Creatine: Not Just A Sports Supplement

Although creatine offers an array of benefits, most people think of it simply as a supplement that bodybuilders and other athletes use to gain strength and muscle mass. Nothing could be further from the truth.

A substantial body of research has found that creatine may have a wide variety of uses. In fact, creatine is being studied as a supplement that may help with diseases affecting the neuromuscular system, such as muscular dystrophy (MD). Recent studies suggest creatine may have therapeutic applications in aging populations for wasting syndromes, muscle atrophy, fatigue, gyrate atrophy, Parkinson's disease, Huntington's disease and other brain pathologies. Several studies have shown creatine can reduce cholesterol by up to 15% and it has been used to correct certain inborn errors of metabolism, such as in people born without the enzyme(s) responsible for making creatine. Some studies have found that creatine may increase growth hormone production.


The article also covered exactly what creatine is, how it works and how much is required to possibly treat the aforementioned pathologies. If you missed that article, refer to the March 2003 issue of Life Extension magazine, or view it at www.lef.org. In this article, we examine some additional properties of creatine, such as its effects on growth hormone release, homocysteine and chronic fatigue syndrome, as well as other important issues surrounding this supplement, such as its safety.

Although data is limited, some research suggests creatine can raise growth hormone equal to that of intense exercise. Growth hormone (GH) is known to play an essential role in the regulation of body fat levels, immunity, muscle mass, wound healing, bone mass and literally thousands of other functions both known and yet unknown. It is well established that GH levels steadily decline as we age and is partially responsible for the steady loss of muscle mass, loss of skin elasticity, immune dysfunction and many other physical changes that take place in the aging human body. Therefore, the possible effects of creatine on GH is worth exploring in aging populations.

One study found creatine could mimic the increased GH levels seen after intense exercise.1 In this comparative cross-sectional study, researchers gave six healthy male subjects 20 grams of creatine in a single dose at resting (non-exercising) conditions. The study found that all subjects showed a "significant" increase of GH in the blood during the six-hour period after creatine ingestion. However, the study also found "a large interindividual variability in the GH response." That is, there were wide differences among individuals in the levels of GH achieved from taking the creatine. For the majority of subjects the maximum GH concentration occurred between two and six hours after ingesting the creatine.

The researchers concluded "In resting conditions and at high dosages creatine enhances GH secretion, mimicking the response of strong exercise which also stimulates GH secretion." These researchers felt that the effects of creatine on GH could be viewed as one of creatine's anabolic properties with the lean mass and strength increases observed after creatine supplementation. Although creatine supplementation has been found to increase lean muscle mass and strength in many studies, the effects of creatine on those tissues via GH enhancement has yet to be elucidated.

What is creatine?

Creatine is formed in the human body from the amino acids methionine, glycine and arginine. The average person's body contains approximately 120 grams of creatine stored as creatine phosphate. Certain foods such as beef, herring and salmon, are fairly high in creatine. However, a person would have to eat pounds of these foods daily to equal what can be obtained in one teaspoon of powdered creatine.

Creatine is directly related to adenosine triphosphate (ATP). ATP is formed in the powerhouses of the cell, the mitochondria. ATP is often referred to as the "universal energy molecule" used by every cell in our bodies. An increase in oxidative stress coupled with a cell's inability to produce essential energy molecules such as ATP, is a hallmark of the aging cell and is found in many disease states. Key factors in maintaining health are the ability to: (a) prevent mitochondrial damage to DNA caused by reactive oxygen species (ROS) and (b) prevent the decline in ATP synthesis, which reduces whole body ATP levels. It would appear that maintaining antioxidant status (in particular intra-cellular glutathione) and ATP levels are essential in fighting the aging process.

It is interesting to note that many of the most promising anti-aging nutrients such as CoQ10, NAD, acetyl-l-carnitine and lipoic acid are all taken to maintain the ability of the mitochondria to produce high energy compounds such as ATP and reduce oxidative stress. The ability of a cell to do work is directly related to its ATP status and the health of the mitochondria. Heart tissue, neurons in the brain and other highly active tissues are very sensitive to this system. Even small changes in ATP can have profound effects on the tissues' ability to function properly. Of all the nutritional supplements available to us currently, creatine appears to be the most effective for maintaining or raising ATP levels.

