Does Creatine interfere with Zoloft? (3+ studies)

In this article, we will answer the question, “Does Creatine interfere with Zoloft?”. We will discuss the potential mechanism through which Creatine can interfere with Zoloft and what research suggests in this regard. We will also discuss what precautions should be taken when using both medications together.

Does Creatine interfere with Zoloft?

Creatine may interfere with Zoloft (Sertraline). Creatine has been found to help with depression and hence may interfere with and potentiate the antidepressant effects of Zoloft.

Zoloft is an antidepressant belonging to the class of selective serotonin reuptake inhibitors (SSRIs) and approved by the FDA for the treatment of various depressive illnesses like major depressive disorder (MDD), panic disorder (PD), obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), social anxiety disorder (SAD) and postmenstrual dysphoric disorder (PMDD) (1).

Zoloft has been used ‘off-label’ for the management of binge eating disorder, improving focus, body dysmorphic disorder, bulimia nervosa (BN), premature ejaculation and generalised anxiety disorder (GAD) (2).

Creatine is generally a naturally occurring substance used by the body for energy. However, creatine-rich foods like meat and fish and even supplements are also available. Some individuals may take external supplements to help improve their energy levels.

Creatine can also improve brain health. Creatine supplements can improve memory and cognitive abilities in adults. It also tends to reduce fatigue. These effects are beneficial for depressed individuals.

How does Creatine interfere with Zoloft?

Cases of decreased creatine kinase activity have been reported in depressed patients, which may explain creatine supplementation and improved depression outcomes.

Creatine has positive interference with Zoloft and may increase the antidepressant effects of this medication. The exact mechanism through which Creatine exerts antidepressant effects has not yet been understood. However, various possible mechanisms have been proposed for the antidepressant effects of Creatine.

A mechanism through which creatine can interfere with Zoloft’s antidepressant effects is the modulation of the neurotransmitter serotonin. Creatine may affect the neurotransmitters serotonin and dopamine which may cause its antidepressant effects. The antidepressant effect of creatine is diminished by compounds inhibiting serotonin synthesis and increased by the coadministration of medications like SSRIs (3,4).

What does research suggest?

Although there has not yet been much research on the coadministration and related effects of Creatine and Zoloft, there are various studies assessing the coadministration of other SSRIs and Creatine.

A study of a patient receiving treatment with citalopram and tramadol for PTSD, depression and fibromyalgia reported an improvement in depressive symptoms after being given creatine supplementation (5).

Another study examining the effects of Creatine monohydrate in five female adolescents, who also were receiving fluoxetine for the treatment of unipolar depression, showed an improvement in depressive symptoms. The effects were reported after 8 weeks of coadministration of the Creatine and fluoxetine (6).

One study assessing the effects of Creatine and escitalopram coadministration in 52 female patients with MDD, reported an improvement in the Hamilton Depression Rating Scale (HDRS or HAM-D) score of individuals receiving both medications when compared to the group receiving only escitalopram (7).

Another study assessing the coadministration of antidepressants and Creatine for 3 weeks reported no significant improvement in the HDRS scores among the individuals receiving Creatine or placebo with the antidepressants. However, two women did show an improvement in depressive symptoms while taking Creatine (8).

What precautions should be taken for using Creatine while on Zoloft?

Although side effects with the coadministration of Creatine and antidepressants have not been reported, some precautions should be taken when coadministering both medications. Some common side effects that may occur include:

These side effects may subside once your body adjusts to the medication. However, if you experience any of these side effects or any other unusual symptoms, which do not resolve after a few weeks, make sure to contact your healthcare provider and seek medical assistance for your symptoms.

To the best of my knowledge and according to research, Creatine may positively interfere with Zoloft’s therapeutic effects and potentiate them. Creatine is known to cause antidepressant effects and when coadministered with antidepressants like Zoloft it can help manage depressive symptoms more effectively.

In my opinion, the coadministration of Creatine and Zoloft can help improve depressive illnesses better than antidepressants alone. However, do not start or stop any medication or supplements without the guidance of your healthcare provider.

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Singh HK, Saadabadi A. Sertraline. [Updated 2023 Feb 13]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from:


Faulkner P, Paioni SL, Kozhuharova P, Orlov N, Lythgoe DJ, Daniju Y, Morgenroth E, Barker H, Allen P. Relationship between depression, prefrontal creatine and grey matter volume. Journal of Psychopharmacology. 2021 Dec;35(12):1464-72.


Kious BM, Kondo DG, Renshaw PF. Creatine for the Treatment of Depression. Biomolecules. 2019 Aug 23;9(9):406.


Amital D, Vishne T, Rubinow A, Levine J. Observed effects of creatine monohydrate in a patient with depression and fibromyalgia. American Journal of Psychiatry. 2006 Oct;163(10):1840-1.


Kondo DG, Sung YH, Hellem TL, Fiedler KK, Shi X, Jeong EK, Renshaw PF. Open-label adjunctive creatine for female adolescents with SSRI-resistant major depressive disorder: a 31-phosphorus magnetic resonance spectroscopy study. Journal of affective disorders. 2011 Dec 1;135(1-3):354-61.


Lyoo IK, Yoon S, Kim TS, Hwang J, Kim JE, Won W, Bae S, Renshaw PF. 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. 2012 Sep;169(9):937-45.


Nemets B, Levine J. A pilot dose-finding clinical trial of creatine monohydrate augmentation to SSRIs/SNRIs/NASA antidepressant treatment in major depression. International clinical psychopharmacology. 2013 May 1;28(3):127-33.

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