Γ-Butyrolactone

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Contents

γ-Butyrolactone [1] [2]
Gamma-Butyrolactone.svg
GBL-from-xtal-3D-balls.png
Names
Preferred IUPAC name
Oxolan-2-one
Other names
Dihydrofuran-2(3H)-one
GBL
Butyrolactone
1,4-Lactone
4-Butyrolactone
4-Hydroxybutyric acid lactone
gamma-Hydroxybutyric acid lactone
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.002.282 OOjs UI icon edit-ltr-progressive.svg
KEGG
PubChem CID
RTECS number
  • LU3500000
UNII
  • InChI=1S/C4H6O2/c5-4-2-1-3-6-4/h1-3H2 Yes check.svgY
    Key: YEJRWHAVMIAJKC-UHFFFAOYSA-N Yes check.svgY
  • InChI=1/C4H6O2/c5-4-2-1-3-6-4/h1-3H2
    Key: YEJRWHAVMIAJKC-UHFFFAOYAC
  • O=C1OCCC1
Properties
C4H6O2
Molar mass 86.090 g·mol−1
AppearanceColorless liquid
Odor Weak characteristic odor, comparable to stale water, synthetic melon aroma or burnt plastic
Density 1.1286 g/mL (15 °C), 1.1296 g/mL (20 °C)
Melting point −43.53 °C (−46.35 °F; 229.62 K)
Boiling point 204 °C (399 °F; 477 K)
Miscible
Solubility Soluble in CCl4, methanol, ethanol, acetone, benzene, ethyl ether
log P −0.76 [3]
Vapor pressure 1.5 kPa (20 °C)
Acidity (pKa)4.5
1.435, 1.4341 (20 °C)
Viscosity 1.7 cP (25 °C)
Hazards
Occupational safety and health (OHS/OSH):
Main hazards
Toxic and flammable
GHS labelling:
GHS-pictogram-acid.svg GHS-pictogram-exclam.svg
Danger
H302, H318, H336
P264, P270, P280, P301+P312, P305+P351+P338, P403+P233, P501
NFPA 704 (fire diamond)
NFPA 704.svgHealth 2: Intense or continued but not chronic exposure could cause temporary incapacitation or possible residual injury. E.g. chloroformFlammability 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g. canola oilInstability 1: Normally stable, but can become unstable at elevated temperatures and pressures. E.g. calciumSpecial hazards (white): no code
2
1
1
Flash point 98 °C (208 °F; 371 K) (closed cup)
455 °C (851 °F; 728 K)
Explosive limits 3.6% v/v (lower)
16% v/v (upper)
Lethal dose or concentration (LD, LC):
1540 mg/kg (oral, rat)
>5640 mg/kg (dermal, rabbit)
>2.68 mg/kg (rat, 4h)
Safety data sheet (SDS) Fisher Scientific
Legal status
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

γ-Butyrolactone (GBL) or gamma-butyrolactone is an organic compound with the formula O=CO(CH2)3. It is a hygroscopic, colorless, water-miscible liquid with a weak characteristic odor. It is the simplest 4-carbon lactone. It is mainly used as an intermediate in the production of other chemicals, such as N-methyl-2-pyrrolidone. [5]

In humans, GBL acts as a prodrug for gamma-hydroxybutyric acid (GHB) and is often used as a recreational drug. GHB acts as a central nervous system (CNS) depressant with effects similar to those of barbiturates. [6]

Occurrence

GBL has been found in extracts from samples of unadulterated wines. [7] [8] This finding indicates that GBL is a naturally occurring component in some wines and may be present in similar products. The concentration detected was approximately 5 μg/mL and was easily observed using a simple extraction technique followed by GC/MS analysis. GBL can be found in cheese flavorings but typically results in a content of 0.0002% GBL in the final foodstuff. [9]

Production and synthesis

γ-Butyrolactone is produced industrially by dehydrogenation of 1,4-butanediol at a temperature of 180–300 °C and atmospheric pressure in the presence of a copper catalyst. [5]

Industrial synthesis of gamma-butyrolactone.svg

The yield of this process is approximately 95%. The purification takes place with a liquid-gas-phase extraction. [5]

In the laboratory, it may also be obtained via the oxidation of tetrahydrofuran (THF), for example with aqueous sodium bromate. [10] An alternative route proceeds from GABA via a diazonium intermediate. [11]

