Gamma-Hydroxybutyrate Toxicity 

Updated: Oct 11, 2019
Author: Theodore I Benzer, MD, PhD; Chief Editor: Sage W Wiener, MD 

Overview

Practice Essentials

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

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; there are several case reports of caustic alkali ingestion from GHB containing 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.

GHB effects appeal to a variety of users; euphoric effects make it a popular party drug, while a reputation to increase growth hormone levels and muscle mass makes it popular with body builders. Its rapid onset of action and formulation as a clear liquid make it popular in drug-facilitated rape. 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's unique attributes have some legitimate uses. In Europe, it is still used as an anesthetic, for alcohol and opiate addiction therapy,[1]  and for narcolepsy therapy.[2]  Only narcolepsy is recognized as an indication by the US Food and Drug Administration (FDA), which in 2002 approved GHB (ie, sodium oxybate [Xyrem]) for treatment of the small subset of patients with narcolepsy who have episodes of weak or paralyzed muscles (ie, cataplexy).[3]  

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 are able to obtain the product only through a single centralized pharmacy.

Recent studies have shown a decrease in the incidence of GHB intoxications. Public health measures to inform young people of the risks of GHB and governmental restrictions on the sale of GHB and its precursors (GBL and 1,4-butanediol [1,4-BD]) have been helpful in promoting this decrease.

Background

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 FDA prohibited the sale and manufacture of GHB in 1990. Since then, GHB has been 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.

Although the manufacture and sale of GBL is now illegal, it was, for a time, 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 discovered this practice and 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 began 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).

 

 

Pathophysiology

GHB is found naturally in the central nervous system (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.[4]

Central nervous system

GHB has a myriad of neurological effects. It binds to GABAB 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 electroencephalograms (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.[5] 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.

Epidemiology

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. GHB use showed a significant decline in the first years of the 21st century. The California Poison Control reported a 76% decrease in GHB exposures between 1999 and 2003.[6]  In 2017, the American Association of Poison Control Centers' (AAPCC) National Poison Data System (NPDS) reported 323 single exposures and no deaths.[7]  

Although data are limited regarding international GHB use, substantial use has been reported worldwide, particularly in the United Kingdom and Australia.[8]  In 2015, Norway reported the prevalence of GHB use at 0.1 % for adults (16–64); prevalence of ketamine, poppers and GHB use combined among young adults (15–34) was estimated at 0.6% in the Czech Republic and the United Kingdom.[9]

The 2017 AAPCC-NPDS reported that 84% of reported GHB exposures were adults aged 20 years or older. GHB exposure among adolescents aged 13-19 years accounted for 6% of reported cases.[7]

Prognosis

Patients with an isolated instance of GHB ingestion generally have a good prognosis. Mortality has been reported with GHB ingestion in combination with other illicit drugs or alcohol. Fatalities secondary to isolated GHB use is rare. The 2017 AAPCC-NPDS reported moderate to major effects from exposure in 58% of cases but no deaths.[7]

The complications most frequently noted with GHB ingestion are coma and respiratory depression,[10]  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. 

GHB is considered to have a high dependence potential, and abrupt discontinuation after long-term use can result in a severe withdrawal syndrome.[11, 12]  The withdrawal may be prolonged, lasting 5-15 days and associated with visual and auditory hallucinations.[12]

Patient Education

Many patients with GHB toxicity mistakenly believe (or claim to have been led to believe) that GHB is a legal substance. Educate these patients about the illegality of GHB manufacture and distribution as well as the potential complications caused by GHB use.

Many patients intubated for severe respiratory depression and hypoxemia spontaneously awaken with no recollection of their brush with mortality. Many refuse to believe that their prior condition was potentially lethal, despite any evidence to the contrary; this may make patient education quite difficult and contribute to recidivism.

The use of GHB as a date rape drug necessitates a more thorough workup and dispositional plan than most other ingestions. Date rape victims should receive proper and prompt forensic and medical examination, sexually transmitted disease (STD) prophylaxis, pregnancy counseling, psychological or other support counseling, and follow-up.

Those patients who have used GHB in an attempt to increase growth hormone levels and enhance a bodybuilding program need to be made aware that no evidence for its effectiveness exists. They need to learn the very real dangers of GHB use.

For patient education resources, see Date-Rape Drugs (GHB, rohypnol).

