Creatine Supplementation And Brain Health

There is a robust and compelling body of evidence supporting the ergogenic and therapeutic role of creatine supplementation in muscle. Creatine Supplementation And Brain Health

Beyond these well-described effects and mechanisms, there is literature to suggest that creatine may also be beneficial to brain health (e.g., cognitive processing, brain function, and recovery from trauma).

This is a growing field of research, and the purpose of this short review is to provide an update on the effects of creatine supplementation on brain health in humans.

There is a potential for creatine supplementation to improve cognitive processing, especially in conditions characterized by brain creatine deficits, which could be induced by acute stressors (e.g., exercise, sleep deprivation) or chronic, pathologic conditions (e.g., creatine synthesis enzyme deficiencies, mild traumatic brain injury, aging, Alzheimer’s disease, depression).

Despite this, the optimal creatine protocol able to increase brain creatine levels is still to be determined. Similarly, supplementation studies concomitantly assessing brain creatine and cognitive function are needed. Collectively, data available are promising and future research in the area is warranted.

Can Supplementing With Creatine Support Your Brain?

Creatine is perhaps the most well-known and well-researched nutritional supplement in the sports performance world. Creatine is beloved by gym rats for its safety and efficacy in supporting the body’s energy needs during exercise and its role in promoting muscle health.*

However, as we further understand brain function and cognitive performance, research is looking at creatine as a possible way to support the brain in some of the same ways creatine has proven to sustain the body during training and injury.

Creatine 101

Common Uses

Creatine is most commonly used as an athletic performance enhancer. It appears creatine has the ability to increase strength and improve lean body mass during high-intensity, short-duration workouts such as weightlifting or sprinting. Creatine may also be effective in treating heart disease. According to the University of Maryland Medical Center, creatine improves low levels of energy, can help lower triglycerides and can lower levels of homocysteine, which is a precursor to having a heart attack or stroke. In addition, creatine has been used to treat depression, bipolar disorder, Parkinson’s disease, Lou Gehrig’s disease, arthritis, an eye disease known as gyrate atrophy, McArdle’s disease and muscular dystrophy.

Creatine is an amino acid that is necessary for creating ATP, the body’s on demand source of energy. Although some creatine is generated in our liver and kidneys, we don’t make enough to fill our tanks.

Creatine is found naturally only in animal products, and it’s susceptible to degradation during cooking processes. Although numbers vary due to the quality of food source, genetics, and demands on the body, it is estimated that the majority of us get a little more than two-thirds of what we need from what we produce and what we eat. And following a plant-based or vegan diet, above-average exercising, highly stimulating activities, and injury, all increase our need for creatine.

Unlike creatine in foods, creatine monohydrate in supplement form is not damaged by cooking and has been shown in hundreds of studies to improve creatine stores in the body. About 95% of creatine is stored in muscle, with the remaining 5% being found in high energy organs like the brain.¹

Creatine supports energy function in two ways. First, to create energy we break down a three-phosphate compound (ATP) to a two-phosphate compound (ADP). To then restart the energy cycle, we must find an extra phosphate to recycle ADP into ATP; this is where creatine comes in.

As creatine intake increases, we stockpile phosphocreatine, a combination of creatine and phosphate, in our muscles and brains. In our energy system, phosphocreatine donates its phosphate to ADP and the process starts over again. A second, more indirect pathway runs through the mitochondria, the powerhouse of our cells.

Phosphocreatine plays a significant role in the process that delivers energy from the mitochondria to other parts of the cell that need energy. The more efficient this pathway is, the less stress is put on the mitochondria.

Creatine And The Brain

After our muscles, the brain is among the highest consumers of energy in the body; and while muscles can rest, the brain runs 24/7. Although the brain takes up only 2% of our body weight, it uses 20% of our calorie intake. When we ask our brain to think and process more, or function under suboptimal conditions, we can see the same performance and recovery issues as muscles when proper nutrients aren’t provided.

In areas where the brain’s performance involves a heavy cognitive load, such as driving a racecar or competing in esports, or in situations where lack of sleep or oxygen occurs, planning to support the brain plays a crucial role in maintaining its optimal function.

Adequate creatine stores in the brain allow for optimal energy production to support brain health and cognitive performance, similar to creatine’s long-studied positive impact on muscle energy and physical performance.* As we age, creatine stores tend to decrease in our muscles and our brains, likely due to disease or decreased physical activity.

Just like we see the benefits of creatine supplementation in skeletal muscle, we are starting to see the potential for similar impacts on the brain.* When brain creatine levels in healthy elderly participants were compared to a younger cohort, they were similar, which has led to new areas of research to better understand what this correlation means.

Creatine And Dehydration

A well-known effect of creatine supplementation is muscle hydration, which involves the retention of body water in your skeletal muscles along with creatine. Muscle hydration may leave less water available for the rest of your body’s cells to function optimally, causing a state of dehydration. Dehydration, or a lack of water, can affect your brain by reducing blood flow and oxygen delivery to brain cells. This may cause you to feel faint or lightheaded and can increase your risk of developing acute anxiety, nervousness and confusion.

