Psychiatry & Psychotherapy Podcast - Creatine and Mental Health

Episode Date: April 18, 2025

In this episode of Psychiatry & Psychotherapy, Dr. David Puder hosts a deep dive with experts Nicholas Fabiano, MD, Brandon Luu, MD, Joshua Mangunsong, MS3, and Liam Browning, MS4 into the exciting potential of creatine supplementation for mental health and cognitive enhancement. They explore cutting-edge research on how creatine can improve mood disorders, including depression and anxiety, enhance cognitive functions such as memory, attention, and reasoning, and support brain metabolism through its role in ATP regeneration. The episode also reviews clinical trials demonstrating creatine's effectiveness in psychiatric disorders, optimal dosing strategies, and its safety profile. Listen to learn how creatine may revolutionize treatment options in psychiatry. By listening to this episode, you can earn 1.5 Psychiatry CME Credits. Link to blog. Link to YouTube video.

All right, welcome back to the podcast. I am joined today with four guests. We've been working on creatine for depression, mood, and we have, right now, what looks to be a 45, 48-page document, kind of breaking down different studies. This may be very new to you, the thought that creatine monohydrate, which is normally thought of something you would give to someone training in sport, increased strength, that it could be used for the brain and used for depression. This may be very new for you, but that's why we're going to go through study by study. And I've compiled my little team of amazing experts here, many experts. It's so new to the field. I don't think you could probably find like the expert or, you know, so it's like you

almost want to look at this study by study and kind of form your own decision. We have Joshua Mangoon Song and we have Liam Browning, Brandon Liu and Nicholas Fabiano. Nicholas Fabiano. was on exercise with me before. Liam's been on a number of episodes, adverse childhood experiences, microdosing exercise. And then Brandon, you were on, this is your first one, Brandon?

Yeah. Yeah. So Brandon is an internal medicine doctor or soon to be internal medicine. Highly active on Twitter has a lot of really good, short, pithy summaries of research studies that are new and novel and that's that's where i met nicholas fabiano as well and then joshua is a medical student pg.i what three or four three three okay

pgwi three over at loma linda so yeah let's get this going so let's go straight into it joshua do you want to give us a short summary of this shirpa at all 2025 on cognitive behavioral therapy with and without creatine, monohydrate? Yeah, sure. So this is a double-blind, randomized controlled trial that they did in India, and they tested five grams a day of creatine as an add-on to CBT for depression. Over eight weeks, those who received creatine showed significantly greater reductions in pHQ-9 scores compared to placebo with an adjusted misdemeanor.

mean difference of minus 2.37. The study showed overall good tolerability, no serious side aspects, and suggest that creatine could be a possible low-cost scalable way to enhance psychotherapy outcomes in the real world. Yeah, excellent summary. So this is new. It's 2025. 100 participants. That's a big, that's a good size study looking at the PhD9. and I know what a 17 score is, it's pretty, it's moderately severe depression. Let's kind of create a discussion around this. So I want everyone to kind of jump in,

what were things that jumped out at you. We could comment on doses, we could comment on before and after scores, stuff like that. Yeah, I think this is a pretty interesting study because like you mentioned, it's the first CBT-based one. Most of the other studies that we'll talk about later are combining creatine with antidepressants.

So it was interesting to see it in this front, because we know one of the benefits of creatine is the cognitive benefits, and perhaps that could be mechanistically something that ties into therapy. For someone who has depression and may have some cognitive deficits with that, having the creatine, being able to kind of engage, that could be something that's there. And looking in the study, as you mentioned too, like you mentioned dose. And it's a common theme we'll see in discussing some of the other things, too. The standard dose that we see is five grams per day, and that's used across studies often.

However, I think there's discussion around, is that dose high enough? Traditionally, that's a dose used for fitness and muscles and stuff of that. But there's more and more research coming out suggesting that higher doses, around 10 grams or even higher per day, could be beneficial. So I think that's an important thing to note in this study and for future studies using CBT or antidepressants is that perhaps there's value in higher doses and you may see better effects. And then the other thing, too, is it was a fairly long trial. like it was about eight weeks, but I do think that there's room for even longer trials, because again, a lot of these X week period is based on more of the fitness research and muscle where most of the creatine goes, but we know it takes longer to get to the brain and accumulates less

than the brain. So those are just some thoughts I have with this study specifically. Great. Yeah. Brandon, any thoughts? Yeah, no, those are some great points. It's a very exciting study. Nick, I think the study you're referring to is that condo study, I think, in 2016. And, you know, a lot of these studies, I think, from kind of bodybuilding or weightlifting strength enhancing doses, five grams a day is kind of the standard, and it seems very reasonable to try that. But they were actually able to measure phosphocritine levels in the frontal lobe. And they found like about a 4% increase with two or four grams a day. But you increase to 10 grams a day. And frontal lobe creatine,

increase to 9.1%. So almost like more than double increase in frontal lobe creatine, suggesting that, you know, if you push past that ceiling of that 5 grams per day, you're significantly enhancing that frontal lobe creatine, which could have a lot of implications for depression treatment. And especially, you know, I'm happy to talk about some of the sleep deprivation or cognitive stress studies. They gave a way higher dose, like up to 20 grams a day or even the one study where they bolus them like 30 grams right before sleep deprivation. and then it's relatively well tolerated too. So I would really love to see some future studies

really pushing the bounds of that creatine dosing. Nice. William, anything jump out to you on this study? Yeah, just following up on the comments about the dosing, I think a lot of the studies that look at the higher doses, those tend to be some of the shorter studies too. So especially if you're looking for a shorter benefit for creatine, you definitely want to push the dose a little bit more.

But I think there's still some question about maybe if you have a smaller dose like five grams, and if you have that consistently throughout multiple weeks because you're saturating the muscle creatine stores, then you're going to have with each dose of creatine that you take in, then you have more plasma creatine that's available to be taken up by the brain. But again, there's the blood brain barrier. So it's really questionable about how much creatine can actually get in. So I definitely think there is probably a benefit. to higher doses that need to be looked at.

But in this specific study, I thought it was really great that they had 100 people, and they did have quite a big dropout rate. I think they had 40 people drop out, but I think what's notable is that there were not more side effects in the creatine group compared to the control group. Maybe aside from gastric discomfort, there weren't any severe side effects, which is one of the main things that I think a lot of people are concerned about, for any new medication or supplement is the risk for side effects. And I think here's a really good example of people aren't dropping out of the study because of the side effects.

Good point. Good point. Yeah, I want to comment a little bit on the score decrease. So we may be familiar with the PHQ9. It's pretty standard. I actually run all my new patients on the PHQ9, just as kind of getting a baseline, put it in the chart. So both groups started at 17.8, 17.6, so very similar with both groups. In the creatine plus CBT group, it dropped at the end to 5.8, which is almost no symptoms. It's like, in my mind, they're doing awesome. In the placebo plus cognitive behavioral therapy group, it dropped to 11.9. So that difference is something that kind of woke me up to being like, okay, wow, I need to re-look at this. I remember looking at this like five, ten years ago recommending it, and then I kind of like lost a little bit of interest.

But this kind of piqued my interest again, like, okay. And then yeah, I love the discussion around how much, what is the, what is the proper dose, what we'll probably see in the future and future studies, like if you were to do, you know, a study in the future, also loading, right? It might makes sense to load it in a new patient. So we'll talk about that as we kind of go along. Okay, so this is five grams. So just give you an idea that's a teaspoon. So we were kind of joking around before we got on.

Like, how much creatine did you take before the session a day? And it's like, how do you take it? It's like almost like a tasteless substance. How do you guys take it? I personally just dry scoved it. I know that's like a bad thing. Wow. You just dry scoop.

