Not Another Boring Creatine Guide: Answers to FAQs and Lesser-Known Benefits

Prefer to listen? Check out the podcast episode on this topic.

Listen to Eric and Greg discuss the link between creatine and hair loss, the interaction between creatine and caffeine, and avoiding stomach discomfort when taking creatine on this episode of the Stronger By Science podcast. The episode also contains an interview with Dr. Peter Fitschen to discuss his research on HMB supplementation, blood flow restricted training, bodybuilding, and more. Listen and subscribe on Apple Podcasts, Google Podcasts, Stitcher, or wherever you get your podcasts.

Without question, creatine is the gold standard by which all strength-related supplements are judged. The basic premise for how and why creatine works so well is pretty straightforward:

We store creatine in our muscles. A phosphate group can be easily attached to creatine, thereby forming phosphocreatine, which is also stored in our muscles. When muscles do work, they use adenosine triphosphate (ATP). The process of “using” ATP involves removing a phosphate group, which turns adenosine triphosphate (three phosphates) into adenosine diphosphate (two phosphates). Phosphocreatine swoops in to rapidly donate its phosphate group, ADP becomes ATP, and we’re ready to do more work in a very short amount of time.

High-intensity exercise is characterized not only by the use of a large amount of total ATP, but more critically by its need for rapid access to ATP. Compared to rest, the rate of ATP demand increases up to 1,000-fold during intense exercise. If ATP isn’t available within a reasonably fast time frame, performance simply cannot be sustained, and intensity drops as a consequence. Phosphocreatine provides rapid ATP replenishment, but a muscle can only store so much creatine and phosphocreatine at a given time. In this sense, creatine can be thought of as a quantitatively limited, but fairly instantaneous, reservoir for the replenishment of ATP. The purpose of creatine supplementation is to increase the amount of stored creatine, thereby bolstering the capacity of this rapid ATP-generating energy system. In addition, creatine has been shown to increase lean body mass, presumably due to increased intramuscular fluid retention and improved resistance training capacity.

I could spend the next 7,000 words recapping hundreds of studies showing that creatine increases strength and power output during short-duration, high-intensity exercise in healthy young adults. Fortunately, I won’t, because that stopped being interesting about 15 years ago. Instead, this article will explore some of the lesser-known aspects of creatine and address some of the most frequently asked questions.

Other Performance-Enhancing Mechanisms of Creatine

While the rapid facilitation of ATP resynthesis is the primary and most straightforward ergogenic mechanism of creatine, there are two additional mechanisms that are less widely known and less frequently discussed. When ATP is used (hydrolyzed), it loses a phosphate group, but a hydrogen ion is also released in the process (Figure 1). Furthermore, anaerobic glycolysis is increased during high-intensity exercise, which further adds to the pool of hydrogen ions. During exercise, accumulation of hydrogen ions results in acidosis, which is associated with the onset of fatigue. When phosphocreatine donates its phosphate group to reform ATP from ADP, a hydrogen ion is consumed in the process. As a result, hydrogen buffering might be a secondary mechanism by which creatine supplementation helps to delay fatigue during intense exercise. Without question, creatine’s direct role in ATP production is the major mechanism by which it improves high-intensity exercise. However, when studies show that creatine enhances short-term, high-intensity exercise that is likely to induce a great deal of acidosis within the muscle, it is possible that pH buffering is making a small contribution to this effect. Frankly, if you’re doing anything at high enough intensity to induce substantial acidosis, you should probably already be taking creatine for its ATP-recycling effects. Nonetheless, if this newfound knowledge of creatine’s pH buffering capacity is the final piece of information required to get you on board with the premise of creatine supplementation, then it is worth drawing attention to.

Figure 1. Creatine (Cr) and phosphocreatine (PCr) play a critical role in regenerating adenosine triphosphate (ATP) from adenosine diphosphate (ADP). Along with inorganic phosphate (Pi ), the hydrolysis of ATP releases a hydrogen ion (H+), which contributes to acidosis. The recycling of ADP to ATP consumes a hydrogen ion in the process, thereby contributing (to a small extent) to the attenuation of acidosis induced by high-intensity exercise.

Creatine has long been known to increase body mass. After only a week of creatine loading, body mass is often increased by 1-2kg, and this rapid increase is attributable to water retention. Creatine is osmolytic; this means that, similarly to glycogen, increased storage of muscle creatine draws water into the muscle cell. As such, short-term loading interventions often cause up to 1-2 liters of water retention. Aside from this water-induced weight gain, and aside from potential hypertrophic adaptations to creatine-induced improvements in training capacity, there is some evidence to suggest that creatine has some direct effects on muscle hypertrophy. As reviewed by Chilibeck et al, creatine may also promote increases in lean body mass by directly affecting myostatin, myogenic regulatory factors, insulin-like growth factor 1, reactive oxygen species, and satellite cell activation. Satellite cell activation is a key step in training-induced hypertrophy; when a muscle is exercised or injured, satellite cells increase the number of myonuclei in the muscle, which increase the muscle’s capacity for protein synthesis. A number of myogenic regulatory factors play a role in promoting satellite cell activation, whereas myostatin inhibits activation. Creatine is thought to directly increase the production of myogenic regulatory factors by increasing cellular swelling via intracellular water storage, and indirectly increase their production by increasing levels of insulin-like growth factor 1. Creatine has also been shown to decrease myostatin activity, thereby simultaneously promoting factors that increase satellite cell activation and inhibiting factors that reduce satellite cell activation. Finally, excessive production of reactive oxygen species promotes inflammation and atrophy; by scavenging reactive oxygen species, creatine has the potential to reduce oxidative stress and inhibit atrophy, ultimately facilitating muscle growth.  

