generation run 2026-05-03
65 min completedmodel pipeline-v5plan not recordedrun/1248f320…Selection
Verification
- record
- seen / partial
- working
The model's own caveats
- sparse_evidence
- dependence_values_unverified
Reproduce
- inputs
- 20 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
17 searches — query, source, results, what was kept and why
| # | source | query | seen | kept | rationale |
|---|---|---|---|---|---|
| 1 | PubChem | Diphenidine | 1 | 1 | Primary chemical identity source; fills missing fields in seed data (formula, weight, SMILES, InChIKey, CID) |
| 2 | ClinicalTrials.gov · absence | Diphenidine | 0 | 0 | N/A - no trials registered |
| 3 | PubMed | diphenidine new psychoactive substance forensic detection analytical | 3 | 3 | Analytical characterization papers for diphenidine |
| 4 | PubMed | Diphenidine toxicology case report adverse effects | 1 | 1 | References a fatal case involving diphenidine - need to find the primary 2015 Forensic Toxicol paper |
| 5 | PubMed | PMID 26811026 | 1 | 1 | Only published study on diphenidine metabolism; critical for pharmacokinetics section |
| 6 | OpenAlex | Diphenidine dissociative drug | 10 | 4 | High-citation papers that cover diphenidine; Helander and Wallach are substance-specific |
| 7 | PubMed | Diphenidine NMDA receptor pharmacology | 10 | 9 | All directly relevant to diphenidine pharmacology, toxicology, or characterization |
| 8 | PubMed | PMID 27314670 | 1 | 1 | Primary pharmacology paper for diphenidine |
| 9 | WebSearch | diphenidine Searle patent 1989 history discovery | 9 | 4 | History and patent information for diphenidine |
| 10 | PubMed Central | PMC4912077 full text Wallach 2016 diphenidine pharmacology | 1 | 5 | Critical quantitative pharmacology data |
| 11 | PubMed | PMID 29642450 Sahai 2018 DPH DAT dopamine | 1 | 1 | Important mechanistic data distinguishing DPH from MXP at DAT |
| 12 | WebSearch | WHO ECDD 43rd expert committee diphenidine critical review schedule II 2021 | 9 | 2 | International scheduling status confirmed |
| 13 | WebSearch | diphenidine legal status scheduling UK US Canada Australia | 10 | 3 | Legal status data |
| 14 | CrossRef DOI verification | DOI 10.1007/s11419-015-0300-y and related diphenidine Forensic Toxicology papers | 4 | 4 | Key Japan case papers and comprehensive review on diphenidine |
| 15 | Canada Gazette | diphenidine DEP Canada scheduling | 1 | 1 | Canadian legal scheduling confirmation |
| 16 | WebSearch | diphenidine EU Germany scheduling narcotic | 9 | 2 | EU/Germany legal status data |
| 17 | GOV.UK ACMD | ACMD review diphenidine use and harms | 1 | 1 | Authoritative UK government toxicological review |
75 claims by section — every cited sentence, checked against its source
safety19 · 15 ok
Claim in safety — inconclusiveinconclusiveworking →
The best-characterized acute toxicity data come from the Swedish STRIDA case series (n = 17 cases, 14 confirmed diphenidine-positive):supported
Case series of 17 patients: 14 diphenidine-positive, 3 MXP-positive. 15563650.2015.1033630
Median hospitalization was 2 days (range 1–3)supported
Hospitalization 1-3 days. 15563650.2015.1033630
A single Italian case additionally documented miotic pupils (atypical for NMDA dissociatives), increased body temperature, and increased respiratory rate, though co-ingestion of methylphenidate and diclazepam confounded the presentation.supported
Tachycardia, miotic pupils, elevated temperature and respiratory rate. Co-detected methylphenidate and diclazepam. 1556-4029.13355
A fatal case in Japan involved diphenidine alongside AB-CHMINACA and 5-fluoro-AMB; tissue distribution was mapped by MALDI-QTOF mass spectrometrysupported
References an autopsy case (Forensic Toxicol 33:45-53, 2015) where death was caused by AB-CHMINACA, 5-fluoro-AMB and diphenidine combined. j.legalmed.2015.07.011
