Journal of Strength and Conditioning Research, 2004, 18(1), 162–167

q 2004 National Strength & Conditioning Association

EFFECTS OF REPEATED CREATINE SUPPLEMENTATION

ON MUSCLE, PLASMA, AND URINE CREATINE LEVELS
ERIC S. RAWSON,1 ADAM M. PERSKY,2 THOMAS B. PRICE,3 AND PRISCILLA M. CLARKSON1
1
Department of Exercise Science, University of Massachusetts, Amherst, Massachusetts 01003; 2Division of Drug
Delivery and Disposition, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599;
3
Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, Connecticut 06520.

ABSTRACT. Rawson, E.S., A.M. Persky, T.B. Price, and P.M. to baseline levels after cessation of creatine supplemen-
Clarkson. Effects of repeated creatine supplementation on mus- tation. However, it is unknown how long decreased mus-
cle, plasma, and urine creatine levels. J. Strength Cond. Res. cle creatine uptake, increased urine creatine losses, and
18(1):162–167. 2004.—The purpose of this case study was to ex- suppressed endogenous creatine synthesis persist follow-
amine the effects of repeated creatine administration on muscle
phosphocreatine, plasma creatine, and urine creatine. One male
ing creatine supplementation. Additionally, it is unknown
subject (age, 32 years; body mass, 78.4 kg; height, 160 cm; re- if these residual effects blunt the response to a second
sistance training experience, 15 years) ingested creatine (20 bout of short-term creatine supplementation, because no
g·d21 for 5 days) during 2 bouts separated by a 30-day washout single study has collectively examined the effects of re-
period. Muscle phosphocreatine was measured before and after peated creatine supplementation on muscle phosphocre-
supplementation. On day 1 of supplementation, blood samples atine, plasma creatine, and urine creatine. The purpose
were taken immediately before and hourly for 5 hours following of this case study was to examine the effects of repeated
ingestion of 5 g of creatine, and a pharmacokinetic analysis of creatine administration on muscle phosphocreatine and
plasma creatine was conducted. Twenty-four-hour urine collec- plasma and urine creatine. We hypothesized that (a) a
tions were conducted before and for 5 days during supplemen-
30-day washout period would be sufficient time for mus-
tation. Muscle phosphocreatine increased 45% following the first
supplementation bout, decreased 22% during the 30-day wash- cle phosphocreatine, plasma creatine, and urine creatine
out period, and increased 25% following the second bout. There levels to return to baseline levels following short-term
were no meaningful differences in plasma creatine pharmaco- creatine supplementation (20 g·d21 for 5 days) and (b)
kinetic parameters between bouts 1 and 2. Total urine creatine changes in muscle phosphocreatine, plasma creatine, and
losses during supplementation were 63.2 and 63.4 g during urine creatine in response to creatine supplementation
bouts 1 and 2, respectively. The major findings were that (a) a (20 g·d21 for 5 days) would be similar to changes in muscle
30-day washout period is insufficient time for muscle phospho- phosphocreatine, plasma creatine, and urine creatine in
creatine to return to baseline following creatine supplementa- response to a second bout of creatine supplementation fol-
tion but is sufficient time for plasma and urine creatine levels lowing a 30-day washout period.
to return to presupplementation values; (b) postsupplementation
muscle phosphocreatine levels were similar following bouts 1
and 2 despite 23% higher presupplementation muscle phospho-
METHODS
creatine before bout 2; and (c) the increased muscle phosphocre- Experimental Approach to the Problem
atine that persisted throughout the 30-day washout period cor-
responded with maintenance of increased body mass (12.0 kg). The current study involved 16 blood draws, 14 24-hour
Athletes should be aware that the washout period for muscle urine collections, 4 muscle phosphocreatine measure-
creatine to return to baseline levels may be longer than 30 days ments (4-hour drive to and from the Department of Di-
in some individuals, and this may be accompanied by a persis- agnostic Radiology at the Yale University School of Med-
tent increase in body mass. icine on 4 occasions), 14 days of diet records, and 10 days
KEY WORDS. creatine monohydrate, ergogenic aid, supplement, of creatine supplementation. Because of the considerable
creatine phosphate, muscle commitment necessary to complete this protocol, we be-
lieved that the likelihood of several subjects completing
the study protocol in full was small. To reduce measure-
INTRODUCTION ment error and ensure the quality of the data collected,
any studies have demonstrated that high- we chose to examine the effects of repeated creatine ad-

