Effects Of Gamma-hydroxybutyrate Research Articles

2167-P: Gamma-Hydroxybutyrate Prevents Lipotoxicity-Induced ß-Cell Dysfunction

Prolonged exposure to high levels of fatty acids impairs the insulin secretory capacity of pancreatic β-cells through mechanisms involving oxidative stress (lipotoxicity). Beta-cell lipotoxicity is thought to play an important role in the β-cell failure of type 2 diabetes. Antioxidants can protect β-cells from lipotoxicity by decreasing oxidative stress. Gammahydroxybutyrate (GHB), an endogenous neurotransmitter currently safely used as a treatment for narcolepsy, is also found in cells as an energy source and antioxidant. Previous studies have shown that GHB can protect mice from streptozotocin and alloxan induced diabetes; both compounds are generators of oxidative stress and yield models of type 1 diabetes. However, the effect of GHB in models of type 2 diabetes has not been investigated. We hypothesized that GHB can protect β-cells from lipotoxicity. We first investigated the effectiveness of GHB in preventing β-cell dysfunction in high-fat treatment (palmitate) in an in vitro model with freshly isolated mouse islets. Beta-cell function was determined by glucose stimulated insulin secretion assays. Islets incubated with GHB were protected from β-cell lipotoxicity that resulted from the concurrent 48h exposure to palmitate. The antioxidant effects of GHB in lipotoxicity were further investigated by measuring reactive oxygen species (ROS) levels. GHB prevented the increase in ROS that was observed with the palmitate treatment while GHB by itself had no effects. While further studies need to be done to elucidate possible mechanisms of action of GHB beyond its antioxidant effect as well as GHB effectiveness in vivo, our findings suggest that GHB or potentially GHB derivatives may be of interest for their β-cell protective properties. Disclosure L. Yeung: None. A. Ivovic: None. Y. Tan: None. B. Batchuluun: None. M. Mamelak: None. A. Giacca: Research Support; Self; Jazz Pharmaceuticals. Funding Jazz Pharmaceuticals plc

Neurophysiological signature of gamma-hydroxybutyrate augmented sleep in male healthy volunteers may reflect biomimetic sleep enhancement: a randomized controlled trial.

Gamma-hydroxybutyrate (GHB) is an endogenous GHB/GABAB receptor agonist, which has demonstrated potency in consolidating sleep and reducing excessive daytime sleepiness in narcolepsy. Little is known whether GHB's efficacy reflects the promotion of physiological sleep mechanisms and no study has investigated its sleep consolidating effects under low sleep pressure. GHB (50 mg/kg p.o.) and placebo were administered in 20 young male volunteers at 2:30 a.m., the time when GHB is typically given in narcolepsy, in a randomized, double-blinded, crossover manner. Drug effects on sleep architecture and electroencephalographic (EEG) sleep spectra were analyzed. In addition, current source density (CSD) analysis was employed to identify the effects of GHB on the brain electrical sources of neuronal oscillations. Moreover, lagged-phase synchronization (LPS) analysis was applied to quantify the functional connectivity among sleep-relevant brain regions. GHB prolonged slow-wave sleep (stage N3) at the cost of rapid eye movement (REM) sleep. Furthermore, it enhanced delta-theta (0.5-8 Hz) activity in NREM and REM sleep, while reducing activity in the spindle frequency range (13-15 Hz) in sleep stage N2. The increase in delta power predominated in medial prefrontal cortex, parahippocampal and fusiform gyri, and posterior cingulate cortex. Theta power was particularly increased in the prefrontal cortex and both temporal poles. Moreover, the brain areas that showed increased theta power after GHB also exhibited increased lagged-phase synchronization among each other. Our study in healthy men revealed distinct similarities between GHB-augmented sleep and physiologically augmented sleep as seen in recovery sleep after prolonged wakefulness. The promotion of the sleep neurophysiological mechanisms by GHB may thus provide a rationale for GHB-induced sleep and waking quality in neuropsychiatric disorders beyond narcolepsy.

Effects of gamma-hydroxybutyrate on neurophysiological correlates of performance and conflict monitoring

Performance and conflict monitoring (PM and CM) represent two essential cognitive abilities, required to respond appropriately to demanding tasks. PM and CM can be investigated using event-related brain potentials (ERP) and associated neural oscillations. Namely, the error-related negativity (ERN) represents a correlate of PM, whereas the N2 component reflects the process of CM. Both ERPs originate in the anterior cingulate cortex (ACC) and PM specifically has been shown to be susceptible to gamma-aminobutyric acid (GABA) A receptor activation. Contrarily, the specific effects of GABAB receptor (GABABR) stimulation on PM and CM are unknown. Thus, the effects of gamma-hydroxybutyrate (GHB; 20 and 35 mg/kg), a predominant GABABR agonist, on behavioral and electrophysiological correlates of PM and CM were here assessed in 15 healthy male volunteers, using the Eriksen–Flanker paradigm in a randomized, double-blind, placebo-controlled, cross-over study. Electroencephalographic (EEG) data were analyzed in the time and time-frequency domains. GHB prolonged reaction times, without affecting error rates or post-error slowing. Moreover, GHB decreased ERN amplitudes and associated neural oscillations in the theta/alpha1 range. Similarly, neural oscillations associated with the N2 were reduced in the theta/alpha1 range, while N2 amplitude was conversely increased. Hence, GHB shows a dissociating effect on electrophysiological correlates of PM and CM. Reduced ERN likely derives from a GABABR-mediated increase in dopaminergic signaling, disrupting the generation of prediction errors, whereas an enhanced N2 suggests an increased susceptibility towards external stimuli. Conclusively, GHB is the first drug reported, thus far, to have opposite effects on PM and CM, underlined by its unique electrophysiological signature.

T97. Neural Underpinnings of the Hedonic Effects of Gamma-Hydroxybutyrate in Humans

T97. Neural Underpinnings of the Hedonic Effects of Gamma-Hydroxybutyrate in Humans

Gamma-hydroxybutyrate increases brain resting-state functional connectivity of the salience network and dorsal nexus in humans

According to the triple network hypothesis the brain is equipped with three core neurocognitive networks: the default mode (DMN), the salience (SN), and the central executive (CEN) network. Moreover, the so called dorsal nexus, has met growing interest as it is a hub region connecting these three networks. Assessment of resting-state functional connectivity (rsFC) of these networks enables the elucidation of drug-induced brain alterations. Gamma-hydroxybutyrate (GHB) is a GHB/GABA-B receptor agonist that induces a paradoxical state of mixed stimulation and sedation at moderate doses, which makes it a valuable tool to investigate neural signatures of subjective drug effects. Employing a placebo-controlled, double-blind, randomized, cross-over design, we assessed the effects of GHB (35 mg/kg p. o.) in 19 healthy male subjects on DMN-, SN-, CEN-, and dorsal nexus-rsFC measured by functional magnet resonance imaging and applying independent component as well as seed-based analyses, while subjective drug effects were investigated using visual analog scales (VAS). Subjectively, GHB increased VAS ratings of a general drug effect, stimulation, and sedation. Intrinsic DMN-, and CEN-rsFC remained largely unchanged under GHB, but the drug increased SN-DMN-rsFC and SN-dorsal nexus-rsFC, while dorsal nexus-rsFC was reciprocally increased to both the SN (right anterior insula) and to the CEN (right middle frontal gyrus). Increased sedation significantly predicted the observed SN-dorsal nexus-rsFC. In conclusion, GHB generates a unique stimulant/sedative subjective state that is paralleled by a complex pattern of increased functional connectivity encompassing all three core neurocognitive networks of the brain, while increased SN-dorsal nexus-rsFC was demonstrated to be a potential signature of the sedative component of the drug effect.

P.6.d.006 - Effects of gamma hydroxybutyrate (GHB) induced coma on long-term memory and brain function

P.6.d.006 - Effects of gamma hydroxybutyrate (GHB) induced coma on long-term memory and brain function

Gamma-Hydroxybutyrate Increases Resting-State Limbic Perfusion and Body and Emotion Awareness in Humans.

Gamma-hydroxybutyrate (GHB) is a GHB-/GABA-B receptor agonist inducing a broad spectrum of subjective effects including euphoria, disinhibition, and enhanced vitality. It is used as treatment for neuropsychiatric disorders including narcolepsy and alcohol withdrawal, but is also a drug of abuse. Non-medical users report enhancement of body and emotion awareness during intoxication. However, the neuronal underpinnings of such awareness alterations under GHB are unknown so far. The assessment of regional cerebral blood flow (rCBF) by pharmacological magnetic resonance imaging (phMRI) enables the elucidation of drug-induced functional brain alterations. Thus, we assessed the effects of GHB (35 mg/kg p.o.) in 17 healthy males on rCBF and subjective drug effects, using a placebo-controlled, double-blind, randomized, cross-over design employing arterial spin labeling phMRI. Compared to placebo, GHB increased subjective ratings for body and emotion awareness, and for dizziness (p<0.01-0.001, Bonferroni-corrected). A whole-brain analysis showed increased rCBF in the bilateral anterior cingulate cortex (ACC) and the right anterior insula under GHB (p<0.05, cluster-corrected). ACC and insula rCBF are correlated with relaxation, and body and emotion awareness (p<0.05-0.001, uncorrected). Interaction analyses revealed that GHB-induced increase of body awareness was accompanied by increased rCBF in ACC, whereas relaxation under GHB was accompanied by elevated rCBF in right anterior insula (p<0.05, uncorrected). In conclusion, enhancement of emotion and body awareness, and increased perfusion of insula and ACC bears implications both for the properties of GHB as a drug of abuse as well as for its putative personalized potential for specific therapeutic indications in affective disorders.

Neuronal oscillations and synchronicity associated with gamma-hydroxybutyrate during resting-state in healthy male volunteers.

Gamma-hydroxybutyrate (GHB) is a putative neurotransmitter, a drug of abuse, an anesthetic agent, and a treatment for neuropsychiatric disorders. In previous electroencephalography (EEG) studies, GHB was shown to induce an electrophysiological pattern of "paradoxical EEG-behavioral dissociation" characterized by increased delta and theta oscillations usually associated with sleep during awake states. However, no detailed source localization of these alterations and no connectivity analyses have been performed yet. We tested the effects of GHB (20 and 35mg/kg, p.o.) on current source density (CSD), lagged phase synchronization (LPS), and global omega complexity (GOC) of neuronal oscillations in a randomized, double-blind, placebo-controlled, balanced cross-over study in 19 healthy, male participants using exact low-resolution electromagnetic tomography (eLORETA) of resting-state high-density EEG recordings. Compared to placebo, GHB increased CSD of theta oscillations (5-7Hz) in the posterior cingulate cortex (PCC) and alpha1 (8-10Hz) oscillations in the anterior cingulate cortex. Higher blood plasma values were associated with higher LPS values of delta (2-4Hz) oscillations between the PCC and the right inferior parietal lobulus. Additionally, GHB decreased GOC of alpha1 oscillations. These findings indicate that alterations in neuronal oscillations in the PCC mediate the psychotropic effects of GHB. Theta oscillations emerging from the PCC in combination with stability of functional connectivity within the default mode network might explain the GHB-related "paradoxical EEG-behavioral dissociation." Our findings related to GOC suggest a reduced number of relatively independent neuronal processes, an effect that has also been demonstrated for other anesthetic agents.

Neural underpinnings of prosexual effects induced by gamma-hydroxybutyrate in healthy male humans

Gamma-hydroxybutyrate (GHB) is a GHB-/GABAB-receptor agonist currently used as treatment for narcolepsy but also as a drug of abuse. Non-medical GHB users have repeatedly reported prosexual effects including libido-enhancement and lowering of attractiveness standards for partner selection. Here, we examined the putative prosexual effects of oral GHB in healthy males in two experiments both employing randomized, placebo-controlled, double-blind, balanced, and cross-over study designs. In experiment I, subjective effects of 20 and 35mg/kg GHB vs. placebo were tested in 32 participants using the Sexual Arousal and Desire Inventory. In experiment II, brain reactivity towards erotic vs. neutral pictures was investigated in 15 participants using functional magnetic resonance imaging after 35mg/kg GHB vs. placebo.In experiment I, prosexual effects of GHB were shown by increased SADI ratings regarding physiological, evaluative, and motivational aspects of sexual arousal. In experiment II, erotic visual stimuli activated the bilateral insula, nucleus accumbens (NAcc), fusiform gyrus, thalamus, and left occipital pole under placebo. After GHB administration, even sexually neutral pictures of persons induced subjective sexual arousal and increased activation of the bilateral NAcc and right anterior cingulate cortex, which significantly correlated (left NAcc by trend). Moreover, a psychophysiological interaction analysis showed that GHB increased connectivity between NAcc and ventromedial prefrontal cortex during processing of visual erotic cues, i.e., in the condition in which subjective sexual arousal was highest. Our data show that GHB stimulates hedonic sexual functioning and lowers the threshold for erotic perception, which is related to increased susceptibility of mesolimbic reward pathways.

The behavioural profile of gamma-hydroxybutyrate, gamma-butyrolactone and 1,4-butanediol in humans.

Gamma-hydroxybutyrate (GHB) is a putative neurotransmitter, a drug of abuse, and a medical treatment for narcolepsy and other neuropsychiatric disorders. Its precursors gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD) are endogenously converted to GHB and thereby exert their psychobehavioural effects. In humans, GHB has a wide spectrum of properties ranging from stimulation and euphoria in lower doses, to sedation, deep sleep, and coma after ingestion of high doses. However, behavioural studies in healthy volunteers remain scarce and are usually limited to psychomotor performance testing. Most available data arise from either qualitative studies with illicit users or clinical trials examining therapeutic properties of GHB (then usually termed sodium oxybate). Here, we present an overview of the behavioural effects of GHB, GBL, and 1,4-BD in these three populations. GHB and its precursors strongly influence behaviours related to core human autonomic functions such as control of food intake, sexual behaviour, and sleep-wake regulation. These effects are instrumentalised by illicit users and clinically utilised in neuropsychiatric disorders such as narcolepsy, fibromyalgia, and binge-eating syndrome. Considering the industry withdrawal from psychopharmacology development, repurposing of drugs according to their behavioural and clinical profiles has gained increasing relevance. As such, GHB seems to be an attractive candidate as an experimental therapeutic in depression.

Gamma-hydroxybutyrate enhances mood and prosocial behavior without affecting plasma oxytocin and testosterone

Gamma-hydroxybutyrate (GHB) is a GHB-/GABAB-receptor agonist. Reports from GHB abusers indicate euphoric, prosocial, and empathogenic effects of the drug. We measured the effects of GHB on mood, prosocial behavior, social and non-social cognition and assessed potential underlying neuroendocrine mechanisms. GHB (20mg/kg) was tested in 16 healthy males, using a randomized, placebo-controlled, cross-over design. Subjective effects on mood were assessed by visual-analogue-scales and the GHB-Specific-Questionnaire. Prosocial behavior was examined by the Charity Donation Task, the Social Value Orientation test, and the Reciprocity Task. Reaction time, memory, empathy, and theory-of-mind were also tested. Blood plasma levels of GHB, oxytocin, testosterone, progesterone, dehydroepiandrosterone (DHEA), cortisol, aldosterone, and adrenocorticotropic-hormone (ACTH) were determined. GHB showed stimulating and sedating effects, and elicited euphoria, disinhibition, and enhanced vitality. In participants with low prosociality, the drug increased donations and prosocial money distributions. In contrast, social cognitive abilities such as emotion recognition, empathy, and theory-of-mind, and basal cognitive functions were not affected. GHB increased plasma progesterone, while oxytocin and testosterone, cortisol, aldosterone, DHEA, and ACTH levels remained unaffected. GHB has mood-enhancing and prosocial effects without affecting social hormones such as oxytocin and testosterone. These data suggest a potential involvement of GHB-/GABAB-receptors and progesterone in mood and prosocial behavior.

Enhancing sexual desire and experience: an investigation of the sexual correlates of gamma-hydroxybutyrate (GHB) use.

Various studies have dealt with gamma-hydroxybutyrate's (GHB) potential role in sexual assaults, while the sexual correlates of intentional recreational GHB use have not well been highlighted. Our study aims to explore GHB's sexual effects, the patterns of choice of sexual partners, the frequency of experienced blackouts, and endured sexual or acquisitory crimes as a result of GHB use. Sixty recreational GHB users filled out a questionnaire on experienced subjective, somatic, and sexual effects of GHB, the frequency of blackouts due to their GHB use, and items on their sexual experiences in relation to GHB use. Of the sample, 25.9% reported increased sexual arousal as well as more intense attraction towards their sexual partners and increased sexual openness when using GHB; 34.8% had sexual intercourse with strangers, or with others, but not with their partners when using GHB; and 8.6% were victims of acquisitory crimes, whereas 3.4% were victims of a sexual assault. Furthermore, 24.6% typically experienced blackouts when using GHB. Gamma-hydroxybutyrate seems to be a potential substitute for both stimulant and depressant substances. Increased sexual desire and disinhibition may lead to a more frequent and potentially more riskful sexual activity. Experienced blackouts need to be considered as risk factors for suffering sexual or acquisitory crimes.

A critical evaluation of the gamma-hydroxybutyrate (GHB) model of absence seizures.

SummaryTypical absence seizures (ASs) are nonconvulsive epileptic events which are commonly observed in pediatric and juvenile epilepsies and may be present in adults suffering from other idiopathic generalized epilepsies. Our understanding of the pathophysiological mechanisms of ASs has been greatly advanced by the availability of genetic and pharmacological models, in particular the γ‐hydroxybutyrate (GHB) model which, in recent years, has been extensively used in studies in transgenic mice. GHB is an endogenous brain molecule that upon administration to various species, including humans, induces not only ASs but also a state of sedation/hypnosis. Analysis of the available data clearly indicates that only in the rat does there exist a set of GHB‐elicited behavioral and EEG events that can be confidently classified as ASs. Other GHB activities, particularly in mice, appear to be mostly of a sedative/hypnotic nature: thus, their relevance to ASs requires further investigation. At the molecular level, GHB acts as a weak GABA‐B agonist, while the existence of a GHB receptor remains elusive. The pre‐ and postsynaptic actions underlying GHB‐elicited ASs have been thoroughly elucidated in thalamus, but little is known about the cellular/network effects of GHB in neocortex, the other brain region involved in the generation of ASs.

Comparative study of equimolar doses of gamma-hydroxybutyrate (GHB), 1,4-butanediol (1,4-BD) and gamma-butyrolactone (GBL) on catalepsy after acute and chronic administration

Gamma-hydroxybutyrate (GHB), and its precursors 1,4-butanediol (1,4-BD) and gamma-butyrolactone (GBL) are known drugs of abuse. The ability of acute and chronic administration of equimolar doses of GHB (200mg/kg), 1,4-BD (174mg/kg) and GBL (166mg/kg) to produce catalepsy in male Swiss Webster mice was examined. GHB, 1,4-BD, GBL produced catalepsy when injected acutely. Drug treatment was then continued for 14days. Tolerance development was determined on days 6, 14, and challenged with a higher dose on day 15 in those chronically pretreated mice, and compared with naïve mice. Chronic GHB produced tolerance to catalepsy, as evidenced from area under the curve (AUC) of catalepsy versus time (min–sec) on days 6 (678±254), 14 (272±247), which were less than those on day 1 (1923±269). However, less tolerance was seen from GBL or 1,4-BD, as AUCs on days 6 and 14 were not significantly lower than that of day 1. In conclusion, although equimolar doses were used, expecting similar levels of GHB in the body, 1,4-BD and GBL shared only some of the in vivo effects of GHB. The rate of metabolic conversion of 1,4-BD and GBL into GHB might be responsible for the differences in the tolerance development to these drugs.

Reconsidering GHB: orphan drug or new model antidepressant?

For six decades, the principal mode of action of antidepressant drugs is the inhibition of monoamine re-uptake from the synaptic cleft. Tricyclic antidepressants, selective serotonin re-uptake inhibitors (SSRIs) and the new generation of dual antidepressants all exert their antidepressant effects by this mechanism. In the early days of the monoaminergic era, other efforts have been made to ameliorate the symptoms of depression by pharmacological means. The gamma-aminobutyric acid (GABA) system was and possibly still is one of the main alternative drug targets. Gammahydroxybutyrate (GHB) was developed as an orally active GABA analogue. It was tested in animal models of depression and human studies. The effects on sleep, agitation, anhedonia and depression were promising. However, the rise of benzodiazepines and tricyclic antidepressants brought GHB out of the scope of possible treatment alternatives. GHB is a GABA(B) and GHB receptor agonist with a unique spectrum of behavioural, neuroendocrine and sleep effects, and improves daytime sleepiness in various disorders such as narcolepsy, Parkinson's disease and fibromyalgia. Although it was banned from the US market at the end of the 1990s because of its abuse and overdose potential, it later was approved for the treatment of narcolepsy. New research methods and an extended view on other neurotransmitter systems as possible treatment targets of antidepressant treatment brought GHB back to the scene. This article discusses the unique neurobiological effects of GHB, its misuse potential and possible role as a model substance for the development of novel pharmacological treatment strategies in depressive disorders.

Functional Reinnervation of the Distal Hindlimb Muscles in Rats after Compression of the Sciatic Nerve

Chronic experiments (12 weeks long) were carried out on two groups of pubertate-age Wistar rats. The sciatic nerve in one hindlimb was compressed, and complex analysis of the dynamics of functional reinnervation of the distal hindlimb muscles was performed. We used videorecording of images of the feet in the course of locomotion for estimation of the level of functional reinnervation of the toe extensors (the technique was modified in our laboratory) and a tensometric technique (measuring of the contraction force of the toe flexors and ankle extensors in the course of realization of the burrowing instinct by the animals). In the first group of animals (n = 21), we studied the dynamics of recovery of the force developed by the toe flexors and ankle extensors and of the functional sciatic index after sciatic nerve traumatization with no additional pharmacological influences. In the second group (n = 29), the same indices were analyzed, but after single injections of gamma-hydroxybutyrate (GHB) into animals before compression of the sciatic nerve and within early and late (3–4 and 14 weeks, respectively) terms after such intervention. Within the first week after compression, the smallest loss of activity was observed in the toe flexors, as compared with that in the toe and ankle extensors. Significant functional reinnervation of the ankle and toe extensors (to 52 and 87%, respectively) was observed on the 3rd to 7th weeks after the nerve injury. Functional reinnervation of the toe flexors was characterized by a relatively greater initial force of concentrations and more rapid recovery than those of the ankle and toe extensors. Practically complete recovery of the functions of the toe flexors was observed on the 10th week, while that of the ankle extensors was found on the 12th week. To make clearer possible reasons for differences between the processes of recovery of functions of the flexor and extensor muscles, we analyzed the effects of GHB on the contractile activity of these muscle groups within different time intervals after traumatization. In the second animal group, injection of GHB before operation resulted in drops of the muscle contraction force. After injury of the right sciatic nerve and injection of GHB on the 3rd posttraumatic week, recovery of the contraction force of all the examined muscles on the side of operation was more considerable. The functional loss of the muscle force in the left (intact) hindlimb in this case was 10 and 7% for the ankle extensors and toe flexors, respectively. Single injections of GHB within a late posttraumatic period resulted in a relative decrease in the contraction force of both flexors and extensors, and the functional loss was the greatest (35%) in the toe flexors.

Gamma-hydroxybutyrate (GHB) for treatment of alcohol withdrawal and prevention of relapses

Chronic excessive alcohol consumption may lead to dependence, and to alcohol withdrawal syndrome (AWS) in case of abrupt drinking cessation. Gamma-hydroxybutyric acid (GHB) can prevent and suppress withdrawal symptoms, and improve the medium-term abstinence rate. A clear balance between effectiveness and harmfulness has not been yet established. To evaluate the efficacy and safety of GHB for treatment of AWS and prevention of relapse We searched Cochrane Drugs and Alcohol Group' Register of Trials (October 2008), PubMed, EMBASE, CINAHL (January 2005 - October 2008), EconLIT (1969 to February 2008), reference list of retrieved articles Randomized controlled trials (RCTs) and Controlled Prospective Studies (CPS) evaluating the efficacy and the safety of GHB vs placebo or other pharmacological treatments. Three authors independently extracted data and assessed the methodological quality of studies. Thirteen RCTs were included. Eleven studies were conducted in Italy.For withdrawal syndrome, comparing GHB 50mg with placebo, results from 1 study, 23 participants favour GHB for withdrawal symptoms: WMD -12.1 (95% CI, -15.9 to -8.29) and side effects were more frequent in the placebo group: RR 16.2 (95% CI, 1.04 to 254.9).In the comparison with Chlormetiazole, for GHB 50mg, results from 1 study, 21 participants favour GHB for withdrawal symptoms: MD -3.40 (95% CI -5.09 to -1.71), for GHB 100mg, results from 1 study, 98 participants favour anticonvulsants for side effects: RR 1.84 (95% CI 1.19 to 2.85).At mid-term, comparing GHB with placebo, results favour GHB for abstinence rate (RR 5.35; 1.28-22.4), controlled drinking (RR 2.13; 1.07-5.54), relapses (RR 0.36; 0.21-0.63), and number of daily drinks (WMD -4.60; -6.18 to -3.02). GHB performed better than NTX and Disulfiram on abstinence (RR 2.59; 1.35-4.98, RR 1.66; 0.99-2.80 respectively). The association of GHB and NTX was better than NTX on abstinence (RR 12.2; 1.79-83.9), as well was the association of NTX, GHB and Escitalopram versus Escitalopram alone (RR 4.58; 1.28-16.5). For Alcohol Craving Scale results favour GHB versus placebo (WMD -1.90; -2.45 to 1.35) and Disulfiram (WMD -1.40; -1.86 to-0.94). GHB 50mg is effective compared to placebo in the treatment of AWS, and in preventing relapses in previously detoxified alcoholics at 3 months follow-up, but the results of this review do not provide sufficient evidence in favour of GHB compared to benzodiazepines and Chlormethiazole for AWS prevention. GHB is better than NTX and Disulfiram in maintaining abstinence and it has a better effect on craving than placebo and Disulfiram. Side effects of GHB are not statistically different from those with BZD, NTX or Disulfiram. However, concern has been raised regarding the risk of developing addiction, misuse or abuse, especially in polydrug abusers.

Calcium and cAMP signaling induced by gamma-hydroxybutyrate receptor(s) stimulation in NCB-20 neurons

