Dr. Rhonda Patrick: There was another, there's some interesting research that you also published kind of 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 days.

Dr. Darren Candow: Yeah, it was colleagues at University of Idaho, Anne 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 6 weeks and they resistance-trained with a Tonal home gym for 2 days a week. And the interesting thing is total sleep duration on the days they trained was substantially higher.

Dr. Darren Candow: I think it was 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 improves strength. There were no big fluctuations in weight gain, which was very, very interesting. No adverse effects. Now, there were 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 about an hour more on average. We still don't know the exact reason, but it is interesting that it improves sleep duration.

Dr. Rhonda Patrick: Yeah. And it's almost kind of the opposite of what we were just talking about.

Dr. Rhonda Patrick: No, we were 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, right, you know, you just, you're not quite, you know, on your game.

Dr. Darren Candow: Yeah. It goes against most of 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 rodent 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. We'd— I'd really like to look at some blood biomarkers, indication of what's happening from an inflammation perspective.

Dr. Darren Candow: So there's a lot of work in that area to go.

Dr. Rhonda Patrick: Yeah. You know, the other thing I was thinking about, Darren, was, I mean, when— so adenosine.

Dr. Darren Candow: Yes. Mm-hmm.

Dr. 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.

Dr. Darren Candow: Yeah. Yeah. I always think of caffeine, the adenosine antagonist. Right, right, right. Yeah. 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 synthesis of creatine. So, there's a lot there. I think we'll talk maybe about homocysteine a little bit later and the methyl. So, God, there's a lot of areas to look at.

Dr. Darren Candow: And, I think we thought we knew everything about creatine and now it's taken on a new life of its own. And again, I'll have a job for maybe 20 or 30 more years looking at this.

Dr. Rhonda Patrick: Oh, yeah. Well, let's go back to the brain and talk about another— so, we talked about brain aging, 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.

Dr. Darren Candow: Yeah. We've looked at the totality of limited evidence and we're not seeing a lot of effects yet.

Dr. Darren Candow: 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 an adequately powered study, there was a big one 5 years in Germany, didn't see any greater effects. So again, maybe the dose was too— when I look at the dose they used, it was 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.

Dr. Darren Candow: 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.

Dr. Rhonda Patrick: Yeah. 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 also unfortunately very common nowadays, even in younger adults and adolescents.

Dr. Rhonda Patrick: So there's been some interesting research with creatine and depression.

Dr. Darren Candow: Yes, there has. It's an emerging area, primarily in Utah, a great psychiatry group there. And as a caveat, no study has ever looked at creatine without antidepressant medications. So they're always as adjuncts. So we're not saying creatine could ever replace anti-anxiety or antidepressant medications, but in these subpopulations, primarily females with clinical depression, it's really starting to 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 brain creatine stores. So maybe creatine supplementation can bring those levels up.

Dr. Darren Candow: Uh, there's potential to increase BDNF, so that has been implicated there as well. And there's another thing called neurofilament light chain. It's an indication of neuronal damage, uh, and 1 gram of creatine in your diet has been shown to reduce that. So there's potential there. But the overarching thing with depression is it increases brain bioenergetics, as you, as you mentioned, and increases mitochondrial health, decreases reactive oxygen species. All these are implicated in 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 behavioral therapy or SSRIs.

Dr. Rhonda Patrick: Yeah, for sure.

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

Dr. Darren Candow: Yeah, yeah.

Dr. Darren Candow: And, 100%. So, the anti-inflammatory role comes back there as well. So, you'll start to hear these 2 words, anti-catabolic and anti-inflammatory. People think of Advil or Tylenol from an anti-inflammatory, but creatine seems to work somewhat similarly to COX inhibitors as well. But it seems to decrease cytokines, so it could be something there to consider.

Dr. Rhonda Patrick: Yeah. Well, what's interesting is, you know, activated lymphocytes, T cells, consume just enormous amounts of energy, right?

Dr. Rhonda Patrick: You know, and, and to, to basically become active and fight off pathogens, right? And so I'm wondering if creatine is taken up by, you know, 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, you know, producing cytokines to fight off things, but who knows if they have— if they have that energetic boost.

Dr. Darren Candow: Yes.

Dr. 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?

Dr. 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 regarding lymphoma, leukemia. So, that's more in vitro. There's a lot of work that needs to be done, but there's a lot of studies now looking at the anti-cancer potential of creatine primarily from the enhanced immune system response.