Posted by pelorojo on April 14, 2003, at 9:12:31
In reply to Re: Xyrem = GHB. Please don't., posted by Larry Hoover on April 12, 2003, at 8:25:15
Hey Larry, could you post the MDMA information also? Thanks : )
> > You guys should ask your doc about it, this seems promising in off-label indications.
>
> GHB? Please tell me you're not serious. The risk of addiction and tolerance, let alone withdrawal, makes this a very risky substance to get involved with. Moreover, there is good evidence that the dose-responsiveness in a single individual varies. In other words, you could get a toxic reaction this week from a dose that was safe last week.
>
> GHB is a neurotransmitter in your brain, complete with its own receptors. It readily crosses the blood-brain barrier, so using it directly mucks around with the control mechanisms. I can't think of anything more dangerous than that.
>
> I copied the following from a site that requires registration. It's a pretty level-headed review of the pharmacology of GHB.
>
> Lar
>
> A Comprehensive Review of MDMA and GHB: Two Common Club Drugs
> from Pharmacotherapy
>
> GHB
>
> History
> 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 GHB such as sodium oxybate, sodium oxybutyrate, -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 GHB in an attempt to create a -aminobutyric acid (GABA) analog that would, unlike GABA, cross the blood-brain barrier.[145] Somewhat simultaneously, in 1963, GHB 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-the-counter 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 dependence[153] 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.[157]
>
> Availability
> 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 g-butyrolactone (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 GHB is colorless and odorless, and because small quantities are required to achieve a desired effect, GHB has been used as a date rape drug. The amnesia produced by GHB often makes victims unable to serve as valid witnesses.
>
> Pharmacokinetics
> Pharmacokinetic Parameters
> The pharmacokinetics of GHB 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 GHB in plasma has been shown to be 0.99, indicating a lack of significant plasma protein binding.[161] The half-life of GHB 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 half-life of 53 minutes in patients with narcolepsy after dosages of GHB 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 GHB or the capacity-limited absorption of GHB.[161] The capacity-limited 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 dispropor-tionate 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 dispropor-tionate increases in AUC.
>
> Metabolism and Synthesis
> The biosynthetic pathway and metabolic degradation of GHB occurs in brain tissue by means of multiple cytosolic and mitochondrial enzymes. -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]-hydroxybutyrate is oxidized into SSA by means of GHB dehydro-genase and GHB-oxoacid transhydrogenase.[172] The SSA is further metabolized to succinate, which then enters the Krebs cycle.[173]
>
>
> (click image to zoom) Figure 4. Mechanism of GHB elimination. g-Butyrolactone (GBL) and 1,4-butanediol (1,4-BD) are converted in the body to GHB.
>
>
>
> Elimination
> Less than 2% of GHB is eliminated unchanged in the urine.[162, 164] Owing to the short half-life, there is no accumulation of GHB with repeated dosing and GHB 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 GHB is so rapid, even in those with compromised liver function, that the drug is completely eliminated within 4-6 hours after ingestion.[162]
>
>
> Pharmacology
> Receptor Biochemistry
> The exact mechanism of GHB action in the CNS has not been determined, but GHB is structurally related to GABA (Figure 4), which is a precursor in GHB formation.[170] Much debate exists regarding whether GHB has neuro-transmitter or neuromodulatory roles,[174-177 ]because GHB 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 amino-transferase 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 GHB in the brain are found in the substantia nigra[179] and hypothalamus, whereas the highest turnover rate of GHB 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 GHB.[181] In addition to being found in the CNS, GHB is found in the kidney, heart, skeletal muscle, and brown fat.[183]
> -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 pathways[184, 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 GHB 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 GHB 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 a-methyltyrosine, which blocks the activity of tyrosine hydroxylase, almost completely blocks the rise in brain dopamine induced by GHB, 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 dopamine[192] 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 GHB.[193, 194]
>
> Dose-Related Effects
> The primary dose-related effects of GHB are related to CNS depression. At 10 mg/kg, GHB is capable of producing amnesia[195] and hypotonia of the skeletal muscles[196, 197] resulting from the depression of neurons in the spinal cord.[166] At 20-30 mg/kg, GHB 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, GHB 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 GHB 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.[146]
>
> Serum Concentrations
> 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 GHB 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 GHB 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 GHB 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 charac-terized by spontaneous movements and occasional opening of the eyes. When the blood GHB levels decrease below 52 µg/ml, subjects wake up.[164]
>
> Abuse Potential and Intoxication
> Factors that seem to contribute to the abuse potential of GHB 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 GHB became a popular drug of abuse is its ability to produce a "high."[155, 202] Those who take GHB 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 dose-response 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 GHB have been described as being similar to those of alcohol, and the two agents may act syner-gistically, further increasing the risk for intoxication or overdose.[203]
>
> Cardiovascular Effects
> Moderate bradycardia appears after the administration of GHB[204, 205] and is likely due to central vagal activity.[166] In addition to bradycardia, GHB 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.[150, 166, 204]
>
> Respiration
