Selegiline transdermal system and MDMA

Yes — there is a documented interaction between these two, and it has a named mechanism. serotonin toxicity.

Critical Selegiline transdermal system + MDMA — MAO inhibition combined with serotonin release

Mechanism: serotonin toxicity

MAO-A is the enzyme that destroys serotonin. Blocking it while a second agent raises serotonin by a different route is the combination behind the fatal cases in the serotonin-toxicity literature. The mechanisms multiply rather than add: one stops removal, the other increases supply.

Timing. This MAO inhibition is IRREVERSIBLE. Enzyme function returns only as new enzyme is made, so the hazard persists for about two weeks after the last dose. Washout intervals are measured in weeks, and for fluoxetine about five weeks in the other direction because of norfluoxetine.

What to watch for. Clonus (especially in the legs), agitation, sweating, tremor with brisk reflexes, fever. Onset is typically within hours of the second agent, not days.

Hunter Serotonin Toxicity Criteria

In the presence of a serotonergic agent, serotonin toxicity is present if ANY ONE of the following holds.

  1. Spontaneous clonus.
  2. Inducible clonus AND (agitation OR diaphoresis).
  3. Ocular clonus AND (agitation OR diaphoresis).
  4. Tremor AND hyperreflexia.
  5. 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.

Sources: Azzaro AJ 2006, Gillman PK 2006, Boyer EW 2005, Dunkley EJC 2003

The mechanism, generalised

Read the mechanism page and you can apply this to substances that are not on it: MAO-A inhibition, Serotonin release.

Substance pages: Selegiline transdermal system · MDMA.

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

  1. Azzaro AJ, VanDenBerg CM, Blob LF, et al. (2006). Tyramine Pressor Sensitivity During Treatment With the Selegiline Transdermal System 6 mg/24 h in Healthy Subjects. The Journal of Clinical Pharmacology. doi:10.1177/0091270006289852
  2. 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
  3. Boyer EW, Shannon M (2005). The Serotonin Syndrome. New England Journal of Medicine. doi:10.1056/NEJMra041867
  4. 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.

Last reviewed . All interaction pages.