risk assessment for creatine monohydrate

Regulatory Toxicology and Pharmacology 45 (2006) 242–251

www.elsevier.com/locate/yrtph

Risk assessment for creatine monohydrate �

Andrew Shao ¤, John N. Hathcock

Council for Responsible Nutrition, 1828 L St., NW, Suite 900,Washington, DC 20036-5114, USA

Received 26 April 2006Available online 30 June 2006

Abstract

Creatine monohydrate (creatine) has become an increasingly popular ingredient in dietary supplements, especially sports nutritionproducts. A large body of human and animal research suggests that creatine does have a consistent ergogenic eVect, particularly withexercises or activities requiring high intensity short bursts of energy. Human data are primarily derived from three types of studies: acutestudies, involving high doses (20 g/d) with short duration (61 week), chronic studies involving lower doses (3–5 g/d) and longer duration(1 year), or a combination of both. Systematic evaluation of the research designs and data do not provide a basis for risk assessment andthe usual safe Upper Level of Intake (UL) derived from it unless the newer methods described as the Observed Safe Level (OSL) or High-est Observed Intake (HOI) are utilized. The OSL risk assessment method indicates that the evidence of safety is strong at intakes up to5 g/d for chronic supplementation, and this level is identiWed as the OSL. Although much higher levels have been tested under acuteconditions without adverse eVects and may be safe, the data for intakes above 5 g/d are not suYcient for a conWdent conclusion oflong-term safety.© 2006 Elsevier Inc. All rights reserved.

Keywords: Creatine; Upper Level of Intake (UL); Observed Safe Level (OSL)

1. Introduction

First discovered in 1832, creatine is a naturally occurringamino acid-like compound made in the liver, kidneys andpancreas from the essential amino acids arginine, glycineand methionine (Balsom et al., 1994). In humans, over 95%of the total creatine content is located in skeletal muscle. A70 kg male possess approximately 120 g of total creatinewith a daily turnover estimated to be around 2 g. Part ofthis turnover can be replaced through exogenous sources ofcreatine in foods, including meat, Wsh and poultry (Balsomet al., 1994). In its phosphorylated intracellular form ascreatine phosphate, it provides the high energy phosphatefor adenosine triphosphate.

As a dietary supplement, creatine is available inpowdered, tablet and liquid forms as primarily creatine

� No funding was speciWc to the production of this manuscript. Thesalaries for authors were provided by the aYliated organization.

* Corresponding author. Fax: +1 202 204 7980.E-mail address: [email protected] (A. Shao).

0273-2300/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.yrtph.2006.05.005

monohydrate, the only form having been included inpublished, randomized, controlled trials. In the last 10years, nearly 70 randomized, controlled trials have beenconducted on or with creatine, with the majority examin-ing creatine’s performance-enhancing beneWts. Themajority of these clinical trials have found beneWcialeVects from creatine supplementation, particularly duringshort, repeated bursts of high-intensity activity (Bembenand Lamont, 2005). Recent research eVorts have alsofocused on the potential beneWts of creatine use inpatients coping with certain neuromuscular disorders(Persky and Brazeau, 2001).

Initial recommendations for creatine use stemmed fromearly research using 5–7 days of “loading” with 20–30 g perday (divided into 4–6 equal, 5 g doses), resulting in increasedmuscle creatine content. Based on new research, reWnementshave been made to this strategy and now many athletes con-sume only one 5 g dose approximately 60 min prior to, orimmediately after training (exercise is known to enhance cre-atine uptake by about 10%) (Bemben and Lamont, 2005).Although responses are quite variable from person to person,

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mailto: [email protected]

A. Shao, J.N. Hathcock / Regulatory Toxicology and Pharmacology 45 (2006) 242–251 243

subjects ingesting creatine average a 2–5 pound greater gainin muscle mass, and 5–15% greater increases in musclestrength and power compared to control (or placebo) sub-jects (Branch, 2003; Bemben and Lamont, 2005). Creatinesupplementation does not appear to enhance endurance-related exercise performance (Bemben and Lamont, 2005).

