generation run 2026-05-11
75 min completedmodel pipeline-v5plan not recordedrun/2000ef9f…Selection
Verification
- record
- seen / partial
- working
The model's own caveats
- sparse_evidence
- structural_inference
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
13 searches — query, source, results, what was kept and why
| # | source | query | seen | kept | rationale |
|---|---|---|---|---|---|
| 1 | PubMed | 4-fluoromethylphenidate pharmacology | 6 | 6 | All directly relevant to 4F-MPH pharmacology, toxicology, and clinical presentation |
| 2 | ClinicalTrials.gov · absence | 4-fluoromethylphenidate | 0 | 0 | No trials found — confirmed absence |
| 3 | PubChem | 4-fluoromethylphenidate | 1 | 1 | Confirmed chemical identity data for the brief's substance |
| 4 | PubMed | methylphenidate analog phenidate new psychoactive substance stimulant | 2 | 2 | Both relevant to forensic characterization of phenidate class |
| 5 | OpenAlex | 4-fluoromethylphenidate dopamine reuptake inhibitor | 9 | 6 | Selected by citation count and direct relevance to 4F-MPH or its class |
| 6 | DOI verification (Crossref) | DOI verification for key papers | 3 | 1 | API verification of citation integrity |
| 7 | Web | 4F-MPH 4-fluoromethylphenidate UK Psychoactive Substances Act 2016 Germany Sweden | 10 | 3 | Additional EU legal status data |
| 8 | Web | 4F-MPH physical properties melting point solubility CAS 1354631-33-6 | 10 | 3 | Physical/chemical property data for Chemical Identity section |
| 9 | Web | 4F-MPH 4-fluoromethylphenidate case report 2021-2024 | 10 | 0 | Confirmed limited case report literature; absence noted |
| 10 | PsychonautWiki | Dose, duration, effects, tolerance, interactions | 1 | 2 | Cross-reference for DB seed dose/duration data; secondary source |
| 11 | ChemicalBook | 4F-MPH physical properties | 1 | 1 | Physical properties confirmation |
| 12 | Web | 4F-MPH synthesis history EMCDDA first notification 2015 | 10 | 2 | History of compound |
| 13 | Web (Bing/Google) | 4-fluoromethylphenidate 4F-MPH legal status scheduled controlled substance UK US Australia Canada | 10 | 3 | Legal status by jurisdiction |
63 claims by section — every cited sentence, checked against its source
safety13 · 11 ok
Given that 4F-MPH is 2–3-fold more potent than methylphenidate at DAT and NET, cardiovascular effects may be more pronounced at equivalent milligram dosessupported
4F-MPH is ~2-3x more potent than MPH at DAT and NET. dta.2167
The single analytically confirmed mono-intoxication case — a 26-year-old female presenting after one week of insufflation — demonstrated clinically significant sympathomimetic toxidrome: agitation, altered mental status, and cardiovascular abnormalities, requiring intravenous diazepam for sedation and subsequent antipsychotic medication (promazine, quetiapine)supported
26-year-old female, sniffed 4F-MPH... neuropsychiatric and cardiologic symptoms lasting 1 week. Required IV diazepam sedation. bkz001
A US fatality with 4F-MPH listed on the death certificate involved femoral blood concentrations of 0.012–0.05 mg/Lsupported
Femoral blood concentration 0.012–0.05 mg/L. bkz061
Based on the methylphenidate pharmacological class, 4F-MPH is expected to produce:supported
Comprehensive safety review of MPH: cardiovascular risks (increased HR, elevated BP, arrhythmias, rare myocardial infarction, sudden cardiac death), psychiatric adverse effects (anxiety, agitation, psychosis, mood disorder exacerbation), abuse/dependence potential via dopaminergic effects. s43440-025-00763-0
Chronic stimulant exposure in the methylphenidate class is associated with sustained cardiovascular stress, potential for cardiomyopathy at high chronic doses, and neurotoxic effects including dopaminergic system dysregulationsupported
cardiovascular risks (increased HR, elevated BP, arrhythmias, rare myocardial infarction, sudden cardiac death)... abuse/dependence potential via dopaminergic effects. s43440-025-00763-0
Methylphenidate-class psychiatric adverse effects, applicable to 4F-MPH by pharmacological inference, include:supported
psychiatric adverse effects (anxiety, agitation, psychosis, mood disorder exacerbation) s43440-025-00763-0
Claim in safety — inconclusiveinconclusiveworking →
Methylphenidate maintained robust self-administration in rhesus monkeys comparable to cocaine under concurrent schedule paradigms, confirming substantial reinforcing efficacy for the DAT-inhibitor classsupported
In rhesus monkeys, methylphenidate maintained robust self-administration behavior (>90% injection lever responses), comparable to cocaine. pmid:15526000
