Analysis of the efficacy, safety, and regulatory status of novel forms of creatine
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- Jäger, R., Purpura, M., Shao, A. et al. Amino Acids (2011) 40: 1369. doi:10.1007/s00726-011-0874-6
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Creatine has become one of the most popular dietary supplements in the sports nutrition market. The form of creatine that has been most extensively studied and commonly used in dietary supplements is creatine monohydrate (CM). Studies have consistently indicated that CM supplementation increases muscle creatine and phosphocreatine concentrations by approximately 15–40%, enhances anaerobic exercise capacity, and increases training volume leading to greater gains in strength, power, and muscle mass. A number of potential therapeutic benefits have also been suggested in various clinical populations. Studies have indicated that CM is not degraded during normal digestion and that nearly 99% of orally ingested CM is either taken up by muscle or excreted in urine. Further, no medically significant side effects have been reported in literature. Nevertheless, supplement manufacturers have continually introduced newer forms of creatine into the marketplace. These newer forms have been purported to have better physical and chemical properties, bioavailability, efficacy, and/or safety profiles than CM. However, there is little to no evidence that any of the newer forms of creatine are more effective and/or safer than CM whether ingested alone and/or in combination with other nutrients. In addition, whereas the safety, efficacy, and regulatory status of CM is clearly defined in almost all global markets; the safety, efficacy, and regulatory status of other forms of creatine present in today’s marketplace as a dietary or food supplement is less clear.
KeywordsCreatine Dietary supplements Ergogenic aids Exercise Performance
Creatine (N-(aminoiminomethyl)-N-methyl glycine) is an ingredient commonly found in food, mainly in fish and meat, and is sold as a dietary supplement in markets around the world. Its use as an ergogenic aid and possible treatment for certain neuromuscular disorders is well documented in scientific literature (Buford et al. 2007; Kreider et al. 2010). In recent years, the popularity of creatine has risen dramatically, especially among athletes. In the USA alone, creatine-containing dietary supplements make up a large portion of the estimated $2.7 billion in annual sales of sports nutrition supplements (NBJ 2009).
Accompanying this explosive growth in sales has been the introduction of different forms of creatine. Creatine monohydrate (CM), first marketed in the early 1990s, is the form most commonly found in dietary supplement/food products and most frequently cited in scientific literature. The introduction into the marketplace of alternate forms of creatine, beginning in the late 1990s, was presumably an attempt to differentiate the multitude of creatine-containing products available to consumers and improve certain attributes such as solubility and efficacy. However, the legal and regulatory status of these various forms of creatine in the USA and other markets around the world is at best uncertain. To date, with the exception of Japan, CM is the only form of creatine to be officially approved or accepted in key markets such as the USA, European Union (EU), Canada and South Korea. The continued presence of other forms of creatine in the marketplace, especially in the US, may be due to a multitude of factors. These include, but may not be limited to, a lack of awareness or understanding on the part of marketers of applicable laws and regulations, intentional noncompliance with the law, and/or inadequate enforcement of the law. The public health implications of widespread distribution and use of these unauthorized forms of creatine is unknown and warrants careful monitoring.
New forms of creatine are marketed with claims of improved physical, chemical, and physiological properties in comparison to CM. Claims include improved stability when combined with other ingredients or in liquids, improved solubility in water, improved bioavailability, and even an increase in performance. This review will evaluate the available literature on new forms of creatine and compare them to available data on CM in terms of efficacy and safety. In addition, the current international regulatory status of the various forms of creatine that are commercially available will be examined.
Creatine content of different forms of creatine
Form of creatine
Creatine content (%)
Difference in CM (%)
Creatine ethyl ester
Creatine malate (3:1)
Creatine methyl ester HCl
Creatine citrate (3:1)
Creatine malate (2:1)
Creatine α-amino butyrate
Sodium creatine phosphate
Creatine orotate (3:1)
For the assessment of the current regulatory status of the various forms of creatine, the Web sites of regulatory bodies for key markets around the world were accessed (USA: US Food and Drug Administration; Canada: Health Canada; EU: European Commission; Japan: Ministry of Health, Labor and Welfare; Korea: Korea Food and Drug Administration). Information derived from these sites was used to determine the legal and regulatory framework governing creatine products in these markets and the current regulatory status of the various forms of creatine as dietary supplements, food supplements, and natural health products.
