What a New Creatine Trial Really Measured

Dr. Rhonda Patrick: Darren, welcome back. Um, to get straight to the point, a recent publication, one somewhat unexpectedly co-authored by you, has sparked media discussion questioning whether the scientific community has been overstating the benefits of creatine. Um, I would appreciate your insights on this, particularly your thoughts on the study's methodology, what went wrong, if anything, and whether it warrants a reassessment of creatine's effectiveness.

Dr. Darren Candow: Uh, no, not at all. It's not surprising. Um, I think anytime you have a study that doesn't show some expected effects, but again the key here is the methodology and the purpose behind the study. So, a little bit of context: the goal here was to see if creatine's wash-in which no study really ever does. Um, so can creatine cause an increase in lean body mass before resistance training starts.

And that's really important because what happens when you measure lean body mass by DEXA or BIA, sometimes that initial water retention without training can sort of dilute any treatment effects. So, a really cool thing with the study is that they looked at five grams of creatine for one week, and that certainly did improve lean body mass. Now, without training, you would expect that increase because lean body mass includes water. It simply showed initial water retention, and there was no subsequent increase in lean body mass with 12 weeks of training. That increase in the initial week was just so large. So, to see a treatment effect over time, it was very difficult to do.

So a lot of people in the media right now are thinking that creatine is not effective. Um, this study does not disprove that whatsoever. All it simply showed was that the initial water retention during the first week is something to consider. So, for future designs, you may want to take a higher dose after the first week or start with a higher dose of creatine to hopefully cause increases in lean body mass that are statistically achievable compared to a placebo.

Dr. Rhonda Patrick: Now, in this study, I would say the press and the media are saying that creatine in addition to resistance training will not increase muscle mass more than training alone. What does the science say when you look at multiple randomized controlled trials in terms of how creatine plus resistance training affects muscle mass compared with resistance training alone? What about training volume, right? Increasing creatine, increasing training volume.

Dr. Darren Candow: Yeah. So, this is one study of the pieces of the puzzle and I would say about 30 to 40% of the studies out there on creatine may not show an effect when it comes to lean tissue. So, we're going to talk about the difference between lean mass and muscle. Um, but when you look at all these studies combined, meta-analyses still show that creatine plus resistance training leads to about a 1.4 kilogram increase in lean body mass. A conservative estimate is that 50% of that lean body mass is dry muscle.

So, at the end of the day, we can probably conclude that creatine and resistance training leads to about 700 to 800 grams of muscle. That's important for the young individuals trying to put on muscle. That is crucially important for older adults or clinical populations. Um, now there's only been a few studies to sort of go a little bit beyond lean body mass and using CT scans or muscle thickness and that's been shown to have some small beneficial effects on regional muscle size. Um, and then there's only about two or three studies that have ever looked at muscle fiber cross-sectional area again showing some benefits with creatine there as well.

What needs to be done is muscle biopsies plus an MRI plus D3 creatine to emphatically conclude that creatine leads to a substantial increase in muscle mass. But we also have so many molecular effects with creatine that are likely explaining why lean body mass and/or muscle mass goes up. It's in response to resistance training primarily. And the nice thing there is it seems to improve training capacity. And then one might ask, well, what's really causing your ability to exercise at a higher capacity?

And, clearly, with and without exercise, creatine leads to a stimulation of satellite cells, transcription factors, insulin-like growth factor. It increases kinases in the mTOR pathway and it also reduces a whole bunch of things regarding inflammation and oxidative stress. So when you combine the molecular or cellular evidence with the practical training applications, it's well established that creatine can augment lean body mass in meta-analyses as well as some small studies that indicate small increases in muscle mass there as well. Um, so this one study has gotten way blown out of proportion because the intent wasn't to show muscle. It was simply to say, "Hey researchers, what should you consider before you design a study?" And it clearly showed that five grams of creatine in the first week is evidence that the elevation in lean body mass might dilute your ability to detect changes over time.

Dr. Rhonda Patrick: And what about the fact that your participant population, it seemed like females were driving some of that? Can you talk a little bit about that?

Dr. Darren Candow: Yeah, the sex subanalysis. It was a small sample size although the overall sample included more than 50 participants. When we look at the bioavailability there as well, we didn't see any major differences and, again, this was in young individuals. We don't know the effects in older adults. Some of the best lean-tissue mass results are in older adults there. So some of these factors all play a role.

There was a lot of skepticism that they didn't do the loading phase. I think the reason for that is one of the main reasons people are really scared of taking creatine, primarily females, is the loading phase or that net water retention. The small amount of lean body mass that was shown with five grams is something to consider and I'm going to be doing this now when we're doing future designs. So for example, if we're measuring lean body mass by DEXA or BIA or whichever, this is something to really pay attention to. Maybe you want to do a pre-supplementation phase, then start the loading phase or resistance training after that because if you get a fluctuation in lean body mass and that might be one of your main dependent variables, you may not get any statistically significant results.

