generation run 2026-05-07
85 min completedmodel pipeline-v5plan not recordedrun/7836ddcb…Selection
Verification
- record
- seen / partial
- working
The model's own caveats
- sparse_evidence
- note
Reproduce
- inputs
- 44 source keys (listed under Sources)
- plan
- not recorded — template version, prompt hash and git SHA are written from 2026-09 onward
- model
- pipeline-v5
- streams
- none — agent transcripts are persisted from 2026-09 onward
21 searches — query, source, results, what was kept and why
| # | source | query | seen | kept | rationale |
|---|---|---|---|---|---|
| 1 | PubMed | scopolamine pharmacology mechanism muscarinic receptor | 12 | 5 | Prioritized papers directly about scopolamine pharmacology, mechanism, and clinical use |
| 2 | OpenAlex | scopolamine pharmacology mechanism action | 10 | 0 | — |
| 3 | PubMed | scopolamine antidepressant rapid depression treatment clinical trial | 12 | 8 | All directly relevant to scopolamine antidepressant efficacy — primary trials and systematic reviews |
| 4 | PubChem | scopolamine | 1 | 1 | Primary chemical identity reference |
| 5 | PubMed | scopolamine pharmacokinetics bioavailability absorption human | 10 | 3 | Selected papers focused on scopolamine PK specifically |
| 6 | ClinicalTrials.gov | scopolamine depression antidepressant | 7 | 4 | Selected the most relevant completed and key terminated trials |
| 7 | PubMed | physostigmine reversal anticholinergic toxicity treatment | 8 | 2 | Primary sources for anticholinergic delirium pharmacological management |
| 8 | WebSearch | scopolamine pharmacokinetics oral bioavailability half-life | 10 | 2 | Key PK studies |
| 9 | PubMed | scopolamine binding affinity Ki muscarinic receptor subtypes M1 M2 | 10 | 0 | No relevant results |
| 10 | PubMed | scopolamine cholinergic hypothesis depression muscarinic receptor pathophysiology mood | 1 | 1 | Review on muscarinic receptors in mood disorder pathophysiology |
| 11 | PubMed | scopolamine motion sickness nausea prevention clinical use | 10 | 4 | Selected those directly relevant to scopolamine's clinical use, adverse events, and history |
| 12 | PubMed · absence | scopolamine overdose poisoning toxicity adverse effects delirium | 0 | — | No results found |
| 13 | WebSearch/Erowid | scopolamine legal status DEA scheduling controlled substance | 10 | 2 | Primary legal status sources for multiple jurisdictions |
| 14 | PubMed | PMID 2762223 - pharmacokinetics oral bioavailability scopolamine | 1 | 1 | Primary PK study for scopolamine |
| 15 | PubMed | PMID 16175141 - pharmacokinetics pharmacodynamics clinical use scopolamine | 1 | 1 | Most comprehensive PK/PD review including metabolism pathways and drug interactions |
| 16 | PubMed | anticholinergic drug interaction additive elderly delirium | 8 | 2 | Drug interaction data for anticholinergic burden and cognitive risk |
| 17 | PubChem REST API | CID 3000322 canonical SMILES, InChI, molecular properties | 1 | 5 | Chemical identity and drug-likeness parameters |
| 18 | Bristol Chemistry/WebFetch | scopolamine history discovery | 1 | 3 | Historical and contextual information about scopolamine |
| 19 | FDA/StatPearls | scopolamine FDA prescribing information Transderm Scop dosage contraindications | 10 | 4 | Official FDA label information for clinical dosing and safety |
| 20 | ChemicalBook | scopolamine CAS 51-34-3 physical properties melting point solubility | 10 | 4 | Physical properties not available via PubMed/OpenAlex |
| 21 | PubMed | anticholinergic cholinergic rebound withdrawal symptoms | 4 | 1 | Withdrawal/discontinuation data for anticholinergic drugs including scopolamine |
84 claims by section — every cited sentence, checked against its source
safety25 · 17 ok
This state can occur at therapeutic doses in vulnerable populations (children, elderly, individuals with pre-existing cognitive impairment).supported
4-year-old developed toxic psychosis from transdermal scopolamine...Case highlights anticholinergic toxic psychosis risk in children. s0929-6646(11)60031-4
Children — increased sensitivity to CNS effects; toxic psychosis reported from standard transdermal patchessupported
4-year-old developed toxic psychosis from transdermal scopolamine. Case highlights anticholinergic toxic psychosis risk in children. s0929-6646(11)60031-4
