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Creatine Monohydrate: A Scientific Investigation of the Physical Benefits and the Physiological Risks

Spencer Summers

October 5, 2009


Purpose of Investigation: Creatine Monohydrate is a naturally occurring organic compound, found naturally in both the human body and in various meats and fish.  Manufacturers of nutritional supplements claim that increasing the amount of Creatine Monohydrate  in one’s diet will provide an increase in athletic performance with no adverse effects.  The purpose of this investigation is to examine what the scientific literature has found regarding the biological pathways of Creatine Monohydrate, and therefore determine the validity of the manufacturer’s claims.


Creatine Monohydrate according to the distributors:



                         Who is selling Creatine Monohydrate?




        Creatine Monohydrate is currently one of the most marketed nutritional supplements available.  At this link -(top creatine products) - one can view the most popular products, distributed by manufacturers such as Optimum, EAS, and Dymatize.  There are well over two hundred individual creatine products.  These manufacturers provide creatine in  pre- or post-workout supplements, as a pill or a powder, and finally as either a pure product or as a mix with other supplements such as B-vitamins, whey protein isolate, or caffeine.  This investigation restricts itself to examining pure Creatine Monohydrate, in either pill or powder form, and taken post-workout.


Why do supplement manufacturers recommend this product?


        Creatine Monohydrate supplements are taken by athletes and bodybuilders for it’s ergogenic, or performance-enhancing effects.  According to creatine manufacturers and distributors, anyone who is “ready to have more energy, build more muscle faster, and have more endurance should try supplementing with creatine monohydrate.” Creatine Monohydrate supplements are also purported to be useful for increasing lean muscle mass, and decreasing muscle fatigue in as little as two weeks.  According to these same sources, the most attractive possibility of creatine supplementation is that there are no adverse affects to the body of the user. (

How does Creatine Monohydrate achieve these gains?

        Creatine is a naturally occurring compound in vertebrates.  It is produced in the kidneys, pancreas, and liver, and can also be ingested through foods such as fish and beef.  Creatine is transferred to the muscles where it is then converted to phosphocreatine.  Phosphocreatine then replenishes the energy source of the muscle cells by converting ADP (adenosine diphosphate) to ATP (adenosine triphosphate).  Creatine Monohydrate is the ideal creatine supplement because it contains the most creatine per mass.  Some distributors claim that creatine promotes intracellular hydration, which aids in muscle recovery and increased strength.  Allegedly, increasing the water retention in muscle cells minimizes the protein breakdown.(Cellular Hydration)    It should be noted that every description of Creatine Monohydrate on a distributor’s web page contains a disclaimer that the Food and Drug Administration have not evaluated their statements.


 Is any scientific evidence provided to support these claims?


According to articles from and, there were over twenty double blind, placebo-controlled studies that had been conducted on creatine since the time the articles were written (September 6, 2002).   Although no specific study is cited or named, the studies allegedly found creatine use to result in “increased energy levels, resulting in increased strength, endurance levels, and recovery rates,” as well as accelerating fat loss. ( and It should be noted that every description of Creatine Monohydrate on a distributor’s web page contains a disclaimer that the Food and Drug Administration have not evaluated their statements.


Scientific Literature     


The natural physiological role of Creatine Monohydrate

95% of creatine, or a-methyl guandino-acetic acid, is found in skeletal muscle, with the remaining 5% found in the brain, liver, kidney, and testes.  Approximately 1 gram/day is ingested in a typical, omnivorous diet, and another 1 gram/day is synthesized in the liver, kidney, and pancreas.  Approximately one-third of the skeletal muscle creatine is found as free creatine, whereas the rest exists as phosphocreatine.  Both phosphocreatine and creatine play an important role in cellular energy regulation because they can rapidly convert ADP to ATP. 

The reaction (creatine + ATP) Û (phosphocreatine + ADP) is reversible, and it’s equilibrium point is determined by the cytosolic pH.  Therefore, during exercise (lactic acid accumulates and pH decreases) the reaction will favor the formation of  ATP.  During rest, the pH increases and the reaction reverses to create more phosphocreatine (Persky et al., 2001).    However, phosphocreatine is the limiting reagent in this reaction and it’s cytosolic presence is typically depleted after approximately 10-15 seconds.  Therefore, according to Paddon-Jones, Borsheim, and Wolfe,  “creatine is involved in temporary energy buffering, and also in spatial energy buffering, proton buffering, and glycolysis regulation.” (2004, pages 2890-2891) 



The effects of Creatine Monohydrate on muscle mass


        Creatine manufacturers and distributors claim that within two weeks of supplementation, users will experience significant gains in lean muscle mass.  Many clinical studies have been performed to examine the efficacy of this claim and the results have been fairly consistent across the board.  Recent clinical studies have found that supplementation of Creatine Monohydrate, in combination with resistance training, results in greater increases in strength than placebo. However, amongst the clinical findings, there is a discrepancy as to the reason behind this increase in strength.

One study by Parise, Mihic, MacLennan, et al. (2001) found that that Creatine Monohydrate supplementation did not result in an increase in either whole or mixed-muscle protein synthesis, but it did result in an increase in strength.  13 men and 14 women took part in their study, and were randomly assigned to either a Creatine Monohydrate group or a placebo group.  The subjects were controlled under dietary and exercise measures.  Before and after the experiment, the researchers used mass spectrometry to measure protein synthesis.  Although no increase in muscle synthesis was found, the researchers concluded that the increase in strength was likely due to an increase in cellular water.  They attributed this increase in cellular water to the Creatine Monohydrate supplementation.

Increased cellular water retention in skeletal muscle has been shown to increase protein synthesis and glycogen storage, thereby increasing the energy potential of the cell.  Saab, Marsh,  Casselman, and Thompson (2002) concluded that increase cellular water retention is directly correlated with creatine supplementation.  In their double blind study, the creatine group achieved an average gain in fat-free mass of 1.3 kg, whereas there was no gain in the placebo group.  The researchers used MR spectroscopy to measure the proton concentration found in the water of skeletal muscles.  There was an increase in proton activity in the creatine group, compared to the placebo group.  This is significant because the change in body mass is due to water retention, which therefore increases the cellular protein synthesis.  (Saab, et al., 2002)

Other studies have shown more concrete results about creatine’s ability to increase muscle mass.  Meta-analyses have shown significant gains in muscle fiber growth for patients taking creatine supplementation complimented with strength training.  Over twelve week training programs, muscle fiber diameter increased by 35% in the creatine groups, compared to 6-15% in placebo groups (Paddon-Jones, Borsheim, Wolfe, 2004). 

A randomized, placebo-controlled, crossover, double-blind study that examined creatine supplementation on 12 men found a significant increase in gene expression due to changes in cellular water retention. Muscle biopsies were taken from the subjects before creatine use, and after creatine use.  According to Safdar, Yardley, Snow, et al. (2007, page 225)

“short-term Creatine Monohydrate supplementation in healthy young men activates genes in the skeletal muscles… resulting in increases in maximal muscle strength and power.”


The effects of Creatine Monohydrate on exercise performance


        Meta-analyses of creatine’s effects on exercise performance are highly varied.  One interesting study found that there was no difference in strength between placebo and creatine groups during an eight-week program.  During the program, the training volume between the groups was held constant, meaning that neither group was allowed to perform more repetitions than the other group.  Therefore, according to Paddon-Jones, Borsheim, and Wolfe (2004, page 2891S):

“the beneficial effects of creatine on muscular strength… probably occur by the following sequence: increased muscle creatine, increased training intensity, greater training stimulus, and enhanced physiological adaptations to training.” 

        The study mentioned above, where the exercise repetitions were kept similar between the two groups, would not permit for the creatine group to make use of the supplement.  Creatine Monohydrate allows for greater cellular energy, which results in the ability to perform more workout repetitions.  This is supported by controlled laboratory tests in which creatine supplementation are shown to improve repeated sprints of less than 30 seconds, but are not beneficial to sprints of more than 90 seconds.  Thus, Creatine Monohydrate allows for quicker recovery time in muscles, but is ineffective for endurance exercises (Paddon-Jones, Borsheim, and Wolfe, 2004).

 Negative effects of Creatine Monohydrate use

As stated by the distributing and manufacturing websites, there is yet to be any proof of negative physiological effects from short term Creatine Monohydrate use.  The majority of negative reports on creatine use come from anecdotal evidence of nausea, vomiting, diarrhea, or renal dysfunction.  However, no published studies have found direct links between short-term creatine supplementation and negative physiological affects.  In a double-blind, crossover study, subjects were administered large doses, 20 grams, of creatine for 5 days.  There was no change in their blood liver enzymes from the supplementation (Persky and Brazeau, 2001).

A similar short-term study by Parise, Mihic, MacLennan, Yareshaski, and Tarnopolsky (2001) two out of 13 men reported mild diarrhea, but no other complaints occurred.  Plasma creatinine concentration between the creatine group and placebo group was identical, indicating that renal functions were not adversely changed. 

Nevertheless, the effects of long-term creatine supplementation are largely unknown.  Clinical studies should be employed in this task.

