Creatine supplements are athletic aids used to increase high-intensity athletic performance. Researchers have known of the use of creatine as an energy source by skeletal muscles since the middle of the 20th century. They were popularized as a performance-enhancing supplement beginning in the 1990s.
- 1 History
- 2 Athletic performance
- 3 Endocrine and other effects
- 4 Side effects and drug interactions
- 5 Creatine ingestion
- 6 Manufacture
- 7 Safety
- 8 Cognitive performance
- 9 References
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. 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 creatine phosphate, and determined that creatine is a key player in the metabolism of skeletal muscle. The substance creatine is naturally formed in vertebrates.
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. 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.
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. Research performed thereafter demonstrated that the consumption of high glycemic carbohydrates in conjunction with creatine increases creatine muscle stores. In 1998, MuscleTech Research and Development launched Cell-Tech, the first creatine-carbohydrate-alpha lipoic acid supplement. Alpha lipoic acid has been demonstrated to enhance muscle phosphocreatine levels and total muscle creatine concentrations. This approach to creatine supplementation was supported by a study performed in 2003.
There is scientific evidence that short term creatine use can increase maximum power and performance in high-intensity anaerobic repetitive work (periods of work and rest) by 5 to 15%. This is mainly bouts of running/cycling sprints and multiple sets of low RM weightlifting. Single effort work shows an increase of 1 to 5%. This refers mainly to single sprints and single lifting of 1-2RM weights. However, some studies show no ergogenic effect at all. Studies in endurance athletes have been less than promising, most likely because these activities are sustained at a given intensity and thus do not allow for significant intra-exercise synthesis of additional creatine phosphate molecules. Ingesting creatine can increase the level of phosphocreatine in the muscles up to 20%. Creatine has no significant effect on aerobic endurance, though it will increase power during short sessions of high-intensity aerobic exercise.
Since body mass gains of about 1 kg can occur in a week's time, many studies suggest that the gain is simply due to greater water retention inside the muscle cells. Other studies, however, have shown that creatine increases the activity of satellite cells, which make muscle hypertrophy possible. 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.
In another study, researchers concluded that changes in substrate oxidation may influence the inhibition of fat mass loss associated with creatine after weight training when they discovered that fat mass did not change significantly with creatine but decreased after the placebo trial in a 12-week study on ten active men. The study also showed that 1-RM bench press and total body mass increased after creatine, but not after placebo. The underlying effect of creatine on body composition has yet to be determined, as another study with a similar timeframe suggests no effect on body composition, but had less overall emphasis on metabolic effects.
Creatine use is not considered doping and is not banned by the majority of sport-governing bodies. However, in the United States, the NCAA recently ruled that colleges could not provide creatine supplements to their players, though the players are still allowed to obtain and use creatine independently.
Endocrine and other effects
In a study from 2010 it was found that 8 weeks of resistance training together with creatine supplementation resulted in lower serum myostatin levels compared to 8 weeks of resistance training and placebo as well as to control (no resistance training or supplementation), ~98 ng/ml, ~110 ng/ml and ~120 ng/ml respectively. In a study from 2011 where broiler chickens were fed creatine for 42 days, myostatin levels were significantly decreased compared to control. Myostatin is a protein that has catabolic effects on skeletal muscle to limit the growth of muscle.
A 2009 study  examined changes in testosterone levels in college-aged male rugby players receiving Creatine supplementation. Subjects were given a 7-day loading phase of creatine supplementation followed by a further 14 days of creatine maintenance supplementation. While testosterone levels in blood serum were unchanged, levels of dihydrotestosterone increased by 56% after the initial 7 days of creatine loading and remained 40% above baseline after 14 days maintenance. The ratio of dihydrotestosterone to testosterone was therefore increased by 36% after the 7 day creatine supplementation and remained elevated by 22% after the maintenance dose.
A study of male college football players published in 2006 found a 22% increase in resting testosterone levels, from 20.0 to 24.4 nmol/L, after a 10-week resistance training program in the creatine supplemented group compared to placebo.
