Chlorpromazine

Limits on what this shows

• Key negative/null findings: None located; all retrieved studies in this specific search were positive for some mitochondrial effect. Absence of a negative study is noted as a search-coverage limitation, not treated as confirmation.
• At-risk subgroups: Not established in humans; theoretical extension to patients with pre-existing mitochondrial disease is plausible but unverified for this drug.
• Counter-evidence on record: All primary data are in vitro or animal; no clinical mitochondrial-function biomarker study (e.g., in vivo muscle biopsy respirometry) in chlorpromazine-treated patients was located.

Regulatory status

Not addressed on the US label.

Population evidence

In vitro/animal only. Spirtes & Guth (1963, PMID 13990190): chlorpromazine-induced changes in liver mitochondrial membranes. Koppikar et al. (1969, PMID 4245420): chlorpromazine-induced contraction of rat liver mitochondria. Tjioe et al. (1972, PMID 5041878): calcium efflux and respiratory inhibition in brain mitochondria from chlorpromazine metabolites. Burkhardt et al. (Ann Neurol 1993, PMID 8098932): chlorpromazine (with haloperidol and thiothixene) inhibits Complex I in vitro in rat brain mitochondria; the same report also describes depressed platelet Complex I activity in neuroleptic-treated patients, though the drug-by-drug cohort breakdown for that specific human sub-finding could not be confirmed from the abstract-level material available in this review.

Mechanism

Named: direct membrane/structural mitochondrial interaction and Complex I (NADH dehydrogenase) inhibition, drug-specific (chlorpromazine was one of the directly tested compounds in each cited study, not a class inference).

Counter-evidence held on record

This is a direct pharmacologic/toxicologic mitochondrial effect, not a nutrient deficiency, and it does not by itself justify a mitochondrial-support supplement regimen (see Coenzyme Q10 entry for the specific, separately graded signal on that point).

Limits on what this shows

• Key negative/null findings: None specifically isolating "no effect at therapeutic dose" was located in the abstract-level material retrieved; this is flagged as a genuine gap in what could be confirmed, not as a negative finding.
• At-risk subgroups: Acute overdose/poisoning presentations (the population in which the human signal is clearest); patients on long-term, higher cumulative dosing by extension of the mechanistic (non-human) literature.
• Counter-evidence on record: The comparator design (therapeutic dose vs. mild vs. severe overdose vs. controls) is itself a strength, but an active-comparator confound applies to any attempt to generalize the overdose finding to routine dosing: overdose pharmacokinetics (much higher peak concentration, possible hypoxia/hypotension contributing independently to oxidative stress) are not equivalent to chronic therapeutic exposure.

Regulatory status

Not a labeled adverse reaction category; oxidative stress is a laboratory/mechanistic construct, not a named label finding.

Population evidence

Human study comparing chlorpromazine patients on therapeutic doses (75-150 mg/day), mild overdose, severe overdose, and healthy controls; total antioxidative status and erythrocyte superoxide dismutase activity were decreased and malondialdehyde elevated in overdosed patients versus controls (Dejanović et al., Vojnosanitetski pregled 2015, PMID 29308860). The abstract text available for this review did not isolate a statistically distinct therapeutic-dose-only effect from the overdose effect, which is why this is graded orange (bounded) rather than red.

Mechanism

Named, drug-specific, and corroborated by independent in vitro work: chlorpromazine induces oxidative stress in cultured porcine aortic endothelial cells (Barraza-Garza et al. 2025, PMID 40916306) and in human HepaRG hepatocytes, where oxidative stress is reported to drive chlorpromazine-induced cholestasis (Anthérieu et al., Toxicol Sci 2013, PMID 23175273) and in short-term human erythrocyte functionality studies (Ficarra et al. 2016, PMID 27579150).

Counter-evidence held on record

This is a measured redox/laboratory finding, not a diagnosed vitamin or mineral deficiency, and no specific antioxidant supplement dose is supported by this evidence. The clearest human data point is from poisoning, not routine dosing; treat the therapeutic-dose magnitude as unconfirmed rather than assume it scales down proportionally.