 

Presentation

History

Patients with gamma-hydroxybutyric acid (GHB) toxicity typically present with altered mental status, making it difficult or impossible to obtain reliable history. Prehospital personnel frequently have valuable information from the scene implicating GHB as the cause of the patient's complaint. History may also be obtained from bystanders or friends since patients frequently ingest GHB in the presence of others at the gym, nightclubs, or parties. The history may include agitation and confusion as well as myoclonus and seizurelike activity.[13]

Many patients present after taking multiple drugs, and efforts should be made to identify everything the patient has ingested. In contrast, patients given GHB surreptitiously as part of a drug-facilitated rape may have no history at all of drug ingestion. 

A history that the GHB was manufactured in a home lab is important since homemade GHB can be contaminated with sodium hydroxide (lye). 

Physical

After GHB ingestion, the patient may have a period of euphoria that is rapidly followed by a period of profoundly depressed level of consciousness. This may progress to coma with a Glasgow Coma Scale of 3. GHB intoxication characteristically produces episodes of agitated delirium that can precede or follow the period of stupor or coma. Seizurelike movements and myoclonus are common during the course of the intoxication. These findings may reverse rapidly, leaving the patient awake, alert, and oriented within minutes after several hours of altered mentation.

Bradycardia occurs in approximately 30-35% of GHB ingestions. Hypotension occurs in approximately 10% of ingestions and is usually mild. More profound cardiovascular changes can be seen with multidrug ingestions.

Respiratory depression leading to frank apnea can occur and is exacerbated by multidrug ingestion. Decreased breath sounds or rales may indicate aspiration of gastric contents. Pulmonary edema is not a finding that is usually associated with GHB.

Nausea and vomiting are common in GHB ingestions, especially during reemergence. Alkali burns to the lips, mouth, and GI tract can be seen when the GHB is contaminated by sodium hydroxide during the manufacturing process. Mild hypothermia is a common finding in these cases.

Signs and symptoms of GHB withdrawal syndrome appear 4  hours after the last dose of GHB. In the initial period of abstinence, these include the following:

  • Tremors
  • Miosis
  • Sweating
  • Tachycardia
  • Palpitations
  • Dyspnea
  • Nausea
  • Vomiting
  • Diarrhea
  • Abdominal painAnxiety-related behaviors

In more severe cases of withdrawal, patients experience hypertension and symptoms such as the following[14] :

  • Insomnia
  • Agitation
  • Paranoia
  • Disorientation
  • Confusion
  • Aggression
  • Auditory and visual hallucinations
 

DDx

 

Workup

Laboratory Studies

Laboratory tests for gamma-hydroxybutyric acid (GHB) in serum or urine are not readily available. The diagnosis is made by history and physical examination. Reference laboratories can perform assays on blood and urine for GHB. These tests take time and are not useful clinically but can be very useful in legal cases (eg, drug-facilitated rape).

If the history is in question, a broad laboratory evaluation should be obtained to elucidate the cause of altered mental status. Such testing may include the following:

  • Complete blood cell count
  • Serum electrolyte levels
  • Liver function tests
  • Toxicologic screens
  • Ammonia level
  • Arterial blood gas levels
  • Osmolality
  • Cultures
  • Spinal fluid analysis
  • Pregnancy test 

Imaging Studies

Imaging will not help in making the diagnosis of GHB ingestion; however, brain imaging (CT or MRI) can be useful to rule out trauma or stroke. Chest radiography is important to exclude aspiration pneumonitis.

Other Tests

An electrocardiogram (ECG) and cardiac monitoring are important. GHB ingestions can be associated with bradycardia. U waves are frequently seen on the ECG even in the absence of hypokalemia. Other co-ingestions may have severe cardiovascular consequences.

Procedures

Lumbar puncture and spinal fluid analysis may be indicated if CNS infection is a concern.

 

Treatment

Approach Considerations

Most cases of gamma-hydroxybutyric acid (GHB) ingestion require only supportive management. In patients with persistent coma or known massive ingestion, a reversal agent may be considered. Several drugs have been studied as potential GHB antagonists, including neostigmine, physostigmine, flumazenil, naloxone, and various antiepileptics. One study from the New York City Poison Control reviewed the literature and concluded that there is insufficient evidence for the routine use of physostigmine for GHB intoxication.[15]

Patients who have ingested the GHB precursor, 1,4 butanediol (BD), may have a prolonged clinical course. BD is converted to GHB by the enzymes alcohol dehydrogenase and aldehyde dehydrogenase. If the patient presents with ethanol and BD ingestion, an initial period of depressed mental status can occur followed by clearing, as the ethanol is metabolized. Then, the BD is metabolized to GHB, and a second period of lethargy or coma ensues. These patients require a prolonged period of observation.