The therapeutic window is notably narrow: toxic psychosis has been reported from standard transdermal patch use in both children and adults.supported
4-year-old developed toxic psychosis from transdermal scopolamine: flushing, hallucinations, bizarre actions, aggressive behavior, hyperactivity, incoherent speech. Resolved after patch removal. s0929-6646(11)60031-4
Claim in safety — inconclusiveinconclusiveworking →
Reproductive: Scopolamine crosses the placenta and is present in breast milk; caution is advised in pregnancy and lactation.supported
Crosses placenta. Compatible with nursing. pmid:16175141
Cumulative anticholinergic medication exposure is associated with increased risk of cognitive decline and incident dementia in older adultssupported
Review of association between anticholinergic medications and dementia risk. Evidence of cognitive impact established but extent unclear. mou.0000000000001211
Perioperative anticholinergic medication use, including scopolamine, has been specifically associated with increased incident dementia among older surgical patientssupported
Inpatient anticholinergic medications associated with higher likelihood of postoperative delirium and potentially long-term cognitive impact in older adults. s40266-025-01185-6
A 4-year-old child developed flushing, hallucinations, bizarre behavior, aggression, hyperactivity, and incoherent speech following application of a standard transdermal scopolamine patch; all symptoms resolved after patch removalsupported
4-year-old developed toxic psychosis from transdermal scopolamine: flushing, hallucinations, bizarre actions, aggressive behavior, hyperactivity, incoherent speech. Resolved after patch removal. s0929-6646(11)60031-4
Claim in safety — inconclusiveinconclusiveworking →
A young woman developed progressive anticholinergic psychosis with ataxia, stereotypic movements, vivid hallucinations, and self-mutilative behavior following intramuscular hyoscine butylbromide injection, requiring weeks of olanzapine treatment for recovery.supported
Young female developed ataxia, slurred speech, vivid visual and auditory hallucinations, self-mutilative behaviors after IM hyoscine butylbromide injection. Olanzapine treatment led to gradual recovery over several weeks. ejhpharm-2020-002583
Claim in safety — inconclusiveinconclusiveworking →
Excessive dosing carries risk of cholinergic toxicity; seizures are reported in up to 2.5% of treated cases. Rivastigmine has been proposed as an alternative when physostigmine is unavailable.supported
Seizures in up to 2.5% with physostigmine. Rivastigmine also logical alternative. bcp.12839
Excessive dosing carries risk of cholinergic toxicity; seizures are reported in up to 2.5% of treated cases. Rivastigmine has been proposed as an alternative when physostigmine is unavailable.partially supported
Rivastigmine emerging as alternative when physostigmine unavailable. j.yrtph.2025.105857
This state can occur at therapeutic doses in vulnerable populations (children, elderly, individuals with pre-existing cognitive impairment).supported
Anticholinergic activity causes drug-induced delirium. Elderly at highest risk. a000116
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Symptoms include nausea, vomiting, abdominal cramping, excessive sweating, headache, muscle spasms, and urinary urgency.partially supported
Abruptly stopping anticholinergic drugs leads to cholinergic rebound: nausea, sweating, urinary urgency. Tapering recommended to minimize discontinuation effects. 02793695-20100506-01
Symptoms worsened with each successive use/withdrawal cycle, suggesting sensitization of the withdrawal response.supported
62-year-old woman developed withdrawal syndrome after 7-day continuous transdermal scopolamine use. More severe with repeated prolonged use. wnf.0000000000000099
Co-administration with other anticholinergic agents — tricyclic antidepressants, first-generation antipsychotics, antihistamines (diphenhydramine, hydroxyzine), bladder antimuscarinics (oxybutynin, tolterodine), and antiparkinsonian agents (trihexyphenidyl, benztropine) — produces cumulative muscarinic blockade with increased risk of toxic delirium, intestinal obstruction, and urinary retention.supported
Anticholinergic activity causes drug-induced delirium. Antipsychotics, antidepressants, antihistamines, and anticholinergics are major classes. a000116