So I dry scoop five in the morning and then five at night. I'm on the 10 gram, true. Okay. Since talking to Brandon and you and reading these studies, if I'm like sleep deprived, I'll take a little bit, I'll take a double scoop for the morning, you know, like so 10 grams. Otherwise I'll take five. And I usually mix it with like maybe an inch of water, swirl it,

chug it, and then puts more water and chug it. and I try to drink it as if there's no creatine in the water, you know, but it's always like this almost sandy thing that ends up in your mouth. Yeah, I take it with as much water as possible. And then also with food, I tend to be a little bit more sensitive to the GI effects when I first started taking creatine. So that seems to be dose-dependent and also can get a little bit better with food. So I try to dissolve it as much as possible and then eat some like peanut butter or something with it.

Nice. Okay. Anyone else want to comment on there? Yeah, I usually take, you know, at least five grams in the morning. And especially when I'm doing like 26-hour shifts, I have some capsules that I bring to work and then take another like five to ten. And I feel like it makes me work a lot better and feel better. There's a little bit of evidence, but it might be a bit of placebo. Now, Brandon, do you take this while you're cold plunging? Like, do you just do it at the same time? I wish. You can barely do anything else when I'm cold plunging. Okay.

And I think it's worthwhile to say that we have no conflicts of interest in this group. None of us are paid by big creatine, which isn't a thing that's pretty cheap. Okay. Joshua, do you take it, Joshua? Have you been convinced from the studies? I have not tried it yet, but I think I'm slowly getting convinced. Okay, so that's good. So we see, this is good.

but sometimes it's better to do an episode with people who are like not total fanboys so joshua did a lot of the writing here and he doesn't even use it okay so let's go leos at all 2012 this was a randomized double-blind placebo-controlled trial of oral creatine monohydrate in patients uh with an sri women with mddd so major depressive disorder so it's like augmentation with creatine for to see if it had an enhanced response with people already taking an SSRI or taking an SSRI. So Joshua, do you want to take us through another like couple sentences on what the study was and what they found? So yeah, this is again another eight week randomized control trial with 52 women with major depressive disorder who were all treated with acetaloprom plus either five grams a day of

creatine or placebo. And the creatine group showed faster and greater improvements in ham D scores with significant effects showing by week two. And the effect size was moderate with the Cohen's D of 0.52. No adverse events were linked to the creatine. And this is also one of the first studies to demonstrate creatine's ability to enhance the antidepressant response. Great. Okay. Yeah, let's go through again and just kind of get people's perspectives. You know, this is smaller dose three grams for one week than five grams for two to seven weeks. Liam, do you want to start this one off?

Yeah, sure. I mean, one of the main things that I just want to mention about this is like I noticed that they got better faster. Like looking at the curve of their ham D scores compared to the placebo group. They dropped statistically significant at two weeks. But I wish this study was a little bit longer because it looks like the placebo group is kind of catching up to that creatine group. So I think it'd be interesting as you give more time to the, I think it was a lexopro that they used here. Do they catch up to the creatine group? Or is there a benefit to having creatine as an adjunct for the longer term here? I think that would be an important question to address with further research. I think another interesting point to bring up is how they started the intervention.

So they randomized people to creatine and their antidepressant or antidepressant placebo at the same time. And I think it's an important distinction because previous research has shown that brain phosphocreatine levels are a predictor to antidepressant response. So if you're starting someone on creatine and an antidepressant at the same time, you're not really giving the time for those phosphoric creatine levels to increase. So it's interesting that there was a benefit at week two. However, mechanistically, based on some previous research, too, it may suggest that someone that's on creatine before, and then you add an antidepressant, may actually have a better response. Again, with that phospho-cretine store that have already built up,

because we know it takes so long. And then the other thing, though, this study, it's quite a low dose, three grounds a day. Don't even know if it's making a huge change to brain creatine levels. But nonetheless, it's good to see that there was a positive response. Nice. Brandon, any thoughts on this one?

Yeah. You know, it's pretty crazy that this was, you know, more than a decade ago. And it did, you know, it does show that it seems to augment that antidepressant response with relatively little side effects.

I'm a little interested by the dropout rate was a little higher. It wasn't statistically significant. It was 32% in the creatine group versus about 18.5%. in the other group. I'm a little, like, without any obvious adverse effects, I'm a little interested by that,

but might just be kind of chance. Regardless, you know, it seems like it was relatively well-tolerated. We know at those doses, there is increases in frontal lobe fossil creatine up to like 4%, similar to that 5 grams. So, yeah, I think it's, you know, very interesting study and very excited to see more similar to it. and even potentially without antidepressants would be really interesting. Yeah.

So I think it's worth going through some of just the numbers for people who know what numbers are. Ham-D started off around 26.7, 26.9, so pretty similar between both groups. And by week eight, the Ham-D in the creatine augmentation group dropped to 5.4, was very low in the placebo group it dropped to 9.8. And, you know, that's a significant difference. Cohen's D was 1.13, which is like an effect size of 1.13 is an exciting effect size. I agree with you guys that it's odd that there was a larger dropout in the creating group. And I wonder if it's partially because it's kind of difficult to take.

five grams of this substance in your mouth, you know? Do you guys know if this was, if they did like pills or if they did just powder in this? I'm not sure if it mentioned specifically. Like they just mentioned creatine monohydrate, but I'm not sure if they, maybe it's in the supplementary material, but in the methods, it's just specifically mentioning creatine supplementation. I'm not sure if anyone else sees anything else. I think when I've started people on this, it's something I have to talk to them about. I almost need to like show them the studies and show them like, look, this does work. So I highly recommend, you know, check out on Psychiatrypodcast.com for those of you who are

thinking about recommending this to clients. We'll have a really good handout on this with this episode. Some pictures you can show them. They need to believe that it's going to help to take something that's kind of a gritty substance in their mouth. It's kind of unpleasant, right? Yeah. So they actually use capsules. The placebo also use a similar capsule.

Okay, so that probably wasn't it? Maybe it was less capsules or less big of a capsule or something like that. But I think my point still stands like talking to patients about why you're recommending it and then the science and getting into the specifics, showing pictures of the slopes of different groups of people, you know, stuff like that I think is important. So, but Cohen's D, you know, of antidepressants themselves is around like 0.3. So this is a large effect size for those of you who haven't looked at a lot of studies.

Now, will this decrease if you did multi-site studies, bigger studies, maybe, and we need those. But there's no big pharma pushing creatine, right? There's no company out there funding these studies. So we need independent funders who are just invested in, helping people rather than like something that's going to make a lot of money. That's probably why there hasn't been a lot of studies on this, honestly. Which is why we as clinicians need to talk about it, because no one's come into your office talking about creatine.

And the effect size is impressive. Okay, let's keep going. Joshua, anything else you wanted to pull out from the study that you found interesting? I think it's all pretty much been covered, but just going back to the safety profile too, I think. Yeah, no serious adverse events were reported. In this one, no mood switching or any liver or kitten concerns too. So just reassuring findings, especially for patients that might be a little more squeamish about taking supplements or medication.

Yeah, that's a great point. Okay, let's go on to this Tonin Olo-E-D-L-2018, a randomized double-blind placebo-controlled proof of concept trial of creatine monohydrate as adjunctive treatment for bipolar depression. So Josh, do you want to take us through a couple lines on this? Yeah, so in this study, they did six grams a day of creatine as an adjunct in 35 people with bipolar depression, and over six weeks, the creatine group did show significant reductions in depression scores, specifically Hamdi and MADRS, as well as improvements in functioning without triggering an pneumatic symptoms.

And the findings are particularly promising for this population where antidepressant options may be limited due to their safety concerns. Brandon, let's start with you this time. Anything jump out to you about this study? Yeah, you know, a pretty significant difference between the groups here, you know, 52.9% versus 11.1% in the placebo group is quite substantial. This is remission. Correct.

