generation run 2026-05-11
63 min completedmodel pipeline-v5plan not recordedrun/aef273d1…Selection
Verification
- record
- seen / partial
- working
The model's own caveats
- sparse_evidence
- safety_data_unverified
- structural_inference_avoided
Reproduce
- inputs
- 30 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
15 searches — query, source, results, what was kept and why
| # | source | query | seen | kept | rationale |
|---|---|---|---|---|---|
| 1 | PubMed | methylphenidate ethanol transesterification ethylphenidate formation metabolism | 9 | 5 | Establish metabolic formation pathway, stereochemistry, and PK interactions |
| 2 | PubMed | ethylphenidate death fatality postmortem Scotland | 2 | 2 | Critical safety data: postmortem concentrations and cause of death analysis |
| 3 | OpenAlex | ethylphenidate pharmacology dopamine transporter | 10 | 2 | High-citation papers covering EPH pharmacology in context of designer drugs |
| 4 | ClinicalTrials.gov · absence | ethylphenidate | 0 | 0 | No trials exist |
| 5 | PubMed | methylphenidate ethylphenidate dopamine transporter binding affinity | 1 | 1 | Key in vitro pharmacology paper |
| 6 | PubMed | ethylphenidate pharmacology | 15 | 9 | Selected papers with direct pharmacological, toxicological, or clinical relevance to ethylphenidate |
| 7 | PubMed | ethylphenidate toxicity case report adverse | 2 | 2 | Both papers directly document EPH toxicology and human exposure |
| 8 | PubChem | ethylphenidate | 1 | 1 | Primary chemical identity verification |
| 9 | ClinicalTrials.gov · absence | ethylphenidate | 0 | 0 | Confirmed no trials exist |
| 10 | Web | ACMD methylphenidate NPS TCDO report | 1 | 1 | UK regulatory history |
| 11 | Web | ethylphenidate SMILES canonical structure CAS 57413-43-1 | 10 | 2 | SMILES and CAS number not in PubChem API response, needed web confirmation |
| 12 | Web | ethylphenidate legal status UK USA scheduling controlled substance 2025 | 10 | 5 | Legal status data for all major jurisdictions |
| 13 | PubMed | Soussan Kjellgren ethylphenidate experiences internet forums | 1 | 1 | Primary source for subjective effects characterization |
| 14 | Web | ethylphenidate first appeared research chemical market history | 10 | 1 | Historical emergence data |
| 15 | PubChem | ethylphenidate CID 3080846 | 1 | 1 | Chemical identity verification |
79 claims by section — every cited sentence, checked against its source
safety24 · 14 ok
Parks et al. reviewed 19 EPH-associated deaths in East and West Scotland (July 2013 – December 2014)supported
19 cases over 18 months (July 2013-Dec 2014) where EPH detected at postmortem. Mostly East Scotland. j.forsciint.2015.08.008
Claim in safety — inconclusiveinconclusiveworking →
Maskell et al. reported seven fatalities in England (February 2013 – January 2015)supported
7 cases with EPH detected in postmortem blood (Feb 2013-Jan 2015). All male, ages 23-49. j.forsciint.2015.12.045
Remaining cases involved at least two other drug classes; causes of death included mixed drug toxicity (n = 4), hanging (n = 2), and EPH toxicity (n = 1).supported
One case sole EPH toxicity as cause of death; 4 cases mixed drug toxicity; 2 cases hanging. j.forsciint.2015.12.045
Users consistently report increased heart rate, elevated blood pressure, and increased body temperature — expected class effects of DAT/NET inhibition. Abnormal heartbeat is documented in community reportssupported
Users reported increased body temperature, heart rate, blood pressure, sweating, muscle tension. sart.s22495
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
McAuley et al. identified IV NPS use, including EPH, as a major risk factor in an HIV outbreak among people who inject drugs in Greater Glasgow and Clyde in 2015 — the largest such outbreak in the United Kingdom in 30 yearssupported
Largest such incident in UK for 30 years. NPS injection including EPH was a major risk factor. s2352-3018(19)30036-0
Soussan and Kjellgren identified compulsive redosing and binge patterns as the most prominent theme in their analysis of international user reportssupported
Seven themes: compulsive redosing/addiction; mental state impacts; bodily agitation; increased sociableness; administration; diverse evaluations; safety/precaution. sart.s22495
At higher doses, users report anxiety, paranoia, cognitive fragmentation, and indecisivenesssupported
Effects included pleasurable stimulation, euphoria, cognitive enhancement, indecisiveness, anxiety, cognitive fragmentation. sart.s22495
Claim in safety — inconclusiveinconclusiveworking →
Animal data reinforce concern about addiction vulnerability: ΔFosB upregulation in the dorsal striatum, nucleus accumbens, and prefrontal cortex following repeated EPH exposure in adolescent mice indicates long-term transcriptional changes associated with compulsive drug-seeking.supported
Increased deltaFosB expression in dorsal striatum, nucleus accumbens, and prefrontal cortex. fnins.2019.00124
Dependence: Physical and psychological dependence liability is assessed as moderate, based on convergent evidence from user self-reports and preclinical datasupported
Seven themes: compulsive redosing/addiction... safety/precaution. sart.s22495
Dependence: Physical and psychological dependence liability is assessed as moderate, based on convergent evidence from user self-reports and preclinical datasupported
EPH induced conditioned place preference even at non-stimulatory doses. Increased deltaFosB expression in dorsal striatum, nucleus accumbens, and prefrontal cortex. fnins.2019.00124
In mice, conditioned place preference at sub-stimulatory doses (5 mg/kg i.p.) demonstrates reward value at exposures below the threshold for overt stimulation, and ΔFosB elevation in striatal and prefrontal regions marks molecular substrates associated with the transition from voluntary to compulsive drug usesupported
EPH induced conditioned place preference even at non-stimulatory doses. Increased deltaFosB expression in dorsal striatum, nucleus accumbens, and prefrontal cortex. fnins.2019.00124
Claim in safety — inconclusiveinconclusiveworking →
Co-ingestion of ethanol with methylphenidate produces EPH endogenously via CES1 transesterification, simultaneously increasing d-methylphenidate C_max by 40–100% through competitive CES1 inhibitionsupported
CES1 enantioselectively transesterifies l-MPH with ethanol to yield l-EPH. Ethanol elevated d-MPH plasma concentrations 44-99% during absorption phase. dmd.112.048595
Co-ingestion of ethanol with methylphenidate produces EPH endogenously via CES1 transesterification, simultaneously increasing d-methylphenidate C_max by 40–100% through competitive CES1 inhibitionsupported
Ethanol elevates plasma d-MPH Cmax by ~40% and AUC by ~25% via CES1 transesterification. l-ethylphenidate formed as predominant transesterification metabolite. pmid:17339864
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — not_supportednot supportedworking →
EPH produces sympathomimetic cardiovascular stimulation including tachycardia, hypertension, and hyperthermiasupported
Users reported increased body temperature, heart rate, blood pressure, sweating, muscle tension. sart.s22495
pharmacology11 · 8 ok
Ethylphenidate is a competitive inhibitor of the dopamine transporter (DAT) with secondary, weaker activity at the norepinephrine transporter (NET) and negligible serotonin transporter (SERT) activitysupported
Binding selectivity for dopamine versus norepinephrine transporters was greater for (+)-ethylphenidate than for cocaine. pmid:15828826
Ethylphenidate is a competitive inhibitor of the dopamine transporter (DAT) with secondary, weaker activity at the norepinephrine transporter (NET) and negligible serotonin transporter (SERT) activitysupported
d-EPH selectively targets the dopamine transporter whereas d-MPH exhibits equipotent actions at dopamine and norepinephrine transporters. jps.24202
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
The active enantiomer, d-threo-ethylphenidate, inhibits DAT with an IC₅₀ of 27 nM — approximately 13.6 times more potent than cocaine (IC₅₀ 367 nM) at the same targetsupported
The IC50 for dopamine reuptake inhibition by (+)-ethylphenidate was 27 nM compared to 367 nM for cocaine. pmid:15828826
The inactive l-threo enantiomer shows an IC₅₀ of 1,730 nM, representing a greater than 60-fold enantioselectivity. d-EPH displays markedly greater DAT-over-NET selectivity compared to d-methylphenidate, which inhibits both transporters with roughly equal potencysupported
1730 nM for (-)-ethylphenidate. Binding selectivity for dopamine versus norepinephrine transporters was greater for (+)-ethylphenidate than for cocaine. pmid:15828826
The inactive l-threo enantiomer shows an IC₅₀ of 1,730 nM, representing a greater than 60-fold enantioselectivity. d-EPH displays markedly greater DAT-over-NET selectivity compared to d-methylphenidate, which inhibits both transporters with roughly equal potencysupported
d-ethylphenidate is a selective DAT inhibitor with less NET activity than methylphenidate; l-ethylphenidate biologically inactive. pmid:17218796
The inactive l-threo enantiomer shows an IC₅₀ of 1,730 nM, representing a greater than 60-fold enantioselectivity. d-EPH displays markedly greater DAT-over-NET selectivity compared to d-methylphenidate, which inhibits both transporters with roughly equal potencysupported
d-EPH selectively targets the dopamine transporter whereas d-MPH exhibits equipotent actions at dopamine and norepinephrine transporters. jps.24202
Luethi et al. conducted the most comprehensive in vitro pharmacological profiling of methylphenidate-based designer drugs including EPH, confirming this DAT-preferring selectivity profile.supported
Characterized pharmacology of methylphenidate-based NPS in vitro including ethylphenidate. Assessed monoamine transporter inhibition and receptor interactions. j.neuropharm.2017.08.020
EPH is metabolized primarily by hydrolysis of its ethyl ester moiety via carboxylesterase 1 (CES1) to yield ritalinic acid (α-phenyl-α-(2-piperidyl)acetic acid) as the principal metabolitesupported
Ritalinic acid is the main metabolite. EPH is pharmacologically active. s13318-016-0362-1
Claim in pharmacology — inconclusiveinconclusiveworking →
summary9 · 9 ok
EPH was first detected in humans as an in vivo transesterification metabolite of methylphenidate co-ingested with ethanolsupported
First detection of EPH in human blood and liver samples from two MPH overdose cases with ethanol co-ingestion. pmid:10440465
Patrick et al. characterized its enantiomers and established its independent pharmacological profile in 2005supported
The IC50 for dopamine reuptake inhibition by (+)-ethylphenidate was 27 nM compared to 367 nM for cocaine and 1730 nM for (-)-ethylphenidate. pmid:15828826
The active enantiomer, d-threo-ethylphenidate, inhibits the dopamine transporter with an IC₅₀ of 27 nM — approximately 13.6 times more potent than cocaine at the same targetsupported
The IC50 for dopamine reuptake inhibition by (+)-ethylphenidate was 27 nM compared to 367 nM for cocaine. pmid:15828826
Unlike d-methylphenidate, which shows roughly equipotent DAT and NET inhibition, d-EPH preferentially blocks DAT with markedly weaker NET activity.supported
d-EPH selectively targets the dopamine transporter whereas d-MPH exhibits equipotent actions at dopamine and norepinephrine transporters. jps.24202
Unlike d-methylphenidate, which shows roughly equipotent DAT and NET inhibition, d-EPH preferentially blocks DAT with markedly weaker NET activity.supported
d-ethylphenidate is a selective DAT inhibitor with less NET activity than methylphenidate. pmid:17218796
The subjective experience is dominated by stimulation, euphoria, focus-enhancement, and a pronounced compulsive redosing urge that constitutes the compound's primary behavioural risksupported
Seven themes: compulsive redosing/addiction; mental state impacts... Effects included pleasurable stimulation, euphoria, cognitive enhancement. sart.s22495
No established human toxic dose exists; postmortem femoral blood concentrations in fatality cases ranged from 0.008–2.18 mg/L, though nearly all deaths involved polydrug combinationspartially supported
EPH concentrations 0.026-2.18 mg/L in femoral blood. One case sole EPH toxicity as cause of death; 4 cases mixed drug toxicity; 2 cases hanging. j.forsciint.2015.12.045
No established human toxic dose exists; postmortem femoral blood concentrations in fatality cases ranged from 0.008–2.18 mg/L, though nearly all deaths involved polydrug combinationssupported
EPH concentrations 0.008-2+ mg/L (median 0.25 mg/L). Drug toxicity factor in 10 cases; EPH specifically named in 5 causes of death. j.forsciint.2015.08.008
Dependence liability is moderate, supported by conditioned place preference at sub-stimulatory doses and ΔFosB upregulation in reward-pathway nuclei in adolescent micesupported
EPH induced conditioned place preference even at non-stimulatory doses. Increased deltaFosB expression in dorsal striatum, nucleus accumbens, and prefrontal cortex. fnins.2019.00124
pharmacokinetic-detail8 · 7 ok
When methylphenidate is co-ingested with ethanol, hepatic and intestinal CES1 enantioselectively transesterifies l-methylphenidate with ethanol to produce l-ethylphenidatesupported
l-ethylphenidate formed as predominant transesterification metabolite. pmid:17339864
All human PK data for EPH derive from studies of the methylphenidate–ethanol metabolic interaction, where EPH is generated in vivo as a transesterification metabolite rather than administered as a standalone drug.supported
Ethanol elevates plasma d-MPH Cmax by ~40% and AUC by ~25% via CES1 transesterification. l-ethylphenidate formed as predominant transesterification metabolite. pmid:17339864
When methylphenidate is co-ingested with ethanol, hepatic and intestinal CES1 enantioselectively transesterifies l-methylphenidate with ethanol to produce l-ethylphenidatesupported
Reviews MPH metabolomics including EPH formation via transesterification with ethanol. s13318-016-0362-1
The reaction simultaneously inhibits CES1-mediated hydrolysis of l-MPH, increasing plasma d-MPH C_max by 40–100%supported
Ethanol elevated d-MPH plasma concentrations 44-99% during absorption phase with subjective effects potentiation. dmd.112.048595
The l-EPH formed via this pathway is biologically inactive; the clinically significant consequence is elevated d-MPH exposure, which amplifies euphorigenic and abuse-liability properties.supported
Ethanol elevated d-MPH plasma concentrations 44-99% during absorption phase with subjective effects potentiation. dmd.112.048595
Patrick further characterized the analytical implications of this interaction, noting that chiral derivatization/gas chromatography methods may underestimate d-methylphenidate bioavailability when EPH formation is not accounted for.supported
Discusses CES1-mediated first-pass metabolism and its implications for d-MPH bioavailability; EPH formation via CES1 transesterification discussed. dmd.119.087189
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
Analytical detection of EPH in biological matrices has been established using liquid chromatography–tandem mass spectrometry (LC-MS/MS) in oral fluid, and chiral separation of enantiomers in blood using supercritical fluid chromatography.supported
Validated LC-MS/MS method for MPH, EPH, and ritalinic acid in oral fluid. j.jchromb.2022.123330
neuroscience7 · 7 ok
Robins et al. demonstrated that repeated EPH administration (15 mg/kg i.p. × 8 days) in adolescent male mice produced elevated ΔFosB expression in the dorsal striatum, nucleus accumbens, and prefrontal cortex. ΔFosB is a truncated splice variant of the FosB transcription factor that accumulates with chronic stimulant exposure and is considered a molecular marker of addiction vulnerability — it enhances sensitivity to drug reward and promotes compulsive drug-seeking by remodeling chromatin at reward-pathway gene promoters.supported
Increased deltaFosB expression in dorsal striatum, nucleus accumbens, and prefrontal cortex. fnins.2019.00124
Robins et al. demonstrated that repeated EPH administration (15 mg/kg i.p. × 8 days) in adolescent male mice produced elevated ΔFosB expression in the dorsal striatum, nucleus accumbens, and prefrontal cortex. ΔFosB is a truncated splice variant of the FosB transcription factor that accumulates with chronic stimulant exposure and is considered a molecular marker of addiction vulnerability — it enhances sensitivity to drug reward and promotes compulsive drug-seeking by remodeling chromatin at reward-pathway gene promoters.supported
Increased deltaFosB expression in dorsal striatum, nucleus accumbens, and prefrontal cortex. fnins.2019.00124
Repeated EPH exposure (15 mg/kg × 8 days) impaired spatial cognitive performance on the Barnes maze in adolescent male micesupported
Repeated EPH exposure in adolescent mice decreased spatial cognitive performance. fnins.2019.00124
EPH produced locomotor stimulation at 15 mg/kg but not at 5 mg/kg in mice, while conditioned place preference occurred at both doses — suggesting that reward valuation and locomotor activation may have different dose thresholds, with potential implications for the development of sensitization-tolerance dissociations during repeated human use.supported
EPH induced conditioned place preference even at non-stimulatory doses. fnins.2019.00124
By blocking DAT in the nucleus accumbens (NAc) and ventral tegmental area (VTA) projection terminals, EPH elevates extracellular dopamine in the circuit most directly implicated in reward valuation, incentive salience, and reinforcement learning.supported
Increased deltaFosB expression in dorsal striatum, nucleus accumbens, and prefrontal cortex. EPH has higher DAT vs NET preference compared to MPH. fnins.2019.00124
At low-to-moderate doses, elevated prefrontal dopamine enhances working memory and sustained attention; at higher doses, excessive dopaminergic stimulation may produce the cognitive fragmentation and decision impairment described in user reports.supported
Effects included cognitive enhancement, indecisiveness, anxiety, cognitive fragmentation. sart.s22495
EPH's strong DAT selectivity and the resulting dopamine elevation in the NAc would be predicted to amplify "wanting" (incentive motivation to re-administer) disproportionately to "liking" (hedonic pleasure), consistent with the dominant user complaint that the urge to redose exceeds the subjective reward of subsequent doses.supported
Seven themes: compulsive redosing/addiction... Effects included pleasurable stimulation, euphoria. sart.s22495
clinical-evidence4 · 3 ok
The sole systematic investigation of human EPH effects is a qualitative analysis of self-reports from international internet drug forums conducted by Soussan and Kjellgrensupported
Investigated EPH experiences via internet forum self-reports. sart.s22495
All remaining human data consist of forensic case reports and postmortem toxicological analyses, epidemiological surveillance of injection-related harms, a retrospective analysis identifying EPH in clinical drug-testing samples in Sweden, and a single case report documenting prolonged psychiatric effects after cessation.supported
19 cases over 18 months where EPH detected at postmortem. j.forsciint.2015.08.008
Claim in clinical-evidence — inconclusiveinconclusiveworking →
All remaining human data consist of forensic case reports and postmortem toxicological analyses, epidemiological surveillance of injection-related harms, a retrospective analysis identifying EPH in clinical drug-testing samples in Sweden, and a single case report documenting prolonged psychiatric effects after cessation.supported
Retrospective NPS identification in 14,367 clinical oral fluid samples from 2019 in Sweden. EPH was among 34 NPS detected. bcpt.13786
comparative-pharmacology4 · 4 ok
Animal data support this interpretation: EPH produces conditioned place preference at doses (5 mg/kg i.p.) below the threshold for locomotor stimulation in mice.supported
EPH induced conditioned place preference even at non-stimulatory doses. fnins.2019.00124
The critical pharmacological distinction is EPH's enhanced DAT selectivity: d-methylphenidate inhibits DAT and NET with approximately equal potency, while d-ethylphenidate preferentially inhibits DAT with markedly weaker NET activity.supported
d-ethylphenidate is a selective DAT inhibitor with less NET activity than methylphenidate. pmid:17218796
The greater DAT selectivity of d-EPH has been interpreted as conferring higher abuse potential relative to methylphenidate, as DAT blockade in the nucleus accumbens is the primary molecular determinant of stimulant rewardsupported
d-EPH selectively targets the dopamine transporter... Reviews abuse liability potentiation with ethanol. jps.24202
Both EPH and cocaine act as DAT inhibitors, but EPH is approximately 13.6 times more potent at DAT on a molar basis (IC₅₀ 27 nM versus 367 nM)supported
The IC50 for dopamine reuptake inhibition by (+)-ethylphenidate was 27 nM compared to 367 nM for cocaine. pmid:15828826
history4 · 2 ok
Its existence was first recognized through forensic toxicology: Markowitz et al. detected EPH in postmortem blood samples from two individuals who had fatally overdosed on methylphenidate after co-ingesting ethanolsupported
First detection of EPH in human blood and liver samples from two MPH overdose cases with ethanol co-ingestion. EPH detected at 8 ng/mL and 1 ng/mL in whole blood. pmid:10440465
Claim in history — not_supportednot supportedworking →
Claim in history — inconclusiveinconclusiveworking →
This injection practice was associated with a surge in harm-reduction service presentations in Lothian and was identified as a contributing factor in the largest HIV outbreak among people who inject drugs in the United Kingdom in three decadessupported
Largest such incident in UK for 30 years. NPS injection including EPH was a major risk factor. s2352-3018(19)30036-0
receptor-pharmacology4 · 2 ok
Claim in receptor-pharmacology — inconclusiveinconclusiveworking →
The l-threo enantiomer is essentially inactive, with a 64-fold lower DAT affinity.supported
1730 nM for (-)-ethylphenidate. pmid:15828826
The defining pharmacological feature of EPH relative to its parent compound methylphenidate is its enhanced DAT selectivity. d-Methylphenidate inhibits DAT and NET with approximately equal potency; d-EPH preferentially blocks DAT with substantially weaker NET inhibitionsupported
d-EPH selectively targets the dopamine transporter whereas d-MPH exhibits equipotent actions at dopamine and norepinephrine transporters. jps.24202
Claim in receptor-pharmacology — inconclusiveinconclusiveworking →
chemistry2 · 0 ok
effects-overview2 · 2 ok
The compulsive redosing urge is the experience's defining feature across all administration routes: the drive to re-administer frequently exceeds the hedonic value of subsequent doses, distinguishing EPH from most stimulants in its class.supported
Seven themes: compulsive redosing/addiction; mental state impacts... administration. sart.s22495
Compared to methylphenidate, the subjective character is described as more recreational and less functionally enhancing, reflecting EPH's enhanced DAT selectivity and reduced noradrenergic contribution to executive arousal.supported
d-ethylphenidate is a selective DAT inhibitor with less NET activity than methylphenidate. pmid:17218796