Ketamine

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psx:substance/ketamine/claim/ea965cb1-8d9a-4e34-85ad-65d4785dbc2a

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derived from · upstream

usedAttenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonismpsx:substance/ketamine/src/doi:10.1176/appi.ajp.2018.18020138

feeds · downstream

informed_bysection/neuroscience.full@1psx:substance/ketamine/section/neuroscience.full@1

psx:substance/ketamine/claim/ea965cb1-8d9a-4e34-85ad-65d4785dbc2a
├─ used  src/doi:10.1176/appi.ajp.2018.18020138  Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism
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    ├─ used  src/doi:10.1097/eja.0000000000000638  History of anaesthesia [Ketamine history editorial]
    ├─ used  src/pmid:16894061  A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression
    ├─ used  src/doi:10.1111/cts.70527  Esketamine Nasal Spray: Mechanism of Action, Clinical, and Translational Science
    ├─ used  src/doi:10.1016/j.neuropharm.2015.07.037  Antidepressant-like effects of ketamine, norketamine and dehydronorketamine in forced swim test: Role of activity at NMDA receptor
    ├─ used  src/pmid:9311667  Norketamine, the main metabolite of ketamine, is a non-competitive NMDA receptor antagonist in the rat cortex and spinal cord
    ├─ used  src/pmid:15852061  Dopamine receptor contribution to the action of PCP, LSD and ketamine psychotomimetics
    ├─ used  src/pmid:8835358  Interaction of the chiral forms of ketamine with opioid, phencyclidine, sigma and muscarinic receptors
    ├─ used  src/doi:10.1126/science.1190287  mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists
    ├─ used  src/doi:10.1038/nature17998  NMDAR inhibition-independent antidepressant actions of ketamine metabolites
    ├─ used  src/doi:10.1080/15563650.2023.2212125  The clinical toxicology of ketamine
    ├─ used  src/doi:10.1002/nau.24341  What urologists need to know about ketamine-induced uropathy: A systematic review
    ├─ used  src/doi:10.1111/adb.12004  Chronic ketamine exposure induces permanent impairment of brain functions in adolescent cynomolgus monkeys
    ├─ used  src/doi:10.1159/000506868  Acute and Persistent Withdrawal Syndromes Following Discontinuation of Psychotropic Medications
    ├─ used  src/doi:10.1111/cns.12099  Ketamine Pharmacology: An Update (Pharmacodynamics and Molecular Aspects, Recent Findings)
    ├─ used  src/pmid:10686270  Antidepressant effects of ketamine in depressed patients
    ├─ used  src/doi:10.1007/s40262-016-0383-6  Ketamine: A Review of Clinical Pharmacokinetics and Pharmacodynamics in Anesthesia and Pain Therapy
    ├─ used  src/doi:10.1523/jneurosci.17-08-02921.1997  Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions
    ├─ used  src/doi:10.1126/science.1222939  Synaptic Dysfunction in Depression: Potential Therapeutic Targets
    ├─ used  src/doi:10.1017/S1461145713001119
    ├─ used  src/doi:10.1016/j.neuropharm.2021.108936  CYP 450 enzymes influence (R,S)-ketamine brain delivery and its antidepressant activity
    ├─ used  src/doi:10.1097/ALN.0000000000003829
    ├─ used  src/doi:10.1111/j.1742-7843.2012.00908.x  Rifampicin has a profound effect on the pharmacokinetics of oral S-ketamine and less on intravenous S-ketamine
    ├─ used  src/doi:10.3389/fpain.2022.946486  S-Ketamine Oral Thin Film-Part 1: Population Pharmacokinetics
    ├─ used  src/doi:10.1016/j.euroneuro.2011.08.002  Evaluation of sigma receptors in the antidepressant-like effects of ketamine in vitro and in vivo
    ├─ used  src/doi:10.1038/s41467-020-18167-4  Disruption of Cav1.2-mediated signaling is a pathway for ketamine-induced pathology
    ├─ used  src/doi:10.1016/j.ejphar.2012.11.023  Sub-anesthetic concentrations of (R,S)-ketamine metabolites inhibit acetylcholine-evoked currents in α7 nicotinic acetylcholine receptors
    ├─ used  src/doi:10.1016/j.bcp.2021.114892  Mechanisms of ketamine and its metabolites as antidepressants
    ├─ used  src/doi:10.1007/s00228-015-1826-y  Population pharmacokinetics of S-ketamine and norketamine in healthy volunteers after intravenous and oral dosing
    ├─ used  src/doi:10.1111/add.15154  Characteristics and circumstances of death related to the self-administration of ketamine
    ├─ used  src/doi:10.1176/appi.ajp.2013.13030392  Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial
    ├─ used  src/doi:10.1093/ijnp/pyae058  Real-World Safety of Esketamine Nasal Spray: A Comprehensive Analysis of Esketamine and Respiratory Depression
    ├─ used  src/doi:10.1016/j.pain.2011.03.026  Drug-induced liver injury following a repeated course of ketamine treatment for chronic pain in CRPS type 1 patients: a report of 3 cases
    ├─ used  src/doi:10.1016/j.biopsych.2008.10.045  Is persistent ketamine use a valid model of the cognitive and oculomotor deficits in schizophrenia?
    ├─ used  src/pmid:14987429  Postmortem blood ketamine distribution in two fatalities
    ├─ used  src/doi:10.52965/001c.38247  Ketamine-Induced Cystitis: A Comprehensive Review of the Urologic Effects of This Psychoactive Drug
    ├─ used  src/doi:10.1111/iju.12841  Possible pathophysiology of ketamine-related cystitis and associated treatment strategies
    ├─ used  src/doi:10.1016/j.ajpath.2015.12.014  Ketamine-Induced Apoptosis in Normal Human Urothelial Cells: A Direct, N-Methyl-d-Aspartate Receptor-Independent Pathway Characterized by Mitochondrial Stress
    ├─ used  src/doi:10.3390/ijms23094666  Norketamine, the Main Metabolite of Ketamine, Induces Mitochondria-Dependent and ER Stress-Triggered Apoptotic Death in Urothelial Cells
    ├─ used  src/doi:10.1097/ADM.0b013e3182399216
    ├─ used  src/doi:10.7759/cureus.99972  Ketamine-Induced Cholangiopathy With Concomitant Hemorrhagic Cystitis
    ├─ used  src/doi:10.1155/2024/8366034  A Case of Hepatotoxicity Induced by Therapeutic Ketamine Use for Sedation
    ├─ used  src/doi:10.7759/cureus.84974  Hepatobiliary Complications Associated With Ketamine Use: Clinical Insights and Future Directions
    ├─ used  src/doi:10.1016/j.schres.2018.02.049  Similar psychotic and cognitive profile between ketamine dependence with persistent psychosis and schizophrenia
    ├─ used  src/doi:10.1007/s00213-019-05342-9  Chronic ketamine abuse is associated with orexin-A reduction and ACTH elevation
    ├─ used  src/pmid:11557159  Effects of ketamine in normal and schizophrenic volunteers
    ├─ used  src/doi:10.1186/1747-597X-9-39
    ├─ used  src/doi:10.3389/fnhum.2016.00612  Ketamine: 50 Years of Modulating the Mind
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      ├─ used  claim/dea2cb21-bc41-4bd6-bdc7-9f89041f910b  Claim in safety — inconclusive  working
      ├─ used  claim/e0ffc6ed-7647-4b28-b648-19a03a2d03e2  Claim in pharmacokinetic-detail — inconclusive  working
      ├─ used  claim/58c87299-7cba-45f5-ba27-2e5232a10a5e  Claim in pharmacology — inconclusive  working
      ├─ used  claim/d8682999-b718-48cd-840f-9b8a46881536  Claim in safety — inconclusive  working
      ├─ used  claim/1111d1da-ef31-4a15-a44d-b2dd674753d9  Claim in pharmacokinetic-detail — inconclusive  working
      ├─ used  claim/d21a1043-1b68-4bda-82bb-e33cf75d8941  Claim in pharmacology — inconclusive  working
      ├─ used  claim/67c972e2-4786-46be-ab4c-4ddaa026ae2f  Claim in pharmacokinetic-detail — inconclusive  working
      ├─ used  claim/4fe51abf-06e1-40ee-849a-6536a8aef93a  Claim in pharmacology — inconclusive  working
      ├─ used  claim/7d2d99da-9fad-4665-bd2f-857559338be4  Claim in pharmacokinetic-detail — inconclusive  working
      ├─ used  claim/96e5d1d7-e4a2-4343-b33a-63cf92afd990  Claim in receptor-pharmacology — inconclusive  working
      ├─ used  claim/afadcede-6c7f-45b0-9924-2723d2df263a  Claim in receptor-pharmacology — supported
      ├─ used  claim/909e67aa-ca77-4b95-9aee-fb06dae9117e  Claim in safety — inconclusive  working
      ├─ used  claim/73c2825a-26d1-464d-b6e7-43e9e00b110f  Claim in receptor-pharmacology — inconclusive  working
      └─ used  claim/332909da-c5db-40bd-ac21-eac08c5f1a99  Claim in safety — inconclusive  working
… closure truncated at 200 nodes

indented by distance from this node, not by parentage

1Provenance card

the boundary, as counts

Sources

4942 with DOI

23 strong · 21 moderate · 5 weak

Compilations

22026-04-20T09:52:08.318Z

pipeline-v5 · prompt hash not recorded — run predates 2026-09 · 1 other run

Decisions

62last ruled 2026-06-04

0 awaiting a ruling

Issued documents

42026-10-19T20:32:25.864Z

notice · info card · emergency

Searches

250 with no results

queries and counts on the build

Claims checked

19923 supported

23 supported · 176 not

Correspondence

0received

consent field ships in Phase 4

Edges

545

derivations recorded for this entity

Complete over 49 sources, 2 compilations, and 62 decisions.Not here: the private journal (never).Working material — drafts, discards, unsupported claims — is listed below and readable on the working page.Cite: psychedex.org/substances/ketamine/archive

2Build

one panel per compilation run

generation run 2026-04-20

5 min failedmodel not recordedplan not recordedrun/5abad3f7…

research

no artifact

draft

no artifact

audit

no artifact

verify

no artifact

simplify

no artifact

publish

no artifact

Selection

results seen0

selected by the model0

consumed as sources48

Verification

claims checked0

supported0

partially supported0

not supported0

inconclusive0

record
seen / partial
working

The model's own caveats

none raised on this run

Reproduce

inputs: 48 source keys (listed under Sources)
plan: not recorded — template version, prompt hash and git SHA are written from 2026-09 onward
model: not recorded
streams: none — agent transcripts are persisted from 2026-09 onward

generation run 2026-04-20

74 min completedmodel pipeline-v5plan not recordedrun/1356ee66…

Selection

results seen120

selected by the model52

consumed as sources48

Verification

claims checked199

supported23

partially supported0

not supported1

inconclusive175

record
seen / partial
working

The model's own caveats

taper_silent

Reproduce

inputs: 48 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

25 searches — query, source, results, what was kept and why

25 searches for this run
#	source	query	seen	kept	rationale
1	OpenAlex	ketamine mechanism action NMDA receptor antagonist pharmacology	10	2	Moghaddam 1997 is landmark for glutamate-NMDA-PFC mechanism; Traynelis 2010 is definitive NMDA receptor structure review
2	OpenAlex	ketamine antidepressant treatment-resistant depression rapid	8	3	The three landmark ketamine antidepressant papers - essential for clinical history and mechanism
3	ClinicalTrials.gov	ketamine treatment depression PTSD	10	4	Completed and recruiting RCTs directly relevant to ketamine clinical use
4	PubMed	ketamine bladder uropathy cystitis toxicity	10	5	Primary and review papers on ketamine uropathy - chronic toxicity section
5	PubMed	ketamine NMDA receptor binding affinity Ki mechanism of action	10	5	Direct Ki binding affinity data for ketamine and metabolites at NMDA, D2 receptors
6	PubChem	ketamine	1	1	Primary chemical identity record confirming formula, weight, InChIKey absent from brief
7	PubMed	ketamine antidepressant rapid treatment-resistant depression clinical trial	10	2	Esketamine PK/PD review (2026), EQUIVALENCE trial protocol comparing IV ketamine vs IN esketamine
8	OpenAlex	ketamine discovery synthesis history Parke-Davis CI-581	5	1	Most comprehensive history of ketamine synthesis and clinical development
9	PubMed	ketamine oral bioavailability norketamine metabolism	10	6	Comprehensive PK data across routes of administration
10	PubMed	ketamine opioid receptor sigma receptor binding chiral	8	2	Opioid and sigma receptor binding data for pharmacological class verification
11	PubMed	ketamine fatal overdose death toxicology	5	2	Fatal overdose data confirming brief's toxicity values
12	PubMed	ketamine neurotoxicity cognitive impairment chronic use	2	1	Primate neurotoxicity data for safety section
13	PubMed	Berman 2000 ketamine antidepressant first RCT	1	1	Foundational first RCT of ketamine in depression
14	PsychonautWiki	—	1	—	Cross-referencing dose data against brief seed values; flags oral threshold discrepancy
15	Crossref/DOI	10.1038/nature17998	1	1	DOI verification confirms journal and authorship
16	PubMed	Zanos 2016 Nature hydroxynorketamine NMDAR-independent	1	1	Landmark 2016 Nature paper on HNK mechanism with 1572 citations
17	PubMed	ketamine cognitive memory users psychomotor	2	2	Cognitive impairment evidence for chronic neurotoxicity section
18	PubMed	ketamine liver toxicity case	10	5	Critical hepatobiliary toxicity evidence for chronic toxicity section
19	PubChem REST API	CID 3821 SMILES InChIKey properties	1	1	SMILES was missing from brief; confirmed via PubChem REST API
20	OpenAlex	ketamine urinary tract uropathy bladder contracted lower urinary symptoms	5	3	Uropathy mechanism (Cav1.2), first report citation, comprehensive cystitis review
21	PubMed	Shahani ketamine cystitis ulcerative 2007	1	1	Confirms Shahani 2007 first case report; indirect citation via Chen 2011
22	PubMed	esketamine nasal spray SPRAVATO FDA approval depression	2	1	Post-marketing safety data for esketamine FDA approval
23	PubMed	Murrough ketamine midazolam randomized antidepressant 2013	2	1	Landmark RCT comparing ketamine to active control (midazolam) in TRD
24	Multiple web/regulatory sources	ketamine DEA schedule UK class UN convention	3	0	Legal status established from Mion 2017 history paper and secondary regulatory knowledge
25	PubMed	PMID 27028535	1	1	Definitive PK review paper confirming metabolism pathways and bioavailability

199 claims by section — every cited sentence, checked against its source

safety70 · 6 ok

Claim in safety — inconclusiveinconclusiveworking →
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Unlike virtually all other general anaesthetics, it preserves upper airway reflexes and spontaneous respiration at anaesthetic concentrations, and produces sympathomimetic-mediated cardiovascular stimulation (increased heart rate and blood pressure) rather than depression.supported
Clinical toxicology review of ketamine: pharmacological mechanisms, toxic dose ranges, clinical presentations, management. 15563650.2023.2212125
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
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Direct urothelial apoptosis via nmda-receptor-independent Ca²⁺/mitochondrial pathwaysupported
Ketamine causes direct urothelial cytotoxicity via mitochondrial stress pathway independent of NMDA receptors. P2Y receptor activation and calcium mobilization implicated in bladder toxicity. j.ajpath.2015.12.014
Claim in safety — inconclusiveinconclusiveworking →
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Lahti et al. (2001) demonstrated dose-related increases in BPRS psychosis and withdrawal subscales in healthy volunteers at 0.1–0.5 mg/kg IV, with effects resolving within 30 minutessupported
Ketamine produces schizophrenia-like psychotic symptoms in both healthy volunteers and schizophrenic patients; foundational study for NMDA antagonist psychotomimetic effects. pmid:11557159
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Opioid receptor engagement may provide an additional reinforcement component.supported
Ketamine produces opioid system activation in addition to NMDA antagonism. appi.ajp.2018.18020138
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
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Claim in safety — inconclusiveinconclusiveworking →
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Uncontrolled hypertension / severe cardiovascular disease: Ketamine's sympathomimetic effects (increased HR, BP) produce additive cardiovascular stresssupported
Clinical toxicology review of ketamine: pharmacological mechanisms, toxic dose ranges, clinical presentations, management. 15563650.2023.2212125
History of psychosis or schizophrenia: Ketamine exacerbates positive symptoms in schizophrenic patients; 70% experienced symptom worsening in controlled studiessupported
Ketamine produces schizophrenia-like psychotic symptoms in both healthy volunteers and schizophrenic patients; foundational study for NMDA antagonist psychotomimetic effects. pmid:11557159
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →

pharmacology33 · 4 ok

Claim in pharmacology — inconclusiveinconclusiveworking →
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At subanesthetic concentrations, NMDA blockade on GABAergic interneurons produces paradoxical disinhibition of glutamate release, increasing prefrontal-cortex glutamate outflow and downstream dopamine release via ampa-receptor/kainate receptor stimulationsupported
Low doses of ketamine increase glutamate outflow in PFC; AMPA/kainate receptor antagonism blocks ketamine-induced dopamine release and cognitive impairment. jneurosci.17-08-02921.1997
Claim in pharmacology — inconclusiveinconclusiveworking →
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pharmacological/opioid-system activation is required for the acute antidepressant effect: pretreatment with naltrexone abolishes ketamine's antidepressant response without affecting dissociative propertiessupported
Naltrexone pretreatment blocked antidepressant but not dissociative effects of ketamine. Suggests opioid system activation required for ketamine's antidepressant effect. appi.ajp.2018.18020138
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
Primary hepatic metabolism via cyp3a4 and CYP2B6 produces N-demethylation to norketaminesupported
Metabolism via CYP3A and CYP2B6 to norketamine. s40262-016-0383-6
Primary hepatic metabolism via cyp3a4 and CYP2B6 produces N-demethylation to norketaminesupported
N-demethylation by CYP3A4, CYP2B6, CYP2C9 to norketamine. j.neuropharm.2021.108936
Claim in pharmacology — inconclusiveinconclusiveworking →
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summary30 · 5 ok

Claim in summary — inconclusiveinconclusiveworking →
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The primary mechanism is noncompetitive, use-dependent blockade of the nmda-receptor ion channel pore (racemic-mixture Ki = 119 nM; S-ketamine Ki = 0.3 µM, approximately 4–5× more potent than the R-enantiomer)supported
S-ketamine Ki 0.3 uM, R-ketamine Ki 1.4 uM at NMDA receptor. S-enantiomer ~5x more potent than R at NMDA receptor. pmid:9311667
Claim in summary — inconclusiveinconclusiveworking →
Secondary targets include the dopamine D2High receptor (Ki = 55 nM), mu and kappa opioid receptors, and sigma receptors — all at micromolar affinitiessupported
Ketamine receptor binding: highest affinity at PCP site. Mu/kappa opioid and sigma receptor binding. pmid:8835358
Claim in summary — inconclusiveinconclusiveworking →
Claim in summary — inconclusiveinconclusiveworking →
The antidepressant mechanism involves convergent NMDA blockade-induced synaptogenesis via mTOR and ampa-receptor activation by the (2R,6R)-hydroxynorketamine metabolite, with opioid system engagement required for acute antidepressant response.supported
Naltrexone pretreatment blocked antidepressant but not dissociative effects of ketamine. Suggests opioid system activation required for ketamine's antidepressant effect. appi.ajp.2018.18020138
Acute toxicity is low relative to other anesthetics — ketamine preserves airway reflexes and respiratory drive, and sole-agent fatality is raresupported
Clinical toxicology review of ketamine: pharmacological mechanisms, toxic dose ranges, clinical presentations, management. 15563650.2023.2212125
Chronic toxicity is high: ketamine-induced uropathy (ulcerative cystitis progressing to contracted bladder) is well-documented in regular users, with hepatobiliary damage and prefrontal neurocognitive impairment as additional chronic sequelae. tolerance develops gradually through NMDA receptor upregulation and glutamatergic compensation, with cross-tolerance to other dissociative NMDA antagonists. Psychological dependence liability is high, driven by D2High agonism activating mesolimbic reward circuits and short duration encouraging compulsive redosingsupported
Systematic review of ketamine-induced uropathy (KIU) in recreational users: clinical presentation, pathophysiology, and treatment. nau.24341
Claim in summary — inconclusiveinconclusiveworking →
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receptor-pharmacology16 · 3 ok

Claim in receptor-pharmacology — inconclusiveinconclusiveworking →
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The S-enantiomer exhibits approximately 4–5× greater potency than the R-enantiomer at NMDA receptors, consistent with its greater clinical potencysupported
S-ketamine Ki 0.3 uM, R-ketamine Ki 1.4 uM at NMDA receptor. S-enantiomer ~5x more potent than R at NMDA receptor. pmid:9311667
Claim in receptor-pharmacology — inconclusiveinconclusiveworking →
While these affinities are 10–100× weaker than classical opioids, clinical significance has been established: pretreatment with the opioid antagonist naltrexone abolishes ketamine's acute antidepressant effect in treatment-resistant depression without affecting dissociative properties.supported
Naltrexone pretreatment blocked antidepressant but not dissociative effects of ketamine. Suggests opioid system activation required for ketamine's antidepressant effect. appi.ajp.2018.18020138
However, the antidepressant-like effect in forced swim test is not attenuated by sigma antagonists, indicating the in vivo antidepressant mechanism does not primarily depend on sigma receptor activation.supported
Antidepressant effects in forced swim test not attenuated by sigma antagonists NE-100 or BD1047. j.euroneuro.2011.08.002
Claim in receptor-pharmacology — inconclusiveinconclusiveworking →
Claim in receptor-pharmacology — inconclusiveinconclusiveworking →
Claim in receptor-pharmacology — not_supportednot supportedworking →
Claim in receptor-pharmacology — inconclusiveinconclusiveworking →

neuroscience12 · 2 ok

Claim in neuroscience — inconclusiveinconclusiveworking →
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This hypothesis explains sustained effects beyond ketamine's pharmacokinetic window but is partially challenged by the Williams et al. (2018) finding that opioid antagonism blocks the acute antidepressant response — HNK does not engage opioid receptors.supported
Naltrexone pretreatment blocked antidepressant but not dissociative effects of ketamine. appi.ajp.2018.18020138
This suggests opioid receptor activation (at micromolar ketamine concentrations) is required for the antidepressant mechanism — potentially through endogenous opioid release secondary to NMDA blockade, or direct ketamine-opioid receptor binding.supported
Ketamine receptor binding: highest affinity at PCP site. Mu/kappa opioid and sigma receptor binding. pmid:8835358

history10 · 0 ok

Claim in history — inconclusiveinconclusiveworking →
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pharmacokinetic-detail10 · 2 ok

Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
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Data derived from clinical pharmacokinetic reviews and population PK modelling.supported
Comprehensive review of ketamine PK/PD. Metabolism via CYP3A and CYP2B6 to norketamine. Oral bioavailability poor due to first-pass metabolism. Nasal administration: rapid Tmax, relatively high bioavailability. s40262-016-0383-6
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
Primary metabolizing enzymes: cyp3a4 and CYP2B6.supported
Metabolism via CYP3A and CYP2B6 to norketamine. s40262-016-0383-6
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →

clinical-evidence8 · 0 ok

Claim in clinical-evidence — inconclusiveinconclusiveworking →
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comparative-pharmacology4 · 1 ok

Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
Source: Ebert et al. (1997) and Peltoniemi et al. (2016).supported
S-ketamine Ki 0.3 uM, R-ketamine Ki 1.4 uM at NMDA receptor. S-norketamine Ki 1.7 uM; R-norketamine 13 uM. pmid:9311667
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →

legal-status4 · 0 ok

Claim in legal-status — inconclusiveinconclusiveworking →
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chemistry2 · 0 ok

Claim in chemistry — inconclusiveinconclusiveworking →
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Other runs

brief run2026-09-27completed3 minrun/668e75ad…

3Sources

48 consumed · sorted by year · feeds = sections resting on it

Sources 1 to 30
year	source	tier	status	feeds
2026	Esketamine Nasal Spray: Mechanism of Action, Clinical, and Translational Sciencevan Hoogdalem MW, Fu DJ, Drevets WC, Zannikos PN · Clinical and Translational Sciencedoi:10.1111/cts.70527	strong	consumed	1 section
2025	Hepatobiliary Complications Associated With Ketamine Use: Clinical Insights and Future DirectionsWaheed HW, Ashraf MR, Sajjad T, et al. · Cureusdoi:10.7759/cureus.84974	strong	consumed	1 section
2025	Ketamine-Induced Cholangiopathy With Concomitant Hemorrhagic CystitisNazir K, Ahmed W, Rafi S, Ahmad A, Khaleeq A · Cureusdoi:10.7759/cureus.99972	weak	consumed	1 section
2024	A Case of Hepatotoxicity Induced by Therapeutic Ketamine Use for SedationYoo N, Thomas S, Bender M, Cheng XJC · Case Reports in Critical Caredoi:10.1155/2024/8366034	weak	consumed	1 section
2024	Real-World Safety of Esketamine Nasal Spray: A Comprehensive Analysis of Esketamine and Respiratory DepressionChepke C, Shelton R, Sanacora G, et al. · International Journal of Neuropsychopharmacologydoi:10.1093/ijnp/pyae058	moderate	consumed	1 section
2023	The clinical toxicology of ketamineSchep LJ, Slaughter RJ, Watts M, Mackenzie E, Gee P · Clinical Toxicologydoi:10.1080/15563650.2023.2212125	strong	consumed	2 sections
2022	CYP 450 enzymes influence (R,S)-ketamine brain delivery and its antidepressant activityNguyen TML, McGowan JC, Gardier AM · Neuropharmacologydoi:10.1016/j.neuropharm.2021.108936	strong	consumed	1 section
2022	Ketamine-Induced Cystitis: A Comprehensive Review of the Urologic Effects of This Psychoactive DrugAnderson DJ, Zhou J, Cao DY, McDonald M, Guenther M · Health Psychology Researchdoi:10.52965/001c.38247	strong	consumed	1 section
2022	Mechanisms of ketamine and its metabolites as antidepressantsHess EM, Riggs LM, Michaelides M, Gould TD · Biochemical Pharmacologydoi:10.1016/j.bcp.2021.114892	strong	consumed	1 section
2022	Norketamine, the Main Metabolite of Ketamine, Induces Mitochondria-Dependent and ER Stress-Triggered Apoptotic Death in Urothelial CellsLin JW, Lin YC, Liu JM, et al. · International Journal of Molecular Sciencesdoi:10.3390/ijms23094666	moderate	consumed	1 section
2022	S-Ketamine Oral Thin Film-Part 1: Population PharmacokineticsSimons P, Olofsen E, van Velzen M, et al. · Frontiers in Pain Researchdoi:10.3389/fpain.2022.946486	strong	consumed	2 sections
2021	Characteristics and circumstances of death related to the self-administration of ketamineDarke S, Duflou J, Farrell M, Peacock A, Lappin J · Addictiondoi:10.1111/add.15154	moderate	consumed	2 sections
2021	Chiral Pharmacokinetics and Metabolite Profile of Prolonged-release Ketamine Tablets in Healthy Human SubjectsHasan M, Modess C, Roustom T, et al. · Anesthesiologydoi:10.1097/aln.0000000000003829	strong	consumed	cited only
2020	Acute and Persistent Withdrawal Syndromes Following Discontinuation of Psychotropic MedicationsCosci F, Chouinard G · Psychotherapy and Psychosomaticsdoi:10.1159/000506868	strong	consumed	2 sections
2020	Chronic ketamine abuse is associated with orexin-A reduction and ACTH elevationHuang MC, Chen CH, Chen LY, Chang HM, Chen CK, Lin SK, Xu K · Psychopharmacologydoi:10.1007/s00213-019-05342-9	moderate	consumed	1 section
2020	Disruption of Cav1.2-mediated signaling is a pathway for ketamine-induced pathologyChen H, Vandorpe DH, Xie X, Alper SL, Zeidel ML · Nature Communicationsdoi:10.1038/s41467-020-18167-4	moderate	consumed	2 sections
2020	What urologists need to know about ketamine-induced uropathy: A systematic reviewCastellani D, Pirola GM, Gubbiotti M, Rubilotta E, Gudaru K, Gregori A, Dellabella M · Neurourology and Urodynamicsdoi:10.1002/nau.24341	strong	consumed	1 section
2018	Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor AntagonismWilliams NR, Heifets BD, Blasey C, Sudheimer K, Pannu J, et al. · American Journal of Psychiatrydoi:10.1176/appi.ajp.2018.18020138	strong	consumed	5 sections
2018	Similar psychotic and cognitive profile between ketamine dependence with persistent psychosis and schizophreniaCheng WJ, Chen CH, Chen CK, Huang MC, Pietrzak RH, Krystal JH, Xu K · Schizophrenia Researchdoi:10.1016/j.schres.2018.02.049	moderate	consumed	1 section
2017	History of anaesthesia [Ketamine history editorial]Mion G · European Journal of Anaesthesiologydoi:10.1097/eja.0000000000000638	moderate	consumed	3 sections
2016	Ketamine-Induced Apoptosis in Normal Human Urothelial Cells: A Direct, N-Methyl-d-Aspartate Receptor-Independent Pathway Characterized by Mitochondrial StressBaker SC, Shabir S, Georgopoulos NT, Southgate J · American Journal of Pathologydoi:10.1016/j.ajpath.2015.12.014	moderate	consumed	1 section
2016	Ketamine: 50 Years of Modulating the MindLi L, Vlisides PE · Frontiers in Human Neurosciencedoi:10.3389/fnhum.2016.00612	strong	consumed	1 section
2016	Ketamine: A Review of Clinical Pharmacokinetics and Pharmacodynamics in Anesthesia and Pain TherapyPeltoniemi MA, Hagelberg NM, Olkkola KT, Saari TI · Clinical Pharmacokineticsdoi:10.1007/s40262-016-0383-6	strong	consumed	4 sections
2016	NMDAR inhibition-independent antidepressant actions of ketamine metabolitesZanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, et al. · Naturedoi:10.1038/nature17998	moderate	consumed	3 sections
2015	Antidepressant-like effects of ketamine, norketamine and dehydronorketamine in forced swim test: Role of activity at NMDA receptorSalat K, Siwek A, Starowicz G, Librowski T, Nowak G, Drabik U, Gajdosz R, Popik P · Neuropharmacologydoi:10.1016/j.neuropharm.2015.07.037	moderate	consumed	2 sections
2015	Population pharmacokinetics of S-ketamine and norketamine in healthy volunteers after intravenous and oral dosingFanta S, Kinnunen M, Backman JT, Kalso E · European Journal of Clinical Pharmacologydoi:10.1007/s00228-015-1826-y	strong	consumed	cited only
2015	Possible pathophysiology of ketamine-related cystitis and associated treatment strategiesJhang JF, Hsu YH, Kuo HC · International Journal of Urologydoi:10.1111/iju.12841	strong	consumed	1 section
2014	Chronic ketamine exposure induces permanent impairment of brain functions in adolescent cynomolgus monkeysSun L, Li Q, Li Q, Zhang Y, Liu D, Jiang H, Pan F, Yew DT · Addiction Biologydoi:10.1111/adb.12004	moderate	consumed	2 sections
2014	Gender differences in subjective discontinuation symptoms associated with ketamine useChen WY, Huang MC, Lin SK · Substance Abuse Treatment, Prevention, and Policydoi:10.1186/1747-597x-9-39	moderate	consumed	cited only
2014	Plasma brain derived neurotrophic factor (BDNF) and response to ketamine in treatment-resistant depressionHaile CN, Murrough JW, Iosifescu DV, et al. · International Journal of Neuropsychopharmacologydoi:10.1017/s1461145713001119	strong	consumed	cited only

Show all 49 sources — 19 more

Sources 31 to 49
year	source	tier	status	feeds
2013	Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trialMurrough JW, Iosifescu DV, Chang LC, Al Jurdi RK, et al. · American Journal of Psychiatrydoi:10.1176/appi.ajp.2013.13030392	strong	consumed	1 section
2013	Ketamine Pharmacology: An Update (Pharmacodynamics and Molecular Aspects, Recent Findings)Mion G, Villevieille T · CNS Neuroscience & Therapeuticsdoi:10.1111/cns.12099	strong	consumed	4 sections
2013	Sub-anesthetic concentrations of (R,S)-ketamine metabolites inhibit acetylcholine-evoked currents in α7 nicotinic acetylcholine receptorsMoaddel R, Abdrakhmanova G, Kozak J, et al. · European Journal of Pharmacologydoi:10.1016/j.ejphar.2012.11.023	moderate	consumed	cited only
2012	Evaluation of sigma receptors in the antidepressant-like effects of ketamine in vitro and in vivoRobson MJ, Elliott M, Seminerio MJ, Matsumoto RR · European Neuropsychopharmacologydoi:10.1016/j.euroneuro.2011.08.002	moderate	consumed	1 section
2012	Ketamine-induced biliary dilatation: from Hong Kong to New YorkGutkin E, Hussain SA, Kim SH · Journal of Addiction Medicinedoi:10.1097/adm.0b013e3182399216	weak	consumed	cited only
2012	Rifampicin has a profound effect on the pharmacokinetics of oral S-ketamine and less on intravenous S-ketaminePeltoniemi MA, Saari TI, Hagelberg NM, Laine K, Kurkinen KJ, Neuvonen PJ, Olkkola KT · Basic & Clinical Pharmacology & Toxicologydoi:10.1111/j.1742-7843.2012.00908.x	strong	consumed	3 sections
2012	Synaptic Dysfunction in Depression: Potential Therapeutic TargetsDuman RS, Aghajanian GK · Sciencedoi:10.1126/science.1222939	strong	consumed	1 section
2011	Drug-induced liver injury following a repeated course of ketamine treatment for chronic pain in CRPS type 1 patients: a report of 3 casesNoppers IM, Niesters M, Aarts LPHJ, et al. · Paindoi:10.1016/j.pain.2011.03.026	weak	consumed	1 section
2010	mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA AntagonistsLi N, Lee B, Liu R, Banasr M, Dwyer JM · Sciencedoi:10.1126/science.1190287	moderate	consumed	3 sections
2009	Is persistent ketamine use a valid model of the cognitive and oculomotor deficits in schizophrenia?Morgan CJ, Huddy V, Lipton M, Curran HV, Joyce EM · Biological Psychiatrydoi:10.1016/j.biopsych.2008.10.045	moderate	consumed	1 section
2006	A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depressionZarate CA, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK · Archives of General Psychiatrypmid:16894061	strong	consumed	2 sections
2005	Dopamine receptor contribution to the action of PCP, LSD and ketamine psychotomimeticsSeeman P, Ko F, Tallerico T · Molecular Psychiatrypmid:15852061	moderate	consumed	3 sections
2004	Postmortem blood ketamine distribution in two fatalitiesLalonde BR, Wallage HR · Journal of Analytical Toxicologypmid:14987429	weak	consumed	1 section
2001	Effects of ketamine in normal and schizophrenic volunteersLahti AC, Weiler MA, Tamara Michaelidis BA, Parwani A, Tamminga CA · Neuropsychopharmacologypmid:11557159	moderate	consumed	1 section
2000	Antidepressant effects of ketamine in depressed patientsBerman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH · Biological Psychiatrypmid:10686270	strong	consumed	2 sections
1997	Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive DisruptionsMoghaddam B, Adams BW, Verma A, Daly D · Journal of Neurosciencedoi:10.1523/jneurosci.17-08-02921.1997	moderate	consumed	1 section
1997	Norketamine, the main metabolite of ketamine, is a non-competitive NMDA receptor antagonist in the rat cortex and spinal cordEbert B, Mikkelsen S, Thorkildsen C, Borgbjerg FM · European Journal of Pharmacologypmid:9311667	moderate	consumed	3 sections
1995	Interaction of the chiral forms of ketamine with opioid, phencyclidine, sigma and muscarinic receptorsHustveit O, Maurset A, Oye I · Pharmacology & Toxicologypmid:8835358	moderate	consumed	2 sections
—	Oral ketamine may offer a solution to the ketamine conundrumdoi:10.1007/s00213-023-06480-x	—	unknown	cited only

4Docket

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0012026-04-20revisionRevision 1
Initial LLM generation (v5 pipeline, wiki)
psx:substance/ketamine/version/1
0022026-06-04proposal59 value proposals approved together
one review action inferred from a shared reviewer and instant — the graph records one activity per proposal
59 items in this filing
- dose_tier · light
- dose_tier · common
- dose_tier · strong
- dose_tier · heavy
- timeline · insufflated · onset
- timeline · insufflated · come_up
- timeline · insufflated · peak
- timeline · insufflated · plateau
- timeline · insufflated · resolution
- timeline · insufflated · afterglow
- timeline · oral · onset
- timeline · oral · come_up
- timeline · oral · peak
- timeline · oral · plateau
- timeline · oral · resolution
- timeline · oral · afterglow
- timeline · intravenous · onset
- timeline · intravenous · come_up
- timeline · intravenous · peak
- timeline · intravenous · resolution
- timeline · intravenous · afterglow
- timeline · intramuscular · onset
- timeline · intramuscular · come_up
- timeline · intramuscular · peak
- timeline · intramuscular · resolution
- timeline · intramuscular · afterglow
- toxicity
- dependence · full
- withdrawal
- tolerance
- dosage · insufflated
- dosage · oral
- dosage · intramuscular
- dosage · intravenous
- duration · insufflated · onset
- duration · insufflated · peak
- duration · insufflated · total
- duration · insufflated · aftereffects
- duration · oral · onset
- duration · oral · peak
- duration · oral · total
- duration · oral · aftereffects
- duration · intravenous · onset
- duration · intravenous · peak
- duration · intravenous · total
- duration · intravenous · aftereffects
- duration · intramuscular · onset
- duration · intramuscular · peak
- duration · intramuscular · total
- duration · intramuscular · aftereffects
- contraindication · cardiovascular
- contraindication · cardiovascular
- contraindication · psychiatric
- contraindication · hepatic
- contraindication · renal
- contraindication · metabolic
- contraindication · pregnancy_breastfeeding
- contraindication · respiratory
psx:substance/ketamine/proposal/dose_tier/5ab91e04-b951-4f4c-bf1d-977d74c755f0
0032026-06-04publicationPublication — backfill
psx:substance/ketamine/pub/a0931234-20ba-45c5-b728-8f0241fd9b94
0042026-09-27revisionr1.a1
brief-overview retired 2026-09-30 (founder): Description reads the essential summary for every substance.
psx:substance/ketamine/version/2

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Issued documents
document	content hash	issued	from version	superseded
info_card	e8741dbb17a08074456d6848…	2026-10-19 20:32	Revision 1	current
emergency	ba304cf8bf8de5b4ec66cb2b…	2026-09-04 04:30	Revision 1	current
info_card	09f4d04a4998ad4289c5dd4a…	2026-09-04 04:30	Revision 1	superseded2026-10-19
notice	b144225354d4bad3733c1aa2…	2026-09-04 04:30	Revision 1	current

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