View source for Creatine

{{Short description|Chemical compound}}
{{distinguish|creatinine|keratin}}
{{pp-pc}}
{{pp-pc}}
{{Use dmy dates|date=January 2018}}

{{chembox
| Verifiedfields = changed
| Watchedfields  = changed
| verifiedrevid  = 464366517
| ImageFile      = CreatineStructure.png
| ImageFile_Ref  = {{chemboximage|correct|??}}
| ImageClass     = skin-invert
| ImageCaption   = Skeletal formula of neutral form of creatine
| ImageName      = Skeletal formula of neutral form of creatine
| ImageFile1     = CreatineZwitter.png
| ImageFile1_Ref = {{chemboximage|correct|??}}
| ImageClass1    = skin-invert
| ImageCaption1  = Skeletal formula of one of the [[zwitterionic]] forms of creatine
| ImageName1     = Skeletal formula of one of [[zwitterionic]] forms of creatine
| ImageFile2     = File:Creatine zwitterion ball.png
| ImageFile2_Ref = {{chemboximage|correct|??}}
| ImageCaption2  = Ball and stick model of one zwitterionic form of creatine
| ImageSize2     = 160
| ImageName2     = Ball and stick model of creatine
| SystematicName = 2-[Carbamimidoyl(methyl)amino]acetic acid
| OtherNames     = ''N''-Carbamimidoyl-''N''-methylglycine; Methylguanidoacetic acid; ''N''-amidinosarcosine
| Section1       = {{Chembox Identifiers
| CASNo = 57-00-1
| CASNo_Ref = {{cascite|correct|CAS}}
| PubChem = 586
| ChemSpiderID = 566
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| UNII = MU72812GK0
| UNII_Ref = {{fdacite|correct|FDA}}
| EINECS = 200-306-6
| DrugBank = DB00148
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| KEGG = C00300
| KEGG_Ref = {{keggcite|correct|kegg}}
| MeSHName = Creatine
| ChEBI = 16919
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 283800
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| RTECS = MB7706000
| Beilstein = 907175
| Gmelin = 240513
| 3DMet = B00084
| SMILES = CN(CC(=O)O)C(=N)N
| StdInChI = 1S/C4H9N3O2/c1-7(4(5)6)2-3(8)9/h2H2,1H3,(H3,5,6)(H,8,9)
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = CVSVTCORWBXHQV-UHFFFAOYSA-N
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
}}
| Section2       = {{Chembox Properties
| C=4 | H=9 | N=3 | O=2
| Appearance = White crystals
| Odor = Odourless
| MeltingPtC = 255
| Solubility = 13.3 g L<sup>−1</sup> (at 18 °C)
| LogP = −1.258
| pKa = 3.429
| pKb = 10.568
| IsoelectricPt = 8.47
| Density = 1.33 g/cm<sup>3</sup>
| VaporPressure = 0.001 mmHg 
}}
| Section5       = {{Chembox Thermochemistry
| DeltaHf = −538.06–−536.30 kJ mol<sup>−1</sup>
| DeltaHc = −2.3239–−2.3223 MJ mol<sup>−1</sup>
| Entropy = 189.5 J K<sup>−1</sup> mol<sup>−1</sup>
| HeatCapacity = 171.1 J K<sup>−1</sup> mol<sup>−1</sup> (at 23.2 °C)
}}
| Section6       = {{Chembox Pharmacology
| ATCCode_prefix = C01
| ATCCode_suffix = EB06
| HalfLife = 3 hours
}}
| Section7       = {{Chembox Hazards
| GHSPictograms = {{gHS exclamation mark}}
| GHSSignalWord = '''WARNING'''
| HPhrases = {{h-phrases|315|319|335}}
| PPhrases = {{p-phrases|261|305+351+338}}
| NFPA-H = 1
| NFPA-F = 1
| NFPA-R = 0
| AutoignitionPt = > 400 °C
| FlashPtC = 118.1
| LD50 = > 2000 mg/kg (dermal, rat)
| ExternalSDS = [https://www.chemicalbook.com/msds/Creatine.htm ChemicalBook]
}}
| Section8       = {{Chembox Related
| OtherFunction_label = alkanoic acids
| OtherFunction = {{unbulleted list|[[Sarcosine]]|[[Dimethylglycine]]|[[Glycocyamine]]|[[n-Methyl-D-aspartic acid|''N''-Methyl-D-aspartic acid]]|[[beta-Methylamino-L-alanine|''beta''-Methylamino-L-alanine]]|[[Guanidinopropionic acid]]}}
| OtherCompounds = [[Dimethylacetamide]]
}}
}}

'''Creatine''' ({{IPAc-en|ˈ|k|r|iː|ə|t|iː|n}} or {{IPAc-en|ˈ|k|r|iː|ə|t|ɪ|n}})<ref>{{cite book|title=Essentials of Creatine in Sports and Health | veditors = Stout JR, Antonio J, Kalman E |year=2008|publisher=Humana|isbn=978-1-59745-573-2}}</ref> is an [[organic compound]] with the nominal formula {{chem2|(H2N)(HN)CN(CH3)CH2CO2H}}. It exists in various [[tautomer]]s in solutions (among which are neutral form and various [[zwitterionic]] forms). Creatine is found in [[vertebrate]]s, 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 group]]s. Creatine also acts as a [[Buffer solution|buffer]].<ref name="pmid26202197">{{cite journal | vauthors = Barcelos RP, Stefanello ST, Mauriz JL, Gonzalez-Gallego J, Soares FA | title = Creatine and the Liver: Metabolism and Possible Interactions | journal = Mini Reviews in Medicinal Chemistry | volume = 16 | issue = 1 | pages = 12–8 | year = 2016 | pmid = 26202197 | doi = 10.2174/1389557515666150722102613 | quote = 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. }}</ref>

==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 [[Ancient Greek|Greek]] word for meat, {{lang|grc|κρέας}} (''{{lang|grc-Latn|kreas}}''). In 1928, creatine was shown to exist in [[Tautomer|equilibrium]] with [[creatinine]].<ref>{{cite journal | vauthors = Cannan RK, Shore A | title = The creatine-creatinine equilibrium. The apparent dissociation constants of creatine and creatinine | journal = The Biochemical Journal | volume = 22 | issue = 4 | pages = 920–9 | year = 1928 | pmid = 16744118 | pmc = 1252207 | doi = 10.1042/bj0220920 }}</ref> 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.<ref>{{cite book|chapter=Overview of Creatine Metabolism| first1 = Jeff S. | last1 = Volek | first2 = Kevin D. | last2 = Ballard | first3 = Cassandra E. | last3 = Forsythe | name-list-style = vanc |title=Essentials of Creatine in Sports and Health | veditors = Stout JR, Antonio J, Kalman E |year=2008|publisher=Humana|isbn=978-1-59745-573-2|pages=1–23}}</ref>

