Introduction
Creatine is a dietary supplement, which is widely used among athletes of many ages. The reported prevalence of creatine use among recreational and elite athletes, and military personnel in survey-based studies has been reported to be 9% to 46%, with similar prevalence seen among high school athletes (1). There is a vast body of research on creatine studying bioavailability, mechanisms of action, supplementation strategies, ergogenic effect, safety and efficacy in different types of sport, and clinical applications. Creatine is found in the human body in two forms, phosphorylated and free, with 95% of the body’s creatine stores being found within skeletal muscle, where it plays a key role in ATP production via phosphocreatine shuttle (2). The remaining 5% is distributed in the brain, liver, kidney, and testes (3). Creatine is endogenously synthesized in the kidney, liver, and pancreas from the amino acids glycine, arginine, and methionine (2). The most common sources of dietary creatine are animal products, such as red meat and fish, and the normal dietary intake of creatine in an omnivorous diet is around 1 g·d−1 (4). The endogenous production of creatine is downregulated during exogenous creatine supplementation; however, the endogenous production returns to baseline after supplementation is discontinued (2). Oral supplementation of high doses of creatine has been shown to significantly increase total muscle creatine concentrations (5). Many factors can influence tissue responsiveness to creatine supplementation including initial intramuscular creatine levels, muscle fiber properties, or habitual dietary creatine intake (6).
During short-duration, high-intensity exercises, ATP needs are met by both anaerobic glycolysis and phosphocreatine shuttle. The phosphocreatine shuttle is the predominant source of ATP during maximal effort exercises lasting less than 10 s, while anaerobic glycolysis drives ATP production between 10 s and 30 s at maximal effort (7). The mechanisms thought to be responsible for any ergogenic effect of creatine supplementation include the following: increased stores of muscle phosphocreatine, faster regeneration of phosphocreatine during exercise recovery, and enhanced ATP production from glycolysis secondary to increased hydrogen ion buffering (8) (Figure).
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Figure: Illustration of the phosphocreatine shuttle model for transport of intracellular energy molecules whereby mitochondrial creatine kinase (CKMITO) cleaves phosphate from ATP generated in the mitochondria (MitoIC) and donated creatine (Cr) to create a phosphocreatine (PCr) molecule. Expended energy within muscle cells (myofibrils) in the form of ADP is recycled to regenerate ATP, driven by enzymatic reaction of intracellular CKIC which removes a phosphate group from PCr and phosphorylates ADP to form new ATP energy to fuel muscular contraction of the myofibrils. ADP, adenosine diphosphate; ATP, adenosine triphosphate.
Various dosing strategies have been investigated to determine the degree of effect on creatine stores and subsequent performance benefits. The most standard effective dosing strategy utilizes a loading phase of 20 g (approximately 0.3 g·kg−1·d−1) divided into four equal doses for 5 d to 7 d (5), followed by a longer maintenance period of 3 to 5 g·d−1 (9). The described loading phase has been shown to increase intramuscular phosphocreatine stores by 20% to 40% (5,10). In the absence of a loading phase, creatine stores accumulate more slowly, so training benefits may appear more slowly (1).
The safety of creatine supplementation has been thoroughly investigated, and when used appropriately, short- and long-term supplementation (up to 30 g·d−1 for 5 years) is safe and well-tolerated in healthy individuals. The only reproducible side effects that have been consistently observed are weight gain (a potential 1 kg to 2 kg increase after creatine loading), primarily as a result of water retention, and decreased urine output (11,12). Other side effects that have been anecdotally reported include nausea, diarrhea, and related gastrointestinal distress, muscle cramps, and heat intolerance. However, these typically occur at similar rates to the placebo groups, and have not been proven to be statistically or clinically significant. Historically, there have been a handful of isolated cases of adverse events with creatine supplementation; however, these were ultimately attributable to preexisting organ failure, excessive dosing, or concurrent use of other potentially harmful substances.
Creatine is not banned by the World Anti-Doping Agency, the International Olympic Committee (IOC), or the National Collegiate Athletic Association (NCAA) (13,14); however, the NCAA does prohibit institutions from distributing creatine supplements to athletes. Creatine is a dietary supplement that falls under the Dietary Supplement Health and Education Act and is not directly regulated by the Food and Drug Administration. In general, those who participate in athletics under the supervision of institutions, such as the NCAA and IOC, should use caution when using any dietary supplement due to possible contaminants, especially in mixed supplement products.
