generation run 2026-04-24
67 min completedmodel pipeline-v5plan not recordedrun/223b7928…Selection
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- 43 source keys (listed under Sources)
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22 searches — query, source, results, what was kept and why
| # | source | query | seen | kept | rationale |
|---|---|---|---|---|---|
| 1 | PubMed | modafinil pharmacokinetics bioavailability metabolism human | 5 | 2 | Definitive pharmacokinetic profile with CYP interactions |
| 2 | PubMed | modafinil mechanism of action dopamine pharmacology | 10 | 2 | Selected key pharmacology review and DAT binding structural study |
| 3 | ClinicalTrials.gov | modafinil | 10 | 3 | Representative completed clinical trials across indications |
| 4 | PubMed | modafinil cognitive enhancement healthy subjects executive function | 3 | 3 | Key cognitive enhancement studies in healthy non-sleep-deprived subjects |
| 5 | WebSearch | modafinil history discovery 1970s Michel Jouvet Lafon Laboratories | 10 | 1 | Primary historical source for modafinil discovery and development |
| 6 | WebSearch/Federal Register | modafinil legal status Schedule IV DEA controlled substance UK Australia | 10 | 1 | Legal scheduling by jurisdiction |
| 7 | PubMed | modafinil dopaminergic D1 D2 receptors arousal | 1 | 1 | Key mechanistic study on dopamine receptor subtypes required for modafinil wakefulness |
| 8 | PubMed | modafinil shift work sleep disorder obstructive sleep apnea FDA approved | 4 | 2 | Evidence-based reviews of approved and off-label uses |
| 9 | PubMed | modafinil abuse potential dependence addiction dopamine | 8 | 1 | Key review on abuse potential and dependence |
| 10 | OpenAlex | modafinil dopamine transporter DAT binding occupancy PET | 8 | 1 | Definitive human PET study showing DAT blockade and dopamine increase in nucleus accumbens |
| 11 | PubChem | modafinil | 1 | 1 | Primary chemical identity data for modafinil |
| 12 | OpenAlex | modafinil wakefulness mechanism pharmacology | 10 | 2 | Most-cited papers on modafinil wakefulness and neurochemistry |
| 13 | PubMed | modafinil narcolepsy clinical trial efficacy randomized controlled | 10 | 4 | Key clinical efficacy trials for approved indications |
| 14 | PubMed | modafinil schizophrenia Parkinson neurological fatigue | 5 | 2 | Off-label neurological and psychiatric uses |
| 15 | WebSearch | modafinil tramadol interaction seizure serotonin mechanism | 10 | 1 | Mechanism of modafinil-tramadol interaction |
| 16 | PubMed | modafinil tolerance narcolepsy long-term use dose escalation | 3 | 2 | Tolerance and dependence data |
| 17 | PubMed | modafinil orexin hypocretin narcolepsy wakefulness mechanism | 5 | 3 | Orexin/hypocretin system interaction with modafinil |
| 18 | WebSearch | modafinil MDMA interaction cardiovascular dangerous | 10 | 2 | Mechanism of modafinil-MDMA interaction risk |
| 19 | WebSearch | modafinil legal status Schedule IV DEA UK Australia international scheduling | 10 | 3 | Legal scheduling by major jurisdiction |
| 20 | PubMed | modafinil cardiovascular effects hypertension blood pressure | 4 | 2 | Cardiovascular safety and autonomic effects |
| 21 | StatPearls/NCBI Bookshelf | modafinil pharmacology mechanism pharmacokinetics adverse effects contraindications overdose | 1 | 1 | Comprehensive authoritative pharmacological summary |
| 22 | WebSearch | modafinil FDA prescribing information contraindications hypersensitivity SJS angioedema pregnancy | 10 | 1 | Official FDA contraindications and safety warnings |
108 claims by section — every cited sentence, checked against its source
pharmacology24 · 6 ok
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
Pharmacological blockade of either receptor abolishes modafinil-induced wakefulness.supported
D1 and D2 receptor antagonists blocked arousal effects of low-dose modafinil. D2R knockout mice exhibited attenuated modafinil-induced wakefulness. D1R antagonist in D2R KO mice completely abolished arousal effects. jneurosci.1819-08.2008
Unlike classical stimulants, modafinil is a low-affinity DAT inhibitor (Ki ≈ 3 µM for R-modafinil, compared to ~300 nM for cocaine)supported
Modafinil R-enantiomer (R-MOD) Ki at DAT = 3 µM. Structural analysis of DAT binding. biom14060713
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
Norepinephrine: Indirect elevation in prefrontal cortex and hypothalamus. At 400 mg, modafinil increases plasma norepinephrine by 33%, orthostatic norepinephrine by 42%, and urinary epinephrine by 81%.partially supported
