generation run 2026-05-12
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25 searches — query, source, results, what was kept and why
| # | source | query | seen | kept | rationale |
|---|---|---|---|---|---|
| 1 | PubMed | promethazine QT prolongation cardiac arrhythmia torsades | 2 | 2 | Documents QT/cardiac safety concerns |
| 2 | PubMed | promethazine codeine lean purple drank misuse abuse | 2 | 2 | Documents recreational use context |
| 3 | ClinicalTrials.gov | promethazine | 10 | 0 | No primary promethazine-specific trials identified from this search |
| 4 | PubMed | promethazine antiemetic nausea vomiting clinical trial | 10 | 5 | High-quality evidence on antiemetic efficacy including Cochrane review |
| 5 | PubMed | promethazine H1 receptor antagonist antihistamine sedation mechanism | 2 | 1 | Comprehensive mechanism review |
| 6 | OpenAlex | promethazine pharmacology mechanism action | 10 | 1 | Classic H1 receptor paper relevant to pharmacological class context |
| 7 | PubMed | promethazine overdose toxicity adverse effects | 9 | 4 | Primary toxicity/overdose data including controlled series |
| 8 | PubMed | promethazine pharmacokinetics bioavailability metabolism | 10 | 4 | Primary PK studies in humans; highly relevant |
| 9 | PubMed | promethazine tissue necrosis injection intravenous extravasation | 1 | 1 | Documents IV safety risk |
| 10 | PubChem | promethazine | 1 | 1 | Only result; confirms core chemical identity |
| 11 | PubMed · absence | promethazine pharmacology receptor binding H1 dopamine muscarinic | 0 | — | — |
| 12 | IUPHAR/BPS Guide to Pharmacology | promethazine receptor binding Ki values | 1 | 1 | Most comprehensive receptor binding profile available for promethazine |
| 13 | WebSearch | promethazine legal status scheduling United States UK Australia prescription 2026 | 10 | 2 | Establishes regulatory/scheduling status across jurisdictions |
| 14 | WebSearch | promethazine metabolism CYP2D6 CYP2C9 | 10 | 2 | Establishes CYP2D6 as primary metabolic enzyme and drug interaction mechanism |
| 15 | WebSearch | promethazine receptor binding Ki values H1 D2 muscarinic PDSP database | 10 | 3 | Primary binding affinity data from authoritative database |
| 16 | StatPearls/NCBI Bookshelf | promethazine clinical overview | 1 | 1 | Authoritative clinical reference covering all key clinical aspects |
| 17 | WebSearch | promethazine history discovery 1945 1946 Rhone-Poulenc Paul Charpentier phenothiazine | 10 | 3 | Primary discovery history |
| 18 | PubMed | promethazine photosensitivity contact dermatitis | 6 | 1 | Documents photosensitivity as adverse effect |
| 19 | WebSearch | promethazine FDA black box warning pediatric respiratory depression | 10 | 2 | Critical safety data - FDA regulatory action |
| 20 | Research output synthesis | all sources | 39 | 1 | Final compilation for handoff |
| 21 | WebSearch | promethazine Canada OTC prescription Health Canada | 10 | 0 | Legal status data for Canada |
| 22 | PubMed | promethazine anticholinergic elderly Beers criteria | 2 | 1 | Beers Criteria listing for promethazine in elderly patients |
| 23 | WebSearch | promethazine Australia scheduling TGA 2026 | 10 | 0 | Legal status data for Australia |
| 24 | PubMed | promethazine enantiomers stereochemistry | 1 | 2 | Establishes stereochemistry details |
| 25 | IUPHAR Guide to Pharmacology | promethazine receptor binding | 1 | 1 | Most authoritative freely available receptor binding database |
78 claims by section — every cited sentence, checked against its source
safety20 · 15 ok
Concurrent QT-prolonging medications — additive cardiac arrhythmia risksupported
Concomitant QT-prolonging drugs significantly associated with TdP events. 14740338.2021.1846717
Intravenous administration risks include thrombophlebitis, unintentional intra-arterial injection, perivascular extravasation, and tissue necrosis or gangrenesupported
IV administration can cause thrombophlebitis, unintentional intra-arterial injection, perivascular extravasation, and tissue necrosis. pmid:38070188
Claim in safety — inconclusiveinconclusiveworking →
Dermal absorption has produced full toxic neurological syndromes including CNS depression, excitomotor manifestations, ataxia, and visual hallucinationssupported