Reactions

As a lactone, GBL is hydrolyzed under basic conditions, for example in a sodium hydroxide solution into sodium gamma-hydroxybutyrate, the sodium salt of gamma-hydroxybutyric acid. In acidic water, a mixture of the lactone and acid forms exists in an equilibrium. These compounds then may go on to form the polymer poly(4-hydroxybutyrate) as well as the dimer 1,6-Dioxecane-2,7-dione. When treated with a non-nucleophilic base, such as lithium diisopropylamide, GBL undergoes deprotonation of the alpha carbon atom to the carbonyl. The related compound caprolactone can be used to make a polyester in this manner.

Polymerization

The ring-opening polymerization of butyrolactone gives polybutyrolactone. The resulting reverts to the monomer by thermal cracking. [12] [13] It is claimed that poly(GBL) is competitive with commercial biomaterial poly(4-hydroxybutyrate), or P4HB. It is further claimed that poly(GBL) is cheaper to make than P4HB, although both are bio-derived. [12] [14]

Uses

Gamma-Butyrolactone is used as a chemical solvent and a cleaning agent, [15] for example in paint stripping or for cleaning graffiti. [16] Butyrolactone is a precursor to other chemicals. Reaction with methylamine gives NMP, and with ammonia gives pyrrolidone. It is also used as a solvent in lotions and some polymers. [5]

2-Methyl-4-chlorophenoxybutyric acid is an herbicide produced from butyrolactone. MCPB.png
2-Methyl-4-chlorophenoxybutyric acid is an herbicide produced from butyrolactone.

Butyrolactone, with its wide liquid range, chemical stability, and high dielectric constant, is used in electrolytic capacitors as the organic solvent. It is frequently mixed with a small ratio of ethylene glycol, "9:1" being common, to vary internal resistivity.[ citation needed ]

It has been used as a solvent in various laboratory experiments, e.g., the preparation of methylammonium lead halide. [17]

GBL is used in the synthesis of DPH-362 Fb: [28916-83-8] (analog of amitriptyline), [18]

DPH-362 synthesis DPH-362 synthesis.svg
DPH-362 synthesis

Atiprosin, Furomazine, [19] GET-73 [202402-01-5] [20] [21]

& 1-chloro-4,4-bis(p-fluorophenyl)butane [3312-04-7] [22] (the side-chain to the diphenylbutylpiperidine agents).

[3312-04-7] from GBL (3312-04-7) from GBL.svg
[3312-04-7] from GBL

It was claimed that the reaction of GBL with benzene in the presence of aluminium trichloride could furnish 1-tetralone in a single step. [23]

Another discovered GBL utility is in the synthesis of nicotine (analogs): [24]

Pharmacology

GBL is not active in its own right; its mechanism of action stems from its identity as a prodrug of GHB.

Pharmacokinetics

GBL is rapidly converted into GHB by paraoxonase (lactonase) enzymes, found in the blood. [25] [26] [27] Animals which lack these enzymes exhibit no effect from GBL. [26] GBL is more lipophilic (fat soluble) than GHB, and so is absorbed faster and has higher bioavailability. Because of these pharmacokinetic differences, GBL tends to be more potent and faster-acting than GHB, but has a shorter duration; whereas the related compound 1,4-butanediol (1,4-B) tends to be slightly less potent and slower to take effect but longer-acting than GHB. [28]

Metabolic pathway of 1,4-butanediol, GBL and GHB GHB metabolic pathway.svg
Metabolic pathway of 1,4-butanediol, GBL and GHB

Nutritional supplement

Due to its property of being a prodrug of GHB which increases sleep related growth hormone (GH) secretion, [29] GBL was sold as a nutritional supplement after the scheduling of GHB, under the names Revivarant and Renewtrient, [30] until they were banned by the FDA.

Recreational drug

GBL is a prodrug of GHB (naturally produced) and its recreational use comes entirely as a result of this. [31] GBL overdose can cause irrational behavior, severe sickness, coma and death. [32]

To bypass GHB restriction laws, home synthesis kits were introduced to transform GBL and/or 1,4-B into GHB.

