Headlines in late 1997 blamed creatine for the deaths of three college wrestlers. Yet, after the dust settled, no evidence linked the supplement to the deaths. Lost in the fray were data supporting creatine's safety and efficacy in improving human performance and body composition. Also overlooked were studies examining the amino acid for various metabolic disorders and diseases.
Creatine is poised to evolve into much more than muscle magic. A variety of published and unpublished research shows creatine may decrease tumor growth, increase body mass, decrease blood glucose, reduce triglycerides and cholesterol, extend exercise endurance in congestive heart failure patients, and even alter metabolism in people with neurodegenerative diseases such as Alzheimer's and Lou Gehrig's diseases.
The history of creatine, a substance that provides energy to muscles, has been documented during nearly 80 years of clinical research. It began in 1926 when two researchers tested it on themselves and found that it changed body weight and urinary markers of protein metabolism.[1]
What percent of a supplement is actually absorbed by the body? Several studies show more than 95 percent of oral creatine is.[1,2] What differs between subjects is the magnitude of muscle creatine uptake. Up to one-third of individuals supplementing with creatine do not show robust increases in muscle creatine and phosphocreatine.[1,3] And, it is unclear whether people supplementing with creatine over a period of time continue to uptake it.
The predominant factors regulating creatine uptake are the amount and activity of creatine transporter protein and circulating insulin concentrations. Creatine can enter muscle cells via a specific transport protein, which is often inaccurately referred to as the creatine "receptor." Recent studies by Theo Wallimann, Ph.D., and associates at the Institute for Cell Biology in Zurich, Switzerland, suggest creatine transporter protein is downregulated in animals following chronic creatine exposure.[4] However, unpublished studies with human subjects by Paul Greenhaff, Ph.D., of the University of Nottingham, and colleagues in England show no downregulation after several weeks of use.[5] Greenhaff's lab has also shown that a large amount of an insulinogenic carbohydrate (93 g glucose, for example), or very high physiological or pharmacological concentrations of insulin, enhance muscle creatine uptake.[2,6] An unpublished study by Jeff Stout, Ph.D., and associates at Creighton University, Omaha, Neb., describes superior increases in muscle performance with a proprietary effervescent creatine preparation. To explain the apparent differences between effervescent and "standard" creatine, the researchers offer the suggestion of increased absorption and/or uptake. The researchers did not, however, attempt to measure true absorption and, more importantly, did not examine muscle creatine uptake.[7] Therefore the issues of superior absorption or uptake remain unaddressed.
The pivotal enzyme in creatine metabolism is creatine kinase, which directs the energy transfer between adenosine triphosphate (ATP) and phosphocreatine (PCr), an energy-liberating compound found in muscles. PCr is produced when creatine is linked with a certain form of phosphorus, a mineral found in food. Creatine kinase works like the fulcrum of a seesaw, fostering the formation of ATP or PCr, depending on metabolic demands. When energy demands are high, ATP is formed at the expense of PCr; when energy demands decline, PCr is reformed at the expense of ATP. This, at a cellular level, is how muscles store and harness energy. Creatine supplementation does not increase ATP but does increase PCr and creatine stores, a bioenergetically favorable alteration.
Some studies show tumors can be identified by their much higher creatine kinase activity.[5] Although this suggests creatine kinase directly influences tumor formation and progression, no cause and effect relationship has been described. Indeed, creatine and its chemical cousin, cyclocreatine, both of which can increase creatine kinase activity, decrease the growth rate of several animal and human tumors implanted in animals.[6,7] Recent research shows tumor concentrations of creatine and cyclocreatine correlate with tumor inhibition in immune-deficient mice implanted with human colon-cancer cells.[7] These data suggest that increasing creatine levels within tumors inhibits them. However, no human studies have been conducted.
Frequent companions of cancerous tumors and immunodeficiency diseases are muscle wasting and general weight loss. HIV/AIDS is probably the most common disease characterized by wasting. The severe and often unremitting weight reductions are not unlike those noted in starvation. One popular strategy to retard this is to increase body mass before the patient advances to a wasting state. With this in mind, I designed a study with Allan Hollister, M.D., Ph.D., of the University of Colorado Health Sciences Center in Denver to assess the impact of creatine supplementation on body composition in the pre-wasting, HIV-infected state. We conducted a double-blind, exploratory study on 30 HIV-positive males without wasting symptoms. For eight-weeks, participants were given either 10 or 15 g creatine/day. The men in both groups significantly increased their lean-body mass and modestly increased fat mass; the increase in lean mass lasted at least four weeks after supplementation ended. As a side benefit, both groups also increased their strength.[8],[9]
If we examine the chemistry of the creatine molecule (see above) we find one portion harbors a nitrogen-rich component called a guanidine group. Metformin, a recently introduced prescription drug for diabetes, contains two guanidine groups and thus is called a biguanide. One of its principal actions is improving tissue sensitivity to insulin, thereby facilitating the disposal of glucose into tissues.
From a chemist's perspective, it is not improbable to suggest creatine would modify glucose disposal since it also contains guanidine. Indeed, preliminary data from animal studies published in 1928 indicate high doses of creatine cause low blood sugar.[10] Recent studies performed in fasting insulin-dependent (Type I) diabetics found a single 3-g dose of creatine produces significant reductions in blood glucose without changing blood insulin.[11,12] Recent studies presented at the 1999 American Diabetes Association annual meeting describe a similar effect in noninsulin dependent (Type II) diabetics. Researchers from the University of Zagreb in Croatia found one 3-g dose of creatine reduced blood glucose in such cases. They also found the effects of creatine equaled those produced by a drug that increases insulin output, but the effects were greatest when the drug and creatine were taken together.[13]
Occasionally in clinical research you look for one thing but find another. In a study conducted with Conrad Earnest, Ph.D., and colleagues at Texas Women's University, in Denton, and the University of Texas Southwestern Medical School, Dallas, we researched the effects of creatine on body composition and strength. In the process we saw a considerable reduction in blood cholesterol concentrations in a few subjects.[14] Eight subjects were asked to maintain their usual diet and training regimen throughout the 28-day study. Although analysis of three-day diet diaries revealed the creatine group ate fewer total calories and had lower carbohydrate and fat intakes, these differences were not statistically significant.
In light of the unexpected results from this study, we undertook a systematic double-blind, placebo-controlled investigation of 34 mildly hyperlipidemic (blood fasting total cholesterol levels between 220 and 250 mg/dL) patients at the Cooper Clinic in Dallas. We found 1020 g creatine/day for eight weeks reduced triglycerides by 22 to 23 percent and total cholesterol by 5 to 6 percent in both men and women aged 32 to 70.[15] There was no effect on high-density lipoprotein (HDL) or low-density lipoprotein (LDL) cholesterol. Surprisingly, we also found these effects persisted at least four weeks after discontinuing creatine supplementation. The men in the study tended to have greater blood lipid-lowering effects and reductions in fasting blood glucose levels than the women. Unfortunately, we did not measure fasting insulin concentrations, which would have provided more data to evaluate whether creatine decreases insulin resistance or improves insulin sensitivity. In a recent study conducted in collaboration with Richard Kreider, Ph.D., and colleagues at the University of Memphis, Tenn., we duplicated the hypolipidemic effects in a group of university football players during off-season training.[16] However, another study by Jeff Volek, Ph.D., and colleagues at Penn State University, University Park, did not corroborate the findings after three months of creatine supplementation in young male weight lifters.[17]
Because elevated triglycerides are a risk factor for cardiovascular disease, especially coronary heart disease, creatine's triglyceride-lowering effect is significant.[18,19] The Stockholm Ischemic Heart Disease Prevention Study conducted on 555 people in the 1980s showed that patients whose triglyceride levels dropped 30 percent halved their risk of dying from a secondary coronary heart disease event. This was related to reductions of triglycerides, not total cholesterol.[20] No pharmaceuticals have hypolipidemic effects limited to the triglyceride fraction. Certainly a larger trial of creatine's triglyceride-lowering effects must be completed to better understand this important potential application.
Congestive heart failure (CHF) patients have greatly compromised exercise tolerance. It seems logical that defects in cardiac metabolism are the cause, but this may not be the case. Since the heart is a collection of smooth and skeletal muscles, it is likely that impaired use of PCr in skeletal muscle also contributes to reduced endurance.[21] In support of this theory, creatine supplementation has been shown to extend exercise endurance in CHF patients[22]--probably a result of creatine's ability to prolong cellular energy production in skeletal muscle under periods of metabolic demand, rather than a direct effect on cardiac function. In addition, studies show that muscle creatine and PCr concentrations increase following supplementation in CHF patients, suggesting improved skeletal muscle performance.
Most creatine is stored in skeletal muscle cells, but the brain and nerves also store it. Investigations by Rima Kaddurah-Daouk, Ph.D., of Avicena Group, Cambridge, Mass., and Flint Beal, Ph.D., of Harvard Medical School, Cambridge, and Massachusetts General Hospital, Boston, have uncovered some novel applications for creatine in several neurodegenerative diseases. Recent studies in an animal model of Lou Gehrig's disease show creatine is equal or superior to riluzole, the current drug of choice, in extending survival time.[23]
A common element in Alzheimer's, Huntington's, Lou Gehrig's and Parkinson's diseases may be impaired energy production in the brain that ultimately leads to increased cell damage.[24] For example, the genetic mutation present in Huntington's disease may impair nerve cell energy production. To test this theory, rats with a chemically induced condition mimicking the lesions found in Huntington's disease were given an oral dose of creatine and cyclocreatine totaling 0.25 to 3 percent of their diet, by weight, for two to three weeks. Following supplementation they showed significant neuroprotection (decreased lesion volume and preservation of PCr and ATP) and reduced oxidative stress.[25] Kaddurah-Daouk and Beal have begun intervention trials with Lou Gehrig's disease patients and other studies with Parkinson's and Alzheimer's patients.
Duchenne's muscular dystrophy (DMD), a gender-specific genetic neuromuscular disease affecting only young boys, may be characterized by elevated intracellular calcium concentrations. A recent report from Swiss scientists suggests creatine supplementation may enable affected muscle cells to regulate calcium concentration within the cell, increase phosphocreatine concentrations, and increase the survivability of DMD mouse muscle cells.[26] A preliminary investigation to assess creatine's effect in DMD boys is being planned. Creatine supplementation for children appears safe based on studies of infants with an enzymatic defect in creatine synthesis who took 400 to 500 mg/kg/day--almost double the adult loading dose--for more than two years.[27,28]
Creatine's potential usefulness has been building through nearly eight decades of research. After entering the laboratory as a "steroid substitute" with questionable efficacy and safety, creatine is now moving into a position of prominence in clinical medicine. Given the role of creatine and phosphocreatine in cellular metabolism, it is easy to imagine other metabolic avenues that may be influenced by creatine. The next century will undoubtedly reveal more about creatine's potential in both health maintenance and disease treatment.