Chemistry:Creatine

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Short description: Chemical compound
Creatine
Skeletal formula of neutral form of creatine
Skeletal formula of neutral form of creatine
Skeletal formula of one of zwitterionic forms of creatine
Skeletal formula of one of the zwitterionic forms of creatine
Ball and stick model of creatine
Ball and stick model of one zwitterionic form of creatine
Names
Systematic IUPAC name
2-[Carbamimidoyl(methyl)amino]acetic acid
Other names
N-Carbamimidoyl-N-methylglycine; Methylguanidoacetic acid; N-amidinosarcosine
Identifiers
3D model (JSmol)
3DMet
907175
ChEBI
ChEMBL
ChemSpider
DrugBank
EC Number
  • 200-306-6
240513
KEGG
MeSH Creatine
RTECS number
  • MB7706000
UNII
Properties
C4H9N3O2
Molar mass 131.135 g·mol−1
Appearance White crystals
Odor Odourless
Melting point 255 °C (491 °F; 528 K)
13.3 g L−1 (at 18 °C)
log P −1.258
Acidity (pKa) 3.429
Basicity (pKb) 10.568
Isoelectric point 8.47
Thermochemistry
171.1 J K−1 mol−1 (at 23.2 °C)
189.5 J K−1 mol−1
−538.06–−536.30 kJ mol−1
−2.3239–−2.3223 MJ mol−1
Pharmacology
1=ATC code }} C01EB06 (WHO)
Pharmacokinetics:
3 hours
Hazards
GHS pictograms GHS07: Harmful
GHS Signal word WARNING
H315, H319, H335
P261, P305+351+338
Related compounds
Related alkanoic acids
Related compounds
 Dimethylacetamide
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references
Tracking categories (test):

Creatine (/ˈkriːətiːn/ or /ˈkriːətɪn/)[1] is an organic compound with the nominal formula (H
2N)(HN)CN(CH
3)CH
2CO
2H. It exists in various tautomers in solutions (among which are neutral form and various zwitterionic forms). Creatine is found in vertebrates where it facilitates recycling of adenosine triphosphate (ATP), primarily in muscle and brain tissue. Recycling is achieved by converting adenosine diphosphate (ADP) back to ATP via donation of phosphate groups. Creatine also acts as a buffer.[2]

History

Creatine was first identified in 1832 when Michel Eugène Chevreul isolated it from the basified water-extract of skeletal muscle. He later named the crystallized precipitate after the Greek word for meat, κρέας (kreas). In 1928, creatine was shown to exist in equilibrium with creatinine.[3] Studies in the 1920s showed that consumption of large amounts of creatine did not result in its excretion. This result pointed to the ability of the body to store creatine, which in turn suggested its use as a dietary supplement.[4]

In 1912, Harvard University researchers Otto Folin and Willey Glover Denis found evidence that ingesting creatine can dramatically boost the creatine content of the muscle.[5][6] In the late 1920s, after finding that the intramuscular stores of creatine can be increased by ingesting creatine in larger than normal amounts, scientists discovered phosphocreatine (creatine phosphate), and determined that creatine is a key player in the metabolism of skeletal muscle. The substance creatine is naturally formed in vertebrates.[7]

The discovery of phosphocreatine[8][9] was reported in 1927.[10][11][9] In the 1960s, creatine kinase (CK) was shown to phosphorylate ADP using phosphocreatine (PCr) to generate ATP. It follows that ATP - not PCr - is directly consumed in muscle contraction. CK uses creatine to "buffer" the ATP/ADP ratio.[12]

While creatine's influence on physical performance has been well documented since the early twentieth century, it came into public view following the 1992 Olympics in Barcelona. An August 7, 1992 article in The Times reported that Linford Christie, the gold medal winner at 100 meters, had used creatine before the Olympics (however, it should also be mentioned that Linford Christie was found guilty of doping later in his career.).[13] An article in Bodybuilding Monthly named Sally Gunnell, who was the gold medalist in the 400-meter hurdles, as another creatine user. In addition, The Times also noted that 100 meter hurdler Colin Jackson began taking creatine before the Olympics.[14][15]

thumb|left|Phosphocreatine relays phosphate to ADP. At the time, low-potency creatine supplements were available in Britain, but creatine supplements designed for strength enhancement were not commercially available until 1993 when a company called Experimental and Applied Sciences (EAS) introduced the compound to the sports nutrition market under the name Phosphagen.[16] Research performed thereafter demonstrated that the consumption of high glycemic carbohydrates in conjunction with creatine increases creatine muscle stores.[17]

left|thumb|The cyclic derivative creatinine exists in equilibrium with its tautomer and with creatine.

