generation run 2026-05-08
71 min completedmodel pipeline-v5plan not recordedrun/8ab2076d…Selection
Verification
- record
- seen / partial
- working
The model's own caveats
- sparse_evidence
- taper_unassessed
Reproduce
- inputs
- 25 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
23 searches — query, source, results, what was kept and why
| # | source | query | seen | kept | rationale |
|---|---|---|---|---|---|
| 1 | OpenAlex | pyrovalerone cathinone alpha-PVP alpha-PHP pharmacology dopamine transporter abuse | 10 | 3 | High-citation review papers providing class-level context for α-PiHP |
| 2 | ClinicalTrials.gov · absence | alpha-PiHP pyrrolidinoisohexanophenone cathinone | 0 | — | Confirms absence of clinical trials |
| 3 | PubChem | alpha-Pyrrolidinoisohexanophenone | 1 | 1 | Primary chemical identity verification for α-PiHP |
| 4 | PubMed | alpha-PiHP dopamine transporter reuptake inhibition pharmacology | 1 | 1 | Already catalogued |
| 5 | OpenAlex | alpha-PiHP pyrrolidinoisohexanophenone novel psychoactive substance | 11 | 7 | High-relevance papers not captured in PubMed search, citation-sorted to find landmark works |
| 6 | PubMed | alpha-PiHP toxicology fatality death cathinone | 2 | 2 | Key postmortem concentration data for α-PiHP fatalities |
| 7 | PubMed | alpha-PiHP pyrrolidinoisohexanophenone cathinone | 8 | 8 | All directly relevant to α-PiHP pharmacology, toxicology, metabolism, and forensic analysis |
| 8 | PubMed | pyrovalerone cathinone dopamine norepinephrine serotonin transporter binding IC50 | 1 | 1 | Key pharmacological binding data for pyrovalerone class including α-PiHP analogs |
| 9 | WebFetch | — | 1 | 1 | User-reported dose/duration data; flagged as unverified, for editorial review |
| 10 | WebSearch | alpha-PiHP Australia Canada scheduling controlled substance legal analog | 10 | 2 | International legal status |
| 11 | WebSearch | alpha-PiHP EMCDDA early warning system scheduling UN convention 2023 | 9 | 2 | EU scheduling and international control documentation |
| 12 | WebFetch | — | 1 | 1 | Chemical identity and scheduling verification |
| 13 | WebSearch | WHO expert committee drug dependence alpha-PiHP critical review 2022 schedule II psychotropic | 9 | 1 | Primary WHO pharmacological assessment and scheduling basis |
| 14 | WebSearch | alpha-PiHP UK legal status Misuse of Drugs Act controlled substance UK | 10 | 2 | UK legal status |
| 15 | WebFetch | — | 1 | 1 | UK specific prevalence and legal data |
| 16 | WebSearch | alpha-PiHP legal status DEA scheduling United States controlled substance | 9 | 1 | Primary legal status for US |
| 17 | OpenAlex | alpha-PiHP pyrrolidinoisohexanophenone intoxication case report overdose | 4 | 1 | New case report not found in PubMed search |
| 18 | WebSearch | alpha-PiHP routes administration snorting vaping smoking intravenous user reports dose | 10 | 2 | Critical human pharmacology paper and dose/ROA data |
| 19 | WebFetch | — | 1 | 1 | Official WHO assessment data for α-PiHP |
| 20 | PubMed | alpha-PVP acute pharmacological effects humans observational naturalistic study | 2 | 2 | Human observational data for α-PiHP and close analog α-PVP |
| 21 | WebFetch | — | 1 | 1 | First human pharmacokinetic data for α-PiHP |
| 22 | Crossref/DOI | verify_doi for key citations | 5 | 1 | DOI verification for most-cited α-PiHP-specific papers |
| 23 | PubMed/OpenAlex/WebSearch synthesis | Final data extraction and synthesis for research output | 31 | 1 | Comprehensive synthesis for generation agent handoff |
114 claims by section — every cited sentence, checked against its source
safety43 · 31 ok
Cardiovascular disease: α-PiHP produces dose-dependent tachycardia and sustained hypertensionpartially supported
More sustained blood pressure elevation than cocaine. fphar.2025.1728824
Sudden cardiac arrest has been documented.supported
Sudden cardiac arrest as cause of death. 12307483pfs.25.010.22917
Claim in safety — inconclusiveinconclusiveworking →
Multi-pyrovalerone cathinone use (e.g., α-PiHP with α-PHP or MDPHP) is documented in forensic case seriessupported
LC-QQQ-MS method for quantifying α-PHP, α-PiHP, MDPHP, MDPiHP. Ten forensic cases analyzed. j.forsciint.2026.112917
Co-detected in death seriessupported
