International Society of Sports Nutrition position stand: safety and efficacy of creatine supplementation in exercise, sport, and medicine

Creatine supplementation can help athletes recover from intense training. For example, Green and coworkers [8] reported that co-ingesting creatine (5 g) with large amounts of glucose (95 g) enhanced creatine and carbohydrate storage in muscle. Additionally, Steenge et al. [49] reported that co-ingesting creatine (5 g) with 47–97 g of carbohydrate and 50 g of protein enhanced creatine retention. Nelson and colleagues [104] reported that creatine loading prior to performing an exhaustive exercise bout and glycogen loading promoted greater glycogen restoration than just carbohydrate loading alone. Since glycogen replenishment is important to promoting recovery and preventing overtraining during intensified training periods [78], creatine supplementation may help athletes who deplete large amounts of glycogen during training and/or performance to maintain optimal glycogen levels.

Evidence also suggests that creatine supplementation may reduce muscle damage and/or enhance recovery from intense exercise. For example, Cooke and associates [105] evaluated the effects of creatine supplementation on muscle force recovery and muscle damage following intense exercise. They reported that participants supplemented with creatine had significantly greater isokinetic (+10%) and isometric (+21%) knee extension strength during recovery from exercise-induced muscle damage. Additionally, plasma CK levels were significantly lower (−84%) after 2, 3, 4, and 7 days of recovery in the creatine supplemented group compared to controls. The authors concluded that creatine improved the rate of recovery of knee extensor muscle function after injury. Santos and coworkers [106] evaluated the effects of creatine loading in experienced marathon runners prior to performing a 30 km race on inflammatory markers and muscle soreness. The researchers reported that creatine loading attenuated the changes in CK (−19%), prostaglandin E2 (−61%), and tumor necrosis factor (TNF) alpha (−34%) and abolished the increase in lactate dehydrogenase (LDH) compared to controls. Similar findings were reported by Demince et al. [107] who reported that creatine supplementation inhibited the increase of inflammatory markers (TNF-alpha and C-reactive protein) in response to intermittent anaerobic sprint exercise. Finally, Volek and colleagues [77] evaluated the effects of creatine supplementation (0.3 g/kg/d) for 4 weeks during an intensified overreaching period followed by a 2 weeks taper. The researchers found that creatine supplementation was effective in maintaining muscular performance during the initial phase of high-volume resistance training overreaching that otherwise results in small performance decrements. These findings suggest that creatine supplementation can help athletes tolerate heavy increases in training volume. Therefore, there is strong evidence that creatine supplementation can help athletes enhance glycogen loading; experience less inflammation and/or muscle enzyme efflux following intense exercise; and tolerate high volumes of training and/or overreaching to a greater degree thereby promoting recovery.

Several studies have reported that creatine supplementation during training and/or competition either has no effect or reduces the incidence of musculoskeletal injury, dehydration, and/or muscle cramping. For example, several initial studies on creatine supplementation provided 15–25 g/day of creatine monohydrate for 4 – 12 weeks in athletes engaged in heavy training with no reported side effects [67, 77, 108‐110]. Kreider and colleagues [109] reported that American collegiate football players ingesting 20 or 25 g/day of creatine monohydrate with a carbohydrate/protein supplement for 12 weeks during off season conditioning and spring football practice experienced greater gains in strength and muscle mass with no evidence of any adverse side effects. Additionally, in a study specifically designed to assess the safety of creatine supplementation, American collegiate football players ingesting about 16 g/day of creatine for 5 days and 5–10 g/day for 21 months had no clinically significant differences among creatine users and controls in markers of renal function, muscle and liver enzymes, markers of catabolism, electrolytes, blood lipids, red cell status, lymphocytes, urine volume, clinical urinalysis, or urine specific gravity [22]. Meanwhile, creatine users experienced less incidence of cramping, heat illness/dehydration, muscle tightness, muscle strains/pulls, non-contact injuries, and total injuries/missed practices than those not taking creatine [111].

