An official website of the United States government

4-Hydroxybutanoic acid

PubChem CID
10413
Structure
4-Hydroxybutanoic acid_small.png
4-Hydroxybutanoic acid_3D_Structure.png
Molecular Formula
Synonyms
  • 4-Hydroxybutanoic acid
  • 4-Hydroxybutyric acid
  • gamma-Hydroxybutyric acid
  • 591-81-1
  • gamma-Hydroxybutyrate
Molecular Weight
104.10 g/mol
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Dates
  • Create:
    2004-09-16
  • Modify:
    2025-01-18
Description
4-hydroxybutyric acid is a 4-hydroxy monocarboxylic acid that is butyric acid in which one of the hydrogens at position 4 is replaced by a hydroxy group. It has a role as a general anaesthetic, a GHB receptor agonist, a sedative and a neurotoxin. It is a 4-hydroxy monocarboxylic acid and a hydroxybutyric acid. It is functionally related to a butyric acid. It is a conjugate base of a 4-hydroxybutyrate.
gamma-hydroxybutyric acid is a DEA Schedule I controlled substance. Substances in the DEA Schedule I have no currently accepted medical use in the United States, a lack of accepted safety for use under medical supervision, and a high potential for abuse. It is a Depressants substance.
Gamma hydroxybutyric acid, commonly abbreviated GHB, is a therapeutic drug which is illegal in multiple countries. It is currently regulated in the US and sold by Jazz Pharmaceuticals under the name Xyrem. However, it is important to note that GHB is a designated Orphan drug (in 1985). Today Xyrem is a Schedule III drug; however GHB remains a Schedule I drug and the illicit use of Xyrem falls under penalties of Schedule I. GHB is a naturally occurring substance found in the central nervous system, wine, beef, small citrus fruits and almost all other living creatures in small amounts. It is used illegally under the street names Juice, Liquid Ecstasy or simply G, either as an intoxicant, or as a date rape drug. Xyrem is a central nervous system depressant that reduces excessive daytime sleepiness and cataplexy in patients with narcolepsy.

1 Structures

1.1 2D Structure

Chemical Structure Depiction
4-Hydroxybutanoic acid.png

1.2 3D Conformer

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 IUPAC Name

4-hydroxybutanoic acid
Computed by Lexichem TK 2.7.0 (PubChem release 2021.10.14)

2.1.2 InChI

InChI=1S/C4H8O3/c5-3-1-2-4(6)7/h5H,1-3H2,(H,6,7)
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.3 InChIKey

SJZRECIVHVDYJC-UHFFFAOYSA-N
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.4 SMILES

C(CC(=O)O)CO
Computed by OEChem 2.3.0 (PubChem release 2024.12.12)

2.2 Molecular Formula

C4H8O3
Computed by PubChem 2.2 (PubChem release 2021.10.14)

2.3 Other Identifiers

2.3.1 CAS

2.3.3 European Community (EC) Number

2.3.4 UNII

2.3.5 ChEBI ID

2.3.6 ChEMBL ID

2.3.7 DEA Code Number

2010 (DEA schedule I controlled substance)

2.3.8 DrugBank ID

2.3.9 DSSTox Substance ID

2.3.10 HMDB ID

2.3.11 KEGG ID

2.3.12 Lipid Maps ID (LM_ID)

2.3.13 Metabolomics Workbench ID

2.3.14 NCI Thesaurus Code

2.3.15 Nikkaji Number

2.3.16 RXCUI

2.3.17 Wikidata

2.3.18 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

  • 4-hydroxybutyric acid
  • gamma-hydroxybutyric acid

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
104.10 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
XLogP3
Property Value
-0.6
Reference
Computed by XLogP3 3.0 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Donor Count
Property Value
2
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Acceptor Count
Property Value
3
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Rotatable Bond Count
Property Value
3
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Exact Mass
Property Value
104.047344113 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Monoisotopic Mass
Property Value
104.047344113 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Topological Polar Surface Area
Property Value
57.5 Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Heavy Atom Count
Property Value
7
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
60
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Isotope Atom Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Covalently-Bonded Unit Count
Property Value
1
Reference
Computed by PubChem
Property Name
Compound Is Canonicalized
Property Value
Yes
Reference
Computed by PubChem (release 2021.10.14)

3.2 Experimental Properties

3.2.1 Physical Description

Solid

3.2.2 Color / Form

Viscid yellow mass
Lewis, R.J. Sr.; Hawley's Condensed Chemical Dictionary 14th Edition. John Wiley & Sons, Inc. New York, NY 2001., p. 592

3.2.3 Boiling Point

180 °C (dec)
Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I. 3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994., p. 1883

3.2.4 Melting Point

48-50 °C
Lewis, R.J. Sr.; Hawley's Condensed Chemical Dictionary 14th Edition. John Wiley & Sons, Inc. New York, NY 2001., p. 592

3.2.5 Solubility

Very soluble in water, alcohol and ether.
Lewis, R.J. Sr.; Hawley's Condensed Chemical Dictionary 14th Edition. John Wiley & Sons, Inc. New York, NY 2001., p. 592

3.2.6 Dissociation Constants

pKa = 4.72 at 25 °C
Lide, D.R. CRC Handbook of Chemistry and Physics 86TH Edition 2005-2006. CRC Press, Taylor & Francis, Boca Raton, FL 2005, p. 8-43

3.2.7 Collision Cross Section

116.04 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

124.34 Ų [M+K]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

Ross et al. JASMS 2022; 33; 1061-1072. DOI:10.1021/jasms.2c00111

3.2.8 Kovats Retention Index

Semi-standard non-polar
933

3.3 Chemical Classes

3.3.1 Drugs

Pharmaceuticals -> unsed in Switzerland 2014-2016
S113 | SWISSPHARMA24 | 2024 Swiss Pharmaceutical List with Metabolites | DOI:10.5281/zenodo.10501043
Pharmaceuticals
S10 | SWISSPHARMA | Pharmaceutical List with Consumption Data | DOI:10.5281/zenodo.2623484
Pharmaceuticals -> Listed in ZINC15
S55 | ZINC15PHARMA | Pharmaceuticals from ZINC15 | DOI:10.5281/zenodo.3247749
3.3.1.1 Human Drugs
Breast Feeding; Lactation; Milk, Human; Anesthetics; Hypnotics and Sedatives; GABA Modulators
Human drug -> Prescription
Human drugs -> Other nervous system drugs -> Human pharmacotherapeutic group -> EMA Drug Category

3.3.2 Lipids

Fatty Acyls [FA] -> Fatty Acids and Conjugates [FA01] -> Hydroxy fatty acids [FA0105]

4 Spectral Information

4.1 1D NMR Spectra

4.1.1 13C NMR Spectra

Copyright
Copyright © 2016-2024 W. Robien, Inst. of Org. Chem., Univ. of Vienna. All Rights Reserved.
Thumbnail
Thumbnail

4.2 Mass Spectrometry

4.2.1 GC-MS

1 of 8
View All
Spectra ID
Instrument Type
GC-MS
Top 5 Peaks

117.0 1

233.0 0.47

143.0 0.21

103.0 0.19

133.0 0.18

Thumbnail
Thumbnail
2 of 8
View All
Spectra ID
Instrument Type
GC-EI-TOF
Ionization Mode
positive
Top 5 Peaks

147.0 100

117.0 31.43

233.0 17.82

148.0 16.72

149.0 8.61

Thumbnail
Thumbnail
Notes
instrument=Leco Pegasus IV

4.2.2 MS-MS

1 of 6
View All
Spectra ID
Instrument Type
QqQ
Ionization Mode
positive
Top 5 Peaks

57.0 100

103.0 100

85.0 100

Thumbnail
Thumbnail
Notes
adduct_type NA original_collision_energy 10->40V CannabisDB spectra from MoNa 2020 June API 3000 ReSpect
2 of 6
View All
Spectra ID
Instrument Type
Orbitrap
Ionization Mode
negative
Top 5 Peaks

103.0399 92.82

85.0294 5.20

101.0244 1.98

Thumbnail
Thumbnail
Notes
adduct_type [M-H]- original_collision_energy 4 nominal CannabisDB spectra from NIST14 2020 June Thermo Finnigan Elite Orbitrap

4.2.3 LC-MS

MoNA ID
MS Category
Experimental
MS Type
LC-MS
MS Level
MS2
Precursor m/z
103
Instrument
API 3000
Instrument Type
QqQ
Ionization
ESI
Ionization Mode
positive
Collision Energy
10->40V
Top 5 Peaks

57 100

85 100

103 100

Thumbnail
Thumbnail

6 Chemical Vendors

7 Drug and Medication Information

7.1 Drug Indication

Used as a general anesthetic, to treat conditions such as insomnia, clinical depression, narcolepsy, and alcoholism, and to improve athletic performance.
Treatment of narcolepsy with cataplexy in adult patients.

7.2 LiverTox Summary

Oxybate is a small, neuroactive molecule (gamma-hydroxybutyrate) that is used to treat catalepsy and daytime sleepiness in patients with narcolepsy. Oxybate has been reported to cause serum enzyme elevations during therapy, but has not been implicated in instances of clinically apparent acute liver injury.

