Background. Creatine is an organic compound that facilitates the recycling of energy-providing adenosine triphosphate (ATP) in muscle and brain tissue. It is a safe, well-studied supplement for strength training. Previous studies have shown that supplementation increases brain creatine levels, which might increase cognitive performance. The results of studies that have tested cognitive performance differ greatly, possibly due to different populations, supplementation regimens and cognitive tasks. This is the largest study on the effect of creatine supplementation on cognitive performance to date. As part of our study, we replicated Rae et al. (2003). Methods. Our trial was cross-over, double-blind, placebo-controlled, and randomised, with daily supplementation of 5g for six weeks each. Like Rae et al. (2003), we tested participants on Raven's Advanced Progressive Matrices (RAPM) and on the Backward Digit Span (BDS). In addition, we included eight exploratory cognitive tests. About half of our 123 participants were vegetarians and half were omnivores. Results. There was no indication that vegetarians benefited more from creatine than omnivores, so we merged the two groups. Participants' scores after creatine and after placebo differed to an extent that was not statistically significant (BDS: p = 0.064, partial eta squared = 0.029; RAPM: p = 0.327, partial eta squared = 0.008). Compared to the null hypothesis of no effect, Bayes factors indicate weak evidence in favour of a small beneficial creatine effect and strong evidence against a large creatine effect. There was no indication that creatine improved the performance of our exploratory cognitive tasks. Side effects were reported significantly more often for creatine than for placebo supplementation (p = 0.002, RR = 4.25). Conclusions. Our results do not support large effects of creatine on the selected measures of cognition. However, our study, in combination with the literature, implies that creatine might have a small beneficial effect. Larger studies are needed to confirm or rule out this effect. Given the safety and broad availability of creatine, this is well worth investigating; a small effect could have large benefits when scaled over time and over many people.

The authors have declared no competing interest.

DRKS00017250

Funding was provided by the non-profit organization Effective Ventures Foundation, 2443 Fillmore St., #380-16662, San Francisco, CA 94115. The trial funders had no role in the design of the study, the collection, analysis or interpretation of data, the writing of the report, or the decision to submit the article for publication.

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Ethical approval was obtained from the ethics committee of the University of Bonn (060/19).

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The appendix, data, code and output of this study are openly available at the Open Science Framework, https://osf.io/xpwkc/.

https://osf.io/xpwkc/