Risk assessment of gamma-hydroxybutyric acid (GHB) in the Netherlands
Highlights
► The number of incidents associated with GHB proved to be relatively high. ► Repeatedly ‘passing out’ due to GHB may impair cognition and memory. ► The prevalence of GHB use is relatively low and treatment demand is small. ► The overall risk potential of GHB use estimated as moderate to high. ► Based on this assessment GHB was categorized in the Netherlands as a hard drug.
Introduction
Gamma-hydroxybutyric acid (GHB) was developed in the early 1960s as an anesthetic. However, as an anesthetic GHB quickly became obsolete due to the occurrence of undesirable side effects such as vomiting and severe cramps. GHB is now mainly used as a sedative agent and clinically prescribed in some countries to treat alcohol withdrawal. In 2005, GHB was approved for the treatment of narcolepsy (Xyrem®). Recreational GHB use (i.e., use that is non-medical and does not correspond to the DSM-IV criteria for abuse or dependence per se) dates back to the 1990s and in 2009 the last month prevalence in the Netherlands (total population 17 million) was about 22,000 (van Rooij et al., 2011).
The overall risk of GHB was assessed for the first time by the Coordination point Assessment and Monitoring new drugs (CAM) in 1999. Following a steady increase in the last decade in the treatment demand by GHB dependent patients, the Dutch Minister of Health requested the CAM to re-assess the overall risk of GHB in 2010. The assessment procedure was performed by experts from a variety of disciplines. The present paper is an extended redraft of a report that formed the scientific basis of the risk evaluation procedure. The report reviews the scientific data available in the international literature about GHB, and contains some specific information for the Netherlands about the prevalence of use, user characteristics, criminal involvement and availability of GHB and its precursors.
Section snippets
Methods
Scientific data of this report were retrieved using Medline literature searches with the search terms GHB, gamma-hydroxybutyric acid, Xyrem, 1,4-BD and GBL, and the references found in the retrieved reports. A-priori inclusion criteria were toxicity, pharmacotoxicity and human studies were preferably cited; casuistic studies were occasionally used if no controlled or population studies were available. Additional data from gray literature were collected via the CAM network.
The assessment was
Pharmacology
GHB is both a “precursor” and a metabolite of GABA (gamma-aminobutyric acid). As such, GHB is an endogenous substance, found at very low concentrations in the brain. Unlike GABA, GHB readily passes the blood brain barrier.
The complex interaction of GHB with receptors in the mesocorticolimbic dopamine system is probably the primary reason for GHB abuse and dependence (Snead and Gibson, 2005). In the striatum and cortex, GHB modulates dopamine release in a dose-dependent manner via two distinct
Pharmacokinetics
Table 3 depicts the main pharmacokinetic features of recreational GHB use. Although the euphoric effects of GBL and 1,4-BD are equivalent to those of GHB, their effects appear less quickly. This implies that users of GBL are at risk to overdose by taking the next dose while the effect of the first dose has still to occur (Dillon, 2009). Using an online questionnaire, GHB users (N = 189) reported that the GHB effects started on average within 17.5 min and lasted for 66 min (Sumnall et al., 2008).
Acute toxicity
GHB has a very narrow therapeutic window, which makes it a relatively hazardous drug. The acute potential lethal dose of GHB for non-habituated persons is only 5–15 times higher than the therapeutic (and recreational) dose (Galloway et al., 2000, Degenhardt et al., 2003). Note that the therapeutic window is even smaller when GHB is combined with other sedatives such as alcohol (McDowell, 2004).
Relatively high oral doses of 50–70 mg/kg (4–5 g single dose) can induce within 5 min sedation followed
Chronic toxicity
In humans, the long term effects of GHB are largely unknown, and human data for GHB effects on reproduction, mutagenicity and carcinogenicity have not been described in literature (EMCDDA, 2000). The elimination half life of GHB in the body is relatively short (20–45 min: see Table 3), however, this does not automatically imply absence of chronic toxicity of GHB, especially in the brain.
Long-term studies in rodents show no toxicity i.e., no decrease in body weight and weight of bone marrow,
Dependence liability
Until a few years ago, the addictive potential of GHB was considered to be low. With typical user levels, only positive effects were attributed to the use of GHB which resulted in a growing popularity of GHB among various target groups and settings. Probably due to the serious lack of awareness of the risks of GHB, previous to 2009, treatment for GHB dependence was not registered in the Netherlands. Meanwhile, it has become clear that GHB use, especially with intensive/frequent use (i.e., >4
Prevalence
Reliable data on the (alleged) increased prevalence of GHB use are not available. A survey in 2009 monitoring substance use in the general population (15–65 years) (van Rooij et al., 2011) showed that lifetime prevalence of GHB use was 1.3% and that men had more experience with GHB than women (1.6% vs. 0.9%). Lifetime use was highest among 25–44 year olds (2.2%), followed by the 15–24 year age group (1.7%) and those 45–64 year olds (0.1%). The number of GHB users was lower than the number of
Use of GHB in combination with other illicit drugs
GHB is often used in combination with other drugs such as cannabis, alcohol and ecstasy (Sumnall et al., 2008, Korf et al., 2002). A total of 36 of 72 interviewed Dutch GHB users reported to combine GHB very often or always with ecstasy use, primarily to cool down and limit the stimulatory effect of MDMA. Other popular combinations are GHB and alcohol or GHB and cannabis. Slightly greater “hangover” effects are reported after combined use of GHB and cannabis as compared to GHB alone (Korf et
Incidents related to recreational GHB use
In recent years, the number of GHB intoxications at “rave parties” and other dance parties rapidly increased and may be related to the limited awareness of many users of the potential adverse effect of ‘passing out’, a condition where the user is unconsciousness (comatose) for several hours. The difference between the desired dose and the dose leading to unconsciousness is small so that adverse events due to GHB overdosing (see Section 10.1) are frequently observed.
In a 12-year observational
Availability
The precursors of GHB, GBL and 1,4-BD, are cheap and can be easily purchased via the Internet. For industrial purposes, GBL is used as a solvent and cleaning agent, and is a raw material in paint thinners, varnishes, nail polish, glue and paint removal solvents. The production of GHB at home, using recipes available on the Internet, is quite easy. The purity and concentration of GHB homemade solutions, often distributed in small units to friends as a gift, show large variations and fluctuations
Criminality
GHB has often been associated with sexual assault and rape, so that in the general press GHB is sometimes referred to as the “date rape” drug (Schwartz et al., 2000). It should be noted in this respect that GHB is colorless and odorless, and can be easily mixed in soft drinks. The extent of this type of abuse is unclear, but occasionally it has also been used as an excuse for unpermitted sexual activity. Indeed, many of these reports appear inaccurate and misleading. For instance, in only two
Current legal status
In the Dutch Opium Act GHB was not classified as a Schedule I drug until 1996, whereas GBL and 1,4-BD were legally used in chemical industry. At that time, GHB was available in Dutch smart shops, but after an incident where six young people fell into a coma after using GHB together with alcohol, the Dutch Health Inspectorate banned the sale of GHB in smart shops (Beltman et al., 1999). In the Netherlands, GHB (as Xyrem®) is registered only as medicinal product for the treatment of narcolepsy,
Assessment by CAM
The overall risk potential of GHB use was estimated by the CAM expert panel as moderate to high, whereas the CAM recently rated the overall risk of khat (Pennings et al., 2008) and magic mushrooms (van Amsterdam et al., 2011) as low and that of cannabis as moderate (CAM, 2008). This conclusion was mainly based on the high score for the dependence potential of GHB of 2.55 (a maximum score of 4 can be given for each aspect). Furthermore, the risk of acute toxicity, but not chronic toxicity was
Critical considerations
The CAM expert panel estimated the overall risk potential of GHB as moderate to high, and based their conclusion mainly on the high dependence potential of GHB (while the overall prevalence of people in treatment for GHB addiction in totality remains small, the relative increase of this group is actually very high over the last years), the increasing number of incidents related to GHB overdosing and the risks of driving under the influence of GHB. Indeed, the narrow safety margin makes GHB a
Conflict of interest statement
The authors declare that there are no conflicts of interest.
Acknowledgments
The present study was financially supported by the Dutch Ministry of Health and Sports. The support of Dr. van Aerts in collecting the data is kindly acknowledged. The expert advice of and final judgement by the CAM members is highly acknowledged.
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