Medications That May Cause Serotonin Syndrome

Serotonin syndrome is a serious drug reaction that occurs because of serotonin toxicity (too much serotonin in the body). This article has been written with the goal of demystifying serotonin syndrome. Please keep reading to learn more about the clinical symptoms of serotonin syndrome as well as some of the medications that can cause this potentially life-threatening condition.

What is serotonin syndrome?

Serotonin is a natural chemical produced in the body. It acts as a neurotransmitter by binding to serotonin receptors, which results as a message carried between nerve cells. Serotonin plays an important role in many functions, such as mood, sleep, digestion, blood clotting, bone health, and sexual desire. However, too much of a good thing is usually bad for you. Consequently, serotonin syndrome is a life-threatening, drug-induced condition in which there is too much serotonin in the body.

What is the most common cause of serotonin syndrome?

The most common cause of serotonin syndrome is the use of serotonergic drugs. These are drugs that affect serotonin metabolism, i.e., they modify the amount of serotonin in the body. Many commonly prescribed antidepressant medications are serotonergic drugs. Since serotonin syndrome occurs when there are high serotonin levels in the body, it is understandable how this can occur when using a medication that increases the amount to help your mood. This can happen due to:

Taking multiple serotonergic antidepressants or other serotonergic drugs together.
Drug-drug interactions between a serotonergic medication and other medications or illicit drugs that affect serotonin levels.
Accidental or intentional overdose of a serotonergic agent.

What are the symptoms of serotonin syndrome?

Mild symptoms of serotonergic syndrome may include shivering, nausea, vomiting, and diarrhea. Moderate symptoms may include agitation, restlessness, sweating, fast heart rate, muscle rigidity, involuntary muscle contractions, confusion, and altered mental status. Severe symptoms of serotonin syndrome can include high fever, irregular heartbeat, unstable blood pressure, tremors, seizures, unconsciousness, and severe kidney damage. Severe serotonin syndrome can be fatal. Doctors use a system called the Hunter serotonin toxicity criteria to make a clinical diagnosis of this complication caused by a serotonin-related medication. If you have or believe you have ingested more of a serotonergic drug than the prescribed amount of your medication or are having these symptoms with multiple serotonergic medications prescribed, go to your nearest Emergency Department.

Note that severe serotonin symptoms can be very similar to another potentially life-threatening adverse reaction called neuroleptic malignant syndrome (NMS). However, white blood cell count and blood levels of certain enzymes help doctors distinguish between the two conditions.

What prescription drugs raise serotonin levels?

Selective serotonin reuptake inhibitors (SSRIs)

Selective serotonin reuptake inhibitors (SSRIs) are a group of antidepressants that regulate mood by blocking the reabsorption (reuptake) of serotonin at the synaptic cleft (space between nerve cells), thereby increasing serotonin levels. Examples of a selective serotonin reuptake inhibitor (SSRI) include fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), and others.

Serotonin norepinephrine reuptake inhibitors (SNRIs)

SNRIs are medications that relieve depression by affecting the levels of two neurotransmitters, serotonin and norepinephrine, which the body also uses as neurotransmitters. Examples of SNRIs include duloxetine (Cymbalta), venlafaxine (Effexor XR), desvenlafaxine (Pristiq), and others.

Tricyclic antidepressants (TCAs)

Tricyclic antidepressants are an older class of drugs that work by blocking the reuptake of serotonin and norepinephrine by nerve cells. Taking TCAs leads to an increased concentration of these neurotransmitters, which can potentially cause serotonin syndrome. Examples of tricyclic antidepressants include amitriptyline, nortriptyline (Pamelor), desipramine (Norpramin), and others.

Monoamine oxidase inhibitors (MAOIs)

Monoamine oxidase inhibitors (MAOIs) are a group of drugs that prevent the removal of neurotransmitters like serotonin, norepinephrine, and dopamine from the brain. Taking these medications can lead to an increased risk of serotonin syndrome because of too much serotonin. Examples of a monoamine oxidase inhibitor include phenelzine (Nardil), tranylcypromine (Parnate), isocarboxazid (Marplan), selegiline (Emsam), and others.

Migraine medications

A group of medications called triptans are used to treat migraines and can cause serotonin syndrome by activating serotonin receptors. Examples of triptans include sumatriptan (Imitrex), rizatriptan (Maxalt), almotriptan (Axert), frovatriptan (Frova), and others.

Opioid pain medications

People taking opioid analgesics such as fentanyl, oxycodone, tramadol, and methadone, along with antidepressant medications or migraine medications, can develop serotonin syndrome due to interactions between these drugs.

Anti-nausea medications

Medications such as metoclopramide (Reglan), ondansetron (Zofran), granisetron (Sustol, Sancuso), and droperidol (Inapsine) can affect serotonin levels and lead to serotonin syndrome.

What over-the-counter medications can cause serotonin syndrome?

Cough suppressants

Some over-the-counter cough and cold medications contain an active ingredient called dextromethorphan, for example, Delsym. Taking high doses of dextromethorphan along with the usual dose of a selective serotonin reuptake inhibitor (SSRI) to treat depression can lead to serotonin syndrome.

Herbal supplements

Dietary supplements like St. John’s Wort, nutmeg, and ginseng can lead to a drug-drug interaction, resulting in serotonin syndrome.

Illicit drugs

Illicit drugs like lysergic acid diethylamide (LSD), amphetamines, cocaine, etc., can affect serotonin levels and cause serotonin syndrome.

Which drug affects serotonin the most?

Antidepressants affect serotonin the most. They are some of the most common causative drugs implicated in serotonin syndrome. Various types of antidepressants, including selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs), may be responsible for causing serotonin syndrome.

How is serotonin syndrome treated?

Doctors treat serotonin syndrome by immediately discontinuing serotonergic agents. Treatment also consists of providing hydration and supportive care to manage fever, high blood pressure, and other cardiac and respiratory complications. Benzodiazepines may be prescribed for sedation. People with refractory or severe serotonin syndrome may be given serotonin antagonists such as cyproheptadine. This medication is an antihistamine, but it works as an antidote for serotonin toxicity because it blocks serotonin receptors. If it is severe, some patients are admitted to the intensive care unit.

How to prevent serotonin syndrome?

The best way to prevent serotonin syndrome is to tell your doctor and pharmacist about all the medications you take before starting any new medications and to take all your medications exactly as prescribed.

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