144: Why Creatine Is One of the Most Important Brain Nutrients

Creatine isn't just for building muscle. It's actually fuel for your brain. Your brain uses about 20% of your body's energy, but it can only store a few seconds of it at a time. So it relies on something called phosphocreatine, basically a backup battery that helps regenerate energy instantly. And when that battery runs low, you feel it. Brain fog, poor focus, low mood. Here's what's fascinating. Studies show creatine can actually increase brain energy and improve improves things like memory, attention, and even mood, especially in people who are under stress. Now, who benefits the most? People with lower creatine levels, of course, like vegans, older adults, and even women. In fact, just one night of bad sleep can drain your brain's energy reserves, and creatine helps restore it. So this isn't just a gym supplement. It's one of the most overlooked tools for brain performance. This is Lecture 144 of The Metabolic Classroom. Welcome to The Metabolic Classroom. I'm Ben Bikman, a metabolic scientist and professor of cell biology. Today's mini lecture aims to teach you about creatine, not just as a muscle supplement, though we'll touch on that a little bit, but specifically what creatine does inside your brain. We're going to get into the physiology, the human clinical evidence, and by the end, I think you'll have a completely different and new appreciation for this molecule. Now, let's just start with the basics. Most people know creatine is something that athletes take to build muscle or to perform better. That reputation is certainly well-earned. It is probably the most extensively studied ergogenic aid or performance helping supplement in the world. But creatine actually isn't a synthetic compound invented in a lab. It is, in fact, something that we make. It's a molecule that our bodies create and in fact depend on, especially tissues that have high metabolic rates like the brain. Now, I mentioned that the body makes it. Yes, uh, this is primarily made in the liver and in the kidneys. And once these tissues make it, the creatine will be transported out of those sources of origin and then travel through the bloodstream and then taken up by tissues with high energy demands. And at the top of that list, of course, is skeletal muscle, who can experience— a tissue that can experience a tremendous increase in energetic demand based on what we're doing, but also the brain. From a dietary perspective, creatine is consumed. It is something we can eat, and it is found almost exclusively in animal products like meat and fish. They're the primary sources. A pound of raw beef, for example, will contain about 1 to 2 grams of creatine. Now, this is important. I highlight this because people who avoid animal products have essentially no creatine intake in their diet. And I'm going to come back to why that's important and we'll highlight some of the studies that shows how this matters for the brain in particular. Now, before we get into those clinical studies, I want you to just further appreciate the mechanism here, some of the biochemistry. Your brain is extraordinarily energy hungry. It only weighs about 2% of your body mass, but it consumes about 20% of your calories with resting. So your resting energy expenditure when you're just sitting around not exercising, because of course in that case your muscles start consuming a lot more, but at rest, about 20% of your energy demands are, are coming from what the brain is demanding. Those neurons up there are firing constantly. They are maintaining electrochemical gradients, you know, shifting the electrolytes around there. The brain is making neurotransmitters and supporting all of this transmission of signals. All of that busy work requires energy in the form of ATP. Now, you've heard ATP before. It's the chemical energy, if you will. But here's the problem. ATP cannot be stored in large quantities. A cell will only usually have just a few seconds worth of ATP ready to go at any moment. So the cells need a rapid backup system, a way to regenerate ATP almost instantaneously when the demand is really, really high. That's exactly what the creatine phosphocreatine system provides. Creatine is activated or phosphorylated by the enzyme creatine kinase. Creatine kinase will take the creatine and add a phosphate, a phosphate group onto it, and that gives us phosphocreatine. And that's a molecule that acts as a temporary kind of reservoir or recharging point. When ATP gets split apart and used for all of these reactions I mentioned earlier, whether it's a muscle contracting or a brain firing neurons, then the byproduct of ADP starts to accumulate. So ATP, the triphosphate, it loses a phosphate and we're left with a diphosphate, ADP. Now, that's not a molecule that can make the cell work. That's not the molecule of energy that we need. And so creatine kinase will rapidly transfer the phosphate group from phosphocreatine back onto the ADP, turning it back into ATP so it can regenerate ATP. I'll say that more clearly. Phosphocreatine can regenerate ATP in just milliseconds. That's important because it's faster than any other source of ATP or energy. It's faster than glycolysis. It's much faster than oxidative phosphorylation, like fat burning or glucose burning in the, in the mitochondria. The phosphocreatine system is the cell's rapid emergency power supply. In the brain, the system is positioned both in the cytoplasm, so the area of the cell outside of the mitochondria, but also at the mitochondrial membrane as well. Creatine kinase is also present in what's called synaptic vesicles, which