Nutrient chapter

Modafinil

Modafinil inhibits dopamine transport and recruits interacting arousal systems. Human target engagement, animal circuit dependencies, drug interactions, food-intake effects and null results are recorded separately. Racemate, R/S enantiomers, metabolites and experimental analogues do not inherit one another's findings.

69 recorded mechanisms · 0 availability situations · 1 preserved sources. Source recording and scientific verification are labeled separately.

Read recorded mechanisms Open recursive mind map

The mechanisms

What the sources say this nutrient does, one relationship at a time. Plain wording comes first; the technical statement follows.

Modafinil is a sulfoxide-containing racemate; armodafinil is its R enantiomer. These are distinct drug identities, not interchangeable exposure profiles.
Modafinil → Armodafinil / R-modafinil Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary abstract and PMC full-text methods, results and Table 1 inspected; XML endpoint unavailable.
experimental_model
Chemical stereoisomers; human-DAT assay results kept separate.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
Modafinil is a sulfoxide-containing racemate; armodafinil is its R enantiomer. These are distinct drug identities, not interchangeable exposure profiles.
primary_references
R-modafinil (armodafinil): a unique dopamine uptake inhibitor and potential medication for psychostimulant abuse. | 2012 | DOI 10.1016/j.biopsych.2012.03.022 | PMID 22537794 | https://pmc.ncbi.nlm.nih.gov/articles/PMC3413742/ | https://pubmed.ncbi.nlm.nih.gov/22537794/
source_locator
Reviewed reference lines 17-17; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 17–17
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Chemical stereoisomers; human-DAT assay results kept separate. · Recorded from source · Recorded from source
Modafinil contains R and S enantiomers; **armodafinil is R-modafinil**. Both affect DAT, but do not have identical pharmacology. In a human-DAT cell assay, the R form had approximately threefold higher binding affinity than the S form. Keep racemate, enantiomers and experimental analogues separately identified. [Enantiomer study](https://pubmed.ncbi.nlm.nih.gov/22537794/)
Complete structured claim and evidence
Armodafinil had higher dose-normalized late exposure than racemic modafinil despite similar approximately 13-hour terminal half-lives in the pooled single-dose studies.
Armodafinil / R-modafinil → Human armodafinil plasma exposure Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary indexed abstract checked; full methods and figures not comprehensively reviewed.
experimental_contrast
{"intervention": "Armodafinil", "comparator": "Dose-normalized racemic modafinil", "endpoint": "Armodafinil had higher dose-normalized late exposure than racemic modafinil despite similar approximately 13-hour terminal half-lives in the pooled single-dose studies.", "effect_direction": "increase", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Three pooled human single-dose pharmacokinetic studies.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
Armodafinil had higher dose-normalized late exposure than racemic modafinil despite similar approximately 13-hour terminal half-lives in the pooled single-dose studies.
primary_references
Armodafinil and modafinil have substantially different pharmacokinetic profiles despite having the same terminal half-lives: analysis of data from three randomized, single-dose, pharmacokinetic studies. | 2009 | DOI 10.2165/11315280-000000000-00000 | PMID 19663523 | https://pubmed.ncbi.nlm.nih.gov/19663523/
source_locator
Reviewed reference lines 19-19; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 19–19
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Three pooled human single-dose pharmacokinetic studies. · Recorded from source · Recorded from source
S-modafinil disappears more rapidly from plasma. A pooled analysis of three single-dose studies found similar terminal half-lives, approximately 13 hours, for racemic modafinil and armodafinil, but higher dose-normalized late exposure with armodafinil. The racemate's early decline reflected removal of its faster-cleared S component. A single terminal half-life therefore conceals meaningful differences in the exposure curve. These data do not establish universal clinical superiority of either formulation. [Comparative human pharmacokinetics](https://pubmed.ncbi.nlm.nih.gov/19663523/)
Complete structured claim and evidence
Food delayed modafinil peak concentration by about one hour without reducing overall exposure.
Modafinil → Human modafinil plasma exposure Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Official label description, pharmacology, pharmacokinetics, indications, interactions and relevant warnings checked.
experimental_contrast
{"intervention": "Fed oral modafinil", "comparator": "Fasted oral modafinil", "endpoint": "Food delayed modafinil peak concentration by about one hour without reducing overall exposure.", "effect_direction": "mixed", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Human oral pharmacokinetics in official product label; time to peak and AUC are different measures.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
Food delayed modafinil peak concentration by about one hour without reducing overall exposure.
primary_references
PROVIGIL U.S. prescribing information | https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3b8d1c32-dac9-50e6-e063-6394a90aa5a5
source_locator
Reviewed reference lines 21-21; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 21–21
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Human oral pharmacokinetics in official product label; time to peak and AUC are different measures. · Recorded from source · Recorded from source
Food can delay peak concentration by about an hour without reducing overall exposure. Metabolism includes hydrolytic deamidation to modafinil acid and S-oxidation to modafinil sulfone; these major metabolites do not appear to explain central arousal. CYP involvement in metabolism and effects on other drugs' CYP-mediated clearance are separate questions. [Official pharmacokinetics](https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3b8d1c32-dac9-50e6-e063-6394a90aa5a5)
Complete structured claim and evidence
Modafinil metabolism includes hydrolytic deamidation to modafinil acid. Major-metabolite formation does not establish those metabolites as the source of central arousal.
Modafinil → Modafinil acid Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Official label description, pharmacology, pharmacokinetics, indications, interactions and relevant warnings checked.
experimental_model
Product-label human pharmacokinetics.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
Modafinil metabolism includes hydrolytic deamidation to modafinil acid. Major-metabolite formation does not establish those metabolites as the source of central arousal.
primary_references
PROVIGIL U.S. prescribing information | https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3b8d1c32-dac9-50e6-e063-6394a90aa5a5
source_locator
Reviewed reference lines 21-21; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 21–21
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Product-label human pharmacokinetics. · Recorded from source · Recorded from source
Food can delay peak concentration by about an hour without reducing overall exposure. Metabolism includes hydrolytic deamidation to modafinil acid and S-oxidation to modafinil sulfone; these major metabolites do not appear to explain central arousal. CYP involvement in metabolism and effects on other drugs' CYP-mediated clearance are separate questions. [Official pharmacokinetics](https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3b8d1c32-dac9-50e6-e063-6394a90aa5a5)
Complete structured claim and evidence
Modafinil metabolism includes S-oxidation to modafinil sulfone. Major-metabolite formation does not establish those metabolites as the source of central arousal.
Modafinil → Modafinil sulfone Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Official label description, pharmacology, pharmacokinetics, indications, interactions and relevant warnings checked.
experimental_model
Product-label human pharmacokinetics.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
Modafinil metabolism includes S-oxidation to modafinil sulfone. Major-metabolite formation does not establish those metabolites as the source of central arousal.
primary_references
PROVIGIL U.S. prescribing information | https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3b8d1c32-dac9-50e6-e063-6394a90aa5a5
source_locator
Reviewed reference lines 21-21; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 21–21
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Product-label human pharmacokinetics. · Recorded from source · Recorded from source
Food can delay peak concentration by about an hour without reducing overall exposure. Metabolism includes hydrolytic deamidation to modafinil acid and S-oxidation to modafinil sulfone; these major metabolites do not appear to explain central arousal. CYP involvement in metabolism and effects on other drugs' CYP-mediated clearance are separate questions. [Official pharmacokinetics](https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3b8d1c32-dac9-50e6-e063-6394a90aa5a5)
Complete structured claim and evidence
In ten healthy men, 200 or 400 mg oral modafinil reduced DAT-radiotracer binding by about 54% in caudate, 47% in putamen and 39% in nucleus accumbens.
Modafinil → Human dopamine transporter / DAT / SLC6A3 Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary indexed abstract checked; full methods and figures not comprehensively reviewed.
experimental_contrast
{"intervention": "Oral modafinil 200 or 400 mg", "comparator": "Baseline/placebo comparison", "endpoint": "In ten healthy men, 200 or 400 mg oral modafinil reduced DAT-radiotracer binding by about 54% in caudate, 47% in putamen and 39% in nucleus accumbens.", "effect_direction": "decrease", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Human PET, ten healthy men; transporter occupancy is not percent dopamine increase.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
In ten healthy men, 200 or 400 mg oral modafinil reduced DAT-radiotracer binding by about 54% in caudate, 47% in putamen and 39% in nucleus accumbens.
primary_references
Effects of modafinil on dopamine and dopamine transporters in the male human brain: clinical implications. | 2009 | DOI 10.1001/jama.2009.351 | PMID 19293415 | https://pubmed.ncbi.nlm.nih.gov/19293415/
source_locator
Reviewed reference lines 36-36; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 36–36
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Human PET, ten healthy men; transporter occupancy is not percent dopamine increase. · Recorded from source · Recorded from source
In a PET study of **10 healthy men**, oral 200 or 400 mg modafinil reduced transporter-radiotracer binding by approximately **54% in caudate, 47% in putamen and 39% in nucleus accumbens**. Separate raclopride measurements supported increased extracellular dopamine. DAT occupancy is not a percentage increase in dopamine; raclopride displacement is an indirect imaging indicator rather than direct chemical sampling. [Volkow et al., 2009](https://pubmed.ncbi.nlm.nih.gov/19293415/)
Complete structured claim and evidence
Separate raclopride PET measurements after oral modafinil supported increased extracellular dopamine; radiotracer displacement is an indirect indicator, not chemical sampling.
Modafinil → Dopamine Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary indexed abstract checked; full methods and figures not comprehensively reviewed.
experimental_contrast
{"intervention": "Oral modafinil", "comparator": "Baseline/placebo comparison", "endpoint": "Separate raclopride PET measurements after oral modafinil supported increased extracellular dopamine; radiotracer displacement is an indirect indicator, not chemical sampling.", "effect_direction": "increase", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Human PET, ten healthy men, 200 or 400 mg oral exposure.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
Separate raclopride PET measurements after oral modafinil supported increased extracellular dopamine; radiotracer displacement is an indirect indicator, not chemical sampling.
primary_references
Effects of modafinil on dopamine and dopamine transporters in the male human brain: clinical implications. | 2009 | DOI 10.1001/jama.2009.351 | PMID 19293415 | https://pubmed.ncbi.nlm.nih.gov/19293415/
source_locator
Reviewed reference lines 36-36; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 36–36
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Human PET, ten healthy men, 200 or 400 mg oral exposure. · Recorded from source · Recorded from source
In a PET study of **10 healthy men**, oral 200 or 400 mg modafinil reduced transporter-radiotracer binding by approximately **54% in caudate, 47% in putamen and 39% in nucleus accumbens**. Separate raclopride measurements supported increased extracellular dopamine. DAT occupancy is not a percentage increase in dopamine; raclopride displacement is an indirect imaging indicator rather than direct chemical sampling. [Volkow et al., 2009](https://pubmed.ncbi.nlm.nih.gov/19293415/)
Complete structured claim and evidence
modafinil had dopamine uptake IC50 13 micromolar in wild-type human DAT expressed in COS-7 cells. Binding and uptake constants are distinct.
Modafinil → Human dopamine transporter / DAT / SLC6A3 Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary abstract and PMC full-text methods, results and Table 1 inspected; XML endpoint unavailable.
experimental_model
Wild-type human DAT expressed in COS-7 cells, 2012 Table 1; point estimates not exposure thresholds.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
modafinil had dopamine uptake IC50 13 micromolar in wild-type human DAT expressed in COS-7 cells. Binding and uptake constants are distinct.
primary_references
R-modafinil (armodafinil): a unique dopamine uptake inhibitor and potential medication for psychostimulant abuse. | 2012 | DOI 10.1016/j.biopsych.2012.03.022 | PMID 22537794 | https://pmc.ncbi.nlm.nih.gov/articles/PMC3413742/ | https://pubmed.ncbi.nlm.nih.gov/22537794/
source_locator
Reviewed reference lines 40-46; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 40–46
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Wild-type human DAT expressed in COS-7 cells, 2012 Table 1; point estimates not exposure thresholds. · Recorded from source · Recorded from source
| Compound, wild-type human DAT expressed in COS-7 cells | Dopamine uptake IC₅₀, µM | Radioligand-displacement Kᵢ, µM | |---|---:|---:| | Racemic modafinil | 13 | 2.3 | | R-modafinil | 4.0 | 0.78 | | S-modafinil | 8.7 | 2.5 | These are reported point estimates, not interchangeable constants. Uptake inhibition and equilibrium binding differ. The racemate's result should not be replaced by a calculated average of its enantiomers. [2012 study, Table 1](https://pmc.ncbi.nlm.nih.gov/articles/PMC3413742/)
Complete structured claim and evidence
modafinil had radioligand-displacement Ki 2.3 micromolar in wild-type human DAT expressed in COS-7 cells. Binding and uptake constants are distinct.
Modafinil → Human dopamine transporter / DAT / SLC6A3 Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary abstract and PMC full-text methods, results and Table 1 inspected; XML endpoint unavailable.
experimental_model
Wild-type human DAT expressed in COS-7 cells, 2012 Table 1; point estimates not exposure thresholds.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
modafinil had radioligand-displacement Ki 2.3 micromolar in wild-type human DAT expressed in COS-7 cells. Binding and uptake constants are distinct.
primary_references
R-modafinil (armodafinil): a unique dopamine uptake inhibitor and potential medication for psychostimulant abuse. | 2012 | DOI 10.1016/j.biopsych.2012.03.022 | PMID 22537794 | https://pmc.ncbi.nlm.nih.gov/articles/PMC3413742/ | https://pubmed.ncbi.nlm.nih.gov/22537794/
source_locator
Reviewed reference lines 40-46; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 40–46
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Wild-type human DAT expressed in COS-7 cells, 2012 Table 1; point estimates not exposure thresholds. · Recorded from source · Recorded from source
| Compound, wild-type human DAT expressed in COS-7 cells | Dopamine uptake IC₅₀, µM | Radioligand-displacement Kᵢ, µM | |---|---:|---:| | Racemic modafinil | 13 | 2.3 | | R-modafinil | 4.0 | 0.78 | | S-modafinil | 8.7 | 2.5 | These are reported point estimates, not interchangeable constants. Uptake inhibition and equilibrium binding differ. The racemate's result should not be replaced by a calculated average of its enantiomers. [2012 study, Table 1](https://pmc.ncbi.nlm.nih.gov/articles/PMC3413742/)
Complete structured claim and evidence
armodafinil had dopamine uptake IC50 4.0 micromolar in wild-type human DAT expressed in COS-7 cells. Binding and uptake constants are distinct.
Armodafinil / R-modafinil → Human dopamine transporter / DAT / SLC6A3 Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary abstract and PMC full-text methods, results and Table 1 inspected; XML endpoint unavailable.
experimental_model
Wild-type human DAT expressed in COS-7 cells, 2012 Table 1; point estimates not exposure thresholds.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
armodafinil had dopamine uptake IC50 4.0 micromolar in wild-type human DAT expressed in COS-7 cells. Binding and uptake constants are distinct.
primary_references
R-modafinil (armodafinil): a unique dopamine uptake inhibitor and potential medication for psychostimulant abuse. | 2012 | DOI 10.1016/j.biopsych.2012.03.022 | PMID 22537794 | https://pmc.ncbi.nlm.nih.gov/articles/PMC3413742/ | https://pubmed.ncbi.nlm.nih.gov/22537794/
source_locator
Reviewed reference lines 40-46; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 40–46
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Wild-type human DAT expressed in COS-7 cells, 2012 Table 1; point estimates not exposure thresholds. · Recorded from source · Recorded from source
| Compound, wild-type human DAT expressed in COS-7 cells | Dopamine uptake IC₅₀, µM | Radioligand-displacement Kᵢ, µM | |---|---:|---:| | Racemic modafinil | 13 | 2.3 | | R-modafinil | 4.0 | 0.78 | | S-modafinil | 8.7 | 2.5 | These are reported point estimates, not interchangeable constants. Uptake inhibition and equilibrium binding differ. The racemate's result should not be replaced by a calculated average of its enantiomers. [2012 study, Table 1](https://pmc.ncbi.nlm.nih.gov/articles/PMC3413742/)
Complete structured claim and evidence
armodafinil had radioligand-displacement Ki 0.78 micromolar in wild-type human DAT expressed in COS-7 cells. Binding and uptake constants are distinct.
Armodafinil / R-modafinil → Human dopamine transporter / DAT / SLC6A3 Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary abstract and PMC full-text methods, results and Table 1 inspected; XML endpoint unavailable.
experimental_model
Wild-type human DAT expressed in COS-7 cells, 2012 Table 1; point estimates not exposure thresholds.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
armodafinil had radioligand-displacement Ki 0.78 micromolar in wild-type human DAT expressed in COS-7 cells. Binding and uptake constants are distinct.
primary_references
R-modafinil (armodafinil): a unique dopamine uptake inhibitor and potential medication for psychostimulant abuse. | 2012 | DOI 10.1016/j.biopsych.2012.03.022 | PMID 22537794 | https://pmc.ncbi.nlm.nih.gov/articles/PMC3413742/ | https://pubmed.ncbi.nlm.nih.gov/22537794/
source_locator
Reviewed reference lines 40-46; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 40–46
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Wild-type human DAT expressed in COS-7 cells, 2012 Table 1; point estimates not exposure thresholds. · Recorded from source · Recorded from source
