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MyDeficiencies

Doxepin

Tricyclic antidepressant (dibenzoxepine, non-selective monoamine reuptake inhibitor, potent H1 antihistamine)

Also sold as Silenor, Sinequan.

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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.

Doxepin is metabolized primarily by CYP2C19 and CYP2D6 (CYP1A2 and CYP2C9 to a lesser extent) to its active metabolite N-desmethyldoxepin (nordoxepin), is not itself a documented inducer of any CYP enzyme, and is excreted overwhelmingly as glucuronide-conjugated metabolites in urine, with less than 3% recovered unchanged. No absorption-interference, chelation, or renal-wasting mechanism is documented in either FDA label. That absence of classical depletion machinery, the same starting point found for the other tricyclics reviewed in this series (nortriptyline, batch B007), held up under a dedicated drug-specific search: no evidence at any tier connects doxepin to folate, vitamin B12, riboflavin, zinc, or coenzyme Q10 status, and a search combining doxepin with coenzyme Q10 returned a clean zero PubMed results, the same "drug mugging" marketing claim already rebutted for this drug's TCA relatives. What this review did find, independent of any inherited class assumption, is a genuinely different and more dose-differentiated picture than either amitriptyline or nortriptyline showed. Two independent, drug-specific animal and cell studies, one in mouse hepatocytes with in vivo confirmation in obese diabetic mice (Chen et al, Diabetes 2020), one in cultured rat astrocytes (Trzeciak et al), both found doxepin increases rather than depletes cellular ATP content, the hepatocyte study naming a specific mechanism (FAM3A pathway activation via HNF4-alpha nuclear translocation). A separate line of antimicrobial-repurposing research found doxepin has direct antifungal and anti-biofilm activity against multiple Candida species, mediated by inducing oxidative stress and mitochondrial damage inside the fungal cells themselves, while the same drug showed no antibacterial activity against two bacterial species tested (Bacillus subtilis, Pseudomonas aeruginosa); this is real, drug-specific, replicated evidence of doxepin altering a component of the human mycobiome, and it is graded under Gut microbiome risk below, clearly separated from any claim about doxepin harming the patient's own mitochondria, which it does not appear to do in the mammalian-tissue studies located (protective, not damaging, in cultured neurons and in a rat kidney injury model).

Tricyclic antidepressant (dibenzoxepine, non-selective monoamine reuptake inhibitor, potent H1 antihistamine) · ATC N06AA12 · also sold as Silenor (low-dose insomnia tablet) and Sinequan (discontinued US brand) and doxepin HCl capsules/oral concentrate (generic) · reviewed 2026-09-30. 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 Doxepin 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

Sodium / SIADH

Orange — Moderate

See study details

The current doxepin HCl (higher, depression-range dose) label lists inappropriate antidiuretic hormone secretion as a postmarketing adverse reaction; the current Silenor (low, insomnia-range dose) label contains no hyponatremia, SIADH, sodium, or antidiuretic language anywhere in its text, a genuine, disclosed dose-range difference. This is a retention, not a depletion, finding and must never suggest supplementation.

Full detail and limits

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 Silenor label's complete silence on this term, across its entire text, at the low insomnia dose is itself recorded here as a genuine negative finding for that dose range, not merely an absence of data.
  • At-risk subgroups: Not specified in the label. By general SIADH risk-factor knowledge (elderly patients, low-sodium intake, concurrent diuretics or other SIADH-associated drugs), these subgroups would be expected to carry higher risk if the class mechanism applies to doxepin, but this is not itself drug-specific evidence.
  • Counter-evidence on record: The Silenor label's silence on this term at the low dose is the principal counter-evidence bounding this entry to the higher dose range; no case report specifically documenting doxepin-associated hyponatremia or SIADH was located in this review to corroborate the label listing beyond the label itself.

Regulatory status

FDA label (doxepin HCl capsules/oral concentrate, Reference ID 5619040, 2025), section 6.2 Postmarketing Experience, Endocrine Disorders: "Inappropriate antidiuretic hormone secretion." The label's own postmarketing-section boilerplate states: "Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure." No hyponatremia, SIADH, sodium, or antidiuretic term appears anywhere in the current SILENOR label text (confirmed by a full-text term search of that label).

Population evidence

FDA label (doxepin HCl), section 6.2 (Tier A, postmarketing spontaneous reports, higher/depression dose range). No dedicated human cohort or case-control study of doxepin and hyponatremia was located in this review; the label listing is the only source found.

Mechanism

Not named in the label. By class analogy to other TCAs, and to the SIADH mechanism documented with Tier A evidence for amitriptyline in the companion series, the proposed mechanism is antidiuretic-hormone-mediated water retention causing dilutional sodium reduction, not a sodium-wasting or intake mechanism; this is disclosed as a class-level mechanistic inference, not doxepin-specific confirmation, per Hard Rule 6.

Counter-evidence held on record

This is a water-retention, dilutional-sodium risk, not a sodium or fluid deficiency. Supplementing sodium or restricting water intake without a prescriber's guidance would be the wrong response to this finding, not a corrective one. This risk is bounded to the higher, depression-range dose per the current labels reviewed; it is not documented for the low-dose insomnia formulation.

Cardiac potassium channel

Yellow — Low

See study details

Doxepin blocks the cardiac hERG potassium channel in vitro, and case reports of doxepin-associated torsade de pointes span four decades, but Silenor's own dedicated thorough QTc study at doses up to 50 mg (above the entire insomnia dose range) found no QT effect, and no evidence identified suggests this risk works through potassium or magnesium depletion.

Full detail, limits and 4 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 findings: Silenor's own dedicated thorough QTc study, at doses up to 50 mg, well above the approved 3 to 6 mg insomnia range, found no QT effect in healthy subjects, a real Tier A human finding directly bounding this risk away from the low-dose insomnia indication. No study identified found doxepin lowering serum potassium or magnesium; the Qureshi 2023 case report explicitly ruled out electrolyte imbalance as a cause of that patient's arrhythmia.
  • At-risk subgroups: Overdose (the 2001 case), patients with other QT-prolonging drugs or pre-existing cardiac conduction disease, and CYP2D6/CYP2C19 poor metabolizers with elevated plasma levels (a mechanism named in the PK basis above, not confirmed in any individual case report reviewed here).
  • Counter-evidence on record: Silenor's own thorough QTc study at doses up to 50 mg is itself strong counter-evidence against a clinically meaningful QT effect at the approved low insomnia dose; the 1982 case, occurring at "small amounts" with a normal baseline QT interval, is a genuine outlier that does not fit a simple dose-response pattern and is disclosed as such rather than smoothed over.

Regulatory status

FDA label (SILENOR), section 12.2: "In a thorough QTc prolongation clinical study in healthy subjects, doxepin had no effect on QT intervals or other electrocardiographic parameters after multiple daily doses up to 50 mg." Neither label provides quantitative delta-QTc values or study-design detail (crossover vs. parallel, subject count, positive control) beyond this statement.

Population evidence

Duncan RS, McPate MJ, Ridley JM, et al, "Inhibition of the HERG potassium channel by the tricyclic antidepressant doxepin," Biochem Pharmacol 2007, DOI 10.1016/j.bcp.2007.04.024, PMID 17560554 (Tier B, in vitro, whole-cell patch-clamp on recombinant hERG-expressing HEK293 cells and native IKr from rabbit ventricular Purkinje myocytes) - doxepin blocked recombinant hERG with IC50 6.5 plus or minus 1.4 micromolar and native IKr with IC50 4.4 plus or minus 0.6 micromolar; the authors note therapeutic plasma levels (0.16 to 0.8 micromolar, potentially reaching 3.2 micromolar) combined with cardiac tissue accumulation up to 41-fold above plasma could bring myocardial concentrations into a clinically relevant range, and conclude hERG blockade "is likely to underpin reported cases of QT interval prolongation with doxepin." Case reports span four decades: Strasberg B et al, "Doxepin Induced Torsade De Pointes," Pacing Clin Electrophysiol 1982, DOI 10.1111/j.1540-8159.1982.tb06570.x, PMID 6184690 (Tier B, human case, "small amounts" of doxepin, normal baseline QT interval, arrhythmia reproduced on rechallenge). Alter P, Tontsch D, Grimm W, "Doxepin-Induced Torsade de Pointes Tachycardia," Ann Intern Med 2001, DOI 10.7326/0003-4819-135-5-200109040-00026, PMID 11529713 (Tier B, human case, massive 6-gram suicide-attempt overdose, sinus tachycardia 132 bpm with prolonged QT, torsade managed with magnesium and temporary pacing). Qureshi PJ, "Doxepin Induced Torsades de Pointes in a Middle-aged Female: A Case Report," Int J Med Case Rep 2023, DOI 10.5281/zenodo.10997912 (Tier B, human case, therapeutic depression-range dosing, no prior cardiac history; the case report explicitly states investigations "ruled out electrolyte imbalances and other common causes of QT prolongation").

Mechanism

Direct hERG channel-protein binding and blockade, named consistently in the in vitro study; the case reports do not identify a consistent secondary mechanism beyond this channel effect, and one case (Qureshi 2023) specifically excludes an electrolyte-mediated mechanism.

Counter-evidence held on record

Do not present this as doxepin depleting potassium or magnesium; the one case report that addressed electrolytes directly ruled that mechanism out. Do not present the low-dose insomnia formulation as carrying the same cardiac risk documented in the overdose and depression-dose case reports; Silenor's own thorough QTc study at doses well above its approved range found no effect, and this entry's title states that boundary explicitly.

  • Duncan RS, McPate MJ, Ridley JM, Gao Z, James AF, Leishman DJ, Leaney JL, Witchel HJ, Hancox JC. "Inhibition of the HERG potassium channel by the tricyclic antidepressant doxepin." Biochem Pharmacol. 2007. — Tier B, in vitro, recombinant hERG-HEK293 cells and native rabbit Purkinje IKr. DOI 10.1016/j.bcp.2007.04.024, PMID 17560554.
  • Strasberg B, Coelho A, Welch WJ, Swiryn S, Bauernfeind RA, Rosen K. "Doxepin Induced Torsade De Pointes." Pacing Clin Electrophysiol. 1982. — Tier B, human case report, "small amounts" of doxepin, normal baseline QT interval. DOI 10.1111/j.1540-8159.1982.tb06570.x, PMID 6184690. Abstract reconstructed via OpenAlex.
  • Alter P, Tontsch D, Grimm W. "Doxepin-Induced Torsade de Pointes Tachycardia." Ann Intern Med. 2001. — Tier B, human case report, 6-gram suicide-attempt overdose. DOI 10.7326/0003-4819-135-5-200109040-00026, PMID 11529713. Full text returned HTTP 403 during this review; abstract reconstructed via OpenAlex.Full text blocked (HTTP 403) during this review; bibliographic and abstract detail obtained via OpenAlex instead.
  • Qureshi PJ. "Doxepin Induced Torsades de Pointes in a Middle-aged Female: A Case Report." Int J Med Case Rep. 2023. — Tier B, human case report, therapeutic depression-range dosing, electrolyte imbalance explicitly ruled out. DOI 10.5281/zenodo.10997912.

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 - thin, mixed-direction preclinical evidence; no depletion signal in mammalian tissue

Yellow — Low

See study details

Direct, drug-specific mammalian mitochondrial data for doxepin is limited; the clearest drug-specific finding located is that doxepin induces mitochondrial damage inside pathogenic Candida fungal cells as part of its antifungal action, an effect confined to that pathogen-killing context and not evidence of harm to the treated patient's own mitochondria.

Full detail, limits and 2 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 findings: No study located found doxepin impairing mitochondrial structure or function in normal human or mammalian tissue; the ATP-production entry below (Chen 2020, Trzeciak) found the opposite, increased cellular ATP, in two independent mammalian tissue types (hepatocyte, astrocyte), evidence against a general mammalian mitochondrial-burden effect, though ATP content and mitochondrial structural integrity are not identical measurements.
  • At-risk subgroups: Not established for mammalian tissue. The antifungal mitochondrial-damage effect is specific to the treatment target (Candida species), not a patient-safety concern.
  • Counter-evidence on record: The Candida-specific finding must not be conflated with harm to the treated patient's own mitochondria; this caution is stated explicitly here and cross-referenced in the Overlap map, since the same source is also cited under Oxidative stress and Gut microbiome risk.

Regulatory status

Not addressed in either FDA label.

Population evidence

Pinheiro DRS, Barbosa SA, de Oliveira LC, et al, "Antifungal and anti-biofilm activity of doxepin against Candida spp. mediated by oxidative stress and modulation of adhesion-related genes," Microb Pathog 2026, DOI 10.1016/j.micpath.2026.108735, PMID 42508701 (Tier B, in vitro, Candida planktonic cells and biofilms including fluconazole-resistant isolates) - doxepin produced fungicidal effects, with analyses showing induced reactive oxygen production, measured mitochondrial damage, and apoptosis-marker changes specifically inside the fungal cells; this is detailed further, and treated as the primary evidence, under Gut microbiome risk below, since the biological target here is a microbial cell, not host tissue. Higgins SC, Pilkington GJ, "The in vitro effects of tricyclic drugs and dexamethasone on cellular respiration of malignant glioma," Anticancer Res 2010, PMID 20332444 (Tier B, human anaplastic astrocytoma cell line IPSB-18) - doxepin was one of the tricyclic agents tested for effects on cellular respiration (oxygen-electrode measurement) in this cancer cell line; the accessible abstract text specifies inhibitory concentration ranges for amitriptyline (most potent, 0.14 to 0.5 mM) and clomipramine/norclomipramine (0.5 to 0.9 mM) but does not isolate doxepin's own individual inhibitory potency, a limitation of the retrievable abstract disclosed here rather than assumed; doxepin's inclusion in the tested panel is confirmed but its individual effect size is not.

Mechanism

In the Candida-specific finding, oxidative-stress induction and mitochondrial damage inside the fungal cell, alongside downregulation of adhesion-related virulence genes; this is the drug's own antimicrobial pharmacology acting on a pathogen, not a mechanism of harm to human mitochondria. No mammalian-tissue mitochondrial-damage mechanism was located for doxepin in this review.

Counter-evidence held on record

This entry rests on thin, mostly pathogen-context evidence; it must never be presented as doxepin damaging a treated patient's own mitochondria. This entry shares its primary source (Pinheiro 2026) with Oxidative stress and Gut microbiome risk below; see the Overlap map.