69-92% had concomitant opioids, stimulants, or sedatives. j.forsciint.2024.112297
Co-detected in German forensic casessupported
High rate of poly-drug use. bkae011
Claim in safety — inconclusiveinconclusiveworking →
Postmortem blood concentrations span 0.3–840 ng/mL across intoxication and fatal exposures, with substantial overlap that precludes reliable lethal threshold estimation.supported
α-PiHP concentrations: 0.3-840 ng/mL in postmortem blood. j.forsciint.2026.112917
α-PiHP intoxication presents as a sympathomimetic toxidrome: tachycardia, hypertension, hyperthermia, psychomotor agitation, and diaphoresispartially supported
More sustained blood pressure elevation than cocaine. fphar.2025.1728824
α-PiHP intoxication presents as a sympathomimetic toxidrome: tachycardia, hypertension, hyperthermia, psychomotor agitation, and diaphoresissupported
Most frequent adverse effects: cardiac, psychiatric, neurologic. life14040429
In the De la Rosa 2025 observational study, blood pressure elevation following intranasal α-PiHP (15–25 mg) was more sustained than following intranasal cocaine (75–90 mg).supported
More sustained blood pressure elevation than cocaine. fphar.2025.1728824
Tachycardia and sustained hypertension at recreational dosessupported
More sustained blood pressure elevation than cocaine. fphar.2025.1728824
Cardiac arrhythmias (class-level evidence for cathinones)supported
Most frequent adverse effects: cardiac, psychiatric, neurologic. life14040429
Sudden cardiac arrest — documented in a fatal case involving α-PiHP co-ingested with tramadol (α-PiHP blood 0.062 μg/mL; tramadol blood 1.60 μg/mL)supported
Sudden cardiac arrest as cause of death. α-PiHP at 0.062 μg/mL (blood). Tramadol at 1.60 μg/mL (blood, toxic concentration). 12307483pfs.25.010.22917
Diagnostic uncertainty between sympathomimetic toxidrome and serotonin syndrome was noted; the minimal SERT activity of pyrovalerone cathinones makes serotonin syndrome less mechanistically plausible but not excludable at extreme doses or with co-ingestions.supported
Diagnostic uncertainty between serotonin syndrome and sympathomimetic toxidrome. cureus.70708
First confirmed fatality: Comprehensive postmortem tissue distribution including blood compartments, vitreous humor, CSF, and adipose tissue; OH-α-PiHP metabolite co-detected in all tissuessupported
α-PiHP and metabolite OH-α-PiHP detected and quantified in all postmortem materials including all major organs, blood compartments, vitreous humor, CSF, and adipose tissue. bkad026
Finnish postmortem series (2018–2023): α-PiHP detected in deaths with median femoral blood concentration 0.14 mg/L (range 0.03–2.1 mg/L); 82% male, median age 35; concomitant opioids, stimulants, or sedatives in 69–92% of casessupported
Median femoral blood concentration of α-PiHP in fatal poisonings: 0.14 mg/L (range 0.03-2.1 mg/L). 82% male, median age 35. 69-92% had concomitant opioids, stimulants, or sedatives. j.forsciint.2024.112297
US forensic case series: Postmortem blood range 0.3–840 ng/mL with considerable overlap between intoxication and fatal exposuressupported
α-PiHP concentrations: 0.3-840 ng/mL in postmortem blood. j.forsciint.2026.112917
Occupational fatality: Coal miner with sudden cardiac arrest; polydrug context (tramadol at toxic concentration)supported
40-year-old coal miner found unresponsive with cardiac arrest. Tramadol at 1.60 μg/mL (blood, toxic concentration). 12307483pfs.25.010.22917
Only 1.7% of synthetic cathinone-related deaths in the Finnish series had a cathinone as the sole detected substancepartially supported
69-92% had concomitant opioids, stimulants, or sedatives. j.forsciint.2024.112297
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Dantrolene may be considered for refractory hyperthermia.supported
Dantrolene administered to control hyperthermia. cureus.70708
At recreational doses, α-PiHP produces anxiety and paranoia — effects documented in intoxication case reports and consistent with the pharmacology of DAT-selective stimulantssupported
Most frequent adverse effects: cardiac, psychiatric, neurologic. life14040429
At recreational doses, α-PiHP produces anxiety and paranoia — effects documented in intoxication case reports and consistent with the pharmacology of DAT-selective stimulantssupported
