generation run 2026-05-12
67 min completedmodel pipeline-v5plan not recordedrun/a6216460…Selection
Verification
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The model's own caveats
- taper_silent
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- not recorded — template version, prompt hash and git SHA are written from 2026-09 onward
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17 searches — query, source, results, what was kept and why
| # | source | query | seen | kept | rationale |
|---|---|---|---|---|---|
| 1 | OpenAlex | methiopropamine synthesis thiophene amphetamine 1942 | 6 | 2 | NPS overview covers legal status; Synthacaine paper identifies product composition |
| 2 | PubMed | methiopropamine pharmacology stimulant | 15 | 11 | All directly relevant to MPA pharmacology, effects, and toxicity |
| 3 | OpenAlex | methiopropamine psychoactive stimulant | 10 | 4 | High-citation review for context; specific MPA metabolism and detection papers |
| 4 | PubMed | methiopropamine metabolism pharmacokinetics analytical detection | 1 | 0 | Not directly about MPA metabolism - marginally relevant forensic case |
| 5 | ClinicalTrials.gov · absence | methiopropamine | 0 | 0 | No trials registered |
| 6 | PubChem | methiopropamine | 1 | 1 | Primary chemical identity verification |
| 7 | PubMed | methiopropamine MPA toxicity adverse effects case report | 1 | 1 | Direct case report of MPA intoxication |
| 8 | Web | methiopropamine legal status UK USA scheduling 2010 2016 | 10 | 0 | Key legal status timeline data |
| 9 | DrugWise | — | 1 | 1 | Physical appearance, effects, key drug interactions |
| 10 | Web | methiopropamine tramadol lethal death case report interaction | 10 | 0 | Interaction verification - unresolved |
| 11 | PubMed | methiopropamine cardiovascular heart rate blood pressure respiratory | 1 | 1 | Already retrieved; confirms cardiovascular effects |
| 12 | Web | methiopropamine SMILES structure stereochemistry physical properties melting point | 10 | 0 | Physical and chemical property data |
| 13 | PubMed · absence | methiopropamine serotonin toxicity aminoindane interaction fatality | 0 | 0 | No published interaction papers found |
| 14 | Web | methiopropamine WHO ECDD critical review 2021 scheduling recommendation | 10 | 0 | International control history |
| 15 | Web/Erowid | — | 1 | 0 | Legal jurisdiction detail |
| 16 | Web | methiopropamine first synthesized 1942 history origin chemical | 10 | 0 | Historical synthesis context |
| 17 | Web | methiopropamine Australia New Zealand legal status controlled substance | 10 | 0 | Australia/NZ legal status |
68 claims by section — every cited sentence, checked against its source
safety25 · 22 ok
Claim in safety — inconclusiveinconclusiveworking →
At doses of 10–30 mg/kg (i.p.) in mice, MPA produced increased heart rate, elevated blood pressure, increased respiratory rate, decreased oxygen saturation, hypothermia, mechanical and thermal analgesia, and motor stereotypiespartially supported
High doses (10-30 mg/kg) in mice: impaired visual placing, increased heart rate/blood pressure/breath rate, hypothermia, motor stereotypies. s00414-020-02302-3
At lower doses corresponding to the human typical-use range, no hazardous physiological effects were observed — a "gray zone" that may encourage dose escalation.supported
Lower doses show no hazardous effects - a 'gray zone'. s00414-020-02302-3
In a chronic mouse model, repeated MPA exposure produced myocardial damage in a pattern consistent with repeated ischemia, alongside ischemic-necrotic lesions in the kidneys and gastrointestinal tractsupported
Chronic MPA administration in CD-1 mice: myocardial damage (ischemia pattern), kidney damage, gastrointestinal ischemic-necrotic lesions. s00414-018-1891-8
Body weight, food intake, thermoregulation, and motor coordination were not affected, suggesting that organ damage progressed without overt behavioral warning signs.supported
Chronic mice showed no changes in body weight, food intake, thermoregulation, muscular strength, motor coordination. s00414-018-1891-8
In human clinical presentations, tachycardia was the most common finding (91% of 11 analytically confirmed cases)supported
tachycardia (10/11) 15563650.2018.1538519