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.<ref>{{cite journal |last1=Folin |first1=Otto |last2=Denis |first2=W |name-list-style=vanc |title=Protein metabolism from the standpoint of blood and tissue analysis |journal=Journal of Biological Chemistry |volume=12 |issue=1 |year=1912 |pages=141–61 |doi=10.1016/S0021-9258(18)88723-3 |url=http://www.jbc.org/content/12/1/141.full.pdf+html |doi-access=free |access-date=8 May 2018 |archive-date=3 May 2018 |archive-url=https://web.archive.org/web/20180503042522/http://www.jbc.org/content/12/1/141.full.pdf+html |url-status=live }}</ref><ref>{{Cite journal |last=Antonio |first=Jose |date=February 8, 2021 |title=Common questions and misconceptions about creatine supplementation: what does the scientific evidence really show? |journal=Journal of the International Society of Sports Nutrition |volume=18 |issue=1 |page=13 |doi=10.1186/s12970-021-00412-w |pmid=33557850 |pmc=7871530 |doi-access=free }}</ref> 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]]. It is naturally formed in vertebrates.<ref>{{cite journal | vauthors = Brosnan JT, da Silva RP, Brosnan ME | title = The metabolic burden of creatine synthesis | journal = Amino Acids | volume = 40 | issue = 5 | pages = 1325–31 | date = May 2011 | pmid = 21387089 | doi = 10.1007/s00726-011-0853-y | s2cid = 8293857 }}</ref>

The discovery of phosphocreatine<ref>{{cite book | last = Saks | first = Valdur | name-list-style = vanc | year = 2007 | title = Molecular system bioenergetics: energy for life | url = https://archive.org/details/molecularsystemb00saks | url-access = limited | place = Weinheim | publisher = Wiley-VCH | page = [https://archive.org/details/molecularsystemb00saks/page/n31 2] | isbn = 978-3-527-31787-5 }}</ref><ref name="ochoa">{{cite book | last = Ochoa | first = Severo | name-list-style = vanc | year = 1989 | editor-last = Sherman | editor-first = E. J. | editor2-last = National Academy of Sciences | title = David Nachmansohn | series = Biographical Memoirs | publisher = National Academies Press | volume = 58 | pages = 357–404 | isbn = 978-0-309-03938-3 }}</ref> was reported in 1927.<ref>{{cite journal | vauthors = Eggleton P, Eggleton GP | title = The Inorganic Phosphate and a Labile Form of Organic Phosphate in the Gastrocnemius of the Frog | journal = The Biochemical Journal | volume = 21 | issue = 1 | pages = 190–5 | year = 1927 | pmid = 16743804 | pmc = 1251888 | doi = 10.1042/bj0210190 }}</ref><ref>{{cite journal | vauthors = Fiske CH, Subbarow Y | title = The nature of the 'inorganic phosphate' in voluntary muscle | journal = Science | volume = 65 | issue = 1686 | pages = 401–3 | date = April 1927 | pmid = 17807679 | doi = 10.1126/science.65.1686.401 | bibcode = 1927Sci....65..401F }}</ref><ref name=ochoa/> In the 1960s, the enzyme [[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.<ref>{{cite book | vauthors = Wallimann T |chapter=Introduction – Creatine: Cheap Ergogenic Supplement with Great Potential for Health and Disease | veditors = Salomons GS, Wyss M |title=Creatine and Creatine Kinase in Health and Disease | url = https://archive.org/details/creatinecreatine00salo | url-access = limited |pages=[https://archive.org/details/creatinecreatine00salo/page/n16 1]–16 |year=2007 |isbn=978-1-4020-6486-9 |publisher=Springer }}</ref>

While creatine's influence on physical performance has been well documented since the early twentieth century, it came into public view following the [[1992 Summer Olympics|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 noted that Christie was found guilty of doping later in his career).<ref>{{cite web | url=https://www.telegraph.co.uk/sport/othersports/athletics/4768790/Shadow-over-Christies-reputation.html | title=Shadow over Christie's reputation | date=22 August 2000 }}</ref> 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.<ref>{{cite web |url=http://www.nationalreviewofmedicine.com/issue/2004_07_30/feature07_14.html |archive-url=https://web.archive.org/web/20061116021537/http://www.nationalreviewofmedicine.com/issue/2004_07_30/feature07_14.html |url-status=dead |archive-date=2006-11-16 |title=Supplement muscles in on the market |publisher=National Review of Medicine |date=2004-07-30 |access-date=2011-05-25 }}</ref><ref>{{cite book |title=Creatine |last=Passwater |first=Richard A. |name-list-style=vanc |year=2005 |isbn=978-0-87983-868-3 |page=9 |publisher=McGraw Hill Professional |url=https://books.google.com/books?id=umy67wOLOckC |access-date=8 May 2018 |archive-date=19 June 2022 |archive-url=https://web.archive.org/web/20220619121759/https://books.google.com/books?id=umy67wOLOckC |url-status=live }}</ref>

[[image:Phosphocreatine.svg|thumb|left|class=skin-invert-image|[[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''.<ref>{{Cite book |last= Stoppani |first= Jim |name-list-style= vanc |title= 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 |publisher= [[Muscle & Fitness]] |date= May 2004 |url= http://findarticles.com/p/articles/mi_m0801/is_5_65/ai_n6005938 |access-date= 2010-03-29 |archive-date= 11 July 2012 |archive-url= https://archive.today/20120711163221/http://findarticles.com/p/articles/mi_m0801/is_5_65/ai_n6005938/ |url-status= live }}</ref> Research performed thereafter demonstrated that the consumption of high [[Glycemic index|glycemic]] carbohydrates in conjunction with creatine increases creatine muscle stores.<ref name=":4">{{cite journal | vauthors = Green AL, Hultman E, Macdonald IA, Sewell DA, Greenhaff PL | title = Carbohydrate ingestion augments skeletal muscle creatine accumulation during creatine supplementation in humans | journal = The American Journal of Physiology | volume = 271 | issue = 5 Pt 1 | pages = E821-6 | date = November 1996 | pmid = 8944667 | doi = 10.1152/ajpendo.1996.271.5.E821 }}</ref>

[[image:Creatinine-tautomerism-2D-skeletal.svg|left|thumb|class=skin-invert-image|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 [[Adenosine triphosphate|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.<ref name="pmid22817979">{{cite journal |vauthors=Cooper R, Naclerio F, Allgrove J, Jimenez A |title=Creatine supplementation with specific view to exercise/sports performance: an update |journal=Journal of the International Society of Sports Nutrition |volume=9 |issue=1 |pages=33 |date=July 2012 |pmid=22817979 |pmc=3407788 |doi=10.1186/1550-2783-9-33 |quote=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]. |doi-access=free }}</ref><ref name="pmid26874700">{{cite journal |vauthors=Brosnan ME, Brosnan JT |title=The role of dietary creatine |journal=Amino Acids |volume=48 |issue=8 |pages=1785–91 |date=August 2016 |pmid=26874700 |doi=10.1007/s00726-016-2188-1 |s2cid=3700484 |quote=The daily requirement of a 70-kg male for creatine is about 2&nbsp;g; up to half of this may be obtained from a typical omnivorous diet, with the remainder being synthesized in the body&nbsp;... 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).&nbsp;... Creatine synthesized in liver must be secreted into the bloodstream by an unknown mechanism (Da Silva et al. 2014a)}}</ref> The typical creatine content of skeletal muscle (as both creatine and phosphocreatine) is 120&nbsp;mmol per kilogram of dry muscle mass, but can reach up to 160&nbsp;mmol/kg through supplementation.<ref name=":2">{{cite journal |vauthors=Hultman E, Söderlund K, Timmons JA, Cederblad G, Greenhaff PL |date=July 1996 |title=Muscle creatine loading in men |journal=Journal of Applied Physiology |volume=81 |issue=1 |pages=232–7 |doi=10.1152/jappl.1996.81.1.232 |pmid=8828669}}</ref> 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.<ref name=":2" /><ref>{{cite journal |vauthors=Balsom PD, Söderlund K, Ekblom B |title=Creatine in humans with special reference to creatine supplementation |journal=Sports Medicine |volume=18 |issue=4 |pages=268–80 |date=October 1994 |pmid=7817065 |doi=10.2165/00007256-199418040-00005|s2cid=23929060 }}</ref><ref name=":5">{{cite journal |vauthors=Harris RC, Söderlund K, Hultman E |title=Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation |journal=Clinical Science |volume=83 |issue=3 |pages=367–74 |date=September 1992 |pmid=1327657 |doi=10.1042/cs0830367 }}</ref> An omnivorous diet provides roughly half of this value, with the remainder synthesized in the liver and kidneys.<ref name="pmid22817979" /><ref name="pmid26874700" /><ref name="pmid21387089">{{cite journal |vauthors=Brosnan JT, da Silva RP, Brosnan ME |date=May 2011 |title=The metabolic burden of creatine synthesis |journal=Amino Acids |volume=40 |issue=5 |pages=1325–31 |doi=10.1007/s00726-011-0853-y |pmid=21387089 |quote=Creatinine loss averages approximately 2&nbsp;g (14.6&nbsp;mmol) for 70&nbsp;kg males in the 20- to 39-year age group.&nbsp;... 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<br />Creatine synthesis (mmol/day)&nbsp;&nbsp;&nbsp;8.3 |s2cid=8293857}}</ref>

Creatine is not an [[essential nutrient]].<ref name="Creatine">{{Cite web|url=http://www.bidmc.org/YourHealth/ConditionsAZ.aspx?ChunkID=21706|title=Creatine|publisher=[[Beth Israel Deaconess Medical Center]]|access-date=23 August 2010|archive-date=28 January 2011|archive-url=https://web.archive.org/web/20110128035754/http://www.bidmc.org/YourHealth/ConditionsAZ.aspx?ChunkID=21706|url-status=live}}</ref> It is an amino acid [[Derivative (chemistry)|derivative]], naturally produced in the human body from the [[amino acid]]s [[glycine]] and [[arginine]], with an additional requirement for [[S-Adenosyl methionine|''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, [http://enzyme.expasy.org/EC/2.1.4.1 EC:2.1.4.1]) mediates the reaction of glycine and arginine to form [[guanidinoacetate]]. This product is then [[methylation|methylated]] by [[guanidinoacetate N-methyltransferase|guanidinoacetate ''N''-methyltransferase]] (GAMT, [http://enzyme.expasy.org/EC/2.1.1.2 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.

[[File:CreatineSynthesis(en).png|500px|center|class=skin-invert-image]]

===Phosphocreatine system===
[[File:Creatine kinase and phosphocreatine energy shuttle.png|thumb|464x464px|class=skin-invert-image|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 [[adenosine triphosphate|ATP]] in skeletal muscle is usually 2–5&nbsp;mM, which would result in a muscle contraction of only a few seconds.<ref name="ncbi.nlm.nih.gov">{{cite journal | vauthors = Wallimann T, Wyss M, Brdiczka D, Nicolay K, Eppenberger HM | title = Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands: the 'phosphocreatine circuit' for cellular energy homeostasis | journal = The Biochemical Journal | volume = 281 ( Pt 1) | issue = Pt 1 | pages = 21–40 | date = January 1992 | pmid = 1731757 | pmc = 1130636 | doi = 10.1042/bj2810021 }}</ref> During times of increased energy demands, the [[phosphagen]] (or ATP/PCr) system rapidly resynthesizes ATP from [[adenosine diphosphate|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&nbsp;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.<ref name="ncbi.nlm.nih.gov" /> A proposed representation has been illustrated by Krieder et al.<ref name=":3" /> 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.<ref>{{cite journal | vauthors = Spillane M, Schoch R, Cooke M, Harvey T, Greenwood M, Kreider R, Willoughby DS | title = The effects of creatine ethyl ester supplementation combined with heavy resistance training on body composition, muscle performance, and serum and muscle creatine levels | journal = Journal of the International Society of Sports Nutrition | volume = 6 | issue = 1 | pages = 6 | date = February 2009 | pmid = 19228401 | pmc = 2649889 | doi = 10.1186/1550-2783-6-6 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Wallimann T, Tokarska-Schlattner M, Schlattner U | title = The creatine kinase system and pleiotropic effects of creatine | journal = Amino Acids | volume = 40 | issue = 5 | pages = 1271–96 | date = May 2011 | pmid = 21448658 | pmc = 3080659 | doi = 10.1007/s00726-011-0877-3 }}.</ref><ref>T. Wallimann, M. Tokarska-Schlattner, D. Neumann u.&nbsp;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.ch7}}C</ref>

Creatine supplementation appears to increase the number of [[myonuclei]] that satellite cells will 'donate' to damaged [[muscle fiber]]s, 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 regulatory factors|myogenic transcription factor]] [[MRF4]].<ref>{{cite journal | vauthors = Hespel P, Eijnde BO, Derave W, Richter EA | title = Creatine supplementation: exploring the role of the creatine kinase/phosphocreatine system in human muscle | journal = Canadian Journal of Applied Physiology | volume = 26 Suppl | pages = S79-102 | year = 2001 | pmid = 11897886 | doi = 10.1139/h2001-045 }}</ref>