So, um, that's why I posted on Instagram that lean body mass is not muscle. One component of lean body mass is muscle, but it includes organs, connective tissue, and water. And that was clearly the purpose here as well.

Dr. Rhonda Patrick: So if there was a much larger sample size, do you think perhaps maybe some statistical significance might be detected in changes in lean body mass? In other words, you'd see more what you're seeing with meta analyses in terms of creatine improving lean body mass of which you said about 50% maybe dry muscle.

Dr. Darren Candow: Yeah, 100%. The gains were substantially in favor of creatine there as well in a little bit longer or higher dose. Um, so again, the dose was small but it did clearly show that creatine is osmotic so it supports all the molecular effects there. Um, and I know it might sound negative in the press but it's actually very positive when you consider: hey, this was a viable source of creatine. It did exactly what we proposed. It increases cellular hydration.

It just might offset your ability to detect any changes over time. So a lot of people thought maybe you should have done the loading phase. That would have led to way more water retention. You may not get the effects. But what it also suggests is that maybe five grams may not be enough once you start weight training to cause those significant increases in lean tissue mass and or muscle mass.

Dr. Rhonda Patrick: So if I understand correctly, you're saying perhaps when you're saying that the increases in hydration of the cell may be offsetting small changes in other you know like

Dr. Darren Candow: Yeah, that's right. That's right. Because when you have the cell swelling that improves lean tissue mass and, given the precision error in a lot of machines we use, you may not know if it's increasing hydration in the body, whether the blood or organs are changing over 12 weeks. So, a higher dose might cause those greater effects which lead to an increase in lean body mass. So, I'll put it this way.

If the study showed that creatine after 12 weeks of training significantly increased lean body mass, there will be no questions. Everybody would say, "Oh, that makes sense." And then the scientists would say, "Okay, what was increasing in lean body mass?" And they're like, "I don't know." And that's the big takehome here. We think half of lean body mass is muscle but until a study shows that we need to rely on the cellular mechanisms.

Dr. Rhonda Patrick: Okay. So the bottom line here other studies have found five grams of creatine a day plus resistance training can increase lean body mass and presumably 50% of that is, you know, muscle mass. So what's the takehome here for?

Dr. Darren Candow: Well, there's other studies with five grams is very viable and not only did it increase lean body mass, but there's been other studies with five grams clearly shown it increases muscle type I and type II muscle fiber area and it also increases total creatine content. So again, it substantiates that five grams is a very viable dose. It just so happened in this study the main purpose was to see could the first week of creatine which some people experience water retention could that dilute any significant effects and that's clearly what the study showed. It had nothing to do with saying creatine is worthless. I don't know where these headlines came from.

That wasn't even an intent of the study. It was to simply show does the first week at five grams cause any water-retention fluctuations and it clearly showed that it had nothing to do with muscle or anything. But the totality of evidence clearly suggests by meta-analyses. Yes, lean body mass goes up and obviously five grams is a very viable dose to improve many factors including muscle creatine content, fiber area and performance.

Dr. Rhonda Patrick: Well, I think the confusion comes from the fact that, you know, after the initial seven days of creatine supplementation without resistance training, you would expect the 12 weeks of resistance training plus creatine supplementation would also cause increases in lean body mass and muscle and that was not found. And so that's I think where the confusion comes in and why do you think that is compared to other studies?

Dr. Darren Candow: Yeah, there's a lot of things we have to look at, including other factors such as dietary intake. It was about 180-gram difference in creatine in favor of creatine, but with the low sample size and the trend over time it just didn't lead to statistical significance. If you look at the practical meaning it was still there as well. And again, the sensitivity of the measurements. But if they were to do muscle biopsies or an MRI, I'm very confident you probably would have actually seen a substantial increase in muscle cross-sectional area. But DEXA, there's about a, you know, anywhere between a 2 to 5% uh standard error of measurement there.

So that had to overcome that as well. Um, so again, if they use more elaborate sophisticated techniques, I'm pretty confident you would see that. So for example, muscle ultrasound, I'm pretty sure you probably would have seen some increases there with creatine as well because a meta-analysis we did before with Brad Schoenfeld clearly showed that muscle ultrasound and pQCT show small but significant increases in regional muscle size. So it could have been based on the technology it could have been based on a number of factors, including young age or training status but likely the small sex subanalysis was one of the limiting factors.

Dr. Rhonda Patrick: Well, um, these were untrained individuals. Is that correct?

Dr. Darren Candow: They were.

Dr. Rhonda Patrick: So, don't untrained individuals respond?

Dr. Darren Candow: Yeah. Yeah.

