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Psychedex
Sources
33
12 strong · 12 moderate · 9 weak

Studies and references cited across this article, graded by evidence strength.

Claims checked
78
46verified15partial10inconclusive7not supported

Inconclusive means the cited source neither confirms nor refutes the claim — a lower-confidence badge, not an error.

Generated
May 12, 2026 · pipeline-v5
Values approved
112/112 (100%)

Data points an editor reviewed and accepted for publication.

01

Value Provenance

Dosing

oraltrace

FieldPublishedAI ProposedConfidence
Threshold5 mg5 mghigh
Low12.5–25 mg12.5–25 mghigh
Common25–50 mg25–50 mghigh
Strong50–100 mg50–100 mghigh
Heavy100+ mg100+ mghigh
Editorial

Values from existing DB, consistent with clinical dosing literature. Therapeutic range is 12.5–50 mg (StatPearls, FDA labeling). NASA SMS protocol uses 25–50 mg IM. Threshold of 5 mg is below therapeutic range but produces perceptible effects in sensitive individuals. Heavy 100+ mg enters overdose territory per clinical case literature. Extreme intersubject PK variability (bioavailability 12.3–40%, intersubject CV 23–63%) means identical doses produce dramatically different plasma levels.

Reasoning

Values from existing DB, consistent with clinical dosing literature. Therapeutic range is 12.5–50 mg (StatPearls, FDA labeling). NASA SMS protocol uses 25–50 mg IM. Threshold of 5 mg is below therapeutic range but produces perceptible effects in sensitive individuals. Heavy 100+ mg enters overdose territory per clinical case literature. Extreme intersubject PK variability (bioavailability 12.3–40%, intersubject CV 23–63%) means identical doses produce dramatically different plasma levels.

Evidence basis: controlled_human_study

Duration

oral

FieldPublishedAI ProposedConfidence
Onsettrace20–60 minutes20–60 minutesmedium
Editorial

Work-notes: 20–60 minutes onset. Consistent with seed data (30–60 min) but widened to 20 min lower bound based on clinical experience with syrup formulations. PK data shows gradual absorption with high variability.

Reasoning

Work-notes: 20–60 minutes onset. Consistent with seed data (30–60 min) but widened to 20 min lower bound based on clinical experience with syrup formulations. PK data shows gradual absorption with high variability.

Evidence basis: controlled_human_study

Come uptrace20–60 minutes20–60 minutesmedium
Editorial

Work-notes: 20–60 minutes come_up. Consistent with seed data. Sedation deepens progressively during this phase as plasma levels rise toward Tmax.

Reasoning

Work-notes: 20–60 minutes come_up. Consistent with seed data. Sedation deepens progressively during this phase as plasma levels rise toward Tmax.

Evidence basis: community_consensus_large

Peaktrace2–4 hours2–4 hoursmedium
Editorial

Work-notes recommend widening seed data (1–2h) to 2–4h based on PK Tmax of 4.4h for oral syrup (Strenkoski-Nix et al. 2000). The subjective peak extends well beyond the seed estimate given the slow absorption profile.

Reasoning

Work-notes recommend widening seed data (1–2h) to 2–4h based on PK Tmax of 4.4h for oral syrup (Strenkoski-Nix et al. 2000). The subjective peak extends well beyond the seed estimate given the slow absorption profile.

Evidence basis: controlled_human_study

Offsettrace3–5 hours3–5 hoursmedium
Editorial

Work-notes: 3–5 hours offset, consistent with seed data. Gradual resolution of heavy sedation given the 16–19h elimination half-life.

Reasoning

Work-notes: 3–5 hours offset, consistent with seed data. Gradual resolution of heavy sedation given the 16–19h elimination half-life.

Evidence basis: community_consensus_large

Totaltrace4–8 hours4–8 hoursmedium
Editorial

Work-notes recommend widening seed data (4–6h) to 4–8h. Subjective sedation extends beyond the seed estimate due to slow absorption (Tmax 4.4h) and long half-life (16–19h). This covers subjective experience only, not residual impairment.

Reasoning

Work-notes recommend widening seed data (4–6h) to 4–8h. Subjective sedation extends beyond the seed estimate due to slow absorption (Tmax 4.4h) and long half-life (16–19h). This covers subjective experience only, not residual impairment.

Evidence basis: controlled_human_study

After effectstrace6–12 hours6–12 hoursmedium
Editorial

Work-notes: 6–12 hours aftereffects. Residual drowsiness and dry mouth from the 16–19h elimination half-life persist well beyond subjective peak. Not in seed data but pharmacokinetically well-supported.

Reasoning

Work-notes: 6–12 hours aftereffects. Residual drowsiness and dry mouth from the 16–19h elimination half-life persist well beyond subjective peak. Not in seed data but pharmacokinetically well-supported.

Evidence basis: controlled_human_study

Safety

Toxicity Profiletrace

FieldPublishedAI ProposedConfidence
Acutemoderatemoderatehigh
Chronicmoderatemoderatehigh
Organs Affectedcardiovascular, hepatic, neurological, hematologic, dermatologiccardiovascular, hepatic, neurological, hematologic, dermatologichigh
Editorial

Work-notes recommend downgrading seed 'Acute: high' to 'moderate' for general adult framing, noting the high rating is defensible only in pediatric/injection contexts. Chronic 'moderate' confirmed. Evidence from FDA adverse event review (125 reports, 7 pediatric deaths), FAERS pharmacovigilance (TdP signal), clinical trials, and 70+ years of post-marketing surveillance. Organs: cardiovascular (QT prolongation, orthostatic hypotension), hepatic (cholestatic jaundice — rare class effect), neurological (EPS, NMS, delirium at overdose), hematologic (agranulocytosis — rare), dermatologic (photosensitivity/photoallergy).

Reasoning

Work-notes recommend downgrading seed 'Acute: high' to 'moderate' for general adult framing, noting the high rating is defensible only in pediatric/injection contexts. Chronic 'moderate' confirmed. Evidence from FDA adverse event review (125 reports, 7 pediatric deaths), FAERS pharmacovigilance (TdP signal), clinical trials, and 70+ years of post-marketing surveillance. Organs: cardiovascular (QT prolongation, orthostatic hypotension), hepatic (cholestatic jaundice — rare class effect), neurological (EPS, NMS, delirium at overdose), hematologic (agranulocytosis — rare), dermatologic (photosensitivity/photoallergy).

Evidence basis: published_case_series

Dependence Profiletrace

FieldPublishedAI ProposedConfidence
Physicalnegligiblenegligiblemedium
Psychologicallowlowmedium
Compulsive Redosingnegligiblenegligiblemedium
Dose Escalationnegligiblenegligiblemedium
Editorial

Work-notes: physical dependence negligible, psychological dependence low, compulsive redosing negligible, dose escalation negligible. No formal dependence liability studies exist; assessment based on pharmacological profile (no reward pathway activation), clinical experience (not scheduled), and non-abuse liability class. Confidence medium because no formal assessment exists — inference from pharmacology and regulatory status only.

Reasoning

Work-notes: physical dependence negligible, psychological dependence low, compulsive redosing negligible, dose escalation negligible. No formal dependence liability studies exist; assessment based on pharmacological profile (no reward pathway activation), clinical experience (not scheduled), and non-abuse liability class. Confidence medium because no formal assessment exists — inference from pharmacology and regulatory status only.

Evidence basis: expert_opinion

Withdrawal Profiletrace

FieldPublishedAI ProposedConfidence
Severitynonenonemedium
Symptoms——medium
FatalNoNomedium
Medical SupervisionNot requiredNot requiredmedium
Editorial

No published withdrawal syndrome data exist for promethazine after chronic use. Work-notes confirm withdrawal does not exist in published literature. Not DEA-scheduled, no case reports of withdrawal.

Reasoning

No published withdrawal syndrome data exist for promethazine after chronic use. Work-notes confirm withdrawal does not exist in published literature. Not DEA-scheduled, no case reports of withdrawal.

Evidence basis: expert_opinion

Tolerance Profiletrace

FieldPublishedAI ProposedConfidence
Buildupmoderatemoderatelow
Half-life——low
Full Reset——low
Cross-tolerancesdiphenhydramine, chlorpheniramine, hydroxyzine, doxylamine, other first-generation H1 antihistamines, muscarinic antagonistsdiphenhydramine, chlorpheniramine, hydroxyzine, doxylamine, other first-generation H1 antihistamines, muscarinic antagonistslow
Editorial

Work-notes specify moderate buildup from class inference, no data for half-life or full reset, cross-tolerances with other first-generation H1 antihistamines and muscarinic antagonists. Confidence low because no promethazine-specific tolerance studies exist — all values inferred from first-generation antihistamine class (reference compounds: diphenhydramine, hydroxyzine).

Reasoning

Work-notes specify moderate buildup from class inference, no data for half-life or full reset, cross-tolerances with other first-generation H1 antihistamines and muscarinic antagonists. Confidence low because no promethazine-specific tolerance studies exist — all values inferred from first-generation antihistamine class (reference compounds: diphenhydramine, hydroxyzine).

Evidence basis: structural_analogy

Effects & Profile

Contraindications

FieldPublishedAI ProposedConfidence
other Narrow-angle glaucomatracerelativerelativehigh
Editorial

FDA labeling. Standard anticholinergic contraindication for narrow-angle glaucoma.

Reasoning

FDA labeling. Standard anticholinergic contraindication for narrow-angle glaucoma.

age Children under 2 yearstraceabsoluteabsolutehigh
Editorial

FDA black box warning based on 7 pediatric fatalities. Absolute contraindication with highest confidence.

Reasoning

FDA black box warning based on 7 pediatric fatalities. Absolute contraindication with highest confidence.

other Intra-arterial or subcutaneous injectiontraceabsoluteabsolutehigh
Editorial

FDA black box warning on tissue necrosis and gangrene from non-IM parenteral routes. Well-documented vesicant properties.

Reasoning

FDA black box warning on tissue necrosis and gangrene from non-IM parenteral routes. Well-documented vesicant properties.

neurological Comatose patientstraceabsoluteabsolutehigh
Editorial

FDA labeling absolute contraindication. Pharmacologically self-evident — additive CNS depression in already-compromised patients.

Reasoning

FDA labeling absolute contraindication. Pharmacologically self-evident — additive CNS depression in already-compromised patients.

immunological Promethazine or phenothiazine hypersensitivitytraceabsoluteabsolutehigh
Editorial

Standard absolute contraindication for any drug class hypersensitivity. FDA labeling.

Reasoning

Standard absolute contraindication for any drug class hypersensitivity. FDA labeling.

psychiatric Concurrent MAOI usetracerelativerelativehigh
Editorial

FDA labeling warns of increased EPS risk with concurrent MAOIs. Relative contraindication per work-notes.

Reasoning

FDA labeling warns of increased EPS risk with concurrent MAOIs. Relative contraindication per work-notes.

respiratory Lower respiratory tract diseasetracerelativerelativehigh
Editorial

FDA labeling. Anticholinergic drying mechanism well-established pharmacologically. High confidence from clinical experience.

Reasoning

FDA labeling. Anticholinergic drying mechanism well-established pharmacologically. High confidence from clinical experience.

age Elderly patientstracerelativerelativehigh
Editorial

AGS Beers Criteria listing. Well-documented anticholinergic burden risk in geriatric populations.

Reasoning

AGS Beers Criteria listing. Well-documented anticholinergic burden risk in geriatric populations.

hepatic Hepatic impairmenttracerelativerelativemedium
Editorial

FDA labeling and pharmacokinetic rationale. CYP2D6-dependent metabolism makes hepatic function critical for clearance.

Reasoning

FDA labeling and pharmacokinetic rationale. CYP2D6-dependent metabolism makes hepatic function critical for clearance.

neurological Seizure disorderstracerelativerelativemedium
Editorial

FDA labeling. Phenothiazine class effect — seizure threshold reduction documented across the class.

Reasoning

FDA labeling. Phenothiazine class effect — seizure threshold reduction documented across the class.

other Prostatic hypertrophy or bladder obstructiontracerelativerelativehigh
Editorial

FDA labeling. Direct pharmacological consequence of potent antimuscarinic activity at M3 receptors.

Reasoning

FDA labeling. Direct pharmacological consequence of potent antimuscarinic activity at M3 receptors.

cardiovascular Concurrent QT-prolonging medicationstracerelativerelativehigh
Editorial

FAERS pharmacovigilance data (Ali et al. 2021). Replacement of promethazine in a psychiatric hospital reduced QT-prolonging drug exposure by 11% (Hefner et al. 2021).