| Compound, wild-type human DAT expressed in COS-7 cells | Dopamine uptake IC₅₀, µM | Radioligand-displacement Kᵢ, µM | |---|---:|---:| | Racemic modafinil | 13 | 2.3 | | R-modafinil | 4.0 | 0.78 | | S-modafinil | 8.7 | 2.5 | These are reported point estimates, not interchangeable constants. Uptake inhibition and equilibrium binding differ. The racemate's result should not be replaced by a calculated average of its enantiomers. [2012 study, Table 1](https://pmc.ncbi.nlm.nih.gov/articles/PMC3413742/)
Complete structured claim and evidence
s-modafinil had dopamine uptake IC50 8.7 micromolar in wild-type human DAT expressed in COS-7 cells. Binding and uptake constants are distinct.
S-modafinil → Human dopamine transporter / DAT / SLC6A3 Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary abstract and PMC full-text methods, results and Table 1 inspected; XML endpoint unavailable.
experimental_model
Wild-type human DAT expressed in COS-7 cells, 2012 Table 1; point estimates not exposure thresholds.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
s-modafinil had dopamine uptake IC50 8.7 micromolar in wild-type human DAT expressed in COS-7 cells. Binding and uptake constants are distinct.
primary_references
R-modafinil (armodafinil): a unique dopamine uptake inhibitor and potential medication for psychostimulant abuse. | 2012 | DOI 10.1016/j.biopsych.2012.03.022 | PMID 22537794 | https://pmc.ncbi.nlm.nih.gov/articles/PMC3413742/ | https://pubmed.ncbi.nlm.nih.gov/22537794/
source_locator
Reviewed reference lines 40-46; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 40–46
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Wild-type human DAT expressed in COS-7 cells, 2012 Table 1; point estimates not exposure thresholds. · Recorded from source · Recorded from source
| Compound, wild-type human DAT expressed in COS-7 cells | Dopamine uptake IC₅₀, µM | Radioligand-displacement Kᵢ, µM | |---|---:|---:| | Racemic modafinil | 13 | 2.3 | | R-modafinil | 4.0 | 0.78 | | S-modafinil | 8.7 | 2.5 | These are reported point estimates, not interchangeable constants. Uptake inhibition and equilibrium binding differ. The racemate's result should not be replaced by a calculated average of its enantiomers. [2012 study, Table 1](https://pmc.ncbi.nlm.nih.gov/articles/PMC3413742/)
Complete structured claim and evidence
s-modafinil had radioligand-displacement Ki 2.5 micromolar in wild-type human DAT expressed in COS-7 cells. Binding and uptake constants are distinct.
S-modafinil → Human dopamine transporter / DAT / SLC6A3 Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary abstract and PMC full-text methods, results and Table 1 inspected; XML endpoint unavailable.
experimental_model
Wild-type human DAT expressed in COS-7 cells, 2012 Table 1; point estimates not exposure thresholds.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
s-modafinil had radioligand-displacement Ki 2.5 micromolar in wild-type human DAT expressed in COS-7 cells. Binding and uptake constants are distinct.
primary_references
R-modafinil (armodafinil): a unique dopamine uptake inhibitor and potential medication for psychostimulant abuse. | 2012 | DOI 10.1016/j.biopsych.2012.03.022 | PMID 22537794 | https://pmc.ncbi.nlm.nih.gov/articles/PMC3413742/ | https://pubmed.ncbi.nlm.nih.gov/22537794/
source_locator
Reviewed reference lines 40-46; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 40–46
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Wild-type human DAT expressed in COS-7 cells, 2012 Table 1; point estimates not exposure thresholds. · Recorded from source · Recorded from source
| Compound, wild-type human DAT expressed in COS-7 cells | Dopamine uptake IC₅₀, µM | Radioligand-displacement Kᵢ, µM | |---|---:|---:| | Racemic modafinil | 13 | 2.3 | | R-modafinil | 4.0 | 0.78 | | S-modafinil | 8.7 | 2.5 | These are reported point estimates, not interchangeable constants. Uptake inhibition and equilibrium binding differ. The racemate's result should not be replaced by a calculated average of its enantiomers. [2012 study, Table 1](https://pmc.ncbi.nlm.nih.gov/articles/PMC3413742/)
Complete structured claim and evidence
DAT knockout abolished the usual modafinil wake-promoting response in mice while caffeine remained effective with enhanced response.
Mouse dopamine transporter / Slc6a3 → Mouse wake duration Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary indexed abstract checked; full methods and figures not comprehensively reviewed.
experimental_condition
Modafinil in wild-type mice drug challenge · Modafinil Condition belongs to the full experimental contrast; do not separate a joint intervention.
experimental_condition
Modafinil in wild-type mice knockout · Mouse dopamine transporter / Slc6a3 Condition belongs to the full experimental contrast; do not separate a joint intervention.
experimental_contrast
{"intervention": "Modafinil in DAT-knockout mice", "comparator": "Modafinil in wild-type mice", "endpoint": "DAT knockout abolished the usual modafinil wake-promoting response in mice while caffeine remained effective with enhanced response.", "effect_direction": "decrease", "combination": "joint", "conditions": [{"entity_slug": "mouse-slc6a3", "state": "knockout"}, {"entity_slug": "modafinil", "state": "drug challenge"}]} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Constitutive mouse DAT knockout; baseline and developmental compensation constrain interpretation.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
DAT knockout abolished the usual modafinil wake-promoting response in mice while caffeine remained effective with enhanced response.
primary_references
Dopaminergic role in stimulant-induced wakefulness. | 2001 | DOI 10.1523/jneurosci.21-05-01787.2001 | PMID 11222668 | https://pubmed.ncbi.nlm.nih.gov/11222668/
source_locator
Reviewed reference lines 50-50; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 50–50
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Constitutive mouse DAT knockout; baseline and developmental compensation constrain interpretation. · Recorded from source · Recorded from source
In DAT-knockout mice, modafinil lost its usual wake-promoting effect; caffeine remained effective and produced an enhanced response. This supports a DAT-dependent route in that model, rather than a general inability of those mice to awaken. Developmental compensation and changed baseline physiology still limit extrapolation from a constitutive knockout. [Wisor et al., 2001](https://pubmed.ncbi.nlm.nih.gov/11222668/)
Complete structured claim and evidence
Mutational/modeling experiments support modafinil compatibility with DAT closed toward the extracellular side, not a permanently locked conformation in patients.
Modafinil → Human dopamine transporter / DAT / SLC6A3 Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Full XML obtained; relevant results/methods inspected. Not exhaustive reanalysis of figures or data.
experimental_model
Transporter mutation, ligand binding and modeling study.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
Mutational/modeling experiments support modafinil compatibility with DAT closed toward the extracellular side, not a permanently locked conformation in patients.
primary_references
The atypical stimulant and nootropic modafinil interacts with the dopamine transporter in a different manner than classical cocaine-like inhibitors. | 2011 | DOI 10.1371/journal.pone.0025790 | PMID 22043293 | https://pmc.ncbi.nlm.nih.gov/articles/PMC3197159/ | https://pubmed.ncbi.nlm.nih.gov/22043293/
source_locator
Reviewed reference lines 54-54; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 54–54
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Transporter mutation, ligand binding and modeling study. · Recorded from source · Recorded from source
Mutational and modeling experiments distinguish modafinil from cocaine-like DAT inhibitors. The evidence supports greater compatibility with a transporter closed toward the extracellular side; it does not demonstrate a permanent, uniquely fixed conformation in patients. [2011 conformation study](https://pubmed.ncbi.nlm.nih.gov/22043293/)
Complete structured claim and evidence
Adding 10 micromolar zinc in sodium-free binding buffer did not significantly improve modafinil affinity for DAT: Ki approximately 2.96 versus 3.47 micromolar.
Zinc(II) ion → Modafinil affinity for human DAT in binding assays Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Full XML obtained; relevant results/methods inspected. Not exhaustive reanalysis of figures or data.
experimental_condition
Same sodium-free buffer without added zinc 10 micromolar added zinc · Zinc(II) ion Condition belongs to the full experimental contrast; do not separate a joint intervention.
experimental_contrast
{"intervention": "10 micromolar zinc in sodium-free buffer", "comparator": "Same sodium-free buffer without added zinc", "endpoint": "Adding 10 micromolar zinc in sodium-free binding buffer did not significantly improve modafinil affinity for DAT: Ki approximately 2.96 versus 3.47 micromolar.", "effect_direction": "no_detected_change", "combination": "joint", "conditions": [{"entity_slug": "zinc-ion", "state": "10 micromolar added zinc"}, {"entity_slug": null, "state": "sodium-free buffer"}]} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Human DAT binding assay, sodium-free buffer +/- 10 micromolar zinc; not dietary sodium deficiency or a supplement interaction.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
Adding 10 micromolar zinc in sodium-free binding buffer did not significantly improve modafinil affinity for DAT: Ki approximately 2.96 versus 3.47 micromolar.
primary_references
The atypical stimulant and nootropic modafinil interacts with the dopamine transporter in a different manner than classical cocaine-like inhibitors. | 2011 | DOI 10.1371/journal.pone.0025790 | PMID 22043293 | https://pmc.ncbi.nlm.nih.gov/articles/PMC3197159/ | https://pubmed.ncbi.nlm.nih.gov/22043293/
source_locator
Reviewed reference lines 56-56; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 56–56
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Human DAT binding assay, sodium-free buffer +/- 10 micromolar zinc; not dietary sodium deficiency or a supplement interaction. · Recorded from source · Recorded from source
A useful **direct nutrient–drug comparison** is contained in that study: in sodium-free binding buffer, adding **10 µM zinc** increased cocaine/methylphenidate binding affinity, but did not significantly improve modafinil affinity. Modafinil Kᵢ was approximately 2.96 µM without zinc and 3.47 µM with it. This is a combined ion-condition experiment, not proof that dietary zinc enhances modafinil or that zinc never affects its response in vivo. Sodium removal is also an assay manipulation, not a model of ordinary dietary sodium deficiency. [Table 2 and methods](https://pmc.ncbi.nlm.nih.gov/articles/PMC3197159/)
Complete structured claim and evidence
s-mk-26 was among the more slowly dissociating modafinil analogues in the 2026 DAT-current-recovery experiments; plasma persistence and target residence are separate.
S-MK-26 modafinil analogue → Human dopamine transporter / DAT / SLC6A3 Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary abstract and publisher experimental procedures, results and discussion inspected; no supplementary-data reanalysis.
experimental_model
DAT-current recovery after inhibitor removal; transporter construct details remain in primary paper, not asserted as human clinical kinetics.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
s-mk-26 was among the more slowly dissociating modafinil analogues in the 2026 DAT-current-recovery experiments; plasma persistence and target residence are separate.
primary_references
Optimizing cognitive enhancement through dopamine transporter modulation. | 2026 | DOI 10.1016/j.neuropharm.2026.110969 | PMID 41980668 | https://doi.org/10.1016/j.neuropharm.2026.110969
source_locator
Reviewed reference lines 67-67; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 67–67
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · DAT-current recovery after inhibitor removal; transporter construct details remain in primary paper, not asserted as human clinical kinetics. · Recorded from source · Recorded from source
**A 2026 update adds actual binding-kinetic experiments.** Investigators measured DAT-current recovery after inhibitor removal, compared R-modafinil with analogues, and studied dopamine dynamics and cognition in rats. More slowly dissociating analogues such as S-MK-26 and (S,S)-CE-158 performed better on selected outcomes, including tasks impaired by scopolamine. Brain exposure also differed. The findings support investigating residence time, but do not isolate it from every pharmacokinetic difference or show that marketed modafinil has no abuse liability. Findings from these analogues belong to their own records. [Niello et al., 2026](https://doi.org/10.1016/j.neuropharm.2026.110969)
Complete structured claim and evidence
More slowly dissociating analogues including s-mk-26 performed better on selected rat cognitive outcomes, including scopolamine-impaired tasks; brain exposure also differed.
S-MK-26 modafinil analogue → Rat cognitive responses to modafinil analogues Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary abstract and publisher experimental procedures, results and discussion inspected; no supplementary-data reanalysis.
experimental_contrast
{"intervention": "Tested analogue", "comparator": "Study comparator", "endpoint": "More slowly dissociating analogues including s-mk-26 performed better on selected rat cognitive outcomes, including scopolamine-impaired tasks; brain exposure also differed.", "effect_direction": "mixed", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Rat cognition, analogue exposure and dopamine experiments; residence-time causality not isolated.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
More slowly dissociating analogues including s-mk-26 performed better on selected rat cognitive outcomes, including scopolamine-impaired tasks; brain exposure also differed.
primary_references
Optimizing cognitive enhancement through dopamine transporter modulation. | 2026 | DOI 10.1016/j.neuropharm.2026.110969 | PMID 41980668 | https://doi.org/10.1016/j.neuropharm.2026.110969
source_locator
Reviewed reference lines 67-67; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 67–67
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Rat cognition, analogue exposure and dopamine experiments; residence-time causality not isolated. · Recorded from source · Recorded from source
**A 2026 update adds actual binding-kinetic experiments.** Investigators measured DAT-current recovery after inhibitor removal, compared R-modafinil with analogues, and studied dopamine dynamics and cognition in rats. More slowly dissociating analogues such as S-MK-26 and (S,S)-CE-158 performed better on selected outcomes, including tasks impaired by scopolamine. Brain exposure also differed. The findings support investigating residence time, but do not isolate it from every pharmacokinetic difference or show that marketed modafinil has no abuse liability. Findings from these analogues belong to their own records. [Niello et al., 2026](https://doi.org/10.1016/j.neuropharm.2026.110969)
Complete structured claim and evidence
ss-ce-158 was among the more slowly dissociating modafinil analogues in the 2026 DAT-current-recovery experiments; plasma persistence and target residence are separate.
(S,S)-CE-158 modafinil analogue → Human dopamine transporter / DAT / SLC6A3 Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary abstract and publisher experimental procedures, results and discussion inspected; no supplementary-data reanalysis.
experimental_model
DAT-current recovery after inhibitor removal; transporter construct details remain in primary paper, not asserted as human clinical kinetics.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
ss-ce-158 was among the more slowly dissociating modafinil analogues in the 2026 DAT-current-recovery experiments; plasma persistence and target residence are separate.
primary_references
Optimizing cognitive enhancement through dopamine transporter modulation. | 2026 | DOI 10.1016/j.neuropharm.2026.110969 | PMID 41980668 | https://doi.org/10.1016/j.neuropharm.2026.110969
source_locator
Reviewed reference lines 67-67; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 67–67
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · DAT-current recovery after inhibitor removal; transporter construct details remain in primary paper, not asserted as human clinical kinetics. · Recorded from source · Recorded from source
**A 2026 update adds actual binding-kinetic experiments.** Investigators measured DAT-current recovery after inhibitor removal, compared R-modafinil with analogues, and studied dopamine dynamics and cognition in rats. More slowly dissociating analogues such as S-MK-26 and (S,S)-CE-158 performed better on selected outcomes, including tasks impaired by scopolamine. Brain exposure also differed. The findings support investigating residence time, but do not isolate it from every pharmacokinetic difference or show that marketed modafinil has no abuse liability. Findings from these analogues belong to their own records. [Niello et al., 2026](https://doi.org/10.1016/j.neuropharm.2026.110969)
Complete structured claim and evidence
More slowly dissociating analogues including ss-ce-158 performed better on selected rat cognitive outcomes, including scopolamine-impaired tasks; brain exposure also differed.
(S,S)-CE-158 modafinil analogue → Rat cognitive responses to modafinil analogues Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary abstract and publisher experimental procedures, results and discussion inspected; no supplementary-data reanalysis.
experimental_contrast
{"intervention": "Tested analogue", "comparator": "Study comparator", "endpoint": "More slowly dissociating analogues including ss-ce-158 performed better on selected rat cognitive outcomes, including scopolamine-impaired tasks; brain exposure also differed.", "effect_direction": "mixed", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Rat cognition, analogue exposure and dopamine experiments; residence-time causality not isolated.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
More slowly dissociating analogues including ss-ce-158 performed better on selected rat cognitive outcomes, including scopolamine-impaired tasks; brain exposure also differed.
primary_references
Optimizing cognitive enhancement through dopamine transporter modulation. | 2026 | DOI 10.1016/j.neuropharm.2026.110969 | PMID 41980668 | https://doi.org/10.1016/j.neuropharm.2026.110969
source_locator
Reviewed reference lines 67-67; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 67–67
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Rat cognition, analogue exposure and dopamine experiments; residence-time causality not isolated. · Recorded from source · Recorded from source
**A 2026 update adds actual binding-kinetic experiments.** Investigators measured DAT-current recovery after inhibitor removal, compared R-modafinil with analogues, and studied dopamine dynamics and cognition in rats. More slowly dissociating analogues such as S-MK-26 and (S,S)-CE-158 performed better on selected outcomes, including tasks impaired by scopolamine. Brain exposure also differed. The findings support investigating residence time, but do not isolate it from every pharmacokinetic difference or show that marketed modafinil has no abuse liability. Findings from these analogues belong to their own records. [Niello et al., 2026](https://doi.org/10.1016/j.neuropharm.2026.110969)
Complete structured claim and evidence
D2 receptor deletion reduced modafinil-induced wakefulness in mice; D1-like antagonist addition abolished the residual response.
Mouse dopamine D2 receptor / Drd2 → Mouse wake duration Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary indexed abstract checked; full methods and figures not comprehensively reviewed.
experimental_condition
Wild-type modafinil exposure drug exposure · Modafinil Condition belongs to the full experimental contrast; do not separate a joint intervention.
experimental_condition
Wild-type modafinil exposure deletion · Mouse dopamine D2 receptor / Drd2 Condition belongs to the full experimental contrast; do not separate a joint intervention.
