Forensic Science Update: Gamma-Hydroxybutyrate (GHB)

Carl S. Hornfeldt
Clinical Manager of Professional Services
Orphan Medical, Incorporated
Minnetonka, Minnesota

Kevin Lothridge
Deputy Director
National Forensic Science Technology Center
Largo, Florida

J. C. Upshaw Downs
Chief Medical Examiner
Alabama Department of Forensic Sciences
Auburn, Alabama

Introduction ....... History ....... Recent Use ....... Physicochemical
Pharmacokinetics ....... Clinical Effects .......Treatment ....... Range of Toxicity
Laboratory ....... Summary ....... References

Introduction

The past decade has seen a dramatic increase in the use of gamma-hydroxybutyrate (GHB) and related substances. Because of their current popularity as recreational compounds of abuse and their unfortunate effectiveness as "drug-facilitated sexual assault" agents, forensic scientists are being called upon to determine the role of these compounds in overdose and sexual assault cases with increasing frequency. The objective of this paper is to provide an update on the history, mechanism, clinical effects, legal status, legitimate use, and laboratory analysis of these compounds.

History

The compound gamma-hydroxybutyrate (GHB) originated about 40 years ago when it was synthesized as a peripherally administered agonist of the inhibitory neurotransmitter, gamma-aminobutyric acid (GABA). In 1963, GHB was reported to be an endogenous compound in the mammalian brain (Bessman and Fishbein 1963). Since that time, several researchers have claimed GHB to be a putative neurotransmitter because it appears to fulfill the necessary requirements (reviewed in Mandel et al. 1987; Tunnicliff 1992; Vayer et al. 1987).

• GHB is synthesized in brain tissue from GABA by way of a succinic semialdehyde intermediate.
• Prior to release into the synaptic cleft, the synthesized GHB is located within discrete storage vesicles.
• The stimulated release of GHB from neural tissue occurs in a calcium-dependent manner.
• A sodium-dependent, high-affinity membrane transport system has been demonstrated.
• Both high- and low-affinity receptors have been described specifically in neural tissue that have high specificity for GHB.
• Within the central nervous system, the administration of GHB is associated with dose-dependent increases in dopamine concentrations suggesting a physiologic role in the regulation of central dopaminergic activity. It also increases serotonin turnover. Electrophysiology studies reveal an inhibitory effect of GHB in the substantia nigra and neocortex.
• When radiolabeled GHB is injected into rats, most of the labeled carbon is recovered as carbon dioxide, suggesting an endogenous metabolic fate through the Kreb's Cycle. In addition, the metabolism of GHB appears to involve conversion to GABA by way of a nonsuccinic semialdehyde intermediate and/or beta-oxidation to carbon dioxide.

That GHB is an endogenous compound has been made even more evident by the recent description of an apparent inborn error of GHB metabolism due to a deficiency in succinic semialdehyde dehydrogenase (SSADH). This deficiency causes an accumulation of endogenous GHB, GABA, and products of gamma-oxidation, leading to motor problems including ataxia, hyporeflexia, and seizures as well as mental retardation, hyperkinesis, psychosis, and numerous other neurologic manifestations (Gibson et al. 1998). Accumulated GHB has been shown to reach plasma concentrations as high as 100 mg/L in affected individuals (Jakobs et al. 1984) which are not normally detected in healthy individuals (Fieler et al. 1998).

Because GHB can be administered peripherally to induce sleep, it has been employed clinically in Europe in the field of anesthesia. As it has no analgesic properties, GHB must be used in combination with an opiate analgesic. Its long half-life, compared with newer agents, and its association with myoclonus have substantially reduced its use in anesthesia, although it has been shown to protect tissues from the damaging effects of hypoxia and ischemia (reviewed in Li et al. 1998).

Recent Use

During the 1980s, GHB was marketed in health food stores, training gyms, fitness centers, and on the Internet. Allegedly providing anabolic benefits by stimulating growth hormone release, it was used by body builders and for strength training. In addition, it was promoted as a natural treatment for insomnia and to induce weight loss. Apparently, the purported euphoric effects of GHB were also discovered at this time. The Food and Drug Administration (FDA) issued a press release warning against the use of GHB, stating that it was illegal and dangerous (FDA 1990). Subsequent sales were curtailed in November 1990. This followed the report of 57 cases of overdose or adverse reactions in 9 states (Centers for Disease Control [CDC] 1991).

The ban on the sale of GHB by the FDA and tighter regulations in various states led to an increase in illegally synthesized GHB and the sale and use of the GHB precursors gamma-butyrolactone (GBL) and 1,4-butandiol (1,4-BD). Products containing these compounds quickly became available through various sources including the Internet. GBL was also sold over the counter in kit form with instructions for the synthesis of GHB. As both analogs are converted to GHB in vivo (Vree et al. 1978), the ingestion of GBL and 1,4-BD can produce clinical effects similar to GHB. GHB had become a substance of abuse at "raves," was being implicated in an increasing number of sexual assault cases (ElSohly and Salamone 1999), and was becoming known as a "date rape" drug. The popular use of GHB and its availability on the Internet has been recently reviewed elsewhere (Galloway et al. 2000).

The passage of the Hilary J. Farias and Samantha Reid Date-Rape Drug Prohibition Act of 2000 amended the Controlled Substances Act and created a bifurcated schedule for GHB. When intended for abuse or misuse, GHB is a Schedule I agent (Federal Register 2000). Federally, the consequences for manufacturing, distributing, and possessing GBL and 1,4-BD for human consumption are the same as for a Schedule I substance. Also, GHB is currently being investigated under the FDA-approved Investigational New Drug Application for the treatment of narcolepsy. If approved, these regulations also permit GHB to be controlled as a Schedule III drug. Although each state has the option of imposing more restrictive scheduling than the federal guidelines, Schedule I/III status consistent with federal actions has been adopted by approximately one half of the states in this country, and it is likely other states will follow suit. Efforts to broaden the legal definitions of "GHB analog" are ongoing in various states.

Several clinical trials have demonstrated the safety and effectiveness of GHB for the treatment of narcolepsy (Lammers et al. 1993; Scharf et al. 1985; Scrima et al. 1990). Once approved, a pharmaceutical formulation of GHB, known by its official generic name, sodium oxybate, will be marketed as Xyrem® (Orphan Medical, Minnetonka, Minnesota). GHB is currently marketed in Italy, Austria, and Hungary as a treatment for ethanol withdrawal (Addolorato et al. 1999; Gallimberti et al. 1992; Poldrugo and Addolorato 1999) and is under investigation for opiate withdrawal (Gallimberti et al. 1993; Gallimberti et al. 2000). GHB has been recently investigated as a possible treatment for the pain and fatigue associated with fibromyalgia (Scharf et al. 1998A). Finally, GHB appears to have some beneficial effects in resuscitation as it protects tissues against hypoxic injury (Li et al. 1998). Several of the potential therapeutic uses of GHB are reviewed elsewhere (Galloway et al. 2000).

Physicochemical

The sodium salt of GHB has a molecular formula of C4H7NaO3 and a molecular weight of 126.09. The Chemical Abstract Society (CAS) Number for the sodium salt of GHB is 502-85-2.

GHB appears to have no legitimate use as an industrial chemical. Interestingly, 1,4-butanediol (1,4-BD) and gamma-butyrolactone (GBL), 2 GHB precursor molecules, are used extensively in chemical manufacturing. In the year 2001, it is estimated that the United States' industrial consumption of 1,4-BD will be an astonishing 387,000 metric tons. Major uses of 1,4-BD are the synthesis of tetrahydrofuran, polybutylene terephthalate resins, GBL, and polyurethanes (Caruso et al. 1997).

Pharmacokinetics

Absorption

Oral doses of GHB appear to be rapidly absorbed from the gastrointestinal tract. In 8 healthy human volunteers, GHB in single oral doses of 12.5, 25, and 50 mg/kg in syrup form reached peak plasma concentrations in 25 (range 20-30), 30 (range 20-45), and 45 (range 30-60) minutes respectively (Palatini et al. 1993). In a series of 6 narcolepsy patients taking two 3-gram doses of GHB powder dissolved in water 4 hours apart, the mean peak serum concentrations occurred in 40.0 and 35.7 minutes, respectively (Scharf et al. 1998B).

In a cross-over design study, 4.5 or 9 g of GHB were administered in 2 equally divided doses (2.25 and 4.5 g/dose, respectively) to 24 healthy volunteers. This resulted in 2 peak plasma concentrations: 26.6 and 60.1 mg/L after the 4.5 g dose and 77.6 and 141.7 mg/L after the 9 g dose (Borgen et al. 2000). Oral absorption appears to be capacity limited (Ferrara et al. 1992).

Distribution

Peak serum concentrations initially decline rapidly, suggesting tissue redistribution and a two-compartment model (Vree et al. 1978). A post hoc review of intravenous doses in humans suggests a volume of distribution of 0.4 L/kg in the first compartment and 0.58 L/kg in the second (Dyer 1991).

Metabolism

In a series of alcohol-dependent patients receiving 25 mg/kg every 12 hours, an average of less than 1% of the ingested dose was recovered as unchanged drug in the urine, suggesting extensive hepatic metabolism (Ferrara et al. 1992). GHB is oxidized to succinic semialdehyde, then to succinic acid, which enters the Krebs cycle (Tunnicliff 1992); the ultimate metabolic fate of GHB is, therefore, carbon dioxide and water (Walkenstein et al. 1964). GBL and 1,4-BD undergo conversion to GHB in vivo (Lettieri and Fung 1978; Snead et al. 1989). The metabolism of 1,4-BD to GHB involves the enzyme alcohol dehydrogenase (Vree et al. 1975).

Elimination

The original work on GHB pharmacokinetics revealed first-order elimination at low doses but capacity-limited (zero order) elimination at higher doses (Vree et al. 1975). These results have recently been replicated in human trials. In 36 healthy human volunteers, oral GHB in a dose of 4.5 g displayed a mean elimination half-life of 34 minutes when taken in a fasted state (Borgen et al. 2000). The administration of 4.5 or 9 g of GHB in 2 equally divided doses (2.25 and 4.5 g/dose, respectively) 4 hours apart in 24 healthy volunteers resulted in half-life elimination rates of 35 and 50 minutes, respectively (Borgen et al. 2000). Similarly, in a series of 6 narcolepsy patients taking two 3-gram doses of GHB dissolved in water 4 hours apart, the mean elimination half-life was 53.0 minutes (Scharf et al. 1998B).

The conversion of the precursor drug 1,4-BD to GHB involves the enzyme alcohol dehydrogenase and, like ethanol, obeys zero order metabolism at doses that saturate this enzyme (Vree et al. 1975).

Urinary excretion of unmetabolized GHB is in the range of 1-5%, with less being excreted under conditions of acidic urine (Vree et al. 1978).

Clinical Effects

During clinical trials, therapeutic doses of GHB have produced adverse reactions that were generally minor and consisted mainly of dizziness, headache, and nausea. Recreational users have reported euphoria, relaxation, disinhibition, and increased libido; however, the doses were not specified (Galloway et al. 1997).

With acute overdose, the central nervous system depressant effects are much more evident, and sedation, ranging from lethargy to coma, has been reported. Other central nervous system effects include nystagmus, miosis, ataxia, combativeness, respiratory depression, apnea, and seizure-like activity (myoclonus). Additional effects include vomiting, hypothermia, bradycardia, atrial fibrillation, and urinary and fecal incontinence (Chin et al. 1998; Dyer 1991). In one case series, hypotension was associated with concomitant ethanol ingestion (Chin et al. 1998). Similar effects have been reported with GBL (Hardy et al. 1999; LoVecchio et al. 1998) and 1,4-BD (Cisek et al. 1999; Dyer et al. 1997).

In a series of 88 patients intoxicated with GHB and related compounds seen in a major metropolitan hospital over a 3-year period, 34 had also ingested ethanol. Other illicit drugs are also common coingestants (Chin et al. 1998; Garrison and Mueller 1998).

Abrupt cessation in GHB abusers has produced withdrawal symptoms. This has been associated with frequent (every 1-3 hours) and excessively high daily doses for several weeks to 3 years (Dyer and Andrews 1997; Dyer et al. 2001; Galloway et al. 1997). Reported symptoms have included anxiety, dizziness, confusion, tremor, insomnia, paranoid behavior, auditory and visual hallucinations, psychosis, tachycardia, and hypertension (Dyer and Andrews 1997; Galloway et al. 1997; Sanguinetti et al. 1997). Withdrawal symptoms have persisted for up to 15 days (Dyer et al. 2001). In a case series of 8 patients suffering GHB withdrawal, one patient died on the 13th day of hospitalization, although the relationship to GHB withdrawal remains unclear (Dyer et al. 2001). At least one case of withdrawal has been reported following the abrupt cessation of a GBL-containing product (Green et al. 1999). Because 1,4-BD is also converted in vivo to GHB, it is not surprising that cases of withdrawal have also been reported following cessation of 1,4-BD-containing products (Zvosec et al. 2001).

