generation run 2026-05-11
64 min completedmodel pipeline-v5plan not recordedrun/0331fb77…Selection
Verification
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- seen / partial
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The model's own caveats
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- structural_inference
Reproduce
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- 20 source keys (listed under Sources)
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- not recorded — template version, prompt hash and git SHA are written from 2026-09 onward
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16 searches — query, source, results, what was kept and why
| # | source | query | seen | kept | rationale |
|---|---|---|---|---|---|
| 1 | WebSearch | hexedrone legal status scheduling United States UK EU 2024 | 10 | 2 | Legal status for key jurisdictions |
| 2 | PubMed · absence | N-ethyl-hexedrone HEXEN metabolism pharmacokinetics urine blood | 0 | — | Searched for pharmacokinetics; no specific results |
| 3 | PubMed | hexedrone cathinone pharmacology | 5 | 4 | All directly relevant to hexedrone or its close analogue NEH pharmacology and toxicology |
| 4 | PubChem | hexedrone | 1 | 1 | Primary chemical identity verification |
| 5 | DEA Orange Book PDF | hexedrone scheduling status | 1 | — | Legal status verification for US |
| 6 | OpenAlex | N-ethyl-hexedrone dopamine transporter inhibitor reuptake stimulant | 13 | 3 | Critical clinical PK data for NEH; relevant SAR and epidemiology reviews |
| 7 | Crossref/DOI | 10.1007/s11419-017-0360-2 | 1 | 1 | Verified the hexedrone primary characterization paper |
| 8 | ClinicalTrials.gov · absence | hexedrone cathinone stimulant | 0 | — | No clinical trials exist |
| 9 | WebSearch | hexedrone first identified market 2016 2017 forensic EMCDDA | 10 | 1 | Primary characterization/history paper for hexedrone |
| 10 | OpenAlex | hexedrone synthetic cathinone | 52 | 5 | High-citation reviews and primary data papers covering hexedrone/NEH class |
| 11 | DEA Orange Book | hexedrone scheduling status | 1 | — | US legal status verification |
| 12 | PubMed | Fatal N-ethylhexedrone intoxication journal analytical toxicology | 2 | 2 | Critical case report data and fatality review |
| 13 | PubMed | Persson cathinone neurotransmitter inhibition fluorescent dye DAT NET SERT | 1 | 1 | Key pharmacological data with specific IC50 values for NEH at monoamine transporters |
| 14 | Crossref DOI | 10.1007/s11419-017-0360-2 | 1 | 1 | Verified primary hexedrone characterization paper |
| 15 | PubMed | N-ethylhexedrone 3-hydroxyphencyclidine severe toxicity analytically confirmed | 1 | 1 | Case report of NEH toxicity |
| 16 | WebSearch | hexedrone Canada Sweden legal status controlled cathinone 2024 | 10 | 4 | International legal status information |
61 claims by section — every cited sentence, checked against its source
safety18 · 16 ok
Kovács et al. (2019): A 23-year-old male with pre-existing cardiac disease (childhood arrhythmia, hypertrophic/dilated cardiomyopathy, severe atherosclerosis, BMI 42.9) died within hours of consuming NEH and the synthetic cannabinoid ADB-FUBINACA. Postmortem blood NEH concentration was 285 ng/mL. Hyperthermia-related pathology was present, with cardiac disease considered a significant co-factor. Suspected non-fatal user blood levels in the same study were ≤83.9 ng/mL.supported
Case: 23-year-old male with prior arrhythmia history. BMI 42.9, hypertrophic/dilated heart, severe atherosclerosis. Postmortem blood NEH: 285 ng/mL; ADB-FUBINACA: 0.08 ng/mL. Suspected user blood levels ≤83.9 ng/mL. NEH concluded primary cause of death; cardiac disease co-factor. j.jflm.2019.04.012
Domagalska et al. (2021): A 21-year-old male with no documented pre-existing disease was admitted with disorientation, aggression, and loss of consciousness. He developed hyperthermia exceeding 41 °C, tachycardia >160 bpm, tachypnea, blood pressure 110/60 mmHg, and acute kidney failure. Death occurred within hours of hospitalization. Postmortem blood NEH concentration was 145 ng/mL. The ingested powder had been initially misidentified as cocaine; re-analysis confirmed NEH. Low concentrations of amphetamine and THC-COOH were also detected.supported
