byJoseph F. Clark, Ph.D.
ATC Department of Biochemistry
Biochemical and Clinical Magnetic Resonance Spectroscopy UnitSouth Parks Rd
University of Oxford
Oxford OX1 3QU
EnglandFax: +44 (1865) 275259
Revised July 18, 1997
Reprinted with the kind permission of the author


Recently there has been a great deal of interest in the use of creatine in exercise and conditioning. Various published works claim exercise enhancement and benefits with the administration of creatine to athletes. This review is an attempt to summarize the current knowledge regarding the application of creatine.

In muscle, creatine is reversibly converted to phospho-creatine (PCr) by the enzyme creatine kinase (CK). PCr acts as a reservoir for ATP in the muscle. ATP (adenosine triphosphate) is the molecule that is used to produce the contraction of the muscle's proteins. Without ATP the muscle is not able to work the cell will die. The concentration of PCr in the muscle is about 4 times greater than ATP and therefore PCr is a larger energy reserve than ATP. The total creatine concentration (PCr + creatine) in skeletal muscle is 4 grams of creatine per kilogram. For this reason, creatine can be described as a muscle extract. When we eat certain red meats we can get 1 gram of creatine in one large serving.

Creatine Synthesis

The cellular concentration of creatine is determined by the muscle's ability to take up creatine because muscle cannot make it. Creatine is synthesized in the liver and kidney and released into the blood stream to be actively taken up by the muscle cells. The liver plays a central role in the control of creatine in the body. The synthesis of creatine requires three amino acids; glycine, arginine, and methionine. The average synthesis of creatine by the body is 1-2 grams per day. A normal diet contains sufficient glycine, arginine, and methionine for the synthesis of creatine, but there is no evidence that supplementing these amino acids increases creatine synthesis.

Creatine Supplementation

Research has shown that feeding creatine at 2-5 grams per day increases muscle creatine and PCr. Volunteers fed 5 grams of creatine four times a day with a daily total of 20 grams have striking increases in muscle creatine in two weeks which is maintained with a daily dose of about 5 grams. This loading dose of 20 grams a day is discontinued after 6-14 days and the maintenance dose of 5 grams per day is continued throughout the period of training. The current evidence is that the best loading of muscle creatine occurs during normal training (not double days or split sessions where several hours of intense training is done twice in one day) with a low fat, high carbohydrate diet.Following oral creatine administration blood creatine rises, and the amount taken into the muscle increases. This increases PCr, which enhances anaerobic exercise and muscle torque. About 70% of the population who have taken creatine report an increase in total muscle creatine and exercise enhancement. However, 30% of the population have a diet and metabolism such that they do not benefit from creatine supplementation.An increase in muscle size is seen with creatine feeding. Creatine and PCr have been shown to cause an increase in protein synthesis. In humans there was a 46% increase in the size of Type II muscle fibers in gyrate atrophy patients fed 1.5 g per day of creatine for one year. Therefore, there is evidence that increasing creatine and PCr will have an anabolic like increase in muscle protein.Creatine is actively taken up into the cell via a specific transport process. Once in the cell, creatine is lost very slowly (about 2 grams per day).In subjects that started with low levels of muscle creatine, supplementation caused a striking increase in creatine content. However, if the subjects started with high levels of creatine, the increase with oral creatine administration was diminished. All individuals' muscle creatine approached a similar maximum, which indicates there are definite limits to the benefits possible from creatine supplementation.

Creatine Supplementation and Water Balance

During the early phase of oral creatine supplementation there is water retention. It is likely that the water retention is because of the extra water taken up into the cells when creatine enters the muscle. This extra water in the cell may be related to the reports of muscle cramps and heat intolerance. Therefore, anyone involved with creatine supplementation should be properly hydrated and avoid strenuous exercise during the initial days of creatine supplementation and especially during the loading dose of 20 grams per day.Creatine is converted spontaneously to creatinine in muscle and must be excreted in the urine because the muscle cannot use creatinine. Urinary creatinine levels increase with creatine supplementation but, within days, return to normal as the creatine intake is stopped. When creatine is taken in high doses the kidneys will begin to excrete it, which also supports the hypothesis of maximal benefit for creatine supplementation.

Creatine and Muscle Bioenergetics

There is a rapid resynthesis of PCr following exercise in athletes with creatine supplementation. This is due to the ability of creatine to stimulate the mitochondria. The mitochondria are the main source of ATP production in muscle cells.Therefore, creatine administration increases anaerobic capacity and also increases aerobic recovery by stimulation of the mitochondria. Following creatine administration there is an increase in muscle torque and there was no change plasma lactate levels. Creatine supplementation however produced a significant decrease in plasma ammonia during exercise.Plasma ammonia generally comes from the degradation from ATP. Therefore, the augmented PCr in muscle protects the total nucleotide concentration. After administration of creatine, there is an increase in the rate of PCr resynthesis following exercise. This correlates with a faster recovery after exercise and the athlete can therefore shorten their rest periods between sets.Glutamine is an amino acid that is very important to the body for a host of reasons. It is an important source of energy for the mitochondria. Therefore, creatine stimulates the mitochondria and glutamine supplies the mitochondria with energy. Also, the body's cells that actually repair damage use glutamine. So if there is some injury during training, glutamine may aid in the healing process. People have reported that glutamine is able to protect the heart when there is low oxygen and it may also be able to protect the skeletal muscle in a similar way. It appears that glutamine and creatine both have beneficial effects on muscle tissue and that these effects may even be complimentary



