generation run 2026-05-07
61 min completedmodel pipeline-v5plan not recordedrun/e3394063…Selection
Verification
- record
- seen / partial
- working
The model's own caveats
- sparse_evidence
Reproduce
- inputs
- 18 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
12 searches — query, source, results, what was kept and why
| # | source | query | seen | kept | rationale |
|---|---|---|---|---|---|
| 1 | WebSearch | 2-fluoroamphetamine 2-FA legal status scheduling UK USA Germany controlled substance | 10 | 2 | Best available sources for legal status given no academic literature covers this |
| 2 | PubChem | 2-fluoroamphetamine | 1 | 1 | Confirmed PubChem entry for 2-FA; seed data had no SMILES, formula, weight or InChIKey — all now confirmed |
| 3 | OpenAlex | 2-fluoroamphetamine pharmacology novel psychoactive substance | 109 | 1 | — |
| 4 | PubMed | 2-FA 2-fluoroamphetamine OR 2-FA stimulant | 7 | 4 | — |
| 5 | PubMed | 2-fluoroamphetamine pharmacology | 15 | 1 | — |
| 6 | WebSearch | 2-fluoroamphetamine CAS number SMILES chemical properties | 10 | 2 | Chemical identity data confirmed from multiple reliable chemical databases |
| 7 | NCATS Inxight Drugs | 2-fluoroamphetamine UNII | 1 | 1 | Provides additional chemical identity confirmation and stereochemistry data |
| 8 | WebSearch | 2-FA pharmacokinetics half-life human | 10 | 1 | Establishes gap in literature; 4-FA PK most relevant available comparison |
| 9 | PubMed | 4-fluoroamphetamine para-fluoroamphetamine serotonin neurotoxicity | 1 | 1 | Provides key data on para-FA vs amphetamine pharmacology; helps distinguish 2-FA from 4-FA |
| 10 | WebSearch | UK Psychoactive Substances Act 2016 fluoroamphetamine | 10 | 2 | Establishes legal status across key jurisdictions |
| 11 | Crossref DOI verification | verify DOIs for key 2-FA papers | 3 | 1 | DOI verification confirms citation accuracy for three key papers |
| 12 | PubMed | serotonin syndrome tramadol amphetamine opioid combination | 2 | 1 | Provides mechanism basis for tramadol interaction danger in amphetamine class; no 2-FA specific data available |
59 claims by section — every cited sentence, checked against its source
pharmacology9 · 9 ok
The amphetamine-class mechanism proceeds through three converging processes: (1) carrier-mediated uptake into presynaptic terminals via DAT and NET, where the compound acts as a competitive substrate; (2) disruption of the vesicular pH gradient through interaction with the vesicular monoamine transporter 2 (VMAT2), causing redistribution of intravesicular dopamine and norepinephrine into the cytoplasm; and (3) reversal of plasma membrane transporter direction (reverse transport), releasing accumulated cytoplasmic monoamines into the synaptic cleftsupported
Demonstrates that amphetamine promotes dopamine release via reverse transport mechanism through the DAT, mediated by vesicular pH gradient disruption, leading to increased cytoplasmic dopamine. pmid:8419534
The amphetamine-class mechanism proceeds through three converging processes: (1) carrier-mediated uptake into presynaptic terminals via DAT and NET, where the compound acts as a competitive substrate; (2) disruption of the vesicular pH gradient through interaction with the vesicular monoamine transporter 2 (VMAT2), causing redistribution of intravesicular dopamine and norepinephrine into the cytoplasm; and (3) reversal of plasma membrane transporter direction (reverse transport), releasing accumulated cytoplasmic monoamines into the synaptic cleftsupported
42 amphetamine-related compounds assessed for VMAT2 interaction. Most agents are VMAT2 substrates that deplete vesicular neurotransmitter via carrier-mediated exchange mechanism. pmid:16835371
