Nitrous

6Node page

what any key link opens

psx:substance/nitrous/value/dependence@1

valuereferenced by edges — no row of its own

derived from · upstream

derived_fromdependence · fullpsx:substance/nitrous/proposal/dependence/1bd7bc88-9288-4c2f-ac52-535cf53a5a59

feeds · downstream

none recorded

psx:substance/nitrous/value/dependence@1
└─ derived_from  proposal/dependence/1bd7bc88-9288-4c2f-ac52-535cf53a5a59  dependence · full

indented by distance from this node, not by parentage

1Provenance card

the boundary, as counts

Sources

5338 with DOI

14 strong · 32 moderate · 7 weak

Compilations

12026-04-26T01:48:12.419Z

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

Decisions

30last ruled 2026-06-04

0 awaiting a ruling

Issued documents

42026-10-19T20:33:21.481Z

notice · info card · emergency

Searches

221 with no results

queries and counts on the build

Claims checked

2730 supported

all 273 inconclusive — working grade

Correspondence

0received

consent field ships in Phase 4

Edges

664

derivations recorded for this entity

Complete over 53 sources, 1 compilation, and 30 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/nitrous/archive

2Build

one panel per compilation run

generation run 2026-04-26

63 min completedmodel pipeline-v5plan not recordedrun/b948ae40…

Selection

results seen122

selected by the model61

consumed as sources53

Verification

claims checked273

supported0

partially supported0

not supported0

inconclusive273

record
seen / partial
working

The model's own caveats

none raised on this run

Reproduce

inputs: 53 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

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

22 searches for this run
#	source	query	seen	kept	rationale
1	PubMed	nitrous oxide opioid system endogenous opioid analgesic	10	5	Opioid mechanism data essential for pharmacology section
2	PubMed	nitrous oxide toxicity adverse effects vitamin B12 myelopathy subacute combined degeneration	10	8	Critical safety/toxicity data
3	PubChem	nitrous oxide	1	1	Primary chemical identity source
4	PubMed	nitrous oxide antidepressant treatment-resistant depression clinical trial	10	6	Clinical trial data for antidepressant effects
5	OpenAlex	nitrous oxide N2O recreational abuse neurotoxicity	10	7	Landmark papers on recreational use and neurotoxicity
6	PubMed	nitrous oxide pharmacology mechanism NMDA receptor anesthesia	12	7	Core pharmacology and mechanism papers
7	PubMed	nitrous oxide minimum alveolar concentration MAC potency anesthetic dose	5	1	Key potency data - establishes N2O is subpotent as sole anesthetic at 1 atm
8	PubMed	nitrous oxide methionine synthase cobalamin vitamin B12 mechanism inactivation	3	2	Metabolic mechanism of toxicity
9	WebSearch/UK Gov	nitrous oxide legal status UK Psychoactive Substances Act 2023 scheduling US DEA Australia	10	2	Legal status for multiple jurisdictions
10	PubMed	nitrous oxide bone marrow hematopoiesis megaloblastic anemia	4	3	Classic hematopoietic toxicity papers
11	PubMed	ENIGMA trial nitrous oxide anesthesia Myles	8	3	Large-scale clinical safety data
12	OpenAlex	Nagele nitrous oxide antidepressant treatment resistant depression 2015	5	1	Original proof-of-concept antidepressant trial, most-cited N2O psychiatric paper
13	PubMed	nitrous oxide history neuropsychiatry	1	1	Primary historical reference
14	ClinicalTrials.gov	nitrous oxide depression anxiety treatment	10	5	Active and completed trials directly relevant to therapeutic use
15	WebSearch	nitrous oxide legal status Australia Canada EU 2023 2024	10	2	Comprehensive legal status across jurisdictions
16	PubMed	nitrous oxide antinociception noradrenergic spinal cord alpha-2 adrenergic	3	2	Key papers establishing noradrenergic descending pathway as analgesic mechanism
17	PubMed	nitrous oxide nausea vomiting postoperative ENIGMA adverse effect	6	2	PONV as key adverse effect of clinical N2O use
18	OpenAlex	Brunt 2022 neurotoxicity abuse liability narrative review N2O	1	1	Best review on abuse liability mechanisms
19	cross_reference · absence	Verify interactions listed as unknown in brief - opioids, alcohol, GHB	0	0	Interaction status confirmed as largely unknown for listed substances
20	PubMed	Past present future nitrous oxide Lew McKay Maze 2018	1	1	Comprehensive modern review covering contraindications, physical properties, clinical use
21	PubMed	Palanca 2023 persistent brain connectivity nitrous oxide	1	1	Neural correlates of persistent N2O effects relevant to antidepressant mechanism
22	cross_reference	Verify chemical identity: PubChem CID 948 vs brief seed data	1	0	Chemical identity verification completed

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

safety90 · 0 ok

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pharmacology57 · 0 ok

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3Sources

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

Sources 1 to 30
year	source	tier	status	feeds
2025	Antidepressant Effects of Nitrous Oxide in Major Depressive Disorder: A Phase 2b Randomized Clinical TrialMyles PS, Kulkarni J, Kasza J et al. · Biological Psychiatry Global Open Sciencedoi:10.1016/j.bpsgos.2025.100504	strong	consumed	cited only
2025	Commentary on Nitrous Oxide: Weighing the Toxic Neuropsychiatric Effects of Abuse Against Potential Therapeutic Benefits for Psychiatric DisordersGarakani A · Journal of Psychiatric Practicedoi:10.1097/pra.0000000000000854	moderate	consumed	cited only
2025	Life style drug laughing gas (nitrous oxide, N2O) and the dependency criteria according to ICD-10Diesing D, Neu P · Der Nervenarztdoi:10.1007/s00115-024-01736-z	moderate	consumed	1 section
2025	Nitrous oxide activates layer 5 prefrontal neurons via SK2 channel inhibition for antidepressant effectCichon J, Joseph TT, Lu X et al. · Nature Communicationsdoi:10.1038/s41467-025-57951-y	moderate	consumed	4 sections
2025	Nitrous oxide for the treatment of depression: a systematic review and meta-analysisGill K et al. · EBioMedicinedoi:10.1016/j.ebiom.2025.106023	strong	consumed	3 sections
2025	Regulation of Nitrous Oxide: Australia, Belgium, Canada, ChinaLaw Library of Congressurl:b19151407fd88892	weak	consumed	cited only
2024	Nitrous oxide induced subacute combined degeneration of the spine cord: A case reportWang S et al. · Medicinedoi:10.1097/md.0000000000037032	weak	consumed	cited only
2023	Brain function changes reveal rapid antidepressant effects of nitrous oxide for treatment-resistant depression: Evidence from task-state EEGShao X et al. · Psychiatry Researchdoi:10.1016/j.psychres.2023.115072	strong	consumed	cited only
2023	Circular 006/2023: Control of nitrous oxide under the Misuse of Drugs Act 1971UK Home Officeurl:94b51326a6f6a007	weak	consumed	cited only
2023	Empirical evidence for the neurocognitive effect of nitrous oxide as an adjunctive therapy in patients with treatment resistant depressionLiu J et al. · Psychiatry Researchdoi:10.1016/j.psychres.2023.115326	strong	consumed	1 section
2023	Nitrous Oxide Abuse: Clinical Outcomes, Pharmacology, Pharmacokinetics, Toxicity and Impact on MetabolismGernez É et al. · Toxicsdoi:10.3390/toxics11120962	moderate	consumed	2 sections
2023	Persistent Brain Connectivity Changes in Healthy Volunteers Following Nitrous Oxide InhalationPalanca BJA, Conway CR, Zeffiro T et al. · Biological Psychiatry Global Open Sciencedoi:10.1016/j.bpsgos.2023.01.006	moderate	consumed	cited only
2023	Proof-of-concept randomized controlled trial of single-session nitrous oxide treatment for refractory bipolar depressionKim WSH et al. · Bipolar Disordersdoi:10.1111/bdi.13288	strong	consumed	cited only
2022	Efficacy and safety of nitrous oxide for patients with treatment-resistant depression, a randomized controlled trialYan D et al. · Psychiatry Researchdoi:10.1016/j.psychres.2022.114867	strong	consumed	1 section
2022	Increasing recreational nitrous oxide use: Should we worry? A narrative reviewvan Amsterdam J, Nabben T, van den Brink W · Journal of Psychopharmacologydoi:10.1177/02698811221082442	moderate	consumed	1 section
2022	Mechanisms Involved in the Neurotoxicity and Abuse Liability of Nitrous Oxide: A Narrative ReviewBrunt TM, van den Brink W, van Amsterdam J · International Journal of Molecular Sciencesdoi:10.3390/ijms232314747	moderate	consumed	2 sections
2022	Nitrous oxide abuse in the emergency practice, and Review of toxicity mechanisms and potential markersJoncquel Chevalier-Curt M, Grzych G, Tard C et al. · Food and Chemical Toxicologydoi:10.1016/j.fct.2022.112894	weak	consumed	1 section
2022	Nitrous oxide abuse induced subacute combined degeneration despite patient initiated B12 supplementationTemple C, Horowitz BZ · Clinical Toxicologydoi:10.1080/15563650.2022.2046772	weak	consumed	1 section
2022	Nitrous Oxide, a Rapid Antidepressant, Has Ketamine-like Effects on Excitatory Transmission in the Adult HippocampusIzumi Y, Hsu FF, Conway CR et al. · Biological Psychiatrydoi:10.1016/j.biopsych.2022.06.016	moderate	consumed	2 sections
2022	Plasma Methionine and Clinical Severity in Nitrous Oxide ConsumptionGernez E, Deheul S, Tard C et al. · Toxicsdoi:10.3390/toxics11010012	moderate	consumed	cited only
2021	A new mechanistic approach for the treatment of chronic neuropathic pain with nitrous oxide integrated from a systems biology narrative reviewBessiere B et al. · Medical Gas Researchdoi:10.4103/2045-9912.310058	moderate	consumed	1 section
2021	A phase 2 trial of inhaled nitrous oxide for treatment-resistant major depressionNagele P et al. · Science Translational Medicinedoi:10.1126/scitranslmed.abe1376	strong	consumed	1 section
2019	Double-sidedness of laughing gas on the N-methyl-d-aspartate receptor: A case report of acute psychosis associated with nitrous oxide-induced hyperhomocysteinemiaKim S, Lee SH, Bang M · Schizophrenia Researchdoi:10.1016/j.schres.2019.02.006	weak	consumed	1 section
2019	Elucidating Unique Axonal Dysfunction Between Nitrous Oxide Abuse and Vitamin B12 DeficiencyTani J et al. · Frontiers in Neurologydoi:10.3389/fneur.2019.00704	moderate	consumed	1 section
2019	Global Burden Related to Nitrous Oxide Exposure in Medical and Recreational Settings: A Systematic Review and Individual Patient Data Meta-AnalysisOussalah A et al. · Journal of Clinical Medicinedoi:10.3390/jcm8040551	strong	consumed	3 sections
2019	Mini-Review: A Brief History of Nitrous Oxide (N2O) Use in NeuropsychiatryGillman MA · Current Drug Research Reviewsdoi:10.2174/1874473711666181008163107	moderate	consumed	2 sections
2018	Nitrous oxide added at the end of isoflurane anesthesia hastens early recovery without increasing the risk for postoperative nausea and vomiting: a randomized clinical trialMraovic B, Simurina T, Gan TJ · Canadian Journal of Anaesthesiadoi:10.1007/s12630-017-1013-y	strong	consumed	1 section
2018	No Laughing Matter: Presence, Consumption Trends, Drug Awareness, and Perceptions of 'Hippy Crack' (Nitrous Oxide) among Young Adults in EnglandEhirim EM, Naughton DP, Petróczi A · Frontiers in Psychiatrydoi:10.3389/fpsyt.2017.00312	moderate	consumed	1 section
2018	Past, present, and future of nitrous oxideLew V, McKay E, Maze M · British Medical Bulletindoi:10.1093/bmb/ldx050	moderate	consumed	6 sections
2017	Nitrous oxide induced subacute combined degeneration with longitudinally extensive myelopathy with inverted V-sign on spinal MRI: a case report and literature reviewYuan JL, Wang SK, Jiang T, Hu WL · BMC Neurologydoi:10.1186/s12883-017-0990-3	weak	consumed	1 section

Show all 54 sources — 24 more

Sources 31 to 54
year	source	tier	status	feeds
2016	Nitrous Oxide, From the Operating Room to the Emergency DepartmentHuang C, Johnson N · Current Emergency and Hospital Medicine Reportsdoi:10.1007/s40138-016-0092-3	moderate	consumed	1 section
2016	Severe Nausea and Vomiting in the Evaluation of Nitrous Oxide in the Gas Mixture for Anesthesia II TrialMyles PS, Chan MT, Kasza J et al. · Anesthesiologydoi:10.1097/aln.0000000000001057	strong	consumed	cited only
2015	Nitrous Oxide and Serious Long-term Morbidity and Mortality in the ENIGMA-II TrialLeslie K, Myles PS, Kasza J et al. · Anesthesiologydoi:10.1097/aln.0000000000000908	strong	consumed	cited only
2015	Nitrous Oxide for Treatment-Resistant Major Depression: A Proof-of-Concept TrialNagele P, Duma A, Kopec M, Gebara MA, Parsoei A, Walker M, Janski A, Panagopoulos VN, Cristancho P, Miller JP, Zorumski CF, Conway CR · Biological Psychiatrydoi:10.1016/j.biopsych.2014.11.016	strong	consumed	2 sections
2015	Treatment-Resistant Major Depression: Rationale for NMDA Receptors as Targets and Nitrous Oxide as TherapyZorumski CF, Nägele P, Mennerick SJ, Conway CR · Frontiers in Psychiatrydoi:10.3389/fpsyt.2015.00172	moderate	consumed	cited only
2014	The safety of addition of nitrous oxide to general anaesthesia in at-risk patients having major non-cardiac surgery (ENIGMA-II): a randomised, single-blind trialMyles PS, Leslie K, Chan MT et al. · Lancetpmid:25142708	strong	consumed	2 sections
2011	Chronic postsurgical pain after nitrous oxide anesthesiaChan MTV, Wan ACM, Gin T, Leslie K, Myles PS · Paindoi:10.1016/j.pain.2011.07.015	moderate	consumed	cited only
2010	A single nitrous oxide (N2O) exposure leads to persistent alleviation of neuropathic pain in ratsBessière B et al. · The Journal of Paindoi:10.1016/j.jpain.2009.05.003	moderate	consumed	1 section
2010	Nitrous oxide-induced NO-dependent neuronal release of beta-endorphin from the rat arcuate nucleus and periaqueductal grayOhgami Y, Chung E, Quock RM · Brain Researchdoi:10.1016/j.brainres.2010.10.010	moderate	consumed	1 section
2009	Deletion of mu-opioid receptor in mice does not affect the minimum alveolar concentration of volatile anaesthetics and nitrous oxide-induced analgesiaKoyama T et al. · British Journal of Anaesthesiadoi:10.1093/bja/aep246	moderate	consumed	3 sections
2008	Biologic effects of nitrous oxide: a mechanistic and toxicologic reviewSanders RD, Weimann J, Maze M · Anesthesiologydoi:10.1097/aln.0b013e3181870a17	strong	consumed	cited only
2007	Advances in understanding the actions of nitrous oxideEmmanouil DE, Quock RM · Anesthesia progresspmid:17352529	moderate	consumed	2 sections
2007	Protein crystallography under xenon and nitrous oxide pressure: comparison with in vivo pharmacology studiesColloc'h N et al. · Biophysical journalpmid:17028130	moderate	consumed	2 sections
2006	Effects of anesthetics on mutant N-methyl-D-aspartate receptors expressed in Xenopus oocytesOgata J et al. · Journal of pharmacology and experimental therapeuticspmid:16622040	moderate	consumed	3 sections
2004	Nitrous oxide (N2O) requires the N-methyl-D-aspartate receptor for its action in Caenorhabditis elegansNagele P, Metz LB, Crowder CM · PNASpmid:15159532	moderate	consumed	2 sections
2003	Occupational hazards of inhalational anaestheticsBurm AG · Best Practice & Research Clinical Anaesthesiologypmid:12751554	moderate	consumed	1 section
2000	Antinociceptive action of nitrous oxide is mediated by stimulation of noradrenergic neurons in the brainstem and activation of alpha2B adrenoceptorsSawamura S, Kingery WS, Davies MF et al. · Journal of Neurosciencepmid:11125002	moderate	consumed	2 sections
2000	Role of brain dynorphin in nitrous oxide antinociception in miceBranda EM, Ramza JT, Cahill FJ, Tseng LF, Quock RM · Pharmacology, biochemistry, and behaviorpmid:10672972	moderate	consumed	3 sections
1996	Antinociceptive response to nitrous oxide is mediated by supraspinal opiate and spinal alpha 2 adrenergic receptors in the ratGuo TZ, Poree L, Golden W et al. · Anesthesiologypmid:8873555	moderate	consumed	3 sections
1982	Incidence and pathogenesis of acute megaloblastic bone-marrow change in patients receiving intensive careAmos RJ, Amess JA, Hinds CJ, Mollin DL · Lancetpmid:6126709	moderate	consumed	1 section
1982	The minimum alveolar concentration of nitrous oxide in manHornbein TF, Eger EI, Winter PM et al. · Anesthesia and Analgesiapmid:7201254	moderate	consumed	3 sections
1981	Human bone marrow biochemical function and megaloblastic hematopoiesis after nitrous oxide anesthesiaO'Sullivan H, Jennings F, Ward K et al. · Anesthesiologypmid:6975588	moderate	consumed	1 section
1978	Megaloblastic haemopoiesis in patients receiving nitrous oxideAmess JA et al. · Lancetpmid:79709	moderate	consumed	1 section
—	Searched cross_reference for "Verify interactions listed as unknown in brief - opioids, alcohol, GHB" — no resultsabsence		no results	—

4Docket

one filing per activity — decisions, correspondence, reports

0012026-04-26revisionRevision 1
Initial LLM generation (v5 pipeline, wiki)
psx:substance/nitrous/version/1
0022026-06-04proposal28 value proposals approved together
one review action inferred from a shared reviewer and instant — the graph records one activity per proposal
28 items in this filing
- dose_tier · light
- dose_tier · common
- dose_tier · strong
- dose_tier · heavy
- timeline · inhaled · onset
- timeline · inhaled · come_up
- timeline · inhaled · peak
- timeline · inhaled · resolution
- timeline · inhaled · afterglow
- toxicity
- dependence · full
- withdrawal
- tolerance
- dosage · inhaled
- duration · inhaled · onset
- duration · inhaled · come_up
- duration · inhaled · peak
- duration · inhaled · offset
- duration · inhaled · total
- duration · inhaled · aftereffects
- contraindication · metabolic
- contraindication · respiratory
- contraindication · other
- contraindication · other
- contraindication · other
- contraindication · neurological
- contraindication · pregnancy_breastfeeding
psx:substance/nitrous/proposal/dose_tier/43e3095f-11f7-4fab-9286-9d53ae450c79
0032026-06-04publicationPublication — backfill
psx:substance/nitrous/pub/efc1bc48-0919-4ddd-8b7e-ffe5a8b3b31a

5Issued documents

what the notice, info card and emergency page said, by hash

Issued documents
document	content hash	issued	from version	superseded
info_card	7cb8b6db5115e96e8bd9f0a0…	2026-10-19 20:33	Revision 1	current
emergency	777b5863d801327b008f5610…	2026-09-04 04:31	Revision 1	current
info_card	0dd86dd7f28d55e64d20096c…	2026-09-04 04:31	Revision 1	superseded2026-10-19
notice	49667bd0105c049ff18ced51…	2026-09-04 04:31	Revision 1	current

Nitrous

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5Issued documents

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