42% higher orthostatic norepinephrine increase, 33% increase in urine NE, 81% increase in urine epinephrine. pmid:15753235
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
Orexin/Hypocretin: Modafinil activates orexin-containing neurons, but orexin is not required for its wake-promoting effects — orexin-null mice show even greater wakefulness responses to modafinil than wild-type littermates.partially supported
Modafinil activates orexin-containing neurons. Orexin regulates sleep/wakefulness states. pmid:10481909
Orexin/Hypocretin: Modafinil activates orexin-containing neurons, but orexin is not required for its wake-promoting effects — orexin-null mice show even greater wakefulness responses to modafinil than wild-type littermates.supported
Modafinil more effectively increased wakefulness time in orexin-null mice than in wild-type mice. The presence of orexin is not required for the wakefulness-prolonging action of modafinil. pmid:15652995
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
The overall elimination half-life is 12–15 hours for racemic modafinil, with marked enantiomeric differences: the R-enantiomer has a half-life of approximately 15 hours and the S-enantiomer approximately 4 hours.supported
Armodafinil is eliminated approximately three times more slowly than the S-isomer of racemic modafinil. 0044011-200929020-00003
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
safety23 · 8 ok
In animal studies, supratherapeutic doses in rats (600 mg/kg over 14 days) caused T-wave negativity in 37.5% of subjects and isolated AV blockadepartially supported
T-wave negativity at 100 and 600 mg/kg doses in 25-37.5% of animals. 01480545.2020.1803906
Modafinil at 400 mg increases resting heart rate by approximately 9.2 bpm, systolic blood pressure by 7.3 mmHg, and diastolic blood pressure by 5.3 mmHgsupported
Modafinil 400mg increased resting heart rate (+9.2 bpm), systolic BP (+7.3 mmHg), diastolic BP (+5.3 mmHg). pmid:15753235
Orthostatic norepinephrine increases by 42% and urinary epinephrine by 81%supported
42% higher orthostatic norepinephrine increase... 81% increase in urine epinephrine. pmid:15753235
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Tolerance to modafinil's wake-promoting effects develops with long-term use, manifesting as loss of efficacy requiring dose escalationsupported
Long-term use of modafinil can lead to tolerance with loss of efficacy and need for continuous dose increase. j.sleep.2023.10.005
Claim in safety — inconclusiveinconclusiveworking →
Drug holidays supported by pitolisant bridging have been described as an effective management strategy.supported
Pitolisant-supported bridging during drug holidays addresses this tolerance. j.sleep.2023.10.005
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
The MDMA interaction involves additive cardiovascular strain — modafinil increases heart rate, blood pressure, and catecholamines, and mdma independently produces massive monoamine releasesupported
Modafinil 400mg increased resting heart rate (+9.2 bpm), systolic BP (+7.3 mmHg), diastolic BP (+5.3 mmHg), and caused 42% higher orthostatic norepinephrine increase. pmid:15753235
No published study of combined modafinil and MDMA use exists; the risk assessment is mechanism-inferred.supported
RCT directly comparing MDMA, methylphenidate, and modafinil at equally cardiostimulant doses in healthy subjects. s00213-017-4650-5
Pre-existing cardiovascular disease, left-ventricular hypertrophy, uncontrolled hypertension, unstable angina, or recent myocardial infarction — modafinil increases heart rate, blood pressure, and catecholamine outputsupported
Autonomic changes encourage caution in cardiovascular disease patients. pmid:15753235
Claim in safety — inconclusiveinconclusiveworking →
summary17 · 6 ok
Claim in summary — inconclusiveinconclusiveworking →
A racemic mixture of R- and S-enantiomers, it occupies a distinctive position among stimulants: low-affinity dopamine transporter (DAT) inhibition (Ki ≈ 3 µM) produces wakefulness promotion and cognitive enhancement over 5–10 hours without the locomotor hyperactivity or robust euphoria characteristic of amphetamines.supported
Modafinil R-enantiomer (R-MOD) Ki at DAT = 3 µM. Structural analysis of DAT binding. biom14060713
Modafinil emerged from adrafinil research at Laboratoire Louis Lafon in France during the 1970s, with neurophysiologist Michel Jouvet driving its clinical development for narcolepsysupported