When studies of considerable length (more than just a few weeks) document weight gain in response to creatine supplementation, this weight gain is sometimes written off as “just water weight” or exclusively attributed to creatine-induced improvements in training volume. Research would suggest that such conclusions fail to acknowledge the likelihood that creatine has more direct effects on promoting muscle hypertrophy, and they discount a mechanism that might contribute to creatine’s benefits for strength and power performance.

Which Type of Creatine is Best?

Creatine monohydrate is the typical, “standard” form of creatine supplement. It was the first to hit the literature, it’s the most affordable, and it’s the most widely studied type of creatine to date. Literally hundreds of studies have shown creatine monohydrate to effectively increase muscle creatine storage and enhance physical performance. However, a wide variety of creatine variations have been evaluated in the search for the best type of creatine. There is no shortage of potential creatine variations, but the ones that have picked up the most steam include creatine citrate, creatine ethyl ester, creatine nitrate, and buffered forms of creatine. The quest for the best creatine serves as a case study that demonstrates two important concepts: don’t focus on mechanisms over outcomes, and don’t search for solutions until you find a problem. Every time a new form of creatine comes around, it comes with technical explanations of why it could or should outperform creatine monohydrate. So far, none of them have been shown to consistently and substantially increase creatine retention, performance, or anything other than price, in comparison to creatine monohydrate. More importantly, these various creatine “solutions” seem to be addressing a non-problem. Creatine monohydrate is quite effective at saturating muscle creatine storage and increasing performance; even if a more effective type of creatine were to come along, it’s hard to imagine it’d do much beyond allowing slightly quicker saturation, a slightly higher (but physiologically irrelevant) degree of saturation, or saturation at a lower daily dose. Despite my skepticism, I’m always open to changing my mind if some incredible form of creatine comes along. But for now, creatine monohydrate is the most well-studied, effective, and affordable type of creatine on the market. If you are really concerned about fully maximizing creatine retention, some research has shown that the addition of carbohydrate (or carbohydrate + protein) improves retention a little bit, but (in my opinion) not enough to really care about.

While the exact type of creatine is not particularly important, the physical state (solid versus liquid) certainly is. Creatine monohydrate powder is remarkably stable; at a temperature of 40° Celsius (104° Fahrenheit), virtually no breakdown is observed over the course of three years. In storage temperatures as high as 60° Celsius (140° Fahrenheit), breakdown starts to be observed after 44 months of heat exposure. In contrast, creatine is quite unstable in liquid solution, especially in the context of high temperatures and/or low pH. Substantial creatine breakdown occurs after only a few days in liquid solutions, even in room-temperature solutions with fairly neutral pH levels. As a result, the best course of action would be to purchase creatine in solid (powder or capsule) form, store it in room temperature conditions (or colder), and consume it immediately after mixing it into a liquid solution. If you must mix the beverage hours before consuming it, using a non-acidic liquid would be preferred, and it should be stored at a cold temperature if possible.

Maximizing Muscle Creatine Saturation: Loading, Cycling, and Timing

The point of creatine supplementation is to saturate muscle creatine storage, but there are two common methods for achieving saturation. Loading is a popular method, which involves taking very high creatine doses (20-25 grams per day, split between 4-5 doses) for 4-7 days in a row. After this loading phase, muscle creatine storage is saturated, and a maintenance dose of 2-5 grams per day is taken thereafter. While loading is certainly effective, it is not necessarily required. Research has shown that moderate daily doses of 3 grams per day can saturate muscle creatine storage after about 3-4 weeks of supplementation (Figure 2). When deciding whether or not to load, the primary factors to consider are time and gastrointestinal comfort. If you really, really need your results to be maximized within seven days of supplementation, loading would be the way to go. However, mild gastrointestinal discomfort is often observed with creatine supplementation; if your stomach struggles with taking in 20-25 grams of creatine over the course of a day, then loading would not be your best bet, and a more patient approach would be preferable.

Figure 2. With creatine supplementation, saturating muscle creatine and phosphocreatine storage is the name of the game. While high-dose loading protocols achieve full saturation more rapidly, you can still obtain the same degree of saturation by taking a more conservative maintenance dose for 3-4 weeks.

Our bodies are pretty good at regulating things. For example, consider a healthy person that uses exogenous estrogen or testosterone; in both cases, administration of these hormones causes inhibition of the feedback loop that promotes their endogenous production. As a result, some have argued that creatine supplementation might suppress endogenous creatine production and should be cycled to prevent long-term downregulation of creatine production. It is true that supplementation with typical doses of creatine reduces short-term production of creatine. However, this is not necessarily a problem if endogenous production recovers after the cessation of supplementation. After all, there is no need to continue producing a great deal of creatine when you’ve got 5 grams (or more) coming in every day. Fortunately, endogenous production kicks right back in when you stop taking creatine, and studies have found no evidence to suggest that long-term creatine supplementation impairs creatine production after supplementation has ceased. In this sense, the only reasons to cycle creatine would be that you’re tired of reminding yourself it take it every day, or you don’t feel like spending the money to replenish your creatine stash.  

