EVERYTHING YOU NEED TO KNOW ABOUT GHB
g-Hydroxybutyric acid (GHB) is a CNS depressant that has become increasingly popular as a drug of abuse over the last 10 years. Many names are used for it such as sodium oxybate, sodium oxybutyrate, g-hydroxybutyrate sodium, g-OH, 4-hydroxy butyrate, and g-hydrate, as well as others. Names used on the street include Liquid Ecstasy, Liquid X, Liquid E, Georgia Home Boy, Grievous Bodily Harm, G-Riffick, Soap, Scoop, Salty Water, Somatomax, and Organic Quaalude. In the 1960s, a French researcher synthesized it in an attempt to create a gaminobutyric acid (GABA) analog that would, unlike GABA, cross the blood-brain barrier.145 Somewhat simultaneously, in 1963, it was found to be a naturally occurring metabolite in the human brain.146 The first accepted medical application of GHB was for intravenous induction of anesthesia.145 However, its use was limited due to the high frequency of vomiting,147 seizure-like activity in animals,148, 149 and inability to produce analgesia.150 In the 1970s, GHB was recommended for narcolepsy because it increases slow-wave sleep and consolidates sleep at night, therefore decreasing sleep during the day.151 In the 1980s, GHB was commonly sold over-thecounter in health food stores where it was alleged to increase the effect of growth hormone.152 In the late 1980s and early 1990s, GHB was advocated for the treatment of alcohol dependence153 and opiate withdrawal.154 During the same time period, GHB was illicitly advertised as a hypnotic to replace tryptophan, which had been removed from the market due to its connection with eosinophilia-myalgia syndrome.155 Since 1990, an increasing number of cases of both abuse and toxic reaction has been noted, and in 1997 GHB was labeled a “date rape” drug by the press.156 In March 2000, GHB became a schedule I controlled substance in the U.S
Most of the GHB available in the U.S. is manufactured clandestinely. Many Internet sites and books that describe the process of making GHB are available.158 Commonly offered for sale on Internet sites, GHB kits provide the chemicals and recipes used to produce GHB.159, 160 Currently, GHB is only legally available in the U.S. for the investigational treatment of narcolepsy. The drug is synthesized by using a combination of sodium hydroxide and gbutyrolactone (GBL; another commonly abused drug). Because sodium hydroxide is very caustic, severe toxic reactions may result if GHB is manufactured improperly. The drug GHB is available as a powder or a colorless, odorless liquid with a salty or soapy taste. Its taste can easily be masked by adding it to flavored beverages. As it is colorless and odorless, and because small quantities are required to achieve a desired effect, it has been used as a date rape drug. The amnesia produced by it often makes victims unable to serve as valid witnesses.
The pharmacokinetics of it are nonlinear in humans over the therapeutic dosage range.161–164 The drug is rapidly absorbed orally,165 with an onset of action within 15 minutes.166 In the rat, oral bioavailability is 52–65%.167 In humans, the free fraction of it in plasma has been shown to be 0.99, indicating a lack of significant plasma protein binding.161 The half-life of it is 22–28 minutes after an oral dose of GHB 25 mg/kg;161, 162 the half-life is slightly longer with higher doses. In one study, GHB exhibited a longer halflife of 53 minutes in patients with narcolepsy after dosages of it 3.0 g twice/night, administered 4 hours apart.163 At lower doses of 25 mg/kg, the Tmax of GHB is approximately 30 minutes. After higher doses of 50 mg/kg, the Tmax occurs around 45 minutes.161, 162 As the dose of GHB increases by a factor of four from 12.5 to 50 mg/kg, the AUC increases by a factor approaching seven. In addition, the Cmax increases, but not to the degree expected in relation to the increase in AUC and the decrease in oral clearance. The oral clearance is halved from 14 to 7 ml/minute/kg when the dose is increased from 12.5 to 50 mg/kg, respectively
Two suggested mechanisms for this nonlinearity include the saturation of one of the metabolic pathways of it or the capacitylimited absorption of it.161 The capacitylimited absorption would explain the relatively small increase in Cmax with increasing dose, relative to the decrease in oral clearance. It is possible that several mechanisms operate concurrently, explaining the pharmacokinetic profile of GHB. In one investigation,162 four of the five subjects exhibiting linear kinetics had normal liver function test results, whereas all of the subjects who displayed nonlinear kinetics (capacity-limited elimination) had elevated values for some of their liver function tests. In the subjects displaying nonlinear kinetics, a doubling of the dose resulted in a disproportionate 3-fold increase in the AUC from approximately 3500 to approximately 10,800 µg/ml/minute. The appearance of nonlinearity was found only in the patients who had abnormal liver function values. The authors suggest a relationship between liver function and saturation of the elimination pathway for GHB. In addition, when the dose was increased from 25 mg/kg to 50 mg/kg, there were proportional changes in Cmax, accompanied by disproportionate increases in AUC.
