Bioavailability, Efficacy, Safety, and Regulatory Status of Creatine and Related Compounds: A Critical Review

Richard B Kreider, Ralf Jäger, Martin Purpura, Richard B Kreider, Ralf Jäger, Martin Purpura

Abstract

In 2011, we published a paper providing an overview about the bioavailability, efficacy, and regulatory status of creatine monohydrate (CrM), as well as other "novel forms" of creatine that were being marketed at the time. This paper concluded that no other purported form of creatine had been shown to be a more effective source of creatine than CrM, and that CrM was recognized by international regulatory authorities as safe for use in dietary supplements. Moreover, that most purported "forms" of creatine that were being marketed at the time were either less bioavailable, less effective, more expensive, and/or not sufficiently studied in terms of safety and/or efficacy. We also provided examples of several "forms" of creatine that were being marketed that were not bioavailable sources of creatine or less effective than CrM in comparative effectiveness trials. We had hoped that this paper would encourage supplement manufacturers to use CrM in dietary supplements given the overwhelming efficacy and safety profile. Alternatively, encourage them to conduct research to show their purported "form" of creatine was a bioavailable, effective, and safe source of creatine before making unsubstantiated claims of greater efficacy and/or safety than CrM. Unfortunately, unsupported misrepresentations about the effectiveness and safety of various "forms" of creatine have continued. The purpose of this critical review is to: (1) provide an overview of the physiochemical properties, bioavailability, and safety of CrM; (2) describe the data needed to substantiate claims that a "novel form" of creatine is a bioavailable, effective, and safe source of creatine; (3) examine whether other marketed sources of creatine are more effective sources of creatine than CrM; (4) provide an update about the regulatory status of CrM and other purported sources of creatine sold as dietary supplements; and (5) provide guidance regarding the type of research needed to validate that a purported "new form" of creatine is a bioavailable, effective and safe source of creatine for dietary supplements. Based on this analysis, we categorized forms of creatine that are being sold as dietary supplements as either having strong, some, or no evidence of bioavailability and safety. As will be seen, CrM continues to be the only source of creatine that has substantial evidence to support bioavailability, efficacy, and safety. Additionally, CrM is the source of creatine recommended explicitly by professional societies and organizations and approved for use in global markets as a dietary ingredient or food additive.

Keywords: dietary ingredients; ergogenic aids; exercise; performance.

Conflict of interest statement

R.J. and M.P. are researchers and principals for Increnovo, LLC, which conducts research, develops intellectual property, and consults with industry about raw ingredients and product formulations. They have filed patents for creatine while being employed by SKW Trostberg/Degussa AG (now Alzchem), from 1999 to 2007, with all the patents being expired or abandoned (WO2006015774A1, US20110123654A1, WO2003071884A1, US20050096392A1, WO2006122809A1, WO2002052957A1, WO2003047367A1, US20040006139A1, US20020072541A1, DE10244281A1, DE10119608A1), and conducted research on various forms of creatine. R.B.K. has conducted sponsored research on dietary supplements including creatine through grants awarded to the universities he has been affiliated with, received honorarium for presenting research related to dietary supplements and creatine at industry-sponsored scientific conferences, has served as an expert witness on cases related to dietary supplements, including past and current cases related to creatine, and is acting Chair of the Scientific Advisory Board on Creatine for Alzchem. He has also presented research related to creatine at a number of international conferences.

Figures

Figure 1
Figure 1
PRISMA flow chart.
Figure 2
Figure 2
Changes in plasma creatine concentrations after administration of 5 g of creatine monohydrate (CrM) in solution (A) [12]; water, 2 g of CrM administered in solution, or 408 g of slightly cooked meat containing 5.4 g of creatine (B) [45]; or 2 g of CrM provided in solution, gel suspension, or in a hard candy lozenge (C) [45].
Figure 3
Figure 3
Chemical structure of creatine and creatine monohydrate.
Figure 4
Figure 4
Conversion of creatine to creatinine (A) and influence of pH on creatine stability in solution (B). Creatine stability figure adapted from Howard and Harris [55].
Figure 5
Figure 5
Influence of pH on creatine stability in solution.
Figure 6
Figure 6
Chemical structure of tri-creatine citrate and creatine pyruvate with plasma creatine changes after oral administration of equal molar doses of creatine monohydrate (CrM), creatine citrate (CC) and creatine pyruvate (CPY). Adapted from Jäger et al. [63].
Figure 7
Figure 7
Chemical structure of magnesium creatine.
Figure 8
Figure 8
Chemical structure of creatine and creatine ethyl ester.
Figure 9
Figure 9
Degradation of creatine ethyl ester to creatinine. Adapted from Jäger et al. [25].
Figure 10
Figure 10
Serum creatine (A), serum creatinine (B), and muscle creatine content (C). * Represents significant change from baseline. † in panel A indicates significantly higher serum creatine concentrations in CrM when compared to PLA (p = 0.007) and CEE (p = 0.005). † in panel B indicates serum creatinine in the CEE group was greater than PLA (p = 0.001) and CrM (p = 0.001). † in panel C shows the PLA group was significantly less than the CrM (p = 0.026) and CEE (p = 0.041) groups. Adapted from Spillane et al. [27].
Figure 11
Figure 11
Comparison of creatine monohydrate and creatine HCl structures.
Figure 12
Figure 12
Chemical structure of creatine nitrate. (A,B) show 5 h area under the curve data after plasma creatine and plasma nitrate, respectively. (C) shows mean changes in muscle creatine content with 95% confidence intervals after 7 days of loading 4 doses/day and 21 days of ingesting 1 those/day. † Represents significant change from baseline, PLA and P represent placebo, CrM represents creatine monohydrate, and CrN represents creatine nitrate.
Figure 13
Figure 13
Changes in muscle creatine content, fat-free mass, and 30 s cycling sprint performance after 7 and 28 days of CrM-Alk supplementation at 1.5 g/day recommended doses (▲), CrM-Alk supplementation of 20 g/day for 7 days and 5 g/day for 21 days (◼), or CrM supplementation of 20 g/day for 7 days and 5 g/day for 21 days (●). Adapted from Jagim et al. [28].
Figure 14
Figure 14
Changes in plasma creatine levels after oral ingestion of water, 5 mL of creatine serum (CS) purportedly providing 2.5 g of CrM, and 2.5 g of CrM in solution (A) [26] and 5 days of 5 mL of CS purportedly providing 2.5 g of creatine (CS-LD), 5 mL of a flavored placebo (PL-LD), 8 × 5 mL of CS (CS-HD) purportedly providing 20 g/day of creatine, 8 × 5 mL of flavored placebo (PL-HD), or 4 × 5 g/day of CrM (B) [26], Adapted from Harris et al. [38] and Kreider et al. [26].
Figure 15
Figure 15
Comparison of creatine, creatine monohydrate, L-leucine, and creatyl-L-leucine chemical structures.
Figure 16
Figure 16
Blood, muscle, and brain creatine content in response to rats fed a control diet, 4.0 g/kg/day of creatine monohydrate (CrM), or 6.56 g/kg/day of creatyl-L-Leucine (CLL) for 7 days. (A) presents arterial plasma creatine concentration, (B) presents portal vein creatine concentration, (C) presents muscle creatine content, and (D) presents brain creatine content data for each group. Data are means ± standard deviations. **** = p < 0.0001, *** = p < 0.001, ** = p < 0.01, * p < 0.05, ns = not statistically significant between groups identified in brackets. Adapted from da Silva [221].
Figure 17
Figure 17
Chemical structure of Creatinol-O-Phosphate.

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