The final dosing consideration with creatine pertains to the time at which creatine is ingested. Countless studies have shown creatine to be efficacious with a wide range of supplement timing approaches. There are very few studies (three, to be precise) directly comparing the effects of pre-exercise creatine supplementation to post-exercise supplementation. The results of these three studies were combined in a small meta-analysis. The results suggested that post-exercise supplementation may lead to slightly greater increases in fat-free mass, with no significant difference observed for effects on strength. The body of literature on this topic is extremely small, so I am hesitant to make firm conclusions, and we have plenty of evidence showing creatine supplementation to be efficacious with a variety of timing strategies. So, taking creatine at a convenient time seems to be entirely sufficient, but it might be prudent to take creatine post-workout if you’re super concerned about fully maximizing the benefit of creatine supplementation. As discussed in the section on types of creatine, I see the topic of creatine timing as a bit of a non-issue. In the quest for perfect creatine timing, we seek to boost creatine monohydrate from “very effective” to “maybe slightly more effective.” Creatine monohydrate, regardless of specific timing strategies, does a very suitable job of saturating muscle creatine storage.

Responders and Non-Responders: A Spectrum

I get a kick out of kinesiology papers that arbitrarily describe “responders” and “non-responders” to an intervention. In the absence of a reasonably well-justified statistical process for categorization or a well-defined physiological basis for this grouping, it often ends up being a tool for researchers to say, “this totally worked, there was just something wrong with about half of our sample.” In the case of creatine, however, there is a well-defined physiological basis for non-response, and non-responders absolutely do exist.

For creatine to improve performance, it needs to meaningfully increase muscle creatine storage. Some people walk around with (just about) fully topped-off muscle creatine saturation, so they obtain no benefit from creatine supplementation. One of the early studies on creatine supplementation measured both muscle creatine content and the rate of phosphocreatine resynthesis during recovery from exercise. Five of their subjects had 25% greater creatine storage and 35% greater phosphocreatine resynthesis after supplementation, but three subjects (37.5% of the sample) did not have substantial increases in either outcome. About a decade later, another research team found that there were three “types” of responses in their study. Of the eleven total subjects, three (27% of the sample) had quite large increases in muscle creatine storage after supplementation, five (45%) had moderate (but substantial) increases, and three (27%) had very minimal increases. Furthermore, the responders improved their leg press after the five-day supplementation intervention, whereas the non-responders did not. Non-responders tended to be people who started the intervention with higher baseline levels of muscle creatine, fewer type 2 muscle fibers, smaller muscle cross-sectional area, and less fat-free mass than the responders. These characteristics provide some helpful information for determining your likelihood of being a non-responder and also help explain why multiple studies have shown creatine supplementation to have larger effects in vegetarians than meat eaters. The prevalence of non-responders reported by these studies suggest that non-responders are certainly not rare, which may be one of several factors contributing to the fact that about 30% of the first few hundred creatine studies did not report significant ergogenic effects. Finally, it’s important to note that non-response to creatine is really a spectrum rather than a rigid category. Some respond extremely favorably, some have virtually no response, and most others fall somewhere in the middle. So when we use the term “non-responder” in the literature, we’re talking about people who display a level of response that most would consider negligible in magnitude.

I’m hesitant to use these studies to estimate the exact percentage of people that are likely to be non-responders. These samples are very small and not truly sampled from the general population at random. When samples are this small, three out of eight can very easily turn into one out of eight or five out of eight, based purely on chance alone. In that scenario, 13% easily becomes 63%, and the global population of non-responders goes from about one billion to about five billion. However, we can fairly comfortably conclude that being a non-responder is by no means rare, but does not appear to be the norm. So, the current “best guess” is around 20-30%, and we can feel pretty confident that the number is probably above 10% and below 50%. In my experience, people who suspect they are non-responders often feel disappointed that they don’t get to join in on the fun and enjoy a performance boost from creatine supplementation. In reality, being a non-responder is great news. You were genetically pre-selected to win a lifetime supply of free creatine!

Creatine and Bones

Bones don’t really get enough credit (or attention). Much like muscle, bone is a metabolically active tissue that exhibits pronounced adaptations in response to resistance training. In the last decade or so, some of the creatine research has started to drift away from muscle and toward bone. The reasoning for this line of inquiry is two-fold. First, resistance training increases muscle mass and strength. As a result, the amount of strain on bones during resistance exercise is increased, and bone strain stimulates bone accretion. Second, bones are metabolically active tissues that rely on ATP. Phosphocreatine’s role in ATP resynthesis should reinforce the ATP supply available for bone cells, which may promote bone formation and reduce bone resorption. As reviewed by Forbes et al, there are a few studies showing reduced levels of a protein associated with bone resorption following creatine supplementation with resistance training compared to resistance training alone. These findings suggest that bone resorption was reduced, which would likely promote increased bone content and density.  

A recent meta-analysis evaluated five studies on creatine supplementation with resistance training in older adults. Pooled analysis did not support the hypothesis that the addition of creatine would enhance bone mineral density, but the details suggest that hope is not entirely lost. There were a few key details that seemed to dictate which studies showed creatine to be beneficial. For example, only one study was a full year in duration, while the others were all six months or less. Bone is metabolically active and responsive to external stimuli, but it’s still pretty damn slow; it takes quite a while to see really substantial changes in bone remodeling, especially when you’re trying to find an effect of creatine that goes “above and beyond” the robust initial changes expected with the onset of resistance exercise. In line with this logic, the sole 12-month study reported a significant beneficial effect on bone density with creatine supplementation. Another key factor appears to be training frequency; while some studies in the meta-analysis had participants perform resistance training 1.5-2 days per week, two studies employed a training frequency of three workouts per week. Both studies with higher frequency observed beneficial effects on bone density or bone mineral content, despite that fact that one of the studies was only three months in duration. In addition, these higher-frequency studies also gave creatine doses that were scaled to body weight (~0.1 gram/kilogram), while the remaining studies (which found no significant benefit) gave a flat 5 gram dose of creatine. As such, it is possible that the flat 5 gram dose of creatine was a bit underdosed for larger individuals in the studies reporting no significant benefit.  

