generation run 2026-05-07
125 min completedmodel pipeline-v5plan not recordedrun/a9c285e8…Selection
Verification
- record
- seen / partial
- working
The model's own caveats
- sparse_evidence
- structural_inference
Reproduce
- inputs
- 17 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
16 searches — query, source, results, what was kept and why
| # | source | query | seen | kept | rationale |
|---|---|---|---|---|---|
| 1 | PubChem | 4-fluoromethamphetamine | 1 | 1 | Confirmed PubChem CID and key chemical identifiers for 4-FMA |
| 2 | PubMed | 4-fluoromethamphetamine pharmacology | 3 | 3 | All three directly relevant to 4-FMA pharmacology and toxicology |
| 3 | Web/UNODC | 4-FMA UNODC substance database | 1 | 1 | Official UNODC classification confirms substance identity |
| 4 | Web/Wikipedia/PsychonautWiki | 4-FMA 4-fluoromethamphetamine legal status history market | 10 | 2 | Legal status and market history not available in academic databases |
| 5 | PubMed | 4-FMA stimulant amphetamine fluorinated | 1 | 0 | Duplicate of prior search |
| 6 | PubMed | 4-fluoroamphetamine 4-FA intoxication blood pressure retrospective | 1 | 1 | Prospective ED data documenting 4-FA's severe hypertensive effects; notes 4-FMA as substitute post-ban |
| 7 | PMC | 4-FA intoxication cardiovascular data | 1 | 1 | Quantitative cardiovascular data for 4-FA analog; confirms 4-FMA market substitution |
| 8 | PubMed | 4-fluoroamphetamine pharmacokinetics human controlled study | 3 | 2 | Human PK data for 4-FA as close structural analog of 4-FMA |
| 9 | PubMed | para-fluoroamphetamine 4-FA 4-FMA new psychoactive substance | 1 | 1 | Direct forensic evidence of 4-FMA in fatal cases |
| 10 | PubMed | fluoroamphetamine cardiovascular cardiac toxicity | 2 | 2 | Critical safety data for 4-FA with direct relevance to 4-FMA risk assessment |
| 11 | ClinicalTrials.gov · absence | 4-fluoromethamphetamine | 0 | 0 | No trials registered; consistent with emerging/unresearched NPS status |
| 12 | Multiple sources | Chemical identity verification: SMILES, InChIKey, CAS, PubChem CID | 4 | 3 | Cross-reference verification of all chemical identifiers |
| 13 | PubMed | fluoroamphetamine postmortem blood concentration forensic death | 2 | 1 | Fatal intoxication blood concentration data for 4-FA; serotonergic interaction mechanism |
| 14 | Federal Register / Web | 4-FMA 4-fluoromethamphetamine DEA scheduling US controlled analog act | 5 | 1 | Legal status documentation |
| 15 | Web/Wikipedia | 4-FMA UK Misuse of Drugs Act Germany Anlage scheduling | 5 | 2 | Comprehensive multi-jurisdiction legal status data |
| 16 | NIST WebBook | 4-fluoromethamphetamine CAS 351031 physical properties | 1 | 1 | Official chemical database confirming physical properties |
77 claims by section — every cited sentence, checked against its source
safety26 · 18 ok
CYP2D6 poor metabolizer phenotype — reduced detoxification capacity for 4-FMAsupported
CYP2D6 and CYP3A4 detoxify. j.tox.2021.152988
Hepatic impairment — impaired CYP-mediated detoxification may increase hepatotoxic risksupported
CYP2D6 and CYP3A4 detoxify. Mitochondrial dysfunction, oxidative stress, apoptosis, necrosis, and autophagy observed. j.tox.2021.152988
Claim in safety — inconclusiveinconclusiveworking →
Cardiovascular disease, hypertension, or cerebrovascular disease — 4-FA analog data demonstrate acute-onset severe hypertension and cerebral hemorrhage at recreational dosessupported
Mean SBP 164 mmHg for 4-FA patients vs 139 MDMA, 135 amphetamine. Complications: Takotsubo cardiomyopathy, subarachnoid hemorrhage, hypertensive urgency. emp2.12813
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
CYP2D6 poor metabolizers and individuals using CYP2E1 inducers (including alcohol) may face elevated hepatotoxic risk at doses that are well-tolerated by the general population.{{/Warning}}supported
CYP2E1 plays toxifying role; CYP2D6 and CYP3A4 detoxify. j.tox.2021.152988
Hondebrink et al. documented fatalities, cerebral hemorrhage, and severe cardiovascular toxicity in a prospective cohort study of 4-FA adverse health effectssupported
Prospective cohort study of adverse health effects after 4-FA use. Documents fatalities, cerebral hemorrhage, and severe cardiovascular toxicity. j.annemergmed.2017.07.482
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
The authors concluded that tachycardia in users is likely indirect (via elevated plasma norepinephrine), while QTc prolongation may result partly from direct drug effects on cardiomyocyte ion channels.supported
Tachycardia in patients likely indirect via norepinephrine release. Prolonged QTc potentially from direct cardiac effects. j.yjmcc.2019.09.007
Claim in safety — inconclusiveinconclusiveworking →
4-FMA's serotonin-releasing capacity — comparable to MDMA — creates a pharmacologically grounded risk for serotonin syndrome when combined with other serotonergic agentssupported
4-FMA releases NE, DA, and 5-HT similarly to MDMA. j.euroneuro.2014.12.012
4-FMA was detected in postmortem blood and urine specimens from fatal cases in Taiwan between 2011 and 2018, frequently in polydrug contexts alongside ketamine and 7-aminonimetazepamsupported
4-FMA found in fatal cases in Taiwan 2011-2018. Ketamine and nimetazepam most common co-ingested substances with 4-FA/4-FMA cases. bkab014
Claim in safety — inconclusiveinconclusiveworking →
Standard amphetamine immunoassays may not reliably detect 4-FMA; confirmatory LC-MS/MS or GC-MS is required for definitive identification.supported
4-Fluoroamphetamine (4-FA) showed 3,354% cross-reactivity with amphetamine ELISA. Novel stimulants (excluding 4-FA) generally showed no cross-reactivity. bkae017
Cross-tolerance with other dopaminergic stimulants (amphetamine, methamphetamine, cocaine) and with MDMA (via the shared serotonergic mechanism) is expected.supported
4-FMA releases NE, DA, and 5-HT similarly to MDMA. Para-fluoroamphetamine has enhanced serotonergic properties vs amphetamine. j.euroneuro.2014.12.012
Anchondo et al. demonstrated full discriminative stimulus substitution for methamphetamine, consistent with abuse potential comparable to methamphetaminesupported
All fluorinated compounds fully substituted for methamphetamine in discriminative stimulus tests (ED50 0.32-0.71 mg/kg). Abuse potential comparable to methamphetamine. j.jpet.2025.103617
4-FMA's SERT-releasing activity, comparable to MDMA, constitutes the pharmacological basis for dangerous interactions with other serotonergic agentssupported
4-FMA releases NE, DA, and 5-HT similarly to MDMA. j.euroneuro.2014.12.012
CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion, ritonavir) and CYP3A4 inhibitors (ketoconazole, grapefruit juice) may impair 4-FMA's detoxification pathways, increasing accumulation of CYP2E1-generated cytotoxic metabolitessupported
CYP2E1 plays toxifying role; CYP2D6 and CYP3A4 detoxify. j.tox.2021.152988
Alcohol induces CYP2E1, potentially increasing the proportion of toxifying metabolism and elevating hepatotoxic risk.supported
CYP2E1 plays toxifying role; CYP2D6 and CYP3A4 detoxify. j.tox.2021.152988
Given the severe hypertensive profile documented with the closely related analog 4-FA (mean systolic 164 ± 31 mmHg in emergency presentations), cardiovascular stacking with additional stimulants is of particular concern.supported
Mean SBP 164 mmHg for 4-FA patients vs 139 MDMA, 135 amphetamine. emp2.12813
Combinations with CNS depressants (GHB, GBL, alcohol, ketamine) may mask cardiovascular warning signs — chest pain, severe headache — that would otherwise prompt medical attention. 4-FMA was detected alongside ketamine in fatal cases in Taiwan, though the individual contribution of each substance to cause of death was not characterized.supported
4-FMA found in fatal cases in Taiwan 2011-2018. Ketamine and nimetazepam most common co-ingested substances with 4-FA/4-FMA cases. bkab014
Cardiovascular disease, hypertension, or cerebrovascular disease — 4-FA analog data demonstrate acute-onset severe hypertension and cerebral hemorrhage at recreational dosessupported
Documents fatalities, cerebral hemorrhage, and severe cardiovascular toxicity. j.annemergmed.2017.07.482
Concurrent CYP2D6 or CYP3A4 inhibitors — metabolic impairment of detoxification pathwayssupported
CYP2D6 and CYP3A4 detoxify. j.tox.2021.152988
pharmacokinetic-detail10 · 7 ok
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
Toennes et al. (2020) characterized urinary excretion of 4-FA and three metabolites following 100 mg (n = 12) and 150 mg (n = 5) oral doses; urine concentrations peaked approximately 4 hours post-ingestion. Identified metabolites included two diastereomers of 4-fluorophenylpropanolamine and one ring-hydroxylated, extensively conjugated 4-FA derivative.supported
12 subjects ingested 100 mg and 5 subjects 150 mg 4-FA. Three metabolites identified: two diastereomers of 4-fluorophenylpropanolamine and one ring-hydroxylated 4-FA conjugated. Urine concentrations 0.7-38 mg/L; maximum 4 h after ingestion. j.jpba.2019.113008
CYP enzyme involvement in 4-FMA metabolism was established by Roque Bravo et al. using primary rat hepatocytes co-exposed with selective CYP inhibitors:supported
Hepatotoxic potential of 4-FMA evaluated in primary rat hepatocytes (PRH, EC50 2.21 mM). CYP2E1, CYP3A4, CYP2D6 implicated in metabolism. j.tox.2021.152988
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
CYP2E1 inducers (chronic alcohol use, obesity, fasting states): increased proportion of toxifying metabolism.supported
CYP2E1 plays toxifying role. j.tox.2021.152988
CYP2D6 or CYP3A4 inhibitors (fluoxetine, paroxetine, ketoconazole, ritonavir, grapefruit juice): pharmacokinetic drug interactions impairing detoxification pathways.supported
CYP2D6 and CYP3A4 detoxify. j.tox.2021.152988
Toennes et al. (2019) measured serum and oral fluid pharmacokinetics after single oral 4-FA doses in healthy volunteers.supported
Controlled study of pharmacokinetic parameters of 4-fluoroamphetamine (4-FA) in humans after oral ingestion. dta.2595
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
Validated analytical methods for 4-FMA detection include GC-MS with a lower limit of quantification (LLOQ) of 2.0 ng/mL in urine and UHPLC-MS/MS in forensic blood and urine matrices.supported
Forensic analytical method for PMA, PMMA, 4-FA, 4-FMA, 4-CA, 4-CMA in postmortem blood/urine. bkab014
The closely related compound 4-FA demonstrates 3,354% cross-reactivity with amphetamine enzyme-linked immunosorbent assay (ELISA), but specific 4-FMA cross-reactivity data with commercially available immunoassays have not been publishedsupported
4-Fluoroamphetamine (4-FA) showed 3,354% cross-reactivity with amphetamine ELISA. Novel stimulants (excluding 4-FA) generally showed no cross-reactivity. bkae017
comparative-pharmacology8 · 7 ok
Anchondo et al. reported 4-FMA as the least potent compound tested among the fluorinated amphetamine and methamphetamine analogs, with a locomotor ED₅₀ of 7.38 mg/kg (i.p.) and lower peak locomotor counts (2,200–3,980 vs. 5,905–7,758 for methamphetamine and 3-position analogs)supported
rank-order: 2-FMA > METH > 3-FMA = 3-FA = 2-FA > 4-FMA; ED50 range 0.38-7.38 mg/kg. 4-FMA showed lower peak locomotor effects (2200-3980 counts) vs methamphetamine. j.jpet.2025.103617
Despite this reduced locomotor potency, 4-FMA fully substituted for methamphetamine in discriminative stimulus assays (ED₅₀ = 0.32–0.71 mg/kg), indicating that the subjective experience is qualitatively similar enough for trained animals to recognize it as methamphetamine-like.supported
All fluorinated compounds fully substituted for methamphetamine in discriminative stimulus tests (ED50 0.32-0.71 mg/kg). j.jpet.2025.103617
All three positional isomers fully substituted for methamphetamine in discriminative stimulus assays with comparable ED₅₀ values (0.32–0.71 mg/kg), suggesting the interoceptive cue is driven primarily by shared dopaminergic/noradrenergic mechanisms rather than the serotonergic differences that distinguish their locomotor profiles.supported
All fluorinated compounds fully substituted for methamphetamine in discriminative stimulus tests (ED50 0.32-0.71 mg/kg). Abuse potential comparable to methamphetamine. j.jpet.2025.103617
This single substitution produces a fundamental pharmacological divergence: methamphetamine is a highly DAT-selective releaser with minimal serotonergic activity, while 4-FMA has a markedly lower DAT:SERT selectivity ratio, releasing serotonin at levels comparable to MDMA.supported
4-FMA releases NE, DA, and 5-HT similarly to MDMA. Para-fluoroamphetamine has enhanced serotonergic properties vs amphetamine. j.euroneuro.2014.12.012
Emergency department presentations with 4-FA intoxication show exaggerated hypertension (mean systolic 164 ± 31 mmHg), severe headache (80% of mono-intoxication cases), and serious complications including Takotsubo cardiomyopathy and subarachnoid hemorrhage in 40% of mono-intoxicationspartially supported
Mean SBP 164 mmHg for 4-FA patients vs 139 MDMA, 135 amphetamine. Severe headache in 80%. Complications: Takotsubo cardiomyopathy, subarachnoid hemorrhage, hypertensive urgency. emp2.12813
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
Anchondo et al. systematically compared all ring-fluorinated amphetamine and methamphetamine positional isomers in locomotor activity and discriminative stimulus paradigms:supported
4-FMA produced time- and dose-dependent locomotor stimulation (rank-order: 2-FMA > METH > 3-FMA = 3-FA = 2-FA > 4-FMA). All fluorinated compounds fully substituted for methamphetamine in discriminative stimulus tests. j.jpet.2025.103617
4-FMA's position as the weakest locomotor stimulant among the fluorinated methamphetamine isomers, combined with its uniquely enhanced serotonergic activity, supports the structure-activity principle that para-substitution on the amphetamine phenyl ring shifts the pharmacological balance away from dopaminergic stimulation and toward serotonergic/entactogenic activitysupported
Para-fluoroamphetamine has enhanced serotonergic properties vs amphetamine. 4-FMA releases NE, DA, and 5-HT similarly to MDMA. j.euroneuro.2014.12.012
pharmacology8 · 3 ok
Claim in pharmacology — inconclusiveinconclusiveworking →
The critical pharmacological distinction between 4-FMA and its parent compound methamphetamine is the enhanced serotonergic activity conferred by para-fluorine substitution. 4-FMA releases serotonin at levels comparable to MDMA, yielding a markedly lower DAT:SERT selectivity ratio than methamphetaminesupported
4-FMA releases NE, DA, and 5-HT similarly to MDMA. Para-fluoroamphetamine has enhanced serotonergic properties vs amphetamine. j.euroneuro.2014.12.012
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
Roque Bravo et al. established that cytochrome P450 enzymes play differential roles in 4-FMA metabolism using primary rat hepatocyte co-exposure studies with selective CYP inhibitors:supported
CYP2E1, CYP3A4, CYP2D6 implicated in metabolism. CYP2E1 plays toxifying role; CYP2D6 and CYP3A4 detoxify. j.tox.2021.152988
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
Toennes et al. measured serum and oral fluid pharmacokinetics of 4-FA after controlled oral administration, and separately characterized urinary excretion of 4-FA and three metabolites — two diastereomers of 4-fluorophenylpropanolamine and one ring-hydroxylated conjugate — after oral doses of 100 mg (n = 12) and 150 mg (n = 5), with urine concentrations peaking approximately 4 hours post-ingestionsupported
12 subjects ingested 100 mg and 5 subjects 150 mg 4-FA. Three metabolites identified: two diastereomers of 4-fluorophenylpropanolamine and one ring-hydroxylated 4-FA conjugated. Urine concentrations 0.7-38 mg/L; maximum 4 h after ingestion. j.jpba.2019.113008
summary8 · 5 ok
Unlike its parent compound methamphetamine, 4-FMA releases serotonin at levels comparable to MDMA — a consequence of the para-fluorine substitution on the phenyl ring — producing a markedly lower DAT:SERT selectivity ratio and a more balanced dopaminergic/serotonergic profilesupported
4-FMA releases NE, DA, and 5-HT similarly to MDMA. Para-fluoroamphetamine has enhanced serotonergic properties vs amphetamine. j.euroneuro.2014.12.012
4-FMA first appeared on Japanese research chemical markets circa 2006 and gained broader international prevalence after 2017, when the scheduling of 4-fluoroamphetamine (4-FA) in the Netherlands drove regulatory displacement toward unscheduled analogspartially supported
Post-ban 4-FMA found as substitute in 4-FA samples. emp2.12813
Claim in summary — inconclusiveinconclusiveworking →
Claim in summary — inconclusiveinconclusiveworking →
Claim in summary — inconclusiveinconclusiveworking →
4-FMA releases norepinephrine, dopamine, and serotonin via transporter-mediated reversal, with additional affinity for the 5-HT₂A receptor and trace amine-associated receptor 1 (TAAR1)supported
4-FMA releases NE, DA, and 5-HT similarly to MDMA. Also has affinity for 5-HT2A receptor. TAAR1 binding assessed. j.euroneuro.2014.12.012
The primary characterized toxicity is hepatotoxicity: in vitro studies demonstrate mitochondrial destabilization, oxidative stress, and apoptotic cell death in hepatocyte models, with CYP2E1 generating toxic metabolites while CYP2D6 and CYP3A4 serve detoxifying roles — creating dose-independent variability based on individual CYP phenotypesupported
CYP2E1 plays toxifying role; CYP2D6 and CYP3A4 detoxify. Mitochondrial dysfunction, oxidative stress, apoptosis, necrosis, and autophagy observed. j.tox.2021.152988
Cardiovascular risk is inferred from the closely related analog 4-FA, which produces exaggerated hypertension and cerebral hemorrhage at recreational dosessupported
Mean SBP 164 mmHg for 4-FA patients vs 139 MDMA, 135 amphetamine. Complications: Takotsubo cardiomyopathy, subarachnoid hemorrhage, hypertensive urgency. emp2.12813
receptor-pharmacology6 · 2 ok
Claim in receptor-pharmacology — inconclusiveinconclusiveworking →
Claim in receptor-pharmacology — inconclusiveinconclusiveworking →
Compounds with high DAT:SERT ratios (methamphetamine, cocaine) produce predominantly stimulant effects with strong reinforcing properties; those with low ratios (MDMA) produce predominantly entactogenic effects. 4-FMA occupies an intermediate position on this spectrum.supported
4-FMA releases NE, DA, and 5-HT similarly to MDMA. Para-fluoroamphetamine has enhanced serotonergic properties vs amphetamine. j.euroneuro.2014.12.012
Luethi et al. demonstrated that in vitro monoamine transporter interaction profiles can predict reported human psychoactive doses for novel stimulants and psychedelics, supporting the use of transporter pharmacology as a proxy for in vivo potency estimation.supported
In vitro pharmacological profiles predict psychoactive doses in humans. DAT/NET potency positively correlated; SERT potency inversely correlated with doses. pyy047
Claim in receptor-pharmacology — inconclusiveinconclusiveworking →
Claim in receptor-pharmacology — inconclusiveinconclusiveworking →
history4 · 1 ok
In Taiwan, 4-FMA was detected in postmortem blood and urine specimens from fatal cases spanning 2011 to 2018, frequently co-ingested with ketamine and 7-aminonimetazepam (a nimetazepam metabolite)supported
4-FMA found in fatal cases in Taiwan 2011-2018. Ketamine and nimetazepam most common co-ingested substances with 4-FA/4-FMA cases. bkab014
Claim in history — inconclusiveinconclusiveworking →
Claim in history — inconclusiveinconclusiveworking →
Claim in history — inconclusiveinconclusiveworking →
neuroscience3 · 2 ok
The following neural mechanisms are inferred from 4-FMA's established pharmacological profile as a triple monoamine releaser with prominent serotonergic activity and from well-characterized neural correlates of amphetamine-class and entactogenic compounds.supported
4-FMA releases NE, DA, and 5-HT similarly to MDMA. Para-fluoroamphetamine has enhanced serotonergic properties vs amphetamine. j.euroneuro.2014.12.012
Anchondo et al. demonstrated that 4-FMA fully substitutes for methamphetamine in discriminative stimulus paradigms, confirming engagement of reward-related neural circuits at the behavioral level.supported
All fluorinated compounds fully substituted for methamphetamine in discriminative stimulus tests (ED50 0.32-0.71 mg/kg). Abuse potential comparable to methamphetamine. j.jpet.2025.103617
Claim in neuroscience — inconclusiveinconclusiveworking →
chemistry1 · 1 ok
The para-fluorine substitution is the defining structural feature: it enhances serotonergic activity relative to the unsubstituted parent compound while retaining dopaminergic and noradrenergic release propertiessupported
4-FMA releases NE, DA, and 5-HT similarly to MDMA. Para-fluoroamphetamine has enhanced serotonergic properties vs amphetamine. j.euroneuro.2014.12.012
clinical-evidence1 · 1 ok
4-FMA's pharmacological profile — triple monoamine release with a serotonergic component comparable to MDMA — shares mechanistic features with MDMA-assisted psychotherapy models being investigated for post-traumatic stress disordersupported
4-FMA releases NE, DA, and 5-HT similarly to MDMA. j.euroneuro.2014.12.012
effects-overview1 · 0 ok
Claim in effects-overview — inconclusiveinconclusiveworking →
legal-status1 · 0 ok
Claim in legal-status — inconclusiveinconclusiveworking →