Can Creatine Help with Depression? Exploring the Science with Dr. Nick Fabiano

Nick: 
I do think there’s a lot of utility across patient populations, particularly in experiencing depression.

Bret: 
Welcome to the Metabolic Mind Podcast. I’m your host, Dr. Bret Scher. Metabolic Mind is a nonprofit initiative of Baszucki Group where we’re providing information about the intersection of metabolic health and mental health and metabolic therapies such as nutritional ketosis as therapies for mental illness.

Thank you for joining us. Although our podcast is for informational purposes only, and we aren’t giving medical advice, we hope. Hope you will learn from our content and it will help facilitate discussions with your healthcare providers to see if you could benefit from exploring the connection between metabolic and mental health.

You’ve probably heard of creatine as a muscle building supplement, but turns out it can also help mood and improve symptoms of depression. So who should be taking creatine? Should everybody be taking it? Maybe not. I’m joined today by Dr. Nick Fabiano, where we discuss what creatine is, the research behind it, and maybe it’ll help you understand if it’s something that might benefit you, and something you should talk to your doctor about.

So here’s the interview with Dr. Nick Fabiano.

Dr. Nick Fabiano, thank you so much for joining me. 

Nick: 
Thank you for having me. 

Bret: 
Yeah. So we’re having you back here on Metabolic Mind. So if people haven’t seen your first episode talking about exercise for depression and mental health, in general, I highly recommend they go back and watch that. But today we’re talking about creatine, and creatine has been sort of resurgence in the in social media and in the press with some new studies about creatine’s benefits for depression and mood.

But before we get into all the details about that, bring everybody up to speed about who you are. 

Nick: 
Yeah, thank you for the introduction. So my name’s Nick. I’m a third year psychiatry resident at the University of Ottawa. My main research interest though lie in looking at different lifestyle measures for mental health.

So as Bret mentioned at our last episode, we discussed exercise for depression specifically. So I’m interested in the avenues of exercise, diet, sleep, and how this may impact someone’s mental health, and more particularly, focusing on depression now. And I’ve also been expanding and again, our episode today is on creatine because it’s a supplement that’s commonly used in exercise.

So my interests are pretty broad looking at these different lifestyle measures, but also looking at the overlap between physical and mental health. And I’ve really been having a good time just exploring that, those different interactions. So yeah, that’s a little bit about me and I’m happy to have a chat today.

Bret: 
Yeah. good. Thank you for that introduction. And just to start, I highly recommend anybody who’s interested to explore your X profile because you’re very prolific doing these long threads, very deep dives, about specific topics, and one of them that you did recently was creatine. So let’s set the stage a little bit.

Creatine, look, I’ve got a teenage boy, so it’s creatine’s all about getting your bulk right. The kids at the gym want to use creatine to bulk up and get stronger. But then all of a sudden now, we’re hearing about creatine and depression. So a lot of people might be like, whoa.

Hang on a second. It’s a supplement that builds your muscles, but now you’re saying it helps with depression? Like how do we connect those dots? So before we get into the research and all that, tell us like just what creatine is and why we’re talking about it. 

Nick: 
Yeah, so as you mentioned, creatine more commonly is regarded as this kind of fitness supplement, so people at varying degrees use it.

So whether you’re a professional athlete, whether you’re a common gym goer, more traditionally it’s viewed as this supplement that can help increase performance. And I think an important distinction to make for the general public that doesn’t completely understand what it is, it’s not an anabolic steroid or anything like that.

I see misconceptions like that online. So I think drawing that thing first is quite important. But essentially how it works and the thought process behind it from a muscular perspective is when you’re going to the gym, when you’re working out, whether it’s weights, whether it’s running, your body uses the energy currency of ATP or adenosine phosphate.

And essentially when you’re working out, you’re depleting those stores over and over. And where creatine comes in is it helps replenish that. So that means you can get more reps in at the gym. Maybe you’re able to run a bit further. What that later translates into is better performance in the current setting, but also better recovery, better muscle gains.

So that’s why you see a lot of the use among people in the fitness community because there’s so many benefits to it. And with a lot of the studies that have been done, there’s not a whole lot of side effects when you look at some of the other scary things that people could be supplementing with compared to creatine.

You see a lot more of those benefits without a scary side effect profile, and I think that’s why it’s been around for so long. It’s such a well-researched compound as well, too. We’ve seen increasing usage and now this interest in the mental health or cognitive sphere of things as well, too. 