In the cell, PCr is not involved in any reactions other than with CK. PCr does however, have another use. It can bind to the cell's membranes and protect the cell by stabilizing the membranes. Intravenous PCr (2 g per day) has been given to athletes during strenuous endurance training. PCr allowed the athletes to train longer and they reported less muscle stiffness. The important drawback for PCr administration is that it must be given intramuscularly or intravenously, because it is readily broken down when taken orally. Most of these effects are attributed to the membrane protective action, but, when PCr is degraded it forms inorganic phosphate (Pi) and creatine. Therefore, PCr has the same benefits as oral creatine administration as well as the membrane effects.


This review has discussed some of the actions of creatine and PCr on muscle metabolism and performance. Twenty grams per day of creatine can be added to the athlete's diet for 1 to 2 weeks and reduced to 5 grams per day for the remainder of the season. The result is that there is more ATP available for muscle contraction, which means the muscles have more energy in them. Because of the apparent maximum for muscle creatine higher doses have little added benefit. The increased creatine and PCr are able to enhance anaerobic capacity as well as by increasing muscle growth. Along with buffering ATP, PCr has the ability to stabilize membranes and protect cells from damage. The draw back for PCr applications in the sports medical field is that it must be administered IV or intramuscularly whereas creatine can be taken orally. The use of any dietary supplement is highly variable and always with limits and should only be taken under a doctor's supervision.

Questions and Answers

How much creatine should I take? A loading dose of 20 grams a day should be taken from 6-14 days and then a maintenance dose of 5 grams per day is continued throughout the period of training.

Why are carbohydrates important to the uptake of creatine? It is not known but it has been shown experimentally (see reference #12 below) to increase muscle creatine during supplementation.

What effects if any does this increased effect of creatine synthesis have on the liver and kidneys? No studies have shown detrimental effects on the kidneys or liver. During supplementation there may be decreased synthesis of creatine, but the synthesis restarts immediately after supplementation is stopped. This is because the biochemical reactions to synthesize creatine are not stopped during supplementation.

Can diabetic taking insulin take creatine as suggested? I do not know, but I can not think of any reason why they would not benefit from creatine supplementation nor do I think they would be at risk.

What are the effects of taking creatine if you have high blood pressure? Is this something that the person should avoid? Many things including heart disease cause high blood pressure. Creatine was given to people with heart disease and there were no reported detrimental effects. The creatine supplementation is not likely to cause problems, but for some people unsupervised exercise may cause or exacerbate the heart disease or other things causing high blood pressure. A person diagnosed with hypertension should consult a physician before beginning a course of exercise - including creatine supplementation.

How does plasma ammonia and plasma lactate effect the body? Ammonia is produced by the breakdown of important molecules in the muscle such as ATP and lactate. Lactate is produced because of incomplete utilization of glucose. Their changes are indicative of the muscles being protected by the creatine supplementation.

So if you take 20 gm/day for 7 days , and your body excretes 2 grams/day, have you increased your body's creatine level approx. (7 x (20 - 2) = 126 grams)? No, if you increase creatine ingestion you increase creatinine and even creatine excretion in the urine. Therefore, supplementation will produce an increase in muscle (total body) creatine but both the muscle and the body will set a maximum level of creatine for a person. Hence very large doses (above 20 grams per day) will have no benefits.

If your body only loses 2 gm/day is this the amount (2 gm/day) a person should take to maintain a given creatine level? No, the amount lost is not constant, but the amount synthesized is. This is why supplementation has benefits.

