Ergogenic Aids: Creatine
What Is Creatine?
 Amino acid derivative found mainly in skeletal muscle
(90% to 95%)
– Small amounts in brain, testes, and cardiac muscle tissues
– Synthesized from glycine, arginine, and S-adenosylmethionine (1 to 2 g/day)
– Found in meats (meat eaters consume 1 to 2 g/day)
 Acts as a reservoir for high-energy phosphate needed for
adenosine triphosphate (ATP) synthesis
– Phosphorylated creatine (creatine phosphate, or phosphocreatine) can
donate a phosphate group to adenosine diphosphate (ADP) to make ATP
 Phosphocreatine stores depleted after 10 to 20 seconds of intense
exercise
Abbreviations: ADP, adenosine diphosphate; ATP, adenosine triphosphate.
Juhn MS, et al. Clin J Sport Med. 1998;8(4):286-297.
The Creatine Phosphate Pathway
 3 different types (isoforms) of creatine kinase (CK)
Urinary excretion
– CK-BB, or CK-1 (brain, lung)
– CK-MB, or CK-2 (cardiac)
– CK-MM, or CK-3 (skeletal muscle)
Abbreviations: ADP, adenosine diphosphate; ATP, adenosine triphosphate; BB, brain/brain; CPK, creatine phosphokinase; MB, muscle/brain; MM, muscle/muscle.
Reprinted from Smith C, et al. Marks’ Basic Medical Biochemistry: A Clinical Approach. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:870-871.
Potential Mechanisms for Benefits of Creatine
for Athletes
 Loading can increase stores of phosphocreatine in muscle cells1
– Increased ATP production during high-intensity exercise
– Diminished dependence on glycolysis and subsequent lactic acid formation
• Indirect buffering of muscle pH
– Faster re-synthesis of ATP after exercise
 Affects muscle cell stretching, which may trigger cell growth2
– Osmotically active inside muscle cells; water follows it into the cell
 Influences other pathways in the cell that increase the ratio of protein
synthesis to protein breakdown3,4
–
–
–
–
Increased myogenic regulatory factors
Increased insulin-like growth factor (IGF-1) expression
Decreased myostatin levels in blood (myostatin reduces muscle growth)
Decreased cellular damage following high-intensity exercise
Abbreviations: ATP, adenosine triphosphate; IGF-1, insulin-like growth factor.
1. Terjung RL, et al. Med Sci Sports Exerc. 2000;32(3):706-717.
2. Haussinger D, et al. Lancet. 1993;341(8856):1330-1332.
3. Saremi A, et al. Mol Cell Endocrinol. 2010;317(1-2):25-30.
4. Deldicque L, et al. J Appl Physiol. 2008;104(2):371-378.
Typical Creatine Feeding Protocol
 Loading period for rapid increase in muscle creatine
– Approximately 20 g/day (~0.3 g/kg/day) for 3 to 5 days
• 5 g, 4×/day
 Maintenance phase
– 2 to 5 g/day indefinitely
 Slower increase in muscle creatine
– 3 g/day for 28 days results in similar muscle creatine levels as
in the loading phase
Mc Ardle WD, et al. Sports and Exercise Nutrition, 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2009:3476-377.
Evidence for Creatine Benefits on Performance and
Strength/Muscle Mass
 > 500 studies have evaluated the benefits of creatine in sports nutrition
– None have shown detrimental effects
– 300 examined performance: ~70% show significant improvements
 Performance benefits include:
–
–
–
–
Maximal power/strength (5% to 15%)
Work performed during sets of maximal effort muscle contractions (5% to 15%)
Single-effort sprint performance (1% to 5%)
Work performed during repetitive sprint performance (5% to 15%)
 Performance benefits generally limited to high-intensity, anaerobic exercise
 Supplementation during training is associated with a 0.5- to 2-kg greater
increase in body mass (BM) and/or fat-free mass (FFM) than training alone
– Includes trained and untrained adolescent, adult, and elderly populations
– Both males and females respond equally well
Abbreviations: BM, body mass; FFM, fat-free mass.
Kreider RB. Mol Cell Biochem. 2003;244(1-2):89-94.
Effects of Creatine Loading on Muscle Creatine Levels
Total creatine, mmol/kg dm
A 160
*
150
140
130
20 g creatine/day for 6 days,
none after
120
110
100
Day 0
Day 7
Day 21
Day 35
*
*
*
Total creatine, mmol/kg dm
B 160
150
140
20 g creatine/day for 6 days,
then 2 g/day for remainder
of study
130
120
110
100
Day 0
Day 7
Abbreviation: dm, dry mass.
*Significantly different from day 0, P < .05.
Reprinted from Hultman E, et al. J Appl Physiol. 1996;81(1-2):232-237.
Day 21
Day 35
Influence of Creatine Loading on Myostatin Levels During
8 Weeks of Resistance Training (Typical 2 Phase Loading Protocol)
Week 0
Week 4
Week 8
Myostatin, ng/mL
140
120
100
80
60
40
20
0
CON
Abbreviations: CON, control; CR, creatine; PL, placebo; RT, resistance training.
