Creatine

Scientific Name(s):Methylguanidine acetic acid, N-amidinosarcosine 1 , 2

Uses

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.

Dosing

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.

Contraindications

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.

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

None well documented.

Adverse Reactions

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.

Toxicology

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.

History

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

Chemistry

Biochemistry

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. 3

Physiology

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 , 29

Pathophysiology

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 Pharmacology

Exercise 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. 50

Muscle 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 , 76

Creatine 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. 81

Sarcopenia (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 , 88

Aging 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. 90

Other 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

Dosage

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

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

None well documented.

Adverse Reactions

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

One trial reported an increase in muscle pain during high-dose creatine treatment (150 mg/kg body weight) in glycogen storage disease type V 60 but the reason was unknown. 51

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

An increase in body mass is well documented in controlled trials with creatine supplementation, 5 , 18 , 93 which could have negative effects on mass-dependent activities. 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

Toxicology

Research reveals little or no information regarding toxicology with the use of this product.

Bibliography

1. Casey A, Greenhaff PL. Does dietary creatine supplementation play a role in skeletal muscle metabolism and performance? Am J Clin Nutr . 2000;72(2 suppl):607S-617S.
2. Ööpik V, Timpmann S, Medijainen L. The role and application of dietary creatine supplementation in increasing physical performance capacity. Biol Sport . 1995;12(4):197-212.
3. Balsom PD, Söderlund K, Ekblom B. Creatine in humans with special reference to creatine supplementation. Sports Med . 1994;18(4):268-280.
4. Graham AS, Hatton RC. Creatine: A review of efficacy and safety. J Am Pharm Assoc . 1999;39(6):803-810.
5. Mujika I, Padilla S. Creatine supplementation as an ergogenic aid for sports performance in highly trained athletes: A critical review. Int J Sports Med . 1997;18(7):491-496.
6. Pearlman JP, Fielding RA. Creatine monohydrate as a therapeutic aid in muscular dystrophy. Nutr Rev . 2006;64(2, pt 1):80-88.
7. Bessman SP, Carpenter CL. The creatine-creatine phosphate energy shuttle. Annu Rev Biochem . 1985;54:831-862.
8. Kraemer WJ, Volek JS. Creatine supplementation. Its role in human performance. Clin Sports Med . 1999;18(3):651-666.
9. Forsberg AM, Nilsson E, Werneman J, Bergström J, Hultman E. Muscle composition in relation to age and sex. Clin Sci (Lond) . 1991;81(2):249-256.
10. Bemben MG, Lamont HS. Creatine supplementation and exercise performance: recent findings. Sports Med . 2005;35(2):107-125.
11. Harris RC, Söderlund K, Hultman E. Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation. Clin Sci (Lond) . 1992;83(3):367-374.
12. Greenhaff PL, Casey A, Short AH, Harris R, Söderlund K, Hultman E. Influence of oral creatine supplementation of muscle torque during repeated bouts of maximal voluntary exercise in man. Clin Sci (Lond) . 1993;84(5):565-571.
13. Balsom PD, Ekblom B, Söderlund K, Sjödin B, Hultman E. Creatine supplementation and dynamic high-intensity intermittent exercise. Scand J Med Sci Sports . 1993;3:143-149.