Metabolic role

Creatine is a naturally occurring non-protein compound and the primary constituent of phosphocreatine, which is used to regenerate ATP within the cell. 95% of the human body's total creatine and phosphocreatine stores are found in skeletal muscle, while the remainder is distributed in the blood, brain, testes, and other tissues.[18][19] The typical creatine content of skeletal muscle (as both creatine and phosphocreatine) is 120 mmol per kilogram of dry muscle mass, but can reach up to 160 mmol/kg through supplementation.[20] Approximately 1–2% of intramuscular creatine is degraded per day and an individual would need about 1–3 grams of creatine per day to maintain average (unsupplemented) creatine storage.[20][21][22] An omnivorous diet provides roughly half of this value, with the remainder synthesized in the liver and kidneys.[18][19][23]

Creatine is not an essential nutrient.[24] It is an amino acid derivative, naturally produced in the human body from the amino acids glycine and arginine, with an additional requirement for S-Adenosyl methionine (a derivative of methionine) to catalyze the transformation of guanidinoacetate to creatine. In the first step of the biosynthesis, the enzyme arginine:glycine amidinotransferase (AGAT, EC:2.1.4.1) mediates the reaction of glycine and arginine to form guanidinoacetate. This product is then methylated by guanidinoacetate N-methyltransferase (GAMT, EC:2.1.1.2), using S-adenosyl methionine as the methyl donor. Creatine itself can be phosphorylated by creatine kinase to form phosphocreatine, which is used as an energy buffer in skeletal muscles and the brain. A cyclic form of creatine, called creatinine, exists in equilibrium with its tautomer and with creatine.

CreatineSynthesis(en).png

Phosphocreatine system

Proposed creatine kinase/phosphocreatine (CK/PCr) energy shuttle. CRT = creatine transporter; ANT = adenine nucleotide translocator; ATP = adenine triphosphate; ADP = adenine diphosphate; OP = oxidative phosphorylation; mtCK = mitochondrial creatine kinase; G = glycolysis; CK-g = creatine kinase associated with glycolytic enzymes; CK-c = cytosolic creatine kinase; CK-a = creatine kinase associated with subcellular sites of ATP utilization; 1 – 4 sites of CK/ATP interaction.

Creatine is transported through the blood and taken up by tissues with high energy demands, such as the brain and skeletal muscle, through an active transport system. The concentration of ATP in skeletal muscle is usually 2–5 mM, which would result in a muscle contraction of only a few seconds.[25] During times of increased energy demands, the phosphagen (or ATP/PCr) system rapidly resynthesizes ATP from ADP with the use of phosphocreatine (PCr) through a reversible reaction catalysed by the enzyme creatine kinase (CK). The phosphate group is attached to an NH center of the creatine. In skeletal muscle, PCr concentrations may reach 20–35 mM or more. Additionally, in most muscles, the ATP regeneration capacity of CK is very high and is therefore not a limiting factor. Although the cellular concentrations of ATP are small, changes are difficult to detect because ATP is continuously and efficiently replenished from the large pools of PCr and CK.[25] A proposed representation has been illustrated by Krieder et al.[26] Creatine has the ability to increase muscle stores of PCr, potentially increasing the muscle's ability to resynthesize ATP from ADP to meet increased energy demands.[27][28][29]

Creatine supplementation appears to increase the number of myonuclei that satellite cells will 'donate' to damaged muscle fibers, which increases the potential for growth of those fibers. This increase in myonuclei probably stems from creatine's ability to increase levels of the myogenic transcription factor MRF4.[30]

Genetic deficiencies

Genetic deficiencies in the creatine biosynthetic pathway lead to various severe neurological defects.[31] Clinically, there are three distinct disorders of creatine metabolism. Deficiencies in the two synthesis enzymes can cause L-arginine:glycine amidinotransferase deficiency caused by variants in GATM and guanidinoacetate methyltransferase deficiency, caused by variants in GAMT. Both biosynthetic defects are inherited in an autosomal recessive manner. A third defect, creatine transporter defect, is caused by mutations in SLC6A8 and inherited in a X-linked manner. This condition is related to the transport of creatine into the brain.[32]

Vegetarians

Some studies suggest that total muscle creatine is significantly lower in vegetarians than non-vegetarians.[33][34][32][19] This finding is due probably to an omnivorous diet being the primary source of creatine.[35] Research shows that supplementation is needed to raise the concentration of creatine in the muscles of lacto-ovo vegetarians and vegans up to non-vegetarian levels.[33]

Pharmacokinetics

Most of the research to-date on creatine has predominantly focused on the pharmacological properties of creatine, yet there is a lack of research into the pharmacokinetics of creatine. Studies have not established pharmacokinetic parameters for clinical usage of creatine such as volume of distribution, clearance, bioavailability, mean residence time, absorption rate, and half life. A clear pharmacokinetic profile would need to be established prior to optimal clinical dosing.[36]

Dosing

Loading phase

An approximation of 0.3 g/kg/day divided into 4 equal spaced intervals has been suggested since creatine needs may vary based on body weight.[26][20] It has also been shown that taking a lower dose of 3 grams a day for 28 days can also increase total muscle creatine storage to the same amount as the rapid loading dose of 20 g/day for 6 days.[20] However, a 28-day loading phase does not allow for ergogenic benefits of creatine supplementation to be realized until fully saturated muscle storage.

