Creatine and depression: what a new systematic review found

Creatine has long held a solid place in the fitness community. Athletes and regular gym users have relied on it for years to help boost strength and support muscle gain.

It is also one of the most thoroughly researched sports supplements available, with extensive work examining how it helps muscles produce energy during short, high-intensity effort.

What is less widely appreciated is that the brain, too, demands a vast supply of energy day in, day out-and scientists have been aware for some time that creatine plays a role in meeting that need.

This has led to a key question: might the same supplement popular in the weights room also offer support to people living with depression?

Looking beyond muscles

To investigate, a recent systematic review assessed six published reports spanning five randomised controlled trials.

Across these trials, blinding was maintained: neither participants nor clinicians knew who had been given creatine and who had received a placebo.

The studies were carried out in South Korea, the United States, Brazil, Israel and India, and included 238 participants at the outset. In total, 126 people took creatine while 112 were assigned a placebo.

Participants averaged 36 years of age. Women made up most of the sample, and two trials enrolled women only.

Four studies focused on major depressive disorder, while one examined depressive states occurring as part of bipolar disorder.

Because the trials varied substantially in design, the reviewers evaluated each study on its own rather than pooling the outcomes into a single combined statistical analysis.

Results that point in different directions

Overall, the evidence did not point clearly in one direction. Two of the five trials produced promising findings-both from the same study of women with major depressive disorder.

In that work, taking five grams of creatine per day in addition to the antidepressant escitalopram led to a larger drop in depressive symptoms after eight weeks compared with placebo.

The effect size was substantial, with a Cohen’s d of 1.13 on the Hamilton Depression Rating Scale, and a higher proportion of women achieved remission.

A separate trial also reported that pairing creatine with cognitive behavioural therapy reduced symptoms more than therapy combined with a placebo.

Effects may vary by disorder

The other three trials painted a contrasting picture.

One study reported no advantage from either five or ten grams of creatine daily among people whose depression had not improved with medication.

Another found no symptom improvement in adolescent girls given varying creatine doses.

A fifth trial likewise observed no benefit for people with bipolar disorder who were in a depressive episode.

Notably, two participants with bipolar disorder who were allocated to creatine developed hypomania or mania, suggesting the supplement could influence different mental health conditions in different ways.

Why scientists became interested

Although it accounts for only a small proportion of body weight, the brain uses around 20 percent of the body’s energy.

Each nerve cell relies on adenosine triphosphate (ATP) to work properly, and creatine supports the replenishment of ATP after it has been expended.

Researchers have identified alterations in brain creatine metabolism in people with mood disorders, raising the possibility that disrupted energy production could play a part in depression.

Creatine may also affect dopamine and serotonin-two neurotransmitters involved in mood that are already targeted by many antidepressant treatments.

The link is still not confirmed

Despite these leads, current findings do not demonstrate that reduced brain creatine causes depression. At present, the association is correlational rather than evidence of cause and effect.

“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, the corresponding author and a psychiatry resident at the University of Ottawa, also advised restraint.

“Creatine appears to be a safe intervention. The adverse events we found were limited to mild gastrointestinal discomfort,” said Fabiano.

“We cannot yet reliably say that creatine helps with depressive symptoms or if the findings are generalizable to everyone.”

More questions than answers

The review also underscores several weaknesses in the evidence base. Trial sizes were modest, gender representation was uneven, and only two studies were assessed as having a low risk of bias.

Three trials raised issues around how participants were allocated to groups and the way missing data were managed.

The authors argue that larger trials are required, particularly studies extending beyond eight weeks.

They also call for research that tests creatine alongside exercise and explores a range of doses, while acknowledging that more is not necessarily better.

An intriguing possibility

Animal studies have additionally suggested that creatine may act differently in males and females, which could help account for stronger outcomes in trials with more women.

At present, creatine remains a supplement with well-established benefits for muscle performance-and a compelling but unproven prospect for the treatment of depression.

Research is progressing, yet the evidence is still not robust enough to alter approaches to depression care.

The complete study appeared in the journal Brain Medicine.