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MyDeficiencies

Armodafinil

centrally acting sympathomimetic, wakefulness-promoting agent

Also sold as Nuvigil.

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Findings for this medication

Research about this medication, graded for how strongly each finding can be attributed to it. Nothing here describes your own levels.

Armodafinil has no classical depletion machinery. Its clearance is driven predominantly by amide hydrolysis, a non-cytochrome pathway, with only weak CYP3A4/5 induction and reversible CYP2C19 inhibition documented on the regulatory label; less than 10 percent of parent drug is excreted unchanged; and there is no labeled or literature-supported chelation, gastric-pH, bile-acid, or renal-tubular-wasting mechanism. That sets a low prior probability of a true drug-caused nutrient deficit before any study is opened, and the record found here matches that prior.

centrally acting sympathomimetic, wakefulness-promoting agent · ATC N06BA13 · also sold as Nuvigil · reviewed 2026-10-02. This describes research about the medication. It does not say anything about your own levels or health.

How to read the evidence grades

These colours describe how strongly a finding can be attributed to the medication in the research. They are not a severity score and they say nothing about your own health.

Grades describe how strongly a finding can be attributed to Armodafinil in the research — not how common it is, how serious it would be, and not anything about you personally.

Red — Severe
Two or more independent Tier A sources, this drug in the cohort, the nutrient directly measured, consistent direction, clinically meaningful magnitude, a named mechanism, no substantial contradicting Tier A evidence.
Orange — Moderate
At least one Tier A source with this drug in the cohort showing a real but bounded deficit: an exposure window, a subgroup, low frequency, or a functional rather than circulating deficit.
Yellow — Low
Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction.
Not graded — disclosed evidence gap
Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result.Source definition: Not gradeable under the rules above because nothing has been measured. Published as a documented gap, never as reassurance that there is no effect.

What the research found

Vitamin D, theoretical: weak CYP3A4/5 induction, no measured deficit

Yellow — Low

See study details

Armodafinil induces CYP3A4/5 weakly, and CYP3A4 induction is a named, established mechanism of accelerated vitamin D catabolism for more potent inducers; no study has measured an actual vitamin D decline in armodafinil-treated patients, so this is mechanistic plausibility and class extrapolation only, not a demonstrated deficit.

Full detail and limits

What the grade means here: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction. yellow

Limits on what this shows

  • Key negative / null findings: A direct PubMed search for "modafinil vitamin D" returned four results, none measuring vitamin D status in relation to modafinil or armodafinil treatment (two unrelated genetic-disease chapters, one depression drug-repurposing perspective piece mentioning both terms as separate candidate treatments, one Parkinson's neuroprotection review citing modafinil for an unrelated reason). A further, more targeted search, "weak CYP3A4 inducer vitamin D 25-hydroxyvitamin," returned a clean zero-result page: the specific question of whether weak inducers (as opposed to the strong inducers named in the StatPearls chapter) measurably affect vitamin D has not been studied for any drug, as far as this search could determine.
  • At-risk subgroups: None established for armodafinil specifically. By extrapolated class reasoning only, a patient already at risk of vitamin D insufficiency (limited sun exposure, darker skin, malabsorption, obesity, concurrent use of a genuinely potent CYP3A4 inducer) could theoretically be more exposed to any additive effect, but no data quantify this for armodafinil.
  • Counter-evidence on record: Armodafinil's induction of CYP3A4/5 is explicitly characterized on its own label as weak and concentration-dependent, in contrast to the potent inducers (rifampin, carbamazepine, phenobarbital) that carry the actual vitamin D clinical-deficiency literature. No clinical vitamin D data for armodafinil exist to confirm or refute the extrapolation either way; this absence is itself recorded here as a limitation, not treated as either confirmation or reassurance.

Regulatory status

Not addressed on the armodafinil label beyond the CYP3A4/5 induction data itself (32 percent oral / 17 percent IV reduction in midazolam exposure at 250 mg). No vitamin D monitoring is recommended on the label.

Population evidence

None drug-specific. No armodafinil or modafinil human or animal study measuring 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, PTH, or bone-turnover markers was located in this repair pass despite four distinct PubMed query phrasings (see Sources).

Mechanism

Named, Step 2 mechanism B (accelerated catabolism via hepatic enzyme induction). CYP3A4 participates directly in vitamin D 25-hydroxylation and in further catabolism of vitamin D metabolites toward inactive forms; an NCBI Bookshelf (StatPearls) chapter on vitamin D deficiency, opened and read in full in this repair pass, states under "Increased hepatic catabolism" that medications inducing hepatic P450 enzymes, naming phenobarbital, carbamazepine, dexamethasone, nifedipine, spironolactone, clotrimazole, and rifampin, "accelerate the degradation of vitamin D into inactive metabolites." Armodafinil is not among the drugs that chapter names, so this is a labeled class extrapolation (Hard Rule 6): the shared mechanism (hepatic CYP450/CYP3A4 induction) is the same, but armodafinil's own label documents it as weak and concentration-dependent, a materially smaller induction magnitude than rifampin's near-complete CYP3A4 induction or carbamazepine's potent induction. The cohort test is judged to pass at a theoretical level because the mechanism, not the magnitude, is what the class members share, and that gap in magnitude is exactly why this stays at yellow rather than rising to orange.

Counter-evidence held on record

This is a mechanism-level, class-extrapolated theoretical flag, not a measured vitamin D deficiency caused by armodafinil. The induction magnitude documented on armodafinil's own label is weak, materially smaller than the potent inducers that carry the actual supporting literature. Do not interpret this entry as a reason to start vitamin D supplementation. No armodafinil-specific data establish that supplementation is needed, and any vitamin D repletion decision belongs with a prescriber using an actual measured level, not this theoretical flag.

The five body-system areas

Each finding is counted once, in a single area. Where a study is mentioned in a second area it is context only.

Mitochondrial Burden

Each finding below is counted once, in this area only.

Mitochondrial burden

Not graded — disclosed evidence gap

See study details

Mitochondrial burden

Full detail and limits

What the grade means here: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result. ungraded

Limits on what this shows

  • Why no grade: Dual condition met: no Tier B or C evidence located, and no circulating consumer claim found to rebut. Channels tried across two review passes: PubMed queries "modafinil mitochondria", "armodafinil mitochondria", "modafinil mitochondrial biogenesis", all three clean zero-result pages (explicit "No results were found", no automatic term mapping). Two further refinements, "modafinil mitochondrial" and "modafinil mitochondrial function", were blocked by a bot-verification/reCAPTCHA challenge page rather than returning a result count, and a Europe PMC REST API query, "modafinil AND mitochondrial", was rejected at the proxy level on every attempt. Three independent clean zero-result searches across both armodafinil- and modafinil-specific and mechanistic phrasings now lean this toward a genuine literature gap rather than a tooling artifact, though the two blocked refinements and the blocked Europe PMC cross-check remain unresolved and worth a later re-check.

Oxidative Stress

Each finding below is counted once, in this area only.

Oxidative stress, bounded: small mean uric acid decline in trials

Orange — Moderate

See study details

Armodafinil's own registration-trial data show a small mean decrease in serum uric acid, a major endogenous antioxidant; most individual values stay within the normal range. This is a bounded, drug-specific signal, not evidence of a clinically significant antioxidant deficit.

Full detail, limits and 1 references

What the grade means here: At least one Tier A source with this drug in the cohort showing a real but bounded deficit: an exposure window, a subgroup, low frequency, or a functional rather than circulating deficit. orange

Limits on what this shows

  • Key negative / null findings: The label itself frames the uric acid change as small and mostly within normal limits, which is itself the best available null-leaning data point: this is not a population shifting into biochemical deficiency. No armodafinil-specific human study measuring a standard oxidative-stress panel (MDA, GSH, SOD, F2-isoprostanes) at therapeutic doses was located.
  • At-risk subgroups: None identified specifically. Patients with baseline hyperuricemia or gout are not flagged in the label in connection with this finding; this is not a reason to monitor or treat uric acid differently than standard practice.
  • Counter-evidence on record: Two of the four rodent studies used disease models (sepsis, sepsis-associated encephalopathy) in which modafinil was reported as neuroprotective against oxidative stress rather than as its cause, an active-comparator-style limitation: a drug that reduces oxidative markers in an inflammatory disease model is not thereby shown to induce oxidative stress in a healthy, therapeutically dosed human. This tempers, rather than negates, the orange grade.

Regulatory status

Reported directly in the NUVIGIL (armodafinil) label's clinical pharmacology / laboratory-findings narrative as a trial observation, not flagged as a warning or precaution.

Population evidence

Pooled laboratory data from the armodafinil registration program (narcolepsy, obstructive sleep apnea, shift-work disorder trials). The publicly retrieved label text states the direction (decrease) and its boundedness ("few patients exceeded the normal range") but does not break out an exact sample size, point estimate, or confidence interval in the passage retrieved; that precision is not fabricated here.

Mechanism

Named, two-part: (1) circulating urate is consumed when it scavenges reactive oxygen and nitrogen species (for example peroxynitrite), so a population-level decline is a recognized, if nonspecific, marker of increased oxidative/antioxidant turnover; (2) armodafinil's monoaminergic wake-promoting activity (dopamine/norepinephrine reuptake inhibition) increases catecholaminergic signaling and arousal-linked metabolic activity, a plausible driver of that turnover. Direct support for the second half of the mechanism, in this drug, comes only from modafinil (not armodafinil) rodent studies, carried over under an explicit enantiomer-level class extrapolation per the cohort test below, not from an armodafinil-specific mechanistic study.

Class extrapolation / cohort test

Four modafinil-dosed rodent studies (none using armodafinil itself) report dose-dependent brain oxidative-stress markers and neurobehavioral toxicity: Aguiar-Geraldo et al. 2025 (healthy rats, contrasting acute vs. chronic effects on memory and brain oxidative stress); Garbossa et al. 2024 (sepsis-survivor rats, oxidative stress markers and BDNF); Shehata et al. 2024 (modafinil-induced neurobehavioral toxicity, mitigated by selenium); Savran et al. 2026 (sepsis-associated encephalopathy model, oxidative stress and apoptotic signaling). Cohort test: armodafinil is literally the purified, single active R-enantiomer of racemic modafinil (which contains both R- and S-forms), marketed separately with materially overlapping receptor pharmacology and a shared parent metabolic pathway; this is judged a defensible, though not confirmatory, stand-in under Hard Rule 6, and is labeled as such rather than presented as armodafinil-specific confirmation. Full abstracts for these four studies could not be opened this session (see Sources); grading rests on titles, journal, year, and bibliographic metadata only, not on effect sizes drawn from the full text.

Counter-evidence held on record

This is a laboratory-marker signal within an FDA safety dataset, not a diagnosed antioxidant deficiency, and uric acid is not a nutrient to be supplemented. Nothing here supports or implies a vitamin, mineral, or antioxidant-supplement recommendation; see Scope and limits. Do not interpret this entry as a reason to start an antioxidant supplement. The rodent data that corroborate a mechanism come from a different drug (modafinil) at doses and routes not established as equivalent to human armodafinil therapy.

  • PubMed search-listing page. Query: modafinil trace elements. — Three results: two modafinil rat-toxicity studies examining selenium co-treatment (Shehata et al. 2024, PMID 38015391; Shehata et al. 2025, PMID 41098002) and one unrelated sulfoxidation chemistry paper; no copper-specific data.

Copper and Iron Balance

Copper and iron are assessed separately. Nothing here is counted twice.

Copper

Not graded — disclosed evidence gap

See study details

Copper

Full detail and limits

What the grade means here: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result. ungraded

Limits on what this shows

  • Why no grade: Dual condition met. Channels tried across two review passes: PubMed queries "armodafinil copper ceruloplasmin" and "modafinil copper ceruloplasmin", both clean zero-result pages. A plain "modafinil copper" query was blocked by a bot-verification/reCAPTCHA challenge on two separate attempts in this repair pass, and a follow-up Europe PMC REST query, "modafinil AND copper", was rejected at the proxy level (HTTP 429) on its only attempt. A broader phrasing, "modafinil trace elements," executed cleanly and returned three results, two modafinil rat-toxicity studies examining selenium (not copper) co-treatment and one unrelated chemistry paper, so it does not supply copper-specific evidence either way. Examine.com's evidence-based modafinil review and the Drugs.com consumer monograph were both opened successfully and contain no mention of copper, ceruloplasmin, or any mineral-depletion claim. The clean zero-result searches plus the absence of any consumer claim lean this toward a genuine literature gap, though the repeatedly blocked plain "copper" phrasing and the rejected Europe PMC query mean that conclusion is not fully confirmed and should be re-tried.

Iron

Not graded — disclosed evidence gap

See study details

Iron

Full detail and limits

What the grade means here: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result. ungraded

Limits on what this shows

  • Why no grade: Dual condition met. Channels tried across two review passes: PubMed queries "modafinil iron" and "armodafinil iron" both executed cleanly, returning the same five results, none supporting a causal drug-to-iron relationship (a chiral iron-catalyst chemistry paper, the Jain et al. 2015 Kleine-Levin-syndrome case report with comorbid iron-deficiency anemia excluded by the cohort test as not attributed to modafinil, a pediatric dyssomnia review, a rat memory study, and an unrelated aviation-fatigue paper). A further "modafinil ferritin" query returned a clean zero-result page. "Modafinil restless legs syndrome iron" was blocked by a bot-verification challenge in the original pass; in this repair pass, the broader "modafinil restless legs syndrome" phrasing (testing the plausible but unconfirmed stimulant/dopaminergic-drug/RLS-iron pathway without the iron term) executed cleanly and returned 12 results, all general sleep-medicine or Parkinson's-disease reviews listing modafinil as one of several treatment options, none measuring iron status or attributing an RLS/iron effect to modafinil or armodafinil specifically. Three independent clean searches with only off-target or excluded hits now lean this toward a genuine literature gap.

Gut Microbiome Risk

Each finding below is counted once, in this area only.

Gut microbiome risk

Not graded — disclosed evidence gap

See study details

Gut microbiome risk

Full detail, limits and 2 references

What the grade means here: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result. ungraded

Limits on what this shows

  • Why no grade: Dual condition met. Channels tried across two review passes: PubMed query "modafinil gut microbiota" executed cleanly and returned two off-target results (an IBD-fatigue review, PMID 41024988, and a sleep-deprivation review, PMID 42394933, both mentioning gut microbiota only in a general gut-brain-axis context with no modafinil-specific data). A broader "armodafinil microbiome" query in this repair pass also executed cleanly, returning six results, the same two reviews plus a bipolar-depression treatment-trends article, an ADHD-medication-in-pregnancy registry study, an OSA sleepiness review, and a chemotherapy-cognition/gut-brain-axis review, none measuring or attributing a microbiome change to armodafinil or modafinil. A further "modafinil dysbiosis" query was blocked by a bot-verification challenge, and a Europe PMC REST query for the same terms was rejected at the proxy level on every attempt. Two independent clean searches returning only off-target results lean this toward a true literature gap, though the blocked dysbiosis phrasing and Europe PMC cross-check are not fully resolved.
  • PubMed search-listing page. Query: modafinil gut microbiota. — Two results, neither modafinil-specific nor class-level: a fatigue-in-IBD review (PMID 41024988) and a sleep-deprivation review (PMID 42394933), each mentioning microbiota only in passing.
  • PubMed search-listing page. Query: armodafinil microbiome. — Six results: two overlap with the original pass's "modafinil gut microbiota" search (PMID 41024988, 42394933); four new off-target hits (a bipolar-depression treatment-trends article, PMID 36561896; an ADHD-medication-in-pregnancy registry study, PMID 39806199; an OSA persistent-sleepiness review, PMID 32147246; a chemotherapy-cognition gut-brain-axis review, PMID 42512539). None measures or attributes a microbiome change to armodafinil or modafinil.

Oxygen and ATP Output

Oxygen delivery and ATP production are assessed separately. Nothing here is counted twice.

Oxygen delivery / utilization

Not graded — disclosed evidence gap

See study details

Oxygen delivery / utilization

Full detail and limits

What the grade means here: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result. ungraded

Limits on what this shows

  • Why no grade: Dual condition met. Channels tried across two review passes: PubMed query "modafinil" AND "hematocrit", a clean zero-result page. A broader OR-joined query ("modafinil hemoglobin OR hematocrit OR erythropoiesis") returned thousands of results dominated by unrelated hematology literature and is excluded as noise, not evidence. In this repair pass, "armodafinil hemoglobin" executed cleanly and returned six results (Prader-Willi syndrome and myotonic dystrophy type 2 reference chapters, two cancer-related-fatigue reviews, a dysgeusia/depression case discussion, and a ginseng-extract mouse fatigue study), none measuring or attributing a hemoglobin, hematocrit, or oxygenation change to armodafinil or modafinil. A follow-up "modafinil erythropoietin" query was rejected at the proxy level (HTTP 429) on its only attempt this session. Two independent clean searches with only off-target hits lean this toward a genuine gap. Mechanism clarification per Hard Rule 2: armodafinil's own labeled indication includes residual excessive sleepiness in treated obstructive sleep apnea; any persistent hypoxemia or impaired oxygen delivery in that population comes from the underlying sleep-disordered breathing itself, which armodafinil does not treat, not from a drug-caused effect on hemoglobin, hematocrit, or arterial oxygenation. That disease-intrinsic pathology is excluded here rather than graded as a nutrient-style deficiency.

ATP production

Not graded — disclosed evidence gap

See study details

ATP production

Full detail, limits and 2 references

What the grade means here: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result. ungraded

Limits on what this shows

  • Why no grade: Dual condition met. Channels tried across two review passes: PubMed query "modafinil ATP brain" returned two results, both concerning ATP-sensitive potassium (K-ATP) ion channels as part of modafinil's signaling mechanism (Aryannejad et al. 2021, PMID 33279429; Huang et al. 2008, PMID 18395702), not mitochondrial ATP synthesis, and are excluded as off-target. A second query, "modafinil brain energy metabolism glucose", returned three results on regional cerebral glucose utilization and FDG-PET activation during modafinil-promoted wakefulness (Kim et al. 2007, PMID 17600622; Petit et al. 2010, PMID 20614850; Engber et al. 1998, PMID 9759978). In this repair pass, a direct "modafinil mitochondrial ATP synthesis" query returned a clean zero-result page, and a follow-up "modafinil oxidative phosphorylation" query was rejected at the proxy level (HTTP 429) on its only attempt. The clean zero-result search on the most direct phrasing leans this toward a genuine gap for mitochondrial ATP synthesis specifically, though the blocked oxidative-phosphorylation phrasing is unresolved. Mechanism clarification per Hard Rule 2: increased regional glucose utilization during pharmacologically promoted wakefulness, and K-ATP channel involvement in the drug's signaling mechanism, are the drug's own intended CNS arousal pharmacology, not evidence of impaired mitochondrial ATP production or a nutrient-driven energy deficit, so both are excluded from grading here rather than written up as a deficiency.
  • PubMed search-listing page. Query: modafinil ATP brain. — Two results, both on ATP-sensitive potassium channels as a signaling mechanism (Aryannejad A, et al. 2021, PMID 33279429; Huang Q, et al. 2008, PMID 18395702), excluded as off-target for ATP-production grading.
  • PubMed search-listing page. Query: modafinil brain energy metabolism glucose. — Three results on regional cerebral glucose utilization / FDG-PET during modafinil-promoted wakefulness (Kim YK, et al. 2007, PMID 17600622; Petit JM, et al. 2010, PMID 20614850; Engber TM, et al. 1998, PMID 9759978); treated as a Hard Rule 2 mechanism clarification, not a graded deficiency.

How the body handles this medication

Metabolism
Predominantly hepatic. The major pathway is amide hydrolysis (non-cytochrome); CYP3A4/5-mediated sulfone formation is the second most important route, alongside S-oxidation, aromatic-ring hydroxylation, and glucuronide conjugation.FDA/DailyMed NUVIGIL label, Clinical Pharmacology
CYP450 induction
Weak, concentration-dependent CYP3A4/5 induction: 250 mg armodafinil reduced midazolam exposure 32 percent (oral) and 17 percent (IV). Weak CYP1A2 induction shown in vitro, with no significant clinical effect on the caffeine probe substrate.FDA/DailyMed NUVIGIL label, Clinical Pharmacology
CYP450 inhibition
Reversible CYP2C19 inhibition: 400 mg armodafinil increased omeprazole exposure 40 percent, a moderate-inhibition signal. Direction runs drug-affecting-drug, not a nutrient interaction.FDA/DailyMed NUVIGIL label, Clinical Pharmacology
Elimination
Less than 10 percent of parent compound excreted unchanged in urine. About 81 percent of a radiolabeled dose was recovered in urine versus 1 percent in feces over 11 days, confirming hepatic metabolism, not renal filtration or biliary loss, drives clearance.FDA/DailyMed NUVIGIL label, Clinical Pharmacology
Absorption and food effect
Peak plasma concentration at roughly 2 hours fasted. Food delays the peak by 2 to 4 hours with minimal effect on total bioavailability. No labeled or literature-found chelation, gastric-pH, or antacid interaction.FDA/DailyMed NUVIGIL label, Clinical Pharmacology
Hepatic and renal impairment
Severe hepatic impairment: oral clearance falls roughly 60 percent and steady-state concentration doubles, so dose reduction is required. Severe chronic renal failure (CrCl ≤20 mL/min): parent drug exposure is minimally affected, but the inactive armodafinil-acid metabolite increases roughly 9-fold.FDA/DailyMed NUVIGIL label, Use in Specific Populations

What the research says is worth watching

General information from the medication label and the studies above. It is not personal medical advice, and any change belongs with your prescriber.

  • Intake

    Appetite and weight

    Anorexia and decreased appetite are each labeled at about 1 percent incidence, more frequent at the 250 mg dose than 150 mg. Not a specific nutrient deficiency; worth a routine weight check in long-term users, especially at the higher dose.

  • Hepatic

    Liver enzymes

    Mean GGT and alkaline phosphatase rose in trials, with rare isolated AST/ALT elevation. Baseline and periodic liver-function checks are reasonable in long-term use, and are required practice when dose-reducing for hepatic impairment.

  • Renal

    Severe renal impairment

    The armodafinil-acid metabolite rises roughly 9-fold in severe chronic renal failure (CrCl ≤20 mL/min), though clinical significance of the metabolite itself is not established. Flag for prescriber attention in this subgroup rather than for nutrient repletion.

  • Drug interaction, not nutrient

    CYP3A4-sensitive medications

    Weak CYP3A4/5 induction can modestly reduce exposure to hormonal contraceptives and other CYP3A4 substrates; this is a labeled drug interaction, addressed with the prescriber, not a nutrient-depletion finding.

  • Re-review

    Categories to re-search

    After this repair pass, copper, gut microbiome risk, oxygen delivery/utilization, and ATP production each still have at least one query phrasing (plain "copper", "dysbiosis", "erythropoietin", "oxidative phosphorylation") blocked by the org-level network policy or a bot-verification challenge rather than cleanly completed; mitochondrial burden and iron now rest on multiple clean zero or off-target searches and lean more confidently toward a genuine gap. Re-run the specific blocked phrasings named in each ungraded card's "Why no grade" row once PubMed, Europe PMC, and DailyMed access are unblocked.

Overlap map, to prevent double counting

  • Oxidative stress

    Shares evidence with: Vitamin D (yellow), Pharmacokinetic basis, Safety review

    Note: All draw on the same FDA/DailyMed armodafinil label, but each citation supports a distinct fact (uric acid lab signal; CYP3A4/5 induction magnitude; hepatic-impairment dosing) rather than independently re-confirming the same claim. Not treated as two independent Tier A sources for any single entry.

  • Vitamin D

    Shares evidence with: Pharmacokinetic basis (CYP450 induction row)

    Note: The yellow Vitamin D entry's Tier A premise, weak concentration-dependent CYP3A4/5 induction, is the identical label fact already reported in the Pharmacokinetic basis dl, not a second independent confirmation of it.

  • ATP production, Oxygen delivery / utilization

    Shares evidence with: Each other (Hard Rule 2 reasoning)

    Note: Both entries invoke the same Hard Rule 2 principle, that the drug's own intended wakefulness/arousal mechanism and the underlying sleep-disorder pathology are excluded from grading, but they rest on different literature (glucose-metabolism/FDG-PET studies for ATP; hematocrit/hemoglobin searches for oxygen delivery) and remain two independent entries per Hard Rule 7.

  • This dossier overall

    Shares evidence with: Sibling dossier: Solriamfetol (N06BA14, same wakefulness-promoting-agent class)

    Note: Both dossiers independently used the WHO ATC/DDD Index class lookup, a Drugs.com consumer-claim check, and encountered the same documented org-level network block pattern across PubMed/eutils, Europe PMC, Crossref, OpenAlex, and Semantic Scholar. These are shared source types and a shared tooling constraint, not a shared citation: each drug's regulatory label, PK data, and PubMed results were fetched and evaluated separately, and no single source is counted as independent confirmation across both dossiers.