Bret: 
Yeah, and one of the things that’s so interesting that you brought up, before we started recording here, is that this is not new.

There’s a new buzz about it on social media. There have been some new studies published about it. But looking into the literature, you can go back 2012, maybe even earlier, that there are studies about creatine benefiting depression and mood. So tell us a little bit about what you know about the historical perspective of using creatine to improve mood.

Nick: 
Yeah, so initially with creatine, again, as I mentioned, and similar to the how exercise was viewed, we knew from a physical side there’s a large body of literature supporting its use. And then over time it became more apparent that perhaps there’s something, it’s having an effect on the mind. In particular with creatine, we noticed that there’s cognitive benefits, so improvements in memory and different aspects from that sort.

So from there and early on in these trials, again, they’re not happening. They are happening now, but they’re also were happening back then, too, where we saw there was an interest from a cognition perspective, but also from a mood perspective, too. So trials were done early on pairing creatine with other first line measures.

So when I say that for depression, we look at things like antidepressants, or SSRI, medications, it found benefits. So not only were there better treatment responses, but there were also improvements earlier on. And that sparked interest because, as we know, antidepressants which are often used first line for depression are not always effective in everyone.

And they also take a long time to have that effect. So there became this interest in seeing what can we do to optimize that. So whether that’s exercise, whether that’s creatine, what different measures we can implement and put these together. So that area has continued to grow to current times where there’s been more trials with antidepressants.

But there’s also been recently a trial looking at the benefits of creatine when paired with cognitive behavioral therapy. And that’s another first line treatment option for depression, where essentially you help rewire your thought process in terms of how you think about different things. Because when you’re experiencing a depression, there’s this kind of overarching negative view on different things, and that can cause you to spiral and have these maladaptive thought patterns and the thought being that creatine might be able to help this.

And mechanistically, there’s not a clear answer in terms of why creatine is going to help that aspect. But the trial that was done found that there was an improved antidepressant response. And perhaps, from what I’m thinking, is we know there’s a cognitive benefit to creatine that may allow someone to engage better in therapy or maybe get more out of that therapy than someone who’s not taking creatine.

The historical perspective and coming to current times has continued to grow, but the trials are all pretty small. They’re not to the same scale that you would see in these large scale antidepressant trials or different things of that sort. And that’s why they’re often underpowered to really detect what we’e hoping to see.

So, hopefully, as the literature continues to grow, we’ll get more support for the creatine side of things and see that flourish because I do think it’s a very promising compound in mental health. 

Bret: 
Yeah, and just to maybe set the stage a little more about the research, there was one big observational paper looking at the NHANES database.

Those who took creatine, those who didn’t, so not interventional, and saw a significant lower risk of depression and mood disorders for those who took creatine. Now as we know, those observational studies don’t really show cause and effect, but they certainly set the stage for their studies, which have gone on.

And so there was one looking at Lexapro with a placebo or Lexapro with creatine. So a randomized controlled trial blinded so that people didn’t know they were taking creatine. And as you said, not only did they see a greater effect, but they saw a quicker, a more rapid effect, and then exactly the same type of results with CBT, with cognitive behavioral therapy.

So this sort of sets the stage though because what we talk about a lot here about metabolic psychiatry at Metabolic Mind is about the energy use in the brain, or maladaptive energy use and energetic dysfunctions in the brain. So one of the potential mechanisms that I’ve seen is that creatine helps with energy utilization, with specifically phosphate energy utilization to create ATP. So when you try and put those together, do you think this is a strong vote for the energy dependency of, or I guess the energy dysfunction in, mental illness and mood disorders?

Nick: 
Yeah, so I think to break up a few of those points. So you brought up a very interesting study, the creatine study, like dietary intake. In that study, essentially what they did was they broke it up into quartiles of dietary intake and then looked at the risk of someone having depression, and as you mentioned, there was this stepwise association between higher creatine levels was essentially protective, again, observational data, but it was protective against having a depression.

What’s interesting with that and where creatine supplementation comes in is when you look at dietary creatine. So you can get creatine from things like red meat and fish, and everything else doesn’t have a whole lot of creatine content in it.

But the big caveat is to get the amount of creatine that you would need to get in a single scoop or five grams of creatine, you would need to eat about three pounds of beef to get what you would get in a little scoop of creatine. So on these dietary levels, we’re looking at small levels of creatine compared to people that are supplementing with it.