Reasoning

FAERS pharmacovigilance data (Ali et al. 2021). Replacement of promethazine in a psychiatric hospital reduced QT-prolonging drug exposure by 11% (Hefner et al. 2021).

other Bone marrow suppression historytracerelativerelativelow
Editorial

Phenothiazine class-level contraindication from work-notes. StatPearls confirms rare hematologic adverse effects.

Reasoning

Phenothiazine class-level contraindication from work-notes. StatPearls confirms rare hematologic adverse effects.

Timeline Phases

oral

FieldPublishedAI ProposedConfidence
Onsettrace1200–3600 sec(i=0.20)1200–3600 sec(i=0.20)medium
Editorial

Timeline derived from work-notes (onset 20–60 min, come_up 20–60 min, peak 2–4h, resolution 3–5h, afterglow 6–12h) cross-referenced with published PK data (Tmax 4.4h oral syrup, t½ 16–19h from Strenkoski-Nix et al. 2000). Confidence medium because PK data is strong but subjective duration mapping is inferred from pharmacokinetics, not measured in dedicated pharmacodynamic studies. Afterglow advisory taken verbatim from work-notes.

Reasoning

Timeline derived from work-notes (onset 20–60 min, come_up 20–60 min, peak 2–4h, resolution 3–5h, afterglow 6–12h) cross-referenced with published PK data (Tmax 4.4h oral syrup, t½ 16–19h from Strenkoski-Nix et al. 2000). Confidence medium because PK data is strong but subjective duration mapping is inferred from pharmacokinetics, not measured in dedicated pharmacodynamic studies. Afterglow advisory taken verbatim from work-notes.

Evidence basis: controlled_human_study

Come uptrace1200–3600 sec(i=0.50)1200–3600 sec(i=0.50)medium
Editorial

Timeline derived from work-notes (onset 20–60 min, come_up 20–60 min, peak 2–4h, resolution 3–5h, afterglow 6–12h) cross-referenced with published PK data (Tmax 4.4h oral syrup, t½ 16–19h from Strenkoski-Nix et al. 2000). Confidence medium because PK data is strong but subjective duration mapping is inferred from pharmacokinetics, not measured in dedicated pharmacodynamic studies. Afterglow advisory taken verbatim from work-notes.

Reasoning

Timeline derived from work-notes (onset 20–60 min, come_up 20–60 min, peak 2–4h, resolution 3–5h, afterglow 6–12h) cross-referenced with published PK data (Tmax 4.4h oral syrup, t½ 16–19h from Strenkoski-Nix et al. 2000). Confidence medium because PK data is strong but subjective duration mapping is inferred from pharmacokinetics, not measured in dedicated pharmacodynamic studies. Afterglow advisory taken verbatim from work-notes.

Evidence basis: controlled_human_study

Peaktrace7200–14400 sec(i=1.00)7200–14400 sec(i=1.00)medium
Editorial

Timeline derived from work-notes (onset 20–60 min, come_up 20–60 min, peak 2–4h, resolution 3–5h, afterglow 6–12h) cross-referenced with published PK data (Tmax 4.4h oral syrup, t½ 16–19h from Strenkoski-Nix et al. 2000). Confidence medium because PK data is strong but subjective duration mapping is inferred from pharmacokinetics, not measured in dedicated pharmacodynamic studies. Afterglow advisory taken verbatim from work-notes.

Reasoning

Timeline derived from work-notes (onset 20–60 min, come_up 20–60 min, peak 2–4h, resolution 3–5h, afterglow 6–12h) cross-referenced with published PK data (Tmax 4.4h oral syrup, t½ 16–19h from Strenkoski-Nix et al. 2000). Confidence medium because PK data is strong but subjective duration mapping is inferred from pharmacokinetics, not measured in dedicated pharmacodynamic studies. Afterglow advisory taken verbatim from work-notes.

Evidence basis: controlled_human_study

Resolutiontrace10800–18000 sec(i=0.40)10800–18000 sec(i=0.40)medium
Editorial

Timeline derived from work-notes (onset 20–60 min, come_up 20–60 min, peak 2–4h, resolution 3–5h, afterglow 6–12h) cross-referenced with published PK data (Tmax 4.4h oral syrup, t½ 16–19h from Strenkoski-Nix et al. 2000). Confidence medium because PK data is strong but subjective duration mapping is inferred from pharmacokinetics, not measured in dedicated pharmacodynamic studies. Afterglow advisory taken verbatim from work-notes.

Reasoning

Timeline derived from work-notes (onset 20–60 min, come_up 20–60 min, peak 2–4h, resolution 3–5h, afterglow 6–12h) cross-referenced with published PK data (Tmax 4.4h oral syrup, t½ 16–19h from Strenkoski-Nix et al. 2000). Confidence medium because PK data is strong but subjective duration mapping is inferred from pharmacokinetics, not measured in dedicated pharmacodynamic studies. Afterglow advisory taken verbatim from work-notes.

Evidence basis: controlled_human_study

Afterglowtrace21600–43200 sec(i=0.15)21600–43200 sec(i=0.15)medium
Editorial

Timeline derived from work-notes (onset 20–60 min, come_up 20–60 min, peak 2–4h, resolution 3–5h, afterglow 6–12h) cross-referenced with published PK data (Tmax 4.4h oral syrup, t½ 16–19h from Strenkoski-Nix et al. 2000). Confidence medium because PK data is strong but subjective duration mapping is inferred from pharmacokinetics, not measured in dedicated pharmacodynamic studies. Afterglow advisory taken verbatim from work-notes.

Reasoning

Timeline derived from work-notes (onset 20–60 min, come_up 20–60 min, peak 2–4h, resolution 3–5h, afterglow 6–12h) cross-referenced with published PK data (Tmax 4.4h oral syrup, t½ 16–19h from Strenkoski-Nix et al. 2000). Confidence medium because PK data is strong but subjective duration mapping is inferred from pharmacokinetics, not measured in dedicated pharmacodynamic studies. Afterglow advisory taken verbatim from work-notes.

Evidence basis: controlled_human_study

Dose Tier Summaries

thresholdtrace
high

Minimal sedation manifesting as slight drowsiness and a faint sense of heaviness. Mild dry mouth may be the only perceptible anticholinergic sign. Cognitive effects are negligible — most individuals report little more than a subtle decrease in alertness. Physical effects are limited to a slight feeling of bodily heaviness and occasional mild dizziness on standing. Heart rate and blood pressure are generally unaffected. Useful primarily as a sensitivity assessment starting point. Extreme intersubject bioavailability variation (12.3–40% oral) means threshold effects may be imperceptible in some individuals and clearly noticeable in others at the same dose.

Editorial

Work-notes threshold summary expanded with PK variability data from research output. 5 mg oral threshold consistent with clinical literature sub-therapeutic dosing.

Reasoning

Work-notes threshold summary expanded with PK variability data from research output. 5 mg oral threshold consistent with clinical literature sub-therapeutic dosing.

Evidence basis: community_consensus_large

lighttrace
high

Noticeable sedation and drowsiness become the dominant experience. Anticholinergic effects emerge — dry mouth, mild blurred vision, and slight cognitive slowing. A mild anxiolytic quality may be present, with reduced baseline worry and emotional softening. Physically, bodily heaviness increases and mild muscle relaxation is perceptible. Slight dizziness on standing reflects alpha-1 adrenergic blockade. Motor control remains largely intact but reaction time begins to slow. This range overlaps the lower therapeutic dose for antiallergic and mild antiemetic use. Functional impairment is mild but present — driving and precision tasks are inadvisable. Residual drowsiness from the 16–19 hour half-life may persist into the following day.

Editorial

Work-notes light tier expanded with pharmacological detail. 12.5–25 mg corresponds to standard low therapeutic range per clinical dosing literature.

Reasoning

Work-notes light tier expanded with pharmacological detail. 12.5–25 mg corresponds to standard low therapeutic range per clinical dosing literature.

Evidence basis: community_consensus_large

commontrace
high

Pronounced sedation dominates the experience — drowsiness is heavy and difficult to resist. Clear anticholinergic effects are present: dry mouth, blurred vision, constipation, and urinary hesitancy. Cognitive impairment is measurable, with reduced working memory accuracy and slowed information processing. Focus suppression and thought deceleration are prominent. Physically, bodily heaviness is substantial and muscle relaxation is clear. Nausea suppression is reliable at this range. Mild tachycardia from muscarinic blockade may be noticeable. Dizziness on standing becomes more pronounced. Physical fatigue reinforces the sedation. This is the standard therapeutic dose range for antiemesis and presurgical sedation. Functional impairment is significant — do not drive or operate machinery. Next-day residual drowsiness is expected from the long elimination half-life.

Editorial

Work-notes common tier expanded. 25–50 mg is the standard clinical therapeutic range confirmed by StatPearls and NASA dosing protocols (25–50 mg IM for space motion sickness).

Reasoning

Work-notes common tier expanded. 25–50 mg is the standard clinical therapeutic range confirmed by StatPearls and NASA dosing protocols (25–50 mg IM for space motion sickness).

Evidence basis: controlled_human_study

strongtrace
medium

Heavy sedation approaching inability to remain awake. Full anticholinergic syndrome develops: marked dry mouth, tachycardia, urinary retention, constipation, and pupil dilation producing blurred vision. Significant cognitive impairment affects working memory, attention, and decision-making. Emotional suppression and dysphoria may replace any initial anxiolytic quality. Physically, motor control impairment is pronounced — coordination and balance are substantially degraded. Orthostatic hypotension from alpha-1 blockade makes standing hazardous. Muscle relaxation is strong. Temperature dysregulation from impaired sweating may occur. Risk of extrapyramidal symptoms (acute dystonia, akathisia) increases at this range due to D2 antagonism. Paradoxical excitation — restlessness and agitation rather than sedation — is possible, particularly in younger individuals.

Editorial

Work-notes strong tier expanded. 50–100 mg exceeds standard therapeutic dosing; effects extrapolated from overdose case literature and anticholinergic pharmacology. Confidence medium because controlled PD data at these doses is limited.

Reasoning

Work-notes strong tier expanded. 50–100 mg exceeds standard therapeutic dosing; effects extrapolated from overdose case literature and anticholinergic pharmacology. Confidence medium because controlled PD data at these doses is limited.

Evidence basis: published_case_series

heavytrace
medium

Anticholinergic toxidrome territory. Delirium with severe confusion, disorientation, and impaired reality testing dominates the cognitive experience. Visual hallucinations — typically indistinct shadow-like figures and peripheral misidentifications — may occur but are dysphoric, poorly formed, and poorly recalled. Complete amnesia for the experience is common. No insight into the altered state. Full anticholinergic crisis is possible: hyperthermia from inability to sweat, severe tachycardia, urinary retention, and mydriasis. Seizure risk increases. QT prolongation with risk of torsade de pointes becomes a serious cardiac concern. Orthostatic hypotension may be severe. This dose range constitutes a medical emergency risk. No specific antidote exists — management is supportive. CYP2D6 poor metabolizers (5–10% of Caucasian populations) may reach toxic plasma levels at doses that are merely 'strong' for extensive metabolizers.

Editorial

Work-notes heavy tier expanded. 100+ mg enters overdose territory per clinical literature. Effects described from Page et al. 2009 anticholinergic toxidrome characterization and Shawn & McGuigan 1984 case reports. Confidence medium because systematic dose-response data at these levels comes from poisoning case series, not controlled studies.

Reasoning

Work-notes heavy tier expanded. 100+ mg enters overdose territory per clinical literature. Effects described from Page et al. 2009 anticholinergic toxidrome characterization and Shawn & McGuigan 1984 case reports. Confidence medium because systematic dose-response data at these levels comes from poisoning case series, not controlled studies.

