GHB: a new and novel drug of abuse
Introduction
Gamma-Hydroxybutyrate (sodium hydroxybutyrate; sodium oxybutyrate; GHB) is a naturally occurring, short-chained fatty acid found in mammalian tissue (Bessman and Fishbein, 1963, Roth and Giarman, 1970). It was initially isolated and investigated by Laborit in 1960 in an effort to develop a gamma-aminobutyric acid (GABA) congener which would readily cross the blood brain barrier (Fig. 1). Early testing demonstrated that GHB could produce a dose-dependent sedation and anesthesia in laboratory animals and humans (Laborit et al., 1960, Laborit, 1964). GHB's action as a CNS depressant was in some ways similar to those of classical sedative/hypnotics such as barbiturates and benzodiazepines. Because of the behavioral effects of exogenously administered GHB, coupled with its chemical similarity to and metabolic relationship with GABA, GHB was initially classified with and often compared to GABAergic compounds (Anden and Stock, 1973, Roth and Nowycky, 1977). While GHB does share some cellular and behavioral effects with classical sedative/hypnotics, many now consider GHB to represent a unique pharmacological entity, which is believed to function as a distinct neurotransmitter or neuromodulator (Vayer et al., 1987, Tunnicliff, 1992, Feigenbaum and Howard, 1996a, Maitre, 1997, Bernasconi et al., 1999).
GHB has a 30-year history of use in medicine, particularly in Europe, and it was also available for many years in the US as a consumer product sold as a dietary supplement. Until the early 1990's, GHB had received only modest attention from medical scientists and little concern from public health officials. There have been several developments over the past 10 years in the US which have changed this situation (Luby et al., 1992, Hernandez et al., 1998). Increasing consumer use of GHB as a growth promoter and mild sedative has generated concerns about its safety and effectiveness for these uses without medical supervision. As word of its intoxicating effects become more widely known, GHB came to be touted as a new recreational ‘club drug’ with increasing attention being paid to it in nearly all media, particularly the Internet. Over this same period, reports began to emerge that GHB had been used, often in combination with alcohol, to render women more vulnerable to sexual assault. This served to further heighten public attention to its availability and use. All of this led the US Food and Drug Administration (FDA) in 1990 to declare GHB-containing products as unsafe and ban public sale (Food and Drug Administration, 1991, Center for Disease Control, 1991). This was not entirely effective as Internet sites and certain stores continued to sell GHB which had become known by street names such as liquid X, liquid ecstasy, GBH-grievous bodily harm, scoop, cherry meth, soap, salty water, organic quaalude and growth hormone booster. One method to circumvent the prohibition on the sale of GHB was through the sale of ‘chemistry kits’ containing precursors of GHB, gamma-butyrolactone (GBL) or 1,4-butanediol, along with instructions on how to convert them to GHB. This has led to increased availability of liquid formulations of GHB for street purchase.
As this is written, there is an active public debate in the US about the abuse liability and dangers of GHB, and it can be expected that this will emerge as a worldwide issue in the near future. This discussion is occurring at the same time that GHB is being developed with the trade name Xyrem® as a new medical treatment for narcolepsy under the FDA's Orphan Drug Program. The challenge has been to formulate a public health response to the GHB abuse problem that is proportional to its risks and that minimally interferes with its legitimate uses and those of its precursors. Since GHB represents a new drug of abuse unfamiliar even to many experts in the field, and because additional research is needed to more fully understand the properties of this compound, we have undertaken this review of its neurobehavioral pharmacology and its effects in humans.
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Physiological role of GHB
A variety of findings suggest that GHB functions as a neurotransmitter or neuromodulator. GHB is heterogeneously distributed in the CNS with levels highest in the hippocampus, basal ganglia, hypothalamus and substantia nigra (Vayer and Maitre, 1988, Mamelak, 1989, Maitre, 1997) with systems present for synthesis and vesicular uptake and storage in synaptic terminals (for review see Maitre, 1997). The primary source of GHB in the brain is believed to be metabolism of GABA, which is first
In vivo depressant effects of GHB
GHB possesses sedative and, at sufficiently high doses, anesthetic properties. However, clear differences can be found in the profile of depressant effects produced by GHB versus those produced by barbiturates and benzodiazepines. In some laboratory animals (rodents, cats and monkeys), primarily at higher doses, GHB produces EEG changes reminiscent of epileptiform patterns (Winters and Spooner, 1965, Godschalk et al., 1977, Snead, 1978) supporting the idea that GHB actually induces a cataleptic
Tolerance and dependence
There have been relatively few controlled studies examining the ability of GHB to produce tolerance and dependence in either animals or humans. Colombo et al. (1995d) showed that tolerance develops to motor impairment effects in rats following 9-day repeated i.g. administration of a high dose (1.0 g/kg) of GHB. GHB was given before daily tests on the rota-rod, therefore the tolerance seen may reflect both cellular neuroadaptive changes as well as learning to perform the task while impaired.
Enhancement of the effects of alcohol and other depressant drugs
Concern has been raised regarding the interactive effects of GHB with other CNS depressants. Much of this concern comes from reports that GHB or GBL has been added to alcoholic beverages of women without their knowledge and the combined CNS effects have rendered them vulnerable to assaults (see below). Not unexpectedly, GHB and depressant drug combinations result in greater CNS depressant effects than seen with either drug alone. Combining GHB/GBL with barbiturates produces a prolongation of
Clinical reports of GHB use, misuse and abuse
There is a fairly extensive history of use of GHB for a variety of purposes, many of which are consistent with claims made for its potential therapeutic actions as a sleep enhancer and growth promoter. GHB had been in clinical use in Europe for decades without reports of severe side-effects and incidents of abuse. Indeed, based on early evaluations of GHB, Vickers (1969) commented on the safety of the compound. However, in the US, when it became widely available as a dietary supplement in the
Epidemiology of GHB abuse
It is difficult to obtain quantitative data on the prevalence of GHB use and abuse from traditional databases used to monitor drug abuse behaviors in the US. As of 1999, questions about GHB have not been included in the nationwide Monitoring the Future survey of high school students conducted annually. There are plans to add it to the next survey (Johnston et al., 1999). There is also no information available about rates of GHB abuse in reports of the National Household Survey on Drug Abuse
Regulatory status in the US
Until fairly recently, GHB was not a controlled substance anywhere in the US, and, as described earlier, was sold legitimately until 1990 when the FDA banned its sale to consumers. As of February 2000, at least 28 states had enacted regulations to control GHB or its chemical precursors. Although the legal definitions for schedules of controlled substances differ from state to state, they generally follow that of the US Controlled Substances Act in which compounds with abuse liability but
Summary and conclusions concerning abuse potential
GHB presents several unique characteristics which must be considered when evaluating its overall abuse potential relative to known drugs of abuse. For one, GHB is a natural constituent of the human body. Although high doses of exogenously administered GHB can reasonably be expected to produce effects that would not occur under normal physiological conditions, the difference from normal may be one of degree and not a qualitative difference. Secondly, GHB is not pharmacologically equivalent to
Acknowledgements
Preparation of this review was supported in part by Orphan Medical, Inc. (Minnetonka, MN) (K.L.N. and R.L.B.), by NIDA training grant DA-07027 (K.L.N.) and by NIDA research grant DA-01442 (K.L.N. and R.L.B.). The help and advice of Dr Patrick Beardsley of Virginia Commonwealth University and Patti Engel of Orphan Medical are gratefully acknowledged. The authors gratefully acknowledge Dr Ian Stolerman who served as editor for this submission.
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