Can Creatine Help Treat Depression?

Creatine has earned a well-established place in the fitness world. Athletes and regular gym users have taken it for years to promote strength and muscle development.

It is also one of the most extensively researched sports supplements available. Substantial research has examined how it enables muscles to produce energy during high-intensity exercise.

Yet comparatively few people realise that the brain needs an enormous supply of energy each day. Researchers have long understood that creatine plays a part in this process.

This has prompted an important question: might the same supplement used for weight training also benefit people experiencing depression?

Looking beyond muscles

A recent systematic review examined this possibility by assessing six published reports from five randomised controlled trials.

Across these studies, both participants and clinicians were unaware of whether creatine or a placebo had been administered.

The trials were conducted in South Korea, the United States, Brazil, Israel and India. They initially included 238 participants, of whom 126 were given creatine and 112 received a placebo.

Participants had an average age of 36. Women made up most of the sample, while two studies enrolled women only.

Four trials focused on major depressive disorder, whereas one investigated depressive states during bipolar disorder.

As the studies varied considerably in their designs, the researchers assessed them separately rather than pooling the findings into one statistical analysis.

Creatine and depression: results pointing in different directions

The results did not provide a straightforward answer. Two of the five trials produced promising findings, and both originated from the same study of women with major depressive disorder.

Women taking five grams of creatine each day in addition to the antidepressant escitalopram had a larger reduction in depressive symptoms after eight weeks than those given a placebo.

The effect was substantial, recording a Cohen’s d of 1.13 on the Hamilton Depression Rating Scale, and remission was achieved by more women.

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

Effects may differ according to the disorder

The other three trials produced contrasting findings.

One detected no benefit among people with depression that had not responded to medication, whether they took five or ten grams of creatine per day.

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

The fifth trial likewise showed no benefit for people with bipolar disorder experiencing a depressive episode.

Two participants with bipolar disorder who were given creatine developed hypomania or mania. This indicates that the supplement could influence different mental health conditions in different ways.

Why researchers became interested

Although it represents only a small proportion of total body weight, the brain uses roughly 20 percent of the body’s energy.

Every nerve cell needs adenosine triphosphate, or ATP, to operate. Once ATP has been used, creatine helps replenish it.

Researchers have identified alterations in brain creatine metabolism among people with mood disorders. This suggests that disrupted energy production may have a role in depression.

Creatine could also affect dopamine and serotonin, two mood-related brain chemicals already targeted by many antidepressant medicines.

The connection remains unconfirmed

Nevertheless, existing evidence does not establish that low levels of brain creatine cause depression. The association is still a correlation, not 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 caution.

“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 identifies several weaknesses. The clinical trials were small, gender representation was uneven, and just two studies were considered to have a low risk of bias.

Three studies raised concerns over the allocation of participants to treatment groups and the handling of missing data.

According to the researchers, larger trials are required, particularly those running for more than eight weeks.

They also call for research assessing creatine alongside exercise and testing different doses, while acknowledging that more is not necessarily better.

An intriguing possibility

Animal studies have also suggested that creatine could affect males and females differently. This may help account for the stronger results in studies with more women.

For the time being, creatine remains a supplement with established benefits for muscle performance and an interesting, though unproven, potential treatment for depression.

Research is progressing, but the evidence is still insufficient to alter depression treatment.

The complete study was published in the journal Brain Medicine.