Armodafinil / R-modafinil

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/)

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/)

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/)

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/)

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)

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)

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)

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)