Does Cyclobenzaprine Interact with Sertraline? (1 serious interaction)

In this article, we will discuss the possible interaction between cyclobenzaprine and sertraline, and the associated risk of sertraline syndrome. We will also discuss the ways to prevent this interaction.

Does Cyclobenzaprine interact with Sertraline?

Yes, Cyclobenzaprine can interact with Sertraline. The interaction may cause a life-threatening condition known as serotonin syndrome (1). Serotonin syndrome is caused when the level of serotonin rises to a toxic level in the brain.

Cyclobenzaprine is a centrally-acting muscle relaxant that manages acute pain in the skeletal muscle. Sertraline is a serotonin reuptake inhibitor (SSRI), an antidepressant, that manages several mental health conditions.

What are the potential interactions between Cyclobenzaprine and Sertraline?

Cyclobenzaprine inhibits serotonin reuptake by blocking 5-hydroxytryptamine subtype 2A in the presynaptic cleft of the brain. However, this action is not as intense as the drug explicitly designed to target this receptor, such as sertraline.

Sertraline is a serotonin reuptake inhibitor that increases the serotonin level in the presynaptic cleft of the brain, and this mechanism is key to the effectiveness of sertraline in managing various mental health conditions.

The brain uses serotonin to alleviate anxiety and depression. Nevertheless, when cyclobenzaprine and sertraline are taken together, a high level of serotonin accumulates in the brain, leading to serotonin syndrome, a life-threatening condition (2).

Serotonin syndrome is a fatal condition manifested by various symptoms, including delirium, confusion, restlessness, agitation, excitement, increased heart rate, sweating, dilated pupil, ocular clonus, increased breathing rate, tremors, rhythmic muscle spasms, Bilateral Babinski sign, increased bowel sounds and increased reflexes, leading to fatal hyperthermia and shock if serotonin levels are not reduced (5).

Most of the time, serotonin toxicity is resolved in 24 to 72 hours after stopping the pro-serotonergic drugs, causing serotonin levels to rise.

Additionally, supportive treatment is given to manage hyperthermia due to increased muscle spasms, increased heart rate, hypertension and other symptoms. Drug-induced serotonin syndrome is generally mild and resolves spontaneously (5).

Cyproheptadine is a histamine receptor 1 antagonist and is used as an antidote for serotonin syndrome (3). Patients with abnormal vital signs require admission to the intensive care unit (ICU) (3).

What does research suggest?

Several case studies have been published that emphasize the role of cyclobenzaprine in serotonin syndrome.

These case studies identified the role of cyclobenzaprine in serotonin syndrome when combined with different medication that involves serotonin reuptake, such as Serotonin reuptake inhibitors, Monoamine oxidase inhibitor, lithium, and linezolid.

Pro-serotonergic polypharmacy caused the increased incidence of serotonin syndrome and cyclobenzaprine is added to the list of medicines that can precipitate serotonin syndrome and taking sertraline and cyclobenzaprine alone do not pose a risk of serotonin syndrome.

The takeaway from all these case reports was to closely monitor the patients given pro-serotonergic agents such as sertraline and cyclobenzaprine, along with proper counselling to the patients about the potential risk, and guidance to identify and report the symptoms immediately (4,5).

Can you prevent the interaction between Cyclobenzaprine and Sertraline?

If your healthcare provider has recommended you to take sertraline and cyclobenzaprine, it is important to stay attentive to potential side effects. If you experience any muscle spasms and mood or behavioural changes, report immediately to your primary healthcare provider.

Also, do not take both medications at the same time. It is clinically observed if these medicines are taken 2-3 hours apart, the risk of Serotonin syndrome becomes relatively low.


Cyclobenzaprine and sertraline, when taken together, pose a risk of interaction that can lead to a life-threatening condition called serotonin syndrome.

Serotonin syndrome is a serious condition characterized by agitation, muscle spasms, increased heart rate and other mental manifestations, and autonomic dysfunction. It requires immediate medical care; otherwise, it can be fatal.  Cyproheptadine is used as an antidote for serotonin syndrome.

To reduce the risk of the potential interaction space the medications apart by 2-3 hours, and if you experience any symptoms suggestive of serotonin syndrome, report them immediately to your healthcare provider. You should always seek advice from your healthcare provider if any side effects occur.

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Keegan MT, Brown DR, Rabinstein AA. Serotonin syndrome from the interaction of cyclobenzaprine with other serotoninergic drugs. Anesth Analg. 2006 Dec;103(6):1466-8. doi: 10.1213/01.ane.0000247699.81580. eb. PMID: 17122225.



Mestres J, Seifert SA, Oprea TI. Linking pharmacology to clinical reports: cyclobenzaprine and its possible association with serotonin syndrome. Clin Pharmacol Ther. 2011 Nov;90(5):662-5. doi: 10.1038/clpt.2011.177. Epub 2011 Oct 5. PMID: 21975349; PMCID: PMC3809033.



Simon LV, Keenaghan M. Serotonin Syndrome. [Updated 2023 Jul 17]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available Form:




Keegan, Mark T. MD*; Brown, Daniel R. MD, PhD, FCCM*; Rabinstein, Alejandro A. MD. Serotonin Syndrome from the Interaction of Cyclobenzaprine with Other Serotoninergic Drugs. Anesthesia & Analgesia 103(6):p 1466-1468, December 2006. DOI: 10.1213/01.ane.0000247699.81580.eb



Day LT, Jeanmonod RK. Serotonin syndrome in a patient taking Lexapro and Flexeril: a case report. Am J Emerg Med. 2008 Nov;26(9):1069.e1-3. doi: 10.1016/j.ajem.2008.03.028. PMID: 19091289.

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