Gamma-hydroxybutyrate--a neurotransmitter, medicine, and drug

Gamma-hydroxybutyrate (GHB) is a short fatty acid and physiologic neurotransmitter. Initially, it was synthesized as a GABA agonist and used as a narcotic agent, because it rapidly induces sleep without major cardiovascular or respiratory side effects. Recently, a specific GHB receptor was identified, but while the clinical use of GHB as an anaesthetic was reduced due to putative pro-convulsive effects, it now is used to treat alcohol withdrawal and sleep disorders. Furthermore, GHB was postulated to be a regulator of energy metabolism, and tissue-protective effects were demonstrated in different animal models. Besides its clinical use, GHB (also called "liquid ecstasy") is increasingly consumed in the disco scene because of its mild sedative and euphoric effects. Intoxication from GHB is common with GHB users. For this reason and because GHB is not easy to detect, it is important to be aware of the symptoms of GHB intoxication. Moreover, some recent case reports document the danger of GHB dependence.     

Gamma-hydroxybutyrate--a drug of abuse

Gamma-hydroxybutyrate (GHB) is a drug of abuse that causes euphoria, anxiolysis, and hypnosis. The recent rise in the recreational intake of GHB, as well as its association with 'drug rape', has turned the attention to GHB in acute hospital settings. Acutely admitted GHB intoxicated patients may display various levels of sedation or coma, but may also show paradoxical agitation, combativeness, or self-injurious behaviors. The symptoms can be nonspecific and the definite diagnosis therefore normally relies on the detection of GHB in blood or body fluids, which is an analysis that may not be promptly available. As a basis for understanding the clinical features of GHB intoxication and abuse, we here review the pharmacological and neurophysiological knowledge about GHB, which stems from decades of clinical and basic GHB research. In addition, we discuss the latest discoveries in the quest for distinct GHB receptors in the brain, and their possible implications for future therapies of GHB abuse.     

A case of gamma-hydroxybutyric acid withdrawal syndrome during alcohol addiction treatment: utility of diazepam administration

Gamma-hydroxybutyric acid (GHB) is an emerging drug for alcoholism therapy. We present a case of GHB withdrawal syndrome secondary to GHB addiction during alcoholism treatment. A complete disappearance of drug withdrawal syndrome was achieved with oral diazepam and the symptoms resolved without sequelae. GHB has been used for alcoholism therapy for only a few years now, but the trend is increasing, and other cases similar to this one are foreseeable. This risk could be higher in some countries in which GHB use is increasing not for alcoholism therapy, but for its euphoric and anabolic effects. The present experience indicates that administration of benzodiazepines would seem to be sufficient to achieve total regression of the withdrawal syndrome in a short time, at least if recognized early.     

Baclofen and Gamma-Hydroxybutyrate Withdrawal

Introduction  Benzodiazepine treatment of life-threatening gamma-hydroxybutyrate (GHB) withdrawal is frequently unsatisfactory. Animal studies suggest strongly that treatment with GABA_B agonists, such as baclofen, will be a more effective strategy. Methods  A case report from the medical intensive care unit (ICU) of the university tertiary care hospital. Results  A 61-year-old woman was admitted to the medical ICU for severe withdrawal symptoms from chronic GHB use. This manifested as delirium, tremor, and seizures despite only small decreases in GHB dose and treatment with benzodiazepines. The addition of baclofen allowed the rapid sequential decreases in the GHB dose without seizure or delirium and resulted in long-term improvement of her tremor. Conclusions  Baclofen, a GABA_B agonist, may be a useful agent in the treatment of severe GHB withdrawal.     

Psychiatric aspects of acute withdrawal from gamma-hydroxybutyrate (GHB) and its analogue gamma-butyrolactone (GBL): implications for psychiatry services in the general hospital

Abstract

Objective. The objective of this study was to describe the psychiatric symptoms, management and outcomes in a consecutive series of patients being managed medically for symptoms of withdrawal from gamma-hydroxybutyrate (GHB) and its analogue gamma-butyrolactone (GBL) in a general hospital setting. Methods. A toxicology database was used to identify patients presenting with a history suggestive of withdrawal from GHB and analogues. Electronic and paper medical records were searched for demographic features, neuropsychiatric symptoms, psychiatric management while in hospital and overall outcome. Results. There were 31 presentations with withdrawal from the drugs involving 20 patients. Of these 17 (54%) were referred to and seen by the liaison psychiatry team. Anxiety (61.3%) and agitation (48.4%) were the most common symptoms. Of the 17 cases seen by the liaison psychiatry team, 52.9% required close constant observation by a mental health nurse and 29.4% required to be detained in hospital under mental health legislation. Conclusions. The significant proportion of patients presenting with neuropsychiatric symptoms and requiring intensive input from the liaison psychiatry team during withdrawal from GHB and its analogues points to the importance of close liaison between medical and psychiatric teams in managing these patients in the general hospital.     

