1,3-Butanediol

# Research Output: 1,3-Butanediol

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## Chemical Identity

**Verified via PubChem API (CID 7896) and ChemicalBook:**

| Property | Value |
|---|---|
| IUPAC name | Butane-1,3-diol |
| CAS number | 107-88-0 |
| PubChem CID | 7896 |
| Molecular formula | C₄H₁₀O₂ |
| Molecular weight | 90.12 g/mol |
| SMILES | CC(O)CCO |
| InChIKey | PUPZLCDOIYMWBV-UHFFFAOYSA-N |
| Melting point | −54 °C |
| Boiling point | 203–204 °C |
| Density | 1.005 g/mL at 25 °C |
| Appearance | Clear, colorless to faintly yellow viscous liquid |
| Taste | Bitter-sweet |
| Solubility | Miscible with water; soluble in ethanol |
| Flash point | 250 °F (121 °C) |

**Seed data gaps corrected:** PubChem CID, molecular formula, molecular weight, SMILES, and InChIKey were all absent from the seed data — all confirmed here via PubChem API [Ref 26].

**CRITICAL SEED DATA ERROR — FLAG FOR EDITORIAL CORRECTION:** The brief's "Street-name candidates" field incorrectly lists "DMT, Dimethyltryptamine, Dmitri." These are the street names for *N,N-dimethyltryptamine*, a completely different substance. This is almost certainly a database contamination or mis-association from another entry (PSX-0001). 1,3-Butanediol has no documented street names in the published literature; it circulates commercially under brand names such as **Avela™** (R-enantiomer), **KetoneAid Hard Ketones**, and **Ketone-IQ**. This error must be corrected before generation.

**Stereochemistry:** 1,3-Butanediol has one chiral center at C-3, giving rise to two enantiomers: **(R)-1,3-butanediol** and **(S)-1,3-butanediol**. The racemic mixture (R,S) is the industrial/synthetic form. Community and clinical sources consistently identify the **(R)-enantiomer as more pharmacologically active** [Ref 19, Ref 27], though controlled head-to-head human PK comparisons are limited. The R-form is now marketed for recreational/supplement use.

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## Pharmacology

### Mechanism of Action

**Primary mechanism: prodrug → β-hydroxybutyrate (BHB)**

1,3-Butanediol is a secondary aliphatic alcohol. After oral ingestion, it undergoes two-step hepatic oxidation:
1. **Alcohol dehydrogenase** → 3-hydroxybutyraldehyde (intermediate)
2. **Aldehyde dehydrogenase** → **(R)-β-hydroxybutyrate (BHB)**

BHB is the principal physiological ketone body and the primary active species responsible for most metabolic and CNS effects [Ref 1, Ref 26]. The CYP450 system does not appear to be the primary metabolic route, unlike ethanol's CYP2E1 pathway at higher doses.

**Direct CNS activity:**

A critical mechanistic finding from Frye et al. (1983 [Ref 13]): when 1,3-BD was *microinjected directly into the inferior colliculus* of ethanol-dependent rats, it was **inactive**, while GABA agonists (muscimol, THIP, chlordiazepoxide) were effective at the same site. This strongly suggests 1,3-BD does NOT directly activate central GABA receptors — its CNS effects require peripheral metabolic conversion.

Separately, Gueldry and Bralet (1994 [Ref 21]) demonstrated that BD (25–50 mmol/kg IP in rats) reduced cerebral glycolytic rate (decreased lactate, increased glucose and glycogen stores). Critically, equivalent hyperketonemia achieved by BHB administration alone did *not* replicate these brain metabolic changes, suggesting possible intracerebral conversion of BD to BHB as one mechanism. They explicitly excluded barbiturate-like depressant action.

