ConditionBrain & nerves
Serotonin Syndrome
Serotonin syndrome is a potentially life-threatening reaction caused by too much serotonin activity in the nervous system, usually from combining two or more serotonergic medicines or drugs, or from an overdose. Symptoms usually start within 24 hours of a new drug or dose increase: agitation, sweating, fast heart rate, diarrhea, tremor, and muscle twitching and jerking that is worst in the legs. Severe cases cause high fever and rigidity. Mild cases improve within 24 hours of stopping the drug; severe cases need intensive care.
Also called: Serotonin toxicity, serotonergic syndrome
At a glance
- What it is
- Excess serotonin activity causing changes in mental state, nerves and muscles, and the autonomic system.
- Common causes
- Combining SSRIs, SNRIs, MAOIs, tramadol, triptans (rarely), linezolid, methylene blue, MDMA, St John's wort or dextromethorphan; overdose.
- Hallmark signs
- Clonus (rhythmic muscle jerks), overactive reflexes, tremor, agitation, sweating, dilated pupils, diarrhea.
- Timing
- Usually within 6 to 24 hours of a new drug or dose change.
- Treatment
- Stop the drug(s), supportive care, benzodiazepines, cyproheptadine; ICU for severe cases.
When to get help
Call 911 or go to the ER
- High temperature above 38.5 °C (101.3 °F) with muscle stiffness, confusion or seizures after taking serotonergic drugs
- Agitation, sweating, a racing heart and uncontrollable muscle jerks after starting or combining medicines
- Any suspected overdose of an antidepressant or other serotonergic drug: call 911 or your local emergency number, or Poison Control at 1-800-222-1222 (US)
See a doctor within a day or two
- New tremor, restlessness, diarrhea, dilated pupils and shivering within a day of a new medicine or dose increase
- Mild symptoms after combining an antidepressant with tramadol, linezolid, dextromethorphan, MDMA or St John's wort
Book a routine appointment
- Questions about combining an antidepressant with other medicines or supplements: ask a pharmacist or doctor before starting
How serotonin syndrome happens
Serotonin is a chemical messenger in the brain and the body's nerves, gut and blood vessels. Many medicines raise serotonin by increasing its release, blocking its reuptake, slowing its breakdown or acting directly on its receptors. When two or more such drugs are combined, or one is taken in overdose, serotonin activity can become excessive.
Drugs that can cause serotonin syndrome
| Group | Examples |
|---|---|
| Antidepressants (used for depression and anxiety) | SSRIs (sertraline, fluoxetine, citalopram), SNRIs (venlafaxine, duloxetine), MAOIs (phenelzine, selegiline), tricyclics (clomipramine), trazodone, mirtazapine (less often) |
| Opioids | Tramadol, tapentadol, meperidine, methadone, fentanyl |
| Antibiotics and dyes | Linezolid, methylene blue (both have MAOI activity) |
| Migraine medicines | Triptans (risk appears low) |
| Anti-nausea drugs | Ondansetron, metoclopramide |
| Cough and cold | Dextromethorphan |
| Recreational drugs | MDMA (ecstasy), cocaine, amphetamines, LSD |
| Supplements | St John's wort, tryptophan, ginseng |
| Others | Lithium, buspirone, valproate |
The highest-risk combinations involve MAOIs (including linezolid and methylene blue) with SSRIs, SNRIs or other serotonergic drugs. When switching antidepressants, a washout period, sometimes several weeks, is needed.
Symptoms
Symptoms usually begin within hours of a new drug, dose increase or overdose.