The NCB-20 neurohybridoma cells differentiated with dibutyryl-cyclic-AMP represent an interesting model to study several components of the gamma-hydroxybutyrate (GHB) system in brain. In particular, an active Na +-dependent uptake and a depolarization-evoked release of GHB is expressed by these cells, together with high affinity specific binding sites for this substance. However, only little is known about cellular mechanisms following GHB receptor(s) stimulation in these neurons. Electrophysiological data indicate that GHB can differently affect Ca 2+ currents. L-type calcium channels were typically inhibited by GHB when NCB-20 cells were depolarized. In contrast, when NCB-20 cells were at resting potential, GHB induced a specific Ca 2+ entry through T-type calcium channels. In this study, we investigated the effect induced on cytosolic free Ca 2+ level and cAMP production by GHB receptor(s) stimulated with micromolar concentrations of GHB or structural analogues of GHB. Ca 2+ movements studied by cellular imaging were dose-dependently increased but disappeared for GHB concentrations >25 μM. In addition, nanomolar doses of GHB inhibited forskolin-stimulated adenylate cyclase. This effect was also rapidly desensitized at higher GHB concentrations. Acting as an antagonist, NCS-382 decreased GHB receptor(s) mediated cAMP and calcium signals. The agonist NCS-356 mimicked GHB effects which were not affected by the GABA B receptor antagonist CGP-55-845. Our results reveal the occurrence of Ca 2+-dependent adenylate cyclase inhibition in NCB-20 neurons after GHB receptor(s) stimulation by GHB concentrations <50 μM. Above this dose, GHB effects were inactivated. In addition, at GHB concentrations exceeding 50 μM, GTP-γS binding was also reduced, confirming the desensitization of GHB receptor(s). Taken together, these results support the existence in NCB-20 neurons of GHB receptors belonging to GPCR family that may recruit various G protein subtypes.

Behavioral Effects of γ-Hydroxybutyrate, Its Precursor γ-Butyrolactone, and GABAB Receptor Agonists: Time Course and Differential Antagonism by the GABAB Receptor Antagonist 3-Aminopropyl(diethoxymethyl)phosphinic Acid (CGP35348)

Gamma-hydroxybutyrate (GHB) is used therapeutically and recreationally. The mechanism by which GHB produces its therapeutic and recreational effects is not entirely clear, although GABA(B) receptors seem to play an important role. This role could be complex, because there are indications that different GABA(B) receptor mechanisms mediate the effects of GHB and the prototypical GABA(B) receptor agonist baclofen. To further explore possible differences in underlying GABA(B) receptor mechanisms, the present study examined the effects of GHB and baclofen on operant responding and their antagonism by the GABA(B) receptor antagonist 3-aminopropyl(diethoxymethyl)phosphinic acid (CGP35348). Pigeons were trained to peck a key for access to food during response periods that started at different times after the beginning of the session. In these pigeons, GHB, its precursor gamma-butyrolactone (GBL), and the GABA(B) receptor agonists baclofen and 3-aminopropyl(methyl)phosphinic acid hydrochloride (SKF97541) decreased the rate of responding in a dose- and time-dependent manner. CGP35348 shifted the dose-response curve of each agonist to the right, but the magnitude of the shift differed among the agonists. Schild analysis yielded a pA(2) value of CGP35348 to antagonize GHB and GBL [i.e., 3.9 (3.7-4.2)] that was different (P = 0.0011) from the pA(2) value to antagonize baclofen and SKF97541 [i.e., 4.5 (4.4-4.7)]. This finding is further evidence that the GABA(B) receptor mechanisms mediating the effects of GHB and prototypical GABA(B) receptor agonists are not identical. A better understanding of the similarities and differences between these mechanisms, and their involvement in the therapeutic effects of GHB and baclofen, could lead to more effective medications with fewer adverse effects.

Cognitive, psychomotor, and subjective effects of sodium oxybate and triazolam in healthy volunteers

Illicit gamma-hydroxybutyrate (GHB) has received attention as a "date rape drug" that produces robust amnesia; however, there is little experimental evidence in support of GHB's amnestic effects. This study compared the cognitive effects of GHB (sodium oxybate) with those of triazolam in healthy volunteers. Doses of sodium oxybate (1.125, 2.25, and 4.5 g/70 kg), triazolam (0.125, 0.25, and 0.5 mg/70 kg), and placebo were administered to 15 volunteers under repeated measures, counterbalanced, double-blind, double-dummy conditions. The time course and peak physiological, psychomotor, subjective, and cognitive effects were examined. Sodium oxybate and triazolam produced similar increases in participant ratings of drug effects. Performance on psychomotor, working memory, and episodic memory tasks was impaired to a greater extent after triazolam than sodium oxybate. Together, these data suggest that sodium oxybate produces less psychomotor and cognitive impairment than triazolam at doses that produce equivalent participant-rated subjective effects in healthy volunteers.