This elevation in muscle creatine storage has been correlated with ergogenic benefits discussed in the research section. However, higher doses for longer periods of time are being studied to offset creatine synthesis deficiencies and mitigating diseases.[37][38][32]

Maintenance phase

After the 5–7 day loading phase, muscle creatine stores are fully saturated and supplementation only needs to cover the amount of creatine broken down per day. This maintenance dose was originally reported to be around 2–3 g/day (or 0.03 g/kg/day),[20] however, some studies have suggested 3–5 g/day maintenance dose to maintain saturated muscle creatine.[17][22][39][40]

Absorption

This graph shows the mean plasma creatine concentration (measured in μmol/L) over an 8-hour period following ingestion of 4.4 grams of creatine in the form of creatine monohydrate (CrM), tri-creatine citrate (CrC), or creatine pyruvate (CrPyr).[41]

Endogenous serum or plasma creatine concentrations in healthy adults are normally in a range of 2–12 mg/L. A single 5 gram (5000 mg) oral dose in healthy adults results in a peak plasma creatine level of approximately 120 mg/L at 1–2 hours post-ingestion. Creatine has a fairly short elimination half life, averaging just less than 3 hours, so to maintain an elevated plasma level it would be necessary to take small oral doses every 3–6 hours throughout the day.

Clearance

It has been shown that once supplementation of creatine stops, muscle creatine stores return to baseline in 4–6 weeks.[20][42][40]

Exercise and sport

Creatine supplements are marketed in ethyl ester, gluconate, monohydrate, and nitrate forms.[43]

Creatine supplementation for sporting performance enhancement is considered safe for short-term use but there is a lack of safety data for long term use, or for use in children and adolescents.[44]

A 2018 review article in the Journal of the International Society of Sports Nutrition said that creatine monohydrate might help with energy availability for high-intensity exercise.[45]

Creatine use can increase maximum power and performance in high-intensity anaerobic repetitive work (periods of work and rest) by 5% to 15%.[46][47][48] Creatine has no significant effect on aerobic endurance, though it will increase power during short sessions of high-intensity aerobic exercise.[49][obsolete source][50][obsolete source]

A survey of 21,000 college athletes showed that 14% of athletes take creatine supplements to try to improve performance.[51] Non-athletes report taking creatine supplements to improve appearance.[51]

Research

Cognitive performance

Creatine is reported to have a beneficial effect on brain function and cognitive processing, although the evidence is difficult to interpret systematically and the appropriate dosing is unknown.[52][53] The greatest effect appears to be in individuals who are stressed (due, for instance, to sleep deprivation) or cognitively impaired.[52][53]

A 2018 systematic review found that "generally, there was evidence that short term memory and intelligence/reasoning may be improved by creatine administration", whereas for other cognitive domains "the results were conflicting".[54] Another 2023 review initially found evidence of improved memory function.[55] However, it was later determined that faulty statistics lead to the statistical significance and after fixing the "double counting", the effect was only significant in older adults.[56]

Muscular disease

A meta-analysis found that creatine treatment increased muscle strength in muscular dystrophies, and potentially improved functional performance.[57] Creatine treatment does not appear to improve muscle strength in people who have metabolic myopathies.[57] High doses of creatine lead to increased muscle pain and an impairment in activities of daily living when taken by people who have McArdle disease.[57]

According to a clinical study focusing on people with various muscular dystrophies, using a pure form of creatine monohydrate can be beneficial in rehabilitation after injuries and immobilization.[58]

Mitochondrial diseases

Parkinson's disease

Creatine's impact on mitochondrial function has led to research on its efficacy and safety for slowing Parkinson's disease. As of 2014, the evidence did not provide a reliable foundation for treatment decisions, due to risk of bias, small sample sizes, and the short duration of trials.[59]

Huntington's disease

Several primary studies[60][61][62] have been completed but no systematic review on Huntington's disease has been completed yet.

ALS

It is ineffective as a treatment for amyotrophic lateral sclerosis.[63]

Testosterone

A 2021 systemic review of studies found that "the current body of evidence does not indicate that creatine supplementation increases total testosterone, free testosterone, DHT or causes hair loss/baldness".[64]

Adverse effects

Side effects include:[65][66]

  • Weight gain due to extra water retention to the muscle
  • Potential muscle cramps / strains / pulls
  • Upset stomach
  • Diarrhea
  • Dizziness

One well-documented effect of creatine supplementation is weight gain within the first week of the supplement schedule, likely attributable to greater water retention due to the increased muscle creatine concentrations by means of osmosis.[67]

A 2009 systematic review discredited concerns that creatine supplementation could affect hydration status and heat tolerance and lead to muscle cramping and diarrhea.[68][69]

Renal function

Long-term creatine supplementation has not been proven safe for kidney patients.[70]

A 2019 systematic review published by the National Kidney Foundation investigated whether creatine supplementation had adverse effects on renal function.[71] They identified 15 studies from 1997 to 2013 that looked at standard creatine loading and maintenance protocols of 4–20 g/day of creatine versus placebo. They utilized serum creatinine, creatinine clearance, and serum urea levels as a measure of renal damage. While in general creatine supplementation resulted in slightly elevated creatinine levels that remained within normal limits, supplementation did not induce renal damage (P value< 0.001). Special populations included in the 2019 Systematic review included type 2 diabetic patients[72] and post-menopausal women,[73] bodybuilders,[74] athletes,[75] and resistance trained populations.[76][77][78] The study also discussed 3 case studies where there were reports that creatine affected renal function.[79][80][81]

In a joint statement between the American College of Sports Medicine, Academy of Nutrition and Dietetics, and Dietitians in Canada on performance enhancing nutrition strategies, creatine was included in their list of ergogenic aids and they do not list renal function as a concern for use.[82]

The most recent position stand on creatine from the Journal of International Society of Sports Nutrition states that creatine is safe to take in healthy populations from infants to the elderly to performance athletes. They also state that long term (5 years) use of creatine has been considered safe.[26]

It is important to mention that kidneys themselves, for normal physiological function, need phosphocreatine and creatine and indeed kidneys express significant amounts of creatine kinases (BB-CK and u-mtCK isoenzymes).[83] At the same time, the first of two steps for endogenous creatine synthesis takes place in the kidneys themselves. Patients with kidney disease and those undergoing dialysis treatment generally show significantly lower levels of creatine in their organs, since the pathological kidneys are both hampered in creatine synthesis capability and are in back-resorption of creatine from the urine in the distal tubules. In addition, dialysis patients lose creatine due to wash out by the dialysis treatment itself and thus become chronically creatine depleted. This situation is exacerbated by the fact that dialysis patients generally consume less meat and fish, the alimentary sources of creatine. Therefore, to alleviate chronic creatine depletion in these patients and allow organs to replenish their stores of creatine, it was proposed in a 2017 article in Medical Hypotheses to supplement dialysis patients with extra creatine, preferably by intra-dialytic administration. Such a supplementation with creatine in dialysis patients is expected to significantly improve the health and quality of the patients by improving muscle strength, coordination of movement, brain function and to alleviate depression and chronic fatigue that are common in these patients.[84][unreliable medical source?]

Safety

Contamination

A 2011 survey of 33 supplements commercially available in Italy found that over 50% of them exceeded the European Food Safety Authority recommendations in at least one contaminant. The most prevalent of these contaminants was creatinine, a breakdown product of creatine also produced by the body.[85] Creatinine was present in higher concentrations than the European Food Safety Authority recommendations in 44% of the samples. About 15% of the samples had detectable levels of dihydro-1,3,5-triazine or a high dicyandiamide concentration. Heavy metals contamination was not found to be a concern, with only minor levels of mercury being detectable. Two studies reviewed in 2007 found no impurities.[86]

Interactions

A National Institutes of Health study suggests that caffeine interacts with creatine to increase the rate of progression of Parkinson's Disease.[87]

Food and cooking

When creatine is mixed with protein and sugar at high temperatures (above 148 °C), the resulting reaction produces carcinogenic heterocyclic amines (HCAs).[88] Such a reaction happens when grilling or pan-frying meat.[89] Creatine content (as a percentage of crude protein) can be used as an indicator of meat quality.[90]

Dietary considerations

Creatine-monohydrate is suitable for vegetarians and vegans, as the raw materials used for the production of the supplement have no animal origin.[91]