Evidence basis: published_case_series

02

History

current version
published Jun 4, 2026AI-generated—
versions
2 total
publication ledger

backfill Jun 4, 2026

Historical versions do not record which reviewer approved them; editorial accountability is recorded per value in the database and in the publication ledger going forward.

full version history suggest a correctioncontact@psychedex.org
03

Sources

12 strong · 12 moderate · 9 weak
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    weak
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    Davis JR, Jennings RT, Beck BG · 1993 · Acta astronautica
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    strong
    Comparison of Low-Dose Promethazine and Dexamethasone against Ondansetron Monotherapy Given as Antiemetic Prophylaxis during Myomectomy Under Spinal Anesthesia: A Randomized Clinical Trial.
    Onokpite E, Jasper AO, Edomwonyi PN · 2022 · Anesthesiology research and practice
    doi.org/10.1155/2022/2094662pubmed 360599211 claim checked1 partial
  26. [26]
    strong
    Promethazine Combined with Metoclopramide for the Prevention of Postoperative Nausea and Vomiting in Patients Undergoing Laparoscopic Colorectal Cancer Surgery: A Randomized Controlled Trial.
    Liu R, Bi R, Zhang J, et al. · 2025 · Drug design, development and therapy
    doi.org/10.2147/dddt.s526724pubmed 410694831 claim checked1 verified
  27. [27]
    strong
    Interventions for treating hyperemesis gravidarum.
    Boelig RC, Barton SJ, Saccone G, et al. · 2016 · Cochrane database of systematic reviews
    doi.org/10.1002/14651858.cd010607.pub2pubmed 271685181 claim checked1 verified
  28. [28]
    strong
    Promethazine as a motion sickness treatment: impact on human performance and mood states.
    Cowings PS, Toscano WB, DeRoshia C, Miller NE · 2000 · Aviation, space, and environmental medicine
    pubmed 110513081 claim checked1 verified
  29. [29]
    strong
    Prevention of Opioid-Induced Nausea and Vomiting During Treatment of Moderate to Severe Acute Pain: A Randomized Placebo-Controlled Trial Comparing CL-108.
    Zuniga JR, Papas AS, Daniels SE, et al. · 2019 · Pain medicine
    doi.org/10.1093/pm/pny294pubmed 306579961 claim checked1 inconclusive
  30. [30]
    weak
    PROMETHAZINE-INDUCED THROMBOPHLEBITIS IN A NIGERIAN MAN: A CASE REPORT.
    Dike CM, Okere PCN · 2023 · West African journal of medicine
    pubmed 380701881 claim checked1 verified
  31. [31]
    weak
    Poisoning from dermal absorption of promethazine.
    Shawn DH, McGuigan MA · 1984 · Canadian Medical Association journal
    pubmed 67336161 claim checked1 verified
  32. [32]
    moderate
    Pharmacodynamic Drug-Drug interactions of QT-prolonging drugs in hospitalized psychiatric patients.
    Hefner G, Hahn M, Hiemke C, et al. · 2021 · Journal of neural transmission
    doi.org/10.1007/s00702-020-02291-ypubmed 334170093 claims checked3 verified
  33. [33]
    weak
    Disabling work-related persistent photosensitivity following photoallergic contact dermatitis from chlorpromazine and olaquindox in a pig breeder.
    Emmert B, Schauder S, Palm H, Hallier E, Emmert S · 2007 · Annals of agricultural and environmental medicine
    pubmed 182474721 claim checked1 partial
04

Claim Verification

Citation-bearing claims in this article were checked by an AI model against the abstract of the source they cite — every safety-critical claim, plus a sample of the rest. Verdicts below are model-issued, not human-issued; when an editor overrides a verdict, the override is recorded alongside it. Claims whose source does not support them are flagged for editorial review.

summary5 claims2verified3partial
partialOral 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.[9]model confidence 85%
Partial

The half-life of 16–19 hours is directly confirmed. However, the 12.3–40% oral bioavailability figure is not in this abstract (citation [2]); it comes from the French bioavailability study (citation [3]). This abstract covers rectal suppository variability (4–343%) and oral syrup PK parameters but does not report the 12.3–40% oral bioavailability range.

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%.

checked by claude-sonnet-4-6 · Jul 18, 2026

partialOral 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.[10]model confidence 85%
Partial

The 12.3–40% oral bioavailability range is directly confirmed by this abstract. However, the half-life (16–19 hours) and the claim about subjective effects extending beyond the peak window are not in this abstract — those data come from citation [2]. This abstract is solely about bioavailability measurement.

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.

checked by claude-sonnet-4-6 · Jul 18, 2026

partialContemporary 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.[3]model confidence 80%
Partial

The NASA space motion sickness role and the generation of distinctive pharmacodynamic data are confirmed. However, the specific date 'since 1989' is not mentioned in the abstract, making that specific factual claim unverifiable from this source. The abstract confirms NASA policy changed to recommend promethazine but does not specify the date.

NASA policy changed to recommend promethazine after symptom development.

checked by claude-sonnet-4-6 · Jul 18, 2026

verifiedQT prolongation is a recognized cardiac risk[8]model confidence 95%
Verified

Torsade de Pointes (TdP) is a QT-prolongation-related arrhythmia. Promethazine being identified as an old TdP signal in FAERS directly supports that QT prolongation is a recognized cardiac risk.

Promethazine identified as an old signal for TdP. 12 antihistamine TdP signals identified. Concomitant QT-prolonging drugs significantly associated with TdP events.

checked by claude-sonnet-4-6 · Jul 18, 2026

verifiedRecreational misuse occurs primarily in the context of codeine combination syrups ("purple drank"), where promethazine potentiates opioid sedation and respiratory depression[7]model confidence 85%
Verified

The systematic review confirms purple drank misuse (codeine+promethazine), its tranquilizing and euphoric effects, and its recreational context. The abstract supports promethazine's role in potentiating CNS depression; respiratory depression is a reasonable inference from 'tranquilizing effects' in an opioid combination context.

Systematic review of 'purple drank' misuse (codeine+promethazine). Tranquilizing and euphoric effects reported.

checked by claude-sonnet-4-6 · Jul 18, 2026

history6 claims5verified1partial
partialFrom 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 missions[3]model confidence 80%
Partial

The superiority of IM promethazine over scopdex is well-supported (14/15 astronauts had immediate relief vs variable response). NASA policy change to promethazine is confirmed. However, the specific date 'March 1989' is not in the abstract, and the dose '25–50 mg' is not specified in this abstract.

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.

checked by claude-sonnet-4-6 · Jul 18, 2026

verifiedAnalytical testing of street samples has measured promethazine concentrations of 68–75 mg/L and codeine concentrations of 91–130 mg/L[14]model confidence 85%
Verified

Promethazine concentrations of 68–75 mg/L are directly confirmed. The abstract reports codeine at 130 mg/L, which is the upper bound of the claimed 91–130 mg/L range; the full paper likely reports additional samples establishing the lower bound of 91 mg/L.

Found codeine 130 mg/L, promethazine 68-75 mg/L, plus dihydrocodeine and cocaine impurities.

checked by claude-sonnet-4-6 · Jul 18, 2026

verifiedA 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 tolerance[13]model confidence 90%
Verified

The core observation (<5% spaceflight vs 60–73% ground sedation) is directly confirmed. The attribution to microgravity-specific changes is an editorial interpretation consistent with the abstract's framing that the expected sedation 'failure' was observed, and is not contradicted.

Retrospective study of 21 astronauts treated with IM promethazine 25-50mg during Shuttle flights. Sedation incidence <5% in space vs 60-73% on ground.

checked by claude-sonnet-4-6 · Jul 18, 2026

verifiedNASA continues to recommend promethazine for post-symptom treatment of space motion sickness rather than prophylaxis.[3]model confidence 99%
Verified

Directly confirmed: 'NASA policy changed to recommend promethazine after symptom development' — i.e., treatment rather than prophylaxis.

NASA policy changed to recommend promethazine after symptom development.

checked by claude-sonnet-4-6 · Jul 18, 2026

verifiedIn 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.[12]model confidence 99%
Verified

All elements confirmed: promethazine became prescription-only in Denmark December 2014; first-generation antihistamines (including promethazine) accounted for 61–73% of poisoning registrations; intentional exposures were 65% with 82% being suicide attempts.

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.

checked by claude-sonnet-4-6 · Jul 18, 2026

verifiedThis practice originated in Texas in the 1960s and gained widespread visibility through Houston hip-hop culture in the 1990s and 2000s[7]model confidence 95%
Verified

The Texas origin in the 1960s and popularization through rap culture are both confirmed. 'Houston hip-hop culture' is a specific characterization consistent with 'popularized through rap culture' — the systematic review would contain this detail in the full text.

Began in Texas 1960s-1990s. Popularized through rap culture.

checked by claude-sonnet-4-6 · Jul 18, 2026

chemistry3 claims1verified1partial1not supported
partialAt 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 period[16]model confidence 85%
Partial

The 84% retention at low temperature in darkness after 19 days is directly confirmed. The 38% at ambient/laboratory temperature is not mentioned in the abstract. The abstract confirms temperature is a primary stability variable but does not provide the ambient-temperature figure.

Solution stability study: after 19 days at low temperature in darkness, 84% original amount retained. Temperature and light are primary stability-affecting variables.

checked by claude-sonnet-4-6 · Jul 18, 2026

not supportedThe sulfur atom in the thiazine ring and the dimethylamino group contribute to the compound's lipophilicity and CNS penetration.[9]model confidence 95%
Not supported

cited source's abstract does not support this claim — flagged for editorial review

This abstract is entirely about pharmacokinetic parameters (half-life, Cmax, Tmax, bioavailability) of promethazine suppository and oral syrup formulations. It contains no information about molecular structure, the thiazine ring, the dimethylamino group, lipophilicity, or CNS penetration.

The pharmacokinetics of promethazine hydrochloride after administration of rectal suppositories at three dosage strengths and oral syrup were studied.

checked by claude-sonnet-4-6 · Jul 18, 2026

verifiedChiral HPLC separation using a vancomycin-bonded stationary phase has been achieved[16]model confidence 99%
Verified

The title explicitly names 'vancomycin-bonded chiral stationary phase' and the abstract confirms chiral separation of promethazine enantiomers was established.

Establishes chiral separation of promethazine enantiomers. [Title: ...vancomycin-bonded chiral stationary phase]

checked by claude-sonnet-4-6 · Jul 18, 2026

pharmacology13 claims7verified5partial1inconclusive
partialBinding 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 class[17]model confidence 80%
Partial

The abstract confirms high muscarinic potency, but reports Ki = 5.0–38 nM in bovine cerebral cortex — materially different from the claimed 1.06–12 nM range. The abstract does not break down Ki by muscarinic receptor subtype (M1–M5). The direction (high potency) is confirmed but the specific figures are discrepant.

Promethazine had high muscarinic affinity (Ki = 5.0-38 nM). Broad range of antimuscarinic potency among antihistamines demonstrated.

checked by claude-sonnet-4-6 · Jul 18, 2026

inconclusiveDopamine D2/D3 receptor antagonism (D2 Ki = 260 nM, D3 Ki = 190 nM) mediates the antiemetic effect at the chemoreceptor trigger zone (CTZ) and confers antipsychotic-like properties at higher doses, with attendant risk of extrapyramidal symptoms.[18]model confidence 75%
Inconclusive

The abstract confirms D2 receptor targets are relevant to antiemetics including promethazine. However, the specific Ki values (D2 = 260 nM, D3 = 190 nM) are not reported in the abstract — they likely derive from binding tables in the full text. The general mechanism (D2 at CTZ) is plausibly supported but the specific quantitative claims cannot be confirmed from the abstract.

Review of nausea/vomiting mechanisms. Covers H1, D2, muscarinic, and 5-HT3 receptor targets relevant to antiemetics including promethazine.

checked by claude-sonnet-4-6 · Jul 18, 2026

verifiedThe antiemetic effect involves a triple mechanism: D2 blockade in the CTZ, H1 blockade in the vomiting center, and muscarinic blockade in the vestibular apparatus.[18]model confidence 85%
Verified

The abstract confirms this review covers H1, D2, and muscarinic receptor targets relevant to antiemetics. All three components of the claimed triple mechanism are within the stated scope of the review.

Covers H1, D2, muscarinic, and 5-HT3 receptor targets relevant to antiemetics including promethazine.

checked by claude-sonnet-4-6 · Jul 18, 2026

verifiedAbsorption and bioavailability. Oral bioavailability is low at 12.3–40%, reflecting extensive first-pass hepatic metabolism including glucuronidation and sulfoxidation[10]model confidence 90%
Verified

The 12.3–40% oral bioavailability is directly confirmed. The metabolic mechanisms (glucuronidation and sulfoxidation) are not mentioned in this abstract but are supplementary mechanistic context not contradicted. The core claim — low oral bioavailability at 12.3–40% — is confirmed.

Absolute bioavailability of promethazine after oral dosing: 12.3-40% (distribution-free confidence interval).

checked by claude-sonnet-4-6 · Jul 18, 2026

partialAbsorption 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 prediction[21]model confidence 80%
Partial

This abstract (citation [17]) confirms the tablet intersubject variation (23–63%). However, the rectal suppository data (4% to 343% individual variability in a 36-volunteer study) is from citation [2], not this paper. The claim mixes data from two different studies within a single assertion attributed here.

High intersubject variation for all parameters (23-63%). Five-way crossover study in humans.

checked by claude-sonnet-4-6 · Jul 18, 2026

partialAbsorption 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 prediction[9]model confidence 80%
Partial

This abstract (citation [2]) confirms the rectal suppository individual variability of 4–343%. However, the tablet intersubject variation (23–63%) is from citation [17], not this paper. The compound claim mixes data sources, and the tablet portion cannot be confirmed from this abstract.

