Creatine FAQ
version 1.01

by David Tolson
dvdtlsn@bulknutrition.com
www.bulknutrition.com

Summary

Creatine monohydrate is arguably the most effective non-hormonal supplement for increasing muscle mass and improving athletic performance, especially in areas such as weight lifting and other activities characterized by brief bouts of high intensity exercise followed by short rest periods. There are over 100 scientific studies in humans supporting the use of creatine for these purposes. Mechanisms of action include increased ATP regeneration and increased protein synthesis. Creatine is very safe and has few side effects. A dosage of 5 g four times daily for 2-3 days ("loading phase") followed by 5 g once or twice daily for any period of time ("maintenance phase") is recommended. Creatine should optimally be taken with high glycemic carbohydrates and at least one dose should be taken prior to exercise. This FAQ covers many of the aspects of creatine supplementation in-depth.

Contents

Section 1. General Information
1.1: What is creatine?
1.2: How does creatine work?
A. The ATP-PCr system
B. Protein synthesis
C. Muscle relaxation
D. Cellular protection

Section 2. Effects on Body Composition & Athletic Performance
2.1: What evidence is there that creatine increases muscle mass?
2.2: Does creatine also cause fat loss? I've heard it hinders fat loss, is this true?
2.3: What types of exercise has creatine been found to improve?
2.4: What influece does gender, training status, and age have on the effectiveness of creatine supplementation?
2.5: What types of athletes can benefit from creatine supplementation?
Weight lifting
Swimming
Soccer
Cycling
Sprinting
Rowing
Wrestling

Section 3. Safety & Side Effects
3.1: What are the primary side effects associated with creatine?
3.2: I just read a news article describing a bodybuilder that got poisoned by creatine and had to have his legs removed and almost died. Is this a likely occurence?
3.3: Many people say that creatine makes you appear bloated by increasing water retention. Is this true?
3.4: Does creatine cause muscle cramps? Heat exhaustion?
3.5: Can creatine harm the kidneys?
3.6: Is creatinine toxic to the kidneys?
3.7: Can creatine harm the liver?
3.8: Can creatine cause cancer?
3.9: Is there a danger of impurities in creatine products?
3.10: Can teenagers take creatine?
3.11: Can pregnant or nursing mothers take creatine?

Section 4. Dosage & Optimal Use
4.1: What dosage should be used? Is a loading phase necessary?
4.2: How and when should creatine be taken?
4.3: Is it necessary to cycle creatine?
4.4: How bioavailable is creatine?
4.5: I've heard that you should not mix creatine in acidic beverages, because it will destroy the creatine. Is this true?
4.6: What methods can be used to increase creatine uptake?
Exercise
Carbohydrates
4.7: What supplements can be taken to maximize the effects of creatine?
Alpha lipoic acid
HMB
4.8: What other ingredients are commonly found in commercial creatine products?
L-arginine
L-citrulline
Taurine
L-glutamine
Glycocyamine
Guanadinopropionic acid
Magnesium
4.9: Does caffeine negate the effects of creatine?
4.10: What is a creatine non-responder?
4.11: Is there any way for creatine to work in a non-responder?
4.12: What are the different forms of creatine available? Are they better than creatine monohydrate?
Micronized creatine
Anhydrous creatine
Effervescent creatine (dicreatine citrate)
Creatine serum
Buffered creatine (Kre-Alkalyn)
Tricreatine malate
Creatine ethyl ester
4.13: What brands of creatine are recommended?

References

This FAQ may be reproduced as long as it is reproduced in its entirety, including all links.

Section 1. General Information

1.1: What is creatine?

Creatine (also known as alpha-methylguanidinoacetic acid) is perhaps the most popular supplement for improving athletic performance and increasing muscle mass. It also has more scientific support for its use than any other non-hormonal performance enhancing supplement on the market. It is popular among all types of athletes, including amateurs and professionals, teenagers and adults, and men and women.

Creatine, which was first identified in 1832, is an amino acid derivative that occurs naturally in the body. It can be found in the brain, eye, kidney, and testes, but over 95% of the creatine in the body is found in skeletal muscle. It can be obtained through dietary sources and also synthesized within the body from the substrate guanidinoacetate via the enzyme S-adenosyl methionine (SAMe). Guanadinoacetate is derived from the amino acids arginine and glycine. This process primarily occurs in the kidney and liver.

Dietary sources high in creatine include herring, salmon, tuna, beef, and other foods. The combination of dietary creatine and creatine synthesized in the body usually results in the consumption/production of two grams of creatine daily, which is approximately the same rate at which creatine is degraded. Although significant quantities of creatine can be consumed through the diet, the amount is still generally small compared to the intake that can be achieved with supplemental creatine.

