generation run 2026-05-07
78 min completedmodel pipeline-v5plan not recordedrun/57e42d9f…Selection
Verification
- record
- seen / partial
- working
The model's own caveats
- sparse_evidence
- structural_inference
- safety_data_unverified
Reproduce
- inputs
- 28 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
20 searches — query, source, results, what was kept and why
| # | source | query | seen | kept | rationale |
|---|---|---|---|---|---|
| 1 | PubChem REST API | CID 163192347 properties | 1 | 2 | Confirmed SMILES and all chemical identity data |
| 2 | WebSearch | hydroxetamine HXE 1620054-73-0 legal status Canada Australia | 10 | 2 | Legal status and toxicology context |
| 3 | PubMed | methoxetamine sigma receptor binding affinity pharmacological profile | 1 | 1 | Pharmacological receptor profiling most relevant to HXE structure |
| 4 | PubMed | ketamine mu opioid receptor interaction antidepressant mechanism | 3 | 2 | Supports MOR activity claim in seed data for arylcyclohexylamine class |
| 5 | Erowid/GOV.UK | methoxetamine legal status UK EU | 1 | 1 | Legal context for HXE as MXE analog — may fall under catch-all clauses |
| 6 | PubChem | hydroxetamine | 1 | 1 | Confirmed chemical identity of HXE |
| 7 | OpenAlex | methoxetamine NMDA receptor dissociative pharmacology | 10 | 3 | Landmark papers on ketamine class pharmacology — highly cited |
| 8 | PubMed | deschloroketamine analogs NMDA receptor dissociative novel psychoactive substances | 1 | 1 | Comprehensive review of arylcyclohexylamine NPS class including ketamine analogs |
| 9 | PsychonautWiki | HXE hydroxetamine | 1 | 2 | Community consensus dosage data cross-check |
| 10 | PubMed | methoxetamine metabolism metabolites pharmacokinetics | 5 | 3 | Metabolic pathway from MXE to HXE; CYP enzyme involvement |
| 11 | PubMed | hydroxetamine pharmacology | 1 | 1 | Only PubMed result for hydroxetamine — key epidemiological data |
| 12 | PubMed | 2-(ethylamino)-2-(3-hydroxyphenyl)cyclohexanone ketamine analog | 1 | 1 | Primary source for HXE NMDAR IC50 — most specific pharmacological data available |
| 13 | WebSearch | hydroxetamine O-desmethyl methoxetamine drug market psychonaut effects | 10 | 3 | Community data and toxicology reference |
| 14 | Federal Register / DEA | methoxetamine MXE Schedule I 2022 | 1 | 1 | Legal precedent for HXE analog status in US |
| 15 | Multiple sources | HXE O-desmethyl methoxetamine identity confirmation | 5 | 4 | Core identity cross-reference |
| 16 | GOV.UK | UK arylcyclohexylamine catch-all definition Class B MDA 1971 | 1 | 1 | UK legal framework determining HXE likely Class B |
| 17 | WebSearch | hydroxetamine HXE legal status Australia Canada | 10 | 2 | Legal status gaps identified |
| 18 | PubMed | methoxetamine toxicity adverse effects case reports | 10 | 4 | Clinical toxicity profile of MXE as basis for HXE risk assessment |
| 19 | PubMed | ketamine bladder cystitis chronic urinary tract | 5 | 3 | Class-level bladder toxicity risk relevant to HXE |
| 20 | CFSRE | hydroxetamine monograph | 1 | 3 | Primary forensic reference for HXE |
74 claims by section — every cited sentence, checked against its source
safety22 · 18 ok
Bladder or urological conditions: Chronic ketamine-class compound use causes progressive urothelial damagesupported
Recreational ketamine users report increased lower urinary tract symptoms. Chronic use leads to LUTS. 000338098
Adamowicz and Zuba reported unintentional fatal MXE intoxication in a 29-year-old male (blood MXE approximately 5.8 µg/mL, urine 85 µg/mL)supported
29-year-old male found dead after MXE use. Blood MXE 5.8 µg/mL, urine 85 µg/mL. Fatal unintentional intoxication confirmed. 1556-4029.12594
