generation run 2026-05-12
64 min completedmodel pipeline-v5plan not recordedrun/4b6ede46…Selection
Verification
- record
- seen / partial
- working
The model's own caveats
- sparse_evidence
- structural_inference
Reproduce
- inputs
- 23 source keys (listed under Sources)
- plan
- not recorded — template version, prompt hash and git SHA are written from 2026-09 onward
- model
- pipeline-v5
- streams
- none — agent transcripts are persisted from 2026-09 onward
28 searches — query, source, results, what was kept and why
| # | source | query | seen | kept | rationale |
|---|---|---|---|---|---|
| 1 | PubMed | propylhexedrine overdose case report | 3 | 3 | Key case reports on propylhexedrine toxicity |
| 2 | FDA.gov | — | 1 | 1 | Official regulatory safety communication |
| 3 | PubMed | propylhexedrine pharmacokinetics metabolism | 4 | 2 | Pharmacokinetics data |
| 4 | PubMed | propylhexedrine Benzedrex inhaler misuse | 1 | 1 | Recent case report directly relevant |
| 5 | WebSearch | propylhexedrine norepinephrine dopamine transporter binding affinity Ki EC50 | 10 | — | No primary binding data available |
| 6 | PubChem | propylhexedrine | 1 | 1 | Primary chemical identity verification |
| 7 | PubMed | propylhexedrine pharmacology mechanism | 2 | 2 | Relevant to pharmacological classification |
| 8 | ClinicalTrials.gov · absence | propylhexedrine | 0 | — | No results |
| 9 | WebSearch | propylhexedrine legal status scheduling USA UK controlled substance | 10 | 3 | Legal status overview |
| 10 | OpenAlex | propylhexedrine | 15 | 3 | Most cited propylhexedrine-specific paper and pharmacological context |
| 11 | PubMed | propylhexedrine pulmonary hypertension | 5 | 5 | Critical clinical papers on propylhexedrine adverse effects |
| 12 | HandWiki | — | 1 | 1 | Comprehensive chemical profile with sourced data |
| 13 | WebSearch | propylhexedrine history synthesis discovery Smith Kline French 1949 Benzedrex | 10 | 2 | Historical documentation |
| 14 | Crossref (via verify_doi) | 10.1016/0002-9343(79)90063-9 | 1 | — | DOI verification for landmark case series |
| 15 | FDA.gov | — | 1 | 2 | Primary regulatory source for epidemiological and safety data |
| 16 | WebSearch | propylhexedrine tramadol death | 10 | — | Confirmed tramadol interaction but could not find specific published case report |
| 17 | PubMed | Fornazzari propylhexedrine brainstem 1986 | 1 | — | Critical paper on neurological toxicity of IV propylhexedrine |
| 18 | WebSearch | propylhexedrine pharmacokinetics half-life human bioavailability CYP | 10 | — | Key PK data for article |
| 19 | Crossref (via verify_doi) | 10.7759/cureus.10868 | 1 | — | DOI verification for comprehensive review |
| 20 | WebSearch | propylhexedrine MAOI interaction contraindication mechanism hypertensive crisis | 10 | — | Interaction mechanism confirmed for MAOI contraindication |
| 21 | PubMed | Wesson propylhexedrine WHO 1986 | 1 | 1 | Key WHO Expert Committee paper on abuse potential assessment |
| 22 | PubMed | barbexaclone clinical antiepileptic human pharmacology | 7 | 2 | Documents propylhexedrine's clinical use in barbexaclone formulation |
| 23 | PubMed | propylhexedrine myocardial infarction psychosis | 2 | — | No new results |
| 24 | ClinicalTrials.gov · absence | propylhexedrine | 0 | — | Documents absence of controlled human trials |
| 25 | WebSearch | propylhexedrine Australia scheduling Canada regulatory 2024 | 10 | — | Updated legal status data |
| 26 | OpenAlex | propylhexedrine pulmonary hypertension sudden death intravenous abuse | 10 | 2 | Teja 2020 is most comprehensive recent review |
| 27 | synthesis | propylhexedrine research output compilation | — | — | Final synthesis step |
| 28 | Crossref | 10.1007/s13181-024-01025-w | 1 | — | DOI verification for 2024 case report |
71 claims by section — every cited sentence, checked against its source
safety21 · 14 ok
Oral misuse has produced neurological impairment with associated MRI abnormalities in a 2024 case report.supported
Propylhexedrine oral misuse causing neurological impairment with MRI findings. s13181-024-01025-w
1.7 mg/L: propylhexedrine toxicity ruled as cause of death, with mitragynine (0.39 mg/L) as possible contributing factorpartially supported
Blood concentration 1.7 mg/L propylhexedrine. Cause of death ruled propylhexedrine toxicity, manner accidental. 35.1.54
3.75 mg/L: suspected fatal intoxicationsupported
Propylhexedrine found at 3.75 mg/L blood concentration postmortem, potentially fatal intoxication. pmid:2573343
Consistent autopsy findings included pulmonary edema, foreign body granulomas (from injected cotton fibers and excipients), pulmonary fibrosis, pulmonary hypertension, and right ventricular hypertrophy (present in 9 of 12 IV abuse deaths)supported
Pulmonary edema, foreign body granulomas, fibrosis, pulmonary hypertension at autopsy. Right ventricular hypertrophy in 9/12. 0002-9343(79)90063-9
Schaiberger et al. documented marked pulmonary hypertension in a patient with a 10-year history of inhaling propylhexedrine and methamphetamine.supported
33-year-old male with 10-year history inhaling methamphetamine and propylhexedrine ('peanut butter methamphetamine') developed marked pulmonary hypertension. pmid:8101799
Cameron et al. reported pulmonary hypertension in a 39-year-old woman after 8 years of daily oral propylhexedrine hydrochloride use as an appetite suppressant — the first documented case of oral-route propylhexedrine causing pulmonary hypertension.supported
39-year-old woman developed pulmonary hypertension after 8 years oral propylhexedrine hydrochloride use as anorectic. First report of oral-route propylhexedrine causing pulmonary hypertension. pmid:6144037
Proposed mechanisms of pulmonary vascular disease include toxic endothelial injury, hypoxic insult, direct vascular spasm, vasculitis, and dysregulation of mediators of vascular tone.supported
Proposed mechanisms: toxic endothelial injury, hypoxic insult, direct spasm, vasculitis, dysregulation of vascular tone mediators. pmid:8101799
Claim in safety — not_supportednot supportedworking →
Claim in safety — not_supportednot supportedworking →
The preparation method involved heating Benzedrex inhaler contents with hydrochloric acid and dissolving the resulting crystals in water.supported
Preparation as 'stove-top speed' via HCl extraction. pmid:2877725
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — not_supportednot supportedworking →
Psychosis, paranoia, and hallucinations are documented in multiple case series spanning both IV and oral routes of abusesupported
History review: replaced amphetamine sulfate 1949; documented psychosis, MI, pulmonary vascular disease, pulmonary hypertension, sudden death. pmid:23061329
Claim in safety — inconclusiveinconclusiveworking →
Barbexaclone dependence (propylhexedrine component) has been documented separately in Europesupported
Case of barbexaclone (phenobarbital + propylhexedrine) abuse in patient with prior cannabis use history. Documents abuse potential of barbexaclone's propylhexedrine component. 08897077.2010.514246
No formal quantitative assessment of propylhexedrine's dependence potential exists.supported
No formal dependence studies exist. pmid:23061329
Claim in safety — inconclusiveinconclusiveworking →
Kratom (mitragynine) is documented in one fatal case: postmortem blood propylhexedrine 1.7 mg/L with mitragynine 0.39 mg/L, where propylhexedrine toxicity was ruled as cause of death and mitragynine may have contributed synergistically.partially supported
Death involving abuse of propylhexedrine and mitragynine. Blood concentration 1.7 mg/L propylhexedrine. Cause of death ruled propylhexedrine toxicity. 35.1.54
Cardiovascular disease or uncontrolled hypertension: Propylhexedrine's sympathomimetic activity increases cardiac workload, blood pressure, and heart rate. The documented association with pulmonary hypertension and myocardial infarction makes pre-existing cardiovascular disease a significant risk amplifier.supported
Pulmonary hypertension at autopsy. Right ventricular hypertrophy in 9/12. 0002-9343(79)90063-9
Cardiovascular disease or uncontrolled hypertension: Propylhexedrine's sympathomimetic activity increases cardiac workload, blood pressure, and heart rate. The documented association with pulmonary hypertension and myocardial infarction makes pre-existing cardiovascular disease a significant risk amplifier.supported
