© Whole Foods Magazine February 2006

Sports Nutrition - Creatinephobia: Part 2

The use of creatine for heart, brain and muscle enhancement is safe.

An interview with Anthony L. Almada, M.Sc.

By Richard A. Passwater, Ph. D.

We have been chatting with Anthony Almada about the effectiveness and safety of creatine. Last month, we discussed Anthony’s extensive background with creatine and oxidative phosphorylation, the process the body uses to produce the energy needed for “life.” We also covered aspects of Anthony’s career and the results of his studies. Now we will focus more on how creatine is best used to improve heart and brain health as well the strengthening of muscle to improve sports performance. We will also further discuss creatine supplementation and safety as well as address a few of the misunderstandings about creatine and performance.

Anthony L. Almada (M.Sc.) is a scientist and a sports supplements pioneer. He performed his undergraduate training (B.S.) in physiology and nutritional biochemistry at the University of California, Irvine and California State University, Long Beach. He then performed his graduate (M.Sc.) research at the University of California, Berkeley, exploring the impact of exercise upon tissue antioxidant status and kinetics, including vitamins C and E, coenzyme Q and glutathione.

In 1992 Anthony co-founded Experimental and Applied Sciences (EAS), which I believe is the largest sports nutrition company on a global scale. During his tenure as chief scientific officer and president, he developed a university research program that completed over 15 clinical studies in the first three years of the company’s history, and also yielded two patents. Abbott Laboratories bought EAS in 2004 to broaden its Columbus, OH-based Ross Products nutrition business beyond the infant formula Similac and nutritional bars and drinks, such as Ensure and Glucerna. In July 2005, EAS obtained a seal of approval from the National Football League and began reaching out to other sports leagues trying to ensure their players remain free of banned substances. EAS products are used by all 32 NFL teams and more than 1,000 players.

Later, Anthony co-founded a medical food company and, working with university researchers, developed a clinically validated product to help prevent HIV wasting. He then created IMAGINutrition, Inc., an innovation and science marketing think tank focusing on nutritional technologies, IP clinical research validation and science-driven media campaigns. He has collaborated on over 50 university clinical trials, ranging from AIDS/HIV and ALS to zinc metabolism in osteoarthritis.

Passwater: Word reached the public of the success of several Olympic athletes using creatine as part of the dietary and exercise program to improve their strength and performance. Creatine became popular with many world-class athletes, but unfortunately, several athletes then turned to overdosing with anabolic (metabolism
that builds) steroid drugs to achieve even greater strength. Anabolic steroids are a class of natural and synthetic steroid hormones that promote the growth of muscle tissue and sometimes bone. Testosterone is the best known natural anabolic steroid, as well as the best known natural androgen.

These anabolic steroids were certainly effective in building muscles, but they are associated with deadly consequences when used at the extremely high dosages sometimes used by athletes striving for “super” results. They were not developed for this use. They were designed to help overcome or avoid muscle wasting in sick individuals.

Such reported side effects associated with the use of high-dose anabolic steroids include the suppression of endogenous sex hormones, impaired production of sperm, and the metabolism of the original steroid to other compounds which also cross-react with estrogen receptors, producing accelerated bone maturation in the young and breast growth in males.

Other reported side effects of anabolic steroid drugs include elevated blood pressure and cholesterol levels, acne, premature baldness, reduced sexual function, and testicular atrophy. In females, anabolic steroids have a masculinizing effect, resulting in more body hair, a deeper voice, smaller breasts, masculinized or enlarged clitoris, and fewer menstrual cycles. Several of these effects are irreversible. In adolescents, abuse of these agents may prematurely stop the lengthening of bones (premature epiphyseal fusion through increased estrogen, resulting in stunted growth. Serious health problems can result from extreme hormone use. Heart enlargement is a risk which increases the chance of an adverse cardiac event occurring in later life. Another health risk is long-term liver damage, particularly if the anabolic steroid compound is 17-alpha-alkylated in order to not be destroyed by the digestive system when taken orally.

For some reason, many people, including sports writers, began confusing anabolic drugs and creatine. Creatine is not a drug nor a stimulant, but a simple nutrient found in foods and also made in our bodies.


Almada: As you mentioned earlier, creatine can be loosely classified as an amino acid, but it is not an amino acid that is incorporated into proteins. In this manner, creatine has similarity with carnitine and taurine. Creatine’s main function is to store energy for muscles to use to work. Creatine’s formal chemical name is methyl guanidinoacetic acid. Organs such as the liver, kidneys and pancreas can combine the amino acids arginine, methionine and glycine to form creatine, which is then circulated in the blood. The body can also obtain creatine from the diet. Meat and fish are good sources of creatine.

About 95% to 98% of the creatine in the body is stored in skeletal muscles, with the remainder found in heart, brain and testes. When the body doesn’t get enough creatine, just as with carnitine, a number of medical problems or degenerative conditions can follow. So there is a semi-essential or even essential role for creatine in human metabolism. That confers a very different status than something that your body does not make. This suggests that if your body is making something, it may have a wider range of safety and less toxic effect than something your body does not make, for example vitamin B-6.


Passwater: You mention creatine being essential. What would a creatine deficiency involve?


Almada: When you look at creatine deficiency syndrome, especially among infants that cannot make creatine, you discover a number of neurological problems, for example, seizures and/or reduced muscular abilities.

Yet, when you supplement these individuals at dosages double the adult loading dose that athletes use—up to 400 mg per kg of body weight—and sustain that for a period of several years, (now up to 10 years) based on studies done in Germany and Switzerland, you find that the only side effect that has been reported is the appearance of creatine crystals in the urine. There are no other negative or adverse effects, and a number of effects that are positive, such as improvement in their neurological abilities, and sometimes reductions in their number of seizures.

Given this, you have to wonder, if creatine is being given in very large doses to infants and children, and there are no toxic side effects in the age range where there would be the highest risk and concern for toxicity, then creatine must indeed be a safe nutrient. But, for some reason, that literature (which has been published in The Lancet, the number two medical journal in the world) is almost always overlooked.

This is especially frustrating when people who are non-experts and non-researchers, but happen to have “M.D.” after their names, start pontificating about how bad creatine is, how it can cause kidney damage, and that there are no studies attesting to its safety. This reflects absolute ignorance and arrogance! I would say that it is not that members of the media are uneducated, it is that they are sensationalists and they avoid or turn away from evidence that would poke a hole in their story.

What really bothers me is that even when you give them the information, they never seem to print a correction or change their attitude. If they do print a correction it is buried at the bottom of page 24 in the newspaper, not on the front page of the section it first appeared in.

Passwater: What is the basis of their concern? Are there instances where there appears to be a safety problem?

Almada: There are a couple of case histories where creatine users have reported problems. One bodybuilder “madman” was consuming over 100 grams per day. In another instance, a person with a history of kidney disease appeared to demonstrate a reduction in kidney function. And a young athlete developed an acute kidney condition, and then a kidney stone, associated with taking creatine at two separate times.

Very few cases show adverse effects, yet many more placebo-controlled and observational or retrospective studies, for up to several years, have shown no adverse effects. You never know what other “things” people are taking in a case report of an adverse effect.

There is no categorical evidence that creatine is unsafe, toxic or causes kidney damage or even causes cramping in muscles. The long-term studies show this is either incorrect or the opposite. I reference the long-term study with Dr. Rick Kreider that we discussed earlier. In this study, the side effects in the placebo group not taking creatine were higher than the creatine-supplemented group. How come these publications in the peer-reviewed scientific literature are overlooked or ignored?

In addition to our own studies, such as that under the leadership of Dr. Kreider, creatine supplementation in healthy individuals has been shownto be safe by Robinson et al. (Dietary creatine supplementation does not affect some haematological indices, or indices of muscle damage and hepatic and renal function. Br J Sports Med. 2000 Aug;34(4):284-8.) and Mayhew et al. (Effects of long-term creatine supplementation on liver and kidney functions in American college football players. Int J Sport Nutr Exerc Metab. 2002 Dec;12(4):453-60.)


Passwater: Interesting question. In that article, I believe you looked at the incidence of muscle cramping in the football players and found no relation to creatine use. I often hear sports commentators referring to creatine cramping, but when I look at the athletes they are referring to as having cramps, they are usually speed athletes who do not use creatine as opposed to the strength athletes who often do use creatine. In your study at Memphis University, the athletes were properly trained in how to take their supplements. Does creatine supplementation require more fluid intake and can the improper use of creatine cause cramping?

Almada: This is a question that has not been adequately addressed. Dr. Paul Greenhaff has some limited data showing changes in urine output. We and others have conducted numerous studies and not shown water retention
and research shows that creatine doesn’t impair heat regulation during exercise.  I would advocate that each creatine dose be taken with 6-8 ounces of some fluid—juice, water, even coffee or tea (as it was done in the first few studies). In relation to improper use causing cramping, it would appear that the primary cause of cramping among athletes is inadequate or improper hydration, whether they are taking creatine or not. Most sports coaches and trainers are grossly underinformed in relation to performance nutrition, or they simply don’t implement what they have been taught.

