Scopolamine

Limits on what this shows

• Dose context: The label dose is 1 mg over 3 days [1]. The rodent injections above are 1 to 3 mg/kg per dose. Reviewer arithmetic, assuming a 70 kg adult: the whole 3-day patch is about 0.014 mg/kg, so a single 1 mg/kg injection is about 70 times that per kilogram before allometric scaling. These studies model a high-exposure central insult, not patch use.
• Key null findings: Wong-Guerra in vitro: no direct effect on mitochondrial function [5]. Tota 2012 measured brain ATP and found no scopolamine effect (see ATP production) [12]. PubMed listing "scopolamine mitochondrial dysfunction" returned 10 records: 8 are scopolamine amnesia models testing a protective agent, one is Zhang 2026, one is a dry-eye model; no human or transdermal-exposure mitochondrial study [26]. Not opened beyond the listing: Tat-Beclin-1 2024, Mdivi-1 2023 (partial abstract only), verapamil 2020 (no abstract retrievable), metoprolol 2025, TSPO dry-eye 2026.
• At-risk subgroups: None identifiable; no human data.

Regulatory status

No mitochondrial or nutrient statement in the Transderm Scop label extracts read [1].

Cohort test and direction

Scopolamine is the administered drug in every study below, so each is Tier B (mechanistic animal study using this medication), not class extrapolation. Direction: drug-induced impairment in an injected toxicity model (excess or toxicity direction, not depletion), with one neutral in vitro result and one reverse-direction result.

Population evidence

(a) Wong-Guerra 2017, rats, scopolamine 1 mg/kg intraperitoneally 30 minutes before testing; abstract (reconstructed from an OpenAlex record, partly garbled): "oxidative stress induced by SCO may involve mitochondrial impairment," while "the in vitro mitochondrial assays suggest that SCO did not affect the organelle function directly" [5]. (b) Salimi 2022, Wistar rats, scopolamine 1 mg/kg intraperitoneally, betanin as the tested treatment; betanin reversed "mitochondrial membrane potential collapse, mitochondrial swelling, decreased activity of succinate dehydrogenase" and ROS production relative to scopolamine-only animals [6]. (c) Garabadu and Sharma 2019, male rats, scopolamine 3 mg/kg/day intraperitoneally for 14 days, eugenol as the tested treatment; the abstract reports scopolamine decreased membrane potential and formazan production (a viability-type mitochondrial assay) [8]. (d) Baghel and Thakur 2018, mice; in scopolamine-induced amnesic mice Vdac1 expression fell and "mitochondrial membrane potential," "cristae organization, and morphology were disrupted"; scopolamine dose and route were not in the abstract [9]. (e) Tyagi and Thakur 2023, mice, capsaicin (oral) as the tested treatment; mitochondrial complex I to IV activities were assessed and restored by capsaicin; scopolamine dose and route were not retrieved and the scopolamine-versus-control values were not in the abstract reconstruction [7]. Reverse direction: Zhang 2026, 12 male Wistar rats in a chronic unpredictable mild stress model, 4 weeks; "scopolamine reversed CUMS-induced mitochondrial ultrastructural damage" and normalized Drp1 and MFF, with Mfn2 restored; scopolamine dose and route not in the abstract, and the study is very small [10].

Mechanism

Not established. The isolated-mitochondria result [5] argues against direct organelle toxicity; the authors of [10] propose an anti-inflammatory route in the opposite direction. Receptor blockade with secondary neuronal injury is the unproven alternative.

Counter-evidence held on record

Counter-evidence and confounding Because these studies exist to test a protective agent against scopolamine, a scopolamine arm with no mitochondrial effect would be less likely to be reported (publication bias). All reads were abstract-level through summarizers. Results conflict across studies (neutral in vitro, adverse in vivo, protective in a stress model), and the exposures are far above the label dose. Shares its model family with Oxidative stress and ATP production (see overlap map). Framing caution Not a human mitochondrial finding and not a depletion. No inference about patch users, and no supplement is implied.

Limits on what this shows

• Key null findings: No oxidative marker was measured in the NTP 2-year bioassay text read [16]. No study of antioxidant vitamin or glutathione status in scopolamine users was found. A PubMed listing with an oxidative-stress query was rate-limited (HTTP 429) and not read [26].
• At-risk subgroups: None identifiable; no human data.

Regulatory status

No oxidative-stress statement in the label extracts read [1].

Cohort test and direction

Scopolamine is the studied drug in all sources below (Tier B). Direction: increase in oxidative markers in injected models (drug-induced, toxicity direction); reverse (antioxidant) direction in the in vitro chemistry and arguably in the stress model.

