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MyDeficiencies

Lemborexant

Also sold as Dayvigo.

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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.

Lemborexant has essentially no classical drug-nutrient depletion machinery. It is cleared predominantly through CYP3A4/3A5 metabolism to fecal and renal metabolites, with less than 1% excreted unchanged in urine; its own in-vitro potential to induce CYP3A or CYP2B6 is explicitly described in its FDA label as weak and is not established as clinically meaningful. It does not chelate minerals, alter gastric pH, interfere with a named nutrient transporter, or disturb renal tubular handling of electrolytes or water. Running the full seven-mechanism screen against the regulatory label and primary literature returned zero present classical depletion mechanisms, which is itself a valid and reportable result, not a shortcut taken to avoid research.

ATC N05CJ02 · also sold as Dayvigo · reviewed 2026-10-01. 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 Lemborexant 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.

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 - class-level, reverse-direction signal only, not lemborexant-specific

Yellow — Low

See study details

A same-class dual orexin receptor antagonist (suvorexant) improved, rather than worsened, stress-induced mitochondrial fission/fusion imbalance in a rodent model; no lemborexant-specific mitochondrial study was located, and the only class-level signal available runs opposite to a depletion narrative.

Full detail, limits and 1 references

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: None located specific to lemborexant. The suvorexant finding is a single rodent study and has not been independently replicated.
  • At-risk subgroups: Not established in humans. The only supporting data is a stress-exposed rodent model, not a human insomnia population.
  • Counter-evidence on record: No study was located suggesting lemborexant or suvorexant impairs mitochondrial structure or function; the available class-level direction is protective. The cohort test passes for class (suvorexant shares target and mechanism) but species (rat vs. human), stress model (PTSD paradigm vs. ordinary insomnia), and molecule identity all differ materially from lemborexant's actual clinical use.

Regulatory status

Not addressed in the FDA label.

Population evidence

Class extrapolation, Tier C (cohort test: suvorexant is a defensible same-class, same-target comparator; lemborexant itself was not studied). Male Wistar rats in a single-prolonged-stress PTSD paradigm. Stress increased mitochondrial fission markers (Drp-1, Fis-1) and decreased fusion markers (Opa-1, Mfn-2); suvorexant (combined with rapamycin) "significantly mitigated" this imbalance and reduced mTOR/MTFP-1 activation. A non-orexinergic comparator, sertraline, improved PTSD-like behavior but did not affect mitochondrial dynamics. Journal of Affective Disorders, 2024, DOI 10.1016/j.jad.2024.01.045.

Mechanism

Orexin receptor blockade intersecting the mTOR-MTFP1 axis that governs mitochondrial fission/fusion balance. Plausible for lemborexant given shared OX1R/OX2R dual antagonism, but untested for this specific molecule.

Counter-evidence held on record

This is theoretical, class-level evidence only, and it trends protective rather than depleting. It is not evidence that lemborexant harms or benefits human mitochondrial function, and it does not support any supplement, antioxidant, or mitochondrial-support intervention.

  • Suvorexant improves mitochondrial dynamics with the regulation of orexinergic and mTOR activation in rats exhibiting PTSD-like symptoms — Male Wistar rats, single-prolonged-stress paradigm. Journal of Affective Disorders, 2024. DOI 10.1016/j.jad.2024.01.045. Tier C for lemborexant (suvorexant studied, not lemborexant; defensible same-class comparator). Graded Mitochondrial burden, yellow.Cohort did not include lemborexant; class extrapolation only.

Oxidative Stress

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

Oxidative stress

Not graded — disclosed evidence gap

See study details

No Tier B/C evidence that could actually be opened and verified was found linking lemborexant, or a class member, to oxidative-stress or antioxidant-capacity markers, and no circulating claim exists to rebut.

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 and re-confirmed this pass. The one query that returned clean, uncached, directly-verified content (lemborexant + oxidative stress) is an explicit zero-result, which is the strongest form of negative evidence this protocol can produce short of a stratified null study. No class member (suvorexant) has qualifying Tier B/C data either, so there is nothing to extrapolate. No circulating consumer claim specifically asserting lemborexant or a DORA causes oxidative stress or antioxidant depletion was found in any source checked across either pass. This is disclosed as a genuine literature gap, with a real but secondary tooling limitation (broadened proxy blocking, PubMed bot-verification) layered on top that a later revision should re-check once those channels are reachable again.

Channels tried, this revision pass (2026-10-01)

WebFetch to the PubMed search-listing page for "lemborexant oxidative stress" returned a clean, explicit zero-result page ("No results were found," meta-log_resultcount: 0) - a confirmed literature negative for this exact term, not a block. A follow-up query combining lemborexant with ATP/mitochondria/energy terms on the same host was rejected with HTTP 429 (rate-limited) immediately after. The companion B009 suvorexant dossier's review of this same category (same DORA class) also found no drug-specific or class-level oxidative-stress/redox-marker study for suvorexant, so there is no class member with qualifying data to extrapolate from either. WebSearch could not be used (session budget exhausted at 200/200, confirmed by the tool itself). Direct curl/CONNECT attempts to pubmed.ncbi.nlm.nih.gov, api.crossref.org, api.semanticscholar.org, api.openalex.org, eutils.ncbi.nlm.nih.gov, www.ebi.ac.uk (Europe PMC), and dailymed.nlm.nih.gov all failed with HTTP 403 at the organization network proxy gateway (connect_rejected, policy denial), confirmed via the proxy status endpoint; this block has widened since the original pass to also cover hosts that worked before (accessdata.fda.gov, en.wikipedia.org, go.drugbank.com, atcddd.fhi.no, www.dovepress.com all now return the same 403 CONNECT rejection via curl, though WebFetch itself reaches some of these through a different path). Subsequent WebFetch attempts to PubMed search pages on this host began returning reCAPTCHA bot-verification challenges rather than content. europepmc.org and search.crossref.org search pages are disallowed by robots.txt for WebFetch.

Copper and Iron Balance

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

Copper

Not graded — disclosed evidence gap

See study details

No Tier B/C or drug/class-specific evidence was found linking lemborexant, or the orexin-antagonist class, to copper status, and no circulating claim exists to rebut.

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 and re-confirmed this pass. The only drug/class-adjacent PubMed hits found across both passes are synthetic-chemistry papers about manufacturing suvorexant, not biological findings, so they do not qualify as Tier B/C evidence under Step 4. No class member has biological copper data to extrapolate from, and no circulating consumer claim exists to rebut. Disclosed as a genuine literature gap, with the broadened proxy/bot-verification tooling limitation noted for a later revision.

Channels tried, this revision pass (2026-10-01)

WebFetch to the PubMed search-listing page for "orexin receptor antagonist copper" returned two results, both opened and read: a 2012 Organic Letters paper on the enantioselective chemical synthesis of suvorexant (a copper-catalyzed amination step used to manufacture the drug, not a biological copper-status effect) and an unrelated 2018 copper-catalysis synthetic-chemistry paper. Neither is biological evidence of a drug effect on copper status. The companion B009 suvorexant dossier's review of this same category also found no drug-specific or class-level biological copper study for suvorexant (its one PubMed attempt on this term was rate-limited before returning results), so there is no class member with qualifying biological data to extrapolate from. WebSearch could not be used (budget exhausted). The same broadened organization-proxy block and PubMed bot-verification pattern described under Oxidative stress above applied to further follow-up attempts on Europe PMC, Semantic Scholar, OpenAlex, and Crossref. No mechanistic pathway linking orexin signaling to copper transport, ceruloplasmin, or copper-dependent enzymes was identified in any source actually opened across either pass of this review. The Blackmores Institute consumer drug-nutrient depletion guide, checked in the original pass, contains no coverage of sleep/hypnotic medications or orexin antagonists at all.

Iron

Not graded — disclosed evidence gap

See study details

No Tier B/C or drug/class-specific evidence was found showing lemborexant affects iron absorption, storage, or status, and no circulating claim exists to rebut.

Full detail, limits and 1 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 and re-confirmed this pass. The only iron-adjacent literature located and opened across either pass either fails the drug-in-cohort test entirely (narcolepsy/RLS, not drug-treated patients) or runs in the wrong direction (endogenous orexin level, not antagonist drug exposure) to count as evidence for or against a lemborexant effect, and the class-level check (suvorexant) returned a confirmed clean zero-result rather than any supporting data. No circulating claim exists to rebut. Disclosed as a genuine literature gap, with the broadened proxy/bot-verification tooling limitation noted for a later revision.

Channels tried, this revision pass (2026-10-01)

WebFetch to the PubMed search-listing page for "orexin iron hypocretin ferritin" returned two results, both opened and read: a 2020 Annals of Clinical and Translational Neurology study (Barateau et al.) comparing CSF/serum ferritin and CSF orexin levels in narcolepsy type 1 with and without restless legs syndrome, finding "no between-group differences... for CSF ferritin, ORX, and serum ferritin levels"; and a 2003 CNS Spectrums paper on restless-legs-syndrome and drug-induced akathisia unrelated to iron or orexin pharmacology. Neither bears on a drug effect: the 2020 study measures endogenous orexin deficiency (narcolepsy type 1) and iron markers in a disease population, not an orexin-antagonist drug's effect on iron status, and under the direction check (Hard Rule 4) a finding about endogenous orexin levels correlating (or not) with iron markers cannot be read as evidence of what blocking orexin receptors does to iron. The companion B009 suvorexant dossier's review of this category found a clean, explicit zero-result PubMed query for "suvorexant iron" specifically, confirming no class-level signal either. The same broadened organization-proxy block and PubMed bot-verification pattern described under Oxidative stress above applied to further follow-up attempts (Europe PMC, Semantic Scholar, OpenAlex, Crossref all blocked or robots-disallowed). No circulating claim that lemborexant or a DORA depletes iron was found in either pass.

Gut Microbiome Risk

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

Gut microbiome risk - compositional shift, bounded to a 12-week uncontrolled pilot in adults 50+

Orange — Moderate

See study details

In a 12-week, open-label pilot of adults 50 and older with insomnia, lemborexant treatment was associated with a statistically significant reduction in Parabacteroides abundance and a rise in the Firmicutes/Bacteroidetes ratio - a real, drug-associated compositional shift, bounded by the absence of a placebo arm and a small, age-restricted sample.

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: Alpha diversity (Shannon's index, Simpson's diversity) showed no significant change. Of seven genera with a nominal between-timepoint difference, only Parabacteroides survived FDR correction; the others are not reported as robust findings.
  • At-risk subgroups: Study population limited to adults 50 and older; the published cohort description is predominantly women in the postmenopausal age range. Findings may not generalize to younger adults or to men.
  • Counter-evidence on record: No placebo or untreated-insomnia comparator arm, so confounding by indication cannot be excluded (Hard Rule 6): the insomnia disorder itself, aging-related microbiome drift over 12 weeks, diet, or other unmeasured factors could plausibly produce part or all of this shift rather than lemborexant specifically. Sleep-efficiency correlations reported for other genera ( Akkermansia, r=-0.754) are exploratory, not independently validated, and are noted here as context, not as part of the graded claim.

Regulatory status

Not addressed in the FDA label; no microbiome-related warning or monitoring requirement exists.

Population evidence

"FLUID" study: open-label, single-arm, single-center pilot. 29 enrolled, 27 completed 12 weeks. Adults ≥50y (mean 58.8y, range 50-72), 48% male, mean insomnia duration 6.3±7.2y. 16S rRNA sequencing at baseline and week 12. Parabacteroides relative abundance fell from 0.0179 to 0.0111 (p=0.0001; q<0.0001 after false-discovery-rate correction across 7 genera tested, the only one to survive correction). Beta diversity (Jaccard dissimilarity) and the Firmicutes/Bacteroidetes ratio both increased at week 12 versus baseline (p<0.05). Nature and Science of Sleep 17:1709-1726, 2025.

Mechanism

Not directly tested. Authors propose a microbiota-gut-brain axis pathway, plausibly linked to orexin's known role in gut motility and circadian signaling, but no causal pathway was isolated in this study.

Counter-evidence held on record

This is a compositional shift documented in one small, uncontrolled pilot study, not an established clinical deficiency and not a probiotic indication. No probiotic, prebiotic, fiber, or other supplement is recommended on the basis of this single study.

Oxygen and ATP Output

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

ATP production - class-level, reverse-direction signal only, not lemborexant-specific

Yellow — Low

See study details

A same-class dual orexin receptor antagonist (suvorexant) increased fat oxidation and reduced protein catabolism during sleep in a human crossover trial, without changing total energy expenditure; no lemborexant-specific ATP or energy-metabolism study was located, and the only class-level signal available runs opposite to a depletion narrative.

Full detail, limits and 1 references

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: No significant change in total energy expenditure in the suvorexant trial, meaning overall ATP-generating output was essentially unchanged even as the fuel source shifted. None located specific to lemborexant. This single human trial has not been independently replicated for either molecule.
  • At-risk subgroups: Not established for lemborexant. The only supporting data is a single small trial (n=14) in healthy men on a different DORA molecule, a single night of dosing, not studied in women, older adults, or with chronic dosing.
  • Counter-evidence on record: No study was located suggesting lemborexant or suvorexant impairs ATP synthesis or cellular energy output; the available class-level direction is favorable/protective, not depleting. The cohort test passes for class (suvorexant shares target and mechanism) but molecule identity, and the single-night/healthy-men-only design, differ materially from lemborexant's actual clinical use. This source is distinct from the suvorexant rat PTSD-model study used to grade Mitochondrial burden above (see Overlap map): that study measured structural fission/fusion proteins, this one measured substrate oxidation and energy expenditure, so citing both here would not double-count a single source.

Regulatory status

Not addressed in the FDA label.

Population evidence

Class extrapolation, Tier C (cohort test: suvorexant is a defensible same-class, same-target comparator reviewed and opened in the companion B009 suvorexant dossier; lemborexant itself was not studied). Park et al., iScience 2024;27(7):110212, DOI 10.1016/j.isci.2024.110212, PMID 38993665: randomized, double-blind, placebo-controlled, crossover, n=14 healthy men, suvorexant 20 mg. Fat oxidation during sleep increased, with the effect persisting after waking the next morning; protein catabolism decreased; total energy expenditure was not significantly affected; REM sleep increased while N1 stage decreased. Tier A for suvorexant (drug in cohort), Tier C for lemborexant (class extrapolation only).

Mechanism

Orexin signaling normally promotes wakefulness-linked catabolic and thermogenic activity; antagonism during the sleep period is proposed to shift substrate utilization toward fat oxidation and spare protein, consistent with reduced orexin-driven catabolic drive while asleep. Plausible for lemborexant given shared OX1R/OX2R dual antagonism, but untested for this specific molecule.

Counter-evidence held on record

This is theoretical, class-level evidence only, from a single small trial on a different molecule, and it trends favorable rather than depleting. It is not evidence that lemborexant harms or benefits human ATP production or energy expenditure, and it does not support any supplement, weight-management, or energy-support product claim.

  • Suvorexant increases fat oxidation and decreases protein catabolism during sleep without changing total energy expenditure — Park et al., randomized, double-blind, placebo-controlled, crossover, n=14 healthy men, suvorexant 20 mg. iScience 27(7):110212, 2024. DOI 10.1016/j.isci.2024.110212, PMID 38993665. Already opened and verified in the companion B009 suvorexant dossier review. Tier A for suvorexant (drug in cohort), Tier C for lemborexant (same-class DORA extrapolation; cohort did not include lemborexant). Graded ATP production, yellow, this revision pass.Cohort did not include lemborexant; class extrapolation only.

Claims checked and not supported

These circulate online for this medication. They are listed here only so they can be answered, never as findings, and they are not graded.

A claim with no supporting evidence is not necessarily disproven. Where evidence actually argues against a claim, that is stated below.

  • Oxygen delivery/utilization

    Where it comes from: General pharmacological concern, echoed in cautious FDA labeling language for sedative-hypnotics used in patients with compromised respiratory function, that an arousal-circuit antagonist could blunt respiratory drive and lower oxygen saturation during sleep, particularly in OSA or COPD.

    Why it fails: Three lemborexant-specific, randomized, double-blind, placebo-controlled crossover trials directly measured SpO2 and apnea-hypopnea index (AHI): (1) healthy adults/elderly, single-dose 10 mg and 25 mg (n=17) - no significant SpO2 difference vs. placebo (10 mg: -0.36; 25 mg: -0.29) and no significant AHI difference; well tolerated. Clinical Drug Investigation 41:449-457, 2021, DOI 10.1007/s40261-021-01018-5. (2) Moderate-to-severe COPD, 10 mg x 8 nights (n=30) - Day 1 SpO2 difference -0.43% (p=0.065, NS), Day 8 SpO2 difference +0.47% (p=0.022, numerically favoring lemborexant and explicitly judged "not clinically meaningful" by the study authors), AHI differences non-significant on both days, and total sleep time significantly longer with lemborexant without a corresponding rise in hypoxic burden. Journal of Sleep Research, 2024, DOI 10.1111/jsr.14334, PMID 39266012. (3) A mild-OSA crossover trial was identified by title via search and by an Eisai conference-presentation summary (SLEEP 2019) as reporting consistent, reassuring respiratory-safety results, but the primary paper itself could not be opened this session (HTTP 429 on repeated attempts) and is not relied on for this verdict; it is listed under Sources as inaccessible. The two fully verified trials actively reverse the claimed direction of harm (Day 8 COPD result favors lemborexant) rather than merely leaving it unproven.

How the body handles this medication

Metabolism
Primarily metabolized by CYP3A4, and to a lesser extent CYP3A5; major circulating metabolite M10 also undergoes CYP3A metabolism.FDA label, accessdata.fda.gov 212028s007lbl.pdf, Clinical Pharmacology 12.3
Enzyme induction / inhibition
In vitro, lemborexant and M10 have the potential to induce CYP3A and CYP2B6 and a weak potential to inhibit CYP3A; no inhibition shown for CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 2E1, and no clinically relevant induction of CYP2C8/2C9/2C19. The label does not describe this induction potential as clinically established.FDA label, Clinical Pharmacology 12.3
Elimination
57.4% of an oral dose recovered in feces, 29.1% in urine, less than 1% as unchanged drug. Effective half-life approximately 17 hours (5 mg) and 19 hours (10 mg).FDA label, Clinical Pharmacology 12.3
Absorption / transport
Tmax 1-3 hours; volume of distribution 1970 L; plasma protein binding approximately 88-94%. Lemborexant is a poor P-glycoprotein substrate (M10 is a P-gp substrate); neither is a substrate of BCRP, OATP1B1, or OATP1B3. A high-fat meal decreases Cmax 23%, increases AUC 18%, and delays Tmax by 2 hours - a food-timing effect on the drug, not a drug effect on nutrient absorption.FDA label, Clinical Pharmacology 12.3
Renal / hepatic handling
No documented effect on renal tubular handling of water or electrolytes. Severe renal impairment increases AUC and somnolence risk; mild/moderate renal impairment needs no dose adjustment. Moderate hepatic impairment increases AUC, Cmax, and terminal half-life; severe hepatic impairment is not recommended and was not studied.FDA label, Use in Specific Populations 8.6, 8.7; Clinical Pharmacology 12.3
Documented food / mineral / antacid interactions
None found beyond the high-fat-meal timing effect above. No chelation, antacid, or mineral-competition interaction is described in the label or in the primary literature located for this review.FDA label, Drug Interactions 7; this review's literature search
All references used above
  1. DAYVIGO (lemborexant) full prescribing information — FDA label, accessdata.fda.gov, revision 212028s007, 2023. Used for pharmacokinetics, drug interactions, adverse-reaction rates, renal/hepatic impairment data.
  2. DAYVIGO- lemborexant tablet, film coated — DailyMed label listing, National Library of Medicine, setid 7074cb65-77b3-45d2-8e8d-da8dc0f70bfd. Cross-checked adverse-reaction table and dosage information.
  3. Lemborexant, DrugBank entry DB11951 — Used for ATC code cross-check, drug class, and brand name.
  4. WHO ATC/DDD Index, code N05CJ02 — Confirmed N05CJ02 = lemborexant; hierarchy N → N05 Psycholeptics → N05C Hypnotics and sedatives → N05CJ Orexin receptor antagonists.
  5. Gut microbiome composition changes during insomnia treatment with lemborexant ("FLUID" study) — Open-label, single-arm, single-center pilot, n=29/27. Nature and Science of Sleep 17:1709-1726, 2025. DOI 10.2147/NSS.S526037. Tier A, this drug in the studied cohort. Graded Gut microbiome risk, orange.
  6. Respiratory safety of lemborexant in healthy adult and elderly subjects — Single-dose, randomized, double-blind, placebo-controlled, three-period crossover, n=17. Clinical Drug Investigation 41:449-457, 2021. DOI 10.1007/s40261-021-01018-5. Tier A. Used in Fails verification (Oxygen delivery/utilization).
  7. Respiratory safety of lemborexant in adult and elderly subjects with moderate-to-severe chronic obstructive pulmonary disease — Multicentre, randomized, double-blind, placebo-controlled, two-period crossover, n=30. Journal of Sleep Research, 2024. DOI 10.1111/jsr.14334, PMID 39266012. Tier A. Used in Fails verification (Oxygen delivery/utilization).
  8. Respiratory safety of lemborexant in healthy adult and elderly subjects with mild obstructive sleep apnea: a randomized, double-blind, placebo-controlled, crossover study — Identified by title via search and referenced in an Eisai SLEEP 2019 conference-presentation summary as showing consistent, reassuring respiratory-safety results. Listed for completeness; not independently verified this session and not relied upon for grading.Could not be opened: repeated HTTP 429 (rate limited) on researchgate.net during this review.
  9. Lemborexant ameliorates tau-mediated sleep loss and neurodegeneration in males in a mouse model of tauopathy — P301S/E4 transgenic mice. Nature Neuroscience 28(7):1460-1472, 2025. DOI 10.1038/s41593-025-01966-7. Tier B, drug-specific, animal. Cited for background on sleep/neuroprotection only; explicitly did not measure oxidative stress or mitochondrial parameters, so not used to grade those categories (see Oxidative stress, ungraded).
  10. Suvorexant improves mitochondrial dynamics with the regulation of orexinergic and mTOR activation in rats exhibiting PTSD-like symptoms — Male Wistar rats, single-prolonged-stress paradigm. Journal of Affective Disorders, 2024. DOI 10.1016/j.jad.2024.01.045. Tier C for lemborexant (suvorexant studied, not lemborexant; defensible same-class comparator). Graded Mitochondrial burden, yellow.Cohort did not include lemborexant; class extrapolation only.
  11. Suvorexant increases fat oxidation and decreases protein catabolism during sleep without changing total energy expenditure — Park et al., randomized, double-blind, placebo-controlled, crossover, n=14 healthy men, suvorexant 20 mg. iScience 27(7):110212, 2024. DOI 10.1016/j.isci.2024.110212, PMID 38993665. Already opened and verified in the companion B009 suvorexant dossier review. Tier A for suvorexant (drug in cohort), Tier C for lemborexant (same-class DORA extrapolation; cohort did not include lemborexant). Graded ATP production, yellow, this revision pass.Cohort did not include lemborexant; class extrapolation only.
  12. Orexin-A effects on mitochondrial biogenesis, mitophagy and structure in an HEK293-APPSWE cell model of Alzheimer's disease — Found by title via search. Not used for grading.Could not be opened: HTTP 403 from publisher (Wiley) on WebFetch.
  13. Physiological Implications of Orexins/Hypocretins on Energy Metabolism and Adipose Tissue Development — Liu L, Wang Q, Liu A, Lan X, Huang Y, Zhao Z, Jie H, Chen J, Zhao Y. ACS Omega, 2019;5(1):12-19. PMID 31956801, DOI 10.1021/acsomega.9b03106. PMID/DOI identified this revision pass via PubMed search-listing lookup (not previously identified). Not used for grading.Still could not be opened this revision pass: HTTP 403 from publisher (pubs.acs.org, both the article-view and PDF paths) on WebFetch; the NCBI PMC mirror (listed as "Free PMC article" on PubMed) returned a reCAPTCHA bot-verification page instead of content on WebFetch. Sci-hub is not a permitted channel. Not cited for content, per this protocol's rule against citing a source not actually opened.
  14. Orexin system is expressed in avian muscle cells and regulates mitochondrial dynamics — Found by title via search in the original pass. Not used for grading.Still could not be identified or opened this revision pass: two separate PubMed search-listing queries ("orexin avian muscle mitochondrial dynamics," "hypocretin orexin avian muscle mitochondria") were attempted via WebFetch; the first returned HTTP 429 (rate-limited) and the second returned a reCAPTCHA bot-verification page rather than results, so even a PMID/DOI could not be confirmed this pass. Europe PMC and Crossref web search pages are disallowed by robots.txt for WebFetch. Not cited for content.
  15. Orexin and energy metabolism, narrative review — Frontiers in Endocrinology, 2022. DOI 10.3389/fendo.2022.931970. Opened and read in full; discusses orexin and "energy homeostasis" generally and an unrelated cancer-apoptosis mitochondrial pathway, with no ATP-synthesis or bioenergetics content. Used only to document the ATP production evidence gap.
  16. Drug-Nutrient Depletions Guide for Healthcare Professionals — Blackmores Institute. Checked for a circulating claim covering lemborexant, Dayvigo, suvorexant, Belsomra, daridorexant, Quviviq, or orexin receptor antagonists generally; none found, and sleep/hypnotic medications are not covered as a class in this guide.
  17. PubMed search-listing query: "lemborexant copper OR iron" — 10 results reviewed; all general iron-physiology reviews unrelated to lemborexant or orexin pharmacology. Used to document the Copper and Iron evidence gaps.
  18. PubMed search-listing query: "orexin receptor antagonist appetite food intake" — 54 results across 6 pages; first 10 reviewed, none specific to suvorexant, lemborexant, or daridorexant. Used to confirm no appetite/intake mechanism signal beyond the FDA label's own adverse-reaction table (no weight/appetite table reported for lemborexant trials).
  19. Increased CSF hypocretin-1 (orexin-A) in restless legs syndrome — Johns Hopkins/Allen et al., Neurology 59(4):639-641, 2002. PMID 12196669. Found by title via search; cited only for the reverse-direction relationship noted under Iron, ungraded (iron status affecting orexin signaling, not the reverse), not as grading evidence for a drug effect.Full text not independently opened this session; relationship direction taken from search-result abstract/title only.
  20. PubMed search-listing query: "orexin antagonist oxidative stress" — Attempted follow-up query for the Oxidative stress category.Could not complete: HTTP 429 (rate limited) on pubmed.ncbi.nlm.nih.gov.
  21. Europe PMC REST API queries (lemborexant + oxidative/copper/iron/ATP/mitochondria; orexin-antagonist class + copper/iron) — Attempted follow-up queries for Oxidative stress, Copper, and Iron categories.Could not complete: HTTP 403, organization-level network policy block at the proxy gateway (confirmed via proxy status endpoint), which also logged the same-window block against pubmed.ncbi.nlm.nih.gov, api.semanticscholar.org, api.openalex.org, api.crossref.org, and eutils.ncbi.nlm.nih.gov.
  22. PubMed search-listing query: "lemborexant oxidative stress" — Revision pass, 2026-10-01. Opened and read via WebFetch. Returned a clean, explicit "No results were found" page (meta-log_resultcount: 0), a confirmed literature negative. Used to strengthen the Oxidative stress ungraded disclosure.
  23. PubMed search-listing query: "lemborexant ATP OR mitochondria energy" — Revision pass, 2026-10-01. Attempted follow-up query for ATP production.Could not complete: HTTP 429 (rate-limited) via WebFetch proxy, with an explicit instruction not to retry the same page.
  24. PubMed search-listing query: "orexin receptor antagonist copper" — Revision pass, 2026-10-01. Opened and read via WebFetch. Returned 2 results, both synthetic-chemistry papers on copper-catalyzed synthesis of suvorexant or unrelated copper catalysis, not biological copper-status findings. Used to strengthen the Copper ungraded disclosure.
  25. PubMed search-listing query: "orexin iron hypocretin ferritin" — Revision pass, 2026-10-01. Opened and read via WebFetch. Returned 2 results: Barateau et al. 2020 ( Ann Clin Transl Neurol, PMID 32432412), narcolepsy type 1 with/without RLS, no between-group difference in CSF/serum ferritin or CSF orexin; and an unrelated 2003 RLS/akathisia paper. Neither passes the cohort test for a lemborexant or DORA drug effect (disease population, endogenous orexin, wrong direction). Used to strengthen the Iron ungraded disclosure.
  26. PubMed search-listing queries: "orexin avian muscle mitochondrial dynamics" and "hypocretin orexin avian muscle mitochondria" — Revision pass, 2026-10-01. Attempted to identify a PMID/DOI for the avian-muscle orexin/mitochondria study.Neither completed: the first returned HTTP 429 (rate-limited); the second returned a reCAPTCHA bot-verification challenge page instead of search results.
  27. Direct publisher/host reachability check, this revision pass (2026-10-01) — curl CONNECT attempts, confirmed via the proxy status endpoint (recentRelayFailures), to pubmed.ncbi.nlm.nih.gov, api.crossref.org, api.semanticscholar.org, api.openalex.org, eutils.ncbi.nlm.nih.gov, www.ebi.ac.uk, dailymed.nlm.nih.gov, api.unpaywall.org, doi.org, pmc.ncbi.nlm.nih.gov, www.ncbi.nlm.nih.gov, scholar.google.com, europepmc.org, www.accessdata.fda.gov, frontiersin.org, www.nature.com, link.springer.com, onlinelibrary.wiley.com, www.mdpi.com, www.sciencedirect.com, www.researchgate.net, www.biorxiv.org, duckduckgo.com, www.bing.com, en.wikipedia.org, go.drugbank.com, atcddd.fhi.no, www.dovepress.com.All rejected at the organization network proxy gateway with HTTP 403 (connect_rejected, policy denial), including several hosts (accessdata.fda.gov, en.wikipedia.org, go.drugbank.com, atcddd.fhi.no, dailymed.nlm.nih.gov, dovepress.com) that were reachable and cited in the original pass of this dossier, confirming the network-policy block widened between passes rather than narrowed. WebFetch (a separate fetch path) still reached some of these hosts (for example en.wikipedia.org), so WebFetch rather than direct curl was used as the primary channel for all research in this revision pass.