Research indicates that once muscle stores of creatineare full, they can remain elevated for an additional 4–5weeks without further supplementation (Snow andMurphy, 2003). Normal healthy adults who continue to usecreatine after their muscle stores have reached peak levelsmay Wnd the additional creatine is converted to creatinineand excreted in the urine (Pline and Smith, 2005). Urinarycreatinine levels are commonly used as a marker of kidneyfunction. Individuals who ingest creatine will frequentlyhave elevated creatinine levels—this is normal andrepresents an increased rate of muscle creatine conversionto creatinine rather than an abnormality of kidneyfunction. The widespread use of this ingredient in dietarysupplements suggests a need to evaluate the safety ofcreatine through quantitative risk assessment.

Most upper safe levels of nutrients and related sub-stances are based on widely applicable risk assessmentmodels used by the US Food and Nutrition Board (FNB)in its Dietary Reference Intakes documents in 1997 andafter (Food and Nutrition Board. Institute of Medicine,1997, 1998a,b, 2000, 2001). The FNB method and reviewsare a formalization and extension of the quantitativemethods widely used earlier in risk assessment of other sub-stances, and by the food and dietary supplement industries.Because of the systematic, comprehensive and authoritativecharacter of the FNB risk assessment method for nutrients,this approach has gathered widespread support and adop-tion by others such as the European Commission ScientiWcCommittee on Food (SCF) (European Commission, 2001),the United Kingdom Expert Group on Vitamins and Min-erals (EVM) (Food Standards Agency, 2003) and morerecently by the Food and Agriculture Organization/WorldHealth Organization project report A Model for Establish-ing Upper Levels of Intake for Nutrients and RelatedSubstances (FAO/WHO, 2006) with some slight modiWca-tions. All these reports reXect the concepts and proceduresestablished much earlier for the risk assessment of non-car-cinogenic chemicals (National Research Council, 1983).

2. Methods

The safety evaluation method applied to orally administered creatinemonohydrate is from the Council for Responsible Nutrition (CRN) Vita-min and Mineral Safety, 2nd Edition (Hathcock, 2004), which contains thebasic features of the FNB method and also the Observed Safe Level (OSL)modiWcation recently adopted as a Highest Observed Intake (HOI) in theFAO/WHO report.

Overall, this risk analysis was derived from the human clinical trialdatabase through the following major steps:

1. Derive a safe Upper Level of Intake (UL) if the data are appropriate:a. Search for data that identify a hazard related to excessive intake.b. Assess the dose–response relationship for the identiWed hazard.

c. Consider uncertainty and assign an uncertainty factor (UF).d. Derive a UL from the No Observed Adverse Intake Level

(NOAEL) or Lowest Observed Adverse EVect Level (LOAEL),and the UL D NOAEL ¥ UF.

2. If no data establish adverse eVects in humans, the above procedurecannot be used. In these circumstances, identify the highest intake levelwith suYcient evidence of safety as a value named the OSL by CRN(Hathcock, 2004) and the HOI by FAO/WHO.

We applied the Wrst procedure to the creatine monohydrate humantrial data and found no basis for a NOAEL or LOAEL, and thus couldnot derive a UL. Consequently, we applied the OSL procedure to the clini-cal trial data, with the results described in the sections below.

No eVorts were made in any of the clinical trials to avoid dietary crea-tine, and therefore the subjects must have been consuming normal dietarylevels of this substance. Thus, the OSL value identiWed from the trials doesnot require correction for dietary intakes or endogenous synthesis, and theOSL can be identiWed as a safe Upper Level for Supplements (ULS).

3. ScientiWc evidence related to safety

Media reports of links between creatine use and musclestrains, muscle cramps, heat intolerance, and other sideeVects are not supported by the scientiWc literature. Studiesconducted in athletes and military personal indicate a sub-stantial level safety of both short- and long-term creatineuse in healthy adults (Poortmans and Francaux, 1999;Robinson et al., 2000; Bennett et al., 2001; Greenwoodet al., 2003a,b; Kreider et al., 2003). Concerns about highdose creatine usage causing kidney damage are based solelyon a total of two published case reports in which one of theaVected individuals was suVering from existing underlyingrenal disease (Pritchard and Kalra, 1998; Koshy et al.,1999). Both comprehensive literature reviews and expertpanels have maintained that there is no conclusive evidenceto support the notion that creatine may adversely aVectkidney function in healthy individuals (Poortmans andFrancaux, 2000; Terjung et al., 2000; Farquhar and Zam-braski, 2002; Yoshizumi and Tsourounis, 2004; Pline andSmith, 2005).

