generation run 2026-04-28
69 min completedmodel pipeline-v5plan not recordedrun/77a4e7e9…Selection
Verification
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The model's own caveats
- sparse_evidence
Reproduce
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- 21 source keys (listed under Sources)
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- not recorded — template version, prompt hash and git SHA are written from 2026-09 onward
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- pipeline-v5
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24 searches — query, source, results, what was kept and why
| # | source | query | seen | kept | rationale |
|---|---|---|---|---|---|
| 1 | PubMed | 1,3-butanediol safety ketone ester human study clinical | 4 | 4 | Critical safety/tolerability data for 1,3-BD in human subjects |
| 2 | ClinicalTrials.gov | 1,3-butanediol ketone supplement | 10 | 5 | Active/recruiting trials most relevant to 1,3-BD pharmacology and clinical applications |
| 3 | PsychonautWiki | 1,3-butanediol psychoactive effects | 1 | 1 | Community-sourced subjective effects data, important for substance characterization given sparse clinical data |
| 4 | PubChem | 1,3-Butanediol | 1 | 1 | Primary chemical identity verification |
| 5 | Web | 1,3-butanediol legal status United Kingdom European Union Australia schedule | 10 | 0 | Legal status research - confirmed uncontrolled status for 1,3-BD |
| 6 | PubMed | butanediol GABA alcohol sedative hypnotic | 9 | 8 | These papers clarify 1,4-BD pharmacology (GHB-mediated) vs 1,3-BD - important for distinguishing isomers |
| 7 | PubMed | PMID 34521698 | 1 | 1 | Most comprehensive toxicologic profile of 1,3-BD in animals; dose-response data |
| 8 | Web | 1,3-butanediol CAS 107-88-0 SMILES LD50 physical properties | 10 | 2 | Retrieved key chemical identity and safety data not available via PubChem API |
| 9 | PubMed | 1,3-butanediol metabolism ketone body | 10 | 10 | All relevant to understanding 1,3-BD pharmacology and metabolic profile |
| 10 | PubMed · absence | 1,3-butanediol pharmacology GABA GHB | 0 | 0 | Empty result; important finding of literature gap for 1,3-BD CNS pharmacology |
| 11 | Frontiers/CrossRef | R-1,3-butanediol Avela clinical trial ketone tolerability | 1 | 1 | Key pharmacokinetic data for R-1,3-BD in humans |
| 12 | PubMed | PMID 1033604 Majchrowicz 1976 Science | 1 | 1 | First major paper showing 1,3-BD as ethanol-cross-tolerant CNS depressant |
| 13 | PubMed | 1,3-butanediol dependence withdrawal ethanol rat | 3 | 3 | All three papers are foundational for understanding 1,3-BD CNS effects and dependence potential |
| 14 | PubMed | 1,3-butanediol cycling time trial dizziness nausea euphoria | 1 | 1 | Critical: documents psychoactive effects (euphoria, dizziness) at human doses |
| 15 | PubMed | 1,3-butanediol running performance exercise carbohydrate | 1 | 1 | Additional human PK and tolerability data |
| 16 | PubMed | PMID 6317842 Frye 1983 GABA microinjection | 1 | 1 | Critical mechanistic paper showing 1,3-BD effects require metabolic conversion |
| 17 | Web | 1,3-butanediol euphoria dose 0.5 g/kg human adverse effects | 10 | 2 | Historical dose safety data and comprehensive literature overview |
| 18 | Web/13bdpapers.com | 1,3-butanediol papers list history | 1 | 1 | Comprehensive reference list confirming historical literature |
| 19 | CrossRef/OpenAlex | DOI 10.1161/JAHA.124.038461 | 1 | 1 | Clinical safety data in cardiovascular patients |
| 20 | Web | 1,3-butanediol legal status US UK EU Australia Canada 2024 2025 | 10 | 0 | Legal status research confirmed uncontrolled status globally |
| 21 | PubMed | 1,3-butanediol cerebral energy metabolism brain beta-hydroxybutyrate comparison | 1 | 1 | Directly addresses mechanism of brain effects; contradicts direct GABA-A PAM classification |
| 22 | Web | 1,3-butanediol metabolism alcohol dehydrogenase CYP2E1 pathway liver | 10 | 0 | Metabolic pathway confirmation |
| 23 | PubMed | ketone supplement alcohol craving withdrawal treatment randomized trial | 2 | 2 | Key data on interaction between 1,3-BD-derived ketones and alcohol/AUD |