7.3 Drug Classes

Breast Feeding; Lactation; Milk, Human; Anesthetics; Hypnotics and Sedatives; GABA Modulators
Narcolepsy Agents

7.4 FDA Medication Guides

Drug
Active Ingredient
SODIUM OXYBATE
Form;Route
SOLUTION;ORAL
Company
JAZZ PHARMS
Date
05/22/2024

7.5 Clinical Trials

7.5.1 ClinicalTrials.gov

7.5.2 EU Clinical Trials Register

7.6 DEA Drug and Chemical Information

Gamma Hydroxybutyric Acid

(Street Names:GHB, G, Liquid Ecstasy, Liquid X, Liquid G, Goop, Georgia Home Boy, Grievous Bodily Harm, Easy Lay)

7.6.1 DEA Drug Facts

What is GHB?
Gamma-Hydroxybutyric acid (GHB) is another name for the generic drug sodium oxybate. Xyrem® (which is sodium oxybate) is the trade name of the Food and Drug Administration (FDA)-approved prescription medication. Xyrem® is approved as a treatment to improve daytime sleepiness and muscle weakness with narcolepsy (a disorder marked by sudden, unexplained, spontaneous fatigue, napping, or falling asleep throughout the day).Analogs that are often substituted for GHB include GBL (gamma butyrolactone) and 1,4 BD (also called just “BD”), which is 1,4-butanediol. These analogs are available legally as industrial solvents used to produce polyurethane, pesticides, elastic fibers, pharmaceuticals, coatings on metal or plastic, and other products. They are also sold illicitly as supplements for bodybuilding, fat loss, reversal of baldness, improved eyesight, and to combat aging, depression, drug addiction, and insomnia.GBL and BD are sold as “fish tank cleaner,” “ink stain remover,” “ink cartridge cleaner,” and “nail enamel remover” for approximately $100 per bottle — much more expensive than comparable products. Attempts to identify the abuse of GHB analogs are hampered by the fact that routine toxicological screens do not detect the presence of these analogs.
Street Title
Easy Lay, G, Georgia Home Boy, GHB, Goop, Grievous Bodily Harm, Liquid Ecstasy, Liquid X, Scoop
How is it abused?
GHB and its analogs are misused for their euphoric and calming effects and because some people believe they build muscles and cause weight loss.GHB and its analogs are also misused for their ability to increase libido, suggestibility, passivity, and to cause amnesia (no memory of events while under the influence of the substance) — traits that make victims who unknowingly consume GHB vulnerable to sexual assault and other criminal acts.
What is its effect on the body?
Euphoria, drowsiness, decreased anxiety, and memory impairment. GHB can produce both visual hallucinations and — paradoxically — excited and aggressive behavior. GHB takes effect in 15 to 30 minutes, and the effects last 3 to 6 hours. Low doses of GHB produce nausea. At high doses, Unconsciousness, seizures, slowed heart rate, greatly slowed breathing, lower body temperature, vomiting, nausea, coma, and death.
What are its overdose effects?
GHB overdose can cause coma and death.
Fact sheet

7.6.2 DEA Controlled Substances

Substance
gamma-hydroxybutyric acid
Synonym(s)
GHB|gamma-hydroxybutyrate|4-hydroxybutyrate|4-hydroxybutanoic acid|sodium oxybate|sodium oxybutyrate
DEA Controlled Substances Code Number
2010
Controlled Substances Act Schedule
Schedule I - Substances in the DEA Schedule I have no currently accepted medical use in the United States, a lack of accepted safety for use under medical supervision, and a high potential for abuse.
Class
Depressants

7.7 EMA Drug Information

Medicine
Category
Human drugs
Therapeutic area
Cataplexy; Narcolepsy
Active Substance
sodium oxybate
INN/Common name
sodium oxybate
Pharmacotherapeutic Classes
Other nervous system drugs
Status
This medicine is authorized for use in the European Union
Company
UCB Pharma Ltd
Market Date
2005-10-13

7.8 Therapeutic Uses

Xyrem (sodium oxybate) oral solution is indicated for the treatment of excessive daytime sleepiness and cataplexy in patients with narcolepsy. /Sodium oxybate/
Thomson Health Care Inc.; Physicians' Desk Reference 62 ed., Montvale, NJ 2008, p. 1723
/Expl:/ To evaluate the efficacy and side-effect profile of off-label sodium oxybate (gamma hydroxy butyrate) therapy in severe childhood narcolepsy-cataplexy. DESIGN: Retrospective; chart review. SETTING: A multidisciplinary tertiary sleep center. PATIENTS: A group of eight children with severe narcolepsy-cataplexy diagnosed on the basis of clinical history, nocturnal polysomnography and the multiple sleep latency test were studied. A modified Epworth Sleepiness Scale and an arbitrary cataplexy severity scale (1 = minimal weakness, 2 = voluntarily preventable falls, 3 = falls to the ground) were utilized. INTERVENTIONS: Sodium oxybate therapy; concurrent medications were maintained. MEASUREMENTS AND RESULTS: Before sodium oxybate therapy, all subjects had suboptimally controlled sleepiness and cataplexy. Following treatment with sodium oxybate, 7/8 subjects (88%) improved. Cataplexy frequency decreased from a median of 38.5 to 4.5/ week (p = 0.0078). Cataplexy severity decreased from 2.75 to 1.75 (p = 0.06). The Epworth Sleepiness Scores improved from a median of 19 to 12.5 (p = 0.02). Suicidal ideation, dissociative episodes, tremor and constipation occurred in one subject each and terminal insomnia in two. Three of the 8 (38%) discontinued therapy. Two stopped the drug owing to side effects and one due to problems with postal delivery of the medication.
Murali H, Kotagal S; Sleep 29 (8): 1025-9 (2006)

7.9 Drug Warnings

Central nervous system depressant with abuse potential. Should not be used with alcohol or other CNS depressants. Sodium oxybate is GHB, a known drug of abuse. Abuse has been associated with some important central nervous system (CNS) adverse events (including death). Even at recommended doses, use has been associated with confusion, depression and other neuropsychiatric events. Reports of respiratory depression occurred in clinical trials. Almost all of the patients who received sodium oxybate during clinical trials were receiving CNS stimulants. Important CNS adverse events associated with abuse of GHB include seizure, respiratory depression and profound decreases in level of consciousness, with instances of coma and death. For events that occurred outside of clinical trials, in people taking GHB for recreational purposes, the circumstances surrounding the events are often unclear (e.g., dose of GHB taken, the nature and amount of alcohol or any concomitant drugs). /Sodium oxybate/
Thomson Health Care Inc.; Physicians' Desk Reference 62 ed., Montvale, NJ 2008, p. 1722
Because misuse and abuse of sodium oxybate (GHB) have been reported, patients with a history of drug abuse should be carefully evaluated and followed closely for signs of misuse or abuse (e.g., dosage escalation, drug-seeking behavior). Clinicians should document the diagnosis and indication for sodium oxybate therapy and be alert to drug-seeking behavior and/or feigned cataplexy. Commercially available sodium oxybate is subject to control as a schedule III drug. Nonmedical use of sodium oxybate is subject to control as a schedule I drug. /Sodium oxybate/
McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 2625
Sodium oxybate is a CNS depressant with the potential to impair respiratory drive, especially in patients with preexisting respiratory impairment. Life-threatening respiratory depression has occurred following overdosage of the drug. Respiratory depression and an increase in obstructive sleep apnea have occurred in patients with narcolepsy receiving sodium oxybate in clinical trials. Most patients receiving sodium oxybate in clinical trials were receiving a CNS stimulant concomitantly; whether concomitant use of a CNS stimulant affected nocturnal respiration remains to be determined. Caution is advised if sodium oxybate is used in patients with respiratory impairment. Clinicians should be aware that a high incidence (50%) of sleep apnea has been reported in some cohorts of narcoleptic patients. /Sodium oxybate/
McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 2625
Confused behavior at night, sometimes associated with wandering (sleepwalking), has occurred in patients receiving sodium oxybate in clinical trials. Since instances of substantial injury or potential injury (e.g., a fall, clothing set on fire while attempting to smoke, attempted ingestion of nail polish remover, sodium oxybate overdose) associated with sleepwalking occurred rarely during clinical trials of sodium oxybate, episodes of such activity in patients receiving the drug should be fully evaluated and appropriate interventions considered. /Sodium oxybate/
McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 2625
For more Drug Warnings (Complete) data for 4-HYDROXYBUTANOIC ACID (21 total), please visit the HSDB record page.

7.10 Biomarker Information

8 Food Additives and Ingredients

8.1 Associated Foods

9 Pharmacology and Biochemistry

9.1 Pharmacodynamics

GHB predominantly works at two distinct binding sites in the central nervous system: it works as an agonist at the newly-characterized excitatory GHB receptor, while acting as a weak agonist at the inhibitory GABAB receptor. Since it is a naturally occurring substance, its physiological action is similar to that of some endogenous neurotransmitters in mammalian brain. GHB is probably synthesized from GABA in GABAergic neurons, and released when the neurons fire.