Jugs of seized GBL GBLjugs.jpg
Jugs of seized GBL
FDA warning against products containing GHB and its prodrugs, such as GBL Dangerous dietary supplements.gif
FDA warning against products containing GHB and its prodrugs, such as GBL

GBL has a distinctive taste and odor, described as being comparable to stale water, synthetic melon aroma or burnt plastic. This differs significantly from GHB, which is described as having a decidedly "salty" taste. [33]

Due to the fact that those with limited chemistry knowledge can make GBL with easy-to-get precursors, it has become quite popular among young people in French nightclubs. [34] [35]

Dangers

If taken undiluted by mouth, GBL can cause esophageal and gastro-intestinal irritation. It is possible for oral ingestion of GBL to cause nausea and other similar problems, possibly more so than with GHB.

GHB has biphasic effects, a euphoric effect at low doses (the reason for the term liquid ecstasy), and a sedative effect [36] at higher doses. As a result of this sedation it can cause unconsciousness. [37] When combined with alcohol the increased sedation and risk of vomiting results in a high risk of fatality. Many harm reduction organisations suggest never mixing the two drugs as a result. [38] [39]

There have been news reports of several deaths associated with GBL, usually in combination with alcohol or other depressants. [40]

Gamma-Butyrolactone is often used as a date rape drug. [41]

Addictiveness and dependence

Frequent use of GHB or GBL, even when taken long-term and in moderate doses, does not appear to cause significant physical dependency in the majority of its users. In many people, quitting or temporarily abstaining from use of the drugs is achieved with minimal or no difficulty. However, when consumed in excessive amounts with a high frequency of dosing, physical and psychological dependence can develop. [42] Management of GBL dependence involves considering the person's age, comorbidity and the pharmacological pathways of GBL. [43]

GHB and GBL users can adopt a '24/7' dosing regime. [44] This is where the user has become tolerant to the effects of the drug, increasing the dosage and frequency of dosage simply to avoid withdrawal symptoms.

For those users who do report withdrawal symptoms upon quitting the use of GHB or GBL, symptoms seem to depend on the dosage and the length of time the drug was used. Light to moderate users often experience insomnia and sleep-related problems, whereas heavy, prolonged use can cause severe withdrawal symptoms similar to Benzodiazepine withdrawal syndrome (BWS).

Dose

A milliliter of pure GBL metabolizes to the equivalent 1.65 g of NaGHB, the common form, so doses are measured in the single milliliter range, either taken all at once or sipped over the course of a night.

Australia: GBL is not classified as a drug but as a health-endangering substance. Legislation entering into force on 1 April 2011 made it possible to handle narcotics for industrial purposes and enabled GBL and 1,4-Butanediol to be classified as controlled substances. [45] As of 2023 there are penalties for possessing, selling or driving under the influence of the substance. [46]

Canada: GBL is a Controlled Substance under Schedule VI of the "Controlled Drugs and Substances Act" in Canada. Schedule VI of the "Controlled Drugs and Substances Act" requires vendors to collect information regarding purchases of GBL. The Act also prohibits the import and export of GBL into or out of Canada classifying it as either an indictable offense punishable with up to 10 years in prison or an offense punishable on summary conviction liable to imprisonment for up to eighteen months. [47] It is not illegal for an individual to possess GBL in Canada.[ citation needed ]

Germany: GBL is not listed in the narcotics law, but its distribution is controlled. Possession is not illegal, but may be punished according to the Medicines Act, when intended to be sold for human consumption or synthesis of GHB. In recent years, an increase of GBL consumption has been observed due to the prohibition of GHB.

Hong Kong SAR: GBL is a dangerous drug controlled under Schedule 1 of the Dangerous Drugs Ordinance, Cap.134 (with exemption clause at Paragraph 16D). Any person who is found to have in his possession of it not in accordance with this Ordinance can be liable, on conviction upon indictment, a fine of HK$1,000,000 and to imprisonment for 7 years.

Israel: GBL was classified as a proscribed substance from 2007. [48]

Netherlands: GBL is unlike GHB not listed in the narcotics law, [49] but its distribution is controlled. Possession is not illegal but may be punished according to the Medicines Act, when intended to be sold for human consumption or synthesis of GHB. [50]

People's Republic of China: GBL was regulated as a Class III drug precursor since 7 June 2021. [51]

Poland: GBL is classified as a drug. A license is mandatory for the manufacture, processing, reworking, importing, distribution of GBL. [52]

Russia: GBL has been classified as a psychotropic substance since 22 February 2012. Its trafficking is limited, and non-licensed selling, buying or any other use is punishable by imprisonment up to 20 years.

