More than one agent raising serotonin, without an MAO inhibitor. Serotonin toxicity from reuptake inhibitors alone is usually mild-to-moderate rather than life-threatening, but it is real, and it is more likely at higher doses and in overdose.
What to watch for. Clonus, tremor with hyperreflexia, agitation, sweating, diarrhoea.
Hunter Serotonin Toxicity Criteria
In the presence of a serotonergic agent, serotonin toxicity is present if ANY ONE of the following holds.
Spontaneous clonus.
Inducible clonus AND (agitation OR diaphoresis).
Ocular clonus AND (agitation OR diaphoresis).
Tremor AND hyperreflexia.
Hypertonia AND temperature above 38 °C AND (ocular clonus OR inducible clonus).
Reported sensitivity 84% and specificity 97% against a gold standard of clinical toxicologist diagnosis, in 2222 overdose admissions — better than the older Sternbach criteria, which are more sensitive to mild cases but far less specific.
CLONUS is the discriminating sign. It is what separates serotonin toxicity from neuroleptic malignant syndrome, anticholinergic delirium and sympathomimetic toxicity, and it is more marked in the legs than the arms.
Severe cases progress over hours: rigidity, hyperthermia above 38.5 °C, rhabdomyolysis, disseminated intravascular coagulation. Hyperthermia in this setting is a medical emergency — it is muscular in origin, so antipyretics do not treat it.
A clean result means NO DOCUMENTED INTERACTION IN THIS DATASET. It does not mean safe, and it is not a clearance. Most substances are not in this dataset at all, and for many pairs that are, nobody has ever studied the combination.
Serotonergic drugs and the serotonin-toxicity mechanism
Dietary tyramine and L-dopa loads
The major cytochrome P450 pathways: CYP3A4, CYP2D6, CYP1A2, CYP2C9, CYP2C19 — inhibition and induction
P-glycoprotein inhibition and induction
11β-HSD2 inhibition (the licorice mechanism) and the potassium consequences that follow it
QT prolongation as an additive pharmacodynamic axis
Culinary seasonings and common foods with documented pharmacological activity
A selected set of narrow-therapeutic-index drugs where those shifts matter most
Not in this dataset
Any substance not named in this dataset — which is most substances. There are tens of thousands of marketed drugs and this table holds fewer than a hundred entries.
Phase-2 conjugation (UGT, SULT, NAT2, COMT) except where a specific entry names it. The oilahuasca corpus turns heavily on phase 2 and this engine models it only in passing.
Pharmacogenomics. CYP2D6 and CYP2C19 are strongly polymorphic; a poor metaboliser and an ultra-rapid metaboliser can have opposite outcomes from the same pair, and this engine does not know your genotype.
Dose, timing, duration, formulation and route — all of which change whether a documented interaction is clinically real for you.
Renal and hepatic impairment, age, pregnancy, and body composition.
Additive sedation, respiratory depression, bleeding risk, hypoglycaemia and most other pharmacodynamic axes beyond the ones listed above.
Herb–herb interactions outside the named entries, and essentially the whole botanical world: most plants have no interaction literature at all.
Allergy, intolerance, and contamination or adulteration of unregulated products.
Anything published after the last-reviewed date below.
72 substances, 20 mechanisms,
64 citations. Last reviewed .
Primary literature (every DOI resolved against the Crossref API) and FDA drug labelling. There is no free, openly-licensed, comprehensive drug-interaction dataset to draw on; NLM retired its Drug Interaction API on 2024-01-02 and DrugBank's interaction set is a commercial licence.
References
Gillman PK (2006). A Review of Serotonin Toxicity Data: Implications for the Mechanisms of Antidepressant Drug Action. Biological Psychiatry. doi:10.1016/j.biopsych.2005.11.016
Boyer EW, Shannon M (2005). The Serotonin Syndrome. New England Journal of Medicine. doi:10.1056/NEJMra041867
Dunkley EJC, Isbister GK, Sibbritt D, Dawson AH, Whyte IM (2003). The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity. QJM. doi:10.1093/qjmed/hcg109
Every DOI above was resolved against the Crossref API on 2026-09-09 and the returned
title checked against the one printed here. Three DOIs in the first draft resolved to real but different
papers and were corrected before publication.