Walk into any gym supplement aisle and creatine is there, sold by the tub to people chasing bigger muscles. It is one of the most studied compounds in sports science. What far fewer people know is that the brain runs on much the same chemistry the muscles do, and that the energy creatine helps supply may matter just as much above the neck as below it. A new systematic review, published today in Brain Medicine, takes that quiet possibility seriously and asks a hard question. Can creatine help treat depression?
What the Researchers Looked At
The team behind the review, led by Bassam Jeryous Fares of the University of Ottawa, did not run a new trial. They gathered the ones that already existed. After screening the literature, they settled on six published reports describing five randomized controlled trials, the kind of study in which neither patient nor doctor knows who received the real compound and who received a placebo. Those trials had been conducted across five countries, in South Korea, the United States, Brazil, Israel, and India, and together they enrolled 238 participants at baseline, 126 on creatine and 112 on placebo. The average age was 36 years. Most participants were women. Two of the trials enrolled women only.
Four of the trials studied major depressive disorder. One studied people with bipolar disorder who were living through a depressive episode. Because the studies differed so widely in design, the authors did not pool the numbers into a single statistic. They summarized them in narrative instead, letting each trial speak for itself.
A Split Decision
Here is where the story refuses to resolve cleanly. Two of the five trials, both drawn from the same study of women with major depressive disorder, found real benefit. When five grams of creatine per day was added to the antidepressant escitalopram, depressive symptoms fell further than they did on placebo after eight weeks. The effect was large by the usual statistical yardsticks, with a Cohen's d of 1.13 on the Hamilton Depression Rating Scale, and more women reached remission. A separate trial paired creatine with cognitive behavioral therapy and saw a steeper drop in symptoms on a standard questionnaire than therapy plus placebo produced.
Then the picture darkens. The remaining three trials found nothing. One saw no effect of creatine, at five or ten grams daily, in people who had already failed to respond to medication. Another, testing several doses in adolescent girls, found no difference from placebo. The last looked at people with bipolar disorder in a depressive episode and again found no treatment benefit. Worse, two of those bipolar patients taking creatine developed hypomania or mania, a sober reminder that the same compound can behave very differently depending on the diagnosis.
Why Creatine Might Matter for the Brain
The logic behind the experiments is not far fetched. The brain is an expensive organ, burning energy at a rate out of all proportion to its size, and creatine helps cells rebuild adenosine triphosphate, the molecule that pays for that work. Studies of people with mood disorders have found altered creatine metabolism in the brain, and impaired energy production has been proposed as one root of depression. Creatine may also nudge the pathways that govern dopamine and serotonin, the neurotransmitters that most antidepressants target. The authors are careful here. They note that the link between brain creatine and mood remains correlational, not proven cause and effect, and that the biology of depression has many moving parts.
“The signal is interesting, but it is not a verdict,” said Bassam Jeryous Fares, first author of the review and a student in the Faculty of Medicine at the University of Ottawa. “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, corresponding author and a psychiatry resident at the University of Ottawa, framed the work as a starting point rather than a conclusion. “Creatine appears to be a safe intervention. 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.”
What Comes Next
The review does not pretend to settle the matter. The authors flag the obvious limitations. The trials were small. The sexes were unbalanced, with two studies enrolling only women. The quality varied, with two trials judged at low risk of bias and three carrying some concern, arising mostly from how patients were assigned and how missing data were handled. The findings, the authors stress, are not yet generalizable.
What they call for is more rigorous work. Larger trials. Longer ones, running past the eight week mark. Studies that test creatine alongside exercise, and studies that explore higher doses, while keeping in mind that more is not always better. There is even a tantalizing clue from animal research, where creatine altered depression like behavior differently in male and female rodents, which may help explain why the human trials with more women showed more promise. For now, creatine remains a promising lead rather than a proven remedy. The molecule that builds muscle has earned a closer look from the people who study the mind.
The peer-reviewed research article in Brain Medicine titled “Creatine as a treatment for depression,” is freely available via Open Access, starting on 30 June 2026 in Brain Medicine at the following hyperlink: https://doi.org/10.61373/bm026l.0039.
The full reference for citation purposes is: Jeryous Fares B, Zhou C, Fabiano N, Wong S. Creatine as a treatment for depression. Brain Medicine 2026. DOI: https://doi.org/10.61373/bm026l.0039. Epub 2026 Jun 30.
