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Creatine

Common Name(s): Creatin, Creatine, Creatine monohydrate, Creatine phosphate, CrP, Kreatin, methylguanidine acetic acid, N-(aminoiminomethyl)-N-methylglycine, N-amidinosarcosine, Phosphocreatine

Clinical Overview

See also: Gocovri

Use

Creatine has enhanced performance in short-duration, high-intensity exercise in limited trials. Creatine supplementation has been extensively studied in myopathies and neurodegenerative disorders, but with limited efficacy. Further trials are ongoing.

Dosing

Dosage regimens in clinical trials vary from 2 to 20 g daily, and from 1 week up to 4 years.

Contraindications

Patients with a history of renal impairment 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

Few adverse reactions have been reported in clinical studies among patients with neurological or muscle disorders, or in healthy individuals.

Concerns regarding renal and hepatic toxicity exist; unequivocal proof of safety is lacking and caution is warranted.

Case reports of adverse reactions among athletes include dehydration, electrolyte imbalance, and muscle cramping. Minor GI upset (diarrhea, GI pain, nausea), dizziness, and short-term loss in body mass have also been reported. The safety of creatine in children has not been established.

Toxicology

Information is limited; however, the French Agency for Food, Environmental and Occupational Health & Safety (ANSES) has warned of the potential for production of cytotoxic compounds, especially at high dosages.

Source

Creatine is a constituent of skeletal muscle tissue of vertebrates, and is obtained through the diet or is endogenously synthesized in the body. Herring contains 6.5 to 10 g/kg of creatine, while beef, pork, salmon, and tuna all contain approximately 4 to 5 g/kg. A typical American/Western diet provides 1 to 5 g/day; vegetarians must meet their daily creatine needs via endogenous synthesis.

Approximately 1 to 2 g/day creatine is synthesized in the kidneys, pancreas, and liver. It is then transported via circulation to various tissues for storage and utilization, particularly in skeletal muscle (95%), with the balance in the brain, kidneys, and testes.

The majority of studies evaluating the effects of oral creatine supplementation have been conducted using creatine monohydrate or the phosphate salt. Creatine monohydrate is available in several doseforms, including bar, capsule, gel, gum, liquid, and powder. Creatine ester and creatine alcohols are marketed as supplements; however, the availability of actual creatine in the preparations is dependent on conversion to creatine within the body. The efficacy of conversion of some of these doseforms has not been demonstrated.1, 2, 3, 4

History

Creatine was discovered in 1832 by the French chemist Michel Chevreul as an organic constituent of meat. "Extractum carnis Liebig," a concentrated meat extract, was sold around the same period by German researcher Justus von Liebig. In 1847, it was observed that the flesh of wild foxes killed in the chase contained 10 times more creatine than those living in captivity, and in 1912 researchers from Harvard Medical School established a link between creatine ingestion and increased creatine in muscle tissue.

In the late 1960s, advances in biopsy techniques allowed researchers to study the breakdown and resynthesis of adenosine triphosphate (ATP) and creatine phosphate; however, it was not until the early 1990s that creatine's influence on exercise performance in humans was studied. Reports followed in 1992 of a 20% increase in human muscle mass subsequent to creatine supplementation, and athletes were reported to have used it prior to the 1992 Olympic Games.2, 5, 6

Chemistry

Creatine is a nitrogenous organic acid synthesized in the body from the amino acids glycine, arginine, and methionine within an enzymatic ally controlled pathway. Genetic deficiencies interrupting the biosynthesis of creatine lead to severe neuromuscular disorders. Creatinine, the product of creatine phosphate metabolism, is filtered from the blood and excreted via the kidneys.2, 7

Uses and Pharmacology

The role of creatine in facilitating energy distribution and responding to energy demand is explained by the "creatine phosphate shuttle." Creatine, released from contracting myofibrils during exercise, moves to the mitochondria and, in the presence of ATP, produces creatine phosphate and releases adenosine diphosphate (ADP). ADP then stimulates oxygen uptake. Creatine phosphate, synthesized in the mitochondria under anaerobic conditions, returns to the myofibril, where creatine kinase catalyzes the resynthesis of ATP as an energy source for subsequent contractions.7

Creatine deficiency syndromes include disorders of creatine synthesis or transport and include guanidinoacetate methyltransferase deficiency, arginine:glycine amidinotransferase deficiency, and X-linked creatine transporter deficiency. Use of creatine in such disorders should be under the guidance of a specialist health care provider.8, 9

Aging

Animal data

Increased lifespan has been demonstrated in mouse models of aging.10

Clinical data

The results of studies using creatine in elderly patients to reduce loss of muscle mass are equivocal. Timing and dose of supplementation, as well as proximity to resistance training sessions, may be important factors controlling efficacy.2, 11, 12 Bone mass trial data are also equivocal, with some studies reporting no effect; however, populations and dosages ranged widely.13

Limited studies suggest that topical and/or systemic administration of creatine or phosphocreatine may have beneficial effects in various skin conditions, such as photoaging and wound healing.14, 15

