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

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.

Analysis of the efficacy, safety, and cost of alternative forms of creatine available for purchase on Amazon.com: are label claims supported by science?

“…While the Kreider et al. [ 35 ] review article has not been validated and the recommendations therein are not specifically adopted or enforced by the Food and Drug Administration (FDA) or the Federal Trade Commission (FTC) that oversee dietary supplements and advertising of dietary supplements, it does provide a detailed summary of the research (or lack thereof) on alternative forms of creatine. We recognize this is an inherent limitation of this study and we disclose some limitations of this reference in our discussion.…”

“…CM itself is marketed and sold in various forms such as micronized CM (CM with smaller mesh sized particles), buffered CM (CM “pH-corrected” to a higher pH), effervescent CM, serum CM, and Creabev® (described as a soluble and stable form of CM to enhance stability in fluid); however, some of these have no evidence of being effective and/or superior forms of CM despite the marketing claims made by supplement manufacturers [ 35 ]. In addition to other forms of CM marketed and sold in the United States that have not been as thoroughly studied as Creapure®, other novel or alternative forms of creatine that are not CM such as creatine salts [e.g., creatine citrate, creatine maleate, creatine pyruvate, creatine orotate, creatine hydrochloride (HCL), etc.…”

“…creatyl-l-leucine) are commonly sold as creatine-containing supplements either as individual products or as part of multi-ingredient products [ 1 , 9 , 26 , 35 , 36 , 58 ]. Similar to some types of CM, research on the efficacy and safety of these novel/alternative forms of creatine is also lacking as relatively few studies have been performed to study their safety and/or effectiveness [ 26 , 35 ]. To this point, a recent review by Fazio et al.…”

International society of sports nutrition position stand: tactical athlete nutrition

“…Additionally, clinical populations have been studied with doses 10–30 g/day for up to 5 years [ 69 , 116 , 133 ]. The interested reader is highly encouraged to read the following reviews to further understand the potential health and performance implications of creatine monohydrate supplementation, including data that summarizes any potential safety concerns for its use [ 116 , 117 , 127 , 134 ].…”

Creatine Monohydrate Supplementation, but not Creatyl-L-Leucine, Increased Muscle Creatine Content in Healthy Young Adults: A Double-Blind Randomized Controlled Trial

“…Many of these molecules are purported to increase the bioavailability, solubility, or safety of Cr supplementation compared with CrM. Despite previous studies demonstrating that many of these putative forms of Cr fail to improve on the ergogenic effects of CrM and augment muscle Cr content (Jagim et al, 2012;Kreider et al, 2022;Spillane et al, 2009), novel supplements continue to be introduced to the market. For example, one such purported analog of Cr, creatyl-L-leucine (CLL), is currently on the market as part of a multi-ingredient blend and is sold under the name "Super Creatine®."…”