generation run 2026-05-12
70 min completedmodel pipeline-v5plan not recordedrun/b414db8d…Selection
Verification
- record
- seen / partial
- working
The model's own caveats
- taper_protocol_no_named_standard
- safety_data_unverified
- neonatal_taper_gap
Reproduce
- inputs
- 57 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
| # | source | query | seen | kept | rationale |
|---|---|---|---|---|---|
| 1 | PubMed | baclofen alcohol use disorder treatment clinical trial | 10 | 5 | — |
| 2 | PubChem | baclofen | 1 | 1 | Core chemical identity data needed to verify brief seed data |
| 3 | PubMed | baclofen withdrawal syndrome delirium seizure discontinuation | 2 | 2 | Both directly relevant to baclofen dependence and withdrawal characterization |
| 4 | PubMed | baclofen pharmacokinetics bioavailability absorption humans | 7 | 4 | — |
| 5 | PubMed | baclofen overdose toxicity case report acute poisoning | 6 | 6 | All selected for clinical toxicity characterization |
| 6 | PubMed | baclofen GABA-B receptor pharmacology mechanism action | 10 | 1 | — |
| 7 | PubMed · absence | baclofen history Keberle 1966 chlorophenyl GABA analog synthesis | 0 | — | — |
| 8 | PubMed | baclofen withdrawal clinical features management treatment | 5 | 2 | Withdrawal and toxicity characterization |
| 9 | PubMed | Classics Chemical Neuroscience baclofen 2020 | 1 | 1 | Primary comprehensive reference for baclofen pharmacology and history |
| 10 | WebSearch | baclofen history discovery Heinrich Keberle Ciba 1962 synthesis GABA analog | 10 | 1 | Key historical context |
| 11 | WebSearch | baclofen legal status scheduling United States FDA DEA controlled substance | 10 | 1 | Legal status data |
| 12 | PubMed | baclofen high dose treatment alcohol dependence Ameisen Olivier | 3 | 3 | Seminal reports that sparked baclofen-for-AUD clinical research |
| 13 | ClinicalTrials.gov | baclofen spasticity multiple sclerosis cerebral palsy intrathecal | 3 | 2 | Relevant for intrathecal/oral baclofen spasticity evidence |
| 14 | ClinicalTrials.gov | baclofen alcohol use disorder | 10 | 4 | Relevant baclofen AUD trials |
| 15 | PubMed · absence | baclofen stereochemistry R-baclofen S-baclofen enantiomer enantioselective | 0 | — | — |
| 16 | Crossref | DOI 10.1021/acschemneuro.0c00254 | 1 | 1 | DOI verification for Classics paper |
| 17 | PubMed | ALPADIR baclofen alcohol high dose randomized trial France | 1 | 1 | French high-dose baclofen RCT |
| 18 | PubMed | baclofen neonatal abstinence withdrawal newborn infant exposure | 4 | 3 | Pregnancy safety and neonatal withdrawal data |
| 19 | PubMed | Addolorato baclofen alcohol cirrhosis liver placebo controlled trial Italy | 1 | 1 | Critical RCT on baclofen use in liver disease - unique safety profile |
| 20 | PubMed | BACLAD baclofen alcohol dependence placebo controlled Germany | 5 | 4 | Primary RCT evidence for high-dose baclofen in AUD |
| 21 | PubMed | baclofen dose response high dose safety adverse effects tolerability | 3 | 2 | Core evidence for dose-response data and AUD efficacy |
| 22 | WebSearch | baclofen France Baclocur approved 2018 alcohol dependence regulation ANSM | 10 | 1 | Regulatory history for legal status section |
| 23 | WebSearch | baclofen pharmacokinetics Tmax half-life protein binding bioavailability oral human | 10 | 2 | Key PK parameters not available via PubMed abstracts |
115 claims by section — every cited sentence, checked against its source
safety37 · 6 ok
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Half-life is prolonged, AUC increases, and CNS toxicity manifests as confusion, encephalopathy, and comasupported
During renal failure, elimination decreases with prolonged half-life, resulting in disproportionate CNS toxicity. cp203243
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Because baclofen undergoes minimal hepatic metabolism and no significant CYP enzyme interactions have been identified, pharmacokinetic drug-drug interactions are not a major concern.supported
