strength training, resistance training studies, what's the common dose that's taken and maybe we can talk a little bit about, I mean there's the loading phase, which I've never done. So I actually take 5 grams a day and although I might start taking more after this podcast. Okay, so I'd love to know like what, what is the average dose that's taken to improve, you know, your strength training, your resistance training, your training volume and then we can go from there.

Darren Candow: Yeah, so I mean, in 1992, Roger Harris came up with a seminal protocol where as you just mentioned, this loading phase, it's the most viable rapid way to really saturate your skeletal muscle. This has nothing to do with the bone or the brain. And so that's 20 grams a day for about seven days is usually what's recogn recommend it. A bit of new information, you only need to do that for two days and then your muscles are saturated. So the loading phase was designed for athletes to really rapidly sort of fill up the room, if you will, from a skeletal muscle perspective. After that you can reduce it as little as 2 grams a day. So again, that's a half a salmon steak, that would be a half a chicken breast or whichever. So it's very viable. They call that the maintenance phase. The only problem with the loading phase is it's so rapid it does cause water to enter a lot of our cells and a lot of individuals do not like this potential, potential net water retention or GI tract irritation. We don't usually use that in our labs for that reason. But for the athletes world championship coming up, the loading phase followed by a maintenance phase is a very viable rapid way. Young females hate it because of that water retention and weight gain. The good news is you can take as little as 2 to 3 grams a day, no loading phase, and take that on a day daily basis, probably for the rest of your life. And that will definitely accumulate and fill up your muscles in about 30 days. We don't know if that low dose will get into the bone or brain on a long period of time. What we've done is look at a relative dose. So that means everybody has a certain weight. We put them on scale and we use 0.1 gram all the way up to 0.14 grams per kilogram. So for example, if you're 70 kilograms, you're taking 7 grams a day, all the way up to about 9 grams a day. You can take that in one bolus dose or split it up into smaller dosages throughout the day. I wouldn't go any less than one gram. One gram doesn't seem to get in the blood as rapidly as we need. So that's something for your viewers. If they're microdosing, no less than one gram, but you can split it up two and a half grams, five grams, whichever you want. I take a lot more than that. Based on our new clinical data. I'm 48 years of age. I know the effects of aging and from a bone and brain perspective, but really all this dosing came from muscle. And we have all these new areas. That's why I think the emergence of new dosing strategies has really come to light.

Rhonda Patrick: Yeah, I definitely want to get into some of these potentially negative effects of the high, high dose. But let's talk a little bit about your new emerging data on bone health. And so you're talking about. So I mentioned 5 grams a day and. Well, maybe before we get to that, how long does, if I'm taking, like, if someone's taking 5 grams a day and you know, how long does it take to, to, to get your muscle stores saturated? And then let's say you're resistance training, right? So you're working, let's say resistance training and endurance training. I mean, you're working out five to six hours a week. Yeah, I'm just talking about my schedule here.

Darren Candow: Yeah, okay. Yeah.

Rhonda Patrick: And then. And I'm. And I'm doing five grams a day, right? Is, am I just constantly saturating my stores even though I'm, you know, pulling down from them as I'm working out, or how does that work?

Darren Candow: Because 5 is the average global recommendation. And that's a fantastic dose overall, we think, to start, especially from a muscle perspective. So It'll take you 21 days to fully saturate your skeletal muscles. So after that, you're going to have some being excreted in your urine, or let's pray here, hopefully some is now being uptaken into your bone because the muscle is pulling on bone. Your bone is a very metabolically active tissue which no one actually sees in the mirror. And then hopefully some is trickling more into your brain. So the thought is, okay, 5 grams is very viable. Easily 21 days, your muscles will be full, taking 5 grams a day thereafter. Some would probably go in the form of creatinine, but hopefully, and we don't know this, maybe some is going into your bone being used by your immune system, your GI tract, your gut health and your brain. So 5 is a great dose. I'd like it to be higher just because of some of the new data to suggest every day we get out of bed, we're a day older. There's some good evidence to suggest bone needs a bit more. And of course, the brain, we still don't know know, but I have some lines of thinking about when we're really metabolically stressed, how much to take. But if you're taking five, rest assured you're doing exceptionally well. Yeah.

Rhonda Patrick: Well, let's talk about bone. So one of the best things you can do for bone health is weight bearing, exercise. These compound lifts the things that we were talking about with improving your, your explosive power and your strength. Right, right. How is creatine adding to that?

Darren Candow: By two ways, a direct and indirect. So let's go with the boring direct. Correct. It sort of increases osteoblast cells. These are cells that sort of create or the formation of our bone cells. So in rodents, osteoblast cells have been energized in the presence of creatine. So it was logical to think in humans maybe our osteoblast cells, the cells that are responsible for increasing bone size and strength, might have more fuel. And these cells do use creatine just like our muscles do for fuel and potentially increase bone density. And if that's true, we've just cured osteoporosis. Basically. The other line of thinking, which is surprising, going back to this anticatabolic phenomenon, is the best lines of evidence with bone are from an anti catabolic perspective, it seems to resemble a bisphosphonate. So a lot of reviewers are maybe taking a bisphosphonate. It sort of preserves your skeleton. I know my mom is taking that as well. So creatine reduces something called the osteoclast activity or bone resorption. So for some reason it really inhibits these osteoclasts from sort of chopping down our bone and increasing blood calcium levels when not needed. And then of course, if it sort of increases osteoblast potential, maybe the recycling of bone gets stronger. It's kind of like laying a foundation of a house. The bricks are stronger. You're sort of putting the bricks together a little bit faster and then inclement weather is not chopping away the bricks or the cement. So that's how we theorize it was working and there's been about 15 studies now showing that it has a lot of anti resorptive effects. So, so think of anti catabolic to the bone. We have not shown in a single study an increased bone mineral density. So this is really crucial. We are not saying that creatine and weight training increases bone mineral density, but it certainly decreases bone mineral density loss. And really specifically around the hip region, which is crucially important for a lot of older adults because when they fall, if they, if they land on their hip, they could be more susceptible to fracture. So there's a lot of anti catabolic effects and we've just shown in a long term clinical trial that improved bone strength. So picture a pen or pencil, you can't crack it as much there. I think weight training is the main driver when it comes to bone. The more muscle you have, from an indirect perspective, there's more muscle pulling on bone. So that's very beneficial. Look at gymnasts, they have phenomenal bone mineral density and muscle mass there. So there's a lot of potential there. It's not overwhelmingly convincing I think because bone takes a long time to turn over. But this is interesting. The lowest dose ever been shown to be effective is 8 grams of monohydrate a day. Now, as we just talked about, 3 to 5 grams is great for muscle, but now you're getting into bone. What needs to happen is a dosing study. Could 5 grams over maybe 2 years be equivalent to 8 grams over 2 years or even higher? That is very expensive to do, but it's been in the back of my mind, I would just speculate that 5 grams over time will still benefit your skeleton. But you need such a large sample size to get these small effects either from a DEXA or CT scan. And that's probably why we haven't seen it yet. But in all our clinical trials, 8 grams, but the Brazilian group have looked at 1 to 3 grams for two straight years and not a single improvement. So weight training is there and I think that's the big driver for many of the muscle bone perspectives. Yeah.

Rhonda Patrick: So you, so you think just supplementing with creatine by itself, even if you're doing 8 grams, isn't really going to necessarily affect your bone health if you're not doing any weight bearing exercise, even, even considering the, you know, preventing the, the breakdown, I mean, preventing the activation of these osteoclasts that are breaking down.

Darren Candow: The bone, I would be very surprised. I think you need that mechanical loading from weight training or weight bearing exercise. Plyometrics that cause the bone to turn over. And then maybe creatine doesn't increase the resorptive or it increases osteoblasts a little bit more. The cool thing with osteoblasts, it releases the cytokine called osteoprotegerin, which acts as a decoy. And that's been shown in in vitro studies there. So there is some cellular data, which is a bit surprising when it comes to the, the skeleton, not just imaging, but if I was to take 8 grams, would I tell my parents to take 8 grams and not work out? If I did, I don't think they'd expect anything on the bone. The bone is really stubborn. It's just like our brain and creatine. It's rarely really stubborn. I think the main force is, is the driver of weight training is, let's.

Rhonda Patrick: Say a postmenopausal woman who, who's experiencing some perhaps osteopenia.

Darren Candow: Yes.

Rhonda Patrick: Do you think before trying some of these other standard of care treatments like bisphosphates, for example, you mentioned doing the weight bearing training and the creatine. Perhaps 8 grams or 10 grams a day would be a good first line of defense to try before trying some of these other drugs that do have negative side effects.

Darren Candow: So if there's, if you're in line for a bisphosphonate, there's no way that creatine or weight training will come close. So a drug effect will always be superior. The, the effects we're seeing, even from a significant perspective with creatine, are so small, we don't even get to a clinical perspective. But let's talk about weight training. I 100 agree. If I had to choose one for bone, it's weight training or plyometrics or anything that you feel to the body. And then consider creatine in your treatment program. Creatine would never replace a pharmaceutical intervention from a bone perspective. And the effects we're seeing are so small, or even over two years at best. It's preserving. Now. This begs the question. Maybe the adults we chose were too healthy. None had diagnosed osteoporosis or osteopenia or frailty. What if we took a population with severe osteoporosis? Maybe creatine could come to the rescue. There's there. That's another thing we're starting to hopefully get governmental funding for down the road. But a lot of young females, a lot of young males, and of course older females, even postmenopausal, their skeleton is still very beneficial and strong. They May not have incidences, osteopenia or fracture risk. But until we do a study and diagnosed osteoporotic males and females, we just don't know if it's the disease or maybe they were just healthy enough.

Rhonda Patrick: Yeah, well, prevention is obviously, I think the key. Right. If we can encourage people before they're experiencing massive breakdown of their bone or osteoporosis, osteopenia to, you know, engage in resistance training and not, and not the single joint exercises where you're making, making biceps bigger. Right. I mean like you need to, you need to be doing these multi joint compound lifts, rows, you know, presses, anything that's multi joint. And then perhaps in combination with creatine, if it's, it's really, if it's preserving bone. Yes, that does really suggest a preventative role, right?

