Safety of creatine supplementation: Analysis of Adverse Events reported in clinical trials and adverse event reports

Background Individual studies have indicated that creatine monohydrate (CrM) supplementation is generally well tolerated and not associated with clinically significant side effects. Nevertheless, anecdotal reports about side effects persist. This comprehensive analysis aimed to analyze the prevalence of adverse event reports (AERs) attributed to creatine supplementation reported in international surveillance systems.Methods We performed a comprehensive literature review on PubMed with the keywords “creatine” and “supplementation.” The prevalence of AERs mentioning creatine reported in the United States Food and Drug Administration Center for Food Safety and Applied Nutrition (CFSAN) Adverse Event Reporting System (CAERS), the Canadian Vigilance Adverse Reaction Online Database, the Australian Department of Health and Aged Care, Therapeutic Goods Administration, the European Database of Suspected Adverse Drug Reaction Reports, and the Side Effect Resource (SIDER) 4.1 Side Effect Resource were assessed. These databases were searched for “creatine’ in dietary supplements or products following accepted protocols. Each report was evaluated to ensure creatine (Cr) was in the product mentioned by conducting an Internet search for the product name and evaluating the list of ingredients. We then categorized reports on products that contained only CrM, reports that involved consuming CrM in multi-ingredient supplements, products containing other “forms” or types of Cr, and whether Cr was consumed with other products. The total number of reports was divided by the total number of reports in the database over the 25, 50, 27, 24, and 10 years of monitoring AERs, respectively, to determine the percentage of reports in the database mentioning Cr. While AERs do not indicate causality, particularly when co-ingested with other nutrients and/or products, a low percentage of mentioning a nutrient or drug in these databases suggests safety from widespread use by the general public.Results Although AERs do not provide enough detail to assess causality and may not be attributed to creatine supplementation, only 203 adverse events mention creatine among 28.4 million reports (0.00072%). In the United States CAERS database, 46.3% of reports listing creatine did not contain creatine when evaluating the ingredients of the product listed. Among the CAERS that contained creatine as an ingredient, 37% listed CrM as the only product the individual was consuming, and 63% contained other nutrients consumed with CrM. Of these, only 15.8% involved ingestion of CrM with other nutrients, 47.3% involved other types of creatine, and 43.6% involved ingesting creatine with nutritional products or drugs, which makes attribution of CAERS to CrM alone impossible. Similar findings were seen when looking at other databases’ products associated with AERs.Conclusions The mention of Cr in worldwide AERs is rare (0.00072%), mostly associated with co-ingestion of other nutrients and/or drugs, and in some cases report symptoms Cr studies never observed in any clinical trial or unrelated to the known effects of Cr supplementation. These findings indicate that Cr supplements are well-tolerated in children through older adults and healthy and medically managed patient populations. Therefore, claims that Cr supplementation increases the risk of untoward side effects or AERs are unfounded. Based on these data, we urge lobbyists, policymakers, and health agencies to consult with leading creatine scientists and consider the full spectrum of scientific data before implementing restrictions with adverse public health and performance implications.