Scopolamine

# Research Output: Scopolamine

## Chemical Identity

**PubChem CID:** 3000322 [Ref 1]

**IUPAC Name:** [(1S,2S,4R,5R)-9-methyl-3-oxa-9-azatricyclo[3.3.1.02,4]nonan-7-yl] (2S)-3-hydroxy-2-phenylpropanoate [Ref 1]

**Canonical SMILES:** `CN1[C@@H]2CC(C[C@H]1[C@H]3[C@@H]2O3)OC(=O)[C@H](CO)C4=CC=CC=C4` [Ref 1]

**InChIKey:** STECJAGHUSJQJN-USLFZFAMSA-N [Ref 1]

**Molecular Formula:** C₁₇H₂₁NO₄ [Ref 1]

**Molecular Weight:** 303.35 g/mol (exact mass: 303.14706 Da) [Ref 1]

**CAS Number:** 51-34-3 (free base); 6533-68-2 (hydrobromide trihydrate) [Ref 36]

**Drug-Likeness Parameters (PubChem):** XLogP = 0.9; TPSA = 62.3 Ų; HBD = 1; HBA = 5; rotatable bonds = 5; complexity = 418 [Ref 1]

**Physical Properties:** Melting point 59°C; boiling point ~444°C (estimated); water solubility 95 g/L at 15°C; freely soluble in ethanol, chloroform, and acetone; slightly soluble in benzene and petroleum ether; density 1.31; pKa 7.55–7.81 (25°C); optical rotation [α]D²⁰ = −28° (c = 2.7), confirming the levorotatory natural (L-) enantiomer; LogP = 0.98 [Ref 36]

**Stereochemistry:** Natural scopolamine is the levo-enantiomer (L-scopolamine, or (−)-scopolamine). The molecule contains four stereocenters. The optical rotation (−28°) is consistent with the (1S,2S,4R,5R) configuration at the tropane ring and (2S) at the tropic acid moiety. Only the L-form is pharmacologically active at muscarinic receptors [Ref 22].

**Seed Data Discrepancies:** The brief seed data for PSX-0411 lacks SMILES, formula, weight, InChIKey, and PubChem CID. All of these have now been confirmed via PubChem CID 3000322 and are provided above. No contradictions with seed data were identified — seed data was simply incomplete.

---

## Pharmacology

### Mechanism of Action

Scopolamine is a competitive, non-selective muscarinic acetylcholine receptor (mAChR) antagonist that binds with approximately equal affinity at all five muscarinic receptor subtypes (M1–M5) [Ref 2]. It competitively inhibits G-protein–coupled post-ganglionic muscarinic receptors for acetylcholine, acting as a nonselective muscarinic antagonist and producing both peripheral antimuscarinic effects and central sedative, antiemetic, and amnestic effects [Ref 35]. A minor affinity at histamine H1 receptors has also been reported [Ref 35].

**Binding affinity:** Scopolamine's Ki values at human cloned M1–M5 receptors fall in the sub-nanomolar range, consistent with other literature using radiolabeled [³H]-N-methylscopolamine (NMS) as a displacement tool [Ref 2, Ref 22]. Precise Ki values at each subtype are reported in the range of 0.3–1.5 nM across subtypes based on radioligand binding data in the literature [Ref 22].

**Central effects** are primarily mediated through M1 receptor antagonism in the hippocampus and prefrontal cortex (cognition, memory), M2 autoreceptor blockade in subcortical regions (increases dopamine release by disinhibiting dopaminergic presynaptic neurons) [Ref 8], and action on the vestibular nuclei and medullary vomiting center (antiemesis). Scopolamine increases theta and delta EEG power bands and decreases alpha band power in a dose-dependent manner, serving as a validated biomarker of central muscarinic antagonism [Ref 34, Ref 46].

**Peripheral effects** result from blockade of muscarinic receptors in smooth muscle, cardiac muscle, secretory glands, and the eye: mydriasis and cycloplegia (M3 in ciliary muscle/iris), dry mouth (M3 in salivary glands), tachycardia (M2 in cardiac SA node), anhidrosis, decreased GI motility, urinary retention, and bronchodilation [Ref 22, Ref 35].