The amphetamine-class mechanism proceeds through three converging processes: (1) carrier-mediated uptake into presynaptic terminals via DAT and NET, where the compound acts as a competitive substrate; (2) disruption of the vesicular pH gradient through interaction with the vesicular monoamine transporter 2 (VMAT2), causing redistribution of intravesicular dopamine and norepinephrine into the cytoplasm; and (3) reversal of plasma membrane transporter direction (reverse transport), releasing accumulated cytoplasmic monoamines into the synaptic cleftsupported
Demonstrates that amphetamine promotes dopamine release via reverse transport mechanism through the DAT, mediated by vesicular pH gradient disruption, leading to increased cytoplasmic dopamine. pmid:8419534
The positional isomer 4-FA exhibits substantially increased SERT activity relative to unsubstituted amphetamine — para-halogenation reduces DAT:SERT selectivity, producing entactogenic effects and heightened serotonergic toxicity risksupported
Para-halogenation reduces DAT:SERT selectivity. fphar.2019.00438
Anchondo et al. (2025) provide the only published study dedicated to 2-FA's pharmacologysupported
2-FA, 3-FA, 2-FMA, 3-FMA, 4-FMA tested in mice and rats. j.jpet.2025.103617
Metabolic pathway inference draws primarily from the N-methyl homolog 2-FMA, for which Ishii et al. (2023) identified N-demethylation (yielding 2-FA as a metabolite), N-hydroxylation, and aliphatic hydroxylation (producing 2-fluoroephedrine diastereomers) as principal metabolic routessupported
2-FA detected in urine as metabolite of 2-FMA in forensic case. N-hydroxylation and aliphatic hydroxylation are characteristic metabolic pathways. bkac026
For comparison, the para-isomer 4-FA has a mean elimination half-life of approximately 8–9 hours (range 5.5–16.8 hours) in human serum after controlled oral administrationsupported
Controlled human pharmacokinetic study of 4-FA. Provides serum half-life data (approximately 8-9 hours, range 5.5-16.8 hours) for the para-isomer. dta.2595
Forensic blood concentrations: DUID case concentrations in Denmark: 0.028, 0.041, and 0.37 mg/kg whole bloodsupported
Three DUID cases with whole blood concentrations 0.028, 0.041 and 0.37 mg/kg. s00414-012-0671-0
A fatal polydrug case in Germany yielded approximately 89 µg/L in femoral bloodsupported
2-FA detected in femoral blood at approx. 89 ug/L alongside designer benzodiazepines and other stimulants. j.forsciint.2019.109959
summary9 · 9 ok
Fluorinated amphetamine analogs have circulated on research chemical markets since the early 2000s. 2-FA was first confirmed in human biological samples in Danish forensic cases in 2010partially supported
Aromatic fluoro analogs on illicit market since early 2000s. bkac026
Fluorinated amphetamine analogs have circulated on research chemical markets since the early 2000s. 2-FA was first confirmed in human biological samples in Danish forensic cases in 2010supported
2-FA first discovered in forensic samples in Denmark in 2010. s00414-012-0671-0
The first dedicated pharmacological investigation — a rodent locomotor and discriminative stimulus study — appeared only in 2025, leaving 2-FA among the least formally characterized stimulants in active circulation.supported
2-FA, 3-FA, 2-FMA, 3-FMA, 4-FMA tested in mice and rats. All produced time- and dose-dependent locomotor stimulation... All fully substituted for methamphetamine in discriminative stimulus tests. j.jpet.2025.103617
2-FA is presumed to act as a substrate-type releaser at the dopamine transporter (DAT) and norepinephrine transporter (NET), consistent with the amphetamine class mechanism of vesicular depletion via VMAT2 disruption and reverse transportsupported
Demonstrates that amphetamine promotes dopamine release via reverse transport mechanism through the DAT, mediated by vesicular pH gradient disruption, leading to increased cytoplasmic dopamine. pmid:8419534
2-FA is presumed to act as a substrate-type releaser at the dopamine transporter (DAT) and norepinephrine transporter (NET), consistent with the amphetamine class mechanism of vesicular depletion via VMAT2 disruption and reverse transportsupported
Most agents are VMAT2 substrates that deplete vesicular neurotransmitter via carrier-mediated exchange mechanism. pmid:16835371
The subjective profile — reported as purely stimulant without the entactogenic warmth characteristic of 4-FA — suggests lower serotonin transporter (SERT) activity than the para-substituted isomer, but this distinction rests on user-report evidence, not transporter assay datasupported
Para-halogenation reduces DAT:SERT selectivity. fphar.2019.00438
Cardiovascular toxicity — tachycardia, hypertension, vasoconstriction — represents the primary acute risk, consistent with the sympathomimetic toxidrome of the amphetamine classsupported
Comprehensive review of methamphetamine clinical toxicology: mechanism of action via monoamine release, cardiovascular toxicity, CNS effects, psychiatric complications, and treatment of intoxication. 15563650.2010.516752
One fatal polydrug case involving 2-FA has been reported, attributed to combined CNS depression from co-administered designer benzodiazepines rather than 2-FA alonesupported
Case report: fatal positional asphyxia due to poly-drug intoxication. 2-FA detected in femoral blood at approx. 89 ug/L alongside designer benzodiazepines and other stimulants. j.forsciint.2019.109959
Dependence liability is rated moderate by community consensus, with rodent data demonstrating full substitution for methamphetamine in discriminative stimulus paradigms — a finding consistent with significant abuse potentialsupported
All fully substituted for methamphetamine in discriminative stimulus tests (ED50 0.32-0.71 mg/kg). j.jpet.2025.103617
chemistry8 · 7 ok
This ortho-fluorine placement distinguishes 2-FA from its positional isomers 3-fluoroamphetamine (3-FA, meta-substituted) and 4-fluoroamphetamine (4-FA, para-substituted), which differ only in the ring position of the halogen. 2-FA is also the des-methyl analog of 2-fluoromethamphetamine (2-FMA); 2-FA is a confirmed metabolite of 2-FMA via N-demethylation.partially supported
Chiral separation of amphetamine derivatives including 2-, 3-, and 4-fluoroamphetamine. Simultaneous chiral separation of all three FA positional isomers accomplished successfully by HPLC. j.scijus.2016.08.007
This ortho-fluorine placement distinguishes 2-FA from its positional isomers 3-fluoroamphetamine (3-FA, meta-substituted) and 4-fluoroamphetamine (4-FA, para-substituted), which differ only in the ring position of the halogen. 2-FA is also the des-methyl analog of 2-fluoromethamphetamine (2-FMA); 2-FA is a confirmed metabolite of 2-FMA via N-demethylation.supported
2-FA detected in urine as metabolite of 2-FMA in forensic case. bkac026
Para-halogenation (as in 4-FA) increases serotonin transporter activity and reduces DAT:SERT selectivity, producing entactogenic qualities absent in the ortho isomersupported
Para-halogenation reduces DAT:SERT selectivity. fphar.2019.00438
Both enantiomers have been isolated and analytically characterized using indirect chiral separation methods including chiral HPLCsupported
Chiral separation of amphetamine derivatives including 2-, 3-, and 4-fluoroamphetamine. Simultaneous chiral separation of all three FA positional isomers accomplished successfully by HPLC. j.scijus.2016.08.007
By analogy with amphetamine — where the (S)-(+)-enantiomer (dextroamphetamine) is 3–5 times more potent than the (R)-(−)-enantiomer at dopamine release — the (S)-enantiomer of 2-FA likely possesses greater pharmacological activity, but this remains experimentally unconfirmed.supported
Chiral separation of amphetamine derivatives including 2-, 3-, and 4-fluoroamphetamine. Simultaneous chiral separation of all three FA positional isomers accomplished successfully by HPLC. j.scijus.2016.08.007
Claim in chemistry — inconclusiveinconclusiveworking →
Definitive identification requires specialized techniques: UPLC-MS/MS with retention time comparison, infrared ion spectroscopy (IRIS), or chiral HPLCsupported
IRIS technique used to distinguish fluoroamphetamine isomers including 2-FA, 3-FA, and 4-FA. Shows forensic significance of distinguishing positional isomers. acs.analchem.0c00915
Definitive identification requires specialized techniques: UPLC-MS/MS with retention time comparison, infrared ion spectroscopy (IRIS), or chiral HPLCsupported
Simultaneous chiral separation of all three FA positional isomers accomplished successfully by HPLC. j.scijus.2016.08.007
safety8 · 8 ok
The primary acute risk is sympathomimetic toxicity, consistent with the amphetamine class: tachycardia, hypertension, vasoconstriction, hyperthermia, and potential cardiac arrhythmiassupported
Comprehensive review of methamphetamine clinical toxicology: mechanism of action via monoamine release, cardiovascular toxicity, CNS effects, psychiatric complications, and treatment of intoxication. 15563650.2010.516752
DUID cases (Denmark, 2010): Three cases with whole blood concentrations of 0.028, 0.041, and 0.37 mg/kg. All involved co-administered amphetamine. No fatalities or severe acute toxicity reported in these cases.supported
Three DUID cases with whole blood concentrations 0.028, 0.041 and 0.37 mg/kg. All cases also contained amphetamine. s00414-012-0671-0
Fatal polydrug case (Germany, 2019): Positional asphyxia in the context of polydrug intoxication. 2-FA detected at approximately 89 µg/L in femoral blood, alongside diclazepam, pyrazolam, and amphetamine. Death was attributed to the combined CNS/respiratory depression from designer benzodiazepines, not to 2-FA alone.supported
Case report: fatal positional asphyxia due to poly-drug intoxication. 2-FA detected in femoral blood at approx. 89 ug/L alongside designer benzodiazepines and other stimulants. j.forsciint.2019.109959
Luethi et al. (2019) demonstrated that para-halogenation of amphetamine increases hepatocellular toxicity (measured as ATP depletion in HepG2 cells)supported
Mitochondrial toxicity in HepG2 cells with ATP depletion at 0.25-2 mM. Toxicity rank order: Cl > F > H. fphar.2019.00438
Compulsive redosing: The short duration (2–4 hours) combined with methamphetamine-like discriminative properties creates conditions conducive to compulsive redosing, with cumulative dose escalation increasing all risks.supported
All fully substituted for methamphetamine in discriminative stimulus tests (ED50 0.32-0.71 mg/kg). j.jpet.2025.103617
The Anchondo et al. (2025) finding that 2-FA fully substitutes for methamphetamine in discriminative stimulus paradigms suggests an interoceptive profile consistent with significant abuse potential, and the authors explicitly note this conclusionsupported
All fully substituted for methamphetamine in discriminative stimulus tests (ED50 0.32-0.71 mg/kg). j.jpet.2025.103617
Serotonergic combinations — serotonin syndrome risk: Combining 2-FA with serotonergic agents poses the risk of serotonin syndrome, a potentially fatal condition characterized by neuromuscular excitation, autonomic instability, and altered mental statussupported
Case report: serotonin syndrome from combined amphetamine-class drug and serotonergic agent. Features neuromuscular hyperactivity, autonomic instability, altered mental status. cureus.79314
The fatal polydrug case involving 2-FA illustrates this pattern: designer benzodiazepines combined with stimulants resulted in positional asphyxia.supported
Case report: fatal positional asphyxia due to poly-drug intoxication. 2-FA detected in femoral blood at approx. 89 ug/L alongside designer benzodiazepines and other stimulants. j.forsciint.2019.109959
comparative-pharmacology7 · 7 ok
Luethi et al. (2019) further demonstrated that para-halogenated amphetamines exhibit increased hepatocellular toxicity (ATP depletion in HepG2 cells) compared to unhalogenated amphetaminesupported
Mitochondrial toxicity in HepG2 cells with ATP depletion at 0.25-2 mM. Toxicity rank order: Cl > F > H. fphar.2019.00438
Published in vitro data demonstrate that para-halogenation of amphetamine markedly increases SERT potency, reducing DAT:SERT selectivitysupported
Para-halogenation reduces DAT:SERT selectivity. fphar.2019.00438
4-FA has a published mean elimination half-life of 8–9 hours (range 5.5–16.8 hours), substantially longer than 2-FA's reported subjective duration. 4-FA also prompted sufficient public health concern in the Netherlands to warrant epidemiological study and eventual Schedule I placement in 2017.supported
Controlled human pharmacokinetic study of 4-FA. Provides serum half-life data (approximately 8-9 hours, range 5.5-16.8 hours) for the para-isomer. dta.2595
4-FA has a published mean elimination half-life of 8–9 hours (range 5.5–16.8 hours), substantially longer than 2-FA's reported subjective duration. 4-FA also prompted sufficient public health concern in the Netherlands to warrant epidemiological study and eventual Schedule I placement in 2017.supported
4-FA first appeared on Dutch drug market 2007-2009. Subjective effects intermediate between amphetamine and MDMA. add.12932
2-FMA is the N-methyl homolog of 2-FA. 2-FA is a confirmed metabolite of 2-FMA via CYP-mediated N-demethylationsupported
2-FA detected in urine as metabolite of 2-FMA in forensic case. bkac026
Published metabolic data for 2-FMA provide the closest available window into 2-FA's likely metabolic fate, as 2-FA represents the primary N-demethylated metabolite.supported
2-FA detected in urine as metabolite of 2-FMA in forensic case. N-hydroxylation and aliphatic hydroxylation are characteristic metabolic pathways. bkac026
Anchondo et al. (2025) tested multiple fluorinated amphetamine and methamphetamine analogs in rats trained to discriminate methamphetamine from saline. 2-FA produced full substitution for methamphetamine, indicating that its interoceptive effects are perceived as methamphetamine-like by the trained animalssupported
All fully substituted for methamphetamine in discriminative stimulus tests (ED50 0.32-0.71 mg/kg). j.jpet.2025.103617
history5 · 4 ok
Three driving-under-the-influence-of-drugs (DUID) cases were documented with whole blood concentrations of 0.028, 0.041, and 0.37 mg/kg; all cases involved co-administration of amphetaminesupported
Three DUID cases with whole blood concentrations 0.028, 0.041 and 0.37 mg/kg. All cases also contained amphetamine. s00414-012-0671-0
Aromatic fluoro analogs of amphetamine, including 2-FA, began appearing on illicit and grey-market research chemical platforms in the early 2000s. 2-FA entered circulation as a "designer drug" and "research chemical" with no prior clinical or therapeutic historysupported
Aromatic fluoro analogs on illicit market since early 2000s. bkac026
Claim in history — inconclusiveinconclusiveworking →
The death was attributed to polydrug intoxication — CNS and respiratory depression from benzodiazepines combined with stimulant-induced postural impairment — rather than to 2-FA alone.supported
Case report: fatal positional asphyxia due to poly-drug intoxication. 2-FA detected in femoral blood at approx. 89 ug/L alongside designer benzodiazepines and other stimulants. j.forsciint.2019.109959
Anchondo et al. evaluated locomotor activity and discriminative stimulus properties in mice and rats, demonstrating methamphetamine-like behavioral effects and concluding that 2-FA carries abuse potential comparable to methamphetaminesupported
2-FA, 3-FA, 2-FMA, 3-FMA, 4-FMA tested in mice and rats. 2-FA showed peak locomotor effects similar to methamphetamine. All fully substituted for methamphetamine in discriminative stimulus tests. j.jpet.2025.103617
clinical-evidence4 · 4 ok
The forensic case literature is limited to three DUID cases in Denmark and one fatal polydrug case in Germany.supported
2-FA first discovered in forensic samples in Denmark in 2010. Three DUID cases with whole blood concentrations 0.028, 0.041 and 0.37 mg/kg. s00414-012-0671-0
The forensic case literature is limited to three DUID cases in Denmark and one fatal polydrug case in Germany.supported
Case report: fatal positional asphyxia due to poly-drug intoxication. 2-FA detected in femoral blood at approx. 89 ug/L alongside designer benzodiazepines and other stimulants. j.forsciint.2019.109959