The abuse potential of monoamine reuptake inhibitors correlates primarily with DAT:SERT selectivity ratio. 4F-MPH's ratio (~144:1) places it among high-liability compounds, comparable to cocaine and methylphenidate and categorically distinct from serotonin-predominant compounds.supported
DAT/SERT ratio predicts stimulant vs entactogen effects. Dopaminergic drugs highly addictive. smw.2015.14043
For the parent compound methylphenidate, co-administration with ethanol results in carboxylesterase 1-mediated transesterification producing ethylphenidate, a distinct psychoactive compound with selective DAT activity, along with increased early exposure to d-methylphenidate and potentiated euphoriasupported
MPH+ethanol interaction produces ethylphenidate via carboxylesterase 1 transesterification. jps.24202
The fatal US case involved polydrug use including amphetamine and methamphetamine alongside 4F-MPH.supported
Polydrug: also 3-methoxy-PCP, amphetamine, methamphetamine, 6-MAM, morphine, codeine, THC. bkz061
The following contraindications are inferred from the methylphenidate pharmacological class and apply with at least equal force given 4F-MPH's enhanced potency:supported
Comprehensive safety review of MPH: cardiovascular risks... psychiatric adverse effects... abuse/dependence potential via dopaminergic effects. s43440-025-00763-0
Claim in safety — inconclusiveinconclusiveworking →
summary11 · 7 ok
4-Fluoromethylphenidate (4F-MPH) is a synthetic stimulant of the substituted phenidate class, acting as a potent catecholamine reuptake inhibitor with approximately twice the potency of its parent compound methylphenidate at the dopamine and norepinephrine transporterssupported
4F-MPH is ~2-3x more potent than MPH at DAT and NET. dta.2167
Claim in summary — inconclusiveinconclusiveworking →
The first published pharmacological characterization established transporter binding affinities in rat brain synaptosomes; a comprehensive in vitro profiling confirmed its mechanistic classification as an uptake blocker without releasing activitysupported
Monoamine transporter studies using rat brain synaptosomes: (±)-threo-4F-MPH DAT IC50=61nM, NET IC50=31nM, SERT IC50=8805nM dta.2167
Claim in summary — inconclusiveinconclusiveworking →
(±)-threo-4F-MPH inhibits the dopamine transporter (DAT) with an IC₅₀ of 61 nM and the norepinephrine transporter (NET) at 31 nM in rat brain synaptosomes — approximately 2.1-fold and 2.7-fold more potent than methylphenidate at these respective targetssupported
(±)-threo-4F-MPH DAT IC50=61nM, NET IC50=31nM; MPH comparison: DAT IC50=131nM, NET IC50=83nM dta.2167
Claim in summary — inconclusiveinconclusiveworking →
Claim in summary — inconclusiveinconclusiveworking →
Cardiovascular toxicity — tachycardia, hypertension, arrhythmia risk — represents the primary acute danger, extrapolated from the methylphenidate class and potentially amplified by 4F-MPH's higher transporter potencysupported
cardiovascular risks (increased HR, elevated BP, arrhythmias, rare myocardial infarction, sudden cardiac death) s43440-025-00763-0
One analytically confirmed non-fatal intoxication produced sympathomimetic toxidrome requiring benzodiazepine sedation; a single US fatality involved severe polydrug co-ingestion, precluding isolation of 4F-MPH's independent contributionsupported
First analytically confirmed non-fatal intoxication by 4F-MPH... neuropsychiatric and cardiologic symptoms lasting 1 week. Required IV diazepam sedation. bkz001
One analytically confirmed non-fatal intoxication produced sympathomimetic toxidrome requiring benzodiazepine sedation; a single US fatality involved severe polydrug co-ingestion, precluding isolation of 4F-MPH's independent contributionsupported
First US case of 4F-MPH in decedent... Polydrug: also 3-methoxy-PCP, amphetamine, methamphetamine, 6-MAM, morphine, codeine, THC. bkz061
The high DAT:SERT selectivity ratio predicts substantial abuse liabilitysupported
DAT/SERT ratio predicts stimulant vs entactogen effects. Dopaminergic drugs highly addictive. smw.2015.14043
pharmacology10 · 8 ok
4F-MPH acts as a potent, catecholamine-selective monoamine reuptake inhibitor, blocking the dopamine transporter (DAT) and norepinephrine transporter (NET) without substrate-type releasing activity at any monoamine transportersupported
(±)-threo-4F-MPH DAT IC50=61nM, NET IC50=31nM, SERT IC50=8805nM dta.2167
Claim in pharmacology — inconclusiveinconclusiveworking →
This mechanistic profile — uptake blockade without efflux — is consistent with the parent compound methylphenidate and distinguishes all phenidate-class compounds from amphetamine-type stimulants, which function as transporter substrates that reverse the direction of monoamine transport.supported
