Examples of agents that can precipitate serotonin syndrome

Mechanism	Agent involved
Increases serotonin formation	Tryptophan, oxitriptan*
Increases release of serotonin	Amphetamines (including dextroamphetamine, methamphetamine)
	MDMA (ecstasy)
	Amphetamine derivatives (including fenfluramine, dexfenfluramine, phentermine)
	Cocaine
	Mirtazapine
Impairs serotonin reuptake from the synaptic cleft into the presynaptic neuron	Cocaine
	MDMA (ecstasy)
	Meperidine
	Tramadol
	Pentazocine
	Dextromethorphan
	Selective serotonin reuptake inhibitors (SSRIs; citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline)
	Serotonin-norepinephrine reuptake inhibitors (SNRIs; desvenlafaxine, duloxetine, levomilnacipran, milnacipran, and venlafaxine)
	Sibutramine
	Bupropion^¶
	Serotonin modulators (nefazodone, trazodone, vilazodone, and vortioxetine)
	Cyclic antidepressants (amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, maprotiline, nortriptyline, protriptyline, trimipramine)
	St. John's wort (Hypericum perforatum)
	5-HT3 receptor antagonists (dolasetron, granisetron, ondansetron, palonosetron)
	Cyclobenzaprine
	Methylphenidate, dexmethylphenidate
Inhibits serotonin metabolism by inhibition of MAO	MAO inhibitors, nonselective (isocarboxazid, linezolid, phenelzine, Syrian rue [Peganum harmala, harmine], and tranylcypromine)
	MAO-A inhibitors^Δ (methylene blue, moclobemide)
	MAO-B inhibitors^Δ (rasagiline, safinamide, and selegiline)
Direct serotonin receptor agonist	Buspirone
	Triptans (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan)
	Ergot derivatives (including dihydroergotamine, ergotamine, methylergonovine)
	Fentanyl
	Lysergic acid diethylamide (LSD)
	Lasmiditan
	Lorcaserin^◊
	Metaxalone
Increases sensitivity of postsynaptic serotonin receptor	Lithium

Serotonin syndrome is a potentially life-threatening condition associated with increased serotonergic activity in the CNS. Serotonin syndrome can occur with therapeutic medication use, overdose, or as the result of additive or synergistic effects due to drug interaction(s). For additional information on clinical use and precautions related to serotonergic effects, refer to UpToDate topic reviews including the serotonin syndrome topic and Lexicomp drug monographs and drug interactions tool included within UpToDate.

MAO: monoamine oxidase; CNS: central nervous system; OTC: over-the-counter.
* Within the United States, tryptophan (L-tryptophan) and oxitriptan are available as OTC supplements. In other areas, these agents may be available OTC or by prescription.
¶ Bupropion inhibits neuronal uptake of dopamine and norepinephrine without known effects on serotonin; however, there have been case reports of serotonin syndrome when co-administered with other serotonergic drugs (eg, SSRIs); in some cases this may have been due to bupropion's inhibition of SSRI metabolism by CYP2D6.
Δ MAO selectivity is lost at higher doses and with drug interactions that increase serum drug concentrations. Inhibition of MAO-A is more likely to result in increased levels of serotonin within the CNS (ie, increased risk of serotonin syndrome) relative to MAO-B inhibition.
◊ Withdrawn from United States market.

Data from:

Boyer EW, Shannon M. The serotonin syndrome. NEJM 2005; 352:1112.
Finberg JPM, Rabey JM. Inhibitors of MAO-A and MAO-B in psychiatry and neurology. Front Pharmacol 2016; 7:340.

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Examples of agents that can precipitate serotonin syndrome