Limited trials have shown creatine to enhance performance of short-duration, high-intensity exercise. A systematic review provided evidence for a beneficial effect in various muscular dystrophies, but the data do not demonstrate the same positive effect in patients with metabolic myopathies. Preliminary data suggest that creatine may be beneficial in neurodegenerative diseases, such as amyotrophic lateral sclerosis and Huntington and Parkinson diseases, but larger clinical studies are required to confirm this benefit. Case reports show benefits of creatine supplementation in 2 of the 3 creatine deficiency syndromes identified, and it is hypothesized that these 2 syndromes may be partly or completely cured by early and long-term creatine supplementation. More clinical trials are needed to confirm this effect.
Oral doses range from 2 to 35 g daily. Loading doses are usually 20 g/day for up to 1 week, and maintenance doses are 5 g/day.
Patients with a history of renal function impairment or diabetes, or those taking nephrotoxic agents, should avoid concomitant creatine supplementation or be monitored closely if supplementation is necessary.
Information regarding safety and efficacy in pregnancy and lactation is lacking.
None well documented.
Most reports of adverse reactions remain anecdotal because they lack documentation in well-controlled trials. The only well-documented adverse reaction is an increase in body mass. Anecdotal reports include minor GI upset, dehydration, heat-related illnesses, reduced blood volume, electrolyte imbalances, and muscle cramping.
Research reveals little or no information regarding toxicology with the use of this product.
Creatine is acquired exogenously through the diet or is endogenously synthesized in the body. It is a constituent of muscle tissue and occurs naturally in meat, fish, and other animal products, with trace amounts found in milk and some plants. Herring contains 6.5 to 10 g/kg of creatine, while beef, pork, salmon, and tuna all contain approximately 4 to 5 g/kg. 3 A typical American/Western diet provides 1 to 2 g/day; vegetarians consume much less and thus, their daily creatine needs are met completely via endogenous synthesis. 2 , 3 , 4 , 5 Endogenous creatine is synthesized from arginine and glycine by 2 enzymatic reactions; in the kidney, guanidinoacetic acid is produced and upon transfer to the liver, is methylated using methionine to form creatine. This process produces approximately 1 to 2 g/day of creatine. 6 Creatine is then transported via circulation to various tissues, in particular skeletal muscle, for utilization. 1 , 3 , 7
The majority of studies evaluating the effects of oral creatine supplementation have been conducted using creatine monohydrate powder. The effects of other supplement formulations, such as creatine citrate or creatine phosphate, have not been determined. Creatine monohydrate is available in several dose forms, including bar, candy, capsules, gel, gum, liquid, and powder. 8 The efficacy of some of these dose forms has not been demonstrated.
Creatine was discovered in 1832 by the French chemist Michel Chevreul as an organic constituent of meat. Muscle work was later associated with creatine in 1847 when it was observed that the flesh of wild foxes killed in the chase contained 10 times more creatine than those living in captivity. 3 In 1911, creatine was reported to be involved in muscle metabolism; it was demonstrated that oxygen consumption could be stimulated by adding creatine to muscle mince. In the early 1930s, it was suggested that creatine phosphate might serve as the source of energy for muscle contraction when its large free energy of hydrolysis (12 kcal/mol) was identified. By 1939, oxygen consumption was shown to be coupled to creatine phosphate synthesis in muscle, which confirmed that oxidative phosphorylation was indeed a function of creatine. 7
In the late 1960s, researchers began using needle biopsy techniques to study the breakdown and resynthesis of adenosine triphosphate (ATP) and creatine phosphate with exercise. It was not until the early 1990s that creatine's influence on exercise performance in humans began to be studied. Reports followed in 1992 of a 20% increase in human muscle mass subsequent to creatine supplementation. 3 , 9 Numerous studies have since been conducted in untrained or moderately trained subjects in the laboratory setting to determine the potential ergogenic value of creatine supplementation. 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 Benefit has extended beyond simple laboratory exercises, with enhanced sprint and weight-lifting performance reported in elite athletes. 10 , 21 , 22 , 23 , 27
Arginine and glycine undergo reversible transamidination in the human liver, pancreas, and kidney to form guanidinoacetic acid and ornithine. 3 , 7 Guanidinoacetic acid is then irreversibly N-methylated by S-adenosylmethionine in the presence of a methyltransferase to form creatine. 3 , 7 Creatine enters the circulation and is carried to utilization sites (eg, brain, heart, muscle, testes) where it is moved against a concentration gradient by a saturable sodium- and chloride-dependent creatine transport protein. 28 At these utilization sites, creatine and creatine phosphate react nonenzymatically to form creatinine, which is subsequently excreted by the kidneys. 3 , 7 , 28
Differing sites of creatine synthesis and utilization allow for independent regulation of each process. 3 Intra- and extracellular creatine regulation is controlled by feedback inhibition of the arginine-glycine amidinotransferase, which is dependent on changes in the relatively small amounts of circulating creatine and its precursors. 3 , 28 Secondary regulation appears to involve factors affecting creatine tissue entry and retention, possibly via control of expression and activity of the creatine transporter protein. 3 , 28 Additionally, a series of hormones have been identified that influence net creatine uptake into muscle cells, including catecholamines (eg, isoproterenol, norepinephrine), insulin (at supraphysiological levels), and insulin-like growth factor Ι. 28
Approximately 95% of the total creatine pool (free and phosphorylated forms) is found in human skeletal muscle. 2 , 3 Most of the remaining 5% is found in the brain, heart, retina, and spermatozoa. 3 , 5 , 29 The size of the total creatine pool is not under strict metabolic control and can be influenced by dietary creatine and the administration of precursor amino acids. Free creatine accounts for one-third of the total body creatine pool, with phosphorylated creatine making up the remaining two-thirds. 3
Creatinine output remains a constant fraction of the total creatine pool and can change independently of lean body mass. 3 , 30 , 31 Approximately 1.5% to 2% of the creatine pool is converted to creatinine daily and is excreted in the urine; in a 70 kg man with a total creatine pool of 120 g, this is equal to approximately 2 g/day. 1 , 3 , 31 Potential creatine uptake is reportedly higher when initial total creatine levels in muscle are low. 3 This is supported by several studies that have reported highest initial uptake on the first day of creatine supplementation relative to subsequent days and higher uptakes in vegetarian study subjects compared with omnivores. 3 Researchers also discovered that this initial high uptake was followed during subsequent days of supplementation by recovery of almost all of the administered supplemental creatine from the urine, indicating a possible upper limit or threshold for creatine storage. 3
Muscle fiber type has been shown to have an effect on muscle creatine concentrations. 3 Fast-twitch muscle fibers (type II) in human skeletal muscle have higher levels of creatine phosphate at rest than slow-twitch fibers (type I). 3 Gender was reported in 1 study to have an effect on total muscle creatine concentrations, but data are equivocal. 9 Other studies with small sample sizes (N < 20) have been unable to duplicate this result and have shown no gender differences in body composition values, total body water, total creatine before supplementation, or magnitude of creatine loading. 18 , 20
Aging does not appear to affect total muscle creatine concentrations. A shift in the creatine phosphate to creatine ratio occurs, which appears to be related to inactivity associated with increased age. 3 , 9 The percentage of creatine phosphate is lower, with corresponding higher free creatine, in elderly subjects. However, when these subjects are placed on a training program, percentages of creatine phosphate and free creatine have been observed to approach those of younger subjects. 3 The results of training on creatine concentrations in skeletal muscle are, however, equivocal. 3 In general, short-term training studies in young adults have failed to show any definite changes in free or phosphorylated creatine between trained and untrained subjects. 3Physiology
The role of creatine in facilitating energy distribution and responding to energy demand can be explained by the concept of the creatine phosphate shuttle, which arose from studies of insulin action. It was proposed that creatine from the contracting muscle provided the stimulus for oxygen uptake in much the same way that insulin causes the phosphorylation of glucose by ATP, yielding adenosine diphosphate (ADP) for respiratory control. 7
Creatine, released from contracting myofibrils during exercise, moves to the mitochondria and, in the presence of ATP, produces creatine phosphate and releases ADP. ADP then stimulates oxygen uptake. Creatine phosphate, synthesized in the mitochondria under anaerobic conditions, returns to the myofibril, where the MM isozyme of creatine kinase catalyzes the resynthesis of ATP as an energy source for subsequent contractions, mimicking the effect of insulin in attaching hexokinase to the mitochondrion during glucose phosphorylation. 7
Three major cell functions have been shown to be terminals for the creatine phosphate shuttle: (1) contraction (myofibrils are reliant on creatine phosphate to provide ATP for normal contraction), (2) macromolecular synthesis (creatine kinase inhibition results in parallel inhibition of lipid and protein synthesis), (3) and maintenance of ion gradients (creatine kinase is associated with ATP-dependent calcium transport and sodium-potassium ATPase). 7
Creatine kinase is most often found in human muscle, heart, and brain tissue, where its role is most important. The creatine pathway is thought to be associated with 2 distinct functions in these tissues: (1) to deliver creatine as the signal or stimulus for oxygen uptake, and (2) to provide creatine phosphate as an energy source. Creatine kinase has also been found in leukocytes and macrophages, as well as spermatozoa and in the uterus, where it is generally associated with contractile proteins and cell movement. 7 , 29Pathophysiology
Possible pathological consequences fall into 3 categories: (1) diseases in which pathogenesis is causally linked with a deficiency of creatine metabolism, (2) diseases in which creatine deficiency is a secondary symptom but still contributes to pathogenesis, or (3) diseases without manifestation of creatine deficiency. 32 , 33 Several diseases are related to energy deficiencies, some of which may be related to creatine metabolism disturbances caused by genetic deficiencies of L-arginine:glycine amidinotransferase or guanidinoacetate methyltransferase. 28 , 32 , 33 Muscular dystrophy may be related to myofibrillar or mitochondrial creatine kinase deficiencies. Heart and muscle disease caused by phosphate depletion may be a result of defects in the creatine phosphate shuttle; liver disease can impair the synthesis of the creatine precursors arginine and glycine. The liver is also the site of guanidinoacetic acid methylation and requires methionine; deficiency of this amino acid might be responsible for muscle weakness, and in the brain, for functional problems caused by creatine deficiency. The gene for the creatine transporter protein has been mapped to the human chromosome Xq28; this locus has also been linked to the genes for several neuromuscular disorders (eg, Emery-Dreifuss muscular dystrophy, Barth syndrome, infantile cardiomyopathy, myotubular myopathy). 28 It is also possible that creatine synthesis from arginine is impaired in gyrate atrophy of the retina, which presents as a failure in retinal energy generation. 7 Muscle hypertrophy of exercise is accompanied by the increased delivery of creatine phosphate to protein synthesis sites, which may provide insight into hypertensive cardiac hypertrophy; increased vascular resistance in hypertension would stimulate increased cardiac contraction and protein synthesis, resulting in an enlarged myocardium. 7
Uses and PharmacologyExercise performance enhancement
There is a large volume of scientific literature dealing with creatine supplementation in exercise performance. While it is hypothesized that creatine can act through a number of possible mechanisms as a potential ergogenic aid, it appears most effective for activities that involve repeated short-duration, high-intensity exercise (eg, jumping, sprinting, weight-lifting). 10 , 27 , 34 , 35 , 36
A recent meta-analysis 37 of 100 studies found an improvement in performance of repetitive, laboratory-based exercise tests but inconsistent results regarding sports-specific performance. 37 , 38 , 39 Some anaerobic studies have reported no ergogenic benefit, and studies of continuous and intermittent endurance exercise have shown decreased performance. One factor that may account for these discrepancies is the increased total body weight associated with creatine ingestion, which could be detrimental in activities in which body mass is an important factor (eg, endurance running, swimming). 5 , 10 , 14 , 20 , 22 , 40 , 41 , 42 , 43 , 44 , 45