Case of fatal NEH intoxication in a 21-year-old male. No pre-existing disease. Admitted for disorientation, aggression, loss of consciousness. Hyperthermia >41°C, tachycardia >160 bpm, tachypnea 20 breaths/min, BP 110/60 mmHg, acute kidney failure. Death after a few hours. Postmortem blood NEH: 145 ng/mL. Amphetamine at low concentration and THC-COOH also detected. Powder initially misidentified as cocaine. bkaa159
Claim in safety — inconclusiveinconclusiveworking →
Dunlop et al. (2020) reported analytically confirmed severe toxicity from combined 3-HO-PCP and NEH use.supported
Analytically confirmed case of acute toxicity from combined 3-HO-PCP and NEH use. NEH identified as the cathinone component. s13181-019-00734-x
Cardiovascular toxicity of cathinone stimulants has been comprehensively reviewed by Mladěnka et al. (2018)supported
Systematic overview of cardiovascular toxicity of drugs. Covers illicit sympathomimetic drugs (cocaine, amphetamines, cathinones). med.21476
Pre-existing cardiac conditions — arrhythmia, cardiomyopathy, atherosclerosis — substantially increase the risk of fatal outcome, as demonstrated in the Kovács (2019) case.supported
Case: 23-year-old male with prior arrhythmia history. BMI 42.9, hypertrophic/dilated heart, severe atherosclerosis. NEH concluded primary cause of death; cardiac disease co-factor. j.jflm.2019.04.012
In vitro, the N-ethyl cathinone series (including NEH) displays greater cytotoxicity than methamphetamine in PC12 neuronal-like cells, with toxicity increasing as the α-carbon chain lengthenssupported
PC12 cells for cytotoxicity. Side-chain elongation increases cytotoxicity (better membrane penetration). All more cytotoxic than methamphetamine. acschemneuro.2c00772
Chronic cathinone use is associated with acute psychosis, hypomania, paranoid ideation, and delusions — a psychiatric risk profile comparable to amphetamine-type stimulantssupported
Chronic cathinone use: acute psychosis, hypomania, paranoid ideation, delusions. fpsyt.2017.00156
Post-intoxication psychiatric symptoms documented in the NEH case series include anxiety, feelings of persecution, anhedonia, abulia, and psychomotor slowingsupported
Clinical effects: anxiety, feelings of persecution, asthenia, anhedonia, abulia, psychomotor slowing, loss of consciousness. bkae040
Class-level expectation: a dopaminergic rebound syndrome characterized by depression, irritability, cognitive fatigue, hypersomnia, and increased appetite following cessation — consistent with the post-intoxication symptoms described in NEH clinical cases.supported
Clinical effects: anxiety, feelings of persecution, asthenia, anhedonia, abulia, psychomotor slowing, loss of consciousness. bkae040
The Domagalska (2021) fatal case involved concomitant amphetamine, and the Kovács (2019) fatality involved co-administration of the synthetic cannabinoid ADB-FUBINACA, though the interaction mechanism with synthetic cannabinoids is poorly understood.supported
Amphetamine at low concentration and THC-COOH also detected. bkaa159
The Domagalska (2021) fatal case involved concomitant amphetamine, and the Kovács (2019) fatality involved co-administration of the synthetic cannabinoid ADB-FUBINACA, though the interaction mechanism with synthetic cannabinoids is poorly understood.supported
Postmortem blood NEH: 285 ng/mL; ADB-FUBINACA: 0.08 ng/mL. ADB-FUBINACA metabolites also identified. j.jflm.2019.04.012
CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion) may increase hexedrone plasma concentrations if CYP2D6 is involved in its metabolism, as inferred from analog datasupported
Key CYPs: CYP2C19 (hydroxylation and dealkylation), CYP2D6 and CYP1A2 (hydroxylation only). dta.3179
Serotonergic agents (SSRIs, SNRIs, triptans) carry theoretical serotonin syndrome risk at high hexedrone doses, though NEH's extreme DAT/SERT selectivity (ratio 264–356) makes this interaction substantially lower-risk than with mixed-mechanism cathinones such as mephedrone.supported
DAT/SERT ratio=264-356. SERT >10 µM. High selectivity for DAT. ijms22158277
