Creatine is an amino acid synthesised from the amino acid precursors arginine, glycine and methionine. The kidneys use arginine and glycine to make guanidinoacetate, which the liver methylates to form creatine. The highest concentrations of creatine are found in skeletal muscle, but high concentrations are also found in heart and smooth muscle, as well as brain, kidney and spermatozoa.
Creatine combines readily with phosphate to form creatine phosphate, which is a source of high-energy phosphate that is released during the anaerobic phase of muscle contraction. The phosphorus from creatine phosphate is transferred to adenosine diphosphate (ADP), creating adenosine triphosphate (ATP) and releasing creatine. Stored creatine phosphate can fuel the first 4–5 s of a sprint, but another fuel must provide the energy to sustain the activity.
Creatine supplements increase the storage of creatine phosphate, thus making more ATP available for the working muscles and enabling them to work harder before becoming fatigued. There appears to be an upper limit for creatine storage in muscle, and supplementation increases levels most in athletes with low stores of creatine, rather than those with high levels.
Creatine is found in food, and the average omnivorous diet supplies about 1–2 g creatinine daily, although vegetarians consume less. This is because creatine is found principally in animal foods, such as fish and meat. Only trace amounts are found in plant foods. If the dietary supply is limited, creatine can be synthesised endogenously.
Creatine has been investigated for a possible role in sports and athletics.
Supplementation increases levels of creatine in plasma and skeletal muscle, and it is used to enhance exercise performance. A study in 1992 was the first to show that creatine supplementation (5 g four to six times a day) for several consecutive days increased the creatine concentration of skeletal muscle; the authors concluded that creatine supplementation might enhance exercise performance in humans.1
The first published investigation into the effect of oral creatine supplementation on exercise performance in humans showed that ingestion of creatine (20 g daily for 5 days) was found to improve performance during repeated bouts of maximal isokinetic knee-extensor exercise, reducing fatigue by 6%.2
In a subsequent more invasive study, subjects performed two bouts of maximal isokinetic cycling exercise before and after creatine ingestion at identical dose (20 g daily for 5 days). Each exercise bout lasted 30 s, and the recovery period between bouts was 4 min. Total work performance increased during both bouts of exercise after creatine supplementation and was related to muscle creatine uptake.3
A randomised, placebo-controlled trial involving 16 male subjects investigated the effects of creatine supplementation (20 g daily for 5 days) on the ability to perform kayak ergo-meter performances of different durations. The results indicated that creatine could significantly increase the amount of work accomplished at durations ranging from 90 to 300 s.4
In a double-blind crossover study, 12 subjects were either creatine loaded (25 g daily for 5 days), or were creatine loaded and took extra creatine (5 g/hour) during an exercise test or placebo on three occasions followed by a 5-week wash-out period. Each subject underwent a 2.5-hour endurance test on their own bicycle followed by five maximal 10-s sprints separated by 2-min recovery intervals. Creatine loading for 5 days, but not creatine loading plus acute ingestion, significantly increased peak and mean sprint power for all five sprints, but endurance time to exhaustion was not affected by either creatine regimen.5
Ten physically active but untrained college-age males received creatine (5 g four times a day) or placebo for 5 days in a double-blind, randomised, balanced, crossover design and were assessed during maximal and three repeated submaximal bouts of isometric knee extension and handgrip exercises. Creatine sig-nificantly increased maximal isometric strength during knee extension, but not during handgrip exercise, and increased time to fatigue during all bouts of exercise. The authors concluded that improvements in maximal isometric strength following creatine supplementation were restricted to movements performed with a large muscle mass.6
Further studies have confirmed the ability of creatine supplements to improve performance during heavy resistance training,7 ice hockey,8 bicycle exercise,9 soccer10 and squash.11
However, several studies have reported no effects of creatine supplementation on exercise performance. There was no effect on power output during two bouts of 15-s maximal exercise separated by a recovery of 20 min, but this finding may reflect the design in that several bouts of exercise and a shorter recovery time may have been needed to show an effect of creatine supplementation.12 However, in another study where subjects were assigned to recovery intervals of 30, 60, 90 or 120 s, creatine 20 g daily for 5 days still had no effect on the subjects’ ability to reproduce or maintain a high percentage of peak power during the second of two bouts of high-intensity cycling.13 This was also the case in a study that showed no effect of creatine supplementation on performance during a single 20-s bout of maximal exercise.14
Another study showed no effect of creatine supplementation on performance during single bouts of maximal exercise lasting 15, 30 and 60 s in elite swimmers,15 and in a further study, no effect of creatine supplementation on performance during a single 30-s bout of maximal exercise,16 but this may also have reflected the short supplementation period of 3 days. In a further study, no changes in performance were found after a small dose of creatine (2 g daily) taken over several weeks.17
There is preliminary evidence that creatine may improve strength in people with CHF,18 chronic obstructive pulmonary disease (COPD),19 and in neuromuscular diseases.20 Creatine supplements may also be an effective adjunct to vitamin supplements for lowering plasma homocysteine.21
Preliminary evidence suggests that supplementation may be a useful therapeutic strategy for older adults to attenuate loss in muscle strength and performance in functional living tasks.22 In addition, when combined with resistance training, creatine supplementation has been shown to increase lean tissue mass and improves leg strength, endurance, and average power in older men.23
Creatine should be used with caution in renal or hepatic disease. However, the increase in urinary excretion of creatinine observed with creatine supplementation does not indicate renal impairment. Rather, it correlates with the increase in muscle creatine storage and the increased rate of muscle creatine degradation to creatinine.