Muscle insulin-like growth factor-I
One study done in 2008 showed that levels of insulin-like growth factor-1 (IGF-I) in muscle increased by 15% with creatine supplementation compared to placebo after 8 weeks of resistance training. In the same study on broiler chickens mentioned above, IGF-I levels increased compared to control after being fed with creatine for 42 days.
Side effects and drug interactions
- Weight gain due to extra water retention to the muscle
- Potential muscle cramps / strains / pulls
- Upset stomach
- High blood pressure due to extra water consumption
At the recommended dose of being loaded with 20 grams per day for 5 days followed by a maintenance dose of 2 or more grams daily (up to 5 grams), creatine is likely safe and most studies have not found significant side effects. However, people with kidney disease, high blood pressure, or liver disease should not take creatine as a dietary supplement. Being a dietary supplement, it is advised that creatine should be taken under the supervision of a health professional.
Creatine taken with medications that can harm the kidney can increase the risk of kidney damage. It is advised to speak with your doctor or pharmacist before taking creatine if you are on these type of medications.
- Non-steroidal anti-inflammatory drugs (NSAIDs) - some examples are ibuprofen (Motrin, Advil) and naproxen (Aleve)
- Caffeine - Caffeine and creatine taken together can increase risk of dehydration and cause kidney damage.
- Diuretics (water pills) - An example is furosemide (Lasix)
- Cimetidine (Tagamet)
Creatine is often taken by many fitness enthusiasts, athletes of all levels, and bodybuilders all around the world to increase performance in anaerobic type activities. There are a number of forms but the most common are creatine monohydrate (creatine complexed with a molecule of water) and creatine ethyl ester (CEE). A number of methods for ingestion exist: as a powder mixed into a drink, or as a capsule or caplet. Once ingested, creatine is highly bioavailable, whether it is ingested as the crystalline monohydrate form, the free form in solution, or even in meat. Creatine salts will become the free form when dissolved in aqueous solution. Conventional wisdom recommends the consumption of creatine with high glycemic index carbohydrates or a combination of 50% protein and 50% carbohydrate mixture for maximal insulin release and creatine retention.
Endogenous serum or plasma creatine concentrations in healthy adults are normally in a range of 2–12 mg/L. A single 5 g (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 blood plasma level it would be necessary to take small oral doses every 3–6 hours throughout the day. Creatine is consumed by the body fairly quickly, and if one wishes to maintain the high concentration of creatine, 2-5 g daily is the standard amount to intake.
Creatine ethyl ester
CEE is a form of commercially available creatine touted to have higher absorption rates and a longer serum half-life than regular creatine monohydrate by several supplement companies. However, no peer-reviewed studies have emerged on creatine ethyl ester which conclusively prove these claims. A study presented at the 4th International Society of Sports Nutrition (ISSN) annual meeting demonstrated that the addition of the ethyl group to creatine actually reduces acid stability and accelerates its breakdown to creatinine. The researchers concluded that creatine ethyl ester is inferior to creatine monohydrate as a source of creatine.
Buffered creatine monohydrate (trademarked as Kre-Alkalyn) is claimed to enhance the effects of creatine through the promotion of greater creatine retention and training adaptations with fewer side effects at lower doses (1.5 g/d for 28-days vs. 4 x 5 g/d for 7-days). Research performed found no significant difference in muscle creatine content, body composition, or training adaptations between buffered creatine monohydrate and creatine monohydrate. There was also no evidence that supplementing the diet with a buffered form of creatine resulted in fewer side effects.
Creatine hydrochloride (Creatine HCL) is a hydrochloride salt patented in 2009 and marketed as an athletic and bodybuilding supplement. A study by Vireo Systems (commissioned by supplement manufacturer ProMera Health) found creatine hydrochloride to be 59 times more soluble in water than creatine monohydrate. Due to its higher solubility, the recommended dosage for creatine hydrochloride is much lower than that for creatine monohydrate.