Wiergowski et al. described fatal MXE-amphetamine co-intoxication in a 31-year-old male, presenting with deep coma, acute respiratory failure, hyperthermia exceeding 39°C, generalized seizures, rhabdomyolysis, hepatic failure, acute renal failure, and multi-organ dysfunction syndrome; blood MXE was 0.32 µg/mL with amphetamine in a non-toxic range, suggesting the combination — not either substance alone — drove the lethal outcome.supported
31-year-old male MXE+amphetamine fatal poisoning. Rhabdomyolysis, hepatic failure, renal failure, multi-organ dysfunction. Blood MXE 0.32 µg/mL. s13382-014-0290-8
Claim in safety — inconclusiveinconclusiveworking →
Imbert et al. reported acute MXE inhalation toxicity featuring seizures, bradycardia, ST-segment elevation, and hyponatremiasupported
21-year-old MXE inhalation case: seizures, bradycardia, ST elevation, hyponatremia. bku052
Chronic use of ketamine-class compounds is associated with ketamine-associated cystitis (KC), a progressive urothelial injury characterized by urinary frequency, urgency, dysuria, reduced bladder capacity, mucosal ulceration, interstitial fibrosis, and bilateral hydronephrosis in severe casessupported
4 patients with ketamine abuse presenting with dysuria, LUTS, bladder ulceration. j.jfma.2011.11.010
Chronic use of ketamine-class compounds is associated with ketamine-associated cystitis (KC), a progressive urothelial injury characterized by urinary frequency, urgency, dysuria, reduced bladder capacity, mucosal ulceration, interstitial fibrosis, and bilateral hydronephrosis in severe casessupported
Recreational ketamine users report increased lower urinary tract symptoms. Chronic use leads to LUTS. 000338098
Chronic use of ketamine-class compounds is associated with ketamine-associated cystitis (KC), a progressive urothelial injury characterized by urinary frequency, urgency, dysuria, reduced bladder capacity, mucosal ulceration, interstitial fibrosis, and bilateral hydronephrosis in severe casessupported
Long-term ketamine abuse causes interstitial cystitis-like syndrome. Mouse model: cDNA microarray shows fibrosis-related gene expression changes. Reduced voiding interval after 20-week administration. mmr.2016.5482
Chronic use of ketamine-class compounds is associated with ketamine-associated cystitis (KC), a progressive urothelial injury characterized by urinary frequency, urgency, dysuria, reduced bladder capacity, mucosal ulceration, interstitial fibrosis, and bilateral hydronephrosis in severe casessupported
Ketamine abuser with bilateral hydronephrosis and bladder thickening on POCUS. Severe urinary urgency and frequency. westjem.2014.4.20571
Claim in safety — inconclusiveinconclusiveworking →
Compulsive redosing is a recognized pattern with NMDAR antagonist use, driven by mesolimbic dopamine stimulation and the characteristically short subjective peak of some dissociativessupported
MXE is NMDA antagonist with abuse liability, stimulates dopamine in mesolimbic reward pathway. j.neuint.2018.10.020
Claim in safety — inconclusiveinconclusiveworking →
Dependence: Ketamine dependence has been documented clinically, characterized by tolerance development, craving, and dose escalation without a prominent physical withdrawal syndrome at typical use levelssupported
Case demonstrating ketamine dependence with significant tolerance development without prominent withdrawal symptoms. Large doses in polysubstance abuser. pmid:12075653
Preclinical evidence indicates that MXE possesses abuse liability via mesolimbic dopamine stimulationsupported
MXE is NMDA antagonist with abuse liability, stimulates dopamine in mesolimbic reward pathway. j.neuint.2018.10.020
