Safety of creatine supplementation: Analysis of the prevalence of reported side effects in clinical trials

Background Individual studies have indicated that creatine monohydrate 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 determine the presence of side effects reported in 685 human clinical trials conducted on creatine supplementation.Methods We performed a comprehensive literature review on PubMed with the keywords “creatine” and “supplementation.” After compiling a list of clinical trials on creatine supplementation in humans, we evaluated each publication and developed a summary table of creatine studies. Based on the side effects reported in these studies, we created a side effect list of 35 types of side effects mentioned in these studies. We categorized the presence of side effects in these studies (No, Yes) to compare the number of studies reporting side effects in participants taking placebos (PLA) and creatine (Cr) supplements. We also categorized each study by supplement groups (creatine, placebo), sex (combined cohort, male, female, unspecified), age (children/adolescents less than 18 yrs, young adults between 18-45 yrs, middle-aged adults between 45-65 yrs, older adults more than 65 yrs), training status (clinical population with physical health issues, clinical populations with cognitive issues, untrained, recreationally active, trained, athletes, military), health status (apparently healthy, clinical populations), clinical category (apparently healthy, cardiometabolic/ cardiopulmonary conditions, neurological conditions, musculoskeletal conditions, renal conditions, and other), and type of creatine ingested (CrM compared to other forms including creatine HCl, Magnesium-Creatine, Creatine Citrate, Creatine Pyruvate, Creatine Methyl-Ester, Creatine H20, Creatine Nitrate, Creatyl-L-Leucine). These categories were used to determine study demographics, dosages studied, and whether studies reported side effects among participants in the PLA and Cr groups. If incomplete demographic information was provided (e.g., body weight), we used an average population value to estimate relative creatine intake. The prevalence of side effects reported in studies (categorized as yes or no) was evaluated using split file means by each category to obtain the number of studies reporting side effects. The percentage prevalence was calculated by dividing the number of studies reporting side effects by the total number of studies. We then analyzed differences in the number of studies reporting side effects for the placebo (PLA) and creatine (Cr) supplemented groups using crosstabs chi-squared tests, likelihood ratios, Fisher Exact tests, and odds ratios for supplementation, not present, and present with corresponding 95% confidence intervals presented as mean [lower bound, upper bound].Results 13,452 participants in 652 studies ingested PLA, while 12,839 participants in 682 studies consumed Cr. In the PLA, 86/652 studies (13.2%) reported side effects, while 94/685 (13.7%) reported side effects in Cr-supplemented (p = 0.776). The prevalence of studies reporting gastrointestinal (GI) issues (PLA 4.3%, Cr 4.9%, p < 0.001) and muscle cramping/pain (PLA 0.9%, Cr 2.9%, p = 0.008) were higher in the Cr group. However, the difference in the prevalence of studies reporting side effects and differences between groups were small. No other significant differences were observed in the studies reporting the remaining 33 side effects between the PLA and Cr-supplemented groups, with the difference in prevalence reported typically ± 0.4%.Conclusions This comprehensive analysis reveals that Cr supplementation does not increase the prevalence of 35 side effects evaluated compared to those reported when taking PLA. 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 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.