Opioids deserve specific mention: they possess intrinsic anticholinergic properties, so the combination increases both sedation and peripheral antimuscarinic effects (constipation, urinary retention).supported
Opioids also have anticholinergic effects. Benzodiazepines cause delirium via sedation. a000116
Claim in safety — not_supportednot supportedworking →
Grapefruit juice increases AUC to ~142% of control valuessupported
Grapefruit juice increases AUC to 142%. pmid:16175141
Elderly with cognitive impairment — high risk of anticholinergic-induced deliriumsupported
Elderly at highest risk. a000116
pharmacology19 · 11 ok
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — not_supportednot supportedworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
The temporal dissociation between the compound's short plasma half-life (4.5 hours) and the persistence of antidepressant effects (onset within 3 days, duration exceeding 2 weeks post-infusion) implies effects on gene expression and synaptic remodeling rather than sustained receptor occupancy.supported
Clinical improvement persisted >2 weeks post-infusion. Mechanism likely beyond direct muscarinic antagonism - gene expression and synaptic plasticity changes suggested. j.biopsych.2012.09.031
mTORC1-dependent synaptic plasticity in the medial prefrontal cortexsupported
Review covers pharmacology, cognitive model, antidepressant evidence, mTORC1-dependent synaptic plasticity mechanisms. molecules31071219
Dephosphorylation of eukaryotic elongation factor 2 (eEF2), a mechanism shared with ketamine's rapid antidepressant actionsupported
Subchronic scopolamine (3-5 days) produced antidepressant effects via eEF2 dephosphorylation - a synaptic plasticity marker. Links to ketamine mechanism via shared signaling pathway. s43440-024-00630-4
Elevation of dopamine, serotonin, and glutamate in the frontal cortexsupported
Both compounds increased dopamine, serotonin, and glutamate in rat frontal cortex. Suggests serotoninergic, glutamatergic, and dopaminergic mechanisms. j.pbb.2025.173996
Claim in pharmacology — inconclusiveinconclusiveworking →
The cholinergic–adrenergic hypothesis of mood disorders posits that depression reflects excess central cholinergic activity relative to noradrenergic tone, providing the theoretical basis for muscarinic antagonism as an antidepressant strategysupported
Based on cholinergic-adrenergic hypothesis of mania and depression. Reviews all available data on scopolamine as antidepressant treatment. wnf.0b013e318278b703
Genetic evidence has associated variation in CHRM2 (encoding the M2 receptor) with elevated depression risk.supported
CHRM2 particularly implicated in MDD/BPD pathophysiology. Scopolamine as pan-CHRM antagonist produces rapid antidepressant effects. pmid:26630954
Following intravenous bolus (0.4 mg), plasma concentrations decline biexponentially with a mean elimination half-life of 4.5 ± 1.7 hours, a volume of distribution of 1.4 ± 0.3 L/kg, and systemic clearance of 65.3 ± 5.2 L/hrsupported
0.4 mg IV and oral in 6 healthy males. Half-life 4.5±1.7 hr, Vd 1.4±0.3 L/kg, systemic clearance 65.3±5.2 L/hr, renal clearance 4.2±1.4 L/hr. pmid:2762223
Claim in pharmacology — inconclusiveinconclusiveworking →
Oral bioavailability is highly variable (10.7–48.2%), attributed to extensive first-pass hepatic metabolism — less than 2.6% of nonmetabolized scopolamine is recovered in urine following oral dosingpartially supported
Oral bioavailability 10.7-48.2% (highly variable). First-pass metabolism suspected. pmid:2762223
Tmax occurs at approximately 30 minutes after oral administration.supported
Tmax oral ~0.5 hr. pmid:16175141
The commercially available transdermal patch (Transderm Scōp) delivers a 140 µg priming dose from the adhesive layer followed by steady-state release at approximately 5 µg/hour over 72 hours, achieving peak plasma concentrations of approximately 100 pg/mL (range 11–240 pg/mL) at approximately 8 hours post-application.supported
TTS-S patch 1.5 mg total; delivers 0.5 mg over 3 days with 140 μg priming dose. Steady state ~100 pg/mL at 8-12 hours. pmid:16719539
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
Scopolamine crosses the blood–brain barrier readily, crosses the placenta, and is present in breast milk.supported
Crosses placenta. Compatible with nursing. qEEG correlates with serum concentrations. pmid:16175141