**⚠️ FLAG — Pharmacological classification in seed data requires scrutiny:**

The seed data classifies 1,3-butanediol as "GABA-A receptor positive allosteric modulator, GHB receptor agonist, NMDA receptor antagonist." Based on published literature:

- **"GABA-A PAM"**: No published direct binding evidence for 1,3-BD at GABA-A receptors. Frye 1983 [Ref 13] explicitly showed central GABA receptor sites are not the site of action. The functional CNS depressant effects resemble GABA-A/B modulation but no Ki/EC50 data against GABA-A exist for 1,3-BD. BHB (the metabolite) may modulate GABAergic signaling indirectly. **This classification is unverified and possibly incorrect for the parent compound.**

- **"GHB receptor agonist"**: 1,3-Butanediol does **not** convert to GHB. This pathway applies to **1,4-butanediol** (a different isomer that is scheduled in multiple jurisdictions). Frye et al. (1981 [Ref 11]) explicitly state 1,3-BD's mechanism differs from GHB-based compounds. **This classification is very likely INCORRECT and may represent confusion between 1,3-BD and 1,4-BD.** Must be flagged for editorial review.

- **"NMDA receptor antagonist"**: No published evidence of direct NMDA receptor antagonism by 1,3-BD or its primary metabolite BHB was found in the literature searched. **This classification is unverified.**

**BHB's known receptor targets** (indirect effects via metabolite):
- HCAR2 / GPR109A agonism (anti-inflammatory, neuroprotective)
- NLRP3 inflammasome inhibition
- HDAC inhibition (epigenetic, via histone β-hydroxybutyrylation) [Ref 6]
- Possible indirect GABA-B modulation (class-level, not established for BHB directly)

### Pharmacokinetics (Human Data)

**Dose:** 34.5 g (R)-1,3-BD consumed as 3 × 11.5 g split servings over 60 min in fasting adults:
- BHB fasting baseline: 0.23 ± 0.21 mmol/L
- BHB Cmax: **2.10 ± 0.97 mmol/L**
- BHB Tmax: **133.85 ± 57.07 min** (~2.25 hours)
- BHB iAUC₀₋₃₀₀min: 376.73 ± 156.76 mmol/L·min
- **Sex difference:** Females showed significantly greater Tmax (p=0.046) and larger iAUC (p=0.06) than males [Ref 17 — Lowder et al. 2023]

**Lower dose (exercise study, Shaw 2019 [Ref 14]):** 0.35 g/kg (R,S)-1,3-BD raised blood D-BHB to 0.44–0.79 mmol/L during exercise, peaking at 1.38 mmol/L post-exercise (approximately 2h post-dose).

**Duration:** Exogenous ketosis (≥0.5 mmol/L BHB elevation) persists for approximately **1–2 hours** after moderate doses; sustained up to **~5 hours** with split-dose protocols at 34.5 g [Ref 9, Ref 17]. Metabolic effects of BHB may persist longer than peak blood concentration.

**Key PK note:** Effects of 1,3-BD are likely biphasic — (1) an early phase of direct alcohol-like CNS action from the parent compound crossing the blood-brain barrier, and (2) a longer secondary phase mediated by circulating BHB. The relative contributions of these two phases to psychoactive effects in humans are not well characterized.

**Metabolism:** Primarily hepatic via alcohol dehydrogenase → aldehyde dehydrogenase. No published data on CYP involvement for 1,3-BD specifically at pharmacological doses.

**Bioavailability:** Orally bioavailable; good GI absorption demonstrated across multiple trials. No published IV or other-route PK in humans.

---

## History

**Synthesis and industrial history:** 1,3-Butanediol is an industrial aliphatic diol with long-standing use as a humectant, plasticizer, and solvent. Its formal chemical synthesis dates to classical organic chemistry; the compound has been commercially available since at least the mid-20th century. No single discoverer has been identified in the literature as the first to synthesize it, unlike 1,4-butanediol (first synthesized 1890). CAS registration: 107-88-0 [Ref 32].

**Research history:** The pharmacological interest in 1,3-BD as a psychoactive compound began in earnest in the **mid-1970s**, driven by investigation of its ketogenic properties and its potential as an alcohol substitute or adjunct in treating alcoholism. The landmark paper was **Majchrowicz, Hunt, and Piantadosi (1976)** published in *Science* [Ref 12], which demonstrated that a "nonintoxicating" oral dose of 1,3-BD (4 g/kg) suppressed the ethanol withdrawal syndrome in rats for 1–5 hours. This established cross-tolerance with ethanol and the substance's CNS depressant profile.

