An emerging role for creatine supplementation in the treatment of depression

Despite the existence of an arsenal of medications that target the neurotransmitters in the brain thought to be responsible for mood disorders, about 30% of individuals with major depressive disorder remain treatment-resistant. This points to other possible factors that may contribute to the condition.

Research to date has implicated impaired energy metabolism as a potential culprit, as the brain requires enormous amounts of energy to function normally. This, in turn, would suggest that interventions known to boost cellular energy production might offer some relief for those suffering from depression, and attention has turned to one such supplement in particular: creatine. Well known for its role in muscular energetics, might creatine have additional benefits in the treatment of depression?

Why creatine?

Most conventional antidepressants are based on the “monoamine hypothesis,” which posits that depression results from a depletion of serotonin, norepinephrine, and/or dopamine. Many antidepressants, including SSRIs (selective serotonin reuptake inhibitors) and SNRIs (serotonin-norepinephrine reuptake inhibitors), therefore aim to increase the availability of these neurotransmitters. But in order to produce neurotransmitters and allow them to function properly in driving neural responses, the brain requires energy. The brain is an especially energy-intensive organ, consuming approximately 20% of the body’s energy despite making up only about 2% of body weight. Given this, disruptions in brain energy balance (or, “bioenergetics”) may influence monoamine function, and thus, deficits in brain bioenergetics may underlie or contribute to mood disorders, including depression.¹

Creatine, widely known for its role in muscle energy metabolism, plays a critical role in maintaining brain energy homeostasis. It serves as both an energy buffer — storing cellular energy in the form of high-energy chemical bonds as phosphocreatine — and an energy shuttle, transporting energy produced by mitochondria to areas of high demand within neurons, such as synapses. With creatine’s ability to cross the blood-brain barrier, increases in brain creatine reserves could thus theoretically improve brain bioenergetics and may act synergistically with monoamine-based treatments (like SSRIs).

Indeed, growing evidence suggests that combining creatine with SSRIs may improve treatment outcomes. In one proof-of-concept study in women with major depressive disorder, adding 5 g of creatine daily to escitalopram (an SSRI marketed under the brand name Lexapro) led to faster and more substantial symptom relief than escitalopram alone.^2,3 Small, unblinded studies have likewise shown promising reductions in depression scores when other SSRIs and SNRIs were paired with creatine.^4,5 Animal research further underscores this synergy, revealing that blocking serotonin synthesis reduces creatine’s antidepressant-like effects, indicating that the benefits of creatine for depression are at least partially mediated by its effect of enhancing neurotransmitter production and function.^6,7  

Human studies, however, have predominantly focused on the combination of creatine with SSRIs, whereas many other antidepressant treatments — both pharmacological and non-pharmacological — are also commonly used by those with major depressive disorder. For instance, cognitive behavioral therapy (CBT) is a frontline treatment focused on addressing the negative thought patterns that fuel depression, providing tools to reframe thinking and develop healthier coping strategies. So this leaves us with a key question: does creatine have potential utility as an adjuvant therapy with CBT? A recent study sought to answer this question.⁸ 

An emerging role for creatine with behavioral therapy

For this double-blind, randomized controlled trial, authors Sherpa et al. examined 100 participants in India with clinical diagnoses of depression. Participants (mean age 30.4 ±7.4 years, 50% female) were randomized to either CBT plus creatine (5 g/day) or CBT plus placebo for a treatment period of 8 weeks.⁸ The CBT protocol for both groups involved a total of five 45-min CBT sessions (one every other week), and the primary outcome — improvement in symptom severity — was assessed by the Patient Health Questionnaire-9 (PHQ-9), a standard method for evaluating depressive symptoms. Scores on the PHQ-9 can range from 0 to 27, with higher scores indicating more severe depression (mild depression: scores of 5–9, moderate: 10–14, moderate-severe: 15–19, and severe: ≥20).

Results indicated that both groups improved significantly in symptom severity from baseline to the 8-week timepoint. However, the creatine group showed statistically significantly greater improvements, with scores dropping an additional 5.12 points compared to placebo (95% CI: −7.20 to −3.52). Specifically, the CBT-creatine group moved from moderately severe depression (17.8±6.1) to mild depression (5.8±4.8), while the CBT-placebo group remained in the moderate range (shifting from 17.6±6.4 to 11.9±6.6). Additionally, twelve participants in the CBT-creatine group achieved remission (PHQ-9 score <5) compared with five in the CBT-placebo group.

While these findings represent the intention-to-treat cohort (i.e., all participants who started treatment, regardless if they completed the entire treatment protocol), dropout rates were high among both groups (around 40%). This certainly may have impacted results, as those who dropped out may have been experiencing less benefit from either treatment. Indeed, the authors also conducted per-protocol analyses (i.e., excluding drop-outs) and reported a slightly greater difference between groups (the mean improvement in the CBT-creatine group exceeded that of the CBT-placebo group by 6.07 points, 95% CI: −7.88 to −4.25).

However, an important limitation of this study is that it lacked any comparison to traditional pharmacological antidepressants, and thus, we are restricted in our ability to fully understand the scale of this effect. A difference of five points on the PHQ-9 scale is unequivocally clinically significant, so these new data from Sherpa et al. suggest that creatine can indeed improve outcomes from CBT compared to placebo (though it’s worth noting that the CBT protocol employed here was very light compared to more typical weekly or twice-weekly sessions). Further, according to a meta-analysis including over 50,000 patients, CBT is often just as effective as pharmacological therapies, and individuals who combine medications with CBT fare better than with either treatment alone,⁹ but is the combination of creatine and CBT as effective as a combination of SSRIs and CBT? If so, this opens new avenues for patients who do not respond to SSRIs or do not tolerate their side effects to achieve comparable relief as others achieve on traditional medications. Perhaps creatine added to both CBT and antidepressants would show still greater benefit, offering hope to those with the most severe forms of depression. We currently have no direct comparisons to answer these questions, so further clinical studies are warranted.

The broader implications

The anti-depressive potential of creatine is appealing for several practical reasons. Creatine monohydrate is inexpensive, widely available, and well-studied for safety, with established benefits for muscle function and exercise performance. Its potential role in treating depression adds a layer of accessibility for individuals who are seeking adjuncts to traditional antidepressants. Since many people already use creatine as part of their supplement routine, it could be an easy addition for those looking to improve mental health without major lifestyle changes. It may also serve as a low-cost option for those with limited resources, though evidence to date has only explored the effects of creatine supplementation for depression in combination with another first-line treatment (i.e., CBT and antidepressants). Thus, at present, creatine should not be considered a replacement for standard care. 

For those wishing to start taking creatine, the most common form used for supplementation is creatine monohydrate powder, typically at a dose of ~5 g/day (also the most common dose in studies on creatine and depression). Mild gastrointestinal upset and water retention (bloating) are among the most commonly reported side effects, but serious complications are rare in healthy adults. Nevertheless, individuals with kidney issues or bipolar disorder should consult a healthcare provider before starting creatine, as they may be at higher risk of adverse effects.

The bottom line

Creatine’s low risk-to-benefit ratio makes it an intriguing option to consider alongside standard treatments for depression, such as SSRIs or CBT. Already readily available as a muscle-boosting supplement, it may be an easy addition to mental health interventions under proper medical guidance. However, it’s crucial to maintain realistic expectations. While evidence so far is positive, it remains largely preliminary, and what works in small, specialized studies may not hold true for everyone.

A central question for future research is whether creatine’s synergistic effect with antidepressants and CBT could become even more robust in a “triple combination” approach, as well as how it might affect other mood and anxiety disorders. As larger, more diverse studies come to light, we’ll gain clearer insights into how creatine might fit into the broader landscape of depression therapies.

All in all, creatine offers a potentially valuable tool in the ongoing effort to find more effective, personalized ways to manage depression. Time — and more rigorous research — will tell exactly where it belongs in the therapeutic toolbox.

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References

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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 disorder. Am J Psychiatry. 2012;169(9):937-945. doi:10.1176/appi.ajp.2012.12010009
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7. Cunha MP, Machado DG, Capra JC, Jacinto J, Bettio LE, Rodrigues ALS. Antidepressant-like effect of creatine in mice involves dopaminergic activation. J Psychopharmacol. 2012;26(11):1489-1501. doi:10.1177/0269881112447989
8. Sherpa NN, De Giorgi R, Ostinelli EG, Choudhury A, Dolma T, Dorjee S. 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 in an under-resourced area. Eur Neuropsychopharmacol. 2025;90:28-35. doi:10.1016/j.euroneuro.2024.10.004
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