Harmen Beurmanjer

9 General Introduction 1 General introduction Gamma-HydroxyButyric acid (GHB) has first been described in 1961 (Laborit, 1964). However, it took until the early nineties before use became more wide spread amongst the general public (The Centers for Disease Control, 1991). Its addictive potential went unnoticed until the mid-nineties, when the first dependent users were reported (Galloway, Frederick, & Staggers, 1994; Galloway et al., 1997). From 2000 onwards a limited number of case-studies from different countries can be found and only in 2013 the first study with more than 10 GHB dependent patients was published (de Weert-van Oene, Schellekens, Dijkstra, Kamal, & de Jong, 2013). To date, there are still fewer than 100 publications on GHB dependence or GHB use disorder (GUD) to be found on Pubmed. These numbers show how limited the research on GUD is. Available studies focus mostly on GHB intoxication and coma’s (Busardo & Jones, 2015; Grund, de Bruin, & van Gaalen, 2018; Mason & Kerns, 2002) and withdrawal management (De Jong, Kamal, Dijkstra, & De Haan, 2011; Dijkstra et al., 2017; Kamal, van Iwaarden, Dijkstra, & de Jong, 2014; McDaniel & Miotto, 2001; Karen Miotto & Roth, 2001; Tarabar & Nelson, 2004). However, studies are only observational and often cross-sectional. Moreover, there’s limited information available about subgroups of GHB users, treatment needs, the clinical relevance of GHB induced coma’s, best detoxification method and effective relapse management. This introductory chapter summarizes the characteristics of GHB and patients with GUD. First the neuropharmacology of GHB will be discussed. Then the prevalence of non-medical GHB use and related acute health risks are described. This is followed by a discussion of the GUD syndrome and currently available treatment strategies. Finally, the chapter ends with an overview of the aims and outline of this thesis. Neuropharmacology of GHB GHB is a short-chain fatty acid that is an endogenous precursor and metabolite of the most important inhibitory neurotransmitter gamma-aminobutyric acid (GABA) (Fig. 1) (Laborit, 1964; Tarabar & Nelson, 2004). GHB itself acts both as neurotransmitter and as neuromodulator after passing the blood-brain barrier. GHB has a rapid onset of action after ingestion (Tmax=25 to 40 minutes) and a short half-life (T½=30-60min) (Brenneisen et al., 2004). The effect of GHB is bidirectional: at low doses, it stimulates the GHB receptor, increasing the flow of the activating neurotransmitter glutamate (Ferraro et al., 2001; O. C. Snead & Gibson, 2005). GHB receptors are primarily located within the prefrontal cortex and the hippocampus, and in a lesser extent within the striatum, thalamus and cerebellum (Kemmel et al. 2006; Snead 2000). At high doses, GHB is responsible for the increased release of GABA, mainly through the GABA B receptor (Andriamampandry et al., 2006; Bay, Eghorn, Klein, & Wellendorph, 2014; Lingenhoehl et al., 1999). This explains why users