**Frye et al. (1981)** at the University of North Carolina then conducted the most comprehensive neuropharmacology comparison with ethanol [Ref 11], establishing that 1,3-BD:
- Is approximately equipotent to ethanol at behavioral level in rats despite lower brain concentrations (suggesting greater CNS potency per brain unit)
- Produces physical dependence with withdrawal CNS hyperexcitability
- Does not produce ethanol's locomotor stimulation
- Causes less endocrine disruption (LH) than equimolar ethanol

**Nutritional research era (1975):** Tobin et al. [Ref 24] published the first controlled human metabolic studies, establishing 1,3-BD as a nontoxic caloric substrate that decreased blood glucose and spared nitrogen. This opened investigations into its use as a food ingredient and energy source.

**Veech/ketone ester era (~2000s–present):** Richard Veech at NIH pursued ketone body esters as therapeutic agents; 1,3-butanediol was incorporated as the diol backbone in ketone esters (e.g., (R)-3-hydroxybutyl (R)-3-hydroxybutyrate) due to its ability to generate BHB after hydrolysis. The DARPA-funded work on soldier endurance contributed to the modern exogenous ketone supplement market [Ref 22].

**Commercial recreational use (~2019–present):** 1,3-Butanediol began appearing in commercially marketed "alcohol alternatives" from approximately 2019, with products like KetoneAid Hard Ketones. Media coverage and recreational community interest expanded significantly post-2020. As of 2026, multiple companies market R-1,3-butanediol beverages as social intoxicants with claimed reduced hangover risk.

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## Subjective Effects

**Published controlled data (human):**

Shaw et al. (2019 [Ref 14]) — cycling study at 0.35 g/kg racemic 1,3-BD:
- Moderate to severe **gastrointestinal symptoms** in 5/9 participants
- **Dizziness, nausea, and euphoria** reported in 2/9 participants
- No measurable impact on performance or sedation

Tobin et al. (1975 [Ref 24]) — dietary supplementation in humans at higher doses:
- Decreased blood glucose (hypoglycemic effect)
- No major subjective CNS effects reported at metabolic doses

Lowder et al. (2023 [Ref 17]) — 34.5 g (R)-1,3-BD in fasting adults:
- **No impact on sleepiness** (Stanford Sleepiness Scale: no significant change)
- Generally well-tolerated; no/mild GI symptoms in most participants
- Mild **headaches** in 5/26 participants (two possibly related to study product)

**Historical reference (dose-escalation):** Per Ketone-IQ/historical source [Ref 19], beverages providing **0.5–0.7 g/kg** (35–49 g for 70 kg person) of racemic 1,3-BD produced **nausea, euphoria, and dizziness**; adverse effects were mitigated with divided dosing.

**Animal models (published):**

Frye et al. (1981 [Ref 11]) — equimolar IP dosing in rats vs. ethanol:
- Impaired aerial righting reflex (sedation/motor impairment)
- Attenuated punishment-suppressed drinking (anxiolytic-like)
- Lowered blood pressure (hypotension)
- Reduced cerebellar cGMP content
- Did NOT cause locomotor stimulation seen with ethanol in mice

**Community-sourced descriptions (PsychonautWiki [Ref 27]):**
- Alcohol-like intoxication with shorter duration than ethanol
- Disinhibition, relaxation, euphoria, dizziness
- Bitter-sweet taste noted as aversive by many users
- GI discomfort common
- Duration described as shorter than alcohol

**Effects taxonomy consistency check (vs. seed data):**
- *Disinhibition* — consistent with published CNS depressant profile [Ref 11, Ref 14]
- *Stimulation* — NOT documented in literature; Frye 1981 explicitly notes NO locomotor stimulation (unlike ethanol). This effect designation may be inaccurate for 1,3-BD.
- *Dizziness* — documented in human trials [Ref 14]
- *Dehydration sensation* — consistent with McCarthy et al. 2021 [Ref 1] showing dehydration at high doses in animals; hypoglycemia may contribute
- *Thought deceleration* — plausible as CNS depressant; no controlled data
- *Analysis suppression* — plausible; no controlled data
- *Anxiety suppression* — consistent with Frye 1981's anxiolytic-like effects (attenuation of punishment-suppressed drinking) [Ref 11]

