California Athletic Trainers Association Meeting, 10/26/99
These are my lecture notes that I used in my presentation.

• Creatine was discovered in 1835 by a French scientist, Chevreul, who isolated creatine in meat extracts.⁵⁴
• Chemical name is methyl guanido-acetic acid.
• It is a nitrogen-containing muscle enzyme derived from amino acids.
• In the liver it is formed from arginine, methionine, and glycine.¹
• Creatine may also be produced in the pancreas and kidneys.¹
• Creatine is obtained from food. Beef, salmon, and tuna all contain approximately 2 gm of creatine per pound. Herring contains 3 gm per pound and, as of late 1998, is the highest food source of creatine tested so far.
• After it is manufactured or ingested, creatine is transported in the blood stream and is absorbed by muscle cells.
• The average human being contains around 100 gm of creatine, 95 of which are located in skeletal muscle.²
• In skeletal muscle, around 30 gm of creatine are in the free form. The remaining 60 gm are phosphorylated.³
• Phosphorylated creatine is creatine that has been converted to creatine phosphate, a.k.a. phosphocreatine.
• Skeletal muscle concentration of creatine averages 125 mmol/kg of dry muscle weight in males.⁴
• It is felt with supplementation muscles can be supersaturated to 160 mmol of creatine per kilogram of dry muscle.⁴
• 160 mmol of creatine per kilogram of dry muscle is the upper physiologic limit which, when reached, cannot be surpassed.⁵⁴
• Loading with creatine can increase levels 25% in one week.⁴
• Muscle cells have the ability to trap creatine; thus, after ingestion intracellular levels will remain elevated.⁵⁴
• After stopping creatine supplementation, it takes around four weeks for body levels to return to normal.^4,39,40
• Creatine is a low molecular weight compound. The kidneys remove it by diffusion, which is nonenergy dependent and, thus, poses little risk to healthy individuals.⁵⁴

Mechanism of Action
ATP (adenosine triphosphate) is a high energy compound stored in our cells and is the power source for all intra- and extracellular activity. ATP is generated three ways. The first is by the ATP phosphocreatine system, which will be discussed below. The second way is by the glycolytic system, which generates ATP from either glucose or glycogen. The third way is through the oxidative system, which requires oxygen, is the most complex (with the most reactions), and has the greatest energy yield.

During brief, explosive exercise and activity, ATP is maintained from the adenosine diphosphate (ADP) phosphocreatine system. Depending on the individual, 100% of energy requirements can be sustained for 3-15 seconds from this system.⁵⁵

During intense exercise ATP is used, and ADP and free creatine are formed. The free creatine can be recycled in the mitochondria or returned from contractile filaments where it is oxidatively rephosphorylated (reformed) to make more phosphocreatine. Free creatine may also be released from the cell. When this occurs, creatinine is formed and released to the blood stream, where it is filtered by the kidneys and excreted in the urine. When athletes supplement with creatine, muscles have higher amounts of both free creatine, 10 25%, and phosphocreatine, 20-40%.^{4,5,10,18,20,52} With more creatine and phosphocreatine present in the muscle cells, the body is able to rephosphorylate ADP to ATP faster.^4,5,52 More ATP enables athletes to perform greater workloads before fatigue. Greater stimulus in the form of increased repetitions or weight of resistance will in turn promote greater physiological adaptations to training. During contraction, some phosphocreatine transported to contractile filaments is picked up along the way by ribosomes, which have an isoenzyme of creatine kinase that enables them to synthesize ATP from ADP and phosphocreatine. Theoretically, this stimulates an increase in protein synthesis and hypertrophy.^6,10

Recent investigators have questioned creatine's ability to increase phosphocreatine resynthesis between sets of exercise as well as following exercise. Two nuclear magnetic resonance studies found that creatine loading increased phosphocreatine levels but did not affect phosphocreatine repletion after isometric⁷³ or isotonic movements.⁸⁸ A third NMR trial found that creatine loading markedly improved power output during dynamic muscle contractions without affecting the rate of phosphocreatine resynthesis.⁶⁰ However, other investigators have stated that nuclear magnetic resonance is not an appropriate measuring device for phosphocreatine resynthesis.⁶⁴

Another mechanism of action was found in a study that used a one week loading dose of 25 gm per day followed by a daily 5 gm intake for 11 weeks.⁸¹ There was a 26% increase in sex hormone binding globulin (SHBG), which is a major binding protein for testosterone. The free androgen index (total testosterone to SHBG) decreased 44%. This indicates that creatine supplementation may affect muscle testosterone uptake from the blood, which in turn could be another explanation of its ergogenic benefits.

