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Serotonin Syndrome Treatments and Medications

Creator: SingleCare
Published: 10-21-2020

Medically reviewed by Karen Berger, Pharm.D.

Licensed Pharmacist

Updated Feb. 10, 2021 • Published Oct. 21, 2020

Fact Checked

Drugs such as selective serotonin reuptake inhibitors (SSRIs) have saved countless lives simply by increasing serotonin levels in the brain. Serotonin-increasing drugs have proliferated in the last few decades. However, when two or more of these drugs get used at the same time, they can raise serotonin levels to toxic levels, sending people to the emergency room. What is serotonin syndrome and how can it be avoided? Read on to learn more.

What is serotonin syndrome?

A rare condition, serotonin syndrome (or serotonin toxicity) is excessive serotonin levels in the body caused by serotonin-raising drugs, such as antidepressants. Similar to an overdose, serotonin syndrome can result from an increase in the dose of a serotonin-raising drug, by taking two or more serotonin-raising drugs or dietary supplements, or from deliberate self-poisoning.

Symptoms can come on very rapidly, anywhere from a few hours to 24 hours after taking a serotonin-raising drug. Most cases are mild and resolve in one to three days after the drug has been discontinued. Severe cases, however, require hospitalization and could be fatal.

Serotonin is one of a family of substances called neurotransmitters, chemicals that pass nerve signals between nerve cells. In the brain, serotonin plays a role in regulating mood, attention, appetite, body temperature, and sleep. Serotonin also helps regulate muscle movements in the digestive system and tightening blood vessels. It is also is one of the many substances responsible for blood clotting.

Drugs that increase serotonin in the body are called serotonergic drugs. All the major classes of antidepressants increase serotonin at nerve junctions, restoring the neurotransmitter balance to give patients more control over their mood and thoughts. Because these drugs are widely used, antidepressants are almost always implicated in serotonin syndrome.

SSRIs (selective serotonin reuptake inhibitors), such as Prozac (fluoxetine), Paxil (paroxetine), Celexa (citalopram), or Zoloft (sertraline) are the most common culprits because they are so widely used. However, SNRIs (serotonin-norepinephrine reuptake inhibitors), such as Effexor (venlafaxine) and Cymbalta (duloxetine), and tricyclic antidepressants such as amitriptyline and nortriptyline, are also common sources of serotonin toxicity. However, life-threatening or prolonged cases of serotonin syndrome are more often related to the use of a class of antidepressants called monoamine oxidase inhibitors (MAOIs), such as Selegiline or Nardil (phenelzine).

Antidepressant medications are safe drugs, so serotonin toxicity most often occurs when the dose is increased or they are combined with other serotonergic drugs such as:

Opioids
Amphetamines
Certain migraine drugs (most often, triptans)
Dextromethorphan, a common over-the-counter cough suppressant (found in various cough and cold medications)
Some types of nausea drugs, anticonvulsants, smoking cessation drugs (bupropion), and antibiotics (linezolid)
Illicit drugs such as Ecstacy, fentanyl, LSD, or amphetamines
Dietary supplements with tryptophan
Herbal supplements that increase serotonin levels such as St. John’s wort or ginseng.

Serotonin syndrome is a rare condition. Most cases are mild and are never reported. In 2016, the Toxic Exposure Surveillance System reported 102 patients died in emergency room visits with serotonin syndrome related to SSRIs.

How is serotonin syndrome diagnosed?

No test can diagnose serotonin syndrome. Instead, healthcare professionals must make a clinical diagnosis based on the symptoms and a medical history. Because serotonin syndrome resembles other adverse drug reactions such as neuroleptic malignant syndrome, a complete drug history is critical. Lab tests, such as blood tests or urinalysis, are only used to rule out other possible conditions.

The only significant risk factor for serotonin syndrome is the use of serotonergic drugs, so the healthcare provider will concentrate on prescription and other drug use when taking a medical history, including the type of drugs, dosages, prescription changes, and dietary supplements.