See also

References

  1. ↑ Essentials of Creatine in Sports and Health. Humana. 2008. ISBN 978-1-59745-573-2. 
  2. ↑ "Creatine and the Liver: Metabolism and Possible Interactions". Mini Reviews in Medicinal Chemistry 16 (1): 12–8. 2016. doi:10.2174/1389557515666150722102613. PMID 26202197. "The process of creatine synthesis occurs in two steps, catalyzed by L-arginine:glycine amidinotransferase (AGAT) and guanidinoacetate N-methyltransferase (GAMT), which take place mainly in kidney and liver, respectively. This molecule plays an important energy/pH buffer function in tissues, and to guarantee the maintenance of its total body pool, the lost creatine must be replaced from diet or de novo synthesis.". 
  3. ↑ "The creatine-creatinine equilibrium. The apparent dissociation constants of creatine and creatinine". The Biochemical Journal 22 (4): 920–9. 1928. doi:10.1042/bj0220920. PMID 16744118. 
  4. ↑ Volek, Jeff S.; Ballard, Kevin D.; Forsythe, Cassandra E. (2008). "Overview of Creatine Metabolism". Essentials of Creatine in Sports and Health. Humana. pp. 1–23. ISBN 978-1-59745-573-2. 
  5. ↑ Folin, Otto; Denis, W (1912). "Protein metabolism from the standpoint of blood and tissue analysis". Journal of Biological Chemistry 12 (1): 141–61. doi:10.1016/S0021-9258(18)88723-3. http://www.jbc.org/content/12/1/141.full.pdf+html. Retrieved 8 May 2018. 
  6. ↑ Antonio, Jose (February 8, 2021). "Common questions and misconceptions about creatine supplementation: what does the scientific evidence really show?". Journal of the International Society of Sports Nutrition 18 (1): 13. doi:10.1186/s12970-021-00412-w. PMID 33557850. 
  7. ↑ "The metabolic burden of creatine synthesis". Amino Acids 40 (5): 1325–31. May 2011. doi:10.1007/s00726-011-0853-y. PMID 21387089. 
  8. ↑ Saks, Valdur (2007). Molecular system bioenergetics: energy for life. Weinheim: Wiley-VCH. p. 2. ISBN 978-3-527-31787-5. https://archive.org/details/molecularsystemb00saks. 
  9. ↑ 9.0 9.1 Ochoa, Severo (1989). Sherman, E. J.; National Academy of Sciences. eds. David Nachmansohn. Biographical Memoirs. 58. National Academies Press. pp. 357–404. ISBN 978-0-309-03938-3. 
  10. ↑ "The Inorganic Phosphate and a Labile Form of Organic Phosphate in the Gastrocnemius of the Frog". The Biochemical Journal 21 (1): 190–5. 1927. doi:10.1042/bj0210190. PMID 16743804. 
  11. ↑ "The nature of the 'inorganic phosphate' in voluntary muscle". Science 65 (1686): 401–3. April 1927. doi:10.1126/science.65.1686.401. PMID 17807679. Bibcode: 1927Sci....65..401F. 
  12. ↑ "Introduction – Creatine: Cheap Ergogenic Supplement with Great Potential for Health and Disease". Creatine and Creatine Kinase in Health and Disease. Springer. 2007. pp. 1–16. ISBN 978-1-4020-6486-9. https://archive.org/details/creatinecreatine00salo. 
  13. ↑ "Shadow over Christie's reputation". https://www.telegraph.co.uk/sport/othersports/athletics/4768790/Shadow-over-Christies-reputation.html. 
  14. ↑ "Supplement muscles in on the market". National Review of Medicine. 2004-07-30. http://www.nationalreviewofmedicine.com/issue/2004_07_30/feature07_14.html. 
  15. ↑ Passwater, Richard A. (2005). Creatine. McGraw Hill Professional. p. 9. ISBN 978-0-87983-868-3. https://books.google.com/books?id=umy67wOLOckC. Retrieved 8 May 2018. 
  16. ↑ Stoppani, Jim (May 2004). Creatine new and improved: recent high-tech advances have made creatine even more powerful. Here's how you can take full advantage of this super supplement. Muscle & Fitness. http://findarticles.com/p/articles/mi_m0801/is_5_65/ai_n6005938. Retrieved 2010-03-29. 
  17. ↑ 17.0 17.1 "Carbohydrate ingestion augments skeletal muscle creatine accumulation during creatine supplementation in humans". The American Journal of Physiology 271 (5 Pt 1): E821-6. November 1996. doi:10.1152/ajpendo.1996.271.5.E821. PMID 8944667. 
  18. ↑ 18.0 18.1 "Creatine supplementation with specific view to exercise/sports performance: an update". Journal of the International Society of Sports Nutrition 9 (1): 33. July 2012. doi:10.1186/1550-2783-9-33. PMID 22817979. "Creatine is produced endogenously at an amount of about 1 g/d. Synthesis predominately occurs in the liver, kidneys, and to a lesser extent in the pancreas. The remainder of the creatine available to the body is obtained through the diet at about 1 g/d for an omnivorous diet. 95% of the bodies creatine stores are found in the skeletal muscle and the remaining 5% is distributed in the brain, liver, kidney, and testes [1].". 