Population evidence

Baghel and Thakur 2018, mice: in scopolamine-induced amnesic hippocampus, "increased ROS generation and reduced SOD and catalase activity" [9]. Garabadu and Sharma 2019, rats, scopolamine 3 mg/kg/day intraperitoneally for 14 days: oxidative stress increased by scopolamine and reduced by eugenol [8]. Wong-Guerra 2017, rats, 1 mg/kg intraperitoneally: increased reactive oxygen generation reported in redox profiles of brain regions (abstract partly garbled in the reconstruction) [5]. Salimi 2022: ROS production reversed by betanin relative to scopolamine-only rats [6]. Reverse direction: Criado 2002, in vitro photolysis and laser flash photolysis; four antimuscarinic drugs including scopolamine were all "moderate chemical and physical quenchers" of singlet oxygen with Rose Bengal as sensitizer; which compound number corresponds to scopolamine was not clear in the reconstructed abstract [17]. Zhang 2026 reports scopolamine altering GPX4 (described as an anti-ferroptotic marker) in the stress model; the direction relative to untreated stress animals was not unambiguous in the abstract reconstruction [10].

Mechanism

Not established. Increased ROS may be a consequence of neuronal injury or mitochondrial change in the model [5][9]; the antioxidant chemistry [17] is a test-tube property with no demonstrated relevance at patch exposure.

Counter-evidence held on record

Counter-evidence and confounding The injected doses (1 to 3 mg/kg) are far above label exposure, and abstract-level reads cannot give the scopolamine-versus-control contrast. Directions conflict: pro-oxidant in vivo, quencher in vitro. Shares evidence with Mitochondrial burden and ATP production (see overlap map). Framing caution A redox marker change in a toxicity model is not a vitamin C, E or glutathione deficiency. No antioxidant supplement is implied.

Limits on what this shows

• Key null findings: No study of ferritin, hemoglobin, serum iron or iron absorption in scopolamine users was found. PubMed listing "scopolamine AND (iron OR ferritin OR ferroptosis)" returned 10 records: dry-eye ferroptosis models, a deferiprone/rasagiline hybrid paper, an avicularin ferroptosis paper (no abstract retrievable) and unrelated chemistry; no scopolamine iron-status study [26]. A listing combining scopolamine, hyoscine, iron absorption and riboflavin returned no scopolamine iron-absorption paper [26].
• At-risk subgroups: None identifiable; people with other iron-risk factors are context, not findings.

Regulatory status

No iron statement in the label extract; the label's statement that scopolamine may delay GI motility and absorption of oral drugs is the only related text [1].

Cohort test and direction

(a) Tier B, scopolamine in cohort; direction: tissue iron excess or redistribution (retention direction). (b) CLASS EXTRAPOLATION, Tier C: scopolamine was NOT confirmed in the cohort; direction unresolved.

Population evidence

(a) Fawzi 2019, male rats, "systemic administration of SCOP for seven days" at 1.14 mg/kg/day (route given as intraperitoneal by the summarizer, from the methods, not verified in the abstract): scopolamine caused "increased... free iron deposition," and deferiprone pretreatment decreased it; the tissue is not named in the abstract and no serum iron or ferritin was reported in the abstract read [18]. Context only: in a scopolamine-induced dry-eye mouse model (scopolamine subcutaneous plus desiccating stress), corneal iron accumulation, Fe2+ and lipid peroxidation increased, but scopolamine was not isolated from the desiccating stress [19]. (b) Schade 1969, animal study; "alpha adrenergic blocking agents" and "parasympathetic blocking agents" slowed intestinal movement and "significantly" increased iron absorption; species and the specific blockers were not named in the abstract read, so scopolamine is not confirmed in the cohort [20]. The 1971 Orrego-Matte study of anticholinergics and 59Fe absorption (humans and rats) could not be opened (Springer 429; no OpenAlex abstract) and no claim rests on it [22].

Mechanism

(a) Not stated. (b) Partly present: label-documented delayed GI motility [1] would predict higher absorption on the Schade mechanism; an effect on a gastric factor could run the other way, but no scopolamine data exist.

Counter-evidence held on record

Counter-evidence and confounding Brain or corneal iron deposition in a toxicity or injury model is a tissue distribution finding, not a nutritional deficit, and the absorption study is decades old, animal-only and not drug-confirmed. Confounding by indication is presumed in any treated population (Hard Rule 6). Shares its GI-motility mechanism with Riboflavin (see overlap map). Framing caution The tissue-iron signal runs toward excess or redistribution, not depletion: supplementation would be the hazard, not the remedy. Not a reason to change iron intake in either direction; no dose is suggested.

