Doxylamine

Doxylamine is a first-generation ethanolamine antihistamine. Its therapeutic and recreational effects come from crossing the blood–brain barrier and acting as an inverse agonist / antagonist at the histamine H1 receptor: blocking central H1 signalling causes the pronounced sedation that makes it an over-the-counter sleep aid (taken as the succinate salt, e.g. Unisom or Hoggar Night, typically 25 mg). Like other first-generation antihistamines it is not selective: it is also a broad antagonist of the muscarinic acetylcholine receptors (M1–M5). This antimuscarinic (anticholinergic) activity produces its characteristic side effects, dry mouth, blurred vision, constipation and urinary retention, and, at high doses, the central anticholinergic delirium that underlies its misuse as a deliriant. In human binding assays its tightest affinity is for H1 (Ki ≈42 nM), with weaker affinity spread across the muscarinic subtypes (M5 ≈180, M4 ≈380, M1 ≈490, M3 ≈650, M2 ≈2100 nM). Beyond its hypnotic use, doxylamine combined with pyridoxine (vitamin B6) is a first-line treatment for nausea and vomiting of pregnancy (brands Diclegis / Bonjesta) and is one of the best-studied drugs in pregnancy (US pregnancy category A: no evidence of fetal harm). It also appears in combination cold, cough and analgesic products alongside paracetamol/acetaminophen, dextromethorphan, codeine or pseudoephedrine. It is well absorbed orally and has a long half-life (~10–12 h), which is why next-day drowsiness ('antihistamine hangover') is common. It is metabolised in the liver by N-demethylation (CYP2D6, CYP1A2, CYP2C9) to N-desmethyl- and N,N-didesmethyldoxylamine and excreted mainly in urine. A toxicologically important feature is that doxylamine overdose is repeatedly associated with rhabdomyolysis (muscle breakdown), sometimes without prolonged immobilisation, which can progress to acute kidney injury. Seizures and a false-positive urine immunoassay for methadone/PCP have also been reported.