Adrafinil identified by L. Lafon Ltd in 1974. Michel Jouvet prescribed adrafinil to narcoleptic patients as early as 1977-78. Modafinil identified as active metabolite. j.sleep.2018.05.027
Claim in summary — inconclusiveinconclusiveworking →
Claim in summary — inconclusiveinconclusiveworking →
Claim in summary — inconclusiveinconclusiveworking →
The compound has since become one of the most extensively studied wake-promoting agents, with research spanning cognitive enhancement in healthy subjects, adjunctive treatment of bipolar depression, and military fatigue countermeasures.supported
Modafinil 300mg and d-amphetamine 20mg both significantly improved mood, fatigue, sleepiness, reaction time, logical reasoning, and short-term memory vs. placebo during 64h sleep deprivation. pmid:10607161
Claim in summary — inconclusiveinconclusiveworking →
Claim in summary — inconclusiveinconclusiveworking →
Claim in summary — inconclusiveinconclusiveworking →
Both D1 and D2 dopamine receptors are required for the arousal responsesupported
D1 and D2 receptors are essential for wakefulness induced by modafinil. jneurosci.1819-08.2008
Claim in summary — inconclusiveinconclusiveworking →
Claim in summary — inconclusiveinconclusiveworking →
Neuroimaging reveals increased prefrontal cortex efficiency and reduced amygdala reactivity to threat stimulisupported
fMRI: modafinil 100mg/day for 7 days decreased amygdala reactivity to fearful stimuli and reduced PFC/ACC BOLD signal during WM and attentional control tasks. Enhances efficiency of prefrontal cognitive processing while dampening amygdala reactivity. npp.2010.83
Tolerance develops with chronic use via D2 receptor isoform changes in the mesocorticolimbic systempartially supported
Long-term use of modafinil can lead to tolerance with loss of efficacy and need for continuous dose increase. j.sleep.2023.10.005
Claim in summary — inconclusiveinconclusiveworking →
Claim in summary — inconclusiveinconclusiveworking →
clinical-evidence12 · 2 ok
Claim in clinical-evidence — inconclusiveinconclusiveworking →
In a 64-hour sleep deprivation paradigm, modafinil 300 mg and d-amphetamine 20 mg both improved mood, fatigue, sleepiness, reaction time, logical reasoning, and short-term memory compared to placebo; modafinil elicited fewer side effectssupported
Modafinil 300mg and d-amphetamine 20mg both significantly improved mood, fatigue, sleepiness, reaction time, logical reasoning, and short-term memory vs. placebo during 64h sleep deprivation. Modafinil elicited fewer side effects than amphetamine. pmid:10607161
Claim in clinical-evidence — inconclusiveinconclusiveworking →
The American Academy of Sleep Medicine recommends modafinil as a first-line treatment for narcolepsy and other hypersomnias of central origin.supported
Modafinil, sodium oxybate, amphetamine... are effective treatments for excessive sleepiness associated with narcolepsy. Modafinil is an effective therapy for idiopathic hypersomnia, Parkinson's disease, myotonic dystrophy, and multiple sclerosis. pmid:18246980
Claim in clinical-evidence — inconclusiveinconclusiveworking →
Claim in clinical-evidence — inconclusiveinconclusiveworking →
Claim in clinical-evidence — inconclusiveinconclusiveworking →
Claim in clinical-evidence — inconclusiveinconclusiveworking →
Claim in clinical-evidence — inconclusiveinconclusiveworking →
Claim in clinical-evidence — inconclusiveinconclusiveworking →
Claim in clinical-evidence — inconclusiveinconclusiveworking →
Claim in clinical-evidence — inconclusiveinconclusiveworking →
history10 · 5 ok
Claim in history — inconclusiveinconclusiveworking →
Claim in history — inconclusiveinconclusiveworking →
Claim in history — inconclusiveinconclusiveworking →
Research programs have explored cognitive enhancement in healthy subjects, adjunctive treatment of bipolar depression, cocaine dependence, neurological fatigue in multiple sclerosis, Parkinson's disease, and traumatic brain injury, and military aviation fatigue countermeasuressupported
Meta-analysis of modafinil for fatigue and EDS associated with neurological disorders (MS, PD, TBI). Inconsistent results across conditions. journal.pone.0081802
Claim in history — inconclusiveinconclusiveworking →
Research programs have explored cognitive enhancement in healthy subjects, adjunctive treatment of bipolar depression, cocaine dependence, neurological fatigue in multiple sclerosis, Parkinson's disease, and traumatic brain injury, and military aviation fatigue countermeasuressupported