Our Memphis study showed no association between creatine and cramping. It seems as if the media has a double standard. They ignore gold-standard clinical trials that compare creatine to placebo and prefer to seek after health professionals with no expertise in the field for their “opinion,” and then confuse opinion with fact. This is not fair and balanced reporting, but it sells papers and magazines. Even the “unbiased” Consumer Reports magazine is guilty of this.


Passwater: What about the incorrect “knock” that creatine merely increases water retention in the muscles? Water retention certainly doesn’t improve one’s strength, and increased strength is the normal result of creatine supplementation and exercise.


Almada: A majority of studies conclude that creatine supplementation increases both total and fat-free body mass. Since large body mass gains of about 1-2 kg can occur in a week's time, some have interpreted this as being simply due to greater water retention inside the muscle cells. However, long-term studies indicate that the body mass gains cannot be explained by increases in intracellular water alone. These studies show that the increase in total body water is proportional to the weight gain and thus the percentage of total body water is not significantly changed. The magnitude of the weight gains during training over a period of several weeks argue against the water-retention theory.

It is possible that an initial increase in intracellular water increases osmotic pressure (the equilibrating force that drives the diffusion of fluid through a semi-permeable membrane from a solution with a low solute concentration to a solution with a higher solute concentration until there is an equal concentration of fluid on both sides of the membrane), which in turn stimulates muscle protein and/or glycogen (the stored form of carbohydrate) synthesis. A few studies have reported changes in the nitrogen balance during creatine supplementation, suggesting that creatine increases protein synthesis and/or decreases protein breakdown.

Some in vitro studies show that creatine supplementation increases the activity of myogenic cells. According to the researchers, these cells, sometimes called satellite cells, are myogenic stem cells that make additional growth of skeletal muscle possible. These stem cells are simply generic or non-specific cells that have the ability to transform themselves into new muscle cells when they are instructed to. The researchers suggest that following proliferation (reproduction) and subsequent differentiation (to become a specific type of cell), these satellite cells fuse with one another or with the adjacent damaged muscle fiber, thereby increasing myonuclei (the DNA ‘control’ centers of cells) numbers necessary for fiber growth and repair. The study, published in the International Journal of Sports Medicine was able to show that creatine supplementation increased the number of myonuclei donated from satellite cells. This increases the potential for growth of those fibers. This increase in myonuclei probably stems from creatine's ability to increase levels of the myogenic transcription factor MRF4 (Hespel, 2001).

Since creatine may allow athletes to train harder and recover faster, the enhanced training stimulus may promote greater muscle mass in the long term. Ultimately, the increase in muscle mass is probably attributable to a combination of all these factors: greater water retention inside the muscle cells, increase in protein synthesis and/or decrease in protein breakdown, increased muscle glycogen, and greater training stimulus.

Passwater: You began your studies working with ALS patients, then through an involved chain of events moved on to studying creatine’s role in building muscles. Many people believe that creatine supplements are only for the development of big muscles for athletes. Creatine is involved in energy production even in brain neurons that use a comparatively high amount of energy. Is creatine being studied or used in disorders such as ALS or even Alzheimer’s Disease?

Almada: This is a very keen and dear area of interest to me. I have given a number of presentations over the past few years where I discuss creatine beyond its use as a muscle-building agent. Creatine is a muscle-response and energy-response modifier. After selling EAS, we created a medical foods company, where we took our creatine-based technology and applied this to HIV patients. We did two clinical trials and found that creatine not only produced favorable body composition improvements but also seemed to produce favorable changes in immune cell profiles. So that was our first foray into disease applications of creatine.

There is a palette of diseases that have responded or may respond to creatine supplementation. There are various metabolic syndromes, diabetes, various neurodegenerative diseases such as ALS, Parkinson’s disease and maybe even Alzheimer’s disease (which is being explored at this time). Some recent studies have shown creatine may help improve muscle strength and fat-free mass in persons with Chronic Obstructive Pulmonary Disease (COPD). (Creatine supplementation during pulmonary rehabilitation in chronic obstructive pulmonary disease. J P Fuld, L P Kilduff, J A Neder, Y Pitsiladis, M E J Lean, S A Ward, M M Cotton. Thorax 2005;60:531–537.