Emerging Research

Although the link between creatine and physical performance has been studied for decades, creatine’s link to the brain is only an emerging area of investigation. Studies show that supplemental creatine monohydrate over 2-4 weeks increases the concentration of creatine in the brain by 5-15%.^3,4

The brain is more selective about what chemicals and nutrients it allows in than are the muscles, so we can’t assume that existing creatine loading protocols can be applied to supporting cognitive performance. The emerging theory is that larger doses will be needed over a longer term to promote optimal creatine levels in the brain.⁵

Although studying creatine’s impact on the brain is more complex than muscle-based studies, one group has made it easier to tease out significant benefits – vegans/vegetarians. As noted earlier, creatine isn’t present in diets that eliminate animal products, leading this group to have a smaller creatine pool than the average population.

Healthy vegan and vegetarian participants that supplemented with creatine performed better than placebo groups on a series of cognitive challenges, including word recall, repeating numbers backward, pattern recognition, and reaction time.*^6-8

Although research has shown that cognitive training by itself can lead to higher brain creatine levels absent supplementation,⁹ creatine supplementation has shown positive benefits as well.* For example, creatine can decrease the impact of fatigue when performing complex tasks after sleep deprivation.* It has also been shown to improve throwing accuracy in rugby athletes.*^10-12

When participants were deprived of oxygen to the brain, mimicking emergency conditions, individuals who had supplemented with creatine for one week restored cognitive performance more readily than the placebo group,* indicating that creatine plays an important role in providing energy to brain cells when usual energy sources are jeopardized.¹³

When examining the impact of creatine supplementation on brain fog, students who supplemented with creatine for five days prior to a math test were found to have more oxygen in brain cells.* This is likely due to an increase in oxygen uptake from the blood and mitochondria efficiency resulting in a decreased need for oxygen.¹⁴

Changes in the brain after injury include membrane disruption, mitochondrial damage, and increased oxidative stress – all things creatine is known to support elsewhere in the body.*

While it is too early in the research to make any definitive connection between creatine supplementation and brain function, further investigating the potential remains a priority in the research community.

Creatine supplementation probably would provide the most benefit for individuals with suboptimal levels.¹⁵ Further research is needed to solidify dosing strategies and to control for variables, including age, diet, activity, and genetic makeup. It will likely continue to be an area of intense interest across the medical, cognitive, and sports performance communities.

Creatine From Meat Seems To Help Us Think

Are you a vegetarian or a vegan? Besides vitamin B12, depending upon what you eat and the supplements you take, you can find your diet somewhat low in zinc, long chain omega 3 fatty acids, and even some amino acids. One of these amino acids is called creatine, and the best source is meat.

Researchers who study cognition and athletic performance simply love giving vegetarians creatine supplements (1)(2)(3). This practice might seem curious until you look at the following facts:

1) Creatine is an amino acid found only in animal flesh but most abundantly in skeletal muscle flesh (like steak). It is not an essential amino acid, as we can synthesize is from other amino acids found also in plant foods, but as with changing the plant-based omega 3 fatty acid ALA to the marine animal based omega 3 acid DHA, the synthesis is inefficient. It is known that vegetarians have lower tissue (measured directly via muscle biopsy) amounts of creatine than omnivores (4).

2) Why should we care if we have creatine? Well, if you recall, our cells run on energy supplied by a molecule called ATP. Think of ATP as the gasoline of the body. Whether we fuel up with glucose or ketones, eventually those raw materials get transformed into ATP, which as it is broken down powers all sorts of energy-requiring processes. We will obviously burn through ATP faster in our muscles when we are running or jumping or performing various feats of strength, but we also burn through ATP faster when we are using our noggins for something a bit complicated. Our little brain (the size of your two fists held together) burns through 20 percent of the energy we use each day, primarily to keep those ion gradients fueled that allow our neurons to charge up and then be discharged to communicate information.

3) Creatine can bind to phosphate (P) to make phosphocreatine, and this acts as a “buffer” to make ATP lickety-split. Turns out we can make ATP 12 times faster using phosphate reserves from phosphocreatine than by using the standard method of oxidative phosphorylation and a whopping 70 times faster than making ATP de novo. When we think hard, brain levels of phosphocreatine can drop pretty acutely while ATP levels stay constant, showing that we can bust into that reserve to keep our thinking sharp. In short, creatine improves brain efficiency. It is the “turbo boost” of the brain and muscles.

So let’s look at these papers, shall we? In both the cognition study papers, healthy college students were recruited (colleges being both a good source of research volunteers and vegetarians) and divided into creatine or placebo supplementation groups. The British study compared vegetarians and vegan young women to omnivores, the Australian study used only vegetarians and vegans, but had a crossover design (all subjects got both placebo and creatine along the way). Both studies did various measures of cognitive and memory testing (number of words you can remember from a list read to you, how many F or P words you can say in two minutes, how many numbers you can repeat backwards from a string of numbers read to you, recognizing strings of three even or odd numbers in a series of numbers read at 100 per second). The British study added a measure of reaction time (subjects had to press a button corresponding to a light as fast as they could once it was lit). The Australian study was six weeks, the British study was five days, and both used 5g creatine monohydrate as the supplement and dextrose (glucose) as the control.