Limits on what this shows

• Key negative/null findings: No modern (post-1980s) human study replicating or refuting the 1956 case series was located.
• At-risk subgroups: Not established; the original 1956 report did not stratify by subgroup.
• Counter-evidence on record: Critical confound: chlorpromazine's own, separate, well-documented extrapyramidal syndrome (dopamine D2 blockade) is a direct labeled pharmacologic effect and must not be attributed to copper metabolism; the 1956 report's interpretation of "Wilson's-disease-like" symptoms as copper-driven, rather than as chlorpromazine's own neurologic pharmacology, has not been independently confirmed and should be read with that caveat (Hard Rule 2).

Regulatory status

Not addressed on the US label.

Population evidence

Azima & Richman, "Alteration of copper metabolism in chlorpromazine-treated cases" (Arch Neurol Psychiatry 1956, PMID 13282535): human case series reporting chlorpromazine-treated patients with extrapyramidal and hepatic findings resembling Wilson's disease and altered copper metabolism. Løvstad, "Interaction of phenothiazine derivatives with human ceruloplasmin" (Biochem Pharmacol 1974, PMID 4151049): chlorpromazine, promazine, triflupromazine and levomepromazine were directly tested and shown to interact with human ceruloplasmin (a copper-dependent oxidase).

Mechanism

Named but dated and unreplicated: proposed interference with copper-dependent hepatic/neurologic handling, structurally plausible given chlorpromazine's direct biochemical interaction with ceruloplasmin.

Counter-evidence held on record

If a real effect exists, the direction implied by the available evidence is altered handling or possible retention/excess, not depletion. Copper supplementation is not supported by this entry and would be the wrong response if this signal is real; extrapyramidal symptoms on chlorpromazine should be worked up as the drug's known dopaminergic pharmacology first, not as a copper disorder. Shares its primary mechanistic source with the Iron entry below; see Overlap map.

Limits on what this shows

• Key negative/null findings: None located. A separate, unrelated psychiatric literature (serum iron and neuroleptic malignant syndrome risk) exists but was not independently opened and verified in this review, and in any case runs in the opposite causal direction from a depletion claim (low pre-existing iron as a risk factor for the syndrome, not the drug causing iron loss), addressed under Fails verification rather than cited here as support.
• At-risk subgroups: Not established.
• Counter-evidence on record: This entry is explicitly theoretical; it should not be read as evidence of measured iron deficiency.

Regulatory status

Not addressed on the US label.

Population evidence

No direct human or animal iron-status study in chlorpromazine-exposed subjects was located despite repeated search attempts (see Why no grade logic below, this is graded, not ungraded, only because the ceruloplasmin mechanism clears the Tier B bar). Indirect: Løvstad 1974 (PMID 4151049), as above, chlorpromazine directly inhibits/interacts with ceruloplasmin in vitro.

Mechanism

Theoretical and indirect: ceruloplasmin is the principal plasma ferroxidase; a drug shown to interact with ceruloplasmin could in principle impair iron mobilization from stores, but this has not been tested for chlorpromazine specifically with an iron-status endpoint.

Counter-evidence held on record

No iron, ferritin, or hemoglobin change has been directly measured in chlorpromazine-treated patients in any source opened for this review. This is a mechanistic flag only; no iron supplementation is recommended or implied. Shares its primary mechanistic source with the Copper entry above; see Overlap map.

Limits on what this shows

• Key negative/null findings: The same multi-omics paper notes that species-abundance estimates were highly consistent across methods, i.e., this is not an artifact of one assay; however, a synthetic 32-species community is not the full complexity of an in vivo human gut, which bounds how far this generalizes.
• At-risk subgroups: Not established in vivo. A separate human study of chlorpromazine-treated schizophrenia patients with constipation (Yang et al. 2024, PMID 38701375) found that adding probiotics and dietary fiber improved constipation scores and neurotrophic-factor markers, which is consistent with, but does not independently confirm, a baseline chlorpromazine-associated dysbiosis.
• Counter-evidence on record: No in vivo human stool-microbiome compositional study directly comparing chlorpromazine-exposed versus unexposed patients was located.

Regulatory status

Not addressed on the US label.