Ergogenic Effects
Resistance Training
It is regularly reported that creatine supplementation, when combined with heavy resistance training leads to enhanced physical performance, fat free mass, and muscle morphology (15,16). Brief but heavy bouts of resistance exercise appear to promote cellular and subcellular adaptations, including more rapid ATP regeneration for muscle recovery, increased production of insulin-like growth factor, increased myogenic transcription factor signaling, and satellite cell proliferation, which are thought to further enhance anabolic performance (17,18). Absence of these changes seen in some studies has been attributed to lack of resistance exercise (19).
Effects on Anaerobic Performance
There is a great deal of evidence in the literature supporting the benefits of supplemental creatine in anaerobic performance, suggesting that it has the most pronounced effect on short duration (<30 s), high-intensity, intermittent exercises (20,21). Creatine supplementation increases intramuscular availability of phosphocreatine for rapid generation of ATP via the anaerobic phosphocreatine shuttle system, minimizing reliance on the aerobic glycolysis pathway. Increased phosphocreatine stores also are thought to enhance the recovery process during short periods of rest, thus attenuating muscle fatigue (20). It also mitigates the acidosis effects on muscles from pH changes that normally occur in anaerobic glycolysis by shunting some of the energy production requirements to the phosphocreatine shuttle system (20). The specific measures of anaerobic endurance performance, which have repeatedly shown improvement with creatine supplementation, are work and power (19,20).
Effects on Aerobic Performance
There does not appear to be any significant improvement in aerobic performance with supplemental creatine use (22). In aerobic exercise the body relies primarily on oxidative phosphorylation for energy production, which is a metabolic pathway that does not directly utilize creatine (19,20). Although it has been suggested that creatine supplementation may alter substrate utilization during aerobic activity leading to improvement in endurance performance, the evidence for this is lacking (22). The ergonomic benefits of creatine supplementation appear to diminish with increasing duration of activity (20).
Mixed Supplementation
Creatine is often commercially distributed as part of multi-ingredient preworkout supplement products or may be taken by athletes in combination with other dietary supplements in an attempt to increase creatine uptake and/or augment its ergogenic benefits. Common adjunctive supplements include branched-chain amino acids, β-alanine, protein, glutamine, β-hydroxy β-methylbutyrate (HMB), carbohydrates, and caffeine (23,24). There is previous evidence that caffeine, carbohydrates, and HMB taken alone can enhance athletic performance. However, the literature examining the added benefits of coingestion of these supplements with creatine has yielded mixed results.
Carbohydrates consumed prior to activity have well-known benefits to increase muscle glycogen energy stores for improving exercise endurance and delaying onset of fatigue. There is some evidence that cosupplementing creatine and carbohydrates can increase creatine phosphate storage and retention (9,25). Likewise, increases in muscle glycogen have been observed with carbohydrates taken after creatine loading (26–28). One study of endurance-trained cyclists and triathletes demonstrated that combined creatine and carbohydrate loading produced increases in power performance for intermittent cycling sprints between longer time trials, and observed increased muscle concentrations of creatine phosphate and glycogen (29). A couple of other studies, however, found no effects of creatine and carbohydrate coingestion on anaerobic performance with Wingate cycling and maximal running tests (30,31).
Caffeine is a stimulant compound that produces well-known multisystem effects on the body which can enhance aerobic and anaerobic performance and activities through various cognitive and physical benefits: promoting alertness and focus, improving reaction time and motor coordination, increasing adrenaline and endorphins, delaying muscle fatigue, and increasing basal metabolic rate and mobilizing fat stores for energy production and lean muscle mass. In combination with creatine, however, the purported coingestion benefits are debatable. Two studies demonstrated overall improvements in exercise performance after caffeine and creatine coingestion (32,33). Another found the effects of combining caffeine with creatine appeared to reduce perception of exertion and fatigue, allowing individuals to endure greater training stress for enhanced creatine performance benefits (34). It also found increases in cycling work and reduced declines in power (34). In contrast, two other studies found that the ergonomic effects of creatine were not affected by caffeine consumption (35,36). One study attributed decreased absorption of creatine due to adverse gastrointestinal effects as a possible hindrance to the creatine loading phase (37).
HMB is a naturally occurring amino acid derivative produced in small amounts in humans that is used as a nutritional supplement for its known ergogenic and rehabilitative benefits of promoting protein production and inhibiting protein breakdown in muscle. It has been shown to improve gains in muscle size, strength, and lean body mass through exercise, as well as improve aerobic exercise performance and recovery time from exercise-induced skeletal muscle damage. Few studies have investigated whether there are additional benefits to combining creatine and HMB. A systematic review of six studies examining effects of creatine and HMB coingestion on sports performance, body composition, and markers of muscle damage found conflicting evidence. They concluded that there may be potential sports performance and body composition benefits, but that it did not appear to affect markers of muscle damage (38). Of these studies, improvements were found in one of two addressing strength performance, two of three on anaerobic performance, one addressing aerobic performance showed no improvement, one of three on body mass, one of two on fat free mass, one of two on fat mass, and none of four on markers of muscle damage or the one addressing aerobic performance showed any benefits (38). One of the studies highlighted the additive effects found with combining creatine and HMB on repeated sprint performance in soccer players (39).
One thing to note, however, is that not all of the coingestion studies used similar variables when it came to study design, so conclusions may have been drawn without considering the individual effects of creatine or comparative supplements on treatment groups. It also is important to recognize that commercial supplements are not strictly regulated by the FDA with respect to full ingredient listings, reliable dosing, and safety (14), and many mixed supplement formulations may contain subtherapeutic amounts of active ingredients, such as creatine and caffeine (24).
Body Composition
The most consistently reported alterations in body composition are in total body mass and lean body mass (20). The majority of intramuscular creatine is found in type II muscle fibers (40), and individuals with a greater proportion and total cross-sectional area of type II muscle fibers appear to derive greater benefit from creatine supplementation (41). Creatine supplementation is known to increase intracellular water content because of osmotic action (11), which may explain the observed increase in total body mass. Creatine does not appear to have a direct effect on protein synthesis; however, it may indirectly stimulate protein synthesis through upregulation of growth factors and increased production of myosatellite cells, which may contribute to muscle hypertrophy (42,43).
Age Specific Performance
While the ergogenic benefits of creatine supplementation have been previously well established in active populations 18 to 35 years old, data regarding adolescent or older populations have been scarce. There have been a few studies directly comparing biological response to creatine supplementation across multiple age groups. There appears to be significant variability in the responsiveness to creatine in aging adults, which may possibly be explained by factors such as initial intramuscular creatine concentration, type II muscle fiber content, and dietary intake of creatine (44).
Decreases in muscle mass and function, as well as decrease in bone mass, which occur with advanced aging, can contribute significantly to mobility impairment, fall related injuries, decreased quality of life, and early mortality (45,46). There is evidence to support the potential usefulness of creatine supplementation in attenuating some of these age-related deficits in body composition, strength, and bone health, which has implications for increasing overall health and functioning and ultimately improving quality of life (6,47,48).
Creatine supplementation combined with resistance training in elderly populations has demonstrated some favorable effects on muscle mass, strength, physical performance, and bone mineral density in older adults (40,44,49–51). In the absence of resistance training, it may take up to two or more years of creatine supplementation to possibly produce some muscular benefits in older adults. Creatine supplementation alone does not appear to affect bone mineral density. There are a number of studies that refute these findings (49,52,53); however, comparison of these studies is difficult because of the wide variability in study design.
Rehabilitation and Recovery
In addition to the well-established ergogenic benefits of creatine supplementation, it is proposed that it also may play a role in enhanced recovery from exercise. Studies examining the effects of creatine supplementation on exercise induced muscle damage have produced equivocal findings. Some report reduction of markers of muscle damage and inflammation (54–56), as well as functional markers of enhanced muscle recovery (10,26,55). Conversely, several studies have shown no effect on biological markers or functional markers of muscle recovery (57,58).
Despite some favorable findings, none of these studies have demonstrated any clinically relevant effects on performance or muscle soreness experienced after high-intensity exercises. Recent systematic review and meta-analysis of these studies concluded that there is no significant effect of creatine supplementation on common markers of exercise induced inflammation (59) and suggest that creatine supplementation has little practical value as a recovery aid following strenuous exercise.