experimental_contrast
{"intervention": "D2 deletion during modafinil exposure", "comparator": "Wild-type modafinil exposure", "endpoint": "D2 receptor deletion reduced modafinil-induced wakefulness in mice; D1-like antagonist addition abolished the residual response.", "effect_direction": "decrease", "combination": "joint", "conditions": [{"entity_slug": "mouse-drd2", "state": "deletion"}, {"entity_slug": "modafinil", "state": "drug exposure"}]} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Mouse receptor knockout and pharmacology; antagonist effects varied with modafinil dose.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
D2 receptor deletion reduced modafinil-induced wakefulness in mice; D1-like antagonist addition abolished the residual response.
primary_references
Dopaminergic D1 and D2 receptors are essential for the arousal effect of modafinil. | 2008 | DOI 10.1523/jneurosci.1819-08.2008 | PMID 18716204 | https://pubmed.ncbi.nlm.nih.gov/18716204/
source_locator
Reviewed reference lines 73-73; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 73–73
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Mouse receptor knockout and pharmacology; antagonist effects varied with modafinil dose. · Recorded from source · Recorded from source
In mice, D2-receptor deletion reduced modafinil-induced wakefulness. Adding a D1-like antagonist abolished the remaining response. In wild-type mice, antagonist effects depended on modafinil dose. This supports dopamine-receptor involvement, not one fixed D1/D2 contribution across exposures. Pharmacological receptor-family blockade should not automatically become proof of a unique receptor subtype or anatomical location. [Qu et al., 2008](https://pubmed.ncbi.nlm.nih.gov/18716204/)
Complete structured claim and evidence
Histamine-neuron ablation or acute chemogenetic inhibition shortened, but did not abolish, modafinil-induced wakefulness in mice.
Mouse histamine-producing neurons → Mouse wake duration Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Full XML obtained; relevant results/methods inspected. Not exhaustive reanalysis of figures or data.
experimental_condition
Modafinil with intact neurons ablated or inhibited · Mouse histamine-producing neurons Condition belongs to the full experimental contrast; do not separate a joint intervention.
experimental_condition
Modafinil with intact neurons drug challenge · Modafinil Condition belongs to the full experimental contrast; do not separate a joint intervention.
experimental_contrast
{"intervention": "Histamine-neuron ablation/inhibition plus modafinil", "comparator": "Modafinil with intact neurons", "endpoint": "Histamine-neuron ablation or acute chemogenetic inhibition shortened, but did not abolish, modafinil-induced wakefulness in mice.", "effect_direction": "decrease", "combination": "joint", "conditions": [{"entity_slug": "mouse-histamine-neurons", "state": "ablated or inhibited"}, {"entity_slug": "modafinil", "state": "drug challenge"}]} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Mouse genetic and chemogenetic experiments; cell dependency not direct drug binding.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
Histamine-neuron ablation or acute chemogenetic inhibition shortened, but did not abolish, modafinil-induced wakefulness in mice.
primary_references
Genetic lesioning of histamine neurons increases sleep-wake fragmentation and reveals their contribution to modafinil-induced wakefulness. | 2019 | DOI 10.1093/sleep/zsz031 | PMID 30722053 | https://pmc.ncbi.nlm.nih.gov/articles/PMC6519916/
source_locator
Reviewed reference lines 79-79; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 79–79
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Mouse genetic and chemogenetic experiments; cell dependency not direct drug binding. · Recorded from source · Recorded from source
Genetic removal or acute chemogenetic inhibition of histamine neurons shortened modafinil-induced waking in mice rather than abolishing it. Histamine-neuron activity therefore contributes to sustained wakefulness in that setting, without being established as the direct drug target. Recovery sleep still showed increased NREM delta power, including after histamine-neuron ablation: a homeostatic response persisted. [Histamine-neuron study, 2019](https://pmc.ncbi.nlm.nih.gov/articles/PMC6519916/)
Complete structured claim and evidence
Recovery sleep showed increased NREM delta power after modafinil, including after histamine-neuron ablation; prolonged waking did not remove this homeostatic response.
Modafinil → Mouse recovery-sleep NREM delta power Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Full XML obtained; relevant results/methods inspected. Not exhaustive reanalysis of figures or data.
experimental_contrast
{"intervention": "Post-modafinil recovery sleep", "comparator": "Study baseline/control", "endpoint": "Recovery sleep showed increased NREM delta power after modafinil, including after histamine-neuron ablation; prolonged waking did not remove this homeostatic response.", "effect_direction": "increase", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Mouse recovery sleep; intact and histamine-neuron-ablated conditions.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
Recovery sleep showed increased NREM delta power after modafinil, including after histamine-neuron ablation; prolonged waking did not remove this homeostatic response.
primary_references
Genetic lesioning of histamine neurons increases sleep-wake fragmentation and reveals their contribution to modafinil-induced wakefulness. | 2019 | DOI 10.1093/sleep/zsz031 | PMID 30722053 | https://pmc.ncbi.nlm.nih.gov/articles/PMC6519916/
source_locator
Reviewed reference lines 79-79; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 79–79
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Mouse recovery sleep; intact and histamine-neuron-ablated conditions. · Recorded from source · Recorded from source
Genetic removal or acute chemogenetic inhibition of histamine neurons shortened modafinil-induced waking in mice rather than abolishing it. Histamine-neuron activity therefore contributes to sustained wakefulness in that setting, without being established as the direct drug target. Recovery sleep still showed increased NREM delta power, including after histamine-neuron ablation: a homeostatic response persisted. [Histamine-neuron study, 2019](https://pmc.ncbi.nlm.nih.gov/articles/PMC6519916/)
Complete structured claim and evidence
Orexin-null mice retained and in one experiment showed greater wake prolongation after modafinil.
Modafinil → Mouse wake duration Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary indexed abstract checked; full methods and figures not comprehensively reviewed.
experimental_contrast
{"intervention": "Modafinil in orexin-null mice", "comparator": "Matched control and wild-type response", "endpoint": "Orexin-null mice retained and in one experiment showed greater wake prolongation after modafinil.", "effect_direction": "increase", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Orexin-null versus wild-type mice; genetic loss not dietary deficit.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
Orexin-null mice retained and in one experiment showed greater wake prolongation after modafinil.
primary_references
Modafinil more effectively induces wakefulness in orexin-null mice than in wild-type littermates. | 2005 | DOI 10.1016/j.neuroscience.2004.10.005 | PMID 15652995 | https://pubmed.ncbi.nlm.nih.gov/15652995/
source_locator
Reviewed reference lines 81-81; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 81–81
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Orexin-null versus wild-type mice; genetic loss not dietary deficit. · Recorded from source · Recorded from source
Orexin-null mice retained—and in one experiment showed greater—wake prolongation after modafinil. However, direct wake-to-REM transitions were not suppressed, and an EEG correlate of alertness was only partly restored. Thus, **wake duration, cataplexy-related phenomena and quality of alertness are separable**. An intact orexin system was unnecessary for one endpoint, not irrelevant to every endpoint. [Orexin-null experiment](https://pubmed.ncbi.nlm.nih.gov/15652995/)
Complete structured claim and evidence
Modafinil did not suppress direct wake-to-REM transitions in the orexin-null mouse experiment despite prolonged waking.
Modafinil → Mouse direct wake-to-REM transitions Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary indexed abstract checked; full methods and figures not comprehensively reviewed.
experimental_contrast
{"intervention": "Modafinil in orexin-null mice", "comparator": "Matched orexin-null control", "endpoint": "Modafinil did not suppress direct wake-to-REM transitions in the orexin-null mouse experiment despite prolonged waking.", "effect_direction": "no_detected_change", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Orexin-null mice; wake duration, direct REM transitions and EEG alertness differ.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
Modafinil did not suppress direct wake-to-REM transitions in the orexin-null mouse experiment despite prolonged waking.
primary_references
Modafinil more effectively induces wakefulness in orexin-null mice than in wild-type littermates. | 2005 | DOI 10.1016/j.neuroscience.2004.10.005 | PMID 15652995 | https://pubmed.ncbi.nlm.nih.gov/15652995/
source_locator
Reviewed reference lines 81-81; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 81–81
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Orexin-null mice; wake duration, direct REM transitions and EEG alertness differ. · Recorded from source · Recorded from source
Orexin-null mice retained—and in one experiment showed greater—wake prolongation after modafinil. However, direct wake-to-REM transitions were not suppressed, and an EEG correlate of alertness was only partly restored. Thus, **wake duration, cataplexy-related phenomena and quality of alertness are separable**. An intact orexin system was unnecessary for one endpoint, not irrelevant to every endpoint. [Orexin-null experiment](https://pubmed.ncbi.nlm.nih.gov/15652995/)
Complete structured claim and evidence
Modafinil inhibited dopamine uptake more potently than norepinephrine uptake in the human-transporter assays.
Modafinil → Human dopamine transporter / DAT / SLC6A3 Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary indexed abstract checked; full methods and figures not comprehensively reviewed.
experimental_contrast
{"intervention": "Modafinil concentration series", "comparator": "Assay control", "endpoint": "Modafinil inhibited dopamine uptake more potently than norepinephrine uptake in the human-transporter assays.", "effect_direction": "decrease", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Human-transporter cell assays; monkey intravenous PET is a separate experiment, not proof of oral-human NET contribution.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
Modafinil inhibited dopamine uptake more potently than norepinephrine uptake in the human-transporter assays.
primary_references
Modafinil occupies dopamine and norepinephrine transporters in vivo and modulates the transporters and trace amine activity in vitro. | 2006 | DOI 10.1124/jpet.106.106583 | PMID 16885432 | https://pubmed.ncbi.nlm.nih.gov/16885432/
source_locator
Reviewed reference lines 85-85; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 85–85
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Human-transporter cell assays; monkey intravenous PET is a separate experiment, not proof of oral-human NET contribution. · Recorded from source · Recorded from source
A rhesus-monkey PET study detected both DAT and NET occupancy after intravenous modafinil. In human-transporter cell assays, dopamine uptake was inhibited more potently than norepinephrine uptake; serotonin uptake inhibition was much weaker. The same work found no direct TAAR1 activation, but altered phenethylamine responses when TAAR1 was coexpressed with particular transporters. This distinguishes **direct receptor agonism from transporter-dependent modulation**. Monkey intravenous target engagement does not establish the contribution of human NET at oral therapeutic exposure. [Madras et al., 2006](https://pubmed.ncbi.nlm.nih.gov/16885432/)
Complete structured claim and evidence
Modafinil inhibited norepinephrine uptake less potently than dopamine uptake in human-transporter assays; rhesus intravenous PET detected NET engagement.
Modafinil → Human norepinephrine transporter / NET / SLC6A2 Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary indexed abstract checked; full methods and figures not comprehensively reviewed.
experimental_contrast
{"intervention": "Modafinil concentration series", "comparator": "Assay control", "endpoint": "Modafinil inhibited norepinephrine uptake less potently than dopamine uptake in human-transporter assays; rhesus intravenous PET detected NET engagement.", "effect_direction": "decrease", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Human-transporter cell assays; monkey intravenous PET is a separate experiment, not proof of oral-human NET contribution.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
Modafinil inhibited norepinephrine uptake less potently than dopamine uptake in human-transporter assays; rhesus intravenous PET detected NET engagement.
primary_references
Modafinil occupies dopamine and norepinephrine transporters in vivo and modulates the transporters and trace amine activity in vitro. | 2006 | DOI 10.1124/jpet.106.106583 | PMID 16885432 | https://pubmed.ncbi.nlm.nih.gov/16885432/
source_locator
Reviewed reference lines 85-85; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 85–85
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Human-transporter cell assays; monkey intravenous PET is a separate experiment, not proof of oral-human NET contribution. · Recorded from source · Recorded from source
A rhesus-monkey PET study detected both DAT and NET occupancy after intravenous modafinil. In human-transporter cell assays, dopamine uptake was inhibited more potently than norepinephrine uptake; serotonin uptake inhibition was much weaker. The same work found no direct TAAR1 activation, but altered phenethylamine responses when TAAR1 was coexpressed with particular transporters. This distinguishes **direct receptor agonism from transporter-dependent modulation**. Monkey intravenous target engagement does not establish the contribution of human NET at oral therapeutic exposure. [Madras et al., 2006](https://pubmed.ncbi.nlm.nih.gov/16885432/)
Complete structured claim and evidence
Serotonin uptake inhibition was much weaker than dopamine and norepinephrine uptake inhibition in the tested human-transporter assays.
Modafinil → Human serotonin transporter SERT / SLC6A4 Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary indexed abstract checked; full methods and figures not comprehensively reviewed.
experimental_contrast
{"intervention": "Modafinil concentration series", "comparator": "Assay control", "endpoint": "Serotonin uptake inhibition was much weaker than dopamine and norepinephrine uptake inhibition in the tested human-transporter assays.", "effect_direction": "decrease", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Human-transporter cell assays; monkey intravenous PET is a separate experiment, not proof of oral-human NET contribution.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
Serotonin uptake inhibition was much weaker than dopamine and norepinephrine uptake inhibition in the tested human-transporter assays.
primary_references
Modafinil occupies dopamine and norepinephrine transporters in vivo and modulates the transporters and trace amine activity in vitro. | 2006 | DOI 10.1124/jpet.106.106583 | PMID 16885432 | https://pubmed.ncbi.nlm.nih.gov/16885432/
source_locator
Reviewed reference lines 85-85; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 85–85
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Human-transporter cell assays; monkey intravenous PET is a separate experiment, not proof of oral-human NET contribution. · Recorded from source · Recorded from source
A rhesus-monkey PET study detected both DAT and NET occupancy after intravenous modafinil. In human-transporter cell assays, dopamine uptake was inhibited more potently than norepinephrine uptake; serotonin uptake inhibition was much weaker. The same work found no direct TAAR1 activation, but altered phenethylamine responses when TAAR1 was coexpressed with particular transporters. This distinguishes **direct receptor agonism from transporter-dependent modulation**. Monkey intravenous target engagement does not establish the contribution of human NET at oral therapeutic exposure. [Madras et al., 2006](https://pubmed.ncbi.nlm.nih.gov/16885432/)
Complete structured claim and evidence
Modafinil did not directly activate TAAR1 but changed phenethylamine responses with particular coexpressed transporters.
Modafinil → TAAR1 receptor activation assay Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary indexed abstract checked; full methods and figures not comprehensively reviewed.
experimental_contrast
{"intervention": "Modafinil alone or with phenethylamine/transporter coexpression", "comparator": "Corresponding receptor-only/ligand controls", "endpoint": "Modafinil did not directly activate TAAR1 but changed phenethylamine responses with particular coexpressed transporters.", "effect_direction": "mixed", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Receptor/transporter coexpression assays; direct agonism separated from transporter-dependent modulation.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
Modafinil did not directly activate TAAR1 but changed phenethylamine responses with particular coexpressed transporters.
primary_references
Modafinil occupies dopamine and norepinephrine transporters in vivo and modulates the transporters and trace amine activity in vitro. | 2006 | DOI 10.1124/jpet.106.106583 | PMID 16885432 | https://pubmed.ncbi.nlm.nih.gov/16885432/
source_locator
Reviewed reference lines 85-85; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 85–85
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Receptor/transporter coexpression assays; direct agonism separated from transporter-dependent modulation. · Recorded from source · Recorded from source
A rhesus-monkey PET study detected both DAT and NET occupancy after intravenous modafinil. In human-transporter cell assays, dopamine uptake was inhibited more potently than norepinephrine uptake; serotonin uptake inhibition was much weaker. The same work found no direct TAAR1 activation, but altered phenethylamine responses when TAAR1 was coexpressed with particular transporters. This distinguishes **direct receptor agonism from transporter-dependent modulation**. Monkey intravenous target engagement does not establish the contribution of human NET at oral therapeutic exposure. [Madras et al., 2006](https://pubmed.ncbi.nlm.nih.gov/16885432/)
Complete structured claim and evidence
DSP-4 removal of forebrain noradrenergic projections did not eliminate modafinil wake promotion, while an adrenergic antagonist still suppressed it.
Mouse forebrain noradrenergic projections → Mouse wake duration Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary indexed abstract checked; full methods and figures not comprehensively reviewed.
experimental_contrast
{"intervention": "Noradrenergic projection lesion plus modafinil", "comparator": "Modafinil without lesion", "endpoint": "DSP-4 removal of forebrain noradrenergic projections did not eliminate modafinil wake promotion, while an adrenergic antagonist still suppressed it.", "effect_direction": "no_detected_change", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Mouse pharmacological lesion experiment; adrenergic involvement does not require a simple obligatory projection relay.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
DSP-4 removal of forebrain noradrenergic projections did not eliminate modafinil wake promotion, while an adrenergic antagonist still suppressed it.
primary_references
