What substances can cause serotonin syndrome?

Substances That Cause Serotonin Syndrome

A wide range of prescription medications, over-the-counter drugs, herbal supplements, and illicit substances can cause serotonin syndrome, with the highest risk occurring when multiple serotonergic agents are combined, particularly MAOIs with other serotonergic drugs. 1

Prescription Medications

Antidepressants (Highest Risk Category)

• SSRIs including fluoxetine, sertraline, paroxetine, citalopram, escitalopram, and fluvoxamine all carry risk, with fluvoxamine showing the highest risk among SSRIs 2, 3
• SNRIs (serotonin-norepinephrine reuptake inhibitors) like venlafaxine create particularly high risk when combined with other serotonergic agents 2, 4
• Tricyclic antidepressants can precipitate serotonin syndrome, especially in combination with MAOIs 4, 5
• MAOIs (monoamine oxidase inhibitors) are involved in the most severe and potentially fatal cases of serotonin syndrome, particularly MAO-A inhibitors that preferentially inhibit serotonin metabolism 6, 7
• Other antidepressants including trazodone and bupropion carry serotonergic risk 2

Opioid Pain Medications (Critical Risk Category)

• Tramadol poses exceptionally high risk due to its dual mechanism as both an opioid and serotonin reuptake inhibitor 2, 3, 8
• Fentanyl is a high-risk opioid with serotonergic properties 4, 5, 3, 8
• Methadone has serotonergic effects beyond its opioid activity 2, 8
• Meperidine (pethidine) is particularly dangerous when combined with MAOIs 8, 6
• Oxycodone and codeine (morphine analogues) have serotonergic properties 8

Antimigraine Medications

• Triptans (sumatriptan, rizatriptan, etc.) increase serotonin syndrome risk when combined with antidepressants 9, 4, 5

Antiemetics

• Various antiemetic medications have been associated with serotonergic activity 1

Antibiotics

• Linezolid acts as a reversible, nonselective MAO inhibitor and should generally not be combined with SSRIs or other serotonergic drugs 10, 4, 5
• Intravenous methylene blue (1-8 mg/kg dose range) functions as an MAOI and is contraindicated with serotonergic medications 4, 5

Other Prescription Medications

• Lithium potentiates serotonergic activity 4, 5
• Buspirone (anxiolytic) has serotonergic properties 4, 5
• Quetiapine (atypical antipsychotic) can contribute to serotonin syndrome 9
• Stimulants including amphetamine-class medications and possibly methylphenidate increase risk 2
• Anticonvulsants have been associated with serotonin syndrome 1
• Anti-Parkinsonism drugs carry serotonergic risk 1
• Muscle relaxants can contribute to the syndrome 1

Over-the-Counter Medications

• Dextromethorphan (cough suppressant) is a common culprit often overlooked by patients and providers 2, 10
• Chlorpheniramine (antihistamine) has serotonergic properties 2
• Diphenhydramine and other antihistamines may contribute 1

Herbal Supplements and Dietary Products

• St. John's Wort is a potent serotonergic agent that should never be combined with prescription antidepressants 9, 2, 10, 4, 5
• L-tryptophan supplements directly increase serotonin synthesis 2, 6
• Weight-reduction or bariatric medications have been associated with serotonin syndrome 1

Illicit Drugs and Substances of Abuse

• MDMA (Ecstasy) is a powerful serotonin releaser and extremely dangerous when combined with prescription serotonergic medications 2
• Methamphetamine has serotonergic activity 2
• Cocaine affects serotonin systems 2
• LSD acts on serotonin receptors 2

Highest-Risk Combinations to Absolutely Avoid

• MAOIs with any other serotonergic drug represent the most dangerous combination and are involved in most severe and fatal cases 9, 10, 6, 7
• MAOIs with tramadol must be completely avoided due to extremely high risk 9, 8
• SSRIs combined with other antidepressants (particularly SNRIs or other SSRIs) create significant risk 2, 3
• SSRIs with high-risk opioids (tramadol, fentanyl, methadone, meperidine) require extreme caution 3, 8

Critical Clinical Pitfalls

• Failure to consider over-the-counter medications and supplements is the most common oversight, as patients often don't report these to providers 2, 10
• Overlooking drug interactions with CYP2D6 inhibitors can increase serotonergic drug levels and precipitate the syndrome 9, 2
• Not recognizing that symptoms typically emerge within 24-48 hours after combining medications or dose changes, making this the highest-risk monitoring window 9, 2, 10
• Underestimating the risk of novel psychoactive substances (NPSs) which are increasingly available and may have serotonergic properties 7