3.1. Human studies

There have been nearly 70 peer-reviewed, publishedhuman clinical trials involving creatine. Of these, the mostrelevant randomized, controlled studies that address safetyare presented in this review (Table 1). Sample size, dosageand duration, controlling of diet, along with other co-inter-ventions (such as various forms of exercise training), andoutcome measures vary considerably between studies.Overall, the literature demonstrates a substantial level ofsafety with creatine when used in healthy individuals. Theprimary side eVect reported in clinical trials is gastrointesti-nal upset due to malabsorption of large doses of creatine.

The only form of creatine to be studied in randomized,controlled clinical trials is creatine monohydrate, eachgram of which provides 0.879 g of creatine. Therefore, forthe purposes of this review, the term “creatine” and accom-panying dosages refers to creatine monohydrate. Other

244A

. Shao, J.N

. Hathcock / R

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harmacology 45 (2006) 242–251

Table 1Published safety observations for human creatine supplementation

rations

m creatinine at the upper range, although thletes, but relatively small sample size and

on argue against use of this study for n of an OSLhy males, but lack of reporting relevant asures and short duration argue against use for identiWcation of an OSL

hy males, but lack of relevant outcome gue against use of this study for n of an OSLmple size and long duration, but study done population argues against use of this study tion of an OSL

e duration, but small sample size, ge, and lack of clinically relevant ts argue against the use of this study for

n of an OSLigher dose, but small sample size and

ort duration argue against the use of this ntiWcation of an OSL

y adults, but relatively short duration argues f this study for identiWcation of an OSL

hy adults, but relatively short duration and e size argues against use of this study for n of an OSL

y adults, substantial duration of exposure; Wndings of the studies above, this study is rve as the basis for the human OSL

Study Study population

Dosage and study design Duration (days)

Key observations OSL conside

Kreider et al. (1998) nD 14

Div IA college football players

15.75 g/d creatine monohydrate with supervised resistance training; randomized, controlled

28 d SigniWcant increase in serum creatinine (22.5% to 125 �mol/La); slight but signiWcant increase in liver enzymes; no adverse eVects observed

15.75 g, serunormal for ashort duratiidentiWcatio

Arciero et al. (2001) n D 10

Healthy adult males

20 g/d (5 d) followed by 10 g/d (23 d) creatine monohydrate with supervised resistance training; randomized, controlled

28 d No outcome measures related to safety reported; no adverse eVects reported

10 g in healtoutcome meof this study

Watsford et al. (2003) n D 9

Healthy adult males

20 g/d (7 d) followed by 10 g/d (21 d) creatine monohydrate; randomized, controlled

28 d No signiWcant increase in muscular strain or injury following exercise regimen; no adverse eVects reported

10 g in healtmeasures aridentiWcatio

Groeneveld et al.(2005) n D 88

ALS patients 10 g/d creatine monohydrate; randomized, controlled

310 d SigniWcant increase in urinary creatine (37-fold to 35.9 mmol/L); no change in serum urea levels or urinary albumin; 3 subjects dropped due to GI side eVects; no other diVerences in adverse eVects observed between creatine and placebo

10 g, large sausing diseasefor identiWca

Chrusch et al. (2001) n D 16

Elderly males 26 g/d (1 wk d) followed by 6 g/d (11 wk) creatine monohydrate with supervised resistance training; randomized, controlled

12 wk (84 d) No clinically relevant outcome measures reported; signiWcantly more side eVects (gastrointestinal, muscle cramping, muscle pulls) vs. placebo

6 g, moderatpopulation ameasuremenidentiWcatio

Bennett et al. (2001) n D 8

Healthy adult males

20 g/d (6 d) followed by 6 g/d (4 wk) creatine monohydrate with supervised military training program; randomized, controlled

34 d SigniWcant increase in serum (3.6-fold to 1061 �mol/L, 6 d; 2.2-fold to 639 �mol/L, 4 wk) and urinary creatine (400-fold to 2898 �mol/L, 6 d; 115-fold to 840 �mol/L, 4 wk); no signiWcant eVect on liver enzymes or core body temperature; no diVerence in adverse eVects observed between creatine and placebo

6 g, slightly hrelatively shstudy for ide

Powers et al. (2003) n D 16

Healthy adults 25 g/d (7 d) followed by 5 g/d (21 d) creatine monohydrate with self-maintained resistance training; randomized, controlled

28 d SigniWcant increases in urinary creatine (32-fold, to 347 �mol/L, 7 d; 24-fold, to 253 �mol/L, 28 d); no change in serum or urinary creatinine levels; no adverse eVects observed