Remission, sorry. Yeah. That's good. Yeah. You know, I don't have much experience whatsoever from, aside for med school, with treating bipolar disorder, but I'd be interested to hear your thoughts on the two patients in the creatine group that switched to hypomania or mania. Do you think that's high enough to trigger a,

worrisome signal. Do you think it kind of plays into the potential mechanism of creatine in this population? It's hard. It's such a small amount of people that I don't think, I think this is where bigger studies are needed, but I think it's a good kind of like warning to those of us who are going to be treating patients to be like, yeah, normal follow-up. If someone seems to be switching to hypomania, then we need to focus on that. Totally. Yeah, no, very, very, exciting results, but I guess you have potentially something to just counsel people on as a potential risk if they're going to try it. Yeah, to build off that point, from the two that switch, I know it's not necessarily something statistically significant that's standing out in such a small study,

but I do think it's interesting when we look at the mechanism of creatine or the supposed mechanism, and we oftentimes hear from creatine or the ketogenic diet from the kind of brain metabolism hypothesis. There's this perceiving the brain as this bioenergetic organ, and that is sometimes how we describe the antidepressant effects of creatine, ketogenic diet, different things like this. So it's interesting to see that there were to patients that switch to this hypomania or mania-like state on top of the antidepressant state. Of course, it's not a good thing, but it also points towards perhaps mechanistically there is something going on. And although this doesn't necessarily show something of statistical significance, it could, as you mentioned, point towards future studies for more

of a mechanistic lens to see, you know, what is the creatine actually doing, particularly in a more treatment-resistant population, like bipolar disorder is a lot more difficult to treat often than depression. So it's promising to see interventions that do help. Yeah. Yeah, that's great. Yeah, anyone else have any thoughts on this before we keep moving? Yeah, well, the next study also shows that two out of the two bipolar patients who were treated, they also switched into hypomania and mania. So I think that kind of adds to the credibility behind this study that there is a potential for creating to exert some sort of bio-energetic effect and to switch someone over to bipolar. Yeah, Liam, I think that's a great point, and I think we need to look at that. Let's get to that

later as we kind of go through that study. Let's jump to now Kondo-at-all 2011. This was an open label adjunctive creatine for female adolescents with SSRI-resistant major depressive disorder. They also looked at magnetic resonance spectroscopy to look at what was going on. So, yeah, let's look at this one first. Joshua, why don't you give us a couple lines on this one? So for this one, this one also showed depression symptoms improving pretty dramatically with CDRSR score. is dropping from 6 to 9 to 30. And phosphorus MRL scans also showed a significant increase in brain

phospholcureatine levels with the P value of 0.02. And this is just one of the first studies to show creatine's ability to shift brain bioenergenics in treatment-resistant use. Great. Nicholas, did you have any thoughts on this one in particular? Yeah, I think a few things. I think it's a small study, but it's interesting because it's in a different age group that we've been previously discussing. So younger age group, we see benefits. But at the same time, too, as Josh mentioned,

you know, actually seeing the brain creatine levels change too is quite significant too, because before that we've just been kind of discussing more on that clinical level and not actually looking at the brain. And obviously, it's much harder to have big trials where you're doing fancy imaging in everyone's brains. But I think it's also necessary to see. Because even though this is promising. It's a pretty small group. It's hard to generalize out from this specific study elsewhere, because again, we're looking at a young female adolescent population, so putting that to anyone else is hard to do. But I think it's promising to kind of see some of those results and kind of build from there. Yeah, Brandon or Liam, do you have any thoughts on this one? Yeah, I totally agree, Nick.

It's super exciting that, you know, they were able to actually measure brain creatine levels. I think, I think, you know, it's, I think, a very expensive modality, but in future studies would be really, really valuable to measure this. And I find an ideal dose that the study I was talking about earlier was that these same authors that tried the two, four, and 10 grams of creatine. So again, you know, very small study, but very interesting results, very applicable to, you know, showing that supplementing creatine orally can significantly increase brain creatine levels. Yeah, one thing I liked about this study too in terms of the methods, they didn't just look at one part of the brain and say, oh, look, the phosphocritin levels went up. They looked at multiple different parts of the brain throughout the entire brain. So I think that lends some pretty good credibility to this study. Great. Okay. Let's keep moving. Let's go to Rotman-at-all 2007, creatine monohydrate in resistant depression. a preliminary study of 10 treatment-resistant depressed patients,

eight were unipolar depression, two were bipolar depression. So Joshua, you want to take us through a couple things on this one? For this one, after four weeks, most patients showed a meaningful reduction in the ham D and the ham A scores. and while the study was pretty small and uncontrolled, it does hint at creatine's rapid antidepressant potential and just helping lay the groundwork for some of the future trials we've seen. Nice. Yeah, and also anxiety. We haven't spoken about anxiety, but anxiety dropped from 18.7 to 12 in this group of people.

Yeah, let's jump in, Nicholas, go ahead. Yeah, for this one, it's interesting. I'll say it's a pretty short trial. It's only four weeks and a pretty low dose. So it's interesting to see such profound benefits on that time frame even. I know we've discussed on other ones, too, we're at two weeks there's already kind of a difference between antidepressant and placebo. But here to see a benefit is interesting because even from a physical health perspective,

sometimes when you're, as we discussed, taking that loading phase, when you take 20 grams a day for a week, and then you go down to what they were using at about five grams per day. sometimes you don't even see physical health benefits until then. So it's interesting to see a change over such a short period of time, which is why I would like to see these trials be longer and perhaps adapt a different dosing strategy because it's quite low, but we're still seeing benefits. So to me, this is just the start.

It's a signal for benefit, but I think there's a lot more from there. Great. Yeah, it's a smaller study. So I kind of want to move on pretty quick. But yeah, any other final thoughts before we move on from the study? Yeah, just that this was a study with the two patients with bipolar who converted to hypomania or mania. And both these patients, the effect was seen after three weeks. So one patient at three weeks was hypomenic.

One patient at four weeks is manic. So that kind of also makes you question like, okay, if they have creatine in the brain earlier than that, is it actually the creatine doing it or is this just like a progression that the patient would naturally experience? So I think more studies need to be seen in bipolar patients. Great. Yeah. Okay, let's go to this. Backyenne et al-2020. This is a very large observational epidemiological study using cross-sectional data.

Joshua, do you want to give us a couple of sentences on this? So for this one, it was examining a dietary creatine intake and participants in the highest quartile of creatine consumption had 31% lower odds of having depression compared to those in the lowest quartile. And while it is an observational study, it is one of the strongest population level ones that we have linking creatine with lower depression risk. Yeah, so Nicholas, jump in and kind of share what you think about this one. Yeah, so this one I actually, I remember I read and I shared before,

And so this is a very interesting study. So as Josh mentioned, like splitting up creatine intake into these four quartiles is an important way to kind of look at it. But the important caveat before we even discuss the findings of the study is when we look at dietary creatine and supplement creatine, you can never really get to the same level of what you're supplementing with. So for context, to have that one scoop of creatine that you have in the morning or at night, that's five grams. To have that much, you need to eat about three pounds of beef. So that's a lot. So people that are supplementing five or 10 grams of creatine, when you're looking at it at a population level in these different quartiles that people are in, we're looking at much lower levels of creatine than those that are supplementing. And again, maybe in the hydrant, those are people that are supplementing, but it represents a lot of different categories. So I think it's interesting to see the signal even from dietary creatine, which mostly is a proxy for red meat consumption. And we're seeing that association in a stepwise association with depression. because sometimes we see population-wise associations, but here we're seeing a dose response association over different intervals at different levels of depression.

So I think that's reassuring, even though this is cross-sectional data and we can't infer causality from it, it's pretty strong to see that association over the different intake levels. And again, points to potentially interventions at a population-based level versus just an individual patient that has depression.