Sweden: GBL is not classified as a drug but as a health-endangering substance. Although recently passed legislation to enter into force on 1 April 2011 will make it possible to handle narcotics for industrial purposes will enable GBL and 1,4-Butanediol to be classified as controlled substances. [53]

United Kingdom: Because of their legitimate uses, regulation 4B of the 2001 regulations makes it lawful to import, export, produce, supply, offer to supply or possess GBL and 1,4-BD, except where a person does so knowing or believing that they will be used for the purpose of human ingestion. [9] [54] Otherwise it is a class B controlled substance. [55]

United States: GBL is regulated as a List I controlled chemical. As a GHB analog, it is also treated as a controlled substance under Schedule I of the Controlled Substances Act if intended for human consumption. [56] Sales and distribution of this product for industrial use is tightly regulated and requires quantity tracing, lock and key storage and 24 hour surveillance and is limited to a very few suppliers who have appropriate DEA registrations and as of 2021 included only Ashland, BASF, and Miami Chemical. Lyondell reportedly stopped commercial sales of this product due to increasingly tight regulations and liabilities but still makes it for internal and downstream production use. To purchase this chemical requires special DEA license and end use certificate approved and a site audit by DEA.

See also

Related Research Articles

γ-Hydroxybutyric acid Chemical compound

γ-Hydroxybutyric acid, also known as gamma-hydroxybutyric acid, GHB, or 4-hydroxybutanoic acid, is a naturally occurring neurotransmitter and a depressant drug. It is a precursor to GABA, glutamate, and glycine in certain brain areas. It acts on the GHB receptor and is a weak agonist at the GABAB receptor. GHB has been used in the medical setting as a general anesthetic and as treatment for cataplexy, narcolepsy, and alcoholism. The substance is also used illicitly for various reasons, including as a performance-enhancing drug, date rape drug, and as a recreational drug.

Depressants, colloquially known as "downers" or central nervous system (CNS) depressants, are drugs that lower neurotransmission levels, decrease the electrical activity of brain cells, or reduce arousal or stimulation in various areas of the brain. Some specific depressants do influence mood, either positively or negatively, but depressants often have no clear impact on mood. In contrast, stimulants, or "uppers", increase mental alertness, making stimulants the opposite drug class from depressants. Antidepressants are defined by their effect on mood, not on general brain activity, so they form an orthogonal category of drugs.

<span class="mw-page-title-main">1,4-Butanediol</span> One of four stable isomers of butanediol

1,4-Butanediol, also called Butane-1,4-diol (other names include 1,4-B, BD, BDO and 1,4-BD), is a primary alcohol and an organic compound with the formula HOCH2CH2CH2CH2OH. It is a colorless viscous liquid first synthesized in 1890 via acidic hydrolysis of N,N'-dinitro-1,4-butanediamine by Dutch chemist Pieter Johannes Dekkers, who called it "tetramethylene glycol".

<span class="mw-page-title-main">Federal Analogue Act</span> Section of the United States Controlled Substances Act

The Federal Analogue Act, 21 U.S.C. § 813, is a section of the United States Controlled Substances Act passed in 1986 which allows any chemical "substantially similar" to a controlled substance listed in Schedule I or II to be treated as if it were listed in Schedule I, but only if intended for human consumption. These similar substances are often called designer drugs. The law's broad reach has been used to successfully prosecute possession of chemicals openly sold as dietary supplements and naturally contained in foods. The law's constitutionality has been questioned by now Supreme Court Justice Neil Gorsuch on the basis of Vagueness doctrine.

<span class="mw-page-title-main">Sodium oxybate</span> Medication to treat symptoms of narcolepsy

Sodium oxybate, sold under the brand name Xyrem among others, is a medication used to treat symptoms of narcolepsy: sudden muscle weakness and excessive daytime sleepiness. It is used sometimes in France and Italy as an anesthetic given intravenously; it is also approved and used in Italy and in Austria to treat alcohol dependence and alcohol withdrawal syndrome.

<span class="mw-page-title-main">SCH-50911</span> Chemical compound

SCH-50911 is a selective GABAB antagonist. Its main applications are in pharmacology research.

