generation run 2026-05-07
81 min completedmodel pipeline-v5plan not recordedrun/39f873d3…Selection
Verification
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- seen / partial
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The model's own caveats
- contradictory_sources
- contradictory_sources
- contradictory_sources
Reproduce
- inputs
- 41 source keys (listed under Sources)
- plan
- not recorded — template version, prompt hash and git SHA are written from 2026-09 onward
- model
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18 searches — query, source, results, what was kept and why
| # | source | query | seen | kept | rationale |
|---|---|---|---|---|---|
| 1 | PubChem | Salvinorin A | 1 | 1 | Primary chemical identity verification |
| 2 | PubMed | Salvinorin A adverse effects psychiatric case report abuse | 3 | 2 | Adverse event case reports relevant to safety section; Chopra was about Coleus, not SalA directly |
| 3 | ClinicalTrials.gov | Salvinorin A Salvia divinorum | 3 | 3 | All three trials directly relevant to SalA effects and safety in humans |
| 4 | PubMed | Salvinorin A pharmacokinetics metabolism bioavailability | 3 | 3 | Key pharmacokinetic and bioavailability data sources |
| 5 | PubMed | Salvinorin A kappa opioid receptor agonist Roth 2002 | 3 | 3 | Foundational pharmacology papers establishing SalA as a KOR agonist |
| 6 | PubMed | Salvinorin A human study psychedelic effects dose | 12 | 4 | Selected direct human studies of salvinorin A effects and pharmacokinetics |
| 7 | PubMed | Salvinorin A pharmacology kappa opioid receptor | 12 | 4 | Systematic reviews and high-quality pharmacology papers selected; some peripheral KOR papers discarded as not directly about SalA |
| 8 | OpenAlex | Salvinorin A kappa opioid receptor pharmacology | 10 | 0 | Most returned papers were not SalA-specific; general KOR papers not directly about SalA excluded from registry |
| 9 | OpenAlex | Salvinorin A Salvia divinorum isolation discovery Valdes Roth | 10 | 3 | Key review papers on history and pharmacology of SalA/S.divinorum; original isolation paper by Valdes (1984) not found via this route |
| 10 | PubMed | Salvinorin A CB1 cannabinoid receptor activity | 8 | 3 | Selected papers addressing CB1 involvement; peripheral CB1 effect documented but CNS CB1 binding uncertain |
| 11 | WebSearch | Salvinorin A isolation Valdes 1984 divinorin A neoclerodane diterpene original discovery | 10 | 2 | Two independent isolation papers confirmed; Ortega 1982 is the first published isolation |
| 12 | WebSearch + Erowid | Salvinorin A Salvia divinorum legal status scheduling DEA United States United Kingdom Australia Canada 2026 | 10 | 2 | Multiple jurisdictional legal status data verified from known sources |
| 13 | PubMed | Salvinorin A Doss Barrett 2020 functional connectivity fMRI Johns Hopkins NCT03418714 | 1 | 1 | First human neuroimaging study of SalA; directly relevant to brain mechanism section |
| 14 | PubMed/DOI verify | Ortega 1982 Salvinorin RSC Perkin Transactions DOI verification | 1 | 1 | Primary source for first isolation and structural characterization of salvinorin A |
| 15 | WebSearch | Salvinorin A Ki kappa opioid receptor binding affinity nM | 10 | 2 | Ki values from primary sources; D2 activity noted but requires verification |
| 16 | WebSearch | Salvinorin A melting point solubility physical properties CAS 83729-01-5 | 10 | 2 | Physical property data from multiple commercial chemistry sources and peer-reviewed review |
| 17 | PMC | Salvinorin A physical and chemical properties | 1 | 1 | Peer-reviewed review specifically on physical/chemical properties for clinical translation |
| 18 | WebSearch | Salvinorin A pharmacokinetics half-life 8 minutes nonhuman primate | 10 | 2 | Two key NHP pharmacokinetic studies providing half-life and distribution data |
94 claims by section — every cited sentence, checked against its source
safety27 · 12 ok
Its aversive phenomenology and suppression of mesolimbic dopamine release are primary factors limiting compulsive usesupported
mesolimbic dopaminergic suppression, fragmentation of large-scale brain networks; low abuse potential due to aversive phenomenology. biomedicines14020476
Martinho and colleagues published the first in vitro cytotoxicity study of salvinorin A, testing across six cell linessupported
First in vitro cytotoxicity study of SalA. Both S. divinorum and SalA are cytotoxic in dose- and time-dependent manner across six cell lines. pmid:26434801
Cardiovascular parameters (heart rate, blood pressure) were monitored in the human studies by Ranganathan and colleagues and Maqueda and colleaguessupported
Dose-related behavioral, subjective, endocrine, and psychophysiological effects of Salvinorin A in humans at Yale. j.biopsych.2012.06.012
Cardiovascular parameters (heart rate, blood pressure) were monitored in the human studies by Ranganathan and colleagues and Maqueda and colleaguessupported
Assessment of KOR and 5-HT2A agonism in the subjective, cardiovascular, and neuroendocrine effects of salvinorin-A in humans. pyw016
Naltrexone fully blocked the cardiovascular effects of salvinorin A, confirming they are KOR-mediatedsupported
Assessment of KOR and 5-HT2A agonism in the subjective, cardiovascular, and neuroendocrine effects of salvinorin-A in humans. pyw016
Salvinorin A produces significant prolactin elevation beginning approximately 5 minutes post-inhalation and peaking at 15 minutessupported
Prolactin elevated beginning 5 min post-inhalation, peaking at 15 min. 0269881116629125
Claim in safety — inconclusiveinconclusiveworking →
At high inhaled doses (1 mg vaporized), salvinorin A produces complete disconnection from external reality, loss of body schema awareness, confusion, amnesia, and complete ego dissolutionsupported
Salvinorin-A induces intense dissociative effects, blocking external sensory perception and modulating interoception and sense of body ownership in humans. pyv065
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
El-Khoury and Sahakian presented two case reports and a literature review associating Salvia divinorum use with the development of psychotic disorders, recommending that clinicians inquire about salvia use in patients presenting with substance use or psychotic disorderssupported
Literature review and two original case reports; hypothesizes that S. divinorum could be associated with psychotic disorders. Advocates clinicians inquire about Salvia use in patients with substance use or psychotic disorders. 02791072.2015.1073815
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
At lower doses, no prolonged receptor changes were observed, indicating a dose-dependent threshold for tolerance induction.supported
At lower doses no prolonged effect on KOR binding; at 0.60 mg/kg a sustained decrease in KOR binding persisted up to 2.5 h post administration. npp.2015.159
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Hutton and colleagues found that salvia use among recreational users is intermittent and infrequent, characterized as a "novel experience" rather than a substance of habitual usesupported
Key themes: intense effects, importance of set/setting, intermittent use. Use characterized as novel experience. 02791072.2016.1179376
Opioid antagonists (naltrexone, naloxone): Fully reverse all subjective, cardiovascular, and neuroendocrine effects of salvinorin A — confirmed in humanssupported
Assessment of KOR and 5-HT2A agonism in the subjective, cardiovascular, and neuroendocrine effects of salvinorin-A in humans. pyw016
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Case reports associate Salvia divinorum use with psychotic episodessupported
Literature review and two original case reports; hypothesizes that S. divinorum could be associated with psychotic disorders. 02791072.2015.1073815
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
pharmacology25 · 17 ok
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
No significant activity was detected across a panel of 50 additional receptors, transporters, and ion channels — including, critically, the 5-HT₂A serotonin receptor.supported
Salvinorin A had no significant activity against a battery of 50 receptors, transporters, and ion channels... Salvinorin A had no actions at the 5-HT(2A) serotonin receptor. pmid:12192085
Claim in pharmacology — inconclusiveinconclusiveworking →
Maqueda and colleagues showed that the opioid antagonist naltrexone completely blocked all subjective, cardiovascular, and neuroendocrine effects of vaporized salvinorin A, while the 5-HT₂A antagonist ketanserin had no effectsupported
Assessment of KOR and 5-HT2A agonism in the subjective, cardiovascular, and neuroendocrine effects of salvinorin-A in humans. pyw016
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
The compound suppresses mesolimbic dopamine release via KOR activation in the ventral tegmental area and nucleus accumbens — a mechanism underlying its aversive properties and lack of positive reinforcement.supported
produces thalamocortical disruption, mesolimbic dopaminergic suppression, fragmentation of large-scale brain networks; low abuse potential due to aversive phenomenology. biomedicines14020476
Claim in pharmacology — inconclusiveinconclusiveworking →
CB1 and CB2 receptor involvement has been documented only in peripheral tissues — specifically the gastrointestinal tract, where salvinorin A reduces colonic motility partly through CB1- and CB2-dependent mechanismssupported
Salvinorin A inhibits colonic motility and ion transport. Effects mediated by kappa-opioid receptors (KORs) and cannabinoid (CB) receptors in vitro, but largely by KORs in vivo. j.1365-2982.2009.01369.x
CB1 and CB2 receptor involvement has been documented only in peripheral tissues — specifically the gastrointestinal tract, where salvinorin A reduces colonic motility partly through CB1- and CB2-dependent mechanismssupported
Salvinorin A inhibits intestinal motility through KOR activation; under inflammatory conditions, cannabinoid CB1 receptor involvement increases due to CB receptor upregulation. bjp.2008.294
CB1 and CB2 receptor involvement has been documented only in peripheral tissues — specifically the gastrointestinal tract, where salvinorin A reduces colonic motility partly through CB1- and CB2-dependent mechanismssupported
Anti-inflammatory and antinociceptive effects in colitis model via KOR and CB1 receptors. ibd.21873
In the central nervous system, Walentiny and colleagues demonstrated that salvinorin A's cannabinoid-like discriminative stimulus effects in rodents are mediated by KOR, not by direct CB1 bindingsupported
Studies show KOR mediates cannabinoid-like drug discriminative effects of SalA in rodents. s00213-010-1827-6
When smoked or vaporized, salvinorin A reaches peak plasma concentrations within approximately 2 minutessupported
Drug levels peaked at 2 min and rapidly decreased. 0269881116629125
PET imaging in baboons demonstrated peak brain uptake at 40 seconds following intravenous administration, with highest concentrations in the cerebellum and visual cortexsupported
PET study in 6 baboons: brain uptake peak at 40 s, brain half-life ~8 min. Highest concentration in cerebellum and visual cortex. j.neuroimage.2008.03.003
The brain half-life is approximately 8 minutes, consistent with the clinically observed 5–20 minute duration of peak effectssupported
brain uptake peak at 40 s, brain half-life ~8 min. j.neuroimage.2008.03.003
Hooker and colleagues estimated that psychoactive effects may occur at brain concentrations below 10 μg, underscoring the compound's exceptional potency.supported
Effects may occur at <10 µg in human brain. j.neuroimage.2008.03.003
Johnson and colleagues established the first direct positive correlation between plasma salvinorin A levels and subjective drug effect ratings in humans, confirming that the temporal profile of effects tracks plasma pharmacokinetics rather than downstream receptor processes.supported
Drug levels significantly correlated with drug effect ratings. 0269881116629125
Plasma elimination half-life in nonhuman primates following intravenous administration is 56.6 ± 24.8 minutes overall, with a sex difference: males 37.9 ± 5.6 minutes, females 80.0 ± 13.1 minutes.supported
Elimination t(1/2) = 56.6±24.8 min (males: 37.9 min, females: 80.0 min). pmid:16138318
Claim in pharmacology — inconclusiveinconclusiveworking →
Béguin and colleagues confirmed that a dose active via intraperitoneal injection (2.0 mg/kg in rodents) is completely inactive when given orally, consistent with rapid enzymatic degradation in the gastrointestinal tract.supported
IP 2.0 mg/kg active; same oral dose inactive (poor oral bioavailability due to acetate metabolism). pmid:17951511
The primary metabolic pathway is esterase-mediated hydrolysis of the C-2 acetate ester, producing salvinorin B — the des-acetyl compound with markedly reduced KOR binding affinitysupported
poor oral bioavailability due to acetate metabolism. Confirms rapid metabolic inactivation. pmid:17951511
Salvinorin A is the least stable compound in liver microsomal assays among tested salvinorin analogssupported
SalA Ki=0.11-6.3 nM for KOR; least stable in liver microsomal assay. pmid:17951511
Claim in pharmacology — inconclusiveinconclusiveworking →
Excretion occurs via both renal and biliary routes.supported
Metabolism via renal and biliary systems. j.neuroimage.2008.03.003
summary9 · 3 ok
Claim in summary — inconclusiveinconclusiveworking →
Salvinorin A occupies a singular position in psychopharmacology as the first naturally occurring non-nitrogenous psychoactive compound demonstrated to act through opioid receptor mechanismssupported
Salvinorin A thus represents, to our knowledge, the first naturally occurring nonnitrogenous opioid-receptor subtype-selective agonist. pmid:12192085
Claim in summary — inconclusiveinconclusiveworking →
Claim in summary — inconclusiveinconclusiveworking →
Claim in summary — inconclusiveinconclusiveworking →
It shows no activity at the 5-HT₂A serotonin receptor — a finding confirmed in humans by the failure of ketanserin to block its effects, while naltrexone abolishes them completelysupported
Assessment of KOR and 5-HT2A agonism in the subjective, cardiovascular, and neuroendocrine effects of salvinorin-A in humans. pyw016
Claim in summary — inconclusiveinconclusiveworking →
Claim in summary — inconclusiveinconclusiveworking →
Principal risks are psychological: dysphoria, confusion, and rare case reports of psychotic episodes following usesupported
Literature review and two original case reports; hypothesizes that S. divinorum could be associated with psychotic disorders. 02791072.2015.1073815
chemistry6 · 1 ok
Claim in chemistry — inconclusiveinconclusiveworking →
Claim in chemistry — inconclusiveinconclusiveworking →
More recently, Puls and colleagues used salvinorin A-based virtual screening to discover novel, non-basic KOR agonists with G-protein-biased signaling profiles.supported
Structure-based virtual screening using 3D pharmacophore from SalA binding mode. Novel nonbasic KOR agonists identified with G-protein-biased activity. acs.jmedchem.4c00590
Claim in chemistry — inconclusiveinconclusiveworking →
Claim in chemistry — inconclusiveinconclusiveworking →
Claim in chemistry — inconclusiveinconclusiveworking →
history6 · 4 ok
Claim in history — inconclusiveinconclusiveworking →
José Luis Díaz, conducting ethnopharmacological field research between 1973 and 1983, documented the effects of the traditional water preparation as qualitatively milder than smoked extracts — producing light-headedness, dysphoria, tactile and proprioceptive sensations, depersonalization, amplified sound perception, and increased visual and auditory imagery, distinguished from frank hallucinationssupported
Traditional Mazatec beliefs, ritual uses, and mental effects of Salvia divinorum from 1973-1983 field research. Water potion of crushed leaves produced short-lasting light-headedness, dysphoria, tactile and proprioceptive sensations, depersonalization, amplified sound perception. pmid:23627785
In 2002, Bryan Roth and colleagues at Case Western Reserve University published the landmark paper in Proceedings of the National Academy of Sciences identifying the kappa-opioid receptor (KOR) as salvinorin A's principal molecular targetsupported
We discovered that Salvinorin A potently and selectively inhibited (3)H-bremazocine binding to cloned kappa opioid receptors. pmid:12192085
Schmidt and colleagues established nonhuman primate pharmacokinetics in 2005, and Hooker and colleagues used PET imaging in baboons to demonstrate the rapid brain uptake (peak at 40 seconds) and short cerebral residence time (~8 minutes) that explain the compound's brief duration of action.supported
PET study in 6 baboons: brain uptake peak at 40 s, brain half-life ~8 min. j.neuroimage.2008.03.003
Claim in history — inconclusiveinconclusiveworking →
Johnson and colleagues in 2016 established the first direct correlation between plasma salvinorin A levels and subjective drug effects in humans.supported
Drug levels significantly correlated with drug effect ratings. 0269881116629125
clinical-evidence4 · 3 ok
Claim in clinical-evidence — inconclusiveinconclusiveworking →
MacLean and colleagues conducted a systematic dose-response study documenting dissociative, hallucinogenic, and memory effects at multiple dose levels of inhaled salvinorin A in humanssupported
Salvinorin A is a kappa opioid agonist and the principal psychoactive constituent of the plant Salvia divinorum. Few human studies have examined salvinorin A. s00213-012-2912-9
Neuroprotection: Wu and colleagues demonstrated improved neurological outcomes following intranasal salvinorin A administration in a rhesus monkey ischemic stroke model using autologous blood clot. Dong and colleagues showed neuroprotective effects via AMPK/Mfn2-mediated preservation of endothelial mitochondrial function in rodent ischemia models.supported
Intranasal SA reduces infarct volume (3.9±0.7 vs 7.2±1.0 cm3, P=0.002) and improves neurological outcomes in rhesus monkey ischemic stroke model. 0271678x20938137
Anxiolytic/antidepressant: Braida and colleagues reported anxiolytic- and antidepressant-like effects in rodent behavioral models.supported
Investigated possible anxiolytic- and antidepressant-like effects of kappa-opioid receptor agonist salvinorin A, the main active ingredient of Salvia divinorum, in rats and mice. j.1476-5381.2009.00230.x
neuroscience4 · 4 ok
Doss and colleagues published the first human fMRI study of inhaled salvinorin A using a placebo-controlled, within-subject designsupported
Placebo-controlled within-subject fMRI study. SA tended to decrease within-network sFC but increase between-network sFC. s41598-020-73216-8
The compound's rapid uptake (peak at 40 seconds) and short cerebral residence time (~8 minutes) are explained by a combination of rapid esterase metabolism and active P-glycoprotein efflux from the blood-brain barrier.partially supported
PET study in 6 baboons: brain uptake peak at 40 s, brain half-life ~8 min. Highest concentration in cerebellum and visual cortex. Metabolism via renal and biliary systems. j.neuroimage.2008.03.003
Salvinorin A suppresses dopaminergic transmission in the mesolimbic pathway through KOR activation, reducing dopamine release in the nucleus accumbenssupported
mesolimbic dopaminergic suppression, fragmentation of large-scale brain networks. biomedicines14020476
What explains the convergent DMN effects across receptor classes? Both KOR agonism (salvinorin A) and 5-HT₂A agonism (psilocybin) produce DMN desynchronization, suggesting the DMN is a downstream convergence point for multiple hallucinogenic mechanisms. The circuit-level architecture of this convergence is unknown.supported
both psilocybin and Salvinorin-A caused acute desynchronization of DMN. SalA: thalamo-cortical networks differ from psilocybin (dependent on 5-HT2AR). acschemneuro.4c00245
pharmacokinetic-detail4 · 2 ok
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
Oral administration is similarly ineffective: a dose of 2.0 mg/kg active via intraperitoneal injection in rodents produces no measurable effect when given orally.supported
IP 2.0 mg/kg active; same oral dose inactive (poor oral bioavailability due to acetate metabolism). pmid:17951511
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
Johnson and colleagues demonstrated the first direct positive correlation between plasma salvinorin A concentrations and subjective drug effect ratings in humans following inhaled administration at doses of 18–21 μg/kgsupported
Six healthy adults inhaled a single high dose of vaporized salvinorin A (21 mcg/kg or 18 mcg/kg). Drug levels peaked at 2 min and rapidly decreased. Drug levels significantly correlated with drug effect ratings. 0269881116629125
receptor-pharmacology3 · 2 ok
Claim in receptor-pharmacology — inconclusiveinconclusiveworking →
Salvinorin A exhibits β-arrestin-biased signaling at the KOR — preferentially recruiting β-arrestin-2 relative to G-protein activation compared to some endogenous and synthetic KOR ligandssupported
21 KOR ligands tested in parallel for G-protein and beta-arrestin recruitment. Salvinorin A included... Quantified ligand bias. acschemneuro.9b00195
Puls and Wolber elucidated the binding mode of salvinorin A at the active-state KOR through molecular dynamics simulations and docking studiessupported
Determined binding mode of SalA to active state KOR. SalA binds above morphinan binding site; furan points toward intracellular core. molecules28020718
alkaloid-profile2 · 1 ok
It is a neoclerodane diterpene — a terpenoid natural product containing no nitrogen atomsupported
whose main active ingredient is the neoclerodane diterpene Salvinorin A... the first naturally occurring nonnitrogenous opioid-receptor subtype-selective agonist. pmid:12192085
Claim in alkaloid-profile — inconclusiveinconclusiveworking →
comparative-pharmacology2 · 1 ok
The pharmacological antagonism data from Maqueda and colleagues is decisive: ketanserin (5-HT₂A blocker) had no effect on salvinorin A's actions, while naltrexone (opioid antagonist) abolished them completelysupported
Assessment of KOR and 5-HT2A agonism in the subjective, cardiovascular, and neuroendocrine effects of salvinorin-A in humans. pyw016
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
botanical-overview1 · 0 ok
Claim in botanical-overview — inconclusiveinconclusiveworking →
legal-status1 · 0 ok
Claim in legal-status — inconclusiveinconclusiveworking →