Three deaths attributed primarily to methoxphenidine also showed diphenidine and hydroxy-diphenidine in post-mortem blood, though it was unclear whether diphenidine arose from MXP biotransformation or separate intake.supported
Three MXP-related deaths. Diphenidine and hydroxy-diphenidine also detected in post-mortem samples (uncertain if metabolite of MXP or separate compound). bkv006
Severe agitation and confusionsupported
Common presentations: anxiety (65%), altered mental status (65%). 15563650.2015.1033630
Severe agitation and confusionsupported
30-year-old male found confused, agitated, unable to communicate. 1556-4029.13355
Claim in safety — inconclusiveinconclusiveworking →
Inability to communicatesupported
30-year-old male found confused, agitated, unable to communicate. 1556-4029.13355
Diphenidine's demonstrated increase in nucleus accumbens dopamine efflux engages the mesolimbic reward pathway and provides a mechanistic basis for potential addictive liabilitysupported
DPH increased DA efflux via DAT binding (autoradiography and voltammetry). DPH suggested to have addictive liability unlike MXP. brainsci8040063
Diclazepam (a designer benzodiazepine) was co-detected in the Italian case report, and ethanol was among co-detected substances in the STRIDA series.supported
Co-detected methylphenidate and diclazepam. 1556-4029.13355
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Diphenidine's SERT IC₅₀ exceeds 10 μM, indicating negligible serotonin reuptake inhibitionsupported
DPH and 2-MXP are relatively selective NMDAR antagonists with weak off-target effects on dopamine and norepinephrine reuptake. journal.pone.0157021
Diphenidine is metabolized by CYP1A2, CYP2B6, CYP2C9, CYP3A4, and CYP2D6supported
CYP1A2, CYP2B6, CYP2C9, CYP3A4 form initial metabolites; CYP2D6 also involved. dta.1946
Pre-existing hypertension, cardiac arrhythmia, or structural heart disease constitute relative contraindications given the 76% hypertension rate and 47% tachycardia rate observed in hospitalized diphenidine casessupported
Common presentations: hypertension (76%), tachycardia (47%). 15563650.2015.1033630
Diphenidine's NMDA antagonism produces hallucinations, delusions, and paranoia and disrupts sensorimotor gating (PPI), consistent with psychotomimetic potentialsupported
DPH inhibited PPI with ED50 9.5 mg/kg in rats. journal.pone.0157021
Diphenidine undergoes extensive hepatic metabolism via multiple CYP enzymessupported
CYP1A2, CYP2B6, CYP2C9, CYP3A4 form initial metabolites; CYP2D6 also involved. Metabolites detectable in rat urine at common user doses. dta.1946
pharmacology10 · 9 ok
Diphenidine functions as an uncompetitive (channel-blocking) NMDA receptor antagonistsupported
DPH and 2-MXP are relatively selective NMDAR antagonists with weak off-target effects on dopamine and norepinephrine reuptake. journal.pone.0157021
Diphenidine functions as an uncompetitive (channel-blocking) NMDA receptor antagonistsupported
DPH at 30 μM reduced NMDA-fEPSPs similarly to ketamine in rat hippocampal slices. dta.1689
A 2026 structure-activity relationship study explicitly characterizes diphenidine as "a prototypical 1,2-diarylethylamine that functions as an uncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist and monoamine reuptake inhibitor".supported
Diphenidine as prototypical 1,2-diarylethylamine - uncompetitive NMDAR antagonist and monoamine reuptake inhibitor. acs.jmedchem.5c02700
At the NMDA receptor phencyclidine binding site, diphenidine displays a Kᵢ of 18.2 ± 2.2 nM — approximately 18-fold more potent than ketamine (~324 nM) at the same sitesupported
Binding studies at 46 CNS receptors for DPH, 2-MXP and analogues. DPH and 2-MXP are relatively selective NMDAR antagonists. journal.pone.0157021
Beyond NMDA antagonism, diphenidine weakly inhibits monoamine reuptake: DAT IC₅₀ = 1.99 μM, NET IC₅₀ = 9.25 μM, and SERT IC₅₀ > 10 μM (effectively inactive)supported
