Promethazine

Limits on what this shows

• Null / negative: No in vivo study of mitochondrial injury from promethazine at clinical doses was found. The leading promethazine-specific signal is neuroprotective, which argues against a burden claim.
• At-risk subgroups: None identified. Not established for any human subgroup.

Regulatory status

The label [1] makes no mitochondrial statement.

Population evidence

Protective direction: a screen of 1,040 approved drugs for mitochondrial permeability transition inhibition (28 hits) found promethazine protective in oxygen-glucose-deprived neuron cultures and in mice after middle cerebral artery occlusion [5]; chronic promethazine reduced striatal lesion volume and apoptosis in the rat 3-nitropropionic acid model, with delayed Ca2+-induced permeability transition reported [3]; attenuated MPTP dopaminergic loss in mice [4]. Opposite direction: dose-dependent loss of mitochondrial membrane potential in K562 leukemia cells [8] and membrane depolarization in azole-resistant Candida tropicalis [7]. A 1964 study tested promethazine on swelling of isolated rat liver mitochondria [6]; only the title and record were available (no abstract), so no result is claimed. No effect estimates with confidence intervals exist; all are in vitro or animal work at concentrations not mapped to human plasma levels in the sources opened.

Mechanism

Named in [5] and [3]: inhibition or delay of the mitochondrial permeability transition. Depolarization at higher exposure [7][8]. Tier C context only: five other phenothiazines (chlorpromazine, fluphenazine, thioridazine, trifluoperazine, triflupromazine) dissipated mitochondrial membrane potential in hepatoma cells [9]; promethazine was not in that cohort and it is not used to grade this entry.

Counter-evidence held on record

Counter-evidence on record The permeability-transition work is protective, and the depolarization data come from cancer, yeast and neurotoxin-model systems rather than from people taking labeled doses. Shared evidence with Oxidative stress and ATP production is disclosed in the Overlap map. Framing caution This is not a mitochondrial toxicity claim and not a nutrient deficiency. Do not imply that supplements such as CoQ10 or antioxidants are needed or protective.

Limits on what this shows

• Null / negative: No clinical study shows a redox deficit or antioxidant-capacity loss in promethazine users. Direction of the net in vivo human effect is unknown.
• At-risk subgroups: None identified.

Regulatory status

The label [1] makes no redox statement.

Population evidence

In isolated rat hepatocytes and microsomes exposed to CCl4, promethazine strongly inhibited formation of all classes of carbonyl products of lipid peroxidation and was concluded to scavenge trichloromethylperoxyl and lipid peroxyl radicals [10]; it prevented malonaldehyde formation in hepatocytes challenged with CCl4, FeCl3 or cumene hydroperoxide [11]. Chlorpromazine plus promethazine combination therapy lowered reactive oxygen species and NADPH oxidase activity in rat middle cerebral artery occlusion and in SH-SY5Y cells [13], and reduced ROS production in rat stroke models [14]; both are combination studies, so promethazine's separate contribution is not isolated. Promethazine improved viability in glutamate-injured HT22 neurons [12]. Opposite direction: promethazine at 50 micromolar induced ROS in K562 leukemia cells, with N-acetylcysteine blocking cytotoxicity [8]; planarians exposed to higher concentrations showed increased malondialdehyde and altered antioxidant enzyme activity [15]. No human redox biomarker (glutathione, malondialdehyde, total antioxidant capacity) in promethazine users was found.

Mechanism

Radical scavenging, phenothiazine ring chemistry [10][11]; at high exposure, AMPK activation with ROS in leukemia cells [8].

Counter-evidence held on record

Counter-evidence on record The weight of the promethazine-specific data is antioxidant and cytoprotective, the reverse of a depletion claim. The pro-oxidant data use exposures and organisms not tied to human therapy. Framing caution Reverse-direction and context flag only. Nothing here supports taking antioxidant supplements; the evidence shows no human antioxidant deficit to correct.

Limits on what this shows

• Why no grade: Dual condition met: no Tier B or C evidence of a copper effect; no circulating copper claim for promethazine located. The PubMed listing "promethazine copper" returned 12 results; the 10 viewed were electrochemical sensor, oxidative degradation chemistry, antiemetic animal models, a coordination-complex mutagenicity paper and similar, none measuring copper status [25].
• Access caveat: Predominantly a genuine gap on the readable channels, with partial tooling limitation (page 2 unread, search channels blocked). Kept as a fully independent entry; never merged with Iron.

Channels tried

PubMed HTML listings for promethazine with copper [25] and a combined micronutrient query (18 results; 10 viewed) [24]: clean zero on viewed pages. PubMed eutils, Crossref, Europe PMC, Semantic Scholar, OpenAlex search, Unpaywall (curl): 403 policy denial. WebSearch ceruloplasmin query: results were generic copper-physiology pages with no promethazine content (titles only). The 2 unseen results on the copper listing page 2 were not read.

Limits on what this shows

• Why no grade: Dual condition met: no Tier B or C evidence of an iron-status effect; no circulating iron claim located. Two promethazine-iron items surfaced and neither measures status: an in vitro coordination-chemistry study of an iron(III)-promethazine complex (PMID 10085782) [21], and a 1972 Polish report titled as an effect of promethazine on subcellular liver iron in CCl4-poisoned animals (PMID 5043939), for which PubMed holds no abstract so no result can be stated [22].
• Access caveat: Partly tooling-limited: 21 of 31 iron listing results were not read, and the full text of [22] was not obtainable. Re-check when access is restored. Kept independent from Copper.

Channels tried

PubMed HTML listing "promethazine iron": 31 results, 10 viewed, none measured iron status, ferritin, transferrin or chelation in treated subjects [26]; combined query [24]. Same blocked and rate-limited channels as the Copper card (403 policy denial; Europe PMC 429).

Limits on what this shows

• Null / negative: No fecal metagenomic, diversity or short-chain fatty acid measurement in promethazine users was found. Short-course use further limits plausibility.
• At-risk subgroups: None identified.

Regulatory status

No microbiome statement in the label [1].

Population evidence

Class-level, in vitro only: 24 percent of drugs with human targets inhibited at least one of 40 representative gut strains, and antipsychotics were overrepresented [20]. The retrieved summary says phenothiazines showed anticommensal activity but does not name promethazine; the supplementary drug-level table was not opened. Cohort test: promethazine's presence in the Prestwick library or among actives is unverified, so this is Tier C and promethazine is treated as absent. A PubMed search for promethazine with microbiome terms returned only three unrelated records (eating-disorder pharmacotherapy review, a galacto-oligosaccharide dermatitis mouse study, a 1996 cycloheximide intolerance mouse study) [27].

Class stand-in justification

The overrepresented class is antipsychotics; promethazine is classed by ATC as an antihistamine, though structurally a phenothiazine [2]. The stand-in is therefore weak and is kept at yellow only because a Tier C source exists and no grade above yellow is allowed.

Mechanism

Direct growth inhibition of commensal strains in monoculture; no mechanism for promethazine established.

Counter-evidence held on record

Counter-evidence on record Monoculture growth inhibition does not predict community-level or in vivo microbiome change. Framing caution Class extrapolation from an in vitro screen. Not a documented promethazine effect; do not recommend probiotics on this basis.

Limits on what this shows

• Null / negative: No promethazine-specific measurement of tissue ATP reduction was found. [16] reports no significant effect on hypoxic brain metabolism.
• At-risk subgroups: None identified.

Regulatory status

No ATP or energy-metabolism statement in the label [1].

Population evidence

In rat brain, promethazine produced a pattern "compatible with cerebral metabolic depression" in normoxic brain and had no significant effect on metabolism of acutely hypoxic brain [16]. Chlorpromazine plus promethazine improved brain ATP and reduced ROS in rat transient and permanent ischemic stroke, with benefit "most likely independent of drug-induced hypothermia" [14] (combination study). Tier C class context, chlorpromazine only, promethazine not studied: chlorpromazine reduced ATP content and beating rate in cultured rat myocardial cells, and coincubated CoQ reversed this [17].

Mechanism

Reduced cerebral metabolic rate in [16] is the drug's own CNS depressant pharmacology, not an energy-substrate deficiency (Hard Rule 2). Any permeability-transition effect is shared with the Mitochondrial burden entry.

Counter-evidence held on record

Counter-evidence on record The chlorpromazine cardiomyocyte ATP loss [17] was observed in a different molecule and at toxic in vitro exposure; promethazine was not tested, so it cannot be carried over. The stroke ATP findings [14] are combination, rodent and acute. Framing caution Do not read reduced brain metabolic rate or sedation as an energy or ATP deficiency. Energy supplements are not indicated by this evidence.

Limits on what this shows

• Why no grade: Dual condition met: no Tier B or C source for a red-cell or oxygen-carrying effect; no circulating claim located. Respiratory depression (label contraindication under 2 years) and leukopenia, thrombocytopenia and agranulocytosis [1] are the drug's own labeled toxicity and are not filed here (Hard Rule 2). The label extraction contained no mention of methemoglobin or G6PD [1].
• Access caveat: Partly tooling-limited. Pages 2 to 4 of the listing were not read, individual PubMed article pages returned empty shells, and WebSearch was exhausted. Two items seen only as listing titles were not opened and are not relied on: a chlorpromazine photo-induced hemolysis report in a neuroleptic phototoxicity paper (PMID 9094460) and a premedication study measuring arterial oxygen saturation (PMID 7889437). Re-check this category when access is restored.

Channels tried

PubMed HTML listing "promethazine AND (methemoglobin OR hemolysis OR hemoglobin OR anemia OR G6PD)": 39 results, only the first 10 viewed; none reported promethazine-induced anemia, hemolysis or methemoglobinemia [28]. WebSearch for promethazine methemoglobinemia or hemolysis case reports returned no promethazine-specific title. DailyMed label opened [1]. PubMed eutils, Crossref, Europe PMC, Semantic Scholar, OpenAlex search and Unpaywall via curl: 403 policy denial. Europe PMC via WebFetch: 429.