Stimulants including phenidate analogs primarily interact with monoamine transporters; sympathomimetic adverse effects. s00204-020-02693-7
In rat brain synaptosomes, (±)-threo-4F-MPH inhibits DAT with an IC₅₀ of 61 nM and NET with an IC₅₀ of 31 nMsupported
(±)-threo-4F-MPH DAT IC50=61nM, NET IC50=31nM dta.2167
All IC₅₀ values determined in rat brain synaptosomes.supported
Monoamine transporter studies using rat brain synaptosomes dta.2167
(±)-threo-4F-MPH is approximately 2.1-fold more potent than methylphenidate at DAT and 2.7-fold more potent at NETsupported
(±)-threo-4F-MPH DAT IC50=61nM, NET IC50=31nM; MPH comparison: DAT IC50=131nM, NET IC50=83nM dta.2167
The high DAT:SERT selectivity ratio (~144:1 for the threo form) is associated with elevated abuse potential within the monoamine reuptake inhibitor class, consistent with the predictive framework described by Liechtisupported
DAT/SERT ratio predicts stimulant vs entactogen effects. Dopaminergic drugs highly addictive. smw.2015.14043
Claim in pharmacology — inconclusiveinconclusiveworking →
Manier and colleagues identified 13 metabolites in rat urine using UHPLC-HRMS/MS: 12 phase I metabolites and 1 phase II (conjugated) metabolitesupported
Found 13 metabolites for 4F-MPH (12 phase I, 1 phase II). UHPLC-HRMS/MS in rat urine. bkz052
Human S9 fraction incubations confirmed the same hydrolytic pattern in vitrosupported
UHPLC-HRMS/MS in rat urine and human S9 fraction... Primary hydrolysis to carboxy metabolites. bkz052
history7 · 5 ok
The compound was not identified in a biological specimen in the United States until 2018, when it appeared in a fatal polydrug case — the first US death with 4F-MPH listed on the death certificate.supported
First detected in drug paraphernalia in Miami-Dade in 2016; first biological specimen detection in 2018. bkz061
Claim in history — inconclusiveinconclusiveworking →
Claim in history — inconclusiveinconclusiveworking →
The compound has been sold online as a "research chemical" and variously marketed as a cognitive enhancer, stimulant, and — inaccurately — as an entactogensupported
sniffed 4F-MPH acquired as entactogen online bkz001
The compound has been sold online as a "research chemical" and variously marketed as a cognitive enhancer, stimulant, and — inaccurately — as an entactogensupported
4F-MPH frequently discussed for ADHD self-medication. j.drugpo.2023.104109
Qualitative research into NPS self-medication practices has documented 4F-MPH use specifically for ADHD symptom management, productivity enhancement, and cognitive tasks among individuals who either lack access to or prefer alternatives to prescribed stimulantssupported
4F-MPH frequently discussed for ADHD self-medication. Substances chosen for access, cost, legality, dissatisfaction with healthcare. j.drugpo.2023.104109
Qualitative research into NPS self-medication practices has documented 4F-MPH use specifically for ADHD symptom management, productivity enhancement, and cognitive tasks among individuals who either lack access to or prefer alternatives to prescribed stimulantssupported
Overview of NPS cognitive enhancers including phenidate analogs. Includes early warning system analysis, psychonaut community usage patterns. fpsyt.2020.546796
clinical-evidence6 · 5 ok
Shoff and colleagues reported the first US fatality with 4F-MPH listed on the death certificatesupported
First US case of 4F-MPH in decedent. bkz061
Papa and colleagues reported the first analytically confirmed clinical intoxication involving 4F-MPHsupported
First analytically confirmed non-fatal intoxication by 4F-MPH. bkz001
Claim in clinical-evidence — inconclusiveinconclusiveworking →
A possible erythro isomer of 4F-MPH was also detected but could not be confirmed due to the absence of certified reference material.supported
Possible erythro isomer also detected. bkz061
Holborn and colleagues conducted qualitative research documenting 4F-MPH use for ADHD self-medication among individuals who reported using NPS as alternatives to prescription stimulantssupported
Reddit qualitative study. 4F-MPH frequently discussed for ADHD self-medication. Substances chosen for access, cost, legality, dissatisfaction with healthcare. j.drugpo.2023.104109
Napoletano and colleagues reviewed "psychonaut" community forums, identifying 4F-MPH among the most frequently discussed NPS cognitive enhancerssupported
Overview of NPS cognitive enhancers including phenidate analogs. Includes early warning system analysis, psychonaut community usage patterns. fpsyt.2020.546796