DPH and 2-MXP are relatively selective NMDAR antagonists with weak off-target effects on dopamine and norepinephrine reuptake. journal.pone.0157021
Autoradiography and fast cyclic voltammetry demonstrate that diphenidine increases dopamine efflux in rat nucleus accumbens slices through its DAT interaction, whereas the structurally related methoxphenidine does not produce this effectsupported
DPH increased DA efflux via DAT binding (autoradiography and voltammetry); MXP had no significant effect on DAT. brainsci8040063
Claim in pharmacology — inconclusiveinconclusiveworking →
The metabolic fate of diphenidine has been elucidated using rat urine and pooled human liver microsomes (pHLM) and cytosol (pHLC)supported
Metabolites identified in rat and human liver preparations. dta.1946
The enzymes CYP1A2, CYP2B6, CYP2C9, CYP3A4, and CYP2D6 are all capable of forming the initial metabolites (hydroxy-aryl, hydroxy-piperidine, bis-hydroxy-piperidine).supported
CYP1A2, CYP2B6, CYP2C9, CYP3A4 form initial metabolites (hydroxy-aryl, hydroxy-piperidine, bis-hydroxy-piperidine); CYP2D6 also involved. dta.1946
Biofluid concentrations from a single analytically confirmed non-fatal intoxication case (30-year-old male, Italy) provide the only published human concentration data: plasma 308 ng/mL and urine 631 ng/mL at emergency department presentationsupported
30-year-old male found confused, agitated, unable to communicate. DPH plasma 308 ng/mL, urine 631 ng/mL. 1556-4029.13355
summary10 · 5 ok
Its binding affinity at the NMDA phencyclidine site (Kᵢ = 18.2 ± 2.2 nM) exceeds that of ketamine (~324 nM) but remains below that of phencyclidinesupported
Binding studies at 46 CNS receptors for DPH, 2-MXP and analogues. DPH and 2-MXP are relatively selective NMDAR antagonists with weak off-target effects on dopamine and norepinephrine reuptake. journal.pone.0157021
Claim in summary — not_supportednot supportedworking →
Claim in summary — inconclusiveinconclusiveworking →
Claim in summary — inconclusiveinconclusiveworking →
Binding and selectivity data across 46 CNS receptor sites were published the following yearsupported
Binding studies at 46 CNS receptors for DPH, 2-MXP and analogues. journal.pone.0157021
Diphenidine blocks the open NMDA receptor ion channel at the phencyclidine binding site (Kᵢ = 18.2 nM), with secondary weak inhibition of dopamine reuptake (IC₅₀ = 1.99 μM) and negligible serotonin transporter activity (IC₅₀ > 10 μM)supported
DPH and 2-MXP are relatively selective NMDAR antagonists with weak off-target effects on dopamine and norepinephrine reuptake. journal.pone.0157021
Unlike the structurally related methoxphenidine, diphenidine increases dopamine efflux in the nucleus accumbens — a functional difference with implications for reinforcement potential.supported
DPH increased DA efflux via DAT binding (autoradiography and voltammetry); MXP had no significant effect on DAT. DPH suggested to have addictive liability unlike MXP. brainsci8040063
Claim in summary — inconclusiveinconclusiveworking →
Claim in summary — inconclusiveinconclusiveworking →
Acute toxicity includes hypertension (76% of hospitalized cases), tachycardia, and severe agitation requiring sedationsupported
Common presentations: hypertension (76%), tachycardia (47%), anxiety (65%), altered mental status (65%). Treatment: benzodiazepines and/or propofol in 50%. 15563650.2015.1033630
history9 · 3 ok
The Swedish STRIDA project identified 14 analytically confirmed diphenidine intoxications by 2015, and a fatal case involving diphenidine in a multi-drug poisoning was reported in Japanpartially supported
Case series of 17 patients: 14 diphenidine-positive, 3 MXP-positive. 15563650.2015.1033630
Claim in history — inconclusiveinconclusiveworking →
Searle & Co. filed European patent EP346791A1, titled "Preparation of 1,2-diarylethylamines for treatment of neurotoxic injury"supported
References 1989 Searle Company patent as original source. 15563650.2014.974264
Claim in history — inconclusiveinconclusiveworking →
Claim in history — inconclusiveinconclusiveworking →
Claim in history — inconclusiveinconclusiveworking →
Claim in history — inconclusiveinconclusiveworking →
A comprehensive pharmacological investigation followed in 2016, profiling diphenidine across 46 CNS receptor sites and establishing its binding affinity and selectivity data.supported
Binding studies at 46 CNS receptors for DPH, 2-MXP and analogues. journal.pone.0157021
Claim in history — inconclusiveinconclusiveworking →
neuroscience6 · 6 ok
PPI disruption in rats (ED₅₀ = 9.5 mg/kg) directly operationalizes the sensorimotor gating deficits central to this framework.supported
DPH inhibited PPI with ED50 9.5 mg/kg in rats. journal.pone.0157021
Does nucleus accumbens dopamine efflux translate to human addiction liability? The mechanistic signal exists but no human dependence cases have been published.supported
DPH increased DA efflux via DAT binding. DPH suggested to have addictive liability unlike MXP. brainsci8040063
Diphenidine's high NMDA affinity (Kᵢ = 18.2 nM) predicts potent disruption of these circuits, consistent with the prominent dissociation and hallucinations observed in clinical cases.supported
Common presentations: altered mental status (65%), anxiety (65%). 15563650.2015.1033630
Diphenidine's demonstrated increase in dopamine efflux within the nucleus accumbens engages the mesolimbic reward pathway (ventral tegmental area → nucleus accumbens)supported
DPH increased DA efflux via DAT binding (autoradiography and voltammetry). DPH suggested to have addictive liability unlike MXP. brainsci8040063
The dopamine efflux data position diphenidine within the incentive salience framework, where mesolimbic dopamine mediates "wanting" (motivational drive to consume) rather than "liking" (hedonic pleasure)supported
DPH increased DA efflux via DAT binding. DPH suggested to have addictive liability unlike MXP. brainsci8040063
What is the enantioselective neuropharmacology? S-ketamine and R-ketamine show divergent neural effects. Diphenidine is used as a racemate, and the individual enantiomers have never been tested in any neural preparation.supported
Real-life samples of DPH and 2-MXP confirmed to be sold as racemic products. j.jpba.2025.116728
chemistry4 · 2 ok
Claim in chemistry — inconclusiveinconclusiveworking →
Claim in chemistry — inconclusiveinconclusiveworking →
Analytical confirmation from real-world market samples demonstrates that diphenidine is sold as a racemic mixturesupported
Real-life samples of DPH and 2-MXP confirmed to be sold as racemic products. j.jpba.2025.116728
Chiral HPLC methods capable of separating the enantiomers have been developed for forensic applicationssupported
Chiral HPLC separation of 32 diphenidine-derived NPS. Real-life samples of DPH and 2-MXP confirmed to be sold as racemic products. Enantiomer elution order reversal observed between different CSP types. j.jpba.2025.116728
pharmacokinetic-detail4 · 3 ok
The metabolic pathway of diphenidine has been characterized using rat urine, pooled human liver microsomes (pHLM), and pooled human liver cytosol (pHLC).supported
Metabolites identified in rat and human liver preparations. dta.1946
The involvement of multiple CYP isoforms in generating the same initial metabolites suggests that no single enzyme is the rate-limiting step in diphenidine clearance, which may reduce the significance of CYP polymorphism-related variabilitysupported
CYP1A2, CYP2B6, CYP2C9, CYP3A4 form initial metabolites; CYP2D6 also involved. dta.1946
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