| 24 | ClinicalTrials.gov | 1,3-butanediol ketone supplement alcohol withdrawal | 10 | 6 | Active clinical trial landscape for 1,3-BD |
79 claims by section — every cited sentence, checked against its source
safety26 · 22 ok
Diabetes mellitus and hypoglycemia susceptibility: 1,3-BD produces documented blood glucose reduction in humanssupported
Decreased blood glucose, less negative nitrogen balance. Nontoxic metabolite providing calories. pmid:1183620
Morris et al. (2026) noted that 1,3-butanediol "is used in some formulations despite limited safety data" at population level.supported
1,3-butanediol (BD) is used in some formulations despite limited safety data. nu18040675
Claim in safety — inconclusiveinconclusiveworking →
12.5–25 g/day for 28 days (BH-BD ketone ester) — no clinically meaningful safety changes; no stimulation or sedation difference from placebosupported
No differences in tolerability, stimulation or sedation scores between BH-BD (bis-hexanoyl-(R)-1,3-butanediol) and placebo at 12.5g and 25g/day. No clinically meaningful changes in safety measures. nu13062066
34.5 g single day (R-1,3-BD, Avela™) — well tolerated; GI symptoms mild in most; 5/26 mild headaches (2 possibly drug-related)supported
No/mild GI symptoms in most participants. Mild headaches in 5 participants. fphys.2023.1195702
Tobin et al. (1975) demonstrated blood glucose reduction in humans receiving 1,3-BD as a dietary supplementsupported
1,3-BD isocaloric substitution for starch in human diets. Decreased blood glucose, less negative nitrogen balance. pmid:1183620
Claim in safety — inconclusiveinconclusiveworking →
Dehydration occurred in rats consuming 1,3-BD at 10–20% in drinking water.partially supported
Only 20% 1,3-BD significantly elevated systemic and urinary βHB concentrations. 20% 1,3-BD caused rapid and sustained reduction in body mass, dehydration, metabolic acidosis, and sinusoidal dilation. jpet.121.000796
Metabolic acidosis was observed only at suprapharmacological doses in animals (20% drinking water for 4 weeks).supported
Only 20% 1,3-BD significantly elevated systemic and urinary βHB concentrations. 20% 1,3-BD caused rapid and sustained reduction in body mass, dehydration, metabolic acidosis, and sinusoidal dilation. jpet.121.000796
Sinusoidal dilation was observed on liver histology in rats at 20% drinking water concentration, but no fatty liver or hepatotoxicity was notedsupported
20% 1,3-BD caused rapid and sustained reduction in body mass, dehydration, metabolic acidosis, and sinusoidal dilation, but no fatty liver or hepatotoxicity. jpet.121.000796
Gastrointestinal distress (nausea, abdominal cramping) — most common adverse effect, dose-relatedsupported
In BD trial: moderate to severe GI symptoms in 5/9 participants; dizziness, nausea, and euphoria reported in 2/9. ijsnem.2018-0284
Gastrointestinal distress (nausea, abdominal cramping) — most common adverse effect, dose-relatedsupported
No/mild GI symptoms in most participants. fphys.2023.1195702
Headache — 5/26 participants at 34.5 g (2 possibly drug-related)supported
Mild headaches in 5 participants. fphys.2023.1195702
Euphoria and dizziness — reported at ≥0.35 g/kg dosessupported
dizziness, nausea, and euphoria reported in 2/9. ijsnem.2018-0284
Frye et al. (1981) demonstrated that chronic 1,3-BD administration in rats produced measurable tolerance and physical dependencesupported
Chronic administration caused physical dependence. pmid:7193248
Majchrowicz et al. (1976) established bidirectional cross-tolerance between 1,3-BD and ethanol: 1,3-BD suppressed ethanol withdrawal, and ethanol-tolerant animals showed reduced response to 1,3-BD.partially supported
Nonintoxicating oral dose of 1,3-BD (4 g/kg) suppressed tremulous and convulsive components of ethanol withdrawal syndrome in rats for 1-5 hours. pmid:1033604
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Cross-tolerance: Bidirectional cross-tolerance at the CNS level is established in animal models.supported
