Doxylamine is an antihistamine medication used to treat insomnia and allergies.
It is used in combination with pyridoxine (vitamin B6)—to treat morning sickness in pregnant women.
It is available over-the-counter and is typically sold under such brand names as Equate or Unisom, among others; and it is used in nighttime cold medicines (NyQuil) and pain medications containing acetaminophen and/or codeine to help with sleep.
The medication is delivered chemically by the salt doxylamine succinate and is taken by mouth.
Pregnancy category AU: A
Routes of administration By mouth
US: OTC
Bioavailability Oral: 24.7%
Metabolism Hepatic (CYP2D6, CYP1A2, CYP2C9)
Elimination half-life 10–12 hours (range 7–15 hours)
Excretion Urine (60%), feces (40%)
Doxylamine is a first-generation antihistamine.
Typical side effects of doxylamine include dizziness, drowsiness, grogginess, and dry mouth, among others.
As an antihistamine, doxylamine is an inverse agonist of the histamine H1 receptor.
As a first-generation antihistamine, it typically crosses the blood–brain barrier into the brain, thereby producing a suite of sedative and hypnotic effects that are mediated by the central nervous system.
Doxylamine is also a potent anticholinergic.
It causes delirum at high doses.
It is an antagonist of the muscarinic acetylcholine receptors M1 through M5.
Its sedative and deliriant effects have in some cases led to using the drug recreationally.
Medical uses:treats sneezing, runny nose, watery eyes, hives, skin rash, itching, and other cold or allergy symptoms.
It is also used as a short-term treatment for insomnia.
A 2015 systematic review of over-the-counter sleep aids including doxylamine found little evidence to inform the use of doxylamine for treatment of insomnia.
A systematic review and meta-analysis of medications for the treatment of insomnia published in 2022 found that doxylamine had an effect size against placebo for treatment of insomnia at 4 weeks of 0.47.
Doses of doxylamine that have been used for sleep range from 5 to 50 mg, with 25 mg being the typical dose.
Doxylamine is used in the combination drug pyridoxine/doxylamine to treat morning sickness of pregnancy.
Doxylamine alone is available over-the-counter, whereas doxylamine in combination with pyridoxine is a prescription-only medication.
The fetal safety rating of doxylamine is “A”.
Side effects of doxylamine include dizziness, drowsiness, and dry mouth.
Doxylamine is a potent anticholinergic and has a side-effect profile common to such drugs, including blurred vision, dry mouth, constipation, muscle incoordination, urinary retention, mental confusion, and delirium.
Due to its relatively long elimination half-life (10–12 hours), doxylamine is associated with next-day effects including sedation, drowsiness, grogginess, dry mouth, and tiredness: a “hangover effect”.
The shorter elimination half-life of diphenhydramine (4–8 hours) compared to doxylamine may give it an advantage over doxylamine as a sleep aid in this regard.
Antihistamines like doxylamine are sedating initially but tolerance occurs.
Repeated use and can result in rebound insomnia upon its discontinuation.
Rare case reports of coma and rhabdomyolysis have been reported with doxylamine.
Studies of doxylamine’s carcinogenicity in mice and rats have produced positive results for both liver and thyroid cancer, especially in the mouse, but carcinogenicity of the drug in humans is not well-studied, and the International Agency for Research on Cancer lists the drug as “not classifiable as to its carcinogenicity to humans”.
Continuous and/or cumulative use of anticholinergic medications, is associated with a higher risk of cognitive decline and dementia in older people.
Doxylamine is generally safe for administration to healthy adults, and doses of doxylamine of up to 1,600 mg/day for 6 months have been given to adults with schizophrenia, with little toxicity.
The median lethal dose (LD50) is estimated to be 50–500 mg/kg in humans.
Symptoms of overdose may include: xerostomia, dilated pupils, insomnia, night terrors, euphoria, hallucinations, seizures, rhabdomyolysis, and death.
Fatalities have been reported from doxylamine overdose, characterized by coma, tonic-clonic seizures and cardiopulmonary arrest.
Children appear to be at a high risk for cardiopulmonary arrest from doxylamine
Rarely, an overdose results in rhabdomyolysis and acute kidney injury.
Doxylamine acts primarily as an antagonist or inverse agonist of the histamine H1 receptor, and is responsible for its antihistamine and sedative properties.
Doxylamine also acts as an antagonist of the muscarinic acetylcholine receptors, an action responsible for its anticholinergic and at high doses deliriant effects.
The bioavailability of doxylamine is 24.7% for oral administration and 70.8% for intranasal administration.
The Tmax of doxylamine is 1.5 to 2.5 hours.
Its elimination half-life is 10 to 12 hours (range 7 to 15 hours).
Doxylamine is metabolized in the liver primarily by the cytochrome P450 enzymes CYP2D6, CYP1A2, and CYP2C9.
Doxylamine is eliminated 60% in the urine and 40% in feces.
It has been the antihistamine component of NyQuil since 1966.
It is the sedating ingredient of NyQuil (generally in combination with dextromethorphan and acetaminophen).
Doxylamine succinate is the active ingredient in many over-the-counter sleep aids branded under various names.
Doxylamine succinate and pyridoxine (Vitamin B6) are the ingredients of Diclegis, approved by the FDA the only drug approved for morning sickness I with a class A safety rating for pregnancy.
Doxylamine preparations are available typically in combination with pyridoxine which may also contain folic acid. Doxylamine usage is thus restricted for pregnant women.