14. Balsom PD, Harridge SD, Söderlund K, Sjödin B, Ekblom B. Creatine supplementation per se does not enhance endurance exercise performance. Acta Physiol Scand . 1993;149(4):521-523.
15. Earnest CP, Snell PG, Rodriguez R, Almada AL, Mitchell TL. The effect of creatine monohydrate ingestion on anaerobic power indices, muscular strength and body composition. Acta Physiol Scand . 1995;153(2):207-209.
16. Casey A, Constantin-Teodosiu D, Howell S, Hultman E, Greenhaff PL. Creatine ingestion favorably affects performance and muscle metabolism during maximal exercise in humans. Am J Physiol . 1996;271(1, pt 1):E31-E37.
17. Hultman E, Söderlund K, Timmons JA, Cederblad G, Greenhaff PL. Muscle creatine loading in men. J Appl Physiol . 1996;81(1):232-237.
18. Grindstaff P, Kreider R, Bishop R, et al. Effects of creatine supplementation on repetitive sprint performance and body composition in competitive swimmers. Int J Sport Nutr . 1997;7(4):330-346.
19. Kreider RB, Ferreira M, Wilson M, et al. Effects of creatine supplementation on body composition, strength, and sprint performance. Med Sci Sports Exerc . 1998;30(1):73-82.
20. McKenna MJ, Morton J, Selig SE, Snow RJ. Creatine supplementation increases muscle total creatine but not maximal intermittent exercise performance. J Appl Physiol . 1999;87(6):2244-2252.
21. Jones AM, Atter T, Georg KP. Oral creatine supplementation improves multiple sprint performance in elite ice-hockey players. J Sports Med Phys Fitness . 1999;39(3):189-196.
22. Deutekom M, Beltman JG, de Ruiter CJ, de Koning JJ, de Haan A. No acute effects of short-term creatine supplementation on muscle properties and sprint performance. Eur J Appl Physiol . 2000;82(3):223-229.
23. Mujika I, Padilla S, Ibañez J, Izquierdo M, Gorostiaga E. Creatine supplementation and sprint performance in soccer players. Med Sci Sports Exerc . 2000;32(2):518-525.
24. Burke DG, Silver S, Holt LE, Smith Palmer T, Culligan CJ, Chilibeck PD. The effect of continuous low dose creatine supplementation on force, power, and total work. Int J Sport Nutr Exerc Metab . 2000;10(3):235-244.
25. Hamilton KL, Meyers MC, Skelly WA, Marley RJ. Oral creatine supplementation and upper extremity anaerobic response in females. Int J Sport Nutr Exerc Metab . 2000;10(3):277-289.
26. Murphy AJ, Watsford ML, Coutts AJ, Richards DA. Effects of creatine supplementation on aerobic power and cardiovascular structure and function. J Sci Med Sport . 2005;8(3):305-313.
27. Rawson ES, Volek JS. Effects of creatine supplementation and resistance training on muscle strength and weightlifting performance. J Strength Cond Res . 2003;17(4):822-831.
28. Guerrero-Ontiveros ML, Wallimann T. Creatine supplementation in health and disease. Effects of chronic creatine ingestion in vivo: down-regulation of the expression of creatine transporter isoforms in skeletal muscle. Mol Cell Biochem . 1998;184(1-2):427-437.
29. Moore NP. The distribution, metabolism and function of creatine in the male mammalian reproductive tract: a review. Int J Androl . 2000;23(1):4-12.
30. Crim MC, Calloway DH, Margen S. Creatine metabolism in men: creatine pool size and turnover in relation to creatine intake. J Nutr . 1976;106:371-381.
31. Crim MC, Calloway DH, Margen S. Creatine metabolism in men: urinary creatine and creatinine excretions with creatine feeding. J Nutr . 1975;105(4):428-438.
32. Derave W, Eijnde BO, Hespel P. Creatine supplementation in health and disease: what is the evidence for long-term efficacy? Mol Cell Biochem . 2003;244(1-2):49-55.
33. Schulae A. Creatine deficiency syndromes. Mol Cell Biochem . 2003;244(1-2):143-150.
34. Racette SB. Creatine supplementation and athletic performance. J Orthop Sports Phys Ther . 2003;33(10):615-621.
35. Volek JS, Rawson ES. Scientific basis and practical aspects of creatine supplementation for athletes. Nutrition . 2004;20(7-8):609-614.
36. Kreider RB. Effects of creatine supplementation on performance and training adaptations. Mol Cell Biochem . 2003;244(1-2):89-94.
