generation run 2026-04-24
29,896 min completedmodel pipeline-v5plan not recordedrun/fa862f62…Selection
Verification
- record
- seen / partial
- working
The model's own caveats
- no_regulatory_approved_protocol
- single_center_evidence
- life_threatening_withdrawal
Reproduce
- inputs
- 46 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
18 searches — query, source, results, what was kept and why
| # | source | query | seen | kept | rationale |
|---|---|---|---|---|---|
| 1 | PubMed | GHB gamma-hydroxybutyrate pharmacokinetics absorption half-life human | 1 | 1 | Foundational human PK study. |
| 2 | PubChem | gamma-hydroxybutyric acid | 1 | 1 | Primary chemical identity source. All key fields confirmed. |
| 3 | PubMed | GHB endogenous neurotransmitter brain succinic semialdehyde | 5 | 3 | Foundational papers on endogenous GHB neurotransmitter system. |
| 4 | PubMed | GHB gamma-hydroxybutyrate dependence withdrawal syndrome | 10 | 6 | All relevant to GHB dependence, withdrawal, and toxicity review. |
| 5 | PubMed | GHB abuse chemsex sexual assault drug facilitated crime | 1 | 1 | Forensic context relevant to harm reduction section. |
| 6 | PubMed · absence | GHB overdose toxicity death case report respiratory depression | 0 | 0 | No usable results. |
| 7 | PubMed | GHB endogenous GABA metabolism blood-brain barrier transport | 4 | 1 | Key BBB transport mechanism paper — MCT substrate. |
| 8 | OpenAlex | gamma-hydroxybutyric acid GHB pharmacology review | 10 | 2 | High-citation landmark papers on GHB sleep effects and comprehensive toxicology review. |
| 9 | PubMed | GHB gamma-hydroxybutyric acid pharmacology receptor binding GABA | 15 | 8 | All selected — directly relevant to GHB pharmacology, receptor binding, and mechanism of action. |
| 10 | ClinicalTrials.gov | GHB gamma-hydroxybutyrate sodium oxybate | 15 | 6 | Key completed trials covering narcolepsy treatment, abuse potential, and special populations. |
| 11 | PubMed | get_pubmed_article PMID 15061684 | 1 | 1 | Primary source for regulatory history. |
| 12 | ClinicalTrials.gov | GHB gamma-hydroxybutyrate sodium oxybate clinical trials | 15 | 6 | Key trials documenting GHB/sodium oxybate clinical evidence base. |
| 13 | PubMed | GHB metabolism succinic semialdehyde beta-oxidation pathway liver | 1 | 1 | Key metabolic pathway characterization study. |
| 14 | PubMed | get_pubmed_article PMID 9060200 | 1 | 1 | Foundational GHB dependence paper; api_verified. |
| 15 | WebSearch | GHB gamma-hydroxybutyrate history synthesis Henri Laborit 1961 discovery | 10 | 1 | Historical context confirmed from multiple secondary sources consistent with published literature. |
| 16 | OpenAlex | GHB gamma-hydroxybutyrate abuse dependence withdrawal treatment | 5 | 2 | High-citation landmark papers on GHB dependence and narcolepsy management. |
| 17 | WebSearch | GHB gamma-hydroxybutyrate legal scheduling status US UK EU Canada Australia DEA Schedule I | 10 | 3 | Comprehensive legal status information obtained from DEA, Federal Register, and web sources. |
| 18 | WebSearch | GHB gamma-hydroxybutyric acid melting point solubility pKa physical properties | 8 | 1 | Physical property data partially confirmed. |
127 claims by section — every cited sentence, checked against its source
safety44 · 28 ok
The steep dose-response arises from capacity-limited (nonlinear) pharmacokinetics: both absorption and elimination are saturable, so small dose increments can produce disproportionately large plasma concentration increasessupported
Both absorption and elimination are capacity-limited. AUC increased disproportionately with dose. pmid:8299669
The steep dose-response arises from capacity-limited (nonlinear) pharmacokinetics: both absorption and elimination are saturable, so small dose increments can produce disproportionately large plasma concentration increasessupported