There may be a preventative aspect to creatine for depression. Nice. Liam? Liam, go ahead. Yeah, I was going to mention. Creatine is found in pretty much any animal protein source. So anything with muscle, you're going to find some creatine. So it's beef, chicken, fish, salmon is pretty high in creatine as well. And in this study, they actually did control for fish intake as a covariate, and they still found a statistical benefit for depression.

So I think that's important to look into. And also the other covariates that they looked into, they adjust for age, sex, education, race, ethnicity, access to health care, BMI. Also, if they're taking antidepressant or anti-anxiety medication, family income, and then also physical activity. So that kind of also takes away from, you know, maybe people who have higher phosphocryatin intake, they're more likely to be exercising because they're more into fitness. So they have a higher protein intake, same with socioeconomic status. But one thing about the study that I thought was interesting is that in females and then people with the younger age, then people not taking antidepressants, they didn't see much of a benefit for looking at higher creatine quartiles compared to the lower quartile. So I don't think it's necessarily a clear dose response in most cases, but I still think the overall finding that there is a potential benefit for depression. I think it is worth looking into a little bit more.

nice yeah I think that they excluded and you guys can correct me the 0.9% that actually took creatine is that right yeah when they did control

for those people that did take creatine they still observed a benefit so yeah can you guys speak to you know in the highest quartile were these people on creatine what percentage were on creatine and did that

change the data at all? Yeah, I think there were about nine participants who were taking creatine, and then when they did take them out in their analyses, they didn't see much of a change and the antidepressant effect or the rates of depression in patients with a high creatine intake compared to those without much creatine intake. So in summary from this one, depression prevalence was 10.2% in the lowest creatine intake quartile versus 5.98% in the highest quartile,

which is significant. Which is significant. It's like, it's impressive. Okay. Let's go on to Faulkner-At-all-2020 relationship between depression, prefrontal creatine, and gray matter volume. And I'll just mention this study

specifically measured creatine in the right medial prefrontal cortex, a region strongly implicated in depression and found that lower creatine concentrations correlated with higher depression scores. Importantly, no other metabolites, glutamate, gaba, myoanacetal, and acetyl-spartate showed significant associations, highlighting the unique and specific relationship

between prefrontal creatine levels and depressive symptoms. So, let's see, Brandon, did you take a look at this one? Yeah, definitely a very interesting study. It was cross-sectional, 84 young adults. I believe none were formally diagnosed with depression, and they measured prefrontal cortex creatine. They found that lower prefrontal,

the medial prefrontal creatine correlated with higher depression scores. And also, I think, a really interesting point was that creatine levels were positively correlated with gray matter volume, which does suggest that it is tied to some sort of energy metabolism and structural brain integrity. Nicholas, any anything jump out at you on this one? Yeah, I think it's interesting. It's a decent size study for an imaging study. There's like 84 people in it, which is always good to see. And it builds upon what we were speaking about before with some of the imaging findings for creating levels for both a treatment perspective,

but also looking at someone in front of you that has depression. Again, we can't directly apply these results yet because of the cross-sectional nature, we still need to do more work. But I think it's helpful to see this as almost like a biomarker or potential biomarker to see if someone has low brain creatine levels or during treatment if we can increase their brain creatine levels, seeing if this is a proxy for treatment effect and even correlating it with different depression treatment scores. So I think this is important for the research moving forward to have it. It's very expensive to do studies like this where you're doing these fancy imaging

modalities. But I also think it's important to tie the clinical findings we have with some sort of a brain marker. And the other thing to say is this is very preliminary. So it's not necessarily saying creatine for sure as working by these altered brain bioenergetics. However, it's important to look into it. And when we're seeing signals like this, it's promising, but we need to really tie it with more clinical data in larger populations, different populations, too, because this was mostly younger adults. It would be interesting to see it in older adults, where we know brain creatine stores actually deplete as you age. And we do know that there is some increases in different mental disorders with age,

but it's not necessarily that maybe creatine is causing the depression alone. But maybe it's one of many factors. So I think it's exciting to see, but I think there's a lot of work to still be done. Liam, anything jump out of you? Yeah, I'm honestly not as excited about this study compared to the previous study looking at the brain creetine levels, just because in the study, like I mentioned with the other one, they were looking at multiple voxels and kind of taking that together. So looking at multiple parts of the brain and compiling that into a composite measure. This one, they mentioned in the

methods that they looked at multiple voxels and selected which ones had differences in phosphicretion levels. So I think there is somewhat of a, like a selective reporting bias in the study where they're looking at one specific fossil or voxel of the meteorproof frontal gortex. and seeing a statistically significant correlation with depression severity, which, I may not to say that the medial prefrontic cortex isn't important for depression. I just think the methods that they used in this study was kind of concerning. And then also to kind of go along with that to look at what covariates they used to look at this correlation between the brain-freeteen levels and depression.

They looked at age, gender, daily cannabis use, and smoking status. So I would have liked to see socioeconomic status, which they did collect in the study, put into this covari, because we know if someone has more access to meats and to like salmon and stuff like that, then they're going to be eating more creatine. They're going to have higher brain creatine levels, maybe less likely to be depressed. So I think it's a study that's pointing in the right direction, but I think there needs to be more, I guess, definitive ways. And also, I think, some control trial looking at depressed patients versus non-depressed patients and really looking at these covariates and kind of determining, okay, is there actually any differences in phosphocritin levels in depressed patients versus non-depress patients? Because I don't think there's been a clear convincing study on that yet.

Great points. I think when we look at a study like this and we're looking at correlation, not causation, right, there may be something else like a mediator that is causing the significant correlation. And so what Liam is pointing out is that socioeconomic status could be more important than the creatine, or it could be linked to the creatine. So it's possible that lower SES people have lower amounts of creatine because they're eating more processed food, and then that could basically be part of the reason for the lower creatine. but also take away the statistical significance of the creatine

that they found in the brain. So it's a nuanced research sort of thing because you don't want to over-control, especially if you're, you know, you could say, well, because we added in the SES and we found decreased correlation, which isn't what they found, but let's say that they did find that.

They could say, therefore, there could be reasons for lower SES people having lower creatine, and we should consider those things as part of like what's going on you know um so kind of a nuanced research take joshua anything else you want to draw from the study no okay let's go to haileem at all 2015 so this one is an open label pilot study evaluating the effects of five gram a day creatine for eight weeks and fourteen women with major depressive disorder and

current methamphetamine use. Despite continued substance use, participants did show a significant reduction in the depressive symptoms with hamdiscores dropping from an average of 24.3 to 10.5. And brain imaging

was done using 31 phosphorus MRS, showing a significant increase in frontal lobe phosphoric creatine, which supports a potential bioenergy mechanism behind the clinical improvement. There were no adverse effects reported and methamphetamine use did not worsen, which also may suggest creatine as a safe and beneficial, you're going to dual diagnosis populations.

Nicholas, do you want to jump in? Yeah, so this one is interesting. So it's a small study again. It's a very specific population, like females using methamphetamine with depression. So it's hard to generalize outward. But the one thing that's interesting about this trial is, is that most of the studies or all of the studies we've spoken about so far are creatine plus something else. So creatine plus cognitive behavioral therapy, creatine plus antidepressants. To my understanding, this study is one of the only studies that exists where it's just creatine as the treatment. Again, it's not an RCT double-blind, you know, the full gold standard. However, it is a monotherapy trial that has a promising signal.

Again, albeit in a population that we can't necessarily generalize this to general population with your mild depression sort of thing. However, it's interesting because it does show a signal with creatine on its own. We do still see the increase in the brain creatine levels. So it does point towards potentially there being benefits to studies being creatine monotherapy in other populations to see what benefits may lie there. Because it could be something where in a population with mild depression, people are offered creatine or oftentimes people choose to not go down the antidepressant or CBT or traditional treatment route, and we may see a small signal there. And on a population level, like we saw with

the dietary study, perhaps that could be beneficial for a condition that's so prevalent. So I think it's a very small study in a very specific population, but it's a signal for potentially future research or pairing it with other things than just CBT or antidepressants. I think what's interesting was the brain phosphocreatein levels increased from 0.223 to 0.23, this is not a large increase, right? It was statistically significant. They show, like in figure four, they show various participants

and how they had an increase. Everyone had an increase except one participant. Once again, this is a lower dose. And it is kind of, yeah, it is a unique group of people, people who are actively, currently using methamphetamines and not required to abstain. So this is kind of like a real-life situation that we see in psychiatry.