Since the early 90's, creatine has been extensively studied for the purpose of improving athletic performance, primarily for high-intensity, short-duration exercise (such as weight lifting and sprinting). There is consistent and overwhelming evidence for a benefit. In addition to research evaluating the effectiveness of creatine in improving athletic performance for a wide variety of types of exercise, research has also begun to evaluate possible benefits in treating muscular, neurological, and cardiovascular diseases.

1.2: How does creatine work?

Research has identified a number of mechanisms involved in creatine's ability to improve athletic performance.

A. The ATP-PCr system

High intensity exercise lasting up to around 2-3 minutes tends to rely on the adenosine triphosphate-phosphocreatine (ATP-PCr) system and anaerobic glycolysis, with the former system being more relied upon during shorter and higher intensity exercises. ATP is the body's primary source of energy, but it is rapidly depleted, forming adenosine diphosphate (ADP).

About 60-70% of the creatine in skeletal muscle is in the form of phosphocreatine (PCr). This is creatine bound to a high energy phosphate, and it is formed by the enzyme creatine kinase. When ATP is utilized for energy and becomes ADP, creatine can donate this phosphate group to the ADP, thus regenerating it back into ATP. By this means, creatine is able to increase the energetic capacity of muscles during high intensity exercise, increasing force output and delaying fatigue.

Although the ATP-PCr system is able to have a significant impact during exercise, PCr quickly becomes depleted. During longer bouts of exercise, energy is primarily derived from glycolysis and fat and carbohydrate oxidation. However, during rest periods, the PCr can be regenerated. Thus, this system is primarily relied upon for very intense bursts of exercise followed by rest periods, such as weight training.

B. Protein synthesis

Creatine may have the ability to increase muscle protein synthesis and/or inhibit protein breakdown, which is supported by the fact that it consistently increases lean body mass in humans. There are multiple mechanisms by which creatine could improve protein balance. The most obvious is that an increase in strength will trigger a greater adaptive response to exercise. A second possible mechanism is that creatine directly serves as a signal for protein synthesis, as it is released following muscle contraction. Also, recent research has indicated the possibility that creatine could increase satellite cell mitotic activity.

It has also been suggested that increasing muscle creatine content leads to an increase in intramuscular water through osmotic action, leading to increased cell hydration, which can stimulate protein synthesis and reduce catabolism. However, whether or not this occurs is still a matter of debate.

Finally, it has been hypothesized that creatine supplementation can increase protein synthesis by downregulating natural creatine production and thus leading to higher levels of the creatine precursor amino acids arginine and glycine, which can then be used for protein synthesis.

C. Muscle relaxation

Creatine loading has been found to shorten muscle relaxation time by about 20% after maximal contraction in humans. It was theorized that shortening muscle relaxation time could improve recovery time after a contraction, thus allowing for quicker recovery. This is possibly because creatine improves the efficiency of the Ca2+-ATPase pump, which regulates muscle relaxation.

D. Cellular protection

The ability of creatine to facilitate membrane stabilization and act as an antioxidant may help in preventing tissue damage during exercise. Maintenance of ATP levels prevents cell damage through multiple mechanisms, and creatine can also act directly as an antioxidant. It is unknown at this time if this plays a role in the performance enhancing effect of creatine.

Section 2. Effects on Body Composition & Athletic Performance

2.1: What evidence is there that creatine increases muscle mass?

A meta-analysis published in 2003 in the International Journal of Sport Nutrition and Exercise Metabolism extensively reviewed the available research on the effect of creatine on body composition and athletic performance. It pooled the results of 100 randomized, blinded, placebo-controlled trials published in peer reviewed journals. About 80% of these studies measured the effects of short-term supplementation only (a single loading phase), while the others measured the effects of loading followed by a maintenance phase. Much of the data in the following sections is derived from this meta-analysis.

According to the meta-analysis, creatine supplementation was associated with an increase in lean body mass from baseline of 1.6% compared to placebo and an increase in total body weight of 0.9% compared to placebo. In a 180 lb. human, this would be a gain of 2.9 lbs. of muscle and 1.6 lbs. of total weight respectively. Since most of the studies consisted solely of a loading phase, this constitutes a significant increase in lean body mass in a short period of time. Studies of longer duration typically find an increase in lean body mass of 4-5 lbs. relative to placebo.

The effect of creatine on muscle fiber size has also been examined in men undergoing resistance training. In one study, 12 weeks of creatine supplementation increased muscle fiber diameter by 35% (relative to 6-15% for placebo). This effect occured in both Type I and Type II muscle fibers.