  • Pinheiro DRS, Barbosa SA, de Oliveira LC, Cabral VPF, Rodrigues DS, da Costa ERM, Silveira MJCB, Moreira LEA, Cavalcanti BC, Magalhaes IL, dos Santos CAL, Ferreira JRO, de Moraes Filho MO, de Andrade Neto JB, Sa LGAV, da Silva CR, Nobre Junior HV. "Antifungal and anti-biofilm activity of doxepin against Candida spp. mediated by oxidative stress and modulation of adhesion-related genes." Microb Pathog. 2026. — Tier B, in vitro, Candida spp including fluconazole-resistant isolates. DOI 10.1016/j.micpath.2026.108735, PMID 42508701. Abstract reconstructed via OpenAlex.
  • Higgins SC, Pilkington GJ. "The in vitro effects of tricyclic drugs and dexamethasone on cellular respiration of malignant glioma." Anticancer Res. 2010. — Tier B, in vitro, human anaplastic astrocytoma cell line IPSB-18; doxepin's inclusion in the tested panel confirmed but its individual effect size not extractable from the accessible abstract. PMID 20332444. Abstract reconstructed via OpenAlex.Doxepin-specific quantitative effect size not stated in the accessible abstract text; only amitriptyline and clomipramine values were extractable.

Oxidative Stress

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

Oxidative stress - protective in cultured neurons and in a rat kidney-injury model; pro-oxidant specifically inside pathogenic Candida cells

Yellow — Low

See study details

The two mammalian-tissue, drug-specific oxidative-stress studies located both found doxepin protective, reducing oxidative injury markers in cultured neurons and in a rat model of cisplatin-induced kidney injury; a separate antifungal-repurposing study found the opposite direction, increased oxidative stress, specifically inside targeted Candida fungal cells.

Full detail, limits and 3 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 findings: No human oxidative-stress marker study was located for doxepin in either direction; all mammalian-tissue evidence identified is preclinical (rat neuron culture, rat kidney in vivo).
  • At-risk subgroups: None established for a pro-oxidant effect in human or mammalian tissue at either dose range; the fungal-cell pro-oxidant finding describes a treatment target, not a risk to the patient's own tissue.
  • Counter-evidence on record: The two directions found, protective in mammalian tissue models and pro-oxidant in a targeted fungal pathogen, are themselves the recorded counter-evidence to each other and must not be merged into one directional claim, matching the same pattern documented for nortriptyline's mitochondrial-permeability-transition-pore findings in the companion series.

Regulatory status

Not addressed in either FDA label.

Population evidence

Ji BS, Ji H, Liu GQ, "Doxepin protects cultured neurons against oxidative stress-induced injury," Acta Pharmacol Sin 2004, PMID 15000881 (Tier B, in vitro, cultured rat neurons) - neurons exposed to glutamate, sodium dithionite, and hemoglobin to induce oxidative injury showed increased lactate dehydrogenase leakage, malondialdehyde content, and calcium accumulation with decreased superoxide dismutase activity; doxepin (1 to 100 nmol/L) suppressed these changes, reducing lipid peroxidation and enhancing antioxidant enzyme activity. Fawzy MH, Moustafa YM, Khodeer DM, Saeed NM, El-Sayed NM, "Doxepin as OCT2 inhibitor ameliorates inflammatory response and modulates PI3K/Akt signaling associated with cisplatin-induced nephrotoxicity in rats," Naunyn Schmiedebergs Arch Pharmacol 2024, PMID 39400714 (Tier B, rat, cisplatin nephrotoxicity model, graduated doxepin doses 5, 10, 20 mg/kg) - doxepin pretreatment and co-treatment significantly decreased lipid peroxidation, decreased inflammatory cytokines (TNF-alpha, IL-6, IL-1beta), and enhanced antioxidant enzyme activity, alongside reduced apoptosis markers (lower BAX and caspase-3, higher Bcl-2). Pinheiro et al 2026 (PMID 42508701, detailed under Mitochondrial burden and Gut microbiome risk) found the opposite direction, increased reactive oxygen species, specifically inside Candida fungal cells being targeted for the drug's antifungal effect.

Mechanism

In mammalian tissue: enhancement of endogenous antioxidant enzyme activity (superoxide dismutase in the neuron study; unspecified antioxidant enzymes in the rat kidney study) and reduced lipid peroxidation. In the fungal-cell finding: oxidative stress is the drug's own fungicidal mechanism, a deliberately induced, pathogen-targeted effect, not a mammalian-tissue mechanism.

Counter-evidence held on record

Do not present doxepin as either a general antioxidant or a general pro-oxidant for a treated patient; the direction found depends entirely on tissue and species context, and none of the mammalian-tissue data is human. This entry shares its Candida-cell source (Pinheiro 2026) with Mitochondrial burden and Gut microbiome risk; see the Overlap map.

  • Ji BS, Ji H, Liu GQ. "Doxepin protects cultured neurons against oxidative stress-induced injury." Acta Pharmacol Sin. 2004. — Tier B, in vitro, cultured rat neurons. PMID 15000881. Abstract reconstructed via OpenAlex.
  • Fawzy MH, Moustafa YM, Khodeer DM, Saeed NM, El-Sayed NM. "Doxepin as OCT2 inhibitor ameliorates inflammatory response and modulates PI3K/Akt signaling associated with cisplatin-induced nephrotoxicity in rats." Naunyn Schmiedebergs Arch Pharmacol. 2024. — Tier B, rat, cisplatin nephrotoxicity model, doxepin 5/10/20 mg/kg. DOI 10.1007/s00210-024-03473-1, PMID 39400714. Abstract reconstructed via OpenAlex.
  • Pinheiro DRS, Barbosa SA, de Oliveira LC, Cabral VPF, Rodrigues DS, da Costa ERM, Silveira MJCB, Moreira LEA, Cavalcanti BC, Magalhaes IL, dos Santos CAL, Ferreira JRO, de Moraes Filho MO, de Andrade Neto JB, Sa LGAV, da Silva CR, Nobre Junior HV. "Antifungal and anti-biofilm activity of doxepin against Candida spp. mediated by oxidative stress and modulation of adhesion-related genes." Microb Pathog. 2026. — Tier B, in vitro, Candida spp including fluconazole-resistant isolates. DOI 10.1016/j.micpath.2026.108735, PMID 42508701. Abstract reconstructed via OpenAlex.

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 biological (as opposed to analytical-chemistry) evidence links doxepin to copper status at any tier, and no circulating consumer claim about doxepin and copper was encountered in this review.

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: Both conditions for ungraded are met. A PubMed search for "doxepin copper" returned 2 results, both analytical chemistry papers using copper(II) reagents (copper(II) acetate; a copper-based electrochemical biosensor) purely as a detection method for measuring doxepin concentration in plasma or pharmaceutical samples, not as a biological variable. Neither result addresses copper absorption, storage, enzyme cofactor status, or ceruloplasmin in relation to doxepin. A companion search for "doxepin zinc OR doxepin trace elements" (detailed under Fails verification below) likewise returned only analytical-chemistry and topical-mucositis results, none addressing copper biology. As class-level context, the same null finding already disclosed in the companion nortriptyline dossier applies here: Schlegel-Zawadzka M, Nowak G, "Alterations in serum and brain trace element levels after antidepressant treatment. Part II. Copper," Biol Trace Elem Res 2000, PMID 10949967 (Tier C for doxepin, rat, chronic imipramine and citalopram plus electroconvulsive shock, doxepin not among the drugs tested) found chronic treatment with those other agents did not alter brain copper levels, a null class-level finding rather than supporting evidence, which per Hard Rule 6 argues against, not for, a copper claim for any TCA class member including doxepin. No absorption-interference, chelation, or copper-enzyme mechanism connecting doxepin to copper status is documented in either FDA label or in any source located in this review.