The illicit home synthesis from gamma-butyrolactone and sodium hydroxide, sold together in kits, has been the source of numerous cases of GHB overdose (Henretig et al. 1998). Several cases of adverse events secondary to improper manufacture from kits have also been reported (Dyer and Reed 1997; Wiley et al. 1998).

Treatment

Following oral ingestion, activated charcoal would be of hypothetical benefit for decreasing exposure to the drug; however, the rapid absorption of GHB makes it unfeasible, and the use of activated charcoal should be reserved for suspected coingestants. Although animal research indicates the opiate antagonist naloxone inhibits some of the central effects of GHB (Fiegenbaum and Howard 1997), clinically it appears ineffective (Dyer 1991; Ross 1995; Thomas et al. 1997; Yates and Viera 2000). Similarly, the benzodiazepine antagonist flumazenil appears ineffective in reversing GHB-induced toxicity (Dyer 1991; Ross 1995; Thomas et al. 1997; Yates and Viera 2000). In contrast, physostigmine proved useful in terminating the sedative effects of GHB when used in anesthesia. In a series of 25 patients anesthetized with GHB receiving 2 mg physostigmine IV, the mean time to awakening was 6.2 minutes (Henderson and Holms 1976). Preliminary reports in unresponsive GHB overdose patients receiving 2 mg physostigmine have produced similar results (Caldicott and Kuhn 2001; Yates and Viera 2000). Bradycardia has been treated with atropine (Chin et al. 1998), whereas the psychosis associated with withdrawal has responded to haloperidol (Sanguinetti et al. 1997). Other treatment of the GHB overdose patient is largely symptomatic. Endotracheal intubation for airway protection and possible ventilation in these patients remains controversial. The possibility of coingested substances must always be considered; however, the decision to intubate is best left to the treating physician.

Range of Toxicity

Early work on GHB as an anesthetic demonstrated altered levels of consciousness associated with the following serum concentrations:

• greater than 260 mg/L, patients were unresponsive to painful stimuli (comatose)
• 156-260 mg/L, patients were asleep but responsive
• 52-156 mg/L, patients exhibited spontaneous movement with occasional eye opening
• less than 52 mg/L, patients awakened (Helrich et al. 1964)

In agreement with these findings, 6 narcolepsy patients receiving therapeutic doses of GHB (3 g at bedtime repeated 4 hours later; total dose 26.4 - 52.4 mg/kg) achieved mean peak serum concentrations of 62.8 and 91.2 mg/L (Scharf et al. 1998B). In animals, the lethal doses ranged from 5-15 times the coma-inducing dose. Ethanol has been shown to have a significant synergistic effect on the sedative action of GHB in rats (McCabe et al. 1971).

Laboratory

Methods

Early gas chromatographic analyses were developed for the measurement of endogenous GHB in tissues. Samples were heated in the presence of mineral acids, converting GHB to GBL, and were capable of measuring GHB concentrations as low as 1.45 ± 0.22 nmoles/gm (0.183 ± 0.028 mg/L)(N=4) of brain tissue in the rat (Roth and Giarman 1970). An isotope dilution method using 14C-gamma hydroxybutyric acid measured GHB concentrations as low as 1.78 ± 0.10 nmoles/gm (0.224 ± 0.013 mg/L)(N=4), also in the rat brain (Roth and Giarman 1970).

Subsequent gas chromatography-mass spectrometry (GC-MS) assays were developed specifically for measuring GHB in human plasma and urine. This technique permitted the measurement of plasma and urine concentrations as low as 0.2 and 0.1 mg/L, respectively, but also required conversion of GHB to GBL (Ferrara et al. 1993). GC-MS assays allowing direct measurement of GHB in urine and blood with detection limits of 0.5-2 mg/L without GBL conversion have been developed (Couper and Logan 2000; Louagie et al. 1997; McCusker et al. 1999). A high-performance-liquid-chromatography assay also has the advantage of being able to measure both GHB and GBL (Beyerle 2000). This may be useful for measuring drugs in the overdose setting when GBL has been ingested and partially metabolized to GHB, resulting in both drugs being present.