The fatal MXE-amphetamine co-intoxication described by Wiergowski et al. — featuring hyperthermia, rhabdomyolysis, and multi-organ failure at MXE blood levels within the typical intoxication range — demonstrates that combining NMDAR antagonists with sympathomimetic stimulants can produce rapidly lethal synergistic toxicity.supported
31-year-old male MXE+amphetamine fatal poisoning. Rhabdomyolysis, hepatic failure, renal failure, multi-organ dysfunction. Blood MXE 0.32 µg/mL. s13382-014-0290-8
Monoamine oxidase inhibitors (MAOIs) pose a theoretical serotonin syndrome risk given the SERT affinity demonstrated for MXE and serotonergic involvement confirmed in MXE behavioral effectssupported
MXE shows appreciable serotonin transporter affinity. journal.pone.0059334
Monoamine oxidase inhibitors (MAOIs) pose a theoretical serotonin syndrome risk given the SERT affinity demonstrated for MXE and serotonergic involvement confirmed in MXE behavioral effectssupported
5-HT2 receptors confirmed as key mediators. j.expneurol.2021.113836
CYP3A4 and CYP2B6 inhibitors may reduce HXE clearance based on the CYP involvement documented for MXE metabolism, potentially prolonging or intensifying effects.supported
N-deethylation catalyzed by CYP2B6 and CYP3A4. O-demethylation pathway produces HXE. s00216-013-7051-6
Hepatic or renal impairment: MXE has been associated with rhabdomyolysis, hepatic failure, and acute renal failure in fatal and near-fatal casessupported
Rhabdomyolysis, hepatic failure, renal failure, multi-organ dysfunction. Blood MXE 0.32 µg/mL. s13382-014-0290-8
Bladder or urological conditions: Chronic ketamine-class compound use causes progressive urothelial damagesupported
4 patients with ketamine abuse presenting with dysuria, LUTS, bladder ulceration. j.jfma.2011.11.010
Claim in safety — inconclusiveinconclusiveworking →
Concurrent MAOI use: Serotonin syndrome risk from potential SERT engagement.supported
MXE shows appreciable serotonin transporter affinity. journal.pone.0059334
pharmacology15 · 14 ok
Irie et al. measured the NMDAR-blocking potency of HXE using whole-cell patch-clamp recordings from NMDAR-expressing cartwheel interneurons in mouse dorsal cochlear nucleus slices, reporting an IC₅₀ of 0.227 µM — the most potent compound in the series tested, exceeding the parent compound methoxetamine (IC₅₀ = 0.524 µM), deoxymethoxetamine (0.679 µM), methoxisopropamine (0.661 µM), and N-desethyl methoxetamine (1.649 µM). In silico molecular docking confirmed that HXE binds to the same site within the NMDAR channel as MXE.supported
IC50s: MXE 0.524 µM, deoxymethoxetamine 0.679 µM, methoxisopropamine 0.661 µM, N-desethyl MXE 1.649 µM, O-desmethyl MXE (HXE) 0.227 µM. HXE is most potent NMDAR blocker of the group. In silico docking confirmed NMDAR interaction. j.jphs.2022.09.005
Irie et al. measured the NMDAR-blocking potency of HXE using whole-cell patch-clamp recordings from NMDAR-expressing cartwheel interneurons in mouse dorsal cochlear nucleus slices, reporting an IC₅₀ of 0.227 µM — the most potent compound in the series tested, exceeding the parent compound methoxetamine (IC₅₀ = 0.524 µM), deoxymethoxetamine (0.679 µM), methoxisopropamine (0.661 µM), and N-desethyl methoxetamine (1.649 µM). In silico molecular docking confirmed that HXE binds to the same site within the NMDAR channel as MXE.supported
IC50s: MXE 0.524 µM, deoxymethoxetamine 0.679 µM, methoxisopropamine 0.661 µM, N-desethyl MXE 1.649 µM, O-desmethyl MXE (HXE) 0.227 µM. HXE is most potent NMDAR blocker of the group. In silico docking confirmed NMDAR interaction. j.jphs.2022.09.005
The classification of HXE as a mu-opioid receptor (MOR) agonist derives from class-level pharmacology: ketamine and related arylcyclohexylamines engage MORs, with recent evidence arguing that bifunctional NMDAR–MOR modulation underlies both the reinforcing properties and antidepressant efficacy of the ketamine classsupported
Ketamine reinforcement and misuse potential stem from bifunctional engagement with NMDA and mu opioid receptors. Synergistic mechanism relevant to antidepressant and SUD treatment. j.biopsych.2025.11.021
The classification of HXE as a mu-opioid receptor (MOR) agonist derives from class-level pharmacology: ketamine and related arylcyclohexylamines engage MORs, with recent evidence arguing that bifunctional NMDAR–MOR modulation underlies both the reinforcing properties and antidepressant efficacy of the ketamine classsupported
Argues ketamine pharmacology should be redefined to include opioid receptor interactions. Synergistic NMDA/MOR mechanism underlies antidepressant effects. appi.ajp.20240378
The classification of HXE as a mu-opioid receptor (MOR) agonist derives from class-level pharmacology: ketamine and related arylcyclohexylamines engage MORs, with recent evidence arguing that bifunctional NMDAR–MOR modulation underlies both the reinforcing properties and antidepressant efficacy of the ketamine classsupported
Comprehensive review of ketamine and metabolite pharmacology. NMDAR mechanisms, opioid receptor interactions, AMPA potentiation, sigma receptor activity, antidepressant mechanisms. pr.117.015198
Roth et al. profiled MXE and related compounds at the NIMH Psychoactive Drug Screening Program (PDSP) and found that sigma receptor affinity was more prominent in non-β-keto PCP analogs (PCP, 3-MeO-PCP, 4-MeO-PCP) than in the β-keto series to which MXE and HXE belongsupported
Sigma receptor affinity noted primarily in PCP analogs. NIMH PDSP pharmacological profiling. journal.pone.0059334
MXE itself showed high affinity primarily at NMDAR and appreciable affinity at the serotonin transporter (SERT), with limited sigma binding.supported
MXE and 3-MeO-PCE are high affinity NMDA receptor PCP-site ligands. MXE shows appreciable serotonin transporter affinity. Sigma receptor affinity noted primarily in PCP analogs. journal.pone.0059334
Roth et al. identified appreciable SERT affinity for MXE, and Marti et al. demonstrated that MXE (0.25–0.5 mg/kg IV, rat) significantly altered serotonin levels in the medial prefrontal cortex and nucleus accumbens, with 5-HT₂ receptor antagonists attenuating MXE-induced behavioral effectssupported
MXE shows appreciable serotonin transporter affinity. journal.pone.0059334
Roth et al. identified appreciable SERT affinity for MXE, and Marti et al. demonstrated that MXE (0.25–0.5 mg/kg IV, rat) significantly altered serotonin levels in the medial prefrontal cortex and nucleus accumbens, with 5-HT₂ receptor antagonists attenuating MXE-induced behavioral effectssupported
MXE (0.25-0.5 mg/kg IV) significantly altered serotonin in rat mPFC and NAcc. 5-HT2A/C antagonists attenuated MXE-induced motor and sensorimotor effects. 5-HT2 receptors confirmed as key mediators. j.expneurol.2021.113836
Preclinical evidence indicates that MXE stimulates dopamine neurotransmission in the mesolimbic reward pathway, contributing to its abuse liabilitysupported
MXE is NMDA antagonist with abuse liability, stimulates dopamine in mesolimbic reward pathway. j.neuint.2018.10.020
Horsley et al. established HXE (O-desmethylmethoxetamine) as the most abundant urinary metabolite of MXE in Wistar ratssupported
Most abundant urinary metabolite in rats = O-desmethylmethoxetamine (HXE), then normethoxetamine. j.brainresbull.2016.05.002
Meyer et al. identified the metabolic pathways producing HXE from MXE: O-demethylation is a primary Phase I reaction, occurring alongside N-deethylation, hydroxylation, and combinations thereof, followed by Phase II glucuronidation or sulfationsupported
8 metabolites of MXE identified. N-deethylation catalyzed by CYP2B6 and CYP3A4. O-demethylation pathway produces HXE. Phase I and II metabolism characterized. s00216-013-7051-6
Claim in pharmacology — inconclusiveinconclusiveworking →
Larabi et al. characterized the metabolism of 3-HO-PCE, a structurally related 3-hydroxy arylcyclohexylamine lacking the ketone at C-2, and identified analogous metabolic routes including extensive glucuronidation.supported
3-HO-PCE metabolism similar to O-PCE (eticyclidine family). Glucuronidation involved. metabo13030432
MXE pharmacokinetic parameters (rodent data, for context): Horsley et al. reported peak brain concentrations at 30 minutes post-administration (subcutaneous), with a brain-to-serum ratio of 2.06–2.93 throughout the observation period and levels approaching zero at 6 hourssupported
Brain:serum ratio 2.06-2.93. Peak brain levels at 30 min, near-zero at 6h. j.brainresbull.2016.05.002
history7 · 3 ok
Claim in history — inconclusiveinconclusiveworking →
MXE itself emerged on designer drug markets around 2010 as a purported 'bladder-friendly' alternative to ketamine, marketed with claims of a longer duration and reduced urological toxicitypartially supported
MXE emerged 2010. Duration exceeds ketamine. j.brainresbull.2016.05.002
Claim in history — inconclusiveinconclusiveworking →
Horsley et al. subsequently confirmed HXE as the most abundant urinary metabolite of MXE in Wistar rats, with normethoxetamine (N-desethyl MXE) as the secondary metabolitesupported
Most abundant urinary metabolite in rats = O-desmethylmethoxetamine (HXE), then normethoxetamine. j.brainresbull.2016.05.002
Hajkova et al. independently synthesized HXE as an in-house analytical reference standard for forensic identification of MXE metabolites in tissue samples.supported
HXE (O-desmethylmethoxetamine) was synthesized in-house for analytical standards. LOQ 2.5 ng/g in tissues. s00216-015-9221-1
Claim in history — inconclusiveinconclusiveworking →
Claim in history — not_supportednot supportedworking →
receptor-pharmacology7 · 5 ok
Claim in receptor-pharmacology — inconclusiveinconclusiveworking →
Claim in receptor-pharmacology — inconclusiveinconclusiveworking →
Mu-opioid receptor: Class-level engagement is supported by recent evidence demonstrating bifunctional NMDAR–MOR activity as a pharmacological property of arylcyclohexylaminessupported
Ketamine reinforcement and misuse potential stem from bifunctional engagement with NMDA and mu opioid receptors. j.biopsych.2025.11.021
Mu-opioid receptor: Class-level engagement is supported by recent evidence demonstrating bifunctional NMDAR–MOR activity as a pharmacological property of arylcyclohexylaminessupported
Synergistic NMDA/MOR mechanism underlies antidepressant effects. appi.ajp.20240378
MXE administration alters serotonin levels in rat mPFC and NAcc, and 5-HT₂ antagonists attenuate its behavioral effectssupported
MXE (0.25-0.5 mg/kg IV) significantly altered serotonin in rat mPFC and NAcc. 5-HT2A/C antagonists attenuated MXE-induced motor and sensorimotor effects. 5-HT2 receptors confirmed as key mediators. j.expneurol.2021.113836
Sigma receptors: Sigma affinity is less prominent in the β-keto arylcyclohexylamine series (MXE, ketamine) than in the non-keto series (PCP, 3-MeO-PCP)supported
Sigma receptor affinity noted primarily in PCP analogs. journal.pone.0059334
Dopamine: MXE stimulates mesolimbic dopamine neurotransmission preclinicallysupported
MXE is NMDA antagonist with abuse liability, stimulates dopamine in mesolimbic reward pathway. j.neuint.2018.10.020
pharmacokinetic-detail6 · 5 ok
HXE is formed from MXE via CYP-mediated O-demethylation, a Phase I reactionsupported
O-demethylation pathway produces HXE. Phase I and II metabolism characterized. s00216-013-7051-6