  19. ↑ 19.0 19.1 19.2 "The role of dietary creatine". Amino Acids 48 (8): 1785–91. August 2016. doi:10.1007/s00726-016-2188-1. PMID 26874700. "The daily requirement of a 70-kg male for creatine is about 2 g; up to half of this may be obtained from a typical omnivorous diet, with the remainder being synthesized in the body ... More than 90% of the body’s creatine and phosphocreatine is present in muscle (Brosnan and Brosnan 2007), with some of the remainder being found in the brain (Braissant et al. 2011). ... Creatine synthesized in liver must be secreted into the bloodstream by an unknown mechanism (Da Silva et al. 2014a)". 
  20. ↑ 20.0 20.1 20.2 20.3 20.4 20.5 "Muscle creatine loading in men". Journal of Applied Physiology 81 (1): 232–7. July 1996. doi:10.1152/jappl.1996.81.1.232. PMID 8828669. 
  21. ↑ "Creatine in humans with special reference to creatine supplementation". Sports Medicine 18 (4): 268–80. October 1994. doi:10.2165/00007256-199418040-00005. PMID 7817065. 
  22. ↑ 22.0 22.1 "Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation". Clinical Science 83 (3): 367–74. September 1992. doi:10.1042/cs0830367. PMID 1327657. 
  23. ↑ "The metabolic burden of creatine synthesis". Amino Acids 40 (5): 1325–31. May 2011. doi:10.1007/s00726-011-0853-y. PMID 21387089. "Creatinine loss averages approximately 2 g (14.6 mmol) for 70 kg males in the 20- to 39-year age group. ... Table 1 Comparison of rates of creatine synthesis in young adults with dietary intakes of the three precursor amino acids and with the whole body transmethylation flux
    Creatine synthesis (mmol/day)   8.3".     
  24. ↑ "Creatine". Beth Israel Deaconess Medical Center. http://www.bidmc.org/YourHealth/ConditionsAZ.aspx?ChunkID=21706. 
  25. ↑ 25.0 25.1 "Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands: the 'phosphocreatine circuit' for cellular energy homeostasis". The Biochemical Journal 281 ( Pt 1) (Pt 1): 21–40. January 1992. doi:10.1042/bj2810021. PMID 1731757. 
  26. ↑ 26.0 26.1 26.2 "International Society of Sports Nutrition position stand: safety and efficacy of creatine supplementation in exercise, sport, and medicine". Journal of the International Society of Sports Nutrition 14: 18. 2017. doi:10.1186/s12970-017-0173-z. PMID 28615996. 
  27. ↑ "The effects of creatine ethyl ester supplementation combined with heavy resistance training on body composition, muscle performance, and serum and muscle creatine levels". Journal of the International Society of Sports Nutrition 6 (1): 6. February 2009. doi:10.1186/1550-2783-6-6. PMID 19228401. 
  28. ↑ "The creatine kinase system and pleiotropic effects of creatine". Amino Acids 40 (5): 1271–96. May 2011. doi:10.1007/s00726-011-0877-3. PMID 21448658. .
  29. ↑ T. Wallimann, M. Tokarska-Schlattner, D. Neumann u. a.: The Phosphocreatine Circuit: Molecular and Cellular Physiology of Creatine Kinases, Sensitivity to Free Radicals, and Enhancement by Creatine Supplementation. In: Molecular System Bioenergetics: Energy for Life. 22. November 2007. doi:10.1002/9783527621095.ch7C
  30. ↑ "Creatine supplementation: exploring the role of the creatine kinase/phosphocreatine system in human muscle". Canadian Journal of Applied Physiology 26 Suppl: S79-102. 2001. doi:10.1139/h2001-045. PMID 11897886. 
  31. ↑ "L-Arginine:Glycine Amidinotransferase". https://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602360. 
  32. ↑ 32.0 32.1 32.2 "Creatine deficiency syndromes and the importance of creatine synthesis in the brain". Amino Acids 40 (5): 1315–24. May 2011. doi:10.1007/s00726-011-0852-z. PMID 21390529. https://serval.unil.ch/resource/serval:BIB_CE3937F9A69E.P001/REF.pdf. Retrieved 8 July 2019. 
  33. ↑ 33.0 33.1 "Effect of creatine and weight training on muscle creatine and performance in vegetarians". Medicine and Science in Sports and Exercise 35 (11): 1946–55. November 2003. doi:10.1249/01.MSS.0000093614.17517.79. PMID 14600563. 