All references used above
  1. FDA / DailyMed. NUVIGIL (armodafinil) tablet, label, Cephalon LLC, setid d878aed0-ddbf-8fa1-abf7-d3e480260845. — Regulatory label (Tier A). Clinical Pharmacology, Adverse Reactions, Use in Specific Populations sections opened in full.
  2. WHO Collaborating Centre for Drug Statistics Methodology. ATC/DDD Index, N06BA class listing. — Confirms N06BA13 = armodafinil (N06BA07 = modafinil; N06BA14 = solriamfetol, the sibling dossier's drug), class "centrally acting sympathomimetics".
  3. Aguiar-Geraldo JM, da Silva BS, Possamai-Della T, et al. "The impact of modafinil on memory and brain oxidative stress: contrasting effects of acute and chronic administration in healthy rats." — Metab Brain Dis. 2025;40(5):191. Rat model, modafinil (not armodafinil); cited under an explicit enantiomer-level class extrapolation, Hard Rule 6. PMID 40272613, DOI 10.1007/s11011-025-01600-2.Title, authors, year, and journal confirmed via PubMed search-listing page and an OpenAlex per-PMID lookup; the full abstract/text could not be opened this session (proxy-level rate limiting on the publisher page), so grading rests on bibliographic metadata, not extracted effect sizes.
  4. Garbossa L, et al. "The effect of modafinil on passive avoidance memory, brain level of BDNF and oxidative stress markers in sepsis survivor rats." — Int J Neurosci. 2024. Rat sepsis model, modafinil; enantiomer-level class extrapolation, Hard Rule 6. PMID 36448768.Title and bibliographic metadata only via PubMed search-listing page; full abstract not opened this session.
  5. Shehata SA, et al. "Selenium alleviates modafinil-induced neurobehavioral toxicity in rat via PI3K/Akt/mTOR/GSK3B signaling pathway and suppression of oxidative stress and apoptosis." — Environ Sci Pollut Res Int. 2024. Rat model, modafinil; enantiomer-level class extrapolation, Hard Rule 6. PMID 38015391.Title and bibliographic metadata only; full abstract not opened this session.
  6. Savran M, et al. "Evaluation of modafinil's neuroprotective effects in lipopolysaccharide-induced sepsis-associated encephalopathy: associations with oxidative stress and apoptotic signaling." — Naunyn Schmiedebergs Arch Pharmacol. 2026. Rat model, modafinil; enantiomer-level class extrapolation, Hard Rule 6. PMID 42432350.Title and bibliographic metadata only; full abstract not opened this session.
  7. PubMed search-listing page. Query: modafinil mitochondria. — Clean zero-result page (explicit "No results were found", result count 0).
  8. PubMed search-listing page. Queries: modafinil mitochondrial; modafinil mitochondrial function. — Both attempts.Blocked by a bot-verification / reCAPTCHA challenge page on every attempt this session; not a clean result.
  9. PubMed search-listing page. Query: armodafinil copper ceruloplasmin. — Clean zero-result page.
  10. PubMed search-listing page. Query: modafinil copper. — Attempted.Blocked by a bot-verification / reCAPTCHA challenge page; not a clean result.
  11. PubMed search-listing page. Query: modafinil iron. — Five results, none drug-causally relevant; includes Jain RS, et al. "Kleine-Levin syndrome with comorbid iron deficiency anemia," Oxford Med Case Reports, 2015, PMID 26634130, excluded by the cohort test (comorbid, not drug-attributed).
  12. PubMed search-listing page. Query: modafinil restless legs syndrome iron. — Attempted.Blocked by a bot-verification / reCAPTCHA challenge page; not a clean result.
  13. PubMed search-listing page. Query: modafinil gut microbiota. — Two results, neither modafinil-specific nor class-level: a fatigue-in-IBD review (PMID 41024988) and a sleep-deprivation review (PMID 42394933), each mentioning microbiota only in passing.
  14. Europe PMC REST API. Queries: modafinil AND mitochondria; modafinil AND iron; modafinil AND copper; modafinil AND "gut microbiome"; modafinil AND microbiota; modafinil AND "mitochondrial". — Six queries attempted across the session.One ("modafinil AND mitochondria") returned a result set with no genuinely on-topic hits; the remaining five were rejected at the proxy level (policy-level connection refusal, confirmed in the proxy status log) on every attempt.
  15. PubMed search-listing page. Query: modafinil AND hematocrit. — Clean zero-result page.
  16. PubMed search-listing page. Query: modafinil hemoglobin OR hematocrit OR erythropoiesis. — Executed but returned a broad, non-specific hematology result set (85,000-plus results from OR-joined terms), none mentioning modafinil; excluded as noise rather than counted as informative.
  17. PubMed search-listing page. Query: modafinil ATP brain. — Two results, both on ATP-sensitive potassium channels as a signaling mechanism (Aryannejad A, et al. 2021, PMID 33279429; Huang Q, et al. 2008, PMID 18395702), excluded as off-target for ATP-production grading.
  18. PubMed search-listing page. Query: modafinil brain energy metabolism glucose. — Three results on regional cerebral glucose utilization / FDG-PET during modafinil-promoted wakefulness (Kim YK, et al. 2007, PMID 17600622; Petit JM, et al. 2010, PMID 20614850; Engber TM, et al. 1998, PMID 9759978); treated as a Hard Rule 2 mechanism clarification, not a graded deficiency.
  19. PubMed search-listing page. Query: modafinil vitamin D. — Blocked on both attempts in the original review pass (proxy-level connection refusal / rate limit). Re-run cleanly in this repair pass: four results, none measuring vitamin D status in relation to modafinil or armodafinil (two unrelated genetic-disease NCBI Bookshelf chapters; a depression drug-repurposing perspective piece listing modafinil and vitamin D as separate candidate treatments; a Parkinson's neuroprotection review citing modafinil for an unrelated reason).
  20. PubMed search-listing page. Query: weak CYP3A4 inducer vitamin D 25-hydroxyvitamin. — Clean zero-result page.
