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All About GHB Report

“All About GHB,” a NIDA Neuroscience Consortium and OSPC “Cutting Edge” colloquium (27 June 2000 at the Doubletree hotel, Rockville), was organized by Drs. Jerry Frankenheim and Minda Lynch in response to the rapid ascent of GHB and its precursors, GBL and 1,4-butanediol, as public health concerns. Drs. Stephen Zukin and Timothy Condon also hosted and participated in the colloquium. The colloquium agenda is attached. Drs. Maitre and Snead were unable to participate in the colloquium, due to circumstances beyond their or our control; however, the presentations they prepared are summarized below.

Mr. Hall: The GHB, GBL, 1,4-BD problem is nationwide and also global. He called GHB the first “Internet Drug,” and characterized the other abuse trends thusly: users are younger than 2 years ago (the users showing up in hospital emergency departments (EDs) are very young), these drugs are more popular, there are more products available, the manufacture is more clandestine, and there are more dangerous mixtures of chemicals being used. The GHB sold on the street is usually a liquid now, due to the way it is manufactured. GHB and its precursors are still represented and sold via the Internet as cleaning fluids.

Failure to seek medical help has led to GHB-related deaths. At least 68 deaths have been reported, most with GHB + alcohol. This is an underestimate of GHB-related deaths, since GHB has a short half-life, and usually is not looked for. Some GHB homicides have occurred. In a survey of ED subjects, 47% had taken GHB (or a precursor) to get high, 9% said they were dependent on GHB, 36% for other psychological effects, and 8% said they were attempting suicide. 93% of these ED subjects were white, and two-thirds were below the age of 25.

In 1995-6, the GHB epidemic went from an incubation period to the expansion phase. It is not known whether the GHB abuse trend has reached its plateau, or is still expanding.

SA Mecir: In the 10 years GHB has been around, it has spread around the world (eg Europe, Australia). Ten years is a short time for it to have spread so widely. Mecir also blames Internet marketing for GHB’s rapid spread.

The regulatory statuses of GHB (gamma-hydroxybutyrate), GBL (gamma-butyrolactone) and 1,4-BD (1,4-butanediol) were discussed. Dr. Christine Sannerud, Deputy Chief, Office of Diversion Control, DEA, attended “All About GHB,” and is our primary DEA contact. In March 2000, GHB jumped to federal schedule I controlled substance status, except for clinical trials in registered narcoleptic patients, supervised by physicians and approved by the FDA, for which it is schedule III. Recently, the FDA declared GBL as a list I chemical, and 1,4-BD a class I health hazard. Thus, the FDA designates these GHB precursors, which are also industrial solvents, as illicit and unapproved new drugs.

People self-administer GHB, usually orally, in their attempts to feel euphoric, relaxed, uninhibited, detachment, and more sexual, much the same as sedative-hypnotics or alcohol. In addition, GHB has been sold since 1990 over-the-counter and over the web as a body building (via release of growth hormone during GHB-induced slow wave sleep), sedative dietary supplement. GHB has also been used in intentional poisonings. Mr. Hall urged we refer to sexual assaults, by surreptitiously administering an unsuspecting victim GHB in a drink (usually an alcoholic drink, a “Mickey Finn”), as “drug-rape,” not “date-rape.” There is disagreement how often these occur, but no doubt that they do occur, and not just for sexual assaults, but also robberies, and to men as well as women. GHB also strongly causes amnesia, so drug assault victims typically remember little of their experience; hence, the assaults are certainly under-reported. These many faces of GHB abuse have led to a remarkable number of street and commercial (dietary supplement) names. The many, changing names and preparations of GHB and GHB precursors (GBL and 1,4-BD) have confused the public and medical care providers as to the nature and toxicity of GHB-related substances.

GHB is not analgesic. High doses are anesthetic. Other acute effects of GHB in man include myoclonus, ataxia, tunnel vision, agitation, confusion, tonic/clonic seizures, hypotonia, altered respiration, tremor, nystagmus, and coma (listed by Dr. Gibson).