Amyotrophic lateral sclerosis/motor neuron disease

Animal data

Mouse models of amyotrophic lateral sclerosis (ALS) have shown increased survival with administration of creatine.16, 17, 18, 19

Clinical data

A Cochrane meta-analysis of 3 randomized, double-blind, placebo controlled trials (N = 386) found no statistical difference in survival or disease progression in ALS for creatine at 5 to 10 g/day.20 Further small, open-label studies have found equivocal results.3 Using magnetic resonance spectroscopy, a phase 1 open-label, dose-escalation study in 6 patients with ALS demonstrated increased in vivo brain creatine concentration at creatine 15 mg twice daily after 19 days.21 Results of a phase 3, multicenter, double-blind, placebo-controlled, randomized study evaluating creatine in ALS are pending.22

Other neurodegenerative disorders

Animal data

Creatine has been studied in animal models of Huntington disease and Parkinson disease.23, 24, 25, 26, 27

Clinical data

Only a few randomized double-blind, placebo-controlled trials have been conducted in Huntington disease with equivocal results. Likewise, results from open-label trials have been inconclusive.3, 28, 29 Limited trials have been conducted in patients with Parkinson disease with more promising, but still inconclusive, findings.3, 28, 30 A long-term phase 3, multicenter, double-blind, parallel-group, placebo controlled, randomized study (N = 1,741) evaluating the effect of creatine on 5-year disease progression in patients with newly disgnosed Parkinson disease (within the past 5 years) and controlled on dopaminergic therapy (for at least 90 days but no more than 2 years) was terminated early based on futility as assessed at a planned interim analysis. Compared with placebo, creatine monohydrate (10 g/day) did not provide any significant differences in clinical decline over at least 5 years.31, 88 A study among patients with Rett syndrome found increases in some, but not all, outcome measures.32

Exercise performance enhancement

Creatine is widely used among professional athletes; however, in 2000 the National Collegiate Athletic Association banned colleges from distributing creatine to student athletes.33

Animal data

Data from animal studies cannot readily be generalized to sports performance in humans.

Clinical data

There is a large volume of scientific literature dealing with creatine supplementation in exercise performance. Wide variations in study populations, types of exercise, dosing regimens, and outcome measures are found in the literature.

Possible mechanisms include increased muscle stores of creatine phosphate, more rapid resynthesis of creatine phosphate and reduced ATP degradation, enhanced oxygen uptake via the creatine-phosphate shuttle, and increased glycogen storage.34, 35, 36, 37, 38, 39

Meta-analyses of studies up to the year 2000 found improvement in the performance of repetitive, laboratory-based exercise tests but also found inconsistent results in sports-specific performance.40, 41

Equivocal results have been obtained for an ergogenic benefit, with some studies finding decreased performance (which may, in part, be due to increased body mass).35, 42, 43, 44, 45, 46, 47, 48 Other studies show improved performance in high-intensity, short-duration, intermittent exercise, and improved fatigue resistance.39, 44, 45, 47, 49, 50, 51, 52

A concept of "nonresponders" has also been discussed. Normal muscle creatine concentrations average 120 mmol/kg (range, 100 to 140 mmol/kg); a maximum total creatine concentration of 150 to 160 mmol/kg is achieved by approximately 20% of subjects, and individuals with an initial total creatine near or at the creatine saturation point do not demonstrate improved performance following creatine ingestion.40, 49, 53 Muscle creatine concentrations return to presupplementation concentrations within 4 weeks of discontinuation, suggesting reversible inhibition of endogenous creatine production.49, 54

Cardiovascular disease

Animal data

Studies in animals are largely irrelevant considering the availability of a meta-analysis of clinical trial data.55

Clinical data

The creatine kinase system is integral to energy homeostasis, cardiovascular contraction, and ischemic resistance; however, there is insufficient evidence to consider a place in therapy for creatine in heart failure or myocardial infarction. There is some evidence from trial data that creatine as an add-on to standard treatment may improve dysrhythmia and dyspnea.55, 56

CNS

Animal data

Studies in rats have been conducted primarily to demonstrate altered concentrations of creatine in different psychological states.57

Clinical data

Most, but not all, studies conducted in elderly patients report some improvement in memory with supplemental creatine. Dosages range widely in these studies (5 to 20 g daily, from 7 days to 6 weeks). No effect on cognition was reported in younger people.2, 3 A number of studies report on altered creatine concentrations in patients with mental health disorders, including major depression and bipolar disorder, with an observed spike in serum creatine kinase at the onset of a major psychotic event. Further trials evaluating a place in therapy for creatine in major depression are needed.2, 57, 58

Chronic obstructive pulmonary disease (COPD)

Animal data

Studies in animals are largely irrelevant considering the availability of clinical trial data.

Clinical data

A meta-analysis of 4 randomized, controlled trials found no improvement in quality of life indices and a lack of muscle strength enhancement. More clearly defined trials may be warranted.3, 59

Mitochondrial disease

Animal data

Clinical studies have been prompted as a result of exercise-related studies in healthy human populations rather than based solely on animal experiments.