M dose creatine supplementation can increase

muscle phosphocreatine levels (6, 7, 9, 15–
18). Because there is a limit to how much
creatine a muscle cell can take up (7, 8),
muscle creatine uptake decreases following high-dose cre-
ministration on muscle, blood, and urine creatine using a
single subject case study design with one of the authors
(E.S.R.) as the subject. Thus, we had strict control over
the subject’s dietary and physical activity behaviors, ex-
ercise training program, and supplement use. Therefore,
atine supplementation. Urine creatine, which is normally we could document with absolute certainty the subject’s
negligible, increases secondary to the combined effects of dietary and physical activity behaviors, such that he did
high-dose creatine intake and decreased muscle creatine not participate in additional training, consumed no ad-
uptake. Reportedly, exogenous creatine administration ditional nutritional supplements, consumed regular
temporarily decreases endogenous creatine synthesis in meals, and ingested no drugs.
humans (19). One resistance-trained male subject (age, 32 years;
A 30-day washout period may be sufficient time for body mass, 78.4 kg; height, 160 cm) completed the current
muscle creatine (5, 8) and urine creatinine (8) to return study. The man is a competitive bodybuilder with 15

162
 REPEATED CREATINE SUPPLEMENTATION 163

years of progressive resistance training experience and subject remained supine with the lower portion of the leg
has successfully competed in bodybuilding contests open (medial head of the gastrocnemius) resting on the stage
nationally. At the time of this study, the man was train- of a surface coil radiofrequency (RF) probe. Subject posi-
ing intensely (3-day split routine of high-intensity work- tioning was verified by an image-guided localization rou-
outs using a combination of free weights and machines) tine that uses a T1-weighted gradient-echo image (repe-
but was not restricting energy intake in preparation for tition time 5 82 milliseconds, echo time 5 21 millisec-
a bodybuilding contest. The primary goal of the resistance onds). During spectral acquisitions, RF power was pulsed
training program was to increase muscle size (3 sets, 70– into the gastrocnemius with a simple, decoupled, pulse
80% 1 repetition maximum, 6–10 repetitions, ,90-second acquire sequence operating at the 31P resonant frequency
rest between sets). The man was informed of the risks (36.2 MHz) using an 8-cm-diameter circular 31P surface
and benefits of participation and signed an informed con- coil RF probe. A microsphere containing a 31P reference
sent document consistent with the university’s policy on standard was fixed at the center of the RF coil and was
human subject testing. The man had not ingested crea- used for calibration of RF pulse widths. The subject’s low-
tine or other nutritional supplements for more than 1 er leg was positioned so that the isocenter of the magnetic
year before the study. field was approximately 2 cm into the medial gastrocne-
Baseline muscle phosphocreatine measurements were mius muscle. By determining the 1808 flip angles at the
taken within 48 hours before beginning the 5-day supple- center of the observation coil from the microsphere stan-
mentation period and again within 24 hours of discon- dard, RF pulse widths were set so that the 908 pulse was
tinuing supplementation. On the first day of supplemen- sent to the center of the muscle. The 1H decoupled 31P RF
tation blood samples were taken immediately before and pulse sequence was designed so that 72 31P transients are
hourly for 5 hours following ingestion of 5 g of creatine. acquired during a 3.1-minute acquisition period. The rep-
Twenty-four-hour urine collections were conducted for 2 etition time for 31P acquisition is 2.6 seconds to allow for
days before the supplementation period and for 5 days the long T1 of the 31P resonance. The continuous wave 1H
during supplementation. Body mass was determined in a decoupling pulse could not be turned on during the entire
fasted state using a calibrated electronic scale (Befour, acquisition time, because RF power deposition would
Inc., Saukville, WI). The man completed a 7-day diet rec- have been excessive. Continuous wave 1H decoupling was
ord beginning on the day of the first muscle phosphocre- therefore applied at the beginning of each acquisition
atine assessment and ending after the last food-fluid in- with a decoupling time of 200 milliseconds. Power depo-
take on the last day of supplementation. Dietary records sition, assessed by the magnetic vector potential specific
were analyzed using Nutritionist Five Dietary Analysis absorption rate calculation (1), has been calculated at ,4
Software Version 2.1 (First Data Bank, San Bruno, CA). W/kg. Concentrations of phosphocreatine were calculated
The man repeated the entire experimental protocol on 2 by comparison with b-adenosine triphosphate (14).
occasions separated by a 30-day washout period.
Plasma Creatine Pharmacokinetic Analysis
Supplementation
Blood samples were collected (7-ml, Vacutainer, glass
Each morning the man received 20 chewable creatine whole blood tube with K3 EDTA), centrifuged, and im-
monohydrate tablets (Createam, NutraSense Company, mediately frozen at 2708 for later analysis. Plasma cre-
Shawnee Mission, KS) and was instructed to consume 5 atine was measured enzymatically using a modified cre-
tablets per serving at 4 equal intervals throughout the atinine kit (kit 839434; Boehringer Mannheim, Mann-
day. The man ingested 20 g·d21 of creatine for 5 days, a heim, Germany). Noncompartmental pharmacokinetic
dosing regimen that has been previously shown to be ef- analysis was performed for each bout after their respec-
fective in elevating muscle phosphocreatine levels in tive baseline creatine levels were subtracted from all data
young subjects (6, 7, 9, 16–18). Because anecdotal reports points, since basal creatine levels remain constant over
of gastrointestinal discomfort resulting from creatine sup- time (10). The following parameters were calculated using
plementation can be eliminated by concurrent consump- the noncompartmental module of Kinetica software pack-
tion of carbohydrate, the man ingested 1 serving of Gat- age (Innasphase, Champs Sur Marne, France): terminal
orade (50 kcal, 14 g of carbohydrate) 30 minutes following half-life (t1/2), peak plasma concentration (CMAX), the re-
each ingestion of the supplement. Empty supplement con- spective time of maximum concentration (tMAX), area un-
tainers were returned each morning to ensure compliance der the curve (AUC`), and oral clearance (CL/F) (CL/F 5
with the supplementation protocol. Dose/AUC`), where F is the oral bioavailability of crea-
tine. Baseline renal clearance (CLREN) was calculated in
Muscle Phosphocreatine
Microsoft Excel using the equation:
Muscle levels of phosphocreatine were assessed within 48
hours of the start of the supplementation protocol using dX U
31
P-nuclear magnetic resonance spectroscopy (31P-NMR). dT
CLREN 5
Muscle phosphocreatine was assessed again within 24 Cp(MID)
hours following cessation of supplementation. 31P-NMR
measurements of muscle phosphocreatine are comparable where dXU/dt is the rate of urinary excretion of urine, and
to the muscle biopsy technique (2, 3), are reliable (coef- Cp(MID) is the plasma creatine concentration at the mid-
ficient of variation, 4%) (20), and have been used to detect point of urine collection.
increases in resting phosphocreatine following high-dose,
Urine Samples
short-term creatine supplementation (9, 15–18). 31P-NMR
was performed at the Yale University School of Medicine Twenty-four-hour urine samples were collected, and an
on a 2.1T Bruker Biospec spectrometer with a 100-cm- aliquot was immediately frozen at 2708 for analysis of
diameter magnet bore. During the measurements, the creatine and creatinine. Analysis of creatine was con-
164 RAWSON, PERSKY, PRICE ET AL.

Table 1. Daily dietary macronutrient intake for 2 days before and during supplementation of 100 g of creatine monohydrate
during 5 days (20 g·d21) on 2 occasions separated by a 30-day washout period.
Presupplementation During supplementation
Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7
Kilocalories
Bout 1 2203 2308 3768 1847 3375 2993 2555
Bout 2 1725 2522 2378 1636 1584 2444 2580
Protein (g·d21)
Bout 1 138 135 207 98 205 129 125
Bout 2 167 152 128 110 95 97 111
Carbohydrate (g·d21)
Bout 1 233 331 447 267 318 334 377
Bout 2 158 314 292 128 163 295 293
Fat (g·d21)
Bout 1 84 53 131 48 146 135 65
Bout 2 46 75 79 80 66 105 91

ducted using the same modified creatinine kit as used for

the plasma creatine analysis (kit 839434, Boehringer
Mannheim). Analysis of creatinine was conducted using
a creatinine kit (kit 555, Sigma Chemical Company, St.
Louis, MO).
Reproducibility of Plasma and Urine Creatine
Because our previous study showed that presupplemen-
tation plasma creatine is stable from day to day (intra-
class R 5 0.98) (13), we averaged the 3 presupplemen-
tation plasma creatine measurements in this study. As
expected, presupplementation urine creatine was negli-
gible, so no reliability coefficient was calculated. Plasma
and urine creatine and urine creatinine measurements
were conducted in duplicate, and the intra-assay coeffi-
cients of variation for these measures in our laboratory
are 2.0% for plasma creatine, 3.9% for urine creatine, and
2.3% for urine creatinine (13).
RESULTS
FIGURE 1. Muscle phosphocreatine (PCr) before and after
Before supplementation, the man weighed 77.9 kg; body supplementation of 100 g of creatine monohydrate during 5
mass increased to 79.3 kg following the first bout of sup- days (20 g·d21) on 2 occasions separated by a 30-day washout
plementation. Following the 30-day washout period, body period.
mass remained elevated (79.9 kg), and the second sup-
plementation bout increased the man’s body mass to 80.1
kg. Daily dietary macronutrient intake is described in Ta- tine pharmacokinetics were similar between bouts 1 and
ble 1. Although there was considerable day-to-day vari- 2 (Table 2) and were similar to previously published val-
ability in dietary composition, on average the man in- ues (11–13).
gested a diet that was 2,799 kcal, 21% protein, 49% car- Urine creatine increased profoundly during both bouts
bohydrate, and 31% fat during bout 1 of supplementation of supplementation (Figure 2), with no obvious differenc-
and 2,124 kilocalories, 23% protein, 43% carbohydrate, es between supplementation bouts. Creatine retained by
and 35% fat during bout 2 of supplementation. the body (total creatine ingested minus total creatine re-
Muscle phosphocreatine increased 45% following bout covered in the urine) was 36.8 g during bout 1 and 36.6
1 of supplementation but only decreased 22% during the g during bout 2 (Table 2). The man excreted 63.2% and
subsequent 30-day washout period. Thus, after the 30- 63.4% of supplemented creatine during bouts 1 and 2, re-
day washout period, muscle phosphocreatine remained spectively. Urine creatinine values were within normal
23% above presupplementation baseline values. Follow- limits during both bouts 1 and 2 of supplementation on
ing bout 2 of supplementation, muscle phosphocreatine all but one testing day, and day-to-day fluctuations were
increased 25%. Postsupplementation muscle phosphocre- typical of a healthy, nonvegetarian adult (Figure 3). On
atine levels were remarkably similar following each bout day 1 of bout 1 of supplementation, the precipitous in-
of creatine supplementation (29.1 mmol·kg21 wet wt vs. crease in urine creatinine corresponds to increased con-
29.8 mmol·kg21 wet wt) (Figure 1) despite the difference sumption of animal protein (0.89 lb [0.40 kg] of beef) by
in presupplementation muscle phosphocreatine. Baseline the man. It does not appear that urine creatinine in-
plasma creatine was within normal limits before both creased as a result of supplementation in either bout 1 or
bouts 1 and 2 of supplementation (Table 2) (4, 7). Crea- 2. This is not surprising, since in our previous study we