γ-Valerolactone Chemical compound

γ-Valerolactone (GVL) or gamma-valerolactone is an organic compound with the formula C5H8O2. This colourless liquid is one of the more common lactones. GVL is chiral but is usually used as the racemate. It is readily obtained from cellulosic biomass and is a potential fuel and green solvent.

<span class="mw-page-title-main">GABA receptor agonist</span> Category of drug

A GABA receptor agonist is a drug that is an agonist for one or more of the GABA receptors, producing typically sedative effects, and may also cause other effects such as anxiolytic, anticonvulsant, and muscle relaxant effects. There are three receptors of the gamma-aminobutyric acid. The two receptors GABA-α and GABA-ρ are ion channels that are permeable to chloride ions which reduces neuronal excitability. The GABA-β receptor belongs to the class of G-Protein coupled receptors that inhibit adenylyl cyclase, therefore leading to decreased cyclic adenosine monophosphate (cAMP). GABA-α and GABA-ρ receptors produce sedative and hypnotic effects and have anti-convulsion properties. GABA-β receptors also produce similar effects. Furthermore, they lead to changes in gene transcription, and are mainly found in autonomic nervous system centers.

γ-Amino-β-hydroxybutyric acid Anticonvulsant drug

γ-Amino-β-hydroxybutyric acid (GABOB), also known as β-hydroxy-γ-aminobutyric acid (β-hydroxy-GABA), sold under the brand name Gamibetal among others, is an anticonvulsant which is used for the treatment of epilepsy in Europe, Japan, and Mexico. It is a GABA analogue, or an analogue of the neurotransmitter γ-aminobutyric acid (GABA), and has been found to be an endogenous metabolite of GABA.

<span class="mw-page-title-main">Embutramide</span> Chemical compound

Embutramide is a potent sedative drug that is structurally related to GHB. It was developed by Hoechst A.G. in 1958 and was investigated as a general anesthetic agent, but was found to have a very narrow therapeutic window, with a 50 mg/kg dose producing effective sedation and a 75 mg/kg dose being fatal. Along with strong sedative effects, embutramide also produces respiratory depression and ventricular arrhythmia. Because of these properties, it was never adopted for medical use as an anesthetic as it was considered too dangerous for this purpose. Instead it is used for euthanasia in veterinary medicine, mainly for the euthanization of dogs.

<span class="mw-page-title-main">GHB receptor</span> GHB receptor coding gene in the species Homo sapiens

The γ-hydroxybutyrate (GHB) receptor (GHBR), originally identified as GPR172A, is an excitatory G protein-coupled receptor (GPCR) that binds the neurotransmitter and psychoactive drug γ-hydroxybutyric acid (GHB). As solute carrier family 52 member 2 (SLC52A2), it is also a transporter for riboflavin.

<span class="mw-page-title-main">Aceburic acid</span> Chemical compound

Aceburic acid (INN), also known as 4-acetoxybutanoic acid or 4-hydroxybutyric acid acetate, is a drug described as an analgesic which was never marketed. It is the acetyl ester of gamma-hydroxybutyrate, and based on its structural relation to GHB, is likely to behave as a prodrug to it.

<span class="mw-page-title-main">T-HCA</span> Chemical compound

trans-4-Hydroxycrotonic acid (T-HCA), also known as γ-hydroxycrotonic acid (GHC), is an agent used in scientific research to study the GHB receptor. It is an analogue of γ-hydroxybutyric acid (GHB), as well as an active metabolite of GHB. Similarly to GHB, T-HCA has been found to be endogenous to the rat central nervous system, and as a metabolite of GHB, is almost certain to be endogenous to humans as well. T-HCA binds to the high-affinity GHB receptor with 4-fold greater affinity than GHB itself, where it acts as an agonist, but does not bind to the low-affinity GHB binding site, the GABAB receptor. Because of this, T-HCA does not produce sedation. T-HCA has been shown to cause receptor activation-evoked increases in extracellular glutamate concentrations, notably in the hippocampus.

γ-Hydroxyvaleric acid Chemical compound

γ-Hydroxyvaleric acid (GHV), also known as 4-methyl-GHB, is a designer drug related to γ-hydroxybutyric acid (GHB). It is sometimes seen on the grey market as a legal alternative to GHB, but with lower potency and higher toxicity, properties which have tended to limit its recreational use.

