What Is Serotonin Syndrome?

Serotonin syndrome is the term for toxicity caused by too much serotonin in the nervous system. It is often associated with combining certain antidepressants with other serotonin-acting drugs.

This article discusses the causes of serotonin syndrome and how to recognize, treat, and prevent it.

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Symptoms of Serotonin Syndrome

Because serotonin has widespread effects on the body and brain, people with serotonin syndrome can present with diverse symptoms.

Symptoms are divided into three categories: effects on the autonomic nervous system, somatic effects (effects on the body), and cognitive effects.

Autonomic effects include:

• Sweating
• Shivering
• Tachycardia (increased heart rate)
• Hyperthermia (increased body temperature)
• Nausea

Somatic effects include:

• Tremor
• Muscle twitching
• Stiffness
• Hyperreflexia (overactive reflexes)

Cognitive effects include:

• Headache
• Agitation
• Hallucinations
• Confusion

In severe cases, serotonin syndrome can be life-threatening, with critical symptoms including loss of consciousness, seizures, and even coma.

Severe symptoms may take longer to develop than mild ones. Therefore, it’s essential to seek urgent medical attention if you suspect somebody may be experiencing serotonin syndrome so they can be treated before more severe symptoms develop.

In the majority of cases, symptoms arise anywhere between one to six hours following the causative event (e.g., ingesting a dangerous drug combination).

What Causes Serotonin Syndrome?

Serotonin syndrome is caused by people combining drugs or overdosing on drugs that increase serotonin in the nervous system.

Under normal circumstances, serotonin acts as a vital chemical messenger in our bodies, playing an essential role in functions such as digestion, blood flow, mood, and breathing.

However, too much of the molecule can cause the nervous system to become dysregulated and produce harmful effects.

What Are the Risk Factors?

Drugs that cause serotonin syndrome can be divided into categories based on their mechanism of action.

These include:

• Drugs that decrease serotonin breakdown, such as monoamine oxidase inhibitors (MAOIs), linezolid (an antibiotic), and Syrian rue.
• Drugs that decrease the reuptake of serotonin, such as SSRIs, SNRIs, tricyclic antidepressants, anti-epileptics, anti-emetics, and St. John’s wort.
• Drugs that increase serotonin precursors and agonists, such as tryptophan (an amino acid found in various foods), lithium, and LSD.
• Drugs that increase serotonin release, such as amphetamines and MDMA.

Furthermore, some of the abovementioned drugs are broken down by CYP2D6 and CYP3A4 enzymes. Therefore, using drugs that inhibit their action can increase the likelihood of serotonin syndrome.

Examples include the antimicrobial agents erythromycin, ciprofloxacin, and fluconazole.

For most published reports on serotonin syndrome, SSRI antidepressants have presented as the most significant risk factor. However, combining an SSRI with an MAOI presents the greatest risk for serotonin syndrome.

Therefore, in the population, patients with depression and co-morbidities (multiple mental health diagnoses) that include depression are most at risk.

What Happens If Serotonin Syndrome Goes Untreated?

In general, serotonin syndrome doesn’t tend to cause any long-term problems if appropriately treated and serotonin levels return to normal.

However, if untreated, severe cases of serotonin syndrome can cause organ failure, resulting in long-term damage and, in some cases, even death.

Too much serotonin in the body can cause muscle rigidity, which can increase the body temperature to dangerously high levels beyond 40 degrees celsius. The resulting hyperthermia can lead to cell damage and enzyme dysfunction, which is what causes organ shutdown and failure.

Therefore, if you suspect anyone is demonstrating signs of muscle rigidity related to serotonin syndrome, it’s critical that they receive medical attention as soon as possible.

Diagnosing Serotonin Syndrome

Because of the overlapping symptoms of serotonin syndrome with other health complications, it’s crucial that serotonin syndrome is carefully and accurately diagnosed so people can receive the proper treatment.

The Hunter Criteria is a method health professionals use to diagnose serotonin syndrome based on physical findings. This method is thought to have the best accuracy compared with other diagnostic methods.

In this criteria, the patient must have taken a serotonin-acting drug and present with at least one of the following symptoms:

• Spontaneous clonus: a type of clonus (uncontrolled muscle contractions often appearing as rhythmic shaking movements) that appears randomly and may also be triggered by minor movements.
• Inducible clonus: a type of clonus that can be onset by the examiner (e.g., by moving a body part), plus agitation (extreme mental tension) or diaphoresis (extreme sweating)
• Ocular clonus: (uncontrollable side-to-side movements of the eyes) plus agitation or diaphoresis.
• Inducible clonus or ocular clonus, plus hypertonia (stiff muscles) and hyperthermia.
• Tremor plus hyperreflexia (overactive reflexes).

Treatment for Serotonin Syndrome

Treatment for serotonin syndrome will vary depending on the person’s symptoms and severity.

Medications used by doctors in treatment include:

• Serotonin-blocking agents to counter elevated serotonin.
• Benzodiazepines to control agitation, seizures, and muscle stiffness.
• Cardiac agents to reverse changes in heart rate and blood pressure.

Patients may need to go to an intensive care unit in severe cases. For example, patients who have lost respiratory function need to be intubated and given mechanical ventilation.

Hyperthermia in serotonin syndrome will require a multi-approached treatment that includes medication, intravenous injection of cooling fluids, oxygen, and careful monitoring of vital signs.

Serotonin Syndrome Prevention

Reducing the incidence of serotonin syndrome requires better public health education about the risk. This includes raising awareness within the medical community and the general population.

Doctors should be made aware of the dangers of combining serotonin-acting drugs so they can choose safer treatment options for patients who may require more than one type of medication.

Furthermore, if a patient changes from one serotonergic-acting drug to another, their doctor should ensure the first drug is first discontinued to prevent any overlap.

People using serotonin-acting medications should be strongly advised against high doses or combining their medication with any of the drugs mentioned above.

Psychedelic users should also be particularly cautious with their doses and mixing drugs to avoid serotonin toxicity. This caution is especially apparent for users of ayahuasca and pharmahuasca, where a combination of MAOIs with natural or synthetic DMT is ingested to produce a prolonged hallucinatory experience.

Summary of Serotonin Syndrome

Serotonin syndrome occurs when a person takes drugs in doses or combinations that give rise to too much serotonin in their nervous system. It causes symptoms that include heart rate changes, restlessness, nausea, and in severe cases, seizures and hyperthermia.

Recognizing and educating others about the risks and symptoms of serotonin syndrome will help decrease the number of cases and the likelihood of casualties.

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