It should also be noted that spontaneous conversion of GBL to GHB occurs in vitro in a pH-dependant manner. At high pH this may occur in minutes, whereas at low pH this may require several days (Ciolono and Mesmer 2000). Due to differences in legal scheduling of these compounds in different states, this interconversion may have significant legal ramifications.

Therapeutic Administration

The peak plasma concentration of therapeutically administered GHB has been measured in several studies. Patients receiving GHB in doses of 25 and 50 mg/kg every 12 hours for alcohol withdrawal and dependence had mean peak plasma concentrations of 55 mg/L (range 24-88) and 90 mg/L (range 51-158), respectively (Ferrara et al. 1993). In a similar study, patients receiving 25 mg/kg twice daily had a mean plasma concentration of 54 mg/L ± 19 (range 24-88, N=10)(Ferrara et al. 1992). In that study, urinary recovery of unmetabolized GHB in the urine was less than 1%. In a study involving 6 patients receiving two 3-gram doses of GHB 4 hours apart for the treatment of narcolepsy, mean peak concentrations (SD) of 62.8 (27.4) and 91.2 (25.6) mg/L were observed for each dose (Scharf et al. 1998B). These data are summarized in Table 1. GHB in therapeutic doses as high as 50 mg/kg produced symptoms of dizziness and drowsiness only (Palatini et al. 1993).

Acute Overdose

The serum and urine concentrations of GHB in a few apparent GHB overdose patients have also been reported. In a comatose patient admitted to a hospital emergency department, the serum GHB concentration was 125 mg/L. The patient had a concomitant serum ethanol concentration of 134 mg/dL, but no other drugs were present. This patient recovered without sequelae (Louagie et al. 1997).

Another comatose patient was found to have serum GHB concentrations of 101 and 3 mg/L at 1 and 5 hours after presentation, respectively. Simultaneous urine GHB concentrations were 141,000 and 857 mg/L. Blood alcohol and urine toxicology screens were negative. The patient recovered uneventfully (Dyer et al. 1994). A patient found asleep in his car was found to have urine GHB concentration of 1,975 mg/L 2 hours after ingesting an unknown quantity of GHB (Stephens and Baselt 1994). These findings are summarized in Table 1.

These case reports indicate that the difference between toxic and therapeutic serum GHB concentrations may be very small. The capacity-limited elimination, which has been demonstrated experimentally (Borgen et al. 2000), may contribute to toxicity when greater than therapeutic amounts are ingested. Also, whereas negligible amounts of GHB are excreted in the urine following therapeutic administration, large amounts are excreted following acute overdose.

Postmortem

Whereas the measurement of postmortem GHB concentrations are of great medico-legal importance, these results must be interpreted cautiously because endogenous postmortem concentrations rise significantly immediately after death (Fieler et al. 1998; Roth 1970; Stephens et al. 1999). Not surprisingly, these elevated endogenous concentrations appear to overlap concentrations reported after alleged fatal GHB overdoses. In one review, blood GHB concentrations following fatal overdose were reported to range from 27-121 mg/L in 4 patients. A random sampling of 20 autopsy blood samples (no GHB ingested) found blood GHB concentrations ranging from 3.2-168 mg/L (mean 25 mg/L) in 15 of them (Fieler et al. 1998). Because postmortem urine GHB concentrations remain relatively unchanged, it has been suggested that urine GHB specimens are preferred during investigation of suspected GHB-related deaths (Stephens et al. 1999); however, more recent evidence indicates this is not the case. Urinary GHB was detected in 12 of 13 GHB-unrelated fatalities in concentrations ranging from 6-217 mg/L (Elliott 2001).

It is also of special concern that the analysis of whole blood containing trisodium citrate-citric acid buffer has yielded false-positive results for GHB (LeBeau et al. 2000). The findings from several reports of postmortem GHB and related drug concentrations have been included in Table 1. In each case the nature of the ingestion has been supported by analysis of ingested material or a history consistent with the reported findings.

Summary

As an endogenous substance in normal physiology and a potential therapeutic agent, GHB is a unique and fascinating substance worthy of study. Regrettably, the abuse and misuse of illicit GHB, GBL, and 1,4-BD are unlikely to disappear from our society in the near future. Therefore, the forensic scientist will continue to act as the primary source of information regarding death, sexual assault, and other tragic events associated with these compounds. Whereas a few misinterpreted measurements and presumptive diagnoses may have clouded some early findings, future studies will more clearly differentiate the toxicokinetics and dose-response profiles of these compounds.

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