Cimetidine

Limits on what this shows

• Null and contrary findings: Goineau and Castagne 2017 [27] (abstract excerpt only): cimetidine at 10 and 50 ug/mL protected cultured gastric cells from indomethacin by preserving mitochondrial function. A 2024 kidney slice paper lists cimetidine as an OCT2 inhibitor that improved ATP recovery against cisplatin, which is a transport effect and not a mitochondrial finding (listing only) [39].

Regulatory status

No mitochondrial statement in either label read [1][2].

Population evidence

None in humans. Ghersi-Egea 1986 [26]: "The presence of cimetidine in the incubation medium of rat brain mitochondria caused decreased oxygen uptake, especially during oxidative phosphorylation (state 3)", with dose-dependent inhibition of respiratory control; the same was seen in hepatic mitochondria. Concentrations were not given in the abstract. Tier B, cimetidine tested directly.

Mechanism

Present in vitro (respiratory chain or coupling inhibition, not specified). Relevance to therapeutic tissue concentrations is not shown.

Counter-evidence held on record

Counter-evidence The gastric cell result [27] runs the opposite way, and the 1986 finding comes from isolated mitochondria without human correlates. Framing caution Mechanistic, in vitro only. Not a claim that cimetidine damages mitochondria in people, and not a supplement indication (for example, no CoQ10 inference).

Limits on what this shows

• Null findings: No MDA or antioxidant enzyme measurement in cimetidine users was found. A 1993 Chemico-Biological Interactions paper on hydroxyl radical scavenging by H2 blockers was found by title only; its abstract was unavailable and it is not used.

Regulatory status

No oxidative stress statement in either label read [1][2].

Population evidence

None in humans. Lambat 2002 [21]: cimetidine reduced superoxide formation and iron-induced lipid peroxidation in rat brain homogenates. Biedrzycki 2023 [28], in vitro plus systematic review (read via summarizer): at 1 mM cimetidine scavenged 20% to 70% of superoxide, hydroxyl, nitric oxide, hydrogen peroxide, ABTS and DPPH radicals, and had the weakest anti-glycation effect of the H2 blockers tested; the review reported inhibition of superoxide and hydrogen peroxide production in human neutrophils. Ahmadi 2011 [29]: DPPH IC50 671 +/- 28 ug/mL; in mice 40 mg/kg reduced carbon tetrachloride elevation of AST and ALP. Gholami 2025 [30]: mouse radiation study including cimetidine; cimetidine-alone results could not be retrieved and are not used.

Mechanism

Direct radical scavenging and metal binding by the drug molecule [21][28]. Not shown to change systemic antioxidant capacity in humans.

Counter-evidence held on record

Counter-evidence Scavenging at millimolar concentrations may not be reached in plasma; in vitro antioxidant activity does not establish a clinical benefit. Framing caution Not an antioxidant benefit claim and not a deficiency claim. Cimetidine should not be described as depleting antioxidants.

Limits on what this shows

• Null and reverse findings: Walan and Strom 1985 [15]: plasma iron and hemoglobin unchanged after three years of cimetidine. Bodenheimer and Thayer 1981 [13]: case report of hemochromatosis with high transferrin saturation during long-term cimetidine; the title carries a question mark and the cause is unestablished. This is an excess direction in one case, and Tier B.

Regulatory status

No iron effect in either generic label read [1][2]. StatPearls says excessive H2 blocker use "may predispose patients to iron deficiency anemia" (Tier B reference, summarized) [4].

Population evidence

Skikne, Lynch and Cook 1981 [12]: radioiron absorption in human volunteers (number not captured); cimetidine 300 mg reduced absorption of dietary non-heme iron 28%; 600 mg and 900 mg reduced it 42% and 65%. The authors conclude recommended doses would not substantially impair iron nutrition. Tier A for cimetidine, abstract only. A 1988 narrative review of H2 blocker hematologic effects discusses iron and cobalamin malabsorption (Tier C narrative, no drug-level stratification for this point) [14].

Mechanism

Present. Acid solubilizes non-heme iron; dose-dependent loss of acid secretion gives dose-dependent loss of absorption [12]. In vitro, cimetidine also binds iron and copper [21], which is chemistry and not a demonstrated absorption block.

Class cohort test

CLASS EXTRAPOLATION (context only): Lam 2017 [11], case-control, 77,046 iron deficiency cases and 389,314 controls (1999 to 2013), H2 blocker use of 2 or more years: adjusted OR 1.58 (95% CI 1.46 to 1.71). No individual H2 blocker is named in the abstract, so cimetidine is not documented in that cohort; Tier C, confounded by indication (GI blood loss).

Direction check (Hard Rule 4)

Ferrous sulfate lowers cimetidine absorption (Campbell 1993, rat jejunal perfusion and in vitro) [37]. That is nutrient affecting drug and belongs to timing, not depletion; see Monitoring panel.

Counter-evidence held on record

Counter-evidence The study authors judged the effect at recommended doses not substantial [12]; three-year plasma iron and hemoglobin were unchanged [15]; the one long-term status report is hemochromatosis, not deficiency [13]. Framing caution Iron deficiency is not anemia (Hard Rule 2). Because one case points toward excess, iron supplementation should not be inferred from this entry in either direction.

Limits on what this shows

• Null findings: No copper, ceruloplasmin or cuproenzyme measurement in cimetidine users was found. A rat study of a copper-cimetidine complex (not cimetidine alone) is not used.

Regulatory status

Not mentioned in either label read [1][2].

