Hyoscyamine

Limits on what this shows

• Null or negative: Hyoscyamine itself: the zebrafish embryo study measured redox and metabolomic endpoints and the abstract reports no mitochondrial finding [10]; PubMed listing "hyoscyamine AND (mitochondria* OR membrane potential OR respiratory chain OR ATP)": seven records, all plant biosynthesis, receptor biochemistry or analytical papers, none a drug mitochondria study [20]; Crossref keyword search "atropine mitochondrial toxicity respiration": fifteen records, none reporting atropine effects on mitochondrial function [21]. PubMed listing "scopolamine AND (mitochondria* OR ATP)" (ten records): five concern scopolamine-induced mitochondrial or energy impairment in rodents and use scopolamine as a model inducer to test a protective agent; four of those five were opened at abstract level, and the fifth (Babanzadeh 2024) returned no abstract text and is not used [29].
• At-risk subgroups: None defined by evidence.
• Counter-evidence: Different drug, rodent model, high parenteral exposure, central tissue, abstract-level reading, no replication for atropine or hyoscyamine, no human data. Because these studies exist to test protective agents, a scopolamine arm with no mitochondrial effect would be unlikely to be reported. Shares the scopolamine-model evidence base with the ATP production entry (see overlap map).

Regulatory status

Neither label contains a mitochondrial statement [1][2]. The Levsin label states the drug passes the blood-brain barrier [1], which is why central-tissue rodent data are at least pharmacologically adjacent.

Population evidence

Tier C. Cohort test: the agent in every study below is scopolamine; hyoscyamine and atropine were in no cohort. (a) Salimi et al. 2022, Wistar rats given scopolamine, with betanin 25 or 50 mg/kg for 9 days as the tested treatment. Abstract, read through a page summarizer on a Crossref record: "Scopolamine (SCO) as a potent drug for inducing memory and learning impairment is associated with mitochondrial dysfunction and oxidative stress," and betanin at 50 mg/kg reversed "mitochondrial membrane potential collapse, mitochondrial swelling, decreased activity of succinate dehydrogenase, and reactive oxygen species (ROS) production." The scopolamine dose was reported by the reader as 1 mg/kg; route and animal numbers were not stated, and the abstract describes the scopolamine-versus-vehicle contrast rather than showing it [22]. (b) Tyagi and Thakur 2023, mice given scopolamine, with capsaicin as the tested treatment. Abstract reconstructed from an OpenAlex record through a page summarizer: capsaicin was "restoring mitochondrial complex" enzyme function (complexes I to IV examined), and the reader reports that scopolamine produced increased pro-inflammatory cytokines and "impaired mitochondrial" function compared with controls. Dose, route and numbers not stated; abstract-level only [23]. (c) Sharaf et al. 2025, rats given metoprolol, scopolamine or both: the abstract attributes disrupted mitochondrial biogenesis signaling (SIRT1/PGC-1alpha/NRF1/TFAM) to metoprolol on top of scopolamine; the scopolamine-alone contribution is not isolated, so this is context only and carries no weight [28]. Scopolamine doses in these models are rodent amnesia-model exposures and are deliberately not restated as recommendations.

What the class link justifies

A review of anisodamine states that, like atropine and scopolamine, it is a non-specific cholinergic antagonist [26], and the dossier's Tier D source gives hyoscyamine as the levorotatory isomer of racemic atropine [5]; atropine therefore contains hyoscyamine and is the nearest class member, but no atropine mitochondrial study was found, so scopolamine is one step further away. This justifies only a candidate hypothesis that muscarinic blockade at high parenteral exposure in rodent central tissue can coincide with mitochondrial dysfunction. It does not justify any statement about oral hyoscyamine at GI-indication exposure, peripheral tissue, or people.

Mechanism

Not established. The sources use scopolamine as a deficit-inducing tool; whether the mitochondrial change arises from receptor blockade, secondary neuronal injury or the molecule itself is not determined in the abstracts read [22][23].

Counter-evidence held on record

Theoretical class extrapolation from animal models using a different drug. Not a statement that hyoscyamine harms mitochondria in people. Not a reason to take mitochondrial or antioxidant supplements. No dose is given.