  34. ↑ "The influence of creatine supplementation on the cognitive functioning of vegetarians and omnivores". The British Journal of Nutrition 105 (7): 1100–5. April 2011. doi:10.1017/S0007114510004733. PMID 21118604. 
  35. ↑ "Effect of age, diet, and tissue type on PCr response to creatine supplementation". Journal of Applied Physiology 23 (2): 407-414. 2017. doi:10.1152/japplphysiol.00248.2017. PMID 28572496. 
  36. ↑ "Clinical pharmacology of the dietary supplement creatine monohydrate". Pharmacological Reviews 53 (2): 161–76. June 2001. PMID 11356982. 
  37. ↑ "Creatine synthesis and exchanges between brain cells: What can be learned from human creatine deficiencies and various experimental models?". Amino Acids 48 (8): 1877–95. August 2016. doi:10.1007/s00726-016-2189-0. PMID 26861125. 
  38. ↑ "Creatine for neuroprotection in neurodegenerative disease: end of story?". Amino Acids 48 (8): 1929–40. August 2016. doi:10.1007/s00726-015-2165-0. PMID 26748651. 
  39. ↑ "Effects of creatine supplementation on performance and training adaptations". Molecular and Cellular Biochemistry 244 (1–2): 89–94. February 2003. doi:10.1023/A:1022465203458. PMID 12701815. 
  40. ↑ 40.0 40.1 "Influence of oral creatine supplementation of muscle torque during repeated bouts of maximal voluntary exercise in man". Clinical Science 84 (5): 565–71. May 1993. doi:10.1042/cs0840565. PMID 8504634. 
  41. ↑ "Comparison of new forms of creatine in raising plasma creatine levels". Journal of the International Society of Sports Nutrition 4: 17. November 2007. doi:10.1186/1550-2783-4-17. PMID 17997838. 
  42. ↑ "Long-term creatine intake is beneficial to muscle performance during resistance training". Journal of Applied Physiology 83 (6): 2055–63. December 1997. doi:10.1152/jappl.1997.83.6.2055. PMID 9390981. http://jap.physiology.org/cgi/pmidlookup?view=long&pmid=9390981. Retrieved 6 September 2020. 
  43. ↑ "Creatine supplementation with specific view to exercise/sports performance: an update". Journal of the International Society of Sports Nutrition 9 (1): 33. July 2012. doi:10.1186/1550-2783-9-33. PMID 22817979. 
  44. ↑ "Creatine Use in Sports". Sports Health 10 (1): 31–34. 2018. doi:10.1177/1941738117737248. PMID 29059531. 
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  52. ↑ 52.0 52.1 Dolan, Eimear; Gualano, Bruno; Rawson, Eric S. (2019-01-02). "Beyond muscle: the effects of creatine supplementation on brain creatine, cognitive processing, and traumatic brain injury" (in en). European Journal of Sport Science 19 (1): 1–14. doi:10.1080/17461391.2018.1500644. ISSN 1746-1391. PMID 30086660. https://www.tandfonline.com/doi/full/10.1080/17461391.2018.1500644. Retrieved 11 October 2021. 
  53. ↑ 53.0 53.1 Rawson, Eric S.; Venezia, Andrew C. (May 2011). "Use of creatine in the elderly and evidence for effects on cognitive function in young and old" (in en). Amino Acids 40 (5): 1349–1362. doi:10.1007/s00726-011-0855-9. ISSN 0939-4451. PMID 21394604. http://link.springer.com/10.1007/s00726-011-0855-9. Retrieved 11 October 2021. 
  54. ↑ Avgerinos, K. I.; Spyrou, N.; Bougioukas, K. I.; Kapogiannis, D. (2018). "Effects of creatine supplementation on cognitive function of healthy individuals: A systematic review of randomized controlled trials". Experimental Gerontology 108: 166–173. doi:10.1016/j.exger.2018.04.013. PMID 29704637. 
  55. ↑ Prokopidis, Konstantinos; Giannos, Panagiotis; Triantafyllidis, Konstantinos K.; Kechagias, Konstantinos S.; Forbes, Scott C.; Candow, Darren G. (2023). "Effects of creatine supplementation on memory in healthy individuals: a systematic review and meta-analysis of randomized controlled trials". Nutrition Reviews 81 (4): 416–27. doi:10.1093/nutrit/nuac064. PMID 35984306. 
  56. ↑ Prokopidis, Konstantinos; Giannos, Panagiotis; Triantafyllidis, Konstantinos K; Kechagias, Konstantinos S; Forbes, Scott C; Candow, Darren G (16 January 2023). "Author's reply: Letter to the Editor: Double counting due to inadequate statistics leads to false-positive findings in "Effects of creatine supplementation on memory in healthy individuals: a systematic review and meta-analysis of randomized controlled trials"". Nutrition Reviews 81 (11): 1497–1500. doi:10.1093/nutrit/nuac111. https://academic.oup.com/nutritionreviews/advance-article-abstract/doi/10.1093/nutrit/nuac111/6987897?redirectedFrom=fulltext&login=false. Retrieved 31 August 2023. 
