Background: Individual studies have indicated that creatine supplementation is generally well tolerated and not associated with clinically significant side effects. Nevertheless, anecdotal reports about side effects persist primarily from popular and social media and on the Internet.
Methods: This study evaluated side effects reported from 685 human clinical trials on creatine supplementation, worldwide adverse event report (AER) databases, and performed a social media sentiment analysis. The presence of side effects (No, Yes) in studies was evaluated using chi-squared analysis. The frequency of side effects among study participants was evaluated using a multivariate analysis of variance.
Results: A total of 13,452 participants in 652 studies ingested placebos (PLA), while 12,839 participants in 685 studies consumed creatine (Cr). Nearly all studies (95%) provided CrM at an average dose of 0.166 [0.159, 0.173] g/kg/d (about 12.5 g/d) for 64.7 [52.0, 77.3] days in studies lasting up to 14 yrs. Side effects were reported in 13.2% of studies in the PLA groups and 13.7% of studies in the Cr-supplemented groups, with no significant differences observed between the groups (p = 0.776). There was a slightly higher percentage 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) with Cr supplementation, but not when the total number of participants in these studies was evaluated (muscle cramping/pain: PLA 0.07%, Cr 0.52%, p = 0.085; GI issues: PLA 4.05%, Cr 5.51%, p = 0.820). Additionally, there was no significant multivariate difference among the 49 side effects evaluated (p = 0.340), no significant difference in the total frequency of side effects reported among participants (PLA 4.21%, Cr 4.60%, p = 0.828), and no significant differences in any of the other side effect evaluated that included markers of renal function and health. The percentage prevalence of side effects was small, with differences between groups generally within ± 0.5%. Analysis of 28.4 million AERs revealed that the mention of Cr was rare (0.00072%), 46.3% of CAERS had no Cr in the products listed, and 63% of AERs with Cr in the product involved the use of other types of Cr or ingestion with other supplements or drugs. The overall sentiment analysis was neutral about perceptions of Cr, although those with strong perceptions about Cr were slightly more negative.
Conclusion: Results demonstrate that Cr supplementation does not increase the prevalence or frequency of side effects when compared to participants ingesting PLA. Therefore, claims that Cr supplementation increases the risk of side effects are unfounded.
Keywords: Ergogenic; adverse events; dietary supplement; safety.