Gamma-hydroxybutyrate (GHB) was originally investigated as an anesthetic agent during the 1960s. It was abandoned because of side effects including myoclonus and emergence delirium. In 2002, it was approved by the FDA (as the pharmaceutical sodium oxybate) for treatment for cataplexy and in 2005 for excessive daytime sleepiness in patients with narcolepsy. GHB is readily available through the illicit drug market and can be made in home laboratories using recipes posted on the internet. GHB without a prescription is regulated as a Schedule I substance. In addition, chemical precursors converted to GHB in the body, including gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD) are regulated as Schedule I (when intended for human consumption) under the Federal Analogue Act. To avoid legal consequences, these chemicals are often sold under a variety of constantly changing product names with varying purported indications (eg, cleaner, paint stripper, solvent). Novel GHB analogs include GHV (4-methyl-GHB) and GVL (gamma-valerolactone), a GHV precursor.

GHB has been promoted as a growth hormone releaser, muscle builder, diet aid, soporific, euphoriant, hallucinogen, antidepressant, alcohol substitute, and enhancer of sexual potency. Its use in clubs and electronic dance music events commonly involves co-ingestion with ethanol, methamphetamine, and other drugs. It has also become known as a “date rape” drug because it can produce a rapid incapacitation or loss of consciousness, facilitating sexual assault.

1. GHB is a structural analog of the neurotransmitter gamma-aminobutyric acid (GABA), and acts on GABA_B receptors as well as on specific endogenous GHB receptors. It readily crosses the blood-brain barrier, leading to general anesthesia and respiratory depression. Death results from injury secondary to abrupt loss of consciousness, apnea, pulmonary edema, or pulmonary aspiration of gastric contents. Fatal potentiation of the depressant effects of GHB has occurred with ethanol and other depressant drugs.
2. Gamma-butyrolactone (GBL) is a solvent that can be chemically converted by sodium hydroxide to GHB. In addition, GBL is rapidly converted in the body by peripheral lactonases to GHB within minutes.
3. 1,4-Butanediol (1,4-BD), an intermediate for chemical synthesis, is readily available through chemical suppliers. 1,4-BD is converted in vivo by alcohol dehydrogenase to gamma-hydroxybutyraldehyde, then by aldehyde dehydrogenase to GHB.
4. Pharmacokinetics. Onset of CNS-depressant effects begins within 10-15 minutes after oral ingestion of GHB and 2-8 minutes after IV injection. Peak levels occur within 25-45 minutes. A recent meal may reduce systemic bioavailability by 37% compared with the fasting state. The duration of effect is 1-2.5 hours after anesthetic doses of 50-60 mg/kg and about 2.5 hours in nonintubated accidental overdoses seen in the emergency department (range, 15 minutes-5 hours). The rate of elimination of GHB is saturable. Plasma blood levels of GHB are undetectable within 4-6 hours after therapeutic doses. The volume of distribution is 0.4 L/kg. GHB is not protein bound.

1. GHB. Response to low oral doses of GHB is unpredictable, with variability between patients and in the same patient. Narcolepsy studies with 30 mg/kg have reported effects including abrupt onset of sleep, enuresis, hallucinations, and myoclonic movements. Anesthetic studies reported unconsciousness with 50 mg/kg and deep coma with 60 mg/kg. Fasting, ethanol, and other depressants enhance the effects of GHB.
2. GBL, a nonionized molecule, has greater bioavailability than GHB when given orally in the same doses. A dose of 1.5 g produced sleep lasting 1 hour.
3. 1,4-BD is equipotent to GHB, although in the presence of ethanol, competition for the metabolic enzyme alcohol dehydrogenase may delay or decrease the peak effect.

Patients with acute GHB overdose commonly present with coma, bradycardia, and myoclonic movements.

1. Soporific effects and euphoria usually occur within 15 minutes of an oral dose; unconsciousness and deep coma may follow within 30-40 minutes. When GHB is ingested alone, the duration of coma is usually short, with recovery within 2-4 hours and complete resolution of symptoms within 8 hours.
2. Delirium and agitation are common. Seizures occur rarely. Bradypnea with increased tidal volume is seen frequently. Cheyne-Stokes respiration and loss of airway-protective reflexes occur. Vomiting is seen in 30-50% of cases, and incontinence may occur. Stimulation may cause tachycardia and mild hypertension, but bradycardia is more common.
3. Alkaline corrosive burns result from misuse of the home manufacture kits; a dangerously basic solution is produced when excess base is added, the reaction is incomplete, or there is inadequate back titration with acid. (The solution can also be acidic from excessive back titration.)
4. Frequent use of GHB in high doses may produce tolerance and dependence. A withdrawal syndrome has been reported when chronic use is discontinued. Symptoms include tremor, paranoia, agitation, confusion, delirium, visual and auditory hallucinations, tachycardia, and hypertension. Rhabdomyolysis, myoclonus, seizure, and death have occurred.
5. See also the discussion of drug-facilitated assault.

Is usually suspected clinically in a patient who presents with abrupt onset of coma and recovers rapidly within a few hours.

1. Specific levels. Laboratory tests for GHB levels are not readily available but can be obtained from a few national reference laboratories. Serum levels greater than 50 mg/L are associated with loss of consciousness, and levels over 260 mg/L usually produce unresponsive coma. In a small series of accidental overdoses, awakening occurred as levels fell into the range of 75-150 mg/L. GBL and 1,4-BD are rapidly converted in vivo to GHB. The duration of detection of GHB in blood and urine is short (6 and 12 hours, respectively, after therapeutic doses). Even if the clinical lab has access to rapid GHB testing, tests are frequently negative if specimens are not collected until several hours after GHB use is suspected.
2. Other useful laboratory studies include glucose, electrolytes, and arterial blood gases or co-oximetry. Consider urine toxicology screening and blood ethanol to rule out other common drugs of abuse that may enhance or prolong the course of poisoning.

1. Emergency and supportive measures
   1. Protect the airway and assist ventilation if needed. Note that patients who require intubation are often awake and are extubated or self-extubate within a few hours.
   2. Treat coma, seizures, bradycardia, and corrosive burns if they occur.
   3. Evaluate for and treat drug-facilitated assault.
2. Specific drugs and antidotes. There are no specific antidotes available. Flumazenil and naloxone are not clinically effective. GHB withdrawal syndrome is managed with benzodiazepine sedation as in other depressant withdrawal syndromes. Large doses may be needed. Withdrawal refractory to benzodiazepines is not uncommon and may benefit from the addition of barbiturates (pp 572-573), baclofen (a GABA_B agonist) or propofol (p 581).
3. Decontamination
   1. Prehospital. Do not give charcoal because of the risk for rapid loss of consciousness and loss of airway-protective reflexes, which may lead to pulmonary aspiration.
   2. Hospital. The small doses of GHB usually ingested are rapidly absorbed, and gastric lavage and activated charcoal are unlikely to be beneficial and may increase the risk for pulmonary aspiration. Consider activated charcoal administration only for recent, large ingestions or when significant coingestion is suspected.
4. Enhanced elimination. There is no role for enhanced removal procedures such as dialysis and hemoperfusion.