Nonlinear absorption and elimination. s12248-020-00543-z
Respiratory depression is the primary mechanism of deathsupported
Overdose causes sedation, respiratory depression, coma, death. s12248-020-00543-z
Claim in safety — inconclusiveinconclusiveworking →
The approximate lethal dose has been estimated at ~60 mg/kg, though the species for this estimate is not specified in the source and the value requires verification against primary toxicology data.supported
Lethal dose ~60 mg/kg. j.yrtph.2023.105435
Claim in safety — inconclusiveinconclusiveworking →
Postmortem femoral blood concentrations in 37 GHB intoxication deaths averaged 637 mg/L (range 30–9,200 mg/L), reflecting the extreme variability in fatal concentrations driven by tolerance, co-ingested substances, and individual pharmacokinetic differences.partially supported
In 37 drug intoxication deaths: mean B-GHB 637 mg/L bky041
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
This amnestic property underlies GHB's use in drug-facilitated sexual assault.supported
Confirms GHB role in drug-facilitated sexual assault. j.forsciint.2025.112734
This amnestic property underlies GHB's use in drug-facilitated sexual assault.supported
GHB identified among substances used for drink spiking. journal.pone.0306191
GHB is a primary chemsex drug among men who have sex with men (MSM) populations, with prevalence reaching 20% in some communitiessupported
in MSM may reach 20% pmid:27677382
Relapse rates exceed 60% within 3 months of detoxification, indicating high reinforcement and significant psychological dependence.supported
relapse rates over 60% within 3 months after detoxification 000500807
Physical dependence is well-established and represents a significant clinical concernsupported
Narrow therapeutic index, physical dependence potential, dangers of combining with other drugs. pmid:9060200
Physical dependence is well-established and represents a significant clinical concernsupported
GHB dependence associated with potentially fulminant withdrawal syndrome. 000545700
Physical dependence is well-established and represents a significant clinical concernsupported
Chronic GHB use can rapidly lead to physical dependence with withdrawal syndrome similar to alcohol or benzodiazepines pmid:37560960
GHB use disorder is characterized by compulsive use despite harm and is described as a growing health problem in several western countries, especially the Netherlands.supported
GHB dependence is a growing health problem especially in the Netherlands. s12888-015-0471-4
Withdrawal onset is more rapid than alcohol or benzodiazepine withdrawal, with potentially fulminant progression from mild to severe symptomspartially supported
onset is more rapid pmid:37560960
Withdrawal onset is more rapid than alcohol or benzodiazepine withdrawal, with potentially fulminant progression from mild to severe symptomssupported
GHB dependence associated with potentially fulminant withdrawal syndrome. Withdrawal symptoms can rapidly progress from mild to severe. 000545700
The foundational description by Galloway et al. identified insomnia, anxiety, and tremor resolving in 3–12 dayssupported
Withdrawal syndrome includes insomnia, anxiety and tremor; resolves in 3-12 days. pmid:9060200
Claim in safety — inconclusiveinconclusiveworking →
Baclofen (GABA-B agonist): promising as adjunct for withdrawal management and relapse preventionsupported
Baclofen showed promise as relapse prevention. s40263-018-0516-6
Baclofen (GABA-B agonist): promising as adjunct for withdrawal management and relapse preventionsupported
Baclofen as anti-craving agent explored. s12888-015-0471-4
Baclofen (GABA-B agonist): promising as adjunct for withdrawal management and relapse preventionsupported
GABA-B agonist baclofen has shown promise as adjunct. pmid:27677382
Pharmaceutical GHB tapering (DeTiTap): titration and gradual dose reduction using pharmaceutical-grade GHB, demonstrated as feasible and safe in 23 patients in a specialist settingsupported
GHB detoxification by titration and tapering (DeTiTap) with pharmaceutical GHB explored in 23 GHB-dependent patients. Feasible and safe approach. j.drugalcdep.2016.11.014
Inpatient management data from Sydney provide limited evidence on optimal medication selectionsupported
Limited data on effective medications for GHB withdrawal. s00213-022-06283-6
Withdrawal management in pregnancy has been described in a single case report, highlighting the absence of evidence-based guidelines for special populations.supported
No evidence- or practice-based guidelines for GHB withdrawal in pregnancy. adm.0000000000001280
Claim in safety — inconclusiveinconclusiveworking →
GABA-B antagonists block the sedative and lethal effects of GHB/GBL, confirming the receptor-level basis of this interaction.supported
GBL-induced hypothermia, motor-incoordination, and sedation/hypnosis completely prevented by GABA-B antagonists. pmid:18270475
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Valproate, salicylate, and phenylacetate inhibit GHB dehydrogenase, potentially elevating brain GHB levelssupported
Valproate, salicylate, phenylacetate significantly increased GHB in brain. pmid:3106576
Claim in safety — inconclusiveinconclusiveworking →
Concurrent CNS depressant use (alcohol, opioids, benzodiazepines, barbiturates, ketamine) is an absolute contraindication due to lethal risk of additive respiratory depression.supported
When used in high doses or with other sedative hypnotics, respiratory depression, coma, and death have occurred. jcph.1922
Claim in safety — inconclusiveinconclusiveworking →
A single case report describes withdrawal management in a pregnant patientsupported
Treatment of Gamma Hydroxybutyrate Withdrawal in a Pregnant Female: A Case Report adm.0000000000001280
Patients on valproate or other GHB dehydrogenase inhibitors: Enhanced GHB effects due to impaired metabolism represent a relative contraindication.supported
Valproate, salicylate, phenylacetate significantly increased GHB in brain. GHB concentration in brain altered by inhibitors of GHB dehydrogenase. pmid:3106576
Plasma concentrations of approximately 100 mg/L produce euphoria and disinhibition; concentrations approaching 500 mg/L are associated with death from cardiorespiratory depressionsupported
~100 mg/L euphoria; 500 mg/L may cause death. 1570159x13666141210215423
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
pharmacology25 · 19 ok
At therapeutic and recreational concentrations, GHB acts as a low-affinity agonist at GABA-B receptors, with the pharmacological and toxicological effects of exogenous GHB attributed primarily to this targetsupported
GHB binds to both GHB and GABA-B receptors. Nonlinear absorption and elimination. MCT transporters are key. Overdose causes sedation, respiratory depression, coma, death. s12248-020-00543-z
Claim in pharmacology — inconclusiveinconclusiveworking →
GABA-B antagonists fully prevent GHB/GBL-induced hypothermia, motor incoordination, and sedation in animal models, while the putative GHB receptor antagonist NCS-382 provides no protectionpartially supported
GBL-induced hypothermia, motor-incoordination, and sedation/hypnosis completely prevented by GABA-B antagonists. Confirms GABA-B as primary mediator of GHB/GBL in vivo effects. pmid:18270475
In brainstem arousal nuclei (laterodorsal tegmentum, dorsal raphe), GHB-induced calcium rises are mediated by GABA-B receptors; neither NCS-382 nor the GHB receptor agonist HOCPCA blocked these effects.supported
GHB induced GABA-B receptor-mediated rises in calcium in LDT and DR neurons. NCS-382 and HOCPCA failed to block GHB-induced effects, indicating GABA-B as primary mechanism. j.neuroscience.2013.06.011
