generation run 2026-05-03
59 min completedmodel pipeline-v5plan not recordedrun/4a557550…Selection
Verification
- record
- seen / partial
- working
The model's own caveats
- sparse_evidence
- no_protocol_sources
Reproduce
- inputs
- 18 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
18 searches — query, source, results, what was kept and why
| # | source | query | seen | kept | rationale |
|---|---|---|---|---|---|
| 1 | PubMed | methoxphenidine pharmacology dissociative | 14 | 13 | All 14 articles selected as directly relevant to MXP pharmacology, toxicology, or clinical reports |
| 2 | WebSearch | methoxphenidine legal status scheduling US UK Australia Canada 2025 | 10 | 3 | Legal status data for key jurisdictions |
| 3 | OpenAlex | methoxphenidine MXP NMDA receptor binding Ki affinity | 1 | 1 | Directly relevant to DAT binding pharmacology distinguishing MXP from DPH |
| 4 | ClinicalTrials.gov · absence | methoxphenidine | 0 | — | No trials to select |
| 5 | PubChem | methoxphenidine | 1 | 1 | Single compound match confirmed as methoxphenidine |
| 6 | PsychonautWiki | — | 1 | 1 | Confirms existing seed data on doses |
| 7 | PubMed · absence | methoxphenidine metabolism CYP cytochrome | 0 | — | No results |
| 8 | OpenAlex | methoxphenidine NMDA dissociative novel psychoactive | 31 | 5 | Selected highly-cited papers directly relevant to MXP and related NPS pharmacology/toxicology |
| 9 | WebSearch | methoxphenidine CAS number SMILES chemical structure | 10 | 2 | Chemical identity confirmation |
| 10 | WebSearch | methoxphenidine Australia Schedule 9 Canada Schedule 1 legal status 2024 | 10 | 2 | Confirmed international scheduling dates |
| 11 | PMC (PubMed Central) | — | 1 | 3 | Key quantitative pharmacology data from primary paper |
| 12 | OpenAlex + PubMed | DAT binding MXP DPH dissociative diarylethylamine dopamine transporter | 1 | 1 | Key distinction between MXP and DPH for dependence liability |
| 13 | Gov.uk Circular 001/2024 | — | 1 | 1 | Primary source for UK scheduling date |
| 14 | WebSearch | methoxphenidine Searle patent 1989 discovery history lefetamine | 10 | 2 | Discovery history |
| 15 | ACMD Gov.uk | — | 1 | 4 | Primary regulatory document containing compiled pharmacology and epidemiology data |
| 16 | PMC / Wallach et al. 2016 | — | 1 | 3 | Primary quantitative binding data source for MXP |
| 17 | DOI verification (Crossref) | verify_doi 10.1177/02698811251349203 | 1 | 1 | Verification of Corkery 2025 systematic review |
| 18 | DOI verification (Crossref) | verify_doi 10.1016/j.snb.2018.11.053 and 10.1016/j.sna.2019.06.029 | 2 | 1 | DOI verification of analytical chemistry papers |
94 claims by section — every cited sentence, checked against its source
safety33 · 26 ok
The French Addictovigilance Network similarly reported cardiovascular complications across MXP cases.supported
Complications included psychiatric, neurological, cardiovascular. fcp.12395
Eight deaths outside Europe were documented (4 Japan, 4 USA).supported
Also 8 deaths outside Europe (4 Japan, 4 USA). 02698811251349203
In the STRIDA diarylethylamine case series, hypertension occurred in 76% and tachycardia in 47% of casessupported
Hypertension (76%), tachycardia (47%), anxiety (65%), altered mental status (65%). 15563650.2015.1033630
The LD₅₀ of methoxphenidine in Wistar rats is approximately 500 mg/kg (SC), classified by the study authors as moderate acute toxicitysupported
LD50 ~500 mg/kg SC in rats. j.pnpbp.2025.111285
Claim in safety — inconclusiveinconclusiveworking →
The wide range of post-mortem blood concentrations in fatal cases (1.36–24.0 mg/L) precludes determination of a reliable lethal threshold and suggests significant individual variation, polydrug confounding, or both.supported
Femoral blood concentrations: 24.0, 2.0, 1.36 mg/L. bkv006
The first reported fatalities (3 cases) were described by Elliott et al. in 2015, with post-mortem femoral blood MXP concentrations of 24.0 mg/L, 2.0 mg/L, and 1.36 mg/Lsupported
Three MXP-related deaths. Femoral blood concentrations: 24.0, 2.0, 1.36 mg/L. bkv006
Claim in safety — inconclusiveinconclusiveworking →
A systematic review by Corkery et al. documented 37 UK deaths involving diarylethylamines (27 England, 7 Scotland, 3 Wales), of which 31 involved MXP alone or in combinationsupported