Creatine magnesium chelate
Creatine magnesium chelate (pronounced key-late) is a form of creatine bound to two magnesium atoms. Its effects are similar to creatine monohydrate.
Creatine malate is a creatine compound containing three creatine monohydrate molecules attached to one molecule of malic acid. Creatine monohydrate supports the production of ATP, the muscles primary source of energy in the body. Malic acid plays a supporting role as an intermediate substance that encourages energy transport to the muscles during physical activity, enhancing the Krebs cycle.
Creatine gluconate is a form of creatine where the molecule is bound to gluconic acid.
Since 2011, products containing micronised creatine monohydrate have been marketed as sports supplements. Micronization involves reducing the size of creatine particles to between 0.36 and 9.08 μm in diameter. Purported benefits of these products include easier mixing into drink format for supplementation and faster absorption of the creatine into the bloodstream. While reducing particle size may make powdered creatine easier to dissolve in water due to exposure of a greater total particle surface area to collisions with solvent molecules (increasing the rate of reaction), it cannot change its overall solubility. There is no evidence that micronized creatine monohydrate offers any physiological benefit over other forms or can reduce the risk of gastrointestinal side effects.
Synthetic creatine is usually made from sarcosine (or its salts) and cyanamide which are combined in a reactor with catalyst compounds. The reactor is heated and pressurized, causing creatine crystals to form. The crystalline creatine is then purified by centrifuge and vacuum dried. The dried creatine compound is milled into a fine powder for improved bioavailability. Milling techniques differ, resulting in final products of varying solubility and bioavailability. For instance, creatine compounds milled to 200 mesh are referred to as micronized.
Current studies indicate that short-term creatine supplementation in healthy individuals is safe, although those with renal disease should avoid it due to possible risks of renal dysfunction, and before using it healthy users should bear these possible risks in mind. Small-scale, longer-term studies have been done and seem to demonstrate its safety. There have been reports of muscle cramping with the use of creatine, though a study showed no reports of muscle cramping in subjects taking creatine on a 15-item panel of qualitative urine markers. Creatine did not cause any clinically significant changes in serum metabolic markers, muscle and liver enzyme efflux, serum electrolytes, blood lipid profiles, red and white whole blood cell hematology, or quantitative and qualitative urinary markers of renal function.
In addition, experiments have shown that creatine supplementation improved the health and lifespan of mice. Whether these beneficial effects would also apply to humans is still uncertain.
Creatine supplementation may accelerate the growth of cysts in humans with polycystic kidney disease. PKD is prevalent in approximately 1 in 1000 people and may not be detectable until affected individuals reach their thirties.
In 2004 the European Food Safety Authority (EFSA) published a record that stated that oral long-term intake of 3 g pure creatine per day is "unlikely to pose any risk". The reports of damage to the kidneys or liver by creatine supplementation have been scientifically refuted.
Creatine administration was shown to significantly improve performance in cognitive and memory tests in vegetarian individuals involved in double-blind, placebo-controlled cross-over trials. Vegetarian supplementation with creatine seems to be especially beneficial as they appear to have lower average body stores, since meat is a primary source of dietary creatine. This study did not, however, compare the differing effects of creatine on vegetarians and non-vegetarians. In a later study, a 20g daily dose of creatine monohydrate over 5 days was shown to improve memory in young adult female vegetarians, compared with young adult female omnivores. Note that the vegetarians and non-vegetarians had similar memory scores at the beginning of the study.
- Folin, Otto; Denis, W (1912). "Protein metabolism from the standpoint of blood and tissue analysis" (PDF). Journal of Biological Chemistry 12 (1): 141–61.
- "Supplement muscles in on the market". National Review of Medicine. 2004-07-30. Retrieved 2011-05-25.
- Passwater, Richard A. (2005). Creatine. p. 9. ISBN 0-87983-868-X. Retrieved 2011-05-25.[page needed]
- 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. Retrieved 2010-03-29.