9.2 FDA Pharmacological Classification

FDA UNII
30IW36W5B2
Active Moiety
4-HYDROXYBUTANOIC ACID
Pharmacological Classes
Established Pharmacologic Class [EPC] - Central Nervous System Depressant
Pharmacological Classes
Physiologic Effects [PE] - Central Nervous System Depression
Pharmacological Classes
Physiologic Effects [PE] - Decreased Central Nervous System Organized Electrical Activity
FDA Pharmacology Summary
4-hydroxybutanoic acid is a Central Nervous System Depressant. The physiologic effect of 4-hydroxybutanoic acid is by means of Central Nervous System Depression, and Decreased Central Nervous System Organized Electrical Activity.

9.3 ATC Code

N07XX04

9.4 Absorption, Distribution and Excretion

Route of Elimination
Animal studies indicate that metabolism is the major elimination pathway for sodium oxybate, producing carbon dioxide and water via the tricarboxylic acid (Krebs) cycle and secondarily by beta-oxidation. Succinic acid enters the Krebs cycle where it is metabolized to carbon dioxide and water. Fecal and renal excretion is negligible. 5% renal elimination.
Volume of Distribution
190 to 384 mL/kg
Clearance

apparent oral cl=9.1 mL/min/kg [healthy adults receiving a single oral dose of 25 mg/kg]

4.5 mL/min/kg [cirrhotic patients without ascites receiving a single oral dose of 25 mg/kg]

4.1 mL/min/kg [cirrhotic patients with ascites receiving a single oral dose of 25 mg/kg]

Gamma-hydroxybutyric acid (GHB) ... absorption and disposition kinetics have been studied in 8 healthy male volunteers following oral administration of single doses of 12.5, 25 and 50 mg/kg The AUC increased disproportionately with the dose and so the apparent oral clearance decreased significantly as the dose was increased, whereas the terminal half-life and mean residence time increased. The peak plasma concentrations normalized to the lowest dose fell significantly with increasing doses, whilst the corresponding peak times increased. These findings suggest that both the oral absorption and the elimination of GHB are capacity-limited processes. GHB did not bind to significant extent to plasma proteins over the therapeutic concentration range. The pharmacokinetic parameters in healthy volunteers were not significantly different from those previously observed in alcohol-dependent patients with compensated alcoholic liver disease.
Palatini P et al; Eur J Clin Pharmacol 45 (4): 3353-6 (1993)
After ingestion, GHB is rapidly absorbed and quickly crosses the blood-brain barrier. It is not protein bound and is rapidly metabolized and excreted through the lungs. It has specific binding sites and selective brain distribution with the highest concentration in the basal ganglia.
Goldfrank, L.R. (ed). Goldfrank's Toxicologic Emergencies. 7th Edition McGraw-Hill New York, New York 2002., p. 940
Sodium oxybate is a hydrophilic compound that is rapidly but incompletely absorbed after oral administration with bioavailability approximately 25%. Administration of sodium oxybate immediately after a high fat meal results in delayed and decreased absorption. /Sodium oxybate/
Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 2638
Monocarboxylate transporter 1 (MCT1) is an important determinant of the renal transport of the drug of abuse, gamma-hydroxybutyric acid (GHB). The objective of this study was to investigate the role of MCT2 and MCT4, present in tissues including intestine, kidney, skeletal muscle, and brain, in the membrane transport of GHB and the MCT substrate l-lactate. mRNA and protein of MCT2 and MCT4 were expressed in MDA-MB231 cells, as detected by reverse transcription-polymerase chain reaction and Western blot analysis; MCT1 and MCT3 were not detected. The uptake of GHB or l-lactate by MDA-MB231 cells was pH-dependent but not sodium-dependent. The concentration-dependent uptake of GHB was best fitted to a single-transporter model with a diffusional clearance component (K(m) of 17.6 +/- 1.5 mM, V(max) of 50.6 +/- 9.0 nmol x mg(-1) min(-1) and diffusional clearance of 0.20 +/- 0.07 microl x mg(-1) min(-1)). On the other hand, the concentration-dependent uptake of l-lactate was best fitted to a two-transporter model (K(m) of 21 +/- 2.5 and 3.0 +/- 1.5 mM, and V(max) of 268 +/- 72 and 62.9 +/- 42.2 nmol x mg(-1)min(-1), respectively). The uptake of GHB and l-lactate was inhibited by MCT inhibitors alpha-cyano-4-hydroxycinnamate (CHC), phloretin, and p-chloromercuribenzoic acid; CHC inhibited GHB and l-lactate uptake with IC(50) values of 1.71 +/- 0.39 and 0.71 +/- 0.11 mM, respectively. Small interfering RNA treatment to silence MCT2 or MCT4 significantly decreased their protein expression and the uptake of l-lactate and GHB; however, the decrease in GHB uptake with MCT2 inhibition was smaller than that for MCT4. This investigation demonstrated that GHB is a substrate for both MCT2 and MCT4; these transporters may be important in the nonlinear disposition of GHB, as well as influencing its tissue distribution.
Wang Q et al; Drug Metab Dispos 35 (8): 1393-9 (2007)
For more Absorption, Distribution and Excretion (Complete) data for 4-HYDROXYBUTANOIC ACID (7 total), please visit the HSDB record page.

9.5 Metabolism / Metabolites

gamma-Hydroxybutyrate (chemical formula HOOC-CH2-CH2- CH2OH) is a four-carbon molecule that is found naturally in the central nervous system and, in higher concentrations, in peripheral tissues. It has a structure much like gamma-aminobutyric acid (GABA), which is better understood than GHB and acts as an inhibitory neurotransmitter in vivo. gamma-Aminobutyric acid is catabolized by transamination to succinate semialdehyde, which is then oxidized to succinate. Brain tissue is capable of reducing succinate semialdehyde to GHB. Concentrations of both GHB and GHB-oxidizing enzymes are 15 to 20 times higher in kidney, heart, skeletal muscle, and brown fat than in the central nervous system.
Chin MY et al; West J Med 156 (4): 380-4 (1992)
Animal studies indicate that metabolism is the major elimination pathway for sodium oxybate, producing carbon dioxide and water via the tricarboxylic acid (Krebs) cycle and secondarily by beta-oxidation. The primary pathway involves a cytosolic NADP+-linked enzyme, GHB dehydrogenase, that catalyses the conversion of sodium oxybate to succinic semialdehyde, which is then biotransformed to succinic acid by the enzyme succinic semialdehyde dehydrogenase. Succinic acid enters the Krebs cycle where it is metabolized to carbon dioxide and water. A second mitochondrial oxidoreductase enzyme, a transhydrogenase, also catalyzes the conversion to succinic semialdehyde in the presence of alpha-ketoglutarate. An alternate pathway of biotransformation involves beta-oxidation via 3,4-dihydroxybutyrate to carbon dioxide and water. No active metabolites have been identified. /Sodium oxybate/
Thomson Health Care Inc.; Physicians' Desk Reference 62 ed., Montvale, NJ 2008, p. 1722

9.6 Biological Half-Life

30 to 60 minutes
Elimination: 0.5 to 1 hour. In a clinical study performed in 16 cirrhotic patients, the elimination half life was significantly longer (mean of 59 and 32 versus 22 minutes in healthy patients. /Sodium oxybate/
Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 2638

9.7 Mechanism of Action

GHB is present at much higher concentrations in the brain, where it activates GABA-B receptors to exert its sedative effects. With high affinity, GHB binds to excitatory GHB receptors that are densely expressed throughout the brain, including the cotex and hippocampus. There is some evidence in research that upon activation of GHB receptors in some brain areas, the excitatory neurotransmitter glutamate is released. GHB stimulates dopamin release at low concentrations by acting on the GHB receptor, and the release of dopamine occurs in a biphasic manner. At higher concentrations, GHB inhibits dopamine release by acting on the GABA-B receptors, which is followed by GHB receptor signaling and increased release of dopamine. This explains the paradoxical mix of sedative and stimulatory properties of GHB, as well as the so-called "rebound" effect, experienced by individuals using GHB as a sleeping agent, wherein they awake suddenly after several hours of GHB-induced deep sleep. It is proposed that overtime, the level of GHB in the brain decreases below the threshold for significant GABA-B receptor activation, leading to preferential activation of GHB receptor over GABA-B receptors and enhanced wakefulness.
Oxybate (GHB) is a metabolite of gamma-aminobutyric acid (GABA) which is synthesised and accumulated by neurones in the brain. It is present at uM concentrations in all brain regions investigated as well as in several peripheral organs, particularly in the gastro-intestinal system. Neuronal depolarization releases GHB into the extracellular space in a Ca2+-dependent manner. A family of GHB receptors in rat brain have been identified and cloned and most probably belong to the G-protein-coupled receptors. High-affinity receptors for GHB are present only in neurones, with a restricted specific distribution in the hippocampus, cortex and dopaminergic structures of rat brain. In general, stimulation of these receptors with low (physiological) amounts of GHB induces hyperpolarization in dopaminergic structures with a reduction of dopamine release. However, in the hippocampus and frontal cortex, GHB seems to induce depolarization with an accumulation of cGMP and an increase in inositol phosphate turnover. However, at higher (therapeutic) exposures, GHB receptors are saturated and probably de-sensitized and down-regulated. Such GHBergic potentiations induce dopaminergic hyperactivity, strong sedation with anaesthesia and EEG changes that are consistent with normal sleep and/or epileptic spikes.
European Medicines Agency (EMEA), Committee for Medicinal Products for Human Use; European Public Assessment Report (EPAR) (Scientific Discussion); Xyrem, p.2 (2007). Available from, as of March 19,2008: https://www.emea.europa.eu/humandocs/PDFs/EPAR/xyrem/324056en6.pdf
Gamma-hydroxybutyrate (GHB), a four-carbon fatty acid and anesthetic, is widely considered to be a relatively specific inhibitor of central dopamine (DA) release. The inhibitory effect of GHB on the latter is thought to occur as a consequence of its diminution of impulse flow in central dopaminergic neurons. However, a number of studies have recently reported that GHB primarily stimulates rather than inhibits central DA release, with any inhibitory effect produced of a modest and transitory nature. GHB has been and continues to be widely used as an important research tool largely because it is one of only a few drugs available that acts primarily on DA release. Consequently, it is important to determine whether GHB inhibits DA release as previously thought, or stimulates DA release, as more recently suggested. Following a critical review of the literature, the present report suggests that GHB does inhibit rather than stimulate presynaptic DA release in consonance with its behavioral and pharmacological activity. Recent in vivo studies indicating that GHB stimulates DA release were done under anesthesia or in the presence of a high concentration of calcium. Both conditions have been found to spuriously enhance striatal DA release in vivo, which may account for the failure of some studies to observe an inhibitory effect of GHB on DA release in vivo.
Feigenbaum JJ, Howard SG; Int J Neurosci 88 (1-2): 53-69 (1996)
Sodium oxybate is an endogenous 4-carbon fatty acid that is thought to act as a neurotransmitter in the regulation of sleep cycles, blood flow, emotion, and memory. Its actions are thought to be mediated through brain receptors specific for GHB as well as through binding to GABA-B receptors. At low doses, the drug inhibits presynaptic dopamine release, while at high doses, dopamine release may be stimulated. It is believed that sodium oxybate decreases the symptoms of narcolepsy by inducing REM sleep and increasing delta sleep. The precise mechanism by which sodium oxybate produces anticataplectic activity in patients with narcolepsy is unknown. /Sodium oxybate/
European Medicines Agency (EMEA), Committee for Medicinal Products for Human Use; European Public Assessment Report (EPAR) (Scientific Discussion); Xyrem, p.13 (2007). Available from, as of March 19,2008: https://www.emea.europa.eu/humandocs/PDFs/EPAR/xyrem/324056en6.pdf

9.8 Human Metabolite Information

9.8.1 Tissue Locations

Placenta

9.9 Biochemical Reactions

9.10 Transformations

10 Use and Manufacturing

10.1 Uses

This is a Schedule I controlled substance.
21 CFR 1308.11(e) (USFDA); U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available from, as of March 20, 2008: https://www.ecfr.gov
This is a Schedule III controlled substance.
21 CFR 1308.13(c) (USFDA); U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available from, as of March 20, 2008: https://www.ecfr.gov
Intermediate
Lewis, R.J. Sr.; Hawley's Condensed Chemical Dictionary 14th Edition. John Wiley & Sons, Inc. New York, NY 2001., p. 592
Therapeutic Category: Anesthetic (intravenous). In treatment of narcolepsy; in treatment of alcoholism.
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 834
For more Uses (Complete) data for 4-HYDROXYBUTANOIC ACID (7 total), please visit the HSDB record page.

Use (kg; approx.) in Germany (2009): >750

Consumption (g per capita; approx.) in Germany (2009): 0.00916

Excretion rate: 0.01

Calculated removal (%): 92.1

10.1.1 Use Classification

Human drugs -> Other nervous system drugs -> Human pharmacotherapeutic group -> EMA Drug Category

10.2 Methods of Manufacturing

gamma-Hydroxybutyric acid is obtained from gamma-butyrolactone by alkaline hydrolysis and isolated as the alkali-metal salt. gamma-Butyrolactone is produced by dehydrocyclization of 1,4-butanediol.
Ullmann's Encyclopedia of Industrial Chemistry. 6th ed.Vol 1: Federal Republic of Germany: Wiley-VCH Verlag GmbH & Co. 2003 to Present, p. V17 323 (2003)
Endogenous constituent of mammalian brain ... Biosynthesized from gamma-aminobutyric acid.
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 834

10.3 Formulations / Preparations

Oral: For solution, concentrate: 500 mg/mL Xyrem (C-III; available with press-in bottle adapter, 10-mL measuring syringe, and two 90-mL dosing cups), (Jazz Pharmaceuticals). /Sodium oxybate/
McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 2626

10.4 General Manufacturing Information

4-Hydroxybutanoic acid is a Schedule I controlled substance (depressant).
21 CFR 1308.11 (2007)

11 Safety and Hazards

11.1 Hazards Identification

11.1.1 GHS Classification

Note
This chemical does not meet GHS hazard criteria for 100% (2 of 2) of all reports. Pictograms displayed are for < 0.1% (0 of 2) of reports that indicate hazard statements.
GHS Hazard Statements

Not Classified

Reported as not meeting GHS hazard criteria by 2 of 2 companies. For more detailed information, please visit ECHA C&L website.

ECHA C&L Notifications Summary

Aggregated GHS information provided per 2 reports by companies from 1 notifications to the ECHA C&L Inventory.

Reported as not meeting GHS hazard criteria per 2 of 2 reports by companies. For more detailed information, please visit ECHA C&L website.

There are 0 notifications provided by 0 of 2 reports by companies with hazard statement code(s).

Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.

11.1.2 Hazard Classes and Categories

Not Classified

11.2 Accidental Release Measures

11.2.1 Disposal Methods

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

11.3 Handling and Storage

11.3.1 Storage Conditions

Store at 25 °C (77 °F), USP controlled room temperature, excursions permitted up to 15 to 30 °C (59 to 86 °F). /Sodium oxybate/
Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 2640

11.4 Regulatory Information

DEA Controlled Substances
DEA schedule I controlled substance

11.4.1 FDA Requirements

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl sodium oxybate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Sodium Oxybate/
DHHS/FDA; Electronic Orange Book-Approved Drug Products with Therapeutic Equivalence Evaluations. Available from, as of February 28, 2008: https://www.fda.gov/cder/ob/
/DEA/ Schedule I shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. Each drug or substance has been assigned the DEA Controlled Substances Code Number set forth opposite it. Unless specifically excepted or unless listed in another schedule, any material, compound, mixture, or preparation which contains any quantity of the following substances having a depressant effect on the central nervous system, including its salts, isomers, and salts of isomers whenever the existence of such salts, isomers, and salts of isomers is possible within the specific chemical designation. gamma-Hydroxybutyric acid (DEA Code Number: 2010) is included on this list.
21 CFR 1308.11(e) (USDEA); U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available from, as of February 8, 2008: https://www.ecfr.gov
/DEA/ Schedule III shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. Each drug or substance has been assigned the DEA Controlled Substances Code Number set forth opposite it. Narcotic drugs. Unless specifically excepted or unless listed in another schedule, any material, compound, mixture, or preparation which contains any quantity of the following substances having a depressant effect on the central nervous system: Any drug product containing gamma hydroxybutyric acid, including its salts, isomers, and salts of isomers, for which an application is approved under section 505 of the Federal Food, Drug, and Cosmetic Act. DEA Code Number: 2012.
21 CFR 1308.13(c) (USDEA); U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available from, as of March 13, 2008: https://www.ecfr.gov

11.5 Other Safety Information

11.5.1 Special Reports

European Medicines Agency (EMEA), Committee for Medicinal Products for Human Use; European Public Assessment Report (EPAR) (Scientific Discussion); Xyrem, p.3 (2007).Available at http://www.emea.europa.eu/humandocs/PDFs/EPAR/xyrem/324056en6.pdf as of March 19,2008

12 Toxicity

12.1 Toxicological Information

12.1.1 Hepatotoxicity

In preregistration clinical trials, serum enzyme elevations were reported in small numbers of treated patients, but no instance of clinically apparent liver injury was reported. Since the approval and more widespread use of oxybate, there have been no published cases of liver injury due to oxybate, and in postmarketing overviews of adverse events hepatotoxicity was not listed. Thus, despite use in high doses (3 to 9 g daily), acute liver injury from oxybate must be very rare, if it occurs at all.

Likelihood score: E (unlikely cause of clinically apparent liver injury).

