Creatine, a popular supplement used by athletes and gymgoers to improve muscle performance, is drawing fresh attention from researchers investigating whether the compound could also influence depression.
A new systematic review led by researchers at the University of Ottawa found that creatine may help ease depressive symptoms in some people when added to standard treatment. But the evidence remains far from conclusive, with randomized trials producing mixed results and researchers cautioning that the supplement is not yet ready to be considered a proven treatment for depression.
Two Studies Found Benefits While Three Did Not
The researchers reviewed six published reports covering five randomized controlled trials involving 238 participants from five countries. Four trials involved people with major depressive disorder, while one focused on people with bipolar disorder experiencing a depressive episode.
The results were split.
Two trials, both based on the same study involving women with major depressive disorder, reported improvements when creatine was added to existing treatment. In one, participants who took 5 grams of creatine daily alongside the antidepressant escitalopram experienced greater reductions in depressive symptoms after eight weeks than those who received a placebo.
Another trial found that creatine combined with cognitive behavioral therapy was associated with a greater decline in depressive symptoms than therapy paired with a placebo.
But three other trials found no significant benefit. One study involving people who had not responded adequately to antidepressants found no meaningful improvement with creatine. Another trial involving adolescent girls also found no difference compared with placebo.
A study involving people with bipolar disorder similarly found no clear antidepressant effect. Two participants taking creatine developed hypomania or mania, highlighting concerns about whether the supplement could affect people with certain psychiatric conditions differently.
Why Scientists Are Looking at Creatine and the Brain
Creatine is naturally produced by the body and is also found in foods such as meat and fish. It helps cells regenerate adenosine triphosphate (ATP), a molecule that provides energy for cellular processes.
While creatine is best known for supporting energy production in muscles, the brain also has high energy demands. Researchers have therefore begun investigating whether changes in the brain's energy metabolism could play a role in mood disorders.
The review authors noted that people with depression may have altered creatine metabolism in the brain.
"The brain is an expensive organ, burning energy at a rate out of all proportion to its size, and creatine helps cells rebuild ATP," the researchers wrote.
They also noted that creatine may affect biological pathways involving neurotransmitters such as serotonin and dopamine.
However, researchers stressed that these mechanisms remain theories under investigation.
"The signal is interesting, but it is not a verdict," Bassam Jeryous Fares said, emphasizing that the findings do not yet establish a direct cause-and-effect relationship between creatine metabolism and depression.
Fares, the review's lead author, said the findings point to an intriguing possibility but do not provide enough evidence to change clinical practice.
The review also found that reported adverse effects were generally limited to mild gastrointestinal discomfort, although the researchers noted the need for additional safety data, particularly among people with psychiatric conditions.
The studies were also relatively small, varied in quality, and included an uneven mix of participants. Two trials enrolled only women, while the overall number of participants was limited. The researchers said these factors make it difficult to determine whether the findings would apply broadly to people with depression.
The researchers are calling for larger and longer clinical trials to determine whether creatine can reliably improve depressive symptoms and which patients, if any, might benefit most.
Future studies could also examine creatine alongside exercise, different dosing strategies and longer treatment periods. Researchers are particularly interested in understanding whether differences in sex, diagnosis or underlying brain metabolism could explain why some trials found benefits while others did not.
