Creatine is one of the most popular sports supplements in the world and is widely used to improve strength and muscle performance. Now, researchers are exploring whether there may be benefits beyond the gym. New systematic review published in brain medicine We investigated whether creatine could help alleviate depression by supporting the brain’s energy needs.
While the findings suggest cautious optimism, they also highlight how much remains unknown. While some clinical trials reported significant improvements in symptoms of depression, others found no effect at all, leaving scientists with interesting questions rather than clear answers.
Review of clinical evidence
Instead of conducting new experiments, the researchers, led by Bassam Gerus Fares at the University of Ottawa, analyzed existing research. After reviewing the available literature, we identified six published reports covering five randomized controlled trials in which participants were given either creatine or a placebo without knowing which treatment they were receiving.
Studies were conducted in South Korea, the United States, Brazil, Israel, and India. There were a total of 238 participants at the start of the study, of whom 126 received creatine and 112 received placebo. The average age of the participants was 36 years, and most were women. Two of the studies included only women.
Four trials involved people with major depressive disorder, and one involved participants with bipolar disorder experiencing a depressive episode. The researchers did not combine the data into a single statistical analysis because the studies had very different designs and methods. Instead, they evaluated each study individually.
Results are mixed across depression studies
Reviews revealed mixed opinions.
Two of the five trials, both in women with major depressive disorder, found that creatine provided additional benefits. In one study, participants who took 5 grams of creatine daily alongside the antidepressant escitalopram had greater reductions in depression symptoms after eight weeks than participants who took escitalopram plus a placebo. The Cohen’s d for the Hamilton Depression Rating Scale was 1.13, an improvement considered large by conventional statistical standards, and more participants achieved remission.
Another study combined creatine with cognitive behavioral therapy. Standardized evaluations showed that participants who received creatine had greater reductions in symptoms of depression than those treated with a placebo.
However, the remaining three trials found no significant benefit.
One study reported that 5 or 10 grams of creatine per day did not improve symptoms in patients with depression who had not responded to drug therapy. Other researchers found no benefit over placebo among adolescent girls, even when testing different doses. A third trial in patients with bipolar disorder showed no improvement.
The researchers also noted important safety concerns. Two participants with bipolar disorder who received creatine developed hypomanic or manic episodes. This suggests that creatine may affect people differently depending on their underlying medical conditions.
Why scientists think creatine may affect the brain
The idea that creatine can affect depression is based on the brain’s enormous energy demands.
Creatine is best known for helping muscles quickly regenerate adenosine triphosphate, a molecule that powers cells, but the brain also relies heavily on this energy system. Previous studies have found changes in brain creatine metabolism in people with mood disorders, leading scientists to investigate whether disruptions in cellular energy production may contribute to depression.
Creatine may also affect dopamine and serotonin, two neurotransmitters that play an important role in mood regulation and are targeted by many antidepressants.
Still, the review’s authors stress that these associations remain theoretical. Existing research shows a correlation rather than evidence that changes in creatine metabolism directly cause depression, and the disorder itself involves many biological pathways.
“The signals are interesting, but they’re not a verdict,” said Bassam Gerus Fares, lead author of the review and a student at the University of Ottawa’s medical school. “Two trials pointed in one direction and three trials pointed in another direction. It’s not the kind of evidence that changes clinical practice. It’s the kind of evidence that shows the problem is worth further investigation.”
Corresponding author Nicholas Fabiano, 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 say with certainty whether creatine has an effect on symptoms of depression or whether the results can be generalized to all people.”
Larger studies are still needed
The researchers stress that current evidence is too limited to support the routine use of creatine for depression.
Clinical trials were relatively small, had disproportionately more female than male participants, and were of variable quality. Two studies were judged 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, this finding cannot yet be widely applied.
The review calls for large-scale, long-term clinical trials lasting more than eight weeks. The researchers also recommend studying creatine alongside exercise to see if different doses produce better results, while recognizing that higher doses don’t necessarily mean greater benefits.
Animal studies may provide another clue. Experiments have shown that creatine can affect depression-like behavior differently in male and female rodents, a finding that may help explain why human studies, primarily in women, have yielded the strongest positive results.
For now, creatine remains an interesting possibility rather than a proven treatment. A supplement long associated with muscle building is now attracting the attention of scientists looking for new ways to treat depression.
The peer-reviewed research paper “Creatine as a treatment for depression” brain medicine It will be available through open access from June 30, 2026.
