Disulfiram

Limits on what this shows

• Key negative/null findings: No human study found; no evidence this occurs with disulfiram monotherapy without co-administered copper at the doses used in these cancer models.
• At-risk subgroups: None established for standard alcohol-aversion dosing. The mechanism is studied specifically because of its therapeutic potential in cancer, i.e., it is being deliberately induced in that context, not observed as an incidental harm in alcohol-use-disorder patients.
• Counter-evidence on record: Schweizer et al 2013 (PMID 23958896), a human pharmacodynamic trial of disulfiram 250-500 mg/day in prostate cancer, reported toxicity but did not identify mitochondrial injury as a defining clinical finding and recommended against further development at those doses, a human exposure closer to standard AUD dosing than the cell-line copper-loading studies, without replicating the mitochondrial signal.

Regulatory status

Not addressed in the label. Excluded from this entry: disulfiram's intended inhibition of mitochondrial aldehyde dehydrogenase (ALDH1A1/ALDH2), which is the drug's labeled mechanism of action for alcohol aversion and is never graded as a nutrient-style finding per protocol.

Population evidence

Cell-based, this drug specifically (disulfiram + copper): osteosarcoma (PMID 34602566, 2021), oral cancer (PMID 33918312, 2021), breast cancer (PMID 27353661, 2016), and a 2026 study (PMID 41438581) directly measuring decreased mitochondrial membrane potential and ATP. One mouse bone-marrow study (PMID 35477543, 2022) found reduced metabolic activity and membrane potential with disulfiram alone. No human data.

Mechanism

Named: the disulfiram-copper complex (CuET) induces mitochondrial fission and collapses membrane potential, distinct from the drug's ALDH-inhibition pathway and requiring, in most of these studies, deliberately added copper above what is present with disulfiram alone.

Framing caution

This signal comes from cancer cell-line systems using disulfiram plus deliberately added copper, not from standard oral alcohol-aversion dosing. It is not evidence that disulfiram monotherapy damages mitochondria in typical patients, and it is not a basis for mitochondrial-support supplementation.

Limits on what this shows

• Key negative/null findings: All of the above are in vitro (cultured cells, isolated enzyme, or yeast) or cancer cell-line work; none measured whole-organism oxidative stress in a person taking oral disulfiram.
• At-risk subgroups: None established in humans. Mechanistically, any copper-dependent antioxidant capacity could in principle be more affected in someone with pre-existing marginal copper or glutathione status, but this is extrapolated reasoning, not a measured finding.
• Counter-evidence on record: None located showing disulfiram is antioxidant/protective in humans; the Jørgensen et al 1988 rat study (PMID 3413028) found disulfiram pretreatment reduced acetaminophen-induced hepatic necrosis, a protective rather than pro-oxidant outcome in that specific model, illustrating that direction is context-dependent and not uniformly pro-oxidant.

Regulatory status

No oxidative-stress-related warning or monitoring parameter in the DailyMed/FDA label.

Population evidence

No human population study measuring oxidative-stress markers (malondialdehyde, total antioxidant capacity, SOD activity, glutathione) in disulfiram-treated patients was located despite repeated search attempts across multiple channels (see Ungraded section and access notes for the channel-level detail).

Mechanism

Named: diethyldithiocarbamate (DDC) is a standard laboratory inhibitor of cytosolic and extracellular Cu/Zn-superoxide dismutase, acting by chelating the enzyme's catalytic copper (Kelner & Alexander 1986, PMID 3003078; Siwik et al 1999, PMID 10417396; Wambi-Kiesse & Katusic 1999, PMID 10070090; Lushchak et al 2005, PMID 16274662, in yeast). The same 1986 study found DDC also depletes cellular glutathione. Separately, disulfiram/copper complexes generate reactive oxygen species that activate the cGAS-STING DNA-damage pathway in cancer cell models (2025, PMID 39990655).

Framing caution

Mechanistic plausibility only. No human data confirms clinically relevant oxidative stress from standard-dose disulfiram, and this is not a basis for antioxidant supplementation.

Counter-evidence held on record

Jørgensen CR et al, 1988, PMID 3413028 (rat): disulfiram pretreatment protected against acetaminophen hepatotoxicity rather than increasing oxidative injury in that model.

Limits on what this shows

• Key negative/null findings: Menkes-disease case series showed an increase, not a decrease, in serum copper/ceruloplasmin. No vitamin/mineral interaction, including copper, is listed in a 221-entry drug-interaction database for disulfiram.
• At-risk subgroups: None established for depletion. The opposite concern, copper redistribution/toxicity, is theoretical outside of investigational cancer dosing with deliberate copper co-administration, which does not reflect standard alcohol-aversion therapy.
• Counter-evidence on record: See above; also, the DDC-copper chelation literature is overwhelmingly mechanistic/in vitro or cancer cell-line work using disulfiram plus exogenous copper loading, a different exposure than oral monotherapy.

Regulatory status

Not mentioned in the DailyMed/FDA label; no copper-related warning, monitoring recommendation, or adverse reaction is listed.

Population evidence

Human: a 3-patient case series in Menkes disease (a congenital copper-deficiency disorder, not alcohol use disorder) found serum copper and ceruloplasmin "slightly increased" in one patient on disulfiram (Ogawa & Kodama, 2012, PMID 22575542), the opposite of a depletion signal, though in a non-representative population and sample size of 3. No study measuring serum/tissue copper in a standard alcohol-use-disorder cohort on disulfiram was located.

Mechanism

Named and well established at the metabolite level: diethyldithiocarbamate (DDC), disulfiram's major reduction product, is a classic experimental copper chelator that removes the catalytic copper from Cu/Zn-superoxide dismutase (SOD1) and from dopamine-beta-hydroxylase, and forms a redox-active bis(diethyldithiocarbamate)-copper complex ("CuET") that is investigationally exploited, with deliberately added copper, as an anti-cancer agent (cuproptosis/copper-ionophore mechanism).

Framing caution

This is an enzyme-level chelation mechanism, not an established nutritional copper deficiency. Nothing here supports copper supplementation, and the one human dataset located argues against a depletion effect at standard dosing.

Counter-evidence held on record

Ogawa E, Kodama H. Effects of disulfiram treatment in patients with Menkes disease and occipital horn syndrome. J Trace Elem Med Biol. 2012;26(2-3):102-104. PMID 22575542. n=3, serum copper/ceruloplasmin trended upward in one patient, not downward.

Limits on what this shows

• Key negative/null findings: No study reports iron deficiency or lowered iron markers with disulfiram; every located finding runs in the excess/redistribution direction.
• At-risk subgroups: None established in humans at standard dosing; theoretical concern would be localized oxidative iron injury in tissue exposed to high disulfiram-copper complex concentrations, a cancer-therapy context, not routine alcohol-aversion therapy.
• Counter-evidence on record: No human hematologic abnormality tied to iron handling was found in the near-clinical-dose human trial (PMID 23958896).

Regulatory status

Not addressed in the label.

Population evidence

Cell-based, this drug plus copper: triple-negative breast cancer (PMID 37664913, 2023), hepatocellular carcinoma (PMID 34482117, 2021), oral squamous cell carcinoma (PMID 37286868, 2024), and leukemia cell/patient-derived models (PMID 39465372, 2024) all report disulfiram/copper increasing the free iron pool and inducing ferroptosis. No human iron-status (ferritin, transferrin saturation, hemoglobin) data in disulfiram-treated patients was located.

Mechanism

Named: disulfiram-copper redox cycling increases labile intracellular iron and drives iron-dependent lipid peroxidation (ferroptosis), a mechanism deliberately exploited for its cytotoxic potential in cancer research, not an incidental systemic iron-deficiency pathway.

Framing caution

This is an iron-excess/redistribution mechanism confined to cancer cell-line research with deliberate copper loading, not an iron-deficiency risk. Nothing here supports changing iron intake, and it is not a basis for iron supplementation or restriction in routine disulfiram therapy.

Limits on what this shows

• Key negative/null findings: Several of these same studies frame the microbiome shift as net beneficial in specific disease models (NASH, atherosclerosis), so direction is context-dependent, not uniformly adverse.
• At-risk subgroups: None established in humans.
• Counter-evidence on record: Beneficial-direction findings above (bile-acid metabolism, atherosclerosis, Akkermansia enrichment) are themselves a counterweight to framing this purely as microbiome "risk."

Regulatory status

Not addressed in the label.

Population evidence

Animal, this drug specifically, disulfiram alone (not requiring added copper): mice, bile-acid/NASH model (PMID 36369291, 2022, Nature Communications); mice, atherosclerosis model with enrichment of specific taxa (PMID 38563369, 2024); mice, documented antimicrobial activity against anaerobic bacteria with compositional change across ileum, cecum, and feces (PMID 39701818, 2025); mice, intestinal microbiota shown to regulate the antitumor effect of disulfiram plus copper (PMID 32750218, 2020); mice, Akkermansia muciniphila identified as mediating a protective effect (PMID 39825784, 2025). No human gut-microbiome study of disulfiram was located.

Mechanism

Named: direct antimicrobial activity against anaerobic gut bacteria, plus secondary effects on bile-acid-metabolizing taxa.

Framing caution

Animal evidence only, direction mixed and model-dependent. Not a basis for probiotic or dietary recommendations in human disulfiram therapy.

Limits on what this shows

• Key negative/null findings: Single-study signal for the ATP endpoint specifically; not yet independently replicated in a second drug-specific source.
• At-risk subgroups: None established in humans.
• Counter-evidence on record: No ATP/bioenergetic measurement was reported in the human prostate-cancer pharmacodynamic trial (PMID 23958896) at near-clinical dosing.

Regulatory status

Not addressed in the label.

Population evidence

Cell-based, this drug plus copper: a 2026 study (PMID 41438581) explicitly measured decreased mitochondrial membrane potential and decreased ATP production together in the same experimental system. No independent confirmation study was located measuring ATP alone, and no human or animal whole-organism bioenergetic data exists.

Mechanism

Named: proposed downstream of the mitochondrial membrane-potential collapse described in the Mitochondrial burden entry; the two are mechanistically linked rather than independent findings (see Overlap map).

Framing caution

Single mechanistic cell-line source, requiring copper co-administration. Not evidence of an ATP deficit in a person taking disulfiram as prescribed, and not a basis for any energy-support supplementation.

Limits on what this shows

• Why no grade: Dual condition met per protocol: no Tier B/C evidence exists to support even a yellow grade, and no circulating claim exists to rebut as white. This is recorded as a disclosed gap, not a safety finding, and is not reworded as reassurance.

Channels tried

PubMed search-listing pages: a combined query ("disulfiram hemoglobin hematocrit oxygen") returned a genuine, clean zero-result page (explicit "no results were found," no automatic term mapping applied). A follow-up PubMed query ("disulfiram anemia hemolysis") was blocked by a bot-verification challenge page rather than returning content. A further PubMed query ("disulfiram case report anemia") and a follow-up ("disulfiram hemolytic anemia") were both rejected by the outbound proxy with HTTP 429 rate-limiting after repeated attempts and cooldowns. Europe PMC REST and Crossref REST were attempted for adjacent copper/iron queries earlier in this review and were rate-limited (429) on every attempt; they were not re-attempted for this category specifically given the persistent 429s on other queries in the same session. Semantic Scholar's Graph API returned 429 on its one attempt this session. OpenAlex's single-record lookup endpoint (by PMID) worked once earlier in this review for an unrelated citation, but its search endpoint returned 429 when tried. DailyMed's structured label content and NCBI Bookshelf/StatPearls (both of which worked reliably elsewhere in this review) contain no mention of hemoglobin, hematocrit, or oxygen-related effects for disulfiram. Drugs.com's side-effects and interactions pages (which worked reliably elsewhere in this review) list no hematologic adverse effect for disulfiram.

Genuine gap vs. tooling limit

The one clean zero-result query plus the consistent absence of any hematologic signal across three reliable, successfully-loaded sources (label, StatPearls, Drugs.com) support a genuine literature gap for this category. The additional blocked/rate-limited attempts mean the search was not as exhaustive across every planned channel (Europe PMC, Crossref, Semantic Scholar, OpenAlex search) as it was for other categories in this dossier, so a later revision should re-run those specific channels for this category before treating the gap as fully confirmed.