neuroscience7 · 4 ok
In healthy human volunteers receiving subcutaneous 0.7 mg, source-localized EEG analysis identified the precuneus as the primary cortical region showing alpha-2 band power reduction — a finding interpreted as relevant to the antiemetic mechanism via modulation of spatial orientation processing.supported
0.7 mg SC scopolamine in 6 participants. EEG showed alpha-2 frequency band decrease in the precuneus (BA7) bilaterally. This brain center contributes to movement control and space orientation - may explain antiemetic mechanism. jcph.83
Scopolamine produces a characteristic dose-dependent EEG signature: increased theta (4–8 Hz) and delta (0.5–4 Hz) power with decreased alpha (8–13 Hz) powersupported
Scopolamine increases theta and delta EEG power bands and decreases alpha power in dose-dependent manner. journal.pone.0207969
Claim in neuroscience — not_supportednot supportedworking →
Claim in neuroscience — inconclusiveinconclusiveworking →
Genetic support comes from association studies linking CHRM2 polymorphisms to depression susceptibilitysupported
CHRM2 particularly implicated in MDD/BPD pathophysiology. pmid:26630954
Claim in neuroscience — inconclusiveinconclusiveworking →
What is the role of sex differences in scopolamine's CNS effects? Women show both larger antidepressant responses and lower intranasal plasma concentrations, suggesting possible sex-dependent pharmacokinetics, pharmacodynamics, or both.supported
Plasma concentrations significantly lower in females than males at 0.4 mg dose. jcph.391
pharmacokinetic-detail7 · 6 ok
The Transderm Scōp patch (1.5 mg total reservoir) delivers a 140 µg priming dose from the adhesive layer, followed by steady-state release at approximately 5 µg/hour over 72 hours, delivering a total of approximately 0.5 mg over 3 dayssupported
TTS-S patch 1.5 mg total; delivers 0.5 mg over 3 days with 140 μg priming dose. pmid:16719539
Intranasal gel formulations exhibit dose-linear pharmacokinetics from 0.1 to 0.4 mg, with faster absorption and higher bioavailability than the oral routepartially supported
PK study of intranasal scopolamine 0.1, 0.2, 0.4 mg in 12 healthy subjects. Dose-linear pharmacokinetics; linear increases in Cmax and AUC. jcph.391
Plasma concentrations are significantly lower in females than males at the 0.4 mg dose, a sex-dependent pharmacokinetic difference of uncertain clinical significance.supported
Plasma concentrations significantly lower in females than males at 0.4 mg dose. Well tolerated. jcph.391
Co-administration with 150 mL grapefruit juice (a CYP3A inhibitor) significantly increases scopolamine exposure: AUC₀–₂₄ rises to approximately 142% of control values, Tmax is delayed (59.5 ± 25.0 min vs. shorter in the water group; P < 0.001), and absolute bioavailability increases (6–37% vs. 3–27% with water)supported
Grapefruit juice increases AUC to 142%. pmid:16175141
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
Peak plasma concentrations reach approximately 100 pg/mL (range 11–240 pg/mL) at approximately 8 hours post-application, with steady-state levels of 56–245 pg/mL maintained over the 72-hour period.partially supported
Steady state ~100 pg/mL at 8-12 hours. pmid:16719539
Oxidative N-demethylation via CYP3A (intestinal and hepatic) is a secondary pathwaysupported
Metabolism via CYP3A oxidative demethylation and glucuronidation. pmid:16175141
summary6 · 3 ok
Claim in summary — inconclusiveinconclusiveworking →
Claim in summary — inconclusiveinconclusiveworking →
Since 2006, intravenous scopolamine (4 µg/kg) has attracted interest as a potential rapid-acting antidepressant following landmark NIMH trials, though a subsequent active-placebo-controlled trial found no separation from glycopyrroniumsupported
Landmark first RCT demonstrating rapid antidepressant effects of scopolamine hydrobromide 4 μg/kg IV vs placebo. Originally discovered serendipitously during cognitive research. pmid:17015814
Since 2006, intravenous scopolamine (4 µg/kg) has attracted interest as a potential rapid-acting antidepressant following landmark NIMH trials, though a subsequent active-placebo-controlled trial found no separation from glycopyrroniumsupported
40 patients RCT; scopolamine 4-6 μg/kg vs glycopyrronium 4 μg/kg. No antidepressant effect of scopolamine vs active placebo (d=0.17). Abandoned for futility. Casts doubt on earlier positive results. jcp.21m14310
Claim in summary — inconclusiveinconclusiveworking →
Long-term anticholinergic exposure is associated with increased dementia risksupported
Review of association between anticholinergic medications and dementia risk. Evidence of cognitive impact established but extent unclear. mou.0000000000001211
clinical-evidence5 · 5 ok
A Cochrane systematic review confirmed efficacy relative to placebo for both transdermal and oral formulations.supported
Cochrane systematic review of scopolamine for motion sickness - first comprehensive review of effectiveness. 14651858.cd002851.pub4
A 2021 Cochrane network meta-analysis positioning scopolamine against newer antiemetics (5-HT₃ antagonists, NK1 antagonists, dexamethasone) ranked scopolamine below several comparators in efficacy and associated it with a higher overall rate of adverse events than placebo.supported
Network meta-analysis of antiemetics for PONV. Scopolamine may increase adverse events vs placebo. Multiple effective alternatives including granisetron, ondansetron, dexamethasone. anae.15295
Subsequent analysis identified significantly larger antidepressant and anxiolytic responses in women (HAM-A reduction significantly greater in female participants).supported
Effect magnitude significantly larger in women than men on both MADRS and HAM-A. npp.2010.131
MADRS improvement was 12.6 points with scopolamine versus 11.2 points with glycopyrronium — a non-significant difference (Bayes factor = 0.32, favoring the null hypothesis).supported
Scopolamine reduced MADRS by 12.6 points at day 3 but glycopyrronium showed similar reductions (11.2 points). No antidepressant effect of scopolamine vs active placebo (d=0.17). jcp.21m14310
A 2013 systematic review had reached cautiously positive conclusions based on the NIMH data available at that time.supported
Systematic review of available data on scopolamine as antidepressant. Based on cholinergic-adrenergic hypothesis of mania and depression. wnf.0b013e318278b703
botanical-overview4 · 1 ok
Scopolamine occurs naturally in numerous species of the Solanaceae (nightshade) family, where it co-occurs with the structurally related tropane alkaloids atropine and hyoscyaminesupported
Review of 43 Datura alkaloids including atropine, hyoscyamine, and scopolamine. toxins17090469
Claim in botanical-overview — inconclusiveinconclusiveworking →
Claim in botanical-overview — inconclusiveinconclusiveworking →
Claim in botanical-overview — inconclusiveinconclusiveworking →
history4 · 2 ok
In 2006, Maura Furey and Wayne Drevets at the NIMH reported that intravenous scopolamine (4 µg/kg) produced rapid antidepressant effects in a pilot trial originally designed to study cholinergic modulation of cognition in depressed patients — the antidepressant efficacy was serendipitoussupported
Landmark first RCT demonstrating rapid antidepressant effects of scopolamine hydrobromide 4 μg/kg IV vs placebo. Originally discovered serendipitously during cognitive research. pmid:17015814
Claim in history — inconclusiveinconclusiveworking →
Claim in history — inconclusiveinconclusiveworking →
The FDA approved transdermal scopolamine specifically for postoperative nausea and vomiting prophylaxis in 2001.supported
TDS FDA approved 2001. Adverse effects: sedation, dry mouth, blurred vision, central cholinergic syndrome, confusion (elderly). j.clinthera.2010.11.014
alkaloid-profile3 · 1 ok
Claim in alkaloid-profile — not_supportednot supportedworking →
Within the anticholinergic tropane subgroup, scopolamine and atropine are closely related — both are tropic acid esters of tropane alcohols and both act as competitive muscarinic antagonists.supported
Anticholinergic mechanism - block ACh at muscarinic and nicotinic receptors. s13659-022-00357-w
Claim in alkaloid-profile — not_supportednot supportedworking →
receptor-pharmacology2 · 0 ok
chemistry1 · 0 ok
Claim in chemistry — inconclusiveinconclusiveworking →
comparative-pharmacology1 · 1 ok
The negative result challenges the central mechanism hypothesis but does not definitively refute it, as the trial had a relatively small sample size.supported
40 patients RCT. No antidepressant effect of scopolamine vs active placebo (d=0.17). Abandoned for futility. Casts doubt on earlier positive results. jcp.21m14310