The symptoms of serotonin syndrome involve changes in mental status (such as euphoria, agitation, or delirium), neuromuscular issues (such as tremor or muscle tightness), or derangements in autonomic functions (such as high blood pressure or excessive sweating).

For mild serotonin syndrome, the most common symptoms include fast heartbeat, mildly high blood pressure, excessive sweating (diaphoresis), shivering, muscle rigidity, spontaneous or inducible involuntary muscle contractions, dilated pupils, and overactive reflexes (hyperreflexia). There may or may not be a fever (hyperthermia). In many mild cases, the only noticeable symptom might be a slight tremor.

Patients with moderate serotonin syndrome will have a serious fever—at least 104—on top of these other symptoms. They will also have noticeable changes in mental status such as anxiety, restlessness, agitation, and rapid speech. Involuntary eye movements (ocular clonus) and bowel movement sounds are also signs of moderate serotonin syndrome.

Severe serotonin syndrome will have many of these symptoms along with a dangerously high fever—106 or more. Vital signs are often erratic, with big swings in heart rate and blood pressure. Mental status has often deteriorated to delirium, confusion or possibility of coma. Rigid muscles, seizures, and blood clotting throughout the body are common.

Serotonin syndrome treatment options

Serotonin syndrome is treated by discontinuing serotonergic drugs, stabilizing vital signs, and managing complications. Patients with severe symptoms may require hospitalization or even admission to an intensive care unit.

Medications

Mild cases of serotonin syndrome typically resolve in one to three days only by discontinuing serotonergic medications. Symptoms such as anxiety, tremor, and fever are brought under control with a drug from a class of sedatives called benzodiazepines. If symptoms do not resolve, a doctor may use drugs that block the action of serotonin. Blood pressure will be brought under control by short-acting blood pressure medications.

Hospitalization

Even mild cases will require at least six hours of monitoring in an emergency room or clinic. Severe serotonin syndrome will require hospital care or admission to an ICU. Sedation, blood pressure medications, serotonin blockers, IV fluids, oxygen, cooling, and vital signs monitoring are the standard therapy. For extremely high fever, a patient may also need to be sedated, put on a mechanical ventilator, and given muscle-paralyzing drugs.

Serotonin syndrome medications

There is no cure for serotonin syndrome. Even the most dangerous incidents of serotonin syndrome resolve relatively quickly when serotonin medications are withdrawn. Medications are only used to manage the symptoms and stabilize vital signs.

Benzodiazepines

Benzodiazepines such as diazepam and lorazepam are sedatives. They are the first-line medication to reduce agitation and stabilize vital signs for mild to moderate serotonin syndrome. In addition to calming the patient, benzodiazepines lower blood pressure, slow down the heart, relax muscles, and help reduce fever caused by increased muscle activity.

Serotonin blockers

Serotonin blockers are used if benzodiazepines fail to calm a patient down. While several medications block serotonin, the most effective drug is cyproheptadine, an antihistamine used to relieve allergy symptoms. In this situation, the drug acts like a serotonin antidote by attaching to serotonin receptors and blocking the action of serotonin. In addition to calming the patient, cyproheptadine relaxes muscles and significantly lowers high fevers.

Blood pressure medications

Dangerously high blood pressure caused by serotonin syndrome will be treated with short-acting antihypertensives (drugs that lower blood pressure) such as esmolol or nitroprusside.

Sympathomimetic agents

Low blood pressure caused by serotonin syndrome will be treated with sympathomimetic agents such as norepinephrine, epinephrine, or phenylephrine. These drugs both speed up the heart and cause blood vessels to constrict, increasing blood pressure.

Paralytic agents

In severe cases of serotonin syndrome, dangerously high fever is caused by excessive muscle contractions rather than the brain’s “thermostat.” For this reason, traditional fever medications (antipyretics) will not work. Instead, the muscle contractions causing the fever must be stopped. Patients will be hospitalized, sedated, put on a mechanical ventilator, and be partially paralyzed with a neuromuscular blocker such as vecuronium.