Two cases of dermal absorption of promethazine resulting in toxic neurological syndrome: CNS depression, acute excitomotor manifestations, ataxia, visual hallucinations, and peripheral anticholinergic effects. pmid:6733616
An autopsy case documented promethazine in the toxic-to-lethal blood concentration range as part of a Vegetamin (phenobarbital + chlorpromazine + promethazine) overdose; cause of death was rhabdomyolysis, and cyp2d6 heterozygous mutations were noted in the subject.supported
Autopsy case death from vegetamin (phenobarbital + chlorpromazine + promethazine) overdose. Promethazine levels in toxic-to-lethal range. Rhabdomyolysis noted. CYP2D6 heterozygous mutations identified. j.jflm.2009.07.020
Promethazine is a recognized signal for torsade de pointes (TdP) in FDA Adverse Event Reporting System pharmacovigilance analysissupported
FAERS pharmacovigilance study. Promethazine identified as an old signal for TdP. 14740338.2021.1846717
In a study of 27,396 psychiatric hospital patients, replacement of promethazine with more tolerable alternatives was estimated to reduce QT-prolonging drug exposure by 11%.supported
Analysis of QT-prolonging drugs in 27,396 psychiatric patients. Promethazine identified as high-risk drug whose replacement could reduce QT-prolonging drug load by 11%. s00702-020-02291-y
Photosensitivity. Promethazine is a recognized phototoxic agent and photoallergen, used as a positive control in phototoxicity testing protocols.partially supported
Case report: positive photo-patch test to promethazine and chlorpromazine. Phenothiazines as phototoxic agents and photoallergens inducing persistent photosensitivity. pmid:18247472
Claim in safety — inconclusiveinconclusiveworking →
Cognitive impairment at clinical doses includes reduced working memory accuracy and slowed response speed, particularly under conditions of concurrent vestibular stimulationsupported
Promethazine 25mg alone had no adverse effect on working memory, but combined with vestibular stimulation (spinning), decreased accuracy and speed. pmid:15451046
The dramatic difference in sedation rates between ground-based subjects (60–73%) and astronauts in spaceflight (<5%) is attributed to microgravity-specific pharmacodynamic changes rather than tolerance.partially supported
Sedation incidence <5% in space vs 60-73% on ground. No operational impact from sedation. pmid:9766972
Claim in safety — inconclusiveinconclusiveworking →
The promethazine–codeine combination in purple drank represents the most prevalent manifestation of this interaction class in recreational settings.supported
Systematic review of 'purple drank' misuse (codeine+promethazine). Began in Texas 1960s-1990s. Popularized through rap culture. 02791072.2020.1797250
CYP2D6 inhibition creates a pharmacokinetically paradoxical interaction with codeine: promethazine inhibits CYP2D6-mediated conversion of codeine to its active metabolite morphine, potentially reducing opioid potency even as net CNS depression increases through additive sedationsupported
Promethazine inhibits CYP2D6-mediated bufuralol hydroxylation. Competitive inhibition at therapeutic concentrations. pmid:11936702
CYP2D6 inhibition creates a pharmacokinetically paradoxical interaction with codeine: promethazine inhibits CYP2D6-mediated conversion of codeine to its active metabolite morphine, potentially reducing opioid potency even as net CNS depression increases through additive sedationsupported
Promethazine also inhibits CYP2D6 in vitro. CYP2D6 is the principal P450 responsible. pmid:8946477
CYP2C9 inhibition (IC₂₀ = 88 µM) extends the interaction risk to warfarin, some NSAIDs, and phenytoin at higher promethazine doses.supported
Promethazine inhibits CYP2C9-mediated tolbutamide hydroxylation (IC20 88 microM). Competitive inhibition at therapeutic concentrations. pmid:11936702
Pharmacovigilance data identify promethazine as a standalone TdP signal, and concomitant use of additional QT-prolonging drugs significantly increases cardiac arrhythmia risk.supported
Promethazine identified as an old signal for TdP. Concomitant QT-prolonging drugs significantly associated with TdP events. 14740338.2021.1846717
Pharmacovigilance data identify promethazine as a standalone TdP signal, and concomitant use of additional QT-prolonging drugs significantly increases cardiac arrhythmia risk.supported
Promethazine identified as high-risk drug. Recommends replacing levomepromazine, melperone, and promethazine with more tolerable alternatives. s00702-020-02291-y
Claim in safety — not_supportednot supportedworking →
Claim in safety — not_supportednot supportedworking →
pharmacology13 · 12 ok
Binding affinities range from Ki = 1.06 nM at M4 to Ki = 12 nM at M2, placing promethazine among the most potent antimuscarinic agents in the antihistamine classpartially supported
Promethazine had high muscarinic affinity (Ki = 5.0-38 nM). Broad range of antimuscarinic potency among antihistamines demonstrated. pmid:2884340
Claim in pharmacology — inconclusiveinconclusiveworking →
The antiemetic effect involves a triple mechanism: D2 blockade in the CTZ, H1 blockade in the vomiting center, and muscarinic blockade in the vestibular apparatus.supported
Covers H1, D2, muscarinic, and 5-HT3 receptor targets relevant to antiemetics including promethazine. ijms22115797
Absorption and bioavailability. Oral bioavailability is low at 12.3–40%, reflecting extensive first-pass hepatic metabolism including glucuronidation and sulfoxidationsupported
Absolute bioavailability of promethazine after oral dosing: 12.3-40% (distribution-free confidence interval). pmid:8147942
Absorption is highly variable across all formulations: intersubject variation for pharmacokinetic parameters in tablet studies ranges from 23–63%, and individual relative bioavailability of rectal suppositories ranged from 4% to 343% in a 36-volunteer study — extreme individual variability that complicates dose predictionpartially supported
High intersubject variation for all parameters (23-63%). Five-way crossover study in humans. pmid:3730528
Absorption is highly variable across all formulations: intersubject variation for pharmacokinetic parameters in tablet studies ranges from 23–63%, and individual relative bioavailability of rectal suppositories ranged from 4% to 343% in a 36-volunteer study — extreme individual variability that complicates dose predictionpartially supported
Relative bioavailability of suppositories 70-97% but individual variability 4-343%. pmid:10965395
Dose proportionality is linear across the range studied.supported
Promethazine exhibits linear dose proportionality. pmid:3730528
Time to peak concentration. Oral syrup reaches mean Tmax at 4.4 hours (wide range, high intersubject variability); rectal suppositories at 6.7–8.6 hourspartially supported
Oral syrup Cmax 19.3 ng/mL at tmax 4.4 hours. pmid:10965395
Peak plasma concentration after 50 mg oral syrup averages 19.3 ng/mL, compared to 9.04 ng/mL for 50 mg rectal suppository.partially supported
Oral syrup Cmax 19.3 ng/mL at tmax 4.4 hours. pmid:10965395
Elimination. Half-life is 16–19 hours across oral and rectal formulations, notably longer than many first-generation antihistaminessupported
Half-life 16-19 hours. pmid:10965395
Metabolism. cyp2d6 is the principal cytochrome P450 enzyme responsible for promethazine metabolism in human liver microsomes, confirmed by microsomal inhibition studies with SKF-525A, propranolol, sparteine, and quinidine, and by expression in CYP2D6-producing B-lymphoblastoid cellssupported
In vitro human liver microsome study. CYP2D6 is the principal P450 responsible. pmid:8946477
Three main metabolic pathways proceed through CYP2D6: ring hydroxylation (low Km — primary pathway), S-oxidation to promethazine sulfoxide, and N-demethylation to nor-promethazine.supported
Promethazine biotransformed to ring-hydroxylated, S-oxidized, and N-demethylated metabolites. CYP2D6 is the principal P450 responsible. Hydroxylation has low Km value. pmid:8946477
Promethazine is also a CYP2D6 inhibitor, competitively inhibiting the enzyme at therapeutic plasma concentrations, and inhibits CYP2C9-mediated tolbutamide 4-methylhydroxylation (IC₂₀ = 88 µM)supported
Promethazine inhibits CYP2D6-mediated bufuralol hydroxylation and also inhibits CYP2C9-mediated tolbutamide hydroxylation (IC20 88 microM). Competitive inhibition at therapeutic concentrations. pmid:11936702
pharmacokinetic-detail10 · 6 ok
An autopsy case documented CYP2D6 heterozygous mutations in a fatal promethazine-containing overdose, suggesting reduced metabolic capacity contributed to toxic accumulation.supported
Autopsy case death from vegetamin (phenobarbital + chlorpromazine + promethazine) overdose. Promethazine levels in toxic-to-lethal range. CYP2D6 heterozygous mutations identified. j.jflm.2009.07.020
In a 36-volunteer study comparing rectal suppositories to oral syrup, individual relative bioavailability of the suppository ranged from 4% to 343% — nearly a 100-fold range between subjectssupported
Relative bioavailability of suppositories 70-97% but individual variability 4-343%. pmid:10965395
Intersubject variation for tablet PK parameters (Cmax, AUC) ranged from 23–63% in a separate study.supported
High intersubject variation for all parameters (23-63%). pmid:3730528
Dose proportionality is linear across the tested dose range, meaning that systemic exposure scales predictably with dose within an individual, even as between-individual differences remain large.supported
Promethazine exhibits linear dose proportionality. High intersubject variation for all parameters (23-63%). pmid:3730528
cyp2d6 is the principal enzyme for all three major metabolic pathways:supported
Promethazine biotransformed to ring-hydroxylated, S-oxidized, and N-demethylated metabolites. CYP2D6 is the principal P450 responsible. pmid:8946477
Promethazine competitively inhibits CYP2D6 at therapeutic plasma concentrations and inhibits CYP2C9-mediated tolbutamide 4-methylhydroxylation with an IC₂₀ of 88 µMsupported
Promethazine inhibits CYP2D6-mediated bufuralol hydroxylation and also inhibits CYP2C9-mediated tolbutamide hydroxylation (IC20 88 microM). Competitive inhibition at therapeutic concentrations. pmid:11936702
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
Claim in pharmacokinetic-detail — not_supportednot supportedworking →
clinical-evidence8 · 7 ok
A randomized clinical trial comparing low-dose promethazine (6.25 mg IV) plus dexamethasone against ondansetron monotherapy for PONV prophylaxis during myomectomy under spinal anesthesia found that the promethazine combination was non-inferior to ondansetron at substantially lower cost.partially supported
RCT in 70 women. Promethazine 12.5mg IV + dexamethasone 8mg vs ondansetron 8mg for PONV prophylaxis during myomectomy. Combination therapy showed comparable efficacy. 2094662
A 2025 RCT evaluated promethazine (6.25 mg IV) combined with metoclopramide for PONV prevention in laparoscopic colorectal cancer surgery, supporting the utility of low-dose promethazine in multimodal antiemetic regimens.supported
RCT examining promethazine combined with metoclopramide for PONV prevention in laparoscopic colorectal cancer surgery. dddt.s526724
Davis et al. compared treatment strategies for SMS and established IM promethazine (25–50 mg) as superior to scopolamine–dextroamphetamine combinationssupported
14 of 15 treated with IM promethazine had immediate (within 1-2h) symptom relief vs. delayed/variable response with oral scopdex. NASA policy changed to recommend promethazine after symptom development. pmid:11541638
Paule et al. quantified cognitive effects, finding that 25 mg oral promethazine alone did not significantly impair working memory, but combined with vestibular stimulation, accuracy and response speed decreased; cognitive impairment ranked: meclizine < scopolamine < promethazine < lorazepam.supported
Promethazine 25mg alone had no adverse effect on working memory, but combined with vestibular stimulation (spinning), decreased accuracy and speed. Rank order of cognitive safety: meclizine > scopolamine > promethazine > lorazepam. pmid:15451046
The highest-quality evidence for promethazine's antiemetic efficacy comes from the Cochrane Network Meta-analysis on drugs for preventing postoperative nausea and vomiting (PONV), which included promethazine among comparator agentssupported
Cochrane network meta-analysis of antiemetics for PONV. Reviews comparative efficacy and side effects of multiple agents including promethazine. 14651858.cd012859.pub2
A Cochrane systematic review examined interventions for hyperemesis gravidarum, including promethazinesupported