The fatal case reported by Kovács et al. (2019) explicitly identified pre-existing cardiac pathology (childhood arrhythmia, hypertrophic/dilated cardiomyopathy, severe atherosclerosis) as a co-factor in the fatal outcome.supported
Case: 23-year-old male with prior arrhythmia history. BMI 42.9, hypertrophic/dilated heart, severe atherosclerosis. NEH concluded primary cause of death; cardiac disease co-factor. j.jflm.2019.04.012
Renal impairment is a relative contraindication, given the acute kidney failure documented in the Domagalska (2021) fatal case.supported
Acute kidney failure. Death after a few hours. Postmortem blood NEH: 145 ng/mL. bkaa159
Claim in safety — not_supportednot supportedworking →
Psychiatric conditions — particularly psychotic spectrum disorders, bipolar disorder, and severe anxiety disorders — represent relative contraindications due to the risk of stimulant-induced psychosis and psychiatric destabilization.supported
Chronic cathinone use: acute psychosis, hypomania, paranoid ideation, delusions. fpsyt.2017.00156
pharmacology8 · 8 ok
Metabolites identified in NEH cases include reduced NEH, dealkyl-NEH, reduced dealkyl-NEH, and hydroxy-NEHsupported
4 metabolites: reduced NEH, dealkyl-NEH, reduced dealkyl-NEH, hydroxy-NEH. bkae040
This classification is established for the closely related N-ethylhexedrone (NEH): Kolaczynska et al. (2021) demonstrated that NEH produces no monoamine efflux at DAT, NET, or SERT in human transporter-expressing HEK293 cells, confirming a pure reuptake inhibition mechanismsupported
No monoamine efflux (reuptake inhibitor, not releaser). Alkyl chain extension enhances NET/DAT inhibition. ijms22158277
NEH — the most closely related compound for which transporter data exist — shows no releasing activity at any monoamine transportersupported
No monoamine efflux (reuptake inhibitor, not releaser). ijms22158277
The compound's high DAT selectivity over SERT (DAT/SERT ratio of 264–356 for NEH) places it in the same pharmacological category as cocaine rather than mixed-mechanism cathinones such as mephedrone or MDMAsupported
DAT/SERT ratio=264-356. High selectivity for DAT indicates strong psychostimulant effects and high abuse liability. ijms22158277
In a controlled administration study of 30 mg intranasal NEH in six volunteer consumers, the compound was detectable in oral fluid within the first hour post-administration, and approximately 0.2% of the administered dose was excreted in sweat over four hourssupported
Controlled administration study: 30 mg NEP and NEH intranasally in 6 consumers. Oral fluid absorption within first hour for intranasal route; sweat excretion ~0.2% of dose for NEH over 4 hours. ijms24119387
A clinical case series of three NEH-intoxicated patients provided the first elimination kinetic estimates: plasma elimination half-life of 19–28 hours, with urine detection persisting up to 10 days post-dosesupported
Half-life: 19-28 hours. NEH detectable up to Day 10. bkae040
By analogy with mexedrone (a structurally related N-methyl cathinone), the primary metabolic pathways likely involve CYP2C19 (hydroxylation and N-dealkylation), CYP2D6 (hydroxylation), and CYP1A2 (hydroxylation)supported
Key CYPs: CYP2C19 (hydroxylation and dealkylation), CYP2D6 and CYP1A2 (hydroxylation only). dta.3179
Flavin monooxygenase (FMO) may contribute to N-oxide formation, as demonstrated for the related pyrovalerone MDPV.supported
FMO responsible for N-oxide metabolite formation. j.jpba.2016.08.025
comparative-pharmacology7 · 5 ok
Nadal-Gratacós et al. (2023) systematically characterized the N-ethyl variants, demonstrating that DAT potency follows an inverted-U relationship with α-carbon chain length: the propyl chain (pentedrone/N-ethylpentedrone) represents peak potency, with the butyl chain (NEH) and longer chains showing progressive potency reduction.supported
Potency increases with side chain from methyl to propyl then decreases (inverted U). acschemneuro.2c00772
NEH's DAT IC₅₀ (44.5–170 nM, depending on assay) places it in the same potency range as cocaine (DAT IC₅₀ = 111 nM by the Persson fluorescent dye method) and substantially more potent than amphetamine (257 nM)supported