Dr. Rhonda Patrick: Well, don't untrained individuals, when you add in resistance training, gain a lot of muscle mass?

Dr. Darren Candow: Right. They can both. That's probably the number one factor. They were untrained, so both are going to respond quite well. The treatment effect has to be of sufficient magnitude to get over those effects.

Would this happen in trained people? No. I would expect the other way. I expect if he took trained individuals with five grams of creatine, they would get a greater significant increase not only in lean mass, but some other measures of muscle and body composition there as well. So the caveat is untrained individuals taking a supplement and then you're also adding exercise.

So it's logical that both populations would respond.

Dr. Rhonda Patrick: Yeah. I mean, that's kind of what I was thinking when I read that they were untrained individuals. I thought, oh, well, the people doing just resistance training with placebo are going to have a pretty good response because they're untrained, right? That's pretty—

Dr. Darren Candow: And if they don't— that's right. And if they don't, then there's a problem with the design of the resistance training. Everybody should respond quite well to resistance training, especially when untrained.

Dr. Rhonda Patrick: And as we talked about in this episode, the effect of creatine on muscle mass is not simply anabolic. There are other mechanisms you mentioned, but it also works through increasing training volume. There are effects on muscle strength, which are important. At the end of the day, like you said, a 700- or 800-gram increase in muscle mass is important to a lot of people. I would be stoked to have that, you know.

Dr. Darren Candow: Yeah. The elegance of creatine is unique. In some studies, it improves muscle training volume quite substantially. But the unique thing is in the studies that they equate muscle training volume, creatine still turns on all those molecular signals which could cause an increase or explain why individuals on creatine seem to be able to do more repetitions, get stronger, have greater recovery, and increase not only lean mass, but it's highly likely an improvement in muscle size. We've seen some muscle-biopsy studies look at that as well and some MRI studies as well.

So, again, 700 grams of muscle may not sound that attractive to a young person but as we get older and clinical populations, its anti-sarcopenia effect is crucially important. Um, so those headlines ask, is it worthless? Absolutely not. If anything, it is the other way. It has so many profound benefits.

Dr. Rhonda Patrick: Yeah. It's too bad that you guys didn't get use ultrasound. I mean I know that wasn't your endpoint. You were looking you were actually looking at lean body mass and so that's why you chose the technique you chose. But it would it would kind of be nice to have that data to see and compare.

Dr. Darren Candow: Yeah. Yeah. And that's why reading the study, you always have to take a little bit of caution in the technology that we use. You know, if we use skinfold, most people they're like, "Oh, there's a lot of error in that." And and yes, it was a whole body x-ray, but it did measure everything. Um, and again, there's a lot of things in lean tissue mass, but we need to do some more elegant studies that look at pure muscle.

And I'm very confident with training, creatine could be advantageous for sure.

Dr. Rhonda Patrick: So, just to recap and make sure that I'm completely understanding this nuanced study correctly: first and foremost, creatine supplementation plus resistance training might very well have increased muscle mass if, one, the tools used were more sensitive, perhaps ultrasound looking at muscle. Two, if the study sample size was larger, it might pick up statistical significance because the effect of creatine plus resistance training is already quite small. Generally speaking, resistance training is the main driver of muscle mass growth, so you need a larger sample size to do that.

And is there a third, perhaps the dose of creatine?

Dr. Darren Candow: The dose or the training status. If these were trained individuals, they would have likely had the bigger effect. And I think, you know, the dose, I'm confident that five grams on a daily basis, although it'll take a little bit longer to saturate your muscle, is a very healthy, viable dose that has been shown in other studies without a loading phase to be effective. But you're 100% correct on all those variables.

Dr. Darren Candow: I think reading the context of the study and what the purpose was is really important. Um, unfortunately, headlines can be a little misconstrued. Um, it is not worthless at all. It is quite substantially beneficial and there's been study after study clearly showing it improves lean body mass regional muscle thickness and there is a high probability it would improve muscle mass from a muscle cross-sectional area or type I and type II muscle fiber area. So, rest assured, for those taking creatine and weight training it's definitely contributing for sure to your gains in the gym.

Um, and that's why meta-analyses and narrative reviews clearly show when you add in all those studies that have looked at a variety of techniques, creatine still leads to about a 1.5-kilogram increase in lean body mass and if we accept 50% of that might be muscle that is substantial and then again for rehabilitation purposes, regional muscle thickness is hugely important so, if anything, I think momentum behind creatine has never been as strong. I don't think studies like this deter that I think if you understand the context to what was being studied, it makes sense when we try to explain it. For sure.

Dr. Rhonda Patrick: Well, thank you so much for explaining that. It makes a lot more sense to me and hopefully others now.

Dr. Darren Candow: Great. Thanks so much.