A small number of studies have investigated the potential role of creatine in rehabilitation and return of muscle mass and function following short periods (7 d to 14 d) of immobilization in young, healthy subjects and athletes recovering from injury (18,60–62). These measure the degree of loss of muscle mass and strength during immobilization, reduction in pain and speed of recovery of muscle mass, and strength. The majority of studies show that creatine supplementation does not attenuate the loss of muscle mass or power from immobilization; however, there is some evidence that it does enhance recovery time (18,60–62). One proposed mechanism for this is creatine-induced stimulation of myogenic transcription factors, specifically MRF4 (18). Despite the small number of these studies, this finding may prove to be clinically relevant in treating athletes recovering from injuries that require a short period of immobilization. Certainly, more research in this area would be beneficial.
Sport-Specific Performance
Ergonomic performance benefits of creatine supplementation are most frequently and consistently observed in weightlifters and bodybuilding athletes, whose activities depend on short bursts of maximum intensity and development of lean body mass, respectively.
Short-distance running, jumping, throwing, and combined track and field events (e.g., heptathlon, decathlon) have demonstrated some performance enhancements with creatine use (63–65), although no benefit has been shown in middle distance (66), long distance (67), ultradistance, and mountain running events (68). Similarly, performance benefits have been seen in short distance swimming, there does not appear to be any effect on longer distance swimmers. In cycling, creatine appears to enhance power in intermittent, high-intensity performance, where bursts of acceleration are often seen, as in the closing sprints of cycling races (29,69,70). In skating performance, one study on elite hockey athletes showed improved skating sprints (53), but another using skate-treadmill testing did not see an effect (71). These findings are in keeping with known differences in the effects of creatine on quick-burst activities, which rely on the phosphocreatine shuttle for energy, and endurance activities, which rely more on other metabolic processes. It also is important to remember that weight gain resulting from creatine use may impede performance in endurance sports (70). Short-term use of creatine in wrestlers did not appear to improve upper body power output in tests designed to imitate competition-day wrestling (72). There does not appear to be any ergogenic advantages of creatine supplementation in tennis players (73–75), and only one lower strength study proposed a benefit in squash players with decreases in sprint times (76). Findings with respect to other individual and team sports are more varied.
There are a number of studies focusing on creatine effects on soccer performance, although results of these are mixed. Benefits were seen in both short- and long-term dosing strategies of creatine supplementation with enhanced muscle power output observed in elite soccer youths after 14 d of low dosing (77), enhanced plyometric training with improvements in jumping and sprinting after 6 wk (78), and improved sprints with a 16-wk low-dose regimen (79). Other benefits of creatine supplementation in soccer relate to improvements seen in postmatch recovery because of creatine phosphate breakdown and glycolysis observed after play (80). Of particular concern with respect to muscle recovery is the depletion of glycogen stores and decreased creatine phosphate resynthesis seen in the context of multiple matches played in a short period (80). While most of these benefits come with little expense to the players' safety, some studies have looked at potential adverse effects limiting soccer athletes. One study found increased airway inflammation and airway hyper responsiveness as a result of creatine supplementation, which was more pronounced in individuals with prior allergic sensitivity (81). It has been proposed that creatine may contribute to increased inflammation of the airway, and possibly exacerbate asthma in predisposed individuals. While this has been demonstrated in multiple animal studies (82,83), it has not translated to any clinical significance affecting performance in human subjects (81). In addition, increased total body water content due to intracellular water retention from the osmotic effects of creatine may result in undesired increases in total body weight (84), which may affect a player’s on field training or performance.
Effects on the Central Nervous System
Compared with skeletal muscle there is very little creatine in the brain. Unlike skeletal muscle, the brain can synthesize creatine and does not appear to rely on circulating creatine or dietary sources. However, central nervous system transporters do exist to allow utilization of exogenous creatine (85). Creatine is absorbed at a much slower rate into the central nervous system when compared with skeletal muscle (86).
While the effects of creatine supplementation on skeletal muscle metabolism and function have been well described, far less is known about the effects of creatine and mechanism of action in the brain. It has been widely demonstrated that exogenous creatine supplementation can increase brain creatine levels in humans (85,87). A handful of studies have failed to demonstrate increases in brain creatine; however, the dosing protocols in these studies were considerably lower than others (88). Still, given that these studies have small sample sizes and considerable experimental heterogeneity with regard to protocols, study populations, and different methods of measuring brain creatine, it remains uncertain precisely to what extent creatine supplementation increases brain creatine content and how this translates clinically (89). Although very few studies directly assess the differences between brain and muscle creatine accumulation after a standardized creatine protocol, it is largely agreed that greater doses of creatine are necessary for the brain creatine compared with those used for muscle loading (48,86).