NEH (N-ethylhexedrone) DAT IC50 = 44.5 nM, more potent than cocaine (111 nM) and amphetamine (257 nM). dta.3547
Cocaine is also a reuptake inhibitor but acts non-selectively across DAT, NET, and SERT, whereas NEH (and by extension hexedrone) is highly DAT-selective.supported
DAT/SERT ratio=264-356. High selectivity for DAT indicates strong psychostimulant effects and high abuse liability. ijms22158277
The pyrovalerone cathinones (α-PVP, MDPV, MPHP) share hexedrone's NDRI mechanism but achieve substantially higher DAT potency — MPHP shows DAT IC₅₀ of 4.53 nM, approximately 10–40 times more potent than NEHsupported
MPHP most potent (IC50 4.53 nM). NEH (N-ethylhexedrone) DAT IC50 = 44.5 nM. dta.3547
In vitro cytotoxicity data from Nadal-Gratacós et al. (2023) demonstrate that the N-ethyl cathinone series, including NEH, displays greater cytotoxicity than methamphetamine in PC12 neuronal-like cellssupported
PC12 cells for cytotoxicity. All more cytotoxic than methamphetamine. acschemneuro.2c00772
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
pharmacokinetic-detail6 · 6 ok
Lefeuvre et al. (2024) reported serial plasma and urine concentrations in three patients hospitalized after intranasal NEH use:supported
Three NEH intoxication cases. Patients admitted to ED 12-24h after nasal intake. Plasma NEH: 97.2→0.7 µg/L (Day 1→7, Case 1); Urine: 724→0.5 µg/L (D1→D7, Case 1). bkae040
Four metabolites have been identified in NEH clinical cases: reduced NEH, dealkyl-NEH, reduced dealkyl-NEH, and hydroxy-NEHsupported
4 metabolites: reduced NEH, dealkyl-NEH, reduced dealkyl-NEH, hydroxy-NEH. bkae040
By analogy with mexedrone (3-methoxy-2-(methylamino)-1-(4-methylphenyl)propan-1-one), the following CYP isoforms are likely involved:supported
In vitro Phase I metabolism of mexedrone using human liver microsomes and recombinant CYP450. Key CYPs: CYP2C19 (hydroxylation and dealkylation), CYP2D6 and CYP1A2 (hydroxylation only). dta.3179
FMO: N-oxide formation (by analogy with MDPV)supported
FMO responsible for N-oxide metabolite formation. j.jpba.2016.08.025
Confirmatory identification requires LC-MS/MS or GC-MS/MSsupported
Validated GC-MS/MS method for 4-CMC, NEP, and NEH (N-ethyl hexedrone). ijms24119387
Confirmatory identification requires LC-MS/MS or GC-MS/MSsupported
Validated LC-MS/MS method (LOD 0.07 ng/mL). bkaa159
receptor-pharmacology6 · 4 ok
Both measurements confirm that NEH is a potent DAT inhibitor exceeding cocaine's DAT potency (cocaine DAT IC₅₀ = 111 nM by the Persson method) and substantially more potent than amphetamine (DAT IC₅₀ = 257 nM).supported
NEH (N-ethylhexedrone) DAT IC50 = 44.5 nM, more potent than cocaine (111 nM) and amphetamine (257 nM). dta.3547
The DAT/SERT selectivity ratio of 264–356 positions NEH — and, by structural inference, hexedrone — firmly in the dopaminergic stimulant category alongside cocaine and the pyrovalerone cathinones, rather than with mixed serotonergic-dopaminergic agents such as mephedrone (DAT/SERT ratio near unity) or MDMA (SERT-preferring).supported
DAT/SERT ratio=264-356. High selectivity for DAT indicates strong psychostimulant effects and high abuse liability. ijms22158277
Kolaczynska et al. additionally confirmed no monoamine releasing activity for NEH at DAT, NET, or SERTsupported
No monoamine efflux (reuptake inhibitor, not releaser). ijms22158277
Persson et al. (2024) ranked DAT inhibitory potency across seven cathinones using their fluorescent dye method:supported
Validated fluorescent dye method for DAT, SERT, NET inhibition in 384-well format. All 7 cathinones showed DAT > NET > SERT profile. MPHP most potent (IC50 4.53 nM). dta.3547
Claim in receptor-pharmacology — inconclusiveinconclusiveworking →
Claim in receptor-pharmacology — inconclusiveinconclusiveworking →
summary6 · 4 ok
Claim in summary — inconclusiveinconclusiveworking →
As a DAT-selective NDRI, hexedrone is presumed to potentiate dopaminergic and noradrenergic signaling without inducing monoamine efflux — a mechanism confirmed for NEH, which shows DAT IC₅₀ values of 44.5–170 nM and negligible serotonin transporter activity (SERT IC₅₀ >10 µM)supported