### Antidepressant Mechanism (Emerging)

Beyond direct muscarinic antagonism, scopolamine's antidepressant effects appear to involve downstream changes in glutamatergic neurotransmission and synaptic plasticity. The temporal profile of the antidepressant response (onset within 3 days, persistence >2 weeks post-infusion) is inconsistent with the short pharmacokinetic half-life of the drug, suggesting effects on gene expression and synaptic plasticity [Ref 4]. Proposed mechanisms include:

- mTORC1-dependent synaptic plasticity in the prefrontal cortex [Ref 2]
- eEF2 protein dephosphorylation (a mechanism shared with ketamine's rapid antidepressant action) [Ref 38]
- Downstream elevation of dopamine, serotonin, and glutamate in the frontal cortex [Ref 19]
- Modulation of BDNF and neurotrophic signalling [Ref 2]

The cholinergic–adrenergic hypothesis of mood disorders proposes that depression reflects an imbalance toward excess central cholinergic activity relative to noradrenergic tone, providing the theoretical basis for muscarinic antagonism as an antidepressant approach [Ref 28]. Genetic evidence has associated variation in CHRM2 (M2 receptor gene) with elevated depression risk [Ref 23].

### Pharmacokinetics

**Oral administration:** Oral bioavailability is highly variable between individuals, ranging from 10.7–48.2% (Putcha et al. 1989 [Ref 21]). Poor and variable bioavailability is attributed to extensive first-pass hepatic metabolism, evidenced by <2.6% of nonmetabolized scopolamine recovered in urine following oral dosing (Renner et al. 2005 [Ref 22]). Peak plasma concentration (Tmax) occurs approximately 30 minutes after oral administration [Ref 22].

**Intravenous administration:** Following IV bolus (0.4 mg), plasma concentrations decline biexponentially (rapid distribution phase followed by slower elimination). Mean peak plasma concentration: 2909.8 ± 240.9 pg/mL (Putcha et al. 1989 [Ref 21]).

**Transdermal administration:** The commercially available Transderm Scōp patch (1.5 mg total reservoir) delivers a 140 µg priming dose from the adhesive layer, followed by a steady-state release rate of approximately 5 µg/hour over 72 hours (total 0.5 mg delivered in 3 days). Peak plasma concentrations reach approximately 100 pg/mL (range 11–240 pg/mL) at approximately 8 hours post-application, with steady-state plasma levels of 56–245 pg/mL maintained over the 72-hour period (Nachum et al. 2006 [Ref 13]). The "protective" plasma concentration for motion sickness prophylaxis is estimated at ≥50 pg/mL; 20–30% of subjects fail to reach this threshold [Ref 13]. Skin binding plays an important role in local drug disposition and priming dose dynamics (Pensado et al. 2021 [Ref 15]).

**Intranasal administration:** Dose-linear pharmacokinetics (0.1–0.4 mg); faster absorption than oral route, higher bioavailability than oral. Plasma concentrations significantly lower in females than males at the 0.4 mg dose (Wu et al. 2015 [Ref 14]).

**Distribution:** Volume of distribution 1.4 ± 0.3 L/kg (Putcha 1989 [Ref 21]). Scopolamine crosses the blood–brain barrier readily (XLogP 0.9; lipo-hydrophilic balance allows CNS penetration). It also crosses the placenta; present in breast milk [Ref 22].

**Elimination:** Half-life: 4.5 ± 1.7 hours (Putcha 1989 [Ref 21]). Systemic clearance: 65.3 ± 5.2 L/hr; renal clearance: 4.2 ± 1.4 L/hr [Ref 21].

**Metabolism:** Primary pathway is glucuronide conjugation (accounting for approximately 30% of an IV dose after enzymatic hydrolysis of urinary metabolites). Oxidative demethylation via CYP3A (intestinal and hepatic) is also documented. The specific chemical structures of all urinary metabolites have not been fully characterized (Renner et al. 2005 [Ref 22]).

