generation run 2026-04-24
61 min completedmodel pipeline-v5plan not recordedrun/aa0cfd9f…Selection
Verification
- record
- seen / partial
- working
The model's own caveats
- taper_silent
- potential_gap
Reproduce
- inputs
- 43 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
20 searches — query, source, results, what was kept and why
| # | source | query | seen | kept | rationale |
|---|---|---|---|---|---|
| 1 | PubMed | amphetamine controlled study human subjective effects dose-response euphoria | 6 | 2 | Human controlled studies of amphetamine cognitive and emotional effects |
| 2 | PubMed | PMID 9482784 Jones et al 1998 DAT knockout amphetamine | 1 | 1 | Most cited specific amphetamine mechanism paper available |
| 3 | PubMed | amphetamine human pharmacokinetics bioavailability half-life metabolism | 8 | 2 | Best comprehensive PK data for amphetamine including bioavailability, Tmax, half-life, metabolism |
| 4 | PubMed | amphetamine pharmacology mechanism dopamine transporter reuptake | 10 | 1 | Selected general stimulant pharmacology review covering amphetamine mechanism |
| 5 | PubMed | PMID 17017961 Rothman Baumann 2006 monoamine transporter substrates | 1 | 1 | Provides mechanistic context for amphetamine as DA/NE substrate-type releaser vs cocaine-type blockers |
| 6 | PubMed | Rothman Baumann amphetamine monoamine EC50 substrate selectivity | 1 | 1 | Provides amphetamine NE/DA selectivity ratio (3.5) and in vivo DA release data in primates |
| 7 | PubMed | amphetamine toxicity cardiovascular overdose adverse effects cardiac | 8 | 3 | Selected cardiovascular toxicity data specific to amphetamine |
| 8 | PubMed | PMID 8994051 Sonders et al 1997 human dopamine transporter conductances | 1 | 1 | Foundational mechanistic paper on how amphetamine interacts with DAT differently from cocaine |
| 9 | OpenAlex | amphetamine dopamine mechanism monoamine releasing agent stimulant | 8 | 1 | Robinson & Becker 1986 is a landmark paper on amphetamine sensitization |
| 10 | ClinicalTrials.gov | amphetamine | 10 | 2 | Selected trials directly relevant to amphetamine withdrawal and use disorders |
| 11 | PubMed | amphetamine TAAR1 trace amine receptor pharmacology binding affinity | 5 | 2 | Best TAAR1 pharmacology data for amphetamine |
| 12 | PubChem | amphetamine | 1 | 1 | Primary chemical identity verification |
| 13 | PubMed | PMID 30097390 Cortese 2018 ADHD NMA Lancet Psychiatry | 1 | 1 | Best clinical evidence for amphetamine ADHD efficacy; systematic review and NMA |
| 14 | PubMed | Robinson Berridge incentive salience dopamine wanting liking dissociation reward | 2 | 1 | Key mechanistic framework explaining amphetamine dependence - wanting without liking pattern cited in brief |
| 15 | PubMed | Fleckenstein Volz amphetamine methamphetamine monoamine neurotoxicity review mechanism | 1 | 1 | Best comprehensive review of amphetamine molecular mechanism including VMAT2, DAT, exchange diffusion, weak base hypothesis, neurotoxicity |
| 16 | PubMed | PMID 27189265 Faraone ADHD Nature Reviews 2015 | 1 | 1 | Key clinical context for amphetamine as ADHD treatment; epidemiology |
| 17 | ClinicalTrials.gov | dextroamphetamine amphetamine treatment ADHD adult | 8 | 4 | Selected most relevant trials for ADHD treatment and dependence |
| 18 | Multiple | Verify key pharmacological data against multiple sources | 4 | — | Data consistency verification across independent sources |
| 19 | PubMed | PMID 11071707 Rothman Baumann 2001 amphetamine NE DA serotonin release | 1 | 1 | Landmark paper establishing relative releasing potencies of amphetamine at NE, DA, 5-HT transporters |
| 20 | Web | amphetamine legal status Schedule II United States UK Class B Australia S8 history discovery 1887 Edeleanu | 10 | 1 | Legal status not available via PubMed; used web search as fallback per protocol |
83 claims by section — every cited sentence, checked against its source
safety24 · 18 ok
Animal data demonstrate long-lasting epigenetic alterations in dopamine transporter regulation following embryonic amphetamine exposure.supported
Chronic embryonic amphetamine exposure causes long-lasting epigenetic modifications in DAT-1 expression in adult C. elegans. ijms241713092
Claim in safety — inconclusiveinconclusiveworking →
The role of antipsychotics remains controversial: a systematic review found limited evidence supporting their use and noted risks including lowered seizure threshold, QT prolongation, and impaired thermoregulation.supported
Antipsychotics discouraged due to lowered seizure threshold, QT prolongation, and decreased heat dissipation. j.ajem.2019.01.001