Population evidence

None in humans. Lambat 2002 [21]: electrochemistry, UV/Vis and HPLC showed metal-ligand interactions between cimetidine and transition metals, framed as binding iron and copper and preventing their role in radical formation. Akrivos 1984 [20]: potentiometric study at 37 C of copper(II) and zinc(II) complexes with computer simulation of plasma distribution at therapeutic levels, concluding "no influence can be expected from cimetidine on the bioavailability of these metal ions". Both Tier B, cimetidine-specific.

Mechanism

Chelation chemistry is demonstrated in vitro; physiologic relevance is argued against by the simulation [20].

Counter-evidence held on record

Counter-evidence The simulation is the direct counter-evidence [20]. No clinical copper deficiency report on cimetidine was found. Framing caution Chemistry curiosity, kept independent of Iron (Hard Rule 7). Not a deficiency claim and not a reason to supplement copper.

Regulatory status

No microbiome statement in either label read [1][2].

Population evidence

CLASS EXTRAPOLATION. Tleyjeh 2013 [31]: systematic review and meta-analysis, 33 studies, 201,834 participants; H2 receptor antagonist use and C. difficile infection pooled OR 1.44 (95% CI 1.22 to 1.70); most studies did not specify the agent, so no cimetidine stratum exists (cimetidine not documented as separately analyzed). Nath 1994 [32]: hospital case-control, 80 cases and 80 controls; GI drugs (ranitidine, famotidine, cimetidine, omeprazole, sucralfate) pooled aOR 3.20 (95% CI 1.39 to 7.34); cimetidine was in the exposure group but no cimetidine-specific estimate exists. Hemodialysis cross-sectional study [33], 193 patients, 32 H2 blocker users: higher dysbiosis index and enrichment of several genera; individual agents not specified, so cimetidine is not documented.

Cimetidine-named data

Kelly 1983 [34]: prospective ICU study; diarrhea was associated with nasogastric feeding (p under 0.01) and cimetidine (p under 0.05), and C. difficile cytotoxin was not detected in any case. A 1985 ICU study of gastric and bronchial aspirates in cimetidine-treated ventilated patients found significant bacterial growth in 72.8% and 79.1% with no comparator group (listing only) [39].

Mechanism

Plausible: less gastric acid weakens the acid barrier to ingested and oral organisms. Not demonstrated for cimetidine in composition studies.

Cohort test result

Cimetidine is inside the pooled exposure of one case-control study [32] but no source gives a cimetidine-specific microbiome or infection estimate. Capped at yellow as class extrapolation.

Counter-evidence held on record

Counter-evidence and confounding Observational data are confounded by hospitalization, antibiotics and illness severity. The ICU diarrhea study found no C. difficile toxin [34]. PubMed listings for cimetidine with microbiota returned only one irrelevant fish-model record. Framing caution Not a dysbiosis claim for cimetidine. Do not borrow PPI microbiome findings.

Limits on what this shows

• Null findings: None directly. See the contrary cultured-cell mitochondrial result under Mitochondrial burden [27].

Regulatory status

No energy-metabolism statement in either label read [1][2].

Population evidence

None in humans. Ghersi-Egea 1986 [26]: the inhibition of respiratory control and of ATP synthesis was dose-dependent in brain mitochondria, and the same in hepatic mitochondria. Tier B.

Mechanism

Secondary to the respiration finding; no separate ATP assay in cells or tissue was found. Kept as its own entry (Hard Rule 7); the shared origin is disclosed in the Overlap map.

Counter-evidence held on record

Counter-evidence No evidence of reduced cellular energy output or fatigue attributable to cimetidine was found; "low energy" claims for cimetidine were not located. Framing caution Not an energy-deficit claim. One in vitro abstract is the whole basis.

Limits on what this shows

• Null findings: Walan and Strom 1985 [15]: hemoglobin unchanged after three years. The 1983 two-patient report found negative antidrug antibody testing, titled as a fallacy of clinical association [36].

Regulatory status

Both labels list agranulocytosis, thrombocytopenia, rare pancytopenia or aplastic anemia, and "extremely rare" immune hemolytic anemia [1][2].

Population evidence

Wu 2021 [35]: 44-year-old man, direct antiglobulin test positive for anti-IgG and anti-C3d, IgM and IgG cimetidine-dependent antibodies detected, markers persisting beyond 41 days. A PubMed listing [36] shows further single-patient reports (Lancet 1979; a 2010 Transfusion report with recurrence on two separate exposures; a 1997 report of recurrence with ranitidine; a 1983 report of two patients in whom antidrug antibody testing was negative), none opened in full. Aymard and colleagues 1988 [14]: of 85 reported H2 blocker cytopenia cases, 75 (88%) were with cimetidine, mainly neutropenia and agranulocytosis, with three proposed mechanisms (stem cell toxicity, immune reaction, interaction with toxic drugs). Tier B for hemolysis; the review is Tier C narrative.

Mechanism

Drug-dependent antibody formation (immune hemolysis) [35]. Not related to oxygen-carrying nutrient supply. Any hemoglobin effect through absorption of iron or B12 is carried in those entries and not counted here.

Hard Rule 2 treatment

Hemolytic anemia is an adverse drug reaction outcome and is not an oxygen-delivery nutrient deficiency. Direction: not applicable as depletion. It is listed because the category must be evaluated and because case reports exist for this drug.

Counter-evidence held on record

Counter-evidence Very rare (label wording), idiosyncratic, with no cohort estimate. Case reports do not give an incidence. Framing caution A safety signal for clinicians, not a nutrient statement. Kept independent of ATP production (Hard Rule 7).