2.2: Does creatine also cause fat loss? I've heard it hinders fat loss, is this true?

Most studies do not report statistically significant effects of creatine on fat mass, either positive or negative. The meta-analysis discussed above indicated trends toward a decrease in fat mass and body fat percentage in subjects supplemented with creatine. An increase in lean body mass without an accompanying increase in fat mass will inevitably decrease body fat percentage. Thus, it is likely that creatine doesn't directly cause fat loss, but does improve body composition by increasing the ratio of muscle to fat. However, not enough studies have measured these variables for the extent of this effect to be scientifically established.

Some individuals believe that creatine will interfere with fat loss. This is based on a single study that found significant fat loss in the placebo group, but not the group supplementing with creatine. This study had relatively poor methodology, and is also inconsistent with the results when the research is pooled together. When the available research is examined as a whole, it appears that creatine either does not significantly affect or mildly facilitates fat loss.

2.3: What types of exercise has creatine been found to improve?

Creatine is most effective for exercise periods of high or maximal intensity and lasting for 30 seconds or less. Variables on which creatine has caused improvement for exercise of this intensity and duration include 1 rep maximum, repetitions lifted, work accomplished, time, force production, cycle ergometer revolutions per minute, and power. Creatine can also improve performance on exercises that last 30 seconds to 2-3 minutes, but is less effective. A greater effect has also been found when subjects undergo multiple exercise bouts as opposed to single-bout or first-bout exercise. Finally, creatine appears to be more effective in improving performance on upper body exercises as opposed to lower body exercises, although it causes improvement in both.

Whether or not creatine can improve performance on longer lasting exercises is a subject of debate. While some of the research has found a benefit from creatine supplementation for endurance exercise, most has not. Reviews of the topic do not yet recommend creatine supplementation to improve endurance performance. High intensity exercise bouts followed by periods of rest seem to be necessary for creatine to produce significant results, although future research may provide further clarification.

2.4: What influence does gender, training status, and age have on the effectiveness of creatine supplementation?

Other variables measured in the meta-analysis included the effect of gender and training status. Creatine appears to be equally effective in males and females, and also equally effective in trained and untrained subjects, although individual studies have had varying results.

Some studies have measured the effectiveness of creatine supplementation in older individuals (55 or older) with mixed results. The increase in muscle phosphocreatine after supplementation is not as great in older subjects. While creatine does still improve body composition and exercise performance in this population, the effect is probably smaller.

2.5: What types of athletes can benefit from creatine supplementation?

The effects of creatine in many types of athletes has been researched, sometimes in sport-specific activities. Some of the various populations and exercises that have improved after creatine supplementation are listed here.

Weight lifting

Many studies have examined the effects of creatine on resistance training performance, using one rep maximum as the performance measure. A meta-analysis of sixteen placebo-controlled studies on resistance trained males published in 2002 found creatine supplementation to increase one rep maximum for bench press by an average of 15.07 lbs. and one rep maximum for squat by an average of 21.47 lbs. Another review looked at improvements in 1, 3, and 10 rep maximums following creatine supplementation and found an average of an 8% greater increase compared to placebo. The review also found an improvement of weight lifting performance measured by an increase in the number of repititions at a given percentage of maximal strength of 14% relative to placebo.

Swimming

The effect of creatine (.3 g/kg loading followed by 2.25 g maintenance) or placebo on swimming performance on 50 and 100 y sprints was measured in fifteen Division III swimmers. The subjects given creatine had improved performance compared to pre-supplementation on both events. Another study in junior swimmers found no improvement in single sprints from creatine supplementation, but did find an enhancement of swim bench test performance. Multiple other studies have also found creatine to improve swimming performance.

Soccer

A recent study examined the effects of three doses of 10 g creatine daily or placebo in twenty male soccer players over the course of seven days. Performance on a number of soccer-related tests was measured. Creatine improved performance on the dribble test, sprint-power test, and vertical jump test. These tasks rely primarily on the ATP-PCr system. Creatine failed to improve endurance performance in these subjects. The authors concluded that creatine improved soccer-specific skills in young soccer players. Four previous studies have also found impoved performance on similar tests from creatine supplementation in highly trained soccer players.

Cycling

A number of studies have found creatine to improve cycling performance, especially sprint performance followed by short rest periods. Additionally, creatine may even improve endurance cycling performance.

Sprinting

Creatine appears to improve sprint performance, but not to the same degree as most other forms of exercise. While some studies indicate a benefit, others do not. It is possible that the increase in body mass makes a larger difference here.