12.1.2 Drug Induced Liver Injury

Compound
gamma hydroxybutyric acid
DILI Annotation
No-DILI-Concern
Label Section
No match
References

M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007

M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

12.1.3 Effects During Pregnancy and Lactation

◉ Summary of Use during Lactation

Sodium, calcium, magnesium and potassium oxybate are salts of gamma-hydroxybutyric acid (GHB). GHB is an endogenous substance and low amounts are normally found in breastmilk. Large doses of GHB have been used as a substance of abuse. Infants have been successfully breastfed by mothers taking sodium oxybate therapeutically for narcolepsy. With the typical 2 doses per night treatment regimen, nursing should usually be withheld from the time of the first dose to 4 to 6 hours after the second dose and breastfeeding can be continued during the day. No information is available on the use or safety of GHB as a drug of abuse during breastfeeding. Monitor the infant for sedation, poor feeding and poor weight gain.

◉ Effects in Breastfed Infants

A woman was taking 4.5 grams of sodium oxybate twice daily (exact times not reported) for narcolepsy and cataplexy throughout pregnancy and lactation. She breastfed her infant (extent and times not stated). No adverse infant effects were reported.

A woman with narcolepsy took sodium oxybate 4 grams each night at 10 pm and 2 am as well as fluoxetine 20 mg and cetirizine 5 mg daily throughout pregnancy and postpartum. She breastfed her infant except for 4 hours after the 10 pm oxybate dose and 4 hours after the 2 am dose. She either pumped breastmilk or breastfed her infant just before each dose of oxybate. The infant was exclusively breastfed or breastmilk fed for 6 months when solids were introduced. The infant was evaluated at 2, 4 and 6 months with the Ages and Stages Questionnaires, which were withing the normal range as were the infant's growth and pediatrician's clinical impressions regarding the infant's growth and development.

◉ Effects on Lactation and Breastmilk

Relevant published information was not found as of the revision date.

12.1.4 Acute Effects

12.1.5 Interactions

Potential pharmacologic interaction (additive sedative effects). Sodium oxybate is contraindicated in patients receiving sedative-hypnotic agents. Sodium oxybate should not be used concomitantly with alcohol or other CNS depressants. /Sodium oxybate/
McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 2625
gamma-Hydroxybutyrate may potentiate other endogenous opiates or exogenous narcotics, and it is potentiated by alcohol, benzodiazepines, and other neuroleptics. While dextroamphetamine, naloxone, trimethadone, and valproate antagonize the electroencephalographic changes produced by GHB, no clinically effective GHB antagonists are consistently described in the published literature.
Chin MY et al; West J Med 156 (4): 380-4 (1992)
Gamma-hydroxybutyrate (GHB) is often abused together with other 'club drugs', such as the N-methyl-D-aspartate (NMDA) receptor antagonists ketamine and phencyclidine (PCP). We recently found that the NMDA antagonist dizocilpine markedly enhanced GHB-induced catalepsy in rats. The present studies explored the generality of this interaction. Different groups of rats were trained to discriminate 2 mg/kg PCP or 3.2 mg/kg of the gamma-aminobutyric acid B receptor agonist baclofen from saline. In the PCP-trained rats, the dose-response (DR) curve for the discriminative stimulus (DS) effects of PCP was shifted 2.5-fold to the left by 178 mg/kg GHB, but not by baclofen. In the baclofen-trained rats, 2 mg/kg PCP shifted the DR curve for the baclofen-like DS effects of GHB 2.2-fold to the left, but did not shift the DR curve for baclofen. These results suggest that (i) NMDA antagonists potentiate not only the cataleptic effects of high doses of GHB, but also the DS effects of low doses, (ii) PCP and GHB enhance one another's DS effects, and (iii) this enhancement might be specific for GHB, because it did not occur with PCP and baclofen. These findings suggest that NMDA antagonists might potentiate the subjective effects of GHB in humans, and are further evidence that glutamatergic systems modulate effects of drugs of abuse.
Koek W et al; Behav Pharmacol 18 (8): 807-10 (2007)
Gamma-hydroxybutyrate (GHB) and ethanol are often co-ingested in settings of drug-facilitated rape and recreational abuse. Little is known about the effects of ethanol on GHB plasma kinetics. Our objective was to evaluate the pharmacokinetic interactions of ethanol and GHB. Method: GHB plasma pharmacokinetic evaluation was conducted as part of a double-blind, placebo-controlled, 4-arm crossover study in eight healthy human volunteers (four men). Subjects ingested 50 mg/kg GHB, 0.6 g/kg ethanol in two doses, or both drugs combined. Serial plasma GHB samples were obtained over a 24 hr period. Primary outcomes were area under the curve (AUC) from 0-24 hr, elimination half-life (t 1/2) and maximum drug concentration (Cmax). Data were analyzed using a paired two-tailed t test. Results: A new gas chromatography-mass spectrometer (GC-MS) method was developed to quantitate GHB in human plasma. Ethanol coadministration increased the AUC and decreased the t 1/2 of GHB. The Cmax of GHB was also increased in the presence of ethanol, although the difference was not statistically significant. Conclusion: The alteration of GHB AUC and clearance by ethanol may be the result of both increased bioavailability and diminished elimination of GHB. These results may help in part to explain the additive effect of GHB and ethanol on cognitive impairment in humans.
Thai D et al; J Toxicol Clin Toxicol 42 (5): 760 (2004)
For more Interactions (Complete) data for 4-HYDROXYBUTANOIC ACID (9 total), please visit the HSDB record page.

12.1.6 Antidote and Emergency Treatment

Emergency and supportive measures: Protect the airway and assist ventilation if needed. Note that patients who require intubation are often awake and are extubated within a few hours. Treat coma, seizures, bradycardia, and corrosive burns if they occur. Evaluate for and treat drug-facilitated assault.
Olson, K.R. (Ed.); Poisoning & Drug Overdose. 5th ed. Lange Medical Books/McGraw-Hill. New York, N.Y. 2007., p. 212
Specific drugs and antidotes: There are no specific antidotes available. Flumazenil and naloxone are not clinically effective. GHB withdrawal syndrome is managed with benzodiazepine sedation as in other depressant withdrawal syndromes. Large doses may be needed. Withdrawal refractory to benzodiazepines is not uncommon and may benefit from the addition of barbiturates or propofol.
Olson, K.R. (Ed.); Poisoning & Drug Overdose. 5th ed. Lange Medical Books/McGraw-Hill. New York, N.Y. 2007., p. 212
Decontaminationn: Prehospital. Do not give charcoal or induce vomiting because of the risk of rapid loss of consciousness and loss of airway-protective reflexes, which may lead to pulmonary aspiration. Hospital. The small doses of GHB usually ingested are rapidly absorbed, and gastric lavage and activated charcoal are of doubtful benefit and may increase the risk of pulmonary aspiration. Consider activated charcoal administration for recent, large ingestions or when significant co-ingestion is suspected.
Olson, K.R. (Ed.); Poisoning & Drug Overdose. 5th ed. Lange Medical Books/McGraw-Hill. New York, N.Y. 2007., p. 212
Enhanced elimination: There is no role for enhanced removal procedures such as dialysis and hemoperfusion.
Olson, K.R. (Ed.); Poisoning & Drug Overdose. 5th ed. Lange Medical Books/McGraw-Hill. New York, N.Y. 2007., p. 212
For more Antidote and Emergency Treatment (Complete) data for 4-HYDROXYBUTANOIC ACID (7 total), please visit the HSDB record page.