means that creatine may play a role in the release of neurotransmitters. So if you think of your brain producing dopamine and releasing dopamine, that would be a neurotransmitter that's produced in a vesicle. And once again, creatine is helpful there. And there's even emerging evidence that it can act as a neuromodulator. So it can influence neuronal signaling directly, not just some passive energy buffer. So creatine clearly plays an important role in the brain. Now, if your brain's emergency battery, this phosphocreatine, starts to run low, well, what happens to your ability to think, to remember, to regulate your mood? That's what the clinical evidence addresses. So let's get into that part. Now, before looking at cognitive outcomes, I just think there is a question that's fair. If does, does the creatine that you take in a supplement form or any form you eat, does it actually make it to your brain? The answer is yes, absolutely. But there are some caveats. Creatine crosses that blood-brain barrier through a specific creatine transporter. So there are absolutely designed doorways for creatine to pass through to get in, into the brain from the blood. but the brain uptake is relatively slow and it's somewhat limited, especially compared to muscle. Muscle takes up blood creatine very, very readily. Now, having said all of this, studies that use, uh, methods to track the movement of, of phosphorus in particular, uh, I'm gonna just refer to this as like phosphorus tracking or, um, creatine tracking because I don't want to get into the nuanced technicality of the devices. But suffice to say, Suffice it to say, we have technologies and methods to track the movement of some injected forms or consumed forms of creatine. And in— by using these methods, we've been able to directly measure brain creatine before and after a supplementation, which is important. So we have absolute confirmed evidence that this happens when healthy adults One particular study found that with these adults, they supplemented with 20 grams of creatine per day for 4 weeks. The total amount of creatine in the brain went up by about 9%. Now, that's not huge, but that's absolutely statistically significant and I'd say quite meaningful in light of the clinical evidence to come. It's clearly having an effect and extended. So you go a little longer, even higher doses. It appears to bump that up even a little more, particularly in different regions of the brain, like the front frontal lobes. Critically, the brain's creatine uptake after supplementation appears to be inversely related to baseline levels. In other words, the lower your brain creatine to begin with, the more you stand to gain from supplementation. Now let's get into the clinical data where the rubber meets the road. You can understand how it could happen. Now let's just show that it does in fact happen and there are real outcomes. The most consistent finding across the literature is that creatine benefits cognition most reliably in people whose brains are either deficient in creatine or under some general stress. Now, stress is a big word, so I'll define that a little bit in this context. And let's walk through some of those key populations. The first one are those who may not be eating, uh, creatine in their diet, so vegetarians and vegans. One of the foundational studies, uh, that came to mind as I prepared these thoughts, it was one that ran a double-blind placebo-controlled crossover trial. So that's— that is, man, the gold— most golden of the gold standards here, where you had the same subjects crossing over from placebo into, into the treatment or crossing over from treatment into placebo. And they looked at this in 45 young, young adults that were vegetarians. They took 5 grams of creatine per day for 6 weeks. That's a pretty modest amount. 5 grams is not a lot. Researchers found in this study a significant improvement in both working memory and what they defined as fluid intelligence. So they were thinking better and smarter. Since vegetarians and vegans consume essentially no dietary creatine— in fact, none, if I'm being frank here— their brain creatine is running entirely on endogenous synthesis. So only what they can make. And so it's right at the lower edge of normal. That's the ideal context for supplementation to make a difference because they're coming in with such a low level and the supplementation can bump it up. So pretty meaningful findings. Again, improvements in intelligence and memory. A follow-up study reinforced this where they had 128 young women, half of whom were vegetarian, half of whom were omnivorous, and they gave them 20 grams per day but for a much shorter time, just 5 days, the vegetarian group showed significantly better memory performance with creatine, whereas the omnivore group had just modest changes. Again, that is consistent with the baseline matters most principle. Now, it's not just those who may be restricting creatine in their diet, but also in older adults. In elderly individuals with a mean age of 76, 1 week of creatine supplementation at, again, that good solid high dose of 20 grams per day produced significant improvements across nearly all cognitive tasks that were tested, including memory. They looked at— they had to recall forward and backward number testing. They had something called spatial recall and even long-term memory. In the most comprehensive systematic review of this population to date, found that 5 of 6 studies reported a positive relationship between creatine and cognition in older adults, with the strongest effects in memory and attention. Now, as a personal aside, that is something that