Limits on what this shows

• Null or negative: PubMed listing "hyoscyamine oxidative stress antioxidant": ten records, of which only the zebrafish study administers hyoscyamine as a compound; the rest are plant biotechnology or plant-extract papers (a Physochlaina extract paper was listed; its abstract was not opened and a whole-plant extract is not hyoscyamine) [20]. PubMed listing "atropine oxidative stress" returned organophosphate and carbamate poisoning models in which atropine is an antidote and atropine alone is not isolated [20][12], so no atropine redox data qualify as class evidence.
• At-risk subgroups: None defined by evidence.
• Counter-evidence: One embryo model, embryotoxic range, no replication, no mammalian data. Embryonic developmental toxicity does not translate to adult oral dosing.

Regulatory status

Neither label contains an oxidative-stress statement [1][2].

Population evidence

Tier B, hyoscyamine itself: Lv et al. 2023, zebrafish (Danio rerio) embryos. The abstract reports an LC10 of 350 microg/ml and a maximum non-lethal concentration of 313 microg/ml, that hyoscyamine exposure "increased the accumulation of ROS and MDA, and altered the activity of antioxidant enzymes (CAT, SOD, and GSH)," and that a metabolomic screen found 38 significantly changed metabolites among 3,551, with pyrimidine, purine, histidine, beta-alanine and glutathione metabolism named as disrupted pathways [10]. Direction of each enzyme change and embryo numbers were not available in the abstract-level read.

Mechanism

Described by the authors as metabolic disruption leading to developmental toxicity; no mitochondrial or ATP finding appears in the abstract [10]. Whether any human tissue concentration approaches the tested range was not established in the material read.

Counter-evidence held on record

Not an antioxidant-depletion claim and not a statement that hyoscyamine causes oxidative stress in people. This is not a reason to take antioxidant supplements. No dose is given.

Limits on what this shows

• Null or negative: The ODS fact sheet states that long-term proton pump inhibitor use does not cause iron depletion in people with normal reserves [16]. PubMed listing "hyoscyamine iron" returned ten records, none measuring iron status or absorption in hyoscyamine users [20]. Absorption of a radioiron dose is not iron status; no study read measured ferritin, hemoglobin or transferrin saturation under an antimuscarinic.
• At-risk subgroups: None defined by evidence.
• Counter-evidence: Study directions conflict [6][7]. Any anemia or low ferritin in people prescribed hyoscyamine has competing explanations under Hard Rule 6: indications include peptic ulcer, spastic colitis and functional bowel disorders [1], where blood loss, diet change and underlying disease are presumed before the drug.

Regulatory status

The Levsin label states that the drug reduces GI motility and gastric acid secretion [1]. Neither label lists an iron or hematologic event among the adverse reactions [1][2].

Population evidence

All class-level; cohort test: hyoscyamine was in no cohort. (a) Orrego-Matte, Fernandez and Mena 1971: rats received atropine and humans received hexocyclium methosulfate (a different antimuscarinic); the abstract states "In both species, anticholinergics produced a decrease in absorption" of 59Fe ferrous citrate, attributed to "an effect on a gastric factor necessary for optimal iron absorption, and not through a decrease in acid secretion." Radioiron delivered to the duodenum in neutralized gastric juice was absorbed normally, while delivery in acid gastric juice or hydrochloric acid reduced absorption. Subject numbers and doses were not stated in the abstract-level read [6]. (b) Schade, Felsher and Conrad 1969: the abstract states that "the parenteral administration of alpha adrenergic blocking agents or parasympathetic blocking agents significantly increases the absorption of iron by decreasing intestinal motility." The agent and species are not named in the abstract text opened, so atropine in the cohort is unconfirmed; this is Tier C and carries less weight than (a) [7]. (c) Brodie 1966, rat: orally dosed atropine sulfate depressed both gastric acid output and gastric emptying at identical doses; hyoscyamine was not among the five drugs compared [9]. The NIH Office of Dietary Supplements states that "gastric acid plays an important role in the absorption of nonheme iron from the diet" [16]; proton pump inhibitors are not antimuscarinics and are cited only for the acid-iron link.

Mechanism

Two opposing candidate routes, neither tested for hyoscyamine: loss of an acid-independent gastric factor needed for iron uptake [6], or slower transit increasing contact time at the absorption site [7]. The net direction in people taking hyoscyamine is unknown.

Counter-evidence held on record

Theoretical and direction-unknown. Not a statement that hyoscyamine lowers or raises iron. Do not add or change iron intake because of hyoscyamine; iron supplementation carries its own risks and is a decision for a prescriber after testing. No dose is given.

Limits on what this shows

• Why no grade: Dual condition met: no Tier B or C evidence and no circulating claim found. Classification: genuine gap on retrieved channels, with a tooling caveat; the class-level copper queries were blocked, not empty. Copper is kept separate from Iron.

Channels tried

PubMed listing "hyoscyamine copper": three records, none relevant (a Datura nanoparticle paper, a plant co-culture paper and an intrauterine-device pain-relief trial in which copper is the device material) [20]. PubMed listing "atropine copper": ten records, none measuring copper status or absorption in atropine-treated subjects (atropine appeared as a transporter inhibitor, a chemical oxidation substrate and a receptor-binding probe) [20]. Crossref and the iron-absorption listings returned no copper study [20][21]. Labels: no copper statement [1][2]. No mechanism class in the screen (chelation, mucosal injury, enzyme induction, renal wasting) applies to copper on the label evidence. Revision pass: a PubMed listing "atropine copper zinc absorption" returned 429 with a request not to refetch and was not read; no scopolamine or anisodamine copper query was completed, and the scopolamine mitochondria and ATP listing [29] returned no copper content. Next queries when access allows: "hyoscyamine ceruloplasmin", "scopolamine copper", "anisodamine copper", "anticholinergic copper absorption".

Limits on what this shows

• Why no grade: Dual condition met: no Tier B or C evidence for the gut microbiome of hyoscyamine users or of atropine-type antimuscarinics, and no circulating consumer claim found. A transit-slowing or secretion-reducing route is a hypothesis with no source. Classification: tooling-limited, partly genuine. Maier 2018 supplementary data, OpenAlex and Europe PMC searches could not be checked, so a later revision must re-check this entry. Not reassurance.

Channels tried

Maier 2018 (screen of more than 1,000 marketed drugs against 40 gut strains): the article text read does not mention hyoscyamine, atropine, scopolamine, anticholinergic, antimuscarinic or antispasmodic drugs; supplementary tables were not opened, so inclusion is unknown [13]. Vich Vila 2020 (41 medication categories): no anticholinergic or antispasmodic category named in the text read [14]. A 2025 NHANES analysis (n = 1,596) found anticholinergic burden scores inversely associated with oral microbiome alpha diversity (Shannon index with the Anticholinergic Drug Scale, beta -0.056, 95% CI -0.081 to -0.031), but the text read does not name hyoscyamine or atropine, it concerns the oral rather than gut microbiome, and it uses burden scales; it fails the cohort test and carries no grade weight [15]. PubMed listings: "hyoscyamine bacteria" (HTTP 429), "hyoscyamine microbiota" (404, unreliable zero), "anticholinergic small intestinal bacterial overgrowth" (three records; one 1978 rat study used mecamylamine, a ganglionic blocker rather than an antimuscarinic, and was not opened; the others concerned acid reduction or were a diarrhea review that lists hyoscyamine only as symptomatic treatment) [20]. Crossref "atropine gut microbiota": fourteen records, none relevant [21]. Revision pass: the PubMed listing "scopolamine gut microbiota" and an MDPI site search for the same terms both returned 429 with a request not to refetch and were not read, so the scopolamine rodent literature (where gut microbiota is plausibly studied in the same amnesia models that generated the mitochondrial data) is untested for this category. Next queries when access allows: "scopolamine gut microbiota", "atropine gut microbiota rodent", "anisodamine gut microbiota".

Limits on what this shows

• Null or negative: For hyoscyamine, the zebrafish study reported disrupted purine and pyrimidine pathway enrichment but no ATP, ADP or energy-charge measurement in the abstract read [10]; the atropine carbofuran-poisoning model that measured ATP and phosphocreatine did not evaluate atropine alone and was excluded [12]. No ATP measurement under hyoscyamine or atropine alone was found in the PubMed and Crossref searches [20][21][29].
• At-risk subgroups: None defined by evidence.
• Counter-evidence: Single abstract-level rat study, direction inferred, tissue unknown, different drug, no human data. A scopolamine-induced fall in ATP would also be a model outcome and not a nutrient deficiency.

Regulatory status

Neither label contains an energy-metabolism statement [1][2]. Fatigue, weakness and drowsiness are listed antimuscarinic adverse reactions [1][2] and are not filed here (Hard Rule 2).

Population evidence

Tier C, one source. Cohort test: scopolamine only; hyoscyamine and atropine not in the cohort. Abu Almaaty et al. 2021, rats, Urtica dioica root or leaf extract tested against scopolamine-induced memory dysfunction, amnesia and oxidative stress; abstract: "Tissue analyses of norepinephrine (NE), dopamine (DA), serotonin (5-HT), malondialdehyde (MDA), nitric oxide (NO), glutathione (GSH, GSSG), AMP, ADP, and ATP were assessed by HPLC" and "UD extracts restored ATP levels and reduced the levels of AMP and ADP compared to SCOP-treated rats." The Springer page is subscription-only and only the abstract was readable: the tissue analyzed, scopolamine dose, route, duration and animal numbers were not available, and the abstract does not state the scopolamine-only versus saline-control comparison, so a scopolamine-induced fall in ATP is inferred from the word "restored" and not read as a measured contrast [24].

What the class link justifies

Same limits as the Mitochondrial burden entry: scopolamine shares non-specific cholinergic antagonism with atropine [26], and atropine contains hyoscyamine [5], but this study does not include either. It supports only a candidate hypothesis that high-exposure scopolamine in a rodent model can coincide with a lower tissue ATP to ADP and AMP balance. It does not justify any statement about hyoscyamine at oral GI-indication exposure or about energy output in people.

Mechanism

Not stated in the abstract. A mitochondrial route is plausible given the scopolamine mitochondrial dysfunction reports [22][23], but that is shared-model evidence, not a demonstrated link (see overlap map).

Counter-evidence held on record

Weakest yellow in this dossier. Not a statement that hyoscyamine lowers ATP or causes low energy in people, and not a reason to take energy or mitochondrial supplements. No dose is given.

Limits on what this shows

• Why no grade: Dual condition met on the oxygen-delivery endpoint itself (class papers evaluated below): no Tier B or C evidence of an oxygen-delivery effect and no circulating claim found. Hard Rule 2 note: tachycardia and palpitations [1][2] and atropine's heart-rate rise in exercise [11] are the drug's intended or expected hemodynamic pharmacology, not an oxygen-delivery deficiency, and are not filed as a nutrient-style finding.

Channels tried

PubMed listing "hyoscyamine hemoglobin": three records, all plant hairy-root papers on a bacterial hemoglobin [20]. PubMed listing "atropine oxygen consumption": ten records, nine of them acute atropine pharmacology in anesthesia, fetal, animal or exercise settings [20]. One was opened through OpenAlex: Ekblom, Goldbarg, Kilbom and Astrand 1972, healthy participants exercising after intravenous atropine 2.0 to 2.5 mg; the reconstructed abstract reports that heart rate was higher under atropine than under propranolol and that oxygen uptake "remained essentially unchanged across conditions" except when both drugs were combined (6% lower) [11]. That is a single-dose, acute, intravenous atropine study in healthy men with no hemoglobin measurement; it does not support a yellow grade and is not reassurance for chronic oral hyoscyamine. The iron listings returned no hemoglobin or anemia study with hyoscyamine [20]. Labels: no anemia or hematologic event listed [1][2], which is not evidence of absence. Revision pass, class check: anisodamine is described as a naturally occurring atropine derivative and a non-specific cholinergic antagonist with weak alpha-1 adrenergic antagonism and thromboxane-related antithrombotic activity [26]. Zhong et al. 2023 (LPS septic-shock rats, intravital microscopy of mesenteric flow) compared anisodamine hydrobromide, anisodine and atropine: all four agents "elevated mean arterial pressure and reduced heart rate," but "only Ani HBr and AT3" (anisodamine hydrobromide and a second agent) "restored the velocity of microcirculation and improved flow patterns," so the atropine arm did not restore microcirculatory velocity [25]. Liu et al. 2026 (cecal ligation and puncture rats, anisodamine hydrobromide) reported reduced pulmonary microvascular leakage with preserved endothelial junction proteins; arterial blood gases were monitored but no oxygenation result appears in the abstract read, and no atropine arm is named [27]. A PubMed listing "anisodamine sepsis microcirculation" returned seven records, including a human septic-shock trial of a different drug (penehyclidine) that was not opened [29].