The gamma-hydroxybutyric acid (GHB) withdrawal syndrome can have a fulminant course, complicated by severe complications such as delirium or seizures. Detoxification by tapering with pharmaceutical GHB is a safe way to manage GHB withdrawal. However, a detailed description of the course of the GHB withdrawal syndrome is currently lacking. This study aimed to (1) describe the course of GHB withdrawal symptoms over time, (2) assess the association between vital signs and withdrawal symptoms, and (3) explore sex differences in GHB withdrawal. In this observational multicenter study, patients with GHB use disorder (n = 285) were tapered off with pharmaceutical GHB. The most reported subjective withdrawal symptoms (SWS) were related to cravings, fatigue, insomnia, sweating and feeling gloomy. The most prevalent objective withdrawal symptoms (OWS) were related to cravings, fatigue, tremors, sweating, and sudden cold/warm feelings. No association between vital signs and SWS/OWS was found. Sex differences were observed in the severity and prevalence of specific withdrawal symptoms. Our results suggest that the GHB withdrawal syndrome under pharmaceutical GHB tapering does not strongly differ from withdrawal syndromes of other sedative drugs. The lack of association between vital signs and other withdrawal symptoms, and the relative stability of vitals over time suggest that vitals are not suitable for withdrawal monitoring. The reported sex differences highlight the importance of a personalized approach in GHB detoxification.

Background: Substance use disorders (SUD) often co-occur with other psychiatric conditions. Research on SUD and comorbid disorders generally flows from a categorical diagnostic or dimensional latent variable perspective, where symptoms are viewed as independent indicators of an underlying disorder. In contrast, the current study took a network analysis perspective to examine the relationships between DSM symptoms of SUD, ADHD, conduct disorder (CD), depression (MDD), and borderline personality disorder (BPD). In addition, we explored possible gender differences in the network structures of these symptoms. Method: In a sample of 722 adult treatment-seeking patients with SUD from the International ADHD in Substance Use Disorders Prevalence Study (IASP) we estimated the network structure for 41 symptoms of SUD, ADHD, CD, MDD, and BPD. We described the structure of symptom networks and their characteristics for the total sample, and we compared the symptom networks for males and females. Results: Network analyses identified seven clusters of symptoms, largely corresponding with the DSM diagnostic categories. There were some connections between clusters, mainly between some hyperactivity symptoms and CD and depressive symptoms. ADHD hyperactivity was most central in the symptom network. Invariance tests revealed no significant gender differences in the structure of symptom networks. Conclusions: The current findings support the categorical DSM classification of mental disorders in treatment-seeking patients with SUD. Future network analyses should include a broader range of symptoms and prospectively explore changes in the symptoms network of patients during treatment.

Introduction: Gamma-hydroxybutyrate (GHB) dependence has been associated with a potentially fulminant withdrawal syndrome. As GHB withdrawal symptoms can rapidly progress from mild to more severe, close monitoring during detoxification is important. However, a concise, GHB-specific withdrawal scale is currently lacking. The aim of this study was to compose a concise GHB-specific withdrawal scale as monitoring instrument. Methods: This study used monitoring data from 285 patients with GHB use disorder (GUD) admitted for inpatient detoxification. A six-step plan for shortening measurement scales was applied. Only subjective GHB withdrawal symptoms were used. To identify the factor structure, a principal component analysis (PCA) with Direct Oblimin Rotation was performed. The pattern matrix was used to assess the factor loading per item. Item selection was based on factor loadings >0.4 and clinical relevance of the symptoms. Multiple lists were created whose psychometric qualities (concurrent validity, convergent validity, reliability) were compared. Results: The PCA resulted in eight components (eigenvalue >1.0). Item selection resulted in five candidate lists with 8, 9, 16 (2x), and 27 items. All lists showed good concurrent and convergent validity. Only one with 16 items combined good psychometric properties with the need for a shortened questionnaire combined with all clinically relevant items. Conclusion: We recommend a novel 16-item GHB Withdrawal Symptoms Questionnaire (GWSQ) to monitor withdrawal during detoxification in patients with GUD. This concise, GHB-specific scale is likely less time-consuming to administer, sensitive to rapid changes in GHB withdrawal symptoms and aids clinicians in their decision-making during GHB titration and tapering. Implementation of this scale should be evaluated to determine its validity and usefulness in clinical practice.

The neurotransmitter γ-hydroxybutyric acid (GHB) is suggested to be involved in neuronal energy homeostasis processes, but the substance is also used as a recreational drug and as a prescription medication for narcolepsy. GHB has several high-affinity targets in the brain, commonly generalized as the GHB receptor. However, little is known about the structural and functional properties of GHB receptor subtypes. This opinion article discusses the literature on the putative structural and functional properties of the GHBh1 receptor subtype. GHBh1 contains 11 transmembrane helices and at least one intracellular intrinsically disordered region (IDR). Additionally, GHBh1 shows a 100% overlap in amino acid sequence with the Riboflavin (vitamin B2) transporter, which opens the possibility of a possible dual-function (transceptor) structure. Riboflavin and GHB also share specific neuroprotective properties. Further research into the GHBh1 receptor subtype may pave the way for future therapeutic possibilities for GHB.

Background and purpose: The use of the recreational drug gamma-hydroxybutyric acid (GHB) has increased over the past decade, concomitantly leading to a higher incidence of GHB use disorder. Evidence-based treatment interventions are hardly available and cognitive effects of long-term GHB use remain elusive. In order to study the development of GUD and the causal effects of chronic GHB consumption, a GHB self-administration model is required. Experimental approach: Long Evans rats had access to GHB in their home cage according to a two-bottle choice procedure for 3 months. Intoxication and withdrawal symptoms were assessed using an automated sensor-based setup for longitudinal behavioral monitoring. Rats were trained in an operant environment according to a fixed ratio (FR) 1, 2, and 4 schedule of reinforcement. Addiction-like behaviors were assessed through progressive ratio-, non-reinforced-, and quinine-adulterated operant tests. In addition, the novel object recognition test and elevated plus maze test were performed before and after GHB self-administration to assess memory performance and anxiety-like behavior, respectively. Key results: All rats consumed pharmacologically relevant levels of GHB in their home cage, and their intake remained stable over a period of 3 months. No clear withdrawal symptoms were observed following abstinence. Responding under operant conditions was characterized by strong inter-individual differences, where only a subset of rats showed high motivation for GHB, habitual GHB-seeking, and/or continued responding for GHB despite an aversive taste. Male rats showed a reduction in long-term memory performance 3 months after home-cage GHB self-administration. Anxiety-like behavior was not affected by GHB self-administration. Conclusion and implications: The GHB self-administration model was able to reflect individual susceptibility for addiction-like behavior. The reduction in long-term memory performance upon GHB self-administration calls for further research into the cognitive effects of chronic GHB use in humans.