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Promethazine
Promethazine is a first-generation antihistamine of the phenothiazine class, developed by French chemists in the mid-1940s.citation needed It functions as a depressant with strong sedative, antiemetic, and anticholinergic properties. Commonly prescribed for allergies, nausea, and motion sickness, it is also known as one of the two active ingredients in 'lean' when combined with codeine.1 At high or toxic doses, its anticholinergic activity can produce deliriant effects.2
Dosage & Duration
Dosage
Doses are population estimates that vary widely between individuals.
Threshold~10 mg
Light10-25 mg
Moderate25-50 mg
Strong50-100 mg
Heavy100+ mg
Bioavailability
25%
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
Onset30-60 minutes
Come Up20-60 minutes
Peak1-2 hours
Offset3-5 hours
After Effects12 hours
Total4-6 hours
Half-life
12-15 hours
Subjective Effects
Legacy content. A statistically backed ontology from Mindstate Design Labs is coming soon.
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
Pharmacology
Pharmacodynamics
Promethazine is a phenothiazine derivative that acts primarily as a potent histamine H1 receptor antagonist, producing antihistamine effects.citation needed It also exhibits moderate muscarinic acetylcholine receptor antagonism, which contributes to its sedative properties and anticholinergic effects. Additionally, promethazine acts as a non-competitive NMDA receptor antagonist, which may contribute to both sedation and mild analgesic effects. 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.3 The compound is predominantly metabolized to promethazine sulfoxide, with minor pathways producing desmethylpromethazine and a hydroxy metabolite.citation needed Hydroxylation is primarily mediated by CYP2D6. 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.
Interactions
Interactions not written up yet
An unlisted combination is an unknown one, not a safe one. Check a dedicated combination chart before mixing.
Tolerance
Tolerance timelines are rules of thumb, not exact schedules, and vary widely between individuals and use patterns.
Full Tolerance
A double-blind, placebo-controlled crossover study in 10 healthy young adults compared promethazine responses on two consecutive days. Reaction-time impairment was less pronounced after the repeat dose, and the tremor response was also reduced.4 This supports short-term adaptation in those motor outcomes only; it does not establish tolerance to antihistamine benefit, sedation as a whole, recreational effects, cross-tolerance, or time to baseline.
Harm Potential
Addiction & Dependence
Psychological
Extremely LowPromethazine is not considered addictive and does not produce significant psychological dependence.
Toxicity
Central Nervous System
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.citation needed
Cardiovascular
Cardiovascular effects including arrhythmias and hypotension may occur; these are considered serious but less frequent side effects.citation needed
Hepatic
Liver damage and cholestatic jaundice have been reported as serious but less frequent adverse effects.citation needed
Hematologic
Bone marrow suppression may occur, potentially resulting in agranulocytosis, thrombocytopenia, and leukopenia.6
Peripheral Tissue
Intravenous or subcutaneous injection carries risk of severe tissue damage including gangrene; one documented case resulted in amputation following improper IV administration.citation needed
Thermoregulatory
Depression of the thermoregulatory mechanism may result in hypothermia or hyperthermia.6
Extrapyramidal
Movement disorders including tardive dyskinesia, pseudoparkinsonism, acute dystonia, and akathisia may occur.6
Psychosis Risk
At high doses, promethazine's anticholinergic properties may cause delirium with symptoms including confusion, hallucinations, and disorientation.citation needed This risk is elevated in elderly patients.
Seizure Risk
Promethazine may reduce seizure threshold.5 Seizures are listed as a rare side effect and may occur atypically in overdose situations, sometimes accompanied by hyperexcitability and convulsions.citation needed
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.citation needed The compound was developed by combining phenothiazine with a diamine side chain derived from diphenhydramine, as researchers sought to improve…
Legality
International
Promethazine does not appear in the INCB schedules of narcotic drugs under the 1961 Convention or psychotropic substances under the 1971 Convention. It also does not appear in the precursor tables of the 1988 Convention.
By Country
Controlled / restricted6
FinlandRestrictedPromethazine is regulated in Finland as a medicinal substance under Fimea's Decision on the Medicines List. The decision treats the substances listed in Appendix 1, including their salts and esters, as medicines; its current version entered into force on 19 May 2025. The medicines list does not itself determine whether a particular product is supplied over the counter, by prescription, as a PKV medicine, or as a narcotic, so the legal classification is medicinal-product regulation rather than a prescription-only or narcotics schedule.
IndiaRestrictedCDSCO list of prohibited fixed-dose combinations21
India's central drug regulator lists several fixed-dose combinations containing promethazine as prohibited for manufacture and sale under section 26A of the Drugs and Cosmetics Act 1940. This listing concerns the named combinations rather than promethazine as a single active ingredient.
New ZealandRestrictedMedsafe New Zealand Data Sheet: AdiraMedica Promethazine31
Promethazine hydrochloride is supplied in New Zealand as AdiraMedica Promethazine 10 mg and 25 mg film-coated tablets. The Medsafe data sheet identifies promethazine hydrochloride as the active ingredient and describes the authorised product.
PolandRestricted
South AfricaRestrictedSAHPRA approved professional information: Phenergan40
Promethazine hydrochloride is registered in South Africa in Phenergan 10 mg and 25 mg coated tablets. SAHPRA's approved professional information identifies the medicine and its active ingredient.
Prescription7
United StatesPrescription onlyPromethazine hydrochloride is marketed in the United States as a human prescription drug. The current FDA drug label designates the product "Rx only"; under 21 U.S.C. § 353(b), a drug subject to prescription status may be dispensed only on a licensed practitioner's prescription, and a pre-dispensing label must bear "Rx only". Promethazine does not appear in the current federal controlled-substances schedules.
By state
Across the 50 states, D.C., and the permanent territories, most jurisdictions treat Promethazine consistently with federal control; listed entries record independently verified differences in state classification or coverage.
GeorgiaRestrictedPromethazine is expressly designated a dangerous drug in Georgia. Georgia separately regulates dangerous drugs that are not controlled substances and prohibits their possession, sale, purchase, or distribution except as authorized by the Dangerous Drug Act. This is a state-specific statutory classification in addition to ordinary prescription-only status.
MainePrescription only17-A M.R.S. § 1102(4)(A)52
Promethazine is a Schedule Z drug in Maine because Schedule Z includes all prescription drugs not placed in Schedules W, X, or Y. It remains available by prescription, but Maine's controlled-drug statute assigns it that state schedule classification. No major-municipality ordinance creating a different promethazine classification was identified.
MassachusettsPrescription onlyMass. Gen. Laws ch. 94C, § 31, Class E(b)53
Promethazine is a Class E controlled substance in Massachusetts because Class E includes prescription drugs other than those placed in Classes A through D or Class E(a). It remains available by prescription, while state law gives it a Class E controlled-substance classification. No major-municipality ordinance creating a different promethazine classification was identified.
DenmarkPrescription onlyDanish Medicines Agency pharmacovigilance update15
Promethazine is prescription-only in Denmark. The Danish Medicines Agency changed the status of specified tablet and oral-solution products from over-the-counter to prescription-only, effective 8 December 2014.
RussiaPrescription onlyRussian Ministry of Health Order No. 100н of 7 March 2025 (registered 9 April 2025 No. 81789), Appendix 1 §§1 and 9, in force from 1 September 2025 through 1 September 2031; Government Resolution No. 681 of 30 June 1998, current consolidation amended 11 June 2025 and effective-content change 27 July 2025.3435363738
The current Russian Pipolfen product-information entry explicitly labels the promethazine injection prescription-only and was updated 08.04.2026, while current Order No. 100н governs dispensing from 01.09.2025. The current consolidation of Resolution No. 681 contains no exact promethazine entry; no narcotic/psychotropic schedule or penalties are specified. The prescription-only classification applies to this product and does not extend to every possible foreign promethazine formulation.
SwedenPrescription onlyPromethazine is a prescription-only medicine in Sweden. The national VARA product register records Prometazin Actavis as a licensed medicinal product, approved on 3 November 2016, and identifies promethazine as its active substance. The record states that it is not narcotic-classified and that a prescription is required for dispensing.
Legal / decriminalized7
FranceLegal (regulated)Base de Données Publique des Médicaments (ANSM), PHENERGAN 2 %, crème18
Promethazine is available in France in at least one regulated medicinal product that is not subject to mandatory prescription. The current ANSM public record for PHENERGAN 2 %, crème identifies promethazine 2 g per 100 g, cutaneous administration, and non-prescription dispensing. The non-prescription classification applies to this cutaneous product and does not establish the classification of oral promethazine products.
JapanLegal (regulated)Promethazine is a designated second-class over-the-counter medicine ingredient under Japan's Pharmaceuticals and Medical Devices Act framework. OTC preparations containing promethazine, its hydrates, or its salts are subject to the special-attention second-class medicine classification; promethazine is also listed among second-class OTC medicine ingredients. This classification regulates retail supply as a medicine and does not make promethazine uniformly prescription-only.
SingaporeLegal (regulated)Singapore HSA Pharmacy-Only medicine classification39
The official HSA record establishes that this registered promethazine product was cancelled.
SpainLegal (regulated)La AEMPS registra Fenergan Crema, cuyo principio activo virtual terapéutico es prometazina, como medicamento comercializado sin receta. Por tanto, la prometazina está legalmente regulada como ingrediente de este medicamento autorizado de uso cutáneo y puede dispensarse sin prescripción en esa presentación.
United KingdomLegal (regulated)UK marketing authorisation PL 53886/0055 (Phenergan 25 mg Tablets), under the Human Medicines Regulations 20124546
Phenergan 25 mg Tablets, which contain promethazine hydrochloride, are classified as a pharmacy medicine (P) in the United Kingdom. They are not subject to general sale and may be sold or supplied only through a registered pharmacy by, or under the supervision of, a pharmacist.
Not scheduled1
BrazilNot scheduledANVISA notice: Prometazina não está sujeita a controle especial13
Promethazine is not subject to Brazil's special-control lists. ANVISA states that it has never been subject to the lists in Portaria SVS/MS 344/98 and will not be added to them.
References
Citations
- Lean/Sizzurp Ingredients, Use, and Coping With Mental Health Symptoms. (2023). https://pmc.ncbi.nlm.nih.gov/articles/PMC10517614/1
- C B Page, S B Duffull, I M Whyte, & G K Isbister. (February 2009). Promethazine overdose: clinical effects, predicting delirium and the effect of charcoal. QJM, 102(2), 123–131. https://doi.org/10.1093/qjmed/hcn1531
- 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.. (n.d.). https://pmc.ncbi.nlm.nih.gov/articles/PMC1427776/1
- Baumann-Birkbeck L, Grant GD, Anoopkumar-Dukie S, Kavanagh JJ. pubmed.ncbi.nlm.nih.gov (n.d.). https://doi.org/10.1016/j.clinph.2014.03.0261
- Promethazine Hydrochloride Injection – DailyMed (SetID 365138a6). DailyMed / NIH National Library of Medicine (n.d.). https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=365138a6-28d8-4881-a3e9-02c80aaf83e812
- Promethazine – StatPearls (NBK544361). StatPearls / NCBI Bookshelf (n.d.). https://www.ncbi.nlm.nih.gov/books/NBK544361/123
- Phenergan (Promethazine HCl) Injection – DailyMed (SetID 481866da). DailyMed / NIH National Library of Medicine (n.d.). https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=481866da-a712-48a5-853f-8e84aacaab6d1
- Paul Charpentier, Henri-Marie Laborit, Simone Courvoisier, Jean Delay, and Pierre Deniker. (n.d.). https://www.sciencehistory.org/education/scientific-biographies/paul-charpentier-henri-marie-laborit-simone-courvoisier-jean-delay-and-pierre-deniker/1
- Promethazine Drug Usage Statistics, United States, 2014 - 2023. ClinCalc (n.d.). https://clincalc.com/DrugStats/Drugs/Promethazine1
- Dextromethorphan; Promethazine Drug Usage Statistics, United States, 2014 - 2023. ClinCalc (n.d.). https://clincalc.com/DrugStats/Drugs/DextromethorphanPromethazine1
Article Status
Step 1 · Automated synthesisAn autonomous workflow built by Josie Kins compiled this article's foundation from information published across the web.
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A first pass manual review and edit of article prose and copy has been performed by subject-matter expert Lyrea. This does not guarantee factual accuracy. An additional human review for each of this article's citations is yet to be performed.
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16 August 2026
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Lyrea · Changed a word in Dosage & Duration › Routes 1 › Dose ranges › Light
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Josie Kins · Updated the article · also 1,4-Butanediol, 1B-LSD, 1cP-AL-LAD and 573 more
Josie Kins · Updated the article · also 1,4-Butanediol, 1B-LSD, 1cP-AL-LAD and 573 more
Josie Kins · Updated the article · also 1,4-Butanediol, 1B-LSD, 1cP-AL-LAD and 573 more
Josie Kins · Updated the article · also 1,4-Butanediol, 1B-LSD, 1cP-AL-LAD and 573 more
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