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MyDeficiencies

Ramelteon

Melatonin receptor agonist (MT1/MT2)

Also sold as Rozerem.

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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.

Ramelteon has no classical nutrient-depletion machinery. It undergoes extensive first-pass hepatic metabolism, chiefly by CYP1A2 with minor CYP2C9/CYP3A4 contribution, yielding an oral bioavailability of only 1.8% despite absorption of at least 84%; it is eliminated almost entirely as metabolites in urine and feces (less than 0.1% excreted unchanged), and it does not itself induce or inhibit any CYP enzyme. Tested against all nine classical depletion mechanisms, every one came back absent: no chelation or gastric-pH-mediated absorption interference, no enzyme-induction-driven catabolism of other compounds, no renal tubular wasting (no dose adjustment is needed in renal impairment), no antagonism of a nutrient cofactor, no dilutional or aldosterone/ADH-type hormonal disturbance, no microbiome-mediated synthesis disruption, and no clinically meaningful intake suppression. That absence of a mechanism is itself the dossier's first finding, not a gap to fill in later.

Melatonin receptor agonist (MT1/MT2) · ATC N05CH02 · also sold as Rozerem · 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 Ramelteon 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, preclinical protective signal, not a human deficiency

Yellow — Low

See study details

In cell and animal injury models, ramelteon itself preserves mitochondrial membrane potential and biogenesis under experimental oxidative, ischemic, and toxic stress, a reverse-direction, protective pharmacological finding, not evidence of a mitochondrial nutrient deficiency caused by the drug.

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: No study was found reporting ramelteon worsening mitochondrial function. The neurotoxicity model (Li et al. 2021) did not measure ATP at all, a gap rather than a contradicting result, and limits how far the mitochondrial-protective claim can be generalized beyond the models that measured ATP directly.
  • At-risk subgroups: None identified; no subgroup is shown at elevated risk of mitochondrial harm from ramelteon.
  • Counter-evidence on record: All four models used disease/injury or stress conditions and concentrations or doses not established as pharmacokinetically equivalent to the clinical 8 mg oral human dose; none is a healthy-tissue or human study, so the finding cannot be read as ramelteon improving baseline mitochondrial status in an ordinary insomnia patient.

Regulatory status

Not addressed in FDA labeling; no mitochondrial safety signal is listed for ramelteon.

Population evidence

No human data. Four independent Tier B drug-specific preclinical models: (1) human SH-SY5Y neuroblastoma cells, MPP+ neurotoxicity; ramelteon 50-100 nM rescued mitochondrial membrane potential from 46% of control (MPP+ alone) to 73% (50 nM) and 95% (100 nM) (Li et al. 2021). (2) C57BL/6 mice plus HK-2 human renal tubular cells, ischemia/hypoxia-reoxygenation injury; ramelteon 3 mg/kg (animal, i.p.) or 60 nM (cell) normalized the mitochondrial fission/fusion balance (reduced Drp1, Fis1, Mff; restored Mfn1, Mfn2) and enhanced membrane potential (Chen et al. 2023). (3) Isolated Langendorff-perfused rat hearts, global ischemia; ramelteon 0.03 µM reduced infarct size from 53% to 34% (P=0.0082) via an MT2-receptor-dependent, mitochondrial-permeability-transition-pore-linked pathway (Stroethoff et al. 2020). (4) Porcine oocytes, in vitro maturation; ramelteon 10⁻¹¹ to 10⁻⁵ M upregulated mitochondrial biogenesis genes (TFAM, NRF1, NRF2, TFB1M, TFB2M, PGC1α) and raised mtDNA copy number (Sun et al. 2022).

Mechanism

Named in part: MT1/MT2 receptor signaling converging on mitochondrial permeability transition pore inhibition and Bax/Bcl-2 rebalancing (cardiac, neuronal, renal models) and on biogenesis gene upregulation (oocyte model). The precise upstream signaling (e.g., Nrf2 involvement) is explicitly flagged as needing further study in the neurotoxicity paper.

Counter-evidence held on record

This is preclinical, disease-model pharmacology, not clinical evidence that ramelteon treats, prevents, or corrects a mitochondrial nutrient deficiency in people taking it for insomnia. No mitochondrial-support supplement or dose is implied or recommended by this entry.

Oxidative Stress

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

Oxidative stress, protective in injury models, with a context-dependent ROS role

Yellow — Low

See study details

The same preclinical injury models, plus a cerebral-toxicity model, show ramelteon lowering reactive oxygen species and restoring antioxidant enzyme activity under experimental stress, a protective, reverse-direction, drug-specific signal in disease models, with one study showing the relationship is more complex than simple antioxidant activity.

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: Stroethoff et al. 2020 is itself a built-in counter-finding: it shows that "ramelteon reduces oxidative stress" is an oversimplification in at least one model, where transient ROS generation is mechanistically necessary rather than harmful.
  • At-risk subgroups: None identified.
  • Counter-evidence on record: See mechanism row: the cardiac model's ROS-dependency finding is recorded here specifically so a reader does not read every oxidative-stress finding in this entry as uniformly "antioxidant." All evidence remains preclinical injury-model data, not a human antioxidant-status finding.

Regulatory status

Not addressed in FDA labeling; no oxidative-stress safety signal is listed.

Population evidence

No human data. Five independent Tier B drug-specific preclinical sources: the same four models as the Mitochondrial burden entry (Li et al. 2021: mitochondrial ROS reduced from 3.5-fold to 2.6-fold [50 nM] and 1.8-fold [100 nM] of control; protein carbonyl and NOX-4 similarly suppressed; Chen et al. 2023: SOD, catalase, and GSH significantly restored in ramelteon-treated mice versus injury alone; Stroethoff et al. 2020: see counter-evidence below; Sun et al. 2022: GSH significantly increased and ROS significantly decreased across all tested concentrations, SOD1 protein elevated at 10⁻¹¹ M), plus a fifth: male Wistar rats, methotrexate-induced cerebral toxicity, ramelteon 10 mg/kg orally for 7 days reversed total oxidant status, total antioxidant status, and oxidative stress index, and lowered TNF-α and caspase-3 activity (Iran J Basic Med Sci, approx. 2022).

Mechanism

Named in four of five models as antioxidant-enzyme restoration (SOD/CAT/GSH) and direct ROS suppression. The cardioprotection model names a more specific, partly opposite mechanism: a brief, MT2-receptor-dependent burst of ROS release is itself required as a signaling trigger for ramelteon's protective effect; scavenging that ROS with the agent MPG abolished cardioprotection entirely (Stroethoff et al. 2020).

Counter-evidence held on record

Preclinical, disease-model pharmacology only, with a model-dependent and in one case opposite-direction relationship to ROS. Not evidence that ramelteon improves antioxidant status in a human taking it for sleep, and no antioxidant supplement or dose is implied or recommended.

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 ramelteon-specific evidence, at any tier, addresses copper status or metabolism, and no circulating consumer claim about ramelteon and copper was found 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: The Step 7 dual condition is met: no Tier B/C evidence exists to support even a yellow grade, and no circulating claim exists to rebut as white. The FDA label contains no copper-related mechanism, laboratory table, or warning. Search channels tried: WebSearch ("ramelteon copper", before the session search budget was exhausted), the Crossref REST API (query "ramelteon copper", 8 results returned, none containing "ramelteon"; a follow-up query "ramelteon copper zinc trace mineral" returned 10 animal-nutrition results, again none containing "ramelteon"), and general pharmacology references (DrugBank, FDA label) consulted for this review. Direct PubMed search-listing queries for this term were blocked by bot-verification/HTTP 429 responses during this review and could not be completed; this is disclosed as a tooling limitation, not folded silently into the gap finding.

Iron

Not graded — disclosed evidence gap

See study details

No ramelteon-specific evidence, at any tier, addresses iron status, hemoglobin, or hematologic parameters, and no circulating consumer claim about ramelteon and iron was found 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: The Step 7 dual condition is met. The FDA label was searched specifically for hematology, hemoglobin, hematocrit, anemia, white-cell, iron, and ferritin terms and contains no such laboratory-abnormality tables or mechanism language from clinical trials. Search channels tried: WebSearch ("ramelteon anemia hemoglobin"), and the Crossref REST API (query "ramelteon iron copper hemoglobin", 10 results returned, all general iron/copper/hemoglobin nutrition-science papers from unrelated fields; none referenced ramelteon). No absorption-chelation, renal-wasting, or GI-bleeding mechanism is present in the pharmacokinetic prescreen that would plausibly implicate iron. Direct PubMed search-listing queries for this term were blocked (bot-verification/HTTP 429) during this review and could not be completed; disclosed as a tooling limitation.

Gut Microbiome Risk

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

Gut microbiome risk

Not graded — disclosed evidence gap

See study details

No primary study tests ramelteon's effect on gut microbiome composition or function, and no circulating consumer claim was found to rebut. Broader circadian-rhythm/melatonin-microbiome literature exists but does not place ramelteon in its studied cohort.

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: The Step 7 dual condition is met on current evidence. Search channels tried, with multiple phrasings: WebSearch ("ramelteon gut microbiome", before budget exhaustion); the Europe PMC REST API with a broad query (ramelteon AND microbiome/microbiota/gut: 183 hits; the first 25 were reviewed and were general circadian-rhythm, melatonin, or insomnia-microbiome literature with no ramelteon-specific cohort, failing the Hard Rule 6 cohort test); and a title-restricted Europe PMC query (ramelteon in title AND microbiome/microbiota/dysbiosis: 1 hit, a 2025 narrative review in Molecules covering melatonin, tasimelteon, ramelteon, and agomelatine collectively). That review's full text was not opened during this review (a follow-up abstract-restricted query was blocked by HTTP 429 before it could be confirmed), so it is listed in Sources as an identified-but-unverified lead, not relied on as supporting evidence; at best it would be a Tier C class-level narrative source, and only once its content is actually confirmed to discuss ramelteon and the microbiome specifically. The Crossref REST API channel for this specific nutrient was also rate-limited (HTTP 429) before a dedicated query could complete. This is disclosed as a genuine current gap with a specific unresolved lead, not a silent omission, and is flagged for re-check in a future revision.

Oxygen and ATP Output

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

ATP production, raised under injury/maturation stress in two models

Yellow — Low

See study details

Two independent preclinical models that directly measured cellular ATP found ramelteon increased it under experimental stress, a mechanistic, reverse-direction signal, not evidence that ramelteon treats or prevents a human energy-metabolism deficiency.

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: The third mitochondrial model in this dossier (Li et al. 2021, neurotoxicity) did not measure ATP at all, so this finding rests on two models rather than the broader four used for the mitochondrial-burden entry. No study was found reporting ramelteon lowering ATP.
  • At-risk subgroups: None identified.
  • Counter-evidence on record: No human pharmacodynamic, metabolic-rate, or energy-expenditure study of any kind exists for ramelteon; both supporting studies are stress/injury or maturation models, not resting-state measurements, and neither establishes a dose equivalent to the clinical 8 mg human dose.

Regulatory status

Not addressed in FDA labeling.

Population evidence

No human data. Two independent Tier B drug-specific sources that directly measured ATP: HK-2 human renal tubular cells under hypoxia/reoxygenation, where ramelteon 60 nM "markedly elevated ATP levels" compared with injury alone (Chen et al. 2023); and porcine oocytes during in vitro maturation, where ramelteon 10⁻¹¹ M raised ATP production alongside mtDNA copy number and biogenesis-gene expression, and improved downstream blastocyst formation (31.9% vs. 13.7% in control) (Sun et al. 2022).

Mechanism

Named: enhanced mitochondrial biogenesis (TFAM/NRF1/NRF2/PGC1α pathway) and reduced fission-driven mitochondrial fragmentation, both of which increase ATP-generating capacity in the two models tested.

Counter-evidence held on record

Preclinical and model-specific. This is not an energy-supplement or "boosts ATP" rationale for consumers; no dose or supplement is implied or recommended.

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 class-level safety concern applied to sedative-hypnotics, including melatonin-receptor agonists: that a sleep medication could blunt respiratory drive and lower overnight oxygen saturation, particularly in patients with COPD or obstructive sleep apnea, by analogy to benzodiazepines and other classical hypnotics.

    Why it fails: Directly and specifically rebutted by two independent Tier A, randomized, double-blind, placebo-controlled crossover polysomnography trials with ramelteon in the cohort. Kryger et al. 2008 (n=26, mild-to-moderate COPD, single 16 mg dose, twice the approved therapeutic dose): mean overnight SaO2 92.9% (ramelteon) vs. 92.9% (placebo), P=0.972; apnea-hypopnea index 9.0 vs. 8.3, P=0.515; no significant difference in time with SaO2 <85% or <90%. Kryger et al. 2009 (n=25, moderate-to-severe COPD, single 8 mg therapeutic dose): mean overnight SaO2 92.2% vs. 92.5%, P=0.576; no significant difference in time with SaO2 <80% or <90%; authors concluded ramelteon "did not produce respiratory depressant effects." A third drug-specific trial in mild-to-moderate obstructive sleep apnea (Kryger, Wang-Weigand, Zhang; PMID 17294232) is reported in the literature as reaching a similar safety conclusion; its full quantitative data could not be independently re-verified in this review because PubMed blocked direct access with a bot-verification page, so it is listed in Sources with an access note and is not required to support this rebuttal, which already rests on two fully-verified Tier A sources.

How the body handles this medication

Metabolism
CYP1A2 is the major hepatic isozyme; CYP2C9 and CYP3A4 contribute to a minor degree. Oxidation to hydroxyl/carbonyl metabolites (M-I through M-IV) with secondary glucuronide conjugation. Absolute oral bioavailability is only 1.8% despite ≥84% absorption, due to extensive first-pass metabolism.FDA label, Rozerem PI, 2018, Sections 12.3
Enzyme induction/inhibition
No evidence that ramelteon itself induces or inhibits any CYP enzyme.FDA label, Rozerem PI, 2018, Section 7
Elimination
Approximately 84% of total radioactivity excreted in urine and 4% in feces, almost entirely as metabolites; less than 0.1% of the dose recovered as unchanged parent drug. No renal tubular or electrolyte-handling effects reported; no dosage adjustment needed in renal impairment.FDA label, Rozerem PI, 2018, Section 12.3
Hepatic impairment
Exposure (AUC) increases approximately 4-fold in mild and more than 10-fold in moderate hepatic impairment; use with caution in moderate impairment and avoid in severe hepatic impairment.FDA label, Rozerem PI, 2018, Section 8.6
Food effect
A high-fat meal increased AUC by 31%, decreased Cmax by 22%, and delayed median Tmax by about 45 minutes; the label recommends not taking ramelteon with or immediately after a high-fat meal.FDA label, Rozerem PI, 2018, Section 12.3
Key CYP-mediated interactions
Contraindicated with fluvoxamine (strong CYP1A2 inhibitor: AUC up ~190-fold). Use with caution with ketoconazole (AUC +84%), fluconazole (AUC +150%), donepezil (AUC +100%), and doxepin (AUC +66%). Rifampin (strong CYP inducer) decreased total exposure by ~80%.FDA label, Rozerem PI, 2018, Sections 4 & 7
All references used above
  1. ROZEREM (ramelteon) tablets, full prescribing information. — FDA label, NDA 21-782/S-021, revised 2018. Regulatory label; Tier A.
  2. Ramelteon (DB00980). — DrugBank Online, accessed 2026. Used to confirm ATC code N05CH02 and class. Reference database; Tier A regulatory cross-reference.
  3. Kryger M, Wang-Weigand S, Zhang J, Roth T. Effect of ramelteon, a selective MT1/MT2-receptor agonist, on respiration during sleep in mild to moderate COPD. — Sleep Breath. 2008;12(3):243-250. doi:10.1007/s11325-007-0156-4. Randomized, double-blind, crossover; n=26, mild-moderate COPD, ramelteon in cohort. Tier A.
  4. Kryger M, Roth T, Wang-Weigand S, Zhang J. The effects of ramelteon on respiration during sleep in subjects with moderate to severe chronic obstructive pulmonary disease. — Sleep Breath. 2009;13(1):79-84. doi:10.1007/s11325-008-0196-4. Double-blind crossover; n=25, moderate-severe COPD, ramelteon in cohort. Tier A.
  5. Kryger M, Wang-Weigand S, Zhang J. Safety of ramelteon in individuals with mild to moderate obstructive sleep apnea. — Sleep Breath. PMID 17294232. Ramelteon-specific OSA safety trial; cited at title/PMID level only.Access note: PubMed returned a bot-verification page and then repeated HTTP 429 responses on every attempt during this review; full abstract/quantitative data could not be independently confirmed and this source was not used to support any graded claim.
  6. Li C, Zhang Y, Liu R, Mai Y. Ramelteon ameliorated 1-methyl-4-phenylpyridinium (MPP+)-induced neurotoxicity in neuronal cells in a mitochondrial-dependent pathway. — Bioengineered. 2021;12(1). doi:10.1080/21655979.2021.1960767. In vitro, human SH-SY5Y neuroblastoma cells, ramelteon 50-100 nM. Tier B.
  7. Chen P, Liu W, Wei Y. Ramelteon attenuates renal ischemia and reperfusion injury through reducing mitochondrial fission and fusion and inflammation. — Transl Androl Urol. 2023;12(12):1859-1870. doi:10.21037/tau-23-543. In vivo (C57BL/6 mice, 0.3-3 mg/kg) and in vitro (HK-2 cells, 10-60 nM). Tier B.
  8. Sun J-T, et al. Ramelteon reduces oxidative stress by maintenance of lipid homeostasis in porcine oocytes. — Antioxidants. 2022;11(9):1640. doi:10.3390/antiox11091640. In vitro, porcine oocytes during in vitro maturation, ramelteon 10⁻¹¹ to 10⁻⁵ M. Tier B.
  9. Stroethoff M, Goetze L, Torregroza C, et al. The melatonin receptor agonist ramelteon induces cardioprotection that requires MT2 receptor activation and release of reactive oxygen species. — Cardiovasc Drugs Ther. 2020;34(3):303-310. doi:10.1007/s10557-020-06972-4. Isolated Langendorff-perfused rat hearts, ramelteon 0.03 µM. Tier B.
  10. Ameliorating effects of ramelteon on oxidative stress, inflammation, apoptosis, and autophagy markers in methotrexate-induced cerebral toxicity. — Iranian Journal of Basic Medical Sciences, article 21026, approx. 2022. Male Wistar rats, ramelteon 10 mg/kg orally x 7 days. Tier B.Access note: exact volume/issue/page and DOI could not be confirmed; a Crossref lookup and a ResearchGate citation-page fetch both returned HTTP 429 during this review. The article page itself was opened directly and its content extracted; only the formal citation metadata is incomplete.
  11. The efficacy of melatonergic receptor agonists used in clinical practice in insomnia treatment: melatonin, tasimelteon, ramelteon, agomelatine, and selected herbs. — Molecules. 2025; PMID 41011705. Narrative review covering five agents collectively.Access note: identified as the sole title-level hit for a ramelteon+microbiome search but not opened during this review (follow-up query blocked by HTTP 429); not used to support any graded or ungraded claim, listed only as an unresolved lead for a future revision of the Gut microbiome risk entry.
  12. Crossref REST API search, query "ramelteon copper" and "ramelteon copper zinc trace mineral." — Negative-evidence search documentation for the Copper entry; no result contained "ramelteon." Accessed via api.crossref.org.
  13. Crossref REST API search, query "ramelteon iron copper hemoglobin." — Negative-evidence search documentation for the Iron entry; 10 results returned, none containing "ramelteon." Accessed via api.crossref.org.
  14. Europe PMC REST API search, query "ramelteon AND (microbiome OR microbiota OR gut)" and a title-restricted variant. — Negative/near-negative-evidence search documentation for the Gut microbiome risk entry; 183 hits on the broad query (top 25 reviewed, none ramelteon-specific), 1 hit on the title-restricted query. Accessed via www.ebi.ac.uk/europepmc/webservices/rest.