5 g in healthagainst use o

KilduV et al. (2003) n D 9

Healthy adult males

22.8 g/d (7 d) followed by 5.7 g/d (21 d) creatine monohydrate with supervised resistance training ; randomized, controlled

28 d SigniWcant increase in urinary creatinine (2.2-fold, to 3.3 g/24 h); no adverse eVects observed

5.7 g in healtsmall samplidentiWcatio

Derave et al. (2004) n D 8

Healthy adults 20 g/d (1 wk) followed by 5 g/d (19 wk) creatine monohydrate; randomized, controlled

20 wk (140 d) SigniWcant increase in serum creatine (8.4-fold to 210 �mol/L, 1 wk; 4-fold to 100 �mol/L, 10 wk; 3.2-fold to 80 �mol/L, 20 wk); signiWcant 72% increase in urinary creatine (to 7.1 g/24 h); no change in serum urea or urinary creatinine; no adverse eVects reported

5 g in healthbased on thechosen to se

A. S

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athcock / Regulatory T

oxicology and Pharm

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Op ’t Eijnde Healthy adults 20 g/d (2 wk) followed by 15 g/d 12 wk (84 d) No outcome measures related to safety 5 g in healthy adults, but lack of relevant outcome ; supports the OSL selected

rate duration, but lack of relevant outcome ; supports the OSL selected

rts the OSL selected

creatinine within the normal range; supports ted

rate duration, but lack of relevant outcome ; supports the OSL selected

ports the OSL selected

rts the OSL selected

rate sample size and long duration, but study g disease population; supports the OSL

sample size and long duration, but study done ase population; supports the OSL selected



oderate sample size and duration, but study g disease population; supports the OSL

(continued on next page)

et al. (2001a) and Hespel et al. (2001) nD 11

(3 wk) followed by 5 g/d (7 wk) creatine monohydrate with supervised resistance training; randomized, controlled

reported; no adverse eVects reported measures

Stevenson and Dudley (2001b) n D 12

Healthy adults 20 g/d (1 wk) followed by 5 g/d (8 wk) creatine monohydrate with self-maintained resistance training; randomized, controlled

9 wk (63 d) No outcome measures related to safety reported; no adverse eVects reported

5 g, modemeasures

Wilder et al. (2001) n D 8

Div IA college football players

20 g/d (1 wk) followed by 5 g/d (9 wk) creatine monohydrate with supervised resistance training; randomized, controlled

10 wk (70 d) No change in urinary creatinine; no adverse eVects reported

5 g, suppo

Robinson et al. (2000) n D 16

Healthy adults 20 g/d (5 d) followed by 3 g/d (8 wk) creatine monohydrate with supervised resistance training; randomized, controlled

61 d SigniWcant increase in serum creatinine (33% to 90 �mol/La); no change in serum urea and other hematological indices; no adverse eVects observed

3 g, serumOSL selec

van Loon et al. (2003) n D 10

Healthy adult males

20 g/d (5 d) followed by 2 g/d (6 wk) creatine monohydrate; randomized, controlled

47 d No outcome measures related to safety reported; no adverse eVects reported

2 g, modemeasures

Derave et al. (2003) n D 22

Healthy adults 15 g/d (2 wk) followed by 2.5 g/d (6 wk) creatine monohydrate with supervised resistance training; randomized, controlled

8 wk (56 d) SigniWcant increase in total muscle creatine content; no adverse eVects reported

2.5 g, sup

Eijnde et al. (2003) n D 23, 10¤

Healthy older adult men

5 g/d creatine monohydrate; with supervised cardiovascular and resistance training; randomized, controlled

6 mo, 1 yr¤ (153 d, 365 d¤)

SigniWcant increase in urinary creatine (4.6-fold to 3.46 g/24 h); signiWcant increase in serum creatine (10% to 95 �mol/L); no diVerence in adverse eVects observed between creatine and placebo

5 g, suppo

Verbessem et al. (2003) n D 26

Huntington’s disease patients

5 g/d creatine monohydrate; randomized, controlled

1 yr (365 d) SigniWcant increase in urinary creatine, serum creatinine (data not provided); no change in serum urea; no diVerence in creatinine clearance vs. placebo; no adverse eVects reported