comparative-pharmacology5 · 5 ok
The key distinction is potency: 4F-MPH is approximately 2.1-fold more potent at DAT and 2.7-fold more potent at NET in rat brain synaptosomes.supported
(±)-threo-4F-MPH DAT IC50=61nM, NET IC50=31nM; MPH DAT IC50=131nM, NET IC50=83nM dta.2167
All IC₅₀ comparisons from the same assay system (rat brain synaptosomes).supported
Monoamine transporter studies using rat brain synaptosomes dta.2167
Luethi and colleagues profiled multiple methylphenidate-based NPS in the same in vitro system, enabling direct comparisonsupported
characterize the pharmacology of methylphenidate-based substances in vitro j.neuropharm.2017.08.020
The DAT:SERT selectivity ratio is the primary predictor of abuse liability within the monoamine modifier class. 4F-MPH's ratio (~144:1) places it in the high-abuse-liability category alongside cocaine and methylphenidate, and distinctly separate from serotonin-predominant compounds such as MDMA (which has a DAT:SERT ratio below 1).supported
DAT/SERT ratio predicts stimulant vs entactogen effects. Dopaminergic drugs highly addictive. smw.2015.14043
Amphetamines induce DAT-mediated dopamine efflux (reverse transport), producing greater maximal synaptic dopamine elevation than reuptake inhibition alone. 4F-MPH, like all phenidates, has a ceiling effect on dopamine elevation determined by endogenous dopamine release rate — it blocks reuptake but does not add exogenous dopamine releasesupported
Stimulants including phenidate analogs primarily interact with monoamine transporters; sympathomimetic adverse effects. s00204-020-02693-7
receptor-pharmacology5 · 4 ok
The complete transporter inhibition profile for 4F-MPH was established by McLaughlin and colleagues using [³H]dopamine, [³H]norepinephrine, and [³H]serotonin uptake inhibition assays in rat brain synaptosomessupported
Monoamine transporter studies using rat brain synaptosomes: (±)-threo-4F-MPH DAT IC50=61nM, NET IC50=31nM, SERT IC50=8805nM dta.2167
The threo diastereomer exhibits a striking stereoselectivity: it is approximately 140-fold more potent than the erythro form at DAT and 122-fold more potent at NETpartially supported
(±)-threo-4F-MPH DAT IC50=61nM, NET IC50=31nM; (±)-erythro-4F-MPH DAT IC50=8528nM [erythro NET IC50 not provided in abstract] dta.2167
Within the framework proposed by Liechti, compounds with high DAT:SERT ratios produce predominantly stimulant effects and carry higher abuse potential than serotonin-predominant compounds.supported
DAT/SERT ratio predicts stimulant vs entactogen effects. Dopaminergic drugs highly addictive. smw.2015.14043
Claim in receptor-pharmacology — inconclusiveinconclusiveworking →
Extrapolation from the methylphenidate class suggests negligible activity at these targets at pharmacologically relevant concentrations, but 4F-MPH-specific receptor binding screens have not been publishedsupported
Stimulants including phenidate analogs primarily interact with monoamine transporters. s00204-020-02693-7
chemistry3 · 2 ok
The (±)-erythro form is virtually inactive: its DAT IC₅₀ (8,528 nM) is approximately 140-fold weaker than the threo form (61 nM).supported
(±)-threo-4F-MPH DAT IC50=61nM; (±)-erythro-4F-MPH DAT IC50=8528nM dta.2167
Claim in chemistry — inconclusiveinconclusiveworking →
Phenidate analogs including 4F-MPH undergo thermal decomposition in gas chromatography (GC) injection ports and on-column, producing artifact peaks (2-aryl-ethyl-acetates and 2,3,4,5-tetrahydropyridines)supported
Thermal decomposition under GC conditions to 2-aryl-ethyl-acetates and 2,3,4,5-tetrahydropyridines occurs in injection port and/or on column. dta.2161
pharmacokinetic-detail2 · 2 ok
Manier and colleagues characterized 4F-MPH metabolism using both rat in vivo and human S9 fraction in vitro modelssupported
UHPLC-HRMS/MS in rat urine and human S9 fraction. bkz052
Human S9 fraction incubations reproduced the hydrolytic pathway, confirming its relevance to human metabolismsupported
UHPLC-HRMS/MS in rat urine and human S9 fraction... Primary hydrolysis to carboxy metabolites. bkz052
neuroscience1 · 1 ok
For methylphenidate, primate self-administration studies demonstrate robust reinforcing efficacy comparable to cocaine, indicating that sensitization of reward-related processes occurs despite concurrent tolerance to some effects.supported
In rhesus monkeys, methylphenidate maintained robust self-administration behavior (>90% injection lever responses), comparable to cocaine. Confirms methylphenidate abuse potential via DAT inhibition. pmid:15526000