Limits on what this shows

• Why no grade: Both conditions of the Step 7 test are met. (1) No Tier B or Tier C evidence supports even a yellow grade: no study measuring copper in scopolamine-exposed subjects, and no class-level copper study with an antimuscarinic. (2) No circulating consumer claim about copper and scopolamine exists to rebut: the consumer pages read mention no nutrient effect [25]. This is a disclosed gap, not a finding of safety.

Channels tried

Label: no copper or mineral statement [1]. PubMed listing "scopolamine AND (copper OR ceruloplasmin)": 10 records, none measuring copper status; they are copper sulfate-induced emesis models in which hyoscine or scopolamine is a comparator antiemetic (copper as an emetic, not a nutrient), copper-chelating compounds tested against scopolamine-induced amnesia, and a 1985 muscarinic receptor review (title and listing text only, not opened) [26]. PubMed listing "scopolamine trace elements": 10 records, none a copper status study (iron-chelator and zinc-compound papers using scopolamine as the amnesia inducer, enzyme chemistry, imaging) [26]. NTP TR-445 text read has no copper finding [16]. Mechanism screen: no chelation, mucosal injury, enzyme induction or renal wasting mechanism applies on the label evidence [1].

Gap type

Mostly a genuine literature gap, partly tooling-limited: WebSearch budget was exhausted, Europe PMC, Semantic Scholar and Crossref keyword searches were unavailable or unhelpful, and PubMed rate-limited several phrasings. Next queries when access allows: "scopolamine ceruloplasmin", "anticholinergic copper absorption", "transdermal scopolamine serum copper zinc".

Limits on what this shows

• Key null findings: Human medication-microbiome analyses did not surface scopolamine: Maier 2018 (more than 1,000 drugs against 40 gut strains) does not name scopolamine, hyoscine or anticholinergics in the article text read, and the supplementary table was not opened [23]; Vich Vila 2020 (41 drug categories) does not name scopolamine, anticholinergic or antiemetic drugs in the text read [24]. C. difficile and human 16S queries for scopolamine were not completed because of rate limits.
• At-risk subgroups: None identifiable; no human data.

Regulatory status

The label extract states scopolamine "can decrease gastrointestinal motility" but has no microbiome statement [1].

Cohort test and direction

Scopolamine is the administered drug (Tier B). Direction: reduced diversity and altered composition (disturbance, not nutrient depletion).

Population evidence

Park 2022, Sprague Dawley rats, n = 10 per group, all on a high-fat diet; scopolamine 2 mg/kg/day intraperitoneally from week 4 to week 7: "The Chao1 and Shannon indices of the fecal bacteria... were lower in the MD than in the normal group (p < 0.001)"; Bacteroides and Bilophila were lower and Clostridium, Escherichia (p < 0.05) and Blautia higher in the scopolamine group; the same paper compared microbiome features of 410 human participants with mild cognitive impairment or Alzheimer's disease, which does not involve scopolamine exposure and is not weighed here [13]. Danggui-Shaoyao-San study 2022, mice, n = 10 per group, scopolamine hydrobromide trihydrate 3 mg/kg/day for 2 weeks (route not stated in the read): tight-junction protein morphology and expression disrupted in the scopolamine group ("ZO-1: p < 0.01; OCLN: p < 0.05, p < 0.001"); Chao1 and Shannon richness "significantly increased in the DSS group compared with the SCO group" (p < 0.05); the scopolamine-versus-untreated diversity contrast itself was not quoted in the text read [14]. A third model study (Flammulina polysaccharides, mice, 2018) reports microbiota shifts with the treatment but the scopolamine-only contrast was not read and carries no weight [15].

Mechanism

Partly present. The Park authors tie the change to suppression of parasympathetic nervous system activity [13]; reduced GI motility [1] is a plausible contributor but was not measured in either study. Feed intake and transit were not reported in the text read.

Counter-evidence held on record

Counter-evidence and confounding Both are model studies with scopolamine at 2 to 3 mg/kg daily by injection (hundreds of times the daily label exposure per kilogram, reviewer arithmetic), high-fat-diet feeding in one, and possible secondary effects of altered intake or transit. Park 2022 and the Danggui study use the same model family, so they are not two independent lines of evidence about patch users. Framing caution Not a finding about patch users and not a prompt for probiotics or antibiotics.

Limits on what this shows

• Key null findings: Tota 2012 as above [12]. PubMed listing "scopolamine ATP" returned 10 records; besides the three above it listed Mdivi-1 2023 (abstract states Mdivi-1 "elevated" ATP production; scopolamine-alone contrast not read) [26], a piracetam study of NTPDase and 5'-nucleotidase enzyme activities (enzyme activity, not ATP level; not opened), and unrelated tissue-pharmacology and analytical papers. Crossref bibliographic searches for "scopolamine ATP" returned no relevant records [27].
• At-risk subgroups: None identifiable; no human data.

Regulatory status

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

Cohort test and direction

Scopolamine is the administered drug in all three studies (Tier B). Direction: decrease (drug-induced, toxicity direction) in two; neutral in one.

Population evidence

Baghel and Thakur 2018, mice, Springer abstract: "The expression of Vdac1 and total ATP level was decreased in the hippocampus of scopolamine-induced amnesic mice"; Vdac1 silencing decreased ATP and membrane potential; scopolamine dose and route not in the abstract [9]. Abu Almaaty 2021, rats, HPLC tissue analysis: "UD extracts restored ATP levels and reduced the levels of AMP and ADP compared to SCOP-treated rats"; the tissue, scopolamine dose, route, duration and group sizes were not available, and the scopolamine-versus-untreated contrast is inferred from the word "restored" and was not read [11]. Null: Tota 2012, mice, scopolamine 3 mg/kg intraperitoneally: "scopolamine had no significant effect on ATP level and mRNA expression of angiotensin receptors and ACE in cortex and hippocampus" [12].

Mechanism

Not demonstrated. A mitochondrial route is plausible given the Mitochondrial burden entry, but the isolated-mitochondria result found no direct effect [5].

Counter-evidence held on record

Counter-evidence and confounding Inconsistent across models, one of the three reads gives only inferred direction, and a decrease in tissue ATP in a memory-impairment model is a model outcome and not a nutrient deficiency or a statement about "low energy" in people. Shares its model family with Mitochondrial burden (see overlap map). Framing caution Not evidence that scopolamine patches lower energy output in people. No supplement is implied.

Limits on what this shows

• Key null findings: The report text read mentions no hemosiderin, iron or spleen pigment findings and no iron indices, ferritin or methemoglobin [16]. PubMed listing "scopolamine hemoglobin" returned 10 records: the NTP report and papers where scopolamine is the amnesia inducer and hemoglobin-derived peptides are the treatment; two clinical sedation or premedication papers listing oxygen saturation in combination regimens (not opened, scopolamine not isolated) [26]. Tota 2012 includes a cerebral blood flow endpoint, but the direction for scopolamine alone was not clearly read and gets no weight [12].
• At-risk subgroups: None identifiable. Dehydration risk context only.

Regulatory status

The label extract has no anemia, hemoglobin or oxygen-delivery statement [1]. Bradycardia and hypotension appear only in the withdrawal syndrome, a drug effect (Hard Rule 2) [1].

Cohort test and direction

Scopolamine hydrobromide trihydrate is the test article (Tier B, animal toxicology study). Direction: mixed. Rat hemoconcentration is a reverse or neutral direction relative to anemia; mouse decrease is a hematologic outcome.

Population evidence

NTP TR-445 (1997): F344/N rats (60 per sex) and B6C3F1 mice (70 per sex), about 6 weeks old at start, dosed by gavage in distilled water at 0, 1, 5 or 25 mg/kg for 2 years, with 16-day and 14-week studies. Quotes from the report summary: rats, "hematocrit was slightly higher in the 25 mg/kg male rats"; mice, "Hematocrit, hemoglobin concentration, and erythrocyte count in 25 mg/kg female mice were slightly lower than those in the control group," described as "minimal normocytic, normochromic nonresponsive anemia" that "is presumed to be due to a decreased nutritional status." In the 14-week rat study, hematocrit, hemoglobin and/or erythrocyte count were slightly higher at 45 mg/kg or greater. Body weights of 25 mg/kg animals were lower than controls (rats after about week 25, mice after week 13). An OpenAlex abstract reconstruction also notes esophageal obstructions from feed or bedding attributed to inhibited salivary secretion and smooth-muscle effects [16].

Mechanism

Hemoconcentration from dehydration and anemia from reduced intake or body weight are the report's own explanations [16]; both stem from the drug's anticholinergic effects at high exposure (inhibited secretions, reduced intake), which are drug effects and not an oxygen-delivery deficiency.

Counter-evidence held on record

Counter-evidence and confounding The 25 mg/kg dose is far above label exposure (about 0.014 mg/kg over 3 days, reviewer arithmetic assuming 70 kg), the finding is in one sex of one species, the effect size is described as slight or minimal, and the report links it to body weight loss. Hematology in humans using the patch was not found. Perioperative and travel populations carry their own confounders (blood loss, fasting, hemodilution). Framing caution Anemia in this study is an outcome, not iron deficiency; no iron was measured, and no iron or vitamin supplement is implied.