Creatine supplementation increases pre-exercise total creatine, increases availability of creatine phosphate, yields smaller decreases in muscle pH, and allows for a higher rate of creatine phosphate resynthesis during recovery. 3 This increased availability augments the physiological capacity for activities that are primarily limited by the rapid availability of ATP to produce a high force of power and short-term repetitive force production. This is supported by the ergogenic benefit reported in most studies: improved performance in high-intensity, short-duration, intermittent exercise; and improved fatigue resistance. 1 , 3 , 8 , 12 , 13 , 15 , 16 , 18 , 19 , 21 , 23 , 24 , 38 , 39 , 41 , 42 , 44
Acute increases in strength or power performance may improve quality of training in some individuals and provide quicker gains toward an individual's genetic potential. 8 This is most likely to be of benefit in elite athletes who are training intensely and would benefit from even the smallest gains in performance. The positive effect of creatine loading on creatine phosphate resynthesis and improvement in exercise performance is highly variable among individuals and appears to be closely related to the extent of muscle creatine uptake during supplementation. 28 , 46
The benefit of creatine supplementation on postexercise creatine phosphate resynthesis was not apparent when creatine uptake of less than 20 mmol/kg. 28 , 46 Approximately 20% to 30% of individuals are considered nonresponders, showing a less than 10 mmol/kg (8%) increase in total creatine following the standard creatine loading regimen used in most studies (20 g/day for 5 to 7 days). 28 , 46 Individuals with an initial total creatine near or at the creatine saturation point (150 to 160 mmol/kg) do not demonstrate improved uptake or performance following creatine ingestion. 1 Normal muscle creatine concentrations average 120 mmol/kg (range, 100 to 140 mmol/kg); the maximum total creatine concentration of 150 to 160 mmol/kg is achieved by only approximately 20% of subjects. 3 , 5 , 7 , 46 , 47
Creatine uptake was augmented by as much as 10% when supplementation was given in conjunction with submaximal exercise and by an average of 60% when given in combination with carbohydrates (creatine 20 g/day for 5 days with 370 g/day simple carbohydrates). 5 , 47 , 48 The administration of carbohydrates yields an increase in insulin that enhances the transfer of creatine into muscle cells and increases skeletal muscle creatine retention. 28 No additional benefit in creatine uptake was observed with carbohydrate ingestion plus exercise. Conversely, muscle creatine loss increased during fasting. 47
Studies evaluating the ergogenic properties of creatine supplementation have routinely used a loading dose of 20 to 30 g/day divided into 4 to 5 equal doses for 5 to 9 days (0.3 g/kg/day), following a 1992 study that first reported an ability to increase skeletal muscle total creatine content after dietary supplementation for more than 2 days. 8 , 9 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 25 , 49 Most studies indicate an increase in total body mass by approximately 0.7 to 1.6 kg following short-term supplementation (20 to 25 g/day for 5 to 7 days), most likely caused by water retention, because protein synthesis changes would probably not be reflected in this time frame. Long-term supplementation trials (20 to 25 g/day for 5 to 7 days and 2 to 25 g/day for up to 84 days) have reported greater gains (0.8 to 3 kg) in total body mass and fat-free mass with no change in the percentage of total body water, suggesting enhanced lean tissue accretion. 5 , 18 One recent study reported improved performance subsequent to a 6-day, low-dose creatine regimen of 0.1 g/kg per lean body mass (average, 7.7 g/day). 24 A maintenance dose of 2 to 5 g/day for up to 10 weeks has been used in an effort to determine the lowest dose required to maintain long-term creatine stores. 8 , 21 , 49 However, further studies are needed, as creatine levels at 1 month did not differ between healthy subjects who ingested only a 6-day loading dose and those who followed the loading dose with 2 g/day for 30 more days. 17
Endogenous production of creatine is reversibly inhibited after creatine supplementation, as indicated by the return of muscle creatine concentrations to presupplementation levels within 4 weeks of discontinuing supplementation. 1 , 17 , 20
It is important to note that creatine is widely used among professional athletes. However, in 2000, the US National Collegiate Athletic Association banned colleges from distributing creatine to collegiate athletes. 50Muscle disorders
Progressive weakness is a symptom of most muscle diseases and, in theory, creatine monohydrate supplementation may be of benefit in improving muscle strength.
In a Cochrane review of randomized controlled trials 51 including 266 participants with muscular dystrophies, there was an increase in maximum voluntary contraction in the creatine group (n = 138) compared with the placebo group, with a weighted mean difference of 8.47% (confidence interval [CI], 3.55 to 13.38). 52 , 53 , 54 , 55 , 56 , 57
There was also an increase in lean body mass during creatine treatment compared with placebo (0.63 kg; CI, 0.02 to 1.25). 55 , 56 , 57 In contrast to previous information, the same Cochrane review 51 concluded that there was no improvement in muscle strength in people with metabolic myopathies. In 3 trials with 33 participants treated with creatine, there was no difference in maximum voluntary contraction between creatine and placebo groups (2.26%; CI, 6.29 to 1.78). 58 , 59 , 60 The discrepancy between the fairly consistent effects noted in muscular dystrophy compared with metabolic myopathies is not clear, although the smaller number of participants in the latter group may have led to a type 2 statistical error.
Given that a reduction in total muscle mass and strength are characteristic hallmarks of muscular dystrophy, even the slightest improvement with creatine supplementation could be of functional importance. The benefits shown in these short- and medium-term studies need to be assessed in long-term studies.Neurodegenerative disorders
Creatine has been linked to neuroprotection in animal models of Huntington disease 61 , 62 , 63 , 64 and also in rats with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson disease. 65 These studies provide preliminary evidence that creatine may slow the progression of Huntington disease, 66 but larger studies measuring clinical outcomes rather than biomarkers for the disease are required. 67
Promising evidence exists for creatine efficacy in animal models of amyotrophic lateral sclerosis. 66 , 68 , 69 , 70 , 71 However, limited clinical trials demonstrated little benefit from creatine supplementation on primary outcomes of survival and respiratory function. 66 , 72 , 73 , 74 Beneficial effects were shown for outcomes such as short-term muscle strength and motor function. 75 , 76Creatine deficiency syndromes
Three types of creatine deficiency syndrome have been explained: (1) guanidinoacetate methyltransferase (GAMT) deficiency; (2) arginine:glycine amidinotransferase deficiency; and (3) X-linked creatine transporter deficiency. 32 , 77 An infant with GAMT deficiency treated with creatine for 25 months demonstrated substantial clinical improvement and normalization of creatine stores. 78 Similarly, creatine supplementation in infants with arginine:glycine amidinotransferase deficiency showed normalization of brain creatine and functional improvement. 79 , 80 However, creatine is of no benefit in X-linked creatine transporter deficiency because the distribution, not the availability, of creatine in the body is impaired. 81Sarcopenia (age-related muscle loss)
The results of studies using creatine in elderly patients to reduce loss of muscle mass are equivocal. 82 In one study, creatine supplementation (5 g/day) increased intramuscular total creatine, strength, and lean-tissue mass in older adults during 14 weeks of resistance training. 83 Other studies found an increase in lean tissue mass in older men after 7 days of creatine supplementation 84 and after 12 weeks of creatine supplementation and resistance training. 85 However, other studies in older men and/or women failed to observe an increase in lower limb muscle mass after 8 weeks of creatine supplementation and resistance training 86 or in muscle mass after creatine supplementation. 87 , 88Aging skin
There are limited in vivo data suggesting that topical and/or systemic administration of creatine or phosphocreatine may have beneficial effects on various skin conditions, such as photoaging and wound healing. 89 , 90 Creatine can activate a wide range of physiological processes in skin cells via improvement in energy levels that are directly available for the repair and protection of mature human skin. 90Other uses
Creatine supplementation demonstrated no effect on the lipid profiles of healthy young men, but preliminary data in men and women with total cholesterol of more than 200 mg/dL suggested that creatine supplementation (5 g/day for 56 days) may modulate lipid metabolism in hyperlipidemia. 91 , 92
Creatine supplementation has been evaluated in patients with various other diseases, including gyrate atrophy of the choroids and retina, myophosphorylase deficiency (glycogenesis type 5), some mitochondrial cytopathies, rheumatoid arthritis, and congestive heart failure. 59 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102
Creatine has been widely studied as an athletic supplement, in Huntington disease, and in muscular dystrophies. Oral doses range from 2 to 35 g daily, 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 usually 20 g/day for up to 1 week for loading doses and 5 g/day for maintenance doses. 110 The observed safe-level risk assessment method indicates that safety evidence is strong at intakes of up to 5 g/day for chronic supplementation. 111 Much higher levels have been used without adverse reactions and may be safe, but long-term safety data are lacking. 111
Information regarding safety and efficacy in pregnancy and lactation is lacking.
None well documented.
Evidence for long- or short-term adverse reactions from creatine monohydrate supplementation taken in recommended doses has not been found in either prospective or retrospective studies in healthy subjects. 111 , 112 , 113 , 114 , 115
Safety results are similar in studies in patients treated with creatine for clinical conditions. Few adverse reactions have been reported in trials in patients with neurological and muscle disorders, 51 , 107 , 116 , 117 , 118 and no adverse effects were reported in small studies of gyrate atrophy patients receiving supplementation of normal dietary intake (1.5 to 2 g/day) for up to 6 years. 92 , 94
Most reports of adverse reactions remain anecdotal because documentation in well-controlled trials is lacking. 112 Creatine supplementation elevates urinary and serum creatinine, which can increase the creatinine load on the kidneys; healthy kidneys appear to manage short-term creatine loading without compromised function. 49 , 119 However, patients with a history of renal function impairment or diabetes or those taking nephrotoxic agents should avoid concomitant creatine supplementation or be monitored closely if supplementation is necessary. 113 , 114 , 120 , 121 , 122 Healthy individuals should consider regular testing to detect any potential renal function impairment because of unknown decreased compensatory mechanisms. 114
Anecdotal reports of adverse reactions include dehydration, heat-related illnesses, reduced blood volume, electrolyte imbalances, and muscle cramping. 2 , 8 , 114 Intracellular fluid retention in the muscle cell may predispose to dehydration, but studies are lacking; a dehydrated state before exercise decreases renal concentrating ability. 114 , 120 Optimal hydration is recommended during supplementation to reduce risk of hydration-related adverse reactions. 114 , 120
Two randomized controlled trials reported minor GI upset (eg, diarrhea, dizziness, GI pain, nausea) 85 , 123 ; however, there was no overall difference in adverse reactions between creatine and placebo groups. 123
Supplementation studies using creatine for up to 8 weeks have reported minimal or no liver enzyme elevation 19 , 124 , 125 ; however, some concern exists regarding the reversibility of endogenous creatine synthesis suppression after long-term supplementation. 120 Additionally, no evidence for alterations in blood pressure, renal indices, or plasma creatine kinase activity was found in a study in young healthy men and women. 113
A theoretical concern exists regarding the neurological effect of oral creatine supplementation. Three of 32 documented complaints to the US Food and Drug Administration regarding creatine supplementation have involved seizures. 114 , 120 No causal relationship has been established. 120
The safety of creatine in children younger than 18 years of age has not been established. 8 , 126 A theoretical concern exists regarding the extra creatine load placed on developing organs, particularly the kidneys, as well as the effects on muscle and bone junctions in the skeletally immature. 120
Data are limited in elderly patients; 1 study (N = 32) evaluating the effects of creatine ingestion in sedentary and weight-trained older adults (67 to 80 years of age) reported no adverse reactions with a 52-day oral supplementation regimen (20 g/day for 5 days, followed by 3 g/day for 47 days). 49
Research reveals little or no information regarding toxicology with the use of this product.
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