The authors from University of Split, Croatia, and Jagiellonian University Medical College, Poland, concluded that marketing claims about purportedly enhanced bioavailability of new creatine formulations are not adequately supported by evidence from clinical trials.
Published in the journal Nutrients, the research analyzed 357 reports corresponding to 343 RCTs from MEDLINE and Embase with the aim to obtain a comprehensive insight of how creatine has been assessed.
“A concerningly large number of studies (15.5%) failed to specify the exact chemical form of creatine supplement,“ wrote the authors.
They added that pharmacokinetic measures, such as circulatory creatine concentrations, should be tracked as many RCTs focus on performance outcomes without adequately linking these results back to direct bioavailability metrics.
“RCTs of oral creatine supplementation rarely address bioavailability and often provide insufficient information on the exact creatine formulation used,” the report noted. “Few trials reported strategies to enhance bioavailability, and direct comparisons between creatine formulations were uncommon and methodologically limited.”
The paper concluded future trials should improve reporting of creatine formulations, incorporate bioavailability-related outcomes, and use non-equimolar dosing when evaluating alternative creatine products.
It additionally highlighted a lack of research to indicate the most effective forms of creatine for supporting cognitive health, with only two addressing creatine’s bioavailability in relation to the enrichment of brain creatine content.
Key findings
The meta-research extracted data on trials published between 1994 and 2023, in which orally administered creatine was used as an intervention or comparator.
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 with four trials (1.2%) reporting specific measures intended to enhance bioavailability.
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.
Boosting bioavailability
Although creatine monohydrate is the most commonly used formulation, concerns over its bioavailability, have prompted the development of supplements with enhanced solubility such as creatine citrate and creatine pyruvate.
However, these deliver creatine together with another nutrient which by itself may have ergogenic properties, therefore the current research highlighted that studies involving these compounds should implement equimolar dosing regimens alongside appropriate control groups to account for non-creatine components of these supplements.
Studies have also investigated the effects of PEGylation, where creatine is attached to a water-soluble polymer polyethylene glycol to enhance the solubility and half-life time of the elimination of pharmaceuticals.
“Such innovative methodologies could be pivotal in enhancing the absorption and efficacy of creatine supplements, yet they are often underrepresented in RCTs,” the report stated.
Enhancing strategies for cognitive health
The vast majority of trials addressing creatine bioavailability aimed to increase muscle creatine content, with only two studies aiming to enhance concentrations within the brain, indicating that this is an understudied research area, according to the report.
The authors noted previous studies indicated that creatine monohydrate supplementation increases brain creatine levels by 5–15%, compared with 20–40% in the muscle, possibly explained by the lack of sufficient number of SLC6A8 transporters at the blood–brain barrier.
“More permeable forms of creatine, which cross membranes via passive diffusion, would facilitate both intestinal absorption and uptake into the brain and allow for more effective treatment of neurological conditions without requiring extremely high doses over extended periods,” according to the report. “Therefore, brain creatine uptake represents the research area where the exploration of bioavailability-enhancing strategies could be more thoroughly integrated and possibly holds the greatest clinical promise.”
They added that novel delivery methods should be explored particularly for central nervous system disorders where bioavailability-optimized formulations hold the greatest therapeutic potential.
Source: Nutrients, https://doi.org/10.3390/nu18162697, “Methodological Approaches to Bioavailability of Oral Creatine in Randomized Controlled Trials: A Meta-Research Study”, Authors: Bučević Popović, V. et al
