DARK Classics in Chemical Neuroscience: Gamma-Hydroxybutyrate (GHB)

Abstract

Gamma-hydroxybutyrate (GHB) is a naturally occurring short-chain fatty acid that rose to prominence as a popular club drug in the 1990s. Originally developed as an anesthetic in the early 1960s, it was later sold as an over-the-counter dietary supplement before becoming a rising substance of abuse in the following decades as one of the “date rape” drugs. Despite its abuse potential, there has been a recent surge in therapeutic interest in the drug due to its clinical viability in the treatment of narcolepsy and alcohol abuse/withdrawal. Its interactions with the GABAergic framework of higher mammals has made it the prototypical example for the study of the chief inhibitory mechanism in the human central nervous system. Though relatively obscure in terms of popular culture, it has a storied history with widespread usage in therapeutic, recreational (“Chemsex”), and some disturbingly nefarious contexts. This Review aims to capture its legacy through review of the history, synthesis, pharmacology, drug metabolism, and societal impact of this DARK classic in chemical neuroscience.

Urinary Profile of Endogenous Gamma-Hydroxybutyric Acid and its Biomarker Metabolites in Healthy Korean Females: Determination of Age-Dependent and Intra-Individual Variability and Identification of Metabolites Correlated With Gamma-Hydroxybutyric Acid

“…It is also present in small amounts in natural food, such as some wines, meats, and fruits but exerts negligible effect on the human body upon ingestion. The sodium salt of GHB, sodium oxybate, used as a CNS depressant in the treatment of narcolepsy and alcoholism, is often misused in drug-facilitated crimes ( Busardo and Jones, 2019 ; Trombley et al, 2019 ).…”

Interpol Review of Drug Analysis 2019-2022

“…2019 complementary approach for accurate determination of carbon isotopic compositions in gamma-hydroxybutyric acid using gas chromatography/combustion-isotope ratio mass spectrometry [ 118 ]; 2020 ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for the simultaneous quantification of GHB, GBL, and 1,4-BD in four popular beverages, including carbonated drinks, tea, apple cider vinegar, and coffee [ 119 ]; H-1-NMR results of seven kinds of beverages spiked GBL indicated that were spiked with GBL where the GBL was transformed into GHB in six popular beverages under certain conditions which could happen during transportation and storage [ 120 ]; detection method based on DLLME and GC-MS/MS for GHB in beverages [ 121 ]; two new oxazole derivatives for detection of gamma-hydroxybutyric acid (GHB) in soft drinks and alcoholic beverages, by color and fluorescence changes [ 122 ]; review [ 123 ]; GC-MS analysis of GHB in energy drinks [ 124 ]; 2021 a total vaporization solid-phase microextraction (TV-SPME) method with GC-MS for the detection of GHB and GBL in alcoholic beverages [ 125 ]; review [ 126 ]; LLE-FTIR based method to GBL in adulterated beverages [ 127 ]; forensic routine cases were measured to consider the potential of additional GC-MS analysis for GHB related acids (3,4-dihydroxy butyric acid, 2,4-dihydroxy butyric acid and glycolic acid) [ 128 ]; colorimetric chemosensor for the real-time in situ detection of GHB in soft drinks and alcoholic beverages [ 129 ]; heteroditopic chemosensors for detecting GHB in soft drinks, alcoholic beverages and synthetic urine [ 130 ]; a colorimetric detection kit was developed to enable rapid GHB detection in beverages [ 131 ]; 2022 development of a fluorescence probe based on a cyanostilbene scaffold for the detection of GHB [ 132 ]; method for in situ colorimetric GHB detection using various self-protection products coated with 2-(3-bromo-4-hydroxystyryl)-3-ethylbenzothiazol-3ium iodide (BHEI) as a chemical receptor embedded in hydrogels [ 133 ].…”

Interaction between γ-Hydroxybutyric Acid and Ethanol: A Review from Toxicokinetic and Toxicodynamic Perspectives

“…Endogenous GHB is produced during the metabolic process of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter that is mainly derived from glutamic acid in neurons, and is again metabolized to GABA. The sodium salt of GHB, sodium oxybate (Xyrem ® ), was approved by the U.S. Food and Drug Administration as a central nervous system depressant for narcolepsy and cataplexy in 2002, while GHB was termed as a date rape drug or a club drug in the 1990s [ 1 , 2 ]. Subsequently, the precursors of GHB, 1,4-butanediol (1,4-BD) and gamma-butyrolactone (GBL), emerged as alternatives for illegal use.…”