Metabolism and Synthesis
The biosynthetic pathway and metabolic degradation of it occurs in brain tissue by means of multiple cytosolic and mitochondrial enzymes. g-Hydroxybutyrate is a natural product of GABA metabolism by way of the intermediate compound, succinic semialdehyde (SSA). The neurotransmitter GABA appears to be the major precursor for SSA, from which GHB is synthesized. In early investigations, it was shown that GABA underwent transamination to SSA,168 that the enzymatic reduction of SSA to GHB occurred in mammalian brain in vitro,169 and that [3 H]GABA was converted to GHB in the rat brain in vivo.170 The finding that GABA is a precursor of GHB was confirmed by other investigators.171 The NADPH-dependent enzyme SSA reductase is responsible for the conversion of SSA to GHB (Figure 4).171 g-Hydroxybutyrate is oxidized into SSA by means of it dehydrogenase and GHB-oxoacid transhydrogenase.172 The SSA is further metabolized to succinate, which then enters the Krebs cycle.
Less than 2% of it is eliminated unchanged in the urine.162, 164 Owing to the short half-life, there is no accumulation of GHB with repeated dosing and it doses of up to 100 mg/kg are no longer detectable in the blood from 2–8 hours or in the urine after 8–12 hours.162, 165 The variability of these findings may depend on the sensitivity of the assay used, or it may be due to interindividual variability. In summary, it has been suggested that regardless of the dose given, the elimination of it is so rapid, even in those with compromised liver function, that the drug is completely eliminated within 4–6 hours after ingestion
The exact mechanism of it action in the CNS has not been determined, but GHB is structurally related to GABA, which is a precursor in it formation.170 Much debate exists regarding whether GHB has neurotransmitter or neuromodulatory roles,174–177 because it has high-affinity brain receptors and undergoes synthesis, release, uptake, and degradation within the CNS.174, 175 The exact location of the biosynthetic pathway of GHB inside the cell (cytosol vs mitochondria) has not been fully established.178 The neurotransmitter GABA is transaminated by GABA aminotransferase to form SSA, which is either further metabolized into succinic acid or reduced to form GHB by the enzyme SSA reductase, a NADPH-dependent enzyme.171, 173 The highest concentrations of it in the brain are found in the substantia nigra179 and hypothalamus, whereas the highest turnover rate of it occurs in the hippocampus.180 The uptake of GHB appears to be the highest in the striatum,181, 182 and this uptake is dependent on a specific sodium-dependent active transport system for it.181 In addition to being found in the CNS, GHB is found in the kidney, heart, skeletal muscle, and brown fat.
g-Hydroxybutyrate appears to have affinity for two receptor sites in the CNS. It binds to GHB receptors, which may be linked to cyclic guanosine 3′5′-monophosphate and inositol phosphate intracellular pathways184, 185 and are most numerous in the hippocampus and cortex.186 It also binds to GABAB receptors,187, 188 but not to GABAA receptors.189 The relevance of this remains unknown but suggests that some of the pharmacologic actions of it are mediated by the GABAB receptor.
The drug GHB alters dopaminergic activity, in some cases increasing and in others decreasing the amount of dopamine released.178 The systemic administration of it to animals results in increased dopamine accumulation in the extrapyramidal system of the brain, which reaches its highest values 1–2 hours after injection, without parallel increases in serotonin or norepinephrine.190 The administration of amethyltyrosine, which blocks the activity of tyrosine hydroxylase, almost completely blocks the rise in brain dopamine induced by it, which occurred within 1 hour in control mice. Therefore, GHB mediates the accumulation of dopamine by increasing the activity of tyrosine hydroxylase.191 In addition, GHB may inhibit the release of newly synthesized dopamine192 and decrease the firing rate of dopaminergic neurons in the substantia nigra with maximal inhibition within 8 minutes.179 The end result seems to be a tissue accumulation of dopamine in the brain,175 which is supported by results of the short-term studies described above. Dopamine release in the striatum may be accompanied by the release of endogenous opioids.193 The exact interactions between GHB and the opioid system are not fully understood, but the administration of naloxone or nalorphine, opioid receptor antagonists, blocks some of the effects of it.