So I think that’s a very important point. And then that bridges, so the next thing that you mentioned from like an energy perspective, and we spoke about depression before and the pathophysiology in terms of what really causes it, and I think we spoke about that kind of bio psychosocial lens, but just looking at the biological side and looking at it from an energy perspective, as you mentioned.

Just to reframe the discussion again, ATP is one of the main energy currencies of the cell, and it’s what the brain uses to function as well. So we know that even though the brain is only 2% of your body weight, it’s 20% of the energy demands of the body. So it’s a very metabolically active organ.

However, usually when stuff is working fine, it’s a healthy state, the body is able to use a process called oxidative phosphorylation to regenerate that ATP to make sure that you have those energy stores there. However, in conditions such as depression, we know that there’s metabolic dysfunction occurring, which doesn’t allow that process to happen as smoothly.

And essentially your body’s struggling to replenish that ABT, or ATP, sorry. And where creatine comes in is it’s this alternative pathway where when you’re ingesting creatine, you have what we call phosphocreatine stores in your body. And what that allows it to do is when you need to regenerate that ATP, they can tap into the creatine, take one of the phosphol groups and make another ATP from that.

What that allows is the body to have an alternative mechanism to replenish that. But what comes into play is when your body’s under continual metabolic stress, essentially what happens is even those phosphocreatine stores that you may have available in your brain can be depleted, and now you’re having troubles with your regular oxidative phosphorylation.

You’re also having issues because you’re running out of those phosphocreatine stores, which can lead to downstream consequences metabolically, but also mitochondrial dysfunction, and a lot of different things from that front, which can manifest potentially as a depression. So that’s where the thought process of creatine supplementation may come in to help supplement some of those stores that are being depleted when you’re in this prolonged depressive state.

But also with those metabolic demands that are increasing, yeah. 

Bret: 
Yeah, thank you for that explanation. And I’m glad you clarified that NHANES study was creatine from food rather than supplementation. So it brings up a good question, though. The standard supplement is five grams, like you said, but is there a threshold?

And I guess we don’t have the robust studies and the number of studies to suggest that there’s like a threshold that you have to be above a certain level. But would it make sense if someone didn’t want to supplement, maybe increase creatine containing foods could make a difference?

Or if you really wanted to test it, then you test it with the five grams? Like how would you approach that? 

Nick: 
Yeah, so I think there’s two things to that is most of the literature that we’ve looked at again, and the two studies that we referenced before for the SSRIs and CBT, they both used a dosing protocol of just five grams.

And across the board, that’s most commonly what’s used even for the physical health side of things. But there’s caveats to that because when you’re intaking creatine, so whether it’s dietary creatine, whether it’s supplement creatine, most of that creatine is going to your muscles. So around 95% of it, and there’s a very small minority that’s going to your brain and other organs.

So again, most of it stays in the skeletal muscle, is phosphocreatine, but that doesn’t mean that the small amount that’s going to your brain isn’t important. And when we look at standard dosing protocols from a fitness perspective, there’s two routes that you can take in terms of optimizing your performance.

So some people just start with the five grams per day sort of thing, and over time it takes four weeks or longer to really saturate your creatine stores and see that benefit. However, there’s alternative methods where sometimes people also will, it’s called the loading phase, where you take 20 grams a day for a week, and then you go to the five grams. But the caveat to this is that this is for muscle performance, and we’ve really extrapolated this to brain as well, too. And we’ve only done the lower threshold. So looking at these five grams per day sort of studies, and although these trials go on for eight weeks, we don’t fully understand as well how long it takes to accumulate in the brain and to what level matters and all these different parameters.

A lot of these studies are purely clinical. We don’t have correlates in terms of brain creatine levels and stuff of that sort. So we don’t really know what’s fully going on there. So I think from that perspective, from a supplementation, from a mental health perspective, there’s a lot of missing points in terms of what is optimal.

And it’s really hard to say because right now most of the trials are again, based on those five grams per day sort of thing, which maybe it’s enough and, as we’ve spoke about, there does seem to be a signal starting even at two weeks where we’re seeing increased benefits. Perhaps there could be even more if we were at a higher dosing protocol.