**Drug interaction — grapefruit juice:** Co-administration of scopolamine with 150 mL grapefruit juice (CYP3A inhibitor) significantly increased AUC₀–₂₄ to approximately 142% of control values and delayed Tmax (59.5 ± 25.0 min vs. shorter in water group; P < 0.001). Absolute bioavailability was significantly higher during the grapefruit juice condition (range 6–37% vs. 3–27% water) (Renner et al. 2005 [Ref 22]). **This interaction should be flagged for human review as a safety-relevant finding.**

**PK–PD correlation:** Direct correlation between serum scopolamine concentrations and alpha-frequency EEG changes has been demonstrated from PK–PD modelling in healthy volunteers [Ref 22].

---

## History

### Discovery and Isolation

Scopolamine was first isolated by German chemist **Albert Ladenburg** in **1880** from *Scopolia carniolica*, a plant in the family Solanaceae. The compound was named after **Antonio Scopoli** (1723–1788), an Italian naturalist and physician who first described *Scopolia carniolica*. The name "hyoscine" (used primarily in the UK and some European countries) derives from *Hyoscyamus niger* (black henbane), another Solanaceae source from which the compound is extracted [Ref 37].

Ladenburg's work built upon earlier isolation of the related alkaloid hyoscyamine from henbane in 1833 and his own earlier synthesis of atropine (the racemate of hyoscyamine) in 1875. Ladenburg was awarded the Davy Medal in 1905 for his work on synthesis of natural alkaloids. Full chemical synthesis of scopolamine was first achieved in 1959.

### Natural Sources

Scopolamine is a natural product of several Solanaceae family plants: *Scopolia carniolica*, *Hyoscyamus niger* (henbane), *Atropa belladonna* (deadly nightshade), *Datura stramonium* (jimsonweed/thorn apple), *Datura metel*, *Mandragora officinarum* (mandrake), *Duboisia* species (Australian corkwood), and *Brugmansia* species (angel's trumpets) [Ref 26, Ref 27, Ref 50]. *Datura* is particularly notable for criminal use ("burundanga"), as it contains high concentrations of scopolamine alongside atropine and hyoscyamine [Ref 26].

The biosynthesis of scopolamine involves CYP450 monooxygenases mediating biocatalytic radical cyclization to form the epoxide ring (3-oxa bridge) of the tropane scaffold [Ref 37]. It is derived biosynthetically from hyoscyamine via an epoxidation step catalyzed by hyoscyamine 6β-hydroxylase and related enzymes.

### Medical History

- **~1900:** Scopolamine begins use as premedication before anesthesia and in ophthalmic procedures.
- **Early 1900s:** "Twilight sleep" (morphine + scopolamine) developed for obstetric analgesia, producing a state of consciousness absent memory of the experience. Widely promoted by feminist advocates as a woman's right to pain-free childbirth; subsequently fell into disrepute due to adverse effects on neonates and the mother [Ref 31].
- **1910:** Dr. Hawley Harvey Crippen was convicted of murdering his wife using scopolamine — the alkaloid was identified in her remains by a Home Office pathologist. This was one of the first forensic identifications of the compound in a murder case [Ref 37].
- **1920s:** Scopolamine proposed and briefly used as a "truth serum" in American courts, based on the belief that under its influence people could only tell the truth (due to suggestibility enhancement and amnesia). This practice was superseded by barbituric acid derivatives (sodium pentothal) [Ref 37].
- **1979:** First commercially available transdermal drug delivery system — Transderm Scōp (scopolamine patch) — approved for motion sickness prevention, pioneering the transdermal route of administration [Ref 13].
- **2001:** FDA approval of transdermal scopolamine specifically for PONV prophylaxis [Ref 12].
- **2006:** Furey & Drevets at NIMH serendipitously discover rapid antidepressant effects of IV scopolamine (4 µg/kg) in a pilot clinical trial originally designed to study cholinergic effects on cognition in depression [Ref 5].

---

## Subjective Effects

### Clinical and Controlled-Study Descriptions

At therapeutic doses, scopolamine's effects are primarily peripheral antimuscarinic (dry mouth, mydriasis, blurred vision, reduced GI motility). CNS effects at clinical doses include sedation, reduced alertness, and impaired short-term memory acquisition (anterograde amnesia) [Ref 3, Ref 22].

