Creatine & Depression

>> Creatine, best known for its role in sports and muscle energy, also supports the brain's energy production and use.

>> Research shows that lower brain creatine levels, especially in the prefrontal cortex, may be linked with higher symptoms of depression and anxiety.

>> Some studies find that taking 5 g of creatine daily can boost the effects of antidepressant medication, helping people feel better sooner — especially women.

>> Adding creatine to cognitive-behavioural therapy (CBT) may also lead to greater symptom improvement than therapy alone.

Brain Energy Metabolism and Mood.

Around one in twenty people experience symptoms of depression at any given time. These conditions affect how people think, feel, and function day to day — and they take a heavy toll on both individuals and healthcare systems.

Scientists are exploring many possible biological factors that may contribute to mood disorders. One area of growing interest is how the brain produces and manages energy. Inside every brain cell, creatine plays a key role in this energy system. It helps quickly recycle energy molecules, working like a backup battery that keeps brain cells powered during stress or high activity.

Studies suggest that low brain creatine levels may contribute to mood symptoms. For example, Kondo et al.¹ found that female adolescents with major depression had lower creatine concentrations in parts of the frontal brain, which were linked to more severe symptoms. Faulkner et al.² found similar results in adults — people with lower creatine in the medial prefrontal cortex reported higher depression scores. Yue et al.³ also found that people with social anxiety disorder had less creatine in the left dorsolateral prefrontal cortex than healthy controls. Animal research adds to this picture. Female rodents given creatine showed antidepressant-like behaviour, while males did not.⁴ This difference may relate to sex-based differences in creatine metabolism⁵ or to estrogen's protective effects on brain energy systems, including reduced oxidative stress.⁶ Abnormal brain metabolism is also more common in women than men,⁷ which might explain why creatine seems more effective in female participants. Together, these findings suggest that boosting brain creatine levels may support mood regulation. While the science is still developing, it opens an interesting window into how the brain's energy system might influence emotional health.

Creatine's Augmenting Anti-Depressant Effect.

One of the first clinical studies to test this idea was conducted by Lyoo et al.⁸ The researchers wanted to see if adding 5 g of creatine monohydrate daily could make the antidepressant escitalopram work more effectively in women with depression. The results were striking. Those taking creatine improved faster than those taking a placebo. By the second week, about a third of participants in the creatine group showed a measurable response compared to just a few per cent in the placebo group. By week eight, over half (52%) had achieved remission, while only 26% in the placebo group had.

Creatine was well tolerated. Most side effects, such as mild nausea or headaches, were likely related to the SSRI itself rather than the creatine.⁹ These findings suggest that creatine may help antidepressants work faster, possibly by improving cellular energy efficiency in the brain. Why might this happen? Creatine acts as an energy stabiliser. It helps cells maintain a balance between adenosine triphosphate (ATP) — the body's primary energy molecule — and phosphocreatine, the stored form of energy.¹⁰ In people with depression, studies often show reduced brain energy activity that improves when treatment works.^7,11,12 Interestingly, another compound involved in creatine production, S-adenosyl-L-methionine (SAMe), also shows strong antidepressant effects, even in people who don't respond to SSRIs.¹³ This supports the idea that brain energy metabolism could be a significant piece of the depression puzzle.

Creatine and CBT

Can creatine also improve talk therapy outcomes? A more recent study by Sherpa et al.¹⁴ explored this question. In their eight-week trial, 100 adults with depression received either 5 g/day of creatine monohydrate or a placebo. Everyone also took part in biweekly cognitive-behavioural therapy (CBT) sessions. Both groups improved, but the creatine group's scores dropped more sharply — about five points lower on the PHQ-9 depression scale than the placebo group.¹⁵ That five-point drop is considered clinically meaningful, meaning most people would feel noticeably better. Unlike earlier studies, the benefits were similar for men and women, suggesting creatine may help across sexes when combined with therapy. This trial adds to the growing view that creatine could enhance different kinds of depression treatments, whether chemical or psychological.

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Although the evidence is promising, research on creatine and mood disorders is still limited and early-stage. Most studies have involved small groups of participants, often short treatment periods, and sometimes female-only samples. There are also practical questions. Brain imaging studies suggest creatine levels rise after supplementation, but the blood–brain barrier (BBB) only allows a small amount of creatine to pass through.¹⁷ Scientists are still trying to determine the best dose and duration needed to produce real changes in brain chemistry. Another uncertainty lies in how creatine works. Current theories point to its ability to improve mitochondrial function, balance energy supply, and protect against oxidative stress — all key factors in brain health.^18,19 More detailed studies are needed to understand these pathways and to see whether creatine works best alongside antidepressants, therapy, or as a preventive strategy.

Overall, studies so far suggest that low brain creatine levels may contribute to symptoms of depression and anxiety, and that taking creatine monohydrate could help improve mood in some individuals. Creatine may speed up antidepressant response, enhance therapy outcomes, and possibly work better in women, though men may benefit too. Still, the research is early. Larger and longer studies are needed to confirm these effects and refine recommendations. For now, creatine looks like a safe and affordable supplement that may one day become a valuable adjunct to traditional depression treatments — by helping restore the brain's natural energy balance.

References.

1. Kondo, D. G. et al. Creatine target engagement with brain bioenergetics: a dose-ranging phosphorus-31 magnetic resonance spectroscopy study of adolescent females with SSRI-resistant depression. Amino Acids 48, 1941–1954 (2016). 
2. Faulkner, P. et al. Relationship between depression, prefrontal creatine and grey matter volume. Journal of Psychopharmacology 35, 1464–1472 (2021).
3. Yue, Q. et al. Quantitative 3.0T MR Spectroscopy Reveals Decreased Creatine Concentration in the Dorsolateral Prefrontal Cortex of Patients with Social Anxiety Disorder. PLOS ONE. 7, e48105 (2012). 
4. Allen, P. J. et al. Chronic creatine supplementation alters depression-like behavior in rodents in a sex-dependent manner. Neuropsychopharmacology. 35, 534–546 (2010). 
5. Gledhill, R. F. et al. Race-gender differences in serum creatine kinase activity: a study among South Africans. J Neurol Neurosurg Psychiatry 51, 301–304 (1988). 
6. Razmara, A. et al. Estrogen suppresses brain mitochondrial oxidative stress in female and male rats. Brain Res 1176, 71–81 (2007). 
7. Renshaw, P. F. et al. Multinuclear magnetic resonance spectroscopy studies of brain purines in major depression. Am J Psychiatry 158, 2048–2055 (2001). 
8. Lyoo, I. K. 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 Disorder. American Journal of Psychiatry 169, 937–945 (2012). 
9. Stahl, S. M. Mechanism of action of serotonin selective reuptake inhibitors. J Affect Disord 51, 215–235 (1998). 
10. Adhihetty, P. J. & Beal, M. F. Creatine and its potential therapeutic value for targeting cellular energy impairment in neurodegenerative diseases. Neuromolecular Med 10, 275–290 (2008). 
11. Iosifescu, D. V. et al. Brain Bioenergetics and Response to Triiodothyronine Augmentation in Major Depressive Disorder. Biological Psychiatry 63, 1127–1134 (2008). 
12. Forester, B. P. et al. 31Phosphorus magnetic resonance spectroscopy study of tissue-specific changes in high-energy phosphates before and after sertraline treatment of geriatric depression. Int J Geriatr Psychiatry 24, 788–797 (2009). 
13. Papakostas, G. I. et al. S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: a double-blind, randomized clinical trial. Am J Psychiatry 167, 942–948 (2010).
14. Sherpa, N. N. et al. Efficacy and safety profile of oral creatine monohydrate in add-on to cognitive-behavioural therapy in depression: An 8-week pilot, double-blind, randomised, placebo-controlled feasibility and exploratory trial. European Neuropsychopharmacology 90, 28–35 (2025).
15. Cuijpers, P. et al. Cognitive behavior therapy vs. control conditions, other psychotherapies, pharmacotherapies and combined treatment for depression: a comprehensive meta-analysis. World Psychiatry 22, 105–115 (2023).
16. Nemets, B. & Levine, J. A pilot dose-finding clinical trial of creatine monohydrate augmentation to antidepressant treatment in major depression. International Clinical Psychopharmacology 28, 127–133 (2013).
17. Lyoo, I. K. et al. Multinuclear magnetic resonance spectroscopy of high-energy phosphate metabolites in human brain following oral supplementation of creatine monohydrate. Psychiatry Res 123, 87–100 (2003). 
18. Klinedinst, N. J. & Regenold, W. T. A mitochondrial bioenergetic basis of depression. Journal of Bioenergetics and Biomembranes 47, 155–171 (2015). 
19. Gardner, A. & Boles, R. G. Beyond the serotonin hypothesis: mitochondria, inflammation and neurodegeneration in major depression and affective spectrum disorders. Progress in Neuro-Psychopharmacology and Biological Psychiatry 35, 730–743 (2011).