Creatine is not on the International Olympic Committee Drug List, but some consider it to be in the ‘grey zone’ between doping and substances allowed to enhance performance.
Pregnancy and breast-feeding
No problems have been reported. However, there have not been sufficient studies to guarantee the safety of creatine in pregnancy and breast-feeding. Creatine is best avoided.
No serious toxic effects have been documented. In a survey of 52 college athletes supplementing with creatine, 16 reported diarrhoea, 13 re-ported muscle cramps and seven dehydration.24 Another survey, which involved 28 male baseball players and 24 male football players aged 18–23, found that 16 (31%) experienced diarrhoea, 13 (25%) experienced muscle cramps, seven (13%) reported unwanted weight gain, seven (13%) reported dehydration and 12 reported various other side-effects.25 In the same survey, 39 (75%) exceeded the maintenance dose of 2–5 g daily.
In a placebo-controlled trial involving 175 subjects and lasting 310 days, creatine mono-hydrate supplementation 10 g daily did not result in significant differences in adverse effects compared with placebo. Occurrence of nausea, gastrointestinal discomfort and diarrhoea was similar in both groups. After 2 months of treat-ment, oedematous limbs were seen more often in subjects using creatine, probably because of water retention. Severe diarrhoea and severe nausea caused three subjects in the creatine group to stop taking it, after which these adverse events subsided.26
In another report a patient with nephrotic syndrome who had been supplementing with creatine experienced deterioration in renal function,27 and a previously healthy 20-year-old man developed interstitial nephritis after taking creatine (20 g daily) for 4 weeks.28
Chronic administration of a large quantity of creatine can increase the production of formaldehyde. Formaldehyde is well known to crosslink proteins and DNA, and may cause potentially serious side-effects.29
Creatine supplementation often causes weight gain, which can be mistaken for increase in muscle mass. Increasing intracellular creatine may cause an osmotic influx of water into the cell because creatine is an osmotically active substance. It is therefore possible that the weight gained is due to water retention and not increased muscle.
The safety of prolonged use of creatine is of concern. Individuals should be advised not to take the loading dose of 20 g daily for more than 5 days and not to supplement for a total period of longer than 30 days until effects are better known.
No known drug interactions. Caffeine may reduce or abolish the ergogenic effects of creatine.
Creatine is available mainly in the form of powder. A review of 13 US products showed that 11 of them contained the weight of creatine claimed. One of the products was found to contain less than the claimed amount and one failed to meet its claim of being free from the impurity dicyandiamide.30
The usual dose regimen used in studies is 5 g creatine monohydrate four times a day for the first 5 days as a loading dose, then 2–5 g daily as maintenance. These doses should not be exceeded because of the risk of adverse effects (see above).
Despite a large number of clinical trials, there remains a dearth of high-quality research on creatine supplementation. Investigations of the effect of creatine on performance, strength and endurance in laboratory studies have yielded roughly equal numbers of studies showing positive effects and no effect. Field studies (i.e. of individuals participating in normal sports activities) have shown less impressive results than laboratory studies.
Creatine supplementation improves performance during exercise of high to maximal intensity, and its use could potentially benefit sports involving either single bouts of high-intensity exercise (e.g. sprint running, swimming, rowing, cycling) or multiple bouts (e.g. soccer, rugby, hockey). It also has the potential to benefit an athlete involved in training that involves repetitive bouts of high-intensity exercise. However, there is no evidence that creatine can benefit pro-longed, submaximal exercise (e.g. middle-or long-distance running), and it may impair endurance exercise by contributing to weight gain.
Harris RC, Soderlund K, Hultman E. Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation. Clin Sci 1992; 83: 367–374.
Greenhaff PL, Casey A, Short AH, et al. Influence of oral creatine supplementation on muscle torque during repeated bouts of maximal voluntary exercise in man. Clin Sci 1993; 84: 565–571.
Casey A, Constantin-Teodosiu D, Howell S, et al. Creatine ingestion favorably influences exercise per-formance and muscle metabolism during maximal exercise in humans. Am J Physiol 1996; 27: E31–E37.