---

## Safety & Toxicity

**LD50 data (animal):**
- Rat, oral: **18,610 mg/kg** (18.61 g/kg) [Ref 26]
- Mouse, oral: 12,980 mg/kg (12.98 g/kg) [web sources]
- Guinea pig, oral: 11,000 mg/kg (11.0 g/kg) [web sources]
- Rabbit, dermal: >20,000 mg/kg [Ref 26]
- Rabbit, oral: 18,610 mg/kg [Ref 26]

**Comparison:** Rat LD50 approximately 2.5× higher than ethanol (rat oral LD50 ~7.1 g/kg) [Ref 1], suggesting lower acute lethality potential per weight.

**Human safety data:**
- 15 g/day for 14 days: no significant adverse effects (historical clinical study, 1973; ref via [Ref 19])
- 40 g/day for 5 days: no significant adverse effects (historical clinical study, 1975; ref via [Ref 19])
- 12.5–25 g/day for 28 days (BH-BD ketone ester): no clinically meaningful changes in safety measures, no stimulation/sedation difference from placebo [Ref 2]
- 34.5 g/day (Avela, R-1,3-BD): well tolerated, mild GI symptoms in most, 5/26 mild headaches [Ref 17]

**FDA status:** Generally Recognized As Safe (GRAS) for use as a food flavoring molecule [Ref 19, Ref 27]

**Adverse effects documented in literature:**
- GI distress (nausea, abdominal cramping): most common, dose-related [Ref 14, Ref 17]
- Headache: 5/26 participants at 34.5g, 2 possibly drug-related [Ref 17]
- Euphoria, dizziness: at ≥0.35 g/kg doses [Ref 14]
- Hypoglycemia: documented in humans and animal models [Ref 24, Ref 1]; clinically relevant at high doses
- Dehydration: at very high doses in animals (10–20% in drinking water) [Ref 1]
- Metabolic acidosis: only at suprapharmacological doses in animals (20% drinking water, 4 weeks) [Ref 1]
- Sinusoidal dilation (liver histology): at 20% drinking water concentration in rats; no fatty liver or hepatotoxicity [Ref 1]

**Safety note on "limited safety data" (Ref 4):** Morris et al. (2026) specifically noted that 1,3-butanediol "is used in some formulations despite limited safety data" at a population level — flagging the gap between current commercial use volumes and available long-term human safety studies.

**⚠️ FLAG — Safety-critical:** No published acute overdose case reports specific to 1,3-butanediol (as opposed to 1,4-BD) were found. The emergency management literature does not appear to include 1,3-BD cases. No published LD50 in humans. No published studies on respiratory depression potential at high doses in humans.

**⚠️ FLAG — Hypoglycemia risk:** The well-documented hypoglycemic effect [Ref 24, Ref 1] poses a risk for diabetic individuals and those on blood glucose–lowering medications. No clinical contraindication guidance in published literature specific to 1,3-BD.

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## Harm Reduction

**Published risk reduction strategies:**
- Divided dosing reduces GI adverse effects and peak psychoactive symptoms (0.5–0.7 g/kg doses were described as causing nausea/euphoria when consumed acutely; divided dosing mitigated this) [Ref 19]
- Consuming with food slows absorption and reduces GI distress [Ref 17]
- The Lowder et al. (2023 [Ref 17]) protocol (34.5 g over 3 servings across 60 min) was developed partly for tolerability

**Contraindications (inferred from published evidence; no published contraindication guidelines specific to 1,3-BD exist):**
- Diabetes mellitus or hypoglycemia susceptibility (documented blood glucose–lowering effect [Ref 24])
- Pregnancy (limited published data; one rat study [Ref 8] showed no adverse fetal effects at 20% drinking water, but human data are absent)
- Concurrent CNS depressant use — additive CNS and respiratory depression risk by class (no 1,3-BD–specific interaction studies found)
- Alcohol use disorder — complex: ketone supplements may reduce alcohol sensitivity [Ref 3] or reduce cravings [Ref 28], but competitive inhibition of alcohol dehydrogenase by ethanol blocks 1,3-BD metabolism

**Identification:** No colorimetric test kits (e.g., reagent tests) for 1,3-BD are documented in published literature. Not detectable by standard drug screening panels (not a scheduled substance).