Taken together, the results would suggest that creatine is most likely to benefit bone in the context of higher frequency resistance training (at least three days per week), when dosed at ~0.1 g/kg of body weight. In addition, the mechanism by which creatine affects bone turnover appears to be more anti-catabolic than anabolic in nature. As such, greater effects are likely to be observed in contexts in which bone turnover is accelerated or bone loss is more pronounced, such as prolonged weight loss, particularly rigorous training, or aging.

Creatine in the Brain

We have long known that creatine plays a critically important role in the brain. While the brain’s pool of creatine only represents about 5% of the total creatine in the human body, the effects of brain creatine deficiency are devastating. There are congenital medical conditions that cause creatine deficiency in the brain, either due to impaired synthesis or impaired transport. When a child is born with such a condition, severe effects on cognitive function and development are often observed. Even in the absence of inborn creatine synthesis or transport deficiencies, researchers have suggested that creatine may play an important role in the severity and progression of a wide variety of brain-related pathologies, including traumatic brain injuries, Huntington’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS). Research has shown that creatine supplementation may increase brain creatine and phosphocreatine storage by up to 10%; as such, the questions asked by creatine researchers have begun migrating from the muscle to the mind.

The putative benefits of creatine supplementation relate to creatine’s ability to facilitate ATP resynthesis. The brain is one of our most metabolically active tissues and comes with a massive burden for energy production. It is always on, whether it is preventing you from sleeping as you consider all of your life’s most soul-crushing regrets, or it is simply reminding your body to breathe and initiate heart beats while you’re watching television. Creatine in the brain functions as an imperative energy source to ensure that neurons always have sufficient ATP to support their metabolic activity; a shortage of brain creatine presents an energy crisis, with damaging effects on the function and integrity of neurons lacking energy. Under normal conditions, cognitive tasks elevate brain activity, thereby increasing ATP demand. As explained by Dolan et al, the role of creatine in facilitating ATP resynthesis is elevated when these cognitive tasks become more complex or are challenged by acute stressors such as sleep deprivation, hypoxia, or fatigue. A recent systematic review summarized the effects of creatine supplementation on cognitive function in healthy people; results indicated that creatine improved performance on tests pertaining to short-term memory and intelligence/reasoning fairly consistently. While some positive findings have been reported for other cognitive outcomes, such as long-term memory, spatial memory, response inhibition, reaction time, and mental fatigue, these outcomes are improved less consistently. The review also found that creatine supplementation was more likely to improve cognitive function in older adults compared to younger adults and in vegans and vegetarians compared to meat-eaters.

The progression and severity of several brain pathologies are directly tied to mitochondrial dysfunction and impairment of ATP production. As such, there is great interest in how the ATP-buffering effects of creatine may relate to brain function, both in health and disease. The progression and severity of brain injuries and many neurodegenerative diseases are also linked to oxidative stress; as a result, it has been suggested that creatine may confer brain benefits via antioxidant effects in addition to other potential non-energetic mechanisms. When it comes to brain injuries, such as ischemia and mild traumatic brain injuries (concussions), animal research indicates that creatine supplementation may reduce injury severity and improve recovery. While it’s difficult to do human research in which serious brain injuries are intentionally induced, these animal studies demonstrate that creatine’s effects on mitochondrial bioenergetics and oxidative stress have potential to attenuate the damage resulting from brain injuries. Human research has also shown benefits of creatine supplementation for humans with inborn creatine synthesis deficiencies, thus demonstrating that oral creatine supplementation can influence brain creatine levels to a clinically meaningful degree, at least in extreme cases. Several animal studies have suggested that creatine may have a promising therapeutic role for a number of neurodegenerative diseases, including Huntington’s disease, Parkinson’s disease, and ALS. Human trials have failed to identify benefits of creatine for ALS; results from studies on Parkinson’s disease and Huntington’s disease have been slightly more promising, particularly when treatment begins before the onset of clinical symptoms, but results have been underwhelming in general.

While the creatine literature pertaining to brain function is fairly thin, Dolan et al provide a concise summary of what we know so far. Studies tend to show that creatine has minimal effects on cognitive function in relatively unstressed states, but its effects become more apparent in the context of stressors. Acute stressors include things like sleep deprivation, fatigue, hypoxia, and concussions; chronic stressors include things like inborn creatine deficiency, depression, and aging. Cognitive benefits of creatine appear to be more pronounced in older adults and vegetarians in comparison to young adults and meat-eaters. There is reason to have hope for creatine as a modestly beneficial adjunct therapy for managing progression and symptoms of certain neurological diseases, but more research is needed to verify the utility of this potential application.

Creatine Side Effects

If you Google creatine side effects, a pretty wide range of results tend to pop up. Muscle cramping, kidney issues, liver issues, dehydration, weight gain, and gastrointestinal symptoms are listed most frequently. Luckily, several hundred creatine studies have been conducted over the last few decades, with some studies lasting up to five years in duration. So, we have a pretty good idea of what creatine does (and does not) cause.

Intuitively, the liver and kidney concerns make sense. The liver and kidney are involved in creatine production and metabolite clearance, and small changes in select biomarkers associated with the function of each organ have been observed. However, more rigorous tests of organ function have, time and time again, failed to document any deleterious effect of creatine supplementation on healthy livers or kidneys in humans consuming creatine at ergogenic doses. For example, one of our creatine studies documented an increase in serum creatinine levels. Creatinine is a breakdown product of creatine, and is used as a marker of kidney function under normal circumstances. However, using creatinine to make inferences about kidney function absolutely and unequivocally relies on the assumption that you are not taking large doses of creatine. As a result, high creatinine values during creatine supplementation are to be expected, and they simply reflect that you have violated an enormous assumption of the serum creatinine test. Abnormal blood test results should never be ignored, but more rigorous testing is required to effectively evaluate kidney function in this case. When it comes to kidney and liver function, thorough assessments have repeatedly shown no harm of creatine supplementation in otherwise healthy individuals.

Much of the discussion about creatine side effects can be attributed to anecdotes and case reports in which creatine has been hastily blamed or implicated. A great example of this is a case study that was discussed in a review by Rawson et al. The patient in the case study presented with rhabdomyolysis, which can lead to kidney failure. The authors of the report felt so strongly about creatine’s role in promoting the case of rhabdomyolysis that creatine was specifically named in the title of the study. However, it’s worth considering that creatine has been studied hundreds of times, using thousands of participants, and I can’t recall reading about a single instance of rhabdomyolysis in any of these studies. Furthermore, the patient in the case study had recently received intravenous non-steroidal anti-inflammatory drugs, undergone a surgery that included the use of a tourniquet, and skied into a tree, which are all tremendously plausible ways to get rhabdomyolysis. It is from anecdotes like these that we see creatine linked to outcomes like dehydration and muscle cramping. Several research studies have confirmed that creatine does not adversely affect outcomes relating to hydration, muscle cramping, or muscle injury. In fact, some research even shows creatine supplementation to reduce the incidence of heat illness/dehydration, muscle cramps, and injuries in competitive football players. The idea of creatine inducing dehydration is a particularly curious notion, as creatine robustly and reliably increases intracellular and total body water. As such, creatine has been shown on multiple occasions to actually enhance hydration status and thermoregulatory responses to exercise in the heat, thereby exerting a protective effect rather than a harmful effect.

Creatine does not appear to induce kidney damage, liver damage, rhabdomyolysis, dehydration, muscle cramping, or muscle strains in otherwise healthy individuals. There are some select kidney and liver pathologies in which creatine supplementation may be contraindicated, so anyone with a pre-existing liver or kidney issue would be wise to consult with a physician before beginning creatine supplementation. Nonetheless, creatine appears to do no harm to otherwise healthy kidneys and livers, and it may even prevent the pathological accumulation of liver fat. Furthermore, it does not impair the body’s ability to make creatine after supplementation has stopped. That is not to say, however, that creatine is entirely without side effects. Some people consider weight gain via water retention to be a side effect, and this certainly occurs for most individuals. It’s also fairly common to observe gastrointestinal discomfort with creatine supplementation; this effect is likely exacerbated if the creatine is poorly dissolved, consumed in large doses, or simultaneous ingested with a lot of caffeine. Finally, there are some fairly specific topics in which creatine’s effects are a bit complicated, and more detailed discussion is warranted. These topics include creatine’s role in immune responses and asthma, the effects of creatine on hair loss, and the potential for caffeine to interfere with the effects of creatine.

Creatine Effects on Inflammation, Oxidative Stress, the Immune System, and Lung Function

When researchers study inflammation, a common method is to cause inflammation in the paw of a lab rodent and measure the ensuing inflammation-induced edema (swelling). This tends to cause responses from a whole host of inflammatory mediators including histamine, prostaglandins, tumor necrosis factor alpha, and a variety of interleukins, and toll-like receptors are heavily involved in the process. As reviewed by Riesberg et al, early rodent studies found that both injected and orally consumed creatine attenuated inflammatory responses when multiple models of acute inflammation were tested. The results also seem to pan out for chronic inflammation; creatine has been shown to have favorable effects on the progression of arthritis using two different rodent models of arthritis. Most importantly, human trials have shown these effects to translate to exercise; studies have demonstrated that creatine reduces markers of inflammation following a 30km race, a half-Ironman triathlon, and a running-based anaerobic test. Creatine may also influence oxidative stress. Numerous studies using cell cultures have shown creatine to protect incubated cells from oxidative damage, and a study in rats demonstrated that 28 days of creatine supplementation had an antioxidant effect on the response to acute exercise. Unfortunately, human research on this topic is fairly limited. One study found a significant reduction in the oxidative stress response to a single bout of resistance exercise in resistance-trained males following creatine supplementation, but a couple of studies have failed to find such benefits. Creatine also appears to modulate immune system activity; treating vascular endothelial cells with creatine (in vitro) reduces adhesion of immune cells, which would theoretically be beneficial with regards to the development of atherosclerotic plaque.

As one might expect, alterations in inflammation, immune function, and oxidative stress are not all unequivocally good things. For instance, a previous review has noted that these effects could collectively have an immunosuppressive effect. Few creatine studies are long enough to make meaningful inferences about illness rates, and illness rates are rarely reported in the few creatine studies that are long enough. A three-year study in college football players found no increase in the prevalence of illness among creatine users, but previously documented immunosuppressive effects could potentially be more meaningful for people with compromised immune systems. Creatine has also been shown to exacerbate changes in airway remodeling and allergic/inflammatory responses in rodent models of asthma. However, research has also shown that aerobic exercise helps to attenuate these negative effects of creatine on asthma-related breathing complications. Furthermore, creatine’s effects for people with lung conditions are not all negative; small, preliminary studies in humans have suggested that creatine has modest beneficial effects for training adaptations and well-being in patients with chronic obstructive pulmonary disease and cystic fibrosis, although lung function was neither positively nor negatively affected in either study. In conclusion, creatine appears to influence immune function, inflammation, and oxidative stress. The potential downsides of creatine with regard to asthma and the immune system are not fully understood yet; nonetheless, if I had asthma or a similar allergy-related inflammatory condition or had a clinically compromised immune system, I would personally err on the side of caution and shy away from creatine supplementation. Aside from those special cases, the effects of creatine on immune function, inflammation, oxidative stress, and lung function appear to be either modestly beneficial or neutral.

Gain Strength, Lose Hair?

If you’ve ever heard that creatine is linked to hair loss, there is a research study that provides the basis for this purported link. A 2009 study investigated the effects of a one-week creatine loading period, plus two weeks of maintenance supplementation, on blood androgen levels in 18- to 19-year-old male rugby players. Several previous studies have evaluated the effects of creatine on testosterone levels, with the majority finding no significant effect. While this study also found no effect on testosterone, a significant increase in dihydrotestosterone (DHT) was observed. This is notable, because DHT is known to play a very direct role in male hair loss. Testosterone is converted to DHT by an enzyme called 5ɑ-reductase; when DHT binds to receptors on hair follicles, hair loss is promoted via miniaturization of the hair follicle.

In the study, subjects started the placebo protocol with a baseline DHT value of 1.26 nmol/L; DHT levels dropped to 1.09 by day 7, and to 1.06 by day 21. It was a crossover trial, so the exact same subjects also completed the creatine protocol. At the beginning of the creatine supplementation phase, baseline DHT was 0.98 nmol/L; it increased to 1.53 by day 7, and settled back to 1.38 by day 21. It’s important to note that values up to around 3.0-3.5 nmol/L are considered “normal,” and DHT levels in the creatine study were fairly unstable. For instance, the baseline differences between the treatments, which should (theoretically) be just about equal, differed by nearly 0.3 nmol/L, and DHT should have been reasonably stable throughout the placebo protocol, but dropped by 0.2 nmol/L. As such, it’s difficult to get too worked up about the findings in the creatine condition, in which a curiously low baseline value (0.98 nmol/L) increased dramatically at the one-week time point before settling back to 1.38 nmol/L, which is only 0.12 nmol/L higher than the baseline value during the placebo protocol. It is also worth noting that both acute and chronic exercise increase male DHT levels; in theory, a modest increase in DHT could potentially be attributed to a creatine-induced increase in training load.

At this point, I’m aware of only one study measuring DHT changes in response to creatine supplementation. The study documented an increase, but DHT levels remained well within the normal range. Further, there are many steps that separate blood DHT levels from hair loss; in order to induce hair loss, the DHT must actually bind to the appropriate receptors on hair follicles and induce the miniaturization of hair follicles. It’s unclear whether or not this magnitude of effect on DHT would have a measurable effect on the rate of hair loss in genetically predisposed individuals. There is certainly no reason to believe that creatine would cause hair loss in individuals who are not genetically predisposed to hair loss. At this time, there is not sufficient evidence to suggest that DHT accelerates hair loss in genetically predisposed individuals, but it is not an entirely far-fetched idea, and there is definitely enough evidence to warrant further investigation.

Creatine and Caffeine

Back in the mid-90s, when creatine research was just starting to gather some steam, a research group suspected that caffeine might improve creatine absorption if they were consumed together. Creatine enters muscle cells via specific, sodium-dependent transporters. As such, the group suspected that caffeine would increase the activity of sodium-potassium ATPase pumps, which would theoretically increase creatine transporter activity (and muscle creatine uptake) by increasing the sodium gradient across the muscle membrane. The researchers were surprised to find that the addition of caffeine had no effect on muscle creatine uptake; muscle creatine storage was effectively increased by creatine supplementation, with or without added caffeine. However, the researchers were even more surprised to find that the addition of caffeine appeared to block the performance-enhancing benefit of creatine supplementation. Even though muscle creatine storage was significantly elevated, the creatine and caffeine treatment did not improve performance on the leg extension exercise test compared to the placebo treatment, while the creatine-only treatment did significantly improve performance. As one might expect, their discussion of the results offered very few concrete suggestions for why this was observed, as it was the complete opposite of what they expected to find.

Six years later, the same research group did another study after brainstorming some potential mechanisms by which caffeine could block the performance effects of creatine. In this follow-up study, they analyzed the effects of creatine and caffeine on muscle relaxation time. In theory, reduced relaxation time is a good thing. Crossbridge cycling (repeated attachment, detachment, and reattachment of actin-myosin crossbridges) is how force production happens, and crossbridges need to detach before they reattach again. Slowed (i.e., increased) muscle relaxation time is a well-known consequence of fatigue, and more rapid detachment could therefore be conducive to generating high forces in a short amount of time via an increased rate of crossbridge cycling and enhanced recovery time between contractions in rapid succession. In the follow-up study, this research group found that creatine alone reduces relaxation time, while chronic (multiple-day) use of caffeine alone actually increases relaxation time. When caffeine was chronically consumed during the creatine loading period, creatine’s effect on muscle relaxation time was blunted, and relaxation time was not significantly reduced. In this sense, the research group had followed up with a plausible mechanism to explain their previous finding.

While this pair of studies would appear to tell a fairly concise story about caffeine blocking the ergogenic effect of creatine via prolonged muscle relaxation time, there might be more to the story. Roger Harris pretty much introduced creatine to the sport science research world, so his input on creatine carries as much weight as anybody’s. After the creatine and caffeine issue started getting some buzz, his group did a small study to see if they found similar effects, which they published in abstract form. Again, using a leg extension protocol, yet another study showed creatine to be effective, whereas the addition of caffeine throughout creatine loading blunted this ergogenic effect. Interestingly, this study reported that four out of ten participants who completed the study complained of gastrointestinal discomfort, which was notably more prevalent when caffeine was ingested with creatine compared to creatine alone. This is not the only study to observe gastrointestinal discomfort in response to the combination of creatine and caffeine; Quesada and Gillum reported similar discomfort in three out of seven subjects, and our group noted the same observation in four out of thirteen subjects.

People love creatine, and they love caffeine. Suggesting that they might have to pick one or the other is like telling them to choose the favorite of their two children. As a result, there are a lot of people who simply refuse to entertain the possibility that caffeine could blunt the performance effects of creatine supplementation. There are a few arguments commonly used to suggest that the creatine and caffeine issue is quite simple and no interaction exists. The first argument pertains to the fact that many early creatine studies allowed, and even encouraged, participants to mix their creatine into hot coffee and/or tea. The recommendation made sense at the time, as creatine dissolves much more effectively in a hot beverage. However, this logic isn’t exactly air-tight. A cup of coffee or tea may yield up to 100mg of caffeine, give or take; this is a far cry from the 5 mg/kg dose used in many of the studies showing a creatine-caffeine interaction. In addition, it’d be wildly inaccurate to view coffee or tea as “caffeine water” and ignore the hundreds of bioactive compounds in each. It’s not implausible to think that one of these many compounds may alter the relationship between creatine and caffeine, or exert independent effects of their own.

The second argument suggests that the “interaction” observed in the creatine/caffeine studies is actually attributable to caffeine withdrawal. This argument contends that providing caffeine for a few days in a row promotes physiological dependence. To circumvent confounding results from the acute ergogenic effects of caffeine, many of the creatine/caffeine studies would disallow caffeine within several hours of exercise testing, which could theoretically hinder performance due to withdrawal symptoms. However, the abstract published by Harris’ group casts doubt on this argument. They tested performance two hours following a caffeine dose, and again a day after caffeine supplementation ceased. The interference between caffeine and creatine was actually more apparent during the testing that occurred two hours after a caffeine dose, a time at which subjects would be far less vulnerable to performance-disrupting withdrawal symptoms than the testing occurring 24 hours after. The third argument is fairly simple: studies have shown multi-ingredient pre-workout supplements, containing both creatine and caffeine, to be effective ergogenic aids. This argument assumes that the creatine actually played a role in the ergogenic effect observed, on top of the benefits subjects may have been obtaining from the caffeine, beta-alanine, and 26 other ergogenic aids included in the formula. This argument also ignores the fact that most multi-ingredient pre-workout supplements also include way less creatine and caffeine than the doses in which the interaction has been observed.   

For a more thorough look at the research question, check out the full-length review paper I published a few years ago. More research is needed on this topic, but Figure 3 summarizes our current understanding. So far, the handful of studies on habitually consuming ergogenic doses of caffeine during creatine loading have either found caffeine to block the performance benefit of creatine, or they have reported no effect of creatine itself; none of them have shown creatine to work despite the addition of high-dose caffeine. The reason for this is up for debate. Some have proposed that caffeine’s diuretic effect opposes the water retention effect of creatine, but we know that their co-ingestion does not alter each others’ pharmacokinetic properties, we know that caffeine does not alter muscle creatine saturation, and I struggle to see how this would have a meaningful impact on performance. While there may be some merit to opposing effects on muscle relaxation time, the combination of high doses of creatine (typically upwards of 10 grams per day) and caffeine (typically up around 5 mg/kg per day) seem to commonly induce gastrointestinal discomfort in around 30-40% of (admittedly small) samples. The case is not closed, but I am increasingly convinced that the creatine/caffeine issue boils down to gastrointestinal discomfort; it’s hard to perform at your best under those circumstances. The most conservative approach would be to fully trust the small amount of data available, accept that caffeine blunts the ergogenic effects of creatine, and pick one or the other. A more moderate approach (and my current approach) would be to keep an eye on gastrointestinal symptoms and alter the dosing and timing of creatine and caffeine accordingly. Such an approach would probably favor restricting high-dose caffeine during loading (or favor the avoidance of loading), keeping caffeine near the lower end of the ergogenic range (3-5 mg/kg), and consuming your creatine and caffeine at different times throughout the day. A third approach would be to simply ignore the data available and assume that no interaction exists, mostly because it feels better and saves you from a difficult decision. Again, I think the more moderate approach provides a prudent strategy that avoids extreme knee-jerk reactions to a small (but growing) body of evidence.

Figure 3. Creatine and caffeine improve performance via distinct mechanisms. Intuitively, this would make them seem like an ideal supplement pairing. However, there is some evidence to suggest that habitual high-dose caffeine intake blunts the performance benefits of high-dose creatine loading. So far, the most plausible explanations for this interaction relate to opposing effects on muscle relaxation time and potential gastrointestinal discomfort when high doses of both ingredients are consumed. While more research on the topic is needed, this figure summarizes our current understanding of the issue. Adapted from: https://www.ncbi.nlm.nih.gov/pubmed/26219105

Conclusion

It’s pretty well-known that creatine supplementation increases muscle storage of free creatine and phosphocreatine, thereby increasing body weight, strength, and sprint performance. However, there’s a lot more to creatine than water retention and helping muscles create ATP during intense exercise, and there are a lot of questions that continue to be asked. Creatine affects a wide range of tissues, including the brain, the bones, and the lungs. Creatine influences inflammation, oxidative stress, and immune function. Questions pertaining to optimal forms of creatine, optimal dosing strategies, side effects, and interactions with other supplements linger. Our current understanding of creatine can be summarized as follows:

  • Creatine improves high-intensity exercise performance, primarily by saturating muscle storage of free creatine and phosphocreatine, which enables rapid ATP recycling during exercise.
  • No form of creatine has been shown to meaningfully and consistently outperform creatine monohydrate. However, creatine monohydrate degrades pretty rapidly in liquid, so it should be mixed pretty close to the time of ingestion.
  • Loading and cycling of creatine are fine, but not necessary.
  • Creatine may confer modest benefits for bone and brain health.
  • Creatine is largely free of side effects in healthy people, aside from occasional stomach discomfort. This discomfort can probably be attenuated by completely dissolving the creatine dose in liquid, avoiding doses above 5 grams at a time, and avoiding co-ingesting high doses (≥3-5 mg/kg) of caffeine at the same time. For individuals with asthma, compromised immune systems, or certain pre-existing kidney or liver conditions, more caution may be required with regards to side effects.
  • One study has shown creatine to increase DHT levels, but DHT remained within the normal reference range, and this does not necessarily equate to hair loss.
  • A few studies have shown that high-dose caffeine blunts the performance benefits of creatine loading, but this might just relate to stomach discomfort caused by combining high doses of both ingredients. It’s possible that this can be avoided by implementing more strategic dosing approaches for both ingredients.

Addendum: May 7, 2019

After this article was published, we received a ton of questions about gastrointestinal (GI) discomfort in response to creatine ingestion. So, I wanted to give a little bit of information about how to avoid GI discomfort associated with creatine supplementation.

As previously noted, there is some evidence suggesting that ingesting loading doses of creatine (i.e., 20+ grams per day) in conjunction with daily ergogenic doses of caffeine anhydrous (i.e., 3-5+ mg per kg of body weight) may upset your stomach. Aside from being generally unpleasant, this could also have a negative effect on performance. There are a few ways to minimize this risk. The most extreme approach would be to avoid consuming caffeine while on creatine. A less extreme approach is to simply keep the dosages in check. For example, this may involve using a maintenance dose of creatine instead of loading, or restricting caffeine dosages to “normal” day-to-day levels (<3 mg/kg per day) that are likely to give you some energy, but unlikely to substantially enhance performance. An even less extreme approach would be to simply separate the timing of your doses; caffeine would ideally be consumed 30-90 minutes before a workout, with creatine consumed at other parts of the day. For a maintenance protocol of creatine supplementation, this could very easily be done by restricting caffeine to early parts of the day and consuming creatine in a single dose later in the evening. I tend to suspect that the latter approach (temporally separating doses) is likely sufficient, but there’s a lack of research available to make any type of firm evidence-based conclusion.

Notably, there are plenty of people who experience stomach discomfort when consuming creatine, even in the absence of caffeine. In this case, there are a few strategies that may be helpful. Research has shown that stomach discomfort is much more likely when consuming a 10-gram dose of creatine once daily, compared to two, 5-gram doses consumed twice daily. So, dividing your creatine dose into multiple, smaller doses may help. If that still doesn’t do the trick, it may be worth lowering the total daily dose. If your stomach doesn’t tolerate a loading protocol for creatine very well, simply ingesting a maintenance dose for 3-4 weeks will get the same job done. Taking creatine on an empty stomach might also increase the likelihood of experiencing an upset stomach, so it’s probably a good idea to take creatine with food if you tend to notice stomach discomfort after supplementation. Finally, it’s likely that stomach issues will be exacerbated if the product is poorly dissolved when you ingest it. Creatine monohydrate is typically OK, but not great, in terms of its ability to fully dissolve. Adding your creatine to a hot beverage, such as coffee, tea, or hot water, greatly enhances its ability to dissolve rapidly. Again, you may prefer to use a decaffeinated beverage if you want to err on the side of caution.

There are some anecdotes floating around that alternate forms of creatine may minimize GI symptoms in comparison to creatine monohydrate. For some novel forms of creatine, such as creatine phosphate and magnesium creatine chelate, GI discomfort has been noted. For some of the more popular alternate forms of creatine, including creatine ethyl ester and alkaline buffered creatine, I am unaware of research directly comparing their GI effects in comparison to creatine monohydrate. However, creatine ethyl ester and alkaline buffered creatine appear to be more susceptible to breakdown to creatinine in the gut, and research has shown them to either be less effective or equally effective when compared to creatine monohydrate. Furthermore, while creatine monohydrate has a large body of evidence supporting its safety and efficacy, the same cannot be said for alternate forms of creatine. The solubility of creatine hydrochloride and micronized creatine monohydrate might be a little better than normal creatine monohydrate, but you could also obtain this enhancement in solubility by simply mixing regular creatine monohydrate into a warm beverage.

So, if you notice stomach discomfort when you take creatine, you’re not alone. Simple strategies to minimize the likelihood of discomfort include taking creatine with food, mixing it into a hot beverage, taking less daily creatine or splitting it into multiple smaller individual doses, opting for a micronized creatine monohydrate product, and avoiding large doses (3-5+ mg per kg of body weight) of caffeine when consuming your creatine. While it’s possible that some of the alternate forms of creatine may have greater water solubility or induce less GI distress, these alternate forms tend to have less research supporting their safety and efficacy.

Supplement this article with the podcast episode on the topic.

Listen to Eric and Greg discuss the link between creatine and hair loss, the interaction between creatine and caffeine, and avoiding stomach discomfort when taking creatine on this episode of the Stronger By Science podcast. The episode also contains an interview with Dr. Peter Fitschen to discuss his research on HMB supplementation, blood flow restricted training, bodybuilding, and more. Listen and subscribe on Apple Podcasts, Google Podcasts, Stitcher, or wherever you get your podcasts.

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Disclaimer: Eric Trexler is not a medical doctor or a dietitian. Speak to a qualified healthcare professional before making any changes to your diet or exercise habits.


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