37 UK deaths (27 England, 7 Scotland, 3 Wales); 31 involving MXP alone or combined. 02698811251349203
Analysis of a street MXP sample revealed bromo- and chloro-zincate complex anion impurities arising from zinc halide salt use during synthesis. In vitro cytotoxicity testing across kidney, liver, and bladder cell lines demonstrated markedly higher toxicity in the street sample compared to laboratory-standard MXPsupported
Street MXP sample contained bromo- and chloro-zincate complex anion impurity. Street sample showed markedly higher cytotoxicity than MXP standard across kidney, liver, bladder cell lines. ijms23042083
Claim in safety — inconclusiveinconclusiveworking →
Clinical case series document anxiety and agitation in 65% of intoxication presentations, and altered mental status including hallucinations and confusion in 65%supported
Hypertension (76%), tachycardia (47%), anxiety (65%), altered mental status (65%). 15563650.2015.1033630
The French Addictovigilance Network reported psychiatric complications including psychosissupported
Complications included psychiatric, neurological, cardiovascular. fcp.12395
Nearly half (47%) of analytically confirmed diarylethylamine intoxications were classified as severe (PSS 3).supported
47% severe intoxication (PSS 3). 15563650.2015.1033630
Animal studies demonstrate schizophrenia-related behavioral dimensions including positive symptoms (hyperactivity, impulsivity), negative symptoms (social withdrawal, depression-like behavior), and cognitive impairmentsupported
Positive symptoms (hyperactivity, impulsivity), negative symptoms (anxiety, social withdrawal, depression), and cognitive impairment observed. bph.15528
User reports describe chronic effects including long-term memory loss and limb numbness.supported
Chronic: memory loss, limb numbness. 02791072.2014.974002
The first documented MXP use disorder was reported to the French Addictovigilance Network.supported
First reported case of MXP use disorder/dependence notified to the French Addictovigilance Network. jcp.0000000000000684
Rodent studies confirm reinforcing properties: MXP maintains intravenous self-administration and produces conditioned place preferencesupported
MXP caused addictive behaviours (IV self-administration, CPP). bph.15528
Claim in safety — inconclusiveinconclusiveworking →
The reinforcement mechanism involves indirect dopaminergic activation via NMDA-mediated disinhibition of mesolimbic circuits, rather than direct DAT reuptake inhibitionsupported
Dopamine pathway overactivation in nucleus accumbens; disruption of hippocampal-prefrontal cortex pathway. bph.15528
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Stimulants (cocaine, amphetamines, cathinones): MXP consistently produces hypertension and tachycardia as standalone effectssupported
Hypertension (76%), tachycardia (47%). 15563650.2015.1033630
Claim in safety — inconclusiveinconclusiveworking →
MXP itself displays stimulant properties at lower doses .supported
Dissociative and stimulant effects lasting days. 02791072.2014.974002
While MXP has minimal direct serotonin transporter activity (SERT >10 μM), NMDA antagonists can modulate serotonergic tone via indirect mechanismssupported
DPH and 2-MXP are relatively selective NMDAR antagonists with weak off-target effects on dopamine and norepinephrine reuptake. journal.pone.0157021
Serotonergic drugs: MXP's negligible SERT affinity substantially reduces the theoretical serotonin syndrome risk relative to more promiscuous NMDA antagonists such as dxmsupported
DPH and 2-MXP are relatively selective NMDAR antagonists with weak off-target effects on dopamine and norepinephrine reuptake. journal.pone.0157021
Pre-existing hypertension or cardiovascular disease: Hypertension and tachycardia are the most frequent clinical findings in MXP intoxication (76% and 47% respectively)supported
Hypertension (76%), tachycardia (47%). 15563650.2015.1033630
Psychotic disorders or active psychosis: MXP produces altered mental status, hallucinations, and psychotic symptoms in clinical presentations, and schizophrenia-like behavioral phenotypes in animal modelssupported
Altered mental status (65%). 47% severe intoxication (PSS 3). 15563650.2015.1033630