Raised creatine kinase — a marker of muscle breakdown (rhabdomyolysis) — was found in 64% of hospitalized patients, though polydrug use in most cases prevents definitive attribution to MPA alone.supported
raised creatine kinase (7/11) 15563650.2018.1538519
Claim in safety — inconclusiveinconclusiveworking →
MPA was detected at approximately 2.2 µg/L in femoral blood in a polydrug fatality; death was attributed to positional asphyxia in the context of designer benzodiazepine and stimulant co-intoxication, and the specific contribution of MPA to the fatal outcome is unclear.supported
MPA detected in femoral blood at ~2.2 µg/L as additional finding. Death attributed to positional asphyxia from poly-drug intoxication. j.forsciint.2019.109959
Confusion (64%), agitation (64%), and hallucinations (45%) were prevalent among hospitalized patientssupported
agitation (7/11), confusion (7/11), hallucinations (5/11) 15563650.2018.1538519
The Synthacaine case report described paranoid delusions, auditory and visual hallucinations, and incoherent speechsupported
admitted in confused state with paranoid delusion, auditory and visual hallucinations, incoherent speech after 'synthacaine' use. pmid:27474360
One IONA patient required transfer for inpatient psychiatric care.supported
10 discharged without sequelae, 1 transferred for psychiatric care. 15563650.2018.1538519
In rodent models, 7-day repeat-dose MPA exposure (1 and 3 mg/kg i.p.) produced recognition memory impairment, working memory deficits, and reference memory impairment persisting at least 24 hours after the last dosepartially supported
MPA at 3 mg/kg (i.p. 7 days) caused significant decline in recognition memory and impaired working/reference memory in 8-arm radial maze. 01480545.2025.2515128
Low-normal doses induced aggressive behavior in mice, with dose-dependent intensification and sensitization upon repeated exposure.supported
MPA induces aggressive behavior even at low doses in CD-1 mice, with dose-dependent increase and time-dependent sensitization. s00213-021-05813-y
Locomotor sensitization develops after as few as 4 repeated doses (5 mg/kg i.p.) in ratssupported
Repeated MPA (5 mg/kg IP, 4 doses) in rats produced locomotor sensitization. j.bbr.2016.05.060
Structural neuroplasticity in the nucleus accumbens core — increased dendritic spine density, particularly thin (immature) spines — develops after 4 repeated MPA injections in rats, a pattern shared with amphetaminesupported
Repeated MPA administration (5 mg/kg IP, 4 doses) in rats increased dendritic spine density (particularly thin spines) in nucleus accumbens core, similar to amphetamine. j.neuint.2019.104487
Claim in safety — inconclusiveinconclusiveworking →
Although MPA is a weak serotonin reuptake inhibitor (SERT IC₅₀ >25 µM), combination with potent serotonergic agents carries additive risksupported
serotonin uptake affected only at high concentrations (IC50 >25 µM). ijms222112002
MPA is metabolized via CYP enzymes (N-demethylation and aromatic hydroxylation)supported
Metabolized by CYP-mediated N-demethylation and aromatic hydroxylation. ftd.0000000000000240
Pre-existing cardiovascular disease (coronary artery disease, cardiomyopathy, arrhythmias, uncontrolled hypertension): MPA produces tachycardia (91% of hospitalized cases), vasoconstriction, and myocardial ischemia in chronic animal models. The 40% sudden death rate in chronically treated mice was attributed to cardiovascular events.partially supported
tachycardia (10/11) 15563650.2018.1538519
Pre-existing cardiovascular disease (coronary artery disease, cardiomyopathy, arrhythmias, uncontrolled hypertension): MPA produces tachycardia (91% of hospitalized cases), vasoconstriction, and myocardial ischemia in chronic animal models. The 40% sudden death rate in chronically treated mice was attributed to cardiovascular events.supported
myocardial damage (ischemia pattern)... Acute MPA increased heart rate and caused vasoconstriction; 40% of chronically treated mice died suddenly. s00414-018-1891-8
Psychiatric conditions (psychotic disorders, bipolar disorder): Acute psychosis, paranoid delusions, and hallucinations are documented in MPA intoxication cases.supported
hallucinations (5/11)... 1 transferred for psychiatric care. 15563650.2018.1538519
