Creatine Supplementation: A Potential Therapeutic Approach for Depression


How can augmenting conventional antidepressants with creatine monohydrate help patients with depression?



Depression, a prevalent neuropsychiatric disorder, poses a significant burden on global health.1 Traditional antidepressants, primarily targeting monoaminergic neurotransmitter systems, often require weeks to manifest their therapeutic effects. Moreover, a significant proportion of patients do not respond adequately to these treatments.2

Thus, there is an increasing interest in exploring novel therapeutic strategies. One such promising approach is the augmentation of conventional antidepressants with creatine monohydrate, a supplement known for its ergogenic benefits and potential neuroprotective properties.3

Creatine and Brain Energy Metabolism

Creatine plays a crucial role in brain energy homeostasis.4 Disruptions in brain energy production, storage, and utilization have been implicated in the pathophysiology of depression.5 Creatine supplementation may modify brain high-energy phosphate metabolism, potentially restoring bioenergetics at the cellular level.2

The brain, being an energy-intensive organ, relies heavily on adenosine triphosphate (ATP) for its functions. Creatine, stored as phosphocreatine in cells, acts as a reservoir for high-energy phosphate, which can be rapidly mobilized during periods of high energy demand. This mechanism is particularly crucial in neurons, which have limited energy reserves.

Clinical Evidence

Several studies have investigated the potential antidepressant properties of creatine (Table).3,6-9

Table. Studies That Have Investigated the Potential Antidepressant Properties of Creatine

Table. Studies That Have Investigated the Potential Antidepressant Properties of Creatine3,6-9

However, although some studies have reported beneficial effects of creatine for depression management, others have found no significant advantage compared to placebo.10

Potential Mechanisms

The exact mechanisms through which creatine exerts its antidepressant effects are still under investigation. However, several theories have been proposed:

  • Enhanced energy metabolism: Creatine might enhance neuronal energy metabolism, ensuring optimal brain function and potentially counteracting the energy deficits observed in depressed individuals.11
  • Neuroprotection: Creatine has been shown to have neuroprotective effects, potentially safeguarding neurons from various forms of stress.9
  • Modulation of neurotransmitter systems: Creatine might influence neurotransmitter systems, including the serotonin and dopamine pathways, which play crucial roles in mood regulation.5

Safety and Tolerability

Creatine is generally well-tolerated, with most reported adverse effects being mild and transitory.6 Common adverse effects include gastrointestinal symptoms and muscle cramping. However, in the context of depression treatment, these adverse effects are often outweighed by the potential benefits.

Concluding Thoughts

Although the current body of research suggests that creatine supplementation may offer a novel therapeutic approach for depression, especially in treatment-resistant cases, further randomized, placebo-controlled trials are warranted. The potential of creatine to restore brain bioenergetics, combined with its safety profile, makes it an attractive candidate for future research in the realm of neuropsychiatric disorders.3

Dr Ajluni is an assistant professor of psychiatry at Wayne State University in Livonia, Michigan.

During the preparation of this work, the author used ChatGBT in order to synthesize and summarize information based on my ideas, input, and conclusions. After using this tool/service, the author reviewed and edited the content as needed and takes full responsibility for the content of the publication.


1. Pazini FL, Cunha MP, Rodrigues ALS. The possible beneficial effects of creatine for the management of depressionProg Neuropsychopharmacol Biol Psychiatry. 2019;89:193-206.

2. Lyoo IK, Yoon S, Kim TS, et al. A randomized, double-blind placebo-controlled trial of oral creatine monohydrate augmentation for enhanced response to a selective serotonin reuptake inhibitor in women with major depressive disorderAm J Psychiatry. 2012;169(9):937-945.

3. Kious BM, Kondo DG, Renshaw PF. Creatine for the treatment of depressionBiomolecules. 2019;9(9):406.

4. Roitman S, Green T, Osher Y, et al. Creatine monohydrate in resistant depression: a preliminary studyBipolar Disord. 2007;9(7):754-758.

5. Faulkner P, Paioni SL, Kozhuharova P, et al. Relationship between depression, prefrontal creatine and grey matter volumeJ Psychopharmacol. 2021;35(12):1464-1472.

6. Kious BM, Sabic H, Sung YH, et al. An open-label pilot study of combined augmentation with creatine monohydrate and 5-hydroxytryptophan for selective serotonin reuptake inhibitor- or serotonin-norepinephrine reuptake inhibitor-resistant depression in adult womenJ Clin Psychopharmacol. 2017;37(5):578-583.

7. Hellem TL, Sung YH, Shi XF, et al. Creatine as a novel treatment for depression in females using methamphetamine: a pilot studyJ Dual Diagn. 2015;11(3-4):189-202.

8. Bakian AV, Huber RS, Scholl L, et al. Dietary creatine intake and depression risk among U.S. adultsTransl Psychiatry. 2020;10(1):52.

9. Forbes SC, Cordingley DM, Cornish SM, et al. Effects of creatine supplementation on brain function and healthNutrients. 2022;14(5):921.

10. Nemets B, Levine J. A pilot dose-finding clinical trial of creatine monohydrate augmentation to SSRIs/SNRIs/NASA antidepressant treatment in major depressionInt Clin Psychopharmacol. 2013;28(3):127-133.

11. Roitman S, Green T, Osher Y, et al. Creatine monohydrate in resistant depression: a preliminary studyBipolar Disord. 2007;9(7):754-758.

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