Everything You Ever Wanted To Know About Creatine
02-07-2003 11:21 PM
Creatine and Side Effects
This is clearly the most frequently asked question about creatine. Understandably, the risks associated with the use of creatine monohydrate concerns many. Numerous side effects have been attributed to creatine use. Some of these side effects have been substantiated in the scientific literature while other side effects have not. Most of the side effects associated with creatine have to do with its propensity to draw water into body compartments where it is located, namely the intestine and skeletal muscle. As a result dehydration is a real concern while supplementing with creatine. Drink at least 1 ounces of water per pound of bodyweight while taking creatine.
Is creatine safe for women, children, the pregnant or the elderly?
Whether creatine is safe for children (preadolescents) is our secondly most frequently asked question. Naturally, what are creatine's side effects is the first. Since the long-term consequences of creatine supplementation are not well understood, it is best to avoid supplementation during childhood. Furthermore, a recent panel of creatine experts has concluded that creatine may be less effective children.
Interestingly, this same panel of experts also suggested that creatine may be less effective in the elderly (greater than 70 years of age). Changes in muscle fiber composition (or mass) may underlie any difference in creatine-sensitivity in the elderly.
The vast majority of creatine studies have been conducted on males between the ages of 18 and 35 years old. Nevertheless, a couple of studies have also demonstrated enhanced exercise performance in women supplementing with creatine, which actually makes sense since creatine's basic mechanism of action wouldn't be expected to differ in women. Nevertheless, differences do exist in how creatine benefits men and women.
Since it is not known whether creatine levels increase in breast milk following supplementation, creatine use should be avoided in nursing women.
Weight gain is the most commonly reported creatine side effect. As much as 3 kilograms (6.6 pounds) of increased weight within the first few weeks has been reported in response to creatine use. This is due mainly to the movement of water from the blood into skeletal muscle. This form of muscle growth has also been termed Volumizing because of the increase in muscle volume that ensues. This side effect may be beneficial in certain sports such as, body building, but be less desirable in other sports such as, distance running or other endurance sports. Also see dehydration.
It's imperative to remain well-hydrated while taking creatine. This concern is valid since much of our body water follows creatine into skeletal muscle, possibly depriving our remaining tissues of fluid. As a consequence urine output often decreases during creatine supplementation. Down the road this may lead to impaired thermoregulation and subsequent heat exhaustion, especially if training heavily in hot environments. This precaution is especially important in combative sports (in particular, wrestling) where athletes strive to make weight before competition. Weight loss under these circumstances is often achieved through fluid restriction which, in combination with creatine use, could lead to excessive dehydration.
Reports of gastrointestinal distress, stomach cramps, nausea and diarrhea have also been attributed to creatine use, especially when taken in large doses. These side effects are most likely due to undissolved creatine drawing water into the intestine and can often be circumvented by completely dissolving creatine in at least 16 ounces of water or juice. The large amounts of sugars often taken with creatine may also complicate gastric emptying. These side effects are rarely observed when taking smaller doses of creatine.
Muscle strains, cramps and tears:
There have been reports of muscle pulls, strains and cramps following creatine use. These injuries may be related to an electrolyte imbalance as a result of dehydration. Drink plenty of fluids while taking creatine!
There is also some concern that creatine supplementation may place undue stress on the liver and kidneys. These concerns are most valid when creatine is taken is large quantities. For example, during the loading phase. Under these conditions the kidneys would have to work harder to clear unabsorbed creatine from the blood stream; there is much more creatine in the urine of person's consuming large amounts of creatine. Persons with pre-existing kidney disorders should probably abstain from creatine use.
There was some concern that the fluid retention as a result of creatine use could increase a person's blood pressure. This issue was recently a topic of a scientific study that found that blood pressure did not increase following 5 days of creatine use.
Cholesterol and Protein Synthesis:
Creatine may have some positive side effects. For example, creatine may improve our cholesterol levels independently of its effect on exercise. In addition, volumizing may in itself stimulate the production of new muscle proteins. Both these effects, however, need to be further substantiated by additional scientific research.
There are many misconceptions and rumors surrounding creatine use. Most of these stem from creatine being wrongly associated with hormonal means of increasing muscle mass. These unsubstantiated side effects include breast formation in men, a reduction in penis size, hair loss in men, hair growth in women and stunted growth in children. Unexplained incidences of aggression and acne have also been linked to creatine use. Furthermore, some of these unexplained side effects may arise from other agents taken with, or in addition to, creatine. To reiterate, creatine increases exercise performance at the level of muscle energetics. Creatine does not substantially alter hormone levels to induce muscle growth, such as is the case with anabolic steroids.
Long term consequences of creatine use?
Since it is a realtively recent practice very little is known of the long term consequences of creatine use. However, some of its alleged side effects may have long term ramifications, especially at the elevated doses typically prescribed for athletics. For example, the time required for transporter function to fullly recover after prolonged exposure to elevated creatine levels is simply not known for humans. This is why creatine we do not advise creatine use for children or pregnant women (see ABOVE).
There are, however, clinical situations for which low doses of creatine have been used over a period of years with no signs of adverse side effects. For example, Gyrate Atrophy is a disease of the eye (retina) that is characterized by progressive narrowing of the visual fields. A secondary component of the disease is a deficiency in creatine synthesis. Consequently, this disease is also characterized by a reduction in the size of fast muscle fibers (see Question #5). Creatine supplementation has been shown to alleviate the muscular symptoms associated with this disease although the visual symptoms persist. Of interest to us; other than mild weight gain, low doses of creatine (1.5 grams/day) when administered for the duration of a year produced no obvious adverse effects.
Does creatine cause cancer?
There has recently been alot of talk about the possible risk of creatine causing cancer. The concern arises from the fact that certain cancer causing agents (AIAs) are produced when meat is cooked at high temperatures. The production of these cancer causing agents correlates with the initial creatine (and creatinine) content of the meat; meats with higher creatine content produce more of these cancer causing agents when cooked. It has thus been hypothesized that by increasing our muscle creatine content, we also increase our chances of getting cancer. It remains, however, to be clearly demonstrated that these same cancer causing agents are produced within the animal under physiological conditions. In other words, in an animal that isn't cooked this effect of creatine may not be manifested.
Finally, since creatine increases the growth rate of some types of tumor cells, it has been suggested that creatine may increase our chances of getting cancer. However, other experiments shows no effect of creatine on tumor cells. Whether creatine has a similar effect on normal cells is still an open issue.
Is it true that creatine might help those with Muscular Dystrophy?
Creatine has been used in clinical trials for several classes of Muscular Dystrophy. Our muscles can become weakened as a result of injury or disease. This is the case for several forms of Muscular Dystrophy. Although creatine would not be expected to cure Muscular Dystrophy, creatine supplementation may improve the quality of life of persons experiencing muscle weakness as a result of these diseases. In fact, preliminary studies have indicated that creatine supplementation improves strength in those inflicted with certain forms of Muscular Dystrophy as well as other Neuromuscular disorders. For more information see the Muscular Dystrophy Association's "Answers to frequently asked questions about creatine".
VIII. CREATINE SIDE EFFECTS: An interview with Professor Jacques R. Poortmans
Dr. Jacques Poortmans of the Free University of Brussels in Belgium is one of the world's foremost creatine experts. His articles examining the consequences of creatine supplementation have appeared in many of the premier sport medicine journals. For this issue of the Creatine Newsletter I was fortunate to be able to interview Dr. Poortmans. I’m sure you’ll find it as enlightening as I did.
NSN: A common concern is that creatine supplementation places undue stress on renal function. Is there any truth to this?
JRP: No, as long as renal functions are normal before any creatine supplementation. We, and others, have given published evidences that in healthy individuals short-term, medium-term and long-term oral creatine monohydrate supplements are safe for the kidney. Of course, one has to be certain that the product is PURE (by analysis) since there are, apparently, many commercial products which do not satisfy the quality imposed by the FDA.
NSN: It is known that creatine absorption by our muscles decreases dramatically after a week of loading and that afterwards most of the ingested creatine is cleared from the body by the kidneys. Given this information, is there harm any in extending the loading phase past one week?
JRP: No, if one respects the loading doses: about 20 grams per day for 5 days and thereafter a 2-3 gram doses per day. One has to know that about 60% of the ingested doses are not taken up by the muscles and are cleared into the urine. What a waste of money!
NSN: What effect does creatine monohydrate have on liver function?
JRP: None. Again, we and others did not observe any impairment of liver tests after oral creatine supplements in healthy subjects (men and women).
NSN: Who should avoid creatine use? Diabetics who are predisposed to renal complications, for example?
JRP: Certainly those patients as well as anyone suffering from ANY kidney impairment. Heavy creatine supplements still remain an extra load on the renal filtration process.
NSN: Is taking creatine with protein a mistake?
JRP: Recent investigations by us and another research team did not observe a difference between creatine alone or creatine protein as far as muscle composition is concerned. What seems important is to provide enough daily protein intake (about 1.2-1.3 g/kg body weight, no more) to sustain protein synthesis.
NSN: I often get asked about secondary sexual side-effects associated with creatine use. As far as you know is there any basis for this concern?
JRP: There is no reason to believe that there is a relationship between creatine and sexual behavior (or capability). But, as usual, it might be of some help for those who sentimentally believe in anything. However, as said before, be careful with the purity of the product. We know that some commercials add anabolic steroids to creatine. This conduct cannot be tolerated. Excess anabolic steroid substances can have negative effects on sex and general health care.
02-07-2003 11:22 PM
Another Creatine and Fat Loss
Obviously, creatine finds its way into skeletal muscle after being ingested. But, how is this process actually accomplished?
From the blood stream creatine is transported into skeletal muscle via the action of transporter molecules distributed along the muscle surface. These are the molecular doors that allow creatine into muscle cells. Our physiological status determines how well these molecular doors work at letting in creatine. For example, the amount of sodium outside the muscle cell, the extramuscular sodium, regulates the activity of these transporter molecules. In this respect, an elevation of extramuscular sodium promotes creatine entry via these transporters.
Based on earlier studies showing that caffeine increases extramuscular sodium, it was proposed that caffeine should augment creatine transport into muscle cells and accentuate the benefits of creatine. Oddly, however, caffeine has the opposite effect than initially expected. Caffeine actually interferes with the enhancement of physical performance afforded by creatine. A possible explanation for this paradoxical finding is the topic of this month's newsletter.
A recent study specifically looked at the consequences of caffeine consumption on the physical benefit normally afforded by creatine supplementation. The study consisted of a cross over design, which simply means that the subjects were divided into either experimental (caffeine and creatine) or control (creatine alone) groups, tested after a week, switched of conditions and then retested.
Nine males participated in the study. Their ages ranged between 20 and 23 years. Initially both groups were given 0.5 grams of creatine/kilogram of body weight for six days. This amount is slightly greater than the typically prescribed loading dose. In addition, the experimental group was also given 0.005 grams of caffeine per kilogram of body weight on days 4, 5 and 6. Therefore, for the last three days of supplementation the experimental group consumed both creatine and caffeine. On the seventh day their physical performance was tested using knee extension torque measurements. This is one entire day after the last dose caffeine.
After a washout period of 3 weeks the groups were switched, such that the experimentals (caffeine and creatine) became controls (creatine alone) and visa versa. The experiment was repeated. In this respect the effect of caffeine could be compared within each individual.
Caffeine consumption negated the physical benefit observed in the creatine group. Surprisingly, the effect of caffeine was observed one entire day after the last dose. This finding was at first paradoxical, because caffeine, at least initially, was proposed to increased creatine absorption into skeletal muscle via its effect on extramuscular sodium.
The amount of caffeine used in this study is equivalent to 2-3 strong cups of coffee for an average sized male, or 350 mg of caffeine for a 70 kilogram (154 pound) male. One important detail might be that caffeine was administered in the form of capsules.
Interestingly, caffeine did not interfere with the rise in muscular phosphocreatine associated with creatine loading. Remember that phosphocreatine is the biologically active form of creatine found within cells. In other words, caffeine neither decreased (nor increased, as expected) creatine transport at the muscle surface. Its inhibitory effect was felt after creatine had entered and formed phophocreatine.
A Possible Resolution
Coordinated movement is the result of opposing muscle groups contracting and relaxing in unison. For example, when performing a curl our biceps (front of arm) contract into a ball, whereas our triceps (back of arm) relax and lengthen. On the downward movement, the triceps contract and the biceps relax.
Another example is sprinting. A sprinter initiates a stride by contracting the front muscles and relaxing the back muscles of one leg. To move forward, however, he must then quickly relax the front muscles and contract the back muscles of that leg, so that his other leg can shoot forward. Therefore, muscle relaxation is part of coordinated movement and thus speed.
Calcium is what causes muscles to either contract or relax. A muscle contracts when calcium is released from storage sites deep inside the muscle. In other words, free calcium is the signal that tells a muscle to contract. Likewise, our muscles relax when calcium is reabsorbed into these internal storage sites. However, the restorage of calcium is an energetically expensive process and in this manner muscle relaxation cost us energy. The energy that pays for muscle relaxation comes from phosphocreatine!
Dr. Hepel's group in Belgium has elegantly shown that phosphocreatine levels determine muscle relaxation rate. When our muscle phosphocreatine levels are high, as a result of supplementation, our muscles relax more rapidly. Conversely, when our phosphocreatine stores are low, muscle relaxation is slowed and our exercise performance drops.
Although caffeine doesn't alter phosphocreatine levels, caffeine may nevertheless retard muscle relaxation by altering muscle calcium levels. Interestingly, caffeine is known to release calcium form internal stores. As outlined previously, this would slow muscle relaxation and jeopardize exercise performance, despite caffeine's know stimulatory properties. Therefore, caffeine may negate creatine's benefit by liberating internal calcium and thereby slowing muscle relaxation time.
Caffeine is a diuretic, meaning that it increases the excretion of water from the body in the urine. There are rumors that caffeine counteracts creatine by interfering with muscle volumizing. This is simply a false rumor and assumes that water retention by skeletal muscle is the source of strength. Although increasing the girth (volume) of our muscles, volumizing per se has no proven effect on strength. This was the topic of a recent newsletter. View it here.
If you pump up on caffeine prior to working out, while at the same time supplementing with creatine monohydrate to increase exercise performance, you could be wasting your time and money. Avoid this practice!