Similar findings were reported by Greenwood and coworkers [112] who examined injury rates during a 4 months American collegiate football season among creatine users (0.3 g/kg/day for 5 days, 0.03 g/kg/day for 4 months) and non-users. The researchers reported that creatine users experienced significantly less incidence of muscle cramping, heat illness/dehydration, muscle tightness, muscle strains, and total injuries compared to athletes who did not supplement their diet with creatine. Likewise, Cancela and associates [113] reported that creatine supplementation (15 g/day x 7-d, 3 g/day x 49-d) during soccer training promoted weight gain but that those taking creating had no negative effects on blood and urinary clinical health markers. Finally, Schroder et al. [114] evaluated the effects of ingesting creatine (5 g/day) for three competitive seasons in professional basketball players. The researchers found that long-term low-dose creatine monohydrate supplementation did not promote clinically significant changes in health markers or side effects. Thus, contrary to unsubstantiated reports, the peer-reviewed literature demonstrates that there is no evidence that: 1) creatine supplementation increases the anecdotally reported incidence of musculoskeletal injuries, dehydration, muscle cramping, gastrointestinal upset, renal dysfunction, etc.; or that 2) long-term creatine supplementation results in any clinically significant side effects among athletes during training or competition for up to 3 years. If anything, evidence reveals that athletes who take creatine during training and competition experience a lower incidence of injuries compared to athletes who do not supplement their diet with creatine.

Like carbohydrate, creatine monohydrate has osmotic properties that help retain a small amount of water. For example, initial studies reported that creatine loading promoted a short-term fluid retention (e.g., about 0.5 – 1.0 L) that was generally proportional to the acute weight gain observed [22, 46]. For this reason, there was interest in determining if creatine supplementation may help hyper-hydrate an athlete and/or improve exercise tolerance when exercising in the heat [76, 115‐126]. For example, Volek and colleagues [76] evaluated the effects of creatine supplementation (0.3 g/kg/day for 7 days) on acute cardiovascular, renal, temperature, and fluid-regulatory hormonal responses to exercise for 35 min in the heat. The researchers reported that creatine supplementation augmented repeated sprint cycle performance in the heat without altering thermoregulatory responses. Kilduff and associates [123] evaluated the effects of creatine supplementation (20 g/day for 7 days) prior to performing exercise to exhaustion at 63% of peak oxygen uptake in the heat (30.3 °C). The researchers reported that creatine supplementation increased intracellular water and reduced thermoregulatory and cardiovascular responses to prolonged exercise (e.g., heart rate, rectal temperature, sweat rate) thereby promoting hyper-hydration and a more efficient thermoregulatory response during prolonged exercise in the heat. Watson and colleagues [117] reported that short-term creatine supplementation (21.6 g/day for 7 days) did not increase the incidence of symptoms or compromise hydration status or thermoregulation in dehydrated (−2%), trained men exercising in the heat. Similar findings were observed by several other groups [118, 119, 127, 128] leading researchers to add creatine to glycerol as a highly effective hyper-hydrating strategy to help athletes better tolerate exercise in the heat [116, 120‐122, 125, 126]. These findings provide strong evidence that creatine supplementation (with or without glycerol) may serve as an effective nutritional hyper-hydration strategy for athletes engaged in intense exercise in hot and humid environments thereby reducing risk to heat related-illness [5, 129].

Since creatine supplementation has been reported to promote gains in muscle mass and improved strength, there has been interest in examining the effects of creatine supplementation on muscle atrophy rates as a result of limb immobilization and/or during rehabilitation [130]. For example, Hespel and coworkers [131] examined the effects of creatine supplementation (20 g/day down to 5 g/day) on atrophy rates and rehabilitation outcomes in individuals who had their right leg casted for 2 weeks. During the 10 week rehabilitation phase, participants performed three sessions a week of knee extension rehabilitation. The researchers reported that individuals in the creatine group experienced greater changes in the cross-sectional area of muscle fiber (+10%) and peak strength (+25%) during the rehabilitation period. These changes were associated with greater changes in myogenic regulating factor 4 (MRF4) and myogenic protein expression. In a companion paper to this study, Op’t Eijnde et al. [132] reported that creatine supplementation offset the decline in muscle GLUT4 protein content that occurs during immobilization and increased GLUT4 protein content during subsequent rehabilitation training in healthy subjects. Collectively, these findings suggest that creatine supplementation lessened the amount of muscle atrophy and detrimental effects on muscle associated with immobilization while promoting greater gains in strength during rehabilitation. Similarly, Jacobs and associates [133] examined the effects of creatine supplementation (20 g/d for 7 days) on upper extremity work capacity in individuals with cervical-level spinal cord injury (SCI). Results revealed that peak oxygen uptake and ventilatory anaerobic threshold were increased following creatine supplementation. Conversely, Tyler et al. [134] reported that creatine supplementation (20 g/day for 7 days, and 5 g/day thereafter) did not significantly affect strength or functional capacity in patients recovering from anterior cruciate ligament (ACL) surgery. Moreover, Perret and colleagues [135] reported that creatine supplementation (20 g/day for 6 days) did not enhance 800 m wheelchair performance in trained SCI wheelchair athletes. While not all studies show benefit, there is evidence that creatine supplementation may help lessen muscle atrophy following immobilization and promote recovery during exercise-related rehabilitation in some populations. Thus, creatine supplementation may help athletes and individuals with clinical conditions recover from injuries.