37. Branch JD. Effect of creatine supplementation on body composition and performance: a meta-analysis. Int J Sport Nutr Exerc Metab . 2003;13(2):198-226.
38. Redondo DR, Dowling EA, Graham BL, Almada AL, Williams MH. The effect of oral creatine monohydrate supplementation on running velocity. Int J Sport Nutr . 1996;6(3):213-221.
39. Skare OC, Skadberg, Wisnes AR. Creatine supplementation improves sprint performance in male sprinters. Scand J Med Sci Sports . 2001;11(2):96-102.
40. Jones AM, Carter H, Pringle JS, Campbell IT. Effect of creatine supplementation on oxygen uptake kinetics during submaximal cycle exercise. J Appl Physiol . 2002;92(6):2571-2577.
41. Syrotuik DG, Game AB, Gillies EM, Bell GJ. Effects of creatine monohydrate supplementation during combined strength and high intensity rowing training on performance. Can J Appl Physiol . 2001;26(6):527-542.
42. Cottrell GT, Coast JR, Herb RA. Effect of recovery interval on multiple-bout sprint cycling performance after acute creatine supplementation. J Strength Cond Res . 2002;16(1):109-116.
43. Preen D, Dawson B, Goodman C, Lawrence S, Beilby J, Ching S. Pre-exercise oral creatine ingestion does not improve prolonged intermittent sprint exercise in humans. J Sports Med Phys Fitness . 2002;42(3):320-329.
44. Finn JP, Ebert TR, Withers RT, et al. Effect of creatine supplementation on metabolism and performance in humans during intermittent sprint cycling. Eur J Appl Physiol . 2001;84(3):238-243.
45. Edwards MR, et al. The effect of creatine supplementation on anaerobic performance in moderately active men. J Strength Cond Res . 2000;14(1):75-79.
46. Greenhaff PL. Creatine supplementation: recent developments. Br J Sports Med . 1996;30(4):276-277.
47. Green AL, Simpson EJ, Littlewood JJ, Macdonald IA, Greenhaff PL. Carbohydrate ingestion augments creatine retention during creatine feeding in humans. Acta Physiol Scand . 1996;158(2):195-202.
48. Green AL, Sewell DA, Simpson L, Hultman E, Macdonald IA, Greenhaff PL. Creatine ingestion augments muscle creatine uptake and glycogen synthesis during carbohydrate feeding in man. J Physiol . 1996;491:63P-64P.
49. Bermon S, Venembre P, Sachet C, Valour S, Dolisi C. Effects of creatine monohydrate ingestion in sedentary and weight-trained older adults. Acta Physiol Scand . 1998;164(2):147-155.
50. NCAA Legislature Assistance. Nutritional Supplements. http://www1.ncaa.org/membership/ed_outreach/health-safety/drug_ed_progs/nutrional_supplements . Accessed: September 10, 2008.
51. Kley RA, Vorgerd M, Tarnopolsky MA. Creatine for treating muscle disorders. Cochrane Database Syst Rev . 2007 Jan 24;(1):CD004760.
52. Escolar DM, Buyse G, Henricson E, et al. CINRG randomized controlled trial of creatine and glutamine in Duchenne muscular dystrophy. Ann Neurol . 2005;58(1):151-155.
53. Louis M, Lebacq J, Poortmans JR, et al. Beneficial effects of creatine supplementation in dystrophic patients. Muscle Nerve . 2003;27(5):604-610.
54. Schneider-Gold C, Beck M, Wessig C, et al. Creatine monohydrate in DM2/PROMM: a double-blind placebo-controlled clinical study. Proximal myotonic myopathy. Neurology . 2003;60(3):500-502.
55. Tarnopolsky MA, Mahoney DJ, Vajsar J, et al. Creatine monohydrate enhances strength and body composition in Duchenne muscular dystrophy. Neurology . 2004;62(10):1771-1777.
56. Tarnopolsky M, Mahoney D, Thompson T, Naylor H, Doherty TJ. Creatine monohydrate supplementation does not increase muscle strength, lean body mass, or muscle phosphocreatine in patients with myotonic dystrophy type I. Muscle Nerve . 2004;29(1):51-58.
57. Walter MC, Reilich P, Lochmüller H, et al. Creatine monohydrate in myotonic dystrophy: a double-blind, placebo-controlled clinical study. J Neurol . 2002;249(12):1717-1722.
58. Kornblum C, Schröder R, Müller K, et al. Creatine has no beneficial effect on skeletal muscle energy metabolism in patients with single mitochondrial DNA deletions: a placebo-controlled, double-blind 31P-MR5 crossover study. Eur J Neurol . 2005;12(4):300-309.