Acute IP equimolar doses of 1,3-BD vs ethanol impaired aerial righting reflex, lowered BP, reduced ethanol withdrawal reactions. Chronic administration caused physical dependence. pmid:7193248
Cross-tolerance: Bidirectional cross-tolerance at the CNS level is established in animal models.supported
Nonintoxicating oral dose of 1,3-BD (4 g/kg) suppressed tremulous and convulsive components of ethanol withdrawal syndrome in rats for 1-5 hours. pmid:1033604
Paradoxical dampening: Li et al. (2024) demonstrated that ketone supplementation dampened both subjective and objective responses to alcohol in healthy volunteerssupported
This study examined KS effects on alcohol sensitivity (subjective and objective responses to alcohol). pyae009
Li et al. (2026) extended this to show ketone-induced shifts in brain energy metabolism and reduced alcohol craving in alcohol use disordersupported
17% reduction in brain glucose metabolism. KE significantly reduced alcohol craving in AUD participants. j.pscychresns.2026.112154
1,3-BD lowers blood glucose in humanssupported
Decreased blood glucose, less negative nitrogen balance. pmid:1183620
Pregnancy: One rat study of periconceptional 1,3-BD supplementation showed no adverse fetal effects at 20% drinking water concentrationsupported
1,3-BD (20% via drinking water) treatment increased plasma BHB. Lowered blood pressure, reduced uterine artery resistance index. No adverse fetal effects. ajpheart.00060.2021
Ketone supplementation may reduce alcohol sensitivity and craving, but competitive inhibition of alcohol dehydrogenase by ethanol blocks 1,3-BD metabolismpartially supported
Ketone supplements reduce alcohol craving, consumption, and withdrawal signs. pyae009
Ketone supplementation may reduce alcohol sensitivity and craving, but competitive inhibition of alcohol dehydrogenase by ethanol blocks 1,3-BD metabolismpartially supported
KE significantly reduced alcohol craving in AUD participants. j.pscychresns.2026.112154
neuroscience10 · 8 ok
Frye et al. (1983) established that the compound is inactive when applied directly to central brain structures, ruling out a primary mechanism involving direct GABA receptor bindingsupported
1,3-Butanediol was INACTIVE when microinjected intracranially (inferior colliculus) but effective peripherally - suggesting CNS effects are mediated indirectly via metabolic conversion, not direct central GABA agonism. pmid:6317842
In rats, 1,3-BD impairs the aerial righting reflex (indicating cerebellar and vestibular disruption), attenuates punishment-suppressed drinking (anxiolytic-like action), lowers blood pressure, and reduces cerebellar cGMP contentpartially supported
Acute IP equimolar doses of 1,3-BD vs ethanol impaired aerial righting reflex, lowered BP, reduced ethanol withdrawal reactions. pmid:7193248
Gueldry and Bralet (1994) demonstrated that 1,3-BD administration (25–50 mmol/kg IP, rats) produces distinctive cerebral metabolic changes: reduced glycolytic rate, decreased lactate, and increased glucose and glycogen storessupported
BD (25 and 50 mmol/kg) increased cortical glucose/plasma glucose ratio, decreased lactate, increased glucose and glycogen stores. pmid:8072465
In individuals with alcohol use disorder, this metabolic shift was associated with reduced alcohol craving.supported
KE significantly reduced alcohol craving in AUD participants. j.pscychresns.2026.112154
Claim in neuroscience — inconclusiveinconclusiveworking →
The metabolic competition model explains the paradoxical finding that ketone supplementation dampens rather than enhances alcohol's effects.supported
Ketone supplements reduce alcohol craving, consumption, and withdrawal signs. This study examined KS effects on alcohol sensitivity (subjective and objective responses to alcohol). pyae009
The metabolic competition model explains the paradoxical finding that ketone supplementation dampens rather than enhances alcohol's effects.supported
17% reduction in brain glucose metabolism. KE significantly reduced alcohol craving in AUD participants. Supports KE as reducing brain glucose reliance and potentially treating AUD. j.pscychresns.2026.112154
Gueldry and Bralet's finding that BHB infusion alone does not replicate 1,3-BD's brain metabolic effects supports the hypothesis that the parent compound has independent central activity, even if it does not directly engage GABA receptors.supported
BHB treatment mimicking equivalent hyperketonemia did NOT modify cerebral glycolysis. BD did not reduce cerebral metabolic rate (excluding barbiturate-like depressant action). Suggests BD reduces cerebral glycolytic rate via intracerebral conversion to BHB rather than systemic ketosis. pmid:8072465
Claim in neuroscience — inconclusiveinconclusiveworking →
Does 1,3-BD produce neuroplastic changes? BHB's HDAC inhibitory activity and epigenetic effects suggest possible neuroplasticity modulation, but no direct assessment (BDNF expression, dendritic spine density, synaptic protein levels) has been conducted for 1,3-BD.supported
Significant transcriptional upregulation via H3K9 BHB-ylation. ajpcell.00453.2025
pharmacology10 · 7 ok
Claim in pharmacology — inconclusiveinconclusiveworking →
BHB is the primary active metabolite responsible for most documented metabolic and CNS effectssupported
1,3-butanediol (1,3-BD) is commonly administered to raise β-hydroxybutyrate (βHB) bioavailability in vivo. jpet.121.000796
Frye et al. (1983) microinjected 1,3-BD directly into the inferior colliculus of ethanol-dependent rats and found it inactive, while GABA agonists (muscimol, THIP, chlordiazepoxide) were effective at the same sitesupported
1,3-Butanediol was INACTIVE when microinjected intracranially (inferior colliculus) but effective peripherally. pmid:6317842
The authors explicitly excluded barbiturate-like depressant action.supported
BD did not reduce cerebral metabolic rate (excluding barbiturate-like depressant action). pmid:8072465
GABA-A receptor positive allosteric modulator — No published direct binding data for 1,3-BD at GABA-A receptors exist. Frye et al. (1983) explicitly demonstrated that central GABA receptor sites are not the site of 1,3-BD's action. Functional CNS depressant effects resemble GABAergic modulation but may be indirect, mediated through BHB or other metabolic pathways. This classification is unverified for the parent compound.supported
1,3-Butanediol was INACTIVE when microinjected intracranially (inferior colliculus) but effective peripherally - suggesting CNS effects are mediated indirectly via metabolic conversion, not direct central GABA agonism. pmid:6317842
Claim in pharmacology — inconclusiveinconclusiveworking →
HDAC inhibition — epigenetic modification via histone β-hydroxybutyrylationsupported
Significant transcriptional upregulation via H3K9 BHB-ylation. ajpcell.00453.2025
At a lower dose of 0.35 g/kg racemic 1,3-BD, blood D-BHB rose to 0.44–0.79 mmol/L during exercise, peaking at 1.38 mmol/L post-exercise approximately 2 hours post-dose.supported
0.35 g/kg BD raised blood D-BHB to 0.44-0.79 mmol/L during exercise, peaked at 1.38 mmol/L post-TT. ijsnem.2018-0284
Exogenous ketosis (≥0.5 mmol/L BHB elevation) persists for approximately 1–2 hours after moderate single doses and up to ~5 hours with split-dose protocols at 34.5 g.supported
EKS ingestion produces acute transient (1-2h) increase in AcAc and βHB. sms.70158
Claim in pharmacology — inconclusiveinconclusiveworking →
summary10 · 8 ok
Pharmacological interest in 1,3-butanediol emerged in the mid-1970s when Majchrowicz et al. demonstrated its capacity to suppress ethanol withdrawal in rats, followed by Frye et al.'s comprehensive CNS comparison with ethanol in 1981supported
Nonintoxicating oral dose of 1,3-BD (4 g/kg) suppressed tremulous and convulsive components of ethanol withdrawal syndrome in rats for 1-5 hours. pmid:1033604
Pharmacological interest in 1,3-butanediol emerged in the mid-1970s when Majchrowicz et al. demonstrated its capacity to suppress ethanol withdrawal in rats, followed by Frye et al.'s comprehensive CNS comparison with ethanol in 1981supported
Acute IP equimolar doses of 1,3-BD vs ethanol impaired aerial righting reflex, lowered BP, reduced ethanol withdrawal reactions. pmid:7193248
Claim in summary — inconclusiveinconclusiveworking →
1,3-Butanediol functions primarily as a prodrug: hepatic alcohol dehydrogenase and aldehyde dehydrogenase convert it to (R)-β-hydroxybutyrate, the principal physiological ketone bodysupported
1,3-butanediol (1,3-BD) is commonly administered to raise β-hydroxybutyrate (βHB) bioavailability in vivo. jpet.121.000796
Direct microinjection into brain tissue produces no effect, confirming that CNS activity requires peripheral metabolic conversion rather than direct receptor engagementsupported
1,3-Butanediol was INACTIVE when microinjected intracranially (inferior colliculus) but effective peripherally - suggesting CNS effects are mediated indirectly via metabolic conversion, not direct central GABA agonism. pmid:6317842
The subjective experience resembles alcohol intoxication — disinhibition, anxiolysis, euphoria, and dizziness — but lacks the locomotor stimulation characteristic of ethanolsupported
Differences: no locomotor stimulation, less effect on LH than ethanol. pmid:7193248
Claim in summary — inconclusiveinconclusiveworking →
Chronic administration in rats produces physical dependence with a withdrawal syndrome characterized by CNS hyperexcitability analogous to sedative-hypnotic withdrawalsupported
Chronic administration caused physical dependence. pmid:7193248
Cross-tolerance with ethanol is established in both directionssupported
Nonintoxicating oral dose of 1,3-BD (4 g/kg) suppressed tremulous and convulsive components of ethanol withdrawal syndrome in rats for 1-5 hours. pmid:1033604
Hypoglycemia is a documented metabolic risk at higher dosessupported
Decreased blood glucose, less negative nitrogen balance. pmid:1183620
clinical-evidence6 · 5 ok
No clinically meaningful changes in safety measures were observed, and no difference in stimulation or sedation was detected between active and placebo groups.supported
No differences in tolerability, stimulation or sedation scores between BH-BD (bis-hexanoyl-(R)-1,3-butanediol) and placebo at 12.5g and 25g/day. No clinically meaningful changes in safety measures. nu13062066
The product was generally well tolerated, with mild gastrointestinal symptoms in most participants and mild headaches in 5/26 (two possibly related to study product).supported
No/mild GI symptoms in most participants. Mild headaches in 5 participants. fphys.2023.1195702
No measurable impact on cycling time-trial performance was observed.supported
No performance benefit. ijsnem.2018-0284
Claim in clinical-evidence — inconclusiveinconclusiveworking →
Li et al. (2024) conducted a randomized crossover trial demonstrating that ketone supplementation dampened both subjective and objective responses to alcohol in healthy volunteerssupported
This study examined KS effects on alcohol sensitivity (subjective and objective responses to alcohol). pyae009
Li et al. (2026) extended this work using neuroimaging to show that ketone supplementation shifts brain energy metabolism from glucose to ketones and reduces alcohol craving in alcohol use disorder.supported
17% reduction in brain glucose metabolism. KE significantly reduced alcohol craving in AUD participants. Tripled cingulate BHB levels. j.pscychresns.2026.112154
comparative-pharmacology6 · 4 ok
The most detailed head-to-head comparison comes from Frye et al. (1981), conducted as equimolar intraperitoneal dosing in rats:supported
Acute IP equimolar doses of 1,3-BD vs ethanol impaired aerial righting reflex, lowered BP, reduced ethanol withdrawal reactions. pmid:7193248
The lower brain concentrations required for equivalent behavioral effects suggest greater intrinsic CNS potency for 1,3-BD compared to ethanol on a per-unit-brain-concentration basis.supported
Brain content of 1,3-BD was only 33% that of ethanol at equimolar doses, suggesting greater CNS potency. pmid:7193248
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
Li et al. (2024) demonstrated that ketone supplementation dampened both subjective and objective responses to alcohol in healthy volunteers — a counterintuitive finding suggesting that co-ingestion may reduce, rather than additively enhance, alcohol's effectssupported
Ketone supplements reduce alcohol craving, consumption, and withdrawal signs. This study examined KS effects on alcohol sensitivity (subjective and objective responses to alcohol). pyae009
Li et al. (2026) extended this to show that ketone supplementation shifts brain energy metabolism from glucose to ketones and reduces alcohol craving in alcohol use disorder, suggesting metabolic competition rather than simple CNS synergy.supported
17% reduction in brain glucose metabolism. KE significantly reduced alcohol craving in AUD participants. Supports KE as reducing brain glucose reliance and potentially treating AUD. j.pscychresns.2026.112154
history5 · 4 ok
They demonstrated that a "nonintoxicating" oral dose of 1,3-BD (4 g/kg) suppressed the ethanol withdrawal syndrome in rats for 1–5 hours, establishing both the compound's CNS depressant properties and its cross-tolerance with ethanol.supported
Nonintoxicating oral dose of 1,3-BD (4 g/kg) suppressed tremulous and convulsive components of ethanol withdrawal syndrome in rats for 1-5 hours. pmid:1033604
The same study documented physical dependence with withdrawal-induced CNS hyperexcitability, absence of locomotor stimulation (unlike ethanol), and less endocrine disruption (LH suppression) than equimolar ethanol.supported
Chronic administration caused physical dependence. Differences: no locomotor stimulation, less effect on LH than ethanol. pmid:7193248
The first controlled human metabolic study was published by Tobin et al. in 1975, establishing 1,3-BD as a nontoxic caloric substrate that decreased blood glucose and spared nitrogen — opening investigation of the compound as a food ingredient and alternative energy source.supported
1,3-BD isocaloric substitution for starch in human diets. Decreased blood glucose, less negative nitrogen balance. Nontoxic metabolite providing calories. No significant adverse effects on most blood parameters. pmid:1183620
In 1983, Frye et al. published a key mechanistic finding: 1,3-BD microinjected directly into the inferior colliculus of ethanol-dependent rats was inactive, while GABA agonists (muscimol, THIP, chlordiazepoxide) were effective at the same site — demonstrating that 1,3-BD's CNS effects require peripheral metabolic conversion rather than direct central receptor engagement.supported
1,3-Butanediol was INACTIVE when microinjected intracranially (inferior colliculus) but effective peripherally - suggesting CNS effects are mediated indirectly via metabolic conversion, not direct central GABA agonism. pmid:6317842
Claim in history — inconclusiveinconclusiveworking →
receptor-pharmacology3 · 2 ok
GABA-A — Frye et al. (1983) demonstrated that direct central application of 1,3-BD is inactive, arguing against a direct GABA-A mechanism for the parent compound.supported
1,3-Butanediol was INACTIVE when microinjected intracranially (inferior colliculus) but effective peripherally - suggesting CNS effects are mediated indirectly via metabolic conversion, not direct central GABA agonism. pmid:6317842
Claim in receptor-pharmacology — inconclusiveinconclusiveworking →
Histone deacetylases (HDACs) — BHB acts as an endogenous HDAC inhibitor, producing epigenetic modifications through histone β-hydroxybutyrylation. This mechanism has been demonstrated in animal models using 1,3-BD as the BHB delivery vehicle.supported
20% vol/vol 1,3-butanediol supplementation in LCR/Tol rats elevated circulating BHB. Significant transcriptional upregulation via H3K9 BHB-ylation. ajpcell.00453.2025
chemistry1 · 0 ok
Claim in chemistry — inconclusiveinconclusiveworking →
effects-overview1 · 1 ok
Compared to ethanol, 1,3-butanediol produces a qualitatively similar depressant profile — relaxation, disinhibition, anxiolysis — but with two key differences: shorter total duration (approximately half that of ethanol at comparable intoxication) and absence of the stimulatory phase that characterizes early alcohol intoxication.partially supported
Differences: no locomotor stimulation, less effect on LH than ethanol. pmid:7193248
pharmacokinetic-detail1 · 0 ok
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →