generation run 2026-05-03
55 min completedmodel pipeline-v5plan not recordedrun/fe69e84d…Selection
Verification
- record
- seen / partial
- working
The model's own caveats
none raised on this run
Reproduce
- inputs
- 16 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
19 searches — query, source, results, what was kept and why
| # | source | query | seen | kept | rationale |
|---|---|---|---|---|---|
| 1 | PubMed | ephenidine pharmacology NMDA dissociative | 2 | 2 | Both directly relevant — Kang et al. is the primary pharmacology paper for ephenidine; Wallach et al. provides class context |
| 2 | PubChem | ephenidine | 1 | 1 | Primary chemical identity data confirming seed data |
| 3 | ClinicalTrials.gov · absence | ephenidine | 0 | 0 | No trials registered |
| 4 | PubMed | diarylethylamine NMDA receptor antagonist dissociative | 4 | 2 | Directly relevant to diarylethylamine class pharmacology and ephenidine context |
| 5 | OpenAlex | get_openalex_work W2508036785 | 1 | 1 | Primary ephenidine paper; checking citation graph to find foundational sources |
| 6 | OpenAlex | ephenidine diarylethylamine dissociative NMDA | 10 | 4 | Selected NPS reviews mentioning ephenidine, analytical identification papers, and dissertation covering ephenidine derivatives |
| 7 | PubMed | toxicokinetics lefetamine diphenylethylamine CYP metabolism | 1 | 1 | Definitive CYP enzyme data for ephenidine |
| 8 | PubMed | lefetamine designer drug metabolism detectability urine GC-MS | 2 | 2 | Definitive metabolism and pharmacokinetics data for ephenidine |
| 9 | WebFetch | ACMD review diphenidine ephenidine methoxphenidine harms | 1 | 1 | Key safety, harms, and UK regulatory context |
| 10 | WebSearch | diphenidine enantiomers stereochemistry R S NMDA receptor selectivity | 10 | 1 | Stereostructure and enantiomeric activity relevant to ephenidine |
| 11 | WebSearch | ephenidine legal status scheduling UK US EU controlled substance | 10 | 2 | Critical legal status and mortality data |
| 12 | WebSearch | ephenidine EMCDDA new psychoactive substance first appearance | 10 | 1 | Adverse event data specific to ephenidine |
| 13 | WebSearch | UK Misuse of Drugs Act 2024 amendment ephenidine Class B | 9 | 1 | Definitive UK legal scheduling date and statutory instrument |
| 14 | ClinicalTrials.gov · absence | ephenidine | 0 | 0 | Confirms no clinical development program for this compound |
| 15 | WebSearch | ephenidine legal status Australia Germany United States analog act scheduling 2024 | 10 | 5 | Legal status across major jurisdictions |
| 16 | WebSearch | WHO ECDD 43rd diphenidine ephenidine scheduling 2021 | 10 | 1 | International scheduling context |
| 17 | Multiple | Stereochemistry ephenidine chiral center enantiomers | 3 | 1 | Stereochemistry assessment |
| 18 | PubChem REST API | CID 110821 property SMILES InChI | 1 | 3 | Core chemical identity data |
| 19 | WebSearch | ephenidine physical properties melting point CAS 60951-19-1 | 10 | 2 | Physical properties for chemical identity section |
69 claims by section — every cited sentence, checked against its source
pharmacology15 · 10 ok
Ephenidine is an uncompetitive, voltage-dependent open-channel blocker of the NMDA receptor, acting at the phencyclidine (PCP) binding site within the ion channel poresupported
Ki: 66 nM at NMDA PCP site... Voltage-dependent NMDA block j.neuropharm.2016.08.004
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
Whole-cell patch clamp recordings in hippocampal pyramidal cells demonstrated that 10 uM ephenidine blocks NMDA receptor-mediated excitatory postsynaptic currents (EPSCs) in a highly voltage-dependent manner, with a block profile described as similar to ketaminesupported
Voltage-dependent NMDA block; blocked LTP in hippocampal CA1 j.neuropharm.2016.08.004
At the same concentration, ephenidine blocked the induction of long-term potentiation (LTP) in CA1 by theta burst stimulation, consistent with disruption of NMDA receptor-dependent synaptic plasticity.supported
blocked LTP in hippocampal CA1 j.neuropharm.2016.08.004
Secondary pharmacological activity at the dopamine transporter (DAT; Ki = 379 nM) and noradrenaline transporter (NET; Ki = 841 nM) confers norepinephrine-dopamine reuptake inhibition, contributing to the stimulant-like components of the subjective effect profile — including euphoria, tachycardia, and hypertensionsupported
Dopamine transporter 379 nM, noradrenaline transporter 841 nM j.neuropharm.2016.08.004
Claim in pharmacology — inconclusiveinconclusiveworking →
Sigma receptor affinities (sigma-1: Ki = 629 nM; sigma-2: Ki = 722 nM) fall within a pharmacologically relevant range, though their specific contribution to subjective effects remains uncharacterised.supported
sigma-1 629 nM, sigma-2 722 nM j.neuropharm.2016.08.004
Claim in pharmacology — inconclusiveinconclusiveworking →
The primary metabolic pathway is N-dealkylation, which cleaves the N-ethyl group to yield diphenidine (N-deethyl-NEDPA) — itself a pharmacologically active NMDA antagonistsupported
Metabolic pathways in rats: N-dealkylation... Key metabolites: N-deethyl-NEDPA (=diphenidine) dta.1621
The primary metabolic pathway is N-dealkylation, which cleaves the N-ethyl group to yield diphenidine (N-deethyl-NEDPA) — itself a pharmacologically active NMDA antagonistpartially supported
Relatively selective NMDAR antagonists with weak off-target effects journal.pone.0157021
Secondary pathways include mono- and bis-hydroxylation of the benzyl ring (with subsequent methylation), hydroxylation of the phenyl ring following N-dealkylation, and Phase II conjugation via glucuronidation and sulfationsupported
mono- and bis-hydroxylation of benzyl ring followed by methylation, hydroxylation of phenyl ring after N-dealkylation, glucuronidation and sulfation dta.1621
Claim in pharmacology — inconclusiveinconclusiveworking →
Human cytochrome P450 contributions to the primary N-dealkylation step, determined by relative activity factor analysis in human microsomes: CYP2B6 (30%), CYP1A2 (27%), CYP2C19 (23%), CYP3A4 (17%), and CYP2D6 (4%)supported
CYP enzymes involved in N-dealkylation of NEDPA (ephenidine): CYP1A2 (27%), CYP2B6 (30%), CYP2C19 (23%), CYP2D6 (4%), CYP3A4 (17%) j.toxlet.2015.08.012
The involvement of four or more CYP enzymes in the primary metabolic step suggests a low risk of clinically significant CYP-mediated drug-drug interactions for this pathwaysupported
Multiple enzyme involvement means low risk of CYP-related drug-drug interactions j.toxlet.2015.08.012
safety13 · 9 ok
In the Corkery et al. (2025) systematic review, 66% of diarylethylamine fatalities involved co-administration of opioids, benzodiazepines, or stimulantssupported
Diphenidine/MXP implicated with other substances in 66% of cases 02698811251349203
Ephenidine's N-dealkylation involves CYP1A2, CYP2B6, CYP2C19, CYP2D6, and CYP3A4supported
CYP enzymes involved in N-dealkylation of NEDPA (ephenidine): CYP1A2 (27%), CYP2B6 (30%), CYP2C19 (23%), CYP2D6 (4%), CYP3A4 (17%) j.toxlet.2015.08.012
The French Addictovigilance Network reported four ephenidine-specific cases between 2012 and 2016, all involving polysubstance usesupported
Ephenidine involved in 4 cases... All polysubstance fcp.12395
Claim in safety — inconclusiveinconclusiveworking →
A systematic review of diarylethylamine-related deaths identified 48 deaths globally, with 40 in Europe and 37 in the United Kingdom occurring between 2014 and 2019supported
48 deaths globally (Europe n=40), 37 in UK 2014-2019 02698811251349203
Two-thirds of deaths involved co-administration of opioids, benzodiazepines, or stimulants, but one-third involved diarylethylamines alone — suggesting intrinsic toxicity potential even without polypharmacy.supported
Diphenidine/MXP implicated with other substances in 66% of cases; one-third of deaths involved MXP/diphenidine alone 02698811251349203
A fatal methoxphenidine poisoning in a 55-year-old man in a chemsex context yielded a postmortem blood concentration of 606 ug/L (femoral) — the only published lethal blood concentration for any diarylethylaminesupported
55-year-old man found dead after chemsex party. MXP in femoral blood (606 μg/L) bkab016
Acute psychological adverse effects documented in ephenidine-related case reports include agitation, confusion, hallucinations, and psychiatric decompensationsupported
Complications: minor (5), moderate (6), serious (4) including psychiatric, neurologic, cardiovascular fcp.12395
Claim in safety — inconclusiveinconclusiveworking →
Compulsive redosing during sessions is documented across multiple sources and is mechanistically consistent with rapid acute tolerance development during a single session.supported
strong addictive potential, high tolerance and compulsive intake 02698811251349203
Claim in safety — inconclusiveinconclusiveworking →
The first formal substance use disorder case in the compound class was documented for methoxphenidine, demonstrating that prolonged, compulsive use can produce clinically diagnosable dependence.supported
First case report of methoxphenidine (structural analog of ephenidine) use disorder reported to the French Addictovigilance Network jcp.0000000000000684
Claim in safety — inconclusiveinconclusiveworking →
history12 · 3 ok
Claim in history — inconclusiveinconclusiveworking →
This work yielded lefetamine (N,N-dimethyl-1,2-diphenylethylamine, L-SPA), which was marketed as an opioid analgesic in Japan and Italy before being controlled due to abuse liabilitysupported
Lefetamine (L-SPA) marketed as opioid analgesic in Japan and Italy, became controlled after abuse s00216-014-8414-3
Claim in history — inconclusiveinconclusiveworking →
Claim in history — inconclusiveinconclusiveworking →
Claim in history — inconclusiveinconclusiveworking →
2008 — First forensic confiscation in Germanysupported
NEDPA (ephenidine) and NPDPA confiscated in Germany in 2008 dta.1621
2013 — Emergence on the NPS market; first French Addictovigilance casepartially supported
18 cases of ephenidine/diphenidine/methoxphenidine complications (2012-2016) fcp.12395
Claim in history — inconclusiveinconclusiveworking →
Claim in history — inconclusiveinconclusiveworking →
Claim in history — inconclusiveinconclusiveworking →
Claim in history — inconclusiveinconclusiveworking →
Claim in history — inconclusiveinconclusiveworking →
summary9 · 6 ok
Ephenidine (N-ethyl-1,2-diphenylethylamine, NEDPA, EPE) is a 1,2-diarylethylamine dissociative that acts as an uncompetitive NMDA receptor antagonist with a binding affinity of Ki = 66 nM at the phencyclidine (PCP) sitesupported
Ki: 66 nM at NMDA PCP site. Voltage-dependent NMDA block j.neuropharm.2016.08.004
First confiscated as a designer drug in Germany in 2008, ephenidine entered wider recreational circulation around 2013 as an alternative to scheduled arylcyclohexylamine dissociativespartially supported
NEDPA (ephenidine) and NPDPA confiscated in Germany in 2008 dta.1621
Claim in summary — inconclusiveinconclusiveworking →
A single primary pharmacology paper — Kang et al. (2017) — established its receptor binding profile and NMDA antagonism mechanism in rat preparationssupported
Ki: 66 nM at NMDA PCP site. Dopamine transporter 379 nM, noradrenaline transporter 841 nM, sigma-1 629 nM, sigma-2 722 nM. Voltage-dependent NMDA block; blocked LTP in hippocampal CA1 j.neuropharm.2016.08.004
Ephenidine blocks the NMDA receptor ion channel pore in a voltage-dependent manner (Ki = 66 nM), with electrophysiological characteristics described as similar to ketaminesupported
Ki: 66 nM at NMDA PCP site... Voltage-dependent NMDA block j.neuropharm.2016.08.004
Secondary inhibition of the dopamine transporter (DAT; Ki = 379 nM) and noradrenaline transporter (NET; Ki = 841 nM) produces stimulant-like components including euphoria and cardiovascular activationsupported
Dopamine transporter 379 nM, noradrenaline transporter 841 nM j.neuropharm.2016.08.004
Claim in summary — inconclusiveinconclusiveworking →
A systematic review of the diarylethylamine class identified 48 deaths globally, though ephenidine-specific mortality is not separately enumeratedsupported
48 deaths globally (Europe n=40), 37 in UK 2014-2019... Diphenidine/MXP implicated 02698811251349203
Claim in summary — inconclusiveinconclusiveworking →
pharmacokinetic-detail6 · 3 ok
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
N-Dealkylation (primary pathway) — cleavage of the N-ethyl group produces diphenidine (N-deethyl-NEDPA), which retains NMDA antagonist activity (Ki approximately 50–130 nM for the racemic mixture)partially supported
Relatively selective NMDAR antagonists with weak off-target effects journal.pone.0157021
N-Dealkylation (primary pathway) — cleavage of the N-ethyl group produces diphenidine (N-deethyl-NEDPA), which retains NMDA antagonist activity (Ki approximately 50–130 nM for the racemic mixture)partially supported
Diphenidine (a direct metabolite of ephenidine via N-deethylation) metabolism studied dta.1946
Key metabolites identified in rat urine include N-deethyl-NEDPA (diphenidine), N-deethyl-hydroxy-NEDPA, hydroxy-NEDPA, and hydroxy-methoxy-NEDPA.supported
Key metabolites: N-deethyl-NEDPA (=diphenidine), N-deethyl-hydroxy-NEDPA, hydroxy-NEDPA, hydroxy-methoxy-NEDPA dta.1621
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
comparative-pharmacology4 · 3 ok
The structural analogue diphenidine inhibited prepulse inhibition (PPI) in rats with an ED50 of 9.5 mg/kg, a standard marker of sensorimotor gating disruption produced by NMDA antagonists and predictive of dissociative effects in humans.supported
DPH inhibited PPI with ED50 9.5 mg/kg in rats journal.pone.0157021
Ephenidine's NMDA affinity (Ki = 66 nM) is approximately 7.5-fold higher than ketamine's and comparable to PCP's, placing it among the more potent NMDA antagonists in this structural classpartially supported
Ki: 66 nM at NMDA PCP site j.neuropharm.2016.08.004
Unlike ketamine, which has minimal monoamine transporter activity at therapeutic concentrations, ephenidine exhibits measurable DAT (Ki = 379 nM) and NET (Ki = 841 nM) inhibitionsupported
Dopamine transporter 379 nM, noradrenaline transporter 841 nM j.neuropharm.2016.08.004
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
chemistry3 · 2 ok
The class is structurally derived from lefetamine (N,N-dimethyl-1,2-diphenylethylamine), a pharmaceutical opioid analgesic that served as the unintentional template for a series of novel psychoactive substancessupported
Lefetamine (L-SPA) marketed as opioid analgesic in Japan and Italy, became controlled after abuse. NEDPA and NPDPA confiscated by German police; lefetamine is the pharmaceutical lead s00216-014-8414-3
Claim in chemistry — inconclusiveinconclusiveworking →
Ephenidine is the N-ethyl member of this series; related compounds include diphenidine (the N-unsubstituted parent amine and primary metabolite of ephenidine), methoxphenidine (2-MeO-diphenidine), and fluorolintane (2'-fluoro-diphenidine).supported
1,2-Diarylethylamines including dissociatives diphenidine, methoxphenidine and ephenidine have appeared as research chemicals. Fluorolintane Ki=87.92 nM at NMDA j.ejphar.2019.172427
neuroscience3 · 3 ok
Ephenidine's electrophysiological effects in hippocampal slices — voltage-dependent channel block and LTP suppression at 10 uM — are consistent with these network-level consequences, though direct confirmation in cortical circuits is absent.supported
Voltage-dependent NMDA block; blocked LTP in hippocampal CA1 j.neuropharm.2016.08.004
The secondary DAT and NET inhibition (Ki = 379 and 841 nM, respectively) would be expected to potentiate mesolimbic dopaminergic signalling, contributing to the euphoric and reinforcing properties that distinguish ephenidine's profile from pure NMDA antagonists.supported
Dopamine transporter 379 nM, noradrenaline transporter 841 nM j.neuropharm.2016.08.004
NMDA-dependent synaptic plasticity disruption: Ephenidine's blockade of LTP induction in hippocampal CA1 directly implicates disruption of synaptic plasticity mechanismssupported
blocked LTP in hippocampal CA1 j.neuropharm.2016.08.004
clinical-evidence2 · 2 ok
A single case of methoxphenidine use disorder — the closest structural analogue with documented dependence — represents the only formal substance use disorder report for the diarylethylamine classsupported
First case report of methoxphenidine (structural analog of ephenidine) use disorder reported to the French Addictovigilance Network jcp.0000000000000684
The French Addictovigilance Network documented four ephenidine-related cases between 2012 and 2016, all involving polysubstance usesupported
Ephenidine involved in 4 cases... All polysubstance fcp.12395
receptor-pharmacology2 · 1 ok
Claim in receptor-pharmacology — inconclusiveinconclusiveworking →
The selectivity ratio between the primary target (NMDA, Ki = 66 nM) and the next most potent target (DAT, Ki = 379 nM) is approximately 5.7-fold, establishing NMDA antagonism as the dominant pharmacological actionsupported
Ki: 66 nM at NMDA PCP site. Dopamine transporter 379 nM j.neuropharm.2016.08.004