Claim in pharmacology — inconclusiveinconclusiveworking →
However, Connelly et al. found no evidence that GHB (10 μM) induced GABA-A receptor current in ventrobasal thalamic neurons, dentate gyrus granule cells, or striatal medium spiny neurons in brain slice preparationssupported
No evidence that GHB (10 µM) induces GABA-A current in thalamic neurons, dentate gyrus granule cells, or striatal neurons. journal.pone.0079062
The molecular identity of high-affinity GHB binding sites remains incompletely established.supported
GHB has both low- and high-affinity receptor targets... Certain GABA-A receptor subtypes identified as high-affinity binding sites. j.bcp.2013.10.028
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
Absorption onset occurs within 5–45 minutes, with peak plasma concentrations (Tmax) at 20–40 minutespartially supported
Absorption time 5-45 min, Vd 0.49±0.9 L/kg, half-life 20-60 min. j.yrtph.2023.105435
The volume of distribution is 0.49 ± 0.9 L/kg, and plasma protein binding is not significantpartially supported
Vd 0.49±0.9 L/kg j.yrtph.2023.105435
The volume of distribution is 0.49 ± 0.9 L/kg, and plasma protein binding is not significantpartially supported
No significant plasma protein binding. pmid:8299669
Plasma half-life ranges from 20 to 60 minutes, with urinary excretion accounting for only 1–5% of the administered dose.partially supported
half-life 20-60 min j.yrtph.2023.105435
Palatini et al. demonstrated in a three-dose crossover study (12.5, 25, 50 mg/kg) in 8 healthy males that area under the curve (AUC) increased disproportionately with dose — both oral absorption and elimination are saturable processessupported
Nonlinear PK in 8 healthy male volunteers (12.5, 25, 50 mg/kg oral). AUC increased disproportionately with dose. Both absorption and elimination are capacity-limited. pmid:8299669
GHB crosses the blood-brain barrier via monocarboxylate transporter 1 (MCT1), with high-capacity, low-affinity kinetics (Vmax = 709 nmol/min/g, Km = 11.0 mM)supported
GHB crosses BBB via high-capacity, low-affinity MCT (monocarboxylate transporter). Vmax=709 nmol/min/g, Km=11.0 mM. MCT1 identified as likely isoform. pmid:15173314
Tissue-specific nonlinear distribution (liver, kidney, heart, brain) consistent with MCT1 and MCT4 involvement has been demonstrated.supported
GHB demonstrates tissue-specific nonlinear distribution consistent with MCT involvement. Nonlinear partitioning in liver, kidney, heart. s12248-017-0180-7
Absorption onset occurs within 5–45 minutes, with peak plasma concentrations (Tmax) at 20–40 minutespartially supported
Cmax 20-40 min 1570159x13666141210215423
Plasma half-life ranges from 20 to 60 minutes, with urinary excretion accounting for only 1–5% of the administered dose.partially supported
Only 1-5% recoverable in urine; window 3-10h. Plasma half-life 30-50 min. 1570159x13666141210215423
Claim in pharmacology — inconclusiveinconclusiveworking →
Additional pathways include a substrate cycle between GHB and GABA via succinic semialdehyde, β-oxidation to glycolyl-CoA and acetyl-CoA, and degradation via 4-phosphobutyryl-CoAsupported
substrate cycle between GHB and GABA via succinic semialdehyde; beta-oxidation to glycolyl-CoA + acetyl-CoA; degradation to acetyl-CoA via 4-phosphobutyryl-CoA. bj20112046
AKR7A2 has been identified as the major succinic semialdehyde reductase responsible for GHB biosynthesis in human neuronssupported
AKR7A2 is the major SSA reductase in human neurons, responsible for GHB biosynthesis. pmid:17591773
Valproate, salicylate, and phenylacetate inhibit GHB dehydrogenase, potentially elevating brain GHB levels — a clinically relevant metabolic drug interaction.supported
Valproate, salicylate, phenylacetate significantly increased GHB in brain. pmid:3106576
Detection windows are short: approximately 6 hours in blood and 10 hours in urinesupported
Detection windows 6h blood, 10h urine. j.yrtph.2023.105435
Endogenous GHB levels in serum range from 0.62–3.24 mg/L (mean 1.14 mg/L), establishing forensic cutoffs of 4 mg/L (serum) and 6 mg/L (urine) for identifying exogenous ingestion.supported
Endogenous GHB in serum 0.62-3.24 mg/L (mean 1.14 mg/L). Cutoff 4 mg/L in serum confirmed; urine cutoff proposed as 6 mg/L. j.forsciint.2010.03.035
Claim in pharmacology — inconclusiveinconclusiveworking →
summary12 · 9 ok
Claim in summary — inconclusiveinconclusiveworking →
GHB is distinguished from other depressants by an exceptionally steep, nonlinear dose-response curve: plasma concentrations of ~100 mg/L produce euphoria, while ~500 mg/L are associated with lethal respiratory depression.supported
~100 mg/L euphoria; 500 mg/L may cause death 1570159x13666141210215423
Following widespread recreational use and association with drug-facilitated sexual assault, illicit GHB was placed on US Schedule I in 2000, while FDA-approved sodium oxybate (Xyrem) received a unique Schedule III exception for narcolepsy with cataplexy in 2002supported
Sodium oxybate approved by FDA in 2002 for cataplexy in narcolepsy. Public Law 106-172 (date-rape prohibition act 2000) modified to allow medical use. pmid:14524654
GHB activates GABA-B receptors in the millimolar range — substantially weaker than baclofen — with GABA-B antagonists fully blocking sedation, hypothermia, and motor impairment in animal modelspartially supported
GBL-induced hypothermia, motor-incoordination, and sedation/hypnosis completely prevented by GABA-B antagonists. pmid:18270475
A distinct high-affinity binding site (EC50 = 140 nM at α4β1δ GABA-A receptors) has been identified but its physiological relevance at native synapses remains contestedsupported
GHB is a partial agonist at α4βδ GABA-A receptors (EC50 = 140 nM at α4β1δ). The δ-subunit is essential for potency. pnas.1204376109
A distinct high-affinity binding site (EC50 = 140 nM at α4β1δ GABA-A receptors) has been identified but its physiological relevance at native synapses remains contestedsupported
No evidence that GHB (10 µM) induces GABA-A current in thalamic neurons, dentate gyrus granule cells, or striatal neurons. High GHB (3 mM) produced only GABA-B current. journal.pone.0079062
Capacity-limited absorption, elimination, and MCT1-mediated BBB transport produce the nonlinear pharmacokinetics underlying the steep dose-response.supported
Both absorption and elimination are capacity-limited. AUC increased disproportionately with dose. pmid:8299669
Slow-wave sleep is robustly promoted, with doubled growth hormone secretionsupported
Bedtime GHB (2.5-3.5g) doubled GH secretion with increased amplitude/duration of first GH pulse. Correlated with increased sleep stage IV. jci119587
Claim in summary — inconclusiveinconclusiveworking →
Physical dependence develops with continuous use; withdrawal onset is more rapid than alcohol or benzodiazepine withdrawal, can progress to life-threatening severity, and lacks any FDA- or EMA-approved treatment protocolsupported
Chronic GHB use can rapidly lead to physical dependence with withdrawal syndrome similar to alcohol or benzodiazepines, but onset is more rapid. High-dose benzodiazepines most commonly used treatment. pmid:37560960
Physical dependence develops with continuous use; withdrawal onset is more rapid than alcohol or benzodiazepine withdrawal, can progress to life-threatening severity, and lacks any FDA- or EMA-approved treatment protocolpartially supported
GHB dependence associated with potentially fulminant withdrawal syndrome. Withdrawal symptoms can rapidly progress from mild to severe. 000545700
Claim in summary — inconclusiveinconclusiveworking →
clinical-evidence9 · 6 ok
Sodium oxybate has been marketed as Alcover in Italy and Austria since the 1990s for alcohol withdrawal syndrome and alcohol dependence maintenance — the only EU countries with domestic approval for this indicationsupported
Sodium oxybate clinically used in Italy and Austria since 1990s for alcohol withdrawal. bs.irn.2024.07.005
Sodium oxybate has been marketed as Alcover in Italy and Austria since the 1990s for alcohol withdrawal syndrome and alcohol dependence maintenance — the only EU countries with domestic approval for this indicationsupported
Clinical use in Austria and Italy for 25+ years. adb.12645
Van Cauter et al. demonstrated in a placebo-controlled crossover study (8 healthy men, 2.5–3.5 g oral doses) that bedtime GHB doubled growth hormone secretion via increased amplitude and duration of the first post-sleep-onset GH pulse, significantly increased stage IV (slow-wave) sleep, and transiently elevated prolactin and cortisol without altering thyrotropin or melatonin profiles.partially supported
Bedtime GHB (2.5-3.5g) doubled GH secretion with increased amplitude/duration of first GH pulse. Correlated with increased sleep stage IV. Prolactin and cortisol transiently elevated. jci119587
Bavato et al. conducted a randomized crossover trial in patients with major depressive disorder (GHB 50 mg/kg vs. trazodone vs. placebo), finding that GHB robustly prolonged slow-wave sleep, increased total sleep time and sleep efficiency, reduced N1, N2, and wake-after-sleep-onset, and reduced next-day vigilance lapses compared to both comparators.supported
RCT of GHB (50 mg/kg) vs trazodone vs placebo in MDD. GHB robustly prolonged SWS, total sleep time, and enhanced sleep efficiency. Reduced wake-after-sleep-onset. Reduced number of lapses on PVT vs comparators. s41386-025-02104-4
Claim in clinical-evidence — inconclusiveinconclusiveworking →
Claim in clinical-evidence — inconclusiveinconclusiveworking →
European guidelines subsequently recommended sodium oxybate as a first-line treatment for narcolepsy with cataplexysupported
Sodium oxybate registered for cataplexy; becoming first-line. j.1468-1331.2006.01473.x
Low-sodium oxybate (Xywav) was approved for narcolepsy in 2020 and for idiopathic hypersomnia in 2021.partially supported
low-sodium oxybate (Xywav) approved 2020 s12325-023-02532-y
Claim in clinical-evidence — inconclusiveinconclusiveworking →
history9 · 5 ok
Claim in history — not_supportednot supportedworking →
In Italy and Austria, sodium oxybate has been marketed as Alcover since the 1990s for alcohol withdrawal syndrome and alcohol dependence maintenance — the only EU countries with domestic approval for this indicationsupported
Sodium oxybate clinically used in Italy and Austria since 1990s for alcohol withdrawal. bs.irn.2024.07.005
In Italy and Austria, sodium oxybate has been marketed as Alcover since the 1990s for alcohol withdrawal syndrome and alcohol dependence maintenance — the only EU countries with domestic approval for this indicationsupported
Clinical use in Austria and Italy for 25+ years. adb.12645
Claim in history — not_supportednot supportedworking →
Claim in history — inconclusiveinconclusiveworking →
The bodybuilding market was driven by demonstrations that GHB at bedtime doubled growth hormone secretion via stimulation of slow-wave sleepsupported
Bedtime GHB (2.5-3.5g) doubled GH secretion with increased amplitude/duration of first GH pulse. Correlated with increased sleep stage IV. jci119587
Sodium oxybate (Xyrem, Jazz Pharmaceuticals) received FDA approval in July 2002 for cataplexy in patients with narcolepsy, designated as an orphan drugsupported
FDA-approved July 2002 as Xyrem for cataplexy in narcolepsy under orphan drug provisions. pmid:15061684
Sodium oxybate (Xyrem, Jazz Pharmaceuticals) received FDA approval in July 2002 for cataplexy in patients with narcolepsy, designated as an orphan drugsupported
In July 2002, sodium oxybate was approved by the US FDA for the treatment of cataplexy. pmid:15757428
Claim in history — not_supportednot supportedworking →
pharmacokinetic-detail8 · 7 ok
GHB crosses the blood-brain barrier via monocarboxylate transporter 1 (MCT1), characterized by high-capacity, low-affinity kinetics: Vmax = 709 nmol/min/g, Km = 11.0 mMsupported
Vmax=709 nmol/min/g, Km=11.0 mM. MCT1 identified as likely isoform. pmid:15173314
Palatini et al. conducted a three-dose crossover study (12.5, 25, and 50 mg/kg oral) in 8 healthy male volunteers, demonstrating that AUC increased disproportionately with dosesupported
Nonlinear PK in 8 healthy male volunteers (12.5, 25, 50 mg/kg oral). AUC increased disproportionately with dose. pmid:8299669
Endogenous GHB concentrations in serum range from 0.62 to 3.24 mg/L (mean 1.14 mg/L) and in urine from 0.64 to 4.20 mg/L (mean 1.21 mg/L), establishing forensic cutoffs of 4 mg/L (serum) and 6 mg/L (urine) for identifying exogenous ingestionpartially supported
Endogenous GHB in serum 0.62-3.24 mg/L (mean 1.14 mg/L). Cutoff 4 mg/L in serum confirmed; urine cutoff proposed as 6 mg/L. j.forsciint.2010.03.035
Postmortem femoral blood concentrations in 37 GHB intoxication deaths averaged 637 mg/L (range 30–9,200 mg/L)partially supported
In 37 drug intoxication deaths: mean B-GHB 637 mg/L bky041
Dave et al. developed a physiologically-based PK/PD model incorporating MCT1-mediated renal reabsorption, hepatic metabolism, and brain uptake to describe these nonlinear kinetics.supported
Semi-mechanistic PK/PD model incorporating MCT1-mediated GHB transport, nonlinear liver metabolism, renal reabsorption, and brain uptake. s12248-017-0111-7
Zhang et al. characterized multiple hepatic metabolic routes using metabolomics and mass isotopomer analysis in perfused rat livers:supported
GHB metabolized by multiple pathways in liver: citric acid cycle via oxidation to succinate; substrate cycle between GHB and GABA via succinic semialdehyde; beta-oxidation to glycolyl-CoA + acetyl-CoA. bj20112046
AKR7A2 (aldo-keto reductase 7A2) has been identified as the major succinic semialdehyde reductase responsible for GHB biosynthesis in human neurons.supported
AKR7A2 is the major SSA reductase in human neurons, responsible for GHB biosynthesis. pmid:17591773
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
neuroscience7 · 6 ok
In patients with major depressive disorder, GHB (50 mg/kg) robustly prolonged slow-wave sleep, increased total sleep time and sleep efficiency, and reduced next-day vigilance lapsessupported
RCT of GHB (50 mg/kg) vs trazodone vs placebo in MDD. GHB robustly prolonged SWS, total sleep time, and enhanced sleep efficiency. Reduced number of lapses on PVT vs comparators. s41386-025-02104-4
What mediates the rapid onset and severity of GHB withdrawal relative to other GABAergic substances? The mechanism underlying faster withdrawal onset compared to alcohol and benzodiazepines has not been characterized.supported
onset is more rapid pmid:37560960
At endogenous concentrations, GHB acts as a neuromodulator with highest density in hippocampus, cortex, and dopaminergic structures — striatum, olfactory areas, frontal cortex, and the ventral tegmental area (VTA; A9, A10, A12 cell groups)supported
GHB is a metabolite of GABA present in micromolar quantities in all brain regions. High-affinity receptors in hippocampus, cortex, dopaminergic structures. pmid:9089792
At low (endogenous) concentrations, GHB-mediated stimulation of high-affinity receptors produces dopaminergic hyperpolarization and reduces dopamine releasesupported
Low GHB induces dopaminergic hyperpolarization. pmid:9089792
Claim in neuroscience — inconclusiveinconclusiveworking →
GABA-B-mediated effects in brainstem arousal nuclei — specifically the laterodorsal tegmentum and dorsal raphe — contribute to GHB's sedative and hypnotic propertiessupported
GHB induced GABA-B receptor-mediated rises in calcium in LDT and DR neurons. j.neuroscience.2013.06.011
Are α4β1δ GABA-A receptors the native high-affinity GHB target? The Absalom et al. identification remains contested by the failure to replicate effects in native tissue. Resolution requires single-cell electrophysiology in δ-subunit-expressing neurons with controlled GHB concentrations.supported
No evidence that GHB (10 µM) induces GABA-A current in thalamic neurons, dentate gyrus granule cells, or striatal neurons. journal.pone.0079062
comparative-pharmacology6 · 4 ok
Baclofen's GABA-B agonism has been exploited therapeutically for GHB dependence: it is used as an adjunct for withdrawal management and relapse prevention, leveraging its ability to partially substitute at GHB's primary receptor targetsupported
Baclofen showed promise as relapse prevention. s40263-018-0516-6
Baclofen's GABA-B agonism has been exploited therapeutically for GHB dependence: it is used as an adjunct for withdrawal management and relapse prevention, leveraging its ability to partially substitute at GHB's primary receptor targetsupported
Baclofen as anti-craving agent explored. s12888-015-0471-4
Baclofen's GABA-B agonism has been exploited therapeutically for GHB dependence: it is used as an adjunct for withdrawal management and relapse prevention, leveraging its ability to partially substitute at GHB's primary receptor targetsupported
GABA-B agonist baclofen has shown promise as adjunct. pmid:27677382
Withdrawal from GHB has a more rapid onset than benzodiazepine or alcohol withdrawal, though the clinical presentation (agitation, tremor, seizures, delirium) shares features with both.supported
Chronic GHB use can rapidly lead to physical dependence with withdrawal syndrome similar to alcohol or benzodiazepines, but onset is more rapid. pmid:37560960
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
receptor-pharmacology5 · 4 ok
Claim in receptor-pharmacology — inconclusiveinconclusiveworking →
GABA-B antagonists fully block GHB/GBL-induced hypothermia, motor incoordination, and sedation, while the putative GHB receptor antagonist NCS-382 has no protective effect.partially supported
GBL-induced hypothermia, motor-incoordination, and sedation/hypnosis completely prevented by GABA-B antagonists. pmid:18270475
Ticku and Mehta characterized two binding site populations in rat brain using [³H]NCS-382, with NCS-382 approximately 10-fold more potent than GHB at displacing the radioligand; Scatchard analysis revealed both high-affinity and lower-affinity populations.supported
NCS-382 was about 10x more potent than GHB. Two different populations of binding sites. annals.1432.048
Connelly et al. found no evidence that GHB at 10 μM induced GABA-A receptor current in ventrobasal thalamic neurons, dentate gyrus granule cells, or striatal medium spiny neurons in native brain slice preparations, raising questions about whether the α4β1δ target is physiologically relevant at native synapsessupported
No evidence that GHB (10 µM) induces GABA-A current in thalamic neurons, dentate gyrus granule cells, or striatal neurons. High GHB (3 mM) produced only GABA-B current. journal.pone.0079062
GHB is an endogenous neuromodulator present in micromolar quantities throughout the mammalian brain, with highest concentrations in hippocampus, cortex, and dopaminergic structures (striatum, olfactory areas, frontal cortex, ventral tegmental area A9, A10, A12 cell groups)supported
GHB is a metabolite of GABA present in micromolar quantities in all brain regions. High-affinity receptors in hippocampus, cortex, dopaminergic structures. pmid:9089792
chemistry2 · 1 ok
GHB does not undergo significant plasma protein bindingsupported
No significant plasma protein binding. pmid:8299669
Claim in chemistry — inconclusiveinconclusiveworking →