The risk of concussions and/or SCI in athletes involved in contact sports has become an international concern among sports organizations and the public. It has been known for a long time that creatine supplementation possesses neuroprotective benefits [29, 38, 40, 136]. For this reason, a number of studies have examined the effects of creatine supplementation on traumatic brain injury (TBI), cerebral ischemia, and SCI. For example, Sullivan et al. [137] examined the effects of 5 days of creatine administration prior to a controlled TBI in rats and mice. The researchers found that creatine monohydrate ameliorated the extent of cortical damage by 36 to 50%. The protection appeared to be related to creatine-induced maintenance of neuronal mitochondrial bioenergetics. Therefore, the researchers concluded that creatine supplementation may be useful as a neuroprotective agent against acute and chronic neurodegenerative processes. In a similar study, Haussmann and associates [138] investigated the effects of rats fed creatine (5 g/100 g dry food) before and after a moderate SCI. The researchers reported that creatine ingestion improved locomotor function tests and reduced the size of scar tissue after the SCI. The authors suggested that pretreatment of patients with creatine may provide neuroprotection in patients undergoing spinal surgery who are at risk to SCI. Similarly, Prass and colleagues [139] reported findings that creatine administration reduced brain infarct size following an ischemic event by 40%.

Adcock et al. [140] reported that neonatal rats fed 3 g/kg of creatine for 3 days observed a significant increase in the ratio of brain PCr to Pi and a 25% reduction in the volume of edemic brain tissue following cerebral hypoxic ischemia. The authors concluded that creatine supplementation appears to improve brain bioenergetics thereby helping minimize the impact of brain ischemia. Similarly, Zhu and colleagues [141] reported that oral creatine administration resulted in a marked reduction in ischemic brain infarction size, neuronal cell death, and provided neuroprotection after cerebral ischemia in mice. The authors suggested that given the safety record of creatine, creatine might be considered as a novel therapeutic agent for inhibition of ischemic brain injury in humans. Allah et al. [142] reported that creatine monohydrate supplementation for 10 weeks reduced the infarction size and improved learning/memory following neonatal hypoxia ischemia encephalopathy in female mice. The authors concluded that creatine supplementation has the potential to improve the neuro-function following neonatal brain damage. Finally, Rabchevsky and associates [143] examined the efficacy of creatine-supplemented diets on hind limb functional recovery and tissue sparing in adult rats. Rats were fed a control diet or 2% creatine-supplemented chow for 4–5 weeks prior to and following SCI. Results revealed that creatine feeding significantly reduced loss of gray matter after SCI. These findings provide strong evidence that creatine supplementation may limit damage from concussions, TBI, and/or SCI [33, 144].

Creatine deficiency syndromes are a group of inborn errors (e.g., AGAT deficiency, GAMT deficiency, and CRTR deficiency) that reduce or eliminate the ability to endogenously synthesize or effect transcellular creatine transport [17]. Individuals with creatine synthesis deficiencies have low levels of creatine and PCr in the muscle and the brain. As a result, they often have clinical manifestations of muscle myopathies, gyrate atrophy, movement disorders, speech delay, autism, mental retardation, epilepsy, and/or developmental problems [13, 17, 145]. For this reason, a number of studies have investigated the use of relatively high doses of creatine monohydrate supplementation (e.g., 0.3 – 0.8 g/kg/day equivalent to 21 – 56 g/day of creatine for a 70 kg person, or 1 – 2.7 times greater than the adult loading dose) throughout the lifespan as a means of treating children and adults with creatine synthesis deficiencies [13, 17, 145‐149]. These studies generally show some improvement in clinical outcomes particularly for AGAT and GAMT with less consistent effects on CRTR deficiencies [145].

For example, Battini et al. [150] reported that a patient diagnosed at birth with AGAT deficiency who was treated with creatine supplementation beginning at 4 months of age experienced normal psychomotor development at 18 months compared to siblings who did not have the deficiency. Stockler-Ipsiroglu and coworkers [151] evaluated the effects of creatine monohydrate supplementation (0.3 – 0.8 g/kg/day) in 48 children with GMAT deficiency with clinical manifestations of global developmental delay/intellectual disability (DD/ID) with speech/language delay and behavioral problems (n = 44), epilepsy (n = 35), or movement disorder (n = 13). The median age at treatment was 25.5 months, 39 months, and 11 years in patients with mild, moderate, and severe DD/ID, respectively. The researchers found that creatine supplementation increased brain creatine levels and improved or stabilized clinical symptoms. Moreover, four patients treated younger than 9 months had normal or almost normal developmental outcomes. Long-term creatine supplementation has also been used to treat patients with creatine deficiency-related gyrate atrophy [152‐156]. These findings and others provide promise that high-dose creatine monohydrate supplementation may be an effective adjunctive therapy for children and adults with creatine synthesis deficiencies [18, 145, 157‐159]. Additionally, these reports provide strong evidence regarding the long-term safety and tolerability of high-dose creatine supplementation in pediatric populations with creatine synthesis deficiencies, including infants less than 1 year of age [157].

A number of studies have investigated the short and long-term therapeutic benefit of creatine supplementation in children and adults with various neuromuscular diseases like muscular dystrophies [160‐165], Huntington’s disease [23, 166‐171]; Parkinson disease [23, 40, 166, 172‐174]; mitochondria-related diseases [29, 175‐177]; and, amyotrophic lateral sclerosis or Lou Gehrig’s Disease [166, 178‐184]. These studies have provided some evidence that creatine supplementation may improve exercise capacity and/or clinical outcomes in these patient populations. However, Bender and colleagues [23] recently reported results of several large clinical trials evaluating the effects of creatine supplementation in patients with Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS). A total of 1,687 patients took an average of 9.5 g/day of creatine for a total of 5,480 patient years. Results revealed no clinical benefit on patient outcomes in patients with PD or ALS. However, there was some evidence that creatine supplementation slowed down progression of brain atrophy in patients with HD (although clinical markers were unaffected). Whether creatine supplementation may have a role in mediating other clinical markers in these patient populations and/or whether individual patients may respond more positively to creatine supplementation than others, remain to be determined. Nevertheless, these studies show that creatine supplementation has been used to treat children and adults with neurodegenerative conditions and is apparently safe and well-tolerated when taking up to 30 g/day for 5 years in these populations.

Creatine and phosphocreatine play an important role in maintaining myocardial bioenergetics during ischemic events [33]. For this reason, there has been interest in assessing the role of creatine or phosphocreatine in reducing arrhythmias and/or improving heart function during ischemia [185‐194]. In a recent review, Balestrino and colleagues [33] concluded that phosphocreatine administration, primarily as an addition to cardioplegic solutions, has been used to treat myocardial ischemia and prevent ischemia-induced arrhythmia and improve cardiac function with some success. They suggested that creatine supplementation may protect the heart during an ischemic event. Thus, prophylactic creatine supplementation may be beneficial for patients at risk for myocardial ischemia and/or stroke.