> 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.[166, 204]
>
> Neuroendocrine Effects
> 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 slow-wave 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.[206]
>
> 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 structures[166] and subcortical centers.[199] The anesthetic effects of GHB are primarily hypnotic[204] as GHB provides little or no analgesia.[150, 204] The transition from wakefulness is described as being a sudden shift from responsivity to unconsciousness.[199]
>
> Sleep Physiology
> The drug GHB stimulates slow-wave sleep.[199, 207-210] It does not appear to suppress REM sleep[207, 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 double-blind conditions, single oral doses of GHB 2.25 g significantly increased the time spent in slow-wave 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.[211]
>
>
> Therapeutic Applications
> 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
> -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]-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.[215]
>
> Narcolepsy and Insomnia
> Owing to the ability of GHB to increase slow-wave 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.[151, 208-210, 216] 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.[151]
>
> 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 long-term 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.[219]
>
> Anabolism
> Although 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.[221]
>
>
> Adverse Effects and Acute Toxic Reactions
> Acute Syndrome
> 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.[151, 166]
>
> CNS Effects
> 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.[223]
>
> Cardiovascular Effects
> Bradycardia has occurred when GHB was given for anesthesia[150, 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 electro-cardiograms 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.[233]
>
> Respiratory System
> Respiratory depression, difficulty breathing, and apnea have been reported after the administration of GHB.[155, 166, 200, 202, 222, 224, 228, 231, 233, 235] 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 Cheyne-Stokes breathing may result.[204]
>
> Psychopathology
> 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.[158, 234]
>
> Ocular Effects
> 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.[199]
>
> 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.[228]
>
> Gastrointestinal System
> 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.[229]
>
> Body Temperature
> 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.[227]
>
> Movements
> There have been many reports of unusual, random clonic movements and uncontrollable shaking associated with GHB use.[150, 155, 166, 200, 202, 225, 227, 229, 234, 235] 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 changes[212] or seizure-like activity.[228]
>
> Miscellaneous
> 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.[159]
>
> Withdrawal and Tolerance
> Data gathered by the DEA indicate that those who take GHB have exhibited chronic self-administration, 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.[242]
>
> 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 GHB withdrawal appears to range from anxiety, tremor, and insomnia to more severe symptoms such as disorientation, paranoia, hallucinations, tachycardia, and possibly extraocular motor impairment.
>
> Death
> Fatalities have been associated with GHB use.[157, 222, 245-247] The DEA has collected inves-tigative, toxicology, and autopsy reports from cases in which GHB 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 GHB, 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, GHB was not found in samples from living subjects who did not take GHB. Because of these findings, the authors suggest that GHB 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 signif-icant to be attributed to postmortem decomposition.[247]
>
>
> Treatment
> Resuscitation
> 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 GHB abuse, it should be considered as a causal agent in any patient with coma of unknown origin at presentation. Since GHB is rapidly cleared from the body, it is often difficult to confirm the definite use of GHB. Furthermore, GHB 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 GHB 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.
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> 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]
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> Neurologic Treatment
> Because many of the symptoms of GHB intoxication are so rapidly reversed, it is difficult to determine if purported helpful pharmacologic treatments have been successful or if the GHB intoxication has simply worn off. In clinical cases of GHB intoxication, both naloxone and flumazenil have been found to be of no benefit in reversing unconsciousness.[155, 200, 223-225, 230, 231, 233, 234]
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> Owing to the association between GHB and absence epilepsy in animals, various anticonvulsant agents have been used as GHB-reversal 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.[233]
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> Case reports[231] and clinical trials[253-255] indicate that neostigmine or physostigmine may be helpful in the treatment of the symptoms of GHB 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 GHB, 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.[253]
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> Cardiovascular Treatment
> Symptomatic bradycardia associated with GHB 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.
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> Withdrawal
> 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 GHB. 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.
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> Supportive Care
> The treatment of GHB 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 GHB intoxication, airway protection becomes even more important to avoid the risk of aspiration. The improper manufacture of GHB can lead to a mixture of GHB 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.
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> Section 3 of 4
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> Pharmacotherapy 21(12):1486-1513, 2001. © 2001 Pharmacotherapy Publications
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poster:pelorojo
thread:218347
URL: http://www.dr-bob.org/babble/20030411/msgs/219183.html