12.1.7 Human Toxicity Excerpts

/SIGNS AND SYMPTOMS/ To describe the clinical features of gamma-hydroxybutyrate (GHB) and gamma-butyrolactone (GBL) toxicity /a/ retrospective case-study of 65 GHB and GBL intoxications seen in an urban emergency department /were reviewed/. 63% of intoxications occurred in male patients. The median age was 24 years (range 16-41 years). 65% co-ingested alcohol or illicit drugs, mostly MDMA and cocaine. 83% presented with coma. The mean+/-S.D. time to regain consciousness among comatose patients was 111+/-61 min and was significantly longer in patients who co-abused illicit drugs such as cocaine or MDMA (155+/-60 min). Bradycardia occurred in 38%, hypotension in 6% and hypothermia in 48%. Agitation was observed in 17% of all patients and was significantly more frequent in patients with alcohol co-use (29%). Vomiting occurred in 31% of all patients and tended to be more frequent in patients who co-used alcohol (39%). Management of GHB and GBL overdose was supportive. Four patients needed admission to an intensive care unit for mechanical ventilation (6%). Overdosing of GHB and GBL frequently results in non-reactive coma reflecting the severity of poisoning. Multiple drug use is common and significantly influences the clinical presentation.
Liechti ME et al; Drug Alcohol Depend 81 (3): 323-6 (2006)
/SIGNS AND SYMPTOMS/ GHB produces a wide range of central nervous system effects, including dose-dependent drowsiness, dizziness, nausea, amnesia, visual hallucinations, hypotension, bradycardia, severe respiratory depression, and coma. The use of alcohol in combination with GHB greatly enhances its depressant effects. Overdose frequently requires emergency room care, and many GHB-related fatalities have been reported.
Drug Enforcement Agency (DEA); Drugs of Abuse p.42, 2005 ed. Available from, as of March 20, 2008: https://www.usdoj.gov/dea/pubs/abuse/index.htm#Contents
/SIGNS AND SYMPTOMS/ Gamma-Hydroxybutyrate (GHB)-related compounds are most commonly described as depressants, with emphasis on somnolence, obtundation, stupor, and coma (SOSC). /Investigators/ sought to demonstrate the full spectrum of clinical presentations of GHB intoxication, including agitation and other nonsedative effects. /This/ observational study identified 66 patients with GHB toxicity, 40 of whom manifested agitation; 25 had agitation before or after SOSC, 10 had agitation alternating abruptly with SOSC, and 5 had agitation only. Fourteen presentations also included "bizarre" or self-injurious behaviors. Of 40 presentations with agitation, 19 had stimulant co-intoxicants confirmed by screen (14) or history (5). The remaining 21 patients with agitation were negative for stimulants by screen (12) or history (9). Gas chromatography/mass spectrometry detected GHB in 25 cases; 12 manifested agitation, 4 of which also screened negative for stimulants. ...
Zvosec DL, Smith SW; Am J Emerg Med 23 (3): 316-20 (2005)
/SIGNS AND SYMPTOMS/ Information about signs and symptoms associated with overdosage with sodium oxybate derives from reports of its illicit use. Patient presentation following overdose is influenced by the dose ingested, the time since ingestion, the co-ingestion of other drugs and alcohol, and the fed or fasted state. Patients have exhibited varying degrees of depressed consciousness that may fluctuate rapidly between a confusional, agitated combative state with ataxia and coma. Emesis (even when obtunded), diaphoresis, headache, and impaired psychomotor skills may be observed. No typical pupillary changes have been described to assist in diagnosis; pupillary reactivity to light is maintained. Blurred vision has been reported. An increasing depth of coma has been observed at higher doses. Myoclonus and tonic-clonic seizures have been reported. Respiration may be unaffected or compromised in rate and depth. Cheyne-Stokes respiration and apnea have been observed. Bradycardia and hypothermia may accompany unconsciousness, as well as muscular hypotonia, but tendon reflexes remain intact. /Sodium oxybate/
Thomson Health Care Inc.; Physicians' Desk Reference 62 ed., Montvale, NJ 2008, p. 1726
For more Human Toxicity Excerpts (Complete) data for 4-HYDROXYBUTANOIC ACID (19 total), please visit the HSDB record page.

12.1.8 Non-Human Toxicity Excerpts

/LABORATORY ANIMALS: Acute Exposure/ GHB consistently decreases respiration by effects on minute volume and respiratory rate, with younger animals being more susceptible to these effects. In halothane-anesthetized rats, GHB (187.5-750 mg/kg ip) dose-dependently decreased basal minute volume and respiratory rate compared to pre-injection control, with a maximum decrease to about 60% of pre-injection values for each parameter at the highest dose of GHB.
European Medicines Agency (EMEA), Committee for Medicinal Products for Human Use; European Public Assessment Report (EPAR) (Scientific Discussion); Xyrem, p.3 (2007). Available from, as of March 19,2008: https://www.emea.europa.eu/humandocs/PDFs/EPAR/xyrem/324056en6.pdf
/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ The present study describes the induction and occurrence of audiogenic seizures as a sign of withdrawal from gamma-hydroxybutyric acid (GHB) and 1,4-butanediol (1,4-BD) in selectively bred Sardinian alcohol-preferring (sP) rats, treated with escalating doses of GHB (1.5-3.5 g/kg, twice daily; i.g.) or 1,4-BD (500-1000 mg/kg, twice daily; i.g.) for 9 consecutive days. Acute administration of the selective GABA(B) receptor antagonist, SCH 50911, dramatically increased seizure occurrence. ...
Carai MA et al; Brain Res Brain Res Protoc 15 (2): 75-8 (2005)
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Reproduction studies conducted in pregnant rats at doses up to 1000 mg/kg (approximately equal to the maximum recommended human daily dose on a mg/sq m basis) and in pregnant rabbits at doses up to 1200 mg/kg (approximately 3 times the maximum recommended human daily dose on a mg/sq m basis) revealed no evidence of teratogenicity.
Thomson Health Care Inc.; Physicians' Desk Reference 62 ed., Montvale, NJ 2008, p. 1724
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ In a study in which rats were given sodium oxybate from Day 6 of gestation through Day 21 post-partum, slight decreases in pup and maternal weight gains were seen at 1000 mg/kg; there were no drug effects on other developmental parameters. /Sodium oxybate/
Thomson Health Care Inc.; Physicians' Desk Reference 62 ed., Montvale, NJ 2008, p. 1724
For more Non-Human Toxicity Excerpts (Complete) data for 4-HYDROXYBUTANOIC ACID (8 total), please visit the HSDB record page.

12.1.9 Non-Human Toxicity Values

LD50 Rat (male) ip 2000 mg/kg /sodium salt/
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 834
LD50 Rat (female) ip 1650 mg/kg /sodium salt/
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 834
LD50 Dog > 1,000 mg/kg
European Medicines Agency (EMEA), Committee for Medicinal Products for Human Use; European Public Assessment Report (EPAR) (Scientific Discussion); Xyrem, p.5 (2007). Available from, as of March 19,2008: https://www.emea.europa.eu/humandocs/PDFs/EPAR/xyrem/324056en6.pdf
LD50 Rabbit iv > 1,000 mg/kg
European Medicines Agency (EMEA), Committee for Medicinal Products for Human Use; European Public Assessment Report (EPAR) (Scientific Discussion); Xyrem, p.5 (2007). Available from, as of March 19,2008: https://www.emea.europa.eu/humandocs/PDFs/EPAR/xyrem/324056en6.pdf
LD50 Mouse ip 2960-3700 mg/kg
European Medicines Agency (EMEA), Committee for Medicinal Products for Human Use; European Public Assessment Report (EPAR) (Scientific Discussion); Xyrem, p.5 (2007). Available from, as of March 19,2008: https://www.emea.europa.eu/humandocs/PDFs/EPAR/xyrem/324056en6.pdf

12.1.10 Populations at Special Risk

Sodium oxybate is contraindicated in patients with succinic semialdehyde dehydrogenase deficiency. This rare disorder is an inborn error of metabolism variably characterized by mental retardation, hypotonia, and ataxia. /Sodium oxybate/
Thomson Health Care Inc.; Physicians' Desk Reference 62 ed., Montvale, NJ 2008, p. 1723
Elimination half-life and systemic exposure to sodium oxybate are increased in patients with hepatic impairment. Dosage of sodium oxybate should be reduced in such patients. /Sodium oxybate/
McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 2625

12.2 Ecological Information

12.2.1 Environmental Fate / Exposure Summary

4-Hydroxybutanoic acid's production and use as an anesthetic, treatment for narcolepsy or alcoholism, or drug of abuse may result in its release to the environment through various waste streams. 4-Hydroxybutanoic acid is an endogenous constituent of mammalian brain. Atmospheric photooxidation of 1,4-dihydroxybutane is a potential source of 4-hydroxybutanoic acid in aerosols. If released to air, an estimated vapor pressure of 0.13 mm Hg at 25 °C indicates 4-hydroxybutanoic acid will exist solely as a vapor in the atmosphere. Vapor-phase 4-hydroxybutanoic acid will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 4.6 days. 4-Hydroxybutanoic acid does not contain chromophores that absorb at wavelengths >290 nm and therefore is not expected to be susceptible to direct photolysis by sunlight. If released to soil, 4-hydroxybutanoic acid is expected to have very high mobility based upon an estimated Koc of less than 1. The pKa of 4-hydroxybutyric acid is 4.72, indicating that this compound will primarily exist in the anion form in the environment, and anions generally do not absorb more strongly to soils containing organic carbon and clay than their neutral counterparts. 4-Hydroxybutanoic acid is unlikely to volatilize from dry soil surfaces based upon its vapor pressure. Biodegradation data were not available. If released into water, 4-hydroxybutanoic acid is not expected to adsorb to suspended solids and sediment based upon the estimated Koc. A pKa of 4.72 indicates 4-hydroxybutanoic acid will exist almost entirely in the anion form at pH values of 5 to 9 and therefore volatilization from water surfaces and moist soil surfaces is not expected to be an important fate process. An estimated BCF of 3.2 suggests the potential for bioconcentration in aquatic organisms is low. Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions. Occupational exposure to 4-hydroxybutanoic acid may occur through inhalation and dermal contact with this compound at workplaces where 4-hydroxybutanoic acid is produced or used. Exposure to 4-hydroxybutanoic acid among the general population may be limited to those taking the drug for therapeutic purposes or as a drug of abuse. (SRC)

12.2.2 Natural Pollution Sources

4-Hydroxybutanoic acid is an endogenous constituent of mammalian brain; biosynthesized from gamma-aminobutyric acid(1). Atmospheric photooxidation of 1,4-dihydroxybutane is a potential source of 4-hydroxybutanoic acid in aerosols(2).
(1) O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., p. 834 (2006)
(2) Yu LE et al; Environ Sci Technol 39: 707-15 (2005)

12.2.3 Artificial Pollution Sources

4-Hydroxybutanoic acid's production and use as an anesthetic or treatment for narcolepsy and alcoholism(1), or as a drug of abuse(2) may result in its release to the environment through various waste streams(SRC).
(1) O'Neil MJ; The Merck Index. 14th ed. Whitehouse Station, NJ: Merck and Co., Inc. p. 834 (2006)
(2) NIH National Institute on Drug Abuse; NIDA InfoFacts - Club Drugs. Available at https://www.drugabuse.gov/pdf/infofacts/ClubDrugs07.pdf as of Jan 15, 2008.