The primary dose-related effects of it are related to CNS depression. At 10 mg/kg, GHB is capable of producing amnesia195 and hypotonia of the skeletal muscles196, 197 resulting from the depression of neurons in the spinal cord.166 At 20–30 mg/kg, it promotes a normal sequence of rapid eye movement (REM) and non-REM (slow-wave) sleep, which lasts from 2–3 hours.151, 198 At 40–50 mg/kg intravenously, it produces a state of somnolence, which appears within 5–15 minutes, and an oral dose of approximately the same amount will produce similar results.166 Anesthesia is associated with doses of 50 mg/kg,164, 166, 199 and doses higher than 50 mg/kg have been associated with profound coma,199 as well as decreased cardiac output, respiratory depression, and seizures. These effects are more pronounced with the coingestion of CNS depressants, particularly ethanol.155 Larger doses of 60–70 mg/kg produce a state of unarousable coma that lasts about 1–2 hours.166 The investigators who initially discovered that it was a natural metabolite of the brain reported that GHB 100 mg/kg administered intravenously produced sleep that begins within 15 minutes of administration and lasts about 1.5–2 hours.
Oral ingestion of GHB 75–100 mg/kg in humans results in peak blood levels of approximately 90–100 µg/ml at 1–2 hours after ingestion.165 Intravenous administration of it 50 and 165 mg/kg results in peak blood levels that reach 180 and 412 µg/ml, respectively. The mean blood GHB level at the commonly used dose of 100 mg/kg is 304 µg/ml.164 When the blood it levels exceed 258 µg/ml, subjects fall into a state of deep sleep, characterized by nonresponse to various stimuli such as touch, pinprick, deep pressure, skin preparations, or vaginal examinations, although there is still reflex response to surgical incision. During this stage of deep sleep, blinking stops and the eyes remain central and fixed with small pupils. A moderate level of sleep is associated with blood it levels ranging from 155–258 µg/ml. This moderate stage of sleep is characterized by spontaneous blinking and responses to deep pressure. Blood GHB levels ranging from 52–155 µg/ml are associated with a light sleep characterized by spontaneous movements and occasional opening of the eyes. When the blood it levels decrease below 52 µg/ml, subjects wake up.
Abuse Potential and Intoxication
Factors that seem to contribute to the abuse potential of it include its intoxicating effects, its purported anabolic effects, its hypnotic effects, and its ability to incapacitate women for purposes of sexual assault.157, 200, 201 One of the main reasons it became a popular drug of abuse is its ability to produce a “high.”155, 202 Those who take it describe it as producing a state of relaxation and tranquility accompanied by feelings of calmness, mild euphoria, a tendency to verbalize, mild numbing, and pleasant disinhibition. Despite these positive feelings attributed to the use of GHB, the doseresponse curve for GHB has been described as being remarkably steep. Therefore, as the dose of GHB is increased, a steep increase in adverse effects may occur.143 The effects of it have been described as being similar to those of alcohol, and the two agents may act synergistically, further increasing the risk for intoxication or overdose
Moderate bradycardia appears after the administration of GHB204, 205 and is likely due to central vagal activity.166 In addition to bradycardia, it reduces stroke volume as well as cardiac output, which reaches a nadir around 30 minutes after ingestion. Atropine reverses the decreases in both heart rate and stroke volume.205 The autonomic centers are fully active during GHB-induced coma, and surgical stimuli result in a cardiovascular response, such as tachycardia, hypertension, and raised cardiac output.
Respiratory rate is often reduced, but this is usually accompanied by an increase in tidal volume.150, 204 The drug GHB also produces a slowing and deepening of respiration sometimes leading to a Cheyne-Stokes pattern.
In an early study that stimulated much interest in the use of GHB by the bodybuilding population, intravenous administration of GHB 2.5 g significantly increased plasma growth hormone levels, which peaked at 60 minutes.152 In a more recent study, after bedtime oral ingestion of GHB 2.5, 3.0, and 3.5 g, a significant increase occurred in the normal secretory pulse of growth hormone during the first 2 hours after sleep onset. The authors suggest that agents such as GHB may increase the release of growth hormone by increasing slowwave sleep, because there is a large pulse in growth hormone secretion during the first stage of slow-wave sleep more than 90% of the time.
Sedation and Anesthesia
The principal actions of GHB have not been fully elucidated. However, the results of early investigations suggest that GHB appears to act on the cerebral cortex with little or no depression of the reticular activating system.150 Some authors speculate that there is depression of the limbic hippocampal structures166 and subcortical centers.199 The anesthetic effects of GHB are primarily hypnotic204 as GHB provides little or no analgesia.150, 204 The transition from wakefulness is described as being a sudden shift from responsivity to unconsciousness.
The drug GHB stimulates slow-wave sleep.199, 207–210 It does not appear to suppress REM sleep207, 209 and may even decrease fragmentation of REM sleep.208 It appears to increase “slow” sleep as evidenced by a slow synchronized electroencephalographic recording.199 In addition, GHB increases slow-wave sleep (stages 3 and 4), whereas light sleep (stage 1) is decreased, and the frequency of awakenings is reduced.210 In healthy subjects, under doubleblind conditions, single oral doses of GHB 2.25 g significantly increased the time spent in slowwave sleep, while sacrificing stage 1 sleep and significantly decreasing slow-wave sleep latency. The efficiency of REM sleep is increased, but the REM latency and time spent in REM sleep do not change.
Most of the therapeutic applications of GHB result from its sedative and hypnotic effects on the CNS. There are no currently accepted medical applications for GHB in the U.S., although it is being evaluated for the symptoms of narcolepsy.157 However, GHB has been extensively administered and studied for a variety of indications in other countries
Sedation and Anesthesia
The first clinical application of GHB was as a hypnotic anesthetic agent.145 It is still given for sedation and anesthesia in Germany, where it is considered safe and effective as long as the doses given are limited to the clinical needs.212 In doses of 10–20 mg/kg, GHB demonstrates hemodynamic stability and lack of severe respiratory depression, while control and recovery are acceptable for clinical purposes.213 However, bradycardia, hypotension, arrhythmias, and severe respiratory depression have been reported during GHB intoxication (see Adverse Effects section).
Cellular and Cerebral Protection
g-Hydroxybutyrate may be an endogenous inhibitor of energy metabolism, protecting tissues when energy supplies are low. Evidence suggests that GHB reduces cellular activity, while depressing the utilization of glucose as well as other energy substrates. This may result in tissues being less sensitive to the damaging effects of anoxia or during periods of excessive metabolic demand. Therefore, the natural function of GHB may include a role as a tissue protective substance.214 g-Hydroxybutyrate reduces tissue oxygenation demands and protects cells during hypoxic states, which has been demonstrated in both human and animal studies as well as in various organ systems. It exerts a protective effect and reduces cellular damage during sepsis, hemorrhagic shock, great vessel or coronary artery occlusion, stroke, organ transplantation, and myocardial infarction. In addition, in humans with brain tumors, GHB decreases intracranial pressure and increases cerebral blood flow. A thorough review of these topics involving the cellular protective effects and cerebral protective effects of GHB, as well as various applications for GHB in anesthesia, has been published.
Narcolepsy and Insomnia
Owing to the ability of GHB to increase slowwave sleep and facilitate REM sleep efficiency, GHB may improve nighttime sleep and therefore improve alertness during the day, which could alleviate some of the symptoms of narcolepsy
In addition, administration of GHB to patients with narcolepsy revealed significant improvements in sleep attacks, daytime drowsiness, cataplexy, hypnogogic hallucinations, and sleep paralysis.209, 217 Because GHB is a CNS depressant, it has been investigated for treating the symptoms of insomnia,165, 207 and in one investigation it was rated by the subjects as being an “excellent hypnotic.”165 However, when being used as a hypnotic, an oral dose of GHB 100 mg/kg resulted in frequent awakenings at either 1.5 or 4–5 hours after ingestion, which accounted for 14 of the 25 adverse effects reported in this dose group.165 Furthermore, GHB reportedly produced sleep paralysis, sleep walking, and cataplexy.
Alcohol and Opiate Withdrawal
The drug GHB 50 mg/kg/day has been given orally to treat the symptoms of acute alcohol withdrawal and to facilitate both short- and longterm abstinence from alcohol. It also was given to treat opiate withdrawal, often in higher dosages of 50–300 mg/kg/day. These applications of GHB were discussed extensively in a recent review of this topic during a symposium hosted by the Italian Society on Biological Psychiatry.218 Despite a possible benefit of taking GHB for these conditions, craving for GHB developed during these trials, with some subjects increasing their dosage up to 6-7 times the recommended levels
GHB is commonly taken for its proposed anabolic effects (related to the ability of GHB to stimulate the release of growth hormone), especially by the bodybuilding community,152, 206, 220 no definitive evidence exists that it increases muscle mass or fat catabolism. In addition, in patients with chronic alcoholism, long-term administration of GHB did not affect muscular mass.
Adverse Effects and Acute Toxic Reactions
The Centers for Disease Control and Prevention (CDC) released two reports describing the toxic effects of GHB.155, 222 These reports document over 120 poisonings and one fatality in individuals from various regions of the U.S. who became ill secondary to taking GHB. The usual course of illness was very similar from case to case. Approximately 15–60 minutes after ingestion, one or more of the following symptoms occurred: vomiting, drowsiness, soporific state, hypotonia, or vertigo. Depending on the dosage taken and concurrent use of other CNS depressants, such as alcohol, any of the following occurred as well: loss of consciousness, respiratory depression, tremors, myoclonus, seizure-like activity, bradycardia, hypotension, or respiratory arrest. In many of these cases, the symptoms spontaneously resolved within 2–96 hours.155, 222 As a result of the increased rate of GHB abuse since the first CDC report in 1990, the number of acute intoxications due to GHB has increased.158, 160, 200, 202, 222–235 Some of the more common and better documented conditions that appear in various reports include coma, respiratory depression, seizure-like activity (uncontrollable or unusual movements), bradycardia, drowsiness or dizziness, confusion, amnesia, headache, nausea, vomiting, mild hypothermia, acidosis, and psychiatric complications (e.g., agitation, delirium). Since 1992, the DEA has documented over 9600 adverse reactions, overdoses, and other cases reported by various law enforcement agencies, poison control centers, and hospitals in 46 states.157 The Food and Drug Administration has issued warnings to inform consumers about the dangers of ingesting two potentially dangerous GHB precursors, g-butyrolactone (GBL) and 1,4 butanediol (BD), which are converted to GHB in the body.236, 237 The doses of GHB that elicit adverse effects vary greatly from report to report and range from 0.25 teaspoon (1.25 ml) to 4 tablespoons (60 ml)200 up to 16 ounces (480 ml).223 However, GHB often is produced in clandestine laboratories, resulting in preparations with a wide range of purity and strength. Therefore, the quantities reported to be ingested in cases of acute intoxications may not be that informative. A 99% pure sample of GHB weighs 2.8 g/level teaspoon (5 ml).200 However, 40 ml of clandestinely produced GHB may weigh from 3–20 g.224 One aspect of GHB that makes it dangerous is that the response to oral ingestion seems to vary within the same patient as well as between patients.
The adverse effects
described in the following sections were found in experimental investigations and in reports of intoxications. The drug GHB affects the CNS, cardiovascular system, and respiratory system but does not have a toxic effect on the kidneys or the liver.
Drowsiness and dizziness induced by GHB are reported frequently in both investigational and toxicity reports. Subjects receiving oral doses of GHB 25–50 mg/kg in a controlled study complained of dizziness and drowsiness.161 Other common CNS adverse effects include vertigo and headache.165 More serious CNS depression during intoxication with GHB commonly occurs. Numerous reports of intoxication with GHB describe patients who present with Glasgow Coma Scale (GCS) scores as low as 3–5.224–231 Recovery appears to be inversely related to GCS score, with a lower GCS score resulting in a longer time to recover.228 Coma induced by GHB usually appears rapidly after ingestion, followed by a rapid and apparent full recovery. Often in the cases of intoxication, the unconsciousness will resolve within 6–7 hours.200, 223, 225–230, 232 One of the distinctively characteristic aspects of GHB intoxication is the rapid recovery, which is often uneventful and may create a false sense of security in the user
Bradycardia has occurred when GHB was given for anesthesia150, 166, 204 as well as in overdose situations.200, 222, 224, 228, 231 In a retrospective review of GHB intoxication, 36% of patients had pulse rates defined as bradycardia (heart rate < 55 beats/minute) and one patient required a single dose of atropine for a heart rate of 24 beats/minute.228 In the same case series, 10 patients had hypotension (systolic blood pressure ≤ 90 mm Hg) at presentation. Six of the patients with hypotension also had concurrent bradycardia, and in all six cases alcohol and/or another drug of abuse were present. In another case series of seven patients, the authors reported that five patients developed U waves on their electrocardiograms after GHB exposure, although none of them was significantly hypokalemic. Three of these five patients had significant abnormalities that included first-degree heart block, right bundle branch block, and ventricular ectopy
Respiratory depression, difficulty breathing, and apnea have been reported after the administration of GHB. The respiratory depression may be very severe, and in some cases the respiratory rate may drop to as low as four breaths/minute.224, 231 Abnormal patterns of breathing such as CheyneStokes breathing may result
Under the influence of GHB, some individuals may become hostile, belligerent, and agitated.223, 225 Patients display loss of consciousness and are extremely combative when stimulated, despite profound respiratory depression. Furthermore, they may require physical restraints to protect themselves and hospital personnel.233 Psychiatric complications such as delirium, paranoia, depression, and hallucinations have been reported in a small number of patients.
During intoxication with GHB, the pupils have been described as being miotic and sluggishly reactive to light,225 and during coma induced by GHB the eyes have been found to be miotic and unresponsive to light.
Acidosis Mild acute
respiratory acidosis is a common finding when GHB has been used as an anesthetic, as well as when it has been abused.228, 233 In one review, 93% of patients had a pH less than 7.40, and 30% had a pH less than 7.30. In addition, 70% of patients had a partial pressure of carbon dioxide of 45 mm Hg or greater
A high frequency of vomiting is associated with the use of GHB,147, 238 especially during induction and on emergence from intravenously induced anesthesia.166, 238 In an early investigation, 52% of patients receiving GHB for anesthesia experienced nausea or vomiting.204 According to one case series, vomiting was also very common and occurred in 30% of 88 cases of GHB intoxication. It typically occurred as the patients were regaining consciousness.228 In another review of 78 cases of GHB overdose, vomiting was reported in 22% of the cases.
Although hypothermia has not been a universal finding during GHB intoxication,233 mild hypothermia has been observed in patients after a GHB overdose.223, 225, 227, 228 In one study of 70 patients, 31% had an initial body temperature of less than 35°C, and the mean body temperature was 35.8 ± 1.1°C.228 In an additional small series of five patients, hypothermia was reported in three patients, with the lowest temperature being 32.8°C.2
There have been many reports of unusual, random clonic movements and uncontrollable shaking associated with GHB use. In anesthesia studies, abnormal movements occurred during induction with GHB but were not accompanied by any seizure-like electroencephalographic tracings and could be reduced by administering a phenothiazine drug.150 Administration of GHB will not necessarily result in abnormal epileptiform electroencephalographic changes212 or seizurelike activity
Cold and heavy extremities have been reported after oral ingestion of GHB 50 mg/kg.165 Diaphoresis was reported in 35% of the 78 cases of GHB overdose in one investigation.229 Home brewing of GHB, often from kits sold on Internet sites or from mail order sources, can lead to various adverse effects due to improper manufacturing of GHB. The manufacture of GHB involves the mixture of g-butyrolactone and the alkaline substance, sodium hydroxide. The inappropriate manufacture of GHB may lead to a very alkaline mixture, resulting in esophageal damage.239 In New York, a 20-year-old man aspirated during vomiting, resulting in damage to his lung tissue that was attributed to the mixture of gastric contents containing sodium hydroxide.222 Hematuria has also occurred after the ingestion of improperly manufactured GHB. Home-brewed GHB was being made with swimming pool chlorine tablets instead of the required sodium hydroxide.
Withdrawal and Tolerance
Data gathered by the DEA indicate that those who take GHB have exhibited chronic selfadministration, compulsive abuse regardless of adverse consequences, as well as drug-seeking behaviors. These data suggest individuals may become psychologically dependent on GHB.157 Physical dependence may develop, with a withdrawal syndrome occurring on abrupt discontinuation.157, 201, 240–242 Tolerance to the effects of GHB results in an increase in dosage and a withdrawal syndrome on cessation of GHB ingestion.201, 241–243 The withdrawal syndrome is characterized by insomnia, tremor, and anxiety that may last approximately 1 week.201 In addition, more severe symptoms have been reported, including confusion, hallucinations, delirium, and autonomic stimulation with tachycardia. The symptoms of withdrawal may begin within 1–6 hours after the last dose of GHB and may last from 5–15 days.
