Dextromethorphan

Individuals with significant respiratory disease (COPD, severe asthma, sleep apnea) face elevated risk from DXM's respiratory depressant effects at high doses. Risk is amplified by concurrent CNS depressant use.

Concurrent use of serotonergic medications substantially increases serotonin syndrome risk. The severity gradient ranges from relative (low-dose SSRI) to near-absolute (high-dose SSRI + CYP2D6 inhibitor properties). Paroxetine and fluoxetine are particularly high-risk due to combined CYP2D6 inhibition and serotonergic effects.

Individuals with schizophrenia, schizoaffective disorder, or other psychotic spectrum conditions face elevated risk of psychotic exacerbation. DXM-induced psychosis with persecutory delusions is documented in case reports of dependent users. Pre-existing psychotic vulnerability lowers the dose threshold for psychotomimetic effects.

Significant hepatic impairment may reduce DXM metabolism, increasing plasma levels and prolonging effects. Substance-specific pharmacokinetic data in hepatic impairment are lacking, but the mechanism is predicted from DXM's extensive hepatic first-pass metabolism.

Known CYP2D6 poor metabolizers (~8-10% of Caucasians) face dramatically elevated exposure to parent DXM at any dose. Effects are intensified and prolonged (half-life extends from 2-3 hours to 15-20 hours). All adverse effects are amplified, including dissociation, serotonin-related toxicity, and CNS depression.

No adequate safety data exist for DXM use during pregnancy or breastfeeding at recreational/supratherapeutic doses. The drug's lipophilicity suggests placental transfer. Standard precautionary principle applies.

Concurrent or recent (within 14 days) use of any monoamine oxidase inhibitor is an absolute contraindication. This is the most dangerous DXM drug interaction, with documented fatalities. Applies to all MAOIs including phenelzine, tranylcypromine, isocarboxazid, selegiline (at systemic doses), and moclobemide.