A supplement best known for boosting athletic performance may also have potential as a depression treatment.
Creatine has long been associated with strength training and muscle growth, making it one of the most popular and extensively researched sports supplements available. But muscles are not the only tissues that depend on creatine for energy. The brain also relies on the same cellular energy system, leading scientists to ask whether the supplement could have benefits beyond the gym.
A new systematic review, published in the journal Brain Medicine, examined whether creatine might play a role in treating depression. While some clinical trials produced encouraging findings, the overall evidence remains mixed, and researchers say it is too early to recommend creatine as a standard treatment.
Reviewing the Existing Clinical Trials
Rather than conducting a new experiment, researchers led by Bassam Jeryous Fares of the University of Ottawa analyzed previously published studies. After reviewing the available literature, they identified six reports covering five randomized controlled trials, in which participants and researchers did not know whether creatine or a placebo had been given.
The studies were carried out in South Korea, the United States, Brazil, Israel, and India. Altogether, they included 238 participants at the start of the trials, with 126 receiving creatine and 112 receiving a placebo. Participants averaged 36 years of age, and most were women. Two of the studies enrolled women exclusively.
Four trials focused on people with major depressive disorder, while one involved participants experiencing depressive episodes related to bipolar disorder. Because the studies differed substantially in their methods and design, the researchers did not combine the results into a single statistical analysis. Instead, they evaluated each study individually.
Mixed Results Across Depression Studies
The findings were far from unanimous.
Two of the five trials, both based on the same study of women with major depressive disorder, reported meaningful improvements. In one trial, participants who took five grams of creatine daily alongside the antidepressant escitalopram experienced a greater reduction in depressive symptoms after eight weeks than those who received a placebo. The improvement was considered large by standard statistical measures, with a Cohen’s d of 1.13 on the Hamilton Depression Rating Scale, and remission rates were also higher.
Another study combined creatine with cognitive behavioral therapy and found that participants experienced a greater reduction in depression scores than those receiving therapy plus a placebo.
The remaining three trials, however, found no measurable benefit. One tested five-gram and ten-gram daily doses in people whose depression had not improved with medication and found no advantage over placebo. Another, involving adolescent girls receiving several different doses, also showed no meaningful difference. A third study examined people with bipolar disorder experiencing depressive episodes and likewise found no improvement.
Researchers also noted an important safety concern. Two participants with bipolar disorder who received creatine developed hypomania or mania, suggesting the supplement may affect people differently depending on their underlying condition.
Why Scientists Think Creatine Could Affect the Brain
Researchers say there are biological reasons to investigate creatine as a possible depression treatment.
The brain consumes enormous amounts of energy relative to its size, and creatine helps cells regenerate adenosine triphosphate, the molecule that powers many cellular processes. Previous studies have found changes in brain creatine metabolism among people with mood disorders, raising the possibility that disrupted energy production could contribute to depression.
Creatine may also influence dopamine and serotonin, two neurotransmitters commonly targeted by antidepressant medications.
Even so, the researchers emphasize that these connections remain theoretical. Current evidence shows an association between brain creatine levels and mood, but it does not prove that one causes the other. Depression is a complex condition influenced by many biological and environmental factors.
“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, also stressed that the review should be viewed as an early step rather than a definitive answer.
“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.”
Larger Studies Are Still Needed
The authors caution that the available evidence has several important limitations. The trials involved relatively small numbers of participants, and women made up most of the study population, with two trials including only female participants. Study quality also varied, with two trials considered at low risk of bias and three raising some concerns, largely because of how participants were assigned to treatment groups and how missing data were handled.
To better understand creatine’s potential, the researchers call for larger and longer clinical trials extending beyond eight weeks. They also recommend studying creatine alongside exercise and investigating whether different doses produce different results, while recognizing that higher doses may not necessarily be more effective.
Animal research offers another clue worth exploring. Studies have suggested that creatine affects depression like behavior differently in male and female rodents, which could help explain why the human studies involving more women appeared to show greater benefit.
For now, the evidence suggests creatine is an intriguing possibility rather than a proven therapy. Best known for helping athletes build muscle, the supplement may also have untapped potential for the brain, but much more research will be needed before doctors can determine whether it belongs in depression treatment.
Reference: “Creatine as a treatment for depression” by Bassam Jeryous Fares, Carl Zhou, Nicholas Fabiano and Stanley Wong, 30 June 2026, Brain Medicine.
DOI: 10.61373/bm026l.0039
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