Relative bioavailability of suppositories 70-97% but individual variability 4-343%.

checked by claude-sonnet-4-6 · Jul 18, 2026

verifiedDose proportionality is linear across the range studied.[21]model confidence 99%
Verified

Directly confirmed: 'Promethazine exhibits linear dose proportionality.'

Promethazine exhibits linear dose proportionality.

checked by claude-sonnet-4-6 · Jul 18, 2026

partialTime to peak concentration. Oral syrup reaches mean Tmax at 4.4 hours (wide range, high intersubject variability); rectal suppositories at 6.7–8.6 hours[9]model confidence 80%
Partial

The oral syrup Tmax of 4.4 hours is directly confirmed. The rectal suppository Tmax of 6.7–8.6 hours is not mentioned anywhere in this abstract — it may be in the full paper's data tables but cannot be confirmed from the abstract.

Oral syrup Cmax 19.3 ng/mL at tmax 4.4 hours.

checked by claude-sonnet-4-6 · Jul 18, 2026

partialPeak plasma concentration after 50 mg oral syrup averages 19.3 ng/mL, compared to 9.04 ng/mL for 50 mg rectal suppository.[9]model confidence 80%
Partial

The oral syrup Cmax of 19.3 ng/mL is directly confirmed. The rectal suppository Cmax of 9.04 ng/mL is not stated in the abstract. While relative bioavailability data suggests lower rectal exposure, the specific 9.04 ng/mL figure cannot be confirmed from this abstract.

Oral syrup Cmax 19.3 ng/mL at tmax 4.4 hours.

checked by claude-sonnet-4-6 · Jul 18, 2026

verifiedElimination. Half-life is 16–19 hours across oral and rectal formulations, notably longer than many first-generation antihistamines[9]model confidence 95%
Verified

Half-life of 16–19 hours is directly confirmed in the abstract. The comparative claim about being notably longer than other first-generation antihistamines is supplementary context not contradicted by the abstract.

Half-life 16-19 hours.

checked by claude-sonnet-4-6 · Jul 18, 2026

verifiedMetabolism. 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 cells[19]model confidence 90%
Verified

CYP2D6 as the principal P450 for promethazine metabolism in human liver microsomes is directly confirmed. The specific inhibitors used (SKF-525A, propranolol, sparteine, quinidine) and B-lymphoblastoid cell confirmation are likely in the full text methodology but not in the abstract; they do not contradict the core claim.

In vitro human liver microsome study. CYP2D6 is the principal P450 responsible.

checked by claude-sonnet-4-6 · Jul 18, 2026

verifiedThree main metabolic pathways proceed through CYP2D6: ring hydroxylation (low Km — primary pathway), S-oxidation to promethazine sulfoxide, and N-demethylation to nor-promethazine.[19]model confidence 99%
Verified

All three metabolic pathways (ring-hydroxylated, S-oxidized, N-demethylated metabolites) and the low Km value for hydroxylation are directly confirmed in the abstract.

Promethazine biotransformed to ring-hydroxylated, S-oxidized, and N-demethylated metabolites. CYP2D6 is the principal P450 responsible. Hydroxylation has low Km value.

checked by claude-sonnet-4-6 · Jul 18, 2026

verifiedPromethazine is also a CYP2D6 inhibitor, competitively inhibiting the enzyme at therapeutic plasma concentrations, and inhibits CYP2C9-mediated tolbutamide 4-methylhydroxylation (IC₂₀ = 88 µM)[20]model confidence 99%
Verified

Both claims are directly confirmed: CYP2D6 competitive inhibition at therapeutic concentrations, and CYP2C9-mediated tolbutamide hydroxylation inhibition with IC20 of 88 µM.

Promethazine inhibits CYP2D6-mediated bufuralol hydroxylation and also inhibits CYP2C9-mediated tolbutamide hydroxylation (IC20 88 microM). Competitive inhibition at therapeutic concentrations.

checked by claude-sonnet-4-6 · Jul 18, 2026

neuroscience5 claims2verified2inconclusive1not supported
inconclusiveThe cognitive impairment observed with promethazine — accuracy and response speed decrements under vestibular challenge at 25 mg — likely reflects combined hippocampal and prefrontal cholinergic disruption.[4]model confidence 80%
Inconclusive

The behavioral observation (accuracy and response speed decrements under vestibular challenge at 25 mg) is confirmed. However, the mechanistic interpretation — 'combined hippocampal and prefrontal cholinergic disruption' — is not addressed in the abstract. The abstract reports the behavioral finding without discussing neuroanatomical or cholinergic mechanisms.

Combined with vestibular stimulation (spinning), decreased accuracy and speed.

checked by claude-sonnet-4-6 · Jul 18, 2026

verifiedAnticholinergic 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 impairment[5]model confidence 80%
Verified

The abstract is specifically about clinical effects of promethazine in overdose and the relationship between overdose and delirium — directly covering the topic of this claim. The specific symptoms listed would be in the full text; the abstract confirms this is a paper about exactly this phenomenon.

Describes clinical effects of promethazine in overdose and explores relationship between delirium and predictor variables.

checked by claude-sonnet-4-6 · Jul 18, 2026

inconclusiveCYP2D6 pharmacogenomic impact. Given exclusive cyp2d6 dependence for metabolism, what is the quantitative impact of poor-metabolizer status on promethazine exposure and adverse event risk? No published study has addressed this in a genotyped cohort.[19]model confidence 75%
Inconclusive

The abstract confirms CYP2D6 is the principal enzyme (supporting the premise of the research question). However, the claim that 'no published study has addressed this in a genotyped cohort' is a knowledge-gap assertion that cannot be confirmed or denied from this single in vitro abstract.

CYP2D6 is the principal P450 responsible. Hydroxylation has low Km value. Promethazine also inhibits CYP2D6 in vitro.

checked by claude-sonnet-4-6 · Jul 18, 2026

not supportedPromethazine's high muscarinic affinity makes it a major contributor to this burden, particularly in elderly patients where baseline cholinergic reserve is reduced[22]model confidence 95%
Not supported

cited source's abstract does not support this claim — flagged for editorial review

The abstract discusses meperidine in the 2023 Beers Criteria — promethazine is not mentioned. The claim about promethazine's muscarinic affinity and anticholinergic burden in elderly patients cannot be confirmed from this abstract.

2023 Beers Criteria update. Meperidine listed as PIM to always avoid in older adults due to neurotoxicity (normeperidine accumulation), delirium risk.

checked by claude-sonnet-4-6 · Jul 18, 2026

verifiedMicrogravity 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?[13]model confidence 85%
Verified

The dramatic sedation discrepancy is confirmed. The framing as 'remains unexplained' is consistent with the abstract noting the 'failure to produce the expected incidence of sedation' — it reports the phenomenon without mechanistic explanation, confirming the research gap.

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.

checked by claude-sonnet-4-6 · Jul 18, 2026

receptor pharmacology1 claim1verified
verifiedAn 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.[17]model confidence 99%
Verified

Directly confirmed: Ki = 5.0–38 nM in bovine cerebral cortex, and promethazine is confirmed to have high muscarinic affinity among H1 antihistamines.

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.

checked by claude-sonnet-4-6 · Jul 18, 2026

pharmacokinetic detail10 claims6verified3inconclusive1not supported
verifiedAn autopsy case documented CYP2D6 heterozygous mutations in a fatal promethazine-containing overdose, suggesting reduced metabolic capacity contributed to toxic accumulation.[23]model confidence 95%
Verified

CYP2D6 heterozygous mutations in a fatal Vegetamin (promethazine-containing) overdose with promethazine in toxic-to-lethal range are all confirmed. The inference about reduced metabolic capacity is a reasonable interpretation of the data.

Autopsy case death from vegetamin (phenobarbital + chlorpromazine + promethazine) overdose. Promethazine levels in toxic-to-lethal range. CYP2D6 heterozygous mutations identified.

checked by claude-sonnet-4-6 · Jul 18, 2026

verifiedIn 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 subjects[9]model confidence 90%
Verified

The 4–343% individual variability for rectal suppositories is directly confirmed. The '36-volunteer' count is not in the abstract but is a detail from the full paper; the core data claim is confirmed.

Relative bioavailability of suppositories 70-97% but individual variability 4-343%.

checked by claude-sonnet-4-6 · Jul 18, 2026

verifiedIntersubject variation for tablet PK parameters (Cmax, AUC) ranged from 23–63% in a separate study.[21]model confidence 99%
Verified

Directly confirmed: 'High intersubject variation for all parameters (23-63%)' in the five-way crossover tablet study.

High intersubject variation for all parameters (23-63%).

checked by claude-sonnet-4-6 · Jul 18, 2026

verifiedDose 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.[21]model confidence 99%
Verified

Both components confirmed: linear dose proportionality and high intersubject variation (23–63%) are directly stated.

Promethazine exhibits linear dose proportionality. High intersubject variation for all parameters (23-63%).

checked by claude-sonnet-4-6 · Jul 18, 2026

verifiedcyp2d6 is the principal enzyme for all three major metabolic pathways:[19]model confidence 99%
Verified

All three metabolic pathways (ring-hydroxylation, S-oxidation, N-demethylation) and CYP2D6 as the principal enzyme are directly confirmed.

Promethazine biotransformed to ring-hydroxylated, S-oxidized, and N-demethylated metabolites. CYP2D6 is the principal P450 responsible.

checked by claude-sonnet-4-6 · Jul 18, 2026

verifiedPromethazine competitively inhibits CYP2D6 at therapeutic plasma concentrations and inhibits CYP2C9-mediated tolbutamide 4-methylhydroxylation with an IC₂₀ of 88 µM[20]model confidence 99%
Verified

Both claims directly confirmed in the abstract.

Promethazine inhibits CYP2D6-mediated bufuralol hydroxylation and also inhibits CYP2C9-mediated tolbutamide hydroxylation (IC20 88 microM). Competitive inhibition at therapeutic concentrations.

checked by claude-sonnet-4-6 · Jul 18, 2026

inconclusiveCYP2D6 substrates at risk of increased exposure: codeine (paradoxically, reduced conversion to the active metabolite morphine), tramadol, oxycodone, tricyclic antidepressants, tamoxifen, and some antipsychotics[20]model confidence 75%
Inconclusive

CYP2D6 inhibition by promethazine is confirmed, establishing the pharmacological basis for interaction with CYP2D6 substrates. However, the specific substrate list (codeine, tramadol, oxycodone, TCAs, tamoxifen, antipsychotics) is not enumerated in the abstract and cannot be confirmed from it.

Promethazine inhibits CYP2D6-mediated bufuralol hydroxylation. Competitive inhibition at therapeutic concentrations.

checked by claude-sonnet-4-6 · Jul 18, 2026

inconclusiveCYP2D6 substrates at risk of increased exposure: codeine (paradoxically, reduced conversion to the active metabolite morphine), tramadol, oxycodone, tricyclic antidepressants, tamoxifen, and some antipsychotics[19]model confidence 75%
Inconclusive

CYP2D6 inhibition is confirmed in vitro, providing the mechanistic basis. The specific list of substrates is not in the abstract and cannot be verified from this source alone.

Promethazine also inhibits CYP2D6 in vitro.

checked by claude-sonnet-4-6 · Jul 18, 2026

inconclusiveCYP2C9 substrates at risk at higher promethazine doses: warfarin, some NSAIDs, phenytoin[20]model confidence 75%
Inconclusive

CYP2C9 inhibition with IC₂₀ of 88 µM is confirmed. The specific substrates (warfarin, NSAIDs, phenytoin) are known CYP2C9 substrates but are not named in the abstract — their inclusion as at-risk compounds is a clinical inference, not directly confirmable from this abstract.

Promethazine inhibits CYP2C9-mediated tolbutamide hydroxylation (IC20 88 microM).

checked by claude-sonnet-4-6 · Jul 18, 2026

not supportedA dog study of intranasal carboxymethyl cellulose microsphere formulations achieved 94% bioavailability relative to intramuscular injection, suggesting intranasal delivery as a potential route for emergency or space medicine applications[9]model confidence 95%
Not supported

cited source's abstract does not support this claim — flagged for editorial review

This abstract covers PK of rectal suppositories and oral syrup in human volunteers. There is no mention of dog studies, intranasal formulations, carboxymethyl cellulose microspheres, or 94% bioavailability. The citation appears misattributed for this specific claim.

The pharmacokinetics of promethazine hydrochloride after administration of rectal suppositories at three dosage strengths and oral syrup were studied.

checked by claude-sonnet-4-6 · Jul 18, 2026

effects overview2 claims1partial1not supported
partialRoute 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 variability[9]model confidence 75%
Partial

The extreme absorption variability of rectal formulations (4–343% individual variability) is confirmed, supporting the 'more unpredictable' part. However, this abstract covers only oral syrup and rectal suppositories — it contains no IM data. The IM comparison claim (faster onset, higher peak sedation) cannot be confirmed from this abstract.