Acute cardiovascular effects include tachycardia, hypertension, vasospasm, and increased cardiac output via catecholamine excess at alpha- and beta-adrenergic receptorssupported
Alpha-adrenergic stimulation causes vasoconstriction; beta-adrenergic causes increased HR, stroke volume. j.tcam.2013.03.002
Chronic high-dose use is associated with cardiomyopathy (both ischemic and non-ischemic), accelerated atherosclerosis, pulmonary hypertension, and arrhythmias.supported
Amphetamine abuse associated with...MI, cardiomyopathy, arrhythmias via excess catecholamines. pmid:16105252
Claim in safety — inconclusiveinconclusiveworking →
A case report documents a 43-year-old with five years of high-dose dextroamphetamine use (45–65 mg/day) who presented with severely reduced left ventricular ejection fraction (10–15%), dilated cardiomyopathy, and severe three-vessel coronary artery disease requiring coronary artery bypass graftingsupported
Case report of ischemic cardiomyopathy (LVEF 10-15%) and 3-vessel CAD with 5-year high-dose Adderall use, requiring CABG. zytu1875
Claim in safety — inconclusiveinconclusiveworking →
Amphetamine abuse is associated with cerebral infarction and intracranial hemorrhage, mediated primarily by acute hypertension, vasospasm, and thrombosis.supported
Amphetamine abuse associated with cerebral infarction, intracranial hemorrhage... pmid:16105252
In VMAT2-heterozygous mice, reduced vesicular storage capacity amplified stimulant-induced neurodegeneration, identifying VMAT2 function as the rate-limiting protective factorsupported
METH-induced degeneration inversely proportional to VMAT2 expression. jneurosci.22-20-08951.2002
Amphetamine use during pregnancy is associated with congenital anomalies and adverse obstetric outcomessupported
Amphetamines can lead to congenital anomalies and poor obstetric outcomes according to Keegan et al. s11095-017-2323-z
Amphetamine use during pregnancy is associated with congenital anomalies and adverse obstetric outcomessupported
Amphetamines in pregnancy can lead to congenital anomalies and other poor obstetric outcomes. 10550881003684723
At high doses or with chronic use, amphetamine can produce paranoid psychosis clinically indistinguishable from paranoid schizophreniasupported
Review of AMPH neurotoxicity and behavioral sensitization as models of amphetamine psychosis. pmid:3527341
This amphetamine psychosis model is the original pharmacological basis for the dopamine hypothesis of psychotic disorderssupported
Foundational paper establishing dopamine as mediator of amphetamine-induced stereotyped behaviour. pmid:5630955
PET imaging confirms that amphetamine-induced striatal dopamine release is greater in individuals with first-episode psychosis, and that sensitization through repeated exposure can bring healthy controls' dopamine release to patient-equivalent levels.supported
patients with first-episode psychosis show greater amphetamine-induced DA release vs controls. Sensitization in healthy volunteers brings DA release to patient levels. s41398-019-0681-5
Claim in safety — not_supportednot supportedworking →
Claim in safety — not_supportednot supportedworking →
The resulting dissociation produces compulsive drug-seeking that persists long after cessation, even when the substance no longer produces significant pleasure.supported
Brain circuitry for wanting (mesolimbic DA) is dissociable from liking. Incentive sensitization posits drug addiction as excessive amplification of wanting without liking. pmid:27977239
This combination is an absolute contraindication across all clinical guidelines.supported
Pharmacodynamic interactions include severe serotonin toxicity with serotonergic drugs and hypertensive crisis with indirect sympathomimetics. j.euroneuro.2017.05.007
Claim in safety — inconclusiveinconclusiveworking →
MAOI co-administration: Hypertensive crisis and serotonin syndrome risk. A minimum 14-day washout is required after MAOI discontinuation.supported
Pharmacodynamic interactions include severe serotonin toxicity with serotonergic drugs and hypertensive crisis with indirect sympathomimetics. j.euroneuro.2017.05.007
Structural heart disease or advanced cardiovascular disease: Catecholamine excess exacerbates cardiac stress in the setting of fixed structural compromise.supported
Amphetamine abuse associated with...MI, cardiomyopathy, arrhythmias via excess catecholamines. pmid:16105252
Pregnancy: Associated with congenital anomalies and adverse obstetric outcomes.supported
Amphetamines can lead to congenital anomalies and poor obstetric outcomes. s11095-017-2323-z
History of psychosis or bipolar disorder: Dopaminergic stimulation can precipitate psychotic episodes or destabilize mood.supported