===Genetic deficiencies===
Genetic deficiencies in the creatine biosynthetic pathway lead to various [[cerebral creatine deficiency|severe neurological defects]].<ref>{{Cite web |url=https://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602360 |title=L-Arginine:Glycine Amidinotransferase |access-date=16 August 2010 |archive-date=24 August 2013 |archive-url=https://web.archive.org/web/20130824195046/http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602360 |url-status=live }}</ref> Clinically, there are three distinct disorders of creatine metabolism, termed [[Cerebral creatine deficiency|cerebral creatine deficiencies]]. Deficiencies in the two synthesis enzymes can cause [[Arginine:glycine amidinotransferase|L-arginine:glycine amidinotransferase deficiency]] caused by variants in ''[[GATM (gene)|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 is inherited in a X-linked manner. This condition is related to the transport of creatine into the brain.<ref name="creatinedefects">{{cite journal | vauthors = Braissant O, Henry H, Béard E, Uldry J | title = Creatine deficiency syndromes and the importance of creatine synthesis in the brain | journal = Amino Acids | volume = 40 | issue = 5 | pages = 1315–24 | date = May 2011 | pmid = 21390529 | doi = 10.1007/s00726-011-0852-z | s2cid = 13755292 | url = https://serval.unil.ch/resource/serval:BIB_CE3937F9A69E.P001/REF.pdf | access-date = 8 July 2019 | archive-date = 10 March 2021 | archive-url = https://web.archive.org/web/20210310001947/https://serval.unil.ch/resource/serval:BIB_CE3937F9A69E.P001/REF.pdf | url-status = live }}</ref>

===Vegans and vegetarians===
Vegan and vegetarian diets are associated with lower levels of muscle creatine, and athletes on these diets may benefit from creatine supplementation.<ref>{{cite journal |vauthors=Rogerson D |title=Vegan diets: practical advice for athletes and exercisers |journal=J Int Soc Sports Nutr |volume=14 |issue= |pages=36 |date=2017 |pmid=28924423 |pmc=5598028 |doi=10.1186/s12970-017-0192-9 |doi-access=free |url=}}</ref>

==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.<ref>{{cite journal | vauthors = Persky AM, Brazeau GA | title = Clinical pharmacology of the dietary supplement creatine monohydrate | journal = Pharmacological Reviews | volume = 53 | issue = 2 | pages = 161–76 | date = June 2001 | pmid = 11356982 }}</ref>

=== Dosing ===

==== Loading phase ====
[[File:Muscle_Total_Creatine_Stores.png|alt=|thumb|485x485px|class=skin-invert-image]]
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.<ref name=":3" /><ref name=":2" /> 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.<ref name=":2" /> However, a 28-day loading phase does not allow for [[Performance-enhancing substance#Ergogenic aids|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.<ref>{{cite journal | vauthors = Hanna-El-Daher L, Braissant O | title = Creatine synthesis and exchanges between brain cells: What can be learned from human creatine deficiencies and various experimental models? | journal = Amino Acids | volume = 48 | issue = 8 | pages = 1877–95 | date = August 2016 | pmid = 26861125 | doi = 10.1007/s00726-016-2189-0 | s2cid = 3675631 }}</ref><ref>{{cite journal | vauthors = Bender A, Klopstock T | title = Creatine for neuroprotection in neurodegenerative disease: end of story? | journal = Amino Acids | volume = 48 | issue = 8 | pages = 1929–40 | date = August 2016 | pmid = 26748651 | doi = 10.1007/s00726-015-2165-0 | s2cid = 2349130 }}</ref><ref name="creatinedefects" />

==== 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),<ref name=":2" /> however, some studies have suggested 3–5 g/day maintenance dose to maintain saturated muscle creatine.<ref name=":4" /><ref name=":5" /><ref>{{cite journal |vauthors=Kreider RB |title=Effects of creatine supplementation on performance and training adaptations |journal=Molecular and Cellular Biochemistry |volume=244 |issue=1–2 |pages=89–94 |date=February 2003 |doi=10.1023/A:1022465203458 |pmid=12701815|s2cid=35050122 }}</ref><ref name=":6">{{cite journal |vauthors=Greenhaff PL, Casey A, Short AH, Harris R, Soderlund K, Hultman E |title=Influence of oral creatine supplementation of muscle torque during repeated bouts of maximal voluntary exercise in man |journal=Clinical Science |volume=84 |issue=5 |pages=565–71 |date=May 1993 |pmid=8504634 |doi=10.1042/cs0840565}}</ref>

=== Absorption ===
[[File:Plasma_creatine_concentration_over_time.jpg|thumb|class=skin-invert-image|This graph shows the mean plasma creatine concentration (measured in {{abbr|μmol/L|micromoles per liter}}) over an 8-hour period following ingestion of 4.4&nbsp;grams of creatine in the form of creatine monohydrate (CrM), tri-creatine citrate (CrC), or creatine pyruvate (CrPyr).<ref name="pmid17997838">{{cite journal | vauthors = Jäger R, Harris RC, Purpura M, Francaux M | title = Comparison of new forms of creatine in raising plasma creatine levels | journal = Journal of the International Society of Sports Nutrition | volume = 4 | pages = 17 | date = November 2007 | pmid = 17997838 | pmc = 2206055 | doi = 10.1186/1550-2783-4-17 | doi-access = free }}</ref>|alt=|259x259px]]
Endogenous serum or plasma creatine concentrations in healthy adults are normally in a range of 2–12&nbsp;mg/L. A single 5 gram (5000&nbsp;mg) oral dose in healthy adults results in a peak plasma creatine level of approximately 120&nbsp;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.

==Exercise and sport==
Creatine supplements are marketed in [[ethyl ester]], [[gluconate]], [[monohydrate]], and [[nitrate]] forms.<ref name="Cooper2012">{{cite journal | vauthors = Cooper R, Naclerio F, Allgrove J, Jimenez A | title = Creatine supplementation with specific view to exercise/sports performance: an update | journal = Journal of the International Society of Sports Nutrition | volume = 9 | issue = 1 | pages = 33 | date = July 2012 | pmid = 22817979 | pmc = 3407788 | doi = 10.1186/1550-2783-9-33 | doi-access = free }}</ref>

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.<ref>{{cite journal |vauthors=Butts J, Jacobs B, Silvis M |title=Creatine Use in Sports |journal=Sports Health |volume=10 |issue=1 |pages=31–34 |date=2018 |pmid=29059531 |pmc=5753968 |doi=10.1177/1941738117737248 |url=}}</ref>

According to a 2018 [[review article]] in the ''Journal of the International Society of Sports Nutrition'' creatine monohydrate is the most effective nutritional supplement to increase high intensity exercise capacity and muscle mass during training.<ref>{{cite journal |vauthors=Kerksick CM, Wilborn CD, Roberts MD, Smith-Ryan A, Kleiner SM, Jäger R, Collins R, Cooke M, Davis JN, Galvan E, Greenwood M, Lowery LM, Wildman R, Antonio J, Kreider RB |display-authors=6 |title=ISSN exercise & sports nutrition review update: research & recommendations |journal=Journal of the International Society of Sports Nutrition |volume=15 |issue=1 |pages=38 |date=August 2018 |pmid=30068354 |pmc=6090881 |doi=10.1186/s12970-018-0242-y |doi-access=free }}</ref>

