NUTRITION, ERGOGENIC AIDS, EXERCISE, PHOSPHOCREATINE
During brief explosive-type exercises,
the energy supplied to rephosphorylate adenosine diphosphate (ADP) to adenosine
triphosphate (ATP) is determined largely by the amount of phosphocreatine
(PCr) stored in the muscle (1,2). As
PCr stores become depleted, performance is likely to rapidly deteriorate,
due to the inability to resynthesize ATP at the rate required (1,2).
Since the availability of PCr stores in the muscle may significantly influence
the amount of energy generated during brief periods of high intensity exercise,
it has been hypothesized that increasing muscle creatine content via creatine
supplementation may increase the availability of PCr and allow for an accelerated
rate of resynthesis of ATP during and following high intensity, short duration
Initial studies indicate that creatine supplementation may increase muscle
creatine content, improve anaerobic sprint exercise, and promote greater
gains in strength and fat-free mass during training. Consequently, creatine
has be come one of the most popular nutritional supplements among athletes
in recent times (7).
The following paper overviews the available
literature regarding the effects of creatine supplementation on muscle
bioenergetics, performance, and body composition. In addition, side effects
and concerns regarding the safety and ethics of creatine supplementation
are discussed. The paper concludes with a summary of findings and suggested
areas for additional research.
Muscle Creatine Content and Phosphocreatine
The TCr pool in the body (free and phosphorylated
form) is about 120 g for a 70 kg person (3). Approximately
95% of the TCr pool is stored in skeletal muscle primarily as PCr ( 66%).
The remaining amount of Cr is found in the heart, brain, and testes. The
normal daily requirement for creatine is approximately 1.6% of the TCr
pool (about 2 g for a 70 kg individual). Of this, about half of the daily
needs of creatine are obtained from the diet primarily from meat, fish,
and animal products. For example, there is approximately 1 g of creatine
in 250 g of raw red meat. The remaining amount of creatine is primarily
synthesized in the liver, kidney and pancreas from the amino acids glycine,
arginine and methionine.
1 provides detailed information regarding studies which have investigated
the effects of creatine supplementation on muscle bioenergetics and exercise
capacity in humans. The normal muscle TCr concentration ranges between
120 and 125 mmol/kg dry mass (4,5,8-19).
Short term creatine supplementation (15 to 30 g/d for 5 to 7-d) has been
reported to increase TCr by 15 to 30% and PCr stores by 10 to 40% (4,5,8-19,42,46).
For example, Harris and coworkers (5) reported that ingesting
20 to 30 g/d of creatine for 5-, 7- and 10-d or on alternate days for 21-d
increased TCr by 20% (127 to 149 mmol/kg dry mass) and PCr by 36% (67 to
91 mmol/kg dry mass). Likewise, Balsom and associates (8)
reported that creatine supplementation (20 g/d for 6-d) increased muscle
TCr by 18% (129 to 152 mmol/kg dry mass). Initial reports suggested that
not all subjects may respond to creatine supplementation. In this regard,
there was some evidence that individuals who observed less than a 20 mmol/kg
dry mass change in muscle creatine content did not respond as well to creatine
However, more recent studies (10,11)
indicated that ingesting creatine (20 g/d) with glucose (380 g/d) for 5-d
increased muscle creatine content by 10% more than when creatine was ingested
alone (143 to 158 mmol/kg dry mass). In addition, glycogen content was
increased by 18% more than when glucose was ingested alone (418 to 489
mmol/kg dry mass). While this increase was not significantly different
between groups due to intra-subject variability, it was significantly correlated
to changes in TCr. Moreover, the enhanced creatine uptake was associated
with a glucose mediated increase in serum insulin (11).
Consequently, these data indicated that when creatine was ingested with
glucose, all subjects responded to creatine supplementation.
Since creatine supplementation increases
intramuscular PCr, a number of studies have evaluated the effects of creatine
supplementation on ATP and PCr resynthesis following repeated bouts of
high-intensity exercise (4,8,
These studies indicate that creatine supplementation does not appear to
alter pre-exercise ATP concentrations (5,9,46,48).
However, the elevated PCr concentrations serve to maintain ATP concentrations
to a greater degree during a maximal effort sprint performance
(19). In addition, creatine supplementation has been reported to enhance
the rate of ATP and PCr resynthesis following intense exercise (4,8,15-17,19).
For example, Balsom and colleagues (8) investigated the
effects of creatine supplementation (20 g/d for 6-d) on PCr resynthesis
rates following sprint performance (5 x 6-s sprints with 30-s rest recovery
between sprints). Results revealed that following creatine supplementation
muscle PCr concentrations were significantly higher after the 5th sprint
(70 vs. 4 6 mmol/kg dry mass). Likewise, Greenhaff and associates (12)
reported that creatine supplementation promoted a 42% greater resynthesis
rate of PCr following 120-s of recovery from 20 electrically evoked isometric
contractions. Collectively, these findings indicate that short-term creatine
supplementation may be effective in increasing muscle TCr and PCr concentrations.
Furthermore, the increased TCr and PCr may serve to help maintain ATP concentrations
during high intensity exercise as well as enhance PCr resynthesis. Theoretically,
creatine supplementation may improve performance in single effort and/or
repetitive sprints involving the phosphagen energy system.
Most studies investigating the ergogenic
value of short-term (5 to 7-d) and/or long-term (7 to 84-d) creatine supplementation
(20 to 25 g/d for 5 to 7-d and 2 to 25 g/d thereafter) have found that
creatine supplementation significantly increases strength, power, sprint
performance, and/or work performed during multiple sets of maximal effort
muscle contractions (see
1 and Table
2). For example, Volek and colleagues (25) reported
that creatine supplementation (25 g/d for 7-d) resulted in a significant
increases in the amount of work performed during five sets of bench press
and jump squats in comparison to a placebo group. Harris and coworkers
reported that sprint performance during a series of 300- and 1,000-m runs
were significantly improved with creatine supplementation (30 g/d for 6-d).
Moreover, Kreider and associates (31) reported that
28-d of creatine supplementation (15.75 g/d) during off-season football
resistance/agility training resulted in significant increases in repetitive
sprint perfor mance (first 5 of 12 x 6-s sprints with 30-s rest recovery
between sprints) and isotonic lifting volume from maximal effort repetition
tests on the bench press, squat, and power clean. The improvement in exercise
capacity has been attributed to increased TCr and PCr content (4,5,8-19,42,46)
particularly in type II muscle fiber (19,46),
greater resynthesis of PCr (4,8,15-17,19),
improved metabolic efficiency (8,19,21,23,44,47),
and/or an enhanced quality of training promoting greater training adaptations
However, not all studies have found that
creatine supplementation improves exercise performance capacity (see Table
3). Supplementation appears to be less ergogenic when supplementation
regimens are less than 20 g/d for 5-d (16,49,54)
or involve low-dose supplementation regimens (2 to 3 g/d) without an initial
higher dose loading period (26,48).
In addition, studies which used relatively small sample sizes (e g., <
6 subjects per group) or employed crossover experimental designs with less
than a 5-wk washout period between trials (9,15,16,49)
typically have found no ergogenic benefit. Creatine supplementation may
also be less ergogenic depending on the amount of work and rest ratios
performed. In this regard, several studies report that creatine supplementation
does not effect performance in sprints lasting 6- to 60-s when prolonged
recovery periods (5- to 25-min) are observed between sprint trials (50-53).
Finally, reports indicate that creatine supplementation does not appear
to enhance endurance exercise (35,46,48,56,57).
Interestingly, several studies report enhanced
exercise capacity during initial sprints but that the ergogenic value dissipates
in latter sprints if the recovery time is too brief to replenish PCr stores
For example, Prevost and associates (33) reported that
the greatest improvement in exercise capacity following creatine supplementation
(18.75 g/d for 5-d) was observed when subjects performed 10-s sprints with
20-s recovery until exhaustion. It is also interesting that studies which
have evaluated long-term supplementation of creatine or creatine containing
supplements (15-25 g/d for 7 to 140-d), or provided maintenance doses of
creatine (3 to 10 g/d) following a high dose loading phase (20-25 g/d for
5 to 7-d), have all reported ergogenic benefit on strength and/or sprint
performance suggesting an enhanced quality of training (18,20,28,22,24,31,39,40,58,59).
Consequently, it appears that creatine supplementation may be more or less
ergogenic depending on the amount and length of su pplementation, the type
of exercise evaluated, and the specific work to rest ratios observed.
4 lists studies which have evaluated the effects of creatine supplementation
on body mass and fat free mass. Most studies indicate that short-term creatine
supplementation (20 to 25 g/d for 5 to 7-d) increases total body mass by
approximately a 0.7 to 1.6 kg (12,15,17,34,35).
The increased body weight has been theorized to be due to a creatine stimulated
water retention and/or protein synthesis (3,15,34,61,62).
For example, Ziegenfuss et al. (34) reported that 5-d
of creatine supplementation increased nitrogen status either by enhancing
protein synthesis or reducing protein degradation. The increase in body
mass was accompanied by a 7% increase thigh muscle volume determined by
magnetic resonance imaging (MRI) and a 2-3% increase in intra- and extracellular
A number of long-term (7 to 140-d) studies
investigating the effects of creatine or creatine containing supplements
(20 to 25 g/d for 5 to 7-d and 2 to 25 g/d thereafter) on body composition
alterations during 2training have reported significantly greater gains
in total body mass (18,20,22,31,58,63-65)
and fat-free mass (18,20,22,24,31,39,58,59,63-65).
The gains in total body mass and fat-free mass observed were typically
0.8 to 3 kg greater than matched-paired controls depending on the length
and amount of supplementation (18,20,22,24,31,39,59,63-65).
Further, these gains were associated with enhanced sprinting capacity and/or
gains in strength (18,20,22,24,31,39,59,63,65)
with no change in total body water expressed as a percentage of total body
Vandenberghe and associates (18)
reported that women administered creatine (20 g/d for 4-d followed by 5
g/d for 66-d) during resistance-training observed significantly greater
gains in fat-free mass in comparison to a placebo group. These gains were
maintained during a subsequent 70-d detraining period with continued supplementation
(5 g/d). Moreover, the gains in fat-free mass were maintained 28-d after
cessation of supplementation despite muscle PCr levels returning toward
pre-supplementation values. Consequently, it is unlikely that a creatine
stimulated fluid retention can account for all the gain in fat-free mass
observed in these studies. Some researchers hypothesize that creatine may
stimulate an initial gain in intracellular fluid serving to increase cellular
osmotic pressure and stimulate protein synthesis (3,31,34).
The gains in fat-free mass and strength observed thereafter may be due
to enhanced protein synthesis and/or the ability of the athlete to maintain
a greater training volume promoting lean tissue accretion. However, additional
research is necessary to evaluate the effects of creatine supplementation
on protein synthesis, fluid retention, and body composition before definitive
conclusions can be drawn.
Effects of Creatine Supplementation
on Markers of Medical Status
Serum creatine levels typically increase
for several hours following ingestion of a 5 g dose of creatine (5,15).
Creatine uptake into the muscle primarily occurs during the first several
days of creatine supplementation (5,42).
Excess creatine ingested thereafter has been reported to be excreted primarily
as creatine in the urine with small amounts converted to creatinine or
Serum creatinine levels have been reported to be either not affected (68,69)
slightly increased (31,67) following
28-d (31), 56-d (68,69)
and 365-d (67) of creatine supplementation. The increased
serum and urinary creatinine have been suggested to reflect an increased
release and cycling of intramuscular creatine as a consequence of enhanced
myofibrillar protein turnover in response to creatine supplementation and
not of pathologic origin (3,31,69).
Studies investigating the effects of creatine
supplementation on muscle and liver enzymes have found either no effect
moderate increases in creatine kinase (31,68),
lactate dehydrogenase (31), and aspartate amino transferase
(31) levels following 28-d and 56-d of supplementation. The increased
CK, LDH and AST levels reported following creatine supplementation were
within normal limits for athletes engaged in heavy training and may reflect
a greater concentration/activity of CK and/or ability to maintain greater
training volume (3,31). Interesting,
the athletes ingesting creatine had a lower urea nitrogen/creatinine ratio
Urea nitrogen is a marker of protein degradation. Typically, intense exercise
promotes some degree of protein degradation. The magnitude of which can
be evaluated, in part, by measuring the magnitude of change in serum and
urinary urea nitrogen excretion. Although intense exercise may also increase
serum and urinary creatinine levels, the increases are relatively small.
Consequently, increases in the ratio of urea nitrogen/creatinine is used
as a general marker of catabolism. Consequently, these findings suggest
that despite modest increases in serum CK, LDH, and AST observed, subjects
ingesting creatine may have experienced less catabolism during training
Creatine supplementation has also been
reported to positively affect lipid profiles in middle-aged male and female
(69) and trained male athletes
In this regard, Earnest and colleagues (69) reported
that 56-d of creatine supplementation resulted in significant decreases
in total cholesterol (-5 and -6% at day 28 and 56-d, respectively) and
triglycerides (-23 and -22% at day 28 and 56-d, respectively) in mildly
hypertriglyceremic patients. A similar response was observed with very
low density lipoproteins (VLDL). In addition, Kreider and coworkers (31)
reported that 28-d of creatine supplementation increased high density lipoproteins
(HDL) by 13%, while decreasing VLDL (-13%) and the ratio of total cholesterol
to HDL (-7%). Although additional research is necessary, these findings
suggest that creatine supplementation may possess health benefits in modifying
Finally, intravenous phosphocreatine administration
has been reported to improve myocardial metabolism and reduced the incidence
of ventricular fibrillation in ischemic heart patients (60,70-74).
Consequently, there has been interest in determining the effects of oral
creatine supplementation on heart function and exercise capacity in patients
with heart disease. Gordon and associates (75) reported
that creatine supplementation (20 g/d for 10-d) did not improve ejection
fraction in heart failure patients with an ejection fraction less than
40%. However, creatine supplementation significantly increased one legged
knee extension exercise performance (21%), peak torque (5%) and cycle ergometry
performance (10%). Collectively, these findings suggest that phosphocreatine
administration and/or oral creatine supplementation may posses some therapeutic
value to heart patients. Although additional research is necessary to evaluate
the long-term effects of creatine supplementation on medical status, available
studies suggest that creatine supplementation is medically safe and may
provide health benefits when taken at dosages described in the literature.
Side Effects and Concerns
The only side effect reported from clinical
studies investigating dosages of 1.5 to 25 g/d for 3- to 365-days in preoperative
and post-operative patients, untrained subjects, and elite athletes has
been weight gain (3). However, a number of concerns about
possible side effects of creatine supplementation have been mentioned in
lay publications, supplement advertisements, and on internet mailing lists
(see Table 5).
It should be noted that these concerns emanate from unsubstantiated anecdotal
reports and may be unrelated to creatine supplementation. There is no evidence
from any well-controlled clinical study indicating that creatine supplementation
causes any of these side effects. Nevertheless, since many of these concerns
have recently received significant media attention, a brief discussion
of the validity of these concerns is warranted.
Some concerns have been expressed whether
creatine supplementation may cause a long-term suppression of endogenous
creatine synthesis. Endogenous creatine synthesis has been reported to
decline during periods of increased dietary creatine intake
(1,3,13). However, there is no
evidence that creatine supplementation causes long-term suppression of
Since creatine is an amino acid, it has
been suggested that creatine supplementation may increase renal stress
or cause liver damage. However, no studies have reported clinically significant
elevations in liver enzymes in response to creatine supplementation (31,68).
Furthermore, Poortmans and colleagues (76) reported
that short-term creatine supplementation (20 g/d for 5-d) does not affect
markers of renal stress. Consequently, there is no evidence that creatine
supplementation increases renal stress when taken at recommended dosages.
There have been some anecdotal claims that
athletes training hard in hot or humid conditions may experience a greater
incidence of severe muscle cramps when taking creatine. Proponents for
this theory suggest that creatine supplementation may cause large fluid
shifts into the muscle serving to alter electrolyte status, promote dehydration,
and/or increase thermal stress. However, no study has reported that creatine
supplementation causes cramping, dehydration, or changes in electrolyte
concentrations, even though some of these studies have evaluated highly
trained athletes undergoing intense training in hot/humid environments
There have also been some anecdotal reports
that creatine supplementation may promote a greater incidence of muscle
strains or pulls. The theory for this is that since creatine supplementation
may promote relatively rapid gains in strength and body mass, additional
stress may be placed on bone, joints and ligaments leading to injury. Yet
no study has documented an increased rate of injury following creatine
supplementation, even though many of these studies evaluated highly trained
athletes during heavy training periods (24,25,31,32,38-42,48,50,
Concern has also been expressed regarding
unknown long-term side effects. While long-term (> one year) well-controlled
clinical trials have yet to be performed, it should be noted that athletes
have been using creatine as a nutritional supplement for over 10 years.
Yet, this author is not aware of any significant medical complications
that have been directly linked to creatine supplementation. Consequently,
from the research evidence currently available, creatine supplementation
appears to be a medically safe practice when taken at dosages described
in the literature.
Summary and Recommendations
Based on available literature, short-term
creatine supplementation improves maximal strength/power by 5 to 15%, work
performed during sets of maximal effort muscle contractions by 5 to 15%,
single-effort sprint performance by 1 to 5%, and work performed during
repetitive sprint performance by 5 to 15% (see Table
2). Moreover, long-term supplementation of creatine or creatine containing
supplements (15 to 25 g/d for 5 to 7-d and 2 to 25 g/d thereafter for 7
to 84-d) has been reported to promote significantly greater gains in strength,
sprint performance, and fat free mass during training in comparison to
matched-paired controls (20,28,22,24,31,39,40,58,59).
However, not all studies have reported ergogenic benefit possibly due to
differences in intra-subject variability in response to creatine supplementation,
the length of supplementation, exercise criterion evaluated, and/or the
amount of recovery observed during repeated bouts of exercise (see Table
3). The only side effect reported in the scientific literature from
creatine supplementation has been weight gain (3). Consequently,
based on available literature, creatine supplementation appears to be a
safe and effective nutritional strategy to enhance exercise performance.
Additional research involving creatine
supplementation should: (a) include protein turnover, creatinine kinetics,
muscle and liver enzyme efflux, lipid and cholesterol metabolism, fluid
retention, and lean tissue accretion; (b) determine the therapeutic value
and medical safety of creatine supplementation; (c) measure the effects
of creatine supplementation on training volume/intensity and performance
in a variety of sports events; and (d) determine whether there is any validity
to anecdotal reports of increased incidence of muscular cramping and/or
musculoskeletal injuries in athletes taking creatine during training.
The author would like to thank the many
subjects, students, research assistants, and colleagues at The University
of Memphis who have contributed to studies investigating the ergogenic
value and medical safety of creatine supplementation.
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