5 g, modedone usinselected

Escolar et al. (2005) n D 15

Pre-adolescent dystrophic patients

5 g/d creatine monohydrate; randomized, controlled

6 mo (180 d) No clinically relevant outcome measures reported; no diVerence in adverse eVects observed between creatine and placebo

5 g, smallusing dise

Tarnopolsky et al. (2004b) nD 30

Pre-adolescent dystrophic patients

5 g/d creatine monohydrate; randomized, controlled, crossover

4 mo (120 d) No change in serum or urinary creatinine or creatinine clearance; no adverse eVects reported


Tarnopolsky et al. (2004a) nD 34

Adult dystrophic patients

5 g/d creatine monohydrate; randomized, controlled, crossover

4 mo (120 d) SigniWcant increase in serum creatinine; no change in creatinine clearance; no adverse eVects reported


Walter et al. (2000) n D 32

Dystrophic patients

5–10 g/d creatine monohydrate; randomized, controlled, crossover

8 wk (56 d) No changes in any clinical chemistry endpoints reported; no adverse eVects observed

5, 10 g, mdone usinselected

246 A. Shao, J.N. Hathcock / Regulatory Toxicology and Pharmacology 45 (2006) 242–251

Tab

le 1

(co

ntin

ued

)

aN

orm

al r

ange

for

ser

um c

reat

inin

eD

50–1

15�

mol

.

Stud

ySt

udy

popu

lati

onD

osag

e an

d st

udy

desi

gnD

urat

ion

(day

s)K

ey o

bser

vati

ons

OSL

con

side

rati

ons

Lou

is e

tal

. (2

003a

) nD

15P

re-a

dole

scen

t an

d ad

oles

cent

dy

stro

phic

pa

tien

ts

3g/

d cr

eati

ne m

onoh

ydra

te;

rand

omiz

ed, c

ontr

olle

d, c

ross

over

3 m

o (9

0d)

Sign

iWca

nt in

crea

se in

ser

um (

2.8-

fold

to

331

�m

ol/L

) an

d ur

inar

y (2

.8-f

old

to

1.7

g/24

h) c

reat

ine;

no

chan

ge in

ser

um

or u

rina

ry c

reat

inin

e or

uri

nary

al

bum

in; n

o ch

ange

in li

ver

enzy

mes

; no

adve

rse

eVec

ts o

bser

ved

3g,

reas

onab

le d

urat

ion

and

all r

elev

ant e

ndpo

ints

ass

esse

d,

but s

tudy

don

e us

ing

dise

ase

popu

latio

n; s

uppo

rts

the

OSL

se

lect

ed

criteria for study inclusion were study duration (more thanone week), and studies had to be randomized, placebo-con-trolled intervention trials. Studies that were uncontrolledand unblinded, observational, those investigating acute bio-availability, pharmacokinetics or postprandial responsesfrom single bolus doses were excluded from this analysis,and are used solely as supportive information.

A large portion of the clinical trials conducted with cre-atine using healthy adults have the used a “loading phase”(typically 20 g/d creatine, for 3 d to 1 wk in duration), fol-lowed by a “maintenance phase” (typically 5–6 g/d, vary-ing duration). The rationale being that the large dose for ashort period at the outset of supplementation may helpfacilitate creatine uptake by skeletal muscle (Bemben andLamont, 2005). For the purposes of this review, ratherthan being used as the basis for short-term recommenda-tions, loading doses are used as support for recommenda-tions for a lower maintenance dose deemed safe for long-term use.

Several human studies have focused speciWcally on thesafety issues of creatine supplementation. In 2003, Kreideret al. and Greenwood et al. published two separate reportson an open label study involving creatine supplementationin Division IA college football players. Both reports con-cluded that creatine doses ranging from 5 to 15 g/day for 21months did not increase the incidence of cramping orinjury, and had no adverse eVects on hepatic or renal func-tion (Greenwood et al., 2003a,b; Kreider et al., 2003). Otheruncontrolled trials have reported similar Wndings in athleteswith respect to renal function and thermoregulation(Poortmans and Francaux, 1999; Schilling et al., 2001;Mayhew et al., 2002; Potteiger et al., 2002; Rosene et al.,2004). Although not randomized, double-blind, controlledtrials, these reports help to provide conWdence in theremaining body of research demonstrating the safety ofcreatine.

Americans consume approximately one gram of creatineper day from the diet, with the equivalent amount producedendogenously (Balsom et al., 1994), suggesting that thedoses used in the reviewed trials are 3- to 12-fold higher andare adequate to assess safety of supplementation. Theabsence of any pattern of adverse eVects related to creatinesupplementation in any of the published human trials pro-vides support for a high level of conWdence in the safety ofthis compound.

