Serotonin toxicity (often referred to as serotonin syndrome), is not, in fact, a true discrete syndrome but represents a spectrum of serotonergic effects, many of which can be seen at therapeutic doses of serotonergic agents while some are only seen with toxicity. It was thought that serotonin toxicity was mediated through 5-HT1 receptors, but now it is clear that the predominant receptors involved are 5-HT2.

Severe serotonin toxicity may be life-threatening with hyperthermia, increased tone that may lead to respiratory failure and secondary rhabdomyolysis.

Management involves, good supportive care with the occasional addition of 5-HT2 blocking agents. More aggressive intervention with muscle paralysis, supported ventilation and active cooling measures may be required in those with severe toxicity.

Serotonin (5–hydroxytryptamine or 5–HT) is a neurotransmitter thought to have a major role in multiple states including aggression, pain, sleep, appetite, anxiety, depression, migraine, and emesis. It is derived from dietary tryptophan, which is converted to 5–hydroxytryptophan by tryptophan hydroxylase and then to 5–HT by a non-specific decarboxylase. 5–HT is then transported into cells by a specific transport system and is degraded mainly by monoamine oxidase both within the cell and after release. Monoamine oxidase A is more significant than monoamine oxidase B in this process. The breakdown products are excreted in the urine as 5–hydroxyindole acetic acid (5–HIAA).

Serotonin predominantly causes excitation of central nervous system neurons but can also produce inhibition of some subsets. It also stimulates peripheral nociceptive nerve endings and has a variety of vascular effects. Serotonin increases gastrointestinal motility, both directly via an action on smooth muscle and indirectly via enteric neurons.

There are at least 7 serotonin receptors that have been identified in man and animals, and several of these have subtypes. The most important receptor groups are 5–HT1 and 5–HT2.

Serotonin toxicity eventuates from an increase in serotonin concentrations in the synaptic cleft. This can occur by several mechanisms, with the most important being – increased release, decreased re-uptake or decreased degradation. Serotonin toxicity can occur from a change in one of these mechanisms (particularly in the setting of overdose), but severe toxicity usually only occurs when more than one is impacted.

Serotonin toxicity develops (usually within a few hours) of:

• Commencing or increasing a drug with serotonergic action
• Overdosing on a serotonergic drug
• An interaction between one or more serotonergic agents

Drugs commonly associated with serotonin toxicity are given below, separated by the mechanism:

Decreased serotonin re-uptake

• SSRIs, SNRIs, TCAs, St John’s Wort, some opioids (e.g. tramadol, pethidine)

Decreased serotonin metabolism

• Irreversible non-selective MAOi (phenelzine, tranylcypromine), Reversible selective (moclobemide, lamotrigine), other (linezolid, methylene blue)

Increase serotonin release

• Stimulants (amfetamines, phentermine, MDMA), most opioids

Increased serotonin synthesis

• L-tryptophan

Serotonin receptor agonists

• Hallucinogens (LSD, 2C-substituted phenyethlamines), mood stabilisers (lithium)

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Serotonin toxicity can range from mild to severe severity. Severe toxicity, whilst not common, is a medical emergency and needs to be treated urgently. Symptoms classically fall into a triad of: mental state changes, neuromuscular excitability and autonomic effects.

Sigs of mild toxicity may be seen with therapeutic use of serotonergic agents or after a small to moderate overdose of a serotonergic agent. Symptom and signs include mild tremor, mild tachycardia, inducible clonus and lower limb hyperreflexia. Patients are often no troubled by the symptoms and no treatment is usually required.

In moderate toxicity, which is often seen after a larger overdose of a serotonergic agent or an mild interaction of two agents (especially if they act via different mechanisms). It usually requires some form of treatment. Presentation often consists of agitation, sustained clonus, tachycardia, mild hyperthermia.

Severe toxicity is life threatening. It most often occurs if there is exposure to two serotonergic agents with differing mechanism – especially if a MAOi is involved. With severe toxicity there is rigidity which can affect respiration, hyperthermia, sustained clonus and possibly seizures.

The flow chart below identifies the risk categories of patients being assessed for serotonin toxicity as well as helping to define the severity of toxicity present.

Other diagnoses to keep in mind (as they may have some crossover in symptoms) include:

• Other toxidromes: anticholinergic, sympathomimetic, neuroleptic malignant syndrome
• CNS infection
• Withdrawal states
• Non convulsive seizures

Treatment of serotonin toxicity depends on its severity. In all cases and serotonergic drugs should be discontinued and good supportive care provided. Symptoms generally resolve over 12-24hours.

Mild toxicity
Patients with mild symptoms do not require any specific treatment beyond the above measures. They usually do not required admission for their symptoms.

Moderate toxicity
These patients will have more severe symptoms and are usually have a degree of distress caused by them. Initially treatment should be with oral sedation. Use:

• Diazepam 5-20mg orally, repeat after 30mins if required.

If symptoms fail to improve with this therapy, then a trial of antidotal therapy with cyproheptadine can be given. Whilst there is clinical experience with using cyproheptadine for this indication, controlled trials of its efficacy are lacking and there remains disagreement between toxicologist as to its usefulness. Use:

• Cyproheptadine 12mg (Child: <7yo:2mg;>7yo:4mg) orally as a single dose.

If symptoms improve but then recur as can happen with some longer acting agents or those that are sustained-released, then repeated doing for 24-48hr may be required. Use:

• Cyproheptadine 8mg (Child: <7yo:2mg; >7yo:4mg) orally 3 times per day.

If oral therapy is not possible, then an intravenous benzodiazepine (such as midazolam) can be substituted for an oral benzodiazepine and chlorpromazine used in place of cyproheptadine. Use:

• Chlorpromazine 25mg in 0.9% sodium chloride 250-1000ml, over 30-60mins. Repeat 8 hourly until symptoms improve.

Severe toxicity
This is a medical emergency and requires prompt treatment. Initial treatment should be with parenteral sedation. If symptoms are not rapidly improving – especially if significant hyperthermia or rigidity that is affecting respiration, then the patient should be intubated and paralysed.

1. Buckley NA, Dawson AH, Isbister GK. Serotonin syndrome. BMJ. 2014 Feb 19;348:g1626. doi: 10.1136/bmj.g1626. PMID: 24554467. PDF
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3. Chiew AL, Isbister GK. Management of serotonin syndrome (toxicity). Br J Clin Pharmacol. 2024 Jun 26. French. doi: 10.1111/bcp.16152. Epub ahead of print. PMID: 38926083. PDF