One case of Wernicke-Korsakoff syndrome has been attributed to the use of GHB.244 According to the authors, the patient had not imbibed alcohol for several months before admission, although there was no mention of an ethanol screen. The patient presented with the classic triad of symptoms of Wernicke-Korsakoff syndrome: global confusion, sixth nerve palsies, and ataxic gait. In addition, paranoid delusions and hallucinations were present. According to the authors, the atypical mental features represented GHB withdrawal and were similar, in part, to delirium tremens without the serious autonomic dysfunction. The patient’s symptoms resolved quickly with thiamine treatment, with the eye movement abnormalities resolving rapidly, followed by resolution of the abnormal gait and mentation.244 The clinical picture of it withdrawal appears to range from anxiety, tremor, and insomnia to more severe symptoms such as disorientation, paranoia, hallucinations, tachycardia, and possibly extraocular motor impairment.
Fatalities have been associated with it use. The DEA has collected investigative, toxicology, and autopsy reports from cases in which it was found in biological samples of the deceased. Since 1990, the DEA reports that they are aware of 68 deaths associated with the use of it, most of which have occurred in the last 4 years. Details of the cases are not given.157 In an article discussing pre- and postmortem GHB blood and urine levels, the authors refer to four fatalities attributed to the use of GHB.246 Three of the fatalities had postmortem blood GHB levels ranging from 52–121 mg/L. In a series of forensic samples submitted for laboratory analysis, blood GHB levels ranging from 3.2–168 mg/L were found in 15 of 20 autopsy specimens, although the deaths were not thought to be GHB related. Furthermore, it was not found in samples from living subjects who did not take GHB. Because of these findings, the authors suggest that it may be a natural product of postmortem decomposition occurring in blood.246 Other investigators suggest that the magnitude of GHB levels found in many fatality cases is too significant to be attributed to postmortem decomposition.
The mainstay of treatment for GHB intoxication is protection of the airway and assisted ventilation if needed. Intubation, to protect the airway, is a common treatment procedure during GHB intoxication, and assisted ventilation may be required in some cases.233, 248 Laboratory monitoring should include serum electrolytes and blood glucose levels in symptomatic patients, and additional monitoring, such as pulse oximetry and arterial blood gases, in patients with respiratory depression. Because of the increased prevalence of it abuse, it should be considered as a causal agent in any patient with coma of unknown origin at presentation. Since it is rapidly cleared from the body, it is often difficult to confirm the definite use of GHB. Furthermore, it will be missed by many conventional first-line urine drug screens,249 and analysis with gas chromatography mass spectrometry is required for detection and quantification.250 Therefore, a history from the patient, or others who witnessed the GHB use, may be important diagnostic information. However, because it has amnestic properties, the patient may not be able to provide a very reliable history. Some suggest that a history of bodybuilding or athletic physique may aid in the diagnosis of GHB abuse,158, 226 as this drug is commonly used in this patient population.
Decontamination and Elimination
The roles of gastric lavage and activated charcoal have been questioned as the volumes of GHB are very small and GHB is rapidly absorbed from the gut,251 but these treatments may be helpful when GHB is coingested with other drugs of abuse. Activated charcoal may be of benefit for recent, large ingestions of GHB.252 Induction of emesis is not recommended because the CNS depression and diminished gag reflex may lead to pulmonary aspiration.252
Because many of the symptoms of it intoxication are so rapidly reversed, it is difficult to determine if purported helpful pharmacologic treatments have been successful or if the it intoxication has simply worn off. In clinical cases of it intoxication, both naloxone and flumazenil have been found to be of no benefit in reversing unconsciousness.
bsence epilepsy in animals, various anticonvulsant agents have been used as GHBreversal agents, but there are no data in the literature indicating that any of these agents have been useful in experimental or clinical situations in humans. Monitoring neurologic function and applying GCS scores are essential. Patients with an initial GCS of 8 or less may have a more serious clinical course, requiring a longer recovery time, so they should be monitored very closely.228 It has been suggested that if a patient has stable mental status and vital signs after 6 hours of observation in the emergency department, he or she could be discharged unless there is some other indication for hospital admission.
Case reports231 and clinical trials253–255 indicate that neostigmine or physostigmine may be helpful in the treatment of the symptoms of it intoxication. Physostigmine is given clinically to reverse the toxic CNS effects caused by anticholinergic agents. Three trials in humans undergoing GHB anesthesia have evaluated the use of physostigmine or neostigmine as reversal agents.253–255 Two of these studies included the use of a neuromuscular blocker in addition to it, which complicate the results. In one study, effective reversal of GHB-induced sedation occurred after the administration of physostigmine alone, given intravenously as 2- mg single or repeated doses
Cardiovascular Treatment Symptomatic
bradycardia associated with it intoxication should be treated with atropine.230, 233 However, although a single case report indicated that atropine was successful in treating a case of severe bradycardia,228 this approach has not been adequately evaluated.