interests me incredibly. The older I get, the more I appreciate my cognitive capacity and my ability to think quickly and speak articulately. So personally speaking, these data here I find very, very compelling. Now we're not done because the population differences continue in those who benefit and those who don't benefit as much, because there is also some interesting evidence on sex differences. A meta-analysis of randomized controlled trials found a significant positive effect of creatine on memory overall, and a subgroup analysis from a separate large meta-analysis found that cognitive benefits were significantly more pronounced in women compared to men. Now, why might this be? Why might ladies benefit so much more from creatine use in the brain than men? There are several mechanisms that have been proposed, and I think they're noteworthy and interesting, so I'm going to share them. Women have naturally lower baseline muscle creatine stores than men, which may mean dietary creatine is less efficiently shuttled to peripheral tissues. Or they're not eating as much. But what you see in the brain— in the muscle could reflect what we see in the brain. We're not able to take brain biopsies to look at the amount of creatine a person has in their brain. But given the lower levels in the muscle in females, it's reasonable to assume that there are lower levels in the brain in women as well. So the female brain may be a little naturally more creatine depleted. There are also sex-based differences in creatine transporter expression and in the hormonal regulation of creatine metabolism. For instance, estrogen may influence creatine kinase activity. This is still being confirmed and worked out mechanistically, so it's a little bit in the realm of speculation, but with some data. But the clinical signal is very real. Women, particularly, um, women who are older or may be adhering to a creatine-poor diet, may be the population with the most to gain from creatine supplementation for brain function. This also has direct implications for the depression data, which I'll come to shortly, since the most robust antidepressant trials with creatine have been conducted specifically in women. Now, part of underlying some of this may be this principle or an idea of the stressed brain, because across all of these populations, vegetarians and vegans or older adults or women, there is a unifying thread, which is that supplementation works best when the brain's creatine system or amount is under some kind of strain. And speaking of straining and stress, let's explore the role of creatine in sleep deprivation. But also there are some studies and data on depression that I wanted to share with you because I found that was so compelling. Now, once again, as a personal aside, you may already be familiar enough with my own personal struggles for sleep and one more reason why I am such an advocate, at least in my own supplement use of creatine. We know from some of these phosphorus tracking studies that I mentioned earlier that creatine movement is compromised with sleep deprivation, that there are measurable reductions in brain phosphocreatine with sleep deprivation. In fact, just losing a night of sleep can significantly reduce your brain's phosphocreatine reserves. This is part of why cognitive impairment from sleep loss is so profound. It's not only because of the adenosine accumulation. That's a different aspect of sleep where adenosine accumulates in your brain and starts to make you feel tired. But it's also, I think, touching on this aspect of an energy crisis that's just playing out in the neural tissue of the brain. The first landmark randomized trial took about 20 healthy young adults and loaded them with 20 grams per day of creatine monohydrate for 7 days. Or they had a placebo. They then subjected them to 24 hours of sleep deprivation with mild intermittent exercise. So just kind of reflecting real life activities. Cognitive tests were run at baseline and at 6, 12, and 24 hours of that sleep deprivation. Creatine produced significant protective effects on executive function and spatial recall compared to the placebo. A follow-up study extended the observation across 18, 24, and 36 hours of sleep deprivation. This time once again using a moderate-intensity exercise. At 36 hours, the most extreme condition, the creatine group significantly outperformed placebo on the central executive task. So just some of these markers of cognitive function. The effect grew with the degree of deprivation, exactly what the depleted brain model would predict. So the more they were deprived of sleep, the more the brain benefited from creatine. The most extraordinary study in this area was a 2024 trial that explored whether a single high dose of creatine provides cognitive protection during sleep deprivation. Researchers administered a single oral dose, and the dosing was based on body mass, so it was 0.35 grams per kilogram of body weight. So that ends up being around 25 or so grams for the average 70-kilogram person. Then they tracked the participants through 21 hours of partial sleep deprivation, measuring the brain chemistry directly with creatine and then tracking alongside some cognitive testing. The results were fantastic and remarkable. Creatine helped sustain normal phosphocreatine and ATP levels in the brain even as participants became severely sleep deprived. And this translated directly into better working memory processing speed performance as well compared to the placebo group. The effects became detectable at about 3.5 hours after administration and lasted up to about 9 hours after the dose was consumed. In that particular study, I found it interesting that the investigators proposed that under conditions of high neural energy demand, like what sleep deprivation creates, the creatine transporter temporarily accepts more exogenous creatine than it would under normal unstressed conditions. The energy crisis, if you will, kind of opens the doors more readily to allow the creatine to come in. It's a pretty brilliant adaptation. And it does suggest that the— that creatine's brain uptake isn't some sort of fixed amount. It's not some fixed rate, but is partly demand-driven. That is a bit of a paradigm shift and a beneficial one when you think of the real practical implications. But think about who this matters for the most. Think of shift workers, medical residents, military personnel, or parents of newborns. I'm far beyond the age of newborns, much to my sadness, as I miss the babies in my home, but I still sleep as if we had newborns. The effects are most pronounced on the prefrontal dependent functions, so working memory and executive control, which are precisely the cognitive capacities that collapse first under sleep deprivation. Now, I mentioned depression. Let's get into that. The brains of people with major depressive disorder show measurable abnormalities in energy metabolism. Specifically, they show reduced phosphocreatine levels in the prefrontal cortex. Depression, at least in part, may be a disease of some neuroenergetic insufficiency. And if that's true, then creatine, the model that can restore the phosphocreatine amount, or capacity becomes a very rational therapeutic approach. And then in addition to this, of course, I just want to remind you of the separate lines of evidence that support the overall neuroenergetic view, but finding similar effects with regards to brain glucose metabolism, where in people with depression there is a demonstrable reduction in their brain's ability to pull in glucose and metabolize it. The pivotal trial that was published in this space enrolled women with major depressive disorder who were already taking an SSRI. That's a commonly used antidepressant medication, of course, with some significant side effects. Half received 5 grams per day of creatine added to their antidepressant. The other half received the SSRI plus placebo over 8 weeks. The creatine group showed significantly faster and greater antidepressant response, with statistically significant improvements appearing as early as just a couple of weeks compared to about 4 or more weeks in the placebo group. So it was twice as fast, or you could say twice as effective. Critically, the— that same trial, it was conducted, as I said, entirely in women. And that's not the only one. A separate study tested adjunctive creatine, so just adding creatine to an existing treatment. And this was in young female adolescents, so in teenagers who were not responding well to SSRI. That is what they called SSRI-resistant depression. So that's normally one of the hardest populations to treat. But not only did the depression scores fall significantly, but great brain scans confirmed objective increases in prefrontal phosphocreatine levels, providing a direct mechanistic window into how the treatment was working. And it was working. In a proof-of-concept randomized controlled trial in bipolar depression, totally separate study, these individuals received 6 grams per day of creatine or placebo for 6 weeks alongside their existing medication regimen. Remission rates were telling. About 53% in the creatine group versus only 11% in the placebo. So this is, you know, about a 5 times greater effect in the group getting the creatine. Now, I should note that in the study, did 2 patients in the creatine arm, um, converted to hypomania. So there's an important caution flag. So that's just some nuance within the study, but for the majority the effect was enormous. And a more recent pilot trial added creatine to cognitive behavior therapy for depression and again found it safe and potentially very effective as an adjunctive approach. So just more evidence of people using creatine to complement existing approaches. And then very recently, a 2025 systematic review which looked at all of the available randomized evidence, it concluded that creatine supplementation significantly reduces depressive symptoms, with the strongest effects when combined with established treatments. Now, why throughout all of this metabolic classroom have I mentioned women specifically? There are several overlapping factors that are likely at play. Women have lower baseline creatine stores, and estrogen appears to influence creatine kinase activity and creatine metabolism. And there is evidence that creatine synthesis rates differ between sexes, with women potentially more dependent on dietary or supplemental creatine to maintain adequate brain levels. This doesn't mean men don't benefit, but it strongly suggests women are a priority population for this application. So men certainly can benefit. Women, I think it's safe to say, certainly benefit more. Now, I'm not suggesting any of this as a recommendation to replace any professional care. Of course, I'm not your clinician. I'm just your friendly neighborhood scientist. But with the data in mind, for anyone who is already going through conventional therapies and is exploring a way to help, this might be a way to do it. Now, another frontier worth discussing before we finish is traumatic brain injury. The mechanistic connection here is especially tight. A concussion or a TBI triggers an immediate neurometabolic crisis. Energy demand spikes at the moment of injury while blood flow and mitochondrial function are simultaneously impaired. Now, I have previously highlighted that glucose metabolism is particularly impaired here, and I'd mentioned again previously that ketones represent a therapeutic approach as well. But in the midst of all of this energy depletion, you want to use any advantage you can, and phosphocreatine is one of those. The energy crisis that follows the TBI is kind of really understood to be a central driver of a lot of the post-concussion symptoms— the cognitive compromised effects, the headaches, the fatigue, and the emotional instability. Importantly, two prospective randomized studies in children and adolescents with TBI provide some compelling human clinical evidence. In both of them, Creatine was supplemented at almost half a gram per kilogram per day for 6 months. The first study found significant improvements in duration of post-traumatic amnesia and the length of ICU stay and other clinical parameters. The follow-up study found significant reductions in 3 of the most disabling post-concussion symptoms: headache, dizziness, and fatigue. This has led to concussion and a discussion rather in Concussions of a preemptive creatine supplementation in populations who are at risk, like athletes in contact sports or military personnel. And the rationale there is that if you can have a, a fully topped up phosphocreatine reserve at the moment of impact, that could attenuate the neurometabolic crisis that would follow it. And there are some human trials underway that are testing the use of creatine as a prophylactic strategy. Now, I want to briefly touch on one other aspect of this that can illuminate the efficacy of creatine here. And there is— there are a group of people who suffer from an unfortunate genetic disorder called creatine deficiency syndromes. These are what's called inborn errors of metabolism, where either creatine synthesis or transport to the brain is impaired. and children who have this syndrome will present with severe intellectual disability, a lot of language delay, seizures, behavioral disorders, and some autistic features. When the brain is deprived of creatine from birth, there are some real neurodevelopmental consequences and they're devastating. And now, importantly, for the syndromes affecting synthesis of creatine rather than transport, creatine supplementation can partially reverse these symptoms. So there's an improvement in seizures, cognitive function, and behavior. So it's definitely worth knowing depending on the family and the child. Now let's wrap all of these thoughts up into some practical takeaways. So who benefits the most? Everyone benefits really, especially anyone who experiences any sort of metabolic stress, even something as seemingly benign as sleep deprivation. Of course, vegans benefit tremendously because they're not eating any creatine. Women, um, across cognition, memory, and depression trials, women consistently show stronger positive responses, maybe due to a lower baseline level or an estrogen-dependent change in creatine kinase activity. And then of course, older adults do as well. The evidence favors heavily improved memory and attention. And then people with depression, once again, particularly women who may be on other therapies, also, also show some benefits. And then lastly, the athletes or anyone who may be likely to experience a concussion. Now, what about the dose? You would have heard a pretty consistent number here when it comes to the brain. It appears to be something around 15 to 20 grams, of course, depending on body mass. Now, what about the form? There are a lot of forms. Thankfully, the cheapest appears to be the best. It's certainly the most studied, and that is creatine monohydrate. Every human clinical trial that I referenced in this mini lecture used creatine monohydrate. That's not to say some of the other forms like HCL or ethyl ester can work as well, but they're all more expensive and they have not been as tested. So why bother? Now, what about safety? The safety profile is excellent. There are decades of research that have found no evidence of kidney harm or liver harm in people. And so I don't think there's any reason to worry about it. The main side effect, you can almost know if your dose is getting too high because your guts will tell you. So you're going to maybe have some kind of diarrhea or GI distress. All right, so to wrap this all up, I hope I have shown you that creatine is an essential player in brain energy homeostasis. The phosphocreatine system is the brain's emergency power reserve. When that reserve gets depleted, maybe through something as seemingly benign as sleep loss, or less benign like aging or injury or disease, um, then the cognitive performance will suffer and mood can destabilize. The human clinical evidence is very compelling and coherent and clear that creatine supplementation is most beneficial for the brain when the brain's creatine system is under some kind of strain in the populations that I've noted previously. Now, one final thought. We spend enormous research effort and healthcare resources on, on pharmaceutical compounds for cognitive support and mood disorders, but we really overlook just a modest molecule that the body can make itself that is present in the food we evolved eating, that is meat, and that has now been shown in multiple randomized controlled trials to support brain functions. And that is just creatine. This all strikes me as something very worth knowing. That brings me to the end of today's metabolic classroom. Thanks for joining me, and I will see you next time. Until then, remember, More knowledge, better health.