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psx:substance/alcohol/proposal/contraindication/5dee8756-ded0-4d82-bc79-aff75eed6b5c

proposal2026-05-07recordapproved

derived from · upstream

none recorded

feeds · downstream

Closure of psx:substance/alcohol/proposal/contraindication/5dee8756-ded0-4d82-bc79-aff75eed6b5c: 0 upstream, 1 downstream.

psx:substance/alcohol/proposal/contraindication/5dee8756-ded0-4d82-bc79-aff75eed6b5c
└─ derived_from  value/contraindication/ddc0c784-aecc-4a5a-bbbd-22e2c533c16c@1

indented by distance from this node, not by parentage

1Provenance card

the boundary, as counts

Sources

4126 with DOI

3 strong · 33 moderate · 5 weak

Compilations

12026-05-07T10:03:51.473Z

pipeline-v5 · prompt hash not recorded — run predates 2026-09 · 9 other runs

Decisions

38last ruled 2026-06-04

1 awaiting a ruling

Issued documents

42026-10-19T20:30:29.097Z

notice · info card · emergency

Searches

230 with no results

queries and counts on the build

Claims checked

9151 supported

51 supported · 40 not

Correspondence

0received

consent field ships in Phase 4

Edges

295

derivations recorded for this entity

Complete over 41 sources, 1 compilation, and 38 decisions.Not here: the private journal (never); 1 proposal awaiting a ruling (listed as pending only).Working material — drafts, discards, unsupported claims — is listed below and readable on the working page.Cite: psychedex.org/substances/alcohol/archive

2Build

one panel per compilation run

generation run 2026-05-07

82 min completedmodel pipeline-v5plan not recordedrun/776f02be…

Selection

results seen119
selected by the model44
consumed as sources41

Verification

claims checked91
supported42
partially supported9
not supported2
inconclusive38
  • record
  • seen / partial
  • working

The model's own caveats

  • safety_data_unverified

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
pipeline-v5
streams
none — agent transcripts are persisted from 2026-09 onward
23 searches — query, source, results, what was kept and why
23 searches for this run
#sourcequeryseenkeptrationale
1PubMedGrant epidemiology DSM-5 alcohol use disorder NESARC-III prevalence41Gold standard US prevalence data
2ClinicalTrials.govalcohol use disorder treatment naltrexone acamprosate83Representative AUD treatment trials
3WebSearchblood alcohol concentration BAC levels clinical effects chart impairment102Standard clinical reference for BAC impairment levels
4WebSearchhistory of distillation alcohol fermentation ancient mesopotamia China Egypt timeline102Historical context for alcohol article
5PubMedLovinger ethanol NMDA receptor inhibition electrophysiology hippocampus 198911Foundational primary pharmacology paper
6PubMedethanol pharmacokinetics metabolism CYP2E1 alcohol dehydrogenase human106Core pharmacokinetics literature
7WebSearchWHO global status report alcohol health 2018 global burden deaths101WHO authoritative source for global alcohol burden
8PubChemethanol (by name and CID 702)11Verified chemical identity data
9PubMedKoob Volkow neurobiology alcohol addiction circuits review 201611Definitive neurobiology of addiction framework
10WebSearchalcohol ethanol legal status worldwide drinking age prohibition countries102Legal status reference data
11PubMedethanol GABA-A receptor positive allosteric modulator mechanism pharmacology103Focused on primary receptor pharmacology and reinforcement mechanisms
12PubMedethanol NMDA receptor antagonism mechanism alcohol neuropharmacology21Relevant NMDA mechanism in alcohol context
13PubMedRehm global burden disease alcohol consumption attributable mortality62Most current and comprehensive global burden estimates
14PubMedalcohol liver disease hepatotoxicity acetaldehyde oxidative stress mechanism review44Essential liver toxicity and carcinogenesis literature
15PubMedalcohol effects sleep REM EEG polysomnography52Key alcohol-sleep interaction evidence
16PubMedalcohol withdrawal clinical review delirium tremens benzodiazepine treatment81AWS clinical review for withdrawal section
17PubMedALDH2 deficiency Asian flushing response acetaldehyde alcohol cancer risk21Critical pharmacogenomic data on ALDH2 and cancer risk
18PubChem + Seed DataEthanol chemical identity verification11Chemical identity verification against seed data
19PubMedalcohol cardiovascular J-curve moderate drinking coronary heart disease21Cardiovascular risk-benefit evidence
20PubMed (PMID 27475769)Koob Volkow neurobiology addiction neurocircuitry 201611Authoritative addiction neurocircuitry framework
21PubMed (PMID 2467382)Lovinger 1989 NMDA ethanol inhibition full text11Critical primary pharmacology landmark
22PubMednaltrexone acamprosate disulfiram nalmefene pharmacotherapy alcohol use disorder84Comprehensive AUD pharmacotherapy literature
23PubMedKoob alcohol neurobiology stress CRF negative reinforcement extended amygdala42Stress-opponent model of alcohol addiction
91 claims by section — every cited sentence, checked against its source
pharmacology24 · 15 ok
  • Claim in pharmacology — inconclusiveinconclusiveworking →