However, it must be mentioned that not all studies demonstrate an inhibitory effect of caffeine on the benefits afforded by creatine and may be a result of how creatine was administered, ie whether in liquid or tablet form.
IV. CREATINE AND FAT
It is common knowledge that creatine causes weight gain. The reason for this gain in weight seems to involve several distinct processes. Early phases of body mass increase involve the retention of water into skeletal muscle. Later phase of mass increase may involve the accretion of new muscle proteins.
Early Stages of Muscle Growth: Water Weight
Creatine monohydrate causes water to be retained in the body compartments where it is located. For this reason our muscles swell (with water) following creatine use. This process has been termed muscle "volumizing" in the scientific literature. This is a relatively fast process and can account for as much as 1-3 kilograms (~2-7 pounds) of added water weight after just a few days of loading. This increase in weight is much too fast to be attributed to the addition of new muscle proteins. Finally, since the faster we pack in creatine, the faster we'll gain water weight, muscle volumizing will be most pronounced during the loading phase.
After about a month of stopping creatine our muscle creatine stores return to normal and so should our body weight. In other words, we'll lose muscle water as our creatine levels return to their previously low values.
We'll also notice a drop in our energy levels. This is because creatine enhances our physical performance by increasing the amount of energy available to our muscles.
Later Stages of Muscle Growth: New Protein Production
There is some indication that the acquisition of new muscle proteins also increases following creatine supplementation. This effect might be related to the greater work capacity afforded by creatine. In other words, we'll build more muscle since we'll be able to train harder.
Alternatively, muscle volumizing itself might stimulate the production of new muscle proteins. In this instance muscle swelling might falsely signal to the cell that it is growing. The muscle cell might then respond by increasing the production of new muscle proteins. The likelihood of this later possibility is currently being debated in the scientific press.
Any increase in muscle proteins as a result of prolonged creatine use should persist after stopping supplementation. These gains, however, will be relatively small in comparison to the initial rise in body weight attributed to water retention.
Lean Muscle Mass
The combined effects of increased muscle hydration and stimulated protein synthesis will increase our amount of lean muscle. In other words, the amount of protein and water contained within our muscles will increase relative to fat. You might have heard this fact being boosted in the popular press.
Fat is Fat and Muscle is Muscle and Never the Twain Shall Meet
It has often been rumored that a person's muscle turns to fat after stopping creatine. There is no more truth in this happening than there is in an apple turning into a banana? They are simply two different entities. Nevertheless, muscle can be replaced by fat given the wrong set of circumstances.
As mentioned above, after stopping creatine you'll lose some size due to loss of muscle water. You'll also experience a drop in energy level because of the slow degradation of surplus creatine stored within our muscles; remember that creatine is an energy source.
There's only one way you'll gain fat. That is if you reduce your energy expenditure dramatically, or stop working our altogether, while not adjusting your caloric intake. Under these circumstances the excess amounts of calories (food) you consume will be stored as fat.
You will lose some size and strength after stopping creatine. This is unavoidable. The lost size, however, results from loss of water and not muscle tissue. The decrease in energy results from less creatine in our muscles. The only way that you will gain fat is if you consume more calories than you burn after stopping creatine.
Therefore, after stopping creatine for a prolonged period, be sure to maintain your exercise intensity, or alternatively, reduce caloric intake.
02-07-2003 11:22 PM
Creatine and Injury Recovery
Mature skeletal muscle is produced from the union of progenitor cells known as myoblasts. These myoblasts lie dormant waiting for the appropriate environmental cue to stimulate them to fuse. One of the most potent of such environmental cues is the loss of muscle tissue arising from inactivity or disease. To summarize, lost or damaged muscle is replaced by new muscle formed from the fusion of thousands of myoblasts.
The loss of muscle tissue because of inactivity or disease is known clinically as disuse atrophy. Anyone who has had a broken limb can testify to this effect. After weeks in a cast the immobilized limb is noticeably smaller and weaker than its unrestrained counterpart. In this instance inactivity resulted in muscle tissue actually being reabsorbed by the body. When the limb again becomes active the body replaces this lost muscle tissue through a process known as myogenesis.
Although muscle loss induces the process of regeneration, the actual triggering signal is a biochemical messenger. These biochemical messengers, also known as myogenic factors, were the focus of a recent study involving creatine.
This study examined the effect of creatine supplementation on the recuperation of muscle function following leg immobilization. Twenty-two college-aged subjects participated in the study. All subjects had their right leg immobilized in a cast for a period of two weeks. Ten weeks of rehabilitation therapy followed the two weeks of cast immobilization.
Throughout the entire study half of the subjects took creatine while the other half took placebo (maltodextrin). During the two weeks of immobilization the subjects supplemented their daily diets with 20 grams of either creatine monohydrate or placebo. During the rehabilitation period the creatine/placebo dose was reduced. For the initial three weeks of rehabilitation the subjects consumed 15 grams of creatine/placebo per day. Thereafter, the creatine dose was reduced to only 5 grams of creatine/placebo for the remaining seven weeks of rehabilitation.
