Creatine Supplementation Dose and Duration Are Not Associated with Increased Side Effects: A Structured Review and Study-Level Dose–Response Analysis of Randomized Controlled Trials

There are concerns that high-dose and/or long-term creatine monohydrate supplementation (CrM) leads to greater side effects (SEs) compared to placebo. This analysis investigated whether the dose or duration of CrM was associated with SEs. Data from trials involving more than 12,800 participants within CrM and placebo study arms of 684 randomized clinical trials were analyzed. SEs were combined into categories and total absolute dose and CrM duration were grouped into tertiles (low, moderate, and high). Crosstabs with chi-square tests were used to compare the prevalence of SEs across CrM dose and duration tertiles. Logistic regression models, adjusted for biological sex, age, and population categories, were used to test dose and duration as continuous predictors. Across 684 randomized controlled trials, reported SEs were infrequent. Although dose and duration tertiles were statistically associated with study-level side effect reporting, the effect sizes were uniformly small, events were infrequent, and the reported symptoms were primarily mild and nonspecific. No consistent exposure-response pattern indicative of clinically meaningful risk was observed. Adjusted logistic regression and frequency-based analyses showed no consistent dose- or duration-dependent increase in SE risk, with placebo groups often reporting similar or greater SE frequencies at the study-reporting level. CrM appears to be well-tolerated and, at the study-level, does not increase the risk of gastrointestinal, renal, liver, musculoskeletal, or other SEs compared to placebo, even at high doses or longer durations.