Creatine can be sourced from food like red meat and fish, but it’s also synthesized in the body, primarily in the liver and kidney, as well as the brain.^[3]

Creatine plays a key role in energy production. It stores high-energy phosphate groups in the form of creatine phosphate, which are donated to ADP to regenerate ATP. Because brain cells require a constant supply of ATP, which is in part provided through the creatine phosphate-reliant phosphagen energy system, creatine is crucial for optimal brain function.^[4]

This is further evidenced by the fact that clinical symptoms of creatine deficiency syndromes, a group of conditions characterized by defects in creatine synthesis or transport, include intellectual disability and epilepsy, among other neurological abnormalities.^[5]

Low brain creatine content and abnormalities in brain bioenergetics (e.g., reduced ATP production) are associated with several neurological disorders (e.g., Huntington’s disease),^[6]^[7] and these findings extend to depression.^[8]^[9]^[10]^[4]

Supplementing with creatine has been found to increase brain creatine content,^[11]^[12]^[9]^[13]^[14] indicating a plausible mechanism by which creatine could improve depression.

Other than affecting brain bioenergetics, preclinical evidence suggests that supplementing with creatine could help with depression by modulating neurotransmitter receptors, for example, by activating dopamine and serotonin receptors and inhibiting N-methyl-D-aspartate receptors.^[15]^[16]^[17] Creatine might also improve depression by decreasing oxidative stress and increasing serum BDNF.^[18]^[19]^[20]

Neurotransmitter systems implicated in the potential antidepressant effect of creatine

D₁ and D₂= dopamine receptors. 5-HT_1A = serotonin receptor. α1 = noradrenaline receptor. A₁ and A_2A = adenosine receptors. NMDA = N-methyl-D-aspartate receptor. Adapted from Pazini et al., 2019, Prog Neuropsychopharmacol Biol Psychiatry.

Creatine has been consistently shown to improve depression-like behavior in female rodents.^[21]^[22]^[23] In humans, preliminary evidence from clinical trials suggests that taking creatine alongside antidepressant medication is an effective intervention for improving depression symptoms in people with MDD.^[24]^[25]^[26] Also, a study in participants with methamphetamine dependence reported that supplementing with creatine (without accompanying antidepressant use) improved depression symptoms.^[12] However, a serious limitation of this data is that none of the studies included a placebo control group.

There is also evidence from randomized controlled trials. A study in participants with bipolar depression who were taking antidepressants found limited evidence that adjunct treatment with creatine was better than a placebo for improving depression symptoms.^[27]

In participants with MDD who were taking antidepressants, an 8-week study that included 52 women reported that taking 5 grams of creatine daily was better than a placebo for improving depression symptoms.^[28] In contrast, a 4-week study in 18 participants (14 women) found no benefit of supplementing with 5 or 10 grams creatine daily,^[29] but this finding should be taken with caution due to the small sample size and relatively short intervention duration.

All in all, a broad spectrum of evidence makes a compelling case that supplementing with creatine could be an effective intervention for improving depression, but further evidence from high-quality randomized controlled trials is needed. The summarized study is a valuable addition to the literature because — unlike previous studies which were conducted in participants taking antidepressants — the researchers found that in participants with MDD who were not taking antidepressants, supplementing with creatine while undergoing low-intensity cognitive behavioral therapy can improve depression symptoms to a clinically meaningful degree.

Creatine may help with depression Original paper