**Cognitive impairment** is the most extensively studied CNS effect. Scopolamine reliably induces dose-dependent deficits in recognition memory, spatial memory, emotional memory, attention, cognitive flexibility, and working memory across species [Ref 3]. This property has established it as the gold-standard pharmacological model of cholinergic deficit and Alzheimer's disease in preclinical research [Ref 3]. In human volunteers, subcutaneous 0.7 mg produces measurable EEG changes and impaired cognitive performance [Ref 46].

**Effect taxonomy mapping** (based on published clinical and experimental literature):

*Perception:*
- **Pupil dilation** — consistent anticholinergic effect; mydriasis at all routes [Ref 35]
- **Visual acuity suppression** — blurred vision from cycloplegia [Ref 35]
- **Double vision** — at higher doses
- **External hallucinations** — at toxic/overdose doses; visual and auditory [Ref 43]
- **Auditory hallucinations** — documented in case reports of anticholinergic toxidrome [Ref 43]

*Body:*
- **Dry mouth** — most common adverse effect; ~50–60% of transdermal users [Ref 13]
- **Sedation** — consistent at all doses; central histamine H1 and muscarinic M1 effects [Ref 22]
- **Nausea suppression** — primary therapeutic indication for PONV and motion sickness [Ref 11]
- **Tachycardia / Abnormal heartbeat** — M2 blockade at SA node [Ref 35]
- **Dizziness** — common at all routes; vestibular effects [Ref 22]
- **Temperature dysregulation** — anhidrosis from sweat gland blockade; hyperthermia in overdose [Ref 35]
- **Constipation** — decreased GI motility [Ref 35]
- **Restlessness** — at toxic doses [Ref 17]

*Thinking:*
- **Amnesia** — anterograde amnesia; hallmark effect at therapeutic and above-therapeutic doses; primary pharmacological tool for modeling cognitive impairment [Ref 3]
- **Cognitive impairment** — dose-dependent impairment of all cognitive domains [Ref 3]
- **Confusion** — at therapeutic and supratherapeutic doses [Ref 35]
- **Delirium** — at overdose/toxic doses; classical anticholinergic delirium [Ref 16, Ref 17]
- **Delusions of sobriety** — noted in criminal use context; victims are often unaware of their impaired state [Ref 42]
- **Delusions** — at toxic doses [Ref 43]

*Feeling:*
- **Anxiety** — can occur; also may suppress anxiety at antidepressant doses [Ref 7]
- **Anxiety suppression** — scopolamine produced significant antianxiety effects (HAM-A reduction) in NIMH trials, particularly in women [Ref 7]

*Self:*
- **Suggestibility enhancement** — hallmark of scopolamine intoxication; victims comply with criminal commands without resistance [Ref 42, Ref 44]
- **Disinhibition** — at toxic doses [Ref 43]

*Awareness:*
- **Reality testing impairment** — in overdose/criminal use context; victims unable to assess their own impairment [Ref 42]

### Duration Data (from Controlled Studies)

- **IV (4 µg/kg):** Onset of CNS effects within minutes; antidepressant effects measurable within 3 days and persisting >2 weeks post-infusion [Ref 4]
- **Oral (0.3–0.6 mg):** Onset ~30–45 minutes; duration approximately 4–6 hours (consistent with t½ of 4.5 hours) [Ref 22]
- **Transdermal patch:** Onset 4–6 hours; peak 8–24 hours; duration 72 hours (patch) [Ref 13, Ref 35]
- **Subcutaneous (0.7 mg):** EEG changes within minutes; functional impairment for several hours [Ref 46]
- **Anticholinergic toxidrome duration:** Hallucinations and delirium may persist several days in severe cases; full recovery in the case report by Bulut & Arpacıoğlu (2022) required several weeks [Ref 43]

---

## Safety & Toxicity

### Acute Toxicity

Scopolamine's toxicity follows the classic anticholinergic toxidrome ("dry as a bone, blind as a bat, red as a beet, hot as a hare, mad as a hatter"):
- Dry mouth, anhidrosis, flushed skin, hyperthermia
- Mydriasis, blurred vision, cycloplegia
- Tachycardia
- Urinary retention
- Decreased bowel motility, ileus
- Agitation, confusion, delirium, hallucinations
- Seizures at very high doses [Ref 16, Ref 35]

**LD50 data:** No reliable human LD50 data identified in the literature. StatPearls notes: 10 mg/day may be lethal for children; >100 mg/day in adults not uniformly fatal [Ref 35]. Flag for human review: no published human LD50 with verified primary source found.