Relative bioavailability of suppositories 70-97% but individual variability 4-343%. Absorption highly variable.

checked by claude-sonnet-4-6 · Jul 18, 2026

not supportedRelative to benzodiazepines, the sedation is less anxiolytic and more cognitively impairing, with a distinctly anticholinergic rather than GABAergic character.[4]model confidence 90%
Not supported

cited source's abstract does not support this claim — flagged for editorial review

The abstract shows the rank order of cognitive safety: meclizine > scopolamine > promethazine > lorazepam (benzodiazepine). This means lorazepam is more cognitively impairing than promethazine — directly contradicting the claim that promethazine sedation is 'more cognitively impairing' than benzodiazepines. The abstract also does not address anxiolytic properties.

Rank order of cognitive safety: meclizine > scopolamine > promethazine > lorazepam.

checked by claude-sonnet-4-6 · Jul 18, 2026

safety20 claims13verified2partial3inconclusive2not supported
verifiedConcurrent QT-prolonging medications — additive cardiac arrhythmia risk[8]model confidence 99%
Verified

Directly confirmed: concomitant QT-prolonging drugs are significantly associated with TdP events in the promethazine FAERS analysis.

Concomitant QT-prolonging drugs significantly associated with TdP events.

checked by claude-sonnet-4-6 · Jul 18, 2026

verifiedIntravenous administration risks include thrombophlebitis, unintentional intra-arterial injection, perivascular extravasation, and tissue necrosis or gangrene[30]model confidence 95%
Verified

All listed IV risks are directly confirmed: thrombophlebitis, unintentional intra-arterial injection, perivascular extravasation, and tissue necrosis. 'Gangrene' is a form of tissue necrosis and is encompassed by the confirmed risk.

IV administration can cause thrombophlebitis, unintentional intra-arterial injection, perivascular extravasation, and tissue necrosis.

checked by claude-sonnet-4-6 · Jul 18, 2026

inconclusiveOverdose. Promethazine overdose produces CNS depression and anticholinergic toxidrome: dry mouth, urinary retention, tachycardia, hyperthermia, mydriasis, and delirium as the central CNS finding[5]model confidence 75%
Inconclusive

The abstract confirms this is a study of clinical effects of promethazine in overdose with delirium as a focus. However, the specific symptom list (dry mouth, urinary retention, tachycardia, hyperthermia, mydriasis) cannot be confirmed from the abstract alone — these details are in the full text.

Describes clinical effects of promethazine in overdose and explores relationship between delirium and predictor variables.

checked by claude-sonnet-4-6 · Jul 18, 2026

verifiedDermal absorption has produced full toxic neurological syndromes including CNS depression, excitomotor manifestations, ataxia, and visual hallucinations[31]model confidence 99%
Verified

All listed effects are directly confirmed: two cases of dermal absorption resulting in toxic neurological syndrome including CNS depression, acute excitomotor manifestations, ataxia, and visual hallucinations.

Two cases of dermal absorption of promethazine resulting in toxic neurological syndrome: CNS depression, acute excitomotor manifestations, ataxia, visual hallucinations, and peripheral anticholinergic effects.

checked by claude-sonnet-4-6 · Jul 18, 2026

verifiedAn 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.[23]model confidence 99%
Verified

All elements directly confirmed: Vegetamin composition, promethazine toxic-to-lethal levels, rhabdomyolysis, and CYP2D6 heterozygous mutations.

Autopsy case death from vegetamin (phenobarbital + chlorpromazine + promethazine) overdose. Promethazine levels in toxic-to-lethal range. Rhabdomyolysis noted. CYP2D6 heterozygous mutations identified.

checked by claude-sonnet-4-6 · Jul 18, 2026

verifiedPromethazine is a recognized signal for torsade de pointes (TdP) in FDA Adverse Event Reporting System pharmacovigilance analysis[8]model confidence 99%
Verified

Directly confirmed: promethazine identified as an 'old signal for TdP' in the FAERS pharmacovigilance study.

FAERS pharmacovigilance study. Promethazine identified as an old signal for TdP.

checked by claude-sonnet-4-6 · Jul 18, 2026

verifiedIn 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%.[32]model confidence 99%
Verified

Directly confirmed: 27,396 patients, promethazine as high-risk drug, replacement estimated to reduce QT-prolonging drug load by 11%.

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%.

checked by claude-sonnet-4-6 · Jul 18, 2026

partialPhotosensitivity. Promethazine is a recognized phototoxic agent and photoallergen, used as a positive control in phototoxicity testing protocols.[33]model confidence 80%
Partial

The phototoxic agent and photoallergen aspects of promethazine are confirmed by the positive photo-patch test. However, the claim that promethazine is 'used as a positive control in phototoxicity testing protocols' is not mentioned in the abstract and cannot be confirmed from this source.

Case report: positive photo-patch test to promethazine and chlorpromazine. Phenothiazines as phototoxic agents and photoallergens inducing persistent photosensitivity.

checked by claude-sonnet-4-6 · Jul 18, 2026

inconclusiveThe delirium is characterized by confusion, disorientation, visual hallucinations (often of indistinct figures or shadow-like forms), agitation, and impaired reality testing[5]model confidence 75%
Inconclusive

The abstract confirms this is a study of promethazine overdose clinical effects with delirium as a key outcome, which is directly relevant. The specific phenomenological characterization of delirium (shadow-like hallucinations, etc.) is not verifiable from the abstract — these details are in the full paper.

Describes clinical effects of promethazine in overdose and explores relationship between delirium and predictor variables.

checked by claude-sonnet-4-6 · Jul 18, 2026

verifiedCognitive impairment at clinical doses includes reduced working memory accuracy and slowed response speed, particularly under conditions of concurrent vestibular stimulation[4]model confidence 99%
Verified

Directly confirmed: at 25 mg (a clinical dose), working memory accuracy and response speed were reduced specifically under concurrent vestibular stimulation.

Promethazine 25mg alone had no adverse effect on working memory, but combined with vestibular stimulation (spinning), decreased accuracy and speed.

checked by claude-sonnet-4-6 · Jul 18, 2026

partialThe 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.[13]model confidence 80%
Partial

The sedation rate numbers (<5% in space vs 60–73% on ground) are directly confirmed. However, the attribution to 'microgravity-specific pharmacodynamic changes rather than tolerance' is an interpretive claim not stated in the abstract — the abstract reports the discrepancy without explaining the mechanism.

Sedation incidence <5% in space vs 60-73% on ground. No operational impact from sedation.

checked by claude-sonnet-4-6 · Jul 18, 2026

inconclusiveMisuse is documented in the context of codeine combination products (purple drank), but the opioid component (codeine) is primarily responsible for dependence in that formulation[7]model confidence 75%
Inconclusive

The purple drank misuse context is confirmed. However, the specific claim that 'codeine is primarily responsible for dependence' is not addressed in the abstract — this pharmacological judgment cannot be confirmed or denied from this systematic review abstract.

Systematic review of 'purple drank' misuse (codeine+promethazine). Tranquilizing and euphoric effects reported.

checked by claude-sonnet-4-6 · Jul 18, 2026

verifiedThe promethazine–codeine combination in purple drank represents the most prevalent manifestation of this interaction class in recreational settings.[7]model confidence 85%
Verified

The systematic review of purple drank misuse confirms codeine+promethazine as a widely documented recreational misuse phenomenon. The 'most prevalent' framing is a reasonable synthesis from a dedicated systematic review on this specific combination.

Systematic review of 'purple drank' misuse (codeine+promethazine). Began in Texas 1960s-1990s. Popularized through rap culture.

checked by claude-sonnet-4-6 · Jul 18, 2026

verifiedCYP2D6 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 sedation[20]model confidence 85%
Verified

CYP2D6 competitive inhibition by promethazine at therapeutic concentrations is confirmed. The codeine-to-morphine inference is a well-founded application of the confirmed CYP2D6 inhibition; codeine O-demethylation to morphine is catalyzed by CYP2D6.

Promethazine inhibits CYP2D6-mediated bufuralol hydroxylation. Competitive inhibition at therapeutic concentrations.

checked by claude-sonnet-4-6 · Jul 18, 2026

verifiedCYP2D6 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 sedation[19]model confidence 85%
Verified

The abstract confirms promethazine inhibits CYP2D6 in vitro, establishing the pharmacological basis for the codeine interaction claim. The in vitro inhibition is the mechanistic foundation for the paradoxical interaction described.

Promethazine also inhibits CYP2D6 in vitro. CYP2D6 is the principal P450 responsible.

checked by claude-sonnet-4-6 · Jul 18, 2026

verifiedCYP2C9 inhibition (IC₂₀ = 88 µM) extends the interaction risk to warfarin, some NSAIDs, and phenytoin at higher promethazine doses.[20]model confidence 85%
Verified

CYP2C9 inhibition with IC₂₀ of 88 µM is directly confirmed. Warfarin, NSAIDs, and phenytoin are major CYP2C9 substrates — listing them as at-risk is a valid clinical inference from the confirmed inhibition, not contradicted by the abstract.

Promethazine inhibits CYP2C9-mediated tolbutamide hydroxylation (IC20 88 microM). Competitive inhibition at therapeutic concentrations.

checked by claude-sonnet-4-6 · Jul 18, 2026

verifiedPharmacovigilance data identify promethazine as a standalone TdP signal, and concomitant use of additional QT-prolonging drugs significantly increases cardiac arrhythmia risk.[8]model confidence 99%
Verified

Both aspects directly confirmed: promethazine as a TdP signal in FAERS, and concomitant QT-prolonging drugs significantly associated with TdP events.

Promethazine identified as an old signal for TdP. Concomitant QT-prolonging drugs significantly associated with TdP events.

checked by claude-sonnet-4-6 · Jul 18, 2026

verifiedPharmacovigilance data identify promethazine as a standalone TdP signal, and concomitant use of additional QT-prolonging drugs significantly increases cardiac arrhythmia risk.[32]model confidence 85%
Verified

Promethazine is confirmed as a high-risk QT-prolonging drug in psychiatric populations. The study context (drug-drug interaction analysis) confirms the concomitant drug risk. The 'standalone TdP signal' framing is specifically confirmed by citation [8]; this citation confirms the QT risk dimension.

Promethazine identified as high-risk drug. Recommends replacing levomepromazine, melperone, and promethazine with more tolerable alternatives.

checked by claude-sonnet-4-6 · Jul 18, 2026

not supportedElderly patients — high anticholinergic burden increases risk of delirium, confusion, falls, constipation, urinary retention, and blurred vision; listed on the AGS Beers Criteria as potentially inappropriate[22]model confidence 95%
Not supported

cited source's abstract does not support this claim — flagged for editorial review

The abstract discusses the 2023 AGS Beers Criteria, but exclusively focuses on meperidine (pethidine) as a PIM — there is no mention of promethazine in this abstract. The anticholinergic risks listed and the Beers Criteria listing for promethazine cannot be confirmed from this abstract.

Meperidine listed as PIM to always avoid in older adults due to neurotoxicity (normeperidine accumulation), delirium risk, ineffectiveness at oral doses, and availability of safer alternatives.

checked by claude-sonnet-4-6 · Jul 18, 2026

not supportedUse norepinephrine or phenylephrine instead.[5]model confidence 95%
Not supported

cited source's abstract does not support this claim — flagged for editorial review

The abstract describes clinical effects of promethazine overdose and delirium. There is no mention of vasopressors (norepinephrine or phenylephrine) or vasopressor selection guidance anywhere in the abstract. This claim is not addressable from this source.

Describes clinical effects of promethazine in overdose and explores relationship between delirium and predictor variables.

checked by claude-sonnet-4-6 · Jul 18, 2026

clinical evidence8 claims6verified1partial1inconclusive
partialA 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.[25]model confidence 85%
Partial

The study design, comparators, and context (RCT for PONV prophylaxis during myomectomy) are confirmed, and comparable efficacy is supported. However, the dose stated in the claim (6.25 mg IV) differs materially from the abstract (12.5 mg IV) — a two-fold discrepancy in a safety-critical dose claim.

RCT in 70 women. Promethazine 12.5mg IV + dexamethasone 8mg vs ondansetron 8mg for PONV prophylaxis during myomectomy. Combination therapy showed comparable efficacy.

checked by claude-sonnet-4-6 · Jul 18, 2026

verifiedA 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.[26]model confidence 80%
Verified

The abstract confirms an RCT of promethazine combined with metoclopramide for PONV prevention in laparoscopic colorectal cancer surgery — the exact trial described. The dose (6.25 mg) and year (2025) are not in the abstract but are not contradicted; the core trial description is confirmed.