Sensitization due to enhanced mesotelencephalic DA release. pmid:3527341
pharmacology20 · 17 ok
Claim in pharmacology — inconclusiveinconclusiveworking →
The mechanism proceeds through several coordinated steps: amphetamine enters presynaptic terminals as a transporter substrate via carrier-mediated "exchange diffusion," displacing a monoamine molecule outward with each inward transport cyclesupported
Mechanisms include exchange diffusion, reverse transport, channel-like phenomena, and weak base properties. pmid:17209801
Once intracellular, amphetamine disrupts vesicular monoamine transporter 2 (VMAT2) function through its weak-base properties — raising vesicular pH, collapsing the proton gradient that drives vesicular storage, and redistributing dopamine from vesicles into the cytoplasmsupported
DAT and VMAT2 are principal targets of amphetamine. Mechanisms include...weak base properties. pmid:17209801
Electrophysiological studies at the human DAT confirmed that amphetamine induces channel-like ionic conductances absent during cocaine binding.supported
Electrophysiology of cloned human DAT. Distinguishes amphetamine-type DA-releasing drugs from cocaine-type blockers. pmid:8994051
The absolute requirement for DAT in amphetamine-mediated dopamine release was demonstrated in DAT-knockout mice: amphetamine produced a 10-fold increase in extracellular dopamine in wild-type animals but no measurable increase in knockouts, despite equivalent vesicular depletion in both genotypes.supported
DAT is required for AMPH-induced DA release but not vesicle depletion. AMPH increases extracellular DA 10-fold in wild-type mice via DAT. jneurosci.18-06-01979.1998
Amphetamine releases norepinephrine more potently than dopamine, and both far more potently than serotoninsupported
NE release is the most potent effect for all amphetamine-type stimulants. pmid:11071707
Claim in pharmacology — inconclusiveinconclusiveworking →
The NE/DA selectivity ratio for (+)-amphetamine is approximately 3.5 in vivo in primatessupported
NE/DA selectivity ratio for (+)-amphetamine is 3.5. pmid:15729739
This NE-preferential profile underlies the compound's pronounced peripheral sympathomimetic, anorectic, and wakefulness-promoting effects, while dopamine-mediated reinforcement and euphoria drive its abuse liability.supported
Amphetamine described as a DA-preferential releaser with abuse liability. pmid:17017961
In functional cAMP assays, amphetamine activated rat and mouse TAAR1 with EC₅₀ < 5 µM; human TAAR1 activation was substantially weaker, revealing prominent species differences (potency rank: rat > mouse > human)supported
Most amphetamines show rat/mouse TAAR1 activation (EC50 < 5 uM); species differences rat > mouse > human. jpet.115.229765
Stereoselective binding is determined primarily by residues Asp¹⁰² and Met²⁶⁸ within the receptor binding pocket, as confirmed by site-directed mutagenesis and homology modelingsupported
Residues Asp102 and Met268 are major contributors to AMPH binding. jm401316v
Repeated intermittent amphetamine exposure produces behavioral sensitization — a progressive, enduring enhancement of both behavioral and neurochemical responses to subsequent amphetamine challenge — mediated by enhanced mesotelencephalic dopamine releasesupported
Sensitization due to enhanced mesotelencephalic DA release. pmid:3527341
This sensitization process is central to the transition from recreational use to compulsive drug-seeking: sensitized incentive-salience circuits drive escalating "wanting" while hedonic capacity ("liking") simultaneously develops tolerance.supported
Incentive sensitization posits drug addiction as excessive amplification of wanting without liking via neural sensitization. pmid:27977239
Amphetamine is well absorbed after oral administration, with good bioavailabilitysupported
Good oral bioavailability pmid:14871155
Peak plasma concentrations (Tmax) are reached at 2–3 hours for immediate-release formulationssupported
Tmax 2-3h cap.2017.0071
Elimination half-life is approximately 10–12 hours in adults and ~7 hours in children, with a range of 6–12 hours across formulations and urinary pH conditions.supported
children T1/2 ~7h, adults ~10-12h cap.2017.0071
Elimination half-life is approximately 10–12 hours in adults and ~7 hours in children, with a range of 6–12 hours across formulations and urinary pH conditions.supported
T1/2 6-12h pmid:14871155
Volume of distribution is approximately 4 L/kg, and plasma protein binding is less than 20%supported
Vd 4 L/kg; protein binding <20% pmid:14871155
Hepatic metabolism is extensive, involving multiple CYP enzymes with stereoselective biotransformations that preferentially metabolize the l-isomersupported
extensive hepatic metabolism with stereoselective biotransformations cap.2017.0071
Claim in pharmacology — inconclusiveinconclusiveworking →
neuroscience9 · 8 ok
Dopaminergic neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) mediate amphetamine's reinforcing and euphoric effects, while projections to the prefrontal cortex underlie its attention-enhancing properties.supported
Sensitization due to enhanced mesotelencephalic DA release. pmid:3527341
Weidenauer et al. (2020) showed that amphetamine-induced striatal dopamine release is significantly greater in patients with first-episode psychosis than in healthy controlssupported
patients with first-episode psychosis show greater amphetamine-induced DA release vs controls. s41398-019-0681-5
Claim in neuroscience — inconclusiveinconclusiveworking →
Repeated intermittent amphetamine exposure produces enduring enhancement of mesotelencephalic dopamine release upon re-challengesupported
Sensitization due to enhanced mesotelencephalic DA release. pmid:3527341
Controlled human studies show d-amphetamine modulates post-error slowing, a measure of performance monitoring linked to anterior cingulate cortex functionsupported
d-Amphetamine effects on cognitive function (post-error slowing) in healthy volunteers. s00213-011-2462-6
The result is a dissociation between wanting and liking: compulsive drug-seeking escalates even as subjective pleasure from consumption diminishessupported
Brain circuitry for wanting (mesolimbic DA) is dissociable from liking. Incentive sensitization posits drug addiction as excessive amplification of wanting without liking. pmid:27977239
Amphetamine psychosis served as the original pharmacological model for the dopamine hypothesis of schizophreniasupported
Review of AMPH neurotoxicity and behavioral sensitization as models of amphetamine psychosis. pmid:3527341
TAAR1 functional significance in humans: TAAR1 agonism by amphetamine is well-established in rodent models (EC₅₀ < 5 µM) but substantially weaker at human TAAR1. The extent to which TAAR1-mediated autoinhibition modulates dopaminergic output at recreational or therapeutic doses in humans remains unresolved.supported
Most amphetamines show rat/mouse TAAR1 activation (EC50 < 5 uM); species differences rat > mouse > human. jpet.115.229765
Epigenetic consequences of developmental exposure: Animal models show long-lasting epigenetic changes in DAT regulation following embryonic amphetamine exposure. Whether prenatal therapeutic amphetamine exposure produces analogous epigenetic programming in humans is unknown.supported
Chronic embryonic amphetamine exposure causes long-lasting epigenetic modifications in DAT-1 expression in adult C. elegans. ijms241713092
clinical-evidence6 · 5 ok
The ATLAS4Dependence trial is a multi-centre, double-blind, placebo-controlled RCT evaluating dextroamphetamine substitution treatment for amphetamine/methamphetamine dependence in marginalized populationssupported
RCT protocol investigating dextroamphetamine substitution treatment for amphetamine dependence. High disease burden: psychiatric comorbidities, cardiovascular complications, injection-related infections. bmjopen-2024-095383
Evidence-based consensus guidelines from the British Association for Psychopharmacology provide current clinical guidance for amphetamine dependence treatment.supported
BAP guidelines including pharmacological management of amphetamine and methamphetamine dependence. 02698811251399593
Amphetamines were identified among the most efficacious medications for ADHD, though comparative effectiveness versus methylphenidate was complex and age-dependent.supported
Network meta-analysis comparing ADHD medications. Amphetamines found to be among most efficacious treatments. s2215-0366(18)30269-4
Claim in clinical-evidence — inconclusiveinconclusiveworking →
Amphetamine has an established FDA-approved indication for narcolepsy with excessive daytime sleepinesssupported
Amphetamines are FDA-approved for EDS in narcolepsy j.sleep.2019.09.001
A series of meta-analyses found that d-amphetamine does not produce statistically significant cognitive enhancement in healthy, non-sleep-deprived adultssupported
d-Amphetamine showed NO significant overall cognitive enhancement effect (k=10 studies, 27 effect sizes). j.euroneuro.2020.07.002
summary6 · 5 ok
Oral duration is 4–8 hours at standard doses, with a plasma half-life of 10–12 hours in adultssupported
children T1/2 ~7h, adults ~10-12h cap.2017.0071
It remains a first-line pharmacotherapy for ADHD across age groups, with network meta-analytic evidence establishing it among the most efficacious treatments availablesupported