How does creatine work?

In a nutshell, creatine works to help generate energy. When ATP loses a phosphate molecule and becomes adenosine diphosphate (ADP), it must be converted back to ATP to produce energy. Creatine is stored in the human body as creatine phosphate (CP) also called phosphocreatine. When ATP is depleted, it can be recharged by CP. That is, CP donates a phosphate molecule to the ADP, making it ATP again. An increased pool of CP means faster and greater recharging of ATP, which means more work can be performed. This is why creatine has been so successful for athletes. For short-duration explosive sports, such as sprinting, weight lifting and other anaerobic endeavors, ATP is the energy system used.

To date, research has shown that ingesting creatine can increase the total body pool of CP which leads to greater generation of energy for anaerobic forms of exercise, such as weight training and sprinting. Other effects of creatine may be increases in protein synthesis and increased cell hydration.

Creatine has had spotty results in affecting performance in endurance sports such as swimming, rowing and long distance running, with some studies showing no positive effects on performance in endurance athletes. Whether or not the failure of creatine to improve performance in endurance athletes was due to the nature of the sport or the design of the studies is still being debated.

Creatine can be found in the form of creatine monohydrate, creatine citrate, creatine phosphate, creatine-magnesium chelate and even liquid versions. However, the vast majority of research to date showing creatine to have positive effects on pathologies, muscle mass and performance used the monohydrate form. Creatine monohydrate is over 90% absorbable. What follows is a review of some of the more interesting and promising research studies with creatine.

Creatine and neuromuscular diseases

One of the most promising areas of research with creatine is its effect on neuromuscular diseases such as MD. One study looked at the safety and efficacy of creatine monohydrate in various types of muscular dystrophies using a double blind, crossover trial. Thirty-six patients (12 patients with facioscapulohumeral dystrophy, 10 patients with Becker dystrophy, eight patients with Duchenne dystrophy and six patients with sarcoglycan-deficient limb girdle muscular dystrophy) were randomized to receive creatine or placebo for eight weeks. The researchers found there was a "mild but significant improvement" in muscle strength in all groups. The study also found a general improvement in the patients' daily-life activities as demonstrated by improved scores in the Medical Research Council scales and the Neuromuscular Symptom scale. Creatine was well tolerated throughout the study period, according to the researchers.1

Another group of researchers fed creatine monohydrate to people with neuromuscular disease at 10 grams per day for five days, then reduced the dose to 5 grams per day for five days. The first study used 81 people and was followed by a single-blinded study of 21 people. In both studies, body weight, handgrip, dorsiflexion and knee extensor strength were measured before and after treatment. The researchers found "Creatine administration increased all measured indices in both studies." Short-term creatine monohydrate increased high-intensity strength significantly in patients with neuromuscular disease.2 There have also been many clinical observations by physicians that creatine improves the strength, functionality and symptomology of people with various diseases of the neuromuscular system.

Creatine and neurological protection/brain injury

If there is one place creatine really shines, it's in protecting the brain from various forms of neurological injury and stress. A growing number of studies have found that creatine can protect the brain from neurotoxic agents, certain forms of injury and other insults. Several in vitro studies found that neurons exposed to either glutamate or beta-amyloid (both highly toxic to neurons and involved in various neurological diseases) were protected when exposed to creatine.3 The researchers hypothesized that "… cells supplemented with the precursor creatine make more phosphocreatine (PCr) and create larger energy reserves with consequent neuroprotection against stressors."