Population evidence

In vitro synthetic-community model, not a human cohort. Wuyts et al., "Consistency across multi-omics layers in a drug-perturbed gut microbial community" (Mol Syst Biol 2023, PMID 37485738): mapped the response of a 32-species synthetic human-gut-bacteria community to three non-antibiotic drugs across five omics layers; chlorpromazine "selectively inhibits Bacteroidota representatives," with metatranscriptome/metaproteome showing induced protein-quality-control stress responses and metabolomics showing decreased oligosaccharide uptake attributed to Bacteroidota depletion. Corroborated by Seewald et al. (2026, PMID 42001429), on chlorpromazine's direct antibacterial activity against bacteria relevant to the gut microbiota.

Mechanism

Named and drug-specific: direct antibacterial activity of chlorpromazine against a defined phylum of gut commensals, with downstream metabolic consequences (reduced oligosaccharide handling) demonstrated in the same synthetic-community system.

Counter-evidence held on record

This is an in vitro synthetic-community finding; it has not been confirmed as a clinical dysbiosis in chlorpromazine-treated patients, and no probiotic dose or specific strain is recommended by this entry.

Limits on what this shows

• Key negative/null findings: The label frames jaundice/cholestasis (a related but separate hepatic finding) as "usually promptly reversible on withdrawal," and the same reversibility is the standard clinical expectation for the hematologic reactions; this bounds the finding as low-frequency and generally reversible rather than a progressive deficiency state.
• At-risk subgroups: Patients with a pre-existing low white-cell count or history of drug-induced leukopenia/neutropenia are specifically flagged on the label for frequent CBC monitoring in the first months of therapy.
• Counter-evidence on record: No chlorpromazine-specific study quantifying incidence or confirming a nutrient-correctable cause was located; the mechanism as labeled is immune/marrow toxicity, which an iron, B12, or folate supplement would not prevent or treat.

Regulatory status

US label, Hematological Disorders: "including agranulocytosis, eosinophilia, leukopenia, hemolytic anemia, aplastic anemia, thrombocytopenic purpura and pancytopenia have been reported." Most agranulocytosis cases occur between weeks 4 and 10 of therapy.

Population evidence

Labeled postmarketing/case-level reporting (Tier A regulatory label); incidence is described as low/rare and not quantified numerically on the label.

Mechanism

Named as idiosyncratic: immune-mediated hemolysis and/or direct bone-marrow suppression, not a nutrient-transport or absorption mechanism. Mechanistically distinct from, but conceptually adjacent to, chlorpromazine's documented erythrocyte membrane and oxidative-stress effects (Ficarra et al. 2016, PMID 27579150; Föller et al., review of eryptosis triggers including chlorpromazine, PMID 18720418).

Counter-evidence held on record

This is drug-induced hematologic toxicity (marrow suppression or immune hemolysis), not a nutrient deficiency, and it must not be marketed or read as one. Supplementation is not the remedy; the correct response is the labeled action (CBC monitoring, prompt discontinuation and antibiotic therapy if cellular depression is found) under prescriber supervision.

Limits on what this shows

• Key negative/null findings: None located for ATP output specifically measured in chlorpromazine-exposed human tissue.
• At-risk subgroups: Not established in humans.
• Counter-evidence on record: The Complex IV finding comes from an oncology mechanism study (AML cells), not a toxicology or nutrition study, and should not be over-read as a general human energy-metabolism finding; it is cited here only because it is drug-specific, direct evidence of a chlorpromazine-ETC interaction.

Regulatory status

Not addressed on the US label.

Population evidence

In vitro/animal and cell-line only. Burkhardt et al. (Ann Neurol 1993, PMID 8098932): chlorpromazine inhibits Complex I in rat brain mitochondria in vitro (same source as the mitochondrial-burden entry; see Overlap map). Tjioe et al. (1972, PMID 5041878): chlorpromazine metabolites inhibit respiration in brain mitochondria. Zhang et al. (2025, PMID 39716856): in a cancer-cell (AML) mitochondrial-homeostasis study, chlorpromazine is used/cited specifically as a Complex IV (COX4I1-linked) inhibitor, a drug-specific mention but in a cancer-biology rather than nutrient-deficiency context.

Mechanism

Named: inhibition of electron-transport-chain complexes that feed the proton gradient driving ATP synthase; drug-specific for Complex I, drug-specific-but-context-limited (cancer cell line) for the Complex IV mention.

Counter-evidence held on record

No ATP level or "low energy" claim is established in chlorpromazine-treated patients; this entry reflects enzyme-level mechanistic plausibility only, see the Overlap map for its shared sourcing with Mitochondrial burden.