We're not always seeing the patient that is this prototypical good research client, right, that's not using any drugs, that's relatively no medical problems. This is a higher risk group of people who had some impact. So interesting. Yeah, anything else or shall we keep going? Let's keep going. Condo et al, 2016. Joshua, give us a couple lines on this one.

So this one is a dose-ranging placebo-controlled study investigating oral creatine supplementation and it specs on grain energy levels. In adolescent females with SSRI-resistant major depressive disorder participates, and this one got either placebo of two grams, four grams, or 10. grams daily of creatine for eight weeks and 31 PMRS brain scans were used to measure the phospho-cretin levels. The results showed a dose response effect with phospho-creatine levels increasing in all creatine treatment groups, but most significantly and the 10 grams a day group, which also showed

the largest reduction in depression scores. While the study wasn't powered to detect statistical differences in clinical hours, outcomes, it was one of the first to demonstrate this. So target engagement of creatine in the brain, showing that oil creatine crossing the blood brain barrier can boost cellular energy stores. Nice. Nicholas, what do you like about this one? Yeah, well, I like that this one again, it's a smaller study, but I like that there are

different dosing groups and that we do see the highest effect in the 10 gram group. So that kind of alludes back to what we were speaking to more near the beginning, where when most of these studies are focusing on five grams per day, perhaps there's benefits at 10, and, you know, hypothesis being even higher than 10 per day. I think a lot of the precautions is taken in the studies, and it makes sense, where

creatine people worry about kidney function, hair loss, stuff like this, where there's actually a lot of evidence to support its safety, but I think there's a lot of caution taken around this because it's not a substance that's been studied much in the mental health realm, as much as it's been in the physical health realm.

So it's good to see that signal for 10 grams because I hope to see research in the future where we do more 10 grams in different populations and even higher, to be honest, because I think, again, not as a blanket statement that it's safe for everyone, but I do think that it's safe for a large majority of people to go to these higher doses. And I do think that we are only tapping at the beginning potential of creatine because it's akin to if you were to do antidepressant trials and you were to start them at their pretreatment doses. You oftentimes start antidepressants at half the dose that you want to have an effect, more from a side effect perspective to see if people tolerate it.

And how I see some of these creatine trials is we're starting them at these half doses and we're keeping them at these half doses for not long enough and then saying, oh, it had a small effect, that's good. And we're not really seeing the full potential. So promising to see this, hope to see more studies with bigger doses and more RCTs that are double-blind, like proper gold standard studies. But that was the main thing I took away from this one. Nice. I actually saw the weight gain, not to freak people out, but the weight gain in the 10 gram group was 5 pounds in the placebo was around 3 pounds in the creatine, 2 and 4 grams, basically.

Now, this is not a statistically significant change. That's important to know because this is a small study. but I'm looking at that and I'm thinking to myself like of course it goes up more because creatine also puts water in the muscles and that's that's a known thing that creatine does which also helps with strength strength against having you know more hydrated muscle is a good thing so one of my thoughts with that is just hydrate yourself of course when you're starting this you know realize that you're going to need more water your your muscles are going to get a little bit more water, which is a good thing, and you may gain a couple pounds, which is water weight.

So don't worry about that. The other thing that interesting was the serum creatine was pretty similar between the two groups, between the lower dose and the higher doses. But the brain creatine went up, which I think is saying, more is getting across the blood brain barrier at that 10 gram.

and I think that that's important. So, yeah, more to be revealed, though, because this is a small study, right? This is pretty significantly. It's hard to do. These are expensive studies, though. Remember, like, whenever you're scanning the brain, that's thousands of dollars per person, potentially.

So, okay, anything else on this before we move on? Liam, did you, I don't think you mentioned anything on this study yet. No, I just wanted to highlight that I think it was pretty impressive. to see the specific dose response relationship. I did mention earlier that I think you might not see that much of a difference between 5 and 10 grams if you take it out multiple weeks. But I think this study is pretty convincing, I'd say, because this is 8 weeks in, usually you see muscle saturation with 5 grams by 4 weeks.

So about one month you'll see most muscle saturation. So then you'd expect with each creatine dose, like the maintenance dose, you need about two grams to maintain that saturation. So that means you'd have three grams left in your plasma, potentially go to the brain, potentially go to the bone, potentially to just be excreted. So I think the 10 grams having the same plasma, but having more brain creatine, I think that is relatively, you know, pretty convincing that you should see some benefit from higher doses and that we need to look into high. higher doses for studies specifically looking at the brain. Awesome. Great. Okay.

Let's go into the mechanism. And I kind of want to back up a little bit as well because I think a lot of people are like, wait, what is creatine? How does phospho-crate phosphate group from ADP to regenerate ATP? Yeah. Who wrote this portion, by the way, of the handout? Was this you, Nicholas? That was me.

This was you. Okay. So, Liam, why don't you take us in? to the potential mechanism. And your writing is just really awesome. So I appreciate you, Liam. As always. And by the way, University of Michigan,

Liam got in. Let's go. Let's go. Congratulations. Yeah, thank you. Not too far from Nicholas and Brandon, right? Hey, we're close to us. You got to go visit.

You guys go visit. I'll buy you all stakes. You can enjoy your stakes and take a picture. I reimburse you. Yeah, we should do it. I'll make it happen. Yeah, so, you know, we've been talking about creatine, but what does it actually do? So creatine is thought to donate a phosphate group to ATP or to ADP to regenerate

ATP in times of high energy demand. So typically, let's first start with muscle cells. Muscle cells, if someone's just sitting there, you're mostly relying on fat oxidation to generate ATP through aerobic respiration. So you're generating ATP from mitochondria. If you're exercising in a higher intensity, say someone's on a bike, they start peddling a little bit faster, they generate lactate, and that's glycolysis. So the cells generate ATP from glycolysis, and that generates lactate as well. If someone is pedaling faster, even sprinting on a bike, then you turn to the phosphocretein system.

to generate that ATP because glycolysis and fat oxidation, they simply take too long to be able to regenerate that ATP. So you have some extra ATP sitting around there available. That's very fast. So in exercising specifically with strength training, you see that benefit for like five to ten seconds. So that can equate to an extra rep or two during a set. And then as far as the brain goes, but what we're talking about in this podcast, the brain cells are a little bit different from muscle cells and that they typically do not undergo glycolysis as much. They don't take in glucose as much compared to muscle cells. Neurons, they rely more so on oxidative phosphorylation, so that aerobic respiration using mitochondria to generate ATP. And they do so by getting a lactate from

astrocytes. Astrocytes are the cells that support neurons, their metabolism, their extracellular ion concentrations. So astrocytes, they take in glucose from the blood-brain barrier and generates lactate from glycolysis. And lactate shuttles across to the neurons, and then neurons can generate ATP from lactate by putting lactate into aerobic respiration and using the mitochondria. So what creatine could potentially help with, the phosphocreatine system is helping in times of high energy demand when a neuron is firing a lot, and it doesn't have enough lactate available to it to shuttle across because it is a time-intensive process, that if you have that phosphocryatin system available to regenerate the ATP, then you can have more ATP to be able to power the sodium potassium pumps to regenerate a neuron's, resting membrane potential to allow it to conduct action potentials and essentially allow the cell to regenerate a little bit faster to be able to fire more sequentially. Well, well said, well said. That's this is exciting. Nicholas Brandon, either of you have any comments on this?

Yeah, no, I think it's a great description of the mechanism. And it's very interesting to see it broken down to the level of the ATP because there's various hypotheses and psychiatry. that break down mental disorders to the level of energy. And that's what kind of this description is doing here, speaking about creatine from that energy perspective. And as Liam mentioned, in states of these increased metabolic demand, and states like that, to clarify, are things like depression, things like sleep deprivation.

That's when you're at, your brain is at this increased metabolic demand. How the creatine works is it essentially acts as this alternative and faster replacement mechanism that your brain can use. However, an important point important to bring up, particularly the point of depression is your brain can only use this for so long. So you have these phosphocreatin stores in your brain as well, too, that your brain can essentially tap into.

So if you're sleep deprived or you're depressed. But again, that's a finite amount that you have in your brain. And if your brain is using it up in a rate more than your body is taking in, so say you're not supplementing creatine, you're on a vegetarian diet, and you're having lower levels than someone who maybe doesn't.

With that, if your brain is in this depressed state or sleep-deprived state, you're running out of that creatine over time. And that's where this hypothesis comes in where potentially, and again, we need to verify this with larger studies, but potentially supplementing creatine can increase those brain creatine levels so that your brain has more of a reserve to use from when you're feeling depressed or when you're sleep deprived. And it doesn't just kind of not work anymore and lead to mitochondrial dysfunction and all the things that Liam was alluding to. So it's interesting to see a mechanistic correlate

attaching the things that we've been speaking more from a clinical lens. Yeah, that's a great discussion. Thanks Liam and Nick. I'm not sure how much more I have to add, but I think you're really driving home the point where, you know, in an average day for someone that's pretty healthy, you know, maybe bumping up their creatine stores might not make a huge difference in their cognitive performance. But when you look at the studies of stress, so, sleep deprivation. There's a few studies in the document where, you know, if people are kept awake for 24, 36 hours exercising, if people have hypoxia induced, and also if people have, you know, neurodegenerative diseases where they just don't have that reserve in the brain,

creatine seems to be that kind of buffer backup energy system where the brain can rapidly tap into that and create more ATP, the kind of energy currency of the body. So it's super exciting and, you know, we're excited to see more research in this field, but that was a great explanation of the mechanism. Thank you. You know, I think this ties into my thought on just the brain metabolically, the mitochondria, how do we optimize mitochondria, sort of the brain energy sources long term? and, you know, if I were to put in the hierarchy of importance of those things, you know, psychotherapy, exercise are up there as well. And psychotherapy, because, like, we handle stress differently if we approach things differently.

I was just watching this, like, Instagram reel of this person who's about to go on to a, about to be dropped into this kind of, like, roller coaster. and the attendants like, oh, you guys got to buckle your seatbelts. And so they're like frantically trying to find their seatbelts. And this guy's messing with them, of course. And then they get launched into this roller coaster and they think that they're going to die because they don't have their seatbelt buckled.

Of course, they're not going to die. But their perception that they're going to die is there, right? And so I think good psychotherapy, what it does is it helps your perception of stresses change potentially on a multiplicity of levels, right? Like, for example, marriage and family therapy, like if you're married to someone who you constantly feel is adversarial, doesn't love you, like, this is going to cause long-term stress.

Now, that being said, like, how we process the stress is the second thing that our brain does. And so processing the stress is, like, how healthy are your mitochondria, how healthy are your brain cells? And I think creatine is just one, of those things that potentially makes you have a little bit of an edge in how you handle stress, how your brain processes stress. It's like with muscle, it gives you that extra, maybe the fifth

and the sixth rep that you couldn't do. Maybe this helps you in this similar way, cognitively, in a multiplicity of ways that are hard to understand. It's easier to understand, like, oh, I can do an extra rep or two of exercise. And, you know, I think as well, Nicholas and Brandon, you guys have been excited about the combination of this with exercise, right? And I'm excited about that as well. You know, as a psychiatrist, I'm not just changing one thing. I'm trying to change multiple things to get someone completely into a place of thriving. So yeah, you guys want to comment on that at all before we move on or shall we keep going?

Yeah, maybe one quick comment. You know, there is one very interesting study. It's quite small, but creatine was given to people with type 2 diabetes in an exercise program. And it actually resulted in significant improvements in metabolic changes. Their A1C dropped by 1.1%. Their glucose was lower. And the authors actually even measured like glute 4, which is an insulin-dependent cellular uptake of glucose on the cells. And that actually increased with the creatine group with exercise.

And, you know, Nicholas, you post all the time about the importance of, you know, getting rid of this kind of arbitrary divide between mental and physical health. And, you know, the more I read the literature, the more I'm convinced, you know, metabolic and mental health are essentially could be considered as one. It's not, it's kind of arbitrary to draw a line between them and there's such a strong link between these. So that, you know, I think it deserves a bit more investigation in the future, you know, is creatine with exercise potentially inducing some metabolic changes? that might be contributing to improvements in mental health. I would love to see a study done with creatine and exercise versus placebo and SSRI or even adding CBT to that. I think it would be really valuable. Yeah, and I think just at one point, from a pure practical standpoint, we know a lot of people that take creatine

and supplement creatine already are exercising. So to answer a question for people that already exist and are doing these protocols, essentially, it makes sense to have a study looking at exercise plus creatine, especially when, you know, we've written actually together about exercise compared to antidepressants and therapy. We know that there's antidepressant effect there too. So combining it with creatine where we're seeing a positive signal only makes sense. Yeah, absolutely.

What I've found is that I can't haphazardly recommend this to people. Like I have to actually sit them down, show them some of the studies. I send them the studies when I'm talking about. creatine and exercise actually. Because like people really need to believe like, no, like, I've had people like where I'm like, yeah, okay, so we're going to add creatine, add exercise. And then they come to the end of the session. They're like, well, are you going to help me treat my depression?

Like, are you going to give me a medicine for my depression? I'm like, no, like exercise and creatine is a medication, you know. And I think people are, a lot of patients are still on this mindset of like, well, if it's not a prescription, that you pick up from a pharmacy, it's not an actual medication. And it's like, no, this is an actual medication. We're going to try this. And often for these people,

they don't want the side effects of an antidepressant or normal antidepressants haven't been helpful. Or, you know, they're struggling with erectile dysfunction and they don't want to increase their Prozac more and cause more erectile issues. Or, you know, there's all these reasons why this might be a good option for some people who are looking for a way out of their suffering.

But let's zoom in on does creatine enhance mitochondrial function in muscles and in the brain? Wash et al-2001 looked at this and yeah, who wants to talk about this one? I can give a quick summary. Okay. So for this one, it's a physiological study

that use permeableized human muscle fibers to understand how creatine and phosphocritine influence mitochondrial respiration. The researchers found that creatine enhances mitochondrial sensitivity to ADP and increases respiration, while phosphocreatine has the opposite effect, dampening respiration by decreasing ADP availability. And these effects mimic what happens during different levels of physical exertion. notably 16 days of creatine supplementation decreased resting respiration so non-ADP stimulated respiration which possibly reflects improved mitochondrial efficiency the findings point to creatine as a nuanced regulatory role in oxidative energy metabolism has implications for performance and possible

neuroenergetics Yeah, anyone else want to jump in and talk about this one? Yeah, I think one of the leading theories about how creatine can enhance mitochondrial functioning is by essentially making more ADP available. So like we mentioned, creatine can take a phosphate from ATP and store it and then give it to an ADP later. So in times when you don't need that much energy production, then the creatine can take the phosphate from the ATP and allow more ADP. to be there. And when you have more ADP available, that means the electron transport chain in the

mitochondria is available to make more ATP. And if you have, say, a bunch of glucose being broken down and you're generating a lot of NEDH and FAD molecules that feed electrons into the electron transfer chain, there's some thinking that you can get a backup of those electrons if you don't have enough ADP available and these electrons might be able to leak leak out of the mitochondrial membrane and to form reactive oxygen species. So this is kind of supporting the idea that people who have like high blood glucose levels are going to have more reactive oxygen species because of the backup of the electron transport chain. So then if you supplement creatine, you free up some of that electron transport chain and have less reactive oxygen species.

I think to add to that, just from a practical lens, as we spoke about before, it's almost like looking at it, like you just have increased reserves. In both a physical perspective, the extra reps, mental you also have extra reps. You can just handle more. Like maybe that day that was stressful for someone that, not that the creatine is a solve all, but maybe you have this extra reserve where it wouldn't bother you or slip you into this more depressive state. Not an overt depression, but you have more of that reserve to move forward with it. So I think it's great that we're speaking at it at such a cellular level because oftentimes in psychiatry, we get stuck in our depression rating scales, we see a change, but to actually speak at it at a cellular level is interesting to see, too, to really appreciate what something's

doing beyond just neurotransmitters, looking at the level of ATP, mitochondria, ADP, electron transport train. I think it's important to look at stuff from that lens. Yeah, and it's significant. Creating increased mitochondrial respiration by 55%. That's really interesting. Okay, let's keep going. Pan and Takashani 2007 Cerebral energetic effects of creatine supplementation in humans.

Joshua, do you want to introduce it? This study explored a seven-day regimen of oral creatine supplementation. It was 20 grams a day and how it affected brain energy metabolism in healthy adults. And they used high-field magnetic resonance spectroscopy.

Researchers found significant increases in phosphoceryotene to ATP ratio, particularly in deeper brain structures like the hippocampus and the stratatum. Interestingly, these effects vary based on individuals' baseline energy states, so the lower baseline PCR

ATP ratio showed the largest improvements. And the study also observed correlations between mitochondrial marker NAA and acetyl aspartate and changes in energy metabolism, which suggests that creatine may enhance cerebral high-energy phosphate turnover

and potentially supporting as well brain resilience and function under metabolic stress. Yeah, anything, jump out to any of you guys that you wanted to point out on this one? I think not specifically within this study in terms of because I think it's kind of reinforcing what we've said about creatine supplementation, changing some of the metabolic markers of creatine,

the stores, and it's really reinforcing that. I think one point that we haven't discussed, which is interesting, though, is a precursor to creatine called glycosamine or GAA. I'm not sure if anyone's heard of that. They've done studies to supplementing that alone or with creatine, and they've actually found greater rises in brain creatine, supplementing the precursor, rather than creatine itself, which is, I think, an important point to discuss in the setting of studies like this, because if we're saying that the antidepressant mechanisms of creatine is mediated by brain creatine levels, it would be interesting to see more studies like this, but in a clinical lens, using the glycosamine to increase brain creatine levels and seeing

what effect that has. Because to my knowledge right now, we don't have any studies looking at that, plus creatine or that alone, and clinical outcomes. There are a handful of smaller studies looking at that, but I think if, again, we're really fixated on the brain levels, studies, like this, but also having a clinical lens with that additional supplement could be promising. Yeah, and I hope that there's a lot more funding for a lot of these studies, multi-site, multiple researchers. I know there's some research funding for these kind of things now, so hopefully we'll get more of that. Let's keep going. I think there's some myths that creatine causes kidney issues. What is the study here that we talked about that basically

shows this is not the case. So in this study, they investigated whether long-term creatine supplementation has any harmful effects on kidney function. And the authors followed 20 high-level male athletes who took oral creatine daily for up to five years and compared them with 20 matched athletes who did not use creatine. And they assessed various markers of kidney health, including serum and urinary, cratining, urea and albumin excruciing, and they found that there were no significant differences

between creatine users and non-users. There were no signs of impaired glomerular filtration or tubular function observed in the creatine group, and this kind of points to some of the earliest and strongest evidence that we have for long-term creatine use and not being harmful to kidney function in healthy individuals. Awesome. Yeah, I think it's pretty safe from what I've seen in most populations.

And I would say if you have a unique population, then you should probably do some digging on that unique population and make sure it's safe. And I think speaking from where this evidence even came from, where there's a signal for people being worried about kidney function, my understanding is it came from a case report many years ago of an athlete that was taking a high-dose creatine, but they were also cutting weight and restricting water. So no wonder you saw an increase in creatine levels or an indicator of kidney damage or acute kidney injury if you're dehydrating yourself. And I think there's a lot of other confounding factors. Since then, beyond this study that we discussed, too, there's meta-analytical data combining lots of studies, which also didn't show any association with kidney damage. Again, at more of the standard dosing ranges, so I can't speak to people that are taking

40 grams a day or something like that. But within the commonly recommended doses, it's generally safe again. apart from other clinical populations. Yeah, I think just to add to that, Nick, I think that was a case of kind of what we call pseudo-renal failure. So, you know, like pretty much every time someone gets admitted to hospital, we do basic lab work.

And one of those is a creatinine, which we use as a marker of kidney function. And, you know, in young bodybuilders, because of their excess muscle, their creatin can actually be falsely elevated. And I think in that case, or in a few cases, creatine supplementation is increased serum creatinin. And even though we look at that and we might be a bit worried about decreased renal

function, it's actually not a marker of decreased renal function. It's stopping the supplement, my understanding, would reverse the creatine levels, creatinine levels back to normal. So that's something to keep an eye out on. If you have someone taking a high dose of creatine, their bodybuilder, and their creatin is high, it might not be renal failure. it might just be from their high muscle mass and the creatine supplementation. That said, I still counsel people.

I would say definitely those with chronic kidney disease, I wouldn't take creatine without talking to their nephrologists. Yeah, just a personal anecdote to that. I used to do a lot of bodybuilding, powerlifting, and I started taking creatine. My creatin went from 0.9 to 1.1 after two months of taking creatine. So it is like a false elevation. and then when I was off of it, then it went back down to 0.9.

So there's the option for using cystatin C to look at GFR that doesn't rely on creatinine. So if you're worried about a patient or if a patient is trying to talk to their doctor, after you put them on creatine, just tell them like, hey, let's run a cystotin C test if you're worried about my kidney function. That's really interesting. I don't think we have that in Canada because we'll have to say, send people to the states to get that done? If you're working out, that could also falsely elevate your cratnin. You know, if you have more muscle mass, right, that can increase it a little bit because

there's more breakdown of muscle. So you have to look at the holistic picture. Okay. Brandon, I want to spend a little bit on these studies that you've looked at with sleep, kind of wrapping it up with that these studies and then we'll we'll we'll tie this in a nice bow so which of the studies do you think is most pertinent to go through or do you just want to take us through a couple um maybe i could do a quick overview and i know nick i wanted to talk about the one study with the large creatine uh bolus as well i think that's a very contemporary and very interesting

one but yeah i'd love to do just a brief overview of creatine and sleep deprivation and you know this has been a big interest to mine over the last few years it only took a few uh 26-hour shifts without any sleep for me to, you know, want to dive into the literature and find ways to perform better, feel better. And yeah, it's a pretty rough go initially, but, you know, honestly, I found exercise, creatine, healthy diet made a huge difference with tolerating that. So I just want to go over a few studies and once a follow-up study, that kind of, I think, drives home a bit of the point that we've been talking about with creatine acting as a really, an energy buffer in times of stress.

So one study by McMorris and all in 2006, the follow-up study in 2007, they took two groups of people. One group got 20 grams of creatine a day for a week. The other one got placebo. Then they sleep deprived these people for 24 hours. And throughout that, they made them exercise to kind of balance their energy output.

