generation run 2026-05-11
109 min completedmodel pipeline-v5plan not recordedrun/3e38b376…Selection
Verification
- record
- seen / partial
- working
The model's own caveats
- sparse_evidence
- sparse_evidence
- safety_data_unverified
Reproduce
- inputs
- 21 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
24 searches — query, source, results, what was kept and why
| # | source | query | seen | kept | rationale |
|---|---|---|---|---|---|
| 1 | PubMed | PMID 36545302 | 1 | — | — |
| 2 | PubChem | 4-fluoroethylphenidate | 1 | 1 | — |
| 3 | PubMed | ethylphenidate abuse recreational use new psychoactive | 4 | 1 | — |
| 4 | PubChem · absence | 4F-EPH | 0 | — | — |
| 5 | PubMed | phenidate designer stimulant piperidine forensic analysis | 1 | 1 | — |
| 6 | PubMed | 4-fluoromethylphenidate 4F-MPH pharmacology dopamine transporter | 1 | 1 | — |
| 7 | OpenAlex | 4-fluoroethylphenidate phenidate stimulant NPS | 3 | 2 | — |
| 8 | PubMed · absence | 4F-EPH 4-fluoroethylphenidate stimulant | 0 | — | — |
| 9 | PubMed | PMID 28823611 | 1 | — | — |
| 10 | PsychonautWiki | 4F-EPH psychonautwiki dosage effects | 1 | — | — |
| 11 | WebSearch | 4F-EPH fluoroethylphenidate Germany Sweden controlled substance NPS | 10 | — | — |
| 12 | PubMed | PMID 25303048 | 1 | — | — |
| 13 | PubMed | 4-fluoromethylphenidate intoxication analytically confirmed clinical case | 1 | — | — |
| 14 | PubMed | PMID 41925822 | 1 | — | — |
| 15 | WebSearch | 4F-EPH EMCDDA European Monitoring Centre drugs report 2016 2017 | 10 | — | — |
| 16 | WebSearch | Luethi 2018 Neuropharmacology methylphenidate designer drugs compounds tested | 10 | — | — |
| 17 | WebSearch | Kim 2026 4-fluoroethylphenidate rodents discriminative stimulus rewarding reinforcing | 10 | — | — |
| 18 | PubMed | methylphenidate MDMA interaction pharmacodynamic serotonin dopamine | 5 | — | — |
| 19 | WebSearch | 4-fluoroethylphenidate SMILES InChI CAS number chemical structure | 10 | — | — |
| 20 | WebSearch | 4F-EPH user reports reddit bluelight effects duration | 10 | — | — |
| 21 | PubMed | fluoromethylphenidate fatal intoxication novel psychoactive substance USA | 1 | — | — |
| 22 | ClinicalTrials.gov · absence | 4-fluoroethylphenidate 4F-EPH phenidate | 0 | — | — |
| 23 | WebSearch | UK Psychoactive Substances Act 2016 phenidate ethylphenidate schedule | 10 | — | — |
| 24 | Bluelight | 4F-EPH Bluelight review user report | 2 | — | — |
79 claims by section — every cited sentence, checked against its source
safety28 · 23 ok
Cardiovascular toxicity — tachycardia, hypertension — represents the primary acute risk, consistent with the sympathomimetic toxidrome of DAT/NET inhibitorssupported
Mechanism: excessive extracellular DA, NE, serotonin. s40263-013-0084-8
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Corkery and Schifano confirmed in 2022 that no relevant pharmacological information on lethal dosage, half-life, or volume of distribution is available for either animal or human subjectssupported
Scientifically-based data on the pharmacological, physiological, psychopharmacological, toxicological, and epidemiological characteristics of this molecule is non-existent. 19253621221142480
The acute toxicity profile of 4F-EPH is predicted to follow the sympathomimetic toxidrome characteristic of phenidate-class compounds:supported
MPH overdose: mydriasis, tremor, agitation, hyperreflexia, hallucinations, delirium, seizures. Mechanism: excessive extracellular DA, NE, serotonin. s40263-013-0084-8
The acute toxicity profile of 4F-EPH is predicted to follow the sympathomimetic toxidrome characteristic of phenidate-class compounds:supported
Stimulants primarily interact with monoamine transporters. Sympathomimetic adverse effects documented. s00204-020-02693-7
Fatalities from phenidate-class overdose in isolation are rare when appropriate medical care is availablesupported
Fatalities rare with appropriate care. s40263-013-0084-8
The only published death involving 4F-EPH occurred in Scotland in 2016 and was described in a Fatal Accident Inquirysupported
details of the first reported death involving 4F-EPH use in 2016. 19253621221142480
A 26-year-old female developed neuropsychiatric and cardiovascular symptoms after one week of intranasal 4F-MPH use (blood concentration: 32 ng/mL; urine: 827 ng/mL), requiring intravenous diazepam and subsequent antipsychotic treatment.supported
First analytically confirmed non-fatal intoxication by 4F-MPH in a 26-year-old female admitted to ED with neuropsychiatric and cardiologic symptoms after sniffing 4F-MPH. Blood concentration 32 ng/mL, urine 827 ng/mL. bkz001
The first 4F-MPH fatality in the United States occurred in Florida in a polydrug context (co-detected substances: 3-MeO-PCP, amphetamine, methamphetamine, 6-MAM, morphine, codeine, THC) with femoral blood 4F-MPH concentrations of 0.012–0.05 mg/L.supported
First 4F-MPH death in USA: first detected in Florida drug paraphernalia 2016, first in biological specimen 2018. Blood femoral concentration 0.012-0.05 mg/L. Polydrug (3-MeO-PCP, amphetamine, methamphetamine, 6-MAM, morphine, codeine, THC). bkz061
Class-based emergency guidance for phenidate/stimulant overdose:supported
Management: benzodiazepines first-line, antipsychotics for refractory cases. s40263-013-0084-8
Stimulant-class psychological risks apply to 4F-EPH based on its DAT/NET inhibitor mechanism:supported
Comprehensive review of designer drug mechanisms and adverse effects. Stimulants primarily interact with monoamine transporters. Sympathomimetic adverse effects documented. s00204-020-02693-7
Stimulant-class psychological risks apply to 4F-EPH based on its DAT/NET inhibitor mechanism:supported
Dopaminergic NPS associated with prolonged stimulation, insomnia, agitation, psychosis, and high addiction risk. smw.2015.14043
Rebound depression: Following sustained dopaminergic stimulation, catecholamine depletion produces depressive symptoms, anhedonia, and fatigue. User reports identify depression and cognitive fatigue as comedown effects of 4F-EPH.supported
Recreational and 'functional' use of this drug has been reported by online user fora... supplemented by netnographic examinations of internet sites. 19253621221142480
Acute tolerance to euphoric effects develops within a single session — user reports describe the initial rush as diminishing with each subsequent dosesupported
Recreational and 'functional' use of this drug has been reported by online user fora... supplemented by netnographic examinations of internet sites. 19253621221142480
Longer-term tolerance develops with sustained use, consistent with class pharmacologysupported
Dopaminergic NPS associated with prolonged stimulation, insomnia, agitation, psychosis, and high addiction risk. smw.2015.14043
Claim in safety — inconclusiveinconclusiveworking →
Dopaminergic reuptake inhibitors carry high addiction liabilitysupported
Dopaminergic NPS associated with... high addiction risk. smw.2015.14043
Dopaminergic reuptake inhibitors carry high addiction liabilitysupported
Comprehensive review of designer drug mechanisms and adverse effects. Stimulants primarily interact with monoamine transporters. s00204-020-02693-7
Claim in safety — inconclusiveinconclusiveworking →
The database classifies this interaction as lethal. tramadol inhibits both the serotonin transporter (SERT) and norepinephrine transporter (NET), in addition to its μ-opioid receptor agonismsupported
Tramadol's serotonin and norepinephrine reuptake inhibitory effects result in a unique adverse effect profile including serotonin syndrome and seizures. j.amjmed.2018.04.025
Claim in safety — inconclusiveinconclusiveworking →
No published case report specifically documents a 4F-EPH + tramadol fatality; the classification may derive from the 2016 Scotland death case.supported
details of the first reported death involving 4F-EPH use in 2016. 19253621221142480
A controlled crossover study in 28 healthy subjects demonstrated that methylphenidate (60 mg) combined with MDMA (125 mg) produced significantly greater hemodynamic effects and more adverse events than either drug alone, without enhancing psychotropic effects. 4F-EPH would be expected to carry similar or greater cardiovascular risk given its predicted potency profile.supported
MPH + MDMA combination significantly enhanced hemodynamic and adverse effects compared with either drug alone, though psychotropic effects not enhanced. s1461145713001132
The CES1-mediated transesterification mechanism that characterizes the methylphenidate-alcohol interaction does not directly apply to 4F-EPH (which already carries an ethyl ester)supported
Ethanol co-administration elevates d-MPH concentrations 44-99% and forms l-ethylphenidate via transesterification. dmd.112.048595
The CES1-mediated transesterification mechanism that characterizes the methylphenidate-alcohol interaction does not directly apply to 4F-EPH (which already carries an ethyl ester)supported
EPH formed via CES1 transesterification of l-MPH with ethanol. jps.24202
Serotonergic agents (SNRIs, SSRIs, serotonergic psychedelics): Potential for serotonin syndrome via additive monoaminergic effects, particularly given that tramadol's dual SERT/NET mechanism creates a documented high-risk profile.supported
Tramadol's serotonin and norepinephrine reuptake inhibitory effects result in a unique adverse effect profile including serotonin syndrome and seizures. j.amjmed.2018.04.025
The following contraindications are inferred from the DAT/NET reuptake inhibitor class mechanism and methylphenidate prescribing precedent:supported
Mechanism: excessive extracellular DA, NE, serotonin. Management: benzodiazepines first-line, antipsychotics for refractory cases. s40263-013-0084-8
neuroscience10 · 3 ok
Claim in neuroscience — inconclusiveinconclusiveworking →
Claim in neuroscience — inconclusiveinconclusiveworking →
This may correlate with user reports of stronger euphoria but less peripheral stimulation relative to 4F-MPH.supported
Recreational and 'functional' use of this drug has been reported by online user fora... supplemented by netnographic examinations of internet sites. 19253621221142480
Claim in neuroscience — inconclusiveinconclusiveworking →
Claim in neuroscience — inconclusiveinconclusiveworking →
Claim in neuroscience — inconclusiveinconclusiveworking →
Claim in neuroscience — inconclusiveinconclusiveworking →
Acute tolerance: Within-session diminution of euphoric effects ("rush fading"), consistent with rapid DAT internalization or presynaptic dopamine depletion. User reports describe the initial euphoric rush of 4F-EPH as diminishing rapidly with repeated dosing within a session.supported
Recreational and 'functional' use of this drug has been reported by online user fora... supplemented by netnographic examinations of internet sites. 19253621221142480
The compulsive redosing urge reported by 4F-EPH users, even when the euphoric rush has faded, is a behavioral manifestation of enhanced wanting that persists after acute tolerance has reduced liking.supported
Recreational and 'functional' use of this drug has been reported by online user fora... supplemented by netnographic examinations of internet sites. 19253621221142480
Claim in neuroscience — inconclusiveinconclusiveworking →
pharmacology8 · 5 ok
This reuptake-inhibitor-only mechanism was confirmed across 10 methylphenidate-based designer drugs by Luethi and colleagues, who found that none of the tested compounds elicited transporter-mediated release of dopamine, norepinephrine, or serotonin. 4F-EPH is therefore pharmacologically distinct from amphetamine-type stimulants, which act as monoamine releasers.supported
The aim of the present study was to characterize the pharmacology of methylphenidate-based substances in vitro. j.neuropharm.2017.08.020
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
The closest fluorinated analog, (±)-threo-4-fluoromethylphenidate (4F-MPH), shows DAT IC₅₀ = 61 nM, NET IC₅₀ = 31 nM, and SERT IC₅₀ > 8,000 nM — approximately twice as potent as methylphenidate at DAT and 2.5 times as potent at NETsupported
(±)-threo-4F-MPH: DAT IC50=61nM, NET IC50=31nM, SERT IC50>8000nM; more potent than MPH at DAT (131nM) and NET (83nM). dta.2167
Claim in pharmacology — inconclusiveinconclusiveworking →
Corkery and Schifano confirmed in their 2022 case report that "there is no relevant pharmacological information on this drug in terms of lethal dosage, LD₅₀, half-life, volume of distribution for either animal or human subjects".supported
Scientifically-based data on the pharmacological, physiological, psychopharmacological, toxicological, and epidemiological characteristics of this molecule is non-existent. 19253621221142480
Methylphenidate — the best-characterized compound in this class — has oral bioavailability of approximately 30% for the d-isomer, limited by extensive first-pass hydrolysis of the methyl ester by carboxylesterase 1 (CES1) in the liver and gutsupported
CES1-mediated enantioselective hydrolysis limits absolute bioavailability of d-MPH to approximately 30%; l-MPH to 1-2%. dmd.112.048595
For methylphenidate, co-ingestion with ethanol triggers CES1-mediated transesterification: l-methylphenidate is converted to l-ethylphenidate, effectively increasing d-methylphenidate plasma concentrations and prolonging its effects. 4F-EPH already carries an ethyl ester, so this specific transesterification pathway would not applysupported
Ethanol co-administration elevates d-MPH concentrations 44-99% and forms l-ethylphenidate via transesterification. dmd.112.048595
summary7 · 5 ok
The compound's evidence base consists of a single forensic case report documenting the first death involving 4F-EPH in Scotland in 2016, a 2026 rodent behavioral pharmacology study confirming high abuse potential, and European early-warning-system identification records.supported
details of the first reported death involving 4F-EPH use in 2016. There are no international controls imposed on 4F-EPH. However, it has been made a controlled drug in several European countries 19253621221142480
Claim in summary — inconclusiveinconclusiveworking →
Based on structural analogy, it is presumed to act as a competitive inhibitor at the dopamine transporter (DAT) and norepinephrine transporter (NET) without inducing transporter-mediated monoamine releasesupported
The aim of the present study was to characterize the pharmacology of methylphenidate-based substances in vitro. j.neuropharm.2017.08.020
Claim in summary — inconclusiveinconclusiveworking →
The parent compound d-ethylphenidate exhibits marked DAT selectivity (DAT IC₅₀ = 27 nM; NET IC₅₀ = 290 nM), and the 4-fluoro substitution approximately doubles DAT potency in the methylphenidate-to-4F-MPH transitionsupported
(±)-threo-4F-MPH: DAT IC50=61nM, NET IC50=31nM, SERT IC50>8000nM; more potent than MPH at DAT (131nM) and NET (83nM). dta.2167
User reports describe potent stimulation, euphoria, focus enhancement, and sociability, with a compulsive redosing urge that is reportedly less pronounced than with ethylphenidate.supported
Recreational and 'functional' use of this drug has been reported by online user fora... supplemented by netnographic examinations of internet sites. 19253621221142480
No controlled toxicity data, LD₅₀, or established lethal concentration exist for 4F-EPHsupported
Scientifically-based data on the pharmacological, physiological, psychopharmacological, toxicological, and epidemiological characteristics of this molecule is non-existent. 19253621221142480
chemistry6 · 5 ok
This dual structural relationship places 4F-EPH at the intersection of two modification axes explored in phenidate structure-activity relationship (SAR) studies: ring halogenation and ester chain extension.supported
Six collected phenidates (4-methylmethylphenidate, 3,4-dichloromethylphenidate, ethylphenidate, 3,4-dichloroethylphenidate, ethylnaphthidate, and N-benzyl-ethylphenidate) were fully characterized. dta.2161
Consistent with class precedent established for methylphenidate and its analogs, the threo racemate is predicted to be the pharmacologically active formsupported
All samples showed threo-configuration. dta.2161
Consistent with class precedent established for methylphenidate and its analogs, the threo racemate is predicted to be the pharmacologically active formsupported
(±)-threo-4F-MPH: DAT IC50=61nM, NET IC50=31nM, SERT IC50>8000nM dta.2167
Claim in chemistry — inconclusiveinconclusiveworking →
Analytical studies of phenidate-class NPS have found only the threo configuration present in seized samples.supported
All samples showed threo-configuration. dta.2161
Klare and colleagues noted that phenidate analogs may undergo thermal decomposition during gas chromatographic analysis, which can complicate analytical identificationsupported
Thermal instability of phenidates under GC-MS conditions noted. dta.2161
clinical-evidence5 · 4 ok
One clinically relevant controlled study examines the pharmacological combination most pertinent to 4F-EPH's interaction profile: Hysek and colleagues conducted a double-blind, placebo-controlled crossover study in 28 healthy subjects examining co-administration of methylphenidate (60 mg) and MDMA (125 mg)supported