**Emergency note:** 1,3-BD produces CNS depression that may be confused with ethanol intoxication; it will NOT be detected by standard breathalyzer or most urine drug tests. No published antidote or reversal protocol specific to 1,3-BD overdose.

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## Tolerance & Dependence

**Tolerance (animal data):**
Frye et al. (1981 [Ref 11]) demonstrated that chronic 1,3-BD administration in rats produced measurable tolerance, consistent with the physical dependence syndrome. No published human tolerance data.

**Physical dependence (animal data):**
- Majchrowicz et al. (1976 [Ref 12]): established that 1,3-BD suppresses ethanol withdrawal syndrome, demonstrating cross-tolerance with ethanol — indicating shared neuroadaptive mechanisms
- Frye et al. (1981 [Ref 11]): chronic administration and withdrawal of 1,3-BD caused CNS hyperexcitability characteristic of physical dependence in rats. This is the same hyperexcitability profile seen in sedative-hypnotic withdrawal syndromes (tremor, seizure susceptibility)
- **⚠️ FLAG — Safety critical:** 1,3-BD produces physical dependence and a withdrawal syndrome in rodent models. Human dependence liability has not been formally assessed in published clinical literature. Given the compound's similarity to ethanol at CNS level, dependence potential in chronic recreational human users is plausible but unquantified.

**Cross-tolerance:** Documented cross-tolerance with ethanol in both directions [Ref 11, Ref 12].

**Withdrawal:** In rats, 1,3-BD withdrawal after chronic administration produced hyperexcitability, analogous to sedative-hypnotic/ethanol withdrawal [Ref 11]. No published human withdrawal case reports.

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## Interactions

**Ethanol (alcohol):**
- **Competitive substrate inhibition:** Both ethanol and 1,3-BD are substrates for alcohol dehydrogenase. Concurrent administration would be expected to competitively inhibit 1,3-BD's metabolism to BHB, potentially extending the half-life of the parent compound and altering its CNS/metabolic profile.
- **Cross-tolerance:** Frye 1981 [Ref 11] and Majchrowicz 1976 [Ref 12] established bidirectional cross-tolerance at CNS level
- **Paradoxical dampening:** Li et al. (2024 [Ref 3]) found that ketone supplementation *dampened* subjective and objective responses to alcohol in healthy volunteers — meaning co-ingestion may *reduce* alcohol's effects, contrary to simple additive CNS depression expectation
- **Brain metabolism shift:** Li et al. (2026 [Ref 28]) demonstrated that ketone supplementation shifts brain energy from glucose to ketones and reduces alcohol craving in AUD, suggesting a metabolic competition rather than CNS synergy

**CNS depressants (general):**
- As a CNS depressant with ethanol-like properties, additive effects with other depressants (benzodiazepines, barbiturates, opioids, GHB/GBL) should be expected at a class level
- **⚠️ FLAG — No published 1,3-BD–specific interaction studies with benzodiazepines, opioids, or other CNS depressants exist.** The interaction profile is inferred from class membership only.

**Blood glucose–lowering agents (insulin, metformin, sulfonylureas, SGLT-2 inhibitors):**
- 1,3-BD lowers blood glucose [Ref 24]; additive hypoglycemic risk with antidiabetics is plausible
- No published interaction studies

**Clinical trials investigating interactions:** NCT05551754 (alcohol response in healthy volunteers), NCT06559995 and NCT06815237 (ketone supplementation in AUD), NCT06807918 (ketones in AUD brain energetics) are all actively investigating the interaction between 1,3-BD/ketone supplements and alcohol — results pending.