Rowing

A study examined the effect of creatine (20 g daily) or placebo for five days on exercise tests in elite rowers. It found that creatine increased the exercise time for anaerobic exercise against a constant load in this study population. However, another study did not find an improvement from creatine supplementation in a high intensity rowing and strength program.

Wrestling

In one study, 20 international level wrestlers were given creatine (four doses of 5 g daily) or placebo and underwent Wingate anaerobic tests. There was significant improvement after supplementation with creatine, but not placebo.

Section 3. Safety & Side Effects

3.1: What are the primary side effects associated with creatine?

Creatine is associated with very few side effects and is quite safe. Most reviews on the topic indicate that short-term supplementation has been established to be safe, but there is less data on long term use. The primary side effect is an increase in body weight. People taking creatine have anecdotally reported heat exhaustion, muscle cramping or strains, nausea, vomiting, diarrhea, kidney problems, and stroke. However, the research on creatine, which is quite extensive, has failed to link creatine with any of these problems. These side effects, as well as other reported side effects, will be discussed in further detail in the following sections.

3.2: I just read a news article describing a bodybuilder that got poisoned by creatine and had to have his legs removed and almost died. Is this a likely occurence?

This news article has been posted on many bodybuilding forums, but these side effects are extremely unlikely from creatine alone. As one author (Brudnak M.) notes in Toxicology Letters:

"Negative aspects [of creatine supplementation] have not been so widely reported [in the peer-reviewed literature].... However, negative effects have been reported in magazines and news stories. These often capture large headlines and captivate the audience with their tone. Some of the work has been reported in well-respected journals but it seems the anecdotal reports are the ones that get the most press."

There are a number of problems with this news article. First, it contains a number of factual errors. For example, it states that a month supply of creatine at 5 g daily costs $50.00, when in reality this much creatine can be easily acquired for less than $3.00. The article also describes many questionable medical procedures.

More importantly, nobody has talked to the doctors involved in this case or seen the medical reports. It has also not been reported in the scientific literature. It is all hearsay from a bodybuilder who claims the doctor said his medical problems were because "[his] body wouldn't process it [creatine]." This bodybuilder was also at 2% bodyfat, which is extremely unhealthy. It is likely that his problems were due to use of illegal drugs, his extremely low bodyfat coupled with an intense training regimen, or a combination of those and other factors. This article is no cause for concern, and is a typical example of media sensationalism.

3.3: Many people say that creatine makes you appear bloated by increasing water retention. Is this true?

Whether or not creatine causes water retention is a matter of debate in the scientific literature. Some argue that the rapid increase in body weight is primarily due to increased protein synthesis, while others argue that it is due to increased water weight. The arguments for both sides will be presented here.

Those who argue that the increase in body weight is due to protein synthesis base it on a number of observations. Most importantly, while creatine leads to measurable increases in total body water (TBW), this is proportional to the increase in body weight. This observation is explained by Kilduff et al. in the International Journal of Sport Nutrition and Exercise Metabolism:

"Supplementation with Cr [creatine] in the present study increased body mass, with the mean increase in the responder group greater than the placebo group after loading and maintenance. This increase in body mass cannot be explained by the increase in TBW, reflecting Cr-stimulated water retention, as there was no significant increase in TBW expressed as percentage of body mass. Despite a significant increase in TBW in absolute terms in the Cr group, if the relative volume of TBW remains constant (as in the present study), the gain in body mass need not be attributed to water retention. Instead, the increase in absolute TBW seen after Cr supplementation may be indicative of intracellular water that normally accompanies dry matter growth. Similar results have previously been found and interpreted in the same manner."

There are other arguments in support of protein synthesis being the primary reason for the increase in body weight as well. Many, but not all, studies support the contention that creatine increases protein synthesis. The rapid strength increases associated with creatine supplementation could not be easily explained by increased water retention. In fact, if the increase in weight was primarily due to water, performance on some activities would likely be hindered, and this is not supported by the research.

On the other hand, there are those who argue that creatine increases TBW relative to body weight. Still, those who argue this call this proposal "speculative" (Powers et al). It is argued that the increase in body weight is too rapid to be explained by protein synthesis. It is also argued that this would explain some of the anecdotal (but as of yet uncomfirmed) side effects, such as cramping, heat exhaustion, and so on, as an increase in intracellular water could decrease extracellular water.

However, the research isn't in agreement over whether the increase in body water from creatine supplementation is primarily intracellular or a more generalized increase in water weight with maintenance of normal fluid distribution. If the latter is the case, as supported by one study, there would not be a mechanistic explanation. Few studies have indicated that creatine increases intracellular water retention in humans, and they have all used bioelectric impedance, which is an unreliable measure.

All in all, while there is some evidence that creatine may cause water retention, the presently available research as a whole suggests that the increased water weight is primarily a consequence of tissue growth. It may also be a combination of the two factors.

3.4: Does creatine cause muscle cramps? Heat exhaustion?

Although some creatine studies find a high incidence of muscle strains and cramps and heat exhaustion, double-blind studies do not report these side effects at a higher incidence than placebo. Many who report these side effects do not experience them again when given creatine a second time. The fact is, these side effects are common among athletes in general, but creatine has not yet been linked with an increased link of any of these occurences.

3.5: Can creatine harm the kidneys?

Going by the presently available evidence, the answer is no. One case report describes a bodybuilder who was taking creatine and had kidney failure, but he was taking 200 g a day along with high doses of anabolic steroids. Every study done in humans on the subject, including controlled studies on athletes who have been taking creatine for up to five years, have found no effect on markers of kidney function at all. It is possible that creatine could pose a problem in individuals that already have impaired kidney function.

3.6: Is creatinine toxic to the kidneys?

Creatinine is the primary breakdown product of creatine. It is not toxic to the kidneys at all. Creatinine levels are commonly used as a tool to determine kidney function, as high creatinine levels are commonly a symptom (not a cause) of impaired kidney function.

3.7: Can creatine harm the liver?

In one animal model, high doses of creatine can lead to inflammation of the liver. It is important to note that rodent models are particularly misleading with creatine, since their physiology differs from humans so much in this respect. A retrospective study found no difference in liver enzyme levels in athletes who took creatine for as long as four years relative to controls. Another study measured the effects of creatine loading on liver enzyme levels in nationally competitive athletes and found no significant change. Thus, there is no evidence that creatine is harmful to the human liver.

3.8: Can creatine cause cancer?

It is theoretically possible that creatine could increase the risk of cancer, but very unlikely. Creatine and creatinine are precursors to some known mutagens, especially in the presence of certain pathogenic bacteria (such as E. coli). In healthy individuals, the bacteria capable of doing this are present only in very low numbers. They may also possibly be kept in check with probiotic supplementation. Also, many antioxidants have been found to reduce the carcinogenic effect of the compounds that may be produced.

Although a theoretical mechanism exists, creatine has not been linked with increased cancer risk. In fact, in some animal studies, it inhibited tumor growth. Coupled with the other health benefits of creatine, it is unlikely that this constitutes a significant concern, although it may with lifelong supplementation. Nevertheless, for those who are worried about this, it would be prudent to supplement with probiotics and some basic antioxidants (vitamins C & E, phytonutrients, etc).

3.9: Is there a danger from impurities in creatine products?

A few years ago there was a media scare related to the possible presence of dihydrotriazine in creatine products. It has been pointed out that this information came from a source with bad methodology, and that test results can be easily misrepresented to show the presence of this compound. The majority of creatine comes from a single company, and their creatine has been tested many times and dihydrotriazine has never been found. It is best to get a brand of creatine that carries the Creapure label.

3.10: Can teenagers take creatine?

Most sources do not recommend that teenagers use creatine. However, many studies have examined the effect of creatine on teenagers and failed to find any adverse effects, nor has a mechanism been proposed by which creatine could pose a danger to teenagers. A large percentage of high school athletes use creatine without reports of serious side effects. Even teenagers who do not take creatine supplements get some creatine through their diet. Therefore, while creatine should be safe in teenagers, this question has not yet been subjected to rigorous scientific study.

3.11: Can pregnant or nursing mothers take creatine?

Pregnant or nursing mothers should not take creatine, as the safety is not established in this population.

Section 4. Dosage & Optimal Use

4.1: What dosage should be used? Is a loading phase necessary?

"Loading" refers to the practice of taking larger than normal doses for the first few days of supplementation to maximize muscle creatine stores as quickly as possible. This is followed by a maintenance phase, during which a smaller dose is taken daily to maintain the high levels of creatine.

Loading is not necessary, but it is beneficial. In one study, a maintenance dose (3 g/day) took thirty days to maximize creatine stores. On the other hand, a loading dose (20 g/day) maximized muscle creatine levels in only two days. Normal maintenance doses fall in the 3-5 g range (2 g has been found to be insufficient), although some take as much as 10 g, while 20-30 g (usually 20 g) is used for loading. Some sources recommend a loading phase of 6-7 days, but this appears to be unnecessary. Given that stores are maximized after two days of loading, 2-3 days should be sufficient. One study indicated that resistance training athletes can utilize around 50 mg/kg daily of creatine. A maintenance dose of 5-10 g daily is recommended to ensure that enough is being taken. Taking more than this for maintenance is generally a waste of creatine.

4.2: How and when should creatine be taken?

Creatine usually comes in powder form. Although capsules are available, they are significantly more expensive and most prefer powder. Creatine can be mixed in most drinks. During loading, it is customary to divide the creatine into 3-4 doses spread throughout the day (3 doses of 10 g or 4 doses of 5 g). During maintenance, 1-2 doses daily (usually of 5 g each) are used. Taking one of the doses pre-exercise on exercise days is recommended. Also, if some meals contain more carbohydrates than others, creatine should be taken with the high carbohydrate meals.

Some believe it is best to take creatine throughout the day to maintain elevated blood levels. However, once muscles are saturated with creatine, it takes a long time for muscle creatine levels to return to baseline (30 days). In the big picture, maintaining elevated blood levels around the clock is relatively inconsequential, as muscle creatine levels will be maintained at near-maximum with once daily dosing.

4.3: Is it necessary to cycle creatine?

When exogenous creatine is administered, natural production of creatine is drastically reduced. Creatine transporters also downregulate as creatine stores are maximized. For this reason, some recommend cyclic use of creatine to allow natural production to return to normal. However, there is no evidence that this is necessary. Because supplemental creatine leads to creatine levels much higher than would be produced naturally, there is no reason to try to maintain natural creatine production while trying to take creatine – it will not alter the effectiveness of the creatine. If creatine is taken consistently, muscle creatine levels are maintained at their maximal level, and do not decrease. Some believe that if creatine is taken for too long it could lead to permanent shutdown or a decrease of natural creatine production, but studies have found that natural production is restored very quickly after supplementation discontinues. Therefore, it should be most effective to use creatine on a constant basis.

4.4: How bioavailable is creatine?

The total bioavailability of creatine is unknown. Some creatine is degraded to creatinine in the GI tract, but the amount is probably low (one study estimated about 2%). It is believed that it is actively transported in the intestine by a saturable transporter. As the dosage of creatine increases, the time to maximal concentration and half-life increase. High doses, such as 20 g, cause an increase followed by a plateau in blood creatine levels lasting about six hours before dropping.

The main limiting factor for muscle creatine uptake is the creatine transporter. This transporter is highly selective for creatine. Another naturally occuring compound, beta-guanidinopropionic acid, also competes for the creatine transporter. As levels of creatine in muscle tissue increase, the creatine transporter downregulates. This makes it so muscle tissue can only store a certain limited amount of creatine. Although this amount is not maximized in most individuals not supplementing with creatine, the limiting role of the creatine transporter makes it so creatine supplementation beyond a certain dosage does not yield any additional benefit.

Other than muscle creatine content, there are some other factors that may influence the creatine transporter. These include exercise and the levels of some hormones, such as catecholamines, thyroid hormone, insulin, and insulin-like growth factor 1 (IGF-1).

4.5: I've heard that you should not mix creatine in acidic beverages, because it will destroy the creatine. Is this true?

The short answer is, no. You do not want to mix creatine in an acidic beverage such as orange juice, or any other liquid for that matter, and then store it for a long time before taking it. However, mixing it with any beverage and drinking it soon thereafter is fine.

Those who point out that creatine is unstable in acids fail to point out exactly how unstable it is, as this is a relative measure. The degradation half-life of creatine follows an inverted U along the pH scale, with the bottom estimated to be somewhere around a pH of 4. In acids about the strength of orange juice (pH of 3), creatine still has a degradation half-life of over seven days. In substances that are even more acidic (such as stomach acid), the degradation half-life is actually much longer – for example, it is 55 days at a pH of 1.4. This means that creatine can easily make it through the digestive tract with very little degradation.

4.6: What methods can be used to increase creatine uptake?

Exercise

Exercise is one of the best ways to increase muscle creatine uptake. It has been demonstrated that when one leg is exercised, but not the other, the exercised leg has a much higher rate of creatine uptake. An increase in blood flow and changes in creatine transporter activity may both contribute to this effect. After the loading phase, it is recommended that maintenance doses be taken 30-90 minutes prior to exercise.

Carbohydrates

After exercise, the second most reliable way to increase muscle creatine uptake is consumption of high glycemic carbohydrates. One study found that when creatine was ingested with carbohydrates, there was a 60% greater increase in muscle creatine levels than with creatine alone. The primary mechanism for this effect has been suggested to be insulin, which may stimulate the creatine transporter.

According to the presently available research, a large amount of carbohydrates is necessary to significantly increase muscle creatine uptake, with a recommended amount of 100 g of carbohydrates per 5 grams of creatine. Another study suggests that the same effect may be achievable by about 50 g each of protein and carbohydrates. Given the benefits of both of these macronutrients during exercise, this regimen may be optimal.

Ideally, both the protein and carbohydrates taken with creatine should be high glycemic. The protein source should be a type of whey protein, and dextrose or another simple sugar should be used for carbohydrates. Fructose should not be used, as it does not produce a significant insulin response.

4.7: What supplements can be taken to maximize the effects of creatine?

Alpha lipoic acid

Alpha lipoic acid (ALA) is a potent antioxidant compound that causes significant improvement in patients with type II diabetes by increasing insulin sensitivity. It has been theorized that ALA could increase muscle creatine uptake in healthy humans by increasing muscle insulin sensitivity and thus enhancing creatine uptake. Although the effects of ALA on insulin sensitivity in healthy humans is not established, one study compared the effects of 20 g creatine (CR), 20 g creatine and 100 g sucrose (CRS), and 20 g creatine, 100 g sucrose, and 1000 mg ALA (CRSLA) daily on healthy, recreational weight liftters (who did not exercise during the study) without impaired glucose metabolism. They found an equivalent increase in body weight in all groups over the duration of the study, while the CRSLA group had greater increases in both phosphocreatine and total muscle creatine, suggesting that ALA did indeed have an effect.

There were a number of problems with this study, so the results should not yet be taken for granted. First, the subjects were not exercising, which does not reflect real world conditions. Second, the increases in muscle creatine content in the groups not given ALA were lesser than they normally are in exercised subjects supplemented with creatine. Therefore, it is unknown if the effects of ALA and exercise can be additive. In any case, taking ALA with creatine may afford a benefit, although 1000 mg is a rather high dose, so 600 mg daily is recommended. This amount of ALA should not be taken without carbohydrates.

HMB

HMB is a metabolite of the amino acid leucine. In the scientific literature, there is a general consensus that after creatine, it has more scientific evidence for its effectiveness than other performance-enhancing supplements. It has also been found that creatine and HMB may additively increase lean body mass and strength. The mechanism of action of HMB is not well known. It is significantly more expensive than creatine, and most products that combine the two inflate the price even further. For those who choose to supplement with HMB, I recommend saving money by buying a pure HMB product and taking it along with creatine rather than buying a product with both ingredients. It is also easier to manipulate dosages this way.

4.8: What other ingredients are commonly found in commercial creatine products?

There are many "creatine replacement" products available today. They are primarily marketed as "improved creatine." The different forms of creatine and the validity of the rationale behind these products will be discussed later on. Following is an examination of some of the ingredients found in these products.

L-arginine

Arginine is an amino acid that has become popular as of late due to its ability to increase nitric oxide (NO) levels. There are also many derivatives that are advertised as being more effective. While the utility and safety of arginine is a subject of much debate, the general consensus is that it has limited ability to improve performance or alter body composition but offers a cosmetic benefit by increasing vascularity. In any case, L-citrulline or citrulline malate is suggested as an alternative (see below).

L-citrulline

Citrulline and citrulline malate are preferable to arginine, as citrulline has a greater ability to increase NO levels, and there is also more evidence that it improves athletic performance in humans. It should also complement creatine well.

Taurine

Taurine is an amino acid that is abundant in the human body. It has a number of positive effects on health. However, the evidence that it improves athletic performance or body composition is presently limited. While it improves exercise endurance in rodents, research in humans is limited. Nevertheless, it is a worthwhile ingredient to take, given the low price.

L-glutamine

Glutamine is another abundant amino acid in the human body that has become popular among bodybuilders. Multiple studies have measured the effects of glutamine in athletes and failed to find a positive effect, although one analysis indicated that it may lower the risk of infection in long-distance endurance athletes. There are also some downsides to glutamine supplementation. For example, it has been found to decrease glutathione levels in healthy people (while it has the opposite effect in those with critical illness). Glutathione is a very important in the body's defense against oxidative stress. Glutamine also may decrease NO levels.

Glycocyamine

Glycocyamine is the precursor to creatine in the body. Although this sounds like a good thing, glycocyamine competes with creatine for the creatine transporter, and unlike creatine it cannot act as a phosphate donor. Therefore, glycocyamine can be expected to reduce the effectiveness of creatine.

Guanadinopropionic acid

Guanadinopropionic acid (GPA) acts similarly to glycocyamine in the body – it competitively inhibits the creatine transporter, depleting creatine levels. GPA is also more potent than glycocyamine.

