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Doxylamine

Doxylamine molecule structureDoxylamine molecule structure
Open in Piru
Chemical Class
Benzhydrol

Doxylamine succinate is a first-generation antihistamine1 that will probably cause marked sleepiness soon after it is taken, lasting for some time afterward.2 It was first described in 1948 or 19493 and is used medically for insomnia,4 allergies, nausea, and vomiting. Its anticholinergic properties can cause delirium in overdose,1 while combining it with opioids may potentiate their effects.

Dosage & Duration

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Dosage

Doses are population estimates that vary widely between individuals.

Threshold10 mg
Light75-200 mg
Moderate200-350 mg
Heavy350+ mg

Duration

Onset20-30 minutes
After Effects1-6 hours
Total6-8 hours

Subjective Effects

Subjective Effects not written up yet

Pharmacology

Pharmacodynamics

Doxylamine antagonizes histamine H1 receptors and has pronounced sedative properties.5 It also antagonizes muscarinic acetylcholine receptors M1 through M5, contributing to potent anticholinergic effects. Doxylamine is readily absorbed and penetrates the brain, consistent with its sedative properties.

Pharmacokinetics

In 16 healthy male volunteers given a single oral dose of 25 mg doxylamine succinate, the mean time to peak plasma concentration was 2.4 hours.6 It undergoes hepatic metabolism primarily through CYP2D6, CYP1A2, and CYP2C9, producing N-desmethyldoxylamine, N,N-didesmethyldoxylamine, and doxylamine N-oxide. In 16 healthy male volunteers given a single oral dose of 25 mg doxylamine succinate, the mean elimination half-life was 10.1 hours.6 Doxylamine induced CYP2B enzymes in mice, but the relevance of this finding to humans has not been established.

Interactions

Interactions not written up yet

An unlisted combination is an unknown one, not a safe one. Check a dedicated combination chart before mixing.

Check TripSit

Tolerance

Tolerance timelines are rules of thumb, not exact schedules, and vary widely between individuals and use patterns.

Full Tolerance
Tolerance to doxylamine’s sedating effects can develop with repeated use.

Harm Potential

Addiction & Dependence

Psychological

Low

Tolerance develops with repeated use, which may lead to dose escalation. Rebound insomnia upon discontinuation can create a cycle of continued use.

Physical

Low

Rebound insomnia occurs upon discontinuation following repeated use, indicating mild physical dependence potential.

Toxicity

Renal

Overdose may rarely result in rhabdomyolysis and subsequent acute kidney injury; this is not a risk at typical therapeutic doses.

Central Nervous System

Continuous and cumulative use of anticholinergic medications including doxylamine is associated with higher risk of cognitive decline and dementia in older people; occasional use at typical doses carries minimal documented risk.

Cardiovascular

Cardiopulmonary arrest has been reported in fatal overdose cases, with children appearing to be at particularly high risk.

Carcinogenicity
Possible

Animal studies have found liver and thyroid cancer signals in mice and rats, with the findings most pronounced in mice. Human carcinogenicity remains poorly studied, and the International Agency for Research on Cancer classifies doxylamine as not classifiable regarding carcinogenicity in humans.

Evidence Basis
Human EpidemiologicalNone
Animal Models
Positive
(mouse, rat)

Psychosis Risk

Delirium occurs at high doses due to potent anticholinergic activity. Overdose symptoms include hallucinations, mental confusion, and delirium. Night terrors and euphoria have also been reported in overdose.

Seizure Risk

Seizures are listed among overdose symptoms. Fatal cases have been characterized by tonic-clonic (grand mal) seizures.

History & Culture

Discovery and commercial use

Doxylamine was discovered by Nathan Sperber and colleagues and first reported in 1948 or 1949. It became the antihistamine component of NyQuil in 1966, contributing to its longstanding use in nighttime cold medicines.

Legality

By Country

Legal / decriminalized1
United States flagUnited StatesLegal (regulated)

References

Citations

  1. Doxylamine succinate overdose: Slurred speech and visual hallucination. The Turkish Journal of Pediatrics (2018). https://doi.org/10.24953/turkjped.2018.04.01512
  2. Doxylamine: MedlinePlus Drug Information. MedlinePlus (n.d.). https://www.medlineplus.gov/druginfo/meds/a682537.html1
  3. Poisoning with Over-the-Counter Doxylamine Preparations: An Evaluation of 109 Cases. Human Toxicology (1987). https://doi.org/10.1177/0960327187006005031
  4. DailyMed - SLEEP AID- doxylamine succinate tablet (Meijer). dailymed.nlm.nih.gov (n.d.). https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=de0a6f68-6988-44df-9fab-b87620fd32e812
  5. Doxylamine - MeSH. NCBI (1991). https://www.ncbi.nlm.nih.gov/mesh/680043191
  6. The pharmacokinetics of doxylamine: use of automated gas chromatography with nitrogen-phosphorus detection. Journal of Clinical Pharmacology / PubMed (1985). https://doi.org/10.1002/j.1552-4604.1985.tb02875.x123
  7. The Delayed-Release Combination of Doxylamine and Pyridoxine (Diclegis/Diclectin) for the Treatment of Nausea and Vomiting of Pregnancy. Clinical Medicine Insights: Reproductive Health (2014). https://pmc.ncbi.nlm.nih.gov/articles/PMC403012512345
  8. Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis. The Lancet (2022). https://doi.org/10.1016/s0140-6736(22)00878-912
  9. openFDA DrugsFDA record — NDA 018066 (Unisom). api.fda.gov (n.d.). https://api.fda.gov/drug/drugsfda.json?search=application_number%3A%22NDA018066%22&limit=11
  10. openFDA DrugsFDA record — ANDA 040564 (doxylamine succinate). api.fda.gov (n.d.). https://api.fda.gov/drug/drugsfda.json?search=application_number%3A%22ANDA040564%22&limit=11

Article Status

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