3.2. Animal and in vitro studies

Although many studies on creatine using animal modelshave been published, few have speciWcally focused on safetyand toxicity. Of these, only one reported adverse eVectsusing a rat model of renal cystic disease (Edmunds et al.,2001). Using a creatine loading dose, followed by a mainte-nance dose (human equivalent of 20 g/d, 1 wk followed by5 g/d, 5 wk) analogous to that used in human trials, Edm-unds et al. reported that this regimen contributed toreduced renal function (increased kidney weight, increased


serum urea level, lower creatinine clearances) in Sprague–Dawley rats with existing cystic kidney disease. Theseresults are in contrast with a study published by Taes et al.(2003), who reported that creatine supplementation doesnot aVect kidney function in rats with pre-existing renalfailure. Researchers provided sham-operated and partiallynephrectomized (eVectively inducing renal failure) ratseither a control diet, or creatine diet (providing 0.9 g/kgbody weight creatine/d; equivalent to approximately 50 g/din 60 kg adult human) for four weeks (Taes et al., 2003).There was no eVect of creatine supplementation on inulinor creatinine clearance rates, urinary protein excretion orurea clearance.

A histological assessment of the eVect of up to one yearof creatine supplementation revealed that 0.05 g/kg bw/d inmice resulted in inXammation of the liver (no other organsaVected), while a supraphysiologic dose in rats (2% creatinediet) caused no pathological eVects in any of the organsanalyzed (Tarnopolsky et al., 2003). These results suggestthat the eVects of creatine are species speciWc and that therat model more closely represents humans.

Other creatine studies conducted using animal models(mice, rats, guinea pigs, dogs; doses ranging from 0.05 to2 g/kg body weight/d for between 2 and 8 wk) examiningserum, muscle and organ concentrations, while not focusedon safety or toxicity, have not reported any adverse eVects(Lowe et al., 1998; Ipsiroglu et al., 2001; Ju et al., 2005).These provide additional support that creatine supplemen-tation at doses analogous to or higher than those used inhumans do not cause adverse eVects in most animals undernormal conditions.

4. Human NOAEL or OSL (HOI)

Research on creatine safety and toxicity has focused pri-marily on its eVect on renal function. This stems from theknowledge that excess creatine is eliminated from the bodyvia glomerular Wltration in the kidney either as creatine orits metabolite, creatinine (Ropero-Miller et al., 2000). Twohuman case reports (Pritchard and Kalra, 1998; Koshyet al., 1999) and a single study in rats with renal disease(Edmunds et al., 2001) have also fueled concerns about cre-atine’s aVect on the kidney. In clinical practice, severalmarker compounds are used to assess renal function,including serum creatinine and urea levels, urinary albuminand inulin clearance (Farquhar and Zambraski, 2002).Elevated serum levels of creatinine well beyond the normalrange (50–115 �mol/L) can be indicative of reduced clear-ance rates, and along with increased urinary albumindenote compromised renal function. Both controlled anduncontrolled clinical trials involving creatine supplementa-tion have demonstrated elevations in one or more of thefollowing markers: serum creatine and creatinine, and uri-nary creatine and creatinine. In all cases these elevationshave been within the normal range.

Although not reviewed in detail here, published clinicaltrials lasting one week or less, which comprise approxi-

mately half of the total number of clinical trials conductedon creatine, are generally supportive of the longer-term tri-als. Regardless of dosage (ranging from 5 to 30 g/d) orstudy population, none of the short-term trials (rangingfrom 3 to 7 d), report any adverse eVects, and where mea-sured, all relevant endpoints are within the normal range(Gordon et al., 1995; Jacobs et al., 1997; Odland et al., 1997;Poortmans et al., 1997; Volek et al., 1997; Maganaris andMaughan, 1998; Smith et al., 1998a,b; Bellinger et al., 2000;Mihic et al., 2000; Nelson et al., 2000; Burke et al., 2001; Op’t Eijnde and Hespel, 2001; Op ’t Eijnde et al., 2001b; Ste-venson and Dudley, 2001a; Volek et al., 2001; Cottrell et al.,2002; Cox et al., 2002; Jacobs et al., 2002; Ziegenfuss et al.,2002; Louis et al., 2003b,c; Anomasiri et al., 2004; Eckersonet al., 2004; Ostojic, 2004; Mendel et al., 2005; Theodorouet al., 2005). Aside from the case reports, none of the clini-cal studies involving healthy adults or those using neuro-muscular disease patients have found reduced renalclearance rates (as indicated by above normal elevations inserum creatinine or urea), or increased urinary albumin.Other alleged adverse eVects of creatine supplementation,such as cramping and increased core body temperaturehave not been observed in any of the controlled oruncontrolled human trials.

4.1. Human NOAEL

Given that none of the clinical trials found a clearadverse eVect related to creatine administration, there is, bydeWnition, no basis for identifying a LOAEL. In theabsence of a LOAEL, a NOAEL is not usually set. Withouteither of these two values the establishment of a UL usuallyis not set (Food and Nutrition Board. Institute of Medicine,1998b).

4.2. Human OSL

Published relevant human clinical trials involved crea-tine doses of up to 26 g/d (“loading” phase) and 6 g/d(“maintenance” phase) (Chrusch et al., 2001). All humanstudies reviewed were double-blind, randomized, controlledtrials (Table 1). A series of non-randomized, open-labelclinical trials has also been published. The dosages involvedin these studies ranges from 1 to 30 g/d for up to Wve years,the results of which are consistent with respect to safety,showing no observed or reported adverse eVects (Poort-mans and Francaux, 1999; Schilling et al., 2001; Mayhewet al., 2002; Potteiger et al., 2002; Greenwood et al., 2003a;Greenwood et al., 2003b; Kreider et al., 2003; Rosene et al.,2004).

Of the randomized, controlled clinical trials reviewed inthis report, two studies reported gastrointestinal side eVects(Chrusch et al., 2001; Groeneveld et al., 2005). One studyinvolved elderly men and described the side eVects as fewand minor (Chrusch et al., 2001). The other reported that afew subjects taking creatine left the study due togastrointestinal upset. The same study reported no


signiWcant diVerence overall in side eVects between creatineand placebo (Groeneveld et al., 2005). The remaining stud-ies report a complete absence of side eVects, do not addressthe issue of side eVects, or report no diVerence in the inci-dence of side eVects between creatine and placebo. Withrespect to clinically relevant markers, none of the studiesreviewed showed clinically relevant changes in serum creat-inine or urea, urinary albumin, or liver enzymes. A total oftwo studies using healthy adult subjects reported statisti-cally signiWcant increases in serum creatinine. Robinsonet al. (2000) reported a 33% increase in serum creatinine (to90 �mol/L) in healthy adults who received 20 g/d creatine(5 d) followed by 3 g/d creatine (8 wk) combined with asupervised resistance training program. Kreider et al. (1998)reported a 22.5% increase in serum creatinine (to 125�mol/L) in Division IA college football players who received15.75 g/d creatine along with a supervised resistance train-ing program for 28 d. Although elevated, these values arestill recognized as being within the normal range for serumcreatinine and likely are reXective of an increased conver-sion of creatine to creatinine within the body and not renaldysfunction (Farquhar and Zambraski, 2002).

4.3. 15.75 g/d

Kreider et al. reported no adverse eVects in Div. IA col-lege football players who ingested 15.75 g/d creatine for 28 d(Kreider et al., 1998), but did observe a signiWcant increasein serum creatinine levels (to 125�mol/L). The interpreta-tion of these results is confounded by the fact that theseathletes were also undergoing an intense exercise trainingregimen. While the serum creatinine level is still within anormal range for this population, the relatively small sam-ple size (nD14) and short duration argue against use of thisstudy for identiWcation of an OSL.

4.4. 10 g/d

Three studies implement the use of a 10 g/d mainte-nance dose. Arciero et al. (2001) and Watsford et al.(2003) use very similar study designs involving healthyadult male subjects and a 20 g/d (5 and 7 d, respectively)and a 10 g/d maintenance dose (up to d 28). While neitherstudy reported any adverse eVects, they also failed to mea-sure or report any clinically relevant safety outcomes(such as serum or urinary markers). This fact, combinedwith the relatively short duration, argue against use of thisstudy for identiWcation of an OSL. The Wnal study using a10 g/d dose involved amyotrophic lateral sclerosis (ALS)patients, who were studied for a total of 310 d (Groene-veld et al., 2005). Although some minor gastrointestinalside eVects were observed, there was no change in serumurea or urinary albumin levels. The long duration andmodest sample size (nD 88) provide conWdence in thesafety of this dose, however, the diseased nature of thestudy population argue against use of these results foridentiWcation of an OSL.

