Skeletal formula of the doxylamine molecule
Ball-and-stick model of the doxylamine molecule
Clinical data
Trade namesUnisom, Vicks Formula 44 (in combination with Dextromethorphan), others
  • AU: A
  • A (Briggs)
Routes of
By mouth
ATC code
Legal status
Legal status
  • AU: S3 (Pharmacist only)
  • US: OTC
Pharmacokinetic data
BioavailabilityOral: 24.7%[1]
Intranasal: 70.8%[1]
MetabolismHepatic (CYP2D6, CYP1A2, CYP2C9)[2]
Elimination half-life10–12 hours (range 7–15 hours)[2][3][4]
ExcretionUrine (60%), feces (40%)[5]
  • (RS)-N,N-dimethyl-2-(1-phenyl-1-pyridin-2-yl-ethoxy)-ethanamine
CAS Number
PubChem CID
CompTox Dashboard (EPA)
ECHA InfoCard100.006.742 Edit this at Wikidata
Chemical and physical data
Molar mass270.376 g·mol−1
3D model (JSmol)
  • n1ccccc1C(c1ccccc1)(C)OCCN(C)C
  • InChI=1S/C17H22N2O/c1-17(20-14-13-19(2)3,15-9-5-4-6-10-15)16-11-7-8-12-18-16/h4-12H,13-14H2,1-3H3 checkY

Doxylamine, sold under the brand name Unisom among others, is an antihistamine medication which is used in the treatment of insomnia and allergies. In combination with pyridoxine (vitamin B6), it is also used to treat morning sickness in pregnant women. Doxylamine is available over-the-counter, and is used in nighttime cold medicines, such as NyQuil, as well as in pain medications containing acetaminophen and codeine, to help with sleep. The medication is taken by mouth.

Side effects of doxylamine include dizziness, drowsiness, grogginess, and dry mouth, among others.[6][4] Doxylamine is an antihistamine—specifically an inverse agonist of the histamine H1 receptor—and to a lesser extent an anticholinergic—specifically an antagonist of the muscarinic acetylcholine receptors M1 through M5. It is a first-generation antihistamine and crosses the blood-brain barrier into the brain, thereby producing centrally mediated sedative and hypnotic effects.

Doxylamine was first described in 1948 or 1949.[7] Several of the first-generation antihistamines, including doxylamine, are the most widely used sleep medications in the world.[8]

Medical uses

Doxylamine is an antihistamine used to treat 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.[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.[8] As of 2004, doxylamine and diphenhydramine, which are both over-the-counter medications, were the agents most commonly used to treat short-term insomnia.[10] 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".[11][12] Neither version of their guidelines explicitly included or mentioned doxylamine, although diphenhydramine was discussed.[11][12] 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 4 weeks of 0.47 (95% CI 0.06 to 0.89).[13] The certainty of evidence was rated as moderate.[13] No data were available for doxylamine in terms of longer-term treatment (3 months).[13] 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.[13]

Doses of doxylamine that have been used for sleep range from 5 to 50 mg, with 25 mg being the typical dose.[14][15][16][17]

Morning sickness

Doxylamine is used in the combination drug pyridoxine/doxylamine to treat morning sickness (nausea and vomiting of pregnancy).[18][19][20] It is the only medication approved by the United States Food and Drug Administration for the treatment of morning sickness.[18][19]

Available forms

See also: Pyridoxine/doxylamine

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).[21] Doxylamine is available alone as immediate-release oral tablets containing 25 mg doxylamine succinate.[21] Oral tablets containing 12.5 mg doxylamine succinate as well as oral capsules containing 25 mg doxylamine succinate were also previously available but were discontinued.[21] The combination of doxylamine and pyridoxine is available in the form of extended- and delayed-release oral tablets containing 10 to 20 mg doxylamine succinate and 10 to 20 mg pyridoxine hydrochloride.[21] Doxylamine alone is available over-the-counter, whereas doxylamine in combination with pyridoxine is a prescription-only medication.[21] Doxylamine is also available in over-the-counter nighttime cold medicine products such as NyQuil Cold & Flu (contains acetaminophen, doxylamine succinate 6.25 to 12.5 mg, and dextromethorphan hydrobromide), where it serves as the sedating component.[22][23]


