Promethazine
Promethazine is a first-generation antihistamine of the phenothiazine class, developed by French chemists in the mid-1940s.1 It functions as a depressant with strong sedative, antiemetic, and anticholinergic properties.2 Commonly prescribed for allergies, nausea, and motion sickness,2 it is also known as one of the two active ingredients in 'lean' when combined with codeine.3 At high or toxic doses, its anticholinergic activity can produce deliriant effects.4
Contents
Dosage & Duration
Dosage
Anticholinergic effects can produce delirium at high doses, and heavy sedation may occur. Combining with other depressants such as opioids, benzodiazepines, barbiturates, or alcohol can cause fatal respiratory depression. The lowest published toxic oral dose in humans is 3.5 mg/kg, corresponding to roughly 245 mg in a 70 kg person.
Duration
Subjective Effects
The effects of promethazine are dominated by sedation arising from strong antihistamine and anticholinergic activity, with drowsiness and a calming of agitation being the most consistently reported features. Duration is generally in the range of four to six hours, though effects can persist for up to twelve. Recreational interest centres on this sedative quality, particularly in combination with codeine. At high or toxic doses the strong anticholinergic action can push the experience into deliriant territory.
Physical
Sedation, dizziness, and fatigue predominate, accompanied by anticholinergic dryness of the mouth and nasal passages, pupil dilation, and suppression of nausea. Motor side effects such as akathisia, restlessness of movement, and disturbances of coordination may occur, and central nervous system and respiratory depression are the primary dangers in overdose.
Autonomic
Coordination
Uncomfortable
Cognitive
The mental state is characterised by drowsiness and a reduction in anxiety, tension, and agitation; confusion is a common side effect and is especially pronounced in the elderly. Long-term cognitive impairment has been associated with the drug's high anticholinergic burden, and delirium along with nightmares may appear at toxic doses.
Impairment
Visual
Reagent Testing
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Pharmacology
Pharmacodynamics
Promethazine is a phenothiazine derivative that acts primarily as a potent histamine H1 receptor antagonist, producing antihistamine effects.5 It also exhibits moderate muscarinic acetylcholine receptor antagonism, which contributes to its sedative properties and anticholinergic effects.5 Additionally, promethazine acts as a non-competitive NMDA receptor antagonist, which may contribute to both sedation and mild analgesic effects.6 The compound shows weaker antagonist activity at dopamine D2 receptors, serotonin 5-HT2A and 5-HT2C receptors, and alpha-1 adrenergic receptors. Promethazine also blocks voltage-gated sodium channels, providing local anesthetic properties.
Pharmacokinetics
Promethazine has low oral bioavailability of approximately 25% due to extensive first-pass metabolism in the liver.7 The compound is predominantly metabolized to promethazine sulfoxide, with minor pathways producing desmethylpromethazine and a hydroxy metabolite.5 Hydroxylation is primarily mediated by CYP2D6.8 Promethazine is highly protein bound at 93%, mostly to albumin, and has a large volume of distribution of approximately 970L. Elimination occurs primarily through urinary excretion, with about 10% excreted as promethazine sulfoxide and less than 1% as unchanged parent drug.7
Tolerance
Harm Potential
Addiction & Dependence
Psychological
Extremely LowPromethazine is not considered addictive and does not produce significant psychological dependence.
Toxicity
CNS depression including drowsiness, dizziness, fatigue, and confusion may occur, with confusion being more common in elderly patients; at high doses, anticholinergic effects may produce delirium.9
Cardiovascular effects including arrhythmias and hypotension may occur; these are considered serious but less frequent side effects.10
Liver damage and cholestatic jaundice have been reported as serious but less frequent adverse effects.9
Intravenous or subcutaneous injection carries risk of severe tissue damage including gangrene; one documented case resulted in amputation following improper IV administration.11
Depression of the thermoregulatory mechanism may result in hypothermia or hyperthermia.10
Movement disorders including tardive dyskinesia, pseudoparkinsonism, acute dystonia, and akathisia may occur.10
Psychosis Risk
At high doses, promethazine's anticholinergic properties may cause delirium with symptoms including confusion, hallucinations, and disorientation.4 This risk is elevated in elderly patients.12
Seizure Risk
Promethazine may reduce seizure threshold.9 Seizures are listed as a rare side effect and may occur atypically in overdose situations, sometimes accompanied by hyperexcitability and convulsions.10
History & Culture
Discovery and Development
Promethazine was first synthesized in the 1940s by a team of scientists at Rhône-Poulenc laboratories in France, led by Paul Charpentier.13 The compound was developed by combining phenothiazine with a diamine side chain derived from diphenhydramine, as researchers sought to…
Legality
By Country
References
Citations
- Cookson J. (2019). Histamine in psychiatry: promethazine as a sedative anticholinergic. 25(4), 265-268. https://doi.org/10.1192/bja.2019.211
- (n.d.). PROMETHAZINE HYDROCHLORIDE injection — DailyMed (setid: c525cb2c-9a01-4a9b-ad2c-08630719953d). U.S. National Library of Medicine / DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c525cb2c-9a01-4a9b-ad2c-08630719953d12
- (2023). Lean/Sizzurp Ingredients, Use, and Coping With Mental Health Symptoms. https://pmc.ncbi.nlm.nih.gov/articles/PMC10517614/1
- (February 2009). Promethazine overdose: clinical effects, predicting delirium and the effect of charcoal. QJM, 102(2), 123–131. https://doi.org/10.1093/qjmed/hcn15312
- (n.d.). Promethazine Hydrochloride Injection — DailyMed Label (setid 4bf3912c). https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=4bf3912c-8339-401e-9711-dad6acf15f11123
- (August 2012). Promethazine inhibits NMDA-induced currents - new pharmacological aspects of an old drug. Neuropharmacology, 63(2), 280–291. https://doi.org/10.1016/j.neuropharm.2012.03.0061
- (n.d.). Taylor DC et al. Pharmacokinetics of promethazine and its sulphoxide metabolite after intravenous and oral administration to man. Br J Clin Pharmacol. 1983;15(3):287-93.. https://pmc.ncbi.nlm.nih.gov/articles/PMC1427776/12
- (n.d.). Nakamura K et al. CYP2D6 is the principal cytochrome P450 responsible for metabolism of the histamine H1 antagonist promethazine in human liver microsomes. Pharmacogenetics. 1996;6(5):449-57.. https://pubmed.ncbi.nlm.nih.gov/8946477/1
- (n.d.). Promethazine Hydrochloride Injection – DailyMed (SetID 365138a6). DailyMed / NIH National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=365138a6-28d8-4881-a3e9-02c80aaf83e812345
- (n.d.). Promethazine – StatPearls (NBK544361). StatPearls / NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK544361/12345
- (n.d.). Phenergan (Promethazine HCl) Injection – DailyMed (SetID 481866da). DailyMed / NIH National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=481866da-a712-48a5-853f-8e84aacaab6d12
- (n.d.). Promethazine Hydrochloride Tablet – DailyMed (SetID 44cd6d46). DailyMed / NIH National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=44cd6d46-fbb9-4836-9426-d8ce2cb6d66d1
- (n.d.). PROMETHAZINE — NCATS Inxight Drugs. https://drugs.ncats.io/drug/FF28EJQ49412
- (n.d.). Paul Charpentier, Henri-Marie Laborit, Simone Courvoisier, Jean Delay, and Pierre Deniker. https://www.sciencehistory.org/education/scientific-biographies/paul-charpentier-henri-marie-laborit-simone-courvoisier-jean-delay-and-pierre-deniker/12
- (n.d.). Promethazine Drug Usage Statistics, United States, 2014 - 2023. ClinCalc. https://clincalc.com/DrugStats/Drugs/Promethazine1
- (n.d.). Dextromethorphan; Promethazine Drug Usage Statistics, United States, 2014 - 2023. ClinCalc. https://clincalc.com/DrugStats/Drugs/DextromethorphanPromethazine1
- (n.d.). Phenergan - Healthdirect Australia. Healthdirect Australia. https://www.healthdirect.gov.au/medicines/brand/amt,22661000168108/phenergan1
- (n.d.). HISTANTIL TAB 50MG - Health Canada Drug Product Database (DIN 00575186). Health Canada Drug Product Database. https://health-products.canada.ca/dpd-bdpp/info?lang=eng&code=53691
- (n.d.). Phenergan 25 mg Tablets - Summary of Product Characteristics (SmPC). electronic Medicines Compendium (emc) / Opella Healthcare UK Limited. https://www.medicines.org.uk/emc/product/5588/smpc1
- (n.d.). PROMETHAZINE HYDROCHLORIDE TABLETS, USP Rx only - DailyMed. US National Library of Medicine / DailyMed. https://www.dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=f91688e2-fd64-476f-b9b9-eb4fa4c5bd11&type=display12
Automated synthesisInformation aggregated and synthesized using an autonomous workflow built by Josie Kins.
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