4.5. 6 g/d

The gastrointestinal side eVects reported by Chrusch weredescribed as few and minor (Chrusch et al., 2001). This studyutilized the largest dose of creatine for the “loading phase”(26 g/d) in healthy subjects and a dose of 6 g/d in the “mainte-nance” phase, but failed to measure or report any clinicallyrelevant safety outcomes. Although it was of moderate dura-tion (84 d), the small sample size, population age (elderlymen), and lack of clinically relevant measurements argueagainst the use of this study for identiWcation of an OSL.Bennett et al. (2001) implemented a very similar dosing regi-men (20 g/d, followed by 6g/d) and found no adverse eVects,including no clinically relevant changes in safety markers.Powers et al. (2003) observed no increase in serum or urinarycreatinine after a dosing regimen of 25 g/d (7 d) followed by5 g/d (21d). KilduV et al. (2003) (22.8 g/d, 7 d, followed by5.7 g/d, 21d) reported no adverse eVects and only a normalrise in urinary creatinine. However, the relatively small sam-ple sizes and short duration employed in these studies argueagainst their use for identiWcation of an OSL.

4.6. 5 g/d

Although a relatively small sample size (nD 8), Deraveet al. (2004) exposed subjects to a relatively large loadingdose (20 g/d, 7 d) followed by 5 g/d for 19 wk, for a totalexposure of 140 d in healthy adults. The study also showedno signiWcant increase in either serum creatinine or urea.Therefore, given the substantial duration of exposure andthe Wndings of the studies including creatine doses at, aboveand below this level, this study is chosen to serve as thebasis for the human OSL of 5 g/d.

The remainder of the relevant studies provided in Table 1employed creatine maintenance doses of 5 g/d or lower fordurations of up to one year in varying populations serve tosupport and provide conWdence in the selected OSL (Robin-son et al., 2000; Walter et al., 2000; Hespel et al., 2001; Op ’tEijnde et al., 2001a; Stevenson and Dudley, 2001b; Wilderet al., 2001; Derave et al., 2003; Eijnde et al., 2003; Louiset al., 2003a; van Loon et al., 2003; Verbessem et al., 2003;Tarnopolsky et al., 2004a,b; Escolar et al., 2005). In all ofthese studies, there were either no adverse eVects observed bythe investigators or none reported. One study (Robinsonet al., 2000) reported a signiWcant increase in serum creati-nine, the level of which (90�mol/L) is still well within thenormal range. The quantities of creatine involved in these tri-als are supplemental amounts well above the estimatedamount consumed in foods consumed in the U.S. (1 g/d (Bal-som et al., 1994)). Therefore, this risk assessment represents adirect approach to an ULS. No correction is needed for thecreatine present in the U.S. food supply.

4.7. Uncertainty evaluation

The study chosen as the basis for the human OSL (Der-ave et al., 2004), on its own merit alone, would necessitate


the application of a relatively high UF, due to its smallsample size (nD8). However, there is a collection of otherrandomized controlled trials conducted in healthy adultsusing creatine doses at, above and below 5 g/d, all demon-strating and/or reporting no adverse eVects. These serve assupport for and provide conWdence in the results of thestudy by Derave et al.

NOAEL and LOAEL: >10 g/dOSL: 5 g/dULS: Because the 5 g/d dose was administered to sub-jects eating normal diets, no correction of the OSL fordietary intake is needed, therefore OSLDULSD5 g/d

5. Conclusions

The body of evidence supporting a beneWcial eVect ofcreatine supplementation performance outcomes continuesto grow. The increased availability and appearance of thisingredient in dietary supplement products, along withcontinuing accusations of potential adverse eVects, war-ranted the present risk assessment. Application of riskassessment methodology to the available published humanclinical trial data involving creatine supports a high level ofconWdence in this ingredient with respect to its safe use indietary supplements. The absence of a well-deWned criticaleVect precludes the selection of a NOAEL, and thereforerequired use of the observed safe level (OSL) or highestobserved intake (HOI) approach established by FAO/WHO to conduct this risk assessment. Evidence from well-designed randomized, controlled human clinical trials indi-cates that the Upper Level for Supplements (ULS) for crea-tine is 5 g per day.

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