Because glucose administration has been shown to (immediately) increase cognitive performance (5), all the cognitive testing was done fasted and on a day with no supplementation.

The results? First off, everyone, vegetarian or omnivore, on placebo or creatine in the British study did worse the second time around on the memory tests (maybe they got bored?). But compared to the placebo group, the omnivores in the British study were about the same as the creatine supplement group (omnivores have been shown to benefit from a maximum of 20 grams a day at first then maintenance 2-5 grams per day supplementing for athletic performance), suggesting that us animal flesh eaters have a physiologically appropriate amount of phophocreatine reserve in the brain for interesting tasks such as pushing buttons in response to light stimuli and complicated mental tasks that involve the prefrontal cortex and the hippocampus.

The vegetarians in the creatine group did much better than the vegetarians in the placebo group on the second battery of tests involving word recall and measures of variability of reaction times. More simple mental tasks didn’t improve in the vegetarians or the omnivores, suggesting, interestingly enough, that complicated thinking burns more energy than uncomplicated thinking (so do smart people burn more calories? I’m not aware of any research to that effect, in fact I thought there wasn’t much of a difference, but we’ll look into it …). In some of the measures, vegetarians were higher than omnivores at baseline, by the way, and in general the memory tests between the two groups did not vary at baseline—the vegetarians just seemed to benefit much more from creatine supplementation.

In the Australian study (using only vegans and vegetarians), creatine supplementation had a significant positive effect on working memory (using backwards digit span) and intelligence measures requiring processing speed. Various cognitive tasks that were worse in the placebo vegetarians compared to creatine vegetarians are similar to those that are affected in ADHD, schizophrenia, dementia, and traumatic brain injury. In addition, people with the Apoe4 allele and therefore more vulnerable to developing Alzheimer’s seem to have lower brain levels of creatine.

Except there are a few wee wrinkles. It turns out that creatine supplementation seems to have an effect on glucose regulation (3)(6). Weirdly, the first study shows a higher glucose level to oral glucose tolerance load (in vegetarians), and the second study (in young athletically active males) shows a lower amount of area under the oral glucose tolerance test curve (that’s good—shows increased glycemic control) with creatine supplementation. But if we consider the fact that a ready supply of glucose in the short term can improve cognitive performance, the British investigators were wondering if creatine supplementation increased glucose in vegetarians, thus increasing cognitive performance. They didn’t bother to measure the glucose in the subjects, though, so who knows. In the Australian study, glucose was measured in the fasting subjects but specific levels were not reported in the paper, but it didn’t seem that anyone had a high level.

In addition, creatine in the tissue doesn’t necessarily equal creatine in the brain. Animal studies have shown that problems with the creatine transporter into the brain shows up as cognitive problems similar to the unsupplemented human vegetarians (compared to their supplemented vegetarian brethren). However, it is likely that the synthesis and transport mechanisms are upregulated in vegetarians (as they have low levels of creatine), so creatine might pack more punch early on for the veggies, until levels become saturated.

Well, I’m not all that interested in supplementing with creatine. But I am interested in continuing to eat steak, and in having the most efficient energy reserves available for my brain. Eating a bit of meat along the way seems like a reasonable way to achieve this goal.

Conflict Of Interest Statement

Hamilton Roschel¹, Bruno Gualano^{1 2}, Sergej M. Ostojic³, Eric S. Rawson⁴

B.G. has received research grants, creatine donation for scientific studies, travel support for participation in scientific conferences and honorarium for speaking at lectures from AlzChem (a company which manufactures creatine). Additionally, he serves as a member of the Scientific Advisory Board for Alzchem. E.S.R. has conducted industry-sponsored research on creatine and received financial support for presenting on creatine at industry-sponsored scientific conferences. Additionally, he serves as a member of the Scientific Advisory Board for AlzChem, who sponsored this special issue. S.M.O. serves as a member of the Scientific Advisory Board on creatine in health and medicine (AlzChem LLC). S.M.O. owns patent “Sports Supplements Based on Liquid Creatine” at the European Patent Office (WO2019150323 A1), and active patent application “Synergistic Creatine” at the UK Intellectual Property Office (GB2012773.4). S.M.O. has served as a speaker at Abbott Nutrition, a consultant of Allied Beverages Adriatic and IMLEK, and an advisory board member for the University of Novi Sad School of Medicine, and has received research funding related to creatine from the Serbian Ministry of Education, Science, and Technological Development, Provincial Secretariat for Higher Education and Scientific Research, AlzChem GmbH, KW Pfannenschmidt GmbH, and ThermoLife International LLC. S.M.O. is an employee of the University of Novi Sad and does not own stocks and shares in any organization.

Creatine Supplementation And Brain Health

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