The fetal safety rating of doxylamine is "A" (no evidence of risk).[24]

Side effects

Side effects of doxylamine include dizziness, drowsiness, and dry mouth, among others.[4] 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.[17][6]

Because of its relatively long elimination half-life (10–12 hours), doxylamine is associated with next-day effects including sedation, drowsiness, grogginess, dry mouth, and tiredness when used as a hypnotic.[25][17] This may be described as a "hangover effect".[17] 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.[26]

Antihistamines like doxylamine are sedating initially but tolerance occurs with repeated use and can result in rebound insomnia upon discontinuation.[6][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.[28] 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".[29]


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.[30] The median lethal dose (LD50) is estimated to be ~500 mg/kg in humans.[31] Symptoms of overdose may include dry mouth, dilated pupils, insomnia, night terrors, euphoria, hallucinations, seizures, rhabdomyolysis, and death.[32] 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.[5] Rarely, an overdose results in rhabdomyolysis and acute kidney injury.[33]



Site Ki (nM) Species Ref
SERT >10,000 Human [35]
NET >10,000 Human [35]
DAT >10,000 Human [35]
5-HT2A >10,000 Human [35]
5-HT2C >10,000 Human [35]
α1B >10,000 Human [35]
α2A >10,000 Human [35]
α2B >10,000 Human [35]
α2C >10,000 Human [35]
H1 42 Human [35]
H3 >10,000 Human [35]
M1 490 Human [35]
M2 2,100 Human [35]
M3 650 Human [35]
M4 380 Human [35]
M5 180 Human [35]
Values are Ki (nM), unless otherwise noted. The smaller the value, the more strongly the drug binds to the site.

Doxylamine acts primarily as an antagonist or inverse agonist of the histamine H1 receptor.[36][35] This action is responsible for its antihistamine and sedative properties.[36][35] To a lesser extent, doxylamine acts as an antagonist of the muscarinic acetylcholine receptors,[36][35] an action responsible for its anticholinergic and (at high doses) deliriant effects.[36][35]


The bioavailability of doxylamine is 24.7% for oral administration and 70.8% for intranasal administration.[1] The Tmax of doxylamine is 1.5 to 2.5 hours.[2] Its elimination half-life is 10 to 12 hours (range 7 to 15 hours).[2][3][4] Doxylamine is metabolized in the liver primarily by the cytochrome P450 enzymes CYP2D6, CYP1A2, and CYP2C9.[2][37] The main metabolites are N-desmethyldoxylamine, N,N-didesmethyldoxylamine, and doxylamine N-oxide.[38] Doxylamine is eliminated 60% in the urine and 40% in feces.[5]

Doxylamine concentrations after a single 25 mg oral dose of doxylamine in healthy volunteers. X-axis represents the time in hours after initial dose.[3]
Doxylamine concentrations after a single 25 mg oral dose of doxylamine in healthy volunteers. X-axis represents the time in hours after initial dose.[3]


Doxylamine is a member of the ethanolamine class of antihistamines.[8] Other antihistamines from this group include bromodiphenhydramine, carbinoxamine, clemastine, dimenhydrinate, diphenhydramine, orphenadrine, and phenyltoloxamine.[8][39]


Doxylamine is a first-generation antihistamine and was discovered by Nathan Sperber and colleagues and was first reported in 1948 or 1949.[40][7][41] It has been the antihistamine component of NyQuil since 1966.[40]

Bendectin, a combination of doxylamine, pyridoxine (vitamin B6), and dicyclomine (an anticholinergic antispasmodic agent), was marketed for treatment of morning sickness in 1956.[42] This product was reformulated in 1976 to remove dicyclomine.[42] 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.[42] However, these concerns have not been supported by studies.[18][19] In 2013, doxylamine/pyridoxine was reintroduced in the United States under the brand name Diclegis.[18][19] The combination was not removed from the market in Canada, where it had been marketed since 1979.[18][19]

Society and culture


Doxylamine is primarily used as the succinic acid salt, doxylamine succinate.


  1. ^ a b c Pelser A, Müller DG, du Plessis J, du Preez JL, Goosen C (2002). "Comparative pharmacokinetics of single doses of doxylamine succinate following intranasal, oral and intravenous administration in rats". Biopharm Drug Dispos. 23 (6): 239–44. doi:10.1002/bdd.314. PMID 12214324. S2CID 32126626.
  2. ^ a b c d e f g Meir H. Kryger; Thomas Roth; William C. Dement (1 November 2010). Principles and Practice of Sleep Medicine E-Book. Elsevier Health Sciences. pp. 925–. ISBN 978-1-4377-2773-9.
  3. ^ a b c Allison M, Hale C (June 2018). "A Phase I Study of the Pharmacokinetics and Pharmacodynamics of Intranasal Doxylamine in Subjects with Chronic Intermittent Sleep Impairment". Drugs R D. 18 (2): 129–136. doi:10.1007/s40268-018-0232-1. PMC 5995792. PMID 29671128.
  4. ^ a b c d e Culpepper L, Wingertzahn MA (2015). "Over-the-Counter Agents for the Treatment of Occasional Disturbed Sleep or Transient Insomnia: A Systematic Review of Efficacy and Safety". Prim Care Companion CNS Disord. 17 (6). doi:10.4088/PCC.15r01798. PMC 4805417. PMID 27057416.
  5. ^ a b c "New Zealand Datasheet: Doxylamine Succinate" (PDF). Medsafe, New Zealand Medicines and Medical Devices Safety Authority. 16 July 2008. Archived from the original on 22 March 2016.
  6. ^ a b c Neubauer DN (August 2007). "The evolution and development of insomnia pharmacotherapies". J Clin Sleep Med. 3 (5 Suppl): S11–5. PMC 1978321. PMID 17824496.
  7. ^ a b Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 546. ISBN 9783527607495.
  8. ^ a b c d Simons, F. Estelle R.; Simons, Keith J. (December 2011). "Histamine and H1-antihistamines: Celebrating a century of progress". Journal of Allergy and Clinical Immunology. 128 (6): 1139–1150.e4. doi:10.1016/j.jaci.2011.09.005. ISSN 0091-6749. PMID 22035879.
  9. ^ "Doxylamine: MedlinePlus Drug Information".
  10. ^ Ringdahl, EN; Pereira, SL; Delzell JE, Jr (2004). "Treatment of primary insomnia". The Journal of the American Board of Family Practice. 17 (3): 212–9. doi:10.3122/jabfm.17.3.212. PMID 15226287.
  11. ^ a b Schutte-Rodin, S; Broch, L; Buysse, D; Dorsey, C; Sateia, M (15 October 2008). "Clinical guideline for the evaluation and management of chronic insomnia in adults" (PDF). Journal of Clinical Sleep Medicine. 4 (5): 487–504. doi:10.5664/jcsm.27286. PMC 2576317. PMID 18853708.
  12. ^ a b Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL (February 2017). "Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults: An American Academy of Sleep Medicine Clinical Practice Guideline". J Clin Sleep Med. 13 (2): 307–349. doi:10.5664/jcsm.6470. PMC 5263087. PMID 27998379.
  13. ^ a b c d De Crescenzo F, D'Alò GL, Ostinelli EG, Ciabattini M, Di Franco V, Watanabe N, Kurtulmus A, Tomlinson A, Mitrova Z, Foti F, Del Giovane C, Quested DJ, Cowen PJ, Barbui C, Amato L, Efthimiou O, Cipriani A (July 2022). "Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis". Lancet. 400 (10347): 170–184. doi:10.1016/S0140-6736(22)00878-9. PMID 35843245.
  14. ^ Perry, Paul J. (2007). Psychotropic Drug Handbook. ISBN 9780781762731.
  15. ^ Dupuis G, Vaugeois JM (February 2020). "Les effets anti-H1 intéressants dans les insomnies de maintien : réflexion sur les intérêts comparés de la doxylamine et de la doxépine" [The interesting anti-H1 effects in maintenance insomnia: A reflection on the comparative advantages of doxylamine and doxepin]. Encephale (in French). 46 (1): 80–82. doi:10.1016/j.encep.2019.01.006. PMID 30879783. S2CID 151085176.
  16. ^ Lie JD, Tu KN, Shen DD, Wong BM (November 2015). "Pharmacological Treatment of Insomnia". P T. 40 (11): 759–71. PMC 4634348. PMID 26609210.
  17. ^ a b c d Shirley DW, Sterrett J, Haga N, Durham C (February 2020). "The therapeutic versatility of antihistamines: A comprehensive review". Nurse Pract. 45 (2): 8–21. doi:10.1097/01.NPR.0000651112.76528.ed. PMID 31913218.
  18. ^ a b c d e Nuangchamnong N, Niebyl J (2014). "Doxylamine succinate-pyridoxine hydrochloride (Diclegis) for the management of nausea and vomiting in pregnancy: an overview". Int J Womens Health. 6: 401–9. doi:10.2147/IJWH.S46653. PMC 3990370. PMID 24748822.
  19. ^ a b c d e Madjunkova S, Maltepe C, Koren G (June 2014). "The delayed-release combination of doxylamine and pyridoxine (Diclegis®/Diclectin ®) for the treatment of nausea and vomiting of pregnancy". Paediatr Drugs. 16 (3): 199–211. doi:10.1007/s40272-014-0065-5. PMC 4030125. PMID 24574047.
  20. ^ Cada, DJ; Demaris, K; Levien, TL; Baker, DE (October 2013). "Doxylamine succinate/pyridoxine hydrochloride". Hospital Pharmacy. 48 (9): 762–6. doi:10.1310/hpj4809-762. PMC 3857125. PMID 24421551.
  21. ^ a b c d e "Drugs@FDA: FDA-Approved Drugs". Retrieved 23 August 2022.
  22. ^ "DailyMed - VICKS NYQUIL COLD AND FLU- acetaminophen, dextromethorphan hydrobromide, and doxylamine succinate capsule, liquid filled".
  23. ^ "Nyquil Cold and Flu: Basics, Side Effects & Reviews".
  24. ^ Briggs, Gerald G.; Freeman, Roger K.; Yaffe, Sumner J. (2008). Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk. Obstetric Medicine. Vol. 2. Lippincott Williams & Wilkins. p. 89. doi:10.1258/om.2009.090002. ISBN 978-0-7817-7876-3. PMC 4989726.
  25. ^ Alon Y. Avidan (29 June 2017). Review of Sleep Medicine E-Book. Elsevier Health Sciences. pp. 394–. ISBN 978-0-323-47349-1.
  26. ^ Paul Professor Rutter; David Newby (11 September 2015). Community Pharmacy ANZ – eBook: Symptoms, Diagnosis and Treatment. Elsevier Health Sciences. pp. 99–. ISBN 978-0-7295-8345-9.
  27. ^ Stahl SM (December 2008). "Selective histamine H1 antagonism: novel hypnotic and pharmacologic actions challenge classical notions of antihistamines". CNS Spectr. 13 (12): 1027–38. doi:10.1017/s1092852900017089. PMID 19179941.
  28. ^ Doxylamine succinate (CAS 562-10-7).
  29. ^ DOXYLAMINE SUCCINATE. International Agency for Research on Cancer (IARC) – Summaries & Evaluations.
  30. ^ Federal Register, Volume 43, Issues 114-121. Office of the Federal Register, National Archives and Records Service, General Services Administration. 1978. pp. 25584–. OCLC 1768512.
  32. ^ Syed, Husnain; Sumit Som; Nazia Khan; Wael Faltas (17 March 2009). "Doxylamine toxicity: seizure, rhabdomyolysis and false positive urine drug screen for methadone". BMJ Case Reports. 2009 (90): 845. doi:10.1136/bcr.09.2008.0879. PMC 3028279. PMID 21686586.
  33. ^ Leybishkis, B.; Fasseas, P.; Ryan, K. F. (2001). "Doxylamine overdose as a potential cause of rhabdomyolysis". American Journal of the Medical Sciences. 322 (1): 48–9. doi:10.1097/00000441-200107000-00009. PMID 11465247.
  34. ^ Roth, BL; Driscol, J. "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 August 2017.
  35. ^ a b c d e f g h i j k l m n o p q r s t Krystal AD, Richelson E, Roth T (2013). "Review of the histamine system and the clinical effects of H1 antagonists: basis for a new model for understanding the effects of insomnia medications". Sleep Med Rev. 17 (4): 263–72. doi:10.1016/j.smrv.2012.08.001. PMID 23357028.
  36. ^ a b c d Vande Griend JP, Anderson SL (2012). "Histamine-1 receptor antagonism for treatment of insomnia". J Am Pharm Assoc (2003). 52 (6): e210–9. doi:10.1331/JAPhA.2012.12051. PMID 23229983.
  37. ^ Krystal AD (August 2009). "A compendium of placebo-controlled trials of the risks/benefits of pharmacological treatments for insomnia: the empirical basis for U.S. clinical practice". Sleep Med Rev. 13 (4): 265–74. doi:10.1016/j.smrv.2008.08.001. PMID 19153052.
  38. ^ Holder, C. L.; Korfmacher, W. A.; Slikker Jr, W.; Thompson Jr, H. C.; Gosnell, A. B. (1985). "Mass spectral characterization of doxylamine and its rhesus monkey urinary metabolites". Biomedical Mass Spectrometry. 12 (4): 151–158. doi:10.1002/bms.1200120403. PMID 2861861. S2CID 6020605.
  39. ^ Kalpaklioglu F, Baccioglu A (2012). "Efficacy and safety of H1-antihistamines: an update". Anti-Inflamm Antiallergy Agents Med Chem. 11 (3): 230–7. doi:10.2174/1871523011202030230. PMID 23173575.
  40. ^ a b Atta-ur-Rahman, ed. (11 July 2018). Frontiers in Clinical Drug Research - Anti-Allergy Agents, Volume 3. Bentham Science Publishers. pp. 30–. ISBN 978-1-68108-337-7. OCLC 1048922805.
  41. ^ Sperber, Nathan.; Papa, Domenick.; Schwenk, Erwin.; Sherlock, Margaret. (1949). "Pyridyl-Substituted Alkamine Ethers as Antihistaminic Agents". Journal of the American Chemical Society. 71 (3): 887–890. doi:10.1021/ja01171a034. PMID 18113525.
  42. ^ a b c Gerald G. Briggs; Roger K. Freeman; Sumner J. Yaffe (28 March 2012). Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk (9 ed.). Lippincott Williams & Wilkins. pp. 453–. ISBN 978-1-4511-5359-0. OCLC 1232803849.
  43. ^ Slaughter, Shelley R.; Hearns-Stokes, Rhonda; van der Vlugt, Theresa; Joffe, Hylton V. (2014). "FDA Approval of Doxylamine–Pyridoxine Therapy for Use in Pregnancy". New England Journal of Medicine. 370 (12): 1081–1083. doi:10.1056/NEJMp1316042. PMID 24645939.