Magnesium

One study conducted at Western Washington University compared the effects of placebo and creatine plus magnesium (800 mg), with the magnesium either in the form of magnesium oxide or magnesium-creatine chelate. The magnesium-creatine chelate increased body weight, knee extension peak torque, and power, while the creatine and magnesium oxide group had increased body weight and power only. Because there was no creatine only group, this cannot be taken as solid evidence that magnesium improves the effects of creatine supplementation (as some companies claim). However, since magnesium is inexpensive and can have multiple benefits for the athlete, it does not hurt to take some magnesium when supplementing with creatine.

4.9: Does caffeine negate the effects of creatine?

Many believe that caffeine will interfere with the effectiveness of creatine. There are a few reasons for this belief. The primary reason is that one study published in 1996 found that while muscle phosphocreatine concentrations were increased by both supplementation with creatine and supplementation with creatine and caffeine for six days, there was a significant improvement in dynamic torque production only in the group that consumed creatine but not caffeine. A second study found that caffeine, which increases muscle relaxation time, kept creatine from decreasing muscle relaxation time.

The results of these studies should be treated with caution. In the study that indicated that caffeine may block the effects of creatine, there were only nine subjects, divided into three groups (placebo, creatine, creatine and caffeine). Another double-blind study (Gill et al.), although not appearing in the peer reviewed literature, compared the effect of creatine and creatine plus caffeine on maximal cycle sprints in fourteen subjects and found no significant differences between the groups, indicating that caffeine may not interfere with the effects of creatine. Another consideration is that in many of the studies showing creatine to improve athletic performance, coffee was the delivery vehicle. Also, the relevance of creatine's effect on muscle relaxation time to its performance enhancing effect has not been established. Finally, caffeine can improve athletic performance through multiple mechanisms, which may help to counteract any negative effects it has. So, while it is possible that caffeine interferes with the effect of creatine, more research is needed before this can be taken as a given.

Outside of the scientific literature some have argued that caffeine would interfere with the effects of creatine by blocking cellular hydration or causing insulin resistance. However, studies have found that caffeine intake has only minimal effects at most on hydration status. Although insulin resistance may be a concern, it is commonly overstated, especially where creatine is concerned. Tolerance quickly develops to the effect, and caffeine does not interfere with exercise-mediated increases in insulin sensitivity. More importantly, two studies (the one mentioned above and a pharmacokinetic study) indicate that caffeine does not blunt the increase in intramuscular creatine from creatine loading.

4.10: What is a creatine non-responder?

Studies have found that about 20% of the population does not respond well to supplementation with creatine. Whether or not someone is classified as a responder to creatine is determined by their muscle creatine uptake after supplementation. If the increase in muscle creatine levels from creatine supplementation is less than 20%, a person is labelled a non-responder.

The reason non-responders exist is not entirely clear. Some, but not all studies have correlated lack of response with high initial levels of creatine in muscle tissue. Since muscle tissue can only store a certain amount of creatine, those with initially high levels will only have a minimal increase from supplementation. People with very low creatine diets, such as vegetarians, have lower levels of creatine and a greater response to creatine supplementation than the rest of the population. However, in the general population as a whole, protein intake has not been correlated with creatine response rate.

One study found that subjects had higher levels of muscle creatine after five months of resistance training, indicating that adaptations due to training could possibly lower the creatine response rate. On the other hand, another study indicated that trained and untrained subjects exhibit the same response from creatine, and creatine also appears to be equally effective in both groups at improving exercise performance.

All in all, the research on who responds to creatine and why is inconsistent and muddled. It can also be said that there is no such thing as a "non-responder," but rather varying degrees of response, since creatine supplementation will likely increase muscle creatine levels by at least a small amount in every individual. While this will not be enough to see a noticeable difference, it will still help. In any case, it would be difficult to determine if one is a non-responder (or low responder) without a muscle biopsy, although whether or not a rapid change in body weight occurs may be an indicator.

4.11: Is there any way for creatine to work in a non-responder?

The only factor that could make a difference that has been identified in the research is carbohydrate intake. When creatine is taken along with high amounts of carbohydrates, there is less variation in response. Many believe that there are certain products that will make non-responders into responders. This is very unlikely – it is much more likely that these products just produce results related to the other ingredients. As noted above, the amount of creatine in muscle tissue simply cannot exceed a certain amount. Therefore, if one has initially high levels of creatine, they will not get a strong response from creatine supplementation no matter what. It is impossible to "supersaturate" muscle tissue with creatine. If one believes they are a non-responder and have tried taking creatine while carbohydrate loading, the best solution is to stop worrying about