Mild
- restlessness, anxiety
- tremor and shivering
- sweating
- dilated pupils
- fast heart rate
- diarrhea, nausea
- overactive reflexes
Moderate
- agitation and hypervigilance
- clonus: rhythmic, involuntary muscle jerking, especially at the ankles, or inducible by flexing the foot; eye clonus (rapid side-to-side eye movements)
- muscle twitching (myoclonus)
- high blood pressure
- temperature around 38 to 40 °C (100.4 to 104 °F)
- increased bowel sounds
Severe
- temperature above 41 °C (106 °F)
- muscle rigidity
- confusion, delirium
- seizures
- breathing and kidney failure, rhabdomyolysis, and blood clotting problems
Diagnosis
There is no laboratory test. Doctors diagnose it from symptoms and a history of serotonergic drug use, often using the Hunter criteria, which focus on clonus, agitation, sweating, tremor, overactive reflexes and high temperature. Blood tests check for complications: kidney function, CK (muscle breakdown), electrolytes and clotting.
Similar conditions
| Serotonin syndrome | Neuroleptic malignant syndrome | Anticholinergic toxicity | |
|---|---|---|---|
| Trigger | Serotonergic drugs | Antipsychotics, stopping Parkinson's drugs | Antihistamines, tricyclics, some plants |
| Onset | Hours | Days to weeks | Hours |
| Muscles | Clonus, overactive reflexes, tremor; rigidity (legs) in severe | "Lead-pipe" rigidity, slow movement | Normal |
| Skin | Sweating | Sweating | Hot, dry, flushed |
| Bowel | Diarrhea, active | Normal or reduced | Reduced, constipation |
| Pupils | Dilated | Normal | Dilated |
Heat stroke, infections such as meningitis, and stimulant toxicity are also considered.
Treatment
- stop all serotonergic drugs
- supportive care: IV fluids, cooling, oxygen and heart monitoring
- benzodiazepines for agitation, tremor and muscle activity
- cyproheptadine, a serotonin-blocking medicine, for moderate cases
- intensive care for severe cases: sedation, paralysis and mechanical ventilation to control very high temperature and rigidity
- avoid physical restraints, which worsen muscle activity and temperature
- standard fever medicines such as acetaminophen do not help, because the heat comes from muscle activity
Outlook
Most cases resolve within 24 to 72 hours of stopping the causative drugs. Drugs with long half-lives, such as fluoxetine or MAOIs, can prolong symptoms. Severe cases can be fatal without prompt intensive care.
Prevention
- tell every prescriber and pharmacist about all medicines, supplements and recreational drugs you use
- check before adding tramadol, dextromethorphan, linezolid, St John's wort or triptans to an antidepressant
- follow washout periods when switching antidepressants, especially to or from MAOIs
- start new serotonergic medicines at low doses and increase gradually
- learn the early signs, and seek help if they appear after a medication change
Frequently asked questions
What are the symptoms of serotonin syndrome?
Symptoms include agitation, restlessness, sweating, fast heart rate, dilated pupils, diarrhea, tremor, muscle twitching and jerking (especially in the legs) and overactive reflexes. Severe cases cause high fever, rigidity, seizures and confusion.
What causes serotonin syndrome?
It is usually caused by combining two or more medicines or drugs that increase serotonin, such as an SSRI with tramadol, linezolid, an MAOI, dextromethorphan, MDMA or St John's wort. It can also follow an overdose or dose increase of a single drug.
How long does serotonin syndrome last?
Mild cases usually improve within 24 hours after stopping the drugs, and most cases resolve within 72 hours. It may last longer with long-acting drugs such as fluoxetine or MAOIs.
Can you get serotonin syndrome from one antidepressant?
It is possible but uncommon at normal doses. It is more likely after a dose increase, an overdose, or when an antidepressant is combined with another serotonergic medicine or supplement.
Sources
This guide was written from current patient and clinical guidance, including:
- New England Journal of Medicine: The serotonin syndrome (Boyer and Shannon review)
- Hunter Serotonin Toxicity Criteria (QJM)
- MedlinePlus: Serotonin syndrome
- US FDA: Drug safety communications on serotonin syndrome with opioids and with linezolid or methylene blue
- America's Poison Centers: Medication safety