The drawbacks of GHB abuse: Dr. Miotto said that 66% of her survey sample reported losing consciousness at least once due to GHB; 28% reported overdosing, and 9% had been treated in the ER. It is remarkable, she said, how cavalierly they regard losing consciousness after GHB. The frequent, unpredictable loss-of-consciousness episodes are due to (1) GHB’s steep dose-effect relation, (2) the dangerous variability in “street” dosages, (3) GHB’s non-linear elimination kinetics, and other factors, such as interactions with other drugs. ERs across the US have treated hundreds of cases of GHB toxicity and overdose, according to Dr. Miotto. (Mr. Hall said that GHB abuse was evenly distributed, not regional, across the US.) GHB overdose is associated with a marked decrease in consciousness, bradycardia, hypothermia, respiratory acidosis, and emesis. The combination of loss of consciousness and emesis has been deadly, due to aspiration. It is not unusual for Intubation to be required. Recovery of consciousness typically occurs within 5 hr after GHB ingestion. Opiate or benzodiazepine antagonists do not reverse GHB coma. A GHB receptor antagonist (NCS-382, 6,7,8,9-tetrahydro-5(H)-5-olylidene acetic acid) exists, but is not approved for use in man. GHB toxicity is potentiated by alcohol, opiates, barbiturates and benzodiazepines. GHB alone, and in combination with other substances, has caused deaths, but generally the prognosis after recovery of consciousness is good.

GHB exhibits non-linear elimination kinetics, which means that GHB's half-life increases with dose. High doses acutely result in much higher plasma levels than would be predicted from the plasma levels resulting from lower doses. This is probably due to saturation of the GHB metabolic pathway. The half-life of an oral dose of 12.5 mg/kg is 20 minutes. The dose of street GHB varies from 500 mg to 5 grams per dose.

Dr. Miotto: GHB produces tolerance and dependence; the withdrawal symptoms are severe and potentially lethal. The addiction and medical community is not aware of the severe psychosis, delirium, tremor, agitation, anxiety, insomnia, and tachycardia that develop after abrupt discontinuation of high dose GHB. GHB withdrawal psychosis is more difficult to treat than delirium tremens because the patients have such a bizarre agitated psychosis. GHB dependent individuals often do not seek treatment because they do not remember their negative experiences with GHB, due to the amnestic effects of the drug.

Research is needed to identify the best treatment for (1) GHB toxicity, and (2) GHB withdrawal.

High affinity GHB receptors have been identified in neurons, and GHB also has weak agonist properties at GABAB receptors. Baclofen (GABAB agonist) use in GHB detoxification was limited in Dr. Miotto’s patients due to concerns that rapid dose increases have been associated with psychosis. Detox regimens have included benzodiazepines, trazadone (atypical antidepressant), gabapentin, and an atypical antipsychotic such as risperidone.

Dr. Maitre: There is good evidence that GHB is a neurotransmitter. It, and its synthesizing enzyme, have a discrete anatomical distribution and distinct ontogeny in the brain. It has a specific receptor. There is Ca++ dependent release and sodium-dependent uptake of GHB in the brain

Dr. Snead: The profound neuropharmacological and behavioral effects of GHB, including psychotropic effects described above, EEG and behavioral effects resembling absence seizures, and effects on dopamine neurotransmission, are all dose related. Snead and others showed that low GHB doses enhance GABA release, probably by a presynaptic GHB-specific mechanism. Snead showed that GABAB antagonists block GHB-induced absence-like seizures by acting “downstream” at the level of thalamocortical circuitry. GHB-induced absence seizures are also blocked by NCS-382. Dr. Snead’s experiments indicate that GHB induces absence by a GHB-specific effect, and not directly via the GABAB receptor, and that these are distinctly different receptors, with different ontogeny and regional distribution. For example, he found that the negative coupling effect of GHB on adenylyl cyclase is observed only in presynaptic tissue preparations, while the negative coupling effect of baclofen is observed in both presynaptic and postsynaptic preparations.

Dr. Snead pointed out that as the concentration of GHB in the brain increases, GABAB receptor-mediated effects are recruited, and that this certainly occurs in GHB abuse and addiction. The normal brain concentration of GHB (rat) is about 2 micromolar, but millimolar concentrations of GHB are achieved with systemic administration of high doses to rats. In all species tested by Snead, including monkey, low doses produce memory deficits with little EEG changes, followed by absence-like seizures, both of which can be reversed by NCS-382 and GABAB antagonists. As the dose and brain concentration increase, EEG slowing associated with a stuporous state emerges, which is only partially reversed by NCS-382, but completely antagonized by GABAB receptor antagonists. With GHB or GBL doses in excess of 300 mg/kg, EEG burst suppression appears with deep coma, irreversible by NCS-382, but reversible by GABAB antagonists. These data suggest that GABAB receptor antagonists, when they become available, could be useful in treating GHB overdose.