12.2.4 Environmental Fate

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of less than 1(SRC), determined from a structure estimation method(2), indicates that 4-hydroxybutanoic acid is expected to have very high mobility in soil(SRC). The pKa of 4-hydroxybutanoic acid is 4.72(3), indicating that this compound will primarily exist in the anion form in the environment, and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). The pKa also indicates that volatilization of 4-hydroxybutanoic acid from moist soil surfaces is not expected to be an important fate process(SRC). 4-Hydroxybutanoic acid is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 0.13 mm Hg(SRC), determined from a fragment constant method(6). Biodegradation data were not available(SRC, 2008).
(1) Swann RL et al; Res Rev 85: 17-28 (1983)
(2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992)
(3) Lide DR; CRC Handbook of Chemistry and Physics 86th Edition 2005-2006; Boca Raton, FL: CRC Press, Taylor & Francis (2005)
(4) Doucette WJ; pp. 141-188 in Handbook of Property Estimation Methods for Chemicals. Boethling RS, Mackay D, eds. Boca Raton, FL: Lewis Publ (2000)
(5) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991)
(6) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985)
AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of less than 1(SRC), determined from a structure estimation method(2), indicates that 4-hydroxybutanoic acid is not expected to adsorb to suspended solids and sediment(SRC). A pKa of 4.72(3) indicates 4-hydroxybutanoic acid will exist almost entirely in the anion form at pH values of 5 to 9 and therefore volatilization from water surfaces is not expected to be an important fate process(4). 4-Hydroxybutanoic acid is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(5). According to a classification scheme(6), an estimated BCF of 3.2(SRC), from an estimated log Kow of -0.40(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data were not available(SRC, 2008).
(1) Swann RL et al; Res Rev 85: 17-28 (1983)
(2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992)
(3) Lide DR; CRC Handbook of Chemistry and Physics 86th Edition 2005-2006; Boca Raton, FL: CRC Press, Taylor & Francis (2005)
(4) Doucette WJ; pp. 141-188 in Handbook of Property Estimation Methods for Chemicals. Boethling RS, Mackay D, eds. Boca Raton, FL: Lewis Publ (2000)
(5) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5 (1990)
(6) Franke C et al; Chemosphere 29: 1501-14 (1994)
(7) US EPA; Estimation Program Interface (EPI) Suite. Ver.3.20. February, 2007. Available at https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm as of Jan 14, 2008.
ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 4-hydroxybutanoic acid, which has an estimated vapor pressure of 0.13 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase 4-hydroxybutanoic acid is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 4.6 days(SRC), calculated from its rate constant of 7.0X10-12 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). 4-Hydroxybutanoic acid does not contain chromophores that absorb at wavelengths >290 nm(4) and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).
(1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988)
(2) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985)
(3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993)
(4) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 8-12 (1990)

12.2.5 Environmental Abiotic Degradation

The rate constant for the vapor-phase reaction of 4-hydroxybutanoic acid with photochemically-produced hydroxyl radicals has been estimated as 7.0X10-12 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 4.6 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). 4-Hydroxybutanoic acid is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(3). 4-Hydroxybutanoic acid does not contain chromophores that absorb at wavelengths >290 nm(3) and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).
(1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993)
(2) Mill T et al; Environmental Fate and Exposure Studies Development of a PC-SAR for Hydrolysis: Esters, Alkyl Halides and Epoxides. EPA Contract No. 68-02-4254. Menlo Park, CA: SRI International (1987)
(3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5, 8-12 (1990)

12.2.6 Environmental Bioconcentration

An estimated BCF of 3.2 was calculated for 4-hydroxybutanoic acid(SRC), using an estimated log Kow of -0.40(1) and a regression-derived equation(2) According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low.
(1) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995)
(2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999)
(3) Franke C et al; Chemosphere 29:1501-14 (1994)

12.2.7 Soil Adsorption / Mobility

Using a structure estimation method based on molecular connectivity indices(1), the Koc of 4-hydroxybutanoic acid can be estimated to be less than 1(SRC). According to a classification scheme(2), this estimated Koc value suggests that 4-hydroxybutanoic acid is expected to have very high mobility in soil. The pKa of 4-hydroxybutanoic acid is 4.72(3), indicating that this compound will primarily exist in the anion form in the environment, and anions generally adsorb less strongly to soils containing organic carbon and clay than their neutral counterparts(4).
(1) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992)
(2) Swann RL et al; Res Rev 85: 17-28 (1983)
(3) Lide DR; CRC Handbook of Chemistry and Physics 86th Edition 2005-2006; Boca Raton, FL: CRC Press, Taylor & Francis (2005)
(4) Doucette WJ; pp. 141-188 in Handbook of Property Estimation Methods for Chemicals. Boethling RS, Mackay D, eds. Boca Raton, FL: Lewis Publ (2000)

12.2.8 Volatilization from Water / Soil

A pKa of 4.72(1) indicates 4-hydroxybutanoic acid will exist almost entirely in the anion form at pH values of 5 to 9 and therefore volatilization from water surfaces is not expected to be an important fate process(2). 4-Hydroxybutanoic acid is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 0.13 mm Hg(SRC), determined from a fragment constant method(3).
(1) Lide DR; CRC Handbook of Chemistry and Physics 86th Edition 2005-2006; Boca Raton, FL: CRC Press, Taylor & Francis (2005)
(2) Doucette WJ; pp. 141-188 in Handbook of Property Estimation Methods for Chemicals. Boethling RS, Mackay D, eds. Boca Raton, FL: Lewis Publ (2000)
(3) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985)

12.2.9 Atmospheric Concentrations

RURAL/REMOTE: 4-Hydroxybutanoic acid was detected in fine aerosols collected from July 5 to August 25, 1995 at the Great Smoky National Park, Tennessee at concns of 5.4-178.4 ng/ cu m during the daytime and 21.2-364.7 ng/cu m during the nighttime(1). Atmospheric photooxidation of 1,4-dihydroxybutane is a potential source of 4-hydroxybutanoic acid in aerosols(1).
(1) Yu LE et al; Environ Sci Technol 39: 707-15 (2005)

12.2.10 Probable Routes of Human Exposure

Occupational exposure to 4-hydroxybutanoic acid may occur through inhalation and dermal contact with this compound at workplaces where 4-hydroxybutanoic acid is produced or used. Exposure to 4-hydroxybutanoic acid among the general population may be limited to those using it for therapeutic purposes or as a drug of abuse. (SRC)

13 Associated Disorders and Diseases

Disease
Succinic semialdehyde dehydrogenase deficiency
References

PubMed: 12127325, 14595661, 11978597

MetaGene: Metabolic & Genetic Information Center (MIC: http://www.metagene.de)

Disease
Colorectal cancer
References

PubMed: 7482520, 22148915, 19006102, 23940645, 24424155, 20156336, 19678709, 25105552, 21773981, 25037050, 27015276, 27107423, 27275383, 28587349

Silke Matysik, Caroline Ivanne Le Roy, Gerhard Liebisch, Sandrine Paule Claus. Metabolomics of fecal samples: A practical consideration. Trends in Food Science & Technology. Vol. 57, Part B, Nov. 2016, p.244-255: http://www.sciencedirect.com/science/article/pii/S0924224416301984

Disease
Glutaric aciduria II
References

PubMed: 6158623, 24453145, 16388731

MetaGene: Metabolic & Genetic Information Center (MIC: http://www.metagene.de)

Disease
Eosinophilic esophagitis
References
Mordechai, Hien, and David S. Wishart
Disease
Attachment loss
References
PubMed: 31026179
Disease
Missing teeth
References
PubMed: 31026179
Disease
Periodontal Probing Depth
References
PubMed: 31026179
Disease
Tooth Decay
References
PubMed: 31026179

14 Literature

14.1 Consolidated References

14.2 NLM Curated PubMed Citations

14.3 Springer Nature References

14.4 Thieme References

14.5 Wiley References

14.6 Chemical Co-Occurrences in Literature

14.7 Chemical-Gene Co-Occurrences in Literature

14.8 Chemical-Disease Co-Occurrences in Literature

15 Patents

15.1 Depositor-Supplied Patent Identifiers

15.2 WIPO PATENTSCOPE

15.3 Chemical Co-Occurrences in Patents

15.4 Chemical-Disease Co-Occurrences in Patents

15.5 Chemical-Gene Co-Occurrences in Patents

16 Interactions and Pathways

16.1 Protein Bound 3D Structures

16.2 Chemical-Target Interactions

16.3 Drug-Drug Interactions

16.4 Pathways

17 Biological Test Results

17.1 BioAssay Results

18 Taxonomy

The LOTUS Initiative for Open Natural Products Research: frozen dataset union wikidata (with metadata) | DOI:10.5281/zenodo.5794106
A metabolome atlas of the aging mouse brain. Nat Commun. 2021 Oct 15;12(1):6021. DOI:10.1038/s41467-021-26310-y. PMID:34654818; PMCID:PMC8519999.
The Metabolome Atlas of the Aging Mouse Brain: https://mouse.atlas.metabolomics.us