The animal studies with ALS models are striking. Some groups have been looking at the role of creatine in the geriatric population. There are studies over the past three or four years looking at cognitive function in the young and old. There are some very interesting studies—one of which was published just a couple of months or so ago—exploring the role of creatine on skin biology in helping to enhance or repair damaged skin cells by improving energy production within skin cells after they have been exposed to the UV radiation. The list goes on and on. Unfortunately, creatine has been typecast—just as a horror films actor can be—and it is tough to break out of that mold. Someday, and hopefully soon, creatine may be better known for its role in general health than in athletic performance, and be embraced both by the medical community and by the consumers or patients.


Passwater: Your experience with ATP and creatine has been mostly with brain disorders and athletic performance; what about creatine and heart function?


Almada: Samuel Bessman, a researcher at the University of Southern California with whom I met in 1993, had done some pioneering work with creatine, which included examining its impact on heart function in animal models. The Russians have been using injections of creatine phosphate in cardiac patients, for decades, with very encouraging results (Creatine phosphate is an injectable drug in several EU countries.) I’m aware of one controlled clinical trial among patients with congestive heart failure (the same type of cardiac condition that has shown to improve with another energy-response modifier, CoQ-10. Oral creatine monohydrate supplementation improved their exercise endurance performance, but not their heart’s pumping ability. (Gordon A, Hultman E, Kaijser L, Krisjansson S, Rolf CJ, Nyquist O, Silver C. Creatine supplementation in chronic heart failure increases skeletal muscle creatine phosphate and muscle performance. Cardiovascular Research 30 (3): 413-418 SEP 1995.) I think a cocktail of creatine, CoQ-10, and L-Carnitine warrants investigation in a placebo-controlled trial in heart patients.


Passwater: Are there people who should not use creatine?

Almada: If a person has a history of kidney disease including renal failure, to me, it would be better to err on the side of conservatism and take creatine only under medical supervision so that the kidney function could be evaluated. This doesn’t mean that creatine causes kidney function impairment, but I would rather be conservative than liberal in this context. To me, that is the only time one should not take creatine.

Passwater: Can creatine be taken improperly?

Almada: Proper hydration is essential, but improper hydration is self-limiting. Taking too high a dose improperly would lead to an acute bout of gastrointestinal distress. That would cause you to be confined to a bathroom for a while. Then the person would realize that he took too much or decide never to take it again. As we discussed before, it may be prudent to take creatine with a fluid.

However, there are studies in which 20 grams of creatine were taken at once as a single dose and there was no gastrointestinal distress or diarrhea. (Acute creatine ingestion in human: consequences on serum creatine and creatinine concentrations. Jean-Marc Schedel, Hiroaki Tanaka, Akira Kiyonaga, Munehiro Shindo, Yves Schutz, Life Sciences Vol. 65, No. 23, pp. 2443-2410,1999.

I think creatine is best taken with a meal. When you look at the scientific literature in totality, that’s what the evidence suggests. Meals raise the insulin level in the blood, which can improve creatine uptake into the muscle cells, and meals reduce the chance of gastrointestinal distress. If one doesn’t take the creatine with meals, then IT should BE TAKEN mixed in warm water or a warm beverage. This enhances the solubility of the creatine in the gut and dilutes it, enabling more creatine to be absorbed rather than passing further into the intestine to cause gastric distress due to an osmotic diarrheal effect.

Passwater: Can athletes achieve improved performance without having to “load” with creatine. If the objective is to have more creatine enter muscle cells, does this have to be done with massive doses or can the muscles build up their creatine supply gradually over a longer period using smaller doses?


Almada: That’s a question that is both incisive and enduring. It is important to understand why that question arises. There is always the goal of achieving the highest effectiveness at the lowest dosage. Scientists have devoted quite a bit of time to studying this relationship.

We have done studies that look at both changes in creatine levels within the muscles and also improvements in athletic performance. You can achieve the same elevation in muscle creatine content with three grams of creatine a day over a month as you can with 20 grams of creatine a day over five days. This would suggest that you would also achieve the same functional improvement. However, that is not necessarily the case.

When you look at studies that compare both high- and low-levels of supplementation, and then look at the physiological effects, on a whole-body scale, the high-dose loading for the high-dose sustained (for up to eight weeks) gives the greater magnitude of consumer-relevant effects than the long-term low-dose supplementation.

Everything in the literature suggests that the low-dose approach does not achieve the same “real world” results as the high-dose approach. People do not take creatine to increase their muscle levels of creatine. They take creatine to get stronger and/or bigger. The evidence points to high-dose sustained supplementation of about 20 grams a day, to get maximum results.

Passwater: Well Anthony, once again I thank you for sharing your extensive knowledge of creatine with us. Your consultation was important in writing my 1997 book on creatine, and it is important to our readers now. WF


© 2006 Whole Foods Magazine and Richard A. Passwater, Ph.D.

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