Harmen Beurmanjer

21 Review on the GHB using Population 2 Introduction Gamma-hydroxybutyrate (GHB) is a short-chain fatty acid derived from the inhibitory neu- rotransmitter gamma-aminobutric acid (GABA) (Snead & Gibson, 2005). GHB can cross the blood brain barrier, where it modifies GABA-ergic activity in the central nervous system, as it binds to GHB, GABA-B, and to a lesser extent also to GABA-A receptors (Bay, Eghorn, Klein, & Wellendorph, 2014; Carter, Koek, & France, 2009; Snead & Gibson, 2005; Xie & Smart, 1992). While GABA-A and GABA-B receptors are widely distributed across the brain, GHB receptors mainly occur in the hippocampus, cortex, thalamus, and amygdala (Bessman & Fishbein, 1963; Schep, Knudsen, Slaughter, Vale, & Megarbane, 2012; Snead & Morley, 1981). GHB was first studied in the 1960s as an anesthetic but use in anesthesia remained limited due to a high occurrence of adverse effects, mainly vomiting and seizures (Kam & Yoong, 1998). Currently, GHB is medically mostly used in the treatment of narcolepsy (Xyrem®, sodium oxybate) (Boscolo-Berto et al., 2012). Over the past decades GHB has emerged as a popular and addictive party drug with a high potential of (ab)use due to its euphoric, relaxing and sexually stimulating effects (Degenhardt, Darke & Dillon, 2002; European Monitoring Centre for Drugs & Drug Addiction, 2018; Nicholson & Balster, 2001). Use of GHB, and its precursors gamma-butyrolactone (GBL) and 1,4-butanediol, is particularly popular in some parts of Europe, the United States, and Australia. In Australia, United Kingdom, The Netherlands and United States the estimated prevalence of current GHB use in the general adult population (>18 years of age) ranges from 0.1% to 1.3%, whereas rates among partygoers are considerably higher (Center for Behavioral Health Statistics & Quality, 2016; Corkery et al., 2015; Degenhardt & Dunn, 2008; European Monitoring Centre for Drugs & Drug Addiction, 2008; van Amsterdam, van Laar, Brunt, & van den Brink, 2012). Despite the low prevalence of GHB use in the general population, GHB was number 4 in the top 20 drug-recorded emergency department (ED) presentations in Europe in 2017 (European Monitoring Centre for Drugs & Drug Addiction, 2018). GHB is associated with a high risk of overdose, due to a narrow window between recreational dose and overdose (Abanades et al., 2007, 2006; Miotto et al., 2001). Importantly, repeated GHB-induced comas have been associated with diminished neurocognitive functions and altered hippocampal functioning (Raposo Pereira et al., 2018a, 2018b, 2019). However, GHB-induced comas are not perceived to be harmful by GHB-users, whomainly emphasize the positive effects of the substance (Beurmanjer et al., 2019; Miotto et al., 2001; Raposo Pereira et al., 2019). Since the early 2000s, there has been a rise in studies reporting people with substance use disorders (SUD) in relation to GHB, in this article referred to GHB use disorder (GUD). Though GUD is not a formal DSM-5 diagnosis, patients with GUD commonly fulfill general criteria for SUD according to DSM-5. A DSM-5 SUD diagnosis comprises 11 behavioral and physical signs and symptoms, for which two are required for a SUD diagnosis. The severity