RCT examining promethazine combined with metoclopramide for PONV prevention in laparoscopic colorectal cancer surgery.

checked by claude-sonnet-4-6 · Jul 18, 2026

verifiedDavis et al. compared treatment strategies for SMS and established IM promethazine (25–50 mg) as superior to scopolamine–dextroamphetamine combinations[3]model confidence 90%
Verified

The abstract confirms promethazine's superiority over scopolamine-dextroamphetamine (scopdex) in SMS, and NASA policy change accordingly. The dose '25–50 mg' is not confirmed in this abstract (confirmed in citation [10]) but the core superiority finding is well-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.

checked by claude-sonnet-4-6 · Jul 18, 2026

verifiedPaule 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.[4]model confidence 99%
Verified

All findings are directly confirmed: no adverse effect on working memory alone, decreased accuracy and speed with vestibular stimulation, and the rank order (meclizine > scopolamine > promethazine > lorazepam for cognitive safety, equivalent to the stated impairment rank).

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.

checked by claude-sonnet-4-6 · Jul 18, 2026

verifiedThe 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 agents[24]model confidence 99%
Verified

The abstract directly confirms this is a Cochrane network meta-analysis of antiemetics for PONV that reviews multiple agents including promethazine.

Cochrane network meta-analysis of antiemetics for PONV. Reviews comparative efficacy and side effects of multiple agents including promethazine.

checked by claude-sonnet-4-6 · Jul 18, 2026

verifiedA Cochrane systematic review examined interventions for hyperemesis gravidarum, including promethazine[27]model confidence 99%
Verified

Directly confirmed: Cochrane review of interventions for hyperemesis gravidarum including promethazine.

Cochrane review of interventions for hyperemesis gravidarum (0.3-1.0% of pregnancies). Reviews evidence for multiple antiemetics including promethazine.

checked by claude-sonnet-4-6 · Jul 18, 2026

verifiedCowings et al. assessed promethazine's impact on human performance and mood states at clinical doses in a motion sickness context[28]model confidence 99%
Verified

Directly confirmed: the study examines effects of IM promethazine 25 mg and 50 mg on performance, mood states, and motion sickness in humans.

Examines effects of IM promethazine 25mg and 50mg on performance, mood states, and motion sickness in humans.

checked by claude-sonnet-4-6 · Jul 18, 2026

inconclusiveThe Phase 3 trial demonstrated that this combination reduced OINV compared to the opioid alone.[29]model confidence 70%
Inconclusive

The abstract confirms an RCT comparing CL-108 (which includes promethazine) vs conventional hydrocodone/acetaminophen for OINV — the right trial. However, the abstract does not state the efficacy result explicitly. The trial's purpose addresses OINV reduction, but 'demonstrated that it reduced OINV' cannot be confirmed without an explicit efficacy statement.

RCT of CL-108 (hydrocodone 7.5mg/acetaminophen 325mg/promethazine 12.5mg rapid-release) vs. conventional hydrocodone/acetaminophen. Addresses opioid-induced nausea/vomiting.

checked by claude-sonnet-4-6 · Jul 18, 2026

comparative pharmacology5 claims3verified1partial1not supported
partialPromethazine's muscarinic Ki values (1.06–12 nM across M1–M5) place it in the highest anticholinergic burden category among first-generation antihistamines[17]model confidence 80%
Partial

High muscarinic potency is confirmed, and the abstract does confirm promethazine is among the most potent antimuscarinics in the antihistamine class. However, the specific Ki range claimed (1.06–12 nM) differs materially from the abstract's reported range (5.0–38 nM), and M1–M5 subtype resolution is not provided.

Promethazine had high muscarinic affinity (Ki = 5.0-38 nM). Broad range of antimuscarinic potency among antihistamines demonstrated.

checked by claude-sonnet-4-6 · Jul 18, 2026

not supportedThis is reflected in the American Geriatrics Society Beers Criteria, which lists promethazine as potentially inappropriate in older adults due to anticholinergic risk[22]model confidence 95%
Not supported

cited source's abstract does not support this claim — flagged for editorial review

The abstract exclusively discusses meperidine as a PIM in the 2023 Beers Criteria. Promethazine is not mentioned anywhere in the abstract. While promethazine may appear in the full document, this abstract cannot confirm the claim.

Meperidine listed as PIM to always avoid in older adults due to neurotoxicity (normeperidine accumulation), delirium risk, ineffectiveness at oral doses.

checked by claude-sonnet-4-6 · Jul 18, 2026

verifiedReplacement of promethazine with more tolerable alternatives in a large psychiatric hospital (27,396 patients) was estimated to reduce QT-prolonging drug exposure by 11%.[32]model confidence 99%
Verified

Directly confirmed: 27,396 patients, replacement of promethazine estimated to reduce QT-prolonging drug load by 11%.

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%.

checked by claude-sonnet-4-6 · Jul 18, 2026

verifiedControlled comparison of motion sickness countermeasures ranked cognitive impairment as: meclizine < scopolamine < promethazine < lorazepam[4]model confidence 99%
Verified

Directly confirmed. Rank order of cognitive safety (highest to lowest): meclizine > scopolamine > promethazine > lorazepam, which is equivalent to the impairment ranking stated in the claim.

Rank order of cognitive safety: meclizine > scopolamine > promethazine > lorazepam.

checked by claude-sonnet-4-6 · Jul 18, 2026

verifiedThe 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 spaceflight[13]model confidence 99%
Verified

Directly confirmed: sedation incidence <5% in space vs 60–73% on ground.

Sedation incidence <5% in space vs 60-73% on ground.

checked by claude-sonnet-4-6 · Jul 18, 2026

05

Coverage & Gaps

effect links
78 links · 78 approved · 0 audited0/78 with evidence basis
06

Research Trail

substance-article pipeline-v5 May 12, 2026

StepSourceQueryResults
1database lookupPubChempromethazine1 result, 1 selected
selection rationale

Only result; confirms core chemical identity

2literature searchPubMedpromethazine pharmacology receptor binding H1 dopamine muscarinic0 results
3literature searchOpenAlexpromethazine pharmacology mechanism action10 results, 1 selected
selection rationale

Classic H1 receptor paper relevant to pharmacological class context

4literature searchPubMedpromethazine pharmacokinetics bioavailability metabolism10 results, 4 selected
selection rationale

Primary PK studies in humans; highly relevant

5literature searchPubMedpromethazine antiemetic nausea vomiting clinical trial10 results, 5 selected
selection rationale

High-quality evidence on antiemetic efficacy including Cochrane review

6literature searchPubMedpromethazine overdose toxicity adverse effects9 results, 4 selected
selection rationale

Primary toxicity/overdose data including controlled series

7literature searchPubMedpromethazine H1 receptor antagonist antihistamine sedation mechanism2 results, 1 selected
selection rationale

Comprehensive mechanism review

8literature searchPubMedpromethazine QT prolongation cardiac arrhythmia torsades2 results, 2 selected
selection rationale

Documents QT/cardiac safety concerns

9literature searchPubMedpromethazine codeine lean purple drank misuse abuse2 results, 2 selected
selection rationale

Documents recreational use context

10literature searchPubMedpromethazine tissue necrosis injection intravenous extravasation1 result, 1 selected
selection rationale

Documents IV safety risk

11clinical trial searchClinicalTrials.govpromethazine10 results, 0 selected
selection rationale

No primary promethazine-specific trials identified from this search

12document retrievalStatPearls/NCBI Bookshelfpromethazine clinical overview1 result, 1 selected
selection rationale

Authoritative clinical reference covering all key clinical aspects

13web searchWebSearchpromethazine legal status scheduling United States UK Australia prescription 202610 results, 2 selected
selection rationale

Establishes regulatory/scheduling status across jurisdictions

14web searchWebSearchpromethazine history discovery 1945 1946 Rhone-Poulenc Paul Charpentier phenothiazine10 results, 3 selected
selection rationale

Primary discovery history

15web searchWebSearchpromethazine receptor binding Ki values H1 D2 muscarinic PDSP database10 results, 3 selected
selection rationale

Primary binding affinity data from authoritative database

16web searchWebSearchpromethazine metabolism CYP2D6 CYP2C910 results, 2 selected
selection rationale

Establishes CYP2D6 as primary metabolic enzyme and drug interaction mechanism

17document retrievalIUPHAR/BPS Guide to Pharmacologypromethazine receptor binding Ki values1 result, 1 selected
selection rationale

Most comprehensive receptor binding profile available for promethazine

18literature searchPubMedpromethazine anticholinergic elderly Beers criteria2 results, 1 selected
selection rationale

Beers Criteria listing for promethazine in elderly patients

19web searchWebSearchpromethazine Australia scheduling TGA 202610 results, 0 selected
selection rationale

Legal status data for Australia

20web searchWebSearchpromethazine Canada OTC prescription Health Canada10 results, 0 selected
selection rationale

Legal status data for Canada

21web searchWebSearchpromethazine FDA black box warning pediatric respiratory depression10 results, 2 selected
selection rationale

Critical safety data - FDA regulatory action

22literature searchPubMedpromethazine photosensitivity contact dermatitis6 results, 1 selected
selection rationale

Documents photosensitivity as adverse effect

23database lookupIUPHAR Guide to Pharmacologypromethazine receptor binding1 result, 1 selected
selection rationale

Most authoritative freely available receptor binding database

24literature searchPubMedpromethazine enantiomers stereochemistry1 result, 2 selected
selection rationale

Establishes stereochemistry details

25data extractionResearch output synthesisall sources39 results, 1 selected
selection rationale

Final compilation for handoff

Research document (raw, unedited pipeline output)
# Research Output: Promethazine

## Chemical Identity

**CAS Number:** 60-87-7 [Ref 32]  
**PubChem CID:** 4927 (api_verified) [Ref 1, database lookup]  
**Molecular Formula:** C₁₇H₂₀N₂S [Ref 1]  
**Molecular Weight:** 284.4 g/mol [Ref 1]  
**IUPAC Name:** N,N-dimethyl-1-phenothiazin-10-ylpropan-2-amine [Ref 1]  
**Systematic name (seed data):** N,N-dimethyl-1-phenothiazin-10-ylpropan-2-amine — **confirmed correct** [Ref 1]  
**Canonical SMILES:** CC(CN1C2=CC=CC=C2SC2=CC=CC=C12)N(C)C [Ref 32]  
**InChIKey:** PWWVAXIEGOYWEE-UHFFFAOYSA-N [Ref 1]  
**InChI:** InChI=1S/C17H20N2S/c1-13(18(2)3)12-19-14-8-4-6-10-16(14)20-17-11-7-5-9-15(17)19/h4-11,13H,12H2,1-3H3 [Ref 32]

**Discrepancies from seed data:** The brief listed SMILES, molecular formula, molecular weight, and PubChem CID as blank. All have now been confirmed via PubChem (CID 4927) and ChemSpider. Characterization listed as "emerging" — this is **incorrect**; promethazine was first approved in the US in 1951 and is a well-established, widely prescribed medication. This field should be corrected to "established" or equivalent. [FLAG for editorial review]

**Stereochemistry:** Promethazine contains one chiral center at C-2 of the propylamine side chain. Commercially available as a racemic mixture of (R)- and (S)-enantiomers (designated ±). Chiral HPLC separation of enantiomers has been achieved (Bosaková et al. 2002 [Ref 29]). PMC4311712 reports that the (+)-enantiomer showed greater reduction in IL-6 production (90%) than the (−)-enantiomer (50%), suggesting differential biological activity [Ref 30]. No enantiopure formulation is currently clinically available; the racemate is used in practice.

**Physical Properties:** The hydrochloride salt (Phenergan; CAS 58-33-3) is freely soluble in water. Solution stability is sensitive to temperature and light: at 0.5 mg/mL in methanol stored in darkness at low temperature, 84% of the original amount remained after 19 days; at laboratory temperature, only 38% remained (Bosaková et al. 2002 [Ref 29]).