---

## Legal Status

**United States:**
- NOT a controlled substance under the Controlled Substances Act (CSA)
- Not scheduled by DEA
- Holds FDA **GRAS (Generally Recognized As Safe)** status as a food flavoring molecule
- Commercially available as food supplement / functional beverage ingredient [Ref 19]

**United Kingdom:**
- NOT listed in Schedules to the Misuse of Drugs Act 1971
- Not a controlled drug; no Home Office licence required
- Note: 1,4-butanediol (a different isomer) was added to UK controls; 1,3-BD was not

**European Union:**
- NOT scheduled; no EU-level controlled substance status identified
- Available as food ingredient in EU jurisdictions

**Canada:**
- NOT a scheduled substance under the Controlled Drugs and Substances Act (CDSA)

**Australia:**
- NOT listed in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP/Poison Scheduling)
- Note: 1,4-butanediol was listed as border-controlled drug from March 2024; 1,3-BD was not affected

**Industrial note:** 40 CFR § 721.11417 references "(3R)-1,3-Butanediol" in a Significant New Use Rule context under EPA environmental regulations (not drug scheduling). No therapeutic or drug scheduling classification in US law.

---

## Clinical Trials

**Active/Recruiting as of April 2026:**

| NCT ID | Title | Phase | Status | Sponsor | Relevance |
|---|---|---|---|---|---|
| NCT06653725 | KETO-AHF: Exogenous Ketone Supplements in Patients Hospitalized for AHF | Phase 2 | Recruiting | Aarhus University Hospital | 1,3-BD vs placebo in acute heart failure/HFrEF [Ref 29] |
| NCT06559995 | Effects of Ketone Supplementation on Alcohol Withdrawal and Brain Metabolism in AUD | Phase 2 | Recruiting | University of Pennsylvania | Ketone (likely 1,3-BD-based) in AUD withdrawal |
| NCT06815237 | Effects of Ketone Supplement and Alcohol on Brain Metabolism | Phase 2 | Recruiting | University of Pennsylvania | Ketone-alcohol interaction |
| NCT06807918 | Effects of Ketones on Brain Energetics and Alcohol Consumption in AUD | Phase 2 | Not Yet Recruiting | University of Pennsylvania | Brain energy, AUD treatment |
| NCT05551754 | Acute Effects of Ketone Supplement on Responses to Alcohol Challenge in Healthy Volunteers | Phase 2 | Active, Not Recruiting | University of Pennsylvania | Alcohol sensitivity interaction |
| NCT06645847 | Targeting Aging With a Ketone Ester for Function in Frailty | N/A | Recruiting | Buck Institute for Research on Aging | KE (1,3-BD based) in frailty |
| NCT07224074 | Impact of Exogenous Ketones on Sleep and Breathing in Healthy Volunteers (K-SLEEP) | Phase 1 | Recruiting | Johns Hopkins University | Sleep/respiratory effects |

**Key completed/published trials relevant to 1,3-BD:**
- NCT04707989 (BH-BD safety, published as Chen et al. 2021 [Ref 2])
- Lowder et al. 2023 (Avela/R-1,3-BD clinical trial [Ref 17])

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## Community Feedback Analysis

No community feedback was submitted in Part A2 of the brief. Per instructions, this section is therefore marked as follows:

**No community feedback submitted.**

---

## Gaps & Flags

### Critical Flags (Must Address Before Generation)

1. **⚠️ CRITICAL — Street name error:** Seed data lists "DMT, Dimethyltryptamine, Dmitri" as street names for 1,3-Butanediol. These belong to *N,N-dimethyltryptamine*, an entirely different substance. 1,3-Butanediol has no established street names in published literature; it is marketed commercially under brand names (Avela™, KetoneAid, Ketone-IQ). The generation agent should NOT use the seed data street names. This requires immediate database correction.