NEH: DAT IC50=0.17 µM, NET IC50=0.18 µM, SERT >10 µM. DAT/SERT ratio=264-356. No monoamine efflux (reuptake inhibitor, not releaser). ijms22158277
As a DAT-selective NDRI, hexedrone is presumed to potentiate dopaminergic and noradrenergic signaling without inducing monoamine efflux — a mechanism confirmed for NEH, which shows DAT IC₅₀ values of 44.5–170 nM and negligible serotonin transporter activity (SERT IC₅₀ >10 µM)supported
NEH (N-ethylhexedrone) DAT IC50 = 44.5 nM, more potent than cocaine (111 nM) and amphetamine (257 nM). All 7 cathinones showed DAT > NET > SERT profile. DAT/SERT ratio for NEH in hundreds (highly selective). dta.3547
Fatal intoxications from NEH have occurred at postmortem blood concentrations of 145–285 ng/mL, with hyperthermia exceeding 41 °C, severe tachycardia, and acute kidney failure documented in case reportssupported
Postmortem blood NEH: 285 ng/mL. NEH concluded primary cause of death. j.jflm.2019.04.012
Claim in summary — not_supportednot supportedworking →
Fatal intoxications from NEH have occurred at postmortem blood concentrations of 145–285 ng/mL, with hyperthermia exceeding 41 °C, severe tachycardia, and acute kidney failure documented in case reportssupported
Hyperthermia >41°C, tachycardia >160 bpm, tachypnea 20 breaths/min, BP 110/60 mmHg, acute kidney failure. Death after a few hours. Postmortem blood NEH: 145 ng/mL. bkaa159
neuroscience4 · 4 ok
The high DAT/SERT selectivity ratio (264–356 for NEH) predicts that dopaminergic reward signaling dominates the acute subjective experience, with minimal serotonergic modulation of mood or perception.supported
DAT/SERT ratio=264-356. High selectivity for DAT indicates strong psychostimulant effects and high abuse liability. ijms22158277
Norepinephrine reuptake inhibition at NET (IC₅₀ ~180 nM for NEH) is expected to enhance prefrontal cortical function at low-to-moderate doses — increasing focused attention, working memory, and task motivation via increased noradrenergic tone in the dorsolateral prefrontal cortexsupported
NEH: DAT IC50=0.17 µM, NET IC50=0.18 µM, SERT >10 µM. ijms22158277
The post-intoxication syndrome described in NEH clinical cases — depression, irritability, anhedonia, abulia, psychomotor slowing — is consistent with temporary dopaminergic depletion following sustained DAT blockadesupported
Clinical effects: anxiety, feelings of persecution, asthenia, anhedonia, abulia, psychomotor slowing, loss of consciousness. bkae040
1. Does hexedrone produce neurotoxicity at recreational doses? In vitro data show that NEH is more cytotoxic than methamphetamine in PC12 cells, but no in vivo neurotoxicity assessment has been published. Whether repeated hexedrone exposure causes dopaminergic terminal damage (as documented for methamphetamine) is unknown.supported
PC12 cells for cytotoxicity. All more cytotoxic than methamphetamine. Swiss CD-1 mice for in vivo effects. NEC and NEB show rewarding properties; all induce anxiety-like behavior at high doses. acschemneuro.2c00772
chemistry2 · 0 ok
clinical-evidence2 · 2 ok
The only controlled administration data come from Nuñez-Montero et al. (2023), who administered 30 mg intranasal NEH to six volunteer consumers in a pharmacokinetic study designed to validate a GC-MS/MS bioanalytical method for oral fluid and sweatsupported
Validated GC-MS/MS method for 4-CMC, NEP, and NEH (N-ethyl hexedrone). Controlled administration study: 30 mg NEP and NEH intranasally in 6 consumers. First preliminary human PK data for NEH. ijms24119387
Lefeuvre et al. (2024) published the most clinically informative case series: three patients admitted to emergency departments 12–24 hours after intranasal NEH usesupported
Three NEH intoxication cases. Patients admitted to ED 12-24h after nasal intake. bkae040
history2 · 1 ok
Claim in history — inconclusiveinconclusiveworking →
NEH rapidly became one of the most widely available cathinone stimulants on European NPS markets; by 2017 it was the most frequently seized stimulant designer drug in Hungary.supported
Hungary: NEH most frequently seized stimulant designer drug in 2017. j.jflm.2019.04.012