Dopaminergic-adrenergic interactions in the wake promoting mechanism of modafinil. | 2005 | DOI 10.1016/j.neuroscience.2005.02.003 | PMID 15857707 | https://pubmed.ncbi.nlm.nih.gov/15857707/
source_locator
Reviewed reference lines 87-87; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 87–87
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Mouse pharmacological lesion experiment; adrenergic involvement does not require a simple obligatory projection relay. · Recorded from source · Recorded from source
In mice, removing forebrain noradrenergic projections with DSP-4 did not eliminate wake promotion, whereas an adrenergic antagonist still suppressed it. The interpretation involved dopamine–adrenergic interactions; the result prevents treating an intact locus-coeruleus projection as an obligatory relay. [2005 intervention study](https://pubmed.ncbi.nlm.nih.gov/15857707/)
Complete structured claim and evidence
Prazosin antagonized modafinil improvement in planning accuracy in a 12-man crossover trial.
Prazosin → Human planning-task accuracy Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary indexed abstract checked; full methods and figures not comprehensively reviewed.
experimental_condition
Modafinil condition alpha1-antagonist exposure · Prazosin Condition belongs to the full experimental contrast; do not separate a joint intervention.
experimental_condition
Modafinil condition joint exposure · Modafinil Condition belongs to the full experimental contrast; do not separate a joint intervention.
experimental_contrast
{"intervention": "Prazosin plus modafinil", "comparator": "Modafinil condition", "endpoint": "Prazosin antagonized modafinil improvement in planning accuracy in a 12-man crossover trial.", "effect_direction": "decrease", "combination": "joint", "conditions": [{"entity_slug": "prazosin", "state": "alpha1-antagonist exposure"}, {"entity_slug": "modafinil", "state": "joint exposure"}]} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Twelve-man crossover trial; drug combination, selected task endpoints; no direct modafinil alpha1-binding conclusion.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
Prazosin antagonized modafinil improvement in planning accuracy in a 12-man crossover trial.
primary_references
Effects of modafinil and prazosin on cognitive and physiological functions in healthy volunteers. | 2010 | DOI 10.1177/0269881109105899 | PMID 19493958 | https://pubmed.ncbi.nlm.nih.gov/19493958/
source_locator
Reviewed reference lines 89-89; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 89–89
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Twelve-man crossover trial; drug combination, selected task endpoints; no direct modafinil alpha1-binding conclusion. · Recorded from source · Recorded from source
There is also **human experimental evidence**, omitted from the supplied account. In a 12-man crossover trial, prazosin antagonized modafinil's improvement in planning accuracy. The combined drugs nevertheless increased completion time and potentiated some physiological responses. Accuracy, speed and autonomic effects therefore cannot be represented by one shared sign. This supports an α1-associated contribution to selected cognitive effects, not direct binding of modafinil to α1 receptors. [Prazosin/modafinil trial](https://pubmed.ncbi.nlm.nih.gov/19493958/)
Complete structured claim and evidence
Combined prazosin and modafinil increased planning-task completion time in the human crossover trial.
Prazosin → Human task completion time Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary indexed abstract checked; full methods and figures not comprehensively reviewed.
experimental_condition
Modafinil condition alpha1-antagonist exposure · Prazosin Condition belongs to the full experimental contrast; do not separate a joint intervention.
experimental_condition
Modafinil condition joint exposure · Modafinil Condition belongs to the full experimental contrast; do not separate a joint intervention.
experimental_contrast
{"intervention": "Prazosin plus modafinil", "comparator": "Modafinil condition", "endpoint": "Combined prazosin and modafinil increased planning-task completion time in the human crossover trial.", "effect_direction": "increase", "combination": "joint", "conditions": [{"entity_slug": "prazosin", "state": "alpha1-antagonist exposure"}, {"entity_slug": "modafinil", "state": "joint exposure"}]} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Twelve-man crossover trial; drug combination, selected task endpoints; no direct modafinil alpha1-binding conclusion.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
Combined prazosin and modafinil increased planning-task completion time in the human crossover trial.
primary_references
Effects of modafinil and prazosin on cognitive and physiological functions in healthy volunteers. | 2010 | DOI 10.1177/0269881109105899 | PMID 19493958 | https://pubmed.ncbi.nlm.nih.gov/19493958/
source_locator
Reviewed reference lines 89-89; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 89–89
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Twelve-man crossover trial; drug combination, selected task endpoints; no direct modafinil alpha1-binding conclusion. · Recorded from source · Recorded from source
There is also **human experimental evidence**, omitted from the supplied account. In a 12-man crossover trial, prazosin antagonized modafinil's improvement in planning accuracy. The combined drugs nevertheless increased completion time and potentiated some physiological responses. Accuracy, speed and autonomic effects therefore cannot be represented by one shared sign. This supports an α1-associated contribution to selected cognitive effects, not direct binding of modafinil to α1 receptors. [Prazosin/modafinil trial](https://pubmed.ncbi.nlm.nih.gov/19493958/)
Complete structured claim and evidence
At 100 mg/kg, modafinil lowered extracellular GABA in rat striatum/pallidum.
Modafinil → Rat regional extracellular GABA Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary indexed abstract checked; full methods and figures not comprehensively reviewed.
experimental_contrast
{"intervention": "Modafinil 100 mg/kg", "comparator": "Study control", "endpoint": "At 100 mg/kg, modafinil lowered extracellular GABA in rat striatum/pallidum.", "effect_direction": "decrease", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Rat regional microdialysis; 100 mg/kg pharmacological exposure, not human therapeutic equivalence.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
At 100 mg/kg, modafinil lowered extracellular GABA in rat striatum/pallidum.
primary_references
The effects of modafinil on striatal, pallidal and nigral GABA and glutamate release in the conscious rat: evidence for a preferential inhibition of striato-pallidal GABA transmission. | 1998 | DOI 10.1016/s0304-3940(98)00629-6 | PMID 9774168 | https://pubmed.ncbi.nlm.nih.gov/9774168/
source_locator
Reviewed reference lines 95-95; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 95–95
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Rat regional microdialysis; 100 mg/kg pharmacological exposure, not human therapeutic equivalence. · Recorded from source · Recorded from source
| GABA and glutamate | Rat microdialysis found lower striatal/pallidal GABA at 100 mg/kg, without local glutamate increases. At 300 mg/kg, glutamate rose in striatum but not pallidum; substantia nigra had another response pattern. | Global GABA suppression, global glutamate elevation, direct GABA-receptor antagonism or glutamate-receptor agonism. [1998 study](https://pubmed.ncbi.nlm.nih.gov/9774168/) |
Complete structured claim and evidence
At 100 mg/kg, modafinil did not increase extracellular glutamate in rat striatum/pallidum.
Modafinil → Rat regional extracellular glutamate Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary indexed abstract checked; full methods and figures not comprehensively reviewed.
experimental_contrast
{"intervention": "Modafinil 100 mg/kg", "comparator": "Study control", "endpoint": "At 100 mg/kg, modafinil did not increase extracellular glutamate in rat striatum/pallidum.", "effect_direction": "no_detected_change", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Rat regional microdialysis; 100 mg/kg pharmacological exposure, not human therapeutic equivalence.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
At 100 mg/kg, modafinil did not increase extracellular glutamate in rat striatum/pallidum.
primary_references
The effects of modafinil on striatal, pallidal and nigral GABA and glutamate release in the conscious rat: evidence for a preferential inhibition of striato-pallidal GABA transmission. | 1998 | DOI 10.1016/s0304-3940(98)00629-6 | PMID 9774168 | https://pubmed.ncbi.nlm.nih.gov/9774168/
source_locator
Reviewed reference lines 95-95; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 95–95
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Rat regional microdialysis; 100 mg/kg pharmacological exposure, not human therapeutic equivalence. · Recorded from source · Recorded from source
| GABA and glutamate | Rat microdialysis found lower striatal/pallidal GABA at 100 mg/kg, without local glutamate increases. At 300 mg/kg, glutamate rose in striatum but not pallidum; substantia nigra had another response pattern. | Global GABA suppression, global glutamate elevation, direct GABA-receptor antagonism or glutamate-receptor agonism. [1998 study](https://pubmed.ncbi.nlm.nih.gov/9774168/) |
Complete structured claim and evidence
At 300 mg/kg, modafinil increased striatal glutamate but not pallidal glutamate; substantia nigra had another response pattern.
Modafinil → Rat regional extracellular glutamate Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary indexed abstract checked; full methods and figures not comprehensively reviewed.
experimental_contrast
{"intervention": "Modafinil 300 mg/kg", "comparator": "Study control", "endpoint": "At 300 mg/kg, modafinil increased striatal glutamate but not pallidal glutamate; substantia nigra had another response pattern.", "effect_direction": "mixed", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Rat regional microdialysis; 300 mg/kg pharmacological exposure, not human therapeutic equivalence.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
At 300 mg/kg, modafinil increased striatal glutamate but not pallidal glutamate; substantia nigra had another response pattern.
primary_references
The effects of modafinil on striatal, pallidal and nigral GABA and glutamate release in the conscious rat: evidence for a preferential inhibition of striato-pallidal GABA transmission. | 1998 | DOI 10.1016/s0304-3940(98)00629-6 | PMID 9774168 | https://pubmed.ncbi.nlm.nih.gov/9774168/
source_locator
Reviewed reference lines 95-95; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 95–95
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Rat regional microdialysis; 300 mg/kg pharmacological exposure, not human therapeutic equivalence. · Recorded from source · Recorded from source
| GABA and glutamate | Rat microdialysis found lower striatal/pallidal GABA at 100 mg/kg, without local glutamate increases. At 300 mg/kg, glutamate rose in striatum but not pallidum; substantia nigra had another response pattern. | Global GABA suppression, global glutamate elevation, direct GABA-receptor antagonism or glutamate-receptor agonism. [1998 study](https://pubmed.ncbi.nlm.nih.gov/9774168/) |
Complete structured claim and evidence
Modafinil increased extracellular serotonin in cortex, amygdala and dorsal raphe at lower doses than required in medial preoptic/posterior hypothalamic regions.
Modafinil → Rat regional extracellular serotonin Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary indexed abstract checked; full methods and figures not comprehensively reviewed.
experimental_contrast
{"intervention": "Modafinil", "comparator": "Matched regional baseline/control", "endpoint": "Modafinil increased extracellular serotonin in cortex, amygdala and dorsal raphe at lower doses than required in medial preoptic/posterior hypothalamic regions.", "effect_direction": "increase", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Awake-rat regional microdialysis; regional exposure-response differences.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
Modafinil increased extracellular serotonin in cortex, amygdala and dorsal raphe at lower doses than required in medial preoptic/posterior hypothalamic regions.
primary_references
Differential enhancement of dialysate serotonin levels in distinct brain regions of the awake rat by modafinil: possible relevance for wakefulness and depression. | 2002 | DOI 10.1002/jnr.10196 | PMID 11933055 | https://pubmed.ncbi.nlm.nih.gov/11933055/
source_locator
Reviewed reference lines 96-96; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 96–96
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Awake-rat regional microdialysis; regional exposure-response differences. · Recorded from source · Recorded from source
| Serotonin | In awake rats, extracellular serotonin increased in cortex, amygdala and dorsal raphe at lower tested doses than those needed in medial preoptic/posterior hypothalamic regions. | Uniform serotonin elevation or identification of SERT as the principal clinical target. [2002 study](https://pubmed.ncbi.nlm.nih.gov/11933055/) |
Complete structured claim and evidence
A modafinil dose ineffective alone augmented selected fluoxetine/imipramine serotonin responses, with dose/region-specific null combinations retained.
Modafinil → Rat regional extracellular serotonin Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary indexed abstract checked; full methods and figures not comprehensively reviewed.
experimental_condition
Antidepressant alone and low-dose modafinil alone low dose · Modafinil Condition belongs to the full experimental contrast; do not separate a joint intervention.
experimental_contrast
{"intervention": "Low-dose modafinil plus antidepressant", "comparator": "Antidepressant alone and low-dose modafinil alone", "endpoint": "A modafinil dose ineffective alone augmented selected fluoxetine/imipramine serotonin responses, with dose/region-specific null combinations retained.", "effect_direction": "mixed", "combination": "joint", "conditions": [{"entity_slug": "modafinil", "state": "low dose"}, {"entity_slug": null, "state": "fluoxetine or imipramine at tested dose"}]} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Rat drug-combination microdialysis; no demonstrated human clinical synergy or isolated hepatic mechanism.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
A modafinil dose ineffective alone augmented selected fluoxetine/imipramine serotonin responses, with dose/region-specific null combinations retained.
primary_references
Modafinil enhances the increase of extracellular serotonin levels induced by the antidepressant drugs fluoxetine and imipramine: a dual probe microdialysis study in awake rat. | 2005 | DOI 10.1002/syn.20111 | PMID 15668907 | https://pubmed.ncbi.nlm.nih.gov/15668907/
source_locator
Reviewed reference lines 97-97; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 97–97
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Rat drug-combination microdialysis; no demonstrated human clinical synergy or isolated hepatic mechanism. · Recorded from source · Recorded from source
| Antidepressant coexposure | A low modafinil dose ineffective alone augmented particular fluoxetine/imipramine serotonin responses; effects depended on region and antidepressant dose, with null combinations retained. | A general prescription to combine drugs, a demonstrated human antidepressant synergy, or proof that the effect is solely a hepatic interaction. [2005 rat study](https://pubmed.ncbi.nlm.nih.gov/15668907/) |
Complete structured claim and evidence
Modafinil enhanced coupling between cortical interneurons and inferior-olive neurons; recovery after pharmacological disruption involved a calcium/calmodulin-dependent kinase II-sensitive step.
Modafinil → Experimental neuronal electrical coupling Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary indexed abstract checked; full methods and figures not comprehensively reviewed.
experimental_contrast
{"intervention": "Modafinil", "comparator": "Control/disrupted coupling comparison", "endpoint": "Modafinil enhanced coupling between cortical interneurons and inferior-olive neurons; recovery after pharmacological disruption involved a calcium/calmodulin-dependent kinase II-sensitive step.", "effect_direction": "increase", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Experimental neuronal preparations, pharmacological disruption/recovery; neither direct connexin binding nor human calcium supplementation demonstrated.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
Modafinil enhanced coupling between cortical interneurons and inferior-olive neurons; recovery after pharmacological disruption involved a calcium/calmodulin-dependent kinase II-sensitive step.
primary_references
Modafinil enhances thalamocortical activity by increasing neuronal electrotonic coupling. | 2007 | DOI 10.1073/pnas.0705087104 | PMID 17640897 | https://pubmed.ncbi.nlm.nih.gov/17640897/
source_locator
Reviewed reference lines 98-98; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 98–98
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Experimental neuronal preparations, pharmacological disruption/recovery; neither direct connexin binding nor human calcium supplementation demonstrated. · Recorded from source · Recorded from source
| Electrical coupling | Experimental neuronal preparations showed enhanced coupling between cortical interneurons and inferior-olive neurons; restoration after pharmacological disruption involved a Ca²⁺/calmodulin-dependent kinase II-sensitive step. | Direct binding to connexin, a uniquely identified human wake mechanism, or evidence that calcium supplementation increases benefit. [Urbano et al., 2007](https://pubmed.ncbi.nlm.nih.gov/17640897/) |
Complete structured claim and evidence
In eleven simulated-shift-work volunteers, 200 and 400 mg modafinil reduced caloric intake about 18% and 38%, respectively, across three exposure days.
Modafinil → Caloric intake Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary indexed abstract checked; full methods and figures not comprehensively reviewed.
experimental_contrast
{"intervention": "200 or 400 mg modafinil", "comparator": "Placebo", "endpoint": "In eleven simulated-shift-work volunteers, 200 and 400 mg modafinil reduced caloric intake about 18% and 38%, respectively, across three exposure days.", "effect_direction": "decrease", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Human double-blind simulated shift work; secondary intake analysis; short exposure, not long-term nutritional-deficiency measurement.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
In eleven simulated-shift-work volunteers, 200 and 400 mg modafinil reduced caloric intake about 18% and 38%, respectively, across three exposure days.
primary_references
Modafinil decreases food intake in humans subjected to simulated shift work. | 2008 | DOI 10.1016/j.pbb.2008.05.018 | PMID 18573275 | https://pubmed.ncbi.nlm.nih.gov/18573275/
source_locator
Reviewed reference lines 106-106; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 106–106
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Human double-blind simulated shift work; secondary intake analysis; short exposure, not long-term nutritional-deficiency measurement. · Recorded from source · Recorded from source
In a double-blind simulated-shift-work study of **11 volunteers**, secondary analysis found approximately **18% and 38% lower caloric intake** with 200 and 400 mg modafinil, respectively. The proportions of calories from carbohydrate, fat and protein did not selectively change. Hunger ratings changed only at particular assessments; reduced intake remained across three exposure days. This supports an intake effect under those conditions, not demonstrated vitamin/mineral deficiency or a long-term weight-loss outcome. [Human food-intake study](https://pubmed.ncbi.nlm.nih.gov/18573275/)
Complete structured claim and evidence
Modafinil did not selectively change the carbohydrate, fat and protein proportions of consumed calories in the short human food-intake study.
Modafinil → Human dietary macronutrient calorie proportions Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary indexed abstract checked; full methods and figures not comprehensively reviewed.
experimental_contrast
{"intervention": "200 or 400 mg modafinil", "comparator": "Placebo", "endpoint": "Modafinil did not selectively change the carbohydrate, fat and protein proportions of consumed calories in the short human food-intake study.", "effect_direction": "no_detected_change", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Eleven human volunteers; macronutrient proportions distinct from absolute energy intake.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
Modafinil did not selectively change the carbohydrate, fat and protein proportions of consumed calories in the short human food-intake study.
primary_references
Modafinil decreases food intake in humans subjected to simulated shift work. | 2008 | DOI 10.1016/j.pbb.2008.05.018 | PMID 18573275 | https://pubmed.ncbi.nlm.nih.gov/18573275/
source_locator
Reviewed reference lines 106-106; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 106–106
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Eleven human volunteers; macronutrient proportions distinct from absolute energy intake. · Recorded from source · Recorded from source
In a double-blind simulated-shift-work study of **11 volunteers**, secondary analysis found approximately **18% and 38% lower caloric intake** with 200 and 400 mg modafinil, respectively. The proportions of calories from carbohydrate, fat and protein did not selectively change. Hunger ratings changed only at particular assessments; reduced intake remained across three exposure days. This supports an intake effect under those conditions, not demonstrated vitamin/mineral deficiency or a long-term weight-loss outcome. [Human food-intake study](https://pubmed.ncbi.nlm.nih.gov/18573275/)
Complete structured claim and evidence
Modafinil competitively and reversibly inhibited CYP2C19 in human liver preparations.
Modafinil → Human cytochrome P450 2C19 Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary indexed abstract checked; full methods and figures not comprehensively reviewed.
experimental_contrast
{"intervention": "Modafinil in hepatic assay", "comparator": "Matched vehicle control", "endpoint": "Modafinil competitively and reversibly inhibited CYP2C19 in human liver preparations.", "effect_direction": "decrease", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Human hepatic preparations/hepatocytes; concentration dependence and assay preparation retained in cited study.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
Modafinil competitively and reversibly inhibited CYP2C19 in human liver preparations.
primary_references
In vitro inhibition and induction of human hepatic cytochrome P450 enzymes by modafinil. | 2000 | DOI 10.1016/s0090-9556(24)15146-x | PMID 10820139 | https://pubmed.ncbi.nlm.nih.gov/10820139/
source_locator
Reviewed reference lines 114-114; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 114–114
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Human hepatic preparations/hepatocytes; concentration dependence and assay preparation retained in cited study. · Recorded from source · Recorded from source
In human liver preparations, modafinil competitively/reversibly inhibited CYP2C19 and induced CYP1A2, CYP2B6 and CYP3A activity in hepatocyte cultures. High-concentration CYP2C9 suppression was also reported. These laboratory findings must retain concentration and preparation rather than become universal clinical interaction rules. [Hepatic enzyme experiments](https://pubmed.ncbi.nlm.nih.gov/10820139/)
Complete structured claim and evidence
Modafinil induced CYP1A2 in human hepatocyte cultures; the laboratory result does not establish a large caffeine exposure change in every user.
Modafinil → Human cytochrome P450 1A2 Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary indexed abstract checked; full methods and figures not comprehensively reviewed.
experimental_contrast
{"intervention": "Modafinil in hepatic assay", "comparator": "Matched vehicle control", "endpoint": "Modafinil induced CYP1A2 in human hepatocyte cultures; the laboratory result does not establish a large caffeine exposure change in every user.", "effect_direction": "increase", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Human hepatic preparations/hepatocytes; concentration dependence and assay preparation retained in cited study.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
Modafinil induced CYP1A2 in human hepatocyte cultures; the laboratory result does not establish a large caffeine exposure change in every user.
primary_references
In vitro inhibition and induction of human hepatic cytochrome P450 enzymes by modafinil. | 2000 | DOI 10.1016/s0090-9556(24)15146-x | PMID 10820139 | https://pubmed.ncbi.nlm.nih.gov/10820139/
source_locator
Reviewed reference lines 114-114; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 114–114
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Human hepatic preparations/hepatocytes; concentration dependence and assay preparation retained in cited study. · Recorded from source · Recorded from source
In human liver preparations, modafinil competitively/reversibly inhibited CYP2C19 and induced CYP1A2, CYP2B6 and CYP3A activity in hepatocyte cultures. High-concentration CYP2C9 suppression was also reported. These laboratory findings must retain concentration and preparation rather than become universal clinical interaction rules. [Hepatic enzyme experiments](https://pubmed.ncbi.nlm.nih.gov/10820139/)
Complete structured claim and evidence
Modafinil induced CYP2B6 in human hepatocyte cultures.
Modafinil → Human cytochrome P450 2B6 / CYP2B6 Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary indexed abstract checked; full methods and figures not comprehensively reviewed.
experimental_contrast
{"intervention": "Modafinil in hepatic assay", "comparator": "Matched vehicle control", "endpoint": "Modafinil induced CYP2B6 in human hepatocyte cultures.", "effect_direction": "increase", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Human hepatic preparations/hepatocytes; concentration dependence and assay preparation retained in cited study.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
Modafinil induced CYP2B6 in human hepatocyte cultures.
primary_references
In vitro inhibition and induction of human hepatic cytochrome P450 enzymes by modafinil. | 2000 | DOI 10.1016/s0090-9556(24)15146-x | PMID 10820139 | https://pubmed.ncbi.nlm.nih.gov/10820139/
source_locator
Reviewed reference lines 114-114; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 114–114
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Human hepatic preparations/hepatocytes; concentration dependence and assay preparation retained in cited study. · Recorded from source · Recorded from source
In human liver preparations, modafinil competitively/reversibly inhibited CYP2C19 and induced CYP1A2, CYP2B6 and CYP3A activity in hepatocyte cultures. High-concentration CYP2C9 suppression was also reported. These laboratory findings must retain concentration and preparation rather than become universal clinical interaction rules. [Hepatic enzyme experiments](https://pubmed.ncbi.nlm.nih.gov/10820139/)
Complete structured claim and evidence
Modafinil induced CYP3A activity in human hepatocyte cultures; clinical substrate responses depend on exposure duration.
Modafinil → Human cytochrome P450 3A4 Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary indexed abstract checked; full methods and figures not comprehensively reviewed.
experimental_contrast
{"intervention": "Modafinil in hepatic assay", "comparator": "Matched vehicle control", "endpoint": "Modafinil induced CYP3A activity in human hepatocyte cultures; clinical substrate responses depend on exposure duration.", "effect_direction": "increase", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Human hepatic preparations/hepatocytes; concentration dependence and assay preparation retained in cited study.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
Modafinil induced CYP3A activity in human hepatocyte cultures; clinical substrate responses depend on exposure duration.
primary_references
In vitro inhibition and induction of human hepatic cytochrome P450 enzymes by modafinil. | 2000 | DOI 10.1016/s0090-9556(24)15146-x | PMID 10820139 | https://pubmed.ncbi.nlm.nih.gov/10820139/
source_locator
Reviewed reference lines 114-114; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 114–114
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Human hepatic preparations/hepatocytes; concentration dependence and assay preparation retained in cited study. · Recorded from source · Recorded from source
In human liver preparations, modafinil competitively/reversibly inhibited CYP2C19 and induced CYP1A2, CYP2B6 and CYP3A activity in hepatocyte cultures. High-concentration CYP2C9 suppression was also reported. These laboratory findings must retain concentration and preparation rather than become universal clinical interaction rules. [Hepatic enzyme experiments](https://pubmed.ncbi.nlm.nih.gov/10820139/)
Complete structured claim and evidence
High-concentration modafinil suppressed CYP2C9 in human liver experiments; this is not a universal therapeutic-exposure rule.
Modafinil → Human cytochrome P450 2C9 Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary indexed abstract checked; full methods and figures not comprehensively reviewed.
experimental_contrast
{"intervention": "Modafinil in hepatic assay", "comparator": "Matched vehicle control", "endpoint": "High-concentration modafinil suppressed CYP2C9 in human liver experiments; this is not a universal therapeutic-exposure rule.", "effect_direction": "decrease", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Human hepatic preparations/hepatocytes; concentration dependence and assay preparation retained in cited study.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
High-concentration modafinil suppressed CYP2C9 in human liver experiments; this is not a universal therapeutic-exposure rule.
primary_references
In vitro inhibition and induction of human hepatic cytochrome P450 enzymes by modafinil. | 2000 | DOI 10.1016/s0090-9556(24)15146-x | PMID 10820139 | https://pubmed.ncbi.nlm.nih.gov/10820139/
source_locator
Reviewed reference lines 114-114; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 114–114
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Human hepatic preparations/hepatocytes; concentration dependence and assay preparation retained in cited study. · Recorded from source · Recorded from source
In human liver preparations, modafinil competitively/reversibly inhibited CYP2C19 and induced CYP1A2, CYP2B6 and CYP3A activity in hepatocyte cultures. High-concentration CYP2C9 suppression was also reported. These laboratory findings must retain concentration and preparation rather than become universal clinical interaction rules. [Hepatic enzyme experiments](https://pubmed.ncbi.nlm.nih.gov/10820139/)
Complete structured claim and evidence
In the six-person cocktail study, caffeine AUC ratios after one 200-mg modafinil dose and seven daily doses were 0.95 and 0.88 (Table 4).
Modafinil → Plasma caffeine exposure Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary abstract and PMC methods, Tables 3/4, results and discussion inspected; numerical inconsistency preserved in evidence-notes.json.
experimental_contrast
{"intervention": "Modafinil single dose and seven daily doses", "comparator": "Baseline without modafinil", "endpoint": "In the six-person cocktail study, caffeine AUC ratios after one 200-mg modafinil dose and seven daily doses were 0.95 and 0.88 (Table 4).", "effect_direction": "mixed", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Human repeated-measures pharmacokinetic study, six participants; one 200-mg dose versus seven 200-mg daily doses, each relative to baseline.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
In the six-person cocktail study, caffeine AUC ratios after one 200-mg modafinil dose and seven daily doses were 0.95 and 0.88 (Table 4).
primary_references
Evaluation of modafinil as a perpetrator of metabolic drug-drug interactions using a model informed cocktail reaction phenotyping trial protocol. | 2018 | DOI 10.1111/bcp.13478 | PMID 29178272 | https://pmc.ncbi.nlm.nih.gov/articles/PMC5809348/
source_locator
Reviewed reference lines 116-126; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 116–126
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Human repeated-measures pharmacokinetic study, six participants; one 200-mg dose versus seven 200-mg daily doses, each relative to baseline. · Recorded from source · Recorded from source
The six-participant human cocktail study compared baseline with one 200-mg dose and seven daily doses. **Table 4** reports the following AUC ratios: | Probe | Single dose | Seven doses | |---|---:|---:| | Caffeine | 0.95 | 0.88 | | Dextromethorphan | 0.97 | 0.78 | | Losartan | 0.96 | 0.97 | | Midazolam | 0.97 | 0.65 | | Omeprazole | 1.36 | 1.85 | These support time-dependent CYP3A induction and CYP2C19 inhibition. The abstract's estimates differ slightly; the draft's approximately 34%/90% changes follow the abstract. **Source discrepancy:** the discussion calls the dextromethorphan interval 0.69–0.88 contained within 0.85–1.20. That statement is mathematically false. Retain the measurement and query the analysis; do not promote it directly to proven CYP2D6 induction or a definite null. [Trial, Table 4 and discussion](https://pmc.ncbi.nlm.nih.gov/articles/PMC5809348/)
Complete structured claim and evidence
In the six-person cocktail study, dextromethorphan AUC ratios after one 200-mg modafinil dose and seven daily doses were 0.97 and 0.78 (Table 4). The reported CYP2D6 interval interpretation is internally inconsistent; do not infer enzyme induction from this ratio alone.
Modafinil → Human dextromethorphan plasma AUC Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary abstract and PMC methods, Tables 3/4, results and discussion inspected; numerical inconsistency preserved in evidence-notes.json.
experimental_contrast
{"intervention": "Modafinil single dose and seven daily doses", "comparator": "Baseline without modafinil", "endpoint": "In the six-person cocktail study, dextromethorphan AUC ratios after one 200-mg modafinil dose and seven daily doses were 0.97 and 0.78 (Table 4). The reported CYP2D6 interval interpretation is internally inconsistent; do not infer enzyme induction from this ratio alone.", "effect_direction": "decrease", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Human repeated-measures pharmacokinetic study, six participants; one 200-mg dose versus seven 200-mg daily doses, each relative to baseline.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
In the six-person cocktail study, dextromethorphan AUC ratios after one 200-mg modafinil dose and seven daily doses were 0.97 and 0.78 (Table 4). The reported CYP2D6 interval interpretation is internally inconsistent; do not infer enzyme induction from this ratio alone.
primary_references
Evaluation of modafinil as a perpetrator of metabolic drug-drug interactions using a model informed cocktail reaction phenotyping trial protocol. | 2018 | DOI 10.1111/bcp.13478 | PMID 29178272 | https://pmc.ncbi.nlm.nih.gov/articles/PMC5809348/
source_locator
Reviewed reference lines 116-126; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 116–126
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Human repeated-measures pharmacokinetic study, six participants; one 200-mg dose versus seven 200-mg daily doses, each relative to baseline. · Recorded from source · Recorded from source
The six-participant human cocktail study compared baseline with one 200-mg dose and seven daily doses. **Table 4** reports the following AUC ratios: | Probe | Single dose | Seven doses | |---|---:|---:| | Caffeine | 0.95 | 0.88 | | Dextromethorphan | 0.97 | 0.78 | | Losartan | 0.96 | 0.97 | | Midazolam | 0.97 | 0.65 | | Omeprazole | 1.36 | 1.85 | These support time-dependent CYP3A induction and CYP2C19 inhibition. The abstract's estimates differ slightly; the draft's approximately 34%/90% changes follow the abstract. **Source discrepancy:** the discussion calls the dextromethorphan interval 0.69–0.88 contained within 0.85–1.20. That statement is mathematically false. Retain the measurement and query the analysis; do not promote it directly to proven CYP2D6 induction or a definite null. [Trial, Table 4 and discussion](https://pmc.ncbi.nlm.nih.gov/articles/PMC5809348/)
Complete structured claim and evidence
In the six-person cocktail study, losartan AUC ratios after one 200-mg modafinil dose and seven daily doses were 0.96 and 0.97 (Table 4).
Modafinil → Human losartan plasma AUC Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary abstract and PMC methods, Tables 3/4, results and discussion inspected; numerical inconsistency preserved in evidence-notes.json.
experimental_contrast
{"intervention": "Modafinil single dose and seven daily doses", "comparator": "Baseline without modafinil", "endpoint": "In the six-person cocktail study, losartan AUC ratios after one 200-mg modafinil dose and seven daily doses were 0.96 and 0.97 (Table 4).", "effect_direction": "mixed", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Human repeated-measures pharmacokinetic study, six participants; one 200-mg dose versus seven 200-mg daily doses, each relative to baseline.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
In the six-person cocktail study, losartan AUC ratios after one 200-mg modafinil dose and seven daily doses were 0.96 and 0.97 (Table 4).
primary_references
Evaluation of modafinil as a perpetrator of metabolic drug-drug interactions using a model informed cocktail reaction phenotyping trial protocol. | 2018 | DOI 10.1111/bcp.13478 | PMID 29178272 | https://pmc.ncbi.nlm.nih.gov/articles/PMC5809348/
source_locator
Reviewed reference lines 116-126; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 116–126
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Human repeated-measures pharmacokinetic study, six participants; one 200-mg dose versus seven 200-mg daily doses, each relative to baseline. · Recorded from source · Recorded from source
The six-participant human cocktail study compared baseline with one 200-mg dose and seven daily doses. **Table 4** reports the following AUC ratios: | Probe | Single dose | Seven doses | |---|---:|---:| | Caffeine | 0.95 | 0.88 | | Dextromethorphan | 0.97 | 0.78 | | Losartan | 0.96 | 0.97 | | Midazolam | 0.97 | 0.65 | | Omeprazole | 1.36 | 1.85 | These support time-dependent CYP3A induction and CYP2C19 inhibition. The abstract's estimates differ slightly; the draft's approximately 34%/90% changes follow the abstract. **Source discrepancy:** the discussion calls the dextromethorphan interval 0.69–0.88 contained within 0.85–1.20. That statement is mathematically false. Retain the measurement and query the analysis; do not promote it directly to proven CYP2D6 induction or a definite null. [Trial, Table 4 and discussion](https://pmc.ncbi.nlm.nih.gov/articles/PMC5809348/)
Complete structured claim and evidence
In the six-person cocktail study, midazolam AUC ratios after one 200-mg modafinil dose and seven daily doses were 0.97 and 0.65 (Table 4).
Modafinil → Plasma midazolam exposure Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary abstract and PMC methods, Tables 3/4, results and discussion inspected; numerical inconsistency preserved in evidence-notes.json.
experimental_contrast
{"intervention": "Modafinil single dose and seven daily doses", "comparator": "Baseline without modafinil", "endpoint": "In the six-person cocktail study, midazolam AUC ratios after one 200-mg modafinil dose and seven daily doses were 0.97 and 0.65 (Table 4).", "effect_direction": "decrease", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Human repeated-measures pharmacokinetic study, six participants; one 200-mg dose versus seven 200-mg daily doses, each relative to baseline.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
In the six-person cocktail study, midazolam AUC ratios after one 200-mg modafinil dose and seven daily doses were 0.97 and 0.65 (Table 4).
