Creatine: Benefits, Side Effects & Safe Consumption

Creatine is one of the most widely consumed dietary supplements globally, accounting for an estimated $520 million dollars-a-year market by 2024. [1] On top of that, dietary supplements are quite popular, with approximately 75% of Americans reported taking at least one in the previous year. [2]

Despite its popularity, many questions remain about supplemental creatine regarding safety, dosing, side effects, and more. In this article, we’ll cover this and much more in an effort to help you make an informed decision about whether or not creatine supplementation is for you. 

What is Creatine?

Creatine was discovered in the 1830’s by French chemist Michel Eugene Chevruel as a naturally occurring component in meat. [3]  In humans, 95% of creatine is found in the skeletal muscle, with 5% spread between the heart, brain, and gonads.  Of the fraction contained in the muscle, about two-thirds is bound to inorganic phosphate to form phosphocreatine , and the other one-third exists as free creatine. 

Creatine levels in the body vary by size, physical activity levels, and more, though sex and age do not appear to influence creatine levels. [4] The body breaks down ~ 1 to 2% of creatine in the muscle per day into creatinine, which is excreted into the urine. Creatine levels in the body are maintained through both endogenous and exogenous sources. Humans are capable of making creatine, e.g. endogenous production, from three other amino acids: arginine, glycine, and methionine in the kidney, liver, pancreas, and brain. [5]  

Creatine is also found in food, e.g. an exogenous source,  with red meat and fish containing about 4 grams of creatine per kilogram. [4] A small amount of creatine is found in dairy, including breast milk, but plant-based foods do not contain creatine. [6]

In individuals who eat more meat and animal products, endogenous production of creatine is decreased to maintain the body’s creatine stores. By the same token, endogenous production of creatine is ramped up in those who eat primarily plant-based diets. [4]

What Does Creatine Do?

Creatine exists in muscle cells as free creatine and bound to phosphate as phosphocreatine. Creatine’s main function is to rapidly produce energy as part of the phosphocreatine system. Energy for human activity is derived from the breakdown of adenosine triphosphate (ATP) into adenosine diphosphate (ADP) and inorganic phosphate (Pi).  Skeletal muscles then use this chemical energy to power contraction. In the phosphocreatine system, phosphocreatine breaks down into inorganic phosphate and creatine using the enzyme creatine kinase. The inorganic phosphate can then help create energy, e.g. adenosine triphosphate (ATP), when added to adenosine diphosphate (ADP). In short, creatine helps maintain cellular energy levels during periods of increased demand such as exercise and some disease states. 

During high intensity exercise, the working muscles’ energy (ATP) demands increase dramatically, up to several hundred-folds higher compared to rest. Despite ATP being used at high rates, the decrease in ATP levels during resistance training is usually small or statistically insignificant. Multiple studies have shown this, suggesting that ATP is being almost entirely regenerated during exercise. In turn, we probably don’t need to rest a lot in order to replenish our ATP stores. 

In contrast, muscle phosphocreatine stores can become nearly exhausted within ~10- to 15-seconds depending on the intensity level, type of exercise, and amount of muscle mass being used,.[7]  Recovery of creatine levels occurs in a fast and slow phase. About half of phosphocreatine is recovered in the first minute of rest,  whereas it takes about 8 minutes to fully replenish PCR levels. [8]   

Now that we know what creatine does in the body and how normal levels are maintained, what would happen if we could get those muscle creatine levels even higher?

What are The Benefits of Creatine?

Regularly consuming supplemental creatine can increase both total creatine and muscle phosphocreatine levels from ~ 10 to 40%. [9] While we can make about 1-2g/day in kidney and liver, supplementing with additional creatine at 3 to 5g/day increases muscle creatine levels further. Thus, by increasing muscle levels of creatine, it is thought that an individual will have larger stores for rapid energy production, although there are a number of mechanisms  that contribute to increasing exercise performance.

Creatine Increases Cellular Energy 

Creatine supplementation increases intracellular phosphocreatine and free creatine storage. Increased phosphocreatine helps make more adenosine triphosphate (ATP) by donating its phosphate to adenosine diphosphate (ADP).  It also helps create more phosphocreatine during recovery periods.  Additional phosphocreatine and ATP can also reduce the formation of reactive oxygen species (ROS), lactate, and hydrogen ions via acting as a buffer and antioxidant. [10]

Creatine Increases Cellular Swelling

Creatine promotes water entry and retention in the muscle cell, subsequently leading to cellular swelling. This increase in cellular swelling  may serve as an anabolic signal for muscle growth by increasing muscle protein synthesis rates and decreasing muscle protein breakdown, although the data on this are mixed. Muscle protein synthesis is a complex phenomenon and there are likely multiple ways that creatine supplementation affects this. [7]

An increase in cellular swelling shouldn’t be confused with water retention, which is a myth based on short-term supplemental creatine studies utilizing a loading period, e.g. 5 or 6 days taking 20 grams per day (4-5x the maintenance dose) of supplemental creatine. In these studies, some people see an increase in total body water in the short-term, but long-term studies lasting 5- to 10-weeks or more generally show that creatine does not increase total body water. [11]

Creatine also does not increase the risk of dehydration. In fact, creatine seems to reduce the risk of cramping when studied directly. In one study of a Division-1 football players taking supplemental creatine or placebo, those taking creatine had less cramping, muscle tightness, strains, and total injuries compared to the placebo group. [12] In a group of individuals with kidney disease on dialysis, patients who frequently reported muscle cramps were given creatine before dialysis and it reduced their frequency of muscle cramps by 60%. [13]

While we’re busting myths, creatine is not stored within fat tissue and creatine supplementation does  not increase fat mass in either the short- or long-term. [14], [15] 

Creatine Increases Satellite Cell Activation 

Supplemental creatine may increase muscle satellite cell cells and subsequent muscle hypertrophy Muscle Satellite cells are a special type of stem cell that, when stimulated, can facilitate muscle repair and ultimately become new muscle cell nuclei (myonuclei). 

Muscle hypertrophy is defined by an increase in muscle mass and, subsequently, an increase in muscle size.  An increase in muscle mass and size requires additional muscle protein synthesis, which is made possible by increasing the amount of muscle protein being made by each myonuclei, and an increased number of myonuclei to support the additional protein synthesis requirements of the larger muscle fibers. 

Both resistance training and creatine supplementation increase muscle satellite cell activation to create additional myonuclei, thus supporting increased muscular hypertrophy. When performed together, the increase in myonuclei is greater than either in isolation. [16]

Regularly taking supplemental creatine can increase the creatine content in the body, thereby increasing energy availability, increasing muscle cell swelling, and muscle satellite cell activation, among other mechanisms. However, mechanisms don’t always tell the whole story and we should talk about whether or not supplemental creatine actually improves performance and health. We’ll do that in the next section. 

Does Supplemental Creatine Improve Performance?

Overwhelmingly, the available evidence shows a clear, albeit modest, benefit to supplemental creatine on physical performance. No studies have reported a performance-reducing effect of creatine, save for early weight gain, which may reduce short-term performance in sports like swimming or running. Still, there is some nuance in how much potential benefit is there, as this differs by outcome of interest.

For example, the average gain in strength/power performance is typically modest, likely being proportional with the increase in muscle phosphocreatine levels and energy requirements of the task. [17]   Compared to placebo, short-term creatine monohydrate supplementation has been reported to improve maximal power/strength and repetitions to failure at a given intensity by ~ 5 to 15% in responders. 1-Repetition-Maximum (1RM)  and sprint performance also appears to increase by a smaller amount, but improve nonetheless. [18, 19 .20] Older individuals also seem to see greater strength gains with creatine supplementation as well. [21]

With respect to muscular size or hypertrophy, a recent meta-analysis showed a small increase in hypertrophy compared with creatine supplementation compared to placebo, likely on the order of a couple of pounds or so in a year. [22] This relationship was also seen in a meta-analysis of creatine’s effect on older individuals. [21]

Endurance training is less clear, particularly in trained athletes, though the signal appears positive in longer term studies.. [23]

A number of potential health benefits have been associated with creatine supplementation, however most are still under investigation. For example, there may be a benefit of creatine supplementation on cognitive performance, but the current evidence is mixed and inconsistent study design makes it hard to feel confident about a large benefit. [24] It’s a similar story with traumatic brain injury, though future potential studies may hold promise. [25] 

In clinical settings like the hospital, there are a number of possible therapeutic targets such as administering creatine phosphate through an IV after a heart attack or during pregnancy to potentially reduce the risk or harms of cerebral, among many others. However, these are all still active areas of research. [26, 27]

Overall, creatine supplementation appears to be useful for improving strength/power-type adaptations including maximal strength, muscular power, strength stamina, and muscular hypertrophy. These improvements tend to be small to moderate in size, with plenty of interindividual variability. Other applications relating to endurance performance and health improvement are less clear, with more research needed to determine supplemental creatine’s effectiveness.

Is Creatine Safe?

Creatine appears to be safe in both short- and long-term studies lasting over 5-years of continuous use with respect to markers of kidney, liver, immune system, and metabolic functions. [9] [28] 

Effect of Creatine on Kidney Function

It should be noted that supplemental creatine has been shown to increase creatinine levels, which is a common blood test used to assess kidney function. A trivial amount of creatine made and stored in the body cyclizes to creatinine. [4] When supplemental creatine is ingested at higher doses however, there may be a far greater amount of creatinine formation from creatine, perhaps mimicking kidney disease when viewed in isolation. This is especially true of supplemental forms of creatine that are poorly absorbed, such as creatine ethyl ester. In one study measuring the short-term effects of two supplemental creatine forms, e.g. creatine monohydrate and creatine ethyl ester, serum creatinine levels peaked at nearly 2.5- and 6.7- times the baseline creatinine level within a few hours of ingestion.*unpublished Kris Hunt and Robert Hoffman Long-term data on supplemental creatine monohydrate do not show any evidence of creatine damage. [29]

Creatine Safety in Children

Despite the robust safety data in adults, there isn’t really any safety data for children or adolescents. A number of studies have shown that children and adolescents respond well to creatine, e.g. their performance increases without adverse effects, but none of the studies otherwise assessed safety. [30]

Creatine in Pregnancy

Similarly, there are no safety studies in pregnant women, though some preclinical trials in animals show there may be some benefit if oxygen supply to the fetus is compromised. [31] Outside of the research setting, supplementing creatine during pregnancy and while breastfeeding is probably not a great idea. During these periods of time, small improvements in muscular strength power adaptations are generally not worth the risk of supplementation. Creatine is made by the body, so it could be argued that that supplemental creatine should be presumed safe. However, the dietary supplement industry leaves much to be desired when it comes to safety. 

Does Creatine Cause Hair Loss?

There is no evidence showing supplemental creatine monohydrate causes hair loss. Rather, the theory about creatine causing hair loss was generated from a single paper from 2009 that looked at college-aged rugby players taking creatine or placebo for 21-days. [32] Hair loss was not measured in these individuals, but rather a hormone called dihydrotestosterone (DHT) was measured in the blood. DHT is a metabolite of testosterone, formed when the enzyme 5-alpha-reductase converts free testosterone to DHT.  

In this study, DHT levels were over 20% lower to start  in the group getting creatine compared to placebo. At the end, the placebo group’s DHT levels went down a little bit and the supplemental creatine’s DHT levels went up to a level near the where the placebo group started. This likely created a statistically significant difference that was artificial, though not necessarily clinically relevant. To date, no other study has measured DHT levels in creatine users versus placebo. Additionally, no long term studies have been done on creatine and hair loss.

In general,  DHT levels are higher in men with male pattern baldness (androgenetic alopecia) than those without.  They also seem to have higher levels of 5-alpha reductase and more androgen receptors in the areas of their scalp that balds.  That said, some studies, but not all, show no statistical significance or correlation of DHT levels with the progression of baldness in some studies. For example, those with male pattern baldness, have an increase in DHT, but so do controls without the hair loss. [33] 

Overall, creatine supplementation probably doesn’t increase the risk of male pattern baldness in men without any sort of genetic predisposition to the condition. 

Are Supplements Like Creatine Safe?

Dietary supplements include vitamins, minerals, botanicals, amino acids, and enzymes that are not intended to treat or prevent disease. The majority of safety issues surrounding dietary supplements is due to contamination with unapproved ingredients and/or mislabeled supplements.

Contamination of a supplement means that an ingredient not accounted for on the label such as bacteria, pharmaceutical adulterant, or heavy metal, has been found in the supplement in amounts above an acceptable cut-off level. Accuracy of labeling refers to the ingredients and the dosing of a particular product.  Because nearly all of the FDA-led supplement monitoring occurs after it hits the market, it’s up to the manufacturer to make sure their product is safe, accurately labeled, and works as described

Based on available data, it seems that ~ 20% of all supplements sold are contaminated, with supplement categories like sexual enhancement, weight loss, and muscle-building being the most common offenders. With respect to mislabeling, the rate is higher, with ~30 to 50% of supplements being incorrectly labeled. Both of these statistics are also likely to be underestimated due to underreporting, lack of research funding, and more.  [34, 35  36]

We would recommend that a person who chooses to use dietary supplements verify that their manufacturer of choice provides ample evidence that their supplements are effective, adhere to cGMP guidelines, and have some form of third party batch testing in place. If you’re looking for dietary supplements that exceed these criteria, we do produce a small line of evidence-based supplements that are rigorously tested. 

How-To Take Creatine

To get the benefits from supplementing with creatine, we need to take the right type and the correct dose. 

What is the Best Form of Creatine?