Researchers have found that creatine supplementation markedly shortens muscle relaxation time following maximal contraction. A shorter relaxation time reduces co-contraction activity, which improves mechanical efficiency of movement. This mechanism could cause a higher power output during single or an intermittent series of maximal rapid dynamic muscle contractions. The authors concluded that this mechanism of action is independent of phosphocreatine resynthesis because the rate of muscle relaxation exceeds the rate of the resynthesis of phosphocreatine.⁶⁰

In two trials it was found that subjects who used creatine while undergoing a training program did not have an increase in the BUN/creatinine ratio, while placebo groups showed a significant increase.^10,75 The BUN/creatinine ratio is a general marker of catabolism; thus, subjects who were exercising vigorously on creatine experienced less catabolism and/or greater nitrogen retention. Thus, another mechanism of action of creatine would be an ability to reduce protein breakdown following training.

Creatine and Performance
In a variety of studies creatine has increased performance with a wide range of protocols in many types of athletes including sprinters, runners, cyclers, rowers, swimmers, skaters, kayakers, and weight lifters.^9-36,58-62 Success has been achieved in trials using a short-term loading protocol only for five to seven days, consisting of 20-25 gm per day, to long-term studies with five-day loading periods of 20-25 gm, and maintenance dosing ranging from 2-25 gm for 7-54 days.^{9-22,24-29,31-36,58,59,62} There have also been positive outcomes seen in studies without loading doses, using 10 gm per day for two weeks,²³ 9 gm per day for three weeks,³⁰ 5 gm a day for two weeks,⁵⁷ and 3 gm per day for two weeks.²⁷ Finally, new research has shown that 25 gm per day for two days was enough to load muscles,⁶⁰ and following a five day loading dose, athletes ingested a 5 gm maintenance dose for 79 days with the only side effects being increases in strength and lean body mass.^59,81

Evidence of Ergogenesis

• Ingesting creatine in supplemental forms stimulates weight gain.^{9,14,18,20,39,59,62,83}
• Studies have shown single and repetitive improvement in sprint times in events ranging from 6-30 seconds in multiple tasks including sprinting, cycling, rowing, swimming, and skating.^{9-20,58,59,63-65,66,83,90}
• Studies show creatine can increase the amount of work performed and time to exhaustion during sets of maximal effort muscular contraction.^{13,14,17,21,22,23,24,60,61,67,74,83}
• Creatine increases strength in single repetition maximum weight lifting.^{9,13,14,25,59,62,83}
• Creatine supplementation can increase vertical jumping.^9,26,27,83
• Creatine supplementation can improve high intensity performance in events ranging from 90 seconds to 5 minutes.^{23,24,28,29,30,31}
• Creatine can increase maximum exercise capacity.^{23,24,31,32,60}
• Creatine can increase total lifting volume.^10,23,33,59
• Creatine supplementation has been shown to increase anaerobic capacity.^34,35,90
• Creatine ingestion increases ATP levels during intense activity and stimulates ATP reformation following that activity.^5,10,52
• Supplementing with creatine is effective with a wide variety of delivery systems. It has increased fat-free, lean body mass when taken with water, glucose, protein shakes, and candy form.^{5,9,10,21,23,25,36,37,59,90}

Analysis of Negative Studies
Not all studies on creatine supplementation have been positive.^{38-43,69,70,71,72,89,91} Negative studies tend to have one or more of the following in common:

• A washout period of less than five weeks.
• A loading dose of less than 20 gm per day.
• No loading dose and a daily dose is 2-3 gm.
• Studies with few subjects.
• Studies testing submaximal aerobic exercise.
• Sprint performance studies of 6-60 seconds when recovery periods are prolonged (5-25 minutes between trials).
• Studies with less than one week of supplementation.
• Studies on performance of a single timed swim.
• For reasons yet to be determined, creatine does not work on 100% of those who take it.