- Green AL, Hultman E, Macdonald IA, Sewell DA, Greenhaff PL; Hultman; MacDonald; Sewell; Greenhaff (November 1996). "Carbohydrate ingestion augments skeletal muscle creatine accumulation during creatine supplementation in humans". Am. J. Physiol. 271 (5 Pt 1): E821–6. PMID 8944667.
- Profiles of Drug Substances, Excipients and Related Methodology By Harry G. Brittain[page needed]
- Burke, Darren G.; Chilibeck, Philip D.; Parise, Gianni; Tarnopolsky, Mark A.; Candow, Darren G. (2003). "Effect of α-Lipoic Acid Combined With Creatine Monohydrate on Human Skeletal Muscle Creatine and Phosphagen Concentration". International Journal of Sport Nutrition and Exercise Metabolism 13 (3): 294–302. PMID 14669930.
- Bird, S. P. (2003). "Creatine Supplementation and Exercise Performance: A Brief Review" (PDF). Journal of Sports Science & Medicine 2 (4): 123–132. PMC 3963244.
- Kreider R, Rasmussen C, Ransom J, Almada AL. (1998). "Effects of creatine supplementation during training on the incidence of muscle cramping, injuries and GI distress". Journal of Strength Conditioning Research 12 (275).
- Engelhardt, Martin; Neumann, Georg; Berbalk, Anneliese; Reuter, Iris (1998). "Creatine supplementation in endurance sports". Medicine & Science in Sports & Exercise 30 (7): 1123–1129. doi:10.1097/00005768-199807000-00016.
- Graham, AS; Hatton, RC (1999). "Creatine: A review of efficacy and safety". Journal of the American Pharmaceutical Association 39 (6): 803–10; quiz 875–7. PMID 10609446.
- Powers, ME; Arnold, BL; Weltman, AL; Perrin, DH; Mistry, D; Kahler, DM; Kraemer, W; Volek, J (2003). "Creatine Supplementation Increases Total Body Water Without Altering Fluid Distribution". Journal of athletic training 38 (1): 44–50. PMC 155510. PMID 12937471.
- Hespel, P; Eijnde, BO; Derave, W; Richter, EA (2001). "Creatine supplementation: Exploring the role of the creatine kinase/phosphocreatine system in human muscle". Canadian journal of applied physiology = Revue canadienne de physiologie appliquee. 26 Suppl: S79–102. doi:10.1139/h2001-045. PMID 11897886.
- Olsen, S.; Aagaard, P; Kadi, F; Tufekovic, G; Verney, J; Olesen, JL; Suetta, C; Kjaer, M (2006). "Creatine supplementation augments the increase in satellite cell and myonuclei number in human skeletal muscle induced by strength training". The Journal of Physiology 573 (2): 525–34. doi:10.1113/jphysiol.2006.107359. PMC 1779717. PMID 16581862.
- Huso, M. Erik; Hampl, Jeffrey S; Johnston, Carol S.; Swan, Pamela D. (2002). "Creatine supplementation influences substrate utilization at rest". Journal of Applied Physiology 93 (6): 2018–22. doi:10.1152/japplphysiol.01170.2001. PMID 12391059.
- Chilibeck, Philip D.; Magnus, Charlene; Anderson, Matthew (2007). "Effect of in-season creatine supplementation on body composition and performance in rugby union football players". Applied Physiology, Nutrition, and Metabolism 32 (6): 1052–7. doi:10.1139/H07-072. PMID 18059577.
- "Creatine". University of Maryland Medical Center. Retrieved 8 April 2013.
- Saremi, A.; Gharakhanloo, R.; Sharghi, S.; Gharaati, M.R.; Larijani, B.; Omidfar, K. (2010). "Effects of oral creatine and resistance training on serum myostatin and GASP-1". Molecular and Cellular Endocrinology 317 (1–2): 25–30. doi:10.1016/j.mce.2009.12.019. PMID 20026378.
