Introduction

Gamma-Butyrolactone is a chemical compound commonly used as an industrial solvent. It serves as a precursor in the synthesis of various chemicals. Gamma-Butyrolactone undergoes conversion into gamma-hydroxybutyric acid, a central nervous system depressant. While Gamma-Butyrolactone has legitimate industrial applications, its potential for misuse and conversion to gamma-hydroxybutyric acid, a controlled substance, raises concerns. Due to its association with recreational drug use, regulatory measures and restrictions govern its distribution and sale. Careful handling is necessary due to its potential health risks and legal implications². It is an endogenous chemical found in the human body. The protonated form is gamma hydrox-ybutyric acid, whereas the deprotonated form of the carboxylic acid moiety is gamma hydroxybutyrate.Gamma-hydroxybutyric acidis also known as sodium oxybate, sodium 4-hydroxybutyrate, and 4-Hydroxy-n-butyric acid. It can also be easily synthesised from readily obtainable ingredients.

Application

Gamma-Butyrolactone plays a multifaceted role across diverse industrial applications. As an industrial solvent, Gamma-Butyrolactone contributes significantly to polymer production, aiding in the manufacture of plastics, resins, and electronics components. Its efficacy as a cleaning agent is evident in surface cleaning and machinery maintenance, ensuring optimal functionality in industrial settings. Gamma-Butyrolactone's paint-stripping capabilities make it valuable for removing coatings in various applications. Moreover, it serves as a reliable solution for adhesive removal, crucial in industrial processes requiring the dissolution of bonding residues. With historical relevance in photography, Gamma-Butyrolactone has been utilized in the production of photographic chemicals. Additionally, its involvement in agricultural formulations for herbicides and pesticides underscores its versatility. Despite its legitimate uses, adherence to strict regulations and safety measures is paramount due to its potential for misuse and conversion to controlled substances, emphasizing responsible industrial practices. The misuse of Gamma-Butyrolactone and these prodrugs increased greatly in Western countries from the early 1990s, especially in the club anddance scenes. The period sincehas been marked by claims that the substances have been implicated in a rising number of deaths in the USA, Western Europe. Australasia, and other developed countries. In other ways, Gamma-Butyrolactone is widely used as an industrial solvent for various applications, including the production of polymers, pharmaceuticals, and electronics. Cleaning Agent: Gamma-Butyrolactone is employed as a cleaning agent for surfaces, machinery, and industrial equipment due to its solvent properties. Paint Stripping: In certain industries, Gamma-Butyrolactone is used as a paint-stripping agent to remove paint and coatings from surfaces. Adhesive Removal: It is utilized for removing adhesive residues, particularly in industrial settings where adhesive materials need to be dissolved. Photographic Chemicals: Gamma-Butyrolactone has historical use in the production of photographic chemicals and as a component in some film development processes. Herbicide and Pesticide Formulations: In agriculture, Gamma-Butyrolactone may be a component in the formulation of certain herbicides and pesticides. It's crucial to note that while Gamma-ButyrolactoneL has legitimate industrial uses, its potential for misuse and conversion to Gamma-Butyrolactone, a controlled substance, has led to strict regulations and controls in many regions. Careful adherence to legal guidelines and safety precautions is essential in its handling and distribution.

Synthesis

Gamma-hydroxybutyrate is synthesized endogenously from γ-aminobutyric acid (GABA) or exogenously from 1,4-butanediol (butane-1,4-diol; 1,4-BD) or γ-butyrolactone (GBL). γ-butyrolactone, and 1,4-BD are rapidly converted to gamma-hydroxybutyrate. Chemical Synthesis Precursor: Gamma-Butyrolactone serves as a precursor in the synthesis of numerous chemicals, such as gamma-hydroxybutyric acid, a compound used for medical and recreational purposes. The synthesis of γ-butyrolactone involves several chemical steps. One common method is the oxidation of tetrahydrofuran (THF), a cyclic ether. The key steps in the synthesis can be outlined as follows: 1. Oxidation of THF: Tetrahydrofuran undergoes oxidation, typically using an oxidizing agent such as sodium or potassium dichromate. This process yields gamma-butyrolactone. 2. Hydrolysis: γ-butyrolactone can undergo hydrolysis in the presence of an acidic or basic catalyst to produce gamma-hydroxybutyric acid. It's important to note that γ-butyrolactone is a precursor to gamma-hydroxybutyrate, a controlled substance due to its potential for abuse. Regulations and restrictions are in place to monitor and control the production and distribution of γ-butyrolactone, emphasizing its responsible use in legitimate industrial applications.

Safety

Gamma-Butyrolactone and 1,4-butanediol (1,4-BD), are drugs of abuse which act primarily as central nervous system (CNS) depressants. Gamma-hydroxybutyrate is an endogenous neurotransmitter that is predominantly distributed within discrete regions of the mammalian brain, though it is also present in the blood, urine,and other peripheral tissues. Gamma-hydroxybutyrate is both a metabolite and a precursor of the inhibitory neurotransmitter gamma hydroxybutyrate (GABA), and acts as a neuromodulator in the GABA system. An overview of its biochemical path way is presented in Fig. 1 with a detailed description in the Toxicokinetics section. Gamma-hydroxybutyrate is synthesized from glutamate, typically within GABA-releasing neurons, that are predominantly located in the hippocampus, cortex, thalamus, and amygdala. Upon depolarization, endogenously released gamma-hydroxybutyrate has a high affinity for gamma-hydroxybutyrate-receptors, present both on pre- and postsynaptic neurons. Gamma-hydroxybutyrate pharmacokinetics have been studied in healthy volunteers, narcoleptics, alcoholics, and patients with liver impairment. A further study monitored gamma-hydroxybutyrate kinetics following 1,4-butanediol administration to healthy volunteers. The pharmacokinetics do not appear to vary significantly among healthy human volunteers, narcoleptic patients, or alcohol-dependent patients. However, when healthy adult volunteers and patients with biopsy-proven liver cirrhosis were compared, there was a marked reduction in clearance following oral administration and significant prolongation of elimination half-life¹. Misuse of gamma butyrolactone has increased greatly since the early 1990s, being implicated in a rising number of deaths. This paper reviews knowledge on Gamma-Butyrolactone and derivatives, and explores the largest series of deaths associated with their non-medical use³.

Figure 1. A summary of the metabolic pathway of Gamma-Butyrolactone

Reference

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3. Corkery JM, Loi B, Claridge H, Goodair C, Corazza O, Elliott S, Schifano F. Gamma hydroxybutyrate (GHB), gamma butyrolactone (GBL) and 1,4-butanediol (1,4-BD; BDO): A literature review with a focus on UK fatalities related to non-medical use. Neurosci Biobehav Rev. 2015 Jun;53:52-78.