  • Claim in pharmacology — inconclusiveinconclusiveworking →

  • Claim in pharmacology — inconclusiveinconclusiveworking →

  • The auxiliary protein Shisa7, associated with GABA-A receptor surface trafficking, has been identified as a key molecular substrate for ethanol's discriminative-stimulus and reinforcing effects; Shisa7 knockdown in rats attenuates both.supported

    Shisa7 knockdown attenuated discriminative-stimulus and reinforcing effects of ethanol, alprazolam, and pentobarbital at GABA-A receptors. j.jpet.2025.103761

  • Ethanol also induces neurosteroid synthesis — notably allopregnanolone — in certain brain regions, providing an indirect additional GABAergic mechanismsupported

    Neurosteroid positive allosteric modulators of GABA-A receptors and their interaction with alcohol acute and chronic effects. 164_2017_82

  • Cross-tolerance with benzodiazepines, barbiturates, and other GABAergic depressants is well-established and reflects shared GABA-A receptor-mediated mechanisms.supported

    Chronic ethanol consumption alters GABA-A receptor function producing cellular tolerance, cross-tolerance to benzodiazepines and barbiturates. pmid:15031000

  • The potency hierarchy for NMDA inhibition across a homologous series of alcohols was linearly correlated with their intoxicating potencysupported

    Potency for inhibition linearly related to intoxicating potency. pmid:2467382

  • The incentive-sensitization theory distinguishes drug wanting (incentive salience, mediated by mesolimbic dopamine sensitization) from drug liking (hedonic pleasure); chronic alcohol use selectively sensitizes wanting circuits, driving compulsive intake even as hedonic response diminishes.supported

    Incentive-sensitization theory of addiction. Drug wanting (incentive salience) vs drug liking (pleasure) distinction. Mesolimbic dopamine sensitization underlies compulsive drug-seeking. j.1360-0443.2001.9611038.x

  • The functional importance of this mechanism is demonstrated by the therapeutic efficacy of mu-opioid antagonists: naltrexone reduces craving and heavy drinking days (NNT approximately 8–12), while nalmefene (mu/delta antagonist, partial kappa agonist) shows comparable efficacy (Hedges g = −0.20 ITT, −0.33 in target population).partially supported

    Naltrexone: opioid receptor antagonist with established moderate efficacy for alcohol dependence. Mechanism: blocks alcohol-stimulated opioid peptide release. pmid:20201811

  • The functional importance of this mechanism is demonstrated by the therapeutic efficacy of mu-opioid antagonists: naltrexone reduces craving and heavy drinking days (NNT approximately 8–12), while nalmefene (mu/delta antagonist, partial kappa agonist) shows comparable efficacy (Hedges g = −0.20 ITT, −0.33 in target population).supported

    Nalmefene: mu/delta opioid antagonist, partial kappa agonist. Meta-analysis confirms efficacy reducing heavy drinking days (Hedges g=-0.20 ITT; -0.33 target population). j.euroneuro.2016.10.008

  • Claim in pharmacology — inconclusiveinconclusiveworking →

  • Claim in pharmacology — inconclusiveinconclusiveworking →

  • This first-pass effect is more pronounced in men than women, partly due to higher gastric alcohol dehydrogenase (ADH) activity in men — contributing to higher blood ethanol concentrations in women at equivalent weight-adjusted doses.supported

    Variability in ethanol pharmacokinetics is related to sex, with women showing higher AUC, Cmax and metabolic rate. ADH1B and ADH1C polymorphisms affect ethanol clearance. hep.23341

  • Claim in pharmacology — inconclusiveinconclusiveworking →

  • Claim in pharmacology — inconclusiveinconclusiveworking →

  • Claim in pharmacology — inconclusiveinconclusiveworking →

  • Pathway 2 — CYP2E1 (microsomal ethanol oxidizing system): An inducible pathway with higher Km (~0.5–0.8 g/L) that contributes proportionally more at elevated BAC and in heavy drinkers with enzyme induction. CYP2E1 generates reactive oxygen species (ROS) alongside acetaldehyde, contributing to oxidative stress and hepatotoxicity.supported

    CYP2E1 activity also results in the production of reactive oxygen species (ROS) that promote oxidative stress. ajpgi.00027.2017

  • Pathway 2 — CYP2E1 (microsomal ethanol oxidizing system): An inducible pathway with higher Km (~0.5–0.8 g/L) that contributes proportionally more at elevated BAC and in heavy drinkers with enzyme induction. CYP2E1 generates reactive oxygen species (ROS) alongside acetaldehyde, contributing to oxidative stress and hepatotoxicity.supported