Darren Candow: Yeah. And that's 100% correct. Like the movement is got to be there. And I think most people are aware the benefits of exercise. And then if creatine or protein or whatever it is you're eating can give you a small beneficial effect, I'm all for it. And I think a lot of people would be there as well. So creatine definitely has the potential. It kind of has a lot of potential for a lot of things. But without protein, you know, those two need to be there. We don't think creatine can rescue a hypocaloric diet especially low in protein, but we just don't know. I argue that creatine falls in line with protein with his aging anabolic resistance. As we get older, my guess is where we have lower creatine in some of our muscles. As we get older, we need more. So now there's a young versus older stereotype. Just like protein, younger individuals may respond from 20 to 25 grams, all the way up to older adults. So I think creatine is definitely a part of my day and I try to promote the evidence based research, especially from an older adult population. If anything we can do to offset chronic disease or getting chronic disease, that's beneficial. And we're starting to really focus on young females. Exercise is so important. Adequate protein and then creatine, it's not just for males. We're seeing a plethora of benefits for young biological females, which is really important.

Rhonda Patrick: It is. You know, when you, when you hear the word creatine, you think about like the gym bro. I mean it's like you're taking the creatine trying to get their muscles bigger. And the reality is that women are also very Susceptible to, I mean they're susceptible to losing muscle mass and strength. But bone is a big one.

Darren Candow: It is, yeah. And when we look at all the data, females get an improvement in muscle performance, primarily strength. That's the population. We've seen the best bone benefits. Now they were postmenopausal, but reduction in bone mineral density, bone strength, and then we're seeing from a sports perspective, agility, balance. So for the females watching, don't shy away from creatine. It's extremely, potentially beneficial in combination with exercise. And if you're worried about weight gain or whichever, do not do the loading phase. It's not needed. You can start as little as 2 to 3 grams a day, divide that up. Even so, I'll tell a lot of our clients or participants. You can take one and a half grams in the morning, wait till the evening to take one and a half grams. That really decreases the chance of water retention. But if you're eating red meat or seafood, you're getting a little bit amount. For the vegans watching, keep in mind you're not getting any. And that's why supplementation, third party tested, they are vegan based, could be considered.

Rhonda Patrick: Yeah, I mean it seems like it'd be very important for that population of people in particular.

Darren Candow: Yeah, we've done some really fascinating studies with vegans and vegetarians and they respond exceptionally well because we're doubling the amount of creatine, which is the high energy compound in our muscle, so they, those individuals can do more repetitions, higher volume, quicker recovery. So it really has favorable effects for male and female vegans and vegetarians. And again, those emphasizing a plant based diet. With everything going on in the world nowadays, a lot of people are looking at more plant based diets for health reasons or whichever and then they might need to consider a supplement. So usually we're not in the market of talking about supplements, but this one is the one that seems to come to mind where it might be difficult to get the amount needed in your diet diet from financial costs, ethical treatment of animals, whatever your own habitual preference is. And if they're third party tested, it's the safest, most effective ergogenic aid out there right now. The, the safety profile is exceptional, especially at the dosages we're talking about. Like when we talk about protein, we're talking hundreds of grams at most. We're talking maybe 10, 20 grams for the athletes, which is basically two teaspoons in, in the run of a day. So it's not a lot, but there is a lot of evidence based research behind it.

Rhonda Patrick: Yeah, yeah. And I let's. We'll definitely dive a little more into the supplement, but I'm interested in the brain and we've gone from the role of creatine. It seems to have multiple roles. Anti inflammatory, anti catabolic. It's obviously important for producing ATP, regenerating the ATP. What about the brain?

Darren Candow: Super exciting. This is such an emerging area. So from the neck up, I think the next 20 to 30 years will be focused almost entirely on this. So our liver produces creatine and our brain actually is unique. It also produces creatine. But the brain is very resistant. We have the blood brain barrier for a really important reason. And the brain says, you know what, circulation, we don't need creatine in the blood, we're making our own. So an individual getting adequate sleep, no chronic disease, no metabolic diseases, no neurodegenerative diseases, is producing adequate amounts of brain creatine. It could be as little as 1 to 3 grams. Now our brain is small from stature, but it uses 20% of our daily energy. And of course, as we all know, when you're really tired, sleep deprivation, running around chasing your children. Most people that I know are really metabolically stressed, primarily from a cognition perspective. And that's where creatine seems to have the best lines of evidence. Sleep deprivation, hypoxia, eye jet lag. I was up at 3 o'clock this morning and flew down. So I'll be taking a really high dose today to hopefully offset the, the, the chance of inflammation or cognitive decline. So when we look at the totality of emerging evidence, it's split. Some studies don't see any effect, but the ones that do is in a population where they're either mentally fatigued, sleep deprivation or during times of aging. And that's where memory comes into play. And the common denominator seems to be the more that the brain is stressed, the more creatine seems to come to the rescue. Same analogy from a muscle and bone perspective. So we can talk for hours just on the brain and it's a very exciting area for sure. Yeah.

Rhonda Patrick: So the brain is stressed. So, so brain aging, brain age, older adult. Yeah, that's, that's. Aging is a stress on the brain.

Darren Candow: It is.

Rhonda Patrick: So supplementing with how much creatine can improve cognition in, let's say older adults.

Darren Candow: Yeah, as little as about 5 grams has been shown to have some potential. But this is interesting. I just, you know, 20 minutes ago said that the loading phase wasn't needed for muscle. The Best studies for the brain look at 20 grams a day for at least a week. So now you're in a conundrum by looking at muscle, bone and brain. And the theory here is that since the blood brain barrier is very resistant to creatine and unfortunately we have this really important glial cell called astrocytes which are the most, the biggest in our central nervous system, it sort of acts as a filter from our blood into our cells and it really determines what gets in. And it says, hey, foreign pathogens, no, you're not getting into the, the neuron or the cell. So unfortunately they don't have the creatine transporter or doorway. So that's why uptake into the brain is very blunted. So the thought is to get an improvement in brain creatine stores, you need longer duration of supplementation or higher dosages. So the best lines of evidence using Mrs. Have shown that higher 20 grams a day seem to be the most viable. There's been a single study looking at about 4 grams a day, but it took three months to accumulate in the brain. Unlike our muscle which acts as like a vacuum, it sucks in all the creatine from our blood. Our brain says no, no, I'm only going to take what's in our blood, I. E. Supplementation when need be. So that's why sleep deprivation seems to have the best lines of evidence or mental fatiguing challenges. Yeah.

Rhonda Patrick: Okay, so let's, if you're, if you're someone like myself who's been supplementing with 5 grams a day for a year, okay. That's enough time for it to eventually accumulate into the brain presumably.

Darren Candow: Yeah, like that low dose, remember you need about 2 to 3 grams. Now I'm not sure about your diet, but you're going to need that just to maintain your muscle. And then comes down to your genetics. What's more in jeopardy? Is it your bones or brain? So again, the 5% that's remaining throughout the body is in your testes, heart, bone and brain. So for me as a biological male, it's going to different areas compared to you as a biological female. But my hope is, wait a minute, let's go a bit higher. So we're sort of, sort of checking off all the boxes. My guess is 5 grams, you'd have a small increase in brain creatine content. But if you have a really non stressful life, the brain says no, go to the bone or we'll excrete it down the toilet. But if you're metabolically stressed, it's Begging for more. I'd like you to be probably higher than 5, but, but I think it'd be interesting to look at some pre post Mrs. Scans and it's viable. It could be there. The study that did 4 grams was in long Covid these individuals, brain fog, fatigue, headaches, things like that. So the brain was really begging for recovery.

Rhonda Patrick: Okay, so you just mentioned the best studies showing any improvement in. And when we're talking about improvement, we're talking about cognition, we're talking about like memory. Memory. Okay, yeah. You said 20 grams, right? Which is definitely what I don't want the, the swelling part of that, which happens around 20 grams.

Darren Candow: Yes.

Rhonda Patrick: So have there been studies looking at 10 grams? Is that like a sweet spot?

Darren Candow: The seminal study was out of Germany and they did 4, 2 versus 4 versus 10. And this is where I personally take at least 10. And they use Mrs. Studies and they only, they showed that about 10 doubled the percent increase in brain creatine content. But they also measured it in the gray matter, the white matter and I leave the thalamus and it all improved by about 10%. Now it was a small sample size because the run on Mrs. Is super expensive. Still statistically it wasn't there, but the percent improvements were a lot higher. And when you look at all the other data, 10 grams seems to be a very viable dose to not only check off the box definitely for muscle, we're now checking off the box for brain and now we're sorry bone. And then we're also checking off the box for brain as well. So I personally take about 10 grams a day on average reach. But during times of metabolic, stress, sleep deprivation or jet lag, I'll increase it to 20. So today I will take 20 grams because I flew down from Canada. I'll take 20 grams again tomorrow. But when I get back home I'll decrease it back down to 10. If any is being excreted down the toilet, I'm totally fine with that. Creatine is very cost effective, but I want to make sure I'm maximizing all my abilities. And the immune system, especially in Canadian winters is really heightened and activated it. And I really have found in the last few years I'm, I'm not getting food like symptoms. Hopefully that's from exercise or diet, but who knows, maybe creatine is helping because there is some anti inflammatory effects.

Rhonda Patrick: You, you, you went to another area that I definitely want to talk about. But like before that. So 20 grams then you're saying acutely when you're in this Sleep deprived state, jet lag, you know, let's say fill in the blank type of, you know, extreme stress.

Darren Candow: Right.

Rhonda Patrick: Is that immediate? So let's say like you, you miss, you're like up late, you had, you're up late one night, night and you have something to do the next morning or the next day, you have to be like on your game. If you take that 20 grams either at night, would you take it at night, like before you go to sleep or in the morning or does it matter and will it have an effect immediately?

Darren Candow: Yeah, and I love learning. And this is just so 20 grams might be too low. It's surprisingly your viewers. So another study came out of Germany, they did is very elegant design, it was a crossover and they gave 0.35 grams per kilogram. So even if you're only 70 kilograms, that's 25 grams in a bowl of stove dose. And they measured it for 21 hours of sleep deprivation and it really improved memory, cognition and it increased brain creatine content. So that high a dose, not only does it get into your plasma or blood really quickly, probably in about three hours, it's peaking when your brain is stressed, it's being taken in quite readily. So during times of metabolic stress, it seems to work. Now the argument is, how do I know I'm going to be stressed tomorrow? How do I know I'm going to have a bad night's sleep? You don't, don't. So that's why I think taking a higher daily dose might be a safety. But the days you're like, oh, I didn't sleep at all and I have a big presentation later, or me as a professor teaching four classes a term, I've really increased the amount. I would say I might be the most saturated person on the planet because I've been taking creatine for decades, there's no reason to stop. We can talk about cycling or continuous, but I'm even taking more in hope that it's getting into my brain brain again. 20 years ago it was just muscle, then we've evolved into the bone and now we're getting into the brain. And I think a university students, midterm week, final exam, staying up all night cramming, maybe creatine could really improve their ability to score better on tests. And when you look at the mental fatiguing studies, that's when creatine seems to work. After you've done a whole bunch of fatiguing exercises or, sorry, taking creatine before, it really speeds up your ability to maintain Memory and cognition. And we can talk about neurofilament things in the brain or bdnf. And that's some of the mechanisms primarily in rodent. So there is some mechanisms showing that creatine is decreasing oxidative stress or really having some potential for neuronal health, which now you think of Alzheimer's, dementia, neurodegenerative diseases. So I'm super excited to see where this is going for the next 20 or 30 years. Yeah.

Rhonda Patrick: I wonder if there's any effect just because sort of a triaging of like it's helping with the energy and so it's like freeing up other energy, you know, for like other, you know, taking care of oxidation.

Darren Candow: And that's like probably the best overall segue. So it increases brain bioenergetics. And if it can, one of the common numbers with depression or concussion is that they have reduced brain creatine stores and bioenergetics compared to a healthy control on average. And so maybe creatine is bringing those values up or even slightly more. And now the brain has more energy capacity to do and deal with all the daily stressors of, of society. Yeah, absolutely.

Rhonda Patrick: So tbi, I mean traumatic brain injury, the way I think of it is like real time brain aging.

Darren Candow: Yes.

Rhonda Patrick: It's just, it's like all of a sudden you just get a knock to your head and it's like accelerated aging. So what would be a protocol for someone that, you know, let's say they take a blow to the head or they get hit with a ball, a soccer ball or, or you know, whatever the football, whatever sport that they're doing, would it be like they should be taking high dose immediately?

Darren Candow: Yeah. So I'm now in the camp and I think a lot of other researchers and a lot of the works come coming from here in the United States. But if you're in contact sports, creatine should be taken on a daily basis because unfortunately if you do get hit in the rodent model when, because you can't do this in humans. But when they've actually forced concussion in rodents taking creatine beforehand, the recovery symptoms are really accelerated. And in the only single human study was in children. As soon as these people in Scotland got head trauma, they put them on 0.4 grams of creatine per kilogram, so about 20 grams. These are just children immediately. And over six months, these children that were taking creatine had substantial improvements in self care and efficacy. No blood biomarkers were taken, but at least it showed the improvement in recovery. So Instead of waiting till you get hit, why not take the preventative role? And that's why again I think for me, and again it's it's opinion but we've seen some data to suggest that 10 grams might be a good viable dose. More or even a little bit less depending on why you're taking it. But I personally take it from a whole body perspective. I don't play any contact sports now, but who knows, I could go and skate and fall and hit my head or skiing or whichever and maybe that would help accelerate recovery. I'm taking it just for any chance to have some potential brain benefits. But the big areas, it does increase the recovery aspects of concussion. So NFL, ncaa, especially down here in the United States, trillion dollar industry, I gotta believe these players are taking creatine in anticipation. I know the quarterback for the Dolphins, I think he's had three concussions this year. So his brain is so compromised right now, massive inflammation. Hopefully his medical team is at least considering high dose with his other treatment program to get there. So.

Rhonda Patrick: Yeah, and they should be taking it for the benefits on muscle, you know, and you know, explosive power.

Darren Candow: Exactly.

Rhonda Patrick: Yeah, those you know, high intensity moments you mentioned earlier, about 0.1 grams per kilogram body weight. So how would you adjust? Let's say, you know, you're taking 10 grams of creatine per day and you're wanting the effects, the benefits of muscle, bone, brain, as do I. However, I do not weigh as much as you do. So would you. Is there a scalable amount per kg body weight you think would be something that, or is it hard?

Darren Candow: That's an excellent question. And the answer would probably be no because when we go on the scale we don't consider the head, even when we do DEXA scans as headless. So you know, if I'm 80 kg, I'm taking about, there's the sweet spot about, about you know, 9 to 10 grams a day. Taking it from a weight perspective to the correlate to the brain is almost impossible because we need to measure the, the weight and where it's a hard tissue, it's a little bit of soft, but it's usually hard tissue. I think overall body weight very similar to how people do protein based on lean mass or a total body structure. So you can take creatine based on lean body mass, but it's very difficult. You would have to have some type of imaging apparatus. So we just usually recommend it. On body mass, mass, they hit the.

Rhonda Patrick: All the aspects that makes sense. And it really does seem like there's this sort of triaging where it's like, okay, the muscles consuming it, it's like the greedy one and then whatever's left over, maybe the bone. But if the brain's stress. Well, maybe, you know, it's funny how the body can figure that out. Like, no, the brain needs it.

Darren Candow: Yeah.

Rhonda Patrick: So, you know, there was another, there's some interesting research that you also published. Kind of in the, in the brain area is sleep. Right. And I'd love for you to talk about that study. I thought it was so interesting. These resistance training females and you gave them creatine and it really seemed to help improve their sleep on training day.

Darren Candow: Yeah, it was colleagues at University of Idaho, Ann Brown and C.J. brush, and they looked at young healthy individuals, biological females, and we gave a pretty high dose here, 5 grams plus we added 5 grams of placebo. So 10 grams a day versus a 10 gram placebo. And this was done for six weeks. Weeks. And they resistance train with a tonal home gym for two days a week. And the interesting thing is total sleep duration on the days they trained was substantially higher. I think it was about almost an hour compared to placebo. And again, these are young university age students that were taking creatine about 5 grams a day. The nice thing is it also improved strength. There was no big fluctuations in weight gain, which was very, very interesting. No adverse effects effects. Now there was no mechanisms assessed, but the logic was that on the days these individuals are training, maybe they put in more effort. So creatine helped recover the body a little bit more, allowed that body to be in repair mechanism a little bit more and they slept more for about an hour on average. More. We still don't know the exact reason, but it is interesting that it improves sleep duration. Yeah.

Rhonda Patrick: And it's almost kind of the opposite of what we were just talking about. Where you're talking about if you're in this context where you're jet lagged, you're sleep deprived and you take the creatine and it kind of helps you get over that brain fog that like.

Darren Candow: Right.

Rhonda Patrick: You know, you just, you're not quite, you know, on your game.

Darren Candow: Yeah, it goes against most the, the comments I get where when people take high dose creatine, some people say they feel like insomnia or intermittent sleep. And the theory there from a road model out of Belgium is that maybe the brain is recovering quicker, that it doesn't need to sleep as long. So we still need a lot of work to do. We need to look at different Stages of sleep. Sleep. We. I'd really like to look at some blood biomarkers, indication of what's happening from an inflammation perspective. So there's a lot of work in that area to go. Yeah.

Rhonda Patrick: You know, the other thing I was thinking about, Darren, was, I mean, when. So adenosine.

Darren Candow: Yes.

Rhonda Patrick: Is there, is there a role? Because, I mean it's downstream of ATP. Right. So I'm wondering if there's any role because adenosine is something that does make you sleepy.

Darren Candow: Yeah, yeah. I always think of caffeine, the adenosine, Anthony. Right, yeah. No, no, it's possibly there. There's been a lot of speculation. They thought also glycine is implicated and where glycine is involved in the, in the synthesis of creatine. So there's a lot there. I think we'll talk maybe about homocysteine a little bit later in the methyl. So. God, there's a lot of areas to look at and I think we thought we knew everything about creatine and now it's taken on a new life, its own. And again, I'll have a jaw for maybe 20 or 30 more years looking at this. So.

Rhonda Patrick: Yeah, well, let's talk, let's go back to the brain and talk about another. So we talked about brain aging, you know, traumatic, traumatic brain injury, which is stress. We talked about lack of sleep, you know, anything that's stressing the brain. Well, I guess, you know, neurodegenerative disease is a very stressful thing on the brain as well. It would be interesting to see if creatine can help in that regard. Although again, prevention is always. Yeah, it's always better. Right? If you can.

Darren Candow: Yeah. We've looked at the totality of limited evidence and we're not seeing a lot of effects yet. There's benefits on young boys with muscular dystrophy, but that's a little bit different. But when we look at als, Parkinson's, Huntington's, multiple sclerosis, all those dementia and Alzheimer's, we're not seeing a lot of promise. There's been a few small scale studies that show benefits, but when you look at a properly sample sized study, there was a big one, five years in Germany, didn't see any greater effects. So again, maybe the dose was too. When I look at the dose, they use it, but very small compared to now our body of evidence suggesting higher dose, big sample size. And then of course, what about the effects of the disease? Can creatine really rescue the effects to give a significant effect? We don't Know, preventing would be the number one thing. But we're starting to do a study in northern Iowa to look at the effects of creatine now in individuals with cognitive decline. And I believe there's a study out of Kansas that are actually looking at people with diagnosed Alzheimer's. So super excited to see these results. If it can have any effect, even help one person, even regardless of a statistical effect, if it can have individual results, I think it's something we need to consider. Yeah.

Rhonda Patrick: Okay. Well, what I was going to get to was the other part of, you know, brain disorders. You have neuropsychiatric disorders, you have depression, anxiety. Those are, those are also unfortunately very common nowadays, even in younger adults and adolescents. So there's been some interesting research with creatine and depression.

Darren Candow: Yes, there has. It's an emerging area, primarily to Utah. There's a great psychiatry group there. And as a caveat, no study has ever looked at creatine without antidepressant medications. So they're always as adjunct. So we're not saying creatine could ever replace anxiety or antidepressant medications. But in these sub populations, primarily females with clinical depression, it's really starting to have some speed up recovery and decrease some of the symptoms. The mechanisms are starting to emerge. It's starting to have a role primarily from rodents, and this is implicated in depression where they have reduced reduce brain creatine stores. So maybe creatine supplementation can bring those levels up. There's potential to increase bdnf, so that has been implicated there as well. And there's another thing called neurofilament or light chain. It's an indication of neuronal damage. And 1 gram of creatine in your diet has been shown to reduce that. So there's potential there. But the overarching thing with antidepressant is it increases brain bioenergetics, as you mentioned, and decreases again. Here we go. Mitochondrial health, health decreases, Reactive oxidative species. All these are implicated in all the brain and cognitive decline and primarily depression. So I'm really excited in that area. A big RCT needs to be done though, because it's always being added to either cognitive behavior therapy or ssri for sure.

Rhonda Patrick: And there's also a big inflammatory component in depression. There's like inflammation. In fact, there have been studies just in healthy young individuals where they induce inflammation. So like LPS, it can cause depressive symptoms?

Darren Candow: Yeah, yeah. And 100%. So the anti inflammatory role comes back there as well. So you'll start to hear these Two words, anti catabolic and anti inflammatory. People think of Advil or Tylenol from an anti inflammatory. But creatine seems to work some very similar in the COX inhibitors as well. And. But it seems to decrease cytokines so it could be something there to consider.

Rhonda Patrick: Yeah, well what's interesting is you know, activated lymphocytes, T cells consume just enormous amounts of energy to basically become active and fight off pathogens. And so I'm wondering if creatine is taken up by these immune cells and it maybe helps in some way. I mean you're saying it reduces cytokines. I mean a lot of these T cells are producing cytokines to fight off things, but who knows if they have that energetic boost.

Darren Candow: Yes.

Rhonda Patrick: How that could affect, you know, just I would say like the broader, like not having this huge kind of war going on. Right.

Darren Candow: Yeah. There's been some cellular data around the immune system cells around creatine specifically around T cells or macrophages. That's where the anti cancer idea came in from. Creatine specifically, like regarding lymphoma, leukemia. So that's more in vitro. There's a lot of work needs to be done done. But there's a lot of studies now looking at the anti cancer potential of creatines, primarily from the anti or the enhyten immune system response. Yeah.

Rhonda Patrick: I wonder if there's any. Has anyone ever looked at, you know, creatine's role in helping prevent infectious, you know, disease or respiratory illness fighting off pathogens? Like just anecdotally I supplement with glutamine and create my 5 grams of. It's about 5.6 grams of glutamine. I take a day and with creatine, 5 grams of creatine. And it has made a insanely big difference in my susceptibility to respiratory illness, which I have a little 7 year old who brings home.

Darren Candow: Everything okay. Yeah.

Rhonda Patrick: Yeah. It's like a vector and it's made a really big difference. And glutamine also is just, it's consumed by activated T cells with a lot of work done.

Darren Candow: Use for cancer. Yeah. And treatment sepsis and things like that. Yeah.

Rhonda Patrick: So it would be interesting to see if there's any effect of both of those. But even just looking at creatine as well, I know glutamine's been shown in endurance athletes like, who are very prone to respiratory illness. Like these marathon runners. Yeah, really, like they're, they're really just getting, getting to that catabolic state. Right.

Darren Candow: Yeah. It's interesting because I was the first to do glutamine, very high dose in weight training based on the premise that, you know, if it did have any catabolic effects or cancer, long duration and, and, and that was my master's thesis and we didn't see any effect probably going back to our initial start where resistance might not be stressful or catabolic enough in continuous duration compared to long duration events. So that's very interesting. Yeah.

Rhonda Patrick: Are you familiar with any of that work of the long distance runners and glutamine? There's like a few studies showing that these, these marathoners and stuff, they, they don't get as much as many respiratory illnesses if they're taking glutamine.

Darren Candow: Yeah, no, I'm very familiar. I had to do the whole literature search and it was a higher dose and they also looked at it for sepsis. But the immune system response, T4 and T8 I don't think were nearly as high. And that was from long duration and a young healthy individual, they probably might not notice any effect. But again that was the idea. The premise behind it was more of an anti catabolic and why it didn't work for me it was a non essential amino acid. Of course for protein synthesis you need all the essentials. So it was a trying moment when I was doing my masters. But it works out in understanding it.

Rhonda Patrick: Yeah, well there certainly doesn't seem to be any shortage of interesting things to study with creatine. And it's like, you know, there's, the field is exploding so maybe someone out there will be looking at that at some point. Another really interesting area is the vascular health. And I mean there's just like we were just chatting about a recent study coming out. Endothelial cells have transporters for creatine.

Darren Candow: They do. Right next to the astrocytes, which don't. So the endothelial cells at the blood brain barrier especially, but around all the smooth muscle they do have the transporter. So that was one of the theories. Mike Orsbee just put out a study in Eric Ralston just recently in older adults. And that makes sense because you look in a population that might get some benefits and they showed some very small favorable effects from creatine supplementation either a week long or for up to four weeks. I believe it was a loading phase and then down to about 5 grams a day. So it has some favorable effects for endothelial I think with macro and microvascular function. So that might have potential down the road for cardiac rehab or individuals with Cardiovascular disease, or even subsets of that like type 2 diabetes or metabolic syndrome. So that's an area to stay tuned for as well. It's emerging. And same with type 2 diabetes. There's potential there as well, potentially improving glucose disposal. Again, if there's more muscle activation, you have more glute, four doorways, maybe more glucose gets in. So the Brazilian group is leading the way there. So it's gone from just athletes to now looking at the health aspects for a lot of different conditions and interesting chronic diseases has come to the forefront, which is very exciting. Yeah.

Rhonda Patrick: I've also come across some other, like cardiometabolic health benefits. So glucose, but also triglycerides with cholesterol in there too. Can you talk about that? Is that maybe some mixed data? I'm not sure if everything is showing the same mixed.

Darren Candow: Some show decrease in triglycerides, LDL and then others don't see the effect. And again, I think it comes back when you look at those studies with the population, if they're compromised as we get older, they're probably going to be more of an effect. And then the question is, was a dietary change that did it or was it the creatine itself? So that's one of the big issues when we give a creatine supplement, if you don't consider what they're already consuming or now they've initiated exercise compared to a triple C by. So there is potential. The mechanisms seem to be, from a triglyceride perspective, it seems to increase energy expenditure, some thermogenic potentially effect. That might explain why creatine decreases body fat in individuals 18 and above. But from the cholesterol perspective, we don't really know the mechanism there. And that's an area I'm sure that'll be exploding down the road. Yeah.

Rhonda Patrick: So creatine decreases body fat in combination with resistance training compared to resistance training alone.

Darren Candow: Correct. Yep. Now small, about 1% or about 0.5 kg. There's some potential mechanisms there, but the thought is maybe increase in lean tissue mass, increase energy expenditure. So a lot of people are very cautious. They don't want to take creatine because they think it's going to increase fat mass. What the research is suggesting is increasing lean body mass, potentially decreasing fat mass. So usually the number on the scale barely changes after you do an intervention. Yeah.

Rhonda Patrick: Well, going. Going back to this loading phase and this higher dose. I mean, when I say higher, I mean 20 grams. All these studies doing that, I mean, barring the brain stuff, is it. Is it really just to like kind of get their stores saturated quickly because the study is you're not going to wait 30 days. So it's really, you know, all these other people trying to do this loading stuff, just kind of following the studies, but really they don't have have to do that unless they like tomorrow when I hit the gym and have that explosive power benefit.

Darren Candow: Or if you need a really quick effect like rehabilitation from an injury, ACL surgery, something where you need to rehabilitate the muscle quickly or you're an athlete. The loading phase to me is not needed from a muscle perspective now because we've talked about bone and brain might need a bit more. So now maybe the new daily loading phase is maybe 5, 10 grams a day or a little bit more. But that athlete, 20 grams a day for seven days followed by the maintenance that is only ever been shown to have beneficial effects to muscle. There's been a few studies that have looked at it now from a brain, but again, that's from a different perspective.

Rhonda Patrick: You just brought up a point that I was thinking of and that is surgery and you know, like, or injury. How does, how does. Because that's a stressful situation we're talking about, you know, really creatine shining in that background of, of some sort of stress, whether it's training or you know, sleep deprivation. But also, you know, you can have something like an injury or a surgery where you're planning a stressful event.

Darren Candow: Yeah, it's multifactorial. The studies that have looked at it from a rehabilitation perspective, creatine seemed to increase these things called myogenic transcription factors. So without boring your audience, these are little guys that sort of tell DNA to sort of increase proteins in a quicker way. So these myogenic regulatory factors went up during rehabilitation. And then we did a study when we got individuals to put on a cast volunteer and creatine seemed to maintain strength. Going back to the mechanism, it probably has to do that reduction in protein breakdown or the anti catabolic, anti inflammatory effect. Again, we don't think it has anything from a synthetic perspective because creatine doesn't. But it does. It has been shown increased satellite cells which are needed for recovery and rehabilitation. Growth factors IGF1 and decreases myostatin, the one that increases protein breakdown. So all of these factors come into play. It's like the caramel secret. There's a whole bunch of things that go into that chocolate bar. Creatine seems to work in a very variety of ways. And then again, on the other side, it's certainly been shown to decrease reactive oxidative species. So it seems to have more of a preservation to the cell effect. But from an injury perspective, it seems to speed up recovery. Do we know would it speed up recovery if you took it before surgery? The jury's out on that. We'd have to do ACL surgery or studies on that. Long term clinical trials, we see a bit of promise in osteoarthritis, but not a lot of other ones. And because basically the studies haven't been done yet.

Rhonda Patrick: And what are the, what's the dose on, on some of those?

Darren Candow: These are usually the loading phase with a slight maintenance phase. Or if they're looking at it from a cellular perspective, it's usually just the loading phase. 7 days pre post they'll do biopsies or cellular data.

Rhonda Patrick: So the 20, 20 gram a day loading phase. Phase and then the maintenance phase being about 5.

Darren Candow: 5. Yeah.

Rhonda Patrick: Okay. And if someone's already taking, let's say 5 or 10 grams a day and then they're gonna have a surgery, do they still need to do the loading or should they just continue on?

Darren Candow: I would just continue on. Or even slightly a bit more. Because when the tissue is under trauma, you get heightened inflammation, reactive oxidative species or stress and then protein breakdown. So maybe could help speed up your ability to recover quicker. We don't know any of the effects of creatine on cross education where if someone has an immobilized link limb and they train the opposite limb, we don't think there's any effect. It's a great study to do and that could have huge applications for professional athletes or individuals that have, or waiting for ACL surgery. Instead of sitting around all day, go to the gym and train the, the healthy limb. And maybe creatine could potentially increase more drive there. It's a study I've always wanted to do. We just haven't done it yet, you know.

Rhonda Patrick: Okay, so it sounds like, you know, in most cases, you know, the creatine plus the, the, the training, resistance training, endurance training is the key. But in some situations when there's just a massive amount of stress from perhaps an injury or surgery or sleep deprivation, creatine can shine on its own. Is that correct?

Darren Candow: Yeah, there's actually a small body of research in healthy individuals, young and old, that say creatine without exercise actually improves muscle performance. So those that I think of disuse, bed rest, immobilization, sedentary individuals, maybe they have functional mobility issues, or people that don't know or have access to weight training Creatine by itself has been shown to improve muscle performance, improve strength, endurance, their ability to perform repetitions to fatigue, primarily in older adults. But there's been studies in younger individuals and that's sort of where creatine research blossom. All the initial studies were very acute, seven days, the loading phase. And then we saw improvements over time, time on muscle performance. And that sort of paved the way to lifelong interventions which include. Exercise is the main thing. For sure.

Rhonda Patrick: Yeah. Exercise is definitely the most important thing. But I know I'm gonna ask you to speculate a little bit here, but let's say, let's say you do have an older adult who is sedentary and just getting up out of a chair is hard. It can be challenging. Do you think that even supplementing with creativity, creatine in that regard, maybe help them a little bit more?

Darren Candow: 2 meta analysis been performed both in Canada. We were fortunate to do one. Stu Phillips, I know, has been a guest, I think for you, and we've done two meta analysis. And then when you look at creatine in older adults with resistance training, though, it did improve tasks of functionality. Sit to stand. So getting out of the bed, off the toilet, getting out of a chair. Again, that was with exercise. Without exercise, nothing has been there. So I would love to say yes, but again, the movement of exercise. But the nice thing is for those willing to do, you know, is it resistance bands, anything that you feel, mechanical stress, creatine will give you a slightly greater benefit. But for those that are in jeopardy of chronic disease, I think you should consider it. Absolutely, yeah.

Rhonda Patrick: So another question of mine, you were talking about where creatine transporters are, where it's synthesized. You mentioned it's created in the liver and the brain, but you mentioned it, it goes to the testes, there's a.

Darren Candow: Little bit down to the testes. So any organ that only has the enzymes to make it. So since it's made in the liver and brain, it'll be dispersed to other areas. So the interesting thing is the area that it's created, it goes through circulation to different transports. So male fertility has become a big issue. And there was a thought that, oh, creatine, since sperm rely, it's a flagella. So since since sperm are relying for movement on creatine so much, maybe it's down regulating sperm production. And my good colleague out of Norway, Sir Josiak, who's one of the world's best creatine researchers, has looked at this in many forms and not showing any effect of anything. It improves the vitality and mobility of sperm. So that could have huge implications for male fertility. So yeah, it's an area that you probably would never think of, but it's an area that has shown some evidence based research beyond it.

Rhonda Patrick: Yeah, and that's, that was going to be my question. Is it affecting fertility? Yeah, because it's going, it's going to, improves it.

Darren Candow: So again, that could have applications for individuals trying to start a family or, or male, male fertility issues. We don't see any down regulation. There's a thought of taking in supplementation. Maybe that'll give your brain and liver a bit of a break. And there's evidence to suggest that maybe if you're taking creatine on a daily basis, those organs don't need to make as much because you're, you're offsetting that. But again, when you stop supplementation it goes back to baseline or it doesn't disrupt any of that. And, and the good thing is from a fertility perspective, there's no evidence to suggest it down regulates a sperm motility health. We can talk about hair follicle loss and thinning. The same idea. If you were, if the viewers were looking at me, but that was the same idea. Maybe creatine was causing baldness. So maybe it must be doing the same thing to sperm. It must be killing off the cell and we just don't see any of that research.

Rhonda Patrick: Yeah, so good. Yeah. Well, let's get into those myths. Before we get into those, I kind of wanted to, to. We've talked a lot about adults, we've talked about older adults, the effect of creatine on many different tissues in those populations. But at the start of this podcast you said something that caught my attention and that was you said children and you said pregnancy and I'm a mother of a seven year old who's quite active and plays soccer and tennis. And I often wondered, can children take creatine? I mean, obviously weight adjusted, but has there been any, any, you know, evidence in children? Has anyone looked at children besides the TBI study?

Darren Candow: Yeah, no, there has. Chad Gersick and Andreagam at the Mayo Clinic here in the United States are the two most profound researchers in that area. And they've looked at study after study in children, young children, adolescents, and there's no adverse effects. And why would there be? If our body doesn't like it, we just excrete in it. There's a big push right now in some states trying to ban creatine in younger individuals and they're just not looking at the evidence based research. So overall all there's no adverse effects. We still need to do a little bit of blood work. But it improves health, agility, coordination, muscle mass. There's no reason. And so that's why I'm one of the big proponents. I argue, including the fetus, why someone couldn't take creatine if we're already producing it. It's not like caffeine, a drug effect. We're already producing it. That's like telling people you can't take protein in your food or supplement. That's just nonsensical. So, so I'm one of the big people say anybody can take creatine. Even if you have chronic kidney disease, there's some benefits because it'll help the kidneys absorb creatine. And so right now there's potential benefits for children, for pregnancy. Stacy Olivery in Australia is the leading researcher there. Nabi Smith Ryan in unc. And so they're actually looking at fetal development, having more brain bioenergetics for the female. We now know that the transporter from breast milk. Milk is, is there. And then when you look at habitual diet again, Serge Osiga has looked at NHANES data and for those children taking less than one gram, it leads to a lot of potential detriments later on. Cognition impairments, lean body mass, bone minerals. So I mean a serving of salmon is about 3 to 4 grams of creatine. A hamburger would even have that. So again, in habitual diet, unless the child is vegan and they're probably getting a little bit of amount and the dose 2 to 3 grams or you can even do 0.1 gram because they're so much smaller. So if I had a child, I just have animals, a dog, I would give my children creatine for sure as early as possible because I'm looking at brain development, bone development, muscle, immune system, it has all those benefits. And keep in mind, if our body didn't like it, we just make expensive urine, like we just excrete it. People see this when they go for their blood requisition. They see creatinine on this blood requisition form and that's all it is a byproduct. So it's very safe. The safety profile is exceptional.

Rhonda Patrick: Wow. I mean, so a few things here. So with respect to the dose with children, so you said 2 to 3 grams or 0.1 gram per kilogram body weight or is that applicable to the children as well?

Darren Candow: I mean if you want to do 5 grams or more I don't see any reason why not not do they need to be taken the 10 and 20 grams. We just don't have the data to support that. But A low dose, 2 to 3, 5 grams is, is totally viable.

Rhonda Patrick: And vegan kids probably even more so. Right. And then pregnancy, has there actually been any human data looking at women supplementing with creatine being safe?

Darren Candow: Just subjective questionnaires, how they're feeling, things like that. It's too dangerous in a sense because we just don't know yet. And to get ethics board approval at a research institution is very difficult, even for teenagers and adults under the age of 18. So I know Stacy is in our Big Myths paper, has concluded that we need more randomized control trials, a big trial, because we definitely want to get this one right and make sure it's 100% safe, not just for the unborn child, but also for the mother. So there's going to be a lot more data to come out. But overall there's no reason to suggest there's any issues whatsoever. Yeah, yeah.

Rhonda Patrick: And again, coming to the back to the vegans that comes to mind, talking about women who are pregnant who are only relying on their liver ability to make creatine. Right. So that would be phenomenal to get a study like that done. But do you think it'll be approved?

Darren Candow: I think down the road, when they look at the hypoxic environment of fetal growth, I think it probably will get approved. But we're going to need a lot more clinical data to suggest it's safe. And maybe a pilot study in that the issues with pilot studies are usually low sample size. So then from a feasibility perspective, it might be how it actually I can see it in a multi country to get a lot of people in different countries to come together and make the sample size that high. So that's something to look forward forward to as well, especially. And in addition to the neurodegenerative diseases.

Rhonda Patrick: Yeah, I know I'm jumping all over the place here. But going back to the kids, you mentioned the creatine supplementation was shown to improve agility. Now why is that? Is that because of the type 2.

Darren Candow: Muscle fiber or the motor unit recruitment or maybe muscle activation? So there's a whole plethora of ideas. From a balance, agility, coordination perspective, it could be that they're able to exercise at a higher capacity, sort of, sort of almost hyper accelerate muscle development. Those are all the things that are in its infancy to look at. Again, there hasn't been a study to look at Blood biomarkers for like liver and kidney enzymes. But I would be very surprised if a low dose study was done and there was any issues. Yeah.

Rhonda Patrick: Okay. Well, getting into some of the supplementation, you know, questions, and I think we've been, we've kind of. You touched on quite a few, but I want to kind of dive a little bit deeper. You first mentioned, of course, I think a lot of people that are familiar with the creatine field know creatine monohydrate. Creatine monohydrate. Is that still the gold standard for supplementing with creatine? If so, why?

Darren Candow: Yeah, it's the only standard. So when I say creatine today, it's monohyd hydrate. And the reason being is based on its safety and efficacy. So monohydrate means that creatine is linked to water. So when it comes to your GI tract, the water diffuses in the hydrochloric acid of your stomach. So that molecule, it's very unique. It can actually get through our small intestine intact. Unlike protein, which gets degraded. Creatine is very unique. It's because the acidity of our stomach is actually too acidic. It doesn't like it so much, so it gets through. And then when it gets in our blood, blood, the creatine that you're taking from supplementation monohydrate is identical to what's being synthesized in the liver. So that's likely why the safety profile is so exceptional. Now, there's probably 50 different other market forms of creatine out there. First, it has to be creatine when it gets into your blood. So whatever market of form you want to try, make sure it is creatine getting into the blood or it's useless. Second, no other creatine has ever gotten into the cell and had superior effects. Effects. There has been a few studies look at creatine hydrochloride and with the ester bond to get sort of through the phospholipid bilayer of your cells quicker. But no study has ever showed it be safer or more effective. So I know monohydrate has been boring. It's been around since the 1990s. But in my opinion, why mess with a good thing? And probably because the efficacy and safety behind it.

Rhonda Patrick: Well, why do people turn to these other forms? Is it because of GI distress that can be experienced with monohydrate? Is it, is it seems as though, like I get mixed reviews. I'll talk to like, like almost like 50% of people say, hey, like I get GI, like some stomach distress, GI problems. If I take creatine monohydrate, some people have to go to another form or they have to lower their dose. Why does that happen? Are there any ways around that? Is there like any, any tricks to improving, you know, the ability of your stomach to digest?

Darren Candow: I think 99% of it is market marketing. I think people get conned into buying something that's more expensive or flashy and maybe they're making some errors with the monohydrate they're taking and probably from the loading phase. So creatine monohydrate has been shown to increase intracellular water. So it's based on the doorway, it sort of brings water with it. And some people get GI tract irritation or some weight gain. And other forms of creatine are marketed to not do that. I argue if it doesn't do that, it's probably not creatine. In other words, creatine is osmotic. If you're taking a form of creatine that doesn't increase intracellular water a little bit, I would question the validity of that type of creatine. So I'm in the camp of 100% monohydrate based on the mechanisms, the structure of the molecule and the efficacy behind it. Do you need to spend more on a fancy type of creatine? If it works for you, I'm all for it, but at the end of it, I don't think you need to.

Rhonda Patrick: Well, the question is like getting back to what you said. If it's not increasing intracellular water, then it may not be doing what it's supposed to do. And ultimately that's the whole point. So the, you know, the question is if you're taking creatine HCL or you know this, there's liposomal, liposomal creatine or does there's a GNC brand that's like, it's a amp creatine HCl. So it's like, you know, at the end of the day, the bulk of the research is done using monohydrate.

Darren Candow: 99% of all the thousands of papers and the one I, I hear a lot is there's a better bioavailable form than monohydrate. And I'm like, wait a minute. Creatine monohydrates bioavailability is near 100%. There might be a little bit extracted from the gut. So how can you get more than 100%? And then if it even got into the cell, I've never seen a study to show that it increased protein synthesis or had any of the effect on satellite cells or whichever. I'm only aware that it increased creatine content. So the good thing there is in those cells, I think it was hydrochloride. That means it is a form of creatine. But did it lead to performance benefits better than monohydrate? I've never seen it. So I just caution people just don't get conned in a lot of these marketing forms, really expensive forms when monohydrate is the one true intelligence. I'm going to Germany and we're going to be talking for four straight days in two weeks. A monohydrate. Why? Because that's what all the evidence based researchers need to talk about. Because it's the only form that seems to be very viable.

Rhonda Patrick: Yeah, well aside from the marketing, I think some people, I know some people personally that even taking like a 5 gram dose of creatine monohydrate experience like stomach issues.

Darren Candow: Yeah.

Rhonda Patrick: So what, what can those individuals do?

Darren Candow: Yeah, so I recommend to these people and it happens quite often the sort of micro dose. So I would say if you're taking five grams, take about two and a half grams in the morning, morning wait at least six hours and two and a half grams later also take it with food. So I put, I have for breakfast, I'm sort of boring but I take Greek yogurt, collagen, protein, whey protein, blueberries and I usually put 10 grams of creatine in my yogurt but some people can't. So if you want, you want to put two and a half grams there. But if you want to start as low as three grams, one and a half in the morning, one and a half in the evening. Or you could do one and a half in the morning, another one half with lunch. With food seems to increase the absorption because of the insulin from carbohydrates and or some of the effects of fat. The most times is when people just drink it with water. I find that's where they get the GI tract irritation. Just because it's going through the GI tract quickly, taking water with it. But with food, whenever we tell people that they say it all went away. Yeah.

Rhonda Patrick: So that would be an interesting experiment for someone to try that's experienced GI problems. So try taking it with food and carbohydrates. Seems, seems, seems like it might be really good. Really good.

Darren Candow: Okay.

Rhonda Patrick: So and then the other thing is you're talking about like lower dose microdosing and spreading it out. Does that, is that something you'd have to do like forever or is that like to, to kind of get your gut used to it or is it kind of both?

Darren Candow: It's almost from a consistency perspective, but there was a study done in 2003 where they showed a smaller, more frequent dosages were better than a super large 20 gram bolus dose. So it's almost like this retention idea. But taking, you know, multiple 1.5 gram dosages or whatever might not be feasible on a daily basis. But you know, a quarter of a teaspoon, two and a half grams, whichever, that would get your body used to it, then slowly titrate up. So the best way I usually tell people is start with three grams, one and a half morning and evening, then move it up to five, two and a half, then move it up to nine. But then I say three, three and three. Then eventually you're sort of getting tolerated. It's like caffeine starting with a small coffee and working up to a large charge. Your body gets used to it and then there's more in circulation.

Rhonda Patrick: Well, you said these smaller doses were more effective at what at?

Darren Candow: The idea was that it would get into the blood, maintain peak or plateauing plasma levels and hopefully you can retain more than some being excreted as creatinine. The thought was a super mega bolus dose of maybe 20 grams. Now there's new evidence it can get in the brain but there's logic like some of that would be cleared from the kidneys and because the muscle may not be able to take that in all at once. Once. Yeah.

Rhonda Patrick: Okay.

Darren Candow: So dosing studies need to be really done.

Rhonda Patrick: Yeah, well this kind of, this kind of goes to a, another question I had which was we talk, we've been talking a lot about dose.

Darren Candow: Right.

Rhonda Patrick: But it's also about, you know, if, if, like if you're taking the cycling of it. So you know, some people like to slam their protein shake right after a workout. Is there any reason to worry about that with creatine? Because you're talking about replenish like saturating the store. So it seems like it's a. Okay, well it's. You're trying to saturate the stores. I don't know that cycling around that's going to do anything.

Darren Candow: So that's a two part answer. I think from a timing perspective and cycling. So from a timing perspective, unlike caffeine, we don't think the timing really plays a major role. There is one area that I would just recommend, it's post exercise or pre exercise and the Reason for that is that we think blood flow or transport kinetics is turned on with muscle contractions. So if you want to take creatine within an hour before your workout, or I drink 5 grams during my workout or right after, that seems like a very viable time. But for the viewers, the timing seems to be irrelevant. But that begs the question, what about cycling? So if you've been taking creatine for maybe two months, three months, it's very likely your muscle stores are so saturated that when you're consuming the extra creatine that you would just be excreting it. So some people say, hey, I don't want to do that. I don't want to waste my money. I'm going to cycle. Tickle it. I now argue you should take it on a daily basis because of the emergence of like, okay, I'm okay with the muscle being full. If someone's going down the toilet in urination, that's okay. But now I'm hoping our bone is taking in some, our brain is taking in some. So we used to be in the camp where you just need creatine on the days you work out. Now I say take it every day and hope some is going to go to your brain and muscle or sorry, bone, because on the days you're not working out, your muscle is not sucking it in as fast. Maybe those other tissues are getting replenished.

Rhonda Patrick: So do you think it's better to take creatine like you're taking it in the morning if you're going to work out in the morning? But what if you work out in the evening? Do you want to take it in the evening?

Darren Candow: Yeah, I would take it. Any in close proximity to exercise, I would take it. So if you work out twice a day, you're taking creatine twice a day. But if you take it in the morning and then work out later in the night, that's totally fine. We're not seeing any big differences. But I'm a big advantageous proponent of taking in close proximity to exercise. And that's within an hour. Pre impose most.

Rhonda Patrick: Okay, so some of the other questions are interaction with other supplements, other compounds. For a very, very, very, very long time. I put creatine in my, my coffee. I put everything in my coffee because it just masks everything and I just didn't do it in one. I've never really had any gi problems with creatine supplementation myself, so. But, but I'm not sure that I'm supposed to be doing that.

Darren Candow: Yes. So I'm one Of the rare people, and most people argue against me, I don't do it either. So there's two ways to look at this. The thermokinetics of creatine and caffeine do not oppose each other, but from a cellular perspective, they certainly do. So remember when I talked about the sarcoplasm reticulum? Caffeine likes to release calcium, but creatine likes to take it in. And some really good research out of Europe have shown that they, the two molecules oppose each other from a muscle relaxation time. But the dose of caffeine seems to be the most important factor. If the dose is over 250 milligrams or even higher, that's when it seems to have the interference effect. If the dose is lower, it doesn't seem to have an interference effect. So the average large black coffee from Starbucks might be 3, 400 milligrams of caffeine. So if you were to put your scoop of creatine in there and sip on it for hours, you probably won't notice an interference effect in a few, few times. But if you did that every day for months, you might notice a blunting effect. If you did it a one time shot, you know, you, you were doing an experimental trial, you might not notice it. So I never combine the two. I always have coffee early in the morning. I love coffee. And then I wait at least two hours before I take my first thing of creating creatine in anticipation of those cellular interference. But other people, other big time creatine researchers, say no. They, I take it together. If it works for you, great. But there's something there that makes me a little cautious. And we've done the only training study. It was underpowered, but they did interfere with each other. Yeah.

Rhonda Patrick: Yeah. Okay. Is, is creatine heat sensitive?

Darren Candow: It is, it denatures a little bit. So if you warm up the solution, some people don't like the grittiness. So when the temperature rises, it will decrease the, or increase the solubility, if you will. It will not degrade it to creatinine unless it's super heated for a long period of time.

Rhonda Patrick: So if you are putting it in.

Darren Candow: Your coffee, the heat is not the, it seems like the caffeine molecule might be the one that might interfere with it.

Rhonda Patrick: Okay. So you don't have to worry so much about it being in like a hot liquid like tea or.

Darren Candow: But if you had a, like a normal K Cup is 80 milligrams, there should be no interference effect. You could have two of those. But if you get up to like a large coffee, so a normal cup of coffee here in the United States, maybe 80 to 100 milligrams should be totally fine. Yeah.

Rhonda Patrick: Yeah. Okay. Well, this is all really good information, I think, addressing some of these, the, the, the myths and you know, questions, the misconceptions. I mean all those things. Because you've published a couple of meta analysis or review articles, I guess, or review articles on this. And so you talked about, let's talk about the fat gain. Right. So that was kind of when you touched on a little bit. I mean especially women. Women. Is it really just because of the lean mass?

Darren Candow: Yeah. There has been some cellular or animal data to show the increases thermogenesis. But overall the decrease in body fat is there, but it's very low. So don't run out and buy creatine. I think you're going to lose 20 or 30 pounds. We're seeing at best about a 1% decrease in body fat fat and about 0.5 kilogram reduction over time in combination with weight training. Now that could have implications for obesity, type 2 diabetes or chronic diseases down the road. But the nice thing is a lot of people had a myth that creatine increased body fat. We don't see any evidence to that.

Rhonda Patrick: Okay, so it's doing the opposite. Yeah, the hydration myth. So what about you hear. I've heard some people talk about cramps. It causes cramps or dehydration.

Darren Candow: It's opposite. It super hydrates the muscle. So it could be from the sodium potassium pump or disruption from dehydration. But if you're metabolically dehydrated, creatine is not the cause. If anything, creatine is trapping water into the cell. It also has been shown to increase extracellular water and total body water in some studies. So from a cramping or dehydration perspective, it's actually opposite. So for those exercising upcoming summer months, NFL football players, two a day practices in July, lie. Creatine might actually help hydrate the muscle and decrease the chance of muscle cramping or dehydration.

Rhonda Patrick: Oh, that's super, super important. Interesting. Has anyone directly looked at that?

Darren Candow: I think Rick Rider's done some studies with that when he looked at NCAA players. But a lot of people don't take the myth was that it was dehydrating and we just don't see where did.

Rhonda Patrick: That myth come from.

Darren Candow: I think what happened was in the inception of creating research, a lot of people were not drinking water or were going through some practices like wrestling, wearing rubber suits, extreme hydration, they happen to be taking creatine. And then they said, well, I'm on creatine since it traps water, therefore my cells must be exploding or muscles, and therefore it was causing cramping. And we just don't see any evidence behind that.

Rhonda Patrick: Yeah, okay, so it was like a correlation thing.

Darren Candow: Yeah, it was the opposite. And then sort of went with, yeah.

Rhonda Patrick: Okay, we've talked a lot about the kidneys and you're talking about creatinine. And I'd love to talk that. That's one that I hear a lot, that it's bad for the kidneys, it's bad for the liver. Can you address that?

Darren Candow: It's probably the biggest concern. So we've looked at study after study, and rest assured, from a clinical perspective, creatine does not adversely affect renal, liver or cardiovascular cells. And we've given 11 grams a day in postmenopausal females to a population where their organs are under a little bit more stress and no adverse effects. The theory here was that when creatine enters your muscle, when it gets metabolized, it's non enzymatically metabolized to something called creatinine. And those watching say, oh, wait a minute, I just saw that. My doctor checked that off. And the reason they do that is creatinine is a byproduct. It's supposed to be filtered by the kidneys. So if you have high blood creatinine, that means your filtration rate in the kidneys is not working properly. Think of your Brita water filter. It's clogged up. Up. So unfortunately, when a lot of people go to their doctor, they don't say, hey to the nephrologist or gp. I'm on creatine supplements. Because it's logical that if you're taking creatine, your creatinine might be acutely raised and then that causes a false positive. Your estimated filtration rate is low. So your doctor says, whatever you're taking, stop. It's killing your kidneys. We know that's not the case because when they do stop, their kidney function just comes back. So it's just the metabolism of the molecule.

Rhonda Patrick: Okay, well, this is really important. I've had a few people reach out to me and tell me that their creatinine was elevated. And I don't think they told their, their GP that they were taking creatine or creatine. And so, so the, so the idea here is that it's it's the metabolism of the creatine to creatinine that's being excreted through urine.

Darren Candow: That's right. So creatine and fossil creatine don't leave the muscle. It gets left in the muscle as creatinine. Creatinine can also be raised with a very, very high protein diet, excessive exercise or dehydration. But make sure, if you're on creatine supplementation, tell your doctor, because it's logical that your creatinine in the blood will be elevated. That's just from the metabolism of the supplement. Now, if your liver enzymes are through the roof, that could be an infection. So again, make sure you go and get medical screening and guidance. But every time we hear this, it's usually a false positive.

Rhonda Patrick: I see. False positive. Okay, so it's really good to talk to your physician about that. That baldness. That's one. That's one. It was that. It was that rugby, was it? Rugby players?

Darren Candow: Yeah, yeah. I was going bald way before I started taking creatine. So a lot of people say, oh, well, obviously. And it's interesting. It was a great study in a sense, that they looked at a novel concept. So they had elite rugby players do a crossover design. And a crossover design is really powerful. That means the group gets both placebo and creatine. So it really controls for diet, genetics, hormones, things like that. That. And when they took 20 grams a day, it might have been even 25 grams a day for seven days. During the creatine supplementation phase, they increased the hormone dihydroxy testosterone, or dht. And most people say, oh, I think I've seen commercials about this. It's a surrogate of testosterone, but it's been highly linked to hair follicle loss and thinning. From a cellular perspective. They measured it in the blood. So the correlation, you know, it's just a surge. Good. But when they went up, I think it went up by about 57%, but it was still within the physiological range. And what I mean by that is when you go to your doctor and they measure your blood glucose and it comes back and doctor says, no, it's within the normal range. Cholesterol's in the normal range, even increasing by 57%. I think that was the number. It was still within the normal range. When they were on placebo, it increased by about 40%. So everybody says, whoa, hormone went up. Correlation causation. Everybody was freaking out that this hormone went up. They did not measure hair follicle Loss, thinning, cross sectional area. No dermatologist was involved, but a lot of people have run with this and to this day they cite this single study that even didn't look at free testosterone. There was no increase. So just because DHT went up a little bit and they started lower so there was more room to improve, people think it causes baldness. I have a assessed easily over a thousand people, males and females. Not a single person said, hey, whatever you're giving to me, blot, double blind is causing my hair to follow. And I gotta believe a participant would say, I'm not taking this anymore, my hair's falling out. And I do know I can't talk about it because I'm not sure. But I do know that there's been a paper submitted that have looked directly at hair follicle loss and thinning with creatine supplementation.

Rhonda Patrick: And I. That was going to be my next question. I mean, has, well, first of all, has anyone replicated this study? It sounds like no, no. And has. Second, has anyone, you know, directly looked at hair follicle?

Darren Candow: It's in, it's in review right now. But if I had to have a magical guess, it doesn't affect hair follicle loss or thinning. So if people are watching me, they're like, oh. And then they look at other creatine researchers. I can blame my parents and primarily my mother for that, for the maternal DNA, but then there's other people with full heads of hair, so it can't be a cure. It's like carbohydrates cause obesity. That's nonsensical. It's. Everybody's different. But I still get this on a daily basis, both from males and females. They don't want to take it or their hair is thinning. And I'm really glad that this study is coming out because the way we should have answered this is we don't know until the study emphatically says no, we didn't see any of the effects. We would have to say we don't have any evidence to suggest it does. And we don't have any evidence to suggest it does. And, and even when the study gets published, we'll probably have to do multiple. But it just has never been done.

Rhonda Patrick: And no rodent studies?

Darren Candow: No rodent studies, nothing. I think it's an area that people said no one cared about and then all of a sudden everybody cared about it.

Rhonda Patrick: Yeah, that's. So is there, is there any other really, I think prevalent misconceptions or myths that you want to talk about or not.

Darren Candow: Oh gee, there's so many. I think the big one that, the big one we're getting a lot is does it increase hypertension or blood pressure? Because if it increases water into the body, could that have any effects? And we're not seeing any adverse effects there. The other one is we do not see any evidence it disrupts sleep. Although we talked about the study earlier, it doesn't have any negative effects there and then cancer. So this is an area that is difficult to answer or talk about because we just don't have a lot of human cellular data from the in vitro data. We're not seeing any in humans, at least from recommended dosages, any malignant growth or any cancer cancer promotion. If anything we're seeing anti cancer properties from improving inflammatory or anti inflammatory responses there. And in our latest paper, the myths and Misconceptions Part two, one of the world's best creatine researchers and medical doctor Mark Tarnopolski read really good section on that. So if anybody's interested read that. And it seems to have some potential for cancer rehabilitation. When you're looking at tissue loss, caxia seems to have some beneficial effects there. And I'm collaborating with Kieran Fairman in University of South Carolina looking at prostate and breast cancer rehabilitation. So I think you're going to start to see some medical applications growing more than just young healthy individuals. Again, the common denominators, all these are sort of asking something for help. It's either rehabilitation or prevention. And that's where I think creatine has really changed. It used to be for just young individuals who are healthy and now it seems to have some of these health, health aspects. So very exciting times to be talking about it.

Rhonda Patrick: Yeah, yeah. Are you familiar with any of the research of Dr. Kerry Kernier out of University Alberta? Yeah.

Darren Candow: So cancer there. I don't think he's ever looked at creatine but he does a lot of community based.

Rhonda Patrick: Yeah, I just had him on the podcast and he was, you know, he does a lot of exercise, the role of exercise in cancer treatment and you know, not just, not just aerobic but resistance training. So that would be interesting for you guys to have a discussion.