Cognitive Processing
There has been much speculation about the benefits of creatine supplementation on cognitive processing in multiple patient populations. When used in athletes, dietary supplementation of creatine has been suggested to improve cognitive performance (90,91), alleviate mental fatigue (91,92), attenuate effects of sleep deprivation (90,93), and improve memory (94). Many studies report an improvement in cognitive processing following creatine supplementation, but these studies are difficult to compare because of the differences in subject population, supplementation protocols, and cognitive outcomes measured (95–97). Also, attempts to translate “improved cognitive processing” to athletes and athletic performance are few. One such study failed to demonstrate that creatine has any mitigating effects on mental fatigue with regard to strength, cognition, or visuomotor skills in soccer players (92). One of these frequently cited studies supporting the idea of increased cognitive processing and sleep deficit attenuation is that of Cook et al. (93). This study asserts that a deficit in performance caused by sleep deprivation was significantly improved following acute supplementation of creatine just 90 min prior to activity (93). However, it has previously been established that a minimum of days to weeks of ongoing creatine supplementation is necessary to even mildly increase CNS stores, which makes it necessary to consider possible confounding factors affecting this study. Overall, significantly more research is necessary to make any definitive claims regarding the impact of creatine on cognitive functioning and what role it may play in athletes.
Traumatic Brain Injury
The risk of concussion, or mild traumatic brain injury (mTBI), is a major concern in athletics. There is a developing body of literature examining the role that creatine supplementation may play in the treatment or prevention of mTBI. It has been demonstrated that brain creatine is significantly decreased following mTBI (98,99) and suggested that supplementation with oral creatine may serve to reduce severity of, or enhanced recovery from mTBI (100,101). Animal data indicate that creatine supplementation, prior to traumatic brain injury, can decrease damage up to 50% (101). Very little experimental data in humans are available; however, existing studies do demonstrate positive neuroprotective effects in clinical cohorts, specifically improvements in cognition, communication, self-care, personality and behavior, and reductions in headaches, dizziness, and fatigue (102–104). In addition, Turner and colleagues (105) showed increased brain creatine and cognitive processing during oxygen deprivation, in a model that mimics the effects of mTBI. While this is an area of great interest and much ongoing research, there are, currently, not enough data to support evidence-based recommendation for creatine use in treatment or prevention of concussion.
Conclusions
Creatine is a natural substance consumed in the diet and synthesized in the body and is widely utilized as an ergogenic aid for strength and performance gains. There is a large body of compelling evidence demonstrating improved high-intensity exercise capacity and lean body mass with creatine supplementation, conferring the most benefit in explosive physical activities that require short to moderate duration bursts of high intensity exertion. When used appropriately, creatine has very few adverse effects and has repeatedly proven to be safe for clinical use with similar beneficial applications across all age groups. Small increases in total body mass because of water retention is common, which may negatively impact weight-sensitive activities or sports with weight restrictions. Creatine supplementation does not confer as much benefit in endurance sports, which do not rely as heavily on the ATP-creatine phosphate system for short-term energy production via ATP recycling and glycogen resynthesis.
Although much of the evidence supporting other clinical applications and benefits of creatine in athletes remains limited, there is a great deal of potential in the ongoing research. Other potential musculoskeletal benefits of creatine supplementation include enhanced recovery from intense exercise, enhanced adaptive response to exercise, reduced symptoms or enhanced recovery from muscle damaging exercise, and enhanced recovery from disuse, immobilization, or extreme inactivity such as after injury. Although the data are conflicting, there is a growing body of evidence in the literature to suggest that there are some additive exercise and sports performance enhancements from coingestion of creatine with caffeine, carbohydrates, or HMB. In addition, creatine demonstrates potential neuroprotective benefits following mTBI and possible cognitive improvement, further research is needed to determine if there is a role for creatine in the treatment of mTBI.
In summary, creatine is an ergogenic supplement which is very effective in augmenting short-duration, maximum-intensity resistance training and, when used appropriately, is safe for use in athletes of all ages. Given its efficacy along with its excellent clinical safety profile, creatine continues to be one of the most widely used ergogenic dietary supplements in athletes.
The authors declare no conflict of interest and do not have any financial disclosures.
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