Methodological Approaches to Bioavailability of Oral Creatine in Randomized Controlled Trials: A Meta-Research Study

Background: Creatine is one of the most widely used dietary supplements for enhancing physical performance and is increasingly investigated for a range of health-related applications. Although creatine monohydrate is the most commonly used formulation, concerns have been raised regarding its oral bioavailability, prompting the development of alternative formulations and delivery strategies. However, it is unclear to what extent randomized controlled trials (RCTs) evaluating oral creatine supplementation address issues related to bioavailability. Therefore, we aimed to assess how bioavailability of oral creatine is considered and reported in RCTs. Methods: We conducted a meta-research study of published RCTs in which orally administered creatine was used as an intervention or comparator, regardless of participant characteristics or outcomes. MEDLINE and Embase were searched from inception to 1 March 2024. We extracted data on trial characteristics, creatine formulations used, mentions of bioavailability, and comparisons between different creatine products. Data were summarized descriptively. Results: We included 357 reports corresponding to 343 RCTs published between 1994 and 2023. Creatine monohydrate was the most commonly used formulation, reported in 275 (80.2%) trials; however, 53 (15.5%) reports did not specify the exact creatine form used. Bioavailability was mentioned in only 38 (11.1%) reports, most frequently in the discussion section. Four trials (1.2%) reported specific measures intended to enhance bioavailability, including instructions regarding supplement dissolution or co-ingestion with food or carbohydrates. Five trials (1.5%) compared more than one creatine formulation, but only three (0.9%) discussed bioavailability. These formulation comparisons were frequently limited by non-equimolar dosing regimens. Conclusions: RCTs of oral creatine supplementation rarely address bioavailability and often provide insufficient information on the exact creatine formulation used. Few trials reported strategies to enhance bioavailability, and direct comparisons between creatine formulations were uncommon and methodologically limited, particularly because of non-equimolar dosing. Future trials should improve reporting of creatine formulations, incorporate bioavailability-related outcomes, and use appropriate dosing strategies when evaluating alternative creatine products.