19 Classification

19.1 MeSH Tree

19.2 NCI Thesaurus Tree

19.3 ChEBI Ontology

19.4 LIPID MAPS Classification

19.5 KEGG: Metabolite

19.6 KEGG: Lipid

19.7 KEGG: Drug Groups

19.8 FDA Pharm Classes

19.9 ChemIDplus

19.10 IUPHAR / BPS Guide to PHARMACOLOGY Target Classification

19.11 ChEMBL Target Tree

19.12 UN GHS Classification

19.13 Drug Enforcement Administration (DEA) Classification

19.14 NORMAN Suspect List Exchange Classification

19.15 CCSBase Classification

19.16 EPA DSSTox Classification

19.17 LOTUS Tree

19.18 EPA Substance Registry Services Tree

19.19 MolGenie Organic Chemistry Ontology

20 Information Sources

  1. CAS Common Chemistry
    LICENSE
    The data from CAS Common Chemistry is provided under a CC-BY-NC 4.0 license, unless otherwise stated.
    https://creativecommons.org/licenses/by-nc/4.0/
  2. ChemIDplus
    ChemIDplus Chemical Information Classification
    https://pubchem.ncbi.nlm.nih.gov/source/ChemIDplus
  3. DrugBank
    LICENSE
    Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode)
    https://www.drugbank.ca/legal/terms_of_use
    gamma-Hydroxybutyric acid
    https://www.drugbank.ca/drugs/DB01440
  4. EPA DSSTox
    CompTox Chemicals Dashboard Chemical Lists
    https://comptox.epa.gov/dashboard/chemical-lists/
  5. European Chemicals Agency (ECHA)
    LICENSE
    Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page.
    https://echa.europa.eu/web/guest/legal-notice
  6. FDA Global Substance Registration System (GSRS)
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  7. Hazardous Substances Data Bank (HSDB)
  8. Human Metabolome Database (HMDB)
    LICENSE
    HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications.
    http://www.hmdb.ca/citing
  9. CCSbase
    CCSbase Classification
    https://ccsbase.net/
  10. ChEBI
  11. Drug Enforcement Administration (DEA)
    LICENSE
    Unless otherwise indicated, information on Department of Justice websites is in the public domain and may be copied and distributed without permission. Citation of the Department of Justice as source of the information is appreciated, as appropriate.
    https://www.justice.gov/legalpolicies
    DEA drug and chemical classification
    https://www.dea.gov/drug-information/drug-scheduling
  12. E. coli Metabolome Database (ECMDB)
    LICENSE
    ECMDB is offered to the public as a freely available resource.
    https://ecmdb.ca/citations
  13. FDA Pharm Classes
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  14. LiverTox
  15. LOTUS - the natural products occurrence database
    LICENSE
    The code for LOTUS is released under the GNU General Public License v3.0.
    https://lotus.nprod.net/
  16. NCI Thesaurus (NCIt)
    LICENSE
    Unless otherwise indicated, all text within NCI products is free of copyright and may be reused without our permission. Credit the National Cancer Institute as the source.
    https://www.cancer.gov/policies/copyright-reuse
  17. Open Targets
    LICENSE
    Datasets generated by the Open Targets Platform are freely available for download.
    https://platform-docs.opentargets.org/licence
  18. ChEMBL
    LICENSE
    Access to the web interface of ChEMBL is made under the EBI's Terms of Use (http://www.ebi.ac.uk/Information/termsofuse.html). The ChEMBL data is made available on a Creative Commons Attribution-Share Alike 3.0 Unported License (http://creativecommons.org/licenses/by-sa/3.0/).
    http://www.ebi.ac.uk/Information/termsofuse.html
  19. ClinicalTrials.gov
    LICENSE
    The ClinicalTrials.gov data carry an international copyright outside the United States and its Territories or Possessions. Some ClinicalTrials.gov data may be subject to the copyright of third parties; you should consult these entities for any additional terms of use.
    https://clinicaltrials.gov/ct2/about-site/terms-conditions#Use
  20. Comparative Toxicogenomics Database (CTD)
    LICENSE
    It is to be used only for research and educational purposes. Any reproduction or use for commercial purpose is prohibited without the prior express written permission of NC State University.
    http://ctdbase.org/about/legal.jsp
  21. Drug Gene Interaction database (DGIdb)
    LICENSE
    The data used in DGIdb is all open access and where possible made available as raw data dumps in the downloads section.
    http://www.dgidb.org/downloads
  22. IUPHAR/BPS Guide to PHARMACOLOGY
    LICENSE
    The Guide to PHARMACOLOGY database is licensed under the Open Data Commons Open Database License (ODbL) https://opendatacommons.org/licenses/odbl/. Its contents are licensed under a Creative Commons Attribution-ShareAlike 4.0 International License (http://creativecommons.org/licenses/by-sa/4.0/)
    https://www.guidetopharmacology.org/about.jsp#license
    Guide to Pharmacology Target Classification
    https://www.guidetopharmacology.org/targets.jsp
  23. Therapeutic Target Database (TTD)
  24. Drug Induced Liver Injury Rank (DILIrank) Dataset
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  25. European Medicines Agency (EMA)
    LICENSE
    Information on the European Medicines Agency's (EMA) website is subject to a disclaimer and copyright and limited reproduction notices.
    https://www.ema.europa.eu/en/about-us/legal-notice
  26. Drugs and Lactation Database (LactMed)
  27. Drugs@FDA
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  28. KNApSAcK Species-Metabolite Database
  29. Natural Product Activity and Species Source (NPASS)
  30. West Coast Metabolomics Center-UC Davis
    4-Hydroxybutyric acid
  31. EU Clinical Trials Register
  32. FDA Medication Guides
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  33. FooDB
    LICENSE
    FooDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (FooDB) and the original publication.
    https://foodb.ca/about
  34. NORMAN Suspect List Exchange
    LICENSE
    Data: CC-BY 4.0; Code (hosted by ECI, LCSB): Artistic-2.0
    https://creativecommons.org/licenses/by/4.0/
    SODIUM OXYBATE
    NORMAN Suspect List Exchange Classification
    https://www.norman-network.com/nds/SLE/
  35. MassBank of North America (MoNA)
    LICENSE
    The content of the MoNA database is licensed under CC BY 4.0.
    https://mona.fiehnlab.ucdavis.edu/documentation/license
  36. NIST Mass Spectrometry Data Center
    LICENSE
    Data covered by the Standard Reference Data Act of 1968 as amended.
    https://www.nist.gov/srd/public-law
    Butanoic acid, 4-hydroxy-
    http://www.nist.gov/srd/nist1a.cfm
  37. SpectraBase
    GHB;4-HYDROXY-BUTANOIC-ACID;GAMMA-HYDROXY-BUTYRIC-ACID
    https://spectrabase.com/spectrum/DvDHPd9hBy8
  38. Japan Chemical Substance Dictionary (Nikkaji)
  39. KEGG
    LICENSE
    Academic users may freely use the KEGG website. Non-academic use of KEGG generally requires a commercial license
    https://www.kegg.jp/kegg/legal.html
  40. LIPID MAPS
    Lipid Classification
    https://www.lipidmaps.org/
  41. MarkerDB
    LICENSE
    This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
    https://markerdb.ca/
  42. Metabolomics Workbench
  43. NLM RxNorm Terminology
    LICENSE
    The RxNorm Terminology is created by the National Library of Medicine (NLM) and is in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from NLM. Credit to the U.S. National Library of Medicine as the source is appreciated but not required. The full RxNorm dataset requires a free license.
    https://www.nlm.nih.gov/research/umls/rxnorm/docs/termsofservice.html
  44. Springer Nature
  45. Thieme Chemistry
    LICENSE
    The Thieme Chemistry contribution within PubChem is provided under a CC-BY-NC-ND 4.0 license, unless otherwise stated.
    https://creativecommons.org/licenses/by-nc-nd/4.0/
  46. Wikidata
    4-(1-Oxobutoxy)butanoic acid
    https://www.wikidata.org/wiki/Q72498582
  47. Wikipedia
  48. Wiley
  49. PubChem
  50. Medical Subject Headings (MeSH)
    LICENSE
    Works produced by the U.S. government are not subject to copyright protection in the United States. Any such works found on National Library of Medicine (NLM) Web sites may be freely used or reproduced without permission in the U.S.
    https://www.nlm.nih.gov/copyright.html
  51. GHS Classification (UNECE)
  52. EPA Substance Registry Services
  53. MolGenie
    MolGenie Organic Chemistry Ontology
    https://github.com/MolGenie/ontology/
  54. PATENTSCOPE (WIPO)
  55. NCBI
CONTENTS