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 with repeated use and can result in rebound insomnia upon discontinuation.Occasional case reports of coma and rhabdomyolysis have been reported with doxylamine. This is in contrast to diphenhydramine.Studies of doxylamines carcinogenicity in mice and rats have produced positive results for both liver and thyroid cancer, especially in the mouse. The 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". Overdose
Doxylamine is generally safe for administration to healthy adults. Doses of doxylamine of up to 1,600 mg/day for 6 months have been given to adults with schizophrenia, with little toxicity encountered. The median lethal dose (LD50) is estimated to be ~500 mg/kg in humans. Symptoms of overdose may include dry mouth, dilated pupils, insomnia, night terrors, euphoria, hallucinations, seizures, rhabdomyolysis, and death. Fatalities have been reported from doxylamine overdose. These have been characterized by coma, tonic-clonic (or grand mal) seizures and cardiorespiratory arrest. Children appear to be at a high risk for cardiorespiratory arrest. A toxic dose for children of more than 1.8 mg/kg has been reported. A 3-year-old child died 18 hours after ingesting 1,000 mg doxylamine succinate. Rarely, an overdose results in rhabdomyolysis and acute kidney injury. Pharmacology
Pharmacodynamics
Doxylamine acts primarily as an antagonist or inverse agonist of the histamine H1 receptor.
As of 2008 and 2017, over-the-counter antihistamines were not recommended by the American Academy of Sleep Medicine for treatment of chronic insomnia "due to the relative lack of efficacy and safety data". Neither version of their guidelines explicitly included or mentioned doxylamine, although diphenhydramine was discussed. 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 major systematic review and network meta-analysis of medications for the treatment of insomnia published in 2022 found that doxylamine had an effect size (standardized mean difference (SMD)) against placebo for treatment of insomnia at 4 weeks of 0.47 (95% CI 0.06 to 0.89). The certainty of evidence was rated as moderate. No data were available for doxylamine in terms of longer-term treatment (3 months). For comparison, the other sedating antihistamines assessed, doxepin and trimipramine, had effect sizes (SMD) at 4 weeks of 0.30 (95% CI –0.05 to 0.64) (very low certainty evidence) and 0.55 (95% CI –0.11 to 1.21) (very low certainty evidence), respectively.Doses of doxylamine that have been used for sleep range from 5 to 50 mg, with 25 mg being the typical dose. Morning sickness
Doxylamine is used in the combination drug pyridoxine/doxylamine to treat morning sickness (nausea and vomiting of pregnancy). It is the only medication approved by the United States Food and Drug Administration for the treatment of morning sickness.