Gamma-Hydroxybutyrate Toxicity 

Gamma-hydroxybutyric acid (GHB) is a naturally occurring, 4-carbon compound with a structure similar to gamma-aminobutyric acid (GABA). GHB is described as a neurotransmitter and a regulator of energy metabolism.

First synthesized in 1960, GHB initially was investigated as an anesthetic because of its capacity to rapidly induce a deep coma with only minor cardiovascular and respiratory depressant effects. Its lack of analgesic properties and tendency to cause seizurelike activity soon dampened enthusiasm for its medicinal use.

Purported to act as a fat burner and growth hormone promoter, a resurgence of GHB occurred in the late 1980s as a food supplement for body builders and dieters. When L-tryptophan, a supplement with similar purported effects, was withdrawn from the market, GHB use increased further. Also used as a hallucinogenic, euphoric, and sleep aid, it was easily obtained at health food stores, gyms, and mail order outlets. This popularity coincided with a rising tide of GHB-related morbidity and mortality that caught the attention of regional poison control centers.

The Food and Drug Administration (FDA) prohibited the sale and manufacture of GHB in 1990. Since then, GHB is associated with a more clandestine popularity as an illicit drug, particularly in the southeastern and western United States. It currently is prevalent in the dance music scene (at raves and nightclubs) as an alternative to "ecstasy" and amphetamines. GHB often is used in conjunction with alcohol. It has been implicated, with flunitrazepam (Rohypnol), as a date rape drug.

GHB generally comes in pure powder form or mixed with water. Its highly concentrated liquid street form is available in small plastic containers similar to hotel shampoo bottles. The bottles generally cost about $10 and contain about 10 "hits." GHB is known by many street names, including grievous bodily harm, scoop, liquid ecstasy, cherry meth, growth hormone booster, liquid x, and Georgia homeboy.

GHB is manufactured readily from its precursor, gamma-butyrolactone (GBL). GBL is a solvent found in floor cleaning products, nail polish, and superglue removers. Saponification of the lactone with sodium hydroxide in the form of lye results in nearly quantitative conversion. This method has drawbacks, however, because several cases have reported caustic alkali ingestion from undissolved lye. GBL also undergoes conversion into GHB in vivo and, accordingly, is associated with the same symptoms. GBL is more bioavailable and more potent than GHB on an equimolar basis.

Although the manufacture and sale of GBL is now illegal, it was, until recently, still available for purchase through the Internet and at health food stores under several brand names, including Firewater, Renewtrient, Revivarant or Revivarant G, Blue Nitro or Blue Nitro Vitality, GH Revitalizer, Gamma G, and Remforce. Several states have discovered this practice and have banned these products. The FDA issued a warning and notice requesting manufacturers to recall GBL-containing products on January 21, 1999. On January 28, 1999, the FDA issued a warning to consumers not to purchase or use GBL products.

In an effort to bypass FDA regulation, several manufacturers have begun marketing 1,4-butanediol (BD), a chemical that is metabolized to GHB in the body by the enzymes alcohol dehydrogenase and aldehyde dehydrogenase. The FDA has declared BD a Class I Health Hazard (ie, a potentially life-threatening drug).

GHB's unique attributes have some legitimate uses. In Europe, it is still used as an anesthetic, for alcohol and opiate addiction therapy, and for narcolepsy therapy. Only this last indication of narcolepsy is recognized by the US Food and Drug Administration, which recently approved GHB (ie, sodium oxybate [Xyrem]) to treat a small subset of patients with narcolepsy who have episodes of weak or paralyzed muscles (ie, cataplexy). Because of sodium oxybate's history of abuse as a recreational drug, the FDA approved it as a Schedule III Controlled Substance. A limited distribution program that includes physician education, patient education, a patient and physician registry, and detailed patient surveillance has been established. Under the program, prescribers and patients will be able to obtain the product only through a single centralized pharmacy.

GHB is found naturally in the CNS, with the highest concentrations in the basal ganglia. GHB binding sites are present in the cortex, midbrain, substantia nigra, basal ganglia, and, most predominantly, in the hippocampus. GHB also is found in the peripheral blood and readily crosses the blood-brain and placental barriers.

GHB is rapidly absorbed after ingestion and takes 20-30 minutes to reach a maximal plasma concentration following the ingestion of a 12.5 mg/kg dose and 30-60 minutes with a dose of 50 mg/kg. Clinical effects become evident approximately 5-15 minutes post ingestion. The elimination half-life is 27 minutes and proceeds in a dose-dependent saturable manner. GHB is ultimately metabolized to CO₂ and eliminated through the lungs.

The pharmacokinetics of GHB in alcoholic persons are similar to those in persons without alcoholism; however, the frequency of serious adverse effects is less in the alcoholic individuals, suggesting a cross-tolerance between alcohol and GHB. Although gas chromatographic and mass spectrometric techniques readily detect GHB in urine and serum, traditional hospital toxicology assays typically do not include GHB.

Central nervous system

GHB has a myriad of neurological effects. It binds to GABA-B receptors in the brain, inhibits noradrenaline release in the hypothalamus, and mediates the release of an opiatelike substance in the striatum. It produces a biphasic dopamine response, increasing release at high doses and inhibiting release at lower doses. True to proponents' bodybuilding claims, GHB has produced an increase in growth hormone in rats and in one small human study. No study, however, has yet demonstrated any weight loss or increased muscle growth associated with GHB use.

Although GHB traditionally has been considered a potent epileptogenic drug and has been noted to cause epileptiform EEGs in animals, a few human volunteer studies have failed to demonstrate EEG changes associated with use. However, case reports commonly report seizures or seizurelike activity in persons ingesting the drug. It is theorized that myoclonic jerks of the face and extremities may be mistaken for evidence of seizures.

CNS depression is the hallmark of GHB use. An oral dose of 10 mg/kg produces short-term amnesia and hypotonia; 20-30 mg/kg produces drowsiness and sleep. After ingestion of approximately 50-70 mg/kg, profound hypnosis and deep coma rapidly ensue. GHB quickly initiates delta wave and rapid eye movement (REM) sleep and produces moderate amnesia but does not produce analgesia or muscle relaxation. It decreases cerebral glucose metabolism and increases cerebral blood flow, yet it reduces intracranial pressure. Myoclonic jerks and respiratory depression accompany the descent into anesthesia.

A Glasgow Coma Scale (GCS) of 3 is not uncommon. One peculiar characteristic of GHB toxicity is that patients often demonstrate extreme combativeness and agitation despite profound CNS and respiratory depression. The coma usually lasts from 3-6 hours and spontaneously resolves. Patients who are intubated for respiratory depression typically have a longer recovery time, but extubation within 8-10 hours is common; extubation in the ED has been described. The resolution is characteristically rapid and usually accompanied by myoclonic jerks and agitation.

Cardiovascular

GHB has been noted to cause bradycardia in approximately 30-35% of ingestions. Studies of GHB infusion in hypovolemic shock have demonstrated an increase in mean arterial pressure and cardiac output when compared with a normal saline infusion. GHB also has been noted to have some antidysrhythmic properties.

Other effects

One study described a syndrome of withdrawal following cessation of chronic heavy GHB use.^[1] Psychosis and severe agitation requiring chemical and physical restraints were uniformly seen. Anxiety, tremor, tachycardia, hypertension, diaphoresis, delirium, and auditory and visual hallucinations were reported. Symptoms began approximately 1-6 hours after last use and lasted 5-15 days. One fatality was noted, although a causal relationship with GHB has not been established. Clinical similarities between GHB withdrawal and other sedative-hypnotic withdrawal syndromes, such as that associated with ethanol, suggest a common mechanism. This has been proposed to be caused by a loss of GABA inhibition, which may allow an increase in excitatory neurotransmitters and produce the agitated, hyperadrenergic, withdrawal state.

Frequency

United States

GHB use was common in the 1990s, with the most prevalent use observed in Florida, Texas, California, and Georgia. One report shows that GHB-related ED visits dramatically increased from 20 in 1992 to 629 in 1996. Approximately 60% of these episodes involved multiple drugs; GHB was taken in combination with alcohol in 76%, cocaine in 6%, marijuana in 5%, and ecstasy in 4% of these cases. GHB was reportedly used for recreational purposes in 91% of cases. Recent monitoring of GHB use has noted a significant decline in the first years of the 21st century. The California Poison Control has reported a 76% decrease in GHB exposures between 1999 and 2003.^[2]

However, data on 173 individuals with recreational drug toxicity requiring "medical" assistance in a large urban nightclub was collected from September 2007 to January 2008.^[3] Clubbers required assistance following use of various recreational drugs, particularly GHB, GBL, and ketamine.

International

Although data are limited regarding international GHB use, substantial use has been reported internationally, particularly in England and Australia.

Mortality/Morbidity

The complications most frequently noted with GHB ingestion are coma and respiratory depression, which occasionally necessitate endotracheal intubation. Frequently stupor and coma alternate with extreme agitation. Myoclonus is common and can mimic seizure activity.

• Other noted complications include bradycardia, mild hypotension, bundle-branch block, and rarely cardiac arrest.
• Aspiration pneumonitis and caustic injury to the GI tract (usually secondary to NaOH exposure from faulty home synthesis) also have been noted.
• Mortality has been reported with GHB ingestion taken in combination with other illicit drugs or alcohol. Fatalities secondary to isolated GHB use is rare.

Sex

Recent data indicate that 79% of GHB users are male.

Age

Two thirds of patients presenting to an ED for GHB ingestion are aged 18-25 years, although use by a 77-year-old patient has been reported.