metabolized by the liver to a minor degree, and excreted unchanged by the kidneys cp203243
Combination with other GABA-B receptor agonists — particularly GHB and its prodrug GBL — produces near-additive receptor activation and synergistic CNS and respiratory depressionsupported
GHB and precursors act as CNS depressants via GABA-B agonism 15563650.2012.702218
Both baclofen and ethanol engage GABA-B and GIRK channel pathwayssupported
Comprehensive review of alcohol's primary molecular targets including GABA-A, GABA-B, NMDA, glycine, 5-HT3, nicotinic receptors, L-type Ca2+ channels and GIRK channels. bjp.2008.30
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Severe renal impairment (eGFR <30 mL/min/1.73 m²): Baclofen accumulates rapidly due to renal-dominant elimination, producing encephalopathy and coma at standard doses.supported
excreted unchanged by the kidneys...During renal failure, elimination decreases with prolonged half-life, resulting in disproportionate CNS toxicity. cp203243
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Moderate renal impairment: Requires dose reduction and close monitoring. CrCl-guided dose adjustment is essential.supported
renal clearance equals creatinine clearance pmid:2336342
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
pharmacology19 · 11 ok
Baclofen is the only FDA-approved selective GABA-B receptor agonistsupported
remaining the only U.S. FDA approved GABA-B agonist acschemneuro.0c00254
The GABA-B receptor is a Class C G protein-coupled receptor (GPCR) that functions as an obligatory heterodimer composed of two subunits: GB1 (ligand-binding) and GB2 (G protein-coupling)supported
Cryo-EM structures of human full-length GB1-GB2 heterodimer in inactive and active states. Agonist binding closes GB1 VFT...induces GB2 signaling via lever-like mechanism. s41586-020-2408-4
The GABA-B receptor is a Class C G protein-coupled receptor (GPCR) that functions as an obligatory heterodimer composed of two subunits: GB1 (ligand-binding) and GB2 (G protein-coupling)supported
Cryo-EM structures of GABA-B heterodimer in antagonist-bound inactive and active states with Gi1. s41422-020-0350-5
Baclofen binds the Venus flytrap (VFT) domain of the GB1 subunit, triggering a conformational rearrangement that propagates through the transmembrane domains and enables the GB2 subunit to couple with Gi/o proteins.supported
Agonist binding closes GB1 VFT, triggers rearrangements in TM domains, induces GB2 signaling via lever-like mechanism. s41586-020-2408-4
This inhibits voltage-gated Ca²⁺ channels — particularly N-type and P/Q-type — reducing calcium influx and suppressing neurotransmitter releasesupported
Baclofen inhibits synaptic transmission and presynaptic Ca2+ currents at calyx of Held; inhibition is G(o)/Gi-dependent pmid:9744963
This inhibits voltage-gated Ca²⁺ channels — particularly N-type and P/Q-type — reducing calcium influx and suppressing neurotransmitter releasesupported
Baclofen suppresses EPSCs and presynaptic Ca2+ currents but not K+ currents at calyx of Held; G-protein-coupled inhibition of Ca2+ channels is primary presynaptic mechanism. pmid:9547222
Claim in pharmacology — inconclusiveinconclusiveworking →
Postsynaptically, GABA-B receptor activation opens G protein-coupled inwardly rectifying K⁺ (GIRK/Kir3) channels, hyperpolarizing the neuronal membrane and reducing excitabilitysupported
Both baclofen and gabapentin induce Kir3 (GIRK) inwardly rectifying K+ currents in CA1 pyramidal cells; baclofen and gabapentin activate GABA-B receptors coupling to Kir3 channels. pmid:12923812
Baclofen reduces dopamine release in the nucleus accumbens shell via presynaptic GABA-B receptors on dopaminergic terminalssupported
Baclofen causes concentration-dependent attenuation of evoked dopamine release in NAc shell. jnr.24843
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
Baclofen also inhibits transient lower esophageal sphincter relaxations (TLESRs) by activating vagal GABA-B receptors, reducing gastroesophageal reflux.supported
Baclofen 40 mg increases postprandial LES pressure and prevents increase in TLESRs in GERD patients dote.12443
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
Because 65–70% of baclofen is excreted unchanged by the kidneys, renal impairment dramatically increases the risk of drug accumulation and toxicity, even at standard therapeutic dosespartially supported
excreted unchanged by the kidneys...During renal failure, elimination decreases with prolonged half-life, resulting in disproportionate CNS toxicity. cp203243
Claim in pharmacology — inconclusiveinconclusiveworking →
Apparent renal clearance approximates creatinine clearance, making CrCl a practical proxy for dose adjustment.supported
renal clearance equals creatinine clearance pmid:2336342
Claim in pharmacology — inconclusiveinconclusiveworking →
clinical-evidence12 · 4 ok
Claim in clinical-evidence — inconclusiveinconclusiveworking →
Claim in clinical-evidence — inconclusiveinconclusiveworking →
Analysis of this cohort demonstrated significant reductions in alcohol consumption and craving at doses exceeding 80 mg/day.supported
Baclofen significantly decreased alcohol consumption and craving. fpsyt.2022.949750
Claim in clinical-evidence — inconclusiveinconclusiveworking →
Claim in clinical-evidence — inconclusiveinconclusiveworking →
Claim in clinical-evidence — inconclusiveinconclusiveworking →
Claim in clinical-evidence — inconclusiveinconclusiveworking →
Claim in clinical-evidence — inconclusiveinconclusiveworking →
The primary outcome was striking: 68.2% of baclofen-treated patients achieved abstinence versus 23.8% on placebo (p = 0.014).supported
68.2% baclofen vs 23.8% placebo maintained total abstinence (p=0.014). j.euroneuro.2015.04.002
A broader meta-analysis covering low- and high-dose baclofen confirmed efficacy across dose ranges while documenting dose-dependent increases in adverse events.supported
Low-dose better efficacy than high-dose. High-dose has low tolerability but rare serious adverse events. j.euroneuro.2018.03.017
Clinical evidence supports its use as add-on therapy for PPI-refractory GERD.supported
Baclofen 40 mg increases postprandial LES pressure and prevents increase in TLESRs in GERD patients dote.12443
Claim in clinical-evidence — inconclusiveinconclusiveworking →
pharmacokinetic-detail11 · 4 ok
Plasma protein binding is low at 30–35%, consistent with extensive tissue distribution.supported
protein binding 35% (±6) pmid:2336342
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
In patients with renal impairment, half-life is prolonged and area under the curve (AUC) increases, leading to drug accumulation and CNS toxicity even at standard therapeutic doses.supported
During renal failure, elimination decreases with prolonged half-life, resulting in disproportionate CNS toxicity. cp203243
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
No specific cytochrome P450 (CYP) enzymes have been identified as responsible for baclofen metabolism in the sources reviewedsupported
metabolized by the liver to a minor degree, and excreted unchanged by the kidneys cp203243
Renal excretion of unchanged drug accounts for 65–70% of total eliminationpartially supported
excreted unchanged by the kidneys cp203243
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
summary9 · 2 ok
Baclofen (β-(4-chlorophenyl)-γ-aminobutyric acid) is a selective GABA-B receptor agonist and the only FDA-approved drug in its mechanistic classsupported
remaining the only U.S. FDA approved GABA-B agonist acschemneuro.0c00254
Claim in summary — inconclusiveinconclusiveworking →
Claim in summary — inconclusiveinconclusiveworking →
Claim in summary — inconclusiveinconclusiveworking →
Claim in summary — inconclusiveinconclusiveworking →
Claim in summary — inconclusiveinconclusiveworking →
Claim in summary — inconclusiveinconclusiveworking →
Claim in summary — inconclusiveinconclusiveworking →
Renal impairment dramatically increases toxicity risk at standard doses, as 65–70% of the drug is excreted unchanged by the kidneyspartially supported
excreted unchanged by the kidneys...During renal failure, elimination decreases with prolonged half-life, resulting in disproportionate CNS toxicity. cp203243
comparative-pharmacology7 · 0 ok
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
neuroscience6 · 2 ok
Claim in neuroscience — inconclusiveinconclusiveworking →
Optimal dose for AUD: The dose-response relationship for anti-craving efficacy versus adverse effects remains incompletely characterized. French TRU data support doses above 80 mg/day, but the formal approval caps at 80 mg/day. Systematic dose-response meta-analysis continues to refine this question.supported
High-dose baclofen (>80 mg/d) not associated with increased adverse events after adjustment...Baclofen significantly decreased alcohol consumption and craving. fpsyt.2022.949750
Claim in neuroscience — inconclusiveinconclusiveworking →
Claim in neuroscience — inconclusiveinconclusiveworking →
Activation of these receptors reduces dopamine release in the NAc shellsupported
Baclofen causes concentration-dependent attenuation of evoked dopamine release in NAc shell. jnr.24843
Claim in neuroscience — inconclusiveinconclusiveworking →
receptor-pharmacology5 · 4 ok
Baclofen is described consistently in the literature as a selective, full agonist at the GABA-B receptorsupported
remaining the only U.S. FDA approved GABA-B agonist acschemneuro.0c00254
Claim in receptor-pharmacology — inconclusiveinconclusiveworking →
Cryo-electron microscopy structures published in 2020 resolved the inactive and active conformations of the receptor complexsupported
Cryo-EM structures of GABA-B heterodimer in antagonist-bound inactive and active states with Gi1. s41422-020-0350-5
Presynaptic: Inhibition of voltage-gated N-type and P/Q-type Ca²⁺ channels via Gβγ subunit interaction, reducing calcium influx at nerve terminals and suppressing neurotransmitter release. This mechanism is responsible for baclofen's antispastic and antinociceptive effects.supported
Baclofen inhibits synaptic transmission and presynaptic Ca2+ currents at calyx of Held; inhibition is G(o)/Gi-dependent pmid:9744963
Postsynaptic: Activation of GIRK (Kir3) potassium channels via Gβγ subunits, generating an outward K⁺ current that hyperpolarizes the postsynaptic membrane and reduces neuronal firing probability. This pathway mediates sedation and anxiolysis.supported
Both baclofen and gabapentin induce Kir3 (GIRK) inwardly rectifying K+ currents in CA1 pyramidal cells; baclofen and gabapentin activate GABA-B receptors coupling to Kir3 channels. pmid:12923812
chemistry4 · 1 ok
Claim in chemistry — inconclusiveinconclusiveworking →
The older systematic name, β-(4-chlorophenyl)-γ-aminobutyric acid, describes the identical structure using GABA positional nomenclature.supported
Baclofen, β-(4-chlorophenyl)-γ-aminobutyric acid acschemneuro.0c00254
Claim in chemistry — inconclusiveinconclusiveworking →
Claim in chemistry — inconclusiveinconclusiveworking →
history4 · 1 ok
Claim in history — inconclusiveinconclusiveworking →
Claim in history — inconclusiveinconclusiveworking →
Claim in history — inconclusiveinconclusiveworking →
Baclofen thus became an approved drug before its molecular target was understood.supported
baclofen received FDA approval before its receptor, GABA-B, was discovered acschemneuro.0c00254
legal-status1 · 0 ok
Claim in legal-status — inconclusiveinconclusiveworking →