The sole published experimental study is the preclinical investigation by Anchondo et al. (2025), which assessed locomotor stimulation in Swiss-Webster mice and discriminative stimulus properties in Sprague-Dawley ratssupported
2-FA, 3-FA, 2-FMA, 3-FMA, 4-FMA tested in mice and rats. All produced time- and dose-dependent locomotor stimulation. All fully substituted for methamphetamine in discriminative stimulus tests. j.jpet.2025.103617
Unlike 4-FA — which generated sufficient public health concern in the Netherlands to prompt epidemiological surveillance — 2-FA has not achieved the prevalence necessary to trigger systematic study in any jurisdiction.supported
4-FA first appeared on Dutch drug market 2007-2009. Used primarily for specific effects, not legal status. add.12932
neuroscience3 · 3 ok
The following neural mechanism framework is derived from the well-characterized neuroscience of the amphetamine class, applied to 2-FA based on its demonstrated methamphetamine-like behavioral profile.supported
2-FA showed peak locomotor effects similar to methamphetamine. All fully substituted for methamphetamine in discriminative stimulus tests. j.jpet.2025.103617
The magnitude of NAc dopamine elevation correlates with subjective reinforcement and abuse liability. 2-FA's full substitution for methamphetamine in discriminative stimulus paradigms implies NAc dopamine elevation of sufficient magnitude to produce methamphetamine-like interoceptive states.supported
All fully substituted for methamphetamine in discriminative stimulus tests (ED50 0.32-0.71 mg/kg). j.jpet.2025.103617
Does 2-FA produce neurotoxicity? Para-substituted amphetamines (e.g., para-chloroamphetamine) are established serotonergic neurotoxins. Whether ortho-fluoroamphetamine produces dopaminergic, noradrenergic, or serotonergic terminal damage with repeated administration is entirely unknown. No in vitro cytotoxicity data and no in vivo neurotoxicity assessments have been published for 2-FA.supported
Para-fluoroamphetamine (4-FA) inhibits NET at submicromolar concentrations, DAT at low micromolar. Mitochondrial toxicity in HepG2 cells with ATP depletion at 0.25-2 mM. Toxicity rank order: Cl > F > H. fphar.2019.00438
pharmacokinetic-detail3 · 2 ok
Toennes et al. (2019) administered 4-FA orally to healthy volunteers under controlled conditions and reported a mean elimination half-life of approximately 8–9 hours (range 5.5–16.8 hours)supported
Controlled human pharmacokinetic study of 4-FA. Provides serum half-life data (approximately 8-9 hours, range 5.5-16.8 hours) for the para-isomer. dta.2595
Metabolic inference draws primarily from the N-methyl homolog 2-FMA:supported
2-FA detected in urine as metabolite of 2-FMA in forensic case. bkac026
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
receptor-pharmacology3 · 3 ok
The positional isomer 4-FA has been characterized in vitro by Luethi et al. (2019): para-halogenation markedly increases SERT potency relative to unsubstituted amphetamine, reducing DAT:SERT selectivity and conferring empathogenic effectssupported
Para-halogenation reduces DAT:SERT selectivity. fphar.2019.00438
Wee et al. (2005) characterized the reinforcing efficacy and serotonergic activity of several amphetamine analogs, establishing that compounds with higher SERT:DAT ratios produce less self-administration in primatessupported
All fluoroamphetamine analogs positive reinforcers in rhesus monkeys. Lower 5-HT:DA ratio = higher reinforcing efficacy. pmid:15677348
Until in vitro characterization is performed — ideally using the Rothman/Baumann synaptosome release assay methodology — all pharmacological claims for 2-FA remain class-level inferencesupported
Establishes methodology for characterizing monoamine transporter substrates using rat brain synaptosomes. Demonstrates that stimulant NPS are substrates for plasma membrane monoamine transporters. npp.2011.304