Serotonin reuptake inhibition
Serotonin reuptake inhibition. Blocks the serotonin transporter (SERT), raising synaptic serotonin. Additive with anything else that raises serotonin; combined with MAO inhibition it is the classic lethal pairing.
Serotonin release. Forces serotonin out of the presynaptic terminal rather than merely blocking its return. The most dangerous of the serotonergic mechanisms to combine with MAO inhibition.
Direct serotonin receptor agonism. Binds serotonin receptors directly (5-HT1A/1B/1D/2A). Contributes to serotonergic load; 5-HT1A/2A agonism is the axis implicated in serotonin toxicity.
What acts on it
- Harmala alkaloids (harmine, harmaline, tetrahydroharmine)
— inhibits, weak
Tetrahydroharmine component. - Ayahuasca (hoasca, daime) — agonist, strong
- Fluoxetine
— inhibits, strong
Because of norfluoxetine's long half-life, the conventional interval before starting an MAOI is about 5 weeks. - Paroxetine — inhibits, strong
- Sertraline
— inhibits, strong
A potent SSRI with a comparatively clean CYP-inhibition profile — unlike fluoxetine and paroxetine it is not a strong CYP2D6 inhibitor, so the serotonergic axis is essentially the whole of its interaction story. - Citalopram / escitalopram — inhibits, strong
- Fluvoxamine — inhibits, strong
- Venlafaxine / desvenlafaxine
— inhibits, strong
Venlafaxine is serotonergic at all doses and adds noradrenaline reuptake inhibition as the dose rises, which is why it appears in serotonin-toxicity series more often than its prescribing volume alone would predict, and why it is the SNRI most associated with toxicity in overdose. - Duloxetine
— inhibits, strong
An SNRI, so it carries the serotonergic hazard of an SSRI with noradrenergic activity on top. It is also a substrate of CYP1A2 and CYP2D6, which means a CYP inhibitor elsewhere in the stack raises the serotonergic load without anyone changing a dose. - Clomipramine — inhibits, strong
- Amitriptyline
— inhibits, weak
Most tricyclics other than clomipramine and imipramine are weak SRIs and are NOT strongly associated with serotonin toxicity. - Tramadol
— inhibits, moderate
Tramadol is the opioid most often named in serotonin-toxicity case reports, and the reason is structural rather than incidental: the molecule was designed with monoamine reuptake activity, so the analgesia and the serotonergic load are not separable by dose adjustment. Gillman's classification puts it with meperidine, methadone and the fentanyls among the SRI opioids, apart from morphine, codeine and oxycodone which are not. - Meperidine (pethidine) — inhibits, strong
- Dextromethorphan
— inhibits, moderate
Dextromethorphan is bought off a supermarket shelf in a cough syrup, so it is absent from the medication list a patient recites and absent from the pharmacy record. Case reports of serotonin toxicity with it involve exactly that: a serotonergic antidepressant plus an over-the-counter cold remedy nobody counted as a drug. - Triptans (sumatriptan, rizatriptan, zolmitriptan…)
— agonist, weak
The AHS position paper concluded the evidence for triptan + SSRI/SNRI serotonin syndrome is insufficient to support the FDA alert as written — the receptor subtypes involved (5-HT1B/1D) are not the ones implicated in serotonin toxicity. Reported here as a documented signal of contested strength, not as a strong hazard. - MDMA
— agonist, strong
Releasers are categorically more dangerous with MAO inhibition than reuptake inhibitors are. A reuptake inhibitor stops serotonin returning to the terminal; a releaser empties the terminal into the synapse, and with MAO blocked there is no route of destruction for what is released. The fatal MAOI cases in the literature are concentrated in this combination. - Psilocybin / psilocin — agonist, strong
- N,N-DMT
— agonist, strong
Rapidly deaminated by MAO-A; oral activity requires MAO-A inhibition. - Lithium
— agonist, weak
Listed among agents contributing to serotonergic load in case series. - Buspirone
— agonist, moderate
5-HT1A partial agonist. - St John's wort
— inhibits, moderate
Serotonin syndrome has been reported with SJW plus SSRIs. - Codeine
— inhibits, none
Explicitly listed as NOT a serotonin reuptake inhibitor. Gillman separates codeine, morphine, oxycodone and buprenorphine from the SRI opioids — this distinction is why "opioid + MAOI" is not one rule but two.
What is affected by it
- Nothing in this dataset.
Recognising serotonin toxicity
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.
What a clean result means here
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.
In this dataset
- Monoamine oxidase inhibition (prescription MAOIs, RIMAs, linezolid, methylene blue, harmala alkaloids)
- 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
- Callaway JC, McKenna DJ, Grob CS, et al. (1999). Pharmacokinetics of Hoasca alkaloids in healthy humans. Journal of Ethnopharmacology. doi:10.1016/S0378-8741(98)00168-8
- Riba J, Valle M, Urbano G, Yritia M, Morte A, Barbanoj MJ (2003). Human Pharmacology of Ayahuasca: Subjective and Cardiovascular Effects, Monoamine Metabolite Excretion, and Pharmacokinetics. The Journal of Pharmacology and Experimental Therapeutics. doi:10.1124/jpet.103.049882
- 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
- Beakley BD, Kaye AM, Kaye AD (2015). Tramadol, Pharmacology, Side Effects, and Serotonin Syndrome: A Review. Pain Physician. doi:10.36076/ppj.2015/18/395
- Gillman PK (2005). Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity. British Journal of Anaesthesia. doi:10.1093/bja/aei210
- Schwartz AR, Pizon AF, Brooks DE (2008). Dextromethorphan-induced serotonin syndrome. Clinical Toxicology. doi:10.1080/15563650701668625
- Evans RW, Tepper SJ, Shapiro RE, Sun-Edelstein C, Tietjen GE (2010). The FDA Alert on Serotonin Syndrome With Use of Triptans Combined With Selective Serotonin Reuptake Inhibitors or Selective Serotonin-Norepinephrine Reuptake Inhibitors: American Headache Society Position Paper. Headache. doi:10.1111/j.1526-4610.2010.01691.x
- Henderson L, Yue QY, Bergquist C, Gerden B, Arlett P (2002). St John's wort (Hypericum perforatum): drug interactions and clinical outcomes. British Journal of Clinical Pharmacology. doi:10.1046/j.1365-2125.2002.01683.x
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.
Last reviewed . All interaction pages.