A final worry of creatine supplementation is the quality of the creatine product.  As Paddon-Jones, Borsheim, and Wolfe (2004) state, “because commercially marketed creatine products do not meet the same quality control standards as pharmaceuticals, there is always a concern of impurities or doses higher or lower than those on the labeling.”

The concern of creatine’s manufacturing is severe, because the reaction that produces synthetic creatine (sarcosine and cyanamide) can yield dangerous contaminants.  These contaminants could be potential health hazards if ingested unknowingly (Persky and Brazeau, 2001). 




The claims about Creatine Monohydrate’s physical benefits are extensive and appear almost too good to be true.  However, one must keep in mind that the manufacturers and distributors of Creatine Monohydrate have a lot to gain, monetarily, by making their products as attractive as possible.  Recent studies estimate that the net worth of the dietary supplement industry is between $24-25 billion U.S..  Therefore, the modern consumer is showing a significant investment in what they will pay for supplements that are allegedly beneficial (

Nevertheless, clinical evidence shows that the claims made by creatine distributors are largely true.  It has been shown that supplementation of Creatine Monohydrate combined with exercise leads to increased fat-free body mass and greater strength.  While these observations are true, the claims made by the creatine distributors are slightly misleading.  While the body mass gained from creatine use is fat-free mass, it is not necessarily lean-body mass as the websites purport.  Body mass gains from Creatine Monohydrate are the result of an increase in cellular water, which therefore increases mRNA transcription and the glycogen stores in the cells (Saab, Marsh, Casselman, and Thompson, 2002).  This cellular water retention can lead to bloating, which is rather at odds with the websites’ claims that one will gain lean-body mass.  Additionally, there does not appear to be any clinical evidence of fat loss or an increase in the speed of the metabolism as a result of creatine consumption as the websites would have you believe (

It cannot be argued, though, that creatine is an effective supplement for certain athletes. Creatine is clinically proven to be effective in specific situations - those activities requiring high-intensity and require short bouts of repeated activity (e.g. weight lifting and football). Athletes in other sports may achieve a significant indirect benefit, as creatine supplements may allow more intense levels of weight training, with strength and power benefits transferring to the sport.

An interesting area of research, with regards to Creatine Monohydrate, is in the field of cognitive performance.  A double-blind, cross-over designed study of 45 young vegan or vegetarian subjects were given 5 grams of either Creatine Monohydrate or a placebo and asked to take the pill each day for six weeks.  At the end of the trial, cognitive tests were administered to the students.  It was found that creatine supplementation reduced mental fatigue and improved recognition memory when compared to the placebo group.  The administered cognitive tests relied on speed of neural processing, so the benefit here to the creatine group is directly paralleled by studies of short-term athletic improvements among athletes using creatine (Rae, Digney, McEwan, and Bates, 2006).

This cognitive study shows the vast potential for the marketing of Creatine Monohydrate.  However, it also makes apparent the need for a clinical study on the long-term affects of creatine supplementation.  As stated before, these data are lacking and, therefore, many current users of creatine supplements are potentially vulnerable to unforeseen complications.












Chung, Y., Alexanderson, H., Pipitone, N., Morrison, C., et al., (2007). Creatine Supplements in Patients With Idiopathic  Inflammatory Myopathies Who Are Clinically  Weak After Conventional Pharmacologic  Treatment: Six-Month, Double-Blind, Randomized,  Placebo-Controlled Trial. American College of Rheumatology, 57(4), 694-702.


Paddon-Jones, D., Borsheim, E., & Wolfe, R. (2004). Potential Ergogenic Effects of Arginine and Creatine Supplementation . The Journal of Nutrition, 134, 2888S - 2894S.


Parise, G., Mihic, S., MacLennan, D., Yarasheski, K., & Tarnopolsky, M. (2001). Effects of acute creatine monohydrate supplementation  on leucine kinetics and mixed-muscle protein synthesis. Journal of applied Physiology, 91, 1041-1047.


Persky, A., & Brazeau, G. (2001). Clinical Pharmacology of the Dietary Supplement Creatine Monohydrate. Pharmacol Rev, 53(2), 161-176.


Rae, C., Digney, A., McEwan, S., & Bates, T. (2003). Oral creatine monohydrate supplementation  improves brain performance: a double-blind,  placebo-controlled, cross-over trial. The Royal Society London, 270, 2147-2150.


Saab, G., Marsh, G., Casselman, M., & Thompson, T. (2002). Changes in human muscle transverse relaxation following  short-term creatine supplementation . Experimental Physiology, 87(3), 383-389.


Safdar, A., Yardley, N., Snow, R., Melov, S., & Tarnopolsky, M. (2007). Global and targeted gene expression and protein content in skeletal muscle  of young men following short-term creatine monohydrate supplementation. Physiological genomics, 32, 219-228.



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