Psychotic disorders or active psychosis: MXP produces altered mental status, hallucinations, and psychotic symptoms in clinical presentations, and schizophrenia-like behavioral phenotypes in animal modelssupported
Complications included psychiatric, neurological, cardiovascular. fcp.12395
Psychotic disorders or active psychosis: MXP produces altered mental status, hallucinations, and psychotic symptoms in clinical presentations, and schizophrenia-like behavioral phenotypes in animal modelssupported
MXP caused addictive behaviours (IV self-administration, CPP) and schizophrenia-like symptoms in rodents. bph.15528
Seizure disorders: Seizures were reported among adverse effects in both user accounts and clinical casessupported
Acute side-effects: hypertension, seizures. 02791072.2014.974002
Seizure disorders: Seizures were reported among adverse effects in both user accounts and clinical casessupported
Complications included psychiatric, neurological, cardiovascular. fcp.12395
pharmacology15 · 7 ok
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
Autoradiography and fast cyclic voltammetry in rat nucleus accumbens slices demonstrated that MXP has no significant effect on dopamine transporter (DAT) binding or evoked dopamine efflux, while diphenidine increases dopamine efflux via DATsupported
MXP had no significant effect on DAT binding or evoked DA efflux (unlike DPH). brainsci8040063
Molecular dynamics simulations confirmed that diphenidine docks into DAT while MXP does notsupported
Computational modeling shows DPH binds DAT; MXP does not. brainsci8040063
Claim in pharmacology — inconclusiveinconclusiveworking →
Despite the absence of direct DAT activity, MXP produces rewarding and reinforcing behaviors in rodents — intravenous self-administration and conditioned place preference — accompanied by dopamine pathway overactivation in the nucleus accumbenssupported
MXP caused addictive behaviours (IV self-administration, CPP)... Dopamine pathway overactivation in nucleus accumbens. bph.15528
In Wistar rats following subcutaneous administration, MXP reaches peak serum and brain concentrations at approximately 30 minutes (Tmax ≈ 0.5 h), rapidly crosses the blood-brain barrier, and accumulates in brain tissue at concentrations substantially higher than serum throughout the observation periodsupported
MXP rapidly crossed BBB, peak brain/serum concentrations at 30 min. j.pnpbp.2025.111285
The elimination half-life in rats is 2.15 hours.supported
Elimination half-life 2.15 h in rats. j.pnpbp.2025.111285
Claim in pharmacology — inconclusiveinconclusiveworking →
The (S)-enantiomer achieves higher brain concentrations than (R)-MXP following racemic dosing, indicating enantioselective CNS distribution.supported
(S)-MXP higher brain concentrations than (R)-enantiomer. j.jchromb.2025.124613
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — not_supportednot supportedworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
Additional metabolites identified in post-mortem forensic cases include hydroxy-MXP (hydroxylation on the piperidine ring) and hydroxylated O-desmethyl-MXPsupported
Metabolites identified: hydroxy-MXP (main, on piperidine ring), O-desmethyl-MXP, hydroxylated O-desmethyl-MXP. bkv006
Claim in pharmacology — inconclusiveinconclusiveworking →
comparative-pharmacology8 · 7 ok
Prepulse inhibition disruption — a translational measure of sensorimotor gating impairment associated with psychotomimetic effects — positions MXP as less potent than diphenidine (DPH ED₅₀ = 9.5 mg/kg vs MXP requiring ≥20 mg/kg IP for significant disruption)partially supported
DPH inhibited PPI with ED50 9.5 mg/kg; 2-MXP also inhibited PPI in rats. journal.pone.0157021
MXP displays a biphasic locomotor response in Wistar rats: stimulant and anxiogenic effects at 10–20 mg/kg (SC), transitioning to sedation and decreased locomotion at 40 mg/kgsupported
Locomotor stimulation at 10–20 mg/kg, sedation at 40 mg/kg. Stimulant and anxiogenic at lower doses, sedative at higher doses. j.pnpbp.2025.111285
NMDA Ki values for MXP from Wallach et al.; DAT comparison from Sahai et al.; PPI data from Wallach et al. and Štefková-Mazochová et al..supported
Binding studies at 46 CNS receptors. DPH inhibited PPI with ED50 9.5 mg/kg; 2-MXP also inhibited PPI in rats. journal.pone.0157021