Validated GC-MS screening methods for 13 diphenidine-derived NPS have been publishedsupported
GC-MS and rapid screening methods for 13 diphenidine-derived NPS encountered in casework. Validated screening and quantification method. pmid:27744478
receptor-pharmacology4 · 4 ok
The negligible SERT activity (IC₅₀ > 10 μM) distinguishes diphenidine from serotonergically active dissociatives such as methoxetamine and suggests low serotonin syndrome risk in the context of monoamine-mediated interactions.supported
DPH and 2-MXP are relatively selective NMDAR antagonists with weak off-target effects on dopamine and norepinephrine reuptake. journal.pone.0157021
Binding studies across 46 CNS receptor sites using rat forebrain preparations provide the most comprehensive receptor pharmacology dataset for diphenidine.supported
Binding studies at 46 CNS receptors for DPH, 2-MXP and analogues. journal.pone.0157021
Beyond transporter binding, autoradiography using [¹²⁵I]RTI-121 displacement in rat striatal sections and fast cyclic voltammetry in nucleus accumbens slices demonstrate that diphenidine increases evoked dopamine effluxsupported
DPH increased DA efflux via DAT binding (autoradiography and voltammetry). brainsci8040063
Computational molecular dynamics simulations support differential binding poses at the transporter as the mechanistic basis for this distinction.supported
Computational modeling supports DPH-DAT interaction. brainsci8040063
clinical-evidence3 · 2 ok
A single analytically confirmed non-fatal intoxication in a 30-year-old male presented with tachycardia, miotic pupils (atypical for NMDA dissociatives; mydriasis is more common), increased body temperature, and increased respiratory ratesupported
Tachycardia, miotic pupils, elevated temperature and respiratory rate. DPH plasma 308 ng/mL, urine 631 ng/mL. 1556-4029.13355
The Swedish STRIDA project (a national clinical-toxicological surveillance system for NPS) identified 17 cases involving diphenidine or its analogue methoxphenidine, of which 14 were analytically confirmed as diphenidine-positivesupported
Case series of 17 patients: 14 diphenidine-positive, 3 MXP-positive. 15563650.2015.1033630
Claim in clinical-evidence — inconclusiveinconclusiveworking →
comparative-pharmacology3 · 3 ok
Prepulse inhibition (PPI) of the acoustic startle reflex — a standard behavioural assay for dissociative potency — provides in vivo confirmation of the binding data:supported
DPH inhibited PPI with ED50 9.5 mg/kg in rats. journal.pone.0157021
In rat hippocampal slices, diphenidine at 30 μM reduced NMDA-mediated field excitatory postsynaptic potentials (fEPSPs) to a similar extent as ketamine at the same concentration, confirming functional NMDA channel blockade in neural tissue.supported
DPH at 30 μM reduced NMDA-fEPSPs similarly to ketamine in rat hippocampal slices. dta.1689
Diphenidine increases evoked dopamine efflux in rat nucleus accumbens; MXP does notsupported
DPH increased DA efflux via DAT binding (autoradiography and voltammetry); MXP had no significant effect on DAT. brainsci8040063
effects-overview3 · 2 ok
Claim in effects-overview — inconclusiveinconclusiveworking →
Compared to ketamine, diphenidine occupies a similar functional space but with higher receptor potency (Kᵢ ~18 nM vs ~324 nM) that does not translate linearly to equipotent dosessupported
Binding studies at 46 CNS receptors for DPH, 2-MXP and analogues. DPH and 2-MXP are relatively selective NMDAR antagonists. journal.pone.0157021
The subjective character is reported as "heavier" and more amnestic than ketamine, with a cardiovascular burden (76% hypertension in clinical cases) that exceeds what is typical for ketamine at recreational doses.supported
Common presentations: hypertension (76%), tachycardia (47%), anxiety (65%), altered mental status (65%). 15563650.2015.1033630