Gamma-Hydroxybutyric Acid (GHB)

Neuropharmacology and metabolism

GHB is naturally present in mammalian brain tissue, where it functions as a neuromodulator or neurotransmitter (Doherty, Hattox, Snead, & Roth, 1978). It is synthesized from GABA through a process involving mitochondrial GABA transaminase and cytosolic succinic semialdehyde reductase (Maitre, 1997; Snead, Furner, & Liu, 1989). The neurobiologic effects of GHB are driven by a dual-receptor mechanism:

• GHB receptors: GHB binds with high affinity to specific, G-protein-coupled GHB receptors in the brain (Snead, 2000).
• GABA_B receptors: GHB binds with low affinity to GABA_B receptors (Mathivet, Bernasconi, DeBarry, Marescaux, & Bittiger, 1997).

The naturally occurring micromolar concentrations of GHB in the brain are only sufficient to activate the GHB-specific receptors (Doherty et al., 1978; Maitre, 1997). However, the supraphysiologic millimolar concentrations achieved through exogenous ingestion allow GHB to compete for binding sites at the GABA_B receptor (Bernasconi, Mathivet, Bischoff, & Marescaux, 1999). Experimental evidence strongly suggests that the vast majority of the clinical, pharmacologic, toxicologic, and behavioral effects of exogenously administered GHB are mediated primarily through this GABA_B receptor (Wu et al., 2004).

Toxicity and overdose

GHB is characterized by a remarkably narrow margin of safety and a brief half-life of 20 to 30 minutes (Brenneisen et al., 2004).

• An overdose is clinically marked by the rapid onset of profound coma, myoclonus, severe respiratory depression, hypoventilation, and bradycardia (Dyer & Haller, 2004).
• Because the drug is cleared rapidly, the depth of the coma is profound but typically short-lived, and patients usually experience a rapid, uneventful recovery (Dyer & Haller, 2004).
• There are no specific antidotes for GHB, meaning agents like naloxone or flumazenil are entirely ineffective (Mokhlesi, Garimella, Joffe, & Velho, 2004).
• Management is strictly supportive, requiring airway stabilization, oxygen supplementation, and atropine for persistent bradycardia (Chin, Sporer, Cullison, Dyer, & Wu, 1998; Dyer & Haller, 2004).
• Toxicity is severely compounded when GHB is co-ingested with ethanol, which acts synergistically to worsen respiratory depression and hypotension, increasing the risk of death (Miotto et al., 2001).

Abuse and drug-facilitated sexual assault

GHB and its precursors, gamma-butyrolactone and 1,4-butanediol, were initially abused by bodybuilders aiming to stimulate growth hormone production (Van Cauter et al., 1997). By the late 1990s, GHB transitioned into a widely used "club drug" at raves and circuit parties, sought for its ability to induce euphoria, emotional warmth, disinhibition, and heightened sexual awareness (McDonough, Kennedy, Glasper, & Bearn, 2004; Miotto et al., 2001).

Additionally, GHB has gained significant notoriety as a compound used to facilitate sexual assault (Raess & Tunnicliff, 2002). Because illicit liquid GHB is generally colorless, odorless, easily dissolved in water, and induces antegrade amnesia, passivity, and suggestibility, it can be surreptitiously added to victims' drinks without detection (Dyer, 2004; Raess & Tunnicliff, 2002). Diagnosing GHB-facilitated assault is clinically challenging because standard toxicologic screens do not detect the drug, and its rapid clearance requires specialized gas chromatography-mass spectrometry testing on samples collected immediately after the event (Couper, Thatcher, & Logan, 2004; Morris-Kukoski, 2004).

Addiction, withdrawal, and neurologic mechanisms

While occasional recreational users rarely develop physical dependence, frequent users who take GHB for sleep or mood enhancement are at severe risk of addiction (Freese, Miotto, & Reback, 2002). Users experiencing rebound insomnia often escalate their dosing to every two to four hours around the clock (Dyer, Roth, & Hyma, 2001).

• Cessation in dependent individuals triggers a severe, potentially life-threatening withdrawal syndrome (Miotto et al., 2001).
• Symptoms typically emerge within one to six hours of the last dose and include profound tremor, tachycardia, insomnia, extreme anxiety, nausea, and delirium (McDonough et al., 2004; Tarabar & Nelson, 2004).
• Inpatient management is frequently required, utilizing massive doses of benzodiazepines or, in refractory cases, pentobarbital to prevent hyperthermia, rhabdomyolysis, and death (McDonough et al., 2004; Sivilotti, Burns, Aaron, & Greenberg, 2001).

The highly addictive nature of GHB is mechanistically tied to the mesocorticolimbic dopaminergic pathways, which are the brain's primary reward and addiction centers (Gardner & Lowinson, 1993). In the presence of high concentrations of GHB, the compound acts on GABA_B autoreceptors to preferentially inhibit GABAergic neurons (Cruz et al., 2004). This action decreases the release of GABA, which subsequently disinhibits dopaminergic neurons in the ventral tegmental area (Cruz et al., 2004; Snead, 2000). The resulting increased activity of dopamine within the mesocorticolimbic circuitry drives the addictive reinforcement of the drug (Cruz et al., 2004).

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