Risk assessment for creatine monohydrate☆
Introduction
First discovered in 1832, creatine is a naturally occurring amino acid-like compound made in the liver, kidneys and pancreas from the essential amino acids arginine, glycine and methionine (Balsom et al., 1994). In humans, over 95% of the total creatine content is located in skeletal muscle. A 70 kg male possess approximately 120 g of total creatine with a daily turnover estimated to be around 2 g. Part of this turnover can be replaced through exogenous sources of creatine in foods, including meat, fish and poultry (Balsom et al., 1994). In its phosphorylated intracellular form as creatine phosphate, it provides the high energy phosphate for adenosine triphosphate.
As a dietary supplement, creatine is available in powdered, tablet and liquid forms as primarily creatine monohydrate, the only form having been included in published, randomized, controlled trials. In the last 10 years, nearly 70 randomized, controlled trials have been conducted on or with creatine, with the majority examining creatine’s performance-enhancing benefits. The majority of these clinical trials have found beneficial effects from creatine supplementation, particularly during short, repeated bursts of high-intensity activity (Bemben and Lamont, 2005). Recent research efforts have also focused on the potential benefits of creatine use in patients coping with certain neuromuscular disorders (Persky and Brazeau, 2001).
Initial recommendations for creatine use stemmed from early research using 5–7 days of “loading” with 20–30 g per day (divided into 4–6 equal, 5 g doses), resulting in increased muscle creatine content. Based on new research, refinements have been made to this strategy and now many athletes consume only one 5 g dose approximately 60 min prior to, or immediately after training (exercise is known to enhance creatine uptake by about 10%) (Bemben and Lamont, 2005). Although responses are quite variable from person to person, subjects ingesting creatine average a 2–5 pound greater gain in muscle mass, and 5–15% greater increases in muscle strength and power compared to control (or placebo) subjects (Branch, 2003, Bemben and Lamont, 2005). Creatine supplementation does not appear to enhance endurance-related exercise performance (Bemben and Lamont, 2005).
Research indicates that once muscle stores of creatine are full, they can remain elevated for an additional 4–5 weeks without further supplementation (Snow and Murphy, 2003). Normal healthy adults who continue to use creatine after their muscle stores have reached peak levels may find the additional creatine is converted to creatinine and excreted in the urine (Pline and Smith, 2005). Urinary creatinine levels are commonly used as a marker of kidney function. Individuals who ingest creatine will frequently have elevated creatinine levels—this is normal and represents an increased rate of muscle creatine conversion to creatinine rather than an abnormality of kidney function. The widespread use of this ingredient in dietary supplements suggests a need to evaluate the safety of creatine through quantitative risk assessment.
Most upper safe levels of nutrients and related substances are based on widely applicable risk assessment models used by the US Food and Nutrition Board (FNB) in its Dietary Reference Intakes documents in 1997 and after (Food and Nutrition Board. Institute of Medicine, 1997, Food and Nutrition Board. Institute of Medicine, 1998a, Food and Nutrition Board. Institute of Medicine, 1998b, Food and Nutrition Board. Institute of Medicine, 2000, Food and Nutrition Board. Institute of Medicine, 2001). The FNB method and reviews are a formalization and extension of the quantitative methods widely used earlier in risk assessment of other substances, and by the food and dietary supplement industries. Because of the systematic, comprehensive and authoritative character of the FNB risk assessment method for nutrients, this approach has gathered widespread support and adoption by others such as the European Commission Scientific Committee on Food (SCF) (European Commission, 2001), the United Kingdom Expert Group on Vitamins and Minerals (EVM) (Food Standards Agency, 2003) and more recently by the Food and Agriculture Organization/World Health Organization project report A Model for Establishing Upper Levels of Intake for Nutrients and Related Substances (FAO/WHO, 2006) with some slight modifications. All these reports reflect the concepts and procedures established much earlier for the risk assessment of non-carcinogenic chemicals (National Research Council, 1983).
Section snippets
Methods
The safety evaluation method applied to orally administered creatine monohydrate is from the Council for Responsible Nutrition (CRN) Vitamin and Mineral Safety, 2nd Edition (Hathcock, 2004), which contains the basic features of the FNB method and also the Observed Safe Level (OSL) modification recently adopted as a Highest Observed Intake (HOI) in the FAO/WHO report.
Overall, this risk analysis was derived from the human clinical trial database through the following major steps:
- 1.