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
All rodent PK values from Horsley et al.; CYP data from Meyer et al..supported
Brain:serum ratio 2.06-2.93. Peak brain levels at 30 min, near-zero at 6h. j.brainresbull.2016.05.002
This CNS penetrance is believed to underlie the greater subjective potency of MXE relative to ketamine at equivalent plasma concentrations.supported
Brain:serum ratio 2.06-2.93. Duration exceeds ketamine. j.brainresbull.2016.05.002
Larabi et al. characterized metabolism of the structurally related compound 3-HO-PCE in human liver microsomes and confirmed analogous routes, with glucuronidation as a major Phase II pathwaysupported
3-HO-PCE metabolism similar to O-PCE (eticyclidine family). Glucuronidation involved. metabo13030432
Xu et al. characterized metabolism of related β-keto arylcyclohexylamines and identified parallel biotransformation patterns.supported
Metabolism of deschloro-N-ethyl-ketamine (O-PCE), fluoro-N-ethyl-ketamine, and bromoketamine. 49 metabolites identified. Hydroxy-DCK metabolites recommended as biomarkers. bkae020
comparative-pharmacology4 · 3 ok
This finding has direct safety implications: individuals calibrating HXE doses based on MXE experience may significantly overestimate appropriate dosessupported
MXE 0.524 µM... O-desmethyl MXE (HXE) 0.227 µM. HXE is most potent NMDAR blocker of the group. j.jphs.2022.09.005
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
Ketamine's oral duration (1–2 hours) is markedly shorter than HXE's community-reported 3–8 hours, consistent with the longer duration observed for the MXE structural series.supported
Duration exceeds ketamine. j.brainresbull.2016.05.002
Among MXE and its characterized derivatives, HXE represents the most potent NMDAR antagonist measured to datesupported
HXE is most potent NMDAR blocker of the group. j.jphs.2022.09.005
neuroscience4 · 3 ok
Claim in neuroscience — inconclusiveinconclusiveworking →
Given HXE's IC₅₀ of 0.227 µM at the NMDAR, the threshold for this disconnection is expected to be reached at lower plasma concentrations than for ketamine or MXE.supported
MXE 0.524 µM... O-desmethyl MXE (HXE) 0.227 µM. HXE is most potent NMDAR blocker of the group. j.jphs.2022.09.005
The mesolimbic dopamine system is engaged by NMDAR antagonists through disinhibition of dopaminergic neurons in the ventral tegmental area (VTA), producing reward signaling in the nucleus accumbenssupported
MXE is NMDA antagonist with abuse liability, stimulates dopamine in mesolimbic reward pathway. j.neuint.2018.10.020
HXE's superior NMDAR potency relative to MXE predicts a steeper dose-response curve for dissociative disconnection.supported
O-desmethyl MXE (HXE) 0.227 µM. HXE is most potent NMDAR blocker of the group. j.jphs.2022.09.005
summary4 · 3 ok
Hydroxetamine (HXE, also known as O-desmethylmethoxetamine or 3-HO-2'-Oxo-PCE) is a β-keto arylcyclohexylamine dissociative with potent NMDA receptor antagonist activity (IC₅₀ = 0.227 µM), approximately twice as potent as its parent compound methoxetamine at the NMDAR ion channelsupported
O-desmethyl MXE (HXE) 0.227 µM. HXE is most potent NMDAR blocker of the group. j.jphs.2022.09.005
HXE was first identified in the scientific literature as the primary urinary metabolite of methoxetamine via CYP-mediated O-demethylationpartially supported
O-demethylation pathway produces HXE. Phase I and II metabolism characterized. s00216-013-7051-6
HXE was first identified in the scientific literature as the primary urinary metabolite of methoxetamine via CYP-mediated O-demethylationsupported
Most abundant urinary metabolite in rats = O-desmethylmethoxetamine (HXE), then normethoxetamine. j.brainresbull.2016.05.002
Claim in summary — inconclusiveinconclusiveworking →