Modafinil 300mg and d-amphetamine 20mg both significantly improved mood, fatigue, sleepiness, reaction time, logical reasoning, and short-term memory vs. placebo during 64h sleep deprivation. pmid:10607161
In 1974, screening for novel compounds identified adrafinil (CRL-40028), a benzhydryl sulfinyl compound that produced dose-dependent increases in motor activity in mice without peripheral sympathomimetic effectspartially supported
Adrafinil identified by L. Lafon Ltd in 1974. j.sleep.2018.05.027
Modafinil's first major operational deployment occurred during the Gulf War (January–February 1991), when the French military administered the compound to personnel to sustain operations — a significant real-world proof of conceptsupported
Used by French army during Gulf War 1991. j.sleep.2018.05.027
Claim in history — inconclusiveinconclusiveworking →
Armodafinil offered a simplified pharmacokinetic profile with the longer-acting enantiomer alone.supported
Armodafinil (R-modafinil) is the R- and longer-lasting isomer of racemic modafinil. 0044011-200929020-00003
neuroscience7 · 3 ok
Claim in neuroscience — inconclusiveinconclusiveworking →
Modafinil at 400 mg produces measurable sympathomedullary activation: resting heart rate increases by ~9.2 bpm, systolic blood pressure by 7.3 mmHg, and diastolic blood pressure by 5.3 mmHg, with 42% orthostatic norepinephrine increase and 81% urinary epinephrine increasesupported
Modafinil 400mg increased resting heart rate (+9.2 bpm), systolic BP (+7.3 mmHg), diastolic BP (+5.3 mmHg), and caused 42% higher orthostatic norepinephrine increase, 33% increase in urine NE, 81% increase in urine epinephrine. pmid:15753235
Claim in neuroscience — inconclusiveinconclusiveworking →
Functional MRI data demonstrate that modafinil increases the efficiency of prefrontal cortex activation during working memory tasks: equivalent or superior behavioral performance is achieved with reduced BOLD signal intensity, suggesting more efficient neural processing rather than brute-force cortical activation.supported
fMRI: modafinil 100mg/day for 7 days... reduced PFC/ACC BOLD signal during WM and attentional control tasks. Enhances efficiency of prefrontal cognitive processing while dampening amygdala reactivity. npp.2010.83
Claim in neuroscience — inconclusiveinconclusiveworking →
What accounts for the disparity between low in vitro DAT affinity and high in vivo occupancy? Structural studies suggest modafinil stabilizes a distinct DAT conformation, but the quantitative pharmacokinetic and pharmacodynamic modeling to fully explain this gap remains incomplete.supported
Structural analysis of DAT binding. biom14060713
Claim in neuroscience — inconclusiveinconclusiveworking →
comparative-pharmacology6 · 2 ok
In a direct comparison during 64 hours of sustained sleep deprivation, modafinil 300 mg and d-amphetamine 20 mg produced comparable improvements in mood, fatigue, cognitive performance, and sleepiness, but modafinil elicited fewer side effects.supported
Modafinil 300mg and d-amphetamine 20mg both significantly improved mood, fatigue, sleepiness, reaction time, logical reasoning, and short-term memory vs. placebo during 64h sleep deprivation. Modafinil elicited fewer side effects than amphetamine. pmid:10607161
DAT affinity: Modafinil binds DAT with Ki ≈ 3 µM — approximately 10-fold lower affinity than cocaine (~300 nM). Despite this, therapeutic doses achieve 65–70% DAT occupancy.supported
Modafinil R-enantiomer (R-MOD) Ki at DAT = 3 µM. biom14060713
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
receptor-pharmacology4 · 0 ok
chemistry3 · 1 ok
Claim in chemistry — inconclusiveinconclusiveworking →
Claim in chemistry — inconclusiveinconclusiveworking →
The parent compound adrafinil (CRL-40028) is a prodrug that undergoes hepatic metabolism to yield modafinil as its primary active metabolitesupported
Modafinil identified as active metabolite. j.sleep.2018.05.027
pharmacokinetic-detail2 · 1 ok
A pharmacokinetic study in healthy Chinese volunteers at 200 mg demonstrated potential variation in drug exposure by gender and ethnicity, though the clinical significance of these differences requires further investigation.supported
Pharmacokinetics of modafinil investigated in relation to sex and ethnicity in healthy young volunteers following a single 200 mg oral dose. pmid:21092715
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →