As an antihistamine, doxylamine is an inverse agonist of the histamineH1 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. (N.b.: An agonist is a molecule that activates certain receptors (i.e., specific cellular proteins} in a cell to produce a specific pharmacological response, causing the cell to modify its activity—while an inverse agonist targets the same receptors as those of a given agonist, but causes a response opposite to that caused by the agonist. An antagonist blocks the action of a given agonist.)
Doxylamine is also a potent anticholinergic, meaning that it causes delirum at high doses—i.e., at much higher doses than recommended.[8] (Specifically it is an antagonist of the muscarinic acetylcholine receptors M1 through M5.) These sedative and deliriant effects have in some cases led to using the drug recreationally. Doxylamine was first described in 1948 or 1949.[9]
The first-generation sedating antihistamines diphenhydramine, doxepin, doxylamine, and pyrilamine are the most widely used medications in the world for preventing and treating insomnia.[6] As of 2004, doxylamine and diphenhydramine, which are both over-the-counter medications, were the agents most commonly used to treat short-term insomnia.[11] 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".[12][13] Neither version of their guidelines explicitly included or mentioned doxylamine, although diphenhydramine was discussed.[12][13] 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.[4]
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 4weeks of 0.47 (95% CITooltip confidence interval 0.06 to 0.89).[14] The certainty of evidence was rated as moderate.[14] No data were available for doxylamine in terms of longer-term treatment (3months).[14] For comparison, the other sedating medicines assessed, doxepin and trimipramine (both of which are tricyclic antidepressants) had effect sizes (SMD) at 4weeks 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.[14]
Doses of doxylamine that have been used for sleep range from 5 to 50mg, with 25mg being the typical dose.[15][16][17][18]
Doxylamine is used medically as doxylamine succinate, the succinate salt of doxylamine, and is available both alone (brand names Decapryn, Doxy-Sleep-Aid, Unisom) and in combination with pyridoxine (a form of vitamin B6) (brand names Bendectin, Bonjesta, Diclegis).[22] Doxylamine is available alone as immediate-release oral tablets containing 25mg doxylamine succinate.[22] Oral tablets containing 12.5mg doxylamine succinate as well as oral capsules containing 25mg doxylamine succinate were also previously available but were discontinued.[22] The combination of doxylamine and pyridoxine is available in the form of extended- and delayed-release oral tablets containing 10 to 20mg doxylamine succinate and 10 to 20mg pyridoxine hydrochloride.[22] Doxylamine alone is available over-the-counter, whereas doxylamine in combination with pyridoxine is a prescription-only medication.[22] Doxylamine is also available in over-the-counter nighttime cold medicine products such as NyQuil Cold & Flu (contains acetaminophen, doxylamine succinate 6.25 to 12.5mg, and dextromethorphan hydrobromide), where it serves as the sedating component.[23][24]
Because of its relatively long elimination half-life (10–12hours), doxylamine is associated with next-day effects including sedation, drowsiness, grogginess, dry mouth, and tiredness when used as a hypnotic.[26][18] This may be described as a "hangover effect".[18] The shorter elimination half-life of diphenhydramine (4–8hours) compared to doxylamine may give it an advantage over doxylamine as a sleep aid in this regard.[27]
Occasional case reports of coma and rhabdomyolysis have been reported with doxylamine.[2] This is in contrast to diphenhydramine.[2]
Studies of doxylamine's carcinogenicity in mice and rats have produced positive results for both liver and thyroid cancer, especially in the mouse.[29] 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".[30]
Continuous and/or cumulative use of anticholinergic medications, including first-generation antihistamines, is associated with a higher risk of cognitive decline and dementia in older people.[31][32]
Doxylamine is a first-generation antihistamine and was discovered by Nathan Sperber and colleagues and was first reported in 1948 or 1949.[43][9][44] It has been the antihistamine component of NyQuil since 1966.[43]
Bendectin, a combination of doxylamine, pyridoxine (vitamin B6), and dicyclomine (an anticholinergicantispasmodic agent), was marketed for treatment of morning sickness in 1956.[45] This product was reformulated in 1976 to remove dicyclomine.[45] The reformulated product was voluntarily discontinued by the manufacturer in the United States in 1983 due to concerns about an alleged association with congenital limb defects.[45] However, these concerns have not been supported by studies.[19][20] In 2013, doxylamine/pyridoxine was reintroduced in the United States under the brand name Diclegis.[19][20] The combination was not removed from the market in Canada, where it had been marketed since 1979.[19][20]
Society and culture
Formulations
Doxylamine is primarily used as the succinic acid salt, doxylamine succinate.
In Commonwealth countries, such as Australia, Canada, South Africa, and the United Kingdom, doxylamine is available prepared with paracetamol (acetaminophen) and codeine under the brand name Dolased, Propain Plus, Syndol, or Mersyndol, as treatment for tension headache and other types of pain.
Doxylamine succinate is used in general over-the-counter sleep-aids branded as Somnil (South Africa), Dozile, Donormyl, Lidène (France, Russian Federation), Dormidina (Spain, Portugal), Restavit, Unisom-2, Sominar (Thailand), Sleep Aid (generic, Australia) and Dorminox (Poland).
In the United States:
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 in April 2013 becoming the only drug approved for morning sickness[46] with a class A safety rating for pregnancy (no evidence of risk).
Doxylamine preparations are available typically in combination with pyridoxine that may also contain folic acid. Doxylamine usage is thus restricted for pregnant women.
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