- Chen, J.; Wang, M.; Kong, Y.; Ma, H.; Zou, S. (2011). "Comparison of the novel compounds creatine and pyruvateon lipid and protein metabolism in broiler chickens". Animal 5 (7): 1082–9. doi:10.1017/S1751731111000085. PMID 22440103.
- Van Der Merwe, Johann; Brooks, Naomi E; Myburgh, Kathryn H (2009). "Three Weeks of Creatine Monohydrate Supplementation Affects Dihydrotestosterone to Testosterone Ratio in College-Aged Rugby Players". Clinical Journal of Sport Medicine 19 (5): 399–404. doi:10.1097/JSM.0b013e3181b8b52f. PMID 19741313.
- Hoffman, J; Ratamess, N; Kang, J; Mangine, G; Faigenbaum, A; Stout, J (2006). "Effect of creatine and beta-alanine supplementation on performance and endocrine responses in strength/power athletes". International journal of sport nutrition and exercise metabolism 16 (4): 430–46. PMID 17136944.
- Burke, DG; Candow, DG; Chilibeck, PD; MacNeil, LG; Roy, BD; Tarnopolsky, MA; Ziegenfuss, T (2008). "Effect of creatine supplementation and resistance-exercise training on muscle insulin-like growth factor in young adults". International journal of sport nutrition and exercise metabolism 18 (4): 389–98. PMID 18708688.
- Ehrlich, Steven D. "Creatine". University of Maryland Medical Center. Retrieved 3 November 2014.
- WebMD, WebMD. "Creatine". WebMD. Natural Medicines Comprehensive Database Consumer Version. Retrieved 3 November 2014.
- Steenge, GR; Simpson, EJ; Greenhaff, PL (2000). "Protein- and carbohydrate-induced augmentation of whole body creatine retention in humans". Journal of applied physiology 89 (3): 1165–71. PMID 10956365.
- Kamber, Matthias; Koster, Markus; Kreis, Roland; Walker, Gianni; Boesch, Chris; Hoppeler, Hans (1999). "Creatine supplementation—Part I: Performance, clinical chemistry, and muscle volume". Medicine & Science in Sports & Exercise 31 (12): 1763–9. doi:10.1097/00005768-199912000-00011. PMID 10613426.
- Deldicque, Louise; Décombaz, Jacques; Zbinden Foncea, Hermann; Vuichoud, Jacques; Poortmans, Jacques R.; Francaux, Marc (2007). "Kinetics of creatine ingested as a food ingredient". European Journal of Applied Physiology 102 (2): 133–43. doi:10.1007/s00421-007-0558-9. PMID 17851680.
- Baselt, Randall Clint (2008). Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, CA: Biomedical Publications. pp. 366–8. ISBN 978-0-9626523-7-0.
- Jäger, R; Purpura, M; Shao, A; Inoue, T; Kreider, R. B. (2011). "Analysis of the efficacy, safety, and regulatory status of novel forms of creatine". Amino Acids 40 (5): 1369–1383. doi:10.1007/s00726-011-0874-6. PMC 3080578. PMID 21424716.
- UNeMed 2003 Annual Report, p.4
- Jagim AR, Oliver JM, Sanchez A, Galvan E, Fluckey J, Riechman S, Greenwood M, Kelly K, Meininger C, Rasmussen C, Kreider RB; Oliver; Sanchez; Galvan; Fluckey; Riechman; Greenwood; Kelly; Meininger; Rasmussen; Kreider (2012). "A buffered form of creatine does not promote greater changes in muscle creatine content, body composition, or training adaptations than creatine monohydrate". J Int Soc Sports Nutr 9 (1): 43. doi:10.1186/1550-2783-9-43. PMC 3479057. PMID 22971354.
- ProMera Health. "CON-CRĒT: FAQ". Retrieved 19 February 2011.
- Selsby, J. T.; Disilvestro, R. A.; Devor, S. T. (2004). "Mg2+-creatine chelate and a low-dose creatine supplementation regimen improve exercise performance". The Journal of Strength and Conditioning Research 18 (2): 311–5. doi:10.1519/R-13072.1. PMID 15142029.
