Creatine is one of the most popular sports supplements in the world, widely used to improve muscle strength and performance. Now, researchers are exploring whether it might have benefits far beyond the gym. A new systematic review published in Brain medicine examined whether creatine could help alleviate depression by meeting the brain’s energy needs.
The findings offer cautious optimism, but also highlight how much is still unknown. While some clinical trials reported significant improvements in depression symptoms, others found no benefit at all, leaving scientists with an intriguing question rather than a clear answer.
Review of 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 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, 126 received creatine and 112 received placebo. The participants had an average age of 36 years and the majority were women. Two of the studies recruited 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 among depression studies
The review revealed a divided picture.
Two of the five trials, involving women with major depressive disorder, found that creatine provided additional benefits. In one study, participants who took five grams of creatine each day along with the antidepressant escitalopram experienced greater reductions in depressive symptoms after eight weeks than those who received 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 combined creatine with cognitive behavioral therapy. Participants who received creatine showed a greater reduction in depression symptoms on a standard assessment than those who received placebo therapy.
However, the remaining three trials did not find any significant 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 study 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.
The researchers also noted a major 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 based on the enormous energy demands of the brain.
Although creatine is best known for helping muscles quickly regenerate adenosine triphosphate, the molecule that fuels cells, the brain also relies heavily on this energy system. Previous research has found changes in brain creatine metabolism among people with mood disorders, leading scientists to investigate whether alterations 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 authors emphasize that these connections remain theoretical. Existing studies show correlations, rather than evidence, 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 at the University of Ottawa Faculty of Medicine. “Two trials pointed in one direction and three in another. That’s not the kind of evidence that can change clinical practice. It’s the kind of evidence that indicates the question deserves further exploration.”
Nicholas Fabiano, corresponding author and 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 whether the findings are generalizable to everyone.”
Larger studies still needed
The researchers emphasize that current evidence is too limited to support the 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 considered to be at low risk of bias, while the remaining three raised some concerns, mainly related to participant allocation and missing data. As a result, the findings cannot yet be widely applied.
The review calls for larger, longer clinical trials that extend beyond eight weeks. The researchers also recommend studying creatine alongside exercise and investigating whether different doses produce better results, although they acknowledge that higher doses do 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 human studies primarily involving 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 looking 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 starting June 30, 2026.