Benzodiazepines may be given to treat the GHB withdrawal syndrome.252 In one reported case, the withdrawal symptoms were so severe that, over a 9-day detoxification period, the patient received propranolol, benzodiazepines, and phenothiazines for paranoia, agitation, and delirium.241 In another report, the patient displayed agitation, hallucinations, tachycardia, and elevated blood pressure after the cessation of it. Over the course of this patient’s treatment, he received lorazepam 507 mg and diazepam 120 mg for agitation over a 90-hour period.243 Although benzodiazepines and other agents have been given to treat the signs and symptoms of GHB withdrawal, no standard treatment protocol exists.
The treatment of it intoxication is mainly supportive because no specific GHB antidote has been proved effective in humans. Because of reduced respiratory function, the patient may require intubation or mechanical ventilation. As vomiting is a common symptom of it intoxication, airway protection becomes even more important to avoid the risk of aspiration. The improper manufacture of it can lead to a mixture of it and sodium hydroxide, which is very caustic and, if aspirated, is likely to cause severe damage to the lung tissue. Therefore, it is important to maintain the airway and establish intravenous access.
The use of MDMA and GHB has risen dramatically over the last couple of years. Evidence indicates that MDMA is toxic to serotonergic neurons in animals. Further evidence indicates that MDMA may be a neurotoxin in humans as well.
The drug MDMA is the most popular of the club drugs and continues to gain popularity despite adverse effects that have been associated with it, such as agitation, tachycardia, hypertension, dilated pupils, trismus, bruxism, sweating, hyperthermia, DIC, rhabdomyolysis, and acute renal failure. Hyperthermia appears to be the most serious complication, sometimes leading to a cascade of events including DIC, rhabdomyolysis, and acute renal failure
No standard protocols exist for treating MDMA intoxication. However, the most important techniques include lowering the body temperature and maintaining adequate hydration to avoid acute renal failure due to rhabdomyolysis and myoglobinuria. The cases of hyponatremia associated with MDMA that have resulted in seizures, coma, and cerebral edema indicate that it is extremely important to avoid overhydration of the patient during treatment.
The use of GHB, although not as popular as MDMA, is also a significant problem. It is used for its sedating, intoxicating, and alleged bodybuilding properties. In addition, in recent years, GHB has been used to facilitate sexual assault and has been labeled a “date rape” drug by the press. Regardless of the initial motive for using GHB, it is a dangerous substance when used outside of a controlled setting. It may cause acute toxic reactions and possibly physical dependence, especially if used at high doses for a prolonged period of time. Acute symptoms of a it toxic reaction include coma (often with a GCS score < 8), respiratory depression, seizurelike activity, bradycardia, drowsiness, confusion, amnesia, nausea, vomiting, mild hypothermia, acidosis, and psychiatric complications. Symptoms associated with acute withdrawal in those who are physically dependent range from anxiety, tremor, and insomnia in milder cases, to confusion, delirium, and hallucinations in more severe cases.
No standard treatment protocols exist for GHB intoxication or withdrawal. However, physostigmine has been suggested as a possible treatment option to reduce the CNS and respiratory depression induced by GHB. Atropine may be beneficial in cases of severe bradycardia. Benzodiazepines are commonly given for it withdrawal symptoms; although, to our knowledge no prospective studies have evaluated their use for this indication.
Because of the increasing popularity of club drugs and their dangerous adverse effects, health care professionals must be familiar with these substances. Early identification and treatment of symptoms associated with these agents is of paramount importance. No standard treatment protocols exist for the intoxication syndromes associated with MDMA or GHB, and supportive care is currently the standard of treatment. Pharmacologic treatments have been given successfully for treating the symptoms associated with MDMA and GHB toxic reactions. However, larger clinical trials evaluating the use of pharmacotherapy during intoxication with, or withdrawal from, either of these agents are lacking. A knowledge of the expected adverse effects and the course and duration of intoxication or withdrawal will help health care providers to identify and treat the consequences of MDMA or GHB abuse.
gamma-Hydroxybutyric acid or γ-Hydroxybutyric acid, also known as 4-hydroxybutanoic acid, is a naturally occurring neurotransmitter and a psychoactive drug. It is a precursor to GABA, glutamate, and glycine in certain brain areas. It acts on the it receptor and is a weak agonist at the GABAB receptor.