NMDA Ki values for MXP from Wallach et al.; DAT comparison from Sahai et al.; PPI data from Wallach et al. and Štefková-Mazochová et al..supported
MXP had no significant effect on DAT binding or evoked DA efflux (unlike DPH). Computational modeling shows DPH binds DAT; MXP does not. brainsci8040063
NMDA Ki values for MXP from Wallach et al.; DAT comparison from Sahai et al.; PPI data from Wallach et al. and Štefková-Mazochová et al..supported
PPI disruption at all doses. j.pnpbp.2025.111285
Diphenidine directly increases dopamine efflux via DAT, conferring a stimulant-reinforcing pharmacological component absent in MXPsupported
DPH has addictive liability via DAT; MXP lacks this mechanism. brainsci8040063
Despite this distinction, both compounds produce rewarding behaviors in animal models, indicating that NMDA-mediated disinhibition of dopamine circuits provides a parallel reinforcement pathway independent of DAT engagement.supported
MXP caused addictive behaviours (IV self-administration, CPP)... Dopamine pathway overactivation in nucleus accumbens. bph.15528
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
neuroscience8 · 5 ok
Claim in neuroscience — inconclusiveinconclusiveworking →
Schizophrenia-related behavioral dimensions observed in MXP-treated rodents include positive symptoms (hyperactivity, impulsivity), negative symptoms (social withdrawal, anxiety, depression-like behavior), and cognitive impairment (novel object recognition deficits)supported
Positive symptoms (hyperactivity, impulsivity), negative symptoms (anxiety, social withdrawal, depression), and cognitive impairment observed. bph.15528
Street sample toxicity mechanism: Zinc halide complex impurities markedly increase cytotoxicity of street MXP. Whether these impurities contribute to the observed human fatalities has not been investigated.supported
Street sample showed markedly higher cytotoxicity than MXP standard across kidney, liver, bladder cell lines. Warns of undetected dangerous impurities in street samples. ijms23042083
MXP's disruption of prepulse inhibition in rats positions it within the NMDA hypofunction model of psychosissupported
2-MXP also inhibited PPI in rats. journal.pone.0157021
MXP's disruption of prepulse inhibition in rats positions it within the NMDA hypofunction model of psychosissupported
PPI disruption at all doses. j.pnpbp.2025.111285
Claim in neuroscience — inconclusiveinconclusiveworking →
MXP produces dopamine overactivation in the nucleus accumbens and disrupts the hippocampal–prefrontal cortex pathway in rodentssupported
Dopamine pathway overactivation in nucleus accumbens; disruption of hippocampal-prefrontal cortex pathway. bph.15528
Claim in neuroscience — inconclusiveinconclusiveworking →
summary8 · 5 ok
Methoxphenidine (MXP, 2-MXP, 2-MeO-diphenidine) is a synthetic dissociative of the 1,2-diarylethylamine structural class, characterized by potent NMDA receptor antagonism (Ki = 36 nM) and a 6–8 hour oral duration that places it among the longer-acting dissociativespartially supported
DPH and 2-MXP are relatively selective NMDAR antagonists with weak off-target effects on dopamine and norepinephrine reuptake. journal.pone.0157021
It emerged on recreational markets in mid-to-late 2013 as a legal alternative to methoxetamine and ketamine following UK restrictions on arylcyclohexylaminessupported
MXP marketed as legal replacement for MXE/ketamine (2013). 02791072.2014.974002
Claim in summary — inconclusiveinconclusiveworking →
It displays moderate sigma-1 affinity (Ki ≈ 124 nM) but negligible activity at monoamine transporters — critically, it does not bind the dopamine transporter or increase dopamine efflux, unlike its structural analog diphenidine.partially supported
MXP had no significant effect on DAT binding or evoked DA efflux (unlike DPH). brainsci8040063
Claim in summary — inconclusiveinconclusiveworking →
Claim in summary — inconclusiveinconclusiveworking →
Multiple fatalities have been documented: 31 UK deaths involved MXP alone or in combination, with post-mortem blood concentrations ranging from 1.36 to 24.0 mg/Lpartially supported
37 UK deaths (27 England, 7 Scotland, 3 Wales); 31 involving MXP alone or combined. 02698811251349203
