Serotonin Syndrome

ByKathleen Yip, MD, David Geffen School of Medicine at UCLA;
David Tanen, MD, David Geffen School of Medicine at UCLA
Diane M. Birnbaumer, MD, David Geffen School of Medicine at UCLA
Reviewed/Revised May 2025
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Serotonin syndrome is a potentially life-threatening condition resulting from increased central nervous system serotonergic activity that is usually medication related. Symptoms may include mental status changes, hyperthermia, and autonomic and neuromuscular hyperactivity. Diagnosis is clinical and treatment is supportive.

Serotonin syndrome can occur with therapeutic medication use, self-poisoning, or, most commonly, unintended drug interactions when 2 serotonergic medications are used (see table Medications That Can Cause Serotonin Syndrome) and can occur in all age groups. The most common cause is the simultaneous use of a selective serotonin reuptake inhibitor (SSRI) and tramadol () and can occur in all age groups. The most common cause is the simultaneous use of a selective serotonin reuptake inhibitor (SSRI) and tramadol (1).

Complications in severe serotonin syndrome can include metabolic acidosis, rhabdomyolysis, seizures, acute kidney injury, and disseminated intravascular coagulation (DIC). Causes of these complications probably include severe hyperthermia and excessive muscle activity.

Table
Table

Reference

  1. 1. Mikkelsen N, Damkier P, Pedersen SA. Serotonin syndrome-A focused review. Basic Clin Pharmacol Toxicol. 2023;133(2):124-129. doi:10.1111/bcpt.13912

Symptoms and Signs of Serotonin Syndrome

In most cases, serotonin syndrome manifests within 24 hours, and usually within 6 hours, of a change in dose or initiation of a medication. Manifestations can range widely in severity. They can be grouped into the following categories:

  • Mental status alterations: Anxiety, agitation and restlessness, easy startling, delirium

  • Autonomic hyperactivity: Tachycardia, hypertension, hyperthermia, diaphoresis, shivering, vomiting, diarrhea

  • Neuromuscular hyperactivity: Tremor, muscle hypertonia or rigidity, myoclonus, hyperreflexia, clonus (including ocular clonus), extensor plantar responses

Neuromuscular hyperactivity may be more pronounced in the lower than the upper extremities.

Symptoms usually resolve in 24 hours, but symptoms may last longer after use of medications that have a long half-life or active metabolites (eg, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors).

Diagnosis of Serotonin Syndrome

  • Primarily history and physical examination

Diagnosis of serotonin syndrome is clinical. Various explicit criteria have been proposed.

The Hunter criteria are currently preferred because of ease of use and high accuracy (almost 85% sensitivity and > 95% specificity compared with diagnosis by a toxicologist) (1, 2). These criteria require that patients have taken a serotonergic medication and have one of the following:

  • Spontaneous clonus

  • Tremor and hyperreflexia

  • Ocular or inducible clonus, plus agitation or diaphoresis, or hypertonia and temperature > 38° C

Systemic infections, drug or alcohol withdrawal syndromes, and toxicity caused by sympathomimetic or anticholinergic drugs should also be considered in the differential diagnosis. Differentiation of serotonin syndrome from neuroleptic malignant syndrome may be difficult because symptoms (eg, muscle rigidity, hyperthermia, autonomic hyperactivity, altered mental status) overlap. Clues to serotonin syndrome include use of serotonergic medications, rapid onset (eg, within 24 hours), and hyperreflexia, in contrast to the often decreased reflex responses in neuroleptic malignant syndrome (2).

There are no confirmatory tests, but patients should have testing to exclude other disorders (eg, cerebrospinal fluid analysis for possible central nervous system infection, urine testing for drugs of abuse). Also, some tests (eg, serum electrolytes, platelet count, renal function tests, creatine kinase, coagulation panel, urine myoglobin) may be necessary to identify complications in severe serotonin syndrome.

Pearls & Pitfalls

  • Among patients with hyperthermia, altered mental status, autonomic hyperactivity, and muscular rigidity, factors that favor serotonin syndrome over neuroleptic malignant syndrome include use of serotonergic medications, onset within 24 hours, and hyperreflexia.

Diagnosis references

  1. 1. Dunkley EJ, Isbister GK, Sibbritt D, et al. The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity. QJM. 2003;96(9):635-642. doi:10.1093/qjmed/hcg109

  2. 2. Mikkelsen N, Damkier P, Pedersen SA. Serotonin syndrome-A focused review. Basic Clin Pharmacol Toxicol. 2023;133(2):124-129. doi:10.1111/bcpt.13912

Treatment of Serotonin Syndrome

  • Discontinue serotonergic medications

  • Supportive measures

  • Sometimes cyproheptadineSometimes cyproheptadine

When serotonin syndrome is recognized and treated promptly, the prognosis is usually good (1).

All serotonergic medications should be discontinued. Mild symptoms are often relieved with sedation using a benzodiazepine, with resolution occurring in 24 to 72 hours. Dexmedetomidine can be considered in refractory cases. Its mechanism as an alpha-2 agonist may treat the underlying pathophysiology of excess serotonin, as well as act as a sedative agent (All serotonergic medications should be discontinued. Mild symptoms are often relieved with sedation using a benzodiazepine, with resolution occurring in 24 to 72 hours. Dexmedetomidine can be considered in refractory cases. Its mechanism as an alpha-2 agonist may treat the underlying pathophysiology of excess serotonin, as well as act as a sedative agent (2, 3). If symptoms resolve more rapidly, patients should be observed for at least several hours. However, most patients require hospitalization for further testing, treatment, and monitoring.

In severe cases, admission to an intensive care unit is required. Hyperthermia is treated by cooling (see Heatstroke: Treatment). Neuromuscular blockade with appropriate sedation, muscle paralysis, and other supportive measures may be necessary. Pharmacologic treatment of autonomic abnormalities (eg, hypertension, tachycardia) should be with shorter-acting medications (eg, nitroprusside, esmolol) because autonomic effects can change rapidly.). Neuromuscular blockade with appropriate sedation, muscle paralysis, and other supportive measures may be necessary. Pharmacologic treatment of autonomic abnormalities (eg, hypertension, tachycardia) should be with shorter-acting medications (eg, nitroprusside, esmolol) because autonomic effects can change rapidly.

If symptoms persist despite supportive measures, the serotonin antagonist cyproheptadine can be given orally or, after crushing, via nasogastric tube, but evidence for this treatment is of low quality (If symptoms persist despite supportive measures, the serotonin antagonist cyproheptadine can be given orally or, after crushing, via nasogastric tube, but evidence for this treatment is of low quality (4, 5).

Consultation with a toxicologist is encouraged and can be accomplished in the United States by calling America's Poison Centers (1-800-222-1222). Expert assistance is also available from the online tool atPoisonHelp.org.

Treatment references

  1. 1. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 352(11):1112-20, 2005. doi: 10.1056/NEJMra041867 Erratum in: N Engl J Med. 356(23):2437, 2007. Erratum in: N Engl J Med. 361(17):1714, 2009.

  2. 2. Baumgartner K, Doering And M, Mullins ME; Toxicology Investigators Consortium. Dexmedetomidine in the treatment of toxicologic conditions: a systematic review and review of the toxicology investigators consortium database. Clin Toxicol (Phila). 2022;60(12):1356-1375. doi:10.1080/15563650.2022.2138761

  3. 3. Rushton WF, Charlton NP. Dexmedetomidine in the treatment of serotonin syndrome. Ann Pharmacother. 2014;48(12):1651-1654. doi:10.1177/1060028014549184

  4. 4. Nguyen H, Pan A, Smollin C, et al. An 11-year retrospective review of cyproheptadine use in serotonin syndrome cases reported to the California Poison Control System. J Clin Pharm Ther. 2019;44(2):327-334. doi:10.1111/jcpt.12796

  5. 5. Chiew AL, Isbister GK. Management of serotonin syndrome (toxicity). Br J Clin Pharmacol. 2025;91(3):654-661. doi:10.1111/bcp.16152

Key Points

  • Medications that increase serotonergic activity can lead to hyperthermia and neuromuscular hyperactivity, with complications of metabolic acidosis, rhabdomyolysis, seizures, acute kidney injury, and disseminated intravascular coagulation (DIC).

  • The diagnosis is likely if a patient has taken a serotonergic medication and presents with any of the following: spontaneous clonus; tremor with hyperreflexia; or a combination of ocular or inducible clonus along with either agitation, diaphoresis, or hypertonia and a temperature > 38° C.

  • Serotonin syndrome can often be differentiated from neuroleptic malignant syndrome by use of serotonergic medications, rapid onset (eg, within 24 hours of its medication trigger), and hyperreflexia.

  • Discontinue all serotonergic medications and give a benzodiazepine.

  • Treat complications aggressively and consider cyproheptadine.Treat complications aggressively and consider cyproheptadine.

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