- "What is Creatine Nitrate?". Examine.com. Retrieved 27 May 2015.
- Cooper, R; Naclerio, F; Allgrove, J; Jimenez, A (2012). "Creatine supplementation with specific view to exercise/sports performance". J Int Soc Sports Nutr 9 (1): 33. doi:10.1186/1550-2783-9-33. PMC 3407788. PMID 22817979.
- Hezave, Ali Zeinolabedini; Aftab, Esmaeilzadeh (November 2010). "Micronization of creatine monohydrate via Rapid Expansion of Supercritical Solution (RESS)". Journal of Supercritical Fluids 5 (1): 316–324. doi:10.1016/j.supflu.2010.05.009.
- Mayhew, DL; Mayhew, JL; Ware, JS (2002). "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. PMID 12500988.
- Kreider, Richard B.; Melton, Charles; Rasmussen, Christopher J.; Greenwood, Michael; Lancaster, Stacy; Cantler, Edward C.; Milnor, Pervis; Almada, Anthony L. (2003). "Long-term creatine supplementation does not significantly affect clinical markers of health in athletes". Molecular and Cellular Biochemistry 244 (1–2): 95–104. doi:10.1023/A:1022469320296. PMID 12701816.
- Bender, A.; Beckers, J.; Schneider, I.; Hölter, S.M.; Haack, T.; Ruthsatz, T.; Vogt-Weisenhorn, D.M.; Becker, L.; et al. (2008). "Creatine improves health and survival of mice". Neurobiology of Aging 29 (9): 1404–11. doi:10.1016/j.neurobiolaging.2007.03.001. PMID 17416441.
- "Opinion of the Scientific Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food on a request from the Commission related to Creatine monohydrate for use in foods for particular nutritional uses Question number EFSA-Q-2003-125". The EFSA Journal 36: 1–6. 2004. doi:10.2903/j.efsa.2004.36 (inactive 2015-09-27).
- Gualano, Bruno; Ugrinowitsch, Carlos; Novaes, Rafael Batista; Artioli, Guilherme Gianini; Shimizu, Maria Heloisa; Seguro, Antonio Carlos; Harris, Roger Charles; Lancha, Antonio Herbert (2008). "Effects of creatine supplementation on renal function: A randomized, double-blind, placebo-controlled clinical trial". European Journal of Applied Physiology 103 (1): 33–40. doi:10.1007/s00421-007-0669-3. PMID 18188581.
- Buford, Thomas W; Kreider, Richard B; Stout, Jeffrey R; Greenwood, Mike; Campbell, Bill; Spano, Marie; Ziegenfuss, Tim; Lopez, Hector; Landis, Jamie; Antonio, Jose (2007). "International Society of Sports Nutrition position stand: Creatine supplementation and exercise". Journal of the International Society of Sports Nutrition 4: 6. doi:10.1186/1550-2783-4-6. PMC 2048496. PMID 17908288.
- Gualano, Bruno; Ferreira, Desire Coelho; Sapienza, Marcelo Tatit; Seguro, Antonio Carlos; Lancha, Antonio Herbert (2010). "Effect of Short-term High-Dose Creatine Supplementation on Measured GFR in a Young Man with a Single Kidney". American Journal of Kidney Diseases 55 (3): e7–9. doi:10.1053/j.ajkd.2009.10.053. PMID 20060630.
- Rae, C.; Digney, A. L.; McEwan, S. R.; Bates, T. C. (2003). "Oral creatine monohydrate supplementation improves brain performance: A double-blind, placebo-controlled, cross-over trial". Proceedings of the Royal Society B: Biological Sciences 270 (1529): 2147–50. doi:10.1098/rspb.2003.2492. PMC 1691485. PMID 14561278.
- Benton, D.; Donohoe, R. (2011). "The influence of creatine supplementation on the cognitive functioning of vegetarians and omnivores". Br J Nutr. 105 (7): 1100–1105. doi:10.1017/S0007114510004733. PMID 21118604.