Serotonin Syndrome
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“Serotonin syndrome is the clinical manifestation of excess serotonin in the central nervous system, resulting from the therapeutic use or overdose of serotonergic drugs.” - BMJ Best Practice: Serotonin Syndrome (2026)
Symptoms
Symptoms of serotonin syndrome can be categorised into three categories: neuromuscular, autonomic and affecting mental state.
Neuromuscular symptoms include tremors, hyperreflexia and clonus. Autonomic includes dilated pupils, sweating, increased heart rate and increased breathing rate. Alterations in mental state include agitation, excitement, restlessness, confusion and delirium.
Causes
Serotonin syndrome (serotonin toxicity) is caused by excess serotonergic activity in the central nervous system. This most commonly occurs when multiple serotonergic drugs are combined, but it can also occur with a single agent at high doses or in overdose.
Examples of some drugs that can cause serotonin toxicity include:
Amphetamines and derivatives, such as dextroamphetamine and methamphetamine
Antidepressants, such as MAOIs, SSRIs, SNRIs, and TCAs
Lithium
Opioids with serotonergic activity, such as tramadol, fentanyl, and pethidine
Other agents, such as linezolid (a weak MAOI), cocaine, 5-hydroxytryptophan (a serotonin precursor), triptans, dextromethorphan, and St John’s Wort
Diagnosis
Diagnosis is made using the Hunter Serotonin Toxicity Criteria (HSTC).
A patient must have the presence of a serotonergic agent and meet one of the following conditions:
Spontaneous clonus
Inducible clonus plus agitation or diaphoresis (sweating)
Ocular clonus plus agitation or diaphoresis (sweating)
Tremor plus hyperreflexia
Hypertonia plus temperature above 38°C PLUS ocular clonus or inducible clonus
- UpToDate: Serotonin syndrome (serotonin toxicity) (2026)
Treatment
Treatment is based on the severity of symptoms.
Mild serotonin toxicity
Treatment is not usually required beyond ceasing or reducing the dose of the offending drug(s), if appropriate.
Symptoms of mild serotonin toxicity include: hyperreflexia, inducible clonus, tremor, myoclonic jerks, sweating, mild hypertension, tachycardia, mydriasis, and shivering. More non-specific symptoms, such as headache or restlessness, may also occur. Hyperreflexia and clonus are most prominent in the lower limbs.
Moderate serotonin toxicity
As with mild toxicity, the priority in management is identifying and stopping or dose-reducing the offending drug(s).
Additional measures include:
Benzodiazepines for anxiety, agitation, and sedation
Cyproheptadine (a non-specific 5-HT2 antagonist with antihistaminic and sedative properties) as a single higher dose for distressing neuromuscular excitation or agitation
For long half-life serotonergic agents (e.g., fluoxetine), repeated lower doses of cyproheptadine may be preferred over a single large dose
Symptoms of moderate serotonin toxicity include: all mild features, plus temperature up to 38°C, hyperactive bowel sounds, ocular clonus, agitation, and hypervigilance. Clonus is often still inducible but may be spontaneous.
Severe serotonin toxicity
This is a medical emergency, usually managed in a critical care setting.
Management includes:
Early sedation, with intubation and ventilation if required, to control agitation, hyperthermia, and muscle rigidity
Cyproheptadine (oral or via NG tube) is used first-line in serious cases. In severe cases, chlorpromazine (IV, with fluid loading first to reduce the risk of hypotension) may be used; if IV chlorpromazine is unavailable, olanzapine (IM/SC) may be considered as an alternative. Neither cyproheptadine nor chlorpromazine is supported by controlled trial evidence, though both have been used successfully in case reports of serotonin toxicity following overdose
Aggressive cooling for hyperthermia
Once stabilised, all serotonergic drugs should remain stopped and reassessed
Symptoms of severe serotonin toxicity include: all mild and moderate features, plus a temperature of more than 38.5°C, dramatic swings in pulse rate and blood pressure, delirium, muscle rigidity, and spontaneous (sustained) clonus.
Restarting serotonergic medication
Depending on the cause of the serotonin toxicity (e.g., a drug interaction versus a single agent at high dose), a serotonergic medication may be cautiously restarted at a lower dose once all symptoms have fully resolved, with close monitoring during reintroduction. If an MAOI was involved, an extended washout period is required before restarting other serotonergic agents. Patients should be educated about the signs and symptoms of serotonin toxicity and advised on what to do if symptoms recur.
References
American Family Physician: Prevention, Diagnosis, and Management of Serotonin Syndrome (https://www.aafp.org/afp/2010/0501/p1139)
BMJ Best Practice: Serotonin Syndrome (https://bestpractice.bmj.com/topics/en-gb/991)
BNF: Antidepressant drugs (https://bnf.nice.org.uk/treatment-summaries/antidepressant-drugs/)
BNF: Appendix 1 Interactions (https://bnf.nice.org.uk/interactions/appendix-1-interactions/)
Geeky Medics: Serotonin Syndrome (https://geekymedics.com/serotonin-syndrome/)
International Journal of Molecular Sciences: The Serotonin Syndrome: From Molecular Mechanisms to Clinical Practice (https://doi.org/10.3390/ijms20092288)
NHS HEE: Serotonin Syndrome (https://www.hee.nhs.uk/sites/default/files/documents/Serotonin_Syndrome.pdf)
Osmosis: Serotonin Syndrome (https://www.osmosis.org/answers/serotonin-syndrome)
Patient: Serotonin Syndrome (https://patient.info/doctor/drug-therapy/serotonin-syndrome)
Right Decision Service: supporting decisions for Scotland’s health and care: Serotonin Syndrome (https://www.rightdecisions.scot.nhs.uk/mypsych-app/working-in-greater-glasgow-clyde/medicines-companion/emergencies-2222/serotonin-syndrome/)
TOXBASE: Serotonin Syndrome (https://www.toxbase.org/poisons-index-a-z/s-products/serotonin-syndrome/)
UpToDate: Serotonin syndrome (serotonin toxicity) (https://www.uptodate.com/contents/serotonin-syndrome-serotonin-toxicity)