Brain-related adverse effects: encephalopathy, coma, convulsions, sympathomimetic toxidrome, excited/agitated delirium syndrome, serotonin syndrome. ijms24076230
At higher doses and during prolonged binge use, psychotic features emerge: auditory and visual hallucinations, persecutory delusions, and severe agitationsupported
Most frequent adverse effects: cardiac, psychiatric, neurologic. Fatal intoxications described. life14040429
Forensic cases frequently document aggressive and violent behavior.supported
Aggressive behavior noted; committed offenses were often violent crimes. bkae011
Excited delirium syndrome — characterized by extreme agitation, hyperthermia, unexpected physical strength, and loss of pain sensitivity — has been documented for the pyrovalerone cathinone class and is a recognized risk in α-PiHP intoxicationsupported
MDPV associated with excited delirium syndrome (ExD). ExD syndrome described in pyrovalerone cathinone class. 00952990.2012.694535
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
The mechanism of reinforcement — high, selective DAT inhibition without SERT modulation — is identical to the pharmacological profile associated with the highest abuse liability among stimulant drugs.supported
DAT/SERT ratio surpassed cocaine by >40-fold. 113 seizures total, 37 toxicological casework findings including 5 autopsies. j.forsciint.2025.112657
In the Finnish postmortem series, concomitant opioids, stimulants, or sedatives were present in 69–92% of synthetic cathinone-related deathssupported
69-92% had concomitant opioids, stimulants, or sedatives. j.forsciint.2024.112297
A fatal case documented cardiac arrest in a patient with α-PiHP (blood 0.062 μg/mL) and tramadol at toxic concentration (blood 1.60 μg/mL)supported
α-PiHP at 0.062 μg/mL (blood). Tramadol at 1.60 μg/mL (blood, toxic concentration). Sudden cardiac arrest as cause of death. 12307483pfs.25.010.22917
Frequently co-detected in intoxication casessupported
High rate of poly-drug use. bkae011
Frequently co-detected in intoxication casessupported
69-92% had concomitant opioids, stimulants, or sedatives. j.forsciint.2024.112297
Claim in safety — inconclusiveinconclusiveworking →
Psychiatric disorders: Psychotic spectrum disorders, bipolar disorder, and severe anxiety disorders represent absolute contraindications. α-PiHP precipitates hallucinations, delusions, and paranoia at high doses, and the dopaminergic mechanism poses specific risk for psychotic decompensation in predisposed individuals.supported
Most frequent adverse effects: cardiac, psychiatric, neurologic. life14040429
Renal impairment: α-PiHP-induced rhabdomyolysis and acute kidney injury are documentedsupported
Hyperthermia, rhabdomyolysis, acute kidney injury. cureus.70708
pharmacology13 · 10 ok
Claim in pharmacology — inconclusiveinconclusiveworking →
In vitro, α-PiHP inhibits DAT with potency equivalent to α-PVP and inhibits NET at slightly lower potencysupported
α-PiHP is a highly potent inhibitor of dopamine (DA) and norepinephrine (NE) reuptake, with potency equivalent to α-PVP for DAT and slightly lower for NET. j.neuro.2025.05.005
Pyrovalerone cathinones as a class exhibit no meaningful SERT inhibition at concentrations below 10 μMsupported
no SERT activity at <10 μM ijms22158277
The high DAT/SERT selectivity ratio documented for methyl-substituted α-PiHP analogs — exceeding 40-fold above cocaine — is consistent with negligible serotonergic activity in the parent compoundsupported
DAT/SERT ratio surpassed cocaine by >40-fold. j.forsciint.2025.112657
This selectivity profile is associated with strong reinforcing effects and correspondingly high abuse liability.supported
DAT/SERT ratio surpassed cocaine by >40-fold. 113 seizures total, 37 toxicological casework findings including 5 autopsies. j.forsciint.2025.112657
Claim in pharmacology — inconclusiveinconclusiveworking →
Class-level IC₅₀ ranges for pyrovalerone cathinones span 0.02–8.7 μM at DAT and 0.03–4.6 μM at NET, but α-PiHP was not individually tested in that series.partially supported
All pyrovalerone cathinones tested were potent DAT (IC50 = 0.02-8.7 μM) and NET inhibitors (IC50 = 0.03-4.6 μM) ijms22158277
Participants self-administered α-PiHP intranasally at 15–25 mg, with intranasal cocaine (75–90 mg) as a within-subjects comparatorsupported