Restless legs syndrome in narcolepsy: a side effect of sodium oxybate?

Gamma-hydroxybutyrate (GHB) has re-emerged as a major treatment for narcolepsy. As dopaminergic transmission is clearly involved in the pathophysiology of restless legs syndrome (RLS), and GHB reduces dopamine release, one may hypothesize that RLS may occur in narcolepsy in the presence of GHB. We report a case of narcolepsy with a severe occurrence of typical RLS with GHB, symptoms never previously experienced by the subject and reversible after withdrawal.     

Clinical efficacy of gamma-hydroxybutyric acid in treatment of opiate withdrawal

This paper describes the role of gamma-hydroxybutyric acid (GHB) in the treatment of opiate withdrawal syndrome. In the two patients described, after having abruptly withdrawn from long-term methadone treatment, GHB was orally administered (each dose given every 4–6 h) for 8–9 days. The GHB showed both a high efficacy (some mild and transient symptoms attributable to opiate withdrawal were observed, but only in the first days of therapy) and a good tolerability (no clinical phenomena interpreted as GHB side effects were found). These results could be of interest in improving the pharmacological treatment of drug addiction.     

Designer drugs in the general hospital.

This article has reviewed the potential complications of acute intoxication and withdrawal from some of the more commonly used club, or designer, drugs. Although limited, acute use of these drugs is claimed by users to be benign, in the context of crowded raves and circuit parties, where multiple drugs may be used, hyperthermia, dehydration, and life-threatening reactions may occur. In addition, mounting evidence of the long-term effects of continued use of these drugs is cause for great concern. Finally, awareness of a severe withdrawal syndrome from GHB and its precursors is particularly important to psychiatrists of the medically ill, who may be called on to help in the management of these patients.     

Unusual presentation of a patient with GBL withdrawal: a case report

GBL (gamma-butyro-lactone) is converted to Gamma hydroxyl butyrate (GHB) in the body. GBL and GHB are available in liquid form and powder form. Once categorised under "legal highs", these two are not associated with any dependence or withdrawal in animal studies. But there are case reports indicating their high dependence potential in humans. We here present a case of a 29 year old who came to the attention of psychiatric services with very bizarre presentation and needed a host of investigations and expert views from various medical disciplines. He was treated mainly symptomatically followed by a sudden dramatic recovery on the 11th day after presentation. GBL is getting popular as a recreational drug and its withdrawal should be seriously considered in the list of medical causes leading to Delirium.     

Withdrawal syndrome from gamma-hydroxybutyric acid (GHB) and 1,4-butanediol (1,4-BD) in Sardinian alcohol-preferring rats

Gamma-hydroxybutyric acid (GHB) and its precursors, 1,4-butanediol (1,4-BD) and gamma-butyrolactone (GBL), are recreational drugs widely abused in the US, Europe and Australasia. A severe withdrawal syndrome from GHB, 1,4-BD and GBL has been increasingly documented over the last years, necessitating the development of a reliable animal model for investigations of potential therapeutic approaches. The present study describes the induction and occurrence of audiogenic seizures as a sign of withdrawal from GHB and 1,4-BD in selectively bred Sardinian alcohol-preferring (sP) rats, treated with escalating doses of GHB (1.5-3.5 g/kg, twice daily; i.g.) or 1,4-BD (500-1000 mg/kg, twice daily; i.g.) for 9 consecutive days. Acute administration of the selective GABA(B) receptor antagonist, SCH 50911, dramatically increased seizure occurrence. We propose that the inherent sensitivity of sP rats to different GHB-associated responses may have contributed to the unraveling of a phenomenon which was otherwise not recognizable in other rat strains.     