Recommended Readings

  1. Conway, M. A., & Clark, J. F. (1996). Creatine and creatine phosphate: Scientific and clinical perspectives. London, England: Academic Press.
  2. Balsom, P. D., Ekblom B., Soderlund, K., Sjodin, B., & Hultman, E. (1993). Creatine supplementation and dynamic high-intensity intermittent exercise. Scandinavian Journal of Medicine and Science in Sports, 3, 143-149.
  3. Balsom, P. D., Harridge, S. D., Soderlund, K., Sjodin, B., & Ekblom B. (1993). Creatine supplementation per se does not enhance endurance performance. Acta Physiologica Scandinavica, 149, 521-523.
  4. Birch, R., Novel, D., & Greenhaff, P. L. (1994). The influence of dietary creatine supplementation on performance during repeated bouts of maximal isokinetic cycling in man. European Journal of Applied Physiology, 69, 268-270.
  5. Casey, A., Constantin-Teodosiu, D., Howell, S., Hultman, E., & Greenhaff, P. L. (1996). Creatine ingestion favorably affects performance and muscle metabolism during maximal exercise in humans. American Journal of Physiology, 271, E31-E37.
  6. Casey, A., Constantin-Teodosiu, D., Howell, S., Hultman, E., & Greenhaff, P. L. (1996). Metabolic response of type I and II muscle fibers during repeated bouts of maximal exercise in humans. American Journal of Physiology, 271, E38-E43.
  7. Clark J. F. (1996). Uses of creatine phosphate and creatine supplementation for the athlete (pp. 217-225). In Conway, M. A. & Clark, J. F. (Eds), Creatine and creatine phosphate: Scientific and clinical perspectives. London, England: Academic Press.
  8. Clark J. F., Odoom, J., Tracey, I., Dunn, J., Boehm, E. A., Paternostro, G., & Radda, G. K. (1996). Experimental observations of creatine and creatine phosphate metabolism (pp. 33-50). In Conway, M. A. & Clark, J. F. (Eds), Creatine and creatine phosphate: Scientific and clinical perspectives. London, England: Academic Press.
  9. Conway M. A., Rajagopalan, B., & Radda, G. K. (1996). Skeletal muscle metabolism in heart failure (pp. 161-184). In Conway, M. A. & Clark, J. F. (Eds), Creatine and creatine phosphate: Scientific and clinical perspectives. London, England: Academic Press.
  10. Conway M. A., Ouwerkerk, R., Rajagopalan, B., & Radda, G. K. Creatine phosphate: in vivo human cardiac metabolism studied by magnetic resonance spectroscopy (pp. 127-160). In Conway, M. A. & Clark, J. F. (Eds), Creatine and creatine phosphate: Scientific and clinical perspectives. London, England: Academic Press.
  11. Ernest, C. P., Snell, P. G., Rodriguez, R., Almada, A. L., & Mitchell, T. L. (1995). The effect of creatine monohydrate ingestion on anaerobic power indices, muscular strength and body composition. Acta Physiologica Scandinavica, 153, 207-209.
  12. Fitch, C. D., & Shields, R. P. (1966). Creatine metabolism in skeletal muscle. I. Creatine movement across muscle membranes. Journal of Biological Chemistry, 241, 3611-3614.
  13. Green, A. L., Hultman, E., Macdonald, I. A., Sewell, D. A., & Greenhaff, P. L. (in press). Carbohydrate ingestion augments skeletal muscle creatine accumulation during creatine supplementation in man. American Journal of Physiology.
  14. Greenhaff, P. L., Casey, A., Short, A. H., Harris, R., Soderlund, K., & Hultman, E. (1993). Influence of oral creatine supplementation of muscle torque during repeated bouts of maximal voluntary exercise in man. Clinical Science, 84, 565-571.
  15. Greenhaff, P. L., Bodin, K., Soderlund, K., & Hultman, E. (1994). Effect of oral creatine supplementation on skeletal muscle phosphocreatine resynthesis. American Journal of Physiology, 266, E725-E730.
  16. Greenhaff, P. L., Bodin, K., Harris, R. C., Hultman, E., Jones, D. A., McIntyre, D. B., Soderlund, K., & Turner, D. L. (1993). The influence of oral creatine supplementation on muscle phosphocreatine resynthesis following intense contraction in man. Journal of Physiology, 467, 75P.
  17. Harris, R. C., Soderlund, K., & Hultman, E. (1992). Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation. Clinical Science, 83, 367-374.
  18. Harris, R. C., Viru, M., Greenhaff, P. L., & Hultman, E. (1993). The effect of oral creatine supplementation on running performance during maximal short term exercise in man. Journal of Physiology, 467, 74P.
  19. Hultman, E., Soderlund, K., Timmons, J. A., Cederblad, G., & Greenhaff, P. L. (1996). Muscle creatine loading in man. Journal of Applied Physiology, 81, 232-237.
  20. Saks, V. A., & Strumia, E. (1993). Phosphocreatine: molecular and cellular aspects of the mechanism of cardioprotective action. Current Therapeutic Research, 53, 565-598.
  21. Saks, V. A., Javadov, S. A., Pozin, E., & Preobrazhensky, A. N. (1987). Biochemical basis of the protective action of phosphocreatine on the ischemic myocardium (pp. 270-273). In Saks, V. A., Bobkov, Y. G., & Strumia, E. (Eds), Creatine phosphate: Biochemistry, Pharmacology, and Clinical Efficiency. Torino, Italy: Edizoni Minerva Medica.
  22. Sipila, I, Rapola, J., Simell, O., & Vannas, A. (1981). Supplementary creatine as a treatment for gyrate atrophy of the choroid and retina. New England Journal of Medicine, 304, 867-870.
  23. Trump M .E., Heigenhauser, G. J., Putman, C. T., & Spriet, L. L. (1996). Importance of muscle phosphocreatine during intermittent maximal cycling. Journal of Applied Physiology, 80, 1574-1580.
  24. Wallimann, T., Wyss, M., Brdczka, D., Nicolay, K., & Eppenberger, H. M. (1992). Intracellular compartmentation structure and function of creatine kinase isozymes in tissue with high and fluctuating energy demands: The phosphocreatine circuit for cellular energy homeostasis. Journal of Biochemistry, 1102, 21-40.

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