Network meta-analysis comparing ADHD medications. Amphetamines found to be among most efficacious treatments. s2215-0366(18)30269-4
Amphetamine enters presynaptic terminals via DAT and NET as a transporter substrate, reverses transporter directionality to drive monoamine efflux, and disrupts vesicular storage through VMAT2 — a mechanism confirmed in DAT-knockout mice, where amphetamine failed to elevate extracellular dopaminesupported
DAT is required for AMPH-induced DA release but not vesicle depletion. AMPH increases extracellular DA 10-fold in wild-type mice via DAT. jneurosci.18-06-01979.1998
Claim in summary — inconclusiveinconclusiveworking →
Cardiovascular toxicity — tachycardia, hypertension, and with chronic high-dose use, cardiomyopathy — is the primary organ-system risksupported
Amphetamine abuse associated with cerebral infarction, intracranial hemorrhage, MI, cardiomyopathy, arrhythmias via excess catecholamines. pmid:16105252
Psychological dependence liability is high, driven by incentive-sensitization of mesolimbic dopamine circuits that progressively amplify "wanting" while hedonic capacity develops tolerancesupported
Incentive sensitization posits drug addiction as excessive amplification of wanting without liking via neural sensitization. pmid:27977239
comparative-pharmacology5 · 3 ok
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
Claim in comparative-pharmacology — not_supportednot supportedworking →
Mechanism: Methylphenidate blocks DAT without reversing transport; amphetamine both blocks and reverses, producing greater maximal dopamine elevationsupported
Distinguishes amphetamine-type DA-releasing drugs from cocaine-type blockers. pmid:8994051
Abuse liability: Both carry Schedule II classification, but amphetamine's release mechanism produces steeper dopamine surges, potentially conferring higher reinforcementsupported
Amphetamine described as a DA-preferential releaser with abuse liability. pmid:17017961
This rate-limited conversion produces a delayed Tmax, blunted Cmax, and reduced abuse potential compared to equivalent doses of immediate-release dextroamphetaminesupported
LDX has lower abuse potential due to prodrug design. hup.2910
pharmacokinetic-detail5 · 4 ok
Hepatic biotransformation involves multiple CYP enzymes with stereoselective processing that preferentially clears the l-isomersupported
extensive hepatic metabolism with stereoselective biotransformations cap.2017.0071
Dose-exposure kinetics are proportional across the therapeutic range.supported
dose-proportional PK cap.2017.0071
At alkaline pH (7.5–8.0), the non-ionized free base is reabsorbed, substantially prolonging half-life.supported
pKa ~9.9; weak base pmid:14871155
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
This rate-limited conversion produces a delayed Tmax, blunted Cmax, and reduced abuse potential relative to immediate-release dextroamphetaminesupported
LDX has lower abuse potential due to prodrug design. hup.2910
chemistry3 · 1 ok
Claim in chemistry — not_supportednot supportedworking →
Claim in chemistry — inconclusiveinconclusiveworking →
Volume of distribution is approximately 4 L/kg, reflecting extensive tissue penetrationsupported
Vd 4 L/kg pmid:14871155
history2 · 2 ok
The foundational demonstration that amphetamine's behavioral effects are dopamine-mediated came from Randrup and Munkvad in 1967, who showed that brain dopamine mediates amphetamine-induced stereotyped behaviorsupported
Foundational paper establishing dopamine as mediator of amphetamine-induced stereotyped behaviour. pmid:5630955
A network meta-analysis in The Lancet Psychiatry confirmed amphetamines among the most efficacious pharmacotherapies for ADHD across age groupssupported
Network meta-analysis comparing ADHD medications. Amphetamines found to be among most efficacious treatments. s2215-0366(18)30269-4
receptor-pharmacology2 · 2 ok
These values indicate a selectivity hierarchy of NE >> DA >>> 5-HT, with an NE/DA potency ratio of approximately 3.5 as confirmed in vivo in baboonssupported
NE/DA selectivity ratio for (+)-amphetamine is 3.5. pmid:15729739
Structural determinants of stereoselective TAAR1 binding include Asp¹⁰² and Met²⁶⁸, identified via site-directed mutagenesis.supported
Residues Asp102 and Met268 are major contributors to AMPH binding. jm401316v
legal-status1 · 1 ok
Its scheduling reflects the parent compound's classification rather than an independent abuse liability assessment, though its pharmacokinetic profile (rate-limited conversion) confers reduced abuse potential relative to immediate-release amphetamine formulations.supported
LDX has lower abuse potential due to prodrug design. hup.2910