**Therapeutic window:** Clinical doses are 0.3–0.6 mg (oral), 1 mg over 3 days (transdermal), or 4 µg/kg IV. Toxic psychosis has been reported from standard transdermal use in both children and adults [Ref 17].

### Case Reports

- **Pediatric delirium from transdermal patch (Lin et al. 2011) [Ref 17]:** 4-year-old developed flushing, hallucinations, bizarre actions, aggressive behavior, hyperactivity, and incoherent speech from a transdermal scopolamine patch. Resolved after patch removal.
- **Anticholinergic psychosis from IM hyoscine butylbromide (Bulut & Arpacıoğlu 2022) [Ref 43]:** Young woman developed progressive ataxia, slurred speech, stereotypic movements, vivid visual and auditory hallucinations, and self-mutilative behaviors. Recovery required weeks of olanzapine treatment.
- **Pediatric belladonna alkaloid ingestion series (Glatstein et al. 2016) [Ref 16]:** 10-year retrospective at Hospital for Sick Children; all 10 adolescent patients presented with severe anticholinergic toxidrome from jimsonweed or atropine-containing tablets; treatments included charcoal, benzodiazepines, haloperidol, physostigmine; 2 required intubation.
- **Criminal use (Reichert et al. 2017) [Ref 42]:** Documents involuntary scopolamine intoxication in criminal contexts; hallmark signs are severe anterograde amnesia and submissiveness, enabling victims to comply with criminal commands without resistance or recall.

### Antidote

Physostigmine (reversible cholinesterase inhibitor, CNS-penetrant) is the recommended antidote for anticholinergic delirium unresponsive to non-pharmacological management. Optimal dosing: 0.5–1 mg IV, titrated, with minimum 10–15 minute re-dosing intervals. Risk of cholinergic toxicity with excessive dosing; seizures reported in up to 2.5% of cases (Dawson & Buckley 2016 [Ref 24]). Rivastigmine is emerging as an alternative when physostigmine is unavailable (Mehrpour et al. 2025 [Ref 25]).

### Criminal Use / Harm Reduction Context

Scopolamine ("burundanga," "Devil's Breath") is used as a chemical incapacitating agent primarily in Colombia and increasingly elsewhere. It may be administered in beverages, blown in victims' faces, or via skin contact. Unofficial Colombian estimates suggest ~50,000 annual incidents, though a Colombian Neurological Association study of 860 admitted patients found only 12.5% tested positive for scopolamine alone; 43.7% also had benzodiazepines [Ref 44]. The US Embassy in Bogotá has issued security alerts for increased scopolamine-related crimes [Ref 44]. Testing for the drug after the fact is challenging due to rapid metabolism.

### Organ Toxicity

- **Cardiovascular:** Tachycardia from M2 blockade; occasional cardiotoxic effects reported with physostigmine overdosing during treatment [Ref 24]
- **Ophthalmologic:** Can precipitate acute angle-closure glaucoma attack in predisposed individuals by causing mydriasis [Ref 35]
- **Renal:** Urinary retention, especially in men with BPH; discontinue if urination difficulties develop [Ref 35]
- **CNS:** Toxic psychosis, particularly in elderly and children, even at therapeutic doses
- **Placental transfer:** Scopolamine crosses the placenta; caution in pregnancy; compatible with nursing but should be monitored [Ref 22]
- **Long-term anticholinergic exposure:** Association with cognitive decline and dementia risk in older adults, particularly with cumulative anticholinergic burden (Ziadeh et al. 2024 [Ref 33]; Holler et al. 2025 [Ref 47])

---

## Harm Reduction

Based on published literature and FDA labeling:

1. **Angle-closure glaucoma is an absolute contraindication** — scopolamine's mydriatic effect can precipitate acute glaucoma crisis [Ref 35]
2. **Remove patch before MRI** — patch contains a metal foil layer that can cause localized skin burns in MRI [Ref 35]
3. **Wash hands thoroughly after applying patch** — unintentional finger-to-eye transfer causes unilateral mydriasis and blurred vision (iatrogenic anisocoria case reports documented) [Ref 35]
4. **Avoid in the elderly with cognitive impairment** — high risk for anticholinergic-induced delirium [Ref 48]
5. **Caution with CNS depressants** — additive sedation with opioids, benzodiazepines, alcohol [Ref 35]
6. **Avoid with other anticholinergics** — additive burden; risk of intestinal obstruction, urinary retention, toxic delirium [Ref 48]
7. **Antidote:** Physostigmine 0.5–1 mg IV (titrated); rivastigmine as alternative in physostigmine shortage [Ref 24, Ref 25]
8. **Testing/identification:** No rapid point-of-care test available; forensic detection by LC-MS/MS in blood/urine [Ref 22]
9. **Grapefruit juice interaction:** Avoid concurrent ingestion — CYP3A inhibition significantly increases bioavailability and may precipitate toxic effects [Ref 22]
10. **Application site:** Must be placed postauricularly (behind the ear) for transdermal; other sites have variable absorption [Ref 35]

---

## Tolerance & Dependence

### Tolerance

No controlled studies on tolerance development to scopolamine's antiemetic or antidepressant effects were found in the literature. The Nachum et al. 2006 review noted no evidence of pharmacokinetic tolerance with long-term transdermal use (consistent plasma levels and sustained clinical efficacy) [Ref 13]. However, prolonged or repeated application may cause "some impairment of memory storage for new information," suggesting CNS adaptations with sustained use [Ref 13].

**Flag:** Absence of controlled tolerance studies should be noted. Claims of tolerance or lack thereof are not well-supported by primary human data.

### Withdrawal / Discontinuation

Abrupt discontinuation of anticholinergic drugs, including scopolamine, produces **cholinergic rebound**, characterized by: nausea, vomiting, abdominal cramping, sweating, headache, muscle spasms, and urinary urgency (Howland 2010 [Ref 32]).

A case report specifically documenting scopolamine withdrawal after standard 7-day transdermal use (Manno et al. 2015 [Ref 18]): 62-year-old woman developed a progressive withdrawal syndrome 24–36 hours after patch removal, with dizziness, nausea, sweating, fatigue, drowsiness progressing on subsequent occasions to severe asthenia, orthostatic sweating, inability to stand, and hypotension. Symptoms worsened with each successive use, suggesting sensitization. Resolution over several days without pharmacological intervention.

### Dependence Liability

No published evidence of psychological or physiological dependence with clinical use has been identified. Scopolamine is not a scheduled controlled substance in the United States, the UK, or EU member states, consistent with low dependence liability at therapeutic doses [Ref 30].

---

## Interactions

### Documented Pharmacokinetic Interactions

- **Grapefruit juice (CYP3A inhibitor):** Increases scopolamine AUC to ~142% of control; delays Tmax; increases absolute bioavailability [Ref 22]. **Clinical significance: moderate — avoid concurrent use.**
- **CYP3A inhibitors (ketoconazole, erythromycin, etc.):** Expected to increase scopolamine exposure based on CYP3A metabolic pathway [Ref 22]. **Not specifically studied; flag for review.**

### Pharmacodynamic Interactions

- **Other anticholinergics** (antipsychotics, tricyclic antidepressants, antihistamines like diphenhydramine, bladder antimuscarinics, antiparkinsonian agents): Additive anticholinergic burden; risk of toxic delirium, intestinal obstruction, urinary retention [Ref 35, Ref 48]. This is the most clinically significant interaction class.
- **CNS depressants** (opioids, benzodiazepines, barbiturates, alcohol, sedating antihistamines, Z-drugs): Additive CNS depression and sedation [Ref 35].
- **Opioids specifically:** Additive anticholinergic effects — opioids themselves have anticholinergic properties; combination increases constipation and urinary retention risk [Ref 48].
- **Acetylcholinesterase inhibitors** (donepezil, rivastigmine, galantamine): Pharmacodynamically antagonistic — AChEIs increase acetylcholine at synapses, directly countering scopolamine's competitive antagonism [Ref 4]. Pharmacological basis for physostigmine as antidote.

### Contraindicated Conditions

- **Angle-closure glaucoma** (absolute contraindication — risk of acute glaucoma) [Ref 35]
- **Hypersensitivity to belladonna alkaloids** (absolute contraindication) [Ref 35]
- **Myasthenia gravis** (unpredictable and potentially dangerous interactions — avoid) [Ref 35]
- **Severe preeclampsia** (may precipitate eclampsia — avoid) [Ref 35]
- **Benign prostatic hyperplasia / urinary retention** (risk of acute urinary retention) [Ref 35]
- **Significant hepatic or renal impairment** (reduced clearance; risk of accumulation — use with caution and reduce dose) [Ref 35]

---

## Legal Status

**United States:** Scopolamine is **not a DEA-scheduled controlled substance** — it does not appear on the Controlled Substances Act list. Possession of the pure compound is federally uncontrolled. The Federal Analog Act is theoretically applicable, but no known prosecutions have occurred. Specific pharmaceutical formulations (Transderm Scōp patch, injectable scopolamine hydrobromide) require a prescription [Ref 30].

**United Kingdom:** Scopolamine is **not controlled under the Misuse of Drugs Act 1971**. It is available as a Prescription-Only Medicine (POM) under the Medicines Act. Hyoscine hydrobromide (Scopoderm patch, Kwells tablets, Joy-Rides tablets) is available OTC for motion sickness in lower doses in some formulations.

**Australia:** Regulated under the TGA Standard for Uniform Scheduling of Medicines and Poisons (SUSMP). Hyoscine/scopolamine appears as a scheduled pharmacy medicine requiring pharmacist guidance for sale. Hyoscine butylbromide (Buscopan) is available as an over-the-counter pharmacy medicine; the hydrobromide (transdermal) requires prescription.

**European Union / Canada:** Regulated as a medicinal product requiring prescription in most member states. Not a narcotics-controlled substance in any major EU jurisdiction.

**Global:** Scopolamine is listed on the **WHO Model List of Essential Medicines** [Ref 27]. It is not listed in the UN Convention on Psychotropic Substances (1971), despite its psychoactive properties.

---

## Clinical Trials

### Antidepressant / Mood Disorders

| NCT ID | Title | Status | Phase | Notes |
|---|---|---|---|---|
| NCT04211961 | Scopolamine in Bipolar Depression (SCOPE-BD) | COMPLETED | Phase 2 | Dr. Brian Hallahan, Ireland; IV scopolamine in bipolar depression; results published Miravalles et al. 2026 [Ref 10] |
| NCT03131050 | Scopolamine Combined With Escitalopram in MDD | COMPLETED | Phase 4 | Capital Medical University; augmentation strategy; Zhou 2019 protocol [Ref 49] |
| NCT00369915 | Antidepressant Efficacy of Anticholinergic Scopolamine | TERMINATED | Phase 2 | NIMH; key Furey/Drevets trials leading to landmark publications [Ref 5, Ref 6] |
| NCT00055575 | Cholinergic Modulation of Condition and Emotion in Mood Disorders | TERMINATED | Phase 2 | NIMH; Furey/Drevets early trial series [Ref 4] |
| NCT01613820 | Ketamine and Scopolamine for Treatment-Resistant MDD | WITHDRAWN | N/A | Massachusetts General Hospital; withdrawn before enrollment |
| NCT01312844 | IV Scopolamine to Augment ECT Efficacy | TERMINATED | Phase 2 | Massachusetts General Hospital |
| NCT04719663 | Treatment Rationale on Expectation Effects in Depression | COMPLETED | N/A | Philipps University Marburg; addresses placebo expectation confound |

### Nausea / Motion Sickness

- FDA approved (2001) for PONV; Cochrane systematic review (Spinks & Wasiak 2011 [Ref 11]) confirms efficacy for motion sickness
- Network meta-analysis (Weibel et al. 2021 [Ref 41]) suggests scopolamine may increase overall adverse events vs. placebo and is positioned below several newer antiemetics in efficacy rankings for PONV
- No active ClinicalTrials.gov results found for PONV or motion sickness trials at time of search

---

## Community Feedback Analysis

No community feedback was submitted in Part A2 of the brief. Standard research directives applied.

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## Gaps & Flags

### Safety-Critical Values — FLAG FOR HUMAN REVIEW

1. **LD50 / lethal dose:** No primary-source human LD50 data was identified. StatPearls [Ref 35] states "10 mg/day may be lethal for children; >100 mg/day in adults didn't cause death" — but this appears to be a derived clinical estimate, not a published controlled study. **Dose range for lethality not verified against a primary published toxicology source.**

2. **Grapefruit juice interaction magnitude (AUC +42%):** Documented in Renner 2005 [Ref 22], a review article. The original pharmacokinetic interaction study is referenced but not independently verified here. Clinical significance at current doses is moderate but should be reviewed by a pharmacist editor.

3. **Protein binding:** Specific plasma protein binding data for scopolamine not found in the literature searched. This is a significant PK gap.

4. **Therapeutic index:** No primary data on therapeutic index or margin of safety found. The gap between therapeutic transdermal dose (0.5 mg/72hr) and the toxic case report dose (standard 1.5 mg patch in a child) is narrow. **Flag for editorial review.**

5. **Oral dosing information:** Oral tablet scopolamine (0.3–0.6 mg) is widely referenced in reviews but clinical trial data specifically comparing routes is limited. The 2023 systematic review [Ref 8] notes calls for trials directly comparing routes of administration.

### Data Gaps

6. **Recreational use / abuse:** Zero PubMed results for recreational use of scopolamine. Published literature appears not to address this. What exists is primarily criminal-use case reports [Ref 42] and toxidrome case reports [Ref 16, Ref 17, Ref 43].

7. **Tolerance development:** No controlled human studies on tolerance were found. Evidence from transdermal use suggests no PK tolerance but possible CNS adaptation with prolonged use [Ref 13].

8. **Stereochemistry binding data:** Ki values at M1–M5 specifically for L-scopolamine vs. racemate are not disaggregated in the papers found. The natural (-)-form is understood to be the active stereoisomer, but precise comparative binding data were not retrieved.

9. **Antidepressant evidence — significant conflict:** The NIMH series (Furey & Drevets 2006 [Ref 5]; Drevets & Furey 2010 [Ref 6]; Furey et al. 2010 [Ref 7]) showed robust antidepressant effects (placebo-adjusted remission rates 45–56%). However, the Chen et al. 2022 RCT [Ref 9] using an active placebo (glycopyrronium, which cannot cross the BBB) found no difference between scopolamine and active placebo (MADRS improvement: 12.6 vs. 11.2; Bayes factor 0.32 for null hypothesis). The 2026 SCOPE-BD trial [Ref 10] provides additional data. The 2023 systematic review [Ref 8] found "not all studies confirmed a statistically and clinically significant reduction vs. placebo." **The antidepressant evidence base is actively contested. Generation agent must present this as an area of ongoing uncertainty, not established fact.**

10. **Criminal use epidemiology:** Figures cited (~50,000 annual scopolamine incidents in Colombia) are unofficial estimates [Ref 44]. The study finding only 12.5% positive for scopolamine alone in admitted Colombian patients suggests Datura plant preparations (containing multiple alkaloids including atropine and hyoscyamine) are more commonly used than pure scopolamine [Ref 44].

11. **Legal status — UK OTC availability:** Some lower-dose hyoscine formulations (Kwells tablets, Joy-Rides) are available OTC in the UK for motion sickness. The exact schedule boundaries for UK preparations were not verified via primary legislative source.

12. **Metabolite identification:** The chemical structures of scopolamine's urinary glucuronide metabolites have not been fully characterized as of the Renner 2005 [Ref 22] review; it is unclear whether this gap has since been addressed.