So I think that’s where the nuances come in because I understand from a safety perspective and people don’t want to be doing these cowboy doses of creatine and stuff of that sort. But I do think that there may be more potential because a lot of the research, again, is focused on more of the muscular aspect of creatine, but not necessarily what it’s doing in the brain. Yeah. 

Bret: 
So I wonder just, think speaking hypothetically, is it possible that people are getting the muscular benefits of creatine, so they’re exercising a little bit more, and then seeing the mood changes? I guess if we’re redeem for mechanisms, is that possible?

They’d have to control for that in the studies? I don’t remember if they did or not. They controlled for the amount of exercise. yeah. 

Nick: 
Yeah. No, that’s a great point because I think even outside of the studies in a real world setting, and this is why creatine is so interesting. It’s applicable to both.

And lots of people already use the supplement that are exercising. And if you can have the benefits from both, and surprisingly, this brings up a second point is although creatines have been studied with antidepressants, it’s been studied with cognitive behavioral therapy, it actually hasn’t been studied with exercise, which is where it’s used together the most.

And we spoke about last episode, we know that exercise has similar antidepressant effects to therapy or to medications. So, logically, it makes sense to try this in an exercise trial, too, because the population that’s likely going to use this the most is that fitness population, or they’re already using it.

So figuring out what it’s doing, and like you mentioned, it might not be possible to fully break apart the antidepressant effects from what’s coming from exercise or lifestyle and just creatine. But if we see a benefit or even a synergistic effect, I think that would be very promising. And it would be great to see trials in that area.

Bret: 
It would be. So, Dr. Fabiano, when can we announce to the world that you’re running this trial? 

Nick: 
We’ll make it happen. 

Bret: 
Yeah, and that was a joke by the way. He is not actually doing it, but hopefully someday, just to make sure nobody thinks, yeah.

Before we continue, I want to take a brief moment to let our practitioners know about a couple of fantastic free CME courses developed in partnership with Baszucki Group by Dr.

Georgia Ede and Dr. Chris Palmer. Both of these free CME sessions provide excellent insight on incorporating metabolic therapies for mental illness into your practice. They’re approved for a MA category one credits, CNE nursing credit hours, and continuing education credits for psychologists, and they’re completely free of charge on mycme.com.

There’s a link in the description. I highly recommend you check them both out. Now, back to the video.

So let me ask you, just a simple question, if someone has a mood disorder, if someone’s diagnosed with depression and symptoms of depression, why wouldn’t they take creatine? Should everybody be doing it?

Nick: 
Yeah, that’s a great question. And I think with any recommendation, I’m always hesitant to say that everyone should take something, but with creatine, the safety profile is very beneficial. And like I said, when you’re looking at a medication, you want to look at the risk-benefit ratio. We know with creatine there’s very low risk with stuff, so I would never across the board recommend creatine to everyone, per se.

But in speaking with individual patients and seeing what their ailments are from the depression, I think it would be beneficial to have a discussion around that because we’ve spoken about the benefits from a physical health perspective, so that may allow someone to get into exercise more and, perhaps that can have the antidepressant effects.

There are also cognitive benefits and we know in someone that’s experiencing a depression, that could be something that’s severely impaired. So perhaps there could be room for that. And then the other aspect of that we didn’t really speak too much about yet is from a sleep deprivation perspective, that’s another type of increased metabolic demand.

And there’s research that’s been done from that perspective, too, that’s shown benefit. There was a study that came out where they essentially had a group of people that were sleep deprived for 21 hours, your average resident, and they gave them a very large dose of creatine, just one dose though. So it was 0.35 grams per kilogram.

So for an a hundred kilogram person, that would be 35 grams in one go. So it’s a very big dose, but they saw reversal of metabolic alterations and also they saw benefits to someone’s cognition with that one dose when a sleep in a sleep deprived state. So, to me, that is very interesting and it makes me wonder what these higher doses can do.

But again, balancing that as well with the safety profile and different aspects there. There’s a lot of missing pieces, but I guess I did a very tangential answer for this, but to the patient in front of me, I would speak to them about what they’re hoping to get from it. Educate them around the benefits of creatine.

Really have that discussion because I do think there’s a lot of utility across patient populations. Particularly in no experiencing depression. 

Bret: 
Yeah. Yeah. And when it comes to supplements, there’s a little concern because it’s a bit of the wild west, right? There’s not a whole lot of regulation.

And I know, I’ll just use one example, like when it comes to fish oil supplementation, I think it’s really important to have a reputable brand because there can be a lot of contaminants and oxidation and stuff you don’t want to get from your supplement from your fish oil supplements. That’s not true for all supplements.

Some supplements are very straightforward and hard to mess up. So when it comes to creatine, do you have concerns about the quality of the supplements out there, or people should be looking for a specific brand or anything? 

Nick: 
Yeah, I would say, as you mentioned, for any supplement, you really want to do your research and just see what’s there because the general rule for creatine, for fish oil or anything, you want to make sure that you’re getting the pure supplement itself and not all of these extra sort of things.

So sometimes there’d be, can be contaminants with metals or different things from that sort. So I wouldn’t necessarily recommend a specific brand or anything, but I would say speaking to your doctor and also doing the research for yourself, too, just to getting a background check in terms of what supplement you’re putting into your body because you’re right that they’re not the same across the board.

And it’s important to just be aware of those things because you can start something, not be sure of it, and then later down the road say, oh, I’ve been taking the supplement that have this contaminant or something. So I would say just really doing that research before speaking to your doctor as well, too, because even recommending a specific brand or something, things change, manufacturers change.

It’s always best to check as you’re ongoing, just to make sure you’re getting that pure supplement itself. 

Bret: 
Yeah. Now, one other interesting parallel, again, hypothesis since we don’t have the studies, is the use of the carnivore diet. So we’ve heard a number of people, anecdotal reports and some clinical experience say, look a keto diet or being in ketosis and metabolic therapy helped. But it wasn’t until I went full carnivore that my mood completely lifted and completely changed. And from a mechanistic standpoint, I wonder if creatine has something to do with it, because then maybe they are getting that, or near that amount of, meat to give you that level of creating exposure.

And look, there still needs to be a lot of research done to learn more about the carnivore diet, but we’re certainly seeing some impressive anecdotal reports, so I just throw that out there. I wonder if creatine has some role there. 

Nick: 
No, I agree because I think that is an extreme example of where I gave the example of, to get one scoop, you need three pounds of raw meat sometimes, and if you’re solely in taking, your diet is just carnivore based, then that might be something where you’re reaching that threshold and indirectly you’re having a similar amount to that artificial supplementation. So it’s interesting to see those reports, and I think it would be interesting to, as you mentioned, to have more research to delineate that too. 

Bret: 
Yeah. It would be really interesting to see creatine supplementation in a meat eater versus a vegetarian or someone who follows a vegan diet and see the impact it has.

Because you would imagine those people would be more deficient or have a lower level of creatine, it might benefit more from supplementation or require a higher level or something. So we’re coming up with a lot of experiments for you to do in the near future. Yeah, building up the work.

Very good, thank you. This has been a very interesting discussion about creatine, about the research behind it, about what it is and about its potential uses. So what do you think the future will hold? Do you think it’ll become like more of a mainstream treatment? 

Nick: 
Yeah, I think over time it will be something that’s picked up more and more.

We do need the research to back it. We’re actually working right now on a meta-analysis, so putting the studies together that exists to see what that effect size is. So I think it will be something that’s more commonly used again as the evidence builds up. Because again, emphasizing that risk-benefit ratio, it’s really in favor of that.

But we just need to have more research to really see what’s the best dose, what’s the best timing, even the form of creatine and all of these different things. But I do think, and I’m hopeful, that this is something that can either be an adjunctive treatment to antidepressants. It can be an adjunctive treatment to therapy.

And I’m hopeful that we can also have trials for exercise as well, too, because as I mentioned, to me, that makes the most sense. The people that are already using it, we want to know what effect it’s having. So yeah, that’s what I think the area will look like in the future. 

Bret: 
Great, I already mentioned your profile on X, which I highly recommend people check out and follow.

Is there anywhere else people can go to learn more about you in the work you’re doing? 

Nick: 
Yeah, I would say I’m mostly active on X, so that’s NTFabiano, but I also, I’ve made a YouTube channel and I have an Instagram, so YouTube is the same handle, NTFabiano, and then the Instagram is just ntfabiano.

But I’m not really too active on those yet. Just busy with other things, but maybe in the future I’ll start up with those too. 

Bret: 
Great. Great. thank you again for joining me. I really appreciate it. 

Nick: 
Yeah, thank you for having me. 

Bret: 
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