primary_references
Evaluation of modafinil as a perpetrator of metabolic drug-drug interactions using a model informed cocktail reaction phenotyping trial protocol. | 2018 | DOI 10.1111/bcp.13478 | PMID 29178272 | https://pmc.ncbi.nlm.nih.gov/articles/PMC5809348/
source_locator
Reviewed reference lines 116-126; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 116–126
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Human repeated-measures pharmacokinetic study, six participants; one 200-mg dose versus seven 200-mg daily doses, each relative to baseline. · Recorded from source · Recorded from source
The six-participant human cocktail study compared baseline with one 200-mg dose and seven daily doses. **Table 4** reports the following AUC ratios: | Probe | Single dose | Seven doses | |---|---:|---:| | Caffeine | 0.95 | 0.88 | | Dextromethorphan | 0.97 | 0.78 | | Losartan | 0.96 | 0.97 | | Midazolam | 0.97 | 0.65 | | Omeprazole | 1.36 | 1.85 | These support time-dependent CYP3A induction and CYP2C19 inhibition. The abstract's estimates differ slightly; the draft's approximately 34%/90% changes follow the abstract. **Source discrepancy:** the discussion calls the dextromethorphan interval 0.69–0.88 contained within 0.85–1.20. That statement is mathematically false. Retain the measurement and query the analysis; do not promote it directly to proven CYP2D6 induction or a definite null. [Trial, Table 4 and discussion](https://pmc.ncbi.nlm.nih.gov/articles/PMC5809348/)
Complete structured claim and evidence
In the six-person cocktail study, omeprazole AUC ratios after one 200-mg modafinil dose and seven daily doses were 1.36 and 1.85 (Table 4).
Modafinil → Human omeprazole plasma AUC Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary abstract and PMC methods, Tables 3/4, results and discussion inspected; numerical inconsistency preserved in evidence-notes.json.
experimental_contrast
{"intervention": "Modafinil single dose and seven daily doses", "comparator": "Baseline without modafinil", "endpoint": "In the six-person cocktail study, omeprazole AUC ratios after one 200-mg modafinil dose and seven daily doses were 1.36 and 1.85 (Table 4).", "effect_direction": "increase", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Human repeated-measures pharmacokinetic study, six participants; one 200-mg dose versus seven 200-mg daily doses, each relative to baseline.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
In the six-person cocktail study, omeprazole AUC ratios after one 200-mg modafinil dose and seven daily doses were 1.36 and 1.85 (Table 4).
primary_references
Evaluation of modafinil as a perpetrator of metabolic drug-drug interactions using a model informed cocktail reaction phenotyping trial protocol. | 2018 | DOI 10.1111/bcp.13478 | PMID 29178272 | https://pmc.ncbi.nlm.nih.gov/articles/PMC5809348/
source_locator
Reviewed reference lines 116-126; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 116–126
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Human repeated-measures pharmacokinetic study, six participants; one 200-mg dose versus seven 200-mg daily doses, each relative to baseline. · Recorded from source · Recorded from source
The six-participant human cocktail study compared baseline with one 200-mg dose and seven daily doses. **Table 4** reports the following AUC ratios: | Probe | Single dose | Seven doses | |---|---:|---:| | Caffeine | 0.95 | 0.88 | | Dextromethorphan | 0.97 | 0.78 | | Losartan | 0.96 | 0.97 | | Midazolam | 0.97 | 0.65 | | Omeprazole | 1.36 | 1.85 | These support time-dependent CYP3A induction and CYP2C19 inhibition. The abstract's estimates differ slightly; the draft's approximately 34%/90% changes follow the abstract. **Source discrepancy:** the discussion calls the dextromethorphan interval 0.69–0.88 contained within 0.85–1.20. That statement is mathematically false. Retain the measurement and query the analysis; do not promote it directly to proven CYP2D6 induction or a definite null. [Trial, Table 4 and discussion](https://pmc.ncbi.nlm.nih.gov/articles/PMC5809348/)
Complete structured claim and evidence
Time-dependent reduction in midazolam exposure after repeated modafinil supports CYP3A induction; a probe-based inference is distinct from direct protein abundance.
Modafinil → Human cytochrome P450 3A4 Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary abstract and PMC methods, Tables 3/4, results and discussion inspected; numerical inconsistency preserved in evidence-notes.json.
experimental_contrast
{"intervention": "Seven daily 200-mg modafinil doses", "comparator": "Baseline without modafinil", "endpoint": "Time-dependent reduction in midazolam exposure after repeated modafinil supports CYP3A induction; a probe-based inference is distinct from direct protein abundance.", "effect_direction": "increase", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Six-person clinical phenotyping study; Table 4 midazolam AUC 0.97 single-dose and 0.65 repeated-dose.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
Time-dependent reduction in midazolam exposure after repeated modafinil supports CYP3A induction; a probe-based inference is distinct from direct protein abundance.
primary_references
Evaluation of modafinil as a perpetrator of metabolic drug-drug interactions using a model informed cocktail reaction phenotyping trial protocol. | 2018 | DOI 10.1111/bcp.13478 | PMID 29178272 | https://pmc.ncbi.nlm.nih.gov/articles/PMC5809348/
source_locator
Reviewed reference lines 126-126; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 126–126
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Six-person clinical phenotyping study; Table 4 midazolam AUC 0.97 single-dose and 0.65 repeated-dose. · Recorded from source · Recorded from source
These support time-dependent CYP3A induction and CYP2C19 inhibition. The abstract's estimates differ slightly; the draft's approximately 34%/90% changes follow the abstract. **Source discrepancy:** the discussion calls the dextromethorphan interval 0.69–0.88 contained within 0.85–1.20. That statement is mathematically false. Retain the measurement and query the analysis; do not promote it directly to proven CYP2D6 induction or a definite null. [Trial, Table 4 and discussion](https://pmc.ncbi.nlm.nih.gov/articles/PMC5809348/)
Complete structured claim and evidence
Increased omeprazole exposure after modafinil supports CYP2C19 inhibition; Table 4 ratios were 1.36 and 1.85 after single and repeated dosing.
Modafinil → Human cytochrome P450 2C19 Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary abstract and PMC methods, Tables 3/4, results and discussion inspected; numerical inconsistency preserved in evidence-notes.json.
experimental_contrast
{"intervention": "Single/repeated modafinil", "comparator": "Baseline without modafinil", "endpoint": "Increased omeprazole exposure after modafinil supports CYP2C19 inhibition; Table 4 ratios were 1.36 and 1.85 after single and repeated dosing.", "effect_direction": "decrease", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Six-person clinical phenotyping study; abstract differs slightly from full Table 4.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
Increased omeprazole exposure after modafinil supports CYP2C19 inhibition; Table 4 ratios were 1.36 and 1.85 after single and repeated dosing.
primary_references
Evaluation of modafinil as a perpetrator of metabolic drug-drug interactions using a model informed cocktail reaction phenotyping trial protocol. | 2018 | DOI 10.1111/bcp.13478 | PMID 29178272 | https://pmc.ncbi.nlm.nih.gov/articles/PMC5809348/
source_locator
Reviewed reference lines 126-126; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 126–126
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Six-person clinical phenotyping study; abstract differs slightly from full Table 4. · Recorded from source · Recorded from source
These support time-dependent CYP3A induction and CYP2C19 inhibition. The abstract's estimates differ slightly; the draft's approximately 34%/90% changes follow the abstract. **Source discrepancy:** the discussion calls the dextromethorphan interval 0.69–0.88 contained within 0.85–1.20. That statement is mathematically false. Retain the measurement and query the analysis; do not promote it directly to proven CYP2D6 induction or a definite null. [Trial, Table 4 and discussion](https://pmc.ncbi.nlm.nih.gov/articles/PMC5809348/)
Complete structured claim and evidence
Four weeks of modafinil reduced triazolam exposure in a controlled study of 41 women; triazolam reduction exceeded the ethinyl-estradiol reduction.
Modafinil → Human triazolam plasma AUC Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary indexed abstract checked; full methods and figures not comprehensively reviewed.
experimental_contrast
{"intervention": "Four weeks of modafinil", "comparator": "Baseline/control exposure", "endpoint": "Four weeks of modafinil reduced triazolam exposure in a controlled study of 41 women; triazolam reduction exceeded the ethinyl-estradiol reduction.", "effect_direction": "decrease", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Human pharmacokinetic trial, 41 women; drug exposure measured, not contraceptive-failure rate.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
Four weeks of modafinil reduced triazolam exposure in a controlled study of 41 women; triazolam reduction exceeded the ethinyl-estradiol reduction.
primary_references
Effect of modafinil on the pharmacokinetics of ethinyl estradiol and triazolam in healthy volunteers. | 2002 | DOI 10.1067/mcp.2002.121217 | PMID 11823757 | https://pubmed.ncbi.nlm.nih.gov/11823757/
source_locator
Reviewed reference lines 128-128; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 128–128
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Human pharmacokinetic trial, 41 women; drug exposure measured, not contraceptive-failure rate. · Recorded from source · Recorded from source
A separate controlled study in 41 women found greater reduction of triazolam exposure than ethinyl-estradiol exposure after four weeks of modafinil. The authors considered intestinal first-pass induction important. A shared enzyme does not imply identical effects on all substrates. The study measured pharmacokinetics, not a contraceptive-failure rate. [Ethinyl estradiol/triazolam study](https://pubmed.ncbi.nlm.nih.gov/11823757/)
Complete structured claim and evidence
Four weeks of modafinil reduced ethinyl-estradiol exposure in a controlled study of 41 women; triazolam reduction exceeded the ethinyl-estradiol reduction.
Modafinil → Human ethinyl-estradiol plasma AUC Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary indexed abstract checked; full methods and figures not comprehensively reviewed.
experimental_contrast
{"intervention": "Four weeks of modafinil", "comparator": "Baseline/control exposure", "endpoint": "Four weeks of modafinil reduced ethinyl-estradiol exposure in a controlled study of 41 women; triazolam reduction exceeded the ethinyl-estradiol reduction.", "effect_direction": "decrease", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Human pharmacokinetic trial, 41 women; drug exposure measured, not contraceptive-failure rate.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
Four weeks of modafinil reduced ethinyl-estradiol exposure in a controlled study of 41 women; triazolam reduction exceeded the ethinyl-estradiol reduction.
primary_references
Effect of modafinil on the pharmacokinetics of ethinyl estradiol and triazolam in healthy volunteers. | 2002 | DOI 10.1067/mcp.2002.121217 | PMID 11823757 | https://pubmed.ncbi.nlm.nih.gov/11823757/
source_locator
Reviewed reference lines 128-128; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 128–128
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Human pharmacokinetic trial, 41 women; drug exposure measured, not contraceptive-failure rate. · Recorded from source · Recorded from source
A separate controlled study in 41 women found greater reduction of triazolam exposure than ethinyl-estradiol exposure after four weeks of modafinil. The authors considered intestinal first-pass induction important. A shared enzyme does not imply identical effects on all substrates. The study measured pharmacokinetics, not a contraceptive-failure rate. [Ethinyl estradiol/triazolam study](https://pubmed.ncbi.nlm.nih.gov/11823757/)
Complete structured claim and evidence
Modafinil increased resting heart rate in a controlled twelve-person human study.
Modafinil → Heart rate Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary indexed abstract checked; full methods and figures not comprehensively reviewed.
experimental_contrast
{"intervention": "Modafinil", "comparator": "Placebo/control", "endpoint": "Modafinil increased resting heart rate in a controlled twelve-person human study.", "effect_direction": "increase", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Controlled twelve-person autonomic physiology study; other sympathetic readouts did not all increase.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
Modafinil increased resting heart rate in a controlled twelve-person human study.
primary_references
Modafinil elicits sympathomedullary activation. | 2005 | DOI 10.1161/01.hyp.0000158267.66763.63 | PMID 15753235 | https://pubmed.ncbi.nlm.nih.gov/15753235/
source_locator
Reviewed reference lines 140-140; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 140–140
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Controlled twelve-person autonomic physiology study; other sympathetic readouts did not all increase. · Recorded from source · Recorded from source
A controlled 12-person human study found increased resting heart rate and blood pressure and higher catecholamine measures after modafinil. However, measured peroneal sympathetic nerve activity during tilt was attenuated. This is a differentiated autonomic response, not every sympathetic output increasing together. Arousal and individual cardiovascular endpoints need separate records. [Autonomic study](https://pubmed.ncbi.nlm.nih.gov/15753235/)
Complete structured claim and evidence
Modafinil increased resting blood pressure in the controlled human autonomic study.
Modafinil → Human blood pressure Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary indexed abstract checked; full methods and figures not comprehensively reviewed.
experimental_contrast
{"intervention": "Modafinil", "comparator": "Placebo/control", "endpoint": "Modafinil increased resting blood pressure in the controlled human autonomic study.", "effect_direction": "increase", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Controlled twelve-person autonomic physiology study; other sympathetic readouts did not all increase.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
Modafinil increased resting blood pressure in the controlled human autonomic study.
primary_references
Modafinil elicits sympathomedullary activation. | 2005 | DOI 10.1161/01.hyp.0000158267.66763.63 | PMID 15753235 | https://pubmed.ncbi.nlm.nih.gov/15753235/
source_locator
Reviewed reference lines 140-140; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 140–140
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Controlled twelve-person autonomic physiology study; other sympathetic readouts did not all increase. · Recorded from source · Recorded from source
A controlled 12-person human study found increased resting heart rate and blood pressure and higher catecholamine measures after modafinil. However, measured peroneal sympathetic nerve activity during tilt was attenuated. This is a differentiated autonomic response, not every sympathetic output increasing together. Arousal and individual cardiovascular endpoints need separate records. [Autonomic study](https://pubmed.ncbi.nlm.nih.gov/15753235/)
Complete structured claim and evidence
Peroneal sympathetic nerve activity during tilt was attenuated after modafinil despite increased resting cardiovascular measures.
Modafinil → Human peroneal sympathetic nerve activity Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary indexed abstract checked; full methods and figures not comprehensively reviewed.
experimental_contrast
{"intervention": "Modafinil with tilt", "comparator": "Control with tilt", "endpoint": "Peroneal sympathetic nerve activity during tilt was attenuated after modafinil despite increased resting cardiovascular measures.", "effect_direction": "decrease", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Human autonomic experiment; tilt nerve recording versus resting heart rate/BP are separate endpoints.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
Peroneal sympathetic nerve activity during tilt was attenuated after modafinil despite increased resting cardiovascular measures.
primary_references
Modafinil elicits sympathomedullary activation. | 2005 | DOI 10.1161/01.hyp.0000158267.66763.63 | PMID 15753235 | https://pubmed.ncbi.nlm.nih.gov/15753235/
source_locator
Reviewed reference lines 140-140; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 140–140
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Human autonomic experiment; tilt nerve recording versus resting heart rate/BP are separate endpoints. · Recorded from source · Recorded from source
A controlled 12-person human study found increased resting heart rate and blood pressure and higher catecholamine measures after modafinil. However, measured peroneal sympathetic nerve activity during tilt was attenuated. This is a differentiated autonomic response, not every sympathetic output increasing together. Arousal and individual cardiovascular endpoints need separate records. [Autonomic study](https://pubmed.ncbi.nlm.nih.gov/15753235/)
Complete structured claim and evidence
Modafinil improved vigilance and objective alertness in human sleep deprivation, while executive-function effects differed by task.
Modafinil → Cognitive task performance Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary indexed abstract checked; full methods and figures not comprehensively reviewed.
experimental_contrast
{"intervention": "Modafinil during sleep deprivation", "comparator": "Placebo", "endpoint": "Modafinil improved vigilance and objective alertness in human sleep deprivation, while executive-function effects differed by task.", "effect_direction": "mixed", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Sleep-deprived human volunteers; modafinil, caffeine and dextroamphetamine comparisons.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
Modafinil improved vigilance and objective alertness in human sleep deprivation, while executive-function effects differed by task.
primary_references
Performance and alertness effects of caffeine, dextroamphetamine, and modafinil during sleep deprivation. | 2005 | DOI 10.1111/j.1365-2869.2005.00468.x | PMID 16120100 | https://pubmed.ncbi.nlm.nih.gov/16120100/
source_locator
Reviewed reference lines 148-148; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 148–148
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Sleep-deprived human volunteers; modafinil, caffeine and dextroamphetamine comparisons. · Recorded from source · Recorded from source
In a human sleep-deprivation comparison, modafinil, caffeine and dextroamphetamine improved vigilance and objective alertness relative to placebo. Executive-function results differed by task. The experiment supports temporary performance mitigation, not preserved judgment across every task or indefinite replacement of sleep. [Sleep-deprivation trial](https://pubmed.ncbi.nlm.nih.gov/16120100/)
Complete structured claim and evidence
A sixty-man trial found selected memory, planning and inhibitory-control improvements with response slowing on some tasks.
Modafinil → Cognitive task performance Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary indexed abstract checked; full methods and figures not comprehensively reviewed.
experimental_contrast
{"intervention": "Modafinil", "comparator": "Placebo", "endpoint": "A sixty-man trial found selected memory, planning and inhibitory-control improvements with response slowing on some tasks.", "effect_direction": "mixed", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Rested human volunteers, randomized trial; selected endpoint improvements do not establish general intelligence enhancement.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
