Dextromethorphan — interactions

An over-the-counter cough suppressant that is a serotonin reuptake inhibitor and a CYP2D6 substrate. Sold without a prescription, which is exactly why it gets missed.

Also known as: DXM, Robitussin DM, Delsym. Category: medication.

What it does, mechanism by mechanism

Serotonin reuptake inhibition — inhibits, moderate

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.

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.

Sources: Schwartz AR 2008, Boyer EW 2005 · more on Serotonin reuptake inhibition

CYP2D6 inhibition — substrate, strong

Slows the enzyme handling many antidepressants, antipsychotics, opioids and psilocin. For a prodrug like codeine the effect inverts — less active drug, not more.

The archetypal CYP2D6 probe substrate. A CYP2D6 inhibitor raises its level several-fold.

Sources: Flockhart DA 2021, U.S. Food and Drug Administration 2023 · more on CYP2D6 inhibition

Specific combinations

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. Schwartz AR, Pizon AF, Brooks DE (2008). Dextromethorphan-induced serotonin syndrome. Clinical Toxicology. doi:10.1080/15563650701668625
  2. Boyer EW, Shannon M (2005). The Serotonin Syndrome. New England Journal of Medicine. doi:10.1056/NEJMra041867
  3. Flockhart DA, Thacker D, McDonald C, Desta Z (2021). The Flockhart Cytochrome P450 Drug-Drug Interaction Table. Division of Clinical Pharmacology, Indiana University School of Medicine. https://drug-interactions.medicine.iu.edu
  4. U.S. Food and Drug Administration (2023). Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. FDA. https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers

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.