Creatine use can increase maximum power and performance in high-intensity anaerobic repetitive work (periods of work and rest) by 5% to 15%.<ref>{{cite journal |vauthors=Bemben MG, Lamont HS |title=Creatine supplementation and exercise performance: recent findings |journal=Sports Medicine |volume=35 |issue=2 |pages=107–25 |year=2005 |pmid=15707376 |doi=10.2165/00007256-200535020-00002|s2cid=57734918 }}</ref><ref>{{cite journal |vauthors=Bird SP |title=Creatine supplementation and exercise performance: a brief review |journal=Journal of Sports Science & Medicine |volume=2 |issue=4 |pages=123–32 |date=December 2003 |pmid=24688272 |pmc=3963244}}</ref><ref>{{cite journal |vauthors=Lanhers C, Pereira B, Naughton G, Trousselard M, Lesage FX, Dutheil F |title=Creatine Supplementation and Lower Limb Strength Performance: A Systematic Review and Meta-Analyses |journal=Sports Medicine |volume=45 |issue=9 |pages=1285–1294 |date=September 2015 |pmid=25946994 |doi=10.1007/s40279-015-0337-4|s2cid=7372700 }}</ref> Creatine supplementation exerts positive ergogenic effects on single and multiple bouts of short-duration, high-intensity exercise activities, in addition to potentiating exercise training adaptations.<ref>{{Cite journal |last1=Wax |first1=B. |last2=Kerksick |first2=C. M. |last3=Jagim |first3=A. R. |last4=Mayo |first4=J. J. |last5=Lyons |first5=B. C. |last6=Kreider |first6=R. B. |date=2021 |title=Creatine for Exercise and Sports Performance, with Recovery Considerations for Healthy Populations |journal=Nutrients |volume=13 |issue=6 |page=1915 |doi=10.3390/nu13061915 |pmc=8228369 |pmid=34199588 |doi-access=free}}</ref> Creatine has no significant effect on aerobic [[Endurance#Endurance exercise|endurance]].<ref>{{cite journal |vauthors=Engelhardt M, Neumann G, Berbalk A, Reuter I |date=July 1998 |title=Creatine supplementation in endurance sports |journal=Medicine and Science in Sports and Exercise |volume=30 |issue=7 |pages=1123–9 |doi=10.1097/00005768-199807000-00016 |pmid=9662683 |doi-access=free}}</ref>{{Obsolete source|date=May 2018}}<ref name="Graham">{{cite journal |vauthors=Graham AS, Hatton RC |year=1999 |title=Creatine: a review of efficacy and safety |journal=Journal of the American Pharmaceutical Association |volume=39 |issue=6 |pages=803–10; quiz 875–7 |doi=10.1016/s1086-5802(15)30371-5 |pmid=10609446}}</ref>{{Obsolete source|date=May 2018}} 

A 2014 survey of 21,000 college athletes showed that 14% of athletes take creatine supplements.<ref name=":1">{{Cite news |title=Office of Dietary Supplements - Dietary Supplements for Exercise and Athletic Performance |url=https://ods.od.nih.gov/factsheets/ExerciseAndAthleticPerformance-HealthProfessional/ |url-status=live |archive-url=https://web.archive.org/web/20180508185512/https://ods.od.nih.gov/factsheets/ExerciseAndAthleticPerformance-HealthProfessional/#creatine |archive-date=8 May 2018 |access-date=2018-05-05 |language=en}}</ref>

==Research ==

===Cognitive performance===
Creatine is sometimes 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.<ref name=":8">{{Cite journal|last1=Dolan|first1=Eimear|last2=Gualano|first2=Bruno|last3=Rawson|first3=Eric S.|date=2019-01-02|title=Beyond muscle: the effects of creatine supplementation on brain creatine, cognitive processing, and traumatic brain injury|url=https://www.tandfonline.com/doi/full/10.1080/17461391.2018.1500644|journal=European Journal of Sport Science|language=en|volume=19|issue=1|pages=1–14|doi=10.1080/17461391.2018.1500644|pmid=30086660|s2cid=51936612|issn=1746-1391|access-date=11 October 2021|archive-date=29 October 2021|archive-url=https://web.archive.org/web/20211029174808/https://www.tandfonline.com/doi/full/10.1080/17461391.2018.1500644|url-status=live|url-access=subscription}}</ref><ref name=":9">{{Cite journal|last1=Rawson|first1=Eric S.|last2=Venezia|first2=Andrew C.|date=May 2011|title=Use of creatine in the elderly and evidence for effects on cognitive function in young and old|url=http://link.springer.com/10.1007/s00726-011-0855-9|journal=Amino Acids|language=en|volume=40|issue=5|pages=1349–1362|doi=10.1007/s00726-011-0855-9|pmid=21394604|s2cid=11382225|issn=0939-4451|access-date=11 October 2021|archive-date=19 June 2022|archive-url=https://web.archive.org/web/20220619121803/https://link.springer.com/article/10.1007/s00726-011-0855-9|url-status=live|url-access=subscription}}</ref> The greatest effect appears to be in individuals who are [[Stress (biology)|stressed]] (due, for instance, to [[sleep deprivation]]) or cognitively impaired.<ref name=":8" /><ref name=":9" /><ref>{{Cite journal|vauthors = Gordji-Nejad|date= 2024 |title= Single dose creatine improves cognitive performance and induces changes in cerebral high energy phosphates during sleep deprivation|journal=Scientific Reports |volume= 14|issue= 1|pages=4937 |doi=10.1038/s41598-024-54249-9 |pmid= 38418482 |pmc=10902318|bibcode= 2024NatSR..14.4937G }}</ref>

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".<ref>{{cite journal |title=Effects of creatine supplementation on cognitive function of healthy individuals: A systematic review of randomized controlled trials |journal=[[Experimental Gerontology]] |date=2018 |volume=108 |pages=166–173 |pmc=6093191 |last1=Avgerinos |first1=K. I. |last2=Spyrou |first2=N. |last3=Bougioukas |first3=K. I. |last4=Kapogiannis |first4=D. |doi=10.1016/j.exger.2018.04.013 |pmid=29704637 }}</ref>

===Muscular disease===
A meta-analysis found that creatine treatment increased muscle strength in [[muscular dystrophies]], and potentially improved functional performance.<ref name="Kley2013">{{cite journal | vauthors = Kley RA, Tarnopolsky MA, Vorgerd M | title = Creatine for treating muscle disorders | journal = The Cochrane Database of Systematic Reviews | issue = 6 | pages = CD004760 | date = June 2013 | volume = 2013 | pmid = 23740606 | pmc = 6492334 | doi = 10.1002/14651858.CD004760.pub4 }}</ref> Creatine treatment does not appear to improve muscle strength in people who have [[Metabolic myopathy|metabolic myopathies]].<ref name="Kley2013" /> High doses of creatine lead to increased muscle pain and an impairment in [[activities of daily living]] when taken by people who have [[Glycogen storage disease type V|McArdle disease]].<ref name="Kley2013" />

===Mitochondrial diseases===
====Parkinson's disease====
Creatine's impact on [[mitochondria]]l 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.<ref>{{cite journal | vauthors = Xiao Y, Luo M, Luo H, Wang J | title = Creatine for Parkinson's disease | journal = The Cochrane Database of Systematic Reviews | issue = 6 | pages = CD009646 | date = June 2014 | volume = 2014 | pmid = 24934384 | doi = 10.1002/14651858.cd009646.pub2 | pmc = 10196714 }}</ref>

==== Huntington's disease ====
Several primary studies<ref>{{cite journal | vauthors = Verbessem P, Lemiere J, Eijnde BO, Swinnen S, Vanhees L, Van Leemputte M, Hespel P, Dom R | display-authors = 6 | title = Creatine supplementation in Huntington's disease: a placebo-controlled pilot trial | journal = Neurology | volume = 61 | issue = 7 | pages = 925–30 | date = October 2003 | pmid = 14557561 | doi = 10.1212/01.wnl.0000090629.40891.4b | s2cid = 43845514 }}</ref><ref>{{cite journal | vauthors = Bender A, Auer DP, Merl T, Reilmann R, Saemann P, Yassouridis A, Bender J, Weindl A, Dose M, Gasser T, Klopstock T | display-authors = 6 | title = Creatine supplementation lowers brain glutamate levels in Huntington's disease | journal = Journal of Neurology | volume = 252 | issue = 1 | pages = 36–41 | date = January 2005 | pmid = 15672208 | doi = 10.1007/s00415-005-0595-4 | s2cid = 17861207 }}</ref><ref>{{cite journal | vauthors = Hersch SM, Schifitto G, Oakes D, Bredlau AL, Meyers CM, Nahin R, Rosas HD | title = The CREST-E study of creatine for Huntington disease: A randomized controlled trial | journal = Neurology | volume = 89 | issue = 6 | pages = 594–601 | date = August 2017 | pmid = 28701493 | pmc = 5562960 | doi = 10.1212/WNL.0000000000004209 }}</ref> 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]].<ref>{{cite journal | vauthors = Pastula DM, Moore DH, Bedlack RS | title = Creatine for amyotrophic lateral sclerosis/motor neuron disease | journal = The Cochrane Database of Systematic Reviews | volume = 2012 | pages = CD005225 | date = December 2012 | issue = 12 | pmid = 23235621 | doi = 10.1002/14651858.CD005225.pub3 | pmc = 11403570 }}</ref>

===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]], [[Dihydrotestosterone|DHT]] or causes hair loss/baldness".<ref>{{cite journal |title=Common questions and misconceptions about creatine supplementation: what does the scientific evidence really show? |journal=Journal of the International Society of Sports Nutrition |date=2021 |volume=18 |issue=13 |pmc=7871530 |last1=Antonio |first1=J. |last2=Candow |first2=D. G. |last3=Forbes |first3=S. C. |last4=Gualano |first4=B. |last5=Jagim |first5=A. R. |last6=Kreider |first6=R. B. |last7=Rawson |first7=E. S. |last8=Smith-Ryan |first8=A. E. |last9=Vandusseldorp |first9=T. A. |last10=Willoughby |first10=D. S. |last11=Ziegenfuss |first11=T. N. |page=13 |doi=10.1186/s12970-021-00412-w |pmid=33557850 |doi-access=free }}</ref>

===Cardiovascular disease===

A 2011 systematic review evaluated the effectiveness of creatine and creatine analogues in adults with cardiovascular disease, including [[Heart failure|heart failure]] and [[Myocardial infarction|myocardial infarction]]. The studies assessed the use of various creatine-based compounds—such as creatine, creatine phosphate, and [[Phosphocreatine|phosphocreatinine]]—administered via oral, intravenous, or intramuscular routes, typically as adjuncts to standard therapy.

The analysis found no conclusive evidence that creatine or its analogues significantly affect mortality, myocardial infarction progression, or ejection fraction. However, some studies suggested a potential improvement in cardiac [[Arrhythmia|dysrhythmias]] and [[Shortness of breath|dyspnoea]]. The trials varied considerably in terms of drug formulation, dosage, treatment duration, and patient populations. Notably, no studies were identified that examined the effects of these compounds in patients with essential hypertension.

Due to the small sample sizes, clinical heterogeneity, and inconsistent outcomes across trials, the authors concluded that more rigorous and larger-scale studies are necessary to establish the clinical utility of creatine analogues in cardiovascular care. <ref>{{cite journal |title= Creatine and creatine analogues in hypertension and cardiovascular disease |journal= Cochrane Database of Systematic Reviews |date=2011 |last1=Horjus |first1=D. L. |last2=Oudman |first2=I. |last3=Montfrans |first3=G.A. V. |last4=Brewster |first4=L. M. |number=11 |doi= 10.1002/14651858.CD005184.pub2 |pmid= 22071819 }}</ref>

==Adverse effects==
Side effects include:<ref>{{cite journal | vauthors = Francaux M, Poortmans JR | s2cid = 21330062 | title = Side effects of creatine supplementation in athletes | journal = International Journal of Sports Physiology and Performance | volume = 1 | issue = 4 | pages = 311–23 | date = December 2006 | pmid = 19124889 | doi = 10.1123/ijspp.1.4.311 }}</ref><ref>{{cite journal | vauthors = Buford TW, Kreider RB, Stout JR, Greenwood M, Campbell B, Spano M, Ziegenfuss T, Lopez H, Landis J, Antonio J | display-authors = 6 | title = International Society of Sports Nutrition position stand: creatine supplementation and exercise | journal = Journal of the International Society of Sports Nutrition | volume = 4 | pages = 6 | date = August 2007 | pmid = 17908288 | pmc = 2048496 | doi = 10.1186/1550-2783-4-6 | publisher = jissn | doi-access = free }}</ref>

* Weight gain due to extra [[Water retention (medicine)|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]].<ref name=":0">{{cite journal | vauthors = Kreider RB, Kalman DS, Antonio J, Ziegenfuss TN, Wildman R, Collins R, Candow DG, Kleiner SM, Almada AL, Lopez HL | display-authors = 6 | title = International Society of Sports Nutrition position stand: safety and efficacy of creatine supplementation in exercise, sport, and medicine | journal = Journal of the International Society of Sports Nutrition | volume = 14 | pages = 18 | date = 2017-06-13 | pmid = 28615996 | pmc = 5469049 | doi = 10.1186/s12970-017-0173-z | doi-access = free }}</ref>

A 2009 systematic review discredited concerns that creatine supplementation could affect hydration status and heat tolerance and lead to muscle cramping and diarrhea.<ref name="Lopez RM, Casa DJ, McDermott BP, Ganio MS, Armstrong LE, Maresh CM 2009 215–23">{{cite journal | vauthors = Lopez RM, Casa DJ, McDermott BP, Ganio MS, Armstrong LE, Maresh CM | title = Does creatine supplementation hinder exercise heat tolerance or hydration status? A systematic review with meta-analyses | journal = Journal of Athletic Training | volume = 44 | issue = 2 | pages = 215–23 | year = 2009 | pmid = 19295968 | pmc = 2657025 | doi = 10.4085/1062-6050-44.2.215 }}</ref><ref name="Dalbo VJ, Roberts MD, Stout JR, Kerksick CM 2008 567–73">{{cite journal | vauthors = Dalbo VJ, Roberts MD, Stout JR, Kerksick CM | title = Putting to rest the myth of creatine supplementation leading to muscle cramps and dehydration | journal = British Journal of Sports Medicine | volume = 42 | issue = 7 | pages = 567–73 | date = July 2008 | pmid = 18184753 | doi = 10.1136/bjsm.2007.042473 | s2cid = 12920206 | url = http://hdl.cqu.edu.au/10018/55591 | access-date = 27 December 2021 | archive-date = 19 June 2022 | archive-url = https://web.archive.org/web/20220619121814/https://acquire.cqu.edu.au/articles/journal_contribution/Putting_to_rest_the_myth_of_creatine_supplementation_leading_to_muscle_cramps_and_dehydration/13449578 | url-status = live | url-access = subscription }}</ref>

Despite weight gain due to water retention and potential cramps being two seemingly "common" side effects, new research indicates that these side effects are likely not the result of creatine usage. In addition, the initial water retention is attributed to more short-term creatine use (the "loading" phase). Studies have shown that creatine usage does not necessarily affect total body water relative to muscle mass in the long-term.<ref>{{Cite journal | last1=Antonio | first1=Jose | date=2022 | title=Common questions and misconceptions about creatine supplementation: what does the scientific evidence really show? | journal=Journal of the International Society of Sports Medicine | volume=18 | issue=1 | page=13 | doi=10.1186/s12970-021-00412-w | doi-access=free | pmid=33557850 | pmc=7871530 }}</ref>

=== Renal function ===
A 2019 systematic review published by the [[National Kidney Foundation]] investigated whether creatine supplementation had adverse effects on renal function.<ref>{{cite journal | vauthors = de Souza E, Silva A, Pertille A, Reis Barbosa CG, Aparecida de Oliveira Silva J, de Jesus DV, Ribeiro AG, Baganha RJ, de Oliveira JJ | display-authors = 6 | title = Effects of Creatine Supplementation on Renal Function: A Systematic Review and Meta-Analysis | journal = Journal of Renal Nutrition | volume = 29 | issue = 6 | pages = 480–489 | date = November 2019 | pmid = 31375416 | doi = 10.1053/j.jrn.2019.05.004 | s2cid = 199388424 }}</ref> 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<ref>{{cite journal | vauthors = Gualano B, de Salles Painelli V, Roschel H, Lugaresi R, Dorea E, Artioli GG, Lima FR, da Silva ME, Cunha MR, Seguro AC, Shimizu MH, Otaduy MC, Sapienza MT, da Costa Leite C, Bonfá E, Lancha Junior AH | display-authors = 6 | title = Creatine supplementation does not impair kidney function in type 2 diabetic patients: a randomized, double-blind, placebo-controlled, clinical trial | journal = European Journal of Applied Physiology | volume = 111 | issue = 5 | pages = 749–56 | date = May 2011 | pmid = 20976468 | doi = 10.1007/s00421-010-1676-3 | s2cid = 21335546 }}</ref> and post-menopausal women,<ref>{{cite journal | vauthors = Neves M, Gualano B, Roschel H, Lima FR, Lúcia de Sá-Pinto A, Seguro AC, Shimizu MH, Sapienza MT, Fuller R, Lancha AH, Bonfá E | display-authors = 6 | title = Effect of creatine supplementation on measured glomerular filtration rate in postmenopausal women | journal = Applied Physiology, Nutrition, and Metabolism | volume = 36 | issue = 3 | pages = 419–22 | date = June 2011 | pmid = 21574777 | doi = 10.1139/h11-014 }}</ref> bodybuilders,<ref>{{cite journal | vauthors = Lugaresi R, Leme M, de Salles Painelli V, Murai IH, Roschel H, Sapienza MT, Lancha Junior AH, Gualano B | display-authors = 6 | title = Does long-term creatine supplementation impair kidney function in resistance-trained individuals consuming a high-protein diet? | journal = Journal of the International Society of Sports Nutrition | volume = 10 | issue = 1 | pages = 26 | date = May 2013 | pmid = 23680457 | pmc = 3661339 | doi = 10.1186/1550-2783-10-26 | doi-access = free }}</ref> athletes,<ref>{{cite journal | vauthors = Kreider RB, Melton C, Rasmussen CJ, Greenwood M, Lancaster S, Cantler EC, Milnor P, Almada AL | display-authors = 6 | title = Long-term creatine supplementation does not significantly affect clinical markers of health in athletes | journal = Molecular and Cellular Biochemistry | volume = 244 | issue = 1–2 | pages = 95–104 | date = February 2003 | doi = 10.1023/A:1022469320296 | pmid = 12701816 | s2cid = 25947100 }}</ref> and resistance trained populations.<ref>{{cite journal | vauthors = Cancela P, Ohanian C, Cuitiño E, Hackney AC | title = Creatine supplementation does not affect clinical health markers in football players | journal = British Journal of Sports Medicine | volume = 42 | issue = 9 | pages = 731–5 | date = September 2008 | pmid = 18780799 | doi = 10.1136/bjsm.2007.030700 | s2cid = 20876433 }}</ref><ref>{{cite journal| vauthors = Carvalho AP, Molina GE, Fontana KE |date=August 2011|title=Creatine supplementation associated with resistance training does not alter renal and hepatic functions|journal=Revista Brasileira de Medicina do Esporte|language=en|volume=17|issue=4|pages=237–241|doi=10.1590/S1517-86922011000400004|issn=1517-8692|doi-access=free}}</ref><ref>{{cite journal | vauthors = Mayhew DL, Mayhew JL, Ware JS | title = Effects of long-term creatine supplementation on liver and kidney functions in American college football players | journal = International Journal of Sport Nutrition and Exercise Metabolism | volume = 12 | issue = 4 | pages = 453–60 | date = December 2002 | pmid = 12500988 | doi = 10.1123/ijsnem.12.4.453 }}</ref> The study also discussed 3 case studies where there were reports that creatine affected renal function.<ref>{{cite journal | vauthors = Thorsteinsdottir B, Grande JP, Garovic VD | title = Acute renal failure in a young weight lifter taking multiple food supplements, including creatine monohydrate | journal = Journal of Renal Nutrition | volume = 16 | issue = 4 | pages = 341–5 | date = October 2006 | pmid = 17046619 | doi = 10.1053/j.jrn.2006.04.025 }}</ref><ref>{{cite journal | vauthors = Taner B, Aysim O, Abdulkadir U | title = The effects of the recommended dose of creatine monohydrate on kidney function | journal = NDT Plus | volume = 4 | issue = 1 | pages = 23–4 | date = February 2011 | pmid = 25984094 | pmc = 4421632 | doi = 10.1093/ndtplus/sfq177 }}</ref><ref>{{cite journal | vauthors = Barisic N, Bernert G, Ipsiroglu O, Stromberger C, Müller T, Gruber S, Prayer D, Moser E, Bittner RE, Stöckler-Ipsiroglu S | display-authors = 6 | title = Effects of oral creatine supplementation in a patient with MELAS phenotype and associated nephropathy | journal = Neuropediatrics | volume = 33 | issue = 3 | pages = 157–61 | date = June 2002 | pmid = 12200746 | doi = 10.1055/s-2002-33679 | s2cid = 9250579 }}</ref>