So it's pretty brutal, you know, staying away for 24 hours, you're exercising, you're probably going to deplete your ATP, or at least a lot of it. And what was really interesting is, you know, they measured all sorts of cognitive tasks. But the ones on random movement generation, which are a measure of executive function, were significantly better in the creatine group, but only at 24 hours. So that goes to show, you know, for several hours, there wasn't any significant differences, but it did catch up at 24 hours where, you know, supplementing with creatine gives you that extra buffer, where it allows you to have improved executive function, to perform better and have faster reaction times. And, you know, for resident doctors that, you know, are making life and death decisions overnight, I think it makes a lot of sense to at least consider relatively harmless supplements.

that could have these cognitive benefits. And I've noticed some huge, huge improvements myself from taking them. Again, it didn't improve all cognitive domains. In a follow-up study where they then took people for 36 hours, and they exercised them even harder with moderate to intense exercise. Again, they cognitive batteryed them. Only at 36 hours did they detect a difference with creatine for markers of executive function. which, again, this is very early evidence, but I think it's very interesting. And it goes to show that,

you know, when you exert yourself, you're very tired, you don't have much reserve left. That extra creatine and ability to rapidly generate ATP does make a cognitive difference in at least some domains. And another study that I thought was really interesting that really drives home this point, was by Turner and colleagues in 2015. This was an amazing study. They took only, 15 people, so again, very, very small trial, but they gave one group 20 grams of creatine a day for a week, another group placebo, and then they starved them for oxygen. So they put masks on them and gave them only 10% FIO2. For context, atmospheric is about 21% fraction of inspired oxygen. And there's a beautiful graph. Their oxygen saturation dropped to 80% in the 10% group. And they

were they were starved for oxygen and they were still making these people do these cognitive tests. It was crazy. And the group that supplemented with creatine improved almost all of their markers to baseline, even though they were still hypoxic. Which is just fantastic. It's such a great study just to show that, you know, in those times of stress, creatine provides that buffer of energy to really improve cognitive performance in those domains. having been sleep deprived, oxygen deprived.

I don't think I've ever been really oxygen deprived, but having been sleep deprived before multiple times, it's a little bit sadistic, honestly, some of these studies. It's like, we're going to take away your oxygen, we're going to sleep deprive you. I was actually a part of a study where I was sleep deprived. Like, I just went through a normal call, but they wouldn't let me sleep at all during the call

and they had like an activity tracker on me. And then they ran a bunch of cognitive studies before and after I was actually part of one of these studies. and I knew that I was not doing as well. I knew it. And, yeah, so it's painful. But how interesting that some of the cognitive performance was, you know, preserved in these high-stress states, right? These are high-stress states.

And with loading a pretty significant dose, I think it was five grams a day or five grams, four times a day, right? Or did they give it all 20 at once? Yeah, I think it was four, I'd have to double check, but I think it was five grams four times a day. Yeah, so it's like they were really giving quite a bit to those people and it made an impact, which is really, really fascinating to me. I would also think that someone who's almost like a highly fit person would probably have preserved capacity to some degree a little bit more maybe. but creatine for the wow that's amazing any any thoughts on these uh nicholas leum want to jump in joshua yeah i think they're both very interesting studies i think they're relevant directly to depression from a sleep mechanism but they're also representations of as i mentioned before states have

increased metabolic demand from various avenues so whether there's depression whether it's sleep whether it's taking away someone's oxygen you're putting someone under stress and they're functioning better. I think that's the common theme that we're seeing across these studies, which is promising to see because there's so many different brain stressors that you can have, whether it's stress in your daily life, whether it's depression, whether it's anything. And to see this benefit across the board is reassuring. Yeah, one thing I wanted to know about the dosing here, the 20 grams per day for seven days, that's like the most common loading protocol. So that you can saturate muscle sores within seven days and presumably get creatine up into the brain. Whereas,

as if you're taking five grams for that seven days, you're probably not going to saturate the muscles that much, not see that much uptake by the brain. So I think that supports the idea that a higher dosage, at least for the acute term, you need a higher dosage to see that benefit. Really, really important. Okay, there's other stuff we're going to have in the handout

that we didn't cover. So go to Psychiatrypodcast.com, get the free handout. All my stuff is out there for free. You can share for free. there's PDFs. I just wanted to disseminate knowledge to everyone. And Nicholas, Brandon, I know you guys are both active on X,

Twitter, formerly known as Twitter. Very valuable breakdowns of studies. I'm really impressed by how you guys just in a very articulate way say so much and so little time. It takes me like one minute to really understand a study and then I look at the study and I'm like, oh, I don't know if I got much more than that one minute.

so I really appreciate you guys and Joshua amazing job we're gonna hopefully get you into a top university just like Liam just got into and really appreciate your work on this and yeah so we'll leave it there

for today maybe any final thoughts final reflections we'll just go one by one Joshua anything that you pulled away from this that you want to just say off the top of your head I think I guess coming from someone that's not necessarily in the yeah the creotene bandwagon yeah i think it is all very just eye-opening you know and i think it's it's a

really refreshing um idea in especially the age where there's a lot of i guess suspicion and um distrust with between medicine and a lot of society and so something like creatine that is more of a natural thing i think can help people be more open to not only treating the psychiatric diagnoses, but with supplementation and medication specific with you. Yeah. Yeah, awesome.

Nicholas, any pearls, takeaways, big things? Yeah, I think for creatine, it's a very interesting thing that we need more research to really delineate where its benefits are the highest and what dose, etc. But I think when you look at any medication, whether it's a pharmaceutical, whether it's a supplement, it's always good to look at the risk

benefit ratio. And we spoke a little bit about the risks, but creatine, even compared to some other medications that we commonly use, is pretty well tolerated. So I think that's an important thing to consider when you're treating someone in front of you and they're worried about risks and different things that may be associated with it, particularly for like a mild depression, where you really have to weigh, is it worth the risk of XYZ treatment versus trying something that may be lower risk like creatine or exercise as a first step? I think it's very promising. And we'll we'll have to see where the research goes with it, but I'm excited to see it paired with other things. Like we've seen it with CBT, we've seen it with antidepressants, but I think I'm really looking

forward to seeing it both as a pairing with exercise, but also as a monotherapy, seeing how it does. I don't know that it'll stand against some of our primary treatments, but I do think it would be interesting to see, does it have a meaningful impact on depression score in more generalizable patient populations? And because that may be a viable option for someone, again, on the more mild end of depression, but we need the research to back that statement. Brendan, any big takeaways? Yeah, just echoing whatever else said,

I think the future of creatine is very bright. We've gone over how it seems to be this great kind of backup energy system in times of stress, and I just really hope we get more funding to export further in future studies. And I think pairing it with exercise just makes sense, especially in all of these different populations, who have known to have benefits from exercise. So, you know, really hoping we get more funding and more studies to go over in the future.

Nice. Liam, any final reflections? Yeah, not too much to add. They're just kind of going along with what Nick was saying about the risk-benefit ratio. I mean, there's so little downside to taking creatine, maybe just like the extra effort to go throughout your day of taking it. But the benefit you don't know until you actually start taking it. And some people are creating hyper responders, at least in the literature for exercise. I myself, I notice a huge difference for my workouts when I take creatine versus when I don't.

So I wonder if there is also a benefit cognitively for that as well. So I think it's worth a try for anyone who's interested after listening to this episode. Yeah, and I would say I think for future research we're going to need to look at a loading phase, you know, 20 grams a day for a week, and then maybe bring it down to five, get that initial like loading sort of benefit, right? And then I think we'll have to have bigger studies, we'll have to have, you know, multi-site studies, sites, you know, repeat studies, before it kind of becomes fully mainstream where it's like, okay, this is a big part of everyone's sort of treatment. But at this point, it's low risk.

You can read the studies for yourself. You should read the studies for yourself. You should think about it if it makes sense for certain populations, certain groups of people. And I'm excited about it. I would say from reading the studies myself, I now daily fight through the chalkiness of consuming five to ten grams depending on how sleep deprived I am. So, good times. All right, guys, thank you so much for your time. This has been awesome. this will be really helpful for people, and we'll leave it there for today.