Prehospital Care

Prehospital personnel can provide invaluable informaitonby obtaining a history of ingestion from the patient, friends, and/or bystanders and securing evidence of potential GHB ingestion (eg, small shampoo bottles).

Prehospital care is supportive. Airway, breathing, and circulatory support are the primary goals. Oxygen should be given. The airway should be maintained with positioning, nasal or oral airway, or endotracheal intubation if airway reflexes are compromised. Observe cervical spine precautions if appropriate.

Intravenous access and fluids are useful for hypotension. Cardiac monitoring should be performed for all patients with altered mental status.

As for all patients presenting with altered mental status, rapid glucose determination or administration of 50 mL of D50W, thiamine 100 mg IV, and naloxone IV should be considered. Naloxone has little use in GHB ingestions, but opioid co-ingestions are common. Clinicians should be aware that an administration of naloxone can precipitate opioid withdrawal in chronic opioid users, resulting in vomiting. In patients who are unconscious due to GHB exposure and are unable to protect their airway, this can result in aspiration of gastric contents and an increase in morbidity/mortality.

Emergency Department Care

Emergency department (ED) management in GHB overdose is primarily supportive. No specific antidotes exist for GHB. The course of GHB ingestion may be short lived, with rapid recovery. Therefore, many of these patients can be discharged from the ED without admission to the hospital.

Airway patency and aspiration precautions are of paramount importance. Usually, respiratory drive and protective airway reflexes are preserved, but if either are compromised, the patient should be intubated. Co-ingestions increase the risk of respiratory compromise. Prior to intubation, sedation may not be necessary if the patient is in a coma. Neuromuscular blockade should be used to avert the combativeness and agitation that can be seen in GHB ingestions.

Consider activated charcoal if co-ingestion is suspected.[16] Gastric lavage would be indicated only if a lethal dose of another drug (eg, acetaminophen, tricyclic antidepressant) had occurred within 1 hour of presentation. Endotracheal intubation should precede gastric lavage to prevent aspiration. Clinicians should be aware that endotracheal intubation does not completely prevent aspiration of the charcoal.

Cardiac monitoring is indicated. Bradycardia is common, and other dysrhythmias have been seen.

A thorough examination of the oropharynx should be performed. Mucosal burns can occur when the GHB ingested is contaminated with sodium hydroxide from the manufacturing process.

Patients with  GHB poisoning who are in stable condition with symptoms that have completely resolved may be released from the ED in the care of a responsible person after 6 hours of observation. If the patient has severe respiratory compromise or a complicated ingestion or if the diagnosis is in question, the patient should be admitted to the hospital for further evaluation and treatment. Admit patients with severe symptoms or evidence of hemodynamic compromise to an intensive care unit.

 

Consultations

The regional poison control center can provide valuable information, especially in complex ingestions. Otolaryngology or gastrointestinal consultation may be needed if evidence of alkali burns to the oropharynx or GI tract is present.

Patients who have ingested GHB as a suicide attempt should be evaluated by a psychiatrist after the intoxication has resolved to determine whether they need inpatient psychiatric care. If there is suspicion that patient was sexually assaulted, appropriate services (social work, police, obstetrician/gynecologist) should be involved in the patient's evaluation and treatment.

 

Medication

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

GI decontaminant

Class Summary

Prevents further absorption of adsorbable toxins from the GI tract if administered soon after ingestion (typically < 1 h).

Activated charcoal (Liqui-Char)

Emergency treatment in poisoning caused by drugs and chemicals. Network of pores present in activated charcoal adsorbs 100-1000 mg of drug per gram of charcoal. Does not dissolve in water.

For maximum effect, administer within 30 min of ingesting poison. Administer cathartic (sorbitol) with first dose.

Cardiovascular agents

Class Summary

Bradycardia may be encountered in GHB overdose. Atropine, as an anticholinergic agent, may be useful for treatment of bradycardia.

Atropine IV/IM (Atropair)

Enhances sinus node automaticity by blocking effects of acetylcholine at the AV node, decreasing refractory time and speeding conduction through the AV node.