Cochrane review of interventions for hyperemesis gravidarum (0.3-1.0% of pregnancies). Reviews evidence for multiple antiemetics including promethazine. 14651858.cd010607.pub2
Cowings et al. assessed promethazine's impact on human performance and mood states at clinical doses in a motion sickness contextsupported
Examines effects of IM promethazine 25mg and 50mg on performance, mood states, and motion sickness in humans. pmid:11051308
Claim in clinical-evidence — inconclusiveinconclusiveworking →
history6 · 6 ok
From March 1989, intramuscular promethazine (25–50 mg) became the standard NASA treatment for space motion sickness (SMS) following demonstrated superiority over scopolamine–dextroamphetamine combinations in Space Shuttle missionspartially supported
14 of 15 treated with IM promethazine had immediate (within 1-2h) symptom relief vs. delayed/variable response with oral scopdex. NASA policy changed to recommend promethazine after symptom development. pmid:11541638
Analytical testing of street samples has measured promethazine concentrations of 68–75 mg/L and codeine concentrations of 91–130 mg/Lsupported
Found codeine 130 mg/L, promethazine 68-75 mg/L, plus dihydrocodeine and cocaine impurities. dta.3116
A retrospective study by Bagian and Ward found that IM promethazine produced sedation in only <5% of astronauts during spaceflight, compared to 60–73% in ground-based subjects — a striking pharmacodynamic discrepancy attributed to microgravity-specific physiological changes rather than tolerancesupported
Retrospective study of 21 astronauts treated with IM promethazine 25-50mg during Shuttle flights. Sedation incidence <5% in space vs 60-73% on ground. pmid:9766972
NASA continues to recommend promethazine for post-symptom treatment of space motion sickness rather than prophylaxis.supported
NASA policy changed to recommend promethazine after symptom development. pmid:11541638
In Denmark, promethazine was reclassified from over-the-counter to prescription-only status in December 2014, following epidemiological data demonstrating that promethazine accounted for a disproportionate share of first-generation antihistamine poisonings, including intentional overdoses.supported
First-gen antihistamines including promethazine accounted for 61-73% of poisoning registrations. Intentional exposures 65% (82% suicide attempts). Promethazine became prescription-only in Denmark Dec 2014. bcpt.12632
This practice originated in Texas in the 1960s and gained widespread visibility through Houston hip-hop culture in the 1990s and 2000ssupported
Began in Texas 1960s-1990s. Popularized through rap culture. 02791072.2020.1797250
comparative-pharmacology5 · 4 ok
Promethazine's muscarinic Ki values (1.06–12 nM across M1–M5) place it in the highest anticholinergic burden category among first-generation antihistaminespartially supported
Promethazine had high muscarinic affinity (Ki = 5.0-38 nM). Broad range of antimuscarinic potency among antihistamines demonstrated. pmid:2884340
Claim in comparative-pharmacology — not_supportednot supportedworking →
Replacement of promethazine with more tolerable alternatives in a large psychiatric hospital (27,396 patients) was estimated to reduce QT-prolonging drug exposure by 11%.supported
Analysis of QT-prolonging drugs in 27,396 psychiatric patients. Promethazine identified as high-risk drug whose replacement could reduce QT-prolonging drug load by 11%. s00702-020-02291-y
Controlled comparison of motion sickness countermeasures ranked cognitive impairment as: meclizine < scopolamine < promethazine < lorazepamsupported
Rank order of cognitive safety: meclizine > scopolamine > promethazine > lorazepam. pmid:15451046
The most striking comparative pharmacodynamic observation is the discrepancy between ground-based and spaceflight sedation rates with IM promethazine: 60–73% on the ground versus <5% during spaceflightsupported
Sedation incidence <5% in space vs 60-73% on ground. pmid:9766972
neuroscience5 · 2 ok
Claim in neuroscience — inconclusiveinconclusiveworking →
Anticholinergic delirium. At overdose doses, the convergence of muscarinic blockade across cortical and subcortical structures produces an anticholinergic toxidrome: delirium, hallucinations (typically visual), agitation, and reality testing impairmentsupported
Describes clinical effects of promethazine in overdose and explores relationship between delirium and predictor variables. hcn153
Claim in neuroscience — inconclusiveinconclusiveworking →
Claim in neuroscience — not_supportednot supportedworking →
Microgravity pharmacodynamics. The mechanism underlying the dramatic reduction in promethazine-induced sedation during spaceflight (<5% vs 60–73% on the ground) remains unexplained. Is this a shift in H1 receptor sensitivity, altered cerebral blood flow in microgravity, vestibular-CNS interaction effects, or an entirely novel pharmacodynamic phenomenon?supported
Retrospective study of promethazine and its failure to produce the expected incidence of sedation during space flight. Sedation incidence <5% in space vs 60-73% on ground. pmid:9766972
summary5 · 5 ok
Oral bioavailability is low and highly variable (12.3–40%), but the half-life is notably long at 16–19 hours, producing subjective effects that extend well beyond the 4–6 hour peak window.partially supported
Half-life 16-19 hours. Absorption highly variable. Oral syrup Cmax 19.3 ng/mL at tmax 4.4 hours. Relative bioavailability of suppositories 70-97% but individual variability 4-343%. pmid:10965395
Oral bioavailability is low and highly variable (12.3–40%), but the half-life is notably long at 16–19 hours, producing subjective effects that extend well beyond the 4–6 hour peak window.partially supported
Absolute bioavailability of promethazine after oral dosing: 12.3-40% (distribution-free confidence interval). Measured by crossover study in 12-14 healthy volunteers using HPLC. pmid:8147942
Contemporary clinical use centers on antiemesis, sedation, and allergic conditions, while its role in NASA's space motion sickness program since 1989 has generated distinctive pharmacodynamic data.partially supported
NASA policy changed to recommend promethazine after symptom development. pmid:11541638
QT prolongation is a recognized cardiac risksupported
Promethazine identified as an old signal for TdP. 12 antihistamine TdP signals identified. Concomitant QT-prolonging drugs significantly associated with TdP events. 14740338.2021.1846717
Recreational misuse occurs primarily in the context of codeine combination syrups ("purple drank"), where promethazine potentiates opioid sedation and respiratory depressionsupported
Systematic review of 'purple drank' misuse (codeine+promethazine). Tranquilizing and euphoric effects reported. 02791072.2020.1797250
chemistry3 · 2 ok
At 0.5 mg/mL in methanol stored in darkness at low temperature, 84% of the original compound remained after 19 days; at laboratory (ambient) temperature, only 38% remained over the same periodpartially supported
Solution stability study: after 19 days at low temperature in darkness, 84% original amount retained. Temperature and light are primary stability-affecting variables. pmid:12013245
Claim in chemistry — not_supportednot supportedworking →
Chiral HPLC separation using a vancomycin-bonded stationary phase has been achievedsupported
Establishes chiral separation of promethazine enantiomers. [Title: ...vancomycin-bonded chiral stationary phase] pmid:12013245
effects-overview2 · 1 ok
Route of administration primarily affects onset speed and sedation intensity: intramuscular injection produces faster onset and higher peak sedation than oral dosing, while rectal administration is slower and more unpredictable due to extreme absorption variabilitypartially supported
Relative bioavailability of suppositories 70-97% but individual variability 4-343%. Absorption highly variable. pmid:10965395
Claim in effects-overview — not_supportednot supportedworking →
receptor-pharmacology1 · 1 ok
An earlier bovine cerebral cortex study placed muscarinic Ki in the 5.0–38 nM range, consistent with the IUPHAR data and confirming that promethazine is among the most potent antimuscarinics in the H1 antihistamine class.supported
Ki values for 27 H1-receptor antagonists at H1 and muscarinic receptors in bovine cerebral cortex. Promethazine had high muscarinic affinity (Ki = 5.0-38 nM). Broad range of antimuscarinic potency among antihistamines demonstrated. pmid:2884340