Reprinted from Saremi A, et al. Mol Cell Endocrinol. 2010;317(1-2):25-30.
RT+PL
RT+CR
Influence of Creatine on Markers of Muscle Damage
After the Ironman Triathlon
*
4000
***
ns
3000
**
2000
1000
0
Placebo
Creatine supplemented
ns
700
600
500
400
300
200
100
0
Placebo
Triathletes
0 hours
ns
*
Plasma activity of LDH, U/L
Plasma activity of CK, U/L
*
36 hours
60 hours
0 hours
Creatine supplemented
Triathletes
36 hours
60 hours
Subjects:
Ironman triathletes
Treatments:
20 g/day creatine + 50 g carbohydrate for 5 days prior to the race
Control: 50 g carbohydrate only
Analysis:
Markers of muscle damage measured at baseline and 36 or 60 hours after the race
Abbreviations: CK, creatine kinase; LDH, lactate dehydrogenase; ns, not significant.
*P < .05; **P < .01; ***P < .001.
Reprinted from Bassit RA, et al. Eur J Appl Physiol. 2010;108(5):945-955.
Example of Anaerobic Performance Benefit From
Creatine
*
Subjects:
14 active, but not “well-trained” males
Treatments:
5 g creatine monohydrate + 1 g glucose polymer for 5 days
Control: 6 g glucose polymer for 5 days
Training:
10 sets of either 5 or 6 x6-second maximal bike sprints with varying recoveries
(24, 54, or 84 seconds between sprints) over a period of 80 minutes
Assessed before (pre-loading) and after (post-loading) 5 days of treatment
Data are mean ± standard error.
*P < .05 vs placebo.
Data from Preen D, et al. Med Sci Sports Exerc. 2001;33(5):814-821.
Example of Creatine Effectiveness For Strength and
Muscle Mass
*
*
Subjects:
Treatments:
Training:
19 healthy, resistance-trained men
25 g creatine/day for 7 days
5 g creatine/day for 11 weeks
Controls: identical amounts of cellulose powder
12-week resistance training
Data are mean ± standard error.
Abbreviations: BM, body mass; FFM, fat-free mass; FM, fat mass.
*P ≤.05 vs placebo.
Data from Volek JS, et al. Med Sci Sports Exerc. 1999;31(8):1147-1156.
Creatine Effects on Increase in Cross-Sectional Area
in Different Muscle Fiber Types
*
*
*
Change in area from Week 0 to Week 12, µm2
Data are mean ± standard error.
*P ≤.05 vs placebo.
Data from Volek JS, et al. Med Sci Sports Exerc. 1999;31(8):1147-1156.
Is the Form of Creatine Important?
 Creatine monohydrate by far the most commonly studied
– Therefore, most evidence for efficacy
 Creatine not stable in liquids over a period of time
– Conversion to creatinine
– Creatine liquids or serums not as effective as powder1
 Limited studies with other forms
– Creatine ethyl ester, creatine pyruvate, creatine with D-pinitol, polyethylene
glycosylated creatine, etc
– No consistent improvements relative to creatine monohydrate
• Hard to improve on bioavailability of creatine monohydrate
– These forms are likely more expensive
1. Gill ND, et al. J Strength Cond Res. 2004;18(2):272-275.
Carbohydrate and Protein in the Facilitation
of Muscle Creatine Uptake
 60% increase in total muscle creatine in experimental group1
– N = 24 males
– 5 g creatine followed by 93 g glucose 30 minutes later; repeated 4×/day
– Control was 5 g creatine 4×/day
 Carbohydrate/Protein (carb/pro) and high-carbohydrate
treatments had similar creatine retention2
– 5 g creatine 4×/day plus one of the following each time:
• Placebo: 5 g glucose
• Carb/pro: 47 g glucose and 50 g protein
• High carb: 96 g glucose
• Low carb: 50 g glucose
– Low-carbohydrate treatment was not significantly different than placebo
 The large insulin response to either the high-carbohydrate or
carb/pro combination is likely responsible for driving further
uptake of creatine by muscle cells
Abbreviation: carb/pro, carbohydrate/protein.
1. Green AL, et al. Am J Physiol Endocrinol Metab. 1996;271(5):E821-E826.
2. Steenge GR, et al. J Appl Physiol. 2000;89(3):1165-1171.
Caffeine + Creatine: Is This a Concern?
 Caffeine eliminated the positive effect of creatine on a knee
extensor exercise in 1 study1
– High caffeine dose (5 mg/kg/day)
– 0.5 g/kg/day creatine for 6 days
– Caffeine did not inhibit the increase in muscle creatine
concentration
 Performance benefits shown in other studies of creatine2,3
– With lower doses of caffeine
– With other nutrients
1. Vandenberghe K, et al. J Appl Physiol. 1996;80(5):452-457.
2. Kraemer WJ, et al. Eur J Appl Physiol. 2007;101(5):637-646.
3. Smith AE, et al. J Int Soc Sports Nutr. 2010;7:10 doi: 10.1186/1550-2783-7-10.
Creatine Nonresponders?
 Individuals with high muscle levels of total creatine
(> 120 mmol/kg dry matter) may not be as responsive to
creatine supplementation1
– Conversely, vegetarians have lower creatine stores and may be more
responsive to creatine supplementation (loading and performance)2
1. Greenhaff PL, et al. Am J Physiol Endocrinol Metab. 1994;266(5):E275-E730.
2. Burke DG, et al. Med Sci Sports Exerc. 2003;35(11):1946-1955.
Creatine Side Effects
 Generally well tolerated in the gastrointestinal tract when
dose is ≤ 5 g1 at one time
 Weight gain is common (may or may not be considered a
“side effect”)
 Early concern was potential muscle cramping and impaired
temperature regulation2,3
– Possibly related to fluid shift to intracellular space (less circulating fluid)
 Several recent studies have dispelled any concern regarding
creatine with regard to muscle cramping, heat tolerance, and
hydration status3,4,5
– May actually augment sprint performance and reduce cramping in the heat6
1. Ostojic SM, et al. Res Sports Med. 2008;16(1):15-22.
2. Dalbo VJ, et al. Br J Sports Med. 2008;42(7):567-573.
3. Lopez RM, et al. J Athl Train. 2009;44(2):215-223.
4. Greenwood M, et al. J Athl Train. 2003;38(3):216-219.
5. Volek JS, et al. Med Sci Sports Exerc. 2001;33(7):1101-1108.
6. Wright GA, et al. J Strength Cond Res. 2007;21(3):655-660.
Creatine Safety
 Most publicized potential safety concern is renal function
 Long-term studies of the safety of creatine in athletes are lacking
 The general safety of creatine is supported via several lines of evidence
– Creatine supplementation (up to 5 years) in athletes have not shown impairment in
renal function or other clinical markers with up to 20 g/day in healthy athletes1,2,3
– Short-term studies have shown no effects of creatine supplementation on renal
parameters or hematologic indices4,5,6,7
• Loading: 15 to 20 g/day for 5 to 7 days
• Maintenance: 3 to 10 g/day for up to 9 weeks
– Comprehensive risk assessment showing an Observed Safe Level (OSL) of 5 g/day for
chronic supplementation8
– Long-term studies of creatine use in clinical populations such as patients with
Parkinson’s disease and gyrate atrophy of the choroid and retina have not shown
adverse effects9,10,11
• Typically maintenance doses (1.5 to 4 g/day) have been used for up to 5 years
1. Poortmans JR, et al. Med Sci Sports Exerc. 1999;31(8):1108-1110; 2. Mayhew DL, et al. Int J Sport Nutr Exerc Metab. 2002;12(4):453-460; 3. Kreider
RB, et al. Mol Cell Biochem. 2003;244(1-2):95-104; 4. Poortmans JR, et al. Eur J Appl Physiol Occup Physiol. 1997;76(6):566-567; 5. Robinson TM, et al.
Br J Sports Med. 2000;34(4):284-288; 6. Gualano B, et al. Eur J Appl Physiol. 2008;103(1):33-40; 7. Cancela P, et al. Br J Sports Med 2008;42(9):731-735;
8. Shao A, et al. Regul Toxicol Pharmacol. 2006;45(3):242-251; 9. Bender A, et al. Nutr Res. 2008;28(3):172-178; 10. Sipila I, et al. N Engl J Med.
1981;304(15):867-870; 11. Vannas-Sulonen K, et al. Ophthalmology. 1985;92(12):1719-1727.
Creatine Safety (continued)
 There have been a few isolated case reports of kidney dysfunction
(interstitial nephritis) that have been associated with creatine
supplementation1,2,3
 In each of these case studies, there are factors that greatly limit
interpretation of the results
– The patient had pre-existing kidney disease1
– The patient took 20 g/day for 4 weeks (exceeded recommended dose) and
symptoms started 4 weeks after stopping creatine2
– The patient took only 15 g creatine/week and was on many other dietary
supplements (17 amino acids, 18 herbal/plant extracts, and
16 other nutritional supplements)3
• Symptoms resolved when ALL supplements were stopped
• Causative agent could not be identified
1. Pritchard NR, et al. Lancet. 1998;351(9111):1252-1253.
2. Koshy KM, et al. N Engl J Med. 1999;340(10):814-815.
3. Thorsteinsdottir B, et al. J Ren Nutr. 2006;16(4):341-345.
Creatine Safety—Summary
 Creatine has an excellent overall safety profile in a
variety of healthy populations when taken as
recommended
– Do not exceed recommended doses:
• Loading: 20 g/day
• Maintenance: 5 g/day
 Creatine should not be taken by persons with
pre-existing kidney disease
 As with any dietary supplement, the user’s physician
should be made aware of its use in the rare event that
an adverse effect is experienced