Failure of gamma-hydroxybutyric acid both to increase neuroactive steroid concentrations in adrenalectomized-orchiectomized rats and to induce tolerance to its steroidogenic effect in intact animals

Gamma-Hydroxybutyric acid (GHB), a drug proposed in the treatment of alcohol withdrawal syndrome, increases the cerebrocortical and plasma concentrations of the neuroactive steroids allopregnanolone and allotetrahydrodeoxycorticosterone (THDOC). In the present study, we examined the role of hypothalamic-pituitary-adrenal (HPA) axis in the effect of GHB by measuring the concentrations of these steroids in the brain and plasma of adrenalectomized-orchiectomized (Adx-Orx) rats. The acute administration of GHB (500 mg/kg, i.p.) induced in 30 min an increase in the concentrations of allopregnanolone, THDOC and their precursors pregnenolone and progesterone in different brain areas (cerebral cortex, hypothalamus and cerebellum) and plasma of sham-operated rats but had no effect on the concentrations of these compounds in Adx-Orx rats, suggesting that activation of the HPA axis mediates the effect of GHB on brain and plasma concentrations of neuroactive steroids. Moreover, we evaluated whether repeated exposure of GHB induces tolerance to its steroidogenic effects. Chronic administration of GHB (500 mg/kg, i.p., twice a day for 10 days) to intact animals failed to affect the levels of progesterone, allopregnanolone, or THDOC measured 3 or 48 h after the last drug administration, whereas a challenge injection of GHB or ethanol was still able to increase the concentrations of these steroids in brain and plasma. These results indicate that repeated exposure to GHB fails to induce tolerance or cross-tolerance to the steroidogenic action of GHB or ethanol, respectively.     

Gamma-butyrolactone (GBL) disruption of passive avoidance learning in the day-old chick appears to be due to its effect on GABAB not gamma-hydroxybutyric [corrected] acid (GHB) receptors

Gamma-butyrolactone (GBL) is a prodrug to gamma-hydroxybutyric acid (GHB) and metabolises to GHB when ingested. Discrimination stimulus studies report generalisation of effects of GHB to GBL. While amnesia is one of the most commonly reported symptoms of GHB's ingestion in human users, as yet few studies have examined this effect. Although an endogenous GHB specific receptor is present in the brain, several studies have indicated that the clinical effects of exogenous doses of GBL/GHB are due to its action on GABA(B) receptors rather than on the GHB receptor. In this series of studies, New Hampshire x White leghorn cockerels were trained using a modified version of the passive avoidance learning task. Subcutaneous injections of GBL induced a memory deficit by 10 min post-training, which persisted for at least 24 h. No effect on memory was seen with administration of the specific GHB agonist NCS-356 (gamma-p-chlorophenyl-trans-4-hydroxycrotonate). The GBL-induced memory deficit appeared similar to the deficit produced by baclofen, where the antagonist facilitated learning. Additionally, GBL-induced memory deficit was ameliorated by application of a GABA(B) antagonist. The results support the hypothesis that GBL exerts its influence on memory via the GABA(B) receptor rather than by the specific GHB receptor.     

Intrathecal baclofen overdose followed by withdrawal: clinical and EEG features

Intrathecal baclofen therapy is increasingly used to alleviate medically intractable spasticity in children with cerebral palsy, spinal cord injuries, and generalized dystonia. Complications like overdose or withdrawal can occur and could be the result of pump malfunction (device-related) or refilling and programming mistakes (human errors). This report describes a case, with emphasis on electroencephalographic changes, of a 12-year old male on long-term intrathecal baclofen therapy who had sequential occurrence of both acute inadvertent baclofen overdose followed by withdrawal symptoms. During baclofen intoxication, electroencephalography documented periodic generalized epileptiform discharges, occasionally followed by intermittent electro-decremental responses on a background of diffuse delta slowing (1-2 Hz). During withdrawal, mild generalized slowing during wakefulness was observed along with the appearance of high-amplitude, sharply contoured delta activity resembling frontal intermittent rhythmic delta activity in sleep. To our knowledge, this temporal profile of electroencephalographic features during baclofen intoxication followed by withdrawal has not been described before in pediatric patients. It is important for treating physicians to recognize the evolution of this electroencephalographic pattern in order to avoid misinterpretation of diagnosis and prognosis.     