Darren Candow: Yeah.

Rhonda Patrick: The other thing that came to my mind that I now remember, I've, I've heard a lot of people talk about is creatine supplementation increasing their urination, particularly during sleep. Like having to go urinate. Yeah, frequently.

Darren Candow: I just answered this question on Instagram. So an individual because I, I said I take a pre sleep Sometimes. And, oh, that'll keep me up peeing all night. And I said, oh, actually, that's interesting. So in this myth and misconception paper as well, there's a section there that the creatine molecule, whichever does not increase urinary output, people thought since it's creating creatinine, you need to filter it. We think it's the increase in fluid ingestion that you're probably taking, either with exercise or what is usually recommended with creatine. That's actually a myth as well. You don't need to increase tons of water consumption, but the molecule doesn't cause an increase in urination. It's not a diuretic, or it doesn't increase urinary flow that way. I do hear that a lot. My logical guess is you're probably putting the creatine in 8 ounces of water, and you're probably drinking more water or exercising, and that's one of the things. But there's no evidence to suggest the molecule itself stimulates urination. Yeah.

Rhonda Patrick: Okay. Well, that's good to know. I think we've covered a lot. There's one area I did want to talk about, and we talked about kind of saving at the end, because there's more speculation here and. Yeah, and this is just an interest of mine. I remember several years ago, a former colleague of mine, Mark Shigenaga, was talking to me about, you know, creatine production in the liver being one of the biggest, biggest sort of sinks for methylation, and that's because you need. You need methyl groups to produce it.

Darren Candow: Yes.

Rhonda Patrick: And as a byproduct, you also make homocysteine. And so he was talking about some at the time. I think it was. Was pretty preliminary, but some evidence showing that if you did supplement with creatine, that the enzymes in the liver that do produce creatine, there was a feedback, and they sensed that, and they didn't use. So much of the methyl groups were being shunted to other methylation pathways. And so I was just wondering if you've come across any evidence looking at creatine supplementation and homocysteine levels, for example.

Darren Candow: Yeah, the most studies don't support it. And that's where we got to the point where, oh, if it doesn't decrease homocysteine levels, then maybe exogenous creatine doesn't reduce our natural creatine synthesis. The. The studies that show it does are in animals, and I believe there was one human trial, but the majority shows it doesn't have any Effect. Now that could be the dose there. But you're totally right. Methionine is donated, getting, I think it's 40% of our methyl groups to creatine synthesis. So if I'm taking more dietary creatine or supplementation, why use that? Why. Why not decrease the amount being synthesized? Because that has huge implications on endothelial health and cardiovascular health. But ironically, the. It's not even equivocal. The majority suggests it doesn't decrease. Maybe the studies are not long enough or maybe they're not in populations that need it as much.

Rhonda Patrick: Yeah, right. So the question is like you, maybe you need to start with a population has elevated homocysteine.

Darren Candow: Correct? Yeah.

Rhonda Patrick: Right.

Darren Candow: Vegans. Yeah, yeah, yeah, yeah.

Rhonda Patrick: Because it's hard. It's hard to detect small changes when you already have.

Darren Candow: It's easy to do. You just look at some of these blood biomarkers. But there's not a lot of. There's probably less than 10 majority in rodents, few inhuman. And I think last time I checked it was probably seven against three supported it. So it's. There's a lot of methodology issues there.

Rhonda Patrick: Well, maybe someone will look at it.

Darren Candow: Absolutely. Especially as we start to get into vascular health for sure. That's a huge area. So I would be shocked if more studies don't come out in vascularity health or angiogenesis or anything like that. Potentially looking at homocysteine as a surrogate marker for potentially explaining some of the effects. Yeah, because if homocysteine comes down, you would speculate endothelial health would go up and some of those things.

Rhonda Patrick: Yeah, right. Well, if you talk to any researchers doing. Doing vascular health. So I think we've covered pretty much just a lot of ground. Really interesting stuff. Did we miss anything? There's anything that you wanted to discuss?

Darren Candow: Oh, geez, no. You hit the caffeine one. I knew that was an important one for people.

Rhonda Patrick: Are there any other interactions with other.

Darren Candow: You know, let's go back to the carbohydrate one because I think people hear this. The best way to augment creatine into the muscle is with muscle contraction, which is great. But the dose of carbohydrates shown to sort of increase, it is almost over 75 grams. And I think most people are not going to consume that. Protein is a great one to add creatine to because it's insulin genic as well. So combining creatine and protein will probably give you a superior effect. There's been two studies that show you get greater increase in, in muscle performance and lean body mass. When you combine creatine with protein, in this protein case it was whey protein, it was only about 30 grams. So now when you're looking at your post exercise meal, pre exercise meal, I think creatine and protein are good friends. Consider them as something that you may want to consider especially in your post exercise meal or like I take at least 50 grams of protein with breakfast, I put my creatine in there, I don't need to worry about it until later on and then I usually drink it or have it with a meal. Most creatine is tasteless. You can put it in food, that's fine. You can, you know, the heat would denature it a little bit, but it's something to consider.

Rhonda Patrick: I'm glad you brought this up because to clarify, maybe some people were confused when we were talking about this earlier. The taking, the timing of the creatine around exercise. It was to improve the uptake of creatine into muscle. And that can be done before or after, like close proximity to the exercise.

Darren Candow: Yeah. And if you don't want to work out, keep in mind it still accumulates, maybe just not as quick. So the study in 1992 was very elevated. They had one leg exercise and that increased creatine uptake by about 37%. And in the other leg that didn't exercise, it still improved by 25%. So at the end of the day, the person, you know, at home, watching tv, taking creatine, whatever, for some time they're still accumulating. But exercise unlocks a lot of the doorways, so to speak, that sort of get it in there more. So it might give you a little bit extra benefit. And that's why I say a proximity exercise is a very viable time to take a. Yeah, but if you're looking.

Rhonda Patrick: For the benefit in terms of improving or increasing your training volume in, you know, that explosive power, the strength that it doesn't necessarily have to be timed around the exercise. Right.

Darren Candow: Just take it, just take it. Like if you don't want to take it all at once, take it in small dosages, I think consistency. I now recommend take it every day, just get it like a multivitamin, whatever you're doing, but just keep in mind is giving you not only exercise benefits, but I'm really happy to see the emergence of the health benefits. And I think in today's society we could all use a little bit of help.

Rhonda Patrick: Yeah, it sounds, it sounds like there's no reason not to take it. I mean, it's, there's a lot of benefits that the muscle, the bone, the brain. Very, very convincing third party testing. You can look for companies that have been vetted that are, that are, you know, reliable brands. And, and that's always like a. Yeah.

Darren Candow: That'S a big thing that we didn't talk about. So if you are considering supplementation, again, you don't necessarily need, need it if you're getting it through your diet. But make sure third party test it. I would really focus on monohydrate based on the evidence based research. Monohydrate has grass status. Creapure is from Germany. It's more scrutinized, it has less purities. That's an excellent form of creatine monohydrate. Make sure it's pharmaceutical grade. So all these things that you would do by putting something in your body, just do a little bit of homework. But if you're not seeing certified safe or third party tested, that's something to be a little cautious. And the other thing is when you're buying a compound or ingredient with a whole bunch of ingredients in there, we don't know if the creatine is going to be effective or not. In these pre workouts, things like that. There's no reason to suggest not. But when I've been talking about creatine in our experimental studies, we're giving 100% pure creatine. We're not giving it with 10 or 12 other compounds that you got at a grocery store, things like that. But again, so there's a little bit more work that needs to be done if you're considering a multi ingredient compound.

Rhonda Patrick: Yeah, yeah, and that's a good point because you're talking, we were talking about taking, you know, 10 grams a day, which is your, your sort of go to. And right now soon will be mine. Okay. You don't want to take 10 grams a day of some, you know, mixture of things. Right. You want it to be just creatine.

Darren Candow: Yeah.

Rhonda Patrick: Now you mentioned crea. Crea Creatine. Pure.

Darren Candow: Pure. Pure monohydrate.

Rhonda Patrick: Yep, that's very pure.

Darren Candow: It's very pure from Germany. It's third party. Test it. Now as a disclosure, I'm on the Advantage advisory board for Korea pure. So full disclosure. And that's help sponsoring the creatine conference in Germany in, in a few weeks. But it has grass status. And when you look at the independent Lab results, it's 100 pure. There has been some issues out of Asia with transportation and not being third party tested. So I think the consumer just needs to do a little bit of work. Most companies nowadays, if they're on the shelves of a product, are very reputable. And again, if it has third party tests, it's safe. Safe. Just look at the ingredients. It should say monohydrate. Or if you're entertaining, another form of creatine that should be the only ingredient or at least the most important ingredient on the product. Yeah.

Rhonda Patrick: What about micro ionized?

Darren Candow: Yeah. That's a new form to get away from some of the things you mentioned on GI tract irritation. So that's just being continually processed. It's very fluffy. I've noticed some of the new products, it dissolves exceptionally well. Get away from that grittiness that the creatine can cause in solution. So these are just coming up with new alternative forms to help please a lot of individuals make it more attractive. But it's another form that can just sort of be sort of. Solubility is very high. Yeah.

Rhonda Patrick: Is there any reason to believe it wouldn't work? It's because it's. It's monohydrate. Right. So it should do the same thing.

Darren Candow: 100. It's just a different way to get it into your body if you like. It really, really micronized. So it's pure fine. I just take normal crete and if there's a little bit of grittiness at the bottom, I. That doesn't bother me. But some people, they do. Yeah.

Rhonda Patrick: Okay.

Darren Candow: Yeah.

Rhonda Patrick: Well, excellent. We've just covered so much wonderful information and thank you so much for taking time to talk about all this research with me today. And thank you for doing all this research. I mean, really, you've just done an amazing job covering so much important ground in terms of the effects of creatine on human health.

Darren Candow: Right. Thank you so much for having me. Had a great time. Thank you.

Rhonda Patrick: Me too. Thanks.

Darren Candow: Yeah, thanks.