α-PHiP 15-25 mg intranasal vs cocaine 75-90 mg intranasal. fphar.2025.1728824
Cardiovascular effects included heart rate increases and blood pressure elevation more sustained than that produced by cocaine at the comparator dosesupported
More sustained blood pressure elevation than cocaine. fphar.2025.1728824
Ten in vivo urinary metabolites have been identified in human users (8 Phase I, 2 Phase II)supported
Ten in vivo urinary metabolites identified (8 Phase I, 2 Phase II). bkac085
In vitro incubation with pooled human liver microsomes confirmed moderate metabolic resistance: 64.7% of α-PiHP remained unmetabolized after 5 hourssupported
After 5h incubation, 64.7% of α-PiHP remained unmetabolised. j.forsciint.2024.112134
Claim in pharmacology — inconclusiveinconclusiveworking →
In postmortem tissue, OH-α-PiHP (4-hydroxy-α-PiHP) co-occurs with the parent compound across all major organs.supported
α-PiHP and metabolite OH-α-PiHP detected and quantified in all postmortem materials including all major organs, blood compartments, vitreous humor, CSF, and adipose tissue. bkad026
summary12 · 11 ok
Claim in summary — inconclusiveinconclusiveworking →
Intranasal administration produces stimulant effects peaking within 20 minutes, with a plasma half-life of approximately 1.1 hours and a primary effect window of 2–4 hours.partially supported
Tmax ~20 min (oral fluid). Half-life ~1.1 h. Effects peaked within first hour. fphar.2025.1728824
α-PiHP first appeared on research chemical markets in China in 2016 and was formally reported to the EMCDDA Early Warning System from Slovenia in December of that yearpartially supported
First reported to EMCDDA from Slovenia in December 2016; in Hungary initially reported August 2016. bkac085
It emerged as a sequential replacement for α-PVP and α-PHP as those compounds were scheduled, and by 2022 it ranked among the top five synthetic cathinones seized by weight across Europesupported
Was among top 5 SCs seized by weight in Europe in 2022. j.neuro.2025.05.005
α-PiHP inhibits the dopamine transporter (DAT) with potency equivalent to α-PVP in vitro and the norepinephrine transporter (NET) at slightly lower potency, while exhibiting no meaningful serotonin transporter (SERT) activity — a pharmacological signature shared across the pyrovalerone classpartially supported
All pyrovalerone cathinones tested were potent DAT (IC50 = 0.02-8.7 μM) and NET inhibitors (IC50 = 0.03-4.6 μM), with no SERT activity at <10 μM. ijms22158277
In vivo, locomotor activation in mice yields an ED₅₀ of 4.0 mg/kg compared to 1.1 mg/kg for α-PVP, a discrepancy attributed to approximately 40% lower peak brain concentrations rather than reduced intrinsic target affinitysupported
ED50 for locomotor activity: α-PiHP 4.0 mg/kg vs α-PVP 1.1 mg/kg (mice). α-PiHP reached ~40% lower Cmax in blood and brain. j.neuro.2025.05.005
The high DAT/SERT selectivity ratio predicts strong reinforcing properties and correspondingly high abuse liability.supported
DAT/SERT ratio surpassed cocaine by >40-fold. 113 seizures total, 37 toxicological casework findings including 5 autopsies. j.forsciint.2025.112657
Cardiovascular toxicity is the primary safety concern: tachycardia and sustained hypertension exceed those of equi-dose cocaine, and sudden cardiac arrest has been documented in fatal casespartially supported
More sustained blood pressure elevation than cocaine. fphar.2025.1728824
Cardiovascular toxicity is the primary safety concern: tachycardia and sustained hypertension exceed those of equi-dose cocaine, and sudden cardiac arrest has been documented in fatal casessupported
Sudden cardiac arrest as cause of death. 12307483pfs.25.010.22917
Life-threatening hyperthermia with rhabdomyolysis and acute kidney injury has been reported following massive oral ingestionsupported
32-year-old male ingested 5 grams of α-PiHP in suicide attempt. Hyperthermia, rhabdomyolysis, acute kidney injury. cureus.70708
No LD₅₀ data exist in any species, and postmortem blood concentrations show substantial overlap between intoxication and fatal exposures (0.3–840 ng/mL), precluding reliable threshold estimationsupported
α-PiHP concentrations: 0.3-840 ng/mL in postmortem blood, 2600 ng/mL in urine, 350 ng/mL in vitreous humor, 88 ng/g in liver. j.forsciint.2026.112917
No substance-specific tolerance, dependence, or withdrawal data have been published; class-level evidence from pyrovalerone cathinones indicates rapid tolerance development during binge use, high psychological dependence liability, and compulsive redosing driven by selective dopaminergic reinforcementsupported
Potential for dependence and abuse well-documented. fpsyt.2017.00156
neuroscience9 · 5 ok
Claim in neuroscience — inconclusiveinconclusiveworking →
At high doses, excessive noradrenergic tone contributes to anxiety, agitation, and the cardiovascular toxicity documented in fatal cases.supported
Sudden cardiac arrest as cause of death. 12307483pfs.25.010.22917
Can blood concentrations predict outcome severity? The wide overlap between intoxication and fatal blood concentrations suggests that pharmacokinetics alone do not determine outcome. Pharmacogenomic variation, body temperature, polydrug context, and environmental factors likely interact with concentration in ways that remain unmodeled.supported
α-PiHP concentrations: 0.3-840 ng/mL in postmortem blood. j.forsciint.2026.112917
Claim in neuroscience — inconclusiveinconclusiveworking →
Claim in neuroscience — inconclusiveinconclusiveworking →
Claim in neuroscience — inconclusiveinconclusiveworking →
At high doses and during prolonged binges, α-PiHP produces hallucinations, delusions, and paranoia consistent with stimulant psychosis — a dopamine-mediated phenomenon involving excessive D₂ receptor activation in mesolimbic circuitssupported
Brain-related adverse effects: encephalopathy, coma, convulsions, sympathomimetic toxidrome, excited/agitated delirium syndrome, serotonin syndrome. ijms24076230
This parallels the psychotomimetic effects of amphetamine and cocaine at high doses and provides a pharmacological explanation for the delirium and violent behavior documented in forensic case series.supported
Aggressive behavior noted; committed offenses were often violent crimes. bkae011
Does α-PiHP produce lasting dopaminergic neurotoxicity? Chronic methamphetamine exposure damages dopaminergic terminals; whether pyrovalerone cathinones, which inhibit rather than release dopamine, produce comparable terminal damage is unknown. The systematic review by Daziani and colleagues identifies neurotoxicity as a plausible but unquantified risk for the synthetic cathinone class.supported
Systematic review of neurotoxic mechanisms of synthetic cathinones. Brain-related adverse effects: encephalopathy, coma, convulsions. ijms24076230
history8 · 6 ok
The first confirmed fatality primarily attributable to α-PiHP, including comprehensive postmortem tissue distribution and identification of the OH-α-PiHP metabolite in postmortem specimens, was published by Wachholz and colleagues in 2023.supported
First reported case of death caused by α-PiHP alone. α-PiHP and metabolite OH-α-PiHP detected and quantified in all postmortem materials including all major organs, blood compartments, vitreous humor, CSF, and adipose tissue. bkad026
The WHO Expert Committee on Drug Dependence evaluated α-PiHP at its 45th meeting in October 2022 and recommended international scheduling, concluding that the compound "can inhibit the uptake of dopamine and norepinephrine more potently than substances with known abuse potential, including methcathinone, cocaine and methamphetamine". α-PiHP was placed into Schedule II of the 1971 Convention on Psychotropic Substances in March 2023partially supported
Scheduled II under international control in March 2023. life14040429
The compound was designed as a structural variant of α-PHP — itself a successor to α-PVP and MDPV — optimized to exploit regulatory gaps as predecessor pyrovalerone cathinones were sequentially scheduled. α-PiHP was first identified in seized material in China in 2016partially supported
Review of 29 synthetic cathinones emerging 2019-2022. α-PiHP discussed in context of emerging cathinone market. s11419-022-00639-5
The compound was designed as a structural variant of α-PHP — itself a successor to α-PVP and MDPV — optimized to exploit regulatory gaps as predecessor pyrovalerone cathinones were sequentially scheduled. α-PiHP was first identified in seized material in China in 2016supported