A growing collection of evidence supports that creatine supplementation may improve health status as individuals age [41, 43‐45, 195]. In this regard, creatine supplementation has been reported to help lower cholesterol and triglyceride levels [67, 196]; reduce fat accumulation in the liver [197]; reduce homocysteine levels [198]; serve as an antioxidant [199‐202]; enhance glycemic control [132, 203‐205]; slow tumor growth in some types of cancers [32, 198, 206, 207]; increase strength and/or muscle mass [37, 41, 44, 45, 82, 208‐212]; minimize bone loss [211, 212]; improve functional capacity in patients with knee osteoarthritis [213] and fibromyalgia [214]; positively influence cognitive function [43, 83, 195]; and in some instances, serve as an anti-depressant [215‐217].

For example, Gualano and associates supplemented patients with type II diabetes with a placebo or creatine (5 g/day) for 12 weeks during training. Creatine supplementation significantly decreased HbA1c and glycemic response to standardized meal as well as increased GLUT-4 translocation. These findings suggest that creatine supplementation combined with an exercise program improves glycemic control and glucose disposal in type 2 diabetic patients. Candow and others [211] reported that low-dose creatine (0.1 g/kg/day) combined with protein supplementation (0.3 g/kg/day) increased lean tissue mass and upper body strength while decreasing markers of muscle protein degradation and bone resorption in older men (59–77 years). Similarly, Chilibeck et al. [212] reported that 12 months of creatine supplementation (0.1 g/kg/day) during resistance training increased strength and preserved femoral neck bone mineral density and increased femoral shaft subperiosteal width in postmenopausal women. A recent meta-analysis [80] of 357 elderly individuals (64 years) participating in an average of 12.6 weeks of resistance training found that participants supplementing their diet with creatine experienced greater gains in muscle mass, strength, and functional capacity. These findings were corroborated in a meta-analysis of 405 elderly participants (64 years) who experienced greater gains in muscle mass and upper body strength with creatine supplementation during resistance-training compared to training alone [37]. These findings suggest that creatine supplementation can help prevent sarcopenia and bone loss in older individuals.

Finally, a number of studies have shown that creatine supplementation can increase brain creatine content generally by 5 – 15% [218‐220]. Moreover, creatine supplementation can reduce mental fatigue [221] and/or improve cognitive function [83, 222‐225]. For example, Watanabe et al. [221] reported that creatine supplementation (8 g/day for 5 days) reduced mental fatigue when subjects repeatedly performed a simple mathematical calculation as well as increased oxygen utilization in the brain. Rae and colleagues [222] reported that creatine supplementation (5 g/day for 6 weeks) significantly improved working memory and intelligence tests requiring speed of processing. McMorris and coworkers [224] found that creatine supplementation (20 g/day for 7 days) after sleep deprivation demonstrated significantly less decrement in performance in random movement generation, choice reaction time, balance and mood state suggesting that creatine improves cognitive function in response to sleep deprivation. This research group also examined the effects of creatine supplementation (20 g/day for 7 days) on cognitive function in elderly participants and found that creatine supplementation significantly improved performance on random number generation, forward spatial recall, and long-term memory tasks. Ling and associates [225] reported that creatine supplementation (5 g/day for 15 days) improved cognition on some tasks. Since creatine uptake by the brain is slow and limited, current research is investigating whether dietary supplementation of creatine precursors like GAA may promote greater increases in brain creatine [226, 227]. One recent study suggested that GAA supplementation (3 g/day) increased brain creatine content to a greater degree than creatine monohydrate [227].

Since creatine supplementation has been shown to improve brain and heart bioenergetics during ischemic conditions and possess neuroprotective properties, there has been recent interest in use of creatine during pregnancy to promote neural development and reduce complications resulting from birth asphyxia [228‐237]. The rationale for creatine supplementation during pregnancy is that the fetus relies upon placental transfer of maternal creatine until late in pregnancy and significant changes in creatine synthesis and excretion occur as pregnancy progresses [230, 232]. Consequently, there is an increased demand for and utilization of creatine during pregnancy. Maternal creatine supplementation has been reported to improve neonatal survival and organ function following birth asphyxia in animals [228, 229, 231, 233‐235, 237]. Human studies show changes in the maternal urine and plasma creatine levels across pregnancy and association to maternal diet [230, 232]. Consequently, it has been postulated that there may be benefit to creatine supplementation during pregnancy on fetal growth, development, and health [230, 232]. This area of research may have broad implications for fetal and child development and health.