The Neurobiological Mechanisms of Gamma-Hydroxybutyrate Dependence and Withdrawal and Their Clinical Relevance: A Review

Abstract

Objective: γ-Hydroxybutyrate (GHB) has gained popularity as a drug of abuse. In the Netherlands the number of patients in treatment for GHB dependence has increased sharply. Clinical presentation of GHB withdrawal can be life threatening. We aim, through this overview, to explore the neurobiological pathways causing GHB dependency and withdrawal, and their implications for treatment choices. Methods: In this work we review the literature discussing the findings from animal models to clinical studies focused on the neurobiological pathways of endogenous but mainly exogenous GHB. Results: Chronic abuse of GHB exerts multifarious neurotransmitter and neuromodulator effects on γ-aminobutyric acid (GABA), glutamate, dopamine, serotonin, norepinephrine and cholinergic systems. Moreover, important effects on neurosteroidogenesis and oxytocin release are wielded. GHB acts mainly via a bidirectional effect on GABA_B receptors (GABA_BR; subunits GABA_B1 and GABA_B2), depending on the subunit of the GIRK (G-protein-dependent ion inwardly rectifying potassium) channel involved, and an indirect effect of the cortical and limbic inputs outside the nucleus accumbens. GHB also activates a specific GHB receptor and β₁-subunits of α₄-GABA_AR. Reversing this complex interaction of neurobiological mechanisms by the abrupt cessation of GHB use results in a withdrawal syndrome with a diversity of symptoms of different intensity, depending on the pattern of GHB abuse. Conclusion: The GHB withdrawal symptoms cannot be related to a single mechanism or neurological pathway, which implies that different medication combinations are needed for treatment. A single drug class, such as benzodiazepines, gabapentin or antipsychotics, is unlikely to be sufficient to avoid life-threatening complications. Detoxification by means of titration and tapering of pharmaceutical GHB can be considered as a promising treatment that could make polypharmacy redundant.

Adolescents at clinical-high risk for psychosis: Circadian rhythm disturbances predict worsened prognosis at 1-year follow-up

“…In addition, given our prior finding of relationships between sleep disturbances and bilateral thalamic volume reductions in CHR youth (Lunsford-Avery et al, 2013), it is important to consider that supplements that enhance GABA B , such as gamma hydroxybutyric acid (GHB), have been shown to improve sleep in adults with schizophrenia (Kantrowitz et al, 2010) and may be useful for targeting sleep and related impairments in CHR teens. However, potential complications and issues associated with use of NIBS and GHB with youth are currently unclear (Davis, 2014; Kamal et al, 2016). Future studies may assess the utility, tolerability, and feasibility of incorporating these treatments into preventative and intervention work with CHR youth.…”

Effects of Recreational GHB Use and Multiple GHB-Induced Comas on Brain Structure and Impulsivity

“…Since it was first synthesized in the 1960s, gamma-hydroxybutyrate acid (GHB) has been regularly used for different therapeutic purposes (1)(2)(3)(4). Over the last three decades, however, the unique profile of GHB, combining stimulant and sedative effects, has contributed to its appeal as a recreational drug (1,3,4).…”

“…Over the last three decades, however, the unique profile of GHB, combining stimulant and sedative effects, has contributed to its appeal as a recreational drug (1,3,4). The appealing effects of the drug start with euphoria, relaxation, and sexual arousal, readily evolving into a state of sedation and altered consciousness when higher doses are used (1)(2)(3)(4)(5)(6). This intangible stimulant-sedative shift is dangerously associated with poor control of dosage and effect duration, which creates a high risk for overdosing (including GHB-induced coma), and can lead to tolerance and addiction (2)(3)(4)(5).…”

“…The appealing effects of the drug start with euphoria, relaxation, and sexual arousal, readily evolving into a state of sedation and altered consciousness when higher doses are used (1)(2)(3)(4)(5)(6). This intangible stimulant-sedative shift is dangerously associated with poor control of dosage and effect duration, which creates a high risk for overdosing (including GHB-induced coma), and can lead to tolerance and addiction (2)(3)(4)(5). Despite the low prevalence of GHB use (last year's prevalence was 0.1-13% worldwide), the number of GHB users seeking treatment for drug withdrawal and GHB addiction is rising, and GHB overdose ranks as the fourth most common drug related overdose in European emergency rooms (2,4,(6)(7)(8).…”

Update on the treatment of narcolepsy: clinical efficacy of pitolisant

“…Sodium oxybate is often well tolerated and does improve the quality of life of narcoleptic patients. However, sodium oxybate has abuse potential due to its anxiolytic, hypnotic and euphoric effects,9 and has possible neurotoxic side effects 1. Sodium oxybate, due to its short half-life, must be taken in a split dose, once at bedtime and again 2.5–4 hours later.…”