What is the best medication for serotonin syndrome?

Mild cases of serotonin syndrome resolve when serotonergic drugs are discontinued. No medication treats or cures serotonin syndrome. Instead, medications are used to treat symptoms and stabilize vital signs. There is, then, no “best” medication for serotonin syndrome, only medications that best fit the patient’s symptoms and vital signs.

Best medications for serotonin syndrome
Drug Name	Drug Class	Administration Route	Standard Dosage	Common Side Effects
Valium (diazepam)	Benzodiazepine	Oral	Dosage depends on doctor’s recommendations	Drowsiness, fatigue, muscle weakness
Ativan (lorazepam)	Benzodiazepine	Oral	Dosage depends on doctor’s recommendations	Drowsiness, dizziness, sleep problems
Cyproheptadine	Antihistamine (serotonin blocker)	Oral tablet or liquid	Initial dose of 12 mg, then 2 mg every two hours until response is seen	Dry mouth, drowsiness, nausea
Brevibloc (esmolol)	Beta blocker (antihypertensive)	Intravenous injection	Dose depends on weight	Low blood pressure, dizziness, headache, nausea
Adrenalin (epinephrine)	Sympathomimetic agent	Intravenous injection	Dosage depends on doctor’s recommendations	Anxiety, tremor, weakness
Norcuron (vecuronium)	Neuromuscular blocking agent (paralytic)	Intravenous injection	Dose depends on weight	Prolonged muscle weakness, weak breathing, loss of movement

The standard dosages above are from the U.S. Food and Drug Administration (FDA). Dosage is determined by your doctor based on your medical condition, response to treatment, age, and weight. Other possible side effects exist. This is not a complete list.

What are the common side effects of serotonin syndrome medication?

Side effects will vary depending on the type of medication used. The following is not a complete list of side effects caused by drugs commonly used to treat serotonin syndrome. For any concerns about potential side effects, talk to a healthcare professional about your specific situation.

Benzodiazepines, the first-line medication for mild to moderate serotonin syndrome, are sedatives. Their principal side effects, then, are related to their sedative properties. These include drowsiness, dizziness, confusion, disorientation, unsteadiness, muscle weakness, and slurred speech. The most serious side effect is the potential for dependence and abuse. Benzodiazepines are controlled substances. For serotonin syndrome, however, benzodiazepines are used over a short period so the risk for dependence is very low.

Serotonin blockers belong to many different drug classes such as antihistamines and antipsychotics. The only drug proven to help with serotonin syndrome is cyproheptadine, a type of antihistamine that blocks or slows down nerve signals. As a result, its most common side effects are drowsiness, dizziness, dry mouth, headache, and muscle weakness. Cyproheptadine is given in larger-than-normal doses for serotonin syndrome, so side effects will be more common and pronounced than when it is used as an allergy medicine.

Short-acting antihypertensive medications rapidly reduce blood pressure and sometimes slow down the heart, so their major side effects are related to these effects. These side effects include low blood pressure, slow heart rate (bradycardia), weak breathing, dizziness, and drowsiness. The most serious side effects are dangerously low blood pressure or heart rate.

Sympathomimetic agents are chemically similar to adrenaline. They increase the heart rate and blood pressure, constrict blood vessels, and stimulate nerves. The most common side effects, then, are high blood pressure, fast heartbeat, and heart arrhythmias. Their most severe side effects include heart attack and stroke.

For paralytic drugs, the most common side effects are due to prolonged or lingering effects of the drug. These include long-term muscle weakness, prolonged inability to move, and weak breathing.

What is the best home remedy for serotonin syndrome?

Serotonin syndrome can be a potentially hazardous condition. While most cases are mild, the condition could rapidly develop into a life-threatening condition. The best home remedy for serotonin syndrome, then, is a trip to the emergency room.

There are, however, measures people should adopt to prevent or be ready for serotonin syndrome.

Know the medications you’re taking

If you are prescribed drugs that raise serotonin levels, particularly an SSRI, get to know what other medications, dietary supplements, over-the-counter drugs (OTC), and illicit drugs should not be taken along with your medication. Ask your healthcare provider if you have any questions.

Talk to your doctor

When getting any prescription, inform the healthcare professional about all the medications, over-the-counter drugs, and dietary supplements you take. If you add medications (whether prescription or OTC) or dietary supplements, inform the doctor first before you take them.

Know the signs of serotonin syndrome

When taking any medication affecting serotonin, get to know the signs and symptoms of serotonin syndrome. Educate your family members as well, so they know what to look out for. There will be no confusion. You will not feel right once serotonin syndrome kicks in. Time is of the essence, so getting emergency medical help will help save your life.

Frequently asked questions about serotonin syndrome

Does Benadryl help serotonin syndrome?

Serotonin syndrome should not be treated at home with over-the-counter medications. The prescription antihistamine, cyproheptadine, works as an antidote for excessive serotonin, but other antihistamines, like Benadryl (diphenhydramine), work differently. In fact, diphenhydramine slightly increases serotonin levels and could make the condition worse.

How is serotonin syndrome treated?

Mild and even moderate cases of serotonin syndrome may be treated with benzodiazepines such as Valium to calm anxiety, relax the muscles, lower blood pressure, and help with fever. More serious cases may involve cyproheptadine to block serotonin or medications to treat associated symptoms such as high blood pressure. Severe cases may involve hospitalization, intubation, sedation, and being injected with drugs to partially paralyze the muscles.

How long does it take serotonin syndrome to develop?

Serotonin syndrome can develop within a few hours after taking a serotonin-enhancing drug (or combination of drugs) that tips the balance into serotonin toxicity. Most patients, though, will see the condition develop within six to 24 hours after taking the offending drug.

How long does it take serotonin syndrome to go away?

On average, mild cases of serotonin syndrome resolve in one to three days if serotonergic drugs are stopped. How fast the condition clears up, however, has everything to do with the drug that’s being taken. Drugs like Lexapro (escitalopram) are almost completely cleared from the body a week, but only half of Prozac (fluoxetine) clears from the body in a week. Some people may experience serotonin syndrome symptoms for several weeks after onset.

How do you lower serotonin levels quickly?

When serotonin syndrome symptoms first appear, there is no way to quickly lower serotonin levels other than to discontinue serotonergic drugs or seek hosipital treatment. The body will naturally reset serotonin levels to normal in a few days.

Is serotonin syndrome reversible?

Serotonin syndrome is an excess of serotonin in the body due to an overdose of serotonergic drugs. The condition fully reverses in a few days when those drugs are discontinued, but may take up to a few weeks, depending on how long the drugs stay in your body.

Which drugs cause serotonin syndrome?

Serotonin syndrome is caused by overdoses of drugs that increase serotonin levels in the body (serotonergic drugs). Serotonin syndrome most commonly affects people taking depression medications who are taking too large a dose or who also start taking other drugs that increase serotonin production or retention. A bewildering wide spectrum of drugs increase serotonin levels:

Depression medications (SSRIs, SNRIs, monoamine oxidase inhibitors, and tricyclic antidepressants)
Opioid pain medications such as tramadol or meperidine
Cough suppressants such as dextromethorphan
Migraine drugs such as sumatriptan, naratriptan, or almotriptan
Nausea drugs such as ondansetron or granisetron
Amphetamines
Levodopa
Smoking cessation aids (bupropion)
Some constipation medications (metoclopramide)
An antibiotic called linezolid
Illicit drugs such as cocaine, Ecstasy, fentanyl, and LSD
Dietary or herbal supplements such as St. John’s wort, ginseng, and tryptophan.

What happens if serotonin syndrome goes untreated?

Most mild and moderate cases of serotonin syndrome will resolve in a few days without treatment, provided medications causing the condition are stopped. Severe cases can be fatal without medical intervention.

Related resources for serotonin syndrome