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.<ref name=":7">{{cite journal | vauthors = Rodriguez NR, Di Marco NM, Langley S | title = American College of Sports Medicine position stand. Nutrition and athletic performance | journal = Medicine and Science in Sports and Exercise | volume = 41 | issue = 3 | pages = 709–31 | date = March 2009 | pmid = 19225360 | doi = 10.1249/MSS.0b013e31890eb86 | doi-access = free }}</ref>

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.<ref name=":3">{{cite journal | vauthors = Kreider RB, Kalman DS, Antonio J, Ziegenfuss TN, Wildman R, Collins R, Candow DG, Kleiner SM, Almada AL, Lopez HL | display-authors = 6 | title = International Society of Sports Nutrition position stand: safety and efficacy of creatine supplementation in exercise, sport, and medicine | journal = Journal of the International Society of Sports Nutrition | volume = 14 | pages = 18 | date = 2017 | pmid = 28615996 | pmc = 5469049 | doi = 10.1186/s12970-017-0173-z | doi-access = free }}</ref>

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).<ref>ML.Guerrero, J.Beron, B.Spindler, P.Grosscurth, T.Wallimann and F.Verrey.''Metabolic support of Na+ pump in apically permeabilized A6 kidney cell epithelia: role of creatine kinase.''In: ''Am J Physiol.'' 1997 Feb;272(2 Pt 1):C697-706. [[doi:10.1152/ajpcell.1997.272.2.C697]], {{PMID|9124314}}</ref> 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.<ref>T. Wallimann, U. Riek, M. M. Möddel: ''Intradialytic creatine supplementation: A scientific rationale for improving the health and quality of life of dialysis patients.''In: ''Medical Hypotheses'' 2017 Febr;99, S. 1-14. [[doi:10.1016/j.mehy.2016.12.002]], {{PMID|28110688}}.</ref>{{Unreliable medical source|date=October 2023}}

==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.<ref>{{cite journal|vauthors=Moreta S, Prevarin A, Tubaro F|date=June 2011|title=Levels of creatine, organic contaminants and heavy metals in creatine dietary supplements|journal=Food Chemistry|volume=126|issue=3|pages=1232–1238|doi=10.1016/j.foodchem.2010.12.028}}</ref> 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 [[1,3,5-Triazine|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.<ref name="ReferenceA">{{cite book|chapter=Safety of Creatine Supplementation|vauthors=Persky AM, Rawson ES|title=Creatine and Creatine Kinase in Health and Disease|date=2007|isbn=978-1-4020-6485-2|series=Subcellular Biochemistry|volume=46|pages=275–89|doi=10.1007/978-1-4020-6486-9_14|pmid=18652082}}</ref>

=== Food and cooking ===
When creatine is mixed with protein and sugar at high temperatures (above 148&nbsp;°C), the resulting reaction produces carcinogenic [[heterocyclic amine]]s (HCAs).<ref>{{cite web|url=http://www.cancer.gov/cancertopics/factsheet/Risk/heterocyclic-amines|title=Heterocyclic Amines in Cooked Meats|date=15 Sep 2004|publisher=National Cancer Institute|access-date=2007-08-09|archive-date=21 December 2010|archive-url=https://web.archive.org/web/20101221034421/http://www.cancer.gov/cancertopics/factsheet/Risk/heterocyclic-amines|url-status=live}}</ref> Such a reaction happens when grilling or pan-frying meat.<ref>{{cite web|url=http://www.cancer.gov/cancertopics/factsheet/Risk/cooked-meats|title=Chemicals in Meat Cooked at High Temperatures and Cancer Risk|date=2 April 2018|publisher=[[National Cancer Institute]]|access-date=22 February 2015|archive-date=6 November 2011|archive-url=https://web.archive.org/web/20111106080003/http://www.cancer.gov/cancertopics/factsheet/Risk/cooked-meats|url-status=live}}</ref> Creatine content (as a percentage of crude protein) can be used as an indicator of meat quality.<ref>{{cite journal| last=Dahl |first=Olle | name-list-style = vanc |date=1 July 1963|title=Meat Quality Measurement, Creatine Content as an Index of Quality of Meat Products|journal=Journal of Agricultural and Food Chemistry|volume=11|issue=4|pages=350–355|doi=10.1021/jf60128a026}}</ref>

== 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.<ref>{{Cite book|last=Gießing|first=Jürgen|name-list-style=vanc|url=https://books.google.com/books?id=_xxgDwAAQBAJ&pg=PP4|title=Kreatin: Eine natürliche Substanz und ihre Bedeutung für Muskelaufbau, Fitness und Anti-Aging|date=20 February 2019|isbn=9783752803969|pages=135–136, 207|publisher=BoD – Books on Demand |access-date=27 December 2021|archive-date=19 June 2022|archive-url=https://web.archive.org/web/20220619121802/https://books.google.com/books?id=_xxgDwAAQBAJ&pg=PP4|url-status=live}}</ref>

== See also ==
* [[Beta-Alanine]]
* [[Creatine methyl ester]]

== References ==
{{Reflist}}

== External links ==
* [http://www.ebi.ac.uk/pdbe-srv/PDBeXplore/ligand/?ligand=CRN Creatine bound to proteins] in the [[Protein Data Bank|PDB]]
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[[Category:Alpha-Amino acids]]
[[Category:Bodybuilding supplements]]
[[Category:Dietary supplements]]
[[Category:Ergogenic aids]]
[[Category:Exercise biochemistry]]
[[Category:Guanidines]]
[[Category:Myostatin inhibitors]]