Spironolactone

Limits on what this shows

• Key negative/null findings: Only one study (Park 2026) directly administered spironolactone and measured mitochondrial parameters; no independent replication in a second Tier B or any Tier A source was located. The finding describes restoration toward control/baseline levels under an induced-damage condition, not enhancement of mitochondrial function above normal baseline, and the cell line is a mouse osteoblast line, not human or cardiac/renal tissue.
• At-risk subgroups: None established; no human data of any kind exists to define a subgroup. The in vitro model used a diabetes-mimicking oxidative stressor, so any eventual human relevance, if established, would plausibly concentrate in patients with hyperglycemia-driven oxidative stress rather than the general spironolactone-treated population.
• Dose/duration: 100µM spironolactone, single in vitro exposure window (Park 2026). No animal or human dosing data exists for this specific mitochondrial-membrane-potential endpoint. This dossier makes no dosing recommendation of any kind.

Regulatory status

The FDA label does not mention mitochondria, mitochondrial function, or mitochondrial toxicity anywhere in its text (confirmed by direct review of the 2025 label already cited in this dossier as the FDA source).

Population evidence

No human population study was located. The only direct, drug-specific data is an in vitro study: MC3T3-E1 mouse pre-osteoblast cells exposed to 2-deoxy-D-ribose (dRib) to induce diabetes-like oxidative/mitochondrial damage, with and without spironolactone (Park et al., Exp Ther Med 2026; PMID 41858771). dRib raised mitochondrial superoxide to 148.0±8.2% of control; 100µM spironolactone reduced it to 105.1±5.8%, and the same paper reports recovery of mitochondrial membrane potential and ATP alongside it (ATP figures are counted separately under the ATP production entry below; see Overlap map).

Mechanism

Named at the Tier B level: spironolactone reduced dRib-induced mitochondrial superoxide production and restored mitochondrial membrane potential in this cell model. A separate line of animal work in aldosterone-infused rats (Kamalov et al., Am J Physiol Heart Circ Physiol 2009; PMID 19915175) documents that aldosterone itself drives mitochondrial H2O2 production, 8-isoprostane formation, and mitochondrial permeability transition pore (mPTP) opening in cardiac myocytes — a pathology that paper states was prevented by spironolactone cotreatment in earlier work, though spironolactone was not itself an arm of this specific paper (see Overlap map; cited here for mechanistic background only, not counted as primary evidence).

Counter-evidence held on record

No contradicting evidence was found, but neither was any second independent confirmation; this is a single in vitro study, not a body of literature, and the Kamalov aldosteronism paper cited for mechanistic context did not itself test spironolactone. This is exactly the kind of thin, single-study evidence base the yellow tier exists to flag rather than overstate. This must never be presented as spironolactone protecting or improving mitochondrial health in a person, or as license to skip mitochondrial-support supplementation for unrelated reasons. It is a single cell-culture finding under an induced-injury model, not a human mitochondrial-health claim, and it must not be inverted into a claim that spironolactone depletes or damages mitochondria either — the located evidence runs the other way.

Limits on what this shows

• Key negative/null findings: The same meta-analysis that supports the oxidative-stress finding reports that across its pooled transplant trials, mineralocorticoid-receptor antagonists (spironolactone and eplerenone together) showed no significant difference from placebo in GFR (P=.13), serum creatinine (P=.32), systolic/diastolic blood pressure (P=.33/.44), albuminuria/proteinuria (P=.71/.18), or graft fibrosis (IFTA) scores (P=.32-.39) — meaning the oxidative-stress benefit in these small trials did not translate into a measured hard-outcome benefit in the same pooled data, which bounds how much clinical weight the oxidative-stress finding alone should carry. The same meta-analysis also found a roughly 4-fold increase in hyperkalemia risk (RR 4.06, P=.007) with MRA use in this population; this is not a new finding, it is the same hyperkalemia signal already graded red under the existing Potassium entry above, and is not double-counted here (see Overlap map).
• At-risk subgroups: Kidney-transplant recipients specifically; both trials were conducted in this population, and confounding by indication (transplant-related ischemia-reperfusion injury and immunosuppressant-driven oxidative stress) is presumed rather than excluded, since neither trial's own methods for isolating spironolactone's independent contribution were reviewed by this dossier directly.
• Dose/duration: Not specified in the meta-analysis summary reviewed; trial durations were 5 days (Ojeda-Cervantes, acute pilot) and 36 months (Morales-Buenrostro, longer-term). No dose figures are stated here because none were independently verified, and none should be read as a recommendation regardless.