59. Tarnopolsky MA, Roy BD, MacDonald JR. A randomized, controlled trial of creatine monohydrate in patients with mitochondrial cytopathies. Muscle Nerve . 1997;20(12):1502-1509.
60. Vorgerd M, Zange J, Kley R, et al. Effect of high-dose creatine therapy on symptoms of exercise intolerance in McArdle disease: double-blind, placebo-controlled crossover study. Arch Neurol . 2002;59(1):97-101.
61. Dedeoglu A, Kubilus JK, Yang L, et al. Creatine therapy provides neuroprotection after onset of clinical symptoms in Huntington's disease transgenic mice. J Neurochem . 2003;85(6):1359-1367.
62. Matthews RT, Yang L, Jenkins BG, et al. Neuroprotective effects of creatine and cyclocreatine in animal models of Huntington's disease. J Neurosci . 1998;18(1):156-163.
63. Andreassen OA, Dedeoglu A, Ferrante RJ, et al. Creatine increases survival and delays motor symptoms in a transgenic animal model of Huntington's disease. Neurobiol Dis . 2001;8(3):479-491.
64. Ferrante RJ, Andreassen OA, Jenkins BG, et al. Neuroprotective effects of creatine in a transgenic mouse model of Huntington's disease. J Neurosci . 2000;20(12):4389-4397.
65. Matthews RT, Ferrante RJ, Klivenyi P, et al. Creatine and cyclocreatine attenuate MPTP neurotoxicity. Exp Neurol . 1999;157(1):142-149.
66. Ellis AC, Rosenfeld J. The role of creatine in the management of amyotrophic lateral sclerosis and other neurogenerative disorders. CNS Drugs . 2004;18(14):967-980.
67. Ryu H, Rosas HD, Hersch SM, Ferrante RJ. The therapeutic role of creatine in Huntington's disease. Pharmacol Ther . 2005;108(2):193-207.
68. Derave W, Van Den Bosch L, Lemmens G, Eijnde BO, Robberecht W, Hespel P. Skeletal muscle properties in a transgenic mouse model for amyotrophic lateral sclerosis: effects of creatine treatment. Neurobiol Dis . 2003;13(3):264-267.
69. Andreassen OA, Jenkins BG, Dedeoglu A, et al. Increases in cortical glutamate concentrations in transgenic amyotrophic lateral sclerosis mice are attenuated by creatine supplementation. J Neurochem . 2001;77(2):383-390.
70. Zhang W, Narayanan M, Friedlander RM. Additive neuroprotective effects of minocycline with creatine in a mouse model of ALS. Ann Neurol . 2003;53(2):267-270.
71. Klivenyi P, Kiaei M, Gardian G, Calingasan NY, Beal MF. Additive neuroprotective effects of creatine and cyclooxygenase 2 inhibitors in a transgenic mouse model of amyotrophic lateral sclerosis. J Neurochem . 2004;88(3):576-582.
72. Shefner J, et al. A clinical trial of creatine in patients with amyotrophic lateral sclerosis. Abstracts from the 14th International Symposium on ALS/MND. Amyotroph Lateral Scler Other Motor Neuron Disord . 2003;4(suppl 1):28-29.
73. Groeneveld GJ, Veldink JH, van der Tweel I, et al. A randomized sequential trial of creatine in amyotrophic lateral sclerosis. Ann Neurol . 2003;53(4):437-445.
74. Drory VE, Gross D. No effect of creatine on respiratory distress in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Disord . 2002;3(1):43-46.
75. Mazzini L, Balzarini C, Colombo R, et al. Effects of creatine supplementation on exercise performance and muscular strength in amyotrophic lateral sclerosis: preliminary results. J Neurol Sci . 2001;191(1-2):139-144.
76. Rosenfeld J, et al. A pilot trial of ultrapure creatine in amyotrophic lateral sclerosis (abstract). Amyotroph Lateral Scler Other Motor Disord . 2001;2 (suppl 2) (1466-0822):20.
77. Salomons GS, van Dooren SJ, Verhoeven NM, et al. X-linked creatine-transporter gene (SLC6A8) defect: a new creatine-deficiency syndrome. Am J Hum Genet . 2001;68(6):1497-1500.
78. Stöckler S, Hanefeld F, Frahm J. Creatine replacement therapy in guanidinoacetate methyltransferase deficiency, a novel inborn error of metabolism. Lancet . 1996;348(9030):789-790.
79. Item CB, Stöckler-Ipsiroglu S, Stromberger C, et al. Arginine:glycine amidinotransferase deficiency: the third inborn error of creatine metabolism in humans. Am J Hum Genet . 2001;69(5):1127-1133.
80. Bianchi MC, Tosetti M, Fornai F, et al. Reversible brain creatine deficiency in two sisters with normal blood creatine level. Ann Neurol . 2000;47(4):511-513.