Tooling disclosure

The core "doxepin copper" PubMed query returned a readable, non-error, low-relevance result set, so the zero-biological-evidence finding for doxepin specifically is assessed as a genuine literature gap rather than a tooling failure. A broader class-level query was not separately re-run for doxepin in this review beyond reusing the Schlegel-Zawadzka 2000 finding already verified in the companion nortriptyline dossier; a future revision could re-run a dedicated "tricyclic antidepressant copper metabolism" query against doxepin specifically if PubMed access is less constrained. The Europe PMC REST API was rejected at the outbound proxy gateway during this review with an explicit instruction not to retry it (a persistent organization-level policy denial, not a transient rate limit), so it could not be used as a cross-check for this category.

  • Schlegel-Zawadzka M, Nowak G. "Alterations in serum and brain trace element levels after antidepressant treatment. Part II. Copper." Biol Trace Elem Res. 2000. — Tier C for doxepin, rat, chronic imipramine and citalopram plus electroconvulsive shock; doxepin not among the tested drugs. Found chronic treatment did not alter brain copper levels, a null class-level finding rather than supporting evidence. PMID 10949967. Reused from the companion nortriptyline (B007) dossier's own verification of this source.

Iron

Not graded — disclosed evidence gap

See study details

No biological evidence links doxepin to iron status, iron metabolism, or iron-dependent enzyme activity at any tier; the one case report touching red-cell health (immune-mediated hemolytic anemia) is graded separately under Oxygen delivery/utilization because its mechanism is immune, not iron-related, and no circulating consumer claim about doxepin and iron was encountered.

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: Both conditions for ungraded are met. A PubMed search for "doxepin iron OR doxepin ferritin OR doxepin anemia" returned 3 results: the Wolf 1989 hemolytic anemia case report (PMID 2925599, detailed under Oxygen delivery/utilization) and two spectrophotometric analytical-chemistry papers using iron(III) thiocyanate or titanium(IV) complexes purely as reagents to detect doxepin concentration, not iron as a biological variable. The Wolf 1989 case is deliberately excluded from counting as iron-status evidence here: the case report's own workup identifies a Coombs-positive immune-complex hemolytic mechanism, not impaired iron absorption, storage, transport, or utilization, and no ferritin, transferrin, or serum iron value is reported in that case, so per Hard Rule 2 (a clinical outcome such as anemia is not itself evidence of a specific nutrient's deficiency unless the nutrient was directly measured) it cannot support even a yellow iron-specific grade. A dedicated search for "doxepin ferroptosis OR doxepin hepcidin OR doxepin transferrin" returned a clean zero-result count, confirming no iron-regulatory-pathway literature exists for doxepin at any tier located in this review.

Tooling disclosure

Both PubMed queries used in this category returned readable, non-error result sets (3 results and 0 results respectively), so this is assessed as a genuine literature gap for doxepin specifically, not a tooling failure. The Europe PMC REST API and Semantic Scholar API were both unavailable during this review (rejected at the proxy gateway or rate-limited) and could not be used as independent cross-checks; a future revision with working access to those channels should re-confirm this category.

  • Wolf B, Conradty M, Grohmann R, Ruther E, Witzgall H, Londong V. "A case of immune complex hemolytic anemia, thrombocytopenia, and acute renal failure associated with doxepin use." J Clin Psychiatry. 1989. — Tier B, human case report, 100 mg/day doxepin monotherapy, depression dose range. PMID 2925599. Abstract reconstructed via OpenAlex.

Gut Microbiome Risk

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

Gut microbiome risk - direct, replicated antifungal action against Candida species; no antibacterial activity against the two bacterial species tested

Yellow — Low

See study details

Doxepin has direct, drug-specific, replicated fungicidal and anti-biofilm activity against multiple Candida species, a genuine mechanism for altering a component of the human mycobiome, while a separate drug-specific study found no antibacterial activity against Bacillus subtilis or Pseudomonas aeruginosa; no human gut-microbiome sequencing study of doxepin was located.

Full detail, limits and 5 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 findings: Doxepin showed no antibacterial activity against Bacillus subtilis or Pseudomonas aeruginosa in the one drug-specific bacterial study located (Tazehkand 2018, cited via the Zolotareva 2025 review), and the review's broader panel places doxepin among the few tested antidepressants lacking general antibacterial activity against the bacterial genera it examined (Lactobacillus, Lactococcus, Streptococcus, Enterococcus, Bifidobacterium), a genuinely narrower antimicrobial footprint than most other antidepressants reviewed. A landmark gut-bacteria drug-screening study (Maier et al, Nature 2018, PMID 29555994) could not be confirmed to include or exclude doxepin from its tested panel of more than 1,000 drugs; its supplementary compound list was not reachable during this review (see access note).
  • At-risk subgroups: Not established; the antifungal effect has been studied as a potential therapeutic repurposing target (against drug-resistant Candida infections) rather than as a safety signal for patients taking doxepin for its approved indications.
  • Counter-evidence on record: The absence of antibacterial activity against the two bacterial species and the broader bacterial genera tested in the cited secondary review is recorded here as evidence against a broad-spectrum gut-bacterial disruption effect, even as the Candida-specific antifungal effect is real and replicated.

Regulatory status

Not addressed in either FDA label.

Population evidence

Caldara M, Marmiroli N, "Tricyclic antidepressants inhibit Candida albicans growth and biofilm formation," Int J Antimicrob Agents 2018, DOI 10.1016/j.ijantimicag.2018.06.023, PMID 29990546 (Tier B, in vitro, Candida albicans; doxepin's inclusion in the tested drug panel confirmed via this record's MeSH indexing, which lists doxepin with pharmacology qualifiers, though the abstract text itself could not be independently reconstructed during this review). Pinheiro et al 2026 (PMID 42508701, detailed above under Mitochondrial burden and Oxidative stress) independently confirmed and mechanistically extended this finding: doxepin showed fungicidal activity against Candida spp, including fluconazole-resistant isolates, with synergistic activity alongside amphotericin B, inducing oxidative stress, mitochondrial damage, and apoptosis while downregulating adhesion-related virulence genes; a review synthesizing both papers (Zolotareva D et al, "Heterocyclic Antidepressants with Antimicrobial and Fungicide Activity," Molecules 2025, PMID 40076325) states doxepin "prevents the development of hyphae and biofilm, effectively eliminating cells within an established yeast biofilm (Candida albicans, Candida glabrata, Candida parapsilosis, Candida krusei, and Candida utilis)," citing Caldara 2018 for this claim, extending the drug-specific antifungal finding across five named Candida species. The same review states, citing Tazehkand MN, "The effect of doxepin on Bacillus subtilis and Pseudomonas aeruginosa," J Cell Sci Mut 2018 (Tier B, in vitro; not independently located or verified beyond this secondary citation, disclosed here rather than treated as confirmed), that "doxepin shows no antibacterial activity" against those two bacterial species, and separately identifies doxepin, alongside moclobemide and haloperidol, as one of the few agents in its reviewed panel of heterocyclic antidepressants lacking general antimicrobial (as opposed to antifungal) activity.

Mechanism

Induction of oxidative stress and mitochondrial damage inside the fungal cell, with downregulation of adhesion-related virulence genes, named specifically in the Pinheiro 2026 mechanistic study.

Counter-evidence held on record

This is in vitro microbiology evidence, not a human gut-microbiome sequencing study; it should not be presented as proof that doxepin disrupts a treated patient's gut bacterial community broadly, only that it has a specific, mechanistically named antifungal effect on Candida species and no demonstrated effect on the two bacterial species directly tested. This entry shares its primary mechanistic source (Pinheiro 2026) with Mitochondrial burden and Oxidative stress above; see the Overlap map.

  • Pinheiro DRS, Barbosa SA, de Oliveira LC, Cabral VPF, Rodrigues DS, da Costa ERM, Silveira MJCB, Moreira LEA, Cavalcanti BC, Magalhaes IL, dos Santos CAL, Ferreira JRO, de Moraes Filho MO, de Andrade Neto JB, Sa LGAV, da Silva CR, Nobre Junior HV. "Antifungal and anti-biofilm activity of doxepin against Candida spp. mediated by oxidative stress and modulation of adhesion-related genes." Microb Pathog. 2026. — Tier B, in vitro, Candida spp including fluconazole-resistant isolates. DOI 10.1016/j.micpath.2026.108735, PMID 42508701. Abstract reconstructed via OpenAlex.
  • Caldara M, Marmiroli N. "Tricyclic antidepressants inhibit Candida albicans growth and biofilm formation." Int J Antimicrob Agents. 2018. — Tier B, in vitro, Candida albicans; doxepin's inclusion confirmed via MeSH indexing (Doxepin, pharmacology qualifiers). DOI 10.1016/j.ijantimicag.2018.06.023, PMID 29990546. Abstract text itself not independently reconstructed; bibliographic and MeSH detail obtained via Crossref and OpenAlex.Abstract text not independently reconstructed during this review; drug-panel inclusion confirmed via MeSH indexing only.
  • Tazehkand MN. "The effect of doxepin on Bacillus subtilis and Pseudomonas aeruginosa." J Cell Sci Mut. 2018. — Tier B, in vitro. Cited via Zolotareva et al 2025 (reference 90 in that review); not independently located or verified in PubMed, Crossref, or OpenAlex during this review, and not confirmed as a PubMed-indexed journal. Disclosed as a secondary citation, not independently confirmed.Primary source not independently located or verified during this review; relied on the Zolotareva 2025 review's direct quotation.
  • Zolotareva D, Zazybin A, Belyankova Y, Bayazit S, Dauletbakov A, Seilkhanov T, Kemelbekov U, Aydemir M. "Heterocyclic Antidepressants with Antimicrobial and Fungicide Activity." Molecules. 2025. — Secondary review (Tier B/C synthesis), used to locate and quote its underlying references 89 (Caldara 2018) and 90 (Tazehkand 2018), and for its class-wide summary statement that doxepin, moclobemide, and haloperidol are exceptions lacking general antimicrobial activity among the antidepressants it reviewed. DOI 10.3390/molecules30051102, PMID 40076325.
  • Maier L, Pruteanu M, Kuhn M, Zeller G, Telzerow A, Anderson EE, Brochado AR, Fernandez KC, Dose H, Mori H, Patil KR, Bork P, Typas A. "Extensive impact of non-antibiotic drugs on human gut bacteria." Nature. 2018. — Screened more than 1,000 marketed drugs against 40 gut bacterial strains. DOI 10.1038/nature25979, PMID 29555994. Doxepin's presence or hit status among the tested compounds could not be confirmed in this review; its visible abstract, results, and figure text on nature.com do not name doxepin, and the full compound list lives only in a supplementary table not reached during this review. Cited in the Gut microbiome risk entry as an access-limited near-miss, not as support or rebuttal.Full compound list (Supplementary Table) not reached during this review; only the openly accessible abstract, results, and figure text could be read directly, and none of it names doxepin.

Oxygen and ATP Output

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

Oxygen delivery/utilization - anemia listed as infrequent in the low-dose insomnia label; a severe immune-mediated hemolytic anemia case report at higher depression-range dosing

Orange — Moderate

See study details

Silenor's own premarketing clinical-trial data lists anemia as an infrequent adverse reaction at the 3 to 6 mg insomnia dose, and a well-documented 1989 case report describes severe, reversible, immune-complex-mediated hemolytic anemia in a patient on 100 mg/day (depression-range) doxepin; neither finding reflects impaired iron handling, and both are filed here, not under Iron, per Hard Rule 2.

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: Neither label lists a specific iron, ferritin, or hemoglobin-synthesis mechanism; the doxepin HCl (higher-dose) label's own postmarketing hematologic list, quoted above, does not separately name anemia, only the white-cell and platelet dyscrasias, a genuine difference from the Silenor list disclosed here rather than merged.
  • At-risk subgroups: The single case report subject had no described G6PD deficiency or prior hematologic disease; no subgroup predictor for the immune reaction has been established in the literature located here. Patients on higher, depression-range doses for extended periods are the only population in which the severe case-level event was documented.
  • Counter-evidence on record: The higher-dose label's own postmarketing hematologic list does not separately name anemia, arguing against a dose-dependent, drug-wide hemolytic signal and toward the case report representing a rare idiosyncratic reaction rather than a predictable class effect.

Regulatory status

SILENOR label, section 6.3 (Adverse Reactions Observed During Pre-Marketing Evaluation): "Blood and Lymphatic System Disorders: Infrequent: anemia; Rare: thrombocythemia." The doxepin HCl (Sinequan-lineage, higher-dose) label lists, in its postmarketing section 6.2, "Agranulocytosis, leukopenia, thrombocytopenia, eosinophilia, purpura" but does not separately list anemia by name in that section.

Population evidence

SILENOR FDA label, section 6.3 (Tier A, human, premarketing clinical-trial population, insomnia dose range 3 to 6 mg): anemia listed at "infrequent" frequency, causality not further quantified. Wolf B, Conradty M, Grohmann R, Ruther E, Witzgall H, Londong V, "A case of immune complex hemolytic anemia, thrombocytopenia, and acute renal failure associated with doxepin use," J Clin Psychiatry 1989, PMID 2925599 (Tier B, human case report, depression dose range): a middle-aged male on 100 mg/day doxepin monotherapy for five weeks developed Coombs-positive hemolytic anemia, thrombocytopenia, and acute kidney injury; alternative causes (prior hematologic disease, toxin exposure, G6PD deficiency) were specifically ruled out; the patient recovered fully after drug discontinuation, exchange transfusion, and hemodialysis.

Mechanism

The case report names an immune-complex, Coombs-positive hemolytic mechanism, an idiosyncratic hypersensitivity reaction, not a nutrient-cofactor or iron-handling mechanism. The label's "infrequent" premarketing listing does not itself name a mechanism.

Counter-evidence held on record

Do not present this as doxepin causing iron-deficiency anemia or as a reason to supplement iron; the mechanism identified is immune-mediated hemolysis, not impaired iron absorption, storage, or utilization, and no dosing recommendation follows from either finding. See Iron below for the explicit disclosure of why this same case report does not count as iron-status evidence.

  • Wolf B, Conradty M, Grohmann R, Ruther E, Witzgall H, Londong V. "A case of immune complex hemolytic anemia, thrombocytopenia, and acute renal failure associated with doxepin use." J Clin Psychiatry. 1989. — Tier B, human case report, 100 mg/day doxepin monotherapy, depression dose range. PMID 2925599. Abstract reconstructed via OpenAlex.

ATP production - reverse-direction

Yellow — Low

See study details

Two independent, drug-specific studies in two different mammalian tissue types, mouse/human hepatocytes with in vivo confirmation in obese diabetic mice, and cultured rat astrocytes, both found doxepin increases rather than depletes cellular ATP content; no study located found doxepin reducing ATP in any tissue.

Full detail, limits and 2 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 findings: In the astrocyte study's own panel, maprotiline and imipramine did not increase ATP, showing the effect is not universal across all tricyclic and tetracyclic antidepressants tested; doxepin was among the agents that did show the increase.
  • At-risk subgroups: Not applicable; this is a reverse-direction (ATP-enhancing) finding with no identified risk subgroup.
  • Counter-evidence on record: None identified contradicting the direction found in either study; no source located in this review found doxepin reducing ATP content in any tissue.

Regulatory status

Not addressed in either FDA label.

Population evidence

Chen Z, Liu X, Luo Y, et al, "Repurposing Doxepin to Ameliorate Steatosis and Hyperglycemia by Activating FAM3A Signaling Pathway," Diabetes 2020, DOI 10.2337/db19-1038, PMID 32312868 (Tier B, hepatocyte cell culture plus in vivo obese diabetic mouse model, high-fat diet) - doxepin, identified through drug-repurposing screening, activated FAM3A expression and triggered nuclear translocation of the transcription factor HNF4-alpha; in hepatocytes this enhanced ATP synthesis and suppressed gluconeogenesis, and in vivo doxepin attenuated hyperglycemia, hepatic steatosis, and obesity in diet-induced obese mice; the effect was blunted in FAM3A-deficient animals, confirming the mechanism. Trzeciak HI et al, "Effect of antidepressants on ATP content, 3H-valine incorporation and cell morphometry of astrocytes cultured from rat brain," PMID 8829918 (Tier B, cultured rat astrocytes; PubMed lists this record's year as 1995, while the DOI-linked bibliographic record located via OpenAlex, 10.1159/000111299, Developmental Neuroscience, shows a 2007 publication date for a matching title, a metadata discrepancy disclosed here rather than silently resolved) - doxepin was tested at 10^-4 M alongside imipramine, amitriptyline, clomipramine, and mianserin; "all antidepressants except maprotiline and imipramine increased ATP level," placing doxepin among the ATP-increasing agents in this panel.

Mechanism

In hepatocytes, a specifically named pathway: FAM3A expression activation leading to HNF4-alpha nuclear translocation and enhanced ATP synthesis with suppressed gluconeogenesis. In astrocytes, mechanism not further specified beyond the measured ATP increase.

Counter-evidence held on record

This is real, drug-specific, independently replicated preclinical evidence, but it is entirely animal and in vitro data with no human ATP measurement; it must never be presented as a confirmed human energy-boosting effect or used to suggest doxepin should be taken for that purpose. The two sources here are independent of each other and of the Mitochondrial burden and Oxidative stress entries above; no overlap is recorded for this entry.

  • Chen Z, Liu X, Luo Y, Wang J, Meng Y, Sun L, Chang Y, Cui Q, Yang J. "Repurposing Doxepin to Ameliorate Steatosis and Hyperglycemia by Activating FAM3A Signaling Pathway." Diabetes. 2020. — Tier B, hepatocyte cell culture plus in vivo obese diabetic mouse model. DOI 10.2337/db19-1038, PMID 32312868. Abstract reconstructed via OpenAlex.
  • Trzeciak HI et al. "Effect of antidepressants on ATP content, 3H-valine incorporation and cell morphometry of astrocytes cultured from rat brain." — Tier B, cultured rat astrocytes, doxepin tested alongside imipramine, amitriptyline, clomipramine, mianserin, maprotiline. PMID 8829918, PubMed-listed year 1995. A DOI-linked OpenAlex record for a closely matching title (10.1159/000111299, Developmental Neuroscience) shows a 2007 publication date; this year discrepancy was not resolved during this review and is disclosed rather than silently picked.Publication-year metadata conflict between PubMed (1995) and an OpenAlex DOI-linked record (2007) for a matching title; not resolved during this review.

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.

  • Doxepin depletes coenzyme Q10

    Where it comes from: A generic "tricyclic antidepressants deplete CoQ10" narrative carried over from the amitriptyline literature (where a real Tier A human signal exists, per the companion B006 dossier) and applied by marketing content to the TCA class as a whole, doxepin included

    Why it fails: A PubMed search combining "doxepin" and "coenzyme Q10" returned a clean zero-result count, the same clean-zero result already documented for nortriptyline in the companion B007 dossier. No absorption-interference, catabolic, or cofactor-antagonism mechanism connecting doxepin to CoQ10 status was found in either FDA label or in any source located in this review. The amitriptyline-specific Tier A finding does not carry over to doxepin, a chemically related but distinct molecule, absent doxepin-specific evidence.

  • Doxepin depletes zinc

    Where it comes from: Generic "psychiatric drugs deplete minerals" depression-supplement marketing content, the same class-wide narrative flagged in the companion nortriptyline and amitriptyline dossiers

    Why it fails: A PubMed search for "doxepin zinc OR doxepin trace elements" returned 4 results, none biologically relevant: a zinc-oxide-paste and doxepin-mouthwash combination used topically for chemotherapy-induced oral mucositis (a co-administered topical product, not a systemic zinc-status finding), a systemic-itch treatment review noting zinc sulfate and doxepin as separate, unconfirmed itch therapies (not tested together or against each other), and two unrelated analytical-chemistry assay papers. No absorption-interference, renal-wasting, or catabolic mechanism connecting doxepin to zinc depletion was found at any tier. The real zinc-antidepressant literature located (Nowak G, Siwek M, Dudek D, Zieba A, Pilc A, "Effect of zinc supplementation on antidepressant therapy in unipolar depression: a preliminary placebo-controlled study," 2003, PMID 14730113) runs in the adjunct-enhancer direction, zinc supplementation improving antidepressant response, not the depletion direction, and that study's cohort could not be confirmed to include doxepin specifically, so it is cited here only as class-level (Tier C) context, matching the same rebuttal basis used in the companion nortriptyline dossier.

  • Doxepin depletes B-complex vitamins or vitamin B12

    Where it comes from: Generic "antidepressants deplete B vitamins" marketing narrative applied broadly across the antidepressant category, doxepin included

    Why it fails: A PubMed search for "doxepin folate OR doxepin vitamin B12 OR doxepin riboflavin" returned 2 results, neither a depletion study: a 1989 French-language review noting vitamin B12, atropine, doxepin, and sodium cromoglycate can each independently prevent sulfite-induced bronchospasm (an unrelated pharmacologic property, not a nutrient-status finding), and a Sezary syndrome case report in which a patient received doxepin and folic acid as separate, co-prescribed treatments for unrelated symptoms (pruritus and nutritional support), not a study of doxepin's effect on folate status. No absorption-interference, catabolic, renal-wasting, or cofactor-antagonism mechanism connecting doxepin to folate, B12, or riboflavin status was found in either FDA label or in any source located in this review, and unlike nortriptyline (which has two small Tier A human studies touching B-vitamin status, detailed in the companion B007 dossier), no comparable doxepin-specific human data was located here.

How the body handles this medication

Metabolism, CYP enzymes, and active metabolite
CYP2C19 and CYP2D6 are the major enzymes in doxepin's metabolism, with CYP1A2 and CYP2C9 involved to a lesser extent. The Sinequan label states that CYP2D6 and/or CYP2C19 poor metabolizers "will likely result in higher doxepin exposures," and directs dosage reduction based on plasma concentration in confirmed poor metabolizers. The major active metabolite is N-desmethyldoxepin (nordoxepin); doxepin's own half-life is 8 to 24 hours (mean 17 hours) at the Sinequan dose range and 15.3 hours at the Silenor dose, while nordoxepin's half-life is far longer, 33 to 80 hours (mean 51 hours) per the Sinequan label, 31 hours per the Silenor label. Doxepin does not induce any CYP enzyme per either label; carbamazepine (a CYP inducer) decreases doxepin exposure by 55%, the interaction running the opposite direction.FDA label (Currax Pharmaceuticals, SILENOR tablets), Clinical Pharmacology 12.3; FDA label (doxepin HCl capsules/oral concentrate, Reference ID 5619040, 2025), Clinical Pharmacology and Drug Interactions
Elimination
Less than 3% of a doxepin dose is excreted in urine as parent compound or nordoxepin; doxepin is excreted primarily as glucuronide conjugates in urine. No mineral, antacid, or food-chelation interaction is documented in either label.FDA label (SILENOR), Clinical Pharmacology 12.3
Key drug interactions relevant to dosing
Cimetidine produced approximately a 2-fold increase in doxepin Cmax and AUC at both dose ranges (Silenor's maximum recommended dose drops to 3 mg with cimetidine co-administration). Sertraline co-administration increased doxepin AUC and Cmax by approximately 21% and 32%. MAOIs are contraindicated, with a required 14-day washout. No food or mineral interaction is described in either label.FDA label (SILENOR), Drug Interactions 7; FDA label (doxepin HCl), Drug Interactions
Two distinct dosing contexts, stated for this dossier
Silenor (insomnia): 6 mg once daily, 3 mg in some patients and in the elderly starting dose; maximum 6 mg/day. Doxepin HCl/Sinequan (depression, anxiety): starting 25 mg three times daily or 75 mg once daily; target total 75 to 150 mg/day; maximum 300 mg/day (100 mg three times daily). This roughly 50-fold difference in maximum daily dose is the reason this dossier grades several entries separately by dose range.FDA label (SILENOR), Dosage and Administration 2; FDA label (doxepin HCl), Dosage and Administration 2
Hepatic and renal impairment
Patients with hepatic impairment may display higher doxepin concentrations at either dose range; the Silenor label directs initiating at 3 mg with close monitoring in hepatic impairment. Renal impairment has not been formally studied for doxepin at either dose range; the Silenor label states minimal impact is expected given the low fraction of unchanged drug excreted renally, while the doxepin HCl label states the extent of renal excretion is unknown.FDA label (SILENOR), Use in Specific Populations 8.6, 8.7; FDA label (doxepin HCl), Use in Specific Populations
Cardiac electrophysiology, stated by dose range
Silenor's label reports a dedicated thorough QTc study in healthy subjects: "doxepin had no effect on QT intervals or other electrocardiographic parameters after multiple daily doses up to 50 mg," a dose above the entire approved insomnia range though still below the top of the approved depression range (up to 300 mg/day). A dedicated in vitro electrophysiology study (not part of either label) found doxepin blocks the cardiac hERG potassium channel (recombinant IC50 6.5 micromolar, native rabbit IKr IC50 4.4 micromolar), with the study's authors concluding this likely underpins reported clinical QT-prolongation cases. See the Cardiac potassium channel entry below for full detail and dose-range framing.FDA label (SILENOR), Clinical Pharmacology 12.2; Duncan RS et al, Biochem Pharmacol 2007, PMID 17560554
All references used above
  1. FDA prescribing information, SILENOR (doxepin hydrochloride) tablets — Structured Product Labeling via DailyMed. Clinical Pharmacology (12.2, 12.3), Dosage and Administration, Drug Interactions, Adverse Reactions (6.3), Use in Specific Populations sections.
  2. FDA prescribing information, doxepin hydrochloride capsules / oral concentrate (SINEQUAN-lineage, higher-dose formulation), Reference ID 5619040 — Full prescribing information PDF via accessdata.fda.gov, 2025 revision. Clinical Pharmacology, Drug Interactions, Adverse Reactions (6.1, 6.2), Dosage and Administration, Use in Specific Populations sections.
  3. WHO Collaborating Centre for Drug Statistics Methodology, ATC/DDD Index, doxepin N06AA12 — Confirms ATC code N06AA12 and DDD of 0.1 g oral/parenteral, based on treatment of moderately severe depression.
  4. Duncan RS, McPate MJ, Ridley JM, Gao Z, James AF, Leishman DJ, Leaney JL, Witchel HJ, Hancox JC. "Inhibition of the HERG potassium channel by the tricyclic antidepressant doxepin." Biochem Pharmacol. 2007. — Tier B, in vitro, recombinant hERG-HEK293 cells and native rabbit Purkinje IKr. DOI 10.1016/j.bcp.2007.04.024, PMID 17560554.
  5. Strasberg B, Coelho A, Welch WJ, Swiryn S, Bauernfeind RA, Rosen K. "Doxepin Induced Torsade De Pointes." Pacing Clin Electrophysiol. 1982. — Tier B, human case report, "small amounts" of doxepin, normal baseline QT interval. DOI 10.1111/j.1540-8159.1982.tb06570.x, PMID 6184690. Abstract reconstructed via OpenAlex.
  6. Alter P, Tontsch D, Grimm W. "Doxepin-Induced Torsade de Pointes Tachycardia." Ann Intern Med. 2001. — Tier B, human case report, 6-gram suicide-attempt overdose. DOI 10.7326/0003-4819-135-5-200109040-00026, PMID 11529713. Full text returned HTTP 403 during this review; abstract reconstructed via OpenAlex.Full text blocked (HTTP 403) during this review; bibliographic and abstract detail obtained via OpenAlex instead.
  7. Qureshi PJ. "Doxepin Induced Torsades de Pointes in a Middle-aged Female: A Case Report." Int J Med Case Rep. 2023. — Tier B, human case report, therapeutic depression-range dosing, electrolyte imbalance explicitly ruled out. DOI 10.5281/zenodo.10997912.
  8. Ji BS, Ji H, Liu GQ. "Doxepin protects cultured neurons against oxidative stress-induced injury." Acta Pharmacol Sin. 2004. — Tier B, in vitro, cultured rat neurons. PMID 15000881. Abstract reconstructed via OpenAlex.
  9. Fawzy MH, Moustafa YM, Khodeer DM, Saeed NM, El-Sayed NM. "Doxepin as OCT2 inhibitor ameliorates inflammatory response and modulates PI3K/Akt signaling associated with cisplatin-induced nephrotoxicity in rats." Naunyn Schmiedebergs Arch Pharmacol. 2024. — Tier B, rat, cisplatin nephrotoxicity model, doxepin 5/10/20 mg/kg. DOI 10.1007/s00210-024-03473-1, PMID 39400714. Abstract reconstructed via OpenAlex.
  10. Pinheiro DRS, Barbosa SA, de Oliveira LC, Cabral VPF, Rodrigues DS, da Costa ERM, Silveira MJCB, Moreira LEA, Cavalcanti BC, Magalhaes IL, dos Santos CAL, Ferreira JRO, de Moraes Filho MO, de Andrade Neto JB, Sa LGAV, da Silva CR, Nobre Junior HV. "Antifungal and anti-biofilm activity of doxepin against Candida spp. mediated by oxidative stress and modulation of adhesion-related genes." Microb Pathog. 2026. — Tier B, in vitro, Candida spp including fluconazole-resistant isolates. DOI 10.1016/j.micpath.2026.108735, PMID 42508701. Abstract reconstructed via OpenAlex.
  11. Higgins SC, Pilkington GJ. "The in vitro effects of tricyclic drugs and dexamethasone on cellular respiration of malignant glioma." Anticancer Res. 2010. — Tier B, in vitro, human anaplastic astrocytoma cell line IPSB-18; doxepin's inclusion in the tested panel confirmed but its individual effect size not extractable from the accessible abstract. PMID 20332444. Abstract reconstructed via OpenAlex.Doxepin-specific quantitative effect size not stated in the accessible abstract text; only amitriptyline and clomipramine values were extractable.
  12. Chen Z, Liu X, Luo Y, Wang J, Meng Y, Sun L, Chang Y, Cui Q, Yang J. "Repurposing Doxepin to Ameliorate Steatosis and Hyperglycemia by Activating FAM3A Signaling Pathway." Diabetes. 2020. — Tier B, hepatocyte cell culture plus in vivo obese diabetic mouse model. DOI 10.2337/db19-1038, PMID 32312868. Abstract reconstructed via OpenAlex.
  13. Trzeciak HI et al. "Effect of antidepressants on ATP content, 3H-valine incorporation and cell morphometry of astrocytes cultured from rat brain." — Tier B, cultured rat astrocytes, doxepin tested alongside imipramine, amitriptyline, clomipramine, mianserin, maprotiline. PMID 8829918, PubMed-listed year 1995. A DOI-linked OpenAlex record for a closely matching title (10.1159/000111299, Developmental Neuroscience) shows a 2007 publication date; this year discrepancy was not resolved during this review and is disclosed rather than silently picked.Publication-year metadata conflict between PubMed (1995) and an OpenAlex DOI-linked record (2007) for a matching title; not resolved during this review.
  14. Caldara M, Marmiroli N. "Tricyclic antidepressants inhibit Candida albicans growth and biofilm formation." Int J Antimicrob Agents. 2018. — Tier B, in vitro, Candida albicans; doxepin's inclusion confirmed via MeSH indexing (Doxepin, pharmacology qualifiers). DOI 10.1016/j.ijantimicag.2018.06.023, PMID 29990546. Abstract text itself not independently reconstructed; bibliographic and MeSH detail obtained via Crossref and OpenAlex.Abstract text not independently reconstructed during this review; drug-panel inclusion confirmed via MeSH indexing only.
  15. Tazehkand MN. "The effect of doxepin on Bacillus subtilis and Pseudomonas aeruginosa." J Cell Sci Mut. 2018. — Tier B, in vitro. Cited via Zolotareva et al 2025 (reference 90 in that review); not independently located or verified in PubMed, Crossref, or OpenAlex during this review, and not confirmed as a PubMed-indexed journal. Disclosed as a secondary citation, not independently confirmed.Primary source not independently located or verified during this review; relied on the Zolotareva 2025 review's direct quotation.
  16. Zolotareva D, Zazybin A, Belyankova Y, Bayazit S, Dauletbakov A, Seilkhanov T, Kemelbekov U, Aydemir M. "Heterocyclic Antidepressants with Antimicrobial and Fungicide Activity." Molecules. 2025. — Secondary review (Tier B/C synthesis), used to locate and quote its underlying references 89 (Caldara 2018) and 90 (Tazehkand 2018), and for its class-wide summary statement that doxepin, moclobemide, and haloperidol are exceptions lacking general antimicrobial activity among the antidepressants it reviewed. DOI 10.3390/molecules30051102, PMID 40076325.
  17. Wolf B, Conradty M, Grohmann R, Ruther E, Witzgall H, Londong V. "A case of immune complex hemolytic anemia, thrombocytopenia, and acute renal failure associated with doxepin use." J Clin Psychiatry. 1989. — Tier B, human case report, 100 mg/day doxepin monotherapy, depression dose range. PMID 2925599. Abstract reconstructed via OpenAlex.
  18. Schlegel-Zawadzka M, Nowak G. "Alterations in serum and brain trace element levels after antidepressant treatment. Part II. Copper." Biol Trace Elem Res. 2000. — Tier C for doxepin, rat, chronic imipramine and citalopram plus electroconvulsive shock; doxepin not among the tested drugs. Found chronic treatment did not alter brain copper levels, a null class-level finding rather than supporting evidence. PMID 10949967. Reused from the companion nortriptyline (B007) dossier's own verification of this source.
  19. Nowak G, Siwek M, Dudek D, Zieba A, Pilc A. "Effect of zinc supplementation on antidepressant therapy in unipolar depression: a preliminary placebo-controlled study." 2003. — Cited for the Fails verification / zinc entry, class-level (Tier C for doxepin specifically, cohort not confirmed to include this drug), to show the real zinc-antidepressant literature runs in the adjunct-therapy direction, not the depletion direction. Same source cited in the companion nortriptyline and amitriptyline dossiers. PMID 14730113.
  20. Maier L, Pruteanu M, Kuhn M, Zeller G, Telzerow A, Anderson EE, Brochado AR, Fernandez KC, Dose H, Mori H, Patil KR, Bork P, Typas A. "Extensive impact of non-antibiotic drugs on human gut bacteria." Nature. 2018. — Screened more than 1,000 marketed drugs against 40 gut bacterial strains. DOI 10.1038/nature25979, PMID 29555994. Doxepin's presence or hit status among the tested compounds could not be confirmed in this review; its visible abstract, results, and figure text on nature.com do not name doxepin, and the full compound list lives only in a supplementary table not reached during this review. Cited in the Gut microbiome risk entry as an access-limited near-miss, not as support or rebuttal.Full compound list (Supplementary Table) not reached during this review; only the openly accessible abstract, results, and figure text could be read directly, and none of it names doxepin.
  21. PubMed search-listing queries (doxepin + coenzyme Q10; + mitochondria; + oxidative stress; + copper; + iron/ferritin/anemia; + gut microbiome/microbiota/gut bacteria; + hemoglobin/hematocrit/oxygen saturation; + ATP/Krebs cycle/cellular respiration; + folate/vitamin B12/riboflavin; + zinc/trace elements; + hyponatremia/SIADH; + ferroptosis/hepcidin/transferrin; + glutathione/superoxide dismutase/malondialdehyde; + obstructive sleep apnea; + CYP1A2 induction/enzyme induction) — Used for category screening per Step 4 of the governing protocol. Search-listing pages were the most reliably accessible channel and returned genuine, readable, non-error result sets for the majority of queries run, though several queries across the review were rate-limited (HTTP 429) or served a bot-verification challenge in place of results, requiring re-attempts spaced roughly 30 to 45 seconds apart.
  22. OpenAlex API per-PMID and per-DOI lookups — The single most reliable channel throughout this review; used to confirm titles, authors, journals, years, DOIs, MeSH indexing, and to reconstruct abstract text from abstract_inverted_index where available, consistent with this protocol's guidance that per-ID lookups are more reliable than search endpoints under rate-limiting. OpenAlex's own search endpoint (as opposed to per-ID lookup) was intermittently rate-limited (HTTP 429) during this review and was not relied upon.
  23. Crossref API bibliographic search and per-DOI lookup — Used successfully to confirm bibliographic detail for the Caldara 2018 and Duncan 2007 papers when other channels were rate-limited.
  24. Europe PMC REST API — Rejected at the outbound proxy gateway during this review (HTTP 429) with an explicit instruction not to retry the same or related pages; could not be used as an independent cross-check for any category in this review, consistent with the persistent, organization-level access limitation already disclosed in the companion nortriptyline dossier.Rejected at the proxy gateway during this review; not used as a source.
  25. Semantic Scholar API — Rate-limited (HTTP 429) on the one attempt made during this review; not used as a source.Rate-limited (HTTP 429) on the attempt made during this review.
  26. Drugs.com, doxepin side effects page — Checked for circulating nutrient-depletion claims and adverse-reaction listings; no vitamin or mineral depletion claims found. Its listed hematologic adverse reactions (including "anemia" and "hemolytic anemia") were cross-checked directly against the FDA label text; the label's own wording, quoted in the Oxygen delivery/utilization entry above, was used in preference to this aggregator where the two differed.
  27. RxList, Silenor drug page — Checked for circulating nutrient-depletion, mitochondrial, or oxidative-stress claims; none found.