α-PiHP first identified in China in 2016. life14040429
The compound remained rare in European forensic casework until approximately 2021, when consumption became widespread in Hungary and other member states.supported
Widespread in Hungary from 2021. bkac085
Claim in history — inconclusiveinconclusiveworking →
In Taiwan, the compound's widespread use and its near-identical analytical profile to α-PHP drove development of specialized mass spectrometric methods to distinguish the two isomers in urinalysis.partially supported
Seven real urine samples analyzed. Machine learning models 100% classification accuracy. j.forsciint.2024.112134
Claim in history — inconclusiveinconclusiveworking →
comparative-pharmacology7 · 4 ok
The critical difference is pharmacokinetic: α-PiHP reaches approximately 40% lower peak concentrations in blood and brain than α-PVP at equivalent doses in mice, yielding a four-fold higher locomotor ED₅₀ (4.0 vs. 1.1 mg/kg)supported
ED50 for locomotor activity: α-PiHP 4.0 mg/kg vs α-PVP 1.1 mg/kg (mice). α-PiHP reached ~40% lower Cmax in blood and brain. j.neuro.2025.05.005
In the De la Rosa 2025 observational study, intranasal α-PiHP (15–25 mg) produced a stimulant profile broadly similar to intranasal cocaine (75–90 mg), with two notable differences: blood pressure elevation was more sustained with α-PiHP, and the dose required for subjectively comparable effects was substantially lower by weightsupported
More sustained blood pressure elevation than cocaine. α-PHiP 15-25 mg intranasal vs cocaine 75-90 mg intranasal. fphar.2025.1728824
In vitro DAT inhibitory potency is equivalent between the two compoundssupported
potency equivalent to α-PVP for DAT j.neuro.2025.05.005
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
Drug checking services have identified mislabeled samples containing unexpected pyrovalerone cathinones, underscoring the practical importance of this distinction.supported
4F-α-PiHP identified at Australian drug checking service CanTEST. dta.3637
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
receptor-pharmacology7 · 6 ok
The negligible SERT activity explains the absence of prosocial or empathogenic effects and the low mechanistic probability of serotonin syndrome in single-substance exposures — though diagnostic uncertainty with serotonin syndrome has been reported in a clinical overdose case involving massive ingestion.supported
Diagnostic uncertainty between serotonin syndrome and sympathomimetic toxidrome. cureus.70708
In vitro, α-PiHP inhibits dopamine reuptake with potency equivalent to α-PVP at the DATsupported
potency equivalent to α-PVP for DAT j.neuro.2025.05.005
The class-level IC₅₀ range for pyrovalerone cathinones at DAT spans 0.02–8.7 μMsupported
DAT (IC50 = 0.02-8.7 μM) ijms22158277
Methyl-substituted analogs (2-Me-, 3-Me-, 4-Me-α-PiHP) exhibit DAT/SERT selectivity ratios exceeding 40-fold above cocaine, placing the parent compound firmly in the high-reinforcement pharmacological category.supported
DAT/SERT ratio surpassed cocaine by >40-fold. j.forsciint.2025.112657
The class-level IC₅₀ range at NET is 0.03–4.6 μMsupported
NET inhibitors (IC50 = 0.03-4.6 μM) ijms22158277
Pyrovalerone cathinones as a class show no meaningful SERT inhibition below 10 μMsupported
no SERT activity at <10 μM ijms22158277
Claim in receptor-pharmacology — inconclusiveinconclusiveworking →
clinical-evidence5 · 5 ok
De la Rosa and colleagues (2025) enrolled 17 healthy adults with prior psychostimulant experience and measured pharmacokinetic and pharmacodynamic outcomes following self-administered intranasal α-PiHP (15–25 mg) with intranasal cocaine (75–90 mg) as a within-subjects comparatorsupported
First human observational study of α-PHiP. n=17 healthy adults with prior psychostimulant experience. α-PHiP 15-25 mg intranasal vs cocaine 75-90 mg intranasal. fphar.2025.1728824
Severe non-fatal intoxication: A 32-year-old male ingested approximately 5 grams of α-PiHP in a suicide attempt, presenting with severe hyperthermia, rhabdomyolysis, and acute kidney injury. Dantrolene (a skeletal muscle calcium channel blocker) was administered when cyproheptadine was unavailable and produced prompt temperature reduction. Diagnostic uncertainty between sympathomimetic toxidrome and serotonin syndrome was noted.supported
32-year-old male ingested 5 grams of α-PiHP in suicide attempt. Hyperthermia, rhabdomyolysis, acute kidney injury. Dantrolene administered to control hyperthermia. Diagnostic uncertainty between serotonin syndrome and sympathomimetic toxidrome. cureus.70708
Fatal polydrug poisoning: A 40-year-old coal miner suffered sudden cardiac arrest; postmortem analysis revealed α-PiHP (blood 0.062 μg/mL, urine 0.163 μg/mL) with OH-α-PiHP metabolite (blood 0.080 μg/mL, urine 1.50 μg/mL) and tramadol at toxic blood concentration (1.60 μg/mL).supported
40-year-old coal miner found unresponsive with cardiac arrest. Toxicology: α-PiHP at 0.062 μg/mL (blood) and 0.163 μg/mL (urine); OH-α-PiHP at 0.080 and 1.50 μg/mL. Tramadol at 1.60 μg/mL (blood, toxic concentration). 12307483pfs.25.010.22917
First confirmed α-PiHP fatality: Wachholz and colleagues (2023) published comprehensive postmortem tissue distribution data from the first death accepted as primarily attributable to α-PiHP following full autopsy, histopathology, and toxicology.supported
First reported case of death caused by α-PiHP alone. α-PiHP and metabolite OH-α-PiHP detected and quantified in all postmortem materials including all major organs, blood compartments, vitreous humor, CSF, and adipose tissue. bkad026
Finnish postmortem series: Among 118 deaths involving synthetic cathinones (2018–2023), α-PiHP was detected with a median femoral blood concentration of 0.14 mg/L (range 0.03–2.1 mg/L). The population was 82% male with a median age of 35. Concomitant opioids, stimulants, or sedatives were present in 69–92% of cases.supported
136 SC findings in 118 death cases in Finland 2018-2023. Median femoral blood concentration of α-PiHP in fatal poisonings: 0.14 mg/L (range 0.03-2.1 mg/L). 82% male, median age 35. 69-92% had concomitant opioids, stimulants, or sedatives. j.forsciint.2024.112297
pharmacokinetic-detail5 · 4 ok
The wide overlap between intoxication and fatal blood concentrations precludes establishing a reliable lethal thresholdsupported
α-PiHP concentrations: 0.3-840 ng/mL in postmortem blood. j.forsciint.2026.112917
The high interindividual variability observed across oral fluid, urine, sweat, and dried blood spots in the De la Rosa study likely reflects differences in nasal mucosal absorption, hepatic metabolism rate, and body composition.supported
High interindividual variability. Samples: oral fluid, urine, sweat, dried blood spots. fphar.2025.1728824
In mice, α-PiHP reaches approximately 40% lower peak concentrations (C_max) in blood and brain compared to α-PVP at equivalent doses, despite comparable in vitro DAT inhibitory potencysupported
α-PiHP reached ~40% lower Cmax in blood and brain. potency equivalent to α-PVP for DAT j.neuro.2025.05.005
Primary Phase I metabolic pathways: β-ketone reduction (most abundant), aliphatic hydroxylation, pyrrolidine ring oxidation, and ring-opening with carboxylationpartially supported
Primary metabolites: β-ketone reduction (M1), aliphatic hydroxylation (M2). Nine Phase I metabolites identified. j.forsciint.2024.112134
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
chemistry2 · 1 ok
Claim in chemistry — inconclusiveinconclusiveworking →
This single structural difference — methyl branch position — is sufficient to produce measurable pharmacokinetic differences while preserving the core pharmacological mechanism.supported
potency equivalent to α-PVP for DAT. α-PiHP reached ~40% lower Cmax in blood and brain. j.neuro.2025.05.005
effects-overview2 · 1 ok
Claim in effects-overview — inconclusiveinconclusiveworking →
The closest experiential comparator is α-PVP, which shares the reuptake-inhibitor-only mechanism and DAT-selective profile but reaches higher peak brain concentrations at equivalent doses, producing greater intensity per milligramsupported
potency equivalent to α-PVP for DAT. α-PiHP reached ~40% lower Cmax in blood and brain. j.neuro.2025.05.005
legal-status1 · 1 ok
α-PiHP is internationally controlled under Schedule II of the 1971 United Nations Convention on Psychotropic Substances, effective March 2023, following the recommendation of the WHO Expert Committee on Drug Dependence at its 45th meetingsupported
Scheduled II under international control in March 2023. life14040429