The EEG and behavioral changes induced by GBL in rat correlate with brain levels of GHB, not brain levels of GBL. Snead and others showed with microinjection and binding studies that the effects of GBL could be attributed to its immediate conversion to GHB by a circulating lactonase. Snead showed that GBL occurs naturally in brain at extremely low concentrations.

Both GHB and GBL have extremely high LD50s in animals. Dr. Snead hypothesizes that an adulterant could be responsible for the morbidity and mortality of “home brew” GHB.

Several researchers agreed that animal models of GHB addiction should be developed to investigate the neuronal circuitry involved, including the involvement of dopamine. GHB and GABAB receptor transgenics and knockouts, as well as the SSADH knockout model developed by Dr. Gibson (see below), could be useful in determining the roles of these receptors in GHB abuse and its consequences.

Dr. Gessa: GHB mimics various CNS actions of ethanol, suppresses ethanol withdrawal signs, and reduces ethanol consumption in rats and humans. GHB also shares with ethanol the ability to inhibit glutamate action at both NMDA and AMPA/kainate receptors, probably by decreasing the probability of release of glutamate. The GHB receptor antagonist, NCS-382, prevents the depressant effect of GHB on the glutamate responses.

Dr. Gibson: Gamma-hydroxybutyric aciduria is a rare inborn defect of human GABA degradation resulting from inherited succinic semialdehyde dehydrogenase (SSADH) deficiency. These patients accumulate GHB, and are characterized by psychomotor retardation, delayed or absent speech, hypotonia, ataxia, hyporeflexia, behavior problems, seizures (uncommon), and EEG abnormalities, and exhibit very large phenotypic heterogeneity. Some of these clinical features are present acutely in GHB users. Dr. Gibson and his colleagues developed a murine knockout of SSADH to explore pathomechanisms and to develop preclinical treatments. The homozygous SSADH knockout mice die of seizures at postnatal days 17-20 (soon after weaning), and phenytoin, phenobarbital, vigabatrin and NCS-382 were ineffective in saving the mice. A GABAB antagonist, CGP 35348, led to survival of most mice for at least several months, as did taurine, a major component of milk. Vigabatrin (gamma-vinyl-GABA, an irreversible GABA-transaminase inhibitor) increased CSF GABA and decreased CSF GHB, but did not change urinary GHB output, and did not work well therapeutically in humans, or in the mice.

GHB is being used experimentally in the treatment of narcolepsy; these are the only clinical trials of GHB permitted in the US. Dr. William Houghton, Chief Operating Officer of Orphan Medical, attended “All About GHB,” and explained this indication. Houghton: Narcolepsy is a disease of fragmented sleep. Narcoleptics have the same amount of sleep as normal people, but it is spread over the whole day. GHB can give narcoleptics regular diurnal patterns of sleep.

Dr. Kaufman: The metabolism of GHB can be regarded as a small loop in which the succinic semialdehyde (SSA) derived from transamination of GABA is reduced to GHB. The reduction of SSA to GHB is catalyzed by a specific aldehyde reductase for which SSA is the only known naturally occurring substrate. Other endogenous sources of GHB include polyamines and 1,4-BD, but the relative contribution of each of these sources has as yet to be determined. The GHB loop is completed by the oxidation of GHB back to SSA. Two enzymes that can catalyze the oxidation of GHB back to SSA have been identified; one of these is the cytosolic GHB dehydrogenase. In contrast to the SSA reductase, this enzyme is inhibited by a number of drugs and biological intermediates. These properties make this enzyme the site in the loop where regulation of tissue concentration of GHB is most likely to occur. Sodium valproate is an example of a drug which inhibits this enzyme and which causes a marked increase in the tissue concentration of GHB. The second enzyme involved in the oxidation of GHB back to SSA is the GHB transhydrogenase, which catalyzes a reaction in which the oxidation of GHB is coupled to the reduction of _-ketoglutarate to D-_-hydroxyglutarate.

Since _-ketoglutarate, a citric acid cycle intermediate, is the co-substrate for GABA transaminase and for GHB transhydrogenase, drugs or physiological changes which affect carbohydrate metabolism should also be considered as potential regulators of tissue levels of both GABA and of GHB.

Once GHB has been metabolized to SSA by either enzyme, SSA is oxidized to succinate by SSA dehydrogenase; the evidence indicates that none is converted back to GABA. SSA dehydrogenase is the deficient enzyme in gamma-hydroxybutyric aciduria, described by Dr. Gibson. The succinate is metabolized eventually to CO2 and H2O via the citric acid cycle.

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