39-year-old woman developed pulmonary hypertension after 8 years oral propylhexedrine hydrochloride use as anorectic. pmid:6144037
Claim in safety — not_supportednot supportedworking →
history11 · 9 ok
Fernandez and Francis published the first case of propylhexedrine dependence in 2012, characterizing the compound as "a vintage drug of abuse, rediscovered".supported
First published case of propylhexedrine dependence. pmid:23061329
The compound was developed specifically to address the abuse crisis surrounding Benzedrine (amphetamine sulfate) inhalers, which had been associated with psychosis, habituation, and sudden death.supported
Replaced amphetamine sulfate in 1949 after abuse/psychosis. pmid:2877725
The compound was developed specifically to address the abuse crisis surrounding Benzedrine (amphetamine sulfate) inhalers, which had been associated with psychosis, habituation, and sudden death.supported
replaced amphetamine sulfate 1949; documented psychosis, MI, pulmonary vascular disease, pulmonary hypertension, sudden death. pmid:23061329
Claim in history — inconclusiveinconclusiveworking →
Long-term oral use of propylhexedrine hydrochloride in this capacity produced at least one documented case of pulmonary hypertension after 8 years of daily administration.supported
39-year-old woman developed pulmonary hypertension after 8 years oral propylhexedrine hydrochloride use as anorectic. pmid:6144037
Clinical trials demonstrated effective seizure control in epileptic patients, though barbexaclone abuse has also been documented.supported
Clinical trial of barbexaclone as anticonvulsant. 70 patients, 96% seizure-free at 18 months. pmid:6105861
Clinical trials demonstrated effective seizure control in epileptic patients, though barbexaclone abuse has also been documented.supported
Case of barbexaclone (phenobarbital + propylhexedrine) abuse in patient with prior cannabis use history. 08897077.2010.514246
Anderson et al. documented 15 propylhexedrine-related deaths in Dallas County from 1973 onward, 12 from IV abusesupported
Propylhexedrine implicated in 15 deaths (Dallas County since 1973). 12 from IV abuse. 0002-9343(79)90063-9
The review concluded that propylhexedrine carries low abuse potential relative to amphetamine, methylphenidate, and phenmetrazine, and found low preference among stimulant abusers when alternatives were availablesupported
Low abuse potential relative to amphetamine, methylphenidate, phenmetrazine. pmid:2874970
Claim in history — inconclusiveinconclusiveworking →
Low retail price (under $10 per inhaler) and online community discussion of extraction methods have contributed to renewed accessibilitysupported
Products available OTC at low price. cureus.10868
pharmacology7 · 4 ok
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
Serotonin release has been described, suggesting activity as a serotonin–norepinephrine–dopamine releasing agent (SNDRA), though norepinephrine and dopamine are considered the primary effectors.partially supported
acts as adrenergic agonist at therapeutic doses, norepinephrine-dopamine releasing agent at higher doses. cureus.10868
Claim in pharmacology — inconclusiveinconclusiveworking →
In mice receiving barbexaclone, Iven and Feldbusch determined a distribution-phase half-life (t½α) of 0.31 hours and an elimination-phase half-life (t½β) of 2.5 hours, with a volume of distribution of 19.3 L/kgsupported
t1/2 alpha 0.31h, t1/2 beta 2.5h, Vd 19.3 L/kg pmid:6139756
Oral bioavailability was approximately 37% (AUC oral/AUC IV = 0.37)supported
oral bioavailability 0.37 pmid:6139756
Propylhexedrine rapidly penetrates the blood–brain barrier.supported
Rapidly penetrates blood-brain barrier. pmid:6139756
summary7 · 5 ok
Claim in summary — inconclusiveinconclusiveworking →
Ullyot and patented in 1948 for Smith, Kline & French, entering national commerce on August 4, 1949 as a replacement for amphetamine sulfate in OTC inhalers following widespread amphetamine abusepartially supported
History review: replaced amphetamine sulfate 1949 pmid:23061329
Ullyot and patented in 1948 for Smith, Kline & French, entering national commerce on August 4, 1949 as a replacement for amphetamine sulfate in OTC inhalers following widespread amphetamine abusepartially supported
Replaced amphetamine sulfate in 1949 after abuse/psychosis. pmid:2877725
The WHO Expert Committee on Drug Dependence reviewed the compound in 1986, concluding it carries low abuse potential relative to amphetamine, methylphenidate, and phenmetrazinesupported
Low abuse potential relative to amphetamine, methylphenidate, phenmetrazine. pmid:2874970
Claim in summary — inconclusiveinconclusiveworking →
Cardiovascular toxicity dominates the risk profile: pulmonary hypertension, right ventricular hypertrophy, and sudden death are documented across oral and intravenous routes of misusepartially supported
12 from IV abuse. Pulmonary edema, foreign body granulomas, fibrosis, pulmonary hypertension at autopsy. Right ventricular hypertrophy in 9/12. 0002-9343(79)90063-9
One published case of propylhexedrine dependence existssupported
First published case of propylhexedrine dependence. pmid:23061329
comparative-pharmacology6 · 6 ok
In a pigeon drug discrimination paradigm, propylhexedrine (10–100 mg/kg) only partially substituted for d-amphetamine, generalizing in 2 of 3 birds, indicating reduced amphetamine-like discriminative stimulus properties.supported
Propylhexedrine partially substituted for d-amphetamine in discriminative stimulus study. Substituted in 2 of 3 pigeons at 10-100 mg/kg. pmid:2885408
Cardiovascular toxicity: Disproportionately high relative to CNS potency — the pulmonary vascular toxicity profile (pulmonary hypertension, right ventricular hypertrophy) is severe relative to the modest subjective stimulant effectssupported
Pulmonary edema, foreign body granulomas, fibrosis, pulmonary hypertension at autopsy. Right ventricular hypertrophy in 9/12. 0002-9343(79)90063-9
The WHO Expert Committee review concluded propylhexedrine carries low abuse potential relative to amphetamine, methylphenidate, and phenmetrazine, with low preference among stimulant abusers when alternative stimulants were availablesupported
Low abuse potential relative to amphetamine, methylphenidate, phenmetrazine. pmid:2874970
CNS stimulant potency: Lower than amphetamine and methamphetamine (partial substitution in drug discrimination; lower abuse preference)supported
Propylhexedrine partially substituted for d-amphetamine in discriminative stimulus study. Substituted in 2 of 3 pigeons at 10-100 mg/kg. pmid:2885408
CNS stimulant potency: Lower than amphetamine and methamphetamine (partial substitution in drug discrimination; lower abuse preference)supported
Low abuse potential relative to amphetamine, methylphenidate, phenmetrazine. pmid:2874970
Propylhexedrine and methamphetamine produce identical base-peak ions (m/z 254 amu) on GC/MS with HFBA derivatization, a forensic consideration not shared by most other sympathomimetic aminessupported
Propylhexedrine base peak ions identical to methamphetamine (254 amu for HFBA) requiring careful differentiation. pmid:1640694
pharmacokinetic-detail6 · 4 ok
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
Mouse tissue distribution data demonstrate high and unequal accumulation, with lung and kidney concentrations exceeding liver and brainsupported
High tissue accumulation: lung=kidney > liver=brain. pmid:6139756
Rapid blood–brain barrier penetration is confirmed in mouse modelssupported
Rapidly penetrates blood-brain barrier. pmid:6139756
Hair analysis demonstrates that the cyclohexyl ring structure results in lower melanin affinity and higher lipophilicity compared to the phenyl ring of methamphetamine, affecting incorporation kinetics into keratinized tissue.supported
Cyclohexyl ring shows lower melanin affinity and higher lipophilicity than benzene ring. pmid:10794512
Propylhexedrine produces a base-peak ion at m/z 254 amu under GC/MS with heptafluorobutyric anhydride (HFBA) derivatization — identical to methamphetamine — creating a documented risk of false-positive methamphetamine results on standard immunoassay drug screenssupported
Propylhexedrine base peak ions identical to methamphetamine (254 amu for HFBA) requiring careful differentiation. pmid:1640694
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
clinical-evidence4 · 4 ok
Key case series include the landmark Anderson et al. (1979) study documenting 15 propylhexedrine-related deaths in Dallas County; Fornazzari et al. (1986) reporting brainstem dysfunction in 7 IV users; and Holler et al. (2011) documenting a fatal propylhexedrine-mitragynine combination at postmortem blood concentration 1.7 mg/L.supported
Propylhexedrine implicated in 15 deaths (Dallas County since 1973). 12 from IV abuse. 0002-9343(79)90063-9
Key case series include the landmark Anderson et al. (1979) study documenting 15 propylhexedrine-related deaths in Dallas County; Fornazzari et al. (1986) reporting brainstem dysfunction in 7 IV users; and Holler et al. (2011) documenting a fatal propylhexedrine-mitragynine combination at postmortem blood concentration 1.7 mg/L.supported
7 cases of brainstem dysfunction from IV propylhexedrine abuse. pmid:2877725
Key case series include the landmark Anderson et al. (1979) study documenting 15 propylhexedrine-related deaths in Dallas County; Fornazzari et al. (1986) reporting brainstem dysfunction in 7 IV users; and Holler et al. (2011) documenting a fatal propylhexedrine-mitragynine combination at postmortem blood concentration 1.7 mg/L.supported
Blood concentration 1.7 mg/L propylhexedrine. Cause of death ruled propylhexedrine toxicity. 35.1.54
Reis et al. demonstrated effective seizure control with barbexaclone including plasma level monitoringsupported
Clinical trial of barbexaclone as anticonvulsant. 70 patients, 96% seizure-free at 18 months. pmid:6105861
neuroscience4 · 3 ok
Claim in neuroscience — inconclusiveinconclusiveworking →
The magnitude and kinetics of dopamine release — and therefore the subjective euphoria and abuse liability — are likely lower than amphetamine, consistent with the compound's partial substitution in drug discrimination assays and the WHO assessment of low abuse potential.supported
Propylhexedrine partially substituted for d-amphetamine in discriminative stimulus study. Substituted in 2 of 3 pigeons at 10-100 mg/kg. pmid:2885408
The magnitude and kinetics of dopamine release — and therefore the subjective euphoria and abuse liability — are likely lower than amphetamine, consistent with the compound's partial substitution in drug discrimination assays and the WHO assessment of low abuse potential.supported
Low abuse potential relative to amphetamine, methylphenidate, phenmetrazine. pmid:2874970
The brainstem dysfunction documented in IV users — internuclear ophthalmoplegia, depressed gag reflex, hemitongue paralysis, and transient diplopia within seconds of injection — suggests direct neurotoxicity or vasospasm-mediated ischemia in brainstem structuressupported
7 cases of brainstem dysfunction from IV propylhexedrine abuse. 2 definite (persistent ophthalmoplegia, tongue paralysis) and 5 transient diplopia. pmid:2877725
receptor-pharmacology2 · 1 ok
Claim in receptor-pharmacology — inconclusiveinconclusiveworking →
The WADA pharmacology review discusses class-level stimulant mechanisms but does not provide propylhexedrine-specific quantitative binding datasupported
Review of 62 WADA-prohibited stimulants. Covers monoaminergic mechanisms including adrenergic, dopaminergic, serotonergic systems. bjp.2008.124
chemistry1 · 1 ok
The compound's cyclohexyl ring confers higher lipophilicity and lower melanin affinity compared to the phenyl ring of methamphetamine.supported
Cyclohexyl ring shows lower melanin affinity and higher lipophilicity than benzene ring. pmid:10794512
effects-overview1 · 1 ok
Relative to amphetamine, propylhexedrine produces weaker subjective stimulation and euphoria with disproportionately greater cardiovascular and pulmonary toxicitypartially supported
Low abuse potential relative to amphetamine, methylphenidate, phenmetrazine. pmid:2874970
legal-status1 · 1 ok
The compound is not currently controlled under the Convention on Psychotropic Substances.supported
WHO Expert Committee review of propylhexedrine. Reviews pharmacology, medicinal uses, toxicity, abuse-potential. pmid:2874970