Toxicology & Substance Use · Topic 12 of 17

Serotonin Syndrome

Toxicology · drug-induced hyperthermia

Serotonin Syndrome

Too much serotonin: clonus and hyperreflexia within a day of a new drug — stop every serotonergic agent and sedate with benzodiazepines.

Key numbers

Onset within 24 hours< 24 h (usually < 6 h)

Temp > 39 °C with rigidity: intubate, paralyzeT > 39 °C

Persistent symptoms: cyproheptadine 12 mg PO/NGcyproheptadine 12 mg

01 · Defined byHunter criteria: clonus or hyperreflexia

Hunter criteria: a serotonergic drug plus one of — spontaneous clonus; inducible or ocular clonus with agitation or diaphoresis; tremor with hyperreflexia; or hypertonia with temperature > 38 °C and ocular or inducible clonus.

02 · Look forOnset within 24 hours

Serotonin syndrome starts within 24 hours — usually within 6 hours — of a new serotonergic drug or dose change: altered mental status, autonomic hyperactivity (tachycardia, hyperthermia, diaphoresis, diarrhea) and neuromuscular hyperactivity.

03 · DoStop serotonergic drugs; give benzodiazepines

Stop every serotonergic drug and sedate with a benzodiazepine; most cases resolve within 24–72 hours with supportive care. Most patients are admitted for monitoring.

Causes & risk factors

Why it happens

Usually two serotonergic drugs, often SSRI plus tramadolMost cases are drug interactions; the commonest is an SSRI plus tramadol. Other culprits: MAOIs including linezolid, SNRIs, TCAs, triptans, fentanyl, meperidine, dextromethorphan, ondansetron, metoclopramide, lithium, MDMA and St John's wort.

Presentation

What you'll see

Clonus and hyperreflexia worse in the legsNeuromuscular hyperactivity — tremor, hypertonia, myoclonus, hyperreflexia, clonus including ocular clonus — is often more pronounced in the lower than the upper extremities.

Do right now

In this order

First moves

Stop serotonergic drugs; give benzodiazepines

→

Temp > 39 °C with rigidity: intubate, paralyzeT > 39 °C

→

Persistent symptoms: cyproheptadine 12 mg PO/NGcyproheptadine 12 mg

Why each step

Stop serotonergic drugs; give benzodiazepinesStop every serotonergic drug and sedate with a benzodiazepine; most cases resolve within 24–72 hours with supportive care. Most patients are admitted for monitoring.

Temp > 39 °C with rigidity: intubate, paralyzeSevere toxicity — temperature rising above 39 °C with muscle rigidity — needs the ICU, early sedation, intubation and neuromuscular paralysis plus active cooling.

Persistent symptoms: cyproheptadine 12 mg PO/NGIf symptoms persist despite supportive care, give the 5-HT2A antagonist cyproheptadine, oral only (crushed via nasogastric tube if needed): 12 mg, then 2 mg every 2 hours while symptoms persist; evidence is low quality.

Management

Orders

Short-acting agents for labile blood pressureAutonomic instability changes quickly, so treat hypertension and tachycardia with short-acting agents such as nitroprusside or esmolol.

Dexmedetomidine for refractory agitationDexmedetomidine can be considered for agitation refractory to benzodiazepines; as an alpha-2 agonist it may also counter the serotonergic excess.

Red flags & don'ts

Avoid harm

Watch for rhabdomyolysis, acidosis, AKI and DIC complicationSevere serotonin syndrome causes metabolic acidosis, rhabdomyolysis, seizures, acute kidney injury and DIC from hyperthermia and muscle activity — check electrolytes, CK, renal function, platelets, coagulation and urine myoglobin.

The rules

Know these

Clinical diagnosis — no confirmatory testThere is no confirmatory test; test to exclude mimics — CNS infection (lumbar puncture), withdrawal syndromes, sympathomimetic or anticholinergic toxicity — and to detect complications.

Serotonin syndrome or NMS?

Commonly confused

Trigger	Serotonergic drug(s), often a new combination
Onset	Within 24 hours (usually < 6)
Neuromuscular	Clonus, tremor, hyperreflexia
Reflexes	Increased
Fever and rigidity	Usually milder; nausea, diarrhea may precede

More detail

Reference

Show 3 reference facts

Symptoms last longer after drugs with long half-lives or active metabolites (fluoxetine, MAOIs); even when symptoms resolve quickly, observe for at least several hours.

IV chlorpromazine is used by some as a parenteral 5-HT2A antagonist in severe cases, but support is animal data and case reports; aggressive supportive care matters more than any antidote.

Consult a toxicologist through America's Poison Centers (1-800-222-1222).

Pearl

Clonus is the clue: clonus and hyperreflexia within hours point to serotonin; lead-pipe rigidity over days points to NMS.

Sources · Merck Manual Professional — Serotonin Syndrome (May 2025) · Chiew AL, Isbister GK. Management of serotonin syndrome (toxicity). Br J Clin Pharmacol 2025;91(3):654–661 · Merck Manual Professional — Neuroleptic Malignant Syndrome (Nov 2025) · Dunkley EJ et al. The Hunter Serotonin Toxicity Criteria. QJM 2003;96(9):635–642 · Varma S, Xavier S, Desai S, Ali S. A Case of Serotonin Syndrome Precipitated by Quetiapine in a Middle-Aged Female on Trazodone and Sertraline (treatment table). Cureus 2022;14:e27668 · Starter sheet built from the verified AGACNP fact map (facts reviewed 2026-10-15).