Regulatory status

The FDA label does not mention oxidative stress, reactive oxygen species, or any related biomarker anywhere in its text (confirmed by direct review of the 2025 label already cited in this dossier).

Population evidence

Two randomized controlled trials, both in kidney-transplant recipients, identified with their design, sample size, and direction confirmed via a 2025 systematic review and meta-analysis of mineralocorticoid-receptor-antagonist trials in transplant patients (PMC12330037, opened directly): Morales-Buenrostro et al. 2019 (living donor kidney transplantation, n=19 spironolactone vs 25 placebo, 36 months; "spironolactone reduces oxidative stress in living donor kidney transplantation"); Ojeda-Cervantes et al. 2013 (renal transplant recipients, n=10 vs 10, 5 days; "mineralocorticoid receptor blockade reduced oxidative stress in renal transplant recipients"). Both trials' own primary full texts returned access errors on direct fetch (see Sources); the design, sample sizes, durations, and direction reported here come from the meta-analysis that reviewed both trials directly, not from this dossier's own reading of either primary paper.

Mechanism

Not fully named at the molecular level in the sources reviewed for this dossier; the transplant literature frames the effect as aldosterone-receptor blockade reducing renal and vascular oxidative injury in the transplant setting, without a single confirmed molecular pathway independently verified by this dossier.

Counter-evidence held on record

This dossier could not independently open either primary trial; both are cited through a secondary meta-analysis rather than direct verification of the original text, and that limitation is disclosed rather than papered over. The same pooled data shows no benefit on GFR, creatinine, blood pressure, proteinuria, or graft fibrosis, and a real hyperkalemia signal already graded elsewhere — the oxidative-stress finding should not be read as evidence of overall benefit from spironolactone in this population. This is not a wellness or antioxidant-supplementation claim and must never be marketed as one. It describes a laboratory biomarker change in a specific surgical/transplant population under trial conditions, not a general protective effect, and it is not a reason to add or withhold any antioxidant supplement without a prescriber's guidance.

Limits on what this shows

• Key negative/null findings: No human in vivo confirmation exists; the entire evidence base is Huh7 cells, primary hepatocytes, and mice. No study was located testing whether long-term spironolactone use measurably changes ferritin, transferrin saturation, or hemoglobin in humans, and the authors explicitly flag this gap themselves.
• At-risk subgroups: None established in humans. The paper's own clinical framing centers on patients who already have pathologically elevated hepcidin (hereditary hemochromatosis, anemia of inflammation), where hepcidin suppression would be a sought-after effect rather than a risk; conversely, any theoretical iron-overload risk from combined hepcidin suppression would apply most to patients already predisposed to iron loading (the paper's own context includes imatinib-treated patients with iron loading, with spironolactone studied as a co-suppressor of hepcidin in that setting), not to the general spironolactone-treated population.
• Dose/duration: 50µM in hepatocyte and Huh7 cell culture; 24mg/kg/day via drinking water for two weeks in mice. No human dose or duration data exists, and none is recommended here.

Regulatory status

The FDA label does not mention iron, hepcidin, ferritin, or transferrin anywhere in its text (confirmed by direct review of the 2025 label already cited in this dossier). Drugs.com's interaction checker was reviewed directly and lists no interaction between iron supplements ("Fer-Iron") and spironolactone.

Population evidence

No human clinical study measuring iron status in spironolactone-treated patients was located. The direct evidence is Mleczko-Sanecka et al., Haematologica 2017 (opened directly): spironolactone suppressed hepcidin expression in Huh7 human hepatoma cells, in primary human and mouse hepatocytes, and in mice in vivo (24mg/kg/day via drinking water for two weeks). The authors themselves state this "needs to be addressed in prospective clinical studies" and report no human patient iron-status parameters (ferritin, hemoglobin, transferrin saturation) anywhere in the paper.

Mechanism

Named and drug-specific at the Tier B level: the paper reports that "aldosterone, but not androgen signaling" cross-talks to hepcidin transcriptional control in primary hepatocytes via the BMP signaling pathway at the hepcidin promoter, and spironolactone, as an aldosterone antagonist, suppresses this. Suppressing hepcidin increases ferroportin-mediated iron export from enterocytes and macrophages, which would raise iron availability rather than lower it — the study frames this as a possible drug-repositioning angle for conditions of hepcidin excess (anemia of inflammation, hereditary hemochromatosis, iron-loading anemias), not as a spironolactone safety signal.

Counter-evidence held on record

The authors' own paper states this mechanism has not been tested in a prospective human clinical study; this dossier is not aware of one having been conducted since. No study reporting spironolactone lowering, rather than raising, iron availability was located, and no study reporting no effect either was located — the honest state of the evidence is mechanistic-only, in one direction, unconfirmed in humans. This must never be presented as spironolactone treating iron deficiency or as a reason to reduce iron supplementation or monitoring. It is a cell-and-mouse mechanistic finding about hepcidin transcription, not a demonstrated human iron-status effect in either direction, and any question about iron status in a patient on spironolactone belongs with a prescriber, not this database.

Limits on what this shows

• Key negative/null findings: Not applicable; there is no positive claim or study to weigh a null finding against. The absence itself, after a multi-angle search across regulatory, mechanistic, and consumer sources, is the finding.
• At-risk subgroups: Not established; none can be inferred without an underlying mechanism or study.
• Dose/duration: Not applicable; no dose-response or duration data of any kind exists for this pairing, and none is recommended here.

Regulatory status

The FDA label does not mention copper, ceruloplasmin, or any copper-related parameter anywhere in its text (confirmed by direct review of the 2025 label already cited in this dossier). The StatPearls spironolactone monograph was also searched directly and contains no mention of copper.

Population evidence

None located at any tier. Searches for spironolactone and copper, serum ceruloplasmin, and the copper transporters ATP7A/ATP7B returned no drug-specific or class-specific results connecting spironolactone or other aldosterone antagonists to copper handling.

Mechanism

None identified. Spironolactone's known mechanism, competitive antagonism at the aldosterone-dependent sodium-potassium exchange site in the distal renal tubule, has no established cross-talk to intestinal copper absorption, ceruloplasmin synthesis, or hepatic copper handling in any source reviewed for this dossier.

Counter-evidence held on record

There is nothing to counter because there is nothing asserted. This entry exists so that a reader searching this database for "spironolactone and copper" finds an honest, explicit statement that the evidence does not exist, rather than silence that could be mistaken for an oversight. This must never be read as proof that spironolactone has no effect on copper status; absence of evidence is not evidence of absence. It must equally never be dressed up as a theoretical risk to fill the section. No copper testing or supplementation guidance is implied in either direction.

Limits on what this shows

• Key negative/null findings: No human data exists in either direction. No animal or mechanistic study was located showing spironolactone causing dysbiosis or microbiome harm, despite a specific search for that direction; the notable finding is the absence of any harm signal in the literature actually reviewed, not a confirmed null result from a study designed to detect harm and find none.
• At-risk subgroups: None established in humans. Both animal models used disease states (myocardial infarction, spontaneous hypertension) that themselves are known to alter the gut microbiome independent of any drug, which is a confounding-by-indication caveat this dossier flags explicitly rather than assumes away.
• Dose/duration: Not stated in the sources reviewed for the mouse MI model; the hypertensive-rat study used 5 weeks of treatment at a dose not confirmed in the abstract-level record reviewed. No human dose or duration data exists, and none is recommended here.

Regulatory status

The FDA label does not mention gut flora or microbiome anywhere in its text; it does list diarrhea, cramping, gastritis, nausea, and vomiting among gastrointestinal adverse reactions (confirmed by direct review of the 2025 label already cited in this dossier), which are clinical GI effects, not microbiome-composition findings, and are not counted toward this entry (see Overlap map).

Population evidence

No human microbiome study of spironolactone was located. Two independent drug-specific animal studies were identified: Li et al., J Microbiol 2024 (opened directly; C57BL/6J mice with surgically induced myocardial infarction, spironolactone treatment, fecal microbiota sequencing; antibiotic-based microbiota depletion abolished spironolactone's cardioprotective benefit, and the drug's effect involved increasing beneficial taxa including Lactobacillus vaginalis); González-Correa et al., Biomed Pharmacother 2023 (spontaneously hypertensive rats vs normotensive controls, 5 weeks of spironolactone; restored the Firmicutes/Bacteroidetes ratio and acetate-producing bacteria toward normotensive-control levels, reduced intestinal aerobic bacteria, and reduced gut permeability and gut sympathetic tone, associated with lower blood pressure). This second study's original journal page could not be opened directly (see Sources); its description here comes from the DOAJ-indexed abstract record, not this dossier's own reading of the full article.

Mechanism

Named in both animal studies: reduced gut sympathetic tone and improved intestinal barrier integrity (González-Correa), and a microbiota-dependent cardioprotective pathway confirmed by antibiotic-depletion experiments (Li). Neither paper proposes or finds a mechanism by which spironolactone would deplete or damage the microbiome.

Counter-evidence held on record

One of the two supporting sources (González-Correa) was reviewed only at the DOAJ abstract-index level, not the full ScienceDirect article, which returned an access error on direct fetch; that limitation is disclosed rather than hidden. Both studies are animal models of specific cardiovascular disease states, not healthy human physiology, and confounding by underlying disease is real and unresolved in this literature. This must never be presented as spironolactone being a probiotic or gut-health intervention for a general consumer. It is animal-model, disease-state-specific mechanistic evidence, not a human gut-health claim, and it must equally not be inverted into a "spironolactone harms your microbiome" claim, since no such evidence was found despite a direct search for it.

Limits on what this shows

• Key negative/null findings: HIF-1α showed no significant between-group difference at baseline or at 7 days post-operatively; the effect was confined to the 24-hour timepoint. No hemoglobin, hematocrit, arterial oxygen saturation, or erythropoietin data were reported in this study, and none specific to spironolactone were located elsewhere.
• At-risk subgroups: Cardiac surgery (CABG) patients with chronic pre-operative spironolactone exposure specifically; this is a single surgical-population cohort and has not been replicated in a non-surgical or non-cardiac population.
• Dose/duration: Chronic use of more than 3 months before surgery; specific milligram dose not stated in the abstract reviewed. No dosing recommendation is made here in either direction.

Regulatory status

The FDA label lists leukopenia (including agranulocytosis) and thrombocytopenia among hematologic adverse reactions, but does not mention anemia, hemoglobin, hematocrit, or oxygen-carrying capacity anywhere in its text (confirmed by direct review of the 2025 label already cited in this dossier). Those white-cell/platelet effects are a separate, already-labeled clinical outcome and are not counted toward this entry (see Overlap map).

Population evidence

Retrospective, propensity-score-matched cohort, n=174 (87 chronic spironolactone users for more than 3 months pre-operatively vs 87 matched controls) undergoing coronary artery bypass grafting (J Cardiovasc Pharmacol 2021; PMID 34173801, abstract reviewed directly via PubMed). Hypoxia-inducible factor-1α (HIF-1α, a marker stabilized under cellular hypoxia) did not differ between groups before surgery or at 7 days after surgery, but was significantly lower in the spironolactone group at 24 hours post-operatively (P<.01). Secondary findings in the same cohort included lower NT-proBNP and lower postoperative atrial-fibrillation incidence with spironolactone use.

Mechanism

Not fully elaborated in the abstract reviewed; the authors interpret the lower 24-hour HIF-1α as consistent with spironolactone "improving myocardial hypoxia," which would run opposite to a claim that the drug impairs oxygen delivery or utilization. This dossier did not independently verify a specific molecular pathway beyond the authors' own interpretive statement.

Counter-evidence held on record

The null timepoints (baseline, 7 days) are reported here rather than omitted; only one of three measured timepoints showed a significant difference. This is a single retrospective cohort in one surgical population, not a body of literature, and it has not been replicated. This must never be presented as spironolactone improving oxygen delivery, athletic performance, or altitude tolerance for a general consumer. It describes a single biomarker at a single post-surgical timepoint in cardiac-surgery patients, and it is not a substitute for any hemoglobin, hematocrit, or oxygenation monitoring a prescriber has ordered.

Limits on what this shows

• Key negative/null findings: This is a single study, in a single non-human, non-cardiac, non-renal cell line, under one induced-injury model; there is no second study to compare it against in either direction. The finding is restoration of an experimentally induced ATP deficit back toward control levels, not an increase in ATP above normal baseline function, and this dossier is careful not to overstate it as the latter.
• At-risk subgroups: None established in humans. If eventually relevant to humans, the induced-damage model (a diabetes-mimicking oxidative stressor) suggests any relevance would concentrate in hyperglycemia-driven cellular stress rather than in the general spironolactone-treated population, but this is speculative extrapolation from one in vitro study, not an established subgroup.
• Dose/duration: 100µM spironolactone, single in vitro exposure window (same experiment as the Mitochondrial Burden entry above). No animal or human dosing data exists for this endpoint, and none is recommended here.

Regulatory status

The FDA label does not mention ATP, cellular energy production, or bioenergetics anywhere in its text (confirmed by direct review of the 2025 label already cited in this dossier).

Population evidence

No human or animal in vivo study was located. The direct evidence is the same in vitro study cited under Mitochondrial Burden above (Park et al., Exp Ther Med 2026; PMID 41858771; see Overlap map for how this single study's endpoints are divided between the two entries): MC3T3-E1 mouse pre-osteoblast cells exposed to 2-deoxy-D-ribose (dRib) to induce diabetes-like cellular damage. dRib lowered ATP levels to 54.3±6.8% of control; 100µM spironolactone co-treatment restored ATP to 103.7±6.9% of control, essentially back to baseline.

Mechanism

Named at the Tier B level within this one study: spironolactone reduced dRib-induced reactive oxygen species and mitochondrial superoxide and restored mitochondrial membrane potential in the same cells in which ATP was restored, consistent with an antioxidant-linked preservation of mitochondrial ATP-generating capacity under this specific stressor. No separate, independent study of spironolactone and ATP production in cardiac, renal, or human tissue was located.

Counter-evidence held on record

No contradicting evidence was found, but this reflects the near-total absence of any literature on spironolactone and ATP production at all, not a body of confirmatory work. This is one study's secondary endpoint, sharing its entire evidence base with the Mitochondrial Burden entry above (see Overlap map), not an independently replicated finding. This must never be presented as spironolactone boosting energy, cellular ATP, or exercise capacity in a person. It is a single cell-culture finding under an induced-injury model measuring restoration of an experimentally created deficit, not a human energy-production claim in either direction.