A sixty-man trial found selected memory, planning and inhibitory-control improvements with response slowing on some tasks.
primary_references
Cognitive enhancing effects of modafinil in healthy volunteers. | 2003 | DOI 10.1007/s00213-002-1250-8 | PMID 12417966 | https://pubmed.ncbi.nlm.nih.gov/12417966/
source_locator
Reviewed reference lines 152-152; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 152–152
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Rested human volunteers, randomized trial; selected endpoint improvements do not establish general intelligence enhancement. · Recorded from source · Recorded from source
In a 60-man randomized trial, modafinil improved selected memory, planning and inhibitory-control measures, while slowing responses on some tasks. Several other measures—including attentional set shifting—did not significantly improve. Objective benefit and null results belong together. [Turner et al.](https://pubmed.ncbi.nlm.nih.gov/12417966/)
Complete structured claim and evidence
Attentional set shifting did not significantly improve in the sixty-man modafinil trial.
Modafinil → Human attentional set-shifting task performance Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary indexed abstract checked; full methods and figures not comprehensively reviewed.
experimental_contrast
{"intervention": "Modafinil", "comparator": "Placebo", "endpoint": "Attentional set shifting did not significantly improve in the sixty-man modafinil trial.", "effect_direction": "no_detected_change", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Human randomized cognitive trial; preserved negative endpoint.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
Attentional set shifting did not significantly improve in the sixty-man modafinil trial.
primary_references
Cognitive enhancing effects of modafinil in healthy volunteers. | 2003 | DOI 10.1007/s00213-002-1250-8 | PMID 12417966 | https://pubmed.ncbi.nlm.nih.gov/12417966/
source_locator
Reviewed reference lines 152-152; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 152–152
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Human randomized cognitive trial; preserved negative endpoint. · Recorded from source · Recorded from source
In a 60-man randomized trial, modafinil improved selected memory, planning and inhibitory-control measures, while slowing responses on some tasks. Several other measures—including attentional set shifting—did not significantly improve. Objective benefit and null results belong together. [Turner et al.](https://pubmed.ncbi.nlm.nih.gov/12417966/)
Complete structured claim and evidence
Modafinil increased task enjoyment in a healthy-volunteer study with benefits concentrated in difficult tasks.
Modafinil → Human cognitive-task enjoyment Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Full XML obtained; relevant results/methods inspected. Not exhaustive reanalysis of figures or data.
experimental_contrast
{"intervention": "Modafinil", "comparator": "Placebo", "endpoint": "Modafinil increased task enjoyment in a healthy-volunteer study with benefits concentrated in difficult tasks.", "effect_direction": "increase", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Healthy human volunteers; subjective enjoyment separate from accuracy.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
Modafinil increased task enjoyment in a healthy-volunteer study with benefits concentrated in difficult tasks.
primary_references
Effects of modafinil on non-verbal cognition, task enjoyment and creative thinking in healthy volunteers. | 2013 | DOI 10.1016/j.neuropharm.2012.07.009 | PMID 22820554 | https://pmc.ncbi.nlm.nih.gov/articles/PMC3485563/
source_locator
Reviewed reference lines 154-154; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 154–154
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Healthy human volunteers; subjective enjoyment separate from accuracy. · Recorded from source · Recorded from source
A separate healthy-volunteer study found benefits concentrated in difficult tasks and increased task enjoyment. Its creativity measures did not show a consistent significant improvement or decrement. These findings do not support either “universal intelligence enhancer” or “only makes tedious tasks tolerable.” [Müller et al.](https://pmc.ncbi.nlm.nih.gov/articles/PMC3485563/)
Complete structured claim and evidence
Creativity measures showed no consistent significant improvement or decrement in the healthy-volunteer modafinil study.
Modafinil → Human creativity-test performance Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Full XML obtained; relevant results/methods inspected. Not exhaustive reanalysis of figures or data.
experimental_contrast
{"intervention": "Modafinil", "comparator": "Placebo", "endpoint": "Creativity measures showed no consistent significant improvement or decrement in the healthy-volunteer modafinil study.", "effect_direction": "no_detected_change", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Healthy-volunteer study; task-specific nonsignificant outcomes.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
Creativity measures showed no consistent significant improvement or decrement in the healthy-volunteer modafinil study.
primary_references
Effects of modafinil on non-verbal cognition, task enjoyment and creative thinking in healthy volunteers. | 2013 | DOI 10.1016/j.neuropharm.2012.07.009 | PMID 22820554 | https://pmc.ncbi.nlm.nih.gov/articles/PMC3485563/
source_locator
Reviewed reference lines 154-154; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 154–154
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Healthy-volunteer study; task-specific nonsignificant outcomes. · Recorded from source · Recorded from source
A separate healthy-volunteer study found benefits concentrated in difficult tasks and increased task enjoyment. Its creativity measures did not show a consistent significant improvement or decrement. These findings do not support either “universal intelligence enhancer” or “only makes tedious tasks tolerable.” [Müller et al.](https://pmc.ncbi.nlm.nih.gov/articles/PMC3485563/)
Complete structured claim and evidence
COMT Val158Met genotype modified waking-function responses to modafinil in a selected sleep-deprivation experiment, while recovery-sleep measures were not similarly modified.
Modafinil → Cognitive task performance Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary indexed abstract checked; full methods and figures not comprehensively reviewed.
experimental_contrast
{"intervention": "Modafinil within COMT genotype strata", "comparator": "Control and alternate genotype strata", "endpoint": "COMT Val158Met genotype modified waking-function responses to modafinil in a selected sleep-deprivation experiment, while recovery-sleep measures were not similarly modified.", "effect_direction": "mixed", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Selected human genotype groups under sleep deprivation; not a validated genotype-based prescribing rule.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
COMT Val158Met genotype modified waking-function responses to modafinil in a selected sleep-deprivation experiment, while recovery-sleep measures were not similarly modified.
primary_references
Pharmacogenetics of modafinil after sleep loss: catechol-O-methyltransferase genotype modulates waking functions but not recovery sleep. | 2009 | DOI 10.1038/clpt.2008.222 | PMID 19037200 | https://pubmed.ncbi.nlm.nih.gov/19037200/
source_locator
Reviewed reference lines 156-156; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 156–156
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Selected human genotype groups under sleep deprivation; not a validated genotype-based prescribing rule. · Recorded from source · Recorded from source
In a selected sleep-deprivation study, COMT Val158Met genotype modified modafinil's effects on waking functions, while recovery-sleep measures were not similarly modified. This is evidence for biological variation in a defined experiment, not a validated genotype-based prescribing rule or proof that IQ reveals a person's dopamine concentration. [Pharmacogenetic study](https://pubmed.ncbi.nlm.nih.gov/19037200/)
Complete structured claim and evidence
Six-volunteer self-administration experiments found modafinil reinforcing under a performance condition but not a relaxation condition.
Modafinil → Human task-dependent modafinil reinforcement Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary indexed abstract checked; full methods and figures not comprehensively reviewed.
experimental_contrast
{"intervention": "Modafinil in performance versus relaxation tasks", "comparator": "Placebo/comparison choice", "endpoint": "Six-volunteer self-administration experiments found modafinil reinforcing under a performance condition but not a relaxation condition.", "effect_direction": "mixed", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Human laboratory self-administration, six volunteers; no population addiction-risk estimate.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
Six-volunteer self-administration experiments found modafinil reinforcing under a performance condition but not a relaxation condition.
primary_references
Reinforcing effects of modafinil: influence of dose and behavioral demands following drug administration. | 2005 | DOI 10.1007/s00213-005-0044-1 | PMID 15986191 | https://pubmed.ncbi.nlm.nih.gov/15986191/
source_locator
Reviewed reference lines 162-162; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 162–162
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Human laboratory self-administration, six volunteers; no population addiction-risk estimate. · Recorded from source · Recorded from source
Modafinil's effects can be reinforcing. In six healthy volunteers, a laboratory self-administration procedure found reinforcing effects under a performance condition but not a relaxation condition. This supports task-dependent reinforcement; it neither quantifies population addiction risk nor equates modafinil with cocaine. [Human reinforcement experiment](https://pubmed.ncbi.nlm.nih.gov/15986191/)
Complete structured claim and evidence
Forty-week open-label narcolepsy extensions reported sustained benefit without observed tolerance during that period, with completer selection and later attrition.
Modafinil → Human narcolepsy-associated excessive sleepiness Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary indexed abstract checked; full methods and figures not comprehensively reviewed.
experimental_contrast
{"intervention": "Continued modafinil in trial completers", "comparator": "Within-study baseline/follow-up", "endpoint": "Forty-week open-label narcolepsy extensions reported sustained benefit without observed tolerance during that period, with completer selection and later attrition.", "effect_direction": "decrease", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Human open-label extension studies, forty weeks; no proof that tolerance never occurs.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
Forty-week open-label narcolepsy extensions reported sustained benefit without observed tolerance during that period, with completer selection and later attrition.
primary_references
Long-term efficacy and safety of modafinil (PROVIGIL((R))) for the treatment of excessive daytime sleepiness associated with narcolepsy. | 2000 | DOI 10.1016/s1389-9457(00)00031-9 | PMID 10828434 | https://pubmed.ncbi.nlm.nih.gov/10828434/
source_locator
Reviewed reference lines 164-164; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 164–164
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Human open-label extension studies, forty weeks; no proof that tolerance never occurs. · Recorded from source · Recorded from source
Reinforcement, tolerance and withdrawal are different endpoints. Forty-week open-label narcolepsy extensions reported sustained benefit without evidence of tolerance during that period, but enrolled completers of prior trials and had subsequent attrition. They cannot demonstrate that tolerance never occurs over years or that all exposure patterns have the same discontinuation effects. [Long-term extension studies](https://pubmed.ncbi.nlm.nih.gov/10828434/)
Complete structured claim and evidence
Official labeling reports serious rash including SJS/TEN and systemic hypersensitivity; pediatric rash discontinuations are not equivalent to SJS incidence.
Modafinil → Human modafinil-associated serious rash and hypersensitivity reports Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Official label description, pharmacology, pharmacokinetics, indications, interactions and relevant warnings checked.
experimental_model
Official U.S. label; safety reports and pediatric trial discontinuations, not supported adult incidence denominator.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
Official labeling reports serious rash including SJS/TEN and systemic hypersensitivity; pediatric rash discontinuations are not equivalent to SJS incidence.
primary_references
PROVIGIL U.S. prescribing information | https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3b8d1c32-dac9-50e6-e063-6394a90aa5a5
source_locator
Reviewed reference lines 166-166; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 166–166
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Official U.S. label; safety reports and pediatric trial discontinuations, not supported adult incidence denominator. · Recorded from source · Recorded from source
The U.S. product is Schedule IV, approved for adult excessive sleepiness associated with narcolepsy, OSA or shift-work disorder. Serious rash is a warning, **not a boxed warning**; 13/1,585 pediatric rash-related discontinuations are not 13 SJS cases. It is not approved for children. Reported reactions include SJS/TEN and systemic hypersensitivity. The cited label provides no supported adult “1 in 3,000–10,000” incidence. It instructs discontinuation at the first rash unless clearly unrelated. [U.S. label](https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3b8d1c32-dac9-50e6-e063-6394a90aa5a5)
Complete structured claim and evidence
Regulatory pregnancy concerns and contraceptive precautions are based on safety assessments, not proof of a specific arousal-circuit teratogenic mechanism.
Modafinil → Human modafinil pregnancy-risk observations and precautions Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Official pregnancy and method-specific contraception guidance read; page dated 2020-11-16. Official safety guidance read; March 2011 article with subsequent pregnancy update. Not a primary intervention study.
experimental_model
Official regulatory safety guidance; precaution distinguished from measured mechanism.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
Regulatory pregnancy concerns and contraceptive precautions are based on safety assessments, not proof of a specific arousal-circuit teratogenic mechanism.
primary_references
MHRA modafinil pregnancy and contraception update | https://www.gov.uk/drug-safety-update/modafinil-provigil-increased-risk-of-congenital-malformations-if-used-during-pregnancy
primary_references
MHRA restricted indication and safety advice | https://www.gov.uk/drug-safety-update/modafinil-provigil-now-restricted-to-narcolepsy
source_locator
Reviewed reference lines 168-168; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 168–168
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Official regulatory safety guidance; precaution distinguished from measured mechanism. · Recorded from source · Recorded from source
Psychiatric, cardiovascular and pregnancy concerns need their own safety records. A proposed circuit mechanism cannot rule them out. Pregnancy risk assessments should distinguish observed associations, uncertainty and precautionary recommendations. [Regulatory safety assessment](https://www.gov.uk/drug-safety-update/modafinil-provigil-now-restricted-to-narcolepsy), [pregnancy advice](https://www.gov.uk/drug-safety-update/modafinil-provigil-increased-risk-of-congenital-malformations-if-used-during-pregnancy)
Complete structured claim and evidence
Modafinil improved residual sleepiness and functioning in a twelve-week trial of CPAP-treated OSA patients; it did not establish correction of airway obstruction.
Modafinil → Residual sleepiness in CPAP-treated human OSA Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary indexed abstract checked; full methods and figures not comprehensively reviewed.
experimental_contrast
{"intervention": "Adjunct modafinil", "comparator": "Placebo adjunct", "endpoint": "Modafinil improved residual sleepiness and functioning in a twelve-week trial of CPAP-treated OSA patients; it did not establish correction of airway obstruction.", "effect_direction": "decrease", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Human twelve-week randomized trial in CPAP-treated OSA.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
Modafinil improved residual sleepiness and functioning in a twelve-week trial of CPAP-treated OSA patients; it did not establish correction of airway obstruction.
primary_references
Modafinil for treatment of residual excessive sleepiness in nasal continuous positive airway pressure-treated obstructive sleep apnea/hypopnea syndrome. | 2005 | DOI 10.1093/sleep/28.4.464 | PMID 16171291 | https://pubmed.ncbi.nlm.nih.gov/16171291/
source_locator
Reviewed reference lines 170-170; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 170–170
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · Human twelve-week randomized trial in CPAP-treated OSA. · Recorded from source · Recorded from source
For OSA, a 12-week randomized trial showed improved residual sleepiness and functioning in CPAP-treated patients and no adverse effect on CPAP use during that study. This is genuine symptomatic benefit; it does not show correction of airway obstruction or prevention of long-term vascular events. [OSA trial](https://pubmed.ncbi.nlm.nih.gov/16171291/)
Complete structured claim and evidence
CPAP use was not adversely affected during the twelve-week modafinil OSA trial; longer-term adherence mediation remains untested here.
Modafinil → Human CPAP use Recorded from sourceungraded
Experimental context and source evidence
evidence_access
Primary indexed abstract checked; full methods and figures not comprehensively reviewed.
experimental_contrast
{"intervention": "Adjunct modafinil", "comparator": "Placebo adjunct", "endpoint": "CPAP use was not adversely affected during the twelve-week modafinil OSA trial; longer-term adherence mediation remains untested here.", "effect_direction": "no_detected_change", "combination": "single", "conditions": []} Explicit extracted experimental comparison; source-derived draft.
experimental_model
CPAP-treated OSA, human randomized trial.
interpretation_status
Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.
limitations
Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.
plain_language
CPAP use was not adversely affected during the twelve-week modafinil OSA trial; longer-term adherence mediation remains untested here.
primary_references
Modafinil for treatment of residual excessive sleepiness in nasal continuous positive airway pressure-treated obstructive sleep apnea/hypopnea syndrome. | 2005 | DOI 10.1093/sleep/28.4.464 | PMID 16171291 | https://pubmed.ncbi.nlm.nih.gov/16171291/
source_locator
Reviewed reference lines 170-170; exact primary location described in quoted passage where extracted.
Modafinil: detailed mechanisms of action (reviewed 3 October 2026) · lines 170–170
Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · supports · CPAP-treated OSA, human randomized trial. · Recorded from source · Recorded from source
For OSA, a 12-week randomized trial showed improved residual sleepiness and functioning in CPAP-treated patients and no adverse effect on CPAP use during that study. This is genuine symptomatic benefit; it does not show correction of airway obstruction or prevention of long-term vascular events. [OSA trial](https://pubmed.ncbi.nlm.nih.gov/16171291/)
Complete structured claim and evidence

