•GHB is often used by experienced drug users in combination with other substances.•Dose and frequency of GHB use are associated with comas, comorbidity and dependency.•People using GHB for ...non-recreational reasons might be at risk for dependence.•Studies are hard to compare due to differences in definitions and lack of information.•It remains unclear who will transit from recreational GHB use to dependency.
Over the past decades gamma-hydroxybutyrate (GHB) has emerged as a popular drug with high potential of (ab)use due to its euphoric and relaxing effects. An overview of different populations using GHB is urgently needed, since this would enable development of adequate prevention and treatment policies to diminish the risks associated with GHB use. We systematically reviewed literature on different GHB using populations, comparing demographic characteristics, GHB use patterns, psychosocial aspects and psychiatric comorbidity.
We conducted a systematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines using Rayyan software. Original studies published from January 1997 up to October 2019 on GHB use were included. Out of 80 full-text articles, 60 articles of 51 unique studies were included. Most studies included people using GHB 1) presenting at emergency departments (n = 22), 2) recruited from the general population (n = 11), or 3) presenting at addiction care (n = 8).
Three main sub-populations of people using GHB are described in the literature: people using GHB recreationally without adverse effects; people using GHB recreationally with adverse effects, and people with dependence on GHB. These groups show considerable overlap in gender, age range, and comorbid substance use, as well as amount of GHB use per occasion. Differences are related to frequency and function of GHB use, the number of comas experienced, as well as work status, and psychiatric comorbidity.
Policy interventions should aim at preventing the transition from recreational substance use to GHB use, as most users are experienced recreational substance users prior to starting GHB use. When people use GHB regularly, interventions should aim at reducing the level of GHB use and preventing GHB use-related harm. Longitudinal studies and population-based probability sampling are required for more insight in the dynamics of GHB use in different sub-populations, and the transition from one group to the other, ultimately leading to dependence on GHB.
•Case report of three narcoleptic patients, who have therapeutically taken GHB, by hair analysis.•Comparison between single and chronic GHB exposure on the basis of GHB and GHB-glucuronide ...concentrations in hair.•Single GHB exposure and chronical GHB intake were not revealed by hair analysis of GHB and GHB-glucuronide.
Gamma-hydroxybutyric acid (GHB) can be used as a knock-out drug in drug facilitated crime (DFC). Due to its rapid metabolism and resulting narrow detection window, uncovering GHB use in DFC still constitutes a problem. In this experiment we determined the GHB and GHB-β-O-glucuronide (GHB-Gluc) concentrations in hair samples after single and chronic GHB exposures. Hair samples of three narcoleptic patients therapeutically taking sodium oxybate (GHB-sodium-salt) were collected. Patients 1 (P1) and 2 (P2) took the medication for nine and six years, respectively. P1 took daily the pharmaceutical Xyrem® in a total dose of 5.78g GHB at bed time (2.89g) and four hours (2.89g) later. P2 took a dose of 3.10g GHB at bed time and an additional dose of 2.68g GHB four hours later. Patient 3 (P3) was newly diagnosed with narcolepsy and started his therapy with oral dose of 6g (divided in three portions of 2g GHB) within 24h. The hair samples were extracted both with and without forerunning washing steps. GHB and GHB-Gluc were determined by a published ultra-high performance liquid chromatography–tandem mass spectrometry method using GHB-d6 and GHB-Gluc-d4 as internal standards. GHB and GHB-Gluc concentrations in unwashed hair samples of P1 and P2 were determined in a range of 0.56–1.30ng/mg and <0.48–0.85ng/mg, respectively. In washed hair samples of P1 and P2 the concentrations were in a range of <0.32–0.68ng/mg and <0.48–1.20ng/mg for GHB and GHB-Gluc, respectively. The determined concentrations were within the published endogenous range. The confirmed results showed that the washing procedure before extraction causes a minor decrease of GHB concentrations in hair (difference: <1ng/mg). The investigations showed that a single GHB exposure might not be determined by hair analysis of GHB and GHB-Gluc. The chronical intake of therapeutic sodium oxybate with doses up to 7g per night was also not confirmed by hair analysis maybe due to hair treatments. Therefore, GHB hair analysis should be assessed critically and determined negative results could not exclude GHB exposures.
•Fast, cheap and reliable method for quantitation of GHB-GLUC in whole blood.•LOD and LLOQ of 0.2mg/L.•First GC–MS/MS method for GHB-GLUC.•First application to post-mortem whole blood samples.
...γ-Hydroxybutyric acid (GHB) is an endogenous compound with a historical use, both in licit and illicit terms. Importantly, the post-mortem behavior of GHB has been studied due to the possibility of using this compound as a biomarker for estimating the post-mortem interval (PMI). However, the post-mortem behavior of the recently discovered glucuronated GHB metabolite (GHB-GLUC) has not been studied. Nevertheless, GHB-GLUC may also have potential both to assist in PMI determination and also to increase the window of detection of GHB consumption.
In this work, for the first time, a reliable method using GC–MS/MS for the quantification of GHB-GLUC in whole blood samples was developed and validated, with a simple, fast and cheap sample pretreatment. The method proved to be specific, precise, linear in a work range between 200 and 5000ng/mL, with LOD and LOQ of 52.65ng/mL and 200ng/mL, respectively, and an extraction recovery of 51%.
Furthermore, the method was applied to a set of real post-mortem blood samples non-related with GHB intoxication and the obtained results were also discussed.
In this paper, the authors present a critical review of different studies regarding hair testing of endogenous γ-hydroxybutyrate (GHB), concentrations in chronic users, and values measured after a ...single GHB exposure in drug facilitated sexual assault (DFSA) cases together with the role of a recently identified GHB metabolite, GHB-glucuronide.
The following databases (up to March 2017) PubMed, Scopus and Web of Science were used, searching the following key words: γ-hydroxybutyrate, GHB, GHB glucuronide, hair. The main key words "GHB" and "γ-hydroxybutyrate" were searched singularly and then associated individually to each of the other keywords.
Of the 2304 sources found, only 20 were considered appropriate for the purpose of this paper. Summing up all the studies investigating endogenous GHB concentration in hair, a very broad concentration range from 0 to 12 ng/mg was found. In order to detect a single GHB dose in hair it is necessary to commonly wait 1 month for collecting hair and a segmental analysis of 3 or 5 mm fragments and the calculation of a ratio between the targeted segment and the others represent a reliable method to detect a single GHB intake considering that the ratios presently proposed vary from 3 and 10. The only two studies so far performed, investigating GHB-Glucuronide in hair, show that the latter does not seem to provide any diagnostic information regarding GHB exposure.
A practical operative protocol is proposed to be applied in all suspected cases of GHB-facilitated sexual assault (GHB-FSA).
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.
Γ-valerolactone (GVL), marketed online as “Tranquilli-G” and “excellent Valium”, is used as a legal substitute for γ-hydroxybutyric acid (GHB); however, until now, GVL has only been connected to one ...Drug-Facilitated Sexual Assault (DFSA) case. Moreover, the pharmaco-toxicological effects of GVL are poorly studied. The aim of this study was to investigate the 1) in vivo effects of gavage administration of GVL (100–3000 mg/kg) on neurological (myoclonia, convulsions), sensorimotor (visual, acoustic, and overall tactile) responses, righting reflex, thermoregulation, motor activity (bar, drag, and accelerod test) and cardiorespiratory changes (heart rate, breath rate, oxygen saturation, and pulse distension) in CD-1 male mice and the 2) in silico ADMET profile of GVL in comparison to GHB and the open active form γ-hydroxyvaleric acid (GHV). The present study demonstrates that GVL inhibits, in a dose-dependent manner, sensorimotor and motor responses and induces cardiorespiratory depression (at a dose of 3000 mg/kg) in mice. The determination of the ED50 in sensorimotor and motor responses revealed that GVL is about 4–5 times less potent than GHB. In silico prediction of ADMET profiles revealed toxicokinetic similarities between GHB and GHV, and differences with GVL. These results suggest that GVL could be used as a substitute for GHB and should be added to forensic toxicology screenings.
•GVL inhibits sensorimotor, motor and cardiorespiratory responses in mice.•GVL is about 4–5 times less potent than GHB.•In silico ADMET prediction reveals toxicokinetic differences between GVL and GHB.
Summary
Clinical guidelines recommend sodium oxybate (SXB; the sodium salt of γ‐hydroxybutyrate) for the treatment of disturbed sleep and excessive daytime sleepiness in narcolepsy, yet the ...underlying mode of action is elusive. In a randomised controlled trial in 20 healthy volunteers, we aimed at establishing neurochemical changes in the anterior cingulate cortex (ACC) following SXB‐enhanced sleep. The ACC is a core neural hub regulating vigilance in humans. At 2:30 a.m., we administered in a double‐blind cross‐over manner an oral dose of 50 mg/kg SXB or placebo, to enhance electroencephalography‐defined sleep intensity in the second half of nocturnal sleep (11:00 p.m. to 7:00 a.m.). Upon scheduled awakening, we assessed subjective sleepiness, tiredness and mood and measured two‐dimensional, J‐resolved, point‐resolved magnetic resonance spectroscopy (PRESS) localisation at 3‐Tesla field strength. Following brain scanning, we used validated tools to quantify psychomotor vigilance test (PVT) performance and executive functioning. We analysed the data with independent t tests, false discovery rate (FDR) corrected for multiple comparisons. The morning glutamate signal (at 8:30 a.m.) in the ACC was specifically increased after SXB‐enhanced sleep in all participants in whom good‐quality spectroscopy data were available (n = 16; pFDR < 0.002). Further, global vigilance (10th–90th inter‐percentile range on the PVT) was improved (pFDR < 0.04) and median PVT response time was shorter (pFDR < 0.04) compared to placebo. The data indicate that elevated glutamate in the ACC could provide a neurochemical mechanism underlying SXB's pro‐vigilant efficacy in disorders of hypersomnolence.
Gamma-hydroxybutyric acid (GHB) is commonly known as a recreation drug or the so-called “date rape drug”. It is also used in medicine to treat narcolepsy and alcohol addiction. GHB has an affinity ...for two types of receptors: GABA
and the relatively recently discovered GHB receptors. GHB receptors were first cloned in 2003 in mice and then in 2007 in humans. So far, evidence has been presented for their impact on dopaminergic transmission, which may imply that they play a role in the pathogenesis of diseases such as schizophrenia. At the same time, it has been demonstrated that benzamide antipsychotic drugs have an affinity for GHB receptors, which is why it is postulated that some of the effects of these drugs may result precisely from this affinity.
The study presents the current state of knowledge about GHB receptors and their potential role in the pathogenesis of schizophrenia, and discusses drugs which show an affinity for this receptor.
The literature review was based on a search of articles indexed between 1965 and 2018 in Medline, Google Scholar, ScienceDirect and Research Gate databases. The following search terms were used: GHB receptor, GHB, sulpiride, and amisulpride.
1. It is possible that GHB receptors are involved in the pathogenesis of schizophrenia, although more research is needed in this area. 2. Part of the effects of some benzamide antipsychotic drugs (such as amisulpride) may be due to their affinity for GHB receptors.
GHB (γ‐hydroxybutyrate) is not only an endogenously present small molecule but also a clinically prescribed drug for the symptomatic treatment of narcolepsy. However, GHB's mechanism of action ...remains to be uncovered. Within the CNS, GHB targets both GABAB receptors and a pharmacologically distinct population of high‐affinity binding sites with unknown molecular identity. HOCPCA (3‐hydroxycyclopent‐1‐enecarboxylic acid) is a structural analog of GHB selectively targeting GHB high‐affinity binding sites. Here, we discuss the usefulness of 3H‐ and 11C‐labeled HOCPCA as radioligands for selectively probing GHB high‐affinity binding sites and their application in drug discovery. As such, 3HHOCPCA's exceptional affinity and selectivity makes it an indispensable tool in drug discovery, and its utility has been demonstrated in, for example, homogenate binding studies, in vitro as well as ex vivo autoradiography. Moreover, the successful synthesis of 11CHOCPCA is a starting point for further ligand development for future in vivo investigations of GHB high‐affinity binding sites.
The usefulness of radiolabeled HOCPCA for selectively labeling brain‐specific GHB high‐affinity binding sites both in vitro and in vivo is reviewed. 3HHOCPCA proves to be a highly useful tool to study GHB's pharmacology.
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