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  58. ↑ "Creatine monohydrate in muscular dystrophies: A double-blind, placebo-controlled clinical study". Neurology 54 (9): 1848–50. May 2000. doi:10.1212/wnl.54.9.1848. PMID 10802796. 
  59. ↑ "Creatine for Parkinson's disease". The Cochrane Database of Systematic Reviews 2014 (6): CD009646. June 2014. doi:10.1002/14651858.cd009646.pub2. PMID 24934384. 
  60. ↑ "Creatine supplementation in Huntington's disease: a placebo-controlled pilot trial". Neurology 61 (7): 925–30. October 2003. doi:10.1212/01.wnl.0000090629.40891.4b. PMID 14557561. 
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  63. ↑ "Creatine for amyotrophic lateral sclerosis/motor neuron disease". The Cochrane Database of Systematic Reviews 12: CD005225. December 2012. doi:10.1002/14651858.CD005225.pub3. PMID 23235621. 
  64. ↑ Antonio, J.; Candow, D. G.; Forbes, S. C.; Gualano, B.; Jagim, A. R.; Kreider, R. B.; Rawson, E. S.; Smith-Ryan, A. E. et al. (2021). "Common questions and misconceptions about creatine supplementation: what does the scientific evidence really show?". Journal of the International Society of Sports Nutrition 18 (13): 13. doi:10.1186/s12970-021-00412-w. PMID 33557850. 
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  70. ↑ Farquhar, William B.; Zambraski, Edward J. (2002). "Effects of creatine use on the athlete's kidney". Current Sports Medicine Reports 1 (2): 103–106. doi:10.1249/00149619-200204000-00007. PMID 12831718. 
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  72. ↑ "Creatine supplementation does not impair kidney function in type 2 diabetic patients: a randomized, double-blind, placebo-controlled, clinical trial". European Journal of Applied Physiology 111 (5): 749–56. May 2011. doi:10.1007/s00421-010-1676-3. PMID 20976468. 
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  74. ↑ "Does long-term creatine supplementation impair kidney function in resistance-trained individuals consuming a high-protein diet?". Journal of the International Society of Sports Nutrition 10 (1): 26. May 2013. doi:10.1186/1550-2783-10-26. PMID 23680457. 
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  77. ↑ "Creatine supplementation associated with resistance training does not alter renal and hepatic functions" (in en). Revista Brasileira de Medicina do Esporte 17 (4): 237–241. August 2011. doi:10.1590/S1517-86922011000400004. ISSN 1517-8692. 
  78. ↑ "Effects of long-term creatine supplementation on liver and kidney functions in American college football players". International Journal of Sport Nutrition and Exercise Metabolism 12 (4): 453–60. December 2002. doi:10.1123/ijsnem.12.4.453. PMID 12500988. 
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  81. ↑ "Effects of oral creatine supplementation in a patient with MELAS phenotype and associated nephropathy". Neuropediatrics 33 (3): 157–61. June 2002. doi:10.1055/s-2002-33679. PMID 12200746. 
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  87. ↑ "Caffeine and Progression of Parkinson Disease: A Deleterious Interaction With Creatine". Clinical Neuropharmacology 38 (5): 163–9. 2015. doi:10.1097/WNF.0000000000000102. PMID 26366971. 
  88. ↑ "Heterocyclic Amines in Cooked Meats". National Cancer Institute. 15 Sep 2004. http://www.cancer.gov/cancertopics/factsheet/Risk/heterocyclic-amines. 
  89. ↑ "Chemicals in Meat Cooked at High Temperatures and Cancer Risk". National Cancer Institute. 2 April 2018. http://www.cancer.gov/cancertopics/factsheet/Risk/cooked-meats. 
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  91. ↑ Gießing, Jürgen (20 February 2019). Kreatin: Eine natürliche Substanz und ihre Bedeutung für Muskelaufbau, Fitness und Anti-Aging. BoD – Books on Demand. pp. 135–136, 207. ISBN 9783752803969. https://books.google.com/books?id=_xxgDwAAQBAJ&pg=PP4. Retrieved 27 December 2021. 

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