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Welcome to the Metabolic Classroom Podcast. I'm Ben Bickman. Thanks for letting me be your guest professor for the next few minutes. Don't worry about any pop quizzes. I'm here to simply make the science of metabolism clear, practical and engaging. Welcome to the Metabolic Classroom, Ben I'm Ben Bickman, 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 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, 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, 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. They're the brain is 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 phosphor creatine 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. 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 the 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 methods to track the movement of phosphorus, in particular, I'm going to just refer to this as like phosphorus tracking or 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 four 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 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 creatine in their diet. So vegetarians and vegans. One of the foundational studies 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, the gold, most golden of the gold standards here, where you had the same subjects crossing over from placebo into. Into the treatment or, or crossing over from treatment into placebo. And they looked at this in 45 young, young adults that were vegetarians. They took five grams of creatine per day for six weeks. That's a pretty modest amount. Five 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 five 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, one 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. And the most comprehensive systematic review of this population to date found that five of six 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 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 in 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 seven 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 creating 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 three and a half hours after administration and lasted up to about nine 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 a 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.