Cross-sectional area of the quadriceps muscle (upper leg), leg extension power and myogenic factor expression were compared in the two groups.
This study demonstrated that leg cross-sectional area and strength recovered more rapidly in those individuals who had supplemented with creatine.
Most importantly, myogenic factor expression was greater for the creatine group during the rehabilitation phase of the study. In particular, one myogenic factor, MRF4 (Myogenic Regulatory Factor 4), correlated strongly with the increase in leg cross-sectional area. It would thus appear that MRF4 is responsible for the muscle regeneration observed in this study. Interestingly, MRF4 exerts its greatest effect over those muscle fibers most sensitive to creatine supplementation; the fast muscle fibers.
This study concluded that creatine supplementation stimulates muscle growth and recovery through the production of myogenic factors, in particular one known as MRF4. The authors of the study openly state that "creatine supplementation is capable of shortening the duration of rehabilitation needed to restore muscle mass following an episode of disuse atrophy".
This study suggests that creatine increases the expression of myogenic factors that induce muscles growth.
02-07-2003 11:23 PM
Creatine and GH
CREATINE AND GROWTH HORMONE
Since creatine increases our exercise capacity, and exercise increases hormone release, it is expected that creatine should also indirectly increase the amounts of anabolic hormones produced while exercising. Indeed, one recent study has possibly demonstrated this predicted effect. Surprisingly, however, in this study Growth Hormone release was observed in non-exercising subjects after ingesting creatine. In other words, just taking creatine was sufficient to increase Growth Hormone production.
The Study: Six males were given a breakfast of 20 grams of creatine monohydrate dissolved in a half-liter of hot water. They were then told to limit their activity (but not fall asleep!) for the rest of the morning. For six hours their blood was monitored at intervals for the presence of creatine and Growth Hormone. As expected, blood creatine levels rose within minutes of taking creatine monohydrate. Blood Growth Hormone levels, on the other hand, required about 2 hours before rising. This lag indicates that the release of Growth Hormone depends on other cellular events occurring first. Growth Hormone increased on average ~80% over baseline values. Albeit provocative, this finding needs to be viewed with caution until corroborated by other studies.
What are the implications of this study?
This study suggests that creatine may have an anabolic property independent from its ability to increase exercise intensity. This result may also explain why some studies have shown that muscle cells raised in "tissue culture" (out side of the animal in plastic dishes) increase their production of muscle proteins when exposed to creatine. As were the subjects in the previously mentioned study, these muscle cells were inactive due to their growth conditions.
Another unexplained observation is why creatine appears to be less effective in the elderly. This situation may be partially explained by the decline in Growth Hormone levels in the aged. In other words, part of the benefit of creatine might be absent in elderly persons with less Growth Hormone. Time will tell if these assumptions are right. We'll just have to wait.
Problems with the Study
Firstly, since these experiments were conducted on a relatively young (~23 years of age) and healthy set of subjects, it is not known whether these findings also apply to the elderly and ill.
Secondly, the sample size was small (six) and the individual responses to creatine varied widely. Three showed strong increases in Growth Hormone levels, two had moderate to low increases in Growth Hormone, and one showed no increase. This variability in Growth Hormone release is somewhat reminiscent of the situation of nonresponders to creatine. In fact, the authors of the study postulated that such differences in Growth Hormone release might underlie creatine-nonresponsiveness.
Finally, the amount of creatine used in the study was comparable to a typical loading dose - taken all at once! This practice is not recommended to the general product.
1. Are other anabolic hormones similarly influenced by creatine?
In this study it was not determined whether other anabolic hormones, such as testosterone or insulin, similarly increase with creatine use.
2. What about Insulin-Like Growth Factor?
Many of the effects of Growth Hormone are mediated by Insulin-Like Growth Factor 1 (IGF-1), which the liver produces when stimulated by Growth Hormone. Interestingly, IGF-1 has also been shown to enhance creatine uptake into isolated muscle cells. Could this work in a feed-forward manner? In other words, does IGF-1-induced creatine uptake, further enhance Growth Hormone release.
3. What is the cellular signal that triggers Growth Hormone release?
Growth Hormone levels increase a few hours after creatine levels do. The biologically active form of creatine is phosphocreatine, creatine to which a phosphate group has been attached. Could phosphocreatine be the signal that triggers the release of creatine from the Anterior Pituitary in our brains?
Creatine enhances exercise performance in most young and healthy individuals. Since exercise induces the release of anabolic hormones, creatine supplementation should also, in theory, indirectly increase the release of Testosterone, Insulin and Growth Hormone during exercise. This study suggests that creatine by itself (in the absence of exercise) may suffice to trigger the release Growth Hormone by the body. This finding is intriguing and might explain the previously unexplained increase in protein synthesis in isolated muscle cells not undergoing activity. Furthermore, if Growth Hormone mediates part of the effect of creatine supplementation, then this study might also explain why creatine supplementation is often less efficacious in the elderly, which have reduced Growth Hormone levels. In conclusion, this study suggests that creatine supplementation may have anabolic properties independent of its effect on energy metabolism. Future scientific investigation will tell if this finding is valid
02-08-2003 04:07 PM
Why you should cycle Creatine
by Bryan Haycock MS
As we approach the new millennium we find the science of building muscle progressing faster than ever before. Long gone are the days of simple trial and error when it comes to building muscle. The modern bodybuilder demands more than just "hear say" if they are to adopt a new training routine or nutritional supplement. This column was created to keep today’s bodybuilder on the cutting edge of scientific research that might benefit them in their quest for body perfection.
Are you cycling your creatine? Find out why you may want to.
Creatine supplementation in health and disease. Effects of chronic creatine ingestion in vivo: down-regulation of the expression of creatine transporter isoforms in skeletal muscle.
Guerrero-Ontiveros ML, Wallimann T.
Institute for Cell Biology, Swiss Federal Institute of Technology, ETH-Honggerberg, Zurich.
Mol Cell Biochem 1998 Jul;184(1-2):427-37
These researchers studied the in vivo effect of dietary creatine as well as 3-GPA (a creatine analog that is a competitive inhibitor of creatine entry) on the expression of the creatine transporter (creatine T). Long term feeding of rats with 3-GPA has been previously shown to decrease creatine levels in skeletal muscles without effecting creatine T expression. In this study, the expression of the creatine T was examined in rats chronically fed either 4% creatine or 2.5% GPA. Dietary creatine administered for 3-6 months, significantly lowered the expression of creatine T polypeptides. The rats fed the creatine analog GPA showed virtually no change (perhaps even a slight increase) in creatine T polypeptide expression.
The wide spread use of creatine among athletes and bodybuilders has raised concerns about possible negative side effects. Of course most of the nay sayers are looking to control its availability with little real concern for the well being of those who use it. This study has answered a question that has rested on the minds of many, which is, "Is there any reason to cycle creatine?" From the study above we see that the abundance and activity of the creatine transporter is negatively effected by long term creatine ingestion. The creatine transporter is down regulated with continued exposure to extracellular creatine.
Human skeletal muscle has an upper limit of creatine that can, or will, be contained within the cell. This limit is around 150-160 mmol/kg of dry muscle. As the intracellular concentration of creatine approaches this level, the synthesis of creatine transporters declines and even stops depending on the amount of creatine ingested over time. In the study above, it was shown that the creatine transporter is regulated by the content of creatine in the cell rather than by the interaction of creatine, or it’s analog 3-GPA, with the transporter.
All the arguments about creatine absorption being a limiting factor in creatine content within the cell are bogus. Creatine does not need to be "micronized" or "effervesent" to lead to an increase in creatine content within your muscles. The activity of the creatine transporter is the limiting factor. Any trick increase in creatine absorption will only hasten creatine transporter down regulation. It only requires about 5 grams per day for 30 days to increase the content of creatine within muscle tissue to the same extent as 30 grams per day for 6 days. The sooner you reach the upper limit the sooner your muscles become unable to take up creatine. It is better to maintain sufficient levels of creatine transporters in order not to cause a rapid decline in creatine content once creatine supplementation is discontinued. Clearly there appears to be good reason to cycle creatine supplementation.
The authors of this study recommend not using creatine for over 3 months at a time. To truly cycle creatine you will have to take at least 4 weeks off. Creatine levels take at least one month to return to pre-supplement levels. It may be important to take the entire month off because one speculated mechanism of creatine transporter downregulation is that when the intracellular levels (levels inside the muscle cell) are increased the creatine transporters are taken down and not replaced as long as creatine levels remain elevated. Thus it might take as long as a month for creatine transporters to return to normal after chronic creatine supplementation. Keep in mind that no one has actually shown that long-term supplementation with creatine is a bad thing.
02-08-2003 04:08 PM
Creatine and Testosterone By Huck Finn
Hey fellas.Just dug up an interesting read out of one of my old Ironman mags.The following excerpts are providided by the notorious Michael Gundill(a.k.a. Dharkam)....Although creatine does have testosterone-like effects,it doesn't act as a steroid hormone.Instead,it's a mediator of some of the androgens' anabolic effects.In fact,steroid users get far more out of their cycles if they take in massive amounts of creatine along with the drugs.Androgens are among the hormones that can force the entry of creatine into muscle cells.While there's a clear relationship between muscle strength gains and increases in muscle creatine stores,unfortunately,the relationship is not as obvious when it comes to increases in muscle mass.Animal-based studies have shown that the muscles of untrained rats take up as much creatine as the muscles of trained rats,but the ANABOLIC effects of creatine are only obvious in trained rats.Therefore,training increases the muscles sensitivity to the anabolic actions of creatine.(Although it's not related to this article,the study also demonstrated that the anabolic effects of creatine are DIRECT,and not mediated by waterretention.In fact,in the 1970s American and Russian studies pointed out a DIRECT anabolic effect of creatine on muscle cells.)Testosterone increases the muscles'sensitivity to the anabolic properties of creatine in addition to enhancing the creatine buildup in muscle fibers.It's also obvious that part of the strength gains people experience while on steroids are mediated by an increase in muscle creatine stores.An interesting discovery A/S users have made is that they should dramatically increase their creatine intake during a cycle to boost the potency of the steroids.Thanks to creatine,people can build more muscle mass with fewer drugs.Anecdotal evidence from A/S users points out that it takes at least 10-15 grams(maintenance)of creatine a day to visibly enhance the the anabolic potency of a steroid stack.There are probably good reasons for the increased creatine requirement when androgen levels are high.As mentioned above,steroids increase the muscle uptake of creatine,and if the muscles are ready to accept more creatine,why not give it to them?I also think that even though steroids enhance creatine synthesis,they may increase creatine degradation as well-so more creatine is used up every day.That could be due to an increase in muscle creatine turnover and also the fact that an elevated muscle protein synthesis rate will likely consume creatine at a faster rate.Other reasons for a higher creatine requirement may be indirect.Because the muscles of drug users are stronger and receive more training,they may waste greater amounts of creatine during training.Once inside the muscle,creatine provides not only an anabolic effect,but also a rapidly mobilized source of fuel.Muscle protein synthesis is a process that wastes great amounts of energy.Anabolism is an ATP-dependent process,which means that it's essential for protein synthesis.If the cellular level of ATP is reduced even a little,IT STOPS ANABOLISM.So even if you can increase the testosterone content of your muscles,nothing will happen if your ATP level is low.Creatine supports anabolism by providing energy to the muscle...Well fellas,it looks like it might be a good idea to stock up on creatine when you're grabbing your protein powder for those bulking cycles,hehheh....Huck
02-11-2003 02:00 PM
Creatine: More than just a sports nutrition supplement
*you'll need adobe acrobat to read it, which can be picked up for free at adobe.com*
02-12-2003 04:41 PM
Glycocyamine - Is it a Creatine Enhancer???
Glycocyamine – Is it a "Creatine-Enhancer?"
by Paul Cribb, B.H.Sci HMS
AST Director of Research
You many have read about a new compound called glycocyamine in the muscle magazines. Some supplement marketers are selling this product as a creatine enhancer.
What is Glycocyamine?
Glycocyamine is the intermediate step of creatine synthesis in the liver. It is often called guanidinoacetate. The first step in creatine synthesis occurs with the transfer of the amidino group of arginine to glycine to yield ornithine and guanidinoacetate via L-arginine:glycine amidinotransferase.
Because of this, glycocyamine (guanidinoacetate) is often used in medical research as a marker for alterations in creatine metabolism and an indicator of conditions such as arginine-glycine amidinotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT) deficiencies.[2,3]
A reduction of guanidinoacetic acid in body fluids is desired for GAMT deficiency (an inborn error of creatine biosynthesis). These diseases are characterized by creatine depletion and accumulation of guanidinoacetate in the brain.
Glycocyamine as a Supplement.
There are no direct studies on glycocyamine as a performance enhancing supplement or a creatine enhancer. Even more important to athletes, there is no theoretical research that even remotely suggests glycocyamine might enhance muscle growth or the effectiveness of creatine supplementation.
One study has examined the effects of supplementing with glycocyamine and creatine on physiological plasma homocysteine levels in rats. It’s from this research that marketers of glycocyamine supplements seem to be drawing their “science-based” sales pitch on glycocyamine.
A number of studies have confirmed a relationship between an increased plasma concentration of homocysteine and the development of cardiovascular disease. Even a small increase in circulating homocysteine increases coronary artery disease risk by 60% for men and 80% for women. Supplementation with creatine is suspected to decrease homocysteine levels.
Because the methylation of guanidinoacetate to creatine via consumes more S-adenosylmethionine than all other methylation reactions combined, the researchers behind the rat study hypothesized that guanidinoacetate and creatine supplementation may have opposite effects on homocysteine levels. Results showed they did. Creatine supplementation was shown to decrease liver homocysteine levels, thus substantiating the possibility of creatine as a supplement that may help people avoid cardiovascular disease. However, guanidinoacetate supplementation was shown to increase homocysteine levels. This is not a good thing if you want to reduce your risk of cardiovascular disease.
Would glycocyamine be effective for bodybuilders?
To provide a theoretical answer this question, we must look at glycocyamine’s role in metabolism and the role of creatine supplementation. Firstly, remember that glycocyamine is an intermediate involved in creatine synthesis within the liver. Without the presence of supplementation the body only synthesizes a small amount of creatine (less than 2-grams) per day. However, from the research it is clear that creatine supplementation reduces the body’s need to synthesize creatine, therefore the role of glycocyamine would be virtually eliminated.
Secondly, compare this to regular doses that bodybuilders supplement (5-20-grams per day). Glycocyamine has no biochemical role what so ever in creatine supplementation and accumulation in muscle. Therefore you can start to understand why glycocyamine would be fairly useless supplement for bodybuilders.
Finally, as muscle cells cannot manufacture creatine, any attempt to increase muscle glycocyamine content via supplementation in an effort to help increase creatine stores would obviously be useless. Also, creatine relies on a highly selective cell transporter, I can’t see how a non-insulin-stimulating compound like glycocyamine could enhance creatine uptake in muscle.
The bottom line . . .
Guanidinoacetate/glycocyamine’s role in the small amount of creatine synthesized by the body has nothing to do with creatine supplementation. Promoting glycocyamine as a supplement that enhances the effects of creatine supplementation is completely without practical or theoretical biological evidence.
While at present there is zero research on guanidinoacetate/glycocyamine’s effect on muscle growth or creatine supplementation, from a theoretical perspective, as I have shown you, I can’t see how glycocyamine supplementation would enhance the effectiveness of creatine supplementation.
It’s becoming commonplace in the supplement industry for marketers to select a little known obscure metabolite from biochemistry (it doesn't matter if the compound is completely irrelevant to bodybuilding), and hype it as a new “magic muscle building catalyst”. This seems to occur because supplement marketers are all too aware that bodybuilders are demanding science-based products.
The problem with this unscrupulous marketing approach is that it’s very difficult for anyone without a biochemistry major to decipher the “science” behind these bogus products (even then, most acedemics still can’t see through the smoke screen). What you can do as a consumer is ask to be provided with the full reports on the research cited. Ask for the clear facts and don’t be intimidated or impressed by scientific marketing spin.
From a research and theoretically-based perspective, the suggestion that glycocyamine is a creatine-enhancing supplement is at present, completely unfounded.
1. Allain, P, LeBouil A, Cordillet E, LeQuay L, Bagheri H, and Montastruc JL. Sulfate and cysteine levels in the plasma of patients with Parkinson's Disease. Neurotoxicol 16: 527–530, 1995.
2. Carducci C, Birarelli M, Leuzzi V, Carducci C, Battini R, Cioni G, Antonozzi I Clin Chem 2002 Oct;48(10):1772-8. Guanidinoacetate and creatine plus creatinine assessment in physiologic fluids: an effective diagnostic tool for the biochemical diagnosis of arginine:glycine amidinotransferase and guanidinoacetate methyltransferase deficiencies. Clin Chem 2002 Oct; 48(10):1772–8.
3. Al Banchaabouchi M, Marescau B, Van Marck E, D'hooge R, De Deyn PP. Long-term effect of partial nephrectomy on biological parameters, kidney histology, and guanidino compound levels in mice. Metabolism 2001 Dec; 50(12):1418-25.
4. Schulze A, Ebinger F, Rating D, Mayatepek E. Improving treatment of guanidinoacetate methyltransferase deficiency: reduction of guanidinoacetic acid in body fluids by arginine restriction and ornithine supplementation. Mol Genet Metab 2001 Dec;74(4):413-9.
5. Lori M. Stead, Keegan P. Au, René L. Jacobs, Margaret E. Brosnan, and John T. Brosnan. Methylation demand and homocysteine metabolism: effects of dietary provision of creatine and guanidinoacetate. Am J Physiol Endocrinol Metab 281: E1095–E1100, 2001
6. Refsum, H, Ueland PM, Nygård O, and Vollset SE. Homocysteine and cardiovascular disease. Annu Rev Med 49: 31-62, 1998.
7. M. F. McCarty. Supplemental creatine may decrease serum homocysteine and abolish the homocysteine `gender gap' by suppressing endogenous creatine synthesis. Med Hypotheses. Jan; 56(1): 5-7,2001.
02-12-2003 05:20 PM
This is also a really interesting article on Creatine. I myself have experienced this side effect before.
02-12-2003 07:51 PM
Very interesting article, deserving of some Karma...
08-13-2003 09:37 AM
Great thread here people, just bumping it for the new members....
02-01-2006 03:18 PM
Bump from the dead!
This post has been an excellent source of creatine information to someone such as myself who is trying get into creatine supplementation but seeking as much education beforehand. So far this has really kept to the well educated or those who are curious and ask questions that are intelligent. I like everything being in a nice neat package here. With so much variable information and opinions floating around, as well as just the sheer mass of posts it makes it hard for someone to find anything. Its like a needle in a haystack. Could someone compare/contrast the differences, advantages, and disadvantages between the different variations of creatines available? (I.E. Monohydrate, CEE, etc)
02-01-2006 10:15 PM
Yeah that would be nice to see. There are so many different kinds out there now and it's hard to keep them all straight.
02-02-2006 10:28 PM
Why was that one guy banned? This info is very useful.
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