Mixed Results
The literature also reveals a variety of mixed results within similar trials. For example, a six day loading dose had little effect on swim velocity during repeated 50 yard intervals. However, when subjects were retested following eight additional days of maintenance supplementation, there was significant improvement noted.⁶⁶ In a two week trial with no loading dose and a small daily dose (3 gm), vertical jumping was improved but bench press and 40 yard sprint were not.²⁷ Another swimming trial showed that creatine did not improve single sprint time but did improve repeated interval time.⁷¹ One study found creatine increased maximum isometric strength and time to fatigue in the leg extension but did not yield this benefit to the same subjects when their hand grip strength was tested.⁶⁷ In a five week trial with football players using either 22 gm or 9 gm per day, both groups were improved when compared to the placebo group in single repetition bench press and squatting. They also had a higher power output, but creatine did not increase the height of their vertical jumping.⁸³ Finally, although it was not in the same trial, there have been mixed results when creatine has been supplemented with caffeine, with studies showing that caffeine both enhanced⁶⁴ and reduced⁹² creatine's ergogenic benefits.

Side Effects
Creatine use can cause gastrointestinal upset, especially during the loading phases. The incidence is low and similar problems have also been reported in placebo groups.²

There have also been anecdotal reports that creatine can provoke herpes simplex outbreaks. This is theoretically possible in those who carry the virus because the creatine molecule does contain arginine. Thus, especially during loading phases, the virus could be provoked in sensitive individuals.

By far the most common complaint with creatine use are the reported increased incidents of muscle tightness, muscle cramping, and muscle strains. This has frustrated researchers because until 1998 there were no published reports in the literature of these problems.⁵¹ This includes both positive^{5,9-37,39,52,58,59,60-68,74} and negative^{38-43,69,70,71,72} studies.

The cramping complains have further puzzled scientists because creatine increases intramuscular fluid levels.⁴

There have been studies focusing specifically on the cramping-strain-tightness problem. The first was a retrospective side-effect questionnaire presented at the 1998 National Strength and Conditioning Conference.⁵³ A questionnaire was mailed to 164 athletes who participated in five blinded creatine trials. When researchers tallied their responses, the only side effects reported were that of gastrointestinal distress in a few respondents. None of the participants complained of muscle cramping, muscle tightness, or muscle strains. However, reports of these problems continue and, thus, more trials have been performed. Creatine did not cause dehydration after five days of loading followed by two 80 minute cycle rides in the heat.⁶⁹ In a study on 34 football players during 43 days of college football training camp, it was found that creatine loading along with 5 gm maintenance dosing did not cause fluid or electrolyte alterations.⁷⁶ In a parallel study on the same group of athletes, it was found that creatine use did not cause an increase in muscle strains or cramping.⁷⁷ Curiously, the researchers found that creatine use actually reduced the amount of injuries sustained during the 43 day football camp.⁷⁸ There is one small study that has found a link between creatine use and muscle cramping. The protocol was as follows: Creatine was dosed at 20 gm per day for five days in one group. A second group received a placebo supplement. There then was an exercise trial that began with 5 five-second maximum sprints on an exercise bike followed by a 75 minute intermediate intensity ride. This protocol was repeated three times consecutively. At the conclusion of the session, three of the seven (43%) creatine users reported muscle cramping or tightness. Only one out of nine (11%) reported muscle cramping or tightness in the placebo group.⁷⁹

It is this author's opinion that reported muscle tightness, cramping, and strains in a subset of creatine users is probably not due to mild dehydration, although acute dehydration could provoke problems. There is a report that creatine shortens muscle relaxation time in humans.¹⁰⁰ Animal studies have found that creatine movement into muscles may be sodium dependent.⁸⁰ If creatine use increases intracellular sodium levels, a secondary increase in intracellular calcium levels will occur,⁹³ which in turn causes a more forceful contraction. A shorter relaxation time coupled with a stronger contraction could, indeed, be a cause of the reported strains, cramping, and tightness in some creatine users.

Laboratory Effects
Creatine loading and maintenance dosing does affect blood and urine chemistry in some individuals. The body of knowledge in this area continues to accumulate. At this time there is no evidence that creatine use can lead to acute toxic conditions.

In a study on liver function, in which subjects took 20 gm of creatine a day for five days and followed that with 10 gm a day maintenance dose for 51 days, there were no elevations in the following enzymes: AST, ALP, GGT, LDH, and CPK in females; in males there was an elevation at week eight in CPK, which returned to normal four weeks after cessation of creatine supplementation.⁴⁴

In a study on hepatorenal function subjects were administered 20 gm a day of creatine for five days and 10 gm a day for 51 days. Total protein, creatinine, and bilirubin remained unchanged for the eight weeks of supplementation. Blood urea nitrogen (BUN) was normal in males. In females, after eight weeks of supplementation, it was elevated and returned to baseline level four weeks after stopping creatine supplementation. The authors concluded that chronic high dose creatine supplementation elicited very minimal changes in renal and hepatic function.⁴⁵

Urine creatinine levels do elevate slightly; however, these are consistent with ranges seen in athletes undergoing rigorous training.^5,10 Urine creatine levels do increase significantly, especially during loading phases.⁶⁰ Serum creatine levels are mildly elevated during loading.^4,8 Creatine's effects on blood lipids are mixed. In a 12 week trial that included a one week loading dose and 5 gm per day maintenance dose, there were no differences in total cholesterol, HDL cholesterol, LDL cholesterol, or triglycerides between creatine users and nonusers.⁸¹ Other studies have shown that creatine use with resistance exercise does lower total cholesterol, triglycerides, and VLDLs during eight weeks of creatine supplementation.^46,47 In another trial 37 days of creatine supplementation significantly reduced blood cholesterol in subjects who also underwent resistance training. The average reduction of total cholesterol was 17 mg. In the same study, subjects who used creatine but did not undergo resistance training did not have any reductions in their blood cholesterol.⁶² Creatine has also been shown to increase HDL cholesterol in athletes and hypertriglyceridemic patients.^15,47

Creatine has been shown to decrease plasma ammonia levels.^13,63 There have been mixed results on blood lactate levels with evidence that creatine use with resistance exercise increases blood lactate,⁶³ decreases blood lactate,⁸² and does not affect blood lactate.⁸³

Therapeutic Uses of Creatine
Creatine has improved heart function and lowered the risk of heart attacks in persons suffering from ischemic heart disease.⁴⁸

Infants with genetic creatine deficiencies have demonstrated improvements in brain function and muscle function with long-term supplementation of over 24 months, ingesting approximately 200 mg per pound of body weight.^49,50

Creatine supplementation has increased exercise capacity in upper extremity arm ergonometers in persons with spinal cord injuries at C5, C6 and C7.⁸⁴

Creatine has been used to treat gyrate atrophy, a deficiency in creatine synthesis that causes a progressive atrophy of type II muscle fibers. Children were given 1.5 gm of creatine a day for one year. Treatment resulted in a marked increase in the diameter of type II fibers.⁸⁵

Creatine has also been used in geriatric patients with femur fractures. Those who supplemented with creatine during rehabilitation showed an accelerated rate of muscle mass recovery.⁸⁶

Creatine has been used on children ages 6 to 12 with various types of muscular dystrophy at doses of 6-10 gm per day, six days a week for 12 months, without side effects.⁸⁷

Forms of Creatine
The vast majority of studies on creatine have been performed on the creatine monohydrate form. Creatine monohydrate consists of one molecule of creatine and one molecule of water. The concentration of pure creatine monohydrate is 880 mg per 1000 mg.² This is the highest percentage of creatine available in the marketplace. Creatine phosphate and creatine citrate have also been marketed from some supplement companies. I found one study that showed creatine monohydrate and creatine phosphate both resulted in similar improvement in bench press and lean body mass when compared to placebo.²¹ Creatine phosphate contains 663 mg of creatine per 1000 gm and creatine citrate contains approximately 450 mg per 1000 gm.² There are an increasing number of other new forms of creatine hitting the market every few months, including creatine pyruvate and creatine lactate. Of course, manufacturers claim that their new forms are the best. However, these claims are based on extrapolations or in-house experiments. At this time, based on the literature as well as athletes around the world, it is recommended that creatine monohydrate is the form of choice.

Creatine Dosing
Creatine appears to work better for some athletes than others.⁵⁴ Persons with lower levels of creatine such as vegetarians tend to have a greater benefit than people with higher amounts of creatine such as women and athletes with a high percentage of fast twitch muscle tissue.^7,54 Creatine is not effective for endurance training and low intensity activity.^56,57,91 Some athletes who do not respond to creatine supplementation alone will do so when they ingest creatine with simple carbohydrate.⁸ In a double-blind, placebo-controlled study of college football players, they were given either a glucose placebo, a creatine preparation, or a creatine and glucose preparation with a ratio of glucose to creatine at 7:1. Results of this study showed that the creatine users outperformed the placebo group in 100 meter sprinting and vertical jumping. They also lost body fat and gained lean body mass. When this group was compared to the group that used the creatine/glucose formula, researchers found that the creatine/glucose group had faster sprinting times and greater vertical jump improvement than the creatine group. The combination group also lost more body fat and gained more body mass than the group taking creatine alone.⁹

Currently, no optimal dosing has yet been defined. There is a wide range of dosing that has yielded improvements in the literature. Dosing suggestions are as follows:

• For short-term performance enhancement, for events 5-7 days away, take 20-25 gm per day in divided doses with simple carbohydrate.*
• For long-term training, three to five day optional loading dose:
  • 15 gm per day under 150 pounds
  • 20 gm per day 150-200 pounds
  • 25 gm per day over 200 pounds
• Maintenance dose ranges from 2-10 gm per day.
• Maintenance dose ranges 5-10 gm per day for athletes who
  1. Do not take a loading dose.
  2. Large athletes.
  3. Athletes with heavy training schedules.
• Creatine is best absorbed with sugars (mix with fruit juice).
• Many brands now come sweetened and work well with water.
• Creatine will also work in protein shakes.
• Athletes have safely taken 15-20 gm per day doses for one month periods.
• Athletes have safely taken maintenance doses for three months.
• Longer term use shows better results (8-12 week cycles).
• One month off will normalize the body's production.
• Anecdotal reports show that a one to two week taper rather than suddenly stopping may prevent muscle tightness following the end of a cycle.
• It is strongly recommended that athletes keep a creatine diary, including their daily intake, training schedule, problems they encounter as well as their improvements during the time they use creatine. This information will enable the development of optimal individualized schedules.

Conclusion
A recent metanalysis of 31 placebo-controlled studies published in peer-reviewed journals totalling 602 participants contained the following conclusions:

1. Creatine supplementation increases strength, power, and total work with a greater effect in trained versus untrained individuals.
2. Creatine supplementation will moderately increase time to exhaustion in trained individuals, but will not do the same in untrained persons.
3. Creatine supplementation caused a small but statistically significant improvement in blood lactate metabolism in trained subjects only.
4. Creatine improvements are related to the length of dosing with the best effects seen in studies where it is used for over 20 days.⁶⁸

It would appear that creatine may be to power athletes what carbohydrates are to endurance athletes. The ergogenic effects of short-term loading are likely due to changes in cellular hydration and possibly an improvement in phosphocreatine or ATP resynthesis. It appears that long-term effects are caused by physiological adaptations of greater force production and power output that creatine users demonstrate. Volec⁵⁹ found significant increases in cross-sectional diameter of types I, IIA, IIAB, and IIB (35%, 36%, 35%, and 29%) respectively after 12 weeks of weight training with creatine supplementation versus placebo (11%, 15%, 6%, and 8%). Vandenberghe⁹⁴ found lean body mass gains were largely retained one month following a 10 week creatine cycle. Thus, long-term weight gain is not due to fluid retention.

Coaches, athletes, and healthcare professionals all want to know the truth about creatine, including its safety, mechanism of action, and optimal dosing. Care must be taken to separate the hype driven by supplement companies and fitness magazines from the scientific truth. For example, unethical insinuations along with blatant fabrications abound in magazines that publicize body builders who clearly use anabolic steroids and growth hormones. Uneducated readers are left with the impression, either direct or indirect, that what they see was accomplished with over-the-counter supplements, including creatine. Conversely, we also must be aware of the alarmist negativity generated by medicine which has a long history of antisupplement bias.⁹⁵ For example, in a recent review, Juhn⁹⁶ plays the cancer card by suggesting concerns of creatine use should include a cancer risk. A close evaluation of his references is a classic illustration of the medical bias against supplements. Papers like "Creatine and Phosphocreatine Analogs: Anticancer Activity and Enzymatic Analysis,"⁹⁷ "Inhibition of Rate of Tumor Growth by Creatine and Cyclocreatine,"⁹⁸ and "Evaluation of Creatine Analogs as a New Class of Anticancer Agents Using Freshly Explanted Human Tumor Cells"⁹⁹ are certainly not the types of studies that would suggest a risk for cancer.

In the meantime, we eagerly await future research and additional information on this novel substance.

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