Derive a safe
Scientific evidence related to safety
Media reports of links between creatine use and muscle strains, muscle cramps, heat intolerance, and other side effects are not supported by the scientific literature. Studies conducted in athletes and military personal indicate a substantial level safety of both short- and long-term creatine use in healthy adults (Poortmans and Francaux, 1999, Robinson et al., 2000, Bennett et al., 2001, Greenwood et al., 2003a, Greenwood et al., 2003b, Kreider et al., 2003). Concerns about high dose creatine
Human NOAEL or OSL (HOI)
Research on creatine safety and toxicity has focused primarily on its effect on renal function. This stems from the knowledge that excess creatine is eliminated from the body via glomerular filtration in the kidney either as creatine or its metabolite, creatinine (Ropero-Miller et al., 2000). Two human case reports (Pritchard and Kalra, 1998, Koshy et al., 1999) and a single study in rats with renal disease (Edmunds et al., 2001) have also fueled concerns about creatine’s affect on the kidney.
Conclusions
The body of evidence supporting a beneficial effect of creatine supplementation performance outcomes continues to grow. The increased availability and appearance of this ingredient in dietary supplement products, along with continuing accusations of potential adverse effects, warranted the present risk assessment. Application of risk assessment methodology to the available published human clinical trial data involving creatine supports a high level of confidence in this ingredient with respect
References (87)
- et al.
Comparison of creatine ingestion and resistance training on energy expenditure and limb blood flow
Metabolism
(2001) - et al.
Creatine supplementation increases renal disease progression in Han:SPRD-cy rats
Am. J. Kidney Dis.
(2001) - et al.
Changes of tissue creatine concentrations upon oral supplementation of creatine-monohydrate in various animal species
Life Sci.
(2001) - et al.
Oral creatine supplementation enhances upper extremity work capacity in persons with cervical-level spinal cord injury
Arch. Phys. Med. Rehabil.
(2002) - et al.
Effects of creatine on thermoregulatory responses while exercising in the heat
Nutrition
(2005) - et al.
Renal dysfunction accompanying oral creatine supplements
Lancet
(1998) - et al.
Creatine supplementation enhances muscular performance during high-intensity resistance exercise
J. Am. Diet Assoc.
(1997) - et al.
Effect of creatine loading on anaerobic performance and skeletal muscle volume in NCAA Division I athletes
Nutrition
(2002) - et al.
Low dose creatine supplementation enhances sprint phase of 400 meters swimming performance
J. Med. Assoc. Thai.
(2004) - et al.
Creatine in humans with special reference to creatine supplementation
Sports Med.
(1994)
Oral creatine supplementation decreases plasma markers of adenine nucleotide degradation during a 1-h cycle test
Acta Physiol. Scand.
Creatine supplementation and exercise performance: recent findings
Sports Med.
Effect of creatine on performance of militarily relevant tasks and soldier health
Mil. Med.
Effect of creatine supplementation on body composition and performance: a meta-analysis
Int. J. Sport Nutr. Exerc. Metab.
The effect of 7 days of creatine supplementation on 24-hour urinary creatine excretion
J. Strength Cond. Res.
Creatine supplementation combined with resistance training in older men
Med. Sci. Sports Exerc.
Effect of recovery interval on multiple-bout sprint cycling performance after acute creatine supplementation
J. Strength Cond. Res.
Acute creatine supplementation and performance during a field test simulating match play in elite female soccer players
Int. J. Sport Nutr. Exerc. Metab.
Combined creatine and protein supplementation in conjunction with resistance training promotes muscle GLUT-4 content and glucose tolerance in humans
J. Appl. Physiol.
Plasma guanidino compounds are altered by oral creatine supplementation in healthy humans
J. Appl. Physiol.
Effect of two and five days of creatine loading on anaerobic working capacity in women
J. Strength Cond. Res.
Effects of creatine supplementation and exercise training on fitness in men 55–75 yr old
J. Appl. Physiol.
CINRG randomized controlled trial of creatine and glutamine in Duchenne muscular dystrophy
Ann. Neurol.
Effects of creatine use on the athlete’s kidney
Curr. Sports Med. Rep.
Creatine supplementation in chronic heart failure increases skeletal muscle creatine phosphate and muscle performance
Cardiovasc. Res.
Cramping and injury incidence in collegiate football players are reduced by creatine supplementation
J. Athl. Train.
Creatine supplementation during college football training does not increase the incidence of cramping or injury
Mol. Cell Biochem.
Few adverse effects of long-term creatine supplementation in a placebo-controlled trial
Int. J. Sports Med.
Vitamin and Mineral Safety
Oral creatine supplementation facilitates the rehabilitation of disuse atrophy and alters the expression of muscle myogenic factors in humans
J. Physiol.
Creatine ingestion increases anaerobic capacity and maximum accumulated oxygen deficit
Can. J. Appl. Physiol.
Creatine feeding increases GLUT4 expression in rat skeletal muscle
Am. J. Physiol. Endocrinol. Metab.
Effects of creatine on body composition and strength gains after 4 weeks of resistance training in previously nonresistance-trained humans
Int. J. Sport Nutr. Exerc. Metab.
Interstitial nephritis in a patient taking creatine
N. Engl. J. Med.
Effects of creatine supplementation on body composition, strength, and sprint performance
Med. Sci. Sports Exerc.
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