More recent studies, in vitro and in vivo in animals, have found creatine to be highly neuroprotective against other neurotoxic agents such as N-methyl-D-aspartate (NMDA) and malonate.4 Another study found that feeding rats creatine helped protect them against tetrahydropyridine (MPTP), which produces parkinsonism in animals through impaired energy production. The results were impressive enough for these researchers to conclude, "These results further implicate metabolic dysfunction in MPTP neurotoxicity and suggest a novel therapeutic approach, which may have applicability in Parkinson's disease."5 Other studies have found creatine protected neurons from ischemic (low oxygen) damage as is often seen after strokes or injuries.6

Yet more studies have found creatine may play a therapeutic and or protective role in Huntington's disease7, 8 as well as ALS (amyotrophic lateral sclerosis).9 This study found that "… oral administration of creatine produced a dose-dependent improvement in motor performance and extended survival in G93A transgenic mice, and it protected mice from loss of both motor neurons and substantia nigra neurons at 120 days of age. Creatine administration protected G93A transgenic mice from increases in biochemical indices of oxidative damage. Therefore, creatine administration may be a new therapeutic strategy for ALS." Amazingly, this is only the tip of the iceberg showing creatine may have therapeutic uses for a wide range of neurological disease as well as injuries to the brain. One researcher who has looked at the effects of creatine commented, "This food supplement may provide clues to the mechanisms responsible for neuronal loss after traumatic brain injury and may find use as a neuroprotective agent against acute and delayed neurodegenerative processes."

Creatine and heart function

Because it is known that heart cells are dependent on adequate levels of ATP to function properly, and that cardiac creatine levels are depressed in chronic heart failure, researchers have looked at supplemental creatine to improve heart function and overall symptomology in certain forms of heart disease. It is well known that people suffering from chronic heart failure have limited endurance, strength and tire easily, which greatly limits their ability to function in everyday life. Using a double blind, placebo-controlled design, 17 patients aged 43 to 70 years with an ejection fraction <40 were supplemented with 20 grams of creatine daily for 10 days. Before and after creatine supplementation, the researchers looked at:

1) Ejection fraction of the heart (blood present in the ventricle at the end of diastole and expelled during the contraction of the heart)
2) 1-legged knee extensor (which tests strength)
3) Exercise performance on the cycle ergometer (which tests endurance)

Biopsies were also taken from muscle to determine if there was an increase in energy-producing compounds (i.e., creatine and creatine phosphate). Interestingly, but not surprisingly, the ejection fraction at rest and during the exercise phase did not increase. However, the biopsies revealed a considerable increase in tissue levels of creatine and creatine phosphate in the patients getting the supplemental creatine. More importantly, patients getting the creatine had increases in strength and peak torque (21%, P < 0.05) and endurance (10%, P < 0.05). Both peak torque and 1-legged performance increased linearly with increased skeletal muscle phosphocreatine (P < 0.05). After just one week of creatine supplementation, the researchers concluded: "Supplementation to patients with chronic heart failure did not increase ejection fraction but increased skeletal muscle energy-rich phosphagens and performance as regards both strength and endurance. This new therapeutic approach merits further attention."10

Another study looked at the effects of creatine supplementation on endurance and muscle metabolism in people with congestive heart failure.11 In particular the researchers looked at levels of ammonia and lactate, two important indicators of muscle performance under stress. Lactate and ammonia levels rise as intensity increases during exercise and higher levels are associated with fatigue. High-level athletes have lower levels of lactate and ammonia during a given exercise than non-athletes, as the athletes' metabolism is better at dealing with these metabolites of exertion, allowing them to perform better. This study found that patients with congestive heart failure given 20 grams of creatine per day had greater strength and endurance (measured as handgrip exercise at 25%, 50% and 75% of maximum voluntary contraction or until exhaustion) and had lower levels of lactate and ammonia than the placebo group. This shows that creatine supplementation in chronic heart failure augments skeletal muscle endurance and attenuates the abnormal skeletal muscle metabolic response to exercise.

It is important to note that the whole-body lack of essential high energy compounds (e.g. ATP, creatine, creatine phosphate, etc.) in people with chronic congestive heart failure is not a matter of simple malnutrition, but appears to be a metabolic derangement in skeletal muscle and other tissues.12 Supplementing with high energy precursors such as creatine monohydrate appears to be a highly effective, low cost approach to helping these patients live more functional lives, and perhaps extend their life spans.