 REPEATED CREATINE SUPPLEMENTATION 165

Table 2. Pharmacokinetic analysis of plasma creatine follow-

ing a 5-g oral bolus of creatine monohydrate and urine creatine
levels during supplementation of 100 g of creatine monohydrate
during 5 days (20 g·d21) on 2 occasions separated by a 30-day
washout period.*
Bout 1 Bout 2
Plasma creatine
Baseline (mg·L21) 8.2 5.4
t1/2 (h) 2 2.6
CMAX (mg·L21) 98.8 95.1
TMAX (h) 2 1
AUC` (mg·h·L21) 373.1 440.2
CL/F (L·h21) 13.5 12.4
Urine creatine
CLREN (baseline) (L/h) 4.8 3.3
Total supplement recovered (g) 63.2 63.4
Supplement Retained (%) 36.8 36.6
* Baseline (mg·L21) 5 plasma creatine concentration in milli-
grams per liter under fasted conditions before supplementation;
t1/2 (h) 5 the terminal elimination half-life in hours, CMAX
(mg·L21) 5 peak plasma creatine concentration in milligrams
per liter; TMAX (h) 5 time of peak plasma creatine in hours; AUC`
(mg·h·L21) 5 area under the plasma creatine time curve through FIGURE 3. Daily urine creatinine during supplementation of
infinite time in milligram hours per liter; CL/F (L·h 21) 5 oral 100 g of creatine monohydrate during 5 days (20 g·d21) on 2
creatine clearance in liters per hour; CLREN 5 the baseline renal occasions separated by a 30-day washout period.
clearance of creatine; total supplement recovered (g) 5 the
amount of creatine recovered in the urine in grams.
bouts 1 and 2 despite 23% higher presupplementation
muscle phosphocreatine before bout 2; and (c) the in-
creased muscle phosphocreatine that persisted through-
out the 30-day washout period corresponded with main-
tenance of increased body mass (12.0 kg). Data from this
case study are novel because no single study has collec-
tively examined the effects of repeated creatine supple-
mentation on muscle phosphocreatine, plasma creatine,
and urine creatine.
Other studies have reported that a 30-day washout
period is sufficient for muscle creatine levels to decrease
to baseline values (5, 8). In the current study, muscle
phosphocreatine increased 45% following the first supple-
mentation bout but only decreased 22% during the 30-
day washout period. Thus, in this man, a 30-day washout
period was insufficient for muscle phosphocreatine to de-
crease to baseline levels. The man in the current study
could be classified as a ‘‘high responder’’ in terms of mus-
cle creatine uptake (6) and because of the large increase
in muscle phosphocreatine resulting from creatine sup-
plementation may have needed a longer washout period
to return to baseline levels of muscle phosphocreatine.
Little is known about intersubject variability in the wash-
FIGURE 2. Daily urine creatine during supplementation of out of muscle phosphocreatine, but it is reported that the
100 g of creatine monohydrate during 5 days (20 g·d21) on 2 average t1/2 for conversion of creatine and phosphocrea-
occasions separated by a 30-day washout period. tine to creatinine is 63 and 26 days, respectively (19). It
is noteworthy that the increased muscle phosphocreatine
that persisted throughout the 30-day washout period cor-
reported that urine creatinine levels did not change dur- responded with maintenance of increased body mass
ing 5 days of creatine supplementation (20 g·d21) (13). (12.0 kg) despite a reduction in mean energy intake
(2675 kcal).
DISCUSSION Although the elevated muscle phosphocreatine levels
The major findings of this study were that (a) a 30-day evident after the 30-day washout period limited muscle
washout period is insufficient time for muscle phospho- phosphocreatine uptake following bout 2 of supplemen-
creatine levels to return to baseline following short-term tation (bout 1: 45%; bout 2: 25%), it did not limit the max-
creatine supplementation (20 g·d21 for 5 days) but is suf- imal level of postsupplementation muscle phosphocrea-
ficient time for plasma and urine creatine levels to return tine attained (bout 1: 29.1 mmol·kg21 wet wt; bout 2: 29.8
to presupplementation values; (b) postsupplementation mmol·kg21 wet wt). Baseline muscle creatine levels are
muscle phosphocreatine levels were similar following known to modulate the increase in muscle creatine fol-
166 RAWSON, PERSKY, PRICE ET AL.

lowing creatine supplementation (i.e., a higher baseline turn to baseline levels may be longer than 30 days in
muscle creatine is associated with a smaller increase in some individuals. This may have important implications
muscle creatine following creatine supplementation), for athletes competing in sports in which weight classes
which was true in this case. However, a more important are used, because the persistent increase in muscle phos-
point is that there is clearly a maximal limit to the phocreatine during the washout period may be accom-
amount of creatine a muscle can take up (ceiling effect) panied by a persistent increase in body mass. Also, chang-
regardless of baseline levels. es in plasma creatine do not necessarily represent chang-
We are the first to report that plasma creatine phar- es in muscle creatine. Data on creatine absorption and
macokinetics, following a 5-g oral creatine bolus, are sim- elimination, obtained from analyses of plasma creatine,
ilar before and after a 30-day washout phase. This finding are sometimes used by manufacturers to imply that one
is intriguing because the man began bout 2 of supple- creatine product has greater bioavailability than another.
mentation with muscle phosphocreatine levels that were It should be stressed that the ergogenic effect of creatine
23% higher than baseline values. This indicates that supplementation is derived from increased muscle phos-
baseline muscle phosphocreatine levels, which are known phocreatine following supplementation, and plasma cre-
to influence muscle creatine uptake, may not influence atine pharmacokinetics without accompanying muscle
plasma creatine pharmacokinetics. In support of this ob- creatine measurements cannot provide information on
servation is a previous study from our laboratory in which muscle creatine uptake in one product vs. another. Fi-
plasma creatine pharmacokinetics were similar between nally, increased baseline muscle phosphocreatine result-
old and young subjects, yet young subjects showed a ing from a previous bout of creatine supplementation does
greater increase (35 vs. 7%) in muscle phosphocreatine not influence a muscle’s capacity to store creatine. How-
uptake and postsupplementation muscle phosphocreatine ever, it results in a smaller absolute increase in muscle
levels were greater in young subjects (27.6 vs. 25.7 phosphocreatine compared with the increase experienced
mmol·kg21 wet wt) (13). when baseline muscle phosphocreatine levels are not ar-
However, interpretation of plasma pharmacokinetics tificially elevated before supplementation. The effects of
after oral dosing cannot differentiate between changes in high-dose creatine supplementation for longer periods
oral bioavailability and clearance. The AUC` is a measure (.5 days) on subsequent bouts of creatine supplementa-
of how much of a nutrient or drug the body is exposed to tion or on endogenous creatine synthesis are unknown.
and can be mathematically defined by:
(DOSE)(F) Note: Eric Rawson is now with the Department of Exercie
AUC` 5 Science and Athletics at Bloomsburg University, Blooms-
CL burg, PA 17815.
where F is the oral bioavailability and CL is clearance.
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