Psychiatric conditions (psychotic disorders, bipolar disorder): Acute psychosis, paranoid delusions, and hallucinations are documented in MPA intoxication cases.supported
admitted in confused state with paranoid delusion, auditory and visual hallucinations, incoherent speech after 'synthacaine' use. pmid:27474360
Renal impairment: Rhabdomyolysis (elevated CK in 64% of hospitalized cases) and renal necrotic lesions in chronic animal models indicate nephrotoxic potential.supported
raised creatine kinase (7/11) 15563650.2018.1538519
Renal impairment: Rhabdomyolysis (elevated CK in 64% of hospitalized cases) and renal necrotic lesions in chronic animal models indicate nephrotoxic potential.supported
kidney damage, gastrointestinal ischemic-necrotic lesions. s00414-018-1891-8
neuroscience10 · 9 ok
Repeated MPA exposure (4 doses of 5 mg/kg i.p.) in rats produced locomotor sensitization — a progressive augmentation of motor response to the same dose that is a standard behavioral index of mesolimbic dopamine system neuroadaptationsupported
Repeated MPA (5 mg/kg IP, 4 doses) in rats produced locomotor sensitization. j.bbr.2016.05.060
In the prefrontal cortex, 7-day MPA exposure (1 and 3 mg/kg i.p.) in mice reduced dopaminergic parameters and phosphorylated ERK1/2 (p-ERK1/2)partially supported
MPA at 3 mg/kg (i.p. 7 days) caused significant decline in recognition memory... Cognitive impairments accompanied by decreased dopaminergic parameters and p-ERK1/2 in prefrontal cortex. 01480545.2025.2515128
Prefrontal cognitive effects: The PFC dopaminergic and p-ERK1/2 reductions observed after 7-day exposure suggest that MPA may impair executive function with repeated use. Whether these effects persist beyond the acute withdrawal window, and at what doses they occur, remains uncharacterized.supported
Cognitive impairments accompanied by decreased dopaminergic parameters and p-ERK1/2 in prefrontal cortex. Suggests MPA neurotoxicity targets dopaminergic transmission in PFC. 01480545.2025.2515128
Cai and colleagues demonstrated that four repeated MPA injections in rats increased dendritic spine density in the NAc core, with a preferential increase in thin (immature) spinessupported
Repeated MPA administration (5 mg/kg IP, 4 doses) in rats increased dendritic spine density (particularly thin spines) in nucleus accumbens core. j.neuint.2019.104487
MPA-induced dopaminergic neurotoxicity has been characterized at the molecular level in micesupported
MPA produces dopaminergic neurotoxicity in dose-dependent manner. Increases ROS, 4-HNE, protein carbonyl. Activates M1 microglia. Pro-apoptotic. Impairs TH, DAT, VMAT-2. j.cbi.2019.03.017
Both D₁ and D₂ receptor antagonism independently protected against neurotoxicity, indicating that downstream dopamine receptor activation — not merely elevated synaptic dopamine — is a necessary step in the toxic cascade.supported
Both D1 (SCH23390) and D2 (sulpiride) receptor antagonists protected against neurotoxicity. j.cbi.2019.03.017
Incentive sensitization (Robinson and Berridge): The locomotor sensitization and NAc spine changes observed with MPA are canonical markers of this process, in which repeated drug exposure progressively amplifies the "wanting" (incentive salience) attributed to drug cues without necessarily increasing "liking" (hedonic impact)supported
Repeated MPA (5 mg/kg IP, 4 doses) in rats produced locomotor sensitization. j.bbr.2016.05.060
Incentive sensitization (Robinson and Berridge): The locomotor sensitization and NAc spine changes observed with MPA are canonical markers of this process, in which repeated drug exposure progressively amplifies the "wanting" (incentive salience) attributed to drug cues without necessarily increasing "liking" (hedonic impact)supported
Supports structural plasticity as a marker of dependence potential. j.neuint.2019.104487
Dopaminergic neurotoxicity and stimulant-induced neurodegeneration: The oxidative-stress-to-apoptosis cascade documented for MPA aligns with the broader literature on stimulant-induced dopaminergic terminal damagesupported
Increases ROS, 4-HNE, protein carbonyl. Activates M1 microglia. Pro-apoptotic (increases Bax, cleaved caspase-3; decreases Bcl-2). Impairs TH, DAT, VMAT-2. j.cbi.2019.03.017
Claim in neuroscience — inconclusiveinconclusiveworking →
pharmacology9 · 7 ok
In vitro uptake inhibition assays using synaptosomal preparations from C57BL/6 mice established the following IC₅₀ values:supported
MPA inhibits norepinephrine uptake (IC50=0.47 µM) and dopamine uptake (IC50=0.74 µM), while serotonin uptake affected only at high concentrations (IC50 >25 µM). ijms222112002
The characterization of MPA as a reuptake inhibitor rather than a releasing agent is supported by multiple independent studiessupported
MPA inhibits norepinephrine uptake (IC50=0.47 µM) and dopamine uptake (IC50=0.74 µM). ijms222112002
The characterization of MPA as a reuptake inhibitor rather than a releasing agent is supported by multiple independent studiessupported
MPA primarily acts as a norepinephrine-dopamine reuptake inhibitor and secondarily as serotonin reuptake inhibitor. s00414-020-02302-3
Claim in pharmacology — inconclusiveinconclusiveworking →
In C57BL/6 mice, MPA administered intraperitoneally was rapidly distributed to blood and brain, with a pharmacokinetic profile qualitatively similar to methamphetaminesupported
MPA rapidly distributed to blood and brain. ijms222112002
Human plasma concentration data are limited to a single case report: 13 hours after emergency presentation following "Synthacaine" consumption, plasma MPA concentration was 14 ng/mLsupported
plasma concentration 14 ng/mL at 13 hours post-presentation. pmid:27474360
Phase I metabolism of MPA proceeds via N-demethylation and aromatic hydroxylationsupported
Metabolized by CYP-mediated N-demethylation and aromatic hydroxylation; phase II glucuronidation/sulfation. ftd.0000000000000240
Urinary excretion profiling in mice identified multiple phase I and phase II metabolites, providing forensic detection markerssupported
MPA metabolized to nor-MPA, oxo-MPA, hydroxy-aryl-MPA, hydroxy-alkyl-MPA (phase I). Phase II: glucuronidation and sulfation. Best forensic markers: unchanged MPA and nor-MPA. dta.2900
Claim in pharmacology — inconclusiveinconclusiveworking →
summary6 · 4 ok
It is approximately five times less potent than methamphetamine in rodent locomotor assays, with an oral duration of 6–10 hours and a subjective character more frequently compared to methylphenidate than to amphetamine or cocaine.partially supported
Potency approximately five times lower than methamphetamine. ijms222112002
Claim in summary — inconclusiveinconclusiveworking →
MPA acts primarily as a norepinephrine-dopamine reuptake inhibitor (NDRI), with IC₅₀ values of 0.47 µM at the norepinephrine transporter (NET) and 0.74 µM at the dopamine transporter (DAT) in mouse synaptosomal preparations; serotonin transporter inhibition is negligible at typical doses (IC₅₀ >25 µM)supported
MPA inhibits norepinephrine uptake (IC50=0.47 µM) and dopamine uptake (IC50=0.74 µM), while serotonin uptake affected only at high concentrations (IC50 >25 µM). ijms222112002
A chronic mouse model produced myocardial ischemia, renal necrotic lesions, and 40% sudden death attributed to vasoconstriction-induced cardiovascular eventssupported
Chronic MPA administration in CD-1 mice: myocardial damage (ischemia pattern), kidney damage, gastrointestinal ischemic-necrotic lesions. Acute MPA increased heart rate and caused vasoconstriction; 40% of chronically treated mice died suddenly. s00414-018-1891-8
Locomotor sensitization and structural neuroplasticity in the nucleus accumbens — hallmark indices of addiction liability — develop after as few as four repeated exposures in ratspartially supported
Repeated MPA administration (5 mg/kg IP, 4 doses) in rats increased dendritic spine density (particularly thin spines) in nucleus accumbens core, similar to amphetamine. j.neuint.2019.104487
Claim in summary — inconclusiveinconclusiveworking →
history5 · 3 ok
Claim in history — inconclusiveinconclusiveworking →
MPA re-emerged in December 2010 on the UK "legal high" market, sold under branded product names including "Blow," "Synthacaine," "Ammo," "Barry White," "Blue Genie," and "Bomb". "Synthacaine" — the most widely distributed brand — was found by HPLC analysis to contain a mixture of MPA and 2-aminoindane (2-AI), marketed explicitly as a cocaine substitutepartially supported
Synthacaine is an NPS branded as 'legal cocaine'. HPLC analysis of street samples reveals it comprises MPA and 2-aminoindane (2-AI). c5an00858a
Claim in history — not_supportednot supportedworking →
The first clinical detection of MPA use was reported in 2011, and in 2012 MPA was detected in anonymous pooled urine samples collected from portable urinals in central London, providing early epidemiological confirmation of significant use in the UK.supported
Pooled urine from London city centre urinals detected MPA and metabolites in 2 of 12 samples, alongside other NPS and classical drugs. hcs219
The first published case report of acute MPA intoxication appeared in 2016, describing a patient who presented with confusion, paranoid delusions, and hallucinations after consuming "Synthacaine".supported
Case report: 30-year-old male admitted in confused state with paranoid delusion, auditory and visual hallucinations, incoherent speech after 'synthacaine' use. pmid:27474360
clinical-evidence4 · 3 ok
The Identification of Novel psychoActive substances (IONA) study reported 11 analytically confirmed cases of MPA-associated acute toxicitysupported
11 patients with analytically confirmed MPA use presenting to 26 UK hospitals (March 2015-April 2018). 15563650.2018.1538519
MPA was detected at approximately 2.2 µg/L in femoral blood in a polydrug fatality involving designer benzodiazepines and stimulants; death was attributed to positional asphyxia, and MPA's specific contribution is unclearsupported
MPA detected in femoral blood at ~2.2 µg/L as additional finding. Death attributed to positional asphyxia from poly-drug intoxication. j.forsciint.2019.109959
Daveluy and colleagues reported a case of acute intoxication following consumption of "Synthacaine" (MPA + 2-aminoindane)supported
Case report: 30-year-old male admitted in confused state with paranoid delusion, auditory and visual hallucinations, incoherent speech after 'synthacaine' use. MPA detected and quantified. pmid:27474360
Claim in clinical-evidence — inconclusiveinconclusiveworking →
comparative-pharmacology3 · 2 ok
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
This steep curve, confirmed in physiological assessments showing a transition from a "gray zone" of no hazardous effects at lower doses to marked cardiovascular toxicity at higher doses, has direct safety implicationssupported
High doses (10-30 mg/kg) in mice: impaired visual placing, increased heart rate/blood pressure/breath rate, hypothermia, motor stereotypies. Lower doses show no hazardous effects - a 'gray zone'. s00414-020-02302-3
Despite lower overall potency, MPA matched methamphetamine in aggression-inducing potential and exceeded amphetamine in aggression assays at comparable dosessupported
MPA potency similar to METH and superior to AMPH. s00213-021-05813-y
receptor-pharmacology3 · 3 ok
The available transporter selectivity profile, based on mouse synaptosomal uptake inhibition:supported
MPA inhibits norepinephrine uptake (IC50=0.47 µM) and dopamine uptake (IC50=0.74 µM), while serotonin uptake affected only at high concentrations (IC50 >25 µM). ijms222112002
MPA-induced dopaminergic neurotoxicity is mediated via both D₁ and D₂ receptors — pretreatment with the D₁ antagonist SCH23390 or the D₂ antagonist sulpiride each independently protected against neurotoxicitysupported
Both D1 (SCH23390) and D2 (sulpiride) receptor antagonists protected against neurotoxicity. j.cbi.2019.03.017
Locomotor sensitization, however, specifically requires D₂ receptor activation: D₂ blockade with sulpiride prevented sensitization, while D₁ blockade with SCH23390 did notpartially supported
expression inhibited by D2 antagonist (eticlopride) but not D1 antagonist (SCH23390). j.bbr.2016.05.060
pharmacokinetic-detail2 · 2 ok
In the mouse i.p. model, MPA reached brain tissue rapidly, consistent with its molecular weight (155.26 g/mol) and expected moderate lipophilicitysupported
MPA rapidly distributed to blood and brain. ijms222112002
The single human plasma measurement (14 ng/mL, 13 h post-presentation) from a Synthacaine intoxication case cannot be used to derive standard PK parameters — the dose, timing of ingestion, co-ingested substances (including 2-aminoindane), and route were all uncertainsupported
plasma concentration 14 ng/mL at 13 hours post-presentation. Confirms toxicity and need for toxicological analysis. pmid:27474360
effects-overview1 · 0 ok
Claim in effects-overview — inconclusiveinconclusiveworking →