Creatine may reduce homocysteine levels

Homocysteine has been recognized as an important independent risk factor of heart disease, more so than cholesterol levels according to some studies. Creatine biosynthesis has been postulated as a major effector of homocysteine concentrations,2 and oral creatine supplements may reduce levels of homocysteine. Many studies have found that methyl donors (such as trimethylglycine (TMG) reduce levels of homocysteine, which also reduces the risk of heart disease. Conversely, pathways that demand large amounts of methyl groups may hinder the body's ability to reduce homocysteine levels. The methylation of guanidinoacetate to form creatine consumes more methyl groups than all other methylation reactions combined in the human body.

Researchers have postulated that increasing or decreasing methyl demands on the body may increase or decrease homocysteine levels. In one study researchers fed rats either guanidinoacetate- or creatine-supplemented diets for two weeks.3 According to the researchers "plasma homocysteine was significantly increased (~50%) in rats maintained on guanidinoacetate-supplemented diets, whereas rats maintained on creatine-supplemented diets exhibited a significantly lower (~25%) plasma homocysteine level." These results suggest that homocysteine metabolism is sensitive to methylation demand imposed by physiological substrates such as creatine.

Creatine and chronic fatigue/fibromyalgia

Because of creatine's apparent abilities to improve the symptoms of other pathologies involving a lack of high energy compounds (e.g., congestive heart failure, etc.) as well as the aforementioned afflictions outlined in the introduction to this article, it has been suggested that creatine may help with chronic fatigue syndrome and fibromyalgia (some researchers now posit that they are in fact the same syndrome). Although the causes of both pathologies is still being debated, a lack of high energy compounds (e.g. ATP) at the level of the mitochondria and general muscle weakness exists. For example, people with fibromyalgia have lower levels of creatine phosphate and ATP levels compared to controls.4 No direct studies exist at this time showing creatine supplementation improves the symptomology of either chronic fatigue or fibromyalgia.

Considering, however, the other data that finds that creatine supplementation increases creatine and ATP levels consistently in other pathologies where low levels of creatine and ATP are found, it stands to reason that people suffering from either syndrome may want to peruse the use of creatine. Another similar syndrome to chronic fatigue and fibromyalgia, is Multiple Chemical Sensitivity Syndrome, which may also be potentially improved by the use of creatine supplements, though more research is clearly needed.

Creatine safety issues: fact or fiction?

After the first article in Life Extension magazine on the many potential medical and anti-aging uses of creatine, I received several letters and many e-mails that basically said "I would like to use creatine for the various reasons stated in the article, but I am worried about its safety." This fear over the safety of creatine was usually generated from some hysterical news report or poorly researched article. It's odd, but predictable that the media and conservative medical establishment have desperately tried to paint creatine as an inherently dangerous or "poorly researched" dietary supplement. The fact is, creatine may be the most extensively researched performance-enhancing supplement of all time, with a somewhat astounding safety record.

True to form, the "don't confuse us with the facts" media and anti-supplement conservative medical groups have had no problems ignoring the extensive safety data on creatine, or simply inventing safety worries where none exists. A perfect example of this was the news report that mentioned the deaths of three high school wrestlers who died after putting on rubber suits and riding a stationary bike in a sauna to lose weight. Amazingly, their deaths were linked to creatine by the media, rather than extreme dehydration! Even more amazingly, on further examination, it was found that two of the three wrestlers were not using creatine!

Creatine has been blamed for all sorts of effects, from muscle cramps to dehydration, to increased injuries in athletes. However, these effects have been looked at extensively by researchers without a single study reporting side effects among several groups taking creatine for various medical reasons over five years.5-8

In some, but not all people, creatine can raise a metabolic byproduct of creatine metabolism known as creatinine. Some people-including some medical professionals who should know better-have mistakenly stated that elevated levels of creatinine could damage the kidneys. Elevated creatinine is often a blood indicator, not a cause, of kidney dysfunction.

That's a very important distinction, and several short- and long-term studies have found creatine supplements have no ill effects on the kidney function of healthy people.9,10 Though it makes sense that people with pre-existing kidney dysfunction should avoid creatine supplements, it is reassuring to know that creatine supplements were found to have no ill effects on the kidney function of animals with pre-existing kidney failure, showing just how non toxic creatine appears to be for the kidneys.11 Bottom line, creatine safety has been extensively researched and is far safer than most over-the-counter (OTC) products, including aspirin.

Conclusion

Though additional research is warranted regarding the pathologies outlined in this article, creatine has a substantial body of research showing it is an effective, safe and worthwhile supplement in a wide range of pathologies and may be the next big find in anti-aging nutrients. Although the dose used in the studies was quite high, recent studies suggest lower doses are just as effective for increasing the overall creatine phosphate pool in the body. The dose of 2 to 3 grams per day appears adequate for healthy people to increase their tissue levels of creatine phosphate.

People with the pathologies mentioned in this article may benefit from higher intakes in the 5 to 10 gram per day range. People interested in more information regarding creatine, in particular the use of creatine and other supplements for athletes, should consider referring to my recent ebook Muscle Building Nutrition found at www.bodybuildingrevealed.com for additional information

Creatine is quickly becoming one of the most well researched and promising supplements for a wide range of diseases. It may have additional uses for pathologies where a lack of high energy compounds and general muscle weakness exist, such as fibromyalgia. People with fibromyalgia have lower levels of creatine phosphate and ATP levels compared to controls.13 Some studies also suggest it helps with the strength and endurance of healthy but aging people as well. Though additional research is needed, there is a substantial body of research showing creatine is an effective and safe supplement for a wide range of pathologies and may be the next big find in anti-aging nutrients. Although the doses used in some studies were quite high, recent studies suggest lower doses are just as effective for increasing the overall creatine phosphate pool in the body. Two to three grams per day appears adequate for healthy people to increase their tissue levels of creatine phosphate. People with the aforementioned pathologies may benefit from higher intakes, in the 5-to-10 grams per day range.

Will Brink is a columnist, contributing consultant, and writer for various health/fitness, medical, and bodybuilding publications. His articles relating to nutrition, supplements, weight loss, exercise and medicine can be found in such publications as Lets Live, Muscle Media 2000, MuscleMag International, The Life Extension Magazine, Muscle n Fitness, Inside Karate, Exercise For Men Only, Body International, Power, Oxygen, Penthouse, Women's World and The Townsend Letter For Doctors.

He is the author of Priming The Anabolic Environment and Weight Loss Nutrients Revealed. He is the Consulting Sports Nutrition Editor and a monthly columnist for Physical magazine and an Editor at Large for Power magazine. Will graduated from Harvard University with a concentration in the natural sciences, and is a consultant to major supplement, dairy, and pharmaceutical companies.

He has been co author of several studies relating to sports nutrition and health found in peer reviewed academic journals, as well as having commentary published in JAMA. He runs the highly popular web site BrinkZone.com which is strategically positioned to fulfill the needs and interests of people with diverse backgrounds and knowledge.

The BrinkZone site has a following with many sports nutrition enthusiasts, athletes, fitness professionals, scientists, medical doctors, nutritionists, and interested lay people. William has been invited to lecture on the benefits of weight training and nutrition at conventions and symposiums around the U.S. and Canada, and has appeared on numerous radio and television programs.

William has also worked with athletes ranging from professional bodybuilders, golfers, fitness contestants, to police and military personnel.

See Will's ebooks online here:

Brink's Bodybuilding Revealed
"Bodybuilding Revealed is a complete blue print to muscle building success. Everything you need to know about diet & muscle building nutrition, over 50 bodybuilding supplements reviewed, weight training routines, high intensity cardio, the mental edge, pre made muscle building diets and an online private members forum, diet planner, meal planner and much more. It's all in Will Brink's ultimate guide to gaining muscle mass."

Fat Loss Revealed
"Fat Loss Revealed is the ultimate fat loss manual. A complete online and offline system used by anybody looking to attain a fantastic lean physique. A complete fat loss diet plan, with pre made diets, over 40+ fat loss supplement reviews, resistance workouts, and cardio , along with motivation and goal setting and a huge online private members area and forum form Will Brink's Ultimate Fat loss Program."