Creatine is one of the world’s most popular sports supplements, widely used to improve strength and muscle performance. Now, researchers are exploring whether it could have benefits far beyond the gym. A new systematic review published in Brain Medicine examined whether creatine might help relieve depression by supporting the brain’s energy needs.
The findings offer cautious optimism, but they also highlight how much remains unknown. While some clinical trials reported meaningful improvements in depression symptoms, others found no benefit at all, leaving scientists with an intriguing question rather than a clear answer.
Reviewing the Clinical Evidence
Instead of conducting a new experiment, researchers led by Bassam Jeryous Fares of the University of Ottawa analyzed existing research. After reviewing the available literature, they identified six published reports covering five randomized controlled trials, in which participants received either creatine or a placebo without knowing which treatment they were taking.
The studies were carried out in South Korea, the United States, Brazil, Israel, and India. Together, they included 238 participants at the start of the trials, with 126 receiving creatine and 112 receiving placebo. Participants averaged 36 years of age, and most were women. Two of the studies enrolled only women.
Four trials focused on people with major depressive disorder, while one involved participants with bipolar disorder who were experiencing a depressive episode. Because the studies differed substantially in their design and methods, the researchers did not combine the data into a single statistical analysis. Instead, they evaluated each study individually.
Mixed Results Across Depression Studies
The review revealed a divided picture.
Two of the five trials, both involving women with major depressive disorder, found that creatine provided additional benefits. In one study, participants who took five grams of creatine each day alongside the antidepressant escitalopram experienced greater reductions in depressive symptoms after eight weeks than those receiving escitalopram with a placebo. The improvement was considered large by conventional statistical standards, with a Cohen’s d of 1.13 on the Hamilton Depression Rating Scale, and more participants achieved remission.
Another study paired creatine with cognitive behavioral therapy. Participants receiving creatine showed a greater reduction in depression symptoms on a standard assessment than those receiving therapy with a placebo.
The remaining three trials, however, found no meaningful benefit.
One study reported that neither five nor ten grams of creatine per day improved symptoms in people whose depression had not responded to medication. Another found no advantage over placebo among adolescent girls, even when different doses were tested. A third trial involving people with bipolar disorder also showed no improvement.
Researchers also noted an important safety concern. Two participants with bipolar disorder who received creatine developed hypomania or mania, suggesting that creatine may affect people differently depending on their underlying condition.
Why Scientists Think Creatine Could Affect the Brain
The idea that creatine could influence depression is grounded in the brain’s enormous energy demands.
Although creatine is best known for helping muscles rapidly regenerate adenosine triphosphate, the molecule that powers cells, the brain also depends heavily on this energy system. Previous research has found changes in brain creatine metabolism among people with mood disorders, leading scientists to investigate whether disruptions in cellular energy production could contribute to depression.
Creatine may also influence dopamine and serotonin, two neurotransmitters that play important roles in mood regulation and are targeted by many antidepressant medications.
Still, the review’s authors emphasize that these connections remain theoretical. Existing studies show correlations rather than proof that altered creatine metabolism directly causes depression, and the disorder itself involves many biological pathways.
“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 urged caution.
“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 researchers stress that the current evidence is too limited to support routine use of creatine for depression.
The clinical trials were relatively small, included disproportionately more women than men, and varied in quality. Two studies were judged to have a low risk of bias, while the remaining three raised some concerns, primarily related to participant assignment and missing data. As a result, the findings cannot yet be applied broadly.
The review calls for larger and longer clinical trials that extend beyond eight weeks. Researchers also recommend studying creatine alongside exercise and investigating whether different doses produce better outcomes, while recognizing that higher doses may not necessarily lead to greater benefits.
Animal studies may offer another clue. Experiments have shown that creatine can affect depression like behavior differently in male and female rodents, a finding that could help explain why the human studies involving mostly women produced the strongest positive results.
For now, creatine remains an intriguing possibility rather than a proven treatment. A supplement long associated with building muscle is now attracting growing interest from scientists searching for new ways to treat depression.
The peer-reviewed research article, “Creatine as a treatment for depression,” was published in Brain Medicine and is available through Open Access beginning June 30, 2026.