Creatine monohydrate is the most studied and commonly used form of creatine for over 30- years. 99% of it is absorbed into tissue or excreted in the urine and unlike other forms of creatine, it doesn’t cyclize into creatinine very much. While other forms are available and marketed as being superior, this is not supported by evidence. 

Within the research world, most creatine monohydrate supplements used are micronized, which is just creatine monohydrate with smaller mesh-size particles. Other forms of creatine monohydrate are available for manufacturers to use with some being micronized and others not. Not every micronized-creatine-containing supplement will have “micronized” listed on the label. Some will list it as Creapure™ and others will just list it as creatine monohydrate, which is what we do with PeriRx.

We would recommend sticking with supplements containing creatine as monohydrate or micronized creatine monohydrate that are 3rd party tested. This is a bigger problem than one might think, as less than 10% of available creatine or creatine-containing supplements on Amazon are 3rd party certified. [37] 

How Much Creatine Should I Take?

Creatine monohydrate has distinct dosing protocols for loading and maintenance.  Creatine loading is defined as taking supplemental creatine for 5 to 7 days, typically at doses of ~ 20 to 25 grams per day or 0.3 grams per kilogram body weight per day. This large dose is typically broken up into smaller doses taken throughout the day. The maintenance dose of supplemental creatine monohydrate is 3 to 5 grams per day or 0.05 to 0.07 grams of creatine monohydrate per kilogram body weight per day.  [17] 

Using a loading phase generally increases creatine content in the muscle faster than maintenance. At the end of about a month however, there’s not really a difference between using a loading phase or starting at maintenance. [38]

If an athlete is at all worried about short-term weight gain, would not recommend a loading phase, as there’s a higher risk of loading-phase-associated weight gain. If someone has a history of gastrointestinal side effects with creatine, e.g. diarrhea or stomach pain, we would not recommend a loading phase, as this has also been associated with higher doses, [39]

Finally, for folks who are going to be taking creatine for over a month 1 month where any performance benefit is not of dire importance to realize before that time has past, we would recommend just starting at maintenance dose.

When Should I Take Creatine?

Contrary to popular belief, it doesn’t really matter when someone takes supplemental creatine or what you take it with, so long as it’s taken daily. While there’s some scant evidence showing that taking creatine post-workout may work better than pre-workout, this isn’t terribly convincing in the grand scheme of things. [40]

Regarding combinations with carbohydrates, protein, and/or caffeine there isn’t much in the way of  long term data showing a difference in muscle creatine content when taken with or without these co-ingredients. It is unlikely any of these ingredients alter muscle or total body levels of creatine significantly with supplementation.  

Regular, daily consumption of supplemental creatine is likely best, though some studies use different frequencies of dosing.  For example, taking creatine two- and three-times per week are both better than placebo for increasing muscle mass, but not different from each other. [41] Still, irregular supplementation may increase the likelihood of  being a non-responder to supplemental creatine, which means not seeing a performance benefit. [42]

Speaking of responders and non-responders, the likelihood of being a responder or non responder has not been adequately investigated.  To date, a single study looking at 11 men showed that the increase in creatine stored in the muscle from supplementing creatine correlated with the increase in performance. Those whose muscles did not store more creatine did not see an increase in performance. Based on muscle biopsies, the general characteristics of responders include having larger and greater amounts of type II, fast-twitch muscle fibers and less creatine stored in the muscle to begin with. In this study, 27% were responders, 45% were quasi responders, and 27% were non-responders. [43]  Outside of that, we don’t really know what proportion of individuals respond well to creatine supplementation. 

Should You Take Creatine?

Given the relatively low risk of supplementation, we feel it’s reasonable to take creatine for a potential modest benefit in performance in most circumstances. Individuals with existing kidney disease, who are pregnant or breastfeeding, or who have adverse reactions to creatine should not use supplemental creatine provided. These individuals should take comfort in the fact that not taking supplemental creatine is unlikely to make or break their athletic career. 

To review:

• Creatine is a naturally occurring amino acid found primarily (95%) in the muscle. It is not a steroid of any kind.
• Supplemental creatine can increase muscle and total body levels of creatine by ~10 to 40%.
• Higher levels of creatine in the muscle increases cellular energy, increases muscle cell swelling, and muscle satellite cell activation.
• Creatine supplementation has good evidence of improving muscle strength and power 
• Creatine supplementation does not adversely affect the kidneys, liver, or heart, nor does it cause water retention, weight gain, hair loss, or an increase in body fat.
• Creatine monohydrate dosed at 3 to 5 grams per day is the recommended dose. It likely doesn’t matter when you take it or what you take it with 
• All supplements should be 3rd party tested.

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