Clinical data

A Cochrane review found no benefit in 2 of 3 included trials; increased muscle (handgrip) strength and improved exercise lactate following exercise was found in 1 trial. Dosages range widely in these studies (150 mg/kg to 20 g daily, from 4 to 6 weeks).3, 60, 61, 62

Muscular dystrophies

Animal data

Clinical studies have been conducted as a result of exercise-related studies in healthy human populations rather than based solely on animal experiments.

Clinical data

An updated Cochrane meta-analysis of 6 trials with 139 participants reported an increase in muscle strength (weighted mean difference of 8.47% [95% confidence interval, 3.55 to 13.38]). In addition, data from 4 of the trials reported a higher number of patients felt better during creatine treatment than with placebo. No clinically important adverse reactions were found.3, 61, 62

Other uses

Creatine supplementation has been evaluated in numerous medical conditions, including muscle wasting,63, 64 brain and spinal cord injury,9 osteoarthritis,65 diabetes,66, 67, 68, 69 cancer,70 and gyrate atrophy.9 Reviews on creatine are available.2, 3, 9

The American Academy of Neurology evidence based guidelines regarding the treatment of chorea in Huntington disease (2012) conclude that creatine (8 mg daily) is possibly ineffective in improving Huntington disease chorea to a very important extent based on a placebo-controlled, randomized trial. Lack of statistical precision suggests that moderate benefit cannot be excluded.87

Dosing

Dosage regimens in clinical trials vary from 2 to 20 g daily, and from 1 week up to 4 years.2, 3, 9

Skeletal muscle enhancement regimens include "high dose, short term" of 20 g daily for 7 days and a "lower dose, longer term" regimen of 2 to 5 g for 4 to 6 weeks.2

Evidence suggests that long-term intake of up to 5 g/day is relatively safe.71 Larger amounts have been used without adverse reactions and may be safe, but long-term safety data are lacking.4, 71

The safety of creatine in children has not been established, and creatine should be given under physician guidance.72

Different forms of creatine products may have differing bioavailability. Bioavailability of dietary creatine is considered to be absolute.4

Pregnancy / Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking. Animal data are inconclusive.73, 74, 75

Interactions

None well documented.

Adverse Reactions

In studies conducted in healthy individuals, reports of adverse reactions due to creatine monohydrate supplementation are lacking.71, 76, 77, 78, 79 Clinical studies in patients with neurological or muscle disorders revealed few adverse reactions.20, 21, 60, 61, 80

Concerns regarding renal and hepatic toxicity exist.81 Healthy kidneys appear to manage short-term creatine loading without compromised function,81, 82 but patients with a history of renal impairment or diabetes, or those taking nephrotoxic agents should avoid creatine supplementation or be closely monitored with supplementation.81, 82 Healthy individuals should consider regular testing to detect potential renal impairment because of possible decreased compensatory mechanisms.78, 81 Supplementation studies using creatine for up to 8 weeks have reported minimal or no elevation of liver enzymes.83, 84 However, some animal studies suggest caution is warranted where hepatic impairment exists, at least until unequivocal evidence is attained.81 No evidence of hepatotoxicity has been reported in meta-analyses.6, 20, 60, 61

Data collected between 2004 and 2013 among 8 US centers in the Drug-induced Liver Injury Network revealed 15.5% (130) of hepatotoxicity cases was caused by herbals and dietary supplements whereas 85% (709) were related to medications. Of the 130 related cases of liver injury related to supplements, 65% were from non-bodybuilding supplements and occurred most often in Hispanic/Latinos compared to non-Hispanic whites and non-Hispanic blacks. Liver transplant was also more frequent with toxicity from non-bodybuilding supplements (13%) than with conventional medications (3%) (P<0.001). Overall, the number of severe liver injury cases was significantly higher from supplements than conventional medications (P=0.02). Of the 217 supplement products implicated in liver injury, creatine was among the 22% (116) of the single-ingredient products.89

Individuals with diabetes should avoid use or at least monitor their blood sugar more closely when using creatine.68, 69

Case reports of adverse reactions among athletes include dehydration, heat-related illnesses, reduced blood volume, electrolyte imbalances, and muscle cramping; however, there is insufficient evidence to support or refute these claims.34, 78, 81, 85 Minor GI upset (diarrhea, GI pain, nausea), dizziness, and short-term loss in body mass have also been reported.34, 79, 81 Case reports of muscle pain and seizures exist, but no causal relationship has been established.78

Toxicology

Short- and long-term doses of creatine did not result in mutagenicity in rats, rabbits, or guinea pigs in limited experiments.4 The French Agency for Food, Environmental and Occupational Health & Safety (ANSES) has warned of the potential for production of cytotoxic methylamine and formaldehyde consequent to creatine consumption, especially at high dosage.81, 86

Production of carcinogenic and mutagenic amino-imidazo-azaarene has also been postulated, but a causal relationship with creatine consumption appears unlikely.6, 81

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