Emerging scientific inquiry is investigating the potential of creatine, a widely recognized dietary supplement primarily associated with enhancing athletic performance and muscle development, to offer therapeutic benefits for individuals experiencing depression. A comprehensive systematic review of existing clinical research, recently published in the journal Brain Medicine, delved into whether creatine’s role in supporting the brain’s energy metabolism could translate into a means of alleviating depressive symptoms. This examination offers a glimmer of cautious optimism, yet simultaneously underscores the significant gaps in our current understanding and the need for further robust investigation. While certain experimental investigations have indicated notable improvements in depression indicators, others have yielded no discernible positive effects, leaving the scientific community with a compelling but unresolved question.
The researchers, spearheaded by Bassam Jeryous Fares from the University of Ottawa, adopted a meta-analytic approach, scrutinizing previously published studies rather than initiating a novel experimental protocol. Their meticulous analysis encompassed six distinct reports, which collectively detailed five randomized controlled trials. In these trials, participants were administered either creatine or an inert placebo, with neither the participants nor the researchers administering the treatment aware of the allocation. The geographical distribution of these studies spanned South Korea, the United States, Brazil, Israel, and India, involving a combined initial cohort of 238 individuals. Of these, 126 participants were assigned to receive creatine, while 112 were given a placebo. The average age of the participants hovered around 36 years, and the majority of the study populations comprised women, with two of the trials specifically enrolling exclusively female participants. The therapeutic focus of these investigations varied; four trials specifically targeted individuals diagnosed with major depressive disorder, whereas one trial included participants with bipolar disorder who were concurrently experiencing a depressive episode. Due to substantial divergences in the methodological designs and execution of these studies, a unified statistical aggregation of the data was not feasible; instead, each study was subjected to an independent evaluation.
The synthesized findings from the reviewed trials presented a decidedly mixed and often contradictory picture. Two of the five evaluated trials, both of which exclusively involved women diagnosed with major depressive disorder, reported ancillary advantages from creatine supplementation. In one such study, individuals who consumed five grams of creatine daily in conjunction with the antidepressant escitalopram exhibited significantly greater reductions in depressive symptomatology after an eight-week period compared to those receiving escitalopram alongside a placebo. This observed improvement was statistically substantial, as measured by the Hamilton Depression Rating Scale, where a Cohen’s d value of 1.13 indicated a large effect size, and a higher proportion of participants in the creatine group achieved remission from their depressive symptoms. In a separate study, creatine was administered as an adjunct to cognitive behavioral therapy, and participants who received this combination demonstrated a more pronounced decrease in depression scores on a standardized assessment than those undergoing therapy with a placebo.
Conversely, the remaining three trials failed to demonstrate any clinically meaningful benefits attributable to creatine. One particular study indicated that neither a daily dose of five grams nor ten grams of creatine per day resulted in any improvement in symptoms for individuals whose depression had proven resistant to conventional antidepressant medications. Another investigation found no discernible advantage over a placebo among adolescent girls, even when various dosages of creatine were administered. Furthermore, a third trial, which focused on individuals experiencing depressive episodes within the context of bipolar disorder, also yielded no evidence of improvement. An additional observation of potential safety concern was also noted: two participants diagnosed with bipolar disorder who were administered creatine developed symptoms of hypomania or mania. This finding suggests that creatine’s impact might be modulated by an individual’s underlying psychiatric condition, necessitating careful consideration for specific patient populations.
The theoretical underpinnings for investigating creatine’s potential role in mood regulation are rooted in the brain’s exceptionally high and constant energy requirements. While creatine is most widely recognized for its function in facilitating the rapid regeneration of adenosine triphosphate (ATP) – the primary energy currency of cells – within muscle tissue, the brain also relies heavily on this same bioenergetic pathway. Prior scientific explorations have identified alterations in brain creatine metabolism in individuals suffering from mood disorders, prompting speculation that dysregulation in cellular energy production might be a contributing factor to the pathophysiology of depression. Moreover, preliminary research suggests that creatine could influence the activity of key neurotransmitters such as dopamine and serotonin, both of which are critically involved in mood regulation and are common targets for established antidepressant medications.
Despite these intriguing theoretical connections, the authors of the review strongly emphasize that these relationships remain largely speculative. The existing studies, at best, illustrate correlations rather than providing definitive proof that disruptions in creatine metabolism directly precipitate depression, a complex disorder known to involve a multitude of intricate biological pathways. Bassam Jeryous Fares, the lead author of the review and a student at the University of Ottawa’s Faculty of Medicine, articulated this sentiment, stating, "The signal is interesting, but it is not a verdict." He further elaborated, "Two trials pointed one way and three pointed another. That is not the kind of evidence on which you change clinical practice. It is the kind that tells you the question is worth further exploration." Nicholas Fabiano, the corresponding author of the review and a psychiatry resident at the University of Ottawa, echoed this call for prudence. "Creatine appears to be a safe intervention," he noted, "The adverse events we found were limited to mild gastrointestinal discomfort. We cannot yet reliably say that creatine helps with depressive symptoms or if the findings are generalizable to everyone."
The researchers unequivocally stress that the current body of evidence is insufficient to advocate for the routine prescription or recommendation of creatine as a standard treatment for depression. The clinical trials included in the review were characterized by relatively small sample sizes, a disproportionate representation of women over men, and considerable variability in methodological quality. While two of the studies were assessed as having a low risk of bias, the remaining three raised certain concerns, primarily related to the methods of participant assignment and the handling of missing data. Consequently, the conclusions drawn from these studies cannot be broadly applied to the general population or all individuals experiencing depression.
In light of these limitations, the review advocates for the initiation of larger-scale, longer-duration clinical trials that extend beyond the typical eight-week timeframe observed in the current literature. The researchers also propose investigating the efficacy of creatine in conjunction with other therapeutic modalities, such as exercise, and exploring whether variations in dosage might yield more favorable outcomes, while acknowledging that higher doses do not automatically equate to enhanced benefits. Furthermore, insights from animal studies could potentially illuminate sex-specific differences in creatine’s effects on depression-like behaviors, a phenomenon observed in rodent experiments that might offer a partial explanation for the stronger positive results reported in human studies predominantly featuring female participants.
For the present time, creatine remains an area of considerable scientific interest and an intriguing possibility, rather than a definitively proven therapeutic intervention for depression. A supplement long synonymous with physical augmentation is now garnering significant attention from scientists actively seeking novel strategies to combat the pervasive challenge of mood disorders. The peer-reviewed research article, titled "Creatine as a treatment for depression," was published in Brain Medicine and has been made accessible through Open Access since June 30, 2026.
About the Author