Availability and dependencies

Each situation shows the normal role first, then what the sources report under a specific condition. A shortfall in the diet, a fault in the machinery, and a low blood reading are kept separate because they are not the same thing.

The sources

Every document behind this chapter is preserved word for word. Open one to read it in full with its recorded conflicts marked in place.

Modafinil: detailed mechanisms of action (reviewed 3 October 2026)Original AI-assisted review of primary studies and, where relevant, official regulatory records. Access level is retained per claim. Corrections, null results and unresolved questions remain explicit. Not publisher full text or independent replication. · Recorded from sourceRead preserved source

Recorded disagreements

Where two sources say different things, both are kept and the difference is explained. You can discuss a disagreement or propose a mechanism that might account for it.

Open questions in this collection

Questions the curators could not answer from the sources in front of them, kept here with the reason each one is still open. These are gaps in this collection, not findings or proof that no one has studied them.

The CYP2D6 discussion calls confidence interval 0.69-0.88 contained within 0.85-1.20, which is mathematically false. Preserve Table 4 values and seek analysis clarification.Reviewer-identified source inconsistency; not a publisher correction, retraction or established CYP2D6 induction.
1. **Target occupancy versus task performance:** which measured exposure/occupancy changes track accuracy, response latency, subjective motivation and cardiovascular effects separately?Open research question from the reviewed reference; not an established causal claim.
2. **Binding kinetics versus brain exposure:** do analogue differences persist when unbound central exposure is matched? The 2026 study changes several properties together.Open research question from the reviewed reference; not an established causal claim.
3. **Ion and metabolic state:** do physiological sodium/zinc conditions or experimentally documented nutritional deficits alter target response? Sodium-free assays and dietary deficiency are not interchangeable models.Open research question from the reviewed reference; not an established causal claim.
4. **Intake feedback:** does sustained reduced eating alter measured nutrient status, sleep recovery or response? The short intake study supplies no long-term deficiency endpoint.Open research question from the reviewed reference; not an established causal claim.
5. **Regional circuit recruitment:** which transmitter changes are necessary for a given benefit, and which accompany it without mediation? Receptor/cell manipulations must preserve baseline and compensatory effects.Open research question from the reviewed reference; not an established causal claim.
6. **Combined medications:** can transporter/circuit interactions be separated from CYP-mediated exposure changes, particularly when coadministration duration differs?Open research question from the reviewed reference; not an established causal claim.
7. **OSA outcomes:** does starting modafinil change device-measured CPAP adherence over longer periods, and does that mediate clinical outcomes after accounting for baseline sleepiness, residual respiratory disturbance and prescribing selection?Open research question from the reviewed reference; not an established causal claim.
8. **Source quality:** what do the raw cocktail-trial data and analysis say about the CYP2D6 comparison? Preserve the discrepancy rather than letting a summary erase it.Open research question from the reviewed reference; not an established causal claim.

Chapters contain source-recorded findings and curated literature summaries. Read each finding's evidence grade, experimental context and review qualifications. The ledger is not medical advice.

Modafinil

The mechanisms

Modafinil is a sulfoxide-containing racemate; armodafinil is its R enantiomer. These are distinct drug identities, not interchangeable exposure profiles.

Armodafinil had higher dose-normalized late exposure than racemic modafinil despite similar approximately 13-hour terminal half-lives in the pooled single-dose studies.

Food delayed modafinil peak concentration by about one hour without reducing overall exposure.

Modafinil metabolism includes hydrolytic deamidation to modafinil acid. Major-metabolite formation does not establish those metabolites as the source of central arousal.

Modafinil metabolism includes S-oxidation to modafinil sulfone. Major-metabolite formation does not establish those metabolites as the source of central arousal.

In ten healthy men, 200 or 400 mg oral modafinil reduced DAT-radiotracer binding by about 54% in caudate, 47% in putamen and 39% in nucleus accumbens.

Separate raclopride PET measurements after oral modafinil supported increased extracellular dopamine; radiotracer displacement is an indirect indicator, not chemical sampling.

modafinil had dopamine uptake IC50 13 micromolar in wild-type human DAT expressed in COS-7 cells. Binding and uptake constants are distinct.

modafinil had radioligand-displacement Ki 2.3 micromolar in wild-type human DAT expressed in COS-7 cells. Binding and uptake constants are distinct.

armodafinil had dopamine uptake IC50 4.0 micromolar in wild-type human DAT expressed in COS-7 cells. Binding and uptake constants are distinct.

armodafinil had radioligand-displacement Ki 0.78 micromolar in wild-type human DAT expressed in COS-7 cells. Binding and uptake constants are distinct.

s-modafinil had dopamine uptake IC50 8.7 micromolar in wild-type human DAT expressed in COS-7 cells. Binding and uptake constants are distinct.

s-modafinil had radioligand-displacement Ki 2.5 micromolar in wild-type human DAT expressed in COS-7 cells. Binding and uptake constants are distinct.

DAT knockout abolished the usual modafinil wake-promoting response in mice while caffeine remained effective with enhanced response.

Mutational/modeling experiments support modafinil compatibility with DAT closed toward the extracellular side, not a permanently locked conformation in patients.

Adding 10 micromolar zinc in sodium-free binding buffer did not significantly improve modafinil affinity for DAT: Ki approximately 2.96 versus 3.47 micromolar.

s-mk-26 was among the more slowly dissociating modafinil analogues in the 2026 DAT-current-recovery experiments; plasma persistence and target residence are separate.

More slowly dissociating analogues including s-mk-26 performed better on selected rat cognitive outcomes, including scopolamine-impaired tasks; brain exposure also differed.

ss-ce-158 was among the more slowly dissociating modafinil analogues in the 2026 DAT-current-recovery experiments; plasma persistence and target residence are separate.

More slowly dissociating analogues including ss-ce-158 performed better on selected rat cognitive outcomes, including scopolamine-impaired tasks; brain exposure also differed.

D2 receptor deletion reduced modafinil-induced wakefulness in mice; D1-like antagonist addition abolished the residual response.

Histamine-neuron ablation or acute chemogenetic inhibition shortened, but did not abolish, modafinil-induced wakefulness in mice.

Recovery sleep showed increased NREM delta power after modafinil, including after histamine-neuron ablation; prolonged waking did not remove this homeostatic response.

Orexin-null mice retained and in one experiment showed greater wake prolongation after modafinil.

Modafinil did not suppress direct wake-to-REM transitions in the orexin-null mouse experiment despite prolonged waking.

Modafinil inhibited dopamine uptake more potently than norepinephrine uptake in the human-transporter assays.

Modafinil inhibited norepinephrine uptake less potently than dopamine uptake in human-transporter assays; rhesus intravenous PET detected NET engagement.

Serotonin uptake inhibition was much weaker than dopamine and norepinephrine uptake inhibition in the tested human-transporter assays.

Modafinil did not directly activate TAAR1 but changed phenethylamine responses with particular coexpressed transporters.

DSP-4 removal of forebrain noradrenergic projections did not eliminate modafinil wake promotion, while an adrenergic antagonist still suppressed it.

Prazosin antagonized modafinil improvement in planning accuracy in a 12-man crossover trial.

Combined prazosin and modafinil increased planning-task completion time in the human crossover trial.

At 100 mg/kg, modafinil lowered extracellular GABA in rat striatum/pallidum.

At 100 mg/kg, modafinil did not increase extracellular glutamate in rat striatum/pallidum.

At 300 mg/kg, modafinil increased striatal glutamate but not pallidal glutamate; substantia nigra had another response pattern.

Modafinil increased extracellular serotonin in cortex, amygdala and dorsal raphe at lower doses than required in medial preoptic/posterior hypothalamic regions.

A modafinil dose ineffective alone augmented selected fluoxetine/imipramine serotonin responses, with dose/region-specific null combinations retained.

Modafinil enhanced coupling between cortical interneurons and inferior-olive neurons; recovery after pharmacological disruption involved a calcium/calmodulin-dependent kinase II-sensitive step.

In eleven simulated-shift-work volunteers, 200 and 400 mg modafinil reduced caloric intake about 18% and 38%, respectively, across three exposure days.

Modafinil did not selectively change the carbohydrate, fat and protein proportions of consumed calories in the short human food-intake study.

Modafinil competitively and reversibly inhibited CYP2C19 in human liver preparations.

Modafinil induced CYP1A2 in human hepatocyte cultures; the laboratory result does not establish a large caffeine exposure change in every user.

Modafinil induced CYP2B6 in human hepatocyte cultures.

Modafinil induced CYP3A activity in human hepatocyte cultures; clinical substrate responses depend on exposure duration.

High-concentration modafinil suppressed CYP2C9 in human liver experiments; this is not a universal therapeutic-exposure rule.

In the six-person cocktail study, caffeine AUC ratios after one 200-mg modafinil dose and seven daily doses were 0.95 and 0.88 (Table 4).

In the six-person cocktail study, dextromethorphan AUC ratios after one 200-mg modafinil dose and seven daily doses were 0.97 and 0.78 (Table 4). The reported CYP2D6 interval interpretation is internally inconsistent; do not infer enzyme induction from this ratio alone.

In the six-person cocktail study, losartan AUC ratios after one 200-mg modafinil dose and seven daily doses were 0.96 and 0.97 (Table 4).

In the six-person cocktail study, midazolam AUC ratios after one 200-mg modafinil dose and seven daily doses were 0.97 and 0.65 (Table 4).

In the six-person cocktail study, omeprazole AUC ratios after one 200-mg modafinil dose and seven daily doses were 1.36 and 1.85 (Table 4).

Time-dependent reduction in midazolam exposure after repeated modafinil supports CYP3A induction; a probe-based inference is distinct from direct protein abundance.

Increased omeprazole exposure after modafinil supports CYP2C19 inhibition; Table 4 ratios were 1.36 and 1.85 after single and repeated dosing.

Four weeks of modafinil reduced triazolam exposure in a controlled study of 41 women; triazolam reduction exceeded the ethinyl-estradiol reduction.

Four weeks of modafinil reduced ethinyl-estradiol exposure in a controlled study of 41 women; triazolam reduction exceeded the ethinyl-estradiol reduction.

Modafinil increased resting heart rate in a controlled twelve-person human study.

Modafinil increased resting blood pressure in the controlled human autonomic study.

Peroneal sympathetic nerve activity during tilt was attenuated after modafinil despite increased resting cardiovascular measures.

Modafinil improved vigilance and objective alertness in human sleep deprivation, while executive-function effects differed by task.

A sixty-man trial found selected memory, planning and inhibitory-control improvements with response slowing on some tasks.

Attentional set shifting did not significantly improve in the sixty-man modafinil trial.

Modafinil increased task enjoyment in a healthy-volunteer study with benefits concentrated in difficult tasks.

Creativity measures showed no consistent significant improvement or decrement in the healthy-volunteer modafinil study.

COMT Val158Met genotype modified waking-function responses to modafinil in a selected sleep-deprivation experiment, while recovery-sleep measures were not similarly modified.

Six-volunteer self-administration experiments found modafinil reinforcing under a performance condition but not a relaxation condition.

Forty-week open-label narcolepsy extensions reported sustained benefit without observed tolerance during that period, with completer selection and later attrition.

Official labeling reports serious rash including SJS/TEN and systemic hypersensitivity; pediatric rash discontinuations are not equivalent to SJS incidence.

Regulatory pregnancy concerns and contraceptive precautions are based on safety assessments, not proof of a specific arousal-circuit teratogenic mechanism.

Modafinil improved residual sleepiness and functioning in a twelve-week trial of CPAP-treated OSA patients; it did not establish correction of airway obstruction.

CPAP use was not adversely affected during the twelve-week modafinil OSA trial; longer-term adherence mediation remains untested here.

Availability and dependencies

The sources

Recorded disagreements

Open questions in this collection