Creatine salts such as citrate, maleate, fumarate, tartrate (Negrisoli and Del Corona 1997), pyruvate (Pischel and Weiss 1996), ascorbate (Pischel et al. 1999), and orotate (Abraham and Jiang 2005) were first introduced to the marketplace as early as the late 1990s. Creatine and acids with multiple acid moieties such as citric acid can form salts as well as complexation products. The first acid moiety of citric acid is strong enough (pka = 3.09) to form a salt with creatine; however, the other two moieties (pka2 = 4.75, pka3 = 5.41) should only be able to form complexes with creatine. A salt, a salt-complex combination, or a simple physical mixture can be differentiated by measurement of the enthalpy changes of neutralization, which ranges usually in the area of −55 to −66 kJ/mole for the salt formation to less than −5 kJ/mole for the change in complexation enthalpy to no changes in enthalpy for a physical mixture (1995). A “tricreatine citrate” is actually a complex of creatine citrate with two additional creatine moieties, resulting in a molecule with a ratio of creatine to citrate of 3:1.
The amount of creatine in different forms of creatine varies. Creatine monohydrate contains 87.9% of creatine, whereas the creatine content in other forms of creatine is lower with the exception of creatine anhydrous (see Table 1). Commercial creatine salts are formed in solution or by mechanical processes such as milling or grinding under the presence of residual water. Complexes are formed by the subsequent replacement of the solvating molecules by the new ligands.
One major limitation of creatine as an ampholytic amino acid is its rather low solubility in water. The solubility of creatine in water increases with temperature and the correlation between solubility and temperature is almost linear. One liter of water dissolves 6 g of creatine at 4°C, 14 g at 20°C, 34 g at 50°C, and 45 g at 60°C. The solubility of creatine can also be increased by lowering the pH of the solution. This principle is the basis for the improved solubility of creatine salts, since creatine salts lower the pH of water due to the nature of acid moiety. Creatine monohydrate dissolves at 14 g/L at 20°C resulting in a neutral pH of 7. A saturated solution of tricreatine citrate in water has a pH of 3.2; whereas a saturated solution of creatine pyruvate even has a pH of 2.6 (pyruvic acid is a stronger acid than citric acid). The decrease in pH results in an increase in solubility: 29 g/L creatine citrate at 20°C, and 54 g/L creatine pyruvate at 20°C. Normalized by the relative amount of creatine per molecule (monohydrate 87.9%, citrate 66%, pyruvate 60%), creatine citrate (19.14 g/L) shows a 1.55-fold and creatine pyruvate (32.4 g/L) a 2.63-fold better solubility when compared with the monohydrate (12.3 g/L). Whereas the creatine derivative creatinol-O-phosphate (5 g/L at 20°C) has inferior solubility, dicreatinol sulfate (1,370 g/L at 20°C) shows superior solubility when compared with CM, creatine salts, or creatine esters (Godfraind et al. 1983; Gastner et al. 2005).
Stability in solid form
Stability in solutions
Stability of other forms of creatine
Some creatine salts appear to be less stable when compared with CM. Tricreatine citrate results in creatinine levels of 770 ppm at 40°C (104°F) after 28 days of storage. However, the addition of carbohydrates has been shown to increase stability of some creatine salts (Purpura et al. 2005). Creatine salts are not expected to have a greater stability in solution; however, the pH lowering effect of the salt might reduce stability compared to CM in the same environment.
These findings are also in accordance with the recent investigations on the stability of CEE at 37ºC in both water and phosphate-buffered saline and the in vitro response of CEE to incubation in human plasma by H-NMR analysis (Giese and Lecher 2009b). The conversion of CEE to creatine by the esterases in human plasma was not detected, and the only species detected after the incubation period was creatinine. It is concluded that CEE is mostly converted into creatinine under physiological conditions encountered during transit through the various tissues, suggesting no ergogenic effect is to be expected from supplementation of CEE. The high stability of CM is well documented, whereas the stability of newer forms of creatine (salts, ester, etc.) either has not been investigated or appears to be inferior. New forms of creatine contain less of the active principal creatine in comparison to CM; however, creatine salts can offer an advantage over CM with regard to solubility.
The uptake of creatine is simplified in a two-step approach: first, uptake into the blood stream; second, uptake into the target tissue. The term ‘bioavailability’ refers to both the intestinal absorption and the use of a substance by the body’s cells and tissues. First indications of a potential change of creatine bioavailability can be gathered from the amount of creatine taken up into the blood plasma after oral administration. However, a change in the total amount of creatine in the blood plasma cannot be directly extrapolated to a potential increase in desired performance. An increased amount of creatine in the plasma could be the result of decreased uptake into the target tissue resulting in an actual decrease in overall bioavailability. On the other hand, an initial rise in plasma creatine levels, followed by a reduction in plasma levels, is an indication of increased uptake into the target tissue. This has been demonstrated in vivo by combining creatine with insulin-stimulating ingredients such as high amounts of glucose or protein (Bessman and Mohan 1992; Haughland and Chang 1975; Rooney et al. 2002). Conclusive proof of an increase in relevant bioavailability can only be gained by assessing the amount of creatine reaching the target tissue, the muscle, measured by muscle biopsy and/or whole body creatine retention assessed by measuring the difference between creatine intake and urinary excretion.
Over the years, there has been significant commercial interest in determining whether creatine could be delivered in a liquid form. The thought has been since CM is relatively insoluble that development of a liquid or suspended form of creatine may be more convenient to consume, be more readily absorbed into the blood stream, and promote a greater efficiency in transport of creatine to the muscle. Some companies have even claimed that minimal amounts of liquid creatine would need to be ingested because of enhanced efficiency in transport through the blood and into the muscle. A limitation with these theories is that CM is not stable for any substantial length of time in liquid. Consequently, while researchers have been working on ways to suspend creatine within gels and fluids, it has been generally considered to be impractical to develop into a product due to limitations in shelf-life. In addition, while people may prefer the taste of liquid or gel versions of creatine, there is no evidence that these delivery forms provide a superior performance benefit.
An alternative dissolved form of creatine is colloidal CM. CM is dissolved in its own crystal water and dispersed into a stable protective matrix containing carbohydrates (Kessel et al. 2004). The product is claimed to be the only solubilized form of powdered creatine in the market, making it more bioavailable and stable. However, no evidence has been published to date to substantiate any performance or ergogenic benefit from this form of creatine.
Several studies have also evaluated whether co-ingestion of creatine with other nutrients may influence creatine retention. Initial work by Green and colleagues (Green et al. 1996a, b) demonstrated that co-ingesting creatine (5 g) with large amounts of glucose (e.g., 95 g) enhanced creatine and carbohydrate storage in muscle. Subsequent studies by Steenge et al. (2000) found ingesting creatine (5 g) with 47–97 g of carbohydrate and 50 g of protein also enhanced creatine retention. The researchers suggested that creatine transport was mediated in part by glucose and insulin. As a result, additional research has been undertaken to assess the effect of co-ingesting creatine with nutrients that may enhance insulin sensitivity on creatine retention.
In a follow-up study, Kerksick et al. (2009) examined whether co-ingestion of d-pinitol with CM would affect training adaptations, body composition, and/or whole-body creatine retention in resistance-trained males. In the study, 24 resistance trained males were randomly assigned in a double-blind manner to CM + d-pinitol or CM alone prior to beginning a supervised 4-week resistance training program. Subjects ingested a typical loading phase (i.e., 20 g/day for 5 days) before ingesting 5 g/day for the remaining 23 days. Results revealed that creatine retention increased in both groups as a result of supplementation. However, no significant differences were observed between groups in training adaptations. Consequently, additional research is needed to determine whether d-pinitol supplementation enhances creatine uptake and/or affects the ergogenicity of creatine supplementation before firm conclusions can be drawn.
In analysis of this literature, it is clear that CM supplementation promotes significant increases in muscle creatine levels in most individuals. There is some evidence that co-ingestion of CM with various nutrients (e.g., carbohydrate, protein, d-pinitol) may enhance creatine uptake to a greater degree. However, there is no evidence that effervescent creatine, liquid creatine, and/or CEE promotes greater uptake of creatine to the muscle. Rather, there is some evidence that some of these forms of creatine may be less effective and/or be of greater clinical concern in terms of safety.
Numerous studies have found that CM supplementation increases muscle phosphagen levels generally by 10–40% (Greenhaff 1997a; Harris et al. 1992a; Hultman et al. 1996). Acute and chronic supplementation of CM has been reported to improve performance primarily during high intensity, intermittent activities (Greenhaff 1997a; Kraemer and Volek 1999; Kreider 2003). The impact on performance has been associated with the magnitude of change in baseline phosphagen levels (Burke et al. 2003a; Greenhaff 1997a). Numerous studies have shown that CM supplementation during training promotes greater gains in performance and/or fat-free mass (Cribb and Hayes 2006; Kreider et al. 1998; Volek et al. 1997, 1999; Willoughby and Rosene 2001; Willoughby and Rosene 2003). The only clinically significant side effect reported in literature has been weight gain, which is an attribute desired by many athletes who desire to increase muscle mass as well as clinical populations concerned about muscle wasting (Bender et al. 2008; Dalbo et al. 2008; Kreider et al. 2003a; Schilling et al. 2001). Consequently, CM has proven to be one of the most effective, safe, and well-studied ergogenic aids.
Creatine has been combined with different organic acids to form creatine salts with the intention of using acids that will create a synergistic effect or simply improve the properties of creatine. A limitation of this approach is that effective daily doses of creatine and the acid will have to match to achieve meaningful physiological effects. In addition, creatine salts will have to outperform the physical mixture of CM and the corresponding acid, showing synergistic effects.
Inorganic salts of pyruvic acid have been shown to improve endurance when ingested in high amounts in rats (Ivy 1998), and consequently creatine has been combined with pyruvic acid to form creatine pyruvate (CPY), with the suggested benefit of a synergistic effect between the two. The potential endurance enhancing effects of CPY has been investigated in several studies, using doses of pyruvate significantly lower than previously found to be effective. Two studies investigating the endurance exercise capacity of short-term CPY supplementation showed mixed results. In this regard, 7 days of 7 g per day CPY supplementation did not beneficially impact endurance capacity or intermittent sprint performance in well-trained cyclists (Van Schuylenbergh et al. 2003), whereas 5 days of 7.5 g per day CPY intake increased paddling speed and resulted in decreased lactate concentrations in Olympic canoeists, suggesting an increase in aerobic metabolism (Nuuttilla 2000). A recent double-blind, placebo-controlled, randomized study evaluated the effect of oral CPY supplementation on exercise performance in healthy young athletes in comparison to placebo and TCC (Jäger et al. 2008b). It was concluded that 4 weeks of supplementation with creatine salts significantly improved performance during intermittent handgrip exercise of maximal intensity and that CPY might benefit endurance, due to enhanced aerobic metabolism. This study is a first indication that the creatine salt CPY may have potential advantage over CM. However, more research is needed to investigate this effect.
Creatine citrate (CC) has been used in several performance studies; however, none of those studies compared the product to CM. High-dose, short-term CC supplementation (4 × 5 g CC per day for 5 days) has been found to increase anaerobic working capacity (AWC) in healthy physically active women (Eckerson et al. 2004) and is able to delay the onset of neuromuscular fatigue during cycle ergometry (Smith et al. 2007). In a recent study, CC supplementation was able to raise the ventilatory threshold during intensity interval training (Graef et al. 2009). Although these studies are interesting, more research is needed particularly comparing CC to CM before it can be concluded that CC has any additional benefits.
To date, Spillane et al. (2009) are the only group that has studied the impact of CEE supplementation on training adaptations in resistance trained individuals. The researchers randomly assigned in a double-blind manner 30 male resistance-trained athletes to ingest 0.30 g/kg per day fat-free mass (about 20 g/day) of either a placebo, CM, or CEE for 42 days. As stated previously, CEE supplementation did not promote greater total muscle creatine levels in comparison to placebo. In terms of training adaptations, CEE supplementation did not promote greater gains in body mass, fat-free mass, strength, or sprint performance. These findings indicate that CEE has no apparent ergogenic value over CM despite widespread claims that it is a more superior form of creatine. Additionally, the significantly higher creatinine levels observed indicate it is degraded to a greater degree and may pose greater safety concerns.
Creatinol in the form of creatinol-O-phosphate (COP) has been described and used in subjects with deficient myocardial circulation (Guglielmi and Mammarella 1979). Based on the findings that intravenous administration of COP in healthy human subjects led to increased values of creatinine in urine, it is speculated that creatinol acts as a precursor of creatine and is metabolized into creatine within the body (Melloni et al. 1979). The increased urinary values are derived from the degradation of creatine into creatinine through the typical biochemical pathways. Only one study investigated the ability of COP to improve muscular performance (Nicaise 1975). Fifty female patients were treated intramuscularly and intravenously with COP and performance tested utilizing a Martin Vigorimeter to measure muscle strength in both hands. The administration of COP resulted in a statistically significant improvement in hand strength.
Creatine-containing nutritional formulations
Since a number of studies have reported that CM supplementation can increase performance and/or training adaptations, there has been interest in determining whether ingesting creatine with other potentially ergogenic nutrients may affect performance and/or training adaptations to a greater degree. For example, studies have indicated that ingesting creatine with vitamin and mineral-fortified carbohydrate and protein supplements promote greater gains in strength and fat-free mass than carbohydrate or carbohydrate and protein supplements alone (Kreider et al. 1996, 1999; Cribb et al. 2007a; Kreider et al. 1998). Additionally, co-ingesting creatine with different types of protein may have differential effects on gains in fat-free mass and/or training adaptations (Kerksick et al. 2007; Cribb et al. 2007b). Several studies have also indicated that co-ingesting CM with other potentially ergogenic nutrients such as beta-hydroxy-beta-methylbutyrate (HMB) (Jowko et al. 2001), beta-alanine (Hoffman et al. 2006), phosphates (Eckerson et al. 2005), and alpha-lipoic acid (Burke et al. 2003b) may have some additive effects. While not all studies have reported statistically significant differences, these studies and others support contentions that including CM in nutritional formulations may promote additive and/or synergistic effects on training and/or performance.
The legal and regulatory status of creatine forms other than CM in the USA, the largest market worldwide for dietary supplements, is somewhat ambiguous. According to US law, a “dietary supplement” is defined as “…a product (other than tobacco) intended to supplement the diet that bears or contains one or more of the following dietary ingredients: a vitamin; a mineral; an herb or other botanical; an amino acid; a dietary substance for use by man to supplement the diet by increasing the total dietary intake; or a concentrate, metabolite, constituent, extract…” (Federal Food, Drug and Cosmetic Act 1938a). Creatine, an amino acid derivative, would appear to satisfy this requirement. A “new dietary ingredient” (NDI) is defined as “…a dietary ingredient that was not marketed in the United States before October 15, 1994…” The law considers a dietary supplement that contains a new dietary ingredient adulterated, unless the ingredient has been present in the food supply as an article used for food in a form in which the food has not been chemically altered, or there is a history of safe use of the ingredient and that the ingredient is the subject of a 75-day premarket notification to the Food and Drug Administration (FDA) (Federal Food, Drug and Cosmetic Act 1938b). The requirement for the notification to FDA prior to entering the market is to demonstrate to the agency that the ingredient, as intended to be used, is reasonably expected to be safe.
the form(s) of creatine may not be legal dietary ingredients as defined by the FD&C Act §201(ff);
inadequate information to conclude that the form(s) of creatine is reasonably expected to be safe due to insufficient safety data and/or failure to establish a history of safe use; and/or,
inadequate information about the chemical identity of the creatine form(s)
In each of its letters of objection, FDA includes the following text: “Therefore, your product may be adulterated under 21 U.S.C 342(f)(1)(B) as a dietary supplement that contains a new dietary ingredient for which there is inadequate information to provide reasonable assurance that such ingredient does not present a significant or unreasonable risk of illness or injury. Introduction of such a product into interstate commerce is prohibited under 21 U.S.C. 331(a) and (v)…”
Due to the nature of the notification process in the USA, a non-response from FDA could, in theory, be considered a “non-objection” from the agency. Thus, the agency’s view on the regulatory status of CPY remains unclear. However, with the notification process, FDA maintains the right to object at any time, whether it has previously responded or not. Thus, with the exception of CM and perhaps CPY, other forms of creatine appear to be on the US market without the proper sanction from FDA or without notification to FDA altogether.
In Canada, creatine is considered a natural health product (NHP), the regulation of which is administered by the Natural Health Products Directorate (NHPD) of Health Canada (NHPD 2003). The NHP regulation requires that all NHP products be licensed and approved by the NHPD, and each is assigned an eight-digit numerical code. With respect to ingredients, the NHPD has developed a compendium of monographs as a tool to assist with the review of the safety and efficacy of many commonly used NHPs (NHPD 2007). This allows applicants to reference an NHPD monograph in support of their product license application and circumvents the need to evaluate ingredients already known to be safe and efficacious when used under the conditions specified in the NHPD monograph. For creatine, only CM has been approved for use in NHPs and was recently assigned a monograph by the NHPD (NHPD 2008). At present, there are 17 creatine-containing licensed and approved NHPs, all of which contain CM (NHPD 2010).
In the EU, creatine is regulated as a food supplement under the Food Supplement Directive (FSD) (EPC 2002) and the directive on substances that may be added for specific nutritional purposes in foods for particular nutritional uses (FPNU) (EPC 2001). In 2004, the European Food Safety Authority (EFSA) issued a positive opinion on CM for FPNU (EFSA 2004). No other opinions have been issued on any other creatine forms, either by EFSA or its predecessor (the Scientific Committee on Food, SCF).
In Japan, dietary substances are legally classified as food, food additives, or “non-drug” (food), and are subject to one of two regulations, both enforced by the Ministry of Health, Labor and Welfare (MHLW). CM is categorized as a “non-drug” (MHLW 2009) and is permitted for use as both a food ingredient and a food additive under the Food Sanitation Law (MHLW 2001), allowing it to be imported, distributed, and produced as food in Japan.
New forms of creatine must be approved by the MHLW before they can be imported, distributed, and produced in Japan, one requirement being that sufficient documentation on the safety and similarity to CM must be provided. Currently, two new forms of creatine, CC, and CPY have been approved for import to Japan.
In South Korea, the category of dietary supplements was established through legislation in 2004 and is regulated by the Korean Food and Drug Administration (KFDA) (Shimizu 2008). New ingredients must be approved by KFDA and are required to have sufficient toxicological and human clinical trial data supporting the safety and efficacy of the recommended daily dosage. An application for registration of CM was filed with the KFDA in 2005 and was approved for use in dietary supplements in 2008, along with an accompanying health claim (KFDA 2009). At present, no other forms of creatine have been approved for use in South Korea.
In Brazil, nonessential nutrients (such as creatine) are regulated as bioactives or novel food ingredients and must receive approval from the Brazilian National Sanitary Surveillance Agency (or ANVISA) before entering the marketplace (Lajolo and Miyazaki 2007) the approval is based on a comprehensive review of the safety and efficacy of the ingredient and establishes specific requirements for dosage and purity levels, and approved label claims, among other important parameters. ANIVSA recently approved the use of CM in foodstuffs for athletes (reference “Regulations concerning foodstuffs for athletes”. Chapter III, Article 10. The National Health Surveillance Agency Collegiate Board of Directors. 2010). Thus far, Brazil is the only Latin American country to approve the use of creatine and this approval applies specifically to CM.
The legal and regulatory status of CM is unequivocal in the major global markets for dietary or food supplements. The status of other creatine forms present in the marketplace and/or subjected, in the case of the USA, to a pre-market notification is less clear. These alternatives to CM are prevalent in the market, yet do not appear to have met the necessary statutory or regulatory requirements in any of the countries examined. In countries where regulatory approval is required prior to use, with the exception of Japan (CC and CPY), none of these forms has achieved approval. However, it is possible that at the time of this review, additional decisions may be pending by regulatory authorities.
Global regulatory status for various forms of creatine
Creatine monohydrate (CM)
Creatine ethyl ester (CEE)
Creatine pyruvate (CPY)
(Di, Tri) Creatine malate (CML)
(Sodium) Creatine phosphate (CP)
Tricreatine orotate (TCO)
Creatine citrate (CC)
Grandfathered dietary ingredient
Objected to by USFDA
NDIN filed; no decision posted to date
Objected to by USFDA
Objected to by USFDA
Approved natural health product
Approved for use in foods for particular nutritional uses
Approved substance used as food additive as generally taken foodstuffs
Approved for importation
Approved for importation
Approved for use in dietary supplements
Approved for use in foodstuffs for athletes
Explanations as to why these alternate creatine forms are prevalent in the marketplace despite not having met the legal and regulatory requirements in the various markets are likely two-fold. Legal definitions of and regulatory requirements for “dietary supplements” (USA and Korea), “food supplements” (EU), “natural health products” (Canada), and “non-drug food additives” (Japan) are complex, differ between countries/regions, and can be confusing. Lack of awareness and/or understanding of the given country’s applicable requirements may be one explanation for the lack of compliance on the part of some marketers. To the extent that the laws and regulations are known and understood, inadequate enforcement by regulators can create an environment where noncompliance is perceived to be without consequences, resulting in the forgoing of required registration or notification requirements. In the USA, the increased prevalence of these alternate forms (CEE in particular) in dietary supplement products, with no enforcement action from FDA, has helped to support this misperception.
The public health implications of having unsanctioned or unapproved forms of creatine on the market remain to be fully realized. While classical animal toxicity data (Mertschenk et al. 2001) and short- and long-term clinical safety studies have been conducted in humans (Kreider et al. 2003a; Schilling et al. 2001; Poortmans and Francaux 1999; Dalbo et al. 2008), the basic safety data on new forms of creatine is lacking. At present, there do not appear to be any imminent or specific safety concerns associated with any of these alternate forms. However, this must be monitored carefully through post-market surveillance and published case reports. As far as the marketplace is concerned, the presence of these newer and typically more expensive forms of creatine in a multitude of consumer products that are often marketed with misleading and/or unsubstantiated claims of greater bioavailability, efficacy, and safety sets a negative precedent. The reality that companies need not fulfill the necessary registration or notification requirements to satisfy regulatory authorities, but still feel free to market their ingredients/products without penalty establishes an “unlevel” playing field among competitors. This undermines any incentive to invest upfront resources to establish ingredients as safe and efficacious prior to reaching consumers. Inevitably, this will result in unintended and unforeseen consequences, which will serve to erode consumer confidence.
Creatine monohydrate supplementation has been consistently reported in the literature to increase muscle phosphagen levels, improve repetitive high-intensity exercise performance, and promote greater training adaptations. Moreover, it has been found to be a stable form of creatine that is not significantly degraded during the digestive process and either taken up by muscle or eliminated in the urine. No medically significant side effects have been reported from CM supplementation despite the widespread worldwide use and the regulatory status of CM not being well established. Conversely, the efficacy, safety, and regulatory status of most of the newer forms of creatine found in dietary supplements have not been well established. Additionally, there is little to no evidence supporting marketing claims that these newer forms of creatine are more stable, digested faster, and more effective in increasing muscle creatine levels and/or associated with fewer side effects than CM.
The authors would like to thank all of the research participants and researchers who have contributed to creatine research.
Conflict of interest
The authors declare that they have no competing interests. AS is fully employed by a US trade association representing the dietary supplement industry.
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