81. Cecil KM, Salomons GS, Ball WS Jr, et al. Irreversible brain creatine deficiency with elevated serum and urine creatine: a creatine transporter defect? Ann Neurol . 2001;49(3):401-404.
82. Candow DG, Chiliback PD. Effect of creatine supplementation during resistance training on muscle accretion in the elderly. J Nutr Health Aging . 2007;11(2):185-188.
83. Brose A, Parise G, Tarnopolsky MA. Creatine supplementation enhances isometric strength and body composition improvements following strength exercise training in older adults. J Gerontol Biol Med Sci . 2003;58(1):11-19.
84. Gotshalk LA, Volek JS, Staron RS, Denegar CR, Hagerman FC, Kraemer WJ. Creatine supplementation improves muscular performance in older men. Med Sci Sports Exerc . 2002;34(3):537-543.
85. Chrusch MJ, Chilibeck PD, Chad KE, Davison KS, Burke DG. Creatine supplementation combined with resistance training in older men. Med Sci Sports Exerc . 2001;33(12):2111-2117.
86. Bermon S, Venembre P, Sachet C, Valour S, Dolisi C. Effects of creatine monohydrate ingestion in sedentary and weight-trained older adults. Acta Physiol Scand . 1998;164(2):147-155.
87. Rawson ES, Wehnert ML, Clarkson PM. Effects of 30 day creatine ingestion in older men. Eur J Appl Physiol Occup Physiol . 1999;80(2):139-144.
88. Rawson ES, Clarkson PM. Acute creatine supplementation in older men. Int J Sports Med . 2000;21(1):71-75.
89. Zemtsov A. Skin phosphocreatine. Skin Res Technol . 2007;13(2):115-118.
90. Blatt T, Lenz H, Koop U, et al. Stimulation of skin's energy metabolism provides multiple benefits for mature human skin. Biofactors . 2005;25(1-4):179-185.
91. Earnest CP, Almada AL, Mitchell TL. High-performance capillary electrophoresis-pure creatine monohydrate reduces blood lipids in men and women. Clin Sci (Lond) . 1996;91(1):113-118.
92. Volek J, Duncan ND, Mazzetti SA, Putukian M, Gómez AL, Kraemer WJ. No effect of heavy resistance training and creatine supplementation on blood lipids. Int J Sport Nutr Exerc Metab . 2000;10(2):144-156.
93. Sipilä I, Rapola J, Simell O, Vannas A. Supplementary creatine as a treatment for gyrate atrophy of the choroid and retina. N Engl J Med . 1981;304(15):867-870.
94. Vannas-Sulonen K, Sipilä I, Vannas A, Simell O, Rapola J. Gyrate atrophy of the choroid and retina. A five-year follow-up of creatine supplementation. Ophthalmology . 1985;92(12):1719-1727.
95. Valtonen M, Näntö-Salonen K, Jääskeläinen S, et al. Central nervous system involvement in gyrate atrophy of the choroid and retina with hyperornithinaemia. J Inherit Metab Dis . 1999;22(8):855-866.
96. Heinänen K, Näntö-Salonen K, Komu M, et al. Creatine corrects muscle 31P spectrum in gyrate atrophy with hyperornithinaemia. Eur J Clin Invest . 1999;29(12):1060-1065.
97. Willer B, Stucki G, Hoppeler H, Brühlmann P, Krähenbühl S. Effects of creatine supplementation on muscle weakness in patients with rheumatoid arthritis. Rheumatology (Oxford) . 2000;39(3):293-298.
98. Vorgerd M, Grehl T, Jager M, et al. Creatine therapy in myophosphorylase deficiency (McArdle disease): a placebo-controlled crossover trial. Arch Neurol . 2000;57(7):956-963.
99. Andrews R, Greenhaff P, Curtis S, Perry A, Cowley AJ. The effect of dietary creatine supplementation on skeletal muscle metabolism in congestive heart failure. Eur Heart J . 1998;19(4):617-622.
100. Schaufelberger M, Swedberg K. Is creatine supplementation helpful for patients with chronic heart failure? Eur Heart J . 1998;19(4):533-534.
101. Sole MJ, Jeejeebhoy KN. Conditioned nutritional requirements and the pathogenesis and treatment of myocardial failure. Curr Opin Clin Nutr Metab Care . 2000;3(6):417-424.
102. Ingwall JS. On the hypothesis that the failing heart is energy starved: lessons learned from the metabolism of ATP and creatine. Curr Hypertens Rep . 2006;8(6):457-464.
103. Kutz MR, Gunter MJ. Creatine monohydrate supplementation on body weight and percent body fat. J Strength Cond Res . 2003;17(4):817-821.