2. **⚠️ CRITICAL — Pharmacological class likely incorrect:** The seed data classifies 1,3-BD as "GHB receptor agonist." No published evidence supports this. GHB receptor agonism is documented for **1,4-butanediol** (which converts to GHB) — not 1,3-BD. This classification is likely a confusion between two different butanediol isomers. The generation agent should NOT perpetuate this classification without explicitly flagging it as unverified/disputed.

3. **⚠️ PHARMACOLOGY FLAG — GABA-A PAM unverified:** The "GABA-A receptor positive allosteric modulator" classification is unverified for 1,3-BD itself. Frye 1983 [Ref 13] showed 1,3-BD is inactive at central GABA sites when applied directly. Effects are likely indirect (via BHB metabolite or systemic ethanol-like mechanisms). No Ki or EC50 data at GABA-A exist for 1,3-BD.

4. **⚠️ PHARMACOLOGY FLAG — NMDA antagonism unverified:** "NMDA receptor antagonist" classification has no published primary source support found in literature searches. Flag as unverified.

### Data Gaps

5. **No published human dose-response curve** for psychoactive effects. Published human data show:
   - GI distress and some euphoria/dizziness at 0.35 g/kg (Shaw 2019 [Ref 14])
   - No sleepiness at 34.5 g in split doses (Lowder 2023 [Ref 17])
   - Nausea/euphoria/dizziness at 0.5–0.7 g/kg acutely (historical ref [Ref 19])
   - No published threshold, light, common, strong, heavy dose ranges in controlled human studies

6. **No published duration data specific to subjective effects** in humans. The PK window (BHB elevation 1–5 hours) is established, but this does not directly map to subjective psychoactive duration.

7. **No human withdrawal or dependence case reports.** Animal dependence data exist [Ref 11, Ref 12], but human addiction liability is unknown. The compound is now in recreational use; clinical literature has not caught up.

8. **No published human overdose or toxicity case reports** specific to 1,3-BD (unlike 1,4-BD, which has extensive emergency medicine literature).

9. **CYP enzyme involvement unknown.** Published metabolic pathway uses alcohol dehydrogenase + aldehyde dehydrogenase, but formal CYP inhibition/induction studies have not been published for 1,3-BD.

10. **Sex differences in PK are documented** (Lowder 2023 [Ref 17]: females show greater Tmax and iAUC) but no sex-disaggregated dose guidance has been published.

11. **Pregnancy contraindication:** Only one animal study (periconceptional rat data [Ref 8] showing no fetal adverse effects); no human pregnancy data.

12. **Dose/duration proposals (per brief directive):** Based on the evidence hierarchy:
    - *Published evidence:* GI/CNS effects at 0.35–0.7 g/kg in single acute dosing; 15–40 g/day documented safe in humans
    - *Structural analog inference:* Effects comparable to but shorter-duration than ethanol (supported by Frye 1981 [Ref 11])
    - *Community reports:* Shorter duration than alcohol (PsychonautWiki [Ref 27])
    - Proposed dose ranges for editorial review: threshold ~0.1 g/kg (~7 g for 70 kg person); light ~0.2–0.3 g/kg; common ~0.35–0.5 g/kg (35 g); strong ~0.5–0.7 g/kg; heavy >0.7 g/kg — NOTE: these are editorial proposals based on limited evidence and should be clearly flagged as unconfirmed
    - Proposed onset: 20–40 min oral (BHB elevation begins ~30–45 min; direct effects possibly faster)
    - Proposed peak: 1–2 hours
    - Proposed total duration: 2–4 hours (shorter than comparable ethanol doses based on Frye 1981 comparison and community reports)

13. **⚠️ "Characterization: emerging" partially accurate.** The compound has been studied since 1975–1981, so it is not newly discovered. However, its *recreational use* and *commercial marketing as alcohol alternative* is indeed recent (post-2019), which may justify the "emerging" characterization in the recreational context.

14. **Interactions with benzodiazepines, opioids, GHB/GBL:** No 1,3-BD-specific data. Inferred class-level additive CNS depression risk. The paradoxical ketone-dampening-of-alcohol effect [Ref 3, Ref 28] complicates simple additive interaction assumptions.