    CYP2E1 induction by ethanol, acetaldehyde production, free radical generation, oxidative stress in alcoholic liver disease. pmid:17567472

  • Acetaldehyde is classified as an IARC Group 1 carcinogen; it forms DNA adducts producing G→T mutations in single-stranded DNA and is causally linked to cancers of the esophagus, oral cavity, liver, head and neck, colorectum, and female breastsupported

    Acetaldehyde (IARC Group 1 carcinogen) generates G→T mutations in ssDNA via translesion synthesis by Pol-zeta. Distinct mutation signature identified in alcohol-associated cancers. gkac570

  • Claim in pharmacology — inconclusiveinconclusiveworking →

  • Approximately 540 million East Asians carry the ALDH2*2 variant allele (dominant negative), causing inefficient acetaldehyde clearance and the characteristic Asian flushing response — facial flushing, tachycardia, nausea — with markedly elevated esophageal cancer risk from alcohol consumption.supported

    ALDH2 deficiency causes alcohol flushing response in East Asians (~540 million people). Those with ALDH2*2 allele have impaired acetaldehyde metabolism, higher acetaldehyde exposure per drink, and dramatically elevated esophageal cancer risk from alcohol. journal.pmed.1000050

  • Elimination at forensically relevant BAC follows approximately zero-order kinetics: 15–20 mg/100 mL/h in non-fasted moderate drinkers, 10–15 mg/100 mL/h in fasted subjects, and 25–35 mg/100 mL/h in heavy drinkers with CYP2E1 induction; the population range spans 10–35 mg/100 mL/hpartially supported

    The physiological range of ethanol elimination rates from blood is from 10 to 35 mg/100mL/h. j.forsciint.2010.02.021

  • Women show higher AUC, higher Cmax, and slightly faster proportional elimination than men, independent of weight-adjusted dosesupported

    women showing higher AUC, Cmax and metabolic rate. hep.23341

  • ADH1B rs1229984 (Arg48His) and ADH1C polymorphisms significantly modulate individual pharmacokinetic parameters.supported

    ADH1B and ADH1C polymorphisms affect ethanol clearance. hep.23341

safety20 · 11 ok
  • Claim in safety — inconclusiveinconclusiveworking →

  • Pathogenic mechanisms include acetaldehyde-induced direct cytotoxicity, CYP2E1-generated reactive oxygen species and oxidative stress, lipid peroxidation products (4-hydroxynonenal) stimulating collagen synthesis, TNF-α activation of Kupffer cells, and mitochondrial damage.supported

    Liver injury caused by acetaldehyde toxicity, NADH-mediated steatosis, CYP2E1-generated reactive oxygen species, oxidative stress, lipid peroxidation, collagen synthesis/fibrosis, and TNF-alpha inflammation. pmid:15670660

  • Claim in safety — inconclusiveinconclusiveworking →

  • Claim in safety — inconclusiveinconclusiveworking →

  • It forms DNA adducts producing characteristic G→T mutations in single-stranded DNAsupported

    Acetaldehyde (IARC Group 1 carcinogen) generates G→T mutations in ssDNA via translesion synthesis by Pol-zeta. gkac570

  • Direct salivary acetaldehyde exposure from alcoholic beverages provides an additional carcinogenic mechanism beyond systemic metabolism.supported

    Salivary acetaldehyde from microbial oxidation contributes to oral/esophageal cancer risk. 1756-9966-30-3

  • Claim in safety — inconclusiveinconclusiveworking →

  • Cancer risk per drink is substantially elevated in carriers of the ALDH2*2 allele due to higher acetaldehyde exposuresupported

    Those with ALDH2*2 allele have impaired acetaldehyde metabolism, higher acetaldehyde exposure per drink, and dramatically elevated esophageal cancer risk from alcohol. journal.pmed.1000050

  • Claim in safety — inconclusiveinconclusiveworking →

  • Chronic metabolic tolerance: CYP2E1 induction by repeated ethanol exposure increases hepatic metabolism rate by 2–3× in heavy drinkers (elimination rate up to 35 mg/100 mL/h vs 15 mg/100 mL/h in non-drinkers).partially supported

    The physiological range of ethanol elimination rates from blood is from 10 to 35 mg/100mL/h. j.forsciint.2010.02.021

  • Chronic neuroadaptive tolerance: GABA-A receptor downregulation (decreased α1 subunit, altered α4/δ expression) and NMDA receptor upregulation reduce sensitivity to ethanol's effects, requiring higher doses for equivalent intoxication. This is the most clinically significant form and drives both escalating consumption and withdrawal risk.partially supported

    Chronic ethanol consumption alters GABA-A receptor function producing cellular tolerance... GABA-A receptor subunit composition changes with dependence. pmid:15031000

  • Chronic neuroadaptive tolerance: GABA-A receptor downregulation (decreased α1 subunit, altered α4/δ expression) and NMDA receptor upregulation reduce sensitivity to ethanol's effects, requiring higher doses for equivalent intoxication. This is the most clinically significant form and drives both escalating consumption and withdrawal risk.supported

    Chronic ethanol exposure causes GABA-A receptor neuroadaptations including subunit expression changes. Sex differences in GABA-A subunit (alpha1, alpha4) changes during dependence and withdrawal. pmid:9689472

  • Cross-tolerance extends to benzodiazepines, barbiturates, and other GABA-A positive modulators — the pharmacological basis for using benzodiazepines to manage alcohol withdrawal.supported

    cross-tolerance to benzodiazepines and barbiturates, sensitization to inverse agonists. pmid:15031000

  • Claim in safety — inconclusiveinconclusiveworking →

  • European poison center data confirm substantially worsened clinical outcomes when GHB/GBL is combined with ethanol.supported

    combination with other substances including alcohol worsens CNS depression and respiratory suppression outcomes. j.toxlet.2017.05.030

  • Controlled human studies confirm enhanced subjective euphoria, elevated heart rate, and elevated cortisol relative to cocaine alonepartially supported

    greater HR increases, euphoria. Augmented subjective euphoria from cocaine+alcohol combination. pmid:9336321

  • Claim in safety — not_supportednot supportedworking →

  • Claim in safety — inconclusiveinconclusiveworking →

  • ALDH2 deficiency (ALDH2*2 carriers) — markedly elevated acetaldehyde exposure and esophageal cancer risk per unit of alcohol consumed.supported

    Those with ALDH2*2 allele have impaired acetaldehyde metabolism, higher acetaldehyde exposure per drink, and dramatically elevated esophageal cancer risk from alcohol. journal.pmed.1000050

  • Claim in safety — inconclusiveinconclusiveworking →

neuroscience12 · 8 ok
  • Sex differences exist in the pattern of GABA-A neuroadaptation: female rats show distinct subunit composition changes compared to males following chronic ethanol exposure, potentially contributing to sex differences in withdrawal severity and treatment response.supported

    Sex differences in GABA-A subunit (alpha1, alpha4) changes during dependence and withdrawal. pmid:9689472

  • Claim in neuroscience — inconclusiveinconclusiveworking →

  • Alcohol addiction progresses through three stages: (1) binge/intoxication (reward circuit engagement), (2) withdrawal/negative affect (stress circuit recruitment via CRF, norepinephrine, dynorphin), and (3) preoccupation/anticipation (executive circuit compromise and cue-driven craving)supported

    Three-stage model. Negative reinforcement driven by decreased dopamine/GABA in ventral striatum; CRF, norepinephrine, dynorphin recruitment in extended amygdala. 7854_2011_129

  • This dissociation between tonic depletion and phasic sensitization is the neural substrate of the wanting/liking dissociation described by incentive-sensitization theory.supported

    Drug wanting (incentive salience) vs drug liking (pleasure) distinction. Mesolimbic dopamine sensitization underlies compulsive drug-seeking. j.1360-0443.2001.9611038.x

  • Claim in neuroscience — inconclusiveinconclusiveworking →

  • Claim in neuroscience — inconclusiveinconclusiveworking →

  • Chronic alcohol use produces structural and functional PFC damage, reducing the capacity for top-down inhibitory control over subcortical reward and stress circuits.supported

    preoccupation/anticipation (glutamate dysregulation in PFC/insula). s2215-0366(16)00104-8

  • This three-component model — reward circuit sensitization, stress circuit recruitment, and executive circuit compromise — forms the neurocircuitry framework for alcohol addiction described by Koob and colleagues.supported

    Three stages: binge/intoxication (dopamine, opioid peptides), withdrawal/negative affect (CRF, dynorphin), preoccupation/anticipation (glutamate dysregulation in PFC/insula). s2215-0366(16)00104-8

  • Claim in neuroscience — inconclusiveinconclusiveworking →

  • GABA-A receptors undergo downregulation and subunit composition changes — decreased α1 subunit expression, increased α4 and δ subunit expression in some regions — reducing the receptor's sensitivity to both endogenous GABA and exogenous modulators including ethanol and benzodiazepinessupported

    Sex differences in GABA-A subunit (alpha1, alpha4) changes during dependence and withdrawal. pmid:9689472

  • Second-half sleep is disrupted regardless of dose, producing characteristic early morning waking and fragmented sleep architecturesupported

    All doses reduce sleep onset latency and consolidate first-half sleep; second-half sleep disrupted. acer.12006

  • EEG studies confirm that ethanol-induced sedation is qualitatively distinct from physiological sleep: ethanol produces dose-dependent enhancement of delta oscillations but does not replicate the full spectral signature of natural NREM sleep.supported

    High-dose ethanol (4.0 g/kg) produces novel anesthetic state (DISCO-T)... promotes delta oscillations. Suppresses faster EEG frequencies. j.neuropharm.2019.107913

pharmacokinetic-detail9 · 3 ok
  • Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →

  • Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →

  • Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →

  • Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →

  • Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →

  • Men have significantly higher gastric ADH activity than women, producing a larger first-pass effect; this sex difference in presystemic metabolism is a major contributor to higher BAC in women at equivalent weight-adjusted oral doses.supported

    women showing higher AUC, Cmax and metabolic rate. ADH1B and ADH1C polymorphisms affect ethanol clearance. hep.23341

  • These pharmacokinetic sex differences — reduced first-pass metabolism and reduced Vd — compound to produce substantially greater ethanol exposure in women and contribute to the faster progression of alcohol-associated liver disease observed in women.partially supported

    women showing higher AUC, Cmax and metabolic rate. hep.23341

  • Population elimination rates:supported

    The physiological range of ethanol elimination rates from blood is from 10 to 35 mg/100mL/h. j.forsciint.2010.02.021

  • Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →

clinical-evidence6 · 2 ok
  • Acamprosate (calcium acetylhomotaurinate, 1998 mg/day in divided doses) is a weak NMDA receptor antagonist (IC50 ~5.5 mM at hippocampal neurons) that also modulates NMDA subunit expression patterns similar to memantine and MK-801supported

    Acamprosate weak NMDA antagonist (IC50 ~5.5 mM in hippocampal neurons). Upregulates NMDA subunits in cortex and hippocampus similar to memantine/MK-801. pmid:11369029

  • Claim in clinical-evidence — inconclusiveinconclusiveworking →

  • Claim in clinical-evidence — inconclusiveinconclusiveworking →

  • Claim in clinical-evidence — inconclusiveinconclusiveworking →

  • Its therapeutic mechanism involves normalization of glutamatergic hyperexcitability during protracted abstinencesupported

    acamprosate (NMDA/GABA modulator). pmid:16545872

  • Claim in clinical-evidence — inconclusiveinconclusiveworking →

history6 · 3 ok
  • Claim in history — not_supportednot supportedworking →

  • Claim in history — inconclusiveinconclusiveworking →

  • Claim in history — inconclusiveinconclusiveworking →

  • The identification of ethanol as an NMDA receptor antagonist in 1989, the characterization of GABA-A receptor subunit specificity for ethanol's reinforcing effects, the development of the allostasis and reward-deficit model of addiction, and the regulatory approval of naltrexone, acamprosate, and disulfiram as AUD pharmacotherapies represent landmarks in the fieldsupported

    NMDA-activated ion current in hippocampal neurons inhibited by ethanol over 5-50 mM range (intoxicating concentrations). pmid:2467382

  • The identification of ethanol as an NMDA receptor antagonist in 1989, the characterization of GABA-A receptor subunit specificity for ethanol's reinforcing effects, the development of the allostasis and reward-deficit model of addiction, and the regulatory approval of naltrexone, acamprosate, and disulfiram as AUD pharmacotherapies represent landmarks in the fieldsupported

    Alpha1, alpha2, alpha3, alpha5 GABA-A receptor subtype roles in behavioral effects of ethanol in rhesus macaques. acer.14000

  • The identification of ethanol as an NMDA receptor antagonist in 1989, the characterization of GABA-A receptor subunit specificity for ethanol's reinforcing effects, the development of the allostasis and reward-deficit model of addiction, and the regulatory approval of naltrexone, acamprosate, and disulfiram as AUD pharmacotherapies represent landmarks in the fieldsupported

    Review on drug addiction neuroscience including reward dysregulation. Key framework for understanding alcohol dependence. s0893-133x(00)00195-0

summary6 · 3 ok
  • Three pharmacotherapies — naltrexone, acamprosate, and disulfiram — hold regulatory approval for alcohol use disorder (AUD), and active clinical investigation continues into GLP-1 receptor agonists and gene therapy approaches targeting mesolimbic dopamine circuits.partially supported

    FDA-approved: disulfiram (ALDH inhibitor causing acetaldehyde accumulation), naltrexone (opioid antagonist), acamprosate (NMDA/GABA modulator). CRF, CB1 as future targets. pmid:16545872

  • Claim in summary — inconclusiveinconclusiveworking →

  • Claim in summary — inconclusiveinconclusiveworking →

  • It inhibits NMDA-activated ion currents by up to 61% at 50 mM — a finding linearly correlated with intoxicating potency across a homologous series of alcoholssupported

    50 mM EtOH reduced NMDA current 61%... Potency for inhibition linearly related to intoxicating potency. pmid:2467382

  • Claim in summary — inconclusiveinconclusiveworking →

  • Tolerance develops through both metabolic (CYP2E1 induction) and neuroadaptive (GABA-A downregulation, NMDA upregulation) mechanismspartially supported

    Chronic ethanol consumption alters GABA-A receptor function producing cellular tolerance... GABA-A receptor subunit composition changes with dependence. pmid:15031000

receptor-pharmacology4 · 3 ok
  • Claim in receptor-pharmacology — inconclusiveinconclusiveworking →

  • In rat models, viral-mediated knockdown of Shisa7 in the nucleus accumbens shell attenuates both ethanol discrimination and self-administration, identifying Shisa7 as a novel molecular node in the ethanol reward pathway.supported

    Shisa7 knockdown attenuated discriminative-stimulus and reinforcing effects of ethanol, alprazolam, and pentobarbital at GABA-A receptors. j.jpet.2025.103761

  • Endogenous opioids: Ethanol stimulates release of β-endorphin and enkephalins, which activate mu-opioid receptors in reward circuits. Naltrexone (mu-opioid antagonist, NNT approximately 8–12 for reducing heavy drinking) and nalmefene (mu/delta antagonist, partial kappa agonist) demonstrate the functional importance of this pathway.partially supported

    Mechanism: blocks alcohol-stimulated opioid peptide release. Naltrexone: opioid receptor antagonist with established moderate efficacy for alcohol dependence. pmid:20201811

  • Endogenous opioids: Ethanol stimulates release of β-endorphin and enkephalins, which activate mu-opioid receptors in reward circuits. Naltrexone (mu-opioid antagonist, NNT approximately 8–12 for reducing heavy drinking) and nalmefene (mu/delta antagonist, partial kappa agonist) demonstrate the functional importance of this pathway.supported

    Nalmefene: mu/delta opioid antagonist, partial kappa agonist. Counters alcohol-induced dysregulation of MOR/endorphin and KOR/dynorphin. j.euroneuro.2016.10.008

comparative-pharmacology3 · 3 ok
  • The combination is classified as lethal because synergistic CNS and respiratory depression can shift rapidly from sedation to coma.supported

    combination with other substances including alcohol worsens CNS depression and respiratory suppression outcomes. j.toxlet.2017.05.030

  • Barbiturate withdrawal, like alcohol withdrawal, can produce fatal seizures — reflecting the shared GABA-A neuroadaptive mechanism.supported

    cross-tolerance to benzodiazepines and barbiturates... GABA-A receptor subunit composition changes with dependence. pmid:15031000

  • Ethanol and benzodiazepines share a primary mechanism (GABA-A receptor positive allosteric modulation) and exhibit bidirectional cross-tolerancesupported

    cross-tolerance to benzodiazepines and barbiturates... GABA-A receptor function. pmid:15031000

chemistry1 · 0 ok
  • Claim in chemistry — inconclusiveinconclusiveworking →

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3Sources

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

Sources 1 to 30
yearsourcetierstatusfeeds
2025Attenuation of the discriminative stimulus and reinforcing effects of positive GABA-A modulators after Shisa7 knockdown in ratsMorris TM, Henderson AS, Melton SM, et al. · Journal of Pharmacology and Experimental Therapeuticsdoi:10.1016/j.jpet.2025.103761moderateconsumed3 sections
2025List of countries with alcohol prohibition - WikipediaWikipedia contributorsurl:2618a3dec1a76053weakconsumedcited only
2024Blood Alcohol Concentration (BAC): Levels and EffectsCleveland Clinicurl:027172c4a8cc8304weakconsumedcited only
2024History of alcohol fermentation and distillationMultiple sourcesurl:7b6c1a92046a8b16weakconsumedcited only
2024Prohibition in the United States - WikipediaWikipedia contributorsurl:3f709ea3bcc355e3weakconsumedcited only
2024Review of Attributes and Outcomes of Hospitalized Patients with Alcohol WithdrawalDesai HR, Hyland JS, Paulos E, et al. · Journal of community hospital internal medicine perspectivesdoi:10.55729/2000-9666.1420moderateconsumed2 sections
2023Alcohol and its associated liver carcinogenesisJacob R, Prince DS, Kench C, Liu K · Journal of gastroenterology and hepatologydoi:10.1111/jgh.16248moderateconsumed1 section
2022Acetaldehyde makes a distinct mutation signature in single-stranded DNAVijayraghavan S, Porcher L, Mieczkowski PA, Saini N · Nucleic acids researchdoi:10.1093/nar/gkac570moderateconsumed3 sections
2021The Global Impact of Alcohol Consumption on Premature Mortality and Health in 2016Sohi I, Franklin A, Chrystoja B, Wettlaufer A, Rehm J, Shield K · Nutrientsdoi:10.3390/nu13093145moderateconsumed1 section
2020Dose-dependent alcohol effects on electroencephalogram: Sedation/anesthesia is qualitatively distinct from sleepAbrahao KP, Pava MJ, Lovinger DM · Neuropharmacologydoi:10.1016/j.neuropharm.2019.107913moderateconsumed1 section
2019Diagnosis and Treatment of Alcohol-Associated Liver Diseases: 2019 Practice Guidance From the AASLDCrabb DW, Im GY, Szabo G, et al. · Hepatologydoi:10.1002/hep.30866moderateconsumed1 section
2019Forensic Drug Profile: CocaethyleneJones AW · Journal of analytical toxicologydoi:10.1093/jat/bkz007moderateconsumed1 section
2019GABA-A Receptor Subtypes and the Abuse-Related Effects of Ethanol in Rhesus MonkeysBerro LF, Ruedi-Bettschen D, Cook JE, et al. · Alcoholism, clinical and experimental researchdoi:10.1111/acer.14000moderateconsumed4 sections
2018Dynamic Adaptation in Neurosteroid Networks in Response to AlcoholFinn DA, Jimenez VA · Handbook of experimental pharmacologydoi:10.1007/164_2017_82moderateconsumed1 section
2018Global Status Report on Alcohol and Health 2018World Health Organizationurl:70632ca6d8b0a7c3weakconsumedcited only
2017Ethanol metabolism by alcohol dehydrogenase or cytochrome P450 2E1 differentially impairs hepatic protein trafficking and growth hormone signalingDoody EE, Groebner JL, Walker JR, et al. · American journal of physiology. Gastrointestinal and liver physiologydoi:10.1152/ajpgi.00027.2017moderateconsumed1 section
2017Intoxication by gamma hydroxybutyrate and related analogues: Clinical characteristics and comparison between pure intoxication and that combined with other substances of abuseMiro O, Galicia M, Dargan P, et al. · Toxicology lettersdoi:10.1016/j.toxlet.2017.05.030moderateconsumed2 sections
2016Nalmefene for the management of alcohol dependence: pharmacology, mechanism of action, and meta-analysis on clinical efficacyMann K, Torup L, Sorensen P, et al. · European neuropsychopharmacologydoi:10.1016/j.euroneuro.2016.10.008strongconsumed2 sections
2016Neurobiology of addiction: a neurocircuitry analysisKoob GF, Volkow ND · The Lancet Psychiatrydoi:10.1016/s2215-0366(16)00104-8moderateconsumedcited only
2015Epidemiology of DSM-5 Alcohol Use Disorder: Results From the National Epidemiologic Survey on Alcohol and Related Conditions IIIGrant BF, Goldstein RB, Saha TD, et al. · JAMA Psychiatrydoi:10.1001/jamapsychiatry.2015.0584moderateconsumed1 section
2014Pharmacokinetic and pharmacodynamic drug interactions with ethanol (alcohol)Chan LN, Anderson GD · Clinical pharmacokineticsdoi:10.1007/s40262-014-0190-xmoderateconsumed2 sections
2013Alcohol and sleep I: effects on normal sleepEbrahim IO, Shapiro CM, Williams AJ, Fenwick PB · Alcoholism, clinical and experimental researchdoi:10.1111/acer.12006strongconsumed1 section
2013Theoretical frameworks and mechanistic aspects of alcohol addiction: alcohol addiction as a reward deficit disorderKoob GF · Current topics in behavioral neurosciencesdoi:10.1007/7854_2011_129moderateconsumed1 section
2012Alcohol metabolismCederbaum AI · Clinics in liver diseasedoi:10.1016/j.cld.2012.08.002moderateconsumed2 sections
2012Beer and wine in antiquity: beneficial remedy or punishment imposed by the Gods?Rosso AM · Acta medico-historica adriaticapmid:23560753moderateconsumed1 section
2011Short-term salivary acetaldehyde increase due to direct exposure to alcoholic beverages as an additional cancer risk factor beyond ethanol metabolismLachenmeier DW, Monakhova YB · Journal of experimental and clinical cancer researchdoi:10.1186/1756-9966-30-3moderateconsumed2 sections
2010Evidence-based survey of the elimination rates of ethanol from blood with applications in forensic caseworkJones AW · Forensic science internationaldoi:10.1016/j.forsciint.2010.02.021moderateconsumed3 sections
2010Naltrexone for the treatment of alcoholism: clinical findings, mechanisms of action, and pharmacogeneticsRay LA, Chin PF, Miotto K · CNS and Neurological Disorders Drug Targetspmid:20201811moderateconsumed3 sections
2010Neurocircuitry of addictionKoob GF, Volkow ND · Neuropsychopharmacologydoi:10.1038/npp.2009.110moderateconsumed1 section
2010Variability in ethanol biodisposition in whites is modulated by polymorphisms in the ADH1B and ADH1C genesMartinez C, Galvan S, Garcia-Martin E, et al. · Hepatologydoi:10.1002/hep.23341moderateconsumed2 sections
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2009The alcohol flushing response: an unrecognized risk factor for esophageal cancer from alcohol consumptionBrooks PJ, Enoch MA, Goldman D, Li TK, Yokoyama A · PLoS medicinedoi:10.1371/journal.pmed.1000050moderateconsumed2 sections
2007Role of microsomal enzymes in development of alcoholic liver diseasesKonishi M, Ishii H · Journal of gastroenterology and hepatologypmid:17567472moderateconsumed1 section
2004Alcoholic fatty liver: its pathogenesis and mechanism of progression to inflammation and fibrosisLieber CS · Alcohol (Fayetteville, N.Y.)pmid:15670660moderateconsumed1 section
2004Ethanol regulation of gamma-aminobutyric acid A receptors: genomic and nongenomic mechanismsKumar S, Fleming RL, Morrow AL · Pharmacology and Therapeuticspmid:15031000moderateconsumed4 sections
2003Role of variability in explaining ethanol pharmacokinetics: research and forensic applicationsNorberg A, Jones AW, Hahn RG, Gabrielsson JL · Clinical pharmacokineticspmid:12489977moderateconsumed2 sections
2001Drug Addiction, Dysregulation of Reward, and AllostasisKoob GF · Neuropsychopharmacologydoi:10.1016/s0893-133x(00)00195-0moderateconsumed2 sections
2001Incentive-sensitization and addictionRobinson TE, Berridge KC · Addictiondoi:10.1046/j.1360-0443.2001.9611038.xmoderateconsumed2 sections
2001The anti-craving compound acamprosate acts as a weak NMDA-receptor antagonist, but modulates NMDA-receptor subunit expression similar to memantine and MK-801Rammes G, Mahal B, Putzke J, et al. · Neuropharmacologypmid:11369029moderateconsumed1 section
1998Influence of gender on chronic ethanol-induced alterations in GABA-A receptors in ratsDevaud LL, Fritschy JM, Morrow AL · Brain researchpmid:9689472moderateconsumed2 sections
1997Cocaine and alcohol interactions in humans: neuroendocrine effects and cocaethylene metabolismFarre M, de la Torre R, Gonzalez ML, et al. · Journal of Pharmacology and Experimental Therapeuticspmid:9336321strongconsumed1 section
1989Ethanol inhibits NMDA-activated ion current in hippocampal neuronsLovinger DM, White G, Weight FF · Sciencepmid:2467382moderateconsumed4 sections

4Docket

one filing per activity — decisions, correspondence, reports

awaiting ruling — 1

  • dependence · taper2026-07-03
  1. 0012026-05-07revisionRevision 1

    Initial LLM generation (v5 pipeline, wiki, prose phase)

    psx:substance/alcohol/version/1
  2. 0022026-06-04proposal34 value proposals approved together

    one review action inferred from a shared reviewer and instant — the graph records one activity per proposal

    34 items in this filing

    • contraindication · respiratory
    • contraindication · respiratory
    • contraindication · respiratory
    • contraindication · metabolic
    • contraindication · hepatic
    • contraindication · other
    • contraindication · metabolic
    • contraindication · psychiatric
    • contraindication · psychiatric
    • contraindication · hepatic
    • contraindication · hepatic
    • contraindication · neurological
    • dose_tier · threshold
    • dose_tier · light
    • dose_tier · common
    • dose_tier · strong
    • dose_tier · heavy
    • timeline · oral · onset
    • timeline · oral · come_up
    • timeline · oral · peak
    • timeline · oral · resolution
    • timeline · oral · afterglow
    • toxicity
    • dependence · full
    • withdrawal
    • tolerance
    • dosage · oral
    • duration · oral · onset
    • duration · oral · come_up
    • duration · oral · peak
    • duration · oral · offset
    • duration · oral · total
    • duration · oral · aftereffects
    psx:substance/alcohol/proposal/contraindication/1abb703f-498a-4dc2-abe3-83f29c3f5431
  3. 0032026-06-04publicationPublication — backfill
  4. 0042026-09-22revisionr1.a1

    brief-overview retired 2026-09-30 (founder): Description reads the essential summary for every substance.

    psx:substance/alcohol/version/2

5Issued documents

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

Issued documents
documentcontent hashissuedfrom versionsuperseded
info_card6240c15f7982f800e587eb57…2026-10-19 20:30Revision 1current
emergencydcd2ca271fbe095dc7fb6211…2026-09-04 04:28Revision 1current
info_card3abb77e5440b224e6bd3445c…2026-09-04 04:28Revision 1superseded2026-10-19
notice07185ae48f2a06b9124c2420…2026-09-04 04:28Revision 1current