104. Havenetidis K, Bourdas D. Creatine supplementation: effects on urinary excretion and anaerobic performance. J Sports Med Phys Fitness . 2003;43(3):347-355.
105. Kinugasa R, Akima H, Ota A, Ohta A, Sugiura K, Kuno SY. Short-term creatine supplementation does not improve muscle activation or sprint performance in humans. Eur J Appl Physiol . 2004;91(2-3):230-237.
106. Rae C, Digney AL, McEwan SR, Bates TC. Oral creatine monohydrate supplementation improves brain performance: a double-blind, placebo-controlled, cross-over trial. Proc Biol Sci . 2003;270(1529):2147-2150.
107. Verbessem P, Lemiere J, Ejinde BO, et al. Creatine supplementation in Huntington's disease: a placebo-controlled pilot trial. Neurology . 2003;61(7):925-930.
108. Chwalbiñska-Moneta J. Effect of creatine supplementation on aerobic performance and anaerobic capacity in elite rowers in the course of endurance training. Int J Sport Nutr Exerc Metab . 2003;13(2):173-183.
109. Louis M, Lebacq J, Poortmans JR, et al. Beneficial effects of creatine supplementation in dystrophic patients. Muscle Nerve . 2003;27(5):604-610.
110. van Loon LJ, Oosterlaar AM, Hartgens F, Hesselink MK, Snow RJ, Wagenmakers AJ. Effects of creatine loading and prolonged creatine supplementation on body composition, fuel selection, sprint and endurance performance in humans. Clin Sci (Lond) . 2003;104(2):153-162.
111. Shao A, Hathcock JN. Risk assessment for creatine monohydrate. Regul Toxicol Pharmacol . 2006;45(3):242-251.
112. Bizzarini E, De Angelis L. Is the use of oral creatine supplementation safe? J Sports Med Phys Fitness . 2004;44(4):411-416.
113. Mihic S, MacDonald JR, McKenzie S, Tarnopolsky MA. Acute creatine loading increases fat-free mass, but does not affect blood pressure, plasma creatinine, or CK activity in men and women. Med Sci Sports Exerc . 2000;32(2):291-296.
114. Poortmans J, Francaux M. Adverse effects of creatine supplementation: fact or fiction? Sports Med . 2000;30(3):155-170.
115. Poortmans JR, Francaux M. Long-term oral creatine supplementation does not impair renal function in healthy athletes. Med Sci Sports Exerc . 1999;31(8):1108-1110.
116. Chetlin RD, Gutmann L, Tarnopolsky MA, Ullrich IH, Yeater RA. Resistance training exercise and creatine in patients with Charcot-Marie-Tooth disease. Muscle Nerve . 2004;30(1):69-76.
117. Hersch SM, Gevorkian S, Marder K, et al. Creatine in Huntington disease is safe, tolerable, bioavailable in brain and reduces serum 8OH2′dG. Neurology . 2006;66(2):250-252.
118. Shefner JM, Cudkowicz ME, Schoenfeld D, et al. A clinical trial of creatine in ALS. Neurology . 2004;63(9):1656-1661.
119. Pline KA, Smith CL. The effect of creatine intake on renal function. Ann Pharmacother . 2005;39(6):1093-1096.
120. Juhn MS, Tarnopolsky M. Potential side effects of oral creatine supplementation: a critical review. Clin J Sport Med . 1998;8(4):298-304.
121. Tarnopolsky MA. Potential benefits of creatine monohydrate supplementation in the elderly. Curr Opin Clin Nutr Metab Care . 2000;3(6):497-502.
122. Yu PH, Deng Y. Potential cytotoxic effect of chronic administration of creatine, a nutrition supplement to augment athletic performance. Med Hypotheses . 2000;54(5):726-728.
123. Groeneveld GJ, Beijer C, Veldink JH, Kalmijn S, Wokke JH, van den Berg LH. Few adverse effects of long-term creatine supplementation in a placebo-controlled trial. Int J Sports Med . 2005;26(4):307-313.
124. Robinson TM, Sewell DA, Casey A, Steenge G, Greenhaff PL. Dietary creatine supplementation does not affect some haematological indices, or indices of muscle damage and hepatic and renal function. Br J Sports Med . 2000;34(4):284-288.
125. Mayhew DL, Mayhew JL, Ware JS. Effects of long-term creatine supplementation on liver and kidney functions in American college football players. Int J Sport Nutr Exerc Metab . 2002;12(4):453-460.
126. Yoshizumi WM, Tsourounis C. Effects of creatine supplementation on renal function. J Herb Pharmacother . 2004;4(1):1-7.

Copyright © 2009 Wolters Kluwer Health

Hide
(web4)