Multiple fatalities have been documented: 31 UK deaths involved MXP alone or in combination, with post-mortem blood concentrations ranging from 1.36 to 24.0 mg/Lpartially supported
Three MXP-related deaths. Femoral blood concentrations: 24.0, 2.0, 1.36 mg/L. bkv006
history6 · 1 ok
Claim in history — inconclusiveinconclusiveworking →
Claim in history — inconclusiveinconclusiveworking →
Claim in history — inconclusiveinconclusiveworking →
Claim in history — inconclusiveinconclusiveworking →
Vendors marketed MXP explicitly as a legal alternative to methoxetamine and ketamine.supported
MXP marketed as legal replacement for MXE/ketamine (2013). 02791072.2014.974002
Claim in history — inconclusiveinconclusiveworking →
chemistry4 · 2 ok
Claim in chemistry — inconclusiveinconclusiveworking →
Claim in chemistry — inconclusiveinconclusiveworking →
The methoxy substituent at the ortho position distinguishes it from the unsubstituted parent compound diphenidine and from the meta- and para-isomers (3-MXP, 4-MXP).supported
Synthesis of 2-, 3-, and 4-MXP isomers. UK internet vendor samples confirmed as 2-MXP. dta.1800
In Wistar rats dosed with racemic MXP, (S)-MXP accumulates to higher brain concentrations than (R)-MXP, indicating enantioselective CNS distributionsupported
(S)-MXP higher brain concentrations than (R)-enantiomer. j.jchromb.2025.124613
clinical-evidence4 · 4 ok
The first analytically confirmed clinical toxicity case was reported by Hofer et al. in 2014, confirming oral MXP as the causative agent.supported
First analytically confirmed case of oral MXP toxicity. 15563650.2014.974264
Three analytically confirmed MXP intoxications from the Swedish STRIDA project (part of a 17-patient diarylethylamine case series) showed hypertension (76% of diarylethylamine cases), tachycardia (47%), anxiety and agitation (65%), and altered mental status including hallucinations and confusion (65%)supported
17-patient case series (Sweden STRIDA project): 3 MXP-positive. Hypertension (76%), tachycardia (47%), anxiety (65%), altered mental status (65%). 15563650.2015.1033630
Treatment consisted of benzodiazepines and/or propofol in approximately 50% of cases.partially supported
Treatment: benzodiazepines and/or propofol. 15563650.2015.1033630
Severity distribution was 5 minor, 6 moderate, and 4 serious cases; 16 of 18 total diarylethylamine cases were classified as "possible" due to polysubstance involvement.partially supported
Minor (5), moderate (6), serious (4) cases. fcp.12395
effects-overview3 · 3 ok
Users consistently describe alternating waves of stimulant-like energy and dissociative sedation rather than a smooth arc, with the balance shifting toward sedation as dose increasessupported
Dissociative and stimulant effects lasting days. 02791072.2014.974002
The slow oral onset (30–60 minutes) creates a deceptive window that drives accidental redosing — a risk consistently flagged in community harm reduction discoursesupported
Five themes on risk perception, harm reduction practices in online communities. 02791072.2016.1207827
Compared to diphenidine, MXP is reported as less euphoric — consistent with its absence of direct dopamine transporter activity — but longer-lasting and with a more gradual resolution.supported
MXP had no significant effect on DAT binding or evoked DA efflux (unlike DPH). DPH has addictive liability via DAT; MXP lacks this mechanism. brainsci8040063
receptor-pharmacology3 · 3 ok
The complete receptor binding profile, determined across 46 CNS targets, establishes MXP as a selective NMDA receptor antagonist with limited off-target activity.supported
Binding studies at 46 CNS receptors. DPH and 2-MXP are relatively selective NMDAR antagonists with weak off-target effects on dopamine and norepinephrine reuptake. journal.pone.0157021
NMDA binding data from Wallach et al.; sigma and transporter values as compiled in the ACMD review.supported
Binding studies at 46 CNS receptors. DPH and 2-MXP are relatively selective NMDAR antagonists with weak off-target effects on dopamine and norepinephrine reuptake. journal.pone.0157021
Molecular dynamics simulations confirmed structural docking of diphenidine into DAT while MXP fails to achieve stable binding.supported
Computational modeling shows DPH binds DAT; MXP does not. brainsci8040063