Gammahydroxybutyrate: An endogenous regulator of energy metabolism

Gammahydroxybutyrate is a naturally occurring metabolite of many mammalian tissues. Although its administration produces a wide range of pharmacological effects, its normal function has never been clearly defined. GHB can induce NREM and REM sleep, anaesthesia, hypothermia, and a trance-like state which has been considered a model for petit mal epilepsy. It markedly increases brain dopamine levels. It has been touted as a central neurotransmitter or neuromodulator, and high affinity brain receptors, as well as central mechanisms for its synthesis, uptake and release have been demonstrated in support of this. But GHB is also found in many peripheral tissues and in some of these in higher concentrations than in the brain. No explanation has been offered for its presence in these tissues. A number of studies indicate that GHB can reduce energy substrate consumption in both brain and peripheral tissues, and that it can protect these tissues from the damaging effects of anoxia or excessive metabolic demand. Indeed there is some evidence to suggest that endogenous GHB levels rise under these circumstances. GHB appears to act through the endogenous opioid system, since in the brain, at least, GHB raises dynorphin levels and its metabolic and pharmacological effects can be blocked by naloxone. These, and other observations detailed in this review, suggest that GHB may function naturally in the induction and maintenance of physiological states, like sleep and hibernation, in which energy utilization is depressed. GHB may also function naturally as an endogenous protective agent when tissue energy supplies are limited.     

Potential link between hallucination and nausea/vomiting induced by alcohol? An empirical clinical finding

Medical records of 1,911 alcoholics admitted to the Alcohol Inpatient Service at the University of New Mexico in Albuquerque (USA) were examined to find the frequencies among there variables: hallucination (H), nausea/vomiting (N/V), and elevated liver enzymes (L). The variable L is thought to be independent of neurotransmissions. By contingency table analysis with chi 2 test, N/V and H are found to be positively significantly correlated (p less than 0.0001) whereas L and H are not found to be correlated. These empirical data suggest that there is a potential link between H and N/V in alcohol intoxication/withdrawal. Careful observation of the symptoms and signs of alcohol intoxication/withdrawal may be a useful research tool for elucidating human neuroreceptors in the central nervous system.     

The treatment of narcolepsy-cataplexy with nocturnal gamma-hydroxybutyrate.

Sixteen patients with narcolepsy and cataplexy were treated with gamma-hydroxybutyrate (GHB) given at night and tailored to achieve as continuous a night's sleep as possible. The dosage usually consisted of 1.5-2.25 gm orally at bedtime and then one or two further 1.0-1.5 gm doses with awakenings during the night, and totaled about 50 mg/kg. Apart from one patient who took only the bedtime dose, the subjective quality of night sleep improved in all patients and the number of irresistible daytime attacks of sleep and cataplexy substantially diminished. Some residual daytime drowsiness remained and this usually responded well to low doses of methylphenidate. Improvement has been maintained for up to 20 months without the development of tolerance. Two patients experienced adverse side effects necessitating withdrawal of GHB treatment, but no serious toxic effects have occurred.     

Alcohol and Marijuana: Effects on Epilepsy and Use by Patients with Epilepsy

We review the safety of alcohol or marijuana use by patients with epilepsy. Alcohol intake in small amounts (one to two drinks per day) usually does not increase seizure frequency or significantly affect serum levels of antiepileptic drugs (AEDs). Adult patients with epilepsy should therefore be allowed to consume alcohol in limited amounts. However, exceptions may include patients with a history of alcohol or substance abuse, or those with a history of alcohol-related seizures. The most serious risk of seizures in connection with alcohol use is withdrawal. Alcohol withdrawal lowers the seizure threshold, an effect that may be related to alcohol dose, rapidity of withdrawal, and chronicity of exposure. Individuals who chronically abuse alcohol are at significantly increased risk of developing seizures, which can occur during withdrawal or intoxication. Alcohol abuse predisposes to medical and metabolic disorders that can lower the seizure threshold or cause symptoms that mimic seizures. Therefore, in evaluating a seizure in a patient who is inebriated or has abused alcohol, one must carefully investigate to determine the cause. Animal and human research on the effects of marijuana on seizure activity are inconclusive. There are currently insufficient data to determine whether occasional or chronic marijuana use influences seizure frequency. Some evidence suggests that marijuana and its active cannabinoids have antiepileptic effects, but these may be specific to partial or tonic-clonic seizures. In some animal models, marijuana or its constituents can lower the seizure threshold. Preliminary, uncontrolled clinical studies suggest that cannabidiol may have antiepileptic effects in humans. Marijuana use can transiently impair short-term memory, and like alcohol use, may increase noncompliance with AEDs. Marijuana use or withdrawal could potentially trigger seizures in susceptible patients.     

