What drugs can cause serotonin syndrome?

Serotonin syndrome is a potentially life-threatening condition caused by an excess of serotonin in the body, usually triggered by medications or drugs that increase serotonin activity. It most commonly occurs when certain antidepressants, migraine medications, opioids, or illicit drugs are taken alone in high doses or, more often, in combination. Common drug classes that can cause serotonin syndrome include selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), and opioids like tramadol.

What is Serotonin Syndrome?

Serotonin syndrome occurs when there is too much serotonin—a chemical messenger—in the central nervous system. This overload is typically due to medication interactions, overdose, or recent changes in drug therapy.

Symptoms of serotonin syndrome can range from mild to severe, and may include:

• Agitation
• Confusion
• Rapid heart rate
• Muscle rigidity
• Tremors
• Sweating
• Fever
• Seizures
• Death (in extreme cases)

What Types of Drugs Can Cause Serotonin Syndrome?

Any drug that increases serotonin levels or activity in the brain can potentially cause serotonin syndrome, especially when combined with other serotonergic agents. These include:

• Antidepressants: SSRIs (e.g., fluoxetine), SNRIs (e.g., venlafaxine), TCAs (e.g., amitriptyline), MAOIs (e.g., phenylzine)
• Migraine medications: triptans (e.g., sumatriptan)
• Opioids: tramadol, fentanyl, meperidine
• Illicit drugs: MDMA (ecstasy), LSD, cocaine
• Stimulants: amphetamines, phentermine
• Others: linezolid (an antibiotic), lithium, buspirone, dextromethorphan, ondansetron, risperidone

What are High-Risk Drug Combinations?

Certain drug combinations significantly increase the risk of serotonin syndrome, particularly:

• SSRIs or SNRIs combined with MAOIs (should never be used together)
• SSRI or SNRI with tramadol or other serotonergic opioids
• SSRI with triptans (migraine medications)
• SSRIs or SNRIs with St. John’s Wort

Polypharmacy (taking multiple serotonergic drugs) or recent changes in medication doses are major risk factors.

Can Over-the-Counter or Recreational Drugs Cause It?

Yes, both over-the-counter (OTC) medications and recreational drugs can cause serotonin syndrome, especially when combined with other substances that also increase serotonin levels.

Some examples include:

• Over-the-counter medications: Dextromethorphan (common in cough medicines)
• Supplements: 5-HTP, St. John’s Wort, ginseng, tryptophan
• Illicit drugs: MDMA, LSD, amphetamines, cocaine
• Marijuana/THC: There is little evidence for a direct link, but it is sometimes discussed in case reports.
• Alcohol: Does not directly cause serotonin syndrome but may worsen symptoms or complicate diagnosis.

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Summary Table: Common Drugs That Can Cause Serotonin Syndrome

This is not a complete table of all medications that can cause serotonin syndrome. If you are taking medications that affect serotonin, always consult your healthcare provider before starting, stopping, or combining drugs or supplements.

Genetic and Metabolic Factors

Emerging evidence points to CYP enzyme variability, especially CYP2D6 and CYP2C19, as a contributor to serotonin syndrome risk. Poor metabolizers of SSRIs, tramadol, and other serotonergic drugs may accumulate higher drug levels, increasing toxicity risk. Discuss your genetic risk for serotonin syndrome with your healthcare provider.

How is Serotonin Syndrome Diagnosed and Treated?

Diagnosis is based on recognizing the pattern of symptoms and recent exposure to serotonergic drugs, as there is no specific laboratory test for serotonin syndrome.

Treatment involves:

• Immediately stopping the offending drugs.
• Supportive care (such as IV fluids, sedation, and cooling).
• In severe cases, hospitalization and administration of serotonin-blocking agents like cyproheptadine may be needed.

When Should Someone Seek Medical Attention?

Seek immediate medical help if you or someone you know develops symptoms such as confusion, agitation, tremors, muscle stiffness, rapid heartbeat, or excessive sweating soon after starting or changing a serotonergic medication. Serotonin syndrome can progress quickly and may be fatal if not treated promptly.

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