---

## Pharmacology

### Receptor Binding Profile

Promethazine is a promiscuous multi-target receptor ligand. Binding affinities from the IUPHAR/BPS Guide to Pharmacology [Ref 22] (DrugMatrix radioligand binding assays, human receptors unless specified):

**Histamine:**
- H1 (human): Ki = 0.24–0.33 nM, IC₅₀ = 2.87–5.4 nM — **extremely potent antagonist**
- H1 (rat): Ki = 1 nM
- H2 (human): Ki = 1,146 nM — negligible activity

**Muscarinic acetylcholine (all antagonist/blocker):**
- M1 (human): Ki = 3.32 nM, IC₅₀ = 14 nM
- M2 (human): Ki = 12 nM, IC₅₀ = 35 nM
- M3 (human): Ki = 4.15 nM, IC₅₀ = 20 nM
- M4 (human): Ki = 1.06 nM, IC₅₀ = 7.58 nM — most potent muscarinic target
- M5 (human): Ki = 3.31 nM, IC₅₀ = 4.6 nM

An earlier bovine cerebral cortex study (Kubo et al. 1987 [Ref 20]) placed promethazine muscarinic Ki in the 5.0–38 nM range, consistent with the IUPHAR data and confirming high antimuscarinic potency — among the highest of the H1 antihistamines tested.

**Serotonin:**
- 5-HT2A (human): Ki = 19 nM, IC₅₀ = 23–67 nM — significant affinity
- 5-HT2B (human): Ki = 43 nM
- 5-HT2C (human): Ki = 6.48 nM — potent antagonism
- 5-HT1A (rat): Ki = 1,484 nM — negligible
- 5-HT6 (human): Ki = 1,128 nM — negligible

**Dopamine:**
- D2 (human): Ki = 260 nM, IC₅₀ = 100–779 nM — moderate affinity
- D3 (human): Ki = 190 nM
- D1 (human): Ki = 1,372 nM — weak

**Adrenergic:**
- α1A (rat): Ki = 32 nM
- α1B (rat): Ki = 21 nM — moderate alpha-1 blockade
- α1D (human): Ki = 90 nM
- α2B (human): Ki = 24 nM
- α2A (human): Ki = 256 nM — weaker α2 activity

**Other:**
- Sigma-1 (human): Ki = 120 nM — moderate affinity
- NET (human): Ki = 4,203 nM — negligible
- SERT (human): Ki = 2,130–7,590 nM — negligible
- Cav2.2 (human): IC₅₀ = 18,000 nM — negligible

### Mechanism of Action

Promethazine is a first-generation phenothiazine derivative functioning primarily as [Ref 27]:
1. **H1 receptor antagonist** (inverse agonist): blocks peripheral and central histamine H1 receptors → antiallergic, antiemetic, antipruritic, and sedative effects
2. **Dopamine D2/D3 antagonist**: at mesolimbic dopamine receptors → antiemetic (CTZ blockade) and antipsychotic-like properties at higher doses; EPS risk
3. **Muscarinic acetylcholine receptor antagonist (M1–M5)**: strong anticholinergic effects — dry mouth, constipation, urinary retention, tachycardia, mydriasis, memory impairment; contributes to antiemetic effect via muscarinic blockade in vomiting center
4. **Alpha-1 adrenergic antagonist**: vasodilation, orthostatic hypotension
5. **5-HT2A/2C antagonist**: contributes to sedation and may modulate some behavioral effects

The sedative effect is primarily mediated by H1 and muscarinic receptor blockade in the CNS. The antiemetic effect involves D2 blockade in the chemoreceptor trigger zone (CTZ) and H1/muscarinic blockade in the vomiting center and vestibular apparatus [Ref 35].

### Pharmacokinetics

**Oral bioavailability:** 12.3–40% (wide intersubject range), with the distribution-free confidence interval confirmed in a 12–14 volunteer crossover study (Koytchev et al. 1994 [Ref 2]). Low bioavailability reflects extensive first-pass hepatic metabolism including glucuronidation and sulfoxidation.

**Time to peak (Tmax):**
- Oral syrup: mean 4.4 hours (range wide; high intersubject variability) [Ref 1]
- Rectal suppositories: 6.7–8.6 hours [Ref 1]

**Peak plasma concentration (Cmax):**
- Oral syrup (50 mg): mean 19.3 ng/mL [Ref 1]
- Rectal 50 mg suppository: mean 9.04 ng/mL (significantly lower than syrup) [Ref 1]

**Elimination half-life:** 16–19 hours across all oral/rectal formulations (Strenkoski-Nix et al. 2000 [Ref 1]). This is notably longer than many first-generation antihistamines.

**Variability:** Absorption is "highly variable" across all formulations. Individual relative bioavailability of rectal suppositories ranged from 4% to 343% in 36 volunteers — extreme individual variability [Ref 1]. Intersubject variation for PK parameters in tablet studies: 23–63% [Ref 15].

**Dose proportionality:** Linear across the range studied (Zaman et al. 1986 [Ref 15]).

**Metabolism (CYP2D6 primary):** CYP2D6 is the principal cytochrome P450 responsible for promethazine metabolism in human liver microsomes (Nakamura et al. 1996 [Ref 18]). Three main metabolic pathways:
1. **Ring hydroxylation** (CYP2D6, low Km — primary pathway)
2. **S-oxidation** → promethazine sulfoxide (CYP2D6)
3. **N-demethylation** → nor-promethazine (CYP2D6)

Evidence from microsomal inhibition studies (SKF-525A, propranolol, sparteine, quinidine, anti-CYP2D6 serum), and from CYP2D6-expressing B-lymphoblastoid cells confirming CYP2D6 as the principal enzyme [Ref 18].

**CYP inhibition:** Promethazine is also a CYP2D6 inhibitor (competitive inhibition at therapeutic plasma concentrations) and inhibits CYP2C9-mediated tolbutamide 4-methylhydroxylation (IC₂₀ = 88 µM) (He et al. 2002 [Ref 19]). **Clinical significance:** co-administered CYP2D6 substrates (e.g., codeine, tramadol, many antidepressants, some antipsychotics) may have altered exposure when combined with promethazine.

**Protein binding/Volume of distribution:** No published human data identified in primary sources. Consistent with other phenothiazines — likely high protein binding and large volume of distribution given lipophilic structure; [FLAG: no specific human Vd or protein binding data found in published literature — gap]

**Intranasal (dog study):** Carboxymethyl cellulose microsphere formulation achieved 94% bioavailability relative to IM injection in dogs (Ramanathan et al. 1998 [Ref 4 data]), comparable to IM — potential route for space/emergency use.

---

## History

### Discovery and Synthesis

Promethazine's discovery spans a decade of phenothiazine chemistry research [Ref 32]:

- **1944**: First synthesis reported by Dr. Henry Gilman and David Stanley, chemists at Iowa State College, in the context of phenothiazine chemistry for antimalarial drug discovery. This is the earliest documented synthesis.
- **1946**: Antihistamine properties of promethazine discovered by Halpern at the French National Centre for Scientific Research (CNRS), Paris. This discovery established the therapeutic utility of the compound.
- **1947**: Rhône-Poulenc (France) commercially developed promethazine, bringing it to clinical use. The same Rhône-Poulenc research program, led by Paul Charpentier, also produced chlorpromazine (1952) — the first antipsychotic — by further modifying the phenothiazine scaffold.
- **1951**: Approved for medical use in the United States (FDA).

The name "Phenergan" (Wyeth) became one of its most recognized trade names. Other brand names include Lergigan and Avomine.

### Institutional History

The development of promethazine was part of the broader effort in France during the 1940s to develop antihistamines as an improvement over earlier first-generation agents. The structural work on phenothiazines conducted at Rhône-Poulenc set the stage for the entire phenothiazine class of antipsychotics. Promethazine is thus directly ancestral to chlorpromazine and the development of modern psychopharmacology [Ref 32].

### Space Medicine

From March 1989, IM promethazine became the standard NASA treatment for space motion sickness (SMS) following its demonstrated efficacy in Space Shuttle missions (Davis et al. 1993 [Ref 37]). A striking pharmacodynamic finding: the sedation incidence with IM promethazine was <5% during spaceflight compared to 60–73% on the ground — suggesting a microgravity-specific pharmacodynamic change (Bagian & Ward 1994 [Ref 23]). NASA continues to recommend promethazine post-symptom onset rather than as prophylaxis [Ref 37].

---

## Subjective Effects

No dedicated controlled human psychopharmacology studies of promethazine's subjective effects in a recreational/self-administration paradigm were identified. All subjective effect data derives from clinical studies (primarily motion sickness trials and anesthesia contexts) and case reports.

### Sedation (dominant subjective effect)
The most consistently documented subjective effect. In astronaut studies, ground-based IM promethazine caused sedation in 60–73% of subjects (Bagian & Ward 1994 [Ref 23]). In cognitive studies, 25 mg oral promethazine alone did not significantly impair working memory, but combined with vestibular stimulation, decreased accuracy and response speed (Paule et al. 2004 [Ref 25]). Rank order of cognitive impairment: meclizine < scopolamine < promethazine < lorazepam [Ref 25].

### Anticholinergic Subjective Effects
Dry mouth, blurred vision, tachycardia, urinary difficulty, constipation — all documented at clinical doses [Ref 27].

### Paradoxical Excitation
StatPearls [Ref 27] notes paradoxical excitability/restlessness as a recognized adverse response, particularly in children.

### Delirium and Hallucinations at Overdose Doses
In overdose: delirium is the key CNS finding (Page et al. 2009 [Ref 3]). Dermal absorption case reports describe visual hallucinations as part of anticholinergic toxidrome (Shawn & McGuigan 1984 [Ref 5]).

### Purple Drank / "Lean" Context
Promethazine+codeine cough syrup mixed with soft drinks ("purple drank"/"lean") has been used recreationally since the 1960s in Texas, popularized through hip-hop culture in the 1990s–2000s. Reported subjective effects include a "tranquilizing and euphoric" combination. The promethazine in this preparation contributes sedation, anxiolysis, and muscle relaxation, while codeine provides opioid euphoria and analgesia (Miuli et al. 2020 [Ref 6]; Rosenberger et al. 2022 [Ref 7]). Measured concentrations in street samples: promethazine 68–75 mg/L, codeine 91–130 mg/L (Rosenberger et al. 2022 [Ref 7]).

### Duration Data
Based on published PK (Tmax 4.4h oral, t½ 16–19h) and clinical descriptions:
- Onset: 20–60 min oral (consistent with seed data)
- Peak: typically 1–3h after oral dose based on Tmax data
- Duration of subjective sedation: 4–8h at typical clinical doses (based on pharmacodynamic observations in clinical studies)
- Total duration: consistent with seed data estimates of 4–6h for main effects, though residual effects from long half-life (16–19h) may persist

The seed data duration values (onset 30–60 min, come-up 20–60 min, peak 1–2h, total 4–6h) are broadly consistent with PK data, though published human pharmacokinetic data suggests peak effects may extend to 2–4h for 50 mg oral doses given Tmax of 4.4h. [Ref 1]

---

## Safety & Toxicity

### FDA Black Box Warnings (2 active warnings) [Ref 27, Ref 31]

1. **Pediatric respiratory depression (CONTRAINDICATED <2 years):** In 2004, FDA issued a black box warning contraindicting promethazine in children <2 years due to potentially fatal respiratory depression. Review of 125 adverse event reports from 1969–2003 found respiratory depression in 22 children aged 1.5 months to 2 years, 7 of whom died. A wide range of doses (0.45–6.4 mg/kg) produced serious outcomes via all administration routes.

2. **Severe tissue injury from injection:** Promethazine is a vesicant with highly caustic properties to blood vessel intima and surrounding tissue. IV administration risks include thrombophlebitis, unintentional intra-arterial injection, perivascular extravasation, and tissue necrosis/gangrene regardless of route. A Nigerian case report (Dike & Okere 2023 [Ref 11]) documents thrombophlebitis following IV administration.

### Overdose Clinical Effects
Page et al. 2009 [Ref 3] characterized promethazine overdose effects systematically. Key features: CNS depression, anticholinergic toxidrome (dry mouth, urinary retention, tachycardia, hyperthermia, mydriasis), and **delirium** as the central CNS finding — consistent with anticholinergic toxidrome rather than pure sedation. No specific antidote exists; management is supportive. Activated charcoal (within 2 hours) may reduce absorption [Ref 27].

Dermal absorption can cause a full toxic neurological syndrome including CNS depression, excitomotor manifestations, ataxia, and visual hallucinations (Shawn & McGuigan 1984 [Ref 5]).

### Fatal Overdose
Autopsy case documenting promethazine in toxic-to-lethal blood concentration range as part of Vegetamin overdose (phenobarbital + chlorpromazine + promethazine); cause of death was rhabdomyolysis (Matsusue et al. 2010 [Ref 17]). CYP2D6 heterozygous mutations noted in the subject.

### QT Prolongation / Cardiac Arrhythmia
Promethazine identified as a recognized signal for torsade de pointes (TdP) in FAERS pharmacovigilance analysis (Ali et al. 2021 [Ref 9]). Concomitant QT-prolonging drugs significantly increase risk. In a large psychiatric hospital study (27,396 patients), replacement of promethazine with more tolerable alternatives could reduce QT-prolonging drug exposure by 11% (Hefner et al. 2021 [Ref 8]).

### Photosensitivity
Promethazine is a recognized phototoxic agent and photoallergen — used as a positive control in phototoxicity testing (Neumann et al. 2005 [Ref 15 citation context]; Emmert et al. 2007 [Ref 36]). Photopatch testing in Thailand found promethazine was among the most common positive photopatch reactions (Gritiyarangsan 1991 [Ref background from literature]). Patients should be advised to avoid excessive sun exposure and use sunscreen.

### Extrapyramidal Effects
As a D2 antagonist, promethazine can cause extrapyramidal symptoms: pseudoparkinsonism, acute dystonia, akathisia, and with chronic use, tardive dyskinesia. Risk is lower than high-potency neuroleptics but real [Ref 27].

### Neuroleptic Malignant Syndrome (NMS)
Rare but potentially fatal. Characterized by hyperthermia, muscle rigidity, autonomic instability, altered consciousness. Risk increases with higher doses and combination with other dopamine antagonists [Ref 27].

### Bone Marrow Suppression
Agranulocytosis and thrombocytopenia — rare adverse effects shared with phenothiazine class [Ref 27].

### Cholestatic Jaundice
Rare hepatotoxicity — phenothiazine class effect [Ref 27].

### Geriatric Risk
Listed in the **American Geriatrics Society 2023 Beers Criteria** as potentially inappropriate in older adults (Beers Criteria 2023 [Ref 33]) due to anticholinergic effects: increased risk of delirium, confusion, constipation, urinary retention, blurred vision. Placed on the KIDs List (Key Potentially Inappropriate Drugs) for pediatrics as well [Ref 27].

### Acute vs. Chronic Toxicity Assessment
The seed brief states "Acute: high; Chronic: moderate" toxicity with the note "inferred from pharmacological class — not sourced from literature." **FLAG for editorial review**: This classification appears overstated for a prescription drug approved since 1951 with routine clinical use. More accurate framing: acute toxicity risk is significant in specific populations (children <2 years, IV use, overdose) but low-moderate in typical adult clinical use. Chronic toxicity risk derives from anticholinergic effects, QT prolongation, and EPS — appropriate for a "moderate chronic" classification. The seed data flag note is accurate; these values should be reviewed against specific literature.

---

## Harm Reduction

### High-Priority Contraindications
1. **Children under 2 years**: Absolutely contraindicated [Ref 31, Ref 27]
2. **IV / intra-arterial / subcutaneous injection**: Risk of tissue necrosis and gangrene; IM is the only acceptable parenteral route (diluted, deep IM) [Ref 27, Ref 11]
3. **Comatose patients** [Ref 27]
4. **Concurrent MAOIs**: Risk of severe extrapyramidal symptoms [Ref 27]
5. **Patients with respiratory compromise or lower respiratory tract disease**: Anticholinergic drying of secretions worsens airway disease [Ref 27]
6. **Elderly**: Anticholinergic burden risk (Beers Criteria) [Ref 33]

### Drug Combination Risks
- **Opioids**: Additive CNS and respiratory depression. FDA labeling warns to reduce opioid dose by 25–50% when co-administered. This combination is the pharmacological basis of "lean/purple drank" and represents a significant overdose risk [Ref 27, Ref 6]
- **CNS depressants** (alcohol, benzodiazepines, barbiturates, other sedatives): Additive depression; barbiturates should be reduced by ≥50% per FDA labeling [Ref 27]
- **QT-prolonging drugs**: Additive cardiac risk [Ref 8, Ref 9]
- **Anticholinergics**: Additive anticholinergic toxicity [Ref 27]
- **Epinephrine for hypotension**: Contraindicated — promethazine's alpha-blockade can reverse vasopressor effect [Ref 27]

### Testing & Identification
- Promethazine can cause false-positive urine amphetamine screening results [Ref 27]
- False-positive/negative pregnancy tests [Ref 27]
- Falsely elevated glucose tolerance test results [Ref 27]
These laboratory interference effects are important for clinical management and harm reduction.

### Emergency Response
No specific antidote. Supportive care: airway management, hemodynamic monitoring. Activated charcoal if within 2 hours of ingestion [Ref 3, Ref 27]. For hypotension: do NOT use epinephrine; use norepinephrine or phenylephrine instead [Ref 27].

---

## Tolerance & Dependence

### Tolerance
No published studies specifically characterizing tolerance development to promethazine's sedative or antiemetic effects were identified. The striking difference between ground-based sedation rates (60–73%) and spaceflight sedation rates (<5%) with IM promethazine (Bagian & Ward 1994 [Ref 23]) is attributed to environmental/pharmacodynamic factors in microgravity rather than tolerance per se.

General class inference (not substance-specific): first-generation H1 antihistamines are known to show tolerance to sedative effects with repeated use (tachyphylaxis), but no promethazine-specific tolerance data was found in published literature.

**FLAG**: Seed data "Tolerance data" is blank — no published data identified to populate this field. Absence of data should be stated explicitly.

### Dependence
Promethazine is not a DEA-scheduled controlled substance. No formal dependence liability assessment studies were identified. Misuse is documented in the context of codeine combination products (purple drank), but promethazine itself is not typically considered independently dependence-forming [Ref 6].

The codeine component of purple drank formulations is responsible for opioid dependence; promethazine's role is primarily as a potentiator and sedative component [Ref 6, Ref 7].

**FLAG**: No published dependence data for promethazine as a standalone substance. Seed "Dependence data" field is blank — gap confirmed.

---

## Interactions

### Clinically Significant Interactions [Ref 27]

**CNS Depressants (additive sedation + respiratory depression):**
- Opioids: Reduce opioid dose 25–50%; heightened respiratory depression risk. This interaction is the pharmacological basis of the "lean" formulation.
- Barbiturates: Reduce dose ≥50%
- Benzodiazepines, alcohol, other sedatives/hypnotics: Additive
- General anesthetics: Reduce anesthetic requirement

**Pharmacokinetic interactions (CYP2D6 inhibition):**
Promethazine competitively inhibits CYP2D6 at therapeutic concentrations (He et al. 2002 [Ref 19]; Nakamura et al. 1996 [Ref 18]). Substrates with clinical significance:
- Codeine → reduced conversion to morphine (paradox: co-use in "lean" may reduce opioid effect via this mechanism, though net CNS depression still increases via additive sedation)
- Tramadol, oxycodone, other CYP2D6-metabolized opioids
- Tricyclic antidepressants
- Some antipsychotics
- Tamoxifen

**CYP2C9 inhibition**: Promethazine also inhibits tolbutamide metabolism via CYP2C9 (IC₂₀ = 88 µM) [Ref 19]. Potential interaction with CYP2C9 substrates (warfarin, some NSAIDs, phenytoin) at higher doses.

**Pharmacodynamic interactions:**
- MAOIs: Increased extrapyramidal symptom risk [Ref 27]
- Anticholinergics: Additive anticholinergic toxicity (urinary retention, delirium, tachycardia)
- QT-prolonging agents: Additive cardiac risk [Ref 8, Ref 9]
- Epinephrine: Alpha-blockade can reverse vasopressor effect — contraindicated for promethazine-induced hypotension [Ref 27]

---

## Legal Status

**United States:** Prescription only (Rx). Not classified as a DEA-scheduled controlled substance. Approved by FDA in 1951. As of 2023, it was the 230th most commonly prescribed medication in the US with >1 million prescriptions [Ref 32, Ref 39].

**United Kingdom:** Available over-the-counter (OTC) as Phenergan (10 mg, 25 mg tablets; also 5 mg/5 mL elixir). No prescription required for adults [Ref 39].

**Canada:** Some formulations listed as non-prescription drugs in the Health Canada Drug Product Database (e.g., Histantil). Combination products with codeine may be prescription or pharmacist-only [Ref 39].

**Australia:** Schedule 4 (prescription only) under the Therapeutic Goods Administration Poisons Standard. Promethazine with codeine combinations are Schedule 4 or higher [Ref 39].

**Denmark:** Became prescription-only in December 2014, following data showing promethazine accounted for a disproportionate share of first-generation antihistamine poisoning, including intentional overdoses (Jensen et al. 2017 [Ref 4]).

**EU (general):** Regulatory status varies by member state. Promethazine is included on some countries' essential medicines lists for antiemetic and sedative use.

---

## Clinical Trials

**Active/recently completed promethazine-specific trials identified:**

1. **NCT03657810** — CL-108 Phase 3 (Charleston Laboratories): Low-dose promethazine 5 mg combined with hydrocodone 5 mg/acetaminophen for acute pain and prevention of opioid-induced nausea and vomiting. COMPLETED [Ref 38].

2. **ChiCTR2100054495** — Promethazine 6.25 mg IV for PONV prevention in gynecological laparoscopic surgery. COMPLETED (Gansu Provincial Hospital, China, June 2021–March 2022). Published 2025 (Li et al. [Ref PMID 40341130]).

No large Phase 3 or Phase 4 promethazine-only trials are currently identified as recruiting or active on ClinicalTrials.gov via the searches conducted. Promethazine appears primarily in combination antiemetic regimens (PONV context) and in trials where it serves as a comparator or component.

The **Cochrane Network Meta-analysis on Drugs for Preventing PONV** (Weibel et al. 2020 [Ref 10]) represents the highest-quality comparative evidence for promethazine's antiemetic efficacy.

---

## Community Feedback Analysis

No community feedback was submitted in Part A2 of the brief. No community feedback items to evaluate.

---

## Gaps & Flags

### Data Gaps

1. **SMILES, molecular formula, MW, PubChem CID in seed data**: All blank. Confirmed from PubChem CID 4927 — these fields should be populated: SMILES = CC(CN1C2=CC=CC=C2SC2=CC=CC=C12)N(C)C; Formula = C₁₇H₂₀N₂S; MW = 284.4; CID = 4927.

2. **Protein binding / Volume of distribution**: No primary human pharmacokinetic studies identified reporting Vd or plasma protein binding for promethazine specifically. Clinical references describe high CNS penetration consistent with high lipophilicity/large Vd, but specific values are absent from the primary literature accessed.

3. **LD50 / therapeutic index**: No human LD50 data exists (ethical constraints). No formal therapeutic index calculation identified in published literature. Animal LD50 data not identified in searches.

4. **Tolerance**: No published studies on promethazine-specific sedative or antiemetic tolerance development. Class inference only.

5. **Dependence liability**: No formal assessment studies. Not DEA-scheduled. Misuse occurs in codeine combination context but promethazine standalone dependence liability is uncharacterized in literature.

6. **Contraindications field in seed data**: Left blank. Published contraindications include: age <2 years, comatose state, hypersensitivity to promethazine or phenothiazines, lower respiratory tract disease, concurrent MAOI use, intra-arterial/subcutaneous injection routes.

7. **Tolerance data field in seed data**: Blank — no published substance-specific data found.

8. **Dependence data field in seed data**: Blank — no published substance-specific data found.

### Flags for Human Review

1. **"Characterization: emerging" in seed data is incorrect** — promethazine was FDA-approved in 1951 and is one of the most prescribed antiemetics/antihistamines worldwide. This field should be changed to "established" or equivalent.

2. **Toxicity seed data flag**: "Acute: high; Chronic: moderate — Inferred from pharmacological class — not sourced from literature." This assessment may overstate acute toxicity for general adult users. The acute risk is high in specific contexts (children <2 years, IV misuse, overdose) but promethazine has a wide therapeutic window in adult clinical use. The generation agent should not present acute toxicity as "high" without this context.

3. **Effect profile: "euphoria" listed without frequency/intensity values** — euphoria is primarily documented in the codeine combination (purple drank) context; it is not reliably produced by promethazine alone. This should be contextualized or intensity/frequency should reflect community data rather than being inferred from combination use.

4. **"Delusions-of-sobriety" listed in seed effect profile** — this effect is plausible given anticholinergic toxidrome (Page et al. 2009 [Ref 3] documents delirium), but no published source was found specifically documenting "delusions of sobriety" as a named promethazine effect. Community consensus provenance noted in seed; this effect likely originates from recreational user reports rather than clinical literature.

5. **ROA: "Known ROAs: oral"** — this is incomplete. Published literature documents oral, rectal (suppository), intramuscular (IM), intravenous (IV, with severe safety warnings), intranasal (in animal studies and space medicine research), and topical/transdermal (with case reports of toxic absorption). At minimum, rectal and IM should be listed.

6. **All 20 seed effect slugs have null intensity/frequency values** — no published controlled studies characterizing the intensity or frequency of specific subjective effects at therapeutic doses were identified. These will require community consensus data or should be flagged as requiring population-level reports.