Pathobiochemistry and pharmacotherapy of alcohol withdrawal delirium]

The spectrum and time course of different symptoms during alcohol withdrawal may be caused by the involvement of various neurotransmitter systems that are differentially vulnerable to the effects of ethanol. Withdrawal symptomatology results from increased activity of excitatory mechanisms (NMDA-receptor, catecholamines among others) and from reduced functioning of inhibitory receptors (GABAA-, alpha 2-adreno-receptor among others). The neuronal mechanisms are subject to different dynamics of restitution following intoxication. Some of these probably contribute to long-lasting changes in CNS functions by "kindling" processes. Therapeutic guidelines are deduced from results of basic research and clinical trials. It is concluded that clomethiazole and benzodiazepines are superior in treating delirium tremens and certain risk-patients, whereas carbamazepine and clonidine may be helpful in moderate withdrawal syndromes or as adjunctive agents. However, the need for improved methodological standards of method in clinical research is evident.     

Encephalopathies caused by valproate

Valproic acid (VPA)-induced encephalopathy is a rarely considered side effect, with somnolence, reduced motor activity and severe deterioration of cognitive and behavioural abilities. In accordance with the increasing clinical importance of valproate clinical symptoms, causes and possibilities of treatment are reviewed by reporting on two cases of valproate-induced encephalopathy. In comparison to VPA intoxication, which is associated to increased VPA blood levels, the mechanisms of encephalopathy may include interactions of the hepatic enzymes, a direct toxic effect on the cerebral receptors, as well as drug interactions, a paradoxical epileptogenic effect and metabolic interactions. In most cases withdrawal of VPA produces regression of the symptoms within a few days; the role of L-carnitin or citrullin supplementation in clinical treatment remains unclear.     

Safety of ipsapirone treatment compared with lorazepam: discontinuation effects.

OBJECTIVE: To determine discontinuation effects of ipsapirone, a novel azapirone and partial 5-HTIA agonist that has anxiolytic effects clinically and has not caused dependence or withdrawal symptoms in animals, and to compare these effects with those of the benzodiazepine lorazepam, owing to concern about dependence or withdrawal symptoms following use of these drugs. DESIGN: Prospective, randomized, double-blind, placebo-controlled trial. SETTING: Outpatient and inpatient treatment. PARTICIPANTS: Sixty-five healthy male volunteers who had experience with sedative-hypnotics or anxiolytics and did not meet DSM-III-R criteria for abuse or dependence. INTERVENTIONS: Participants were randomized to receive ipsapirone 15 mg per day (n = 17), ipsapirone 22.5 mg per day (n = 16), lorazepam 3 mg per day (n = 16), or placebo (n = 16) as outpatients for 36 days (treatment) followed by single-blind placebo as inpatients for 3 days and as outpatients for 6 days (withdrawal). OUTCOME MEASURES: Hamilton Anxiety Rating Scale (HAM-A), Hamilton Depression Scale (HAM-D), Spielberger State Anxiety Scale, Sleep Quality Questionnaire, General Symptom Checklist, self-rated intoxication, Clinical Institute Withdrawal Assessment--Benzodiazepines (CIWA-Benzo), psychomotor testing and urine drug screen. RESULTS: Only 45 subjects completed the study; discontinuation rates did not significantly differ among treatment groups. At day 39, fewer and less severe symptoms (e.g., insomnia and fatigue) were found on the CIWA-Benzo scale after treatment with ipsapirone or placebo than after treatment with lorazepam (p < 0.05). Subjects reported longer sleep latency and poorer sleep quality after receiving lorazepam than after receiving ipsapirone or placebo. Scores on the HAM-D, Spielberger State Anxiety and HAM-A scales did not change from baseline. CONCLUSIONS: Withdrawal symptoms were detected after discontinuation of therapeutic doses of lorazepam. Significantly fewer symptoms were observed after withdrawal from anxiolytic doses of ipsapirone.