McNaughton LR, Dalton B, Tarr J. The effects of creatine supplementation on high-intensity exercise performance in elite performers. Eur J Appl Physiol Occup Physiol 1998; 78: 236–240.
Vandebuerie F, Vanden Eynde B, Vandenberghe K, Hespel P. Effect of creatine loading on endurance capacity and sprint power in cyclists. Int J Sports Med 1998; 19: 490–495.
Urbanski RL, Vincent WJ, Yaspelkis BB III. Creatine supplementation differentially affects maximal iso-metric strength and time to fatigue in large and small muscle groups. Int J Sport Nutr 1999; 9: 136–145.
Volek JS, Duncan ND, Mazzetti SA, et al. Per-formance and muscle fiber adaptation to creatine supplementation and heavy resistance training. Med Sci Sports Exerc 1999; 31: 1147–1156.
Jones AM, Atter T, Georg TP. Oral creatine supple-mentation improves multiple sprint performance in elite ice-hockey players. J Sports Med Phys Fitness 1999; 39: 189–196.
Rici-Sanz J, Mendez Marco MT. Creatine enhances oxygen uptake and performance during alternating intensity exercise. Med Sci Sports Exerc 2000; 32: 379–385.
Mujika I, Padilla S, Ibanez J, et al. Creatine supple-mentation and sprint performance in soccer players. Med Sci Sports Exerc 2000; 32: 518–525.
Romer LM, Barrington JP, Jeukendrup AE. Effects of oral creatine supplementation on high intensity, intermittent exercise performance in competitive squash players. Int J Sports Med 2001; 22: 546–552.
Cooke WH, Grandjean PW, Barnes WS. Effect of oral creatine supplementation on power output and fatigue during bicycle egometry. J Appl Physiol 1995; 78: 670–673.
Cooke WH, Barnes WS. The influence of recovery duration on high intensity exercise performance after oral creatine supplementation. Can J Appl Physiol 1997; 22: 454–467.
Snow RJ, McKenna MJ, Selig SE, et al. Effect of creatine supplementation on sprint exercise perfor-mance and muscle metabolism. J Appl Physiol 1998; 1667–1673.
Mukija I, Chatard JC, Lacoste L, et al. Creatine supplementation does not improve sprint perfor-mance in competitive swimmers. Med Sci Sports Exerc 1996; 28: 1435–1441.
Odland LM, MacDougall JD, Tarnopolsky MA, et al. Effect of oral creatine supplementation on muscle (PCr) and short-term maximum power output. Med Sci Sports Exerc 1997; 29: 216–219.
Thompson CH, Kemp GJ, Sanderson AL, et al. Effect of creatine on aerobic and anaerobic metabolism in skeletal muscle in swimmers. Br J Sports Med 1996; 222–225.
Andrews R, Greenhaff P, Curtis S, et al. The effect of dietary creatine supplementation on skeletal muscle metabolism in congestive heart failure. Eur Heart J 1998; 19: 617–622.
Fuld JP, Kilduff LP, Neder JA, et al. Creatine supplementation during pulmonary rehabilitation in chronic obstructive pulmonary disease. Thorax 2005; 60: 531–537.
Tarnoplosky M, Martin J. Creatine monohydrate increases strength in patients with neuromuscular disease. Neurology 1999; 52: 854–857.
Korzun WJ. Oral creatine supplements lower plasma homocysteine concentrations in humans. Clin Lab Sci 2004; 17: 102–106.
Gotshalk LA, Volek JS, Staron RS, et al. Creatine supplementation improves muscular performance in older men. Med Sci Sports Exerc 2002; 34: 537–543.
Chrusch MJ, Chilibeck PD, Chad KE, et al. Creatine supplementation combined with resistance training in older men. Med Sci Sports Exerc 2001; 33: 2111–2117.
Juhn MS, Tarnopolsky M. Potential side effects of oral creatine supplementation: a critical review. J Am Diet Ass 1998; 8: 298–304.
Juhn MS, O’Kane JW, Vinci DM. Oral creatine supplementation in male college athletes: a survey of dosing habits and side effects. J Am Diet Assoc 1999; 99: 593–595.
Groenveld GJ, Beijer C, Veldink JH, et al. Few ad-verse effects of long-term creatine supplementation in a placebo-controlled trial. Int J Sports Med 2005; 307–313.
Pritchard NR, Kalra PA, Renal dysfunction accom-panying oral creatine supplements. Lancet 1998; 1252–1253.
Koshy KM, Griswold E, Schneeberger EE. Interstitial nephritis in a patient taking creatine. N Engl J Med 1999; 340: 814–815.
Yu PH, Deng Y. Potential cytotoxic effect of chronic administration of creatine, a nutrition supplement to augment athletic performance. Med Hypotheses 2000; 54: 726–728.