<span class="mw-page-title-main">CGP-35348</span> Chemical compound

CGP-35348 is a compound used in scientific research which acts as an antagonist at GABAB receptors.

γ-Hydroxybutyraldehyde Chemical compound

γ-Hydroxybutyraldehyde (GHBAL) is the organic compound with the formula HOCH2CH2CH2CHO. It is a colorless liquid. The compound occurs in nature and is produced commercially.

<span class="mw-page-title-main">GABA analogue</span> Class of drugs

A GABA analogue is a compound which is an analogue or derivative of the neurotransmitter gamma-Aminobutyric acid (GABA).

γ-Aminobutyraldehyde, also known as 4-aminobutanal, 4-aminobutyraldehyde, or GABA aldehyde, is a metabolite of putrescine and a biological precursor of γ-aminobutyric acid (GABA). It can be converted into GABA by the actions of diamine oxidase (DAO) and aminobutyraldehyde dehydrogenase (ABALDH). Putrescine is converted into ABAL via monoamine oxidase B (MAO-B). However, biosynthesis of GABA from polyamines like putrescine is a minor metabolic pathway in the brain.

4-Amino-1-butanol, or 4-aminobutanol, also known as 4-hydroxybutylamine, is an alkanolamine and an analogue and precursor of the neurotransmitter γ-aminobutyric acid (GABA).

<span class="mw-page-title-main">Neurotransmitter prodrug</span> A prodrug of a neurotransmitter

A neurotransmitter prodrug, or neurotransmitter precursor, is a drug that acts as a prodrug of a neurotransmitter. A variety of neurotransmitter prodrugs have been developed and used in medicine. They can be useful when the neurotransmitter itself is not suitable for use as a pharmaceutical drug owing to unfavorable pharmacokinetic or physicochemical properties, for instance high susceptibility to metabolism, short elimination half-life, or lack of blood–brain barrier permeability. Besides their use in medicine, neurotransmitter prodrugs have also been used as recreational drugs in some cases.

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  22. ↑ Junying Yuan, et al. WO2011143444 ().
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  34. ↑ "'There could be 100 comas in the year': Paris police chief reacts to rise of GBL, GHB overdoses in clubs". Resident Advisor. Archived from the original on 2018-04-20. Retrieved 2018-04-19.
  35. ↑ "Drogue : " L'interdiction de vente au public du GBL n'a rien changé à la consommation "". Le Monde.fr (in French). 17 April 2018. Retrieved 2018-04-19.
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  39. ↑ "GHB and GBL". GMFA. Archived from the original on 20 June 2020. Retrieved 18 August 2014.
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  45. ↑ "LAW AND JUSTICE LEGISLATION AMENDMENT (SERIOUS DRUG OFFENCES AND OTHER MEASURES) ACT 2005 NO. 129, 2005 - SCHEDULE 1 - Serious drug offences".
  46. ↑ "GHB - Alcohol and Drug Foundation". adf.org.au. Retrieved 2023-07-17.
  47. ↑ Legislative Services Branch (May 19, 2023). "Consolidated federal laws of Canada, Controlled Drugs and Substances Act". laws-lois.justice.gc.ca.
  48. ↑ "section 7c of chapter B of part A of the 1st appendix of the Dangerous Drugs Act 1973". www.nevo.co.il.
  49. ↑ "wetten.nl - Regeling - Opiumwet - BWBR0001941". Wetten.nl (in Dutch). 19 July 2019. Retrieved 19 July 2019.
  50. ↑ "Webwinkels gestopt met handel in GBL". Emerce (in Dutch). 9 December 2013. Retrieved 9 December 2013.
  51. ↑ "国务院办公厅关于同意将α-苯乙酰乙酸甲酯等6种物质列入易制毒化学品品种目录的函" (in Simplified Chinese). The State Council - The People's Republic of China. 7 June 2021. Retrieved 11 October 2021.
  52. ↑ "Główny Inspektorat Farmaceutyczny".
  53. ↑ "Socialutskottets betänkande 2010/11:SoU5 - Riksdagen".
  54. ↑ "UK Statutory Instrument 2011 No. 448". 2011-02-18.
  55. ↑ "The Misuse of Drugs Act 1971 (Amendment) Order 2022".
  56. ↑ "Information Bulletin: GHB Analogs; GBL, BD, GHV, and GVL". www.justice.gov.
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