Human double-blind crossover study: MPH + MDMA combination significantly enhanced hemodynamic and adverse effects compared with either drug alone. s1461145713001132
A separate 4F-MPH fatality in Florida occurred in a polydrug context (3-MeO-PCP, amphetamine, methamphetamine, 6-MAM, morphine, codeine, THC) with femoral blood 4F-MPH concentrations of 0.012–0.05 mg/Lsupported
Blood femoral concentration 0.012-0.05 mg/L. Polydrug (3-MeO-PCP, amphetamine, methamphetamine, 6-MAM, morphine, codeine, THC). bkz061
The only published human data involving 4F-EPH is a single forensic case report documenting a death in Scotland in 2016supported
details of the first reported death involving 4F-EPH use in 2016. 19253621221142480
A case report of analytically confirmed 4-fluoromethylphenidate (4F-MPH) intoxication documented neuropsychiatric and cardiologic symptoms in a 26-year-old female after one week of intranasal use (blood concentration: 32 ng/mL; urine: 827 ng/mL), requiring intravenous diazepam sedation and antipsychotic treatmentsupported
First analytically confirmed non-fatal intoxication by 4F-MPH in a 26-year-old female admitted to ED with neuropsychiatric and cardiologic symptoms after sniffing 4F-MPH. Blood concentration 32 ng/mL, urine 827 ng/mL. bkz001
Claim in clinical-evidence — inconclusiveinconclusiveworking →
comparative-pharmacology5 · 3 ok
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
Patrick and colleagues characterized d-EPH as "a selective dopaminergic agonist" in contrast to methylphenidate's mixed DAT/NET profilesupported
d-EPH selectively targets the dopamine transporter, whereas d-MPH exhibits equipotent actions at dopamine and norepinephrine transporters. jps.24202
The addition of fluorine at the 4-position of the phenyl ring (MPH → 4F-MPH) approximately doubles transporter binding potency: 4F-MPH DAT IC₅₀ = 61 nM versus MPH DAT IC₅₀ = 131 nM (racemic); 4F-MPH NET IC₅₀ = 31 nM versus MPH NET IC₅₀ = 78 nM (racemic)partially supported
(±)-threo-4F-MPH: DAT IC50=61nM, NET IC50=31nM, SERT IC50>8000nM; more potent than MPH at DAT (131nM) and NET (83nM). dta.2167
User reports compiled by Corkery and Schifano describe 4F-EPH as "more euphoric than its MPH counterpart" and "far superior to its MPH counterpart" in terms of recreational effectssupported
Recreational and 'functional' use of this drug has been reported by online user fora... supplemented by netnographic examinations of internet sites. 19253621221142480
pharmacokinetic-detail4 · 3 ok
Corkery and Schifano explicitly confirmed the absence of data on lethal dosage, LD₅₀, half-life, and volume of distribution for both animal and human subjectssupported
Scientifically-based data on the pharmacological, physiological, psychopharmacological, toxicological, and epidemiological characteristics of this molecule is non-existent. 19253621221142480
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
A distinctive feature of methylphenidate pharmacokinetics is CES1-mediated transesterification in the presence of ethanol: l-methylphenidate (the less active enantiomer) is converted to l-ethylphenidate, functionally increasing the proportion of the more active d-methylphenidate and prolonging stimulant effectssupported
Ethanol co-administration elevates d-MPH concentrations 44-99% and forms l-ethylphenidate via transesterification. dmd.112.048595
A distinctive feature of methylphenidate pharmacokinetics is CES1-mediated transesterification in the presence of ethanol: l-methylphenidate (the less active enantiomer) is converted to l-ethylphenidate, functionally increasing the proportion of the more active d-methylphenidate and prolonging stimulant effectssupported
EPH formed via CES1 transesterification of l-MPH with ethanol. jps.24202
history3 · 1 ok
Claim in history — inconclusiveinconclusiveworking →
Corkery and Schifano published the case report and accompanying literature review in Academic Forensic Pathology in 2022, constituting the first peer-reviewed publication to address 4F-EPH in any depthsupported
Scientifically-based data on the pharmacological, physiological, psychopharmacological, toxicological, and epidemiological characteristics of this molecule is non-existent. The aim of this paper is to remedy this situation. 19253621221142480
Claim in history — inconclusiveinconclusiveworking →