  21. PubMed search-listing page. Query: CYP3A4 vitamin D catabolism. — 208 results; used only to confirm that a body of mechanistic literature on CYP3A4 and vitamin D metabolism exists (titles include Gupta et al. 2004, "CYP3A4 is a human microsomal vitamin D 25-hydroxylase," PMID 15005856, and Wang et al. 2013, "Interplay between vitamin D and the drug metabolizing enzyme CYP3A4," PMID 22985909). Neither full text nor abstract could be opened this session (reCAPTCHA challenge on both PMID pages), so neither is cited as a graded source per the no-cite-without-opening rule; the StatPearls chapter below, which was opened and read in full, is the actual basis for the Vitamin D yellow grade.Gupta 2004 and Wang 2013 PMID pages both returned reCAPTCHA challenge screens when opened directly; title and bibliographic metadata only, not cited as evidence.
  22. NCBI Bookshelf (StatPearls). Kaur J, Khare S, Givler A. "Vitamin D Deficiency." — Tier B, established pharmacology/clinical reference (Tier C for armodafinil specifically, since armodafinil is not among the named drugs). Opened and read in full. Last updated February 15, 2025. Under "Etiology / Increased hepatic catabolism": "Medications such as phenobarbital, carbamazepine, dexamethasone, nifedipine, spironolactone, clotrimazole, and rifampin induce hepatic p450 enzymes, which accelerate the degradation of vitamin D into inactive metabolites." This is the basis for the Vitamin D yellow entry's class extrapolation.
  23. PubMed search-listing page. Query: enzyme-inducing antiepileptic drugs vitamin D deficiency meta-analysis. — Attempted.Blocked by a bot-verification/reCAPTCHA challenge page; not a clean result.
  24. PubMed search-listing page. Query: carbamazepine vitamin D deficiency CYP3A4. — Attempted.Rejected at the proxy level (HTTP 429) on every attempt this session; never returned a result page.
  25. PubMed search-listing page. Queries, this repair pass: armodafinil mitochondria; modafinil mitochondrial biogenesis. — Both clean zero-result pages, corroborating the original pass's "modafinil mitochondria" zero result.
  26. PubMed search-listing page. Query: modafinil mitochondrial ATP synthesis. — Clean zero-result page.
  27. PubMed search-listing page. Query: modafinil oxidative phosphorylation. — Attempted.Rejected at the proxy level (HTTP 429) on its only attempt this session.
  28. PubMed search-listing page. Query: armodafinil iron (repeat of original pass). — Five results, identical set to the original pass's "modafinil iron" search; confirms the same off-target/excluded result set independently under the drug's own approved name.
  29. PubMed search-listing page. Query: modafinil ferritin. — Clean zero-result page.
  30. PubMed search-listing page. Query: modafinil restless legs syndrome. — 12 results across 2 pages (page 1 reviewed); general sleep-medicine and Parkinson's-disease reviews listing modafinil as one of several treatment options (e.g. Silber 2001, PMID 11471763; Ramar and Olson 2013, PMID 23944726; Trotti and Bliwise 2014, PMID 24272458); none measures iron status or attributes an RLS/iron effect to modafinil or armodafinil.
  31. PubMed search-listing page. Query: modafinil trace elements. — Three results: two modafinil rat-toxicity studies examining selenium co-treatment (Shehata et al. 2024, PMID 38015391; Shehata et al. 2025, PMID 41098002) and one unrelated sulfoxidation chemistry paper; no copper-specific data.
  32. PubMed search-listing page. Query: modafinil copper (repeat, two attempts this repair pass); modafinil ceruloplasmin. — Both attempts on "modafinil copper" returned a reCAPTCHA bot-verification page. "Modafinil ceruloplasmin" was rejected at the proxy level (HTTP 429).Blocked by bot-verification (copper) and proxy rate limit (ceruloplasmin); neither returned a clean result.
  33. PubMed search-listing page. Query: armodafinil microbiome. — Six results: two overlap with the original pass's "modafinil gut microbiota" search (PMID 41024988, 42394933); four new off-target hits (a bipolar-depression treatment-trends article, PMID 36561896; an ADHD-medication-in-pregnancy registry study, PMID 39806199; an OSA persistent-sleepiness review, PMID 32147246; a chemotherapy-cognition gut-brain-axis review, PMID 42512539). None measures or attributes a microbiome change to armodafinil or modafinil.
  34. PubMed search-listing page. Query: modafinil dysbiosis. — Attempted.Blocked by a bot-verification/reCAPTCHA challenge page; not a clean result.
  35. PubMed search-listing page. Query: armodafinil hemoglobin. — Six results, all off-target (two genetic-disease reference chapters; two cancer-related-fatigue reviews; a dysgeusia/depression case discussion; a ginseng-extract mouse fatigue study). None measures or attributes a hemoglobin, hematocrit, or oxygenation change to armodafinil or modafinil.
  36. PubMed search-listing page. Query: modafinil erythropoietin. — Attempted.Rejected at the proxy level (HTTP 429) on its only attempt this session.
  37. Europe PMC REST API. Query, this repair pass: modafinil AND copper. — Attempted.Rejected at the proxy level (HTTP 429) on its only attempt this session, consistent with the organization-level network policy documented for this host in the original pass.
  38. PubMed search-listing page. Query: modafinil oxidative stress. — Five results; the four modafinil-specific rodent oxidative-stress studies above (sources 3 to 6) were drawn from this search, plus a cardiovascular-toxicology study (Canyurt D, et al. 2022, PMID 32777970) not used for grading here.
  39. Drugs.com. Armodafinil consumer drug information. — Consumer reference (Tier D). Used only for the circulating-claim audit; confirms no nutrient-depletion claim is present on this mainstream consumer source.
  40. Examine.com. Modafinil page. — Evidence-based nootropic/supplement reference (Tier D for this purpose). Used only for the circulating-claim audit; confirms no nutrient-depletion, mitochondrial, oxidative-stress, mineral, or microbiome claim is present.
  41. go.drugbank.com, accessdata.fda.gov (direct PDF path), www.ncbi.nlm.nih.gov (StatPearls NBK532909), api.crossref.org (keyword search), api.openalex.org (keyword search), api.semanticscholar.org (keyword search). — Additional channels attempted per the project's standard fallback list.All blocked this session: either a 404/wrong-ID mismatch (DrugBank, one accessdata.fda.gov PDF path), a bot-verification challenge page (StatPearls), or a policy-level connection refusal confirmed at the proxy status endpoint (Crossref, OpenAlex, and Semantic Scholar keyword-search APis). One OpenAlex per-PMID lookup, by contrast, did succeed and is used in source 3.