Oral Creatine Supplementation

Separating Fact From Hype

Mark S. Juhn, DO

THE PHYSICIAN AND SPORTSMEDICINE - VOL 27 - NO. 5 - MAY 1999

In Brief: Many athletes—especially those participating in sports that emphasize strength—are taking oral creatine. Creatine supplements appear to enhance performance in repeated short bursts of stationary cycling and weight lifting, but the data on running, swimming, and single cycle sprints are not convincing of an ergogenic effect. Commonly reported side effects include muscle cramping, GI disturbances, and renal dysfunction, but creatine's effect on the heart, brain, reproductive organs, and other organs has yet to be determined. Comprehensive studies with larger samples and crossover design are needed. If patients decide to take oral creatine, physicians need to provide guidance for proper dosing as well as education about potential harmful effects.

Consumption of synthetically manufactured creatine by athletes and bodybuilders attempting to enhance athletic performance has become very popular. A surge in use began in 1992, when Harris et al (1) showed that oral supplementation with high doses of creatine resulted in a 20% increase in skeletal muscle creatine concentration. Although no claims could be made with regard to its effect on athletic performance, companies were quick to market the ergogenic potential of this legal substance. Creatine is not banned by the National Collegiate Athletic Association or the International Olympic Committee.

How Creatine Is Metabolized

Creatine is a nitrogenous amino acid compound found naturally in skeletal muscle, heart, brain, testes, retina, and other tissues (2), In skeletal muscle, approximately one-fourth exists as free creatine and three-fourths as phosphocreatine (PCr) (3,4). Creatine is synthesized primarily by the liver, kidneys, and pancreas at a rate of 1 to 2 g/day (3-5). An additional 1 to 2 g/day is obtained in the diet, mainly from fish and meats (3,6). Excretion of creatine by the kidneys at a rate of 1 to 2 g/day is via irreversible conversion to creatinine in skeletal muscle (3). The reader should use caution not to confuse creatine with creatinine.

Total creatine is the sum of free creatine and phosphocreatine (PCr). Both types play important roles in anaerobic adenosine triphosphate (ATP) production during maximal anaerobic burst-type exercise via the creatine kinase system (4,7) (figure 1: not shown). Creatine and PCr exist in a reversible equilibrium in skeletal muscle (4,7,8). During intense muscle contraction, the flux in the forward direction increases, which rapidly produces more ATP for energy, anaerobically (4,7,9). The PCr reaction contributes significantly to ATP resynthesis for about 10 to 20 seconds of maximal exercise. This is followed by a proportionate increase in other pathways of ATP resynthesis, such as anaerobic glycolysis or aerobic oxidation of carbohydrate and fat (9).

Creatine supplementation can increase muscle PCr concentration by 6% to 16% (1,10-14), theoretically enhancing ATP turnover during maximal exercise. Additionally, creatine supplementation may enhance resynthesis of PCr during rest periods between repeated short bouts of exercise (15), though a recent study (14) did not support this theory. There is also some evidence that prolonged creatine supplementation increases myofibrillar protein synthesis, which results in muscle accretion (16,17), a controversial topic that will be discussed later.

In summary then, oral creatine supplementation may be ergogenic for the following reasons:

Higher PCr concentration in skeletal muscle, allowing for enhanced anaerobic ATP production during maximal exercise;
Enhanced resynthesis of PCr during recovery periods between short bouts of maximal exercise; and
Possible muscle accretion.

It should be noted that the PCr reaction is anaerobic (4,7), meaning that oral creatine supplementation is potentially ergogenic only for activity that has a high anaerobic component, not for endurance activity (18,19). The possibility exists, however, that creatine may be ergogenic for endurance events that involve intermittent bursts of anaerobic activity.

Usual Dosage

The typical creatine supplementation protocol begins with a loading dose of 20 g/day (or 0.3 g/kg) for 5 days, followed by a "maintenance" dose of 2 g/day (or 0.03 g/kg) (12), though the maintenance dose is often unnecessarily exceeded (20). Although a 5-day loading period is typical, 2 days of loading has been shown to yield similar muscle creatine concentration and performance results (14). Without loading, 3 g/day for 28 days results in muscle creatine concentrations similar to 5 days of loading (12).

A study by Green et al (21) found that the addition of a carbohydrate solution (90 g four times daily during the loading phase) further enhanced the increase in muscle creatine concentration relative to taking creatine alone. Based on this study, the combination of creatine with sports drinks has become popular.

It is important to note, however, that skeletal muscle has a creatine storage capacity of 150 to 160 mmol/kg (normal is 125 mmol/kg) (1,10), which makes oversupplementation futile. This is important information for those who think that more is better. Any excess creatine ingestion will not further increase muscle creatine but will simply increase urinary creatine and creatinine excretion.

Muscle concentrations of creatine and PCr return to baseline levels approximately 28 days after discontinuing creatine supplementation (13,22).

Does Creatine Aid Performance?

In controlled laboratory studies, oral creatine supplementation has been shown to be ergogenic in repeated stationary cycling sprints (23-28), weight lifting (13,26,27,29), repetitive sets of muscle contractions such as knee extensions (14,30), and kayak ergometry (31). However, the media and even some in the scientific community often extrapolate these studies to a much broader generalization regarding athletic performance, seemingly omitting mention of many studies that do not demonstrate an ergogenic effect. This can be misleading for the athlete and clinician alike.

Common misconceptions. There are two common misconceptions about creatine's ergogenic potential. The first is a gross generalization that creatine supplementation is ergogenic for all types of "sprinting," including running, swimming, and cycling. The fact is, the literature has shown reasonable support for an ergogenic benefit only in repeated bouts of stationary cycling sprints in a laboratory setting (table 1) (23-28). And unanimity is lacking even here, as there are several studies (22,32-34) of repeated cycling sprints that did not demonstrate an ergogenic effect.

Table 1. Effect of Oral Creatine Supplementation on Specific Activities

Activity Summary of Studies Comments

Stationary cycling sprints Several studies support an ergogenic effect in repeated sprints but are not convincing for single sprints Field studies with bicycles on a track are needed to simulate actual competition

Running sprints (repeated or single) Conflicting results regarding performance enhancement Speculation is that weight gain offsets any potential benefit

Swimming sprints (repeated or single) Conflicting results regarding performance enhancement Speculation is that weight gain offsets any potential benefit

Weight lifting Some evidence of an ergogenic effect Whether creatine supplementation truly increases muscle synthesis is being investigated. Creatine-induced weight gain may make true double-blindness difficult to achieve

As for creatine's effect on running sprints and swimming sprints (35), more studies (36-40) have demonstrated no benefit with supplementation than have demonstrated a benefit (41). (Some studies produced mixed results: Both Bosco et al (42) and Peyrebrune et al (43) found one protocol to show no benefit and one protocol to show a benefit, while Grindstaff et al (44) found no benefit in two swimming heats and some benefit in one.)

It is speculated that the weight gain from water retention that occurs with creatine supplementation (12,13) may impede performance in runners and swimmers. The effect of weight gain on performance may not be as significant in a weight-supported activity such as stationary cycling or weight lifting. Also, the cycling studies are performed on stationary cycle ergometers, not on bicycles on a track or road. This has led some to question whether creatine is truly ergogenic outside of a laboratory. In general, the vague term "sprinting" should be avoided when discussing creatine's ergogenic potential.

The second common misconception is that creatine supplementation is beneficial in a single timed event, such as a single sprint. The fact is that, even with stationary cycling, creatine has not been shown to enhance single-event performance (25,45-47). Again, the strongest support for the ergogenic potential of creatine supplementation is in repeated maximal bursts of activity, specifically 6- to 30-second bouts of stationary cycling with 20 seconds to 5 minutes of rest between bouts (23-28). However, some multiple-bout studies (24,25,27) did demonstrate an improvement in the first bout, which can be construed as single-bout performance.

Because the evidence does not strongly support an ergogenic effect of oral creatine on single-sprint activity and because most competition involves single timed events rather than repetitive burst activity, some have expressed skepticism that creatine can truly help athletic performance. The argument can be made, however, that athletes in sports such as football, which involves repeated bursts of maximal exercise, may gain an ergogenic effect from creatine supplementation. On the other hand, players need to consider the possible detriment of weight gain, though some athletes may find the weight gain desirable, depending on the sport and position they play.

Conflicting results. The variable results in creatine studies are difficult to explain but may be due to study design, author bias, or subject variability. Very few studies incorporated a crossover design, in which the control group becomes the experimental group and vice versa after a washout period. Crossover designs reduce the sample size required and reduce the chances of a type 2 statistical error (an acceptance of the null hypothesis when in fact it is false).

Author bias may also contribute to the different conclusions seen. According to disclosure statements accompanying the articles, several studies were funded by grants from sport supplement companies or have one or more authors who serve as consultants for such companies (26,27,44). Such affiliations would, of course, not affect results, but they may unintentionally influence the discussion and ultimately the authors' conclusions. Finally, a simple yet very plausible hypothesis to explain conflicting study results is subject variability.

Water Mass or Muscle Mass?

Creatine supplementation results in weight gain, from 0.5 to 1.6 kg during the 5-day loading phase (15,25,26,29,32,33,38,47), and even more with prolonged use (13,27). The weight gain is initially due to water retention (12,13). After 1 year of use, muscle accretion may occur (17), although this is unproved and still under study.

Several studies (13,26,27,29) have demonstrated an ergogenic effect of creatine supplementation in weight lifting. Weight gain, however, is noted even after 1 to 2 days of creatine loading, which is too short a time for appreciable muscle accretion to occur. Furthermore, it is possible that despite investigators' efforts to maintain double-blindness, the weight gain experienced by those in the creatine group can result in a placebo effect of feeling "stronger."

Further study is needed to determine if oral creatine supplementation per se enhances muscle accretion and truly increases strength. However, even without muscle accretion, the ergogenic effect observed may be due to enhanced ATP turnover as discussed previously.

Potential Adverse Effects

Adverse effects of oral creatine supplementation have not been extensively studied, though concerns have been prevalent in the media and training rooms. In the United States, creatine is considered a dietary supplement. Therefore, in accordance with the Dietary Supplement Health and Education Act of 1994 (48), claims regarding performance and safety do not need to be substantiated by the US Food and Drug Administration (FDA).

Muscle cramping. It is common to hear reports from athletic trainers about muscle cramping or strains in athletes taking creatine. Since water retention occurs with creatine supplementation (12,13), it is speculated that this effect increases skeletal muscle compartment pressure, leading to the risk of muscle dysfunction. In some studies that have evaluated performance (11,13,14,27,44), none of the subjects experienced muscle cramping. However, such studies had sample sizes of 25 or fewer, which is suboptimal for comprehensive statistical analysis.

To elaborate, if a side effect is present in 50% of an experimental group versus 30% of a control group, and the researcher wishes to achieve a statistical significance level of 0.05 with 80% power, then a sample size of 146 (73 in each group) is needed (49). The sample size required is much larger if 90% power is the goal, or if the difference between groups is less, such as 40% versus 30%.

In one survey of 52 male collegiate athletes (20), muscle cramping was reported by 25% of those who took creatine. However, this was not a controlled study, and, in most cases, such complaints did not cause the athlete voluntarily to stop taking creatine. While theoretical concerns and anecdotal reports abound, randomized double-blind studies with larger numbers of subjects and crossover design are needed to more accurately assess this controversial aspect.

Gastrointestinal effects. Diarrhea and gastrointestinal pain have also been reported anecdotally. Authors of several performance studies (11,13,14,27,44) noted that none of their subjects experienced gastrointestinal symptoms of any kind, but, again, sample sizes were extremely small (fewer than 12 in the experimental group). Since the average diet includes 1 to 2 g of creatine daily, it may be reasonable to assume that a loading dose of 20 g daily for 5 days is excessive for some people's digestive systems.

Renal dysfunction. Anecdotal reports and two published case reports (50,51) of renal dysfunction in subjects taking creatine have raised concern about the effects of creatine supplementation on the kidneys. Short-term (5-day) creatine supplementation does not appear to impair function in the healthy kidney (52). However, supplementation significantly increases the urinary creatine excretion rate, as much as 90-fold during the loading phase (13,52), and whether this has long-term adverse effects is unclear. Urinary creatinine also increases, but to a much lesser degree (12-14,53). Currently, creatine supplementation should not be used by people with preexisting renal disease or by those with a potential for renal dysfunction (eg, those who have diabetes).

Dehydration. There is anecdotal concern that the water retention resulting from creatine supplementation can increase the risk of dehydration via fluid shifts into the skeletal muscle cells (intracellular water retention). While an increased risk of dehydration has not been proven, most creatine manufacturers advocate proper hydration while taking creatine, theoretically to reduce this chance.

Unstudied Potential Effects

Creatine is naturally found in many other places in the body, including the heart, brain, and testicles (2). The fact that possible side effects in these areas receive less attention than muscle cramping and gastrointestinal effects is surprising and of concern. It is unknown, for example, what effect oral creatine supplementation has on creatine concentration in the heart, brain, and reproductive organs. Furthermore, oral creatine supplementation results in the attenuation or suppression of endogenous creatine synthesis by the liver (13), and the long-term effects of this on the liver or other organ systems are not known. In addition, creatine is found and synthesized in the testes (54,55), and animal studies have shown that creatine is involved in sperm metabolism (56).

Other potential areas of concern have been addressed in a recent critical review (57), which is summarized in table 2 (not shown) (2,11-13,17,27,38,52,53,55,56,58-64). One notable area that remains unstudied is the pediatric population, perhaps the most susceptible population when it comes to ergogenics and athletic performance. Clearly, human studies evaluating the effects of oral creatine supplementation beyond just muscle cramping and diarrhea are indicated.

The FDA has officially logged 32 complaints regarding people who used creatine (65). These complaints include seizure, cardiac arrhythmia, cardiomyopathy, deep venous thrombosis, rhabdomyolysis, and death. Thus far, no conclusions linking these reports to creatine supplementation have been made. A well-publicized case series of three wrestlers who died after taking severe dehydration measures implicated creatine as a contributor, but this claim was not supported by an investigation by the Centers for Disease Control and Prevention (66). In addition, ethical and legal issues need to be resolved (see "Creatine: Ethical and Medicolegal Issues," below).

Advice for Patients

Physicians will continue to encounter patients who insist on using creatine. When this occurs, informing patients of the following would be a reasonable start:

Creatine may or may not help patients achieve what they want.
After the loading phase of 20 g daily (or 0.3 g/kg) for 2 to 5 days, maintenance should be 2 g/day, or 0.03 g/kg. Any extra is simply urinated out.
Creatine users will gain weight because of water retention, which may slow them down.
Creatine is not regulated by the FDA, and its safety profile is not established.
Patients take creatine at their own risk.

It is up to the physician whether or not to monitor patients with regular laboratory tests. A baseline set of renal and liver function lab values would be advisable, as would a screening physical examination.

Supplemental Information

There is evidence that oral creatine supplementation enhances performance in repeated short bouts of stationary cycling in a laboratory setting. The most accepted hypothesis is that enhanced ATP turnover as a result of greater muscle PCr concentration after supplementation enhances muscle contractility. However, the data on creatine supplementation and single sprints of any kind do not support an ergogenic effect. Additionally, the evidence that creatine improves running and swimming performance is not convincing, perhaps because of weight gain from water retention. Also, it remains to be seen if long-term creatine supplementation enhances muscle accretion. Finally, creatine has not been shown to be ergogenic outside the laboratory setting.

Commonly reported adverse effects of creatine supplementation include muscle cramping and gastrointestinal disturbances, but studies with larger sample sizes are needed to identify the scope of the problem. The greater concern lies in the unknown effects of creatine supplementation on various organ systems, particularly the kidneys, liver, heart, brain, and reproductive organs.

Though physicians can educate patients about oral creatine use, the decision on supplementation will ultimately be made by the patient. Physicians, though, can provide valuable guidance.

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Creatine: Ethical and Medicolegal Issues

There is concern that the "win at all costs" attitude has become too prevalent in today's sports-oriented society. Adolescents are the most easily influenced age-group, yet they are the least studied with respect to sport supplementation. Regardless of whether creatine is ergogenic or not, does its prevalent use send the wrong message? Would the use of creatine and other supplements steer athletes away from the most reliable and safe method of enhancing performance, namely practice and dedicated training?

Medicolegal concerns are being addressed at the high school and college level. For example, several institutions have abandoned the practice of freely distributing creatine in training rooms for fear of potential litigation should adverse effects occur in a student-athlete. Medicolegally, physicians are advised to let athletes decide for themselves to take creatine or not. However, physicians can educate athletes to help them make informed decisions.

It should not be forgotten that although the term "athlete" is often used in sports medicine, every athlete cared for is also a patient.

Dr Juhn is an attending physician in the Family Medicine Clinic and Sports Medicine Clinic at the University of Washington's Hall Health Primary Care Center in Seattle. He is also a clinical instructor in the Department of Family Medicine at the University of Washington School of Medicine. Address correspondence to Mark S. Juhn, DO, Hall Health Primary Care Sports Medicine Center, University of Washington, Box 354410, Seattle, WA 98195-4410.

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