Terbinafine

Limits on what this shows

• Null findings: Mitochondrial effects were not measured in the human keratinocyte studies [10][12]. No mitochondrial function assay in human cells or tissue with terbinafine was located.
• At-risk subgroups: Not defined.

Regulatory status

The label contains no mitochondrial statement [1].

Population evidence

None in humans. Shekhova 2017 [13] (A. fumigatus, abstract via OpenAlex record): itraconazole, terbinafine and amphotericin B each raised intracellular ROS; blocking mitochondrial complex I with rotenone abolished the rise, and a mitochondria-specific probe showed mitochondrial ROS and oxidized mitochondrial membranes with terbinafine and amphotericin B. Rat study [14]: 48 adult male albino rats, therapeutic-dose terbinafine for 2, 6 or 12 weeks (or 12 weeks plus one month off); electron microscopy showed "some changes in the mitochondria" alongside endoplasmic reticulum, lysosome and lipid-droplet changes; all changes resolved after one month off the drug. The abstract gives no measurements, and the journal and year were not shown on the retrieved page.

Mechanism

Fungal: mitochondrial complex I as the ROS source under drug challenge [13]. Human or mammalian mitochondrial mechanism: not established.

Cohort test

Terbinafine was the tested drug in both sources. Tier B (fungal in vitro and rat). Species differences make human relevance uncertain.

Counter-evidence held on record

Counter-evidence and confounding The fungal result concerns the drug's intended target organism. The rat dose was described as therapeutic but its mg/kg value was not retrieved, and a single group of authors reported the effect. Framing caution Not evidence of mitochondrial damage in people taking terbinafine. No CoQ10 or other mitochondrial supplement is recommended from this entry.

Limits on what this shows

• Null findings: Catalase and glutathione peroxidase unchanged. Malondialdehyde and glutathione were not measured in [10]. The earlier preprint version of the same experiment [11] reports SOD as not significantly changed with terbinafine alone, which conflicts with the published figure; both were read through a summarizing fetch tool, so the discrepancy is recorded and the SOD result is held as uncertain.
• At-risk subgroups: None defined. Concentrations and exposure routes in cell culture were not mapped to oral plasma exposure in this review.

Regulatory status

The label mentions no antioxidant or redox effect [1].

Population evidence

No human in vivo study. In vitro, HaCaT keratinocytes: Perez-Gonzalez 2024 [10], terbinafine 1 uM alone reduced viability by 33.66 +/- 6.70% (p<0.0001), raised ROS by 30 +/- 9.2% (p<0.001) after two days, and lowered SOD expression to 26.5 +/- 17.47% of control (p<0.01); catalase and glutathione peroxidase expression did not change significantly. Lam 2020 [12]: terbinafine IC50 12.5 to 25 ug/mL with a significant ROS rise versus control (p<0.05) at its IC50, about half the rise seen with miconazole. Liver microsomes: a reactive allylic aldehyde (TBF-A) forms by N-dealkylation, is trapped as glutathione conjugates by reversible Michael addition, and leaves a second electrophilic site that could bind protein [15]; the pathways were mapped further by Barnette 2018 and Davis 2019 [16][17].

Mechanism

Named for the in vitro ROS: fungal and cell-model ROS accumulation (also see the fungal mitochondrial complex I source under Mitochondrial burden [13]). Glutathione conjugation of TBF-A is a detoxification route, not a measured glutathione loss.

Cohort test

Terbinafine was the tested drug in [10][11][12][15][16][17]. Tier B (in vitro, one cell line, no human subjects). Hepatotoxicity is a drug toxicity (immune-mediated per LiverTox [3]) and is not filed here as an antioxidant deficiency.

Counter-evidence held on record

Counter-evidence and confounding Cell-culture ROS at cytotoxic concentrations (IC50 range) in a skin cell line may not reflect systemic redox status after oral dosing. The preprint and the journal paper are one study and count once. Framing caution This is not an antioxidant-depletion claim. Do not recommend antioxidant, glutathione precursor or vitamin supplements from this entry.

Limits on what this shows

• Null findings: The human anemia and neutropenia reports were not iron-related as far as the abstracts show; no ferritin or serum iron measurement with terbinafine was located.
• At-risk subgroups: None.

Regulatory status

No iron statement in the label [1].

Population evidence

No human study. Jordá 2022 [18] (OpenAlex abstract, summarized; full text not read): chemical and genetic iron depletion lowered ERG1 expression and raised terbinafine resistance in yeast; deleting ROX1, CTH1 or CTH2 raised Erg1 and resistance, and overexpressing CTH2 did the opposite; clinical strains were reported to respond similarly to the laboratory strain.

Mechanism

Present in fungi: iron-regulated control of the squalene epoxidase gene. Not shown in humans.

Cohort test

Terbinafine was the drug, but the organism is yeast. Tier B. Under Hard Rule 4 this is a nutrient-to-drug interaction, so it is graded yellow at most; it does not establish a separation interval or any timing advice for humans.

Counter-evidence held on record

Counter-evidence and confounding It is unknown whether human iron status alters terbinafine efficacy; the yeast data do not support changing iron intake. Framing caution This is not an iron-depletion or iron-supplementation entry. Iron supplements are not recommended or discouraged from this evidence.

Limits on what this shows

• Why no grade: Dual condition met: no Tier B or C copper evidence for terbinafine was opened, and no circulating copper claim for terbinafine was found. This is a disclosed gap, not a finding of safety, and it is kept separate from Iron (Hard Rule 7). Re-check with a fuller PubMed and Embase search if access allows.

What was searched

Web search "terbinafine copper OR iron chelation OR metal binding complex allylamine antifungal" returned a 2024 Inorganics paper on copper(II) binding of azole-hydroxyquinoline derivatives that does not mention terbinafine [24]. "terbinafine copper homeostasis OR copper yeast ergosterol terbinafine susceptibility metal" returned only the iron study [18]. The label was read for copper content: none [1]. Repair pass: PubMed listing for terbinafine AND (copper OR ceruloplasmin) returned six records, none about host copper status or terbinafine copper binding (titles: a bladder-cancer cuproptosis nanotherapeutic, two chromoblastomycosis case reports, a terbinafine hepatotoxicity case report, copper-impregnated socks for dermatophytosis, and a Trichophyton rubrum gene-expression study); these were judged from titles and the tool's per-record notes and were not opened. Crossref title queries for terbinafine with copper or metal returned only generic Terbinafine monograph and Reactions Weekly case-report entries.

Channel outcomes

Original pass: PubMed listing 429, PMC reCAPTCHA. Repair pass: one PubMed listing succeeded (six unrelated records); Europe PMC returned 429 with a request not to retry; the web-search budget for the session was exhausted. No copper or ceruloplasmin measurement was found in the human terbinafine studies opened. Likely a genuine literature gap, with the limitation that only one database listing was obtained.

Limits on what this shows

• Null findings: No bacterial abundance change, no beta-diversity change and no change in most translocation markers [8].
• At-risk subgroups: Not defined; the cohort was young, mostly male and people living with HIV on antiretroviral therapy. People with intestinal disease or diabetes were excluded [8].

Regulatory status

Label sec 6.1: diarrhea 5.6% on terbinafine versus 2.9% on placebo; the label does not mention microbiome or Clostridioides difficile in the sections retrieved [1].

Population evidence

Ouyang 2023 [8]: prospective single-arm pilot, 23 enrolled and 20 completers (mean age 41.7 years, all on antiretroviral therapy with undetectable viral load, median CD4 309 cells/uL), terbinafine 250 mg daily for 12 weeks, stool sampled before, during, at week 12 and 12 weeks after stopping. Total fungal abundance (18S qPCR) fell from short-term to week 12 (p = 0.021, fold change 0.19) the week 12 versus 12-weeks-off comparison was not significant (p = 0.653), and baseline versus 12-weeks-off was not significant (p = 0.435). Fungal Chao1 diversity rose transiently; Shannon, ACE and Simpson did not change; no change in fungal beta diversity; no genus separated visits by LEfSe; Cladosporium, Pichia and Trichosporon fell at end of treatment (no p-values). Total bacterial abundance did not change significantly (baseline versus 12 weeks off, 1.000 versus 1.620, p = 0.185). Plasma intestinal fatty acid binding protein rose at week 12 (0.38 +/- 0.69, significant per figure legend, exact p not stated) and returned to baseline; lipopolysaccharide, beta-D-glucan, sCD14, REG3a, IL-10 and TNF-alpha did not differ. The protocol paper [9] describes the same study and is not a second source.

Mechanism

Present: terbinafine is fungicidal for dermatophytes and active against some yeasts, so a lower gut fungal load is expected. A bacterial or functional microbiome mechanism is not established.

Cohort test

Terbinafine was the study drug. No class extrapolation. One study counts once (the protocol paper [9] is the same cohort). The text read through a summarizing fetch tool reports internal inconsistencies (abstract versus results on significance; paired t-test versus Wilcoxon), so the p-values are quoted as reported and treated as soft.

Counter-evidence held on record

Counter-evidence and confounding No control group, 20 completers, and the comparison is within-person against a baseline in people on antiretroviral therapy, whose gut microbiota are already altered. The fungal reduction is the intended pharmacology and was not linked to a clinical outcome. Framing caution This does not show that terbinafine causes dysbiosis. Do not recommend probiotics or any supplement from this entry.

Limits on what this shows

• Null findings: Label lymphopenia was no more frequent than placebo (1.7% versus 2.2%). No hemoglobin change is listed in the adverse-reaction tables retrieved.
• At-risk subgroups: Not defined by the sources retrieved. People who develop fever, infection, bruising or unexplained fatigue on treatment are the practical signal.

Regulatory status

Label sec 5.5: transient lymphocyte count below 1000/mm3 in 1.7% (8/465) on terbinafine versus 2.2% (3/137) on placebo; severe neutropenia reported, usually reversible, stop if neutrophils are 1000/mm3 or less. Sec 5.8: thrombotic microangiopathy (TTP, HUS), some fatal; unexplained thrombocytopenia or anemia should prompt evaluation. Sec 6.2 postmarketing: pancytopenia, agranulocytosis, neutropenia, thrombocytopenia, anemia. Sec 6.1 lists no hemoglobin or neutrophil change [1] (via summarizing fetch).

Population evidence

Case reports only: aplastic anemia on oral terbinafine with a literature review of terbinafine hematologic toxicities (Turkish Journal of Hematology, 2014) [19] and a further aplastic anemia case (EJCRIM, 2024) [20]. Both were read as abstract and metadata only, so patient details, doses and outcomes were not retrieved. No cohort with a hemoglobin or red-cell outcome was located.

Mechanism

Idiosyncratic hematologic toxicity; no nutrient mechanism is named. Any iron, B12 or folate pathway to anemia would be a separate claim (see Iron and the ungraded B12/folate entry).

Cohort test

Terbinafine was the drug in [1][19][20]. Anemia is an outcome and is not filed as iron deficiency (Hard Rule 2). Not counted as an oxygen-delivery deficiency of nutrient origin.

Counter-evidence held on record

Counter-evidence and confounding The events are rare and idiosyncratic; case reports cannot give an incidence. Onychomycosis patients are often older and on other drugs, so alternative causes of cytopenia are possible. Framing caution This is a drug-toxicity outcome entry. It does not mean terbinafine impairs oxygen delivery through a nutrient, and no iron, B12 or folate supplement is recommended.

Limits on what this shows

• Null findings: No consistent ATP direction across the three donors, and ATP was less affected than GSH [27]. No ATP, oxygen consumption or membrane potential was reported at abstract level in [28] or [29]. No ATP or energy marker in any terbinafine user.
• At-risk subgroups: None defined. The one human-tissue source had three donors with divergent responses.

Regulatory status

The label contains no ATP, respiration or energy-metabolism statement [1].

Population evidence

No in vivo human study. Vickers 2017 [27] (ex vivo three-dimensional human liver slices from three donor livers, open-access full text read through a summarizing fetch tool): terbinafine 100 uM dosed daily, 10 control and 6 treated slices per time point per liver. ATP at 24 hours was raised or lowered by about 15%, was back at control at 48 hours, and at 72 hours fell significantly by 25% in one liver and rose significantly by 30% in another; after three doses ATP was reduced in only one liver. Glutathione (GSH) rose by 20% in one liver and 39% in another, and the authors state GSH was affected more than ATP. Aging Cell 2026 [28] (abstract-level record): terbinafine activated the mitochondrial unfolded protein response in C. elegans through ATFS-1 and, in human HEK293T cells, induced the mitochondrial stress response and modulated mitochondrial function; ATP, oxygen consumption and concentrations were not in the record. Oncogene 2025 [29] (abstract-level record): squalene epoxidase (SQLE) stabilizes TFAM and boosts oxidative phosphorylation and mitochondrial ROS in bladder cancer models, and terbinafine, an SQLE inhibitor, suppressed tumor progression; whether terbinafine itself lowered ATP was not stated at abstract level, and the setting is cancer.

Mechanism

Named but unproven in normal human tissue: inhibition of squalene epoxidase (the drug's target) is linked in a tumor model to reduced TFAM-driven oxidative phosphorylation [29], and terbinafine activates a mitochondrial stress response in worms and cells [28]. In the liver slices the mitochondrial gene array changed 1 of 3 energy genes (CYC1, 1.3-fold in one liver) [27]. The 100 uM concentration was not mapped to oral plasma exposure in this review.

Cohort test

Terbinafine was the tested drug in [27][28][29]. Tier B only (ex vivo human tissue, worm and cell models, mouse tumor models); no Tier A source. No class extrapolation. Orange is not available because no in vivo human ATP measurement exists and the direction is inconsistent. Kept independent of Mitochondrial burden and Oxygen delivery/utilization (Hard Rule 7); shared origins are in the Overlap map.

Counter-evidence held on record

Counter-evidence and confounding Three donors, one concentration, and ATP varied in both directions, so the slice data cannot support a decrease. The tumor and worm data come from systems where SQLE or the stress response is studied for other purposes, and the two newer sources were read as abstracts only. Framing caution This is not a low-energy or fatigue claim and not a mitochondrial-damage claim. Do not recommend CoQ10, carnitine, B vitamins or any other supplement from this entry.