new england journal
`The
`
` medicine
`
`of
`
`review article
`
`drug therapy
`-Hydroxybutyric Acid
`g
`
`O. Carter Snead III, M.D., and K. Michael Gibson, Ph.D.
`
`t
`
`-hydroxybutyric acid (ghb) was syn-
`he short-chain fatty acid
`g
`thesized in 1960 in an attempt to create an analogue of the ubiquitous inhibi-
`tory brain neurotransmitter
`-aminobutyric acid (GABA) that would cross the
`g
`1
`blood–brain barrier.
` GHB turned out to have sedative properties similar to those that
`2
`had been reported for
`-butyrolactone 13 years earlier.
` In fact,
`-butyrolactone has
`g
`g
`3,4
`since been shown to be biologically inactive,
` since all its biologic and behavioral ef-
`5
`fects are due to its rapid conversion to GHB by an active lactonase.
` Although GHB has
`6-8
`9
`found limited clinical use as an anesthetic agent
` and in the treatment of narcolepsy
`10
`and alcoholism,
` widespread interest has developed during the past 5 to 10 years be-
`cause GHB has emerged as a major recreational drug and public health problem in the
`United States. GHB has diverse neuropharmacologic and neurobiologic properties and
`appears to have dual neuronal mechanisms of action that include activation of both the
`-aminobutyric acid type B (GABA
`) receptor and a separate, GHB-specific receptor
`g
`B
` receptors
`(Table 1). This complex interaction between GHB and the GHB and GABA
`B
`within mesocorticolimbic dopamine pathways is probably responsible for the addictive
`nature of GHB and for symptoms of withdrawal from it.
`
`From the Department of Pediatrics, Uni-
`versity of Toronto, and the Division of Neu-
`rology and the Brain and Behavior Research
`Program, Hospital for Sick Children — both
`in Toronto (O.C.S.); and the Department of
`Molecular and Medical Genetics, Oregon
`Health and Science University, Portland
`(K.M.G.). Address reprint requests to Dr.
`Snead at the Division of Neurology, Hos-
`pital for Sick Children, 555 University Ave.,
`Toronto, ON M5G 1X8, Canada, or at
`csnead@sickkids.ca.
`
`N Engl J Med 2005;352:2721-32.
`Copyright © 2005 Massachusetts Medical Society.
`
`neuropharmacologic features
`
`metabolism and neuromodulatory properties
`31
`GHB occurs naturally in mammalian brain tissue,
` where it is derived from the con-
`32
`version of its parent neurotransmitter, GABA,
` to succinic semialdehyde through mi-
`tochondrial GABA transaminase (Fig. 1). Succinic semialdehyde is then reduced to
`14
` GHB may be metabolized through
`GHB by cytosolic succinic semialdehyde reductase.
`the action of GHB dehydrogenase to succinic semialdehyde, which may be further me-
`tabolized either to GABA by GABA transaminase or to succinate through the action of
`33
`mitochondrial succinic semialdehyde dehydrogenase.
`GHB exerts ubiquitous pharmacologic and physiological effects when it is adminis-
`34
` However, GHB also has many of the requisite
`tered systemically to animals (Table 1).
`35
`properties of a neurotransmitter or neuromodulator,
` including a discrete, subcellular
`anatomical distribution in neuronal presynaptic terminals, along with its synthesizing
`36
`enzyme. GHB is released by neuronal depolarization in a calcium-dependent fashion.
`37
`A sodium-dependent GHB-uptake system in the brain has also been described,
` and an
`active vesicular uptake system that is most likely driven by a vesicular inhibitory amino
`38
`acid transporter has been reported.
`
`ghb receptors
`The existence of a specific GHB receptor is suggested by specific, high-affinity GHB-
`binding sites that are observed in the brains of rats and humans. The kinetics of the
`GHB receptor are related to the 1-to-4-μm concentration of GHB that is typically found
`14,31
`39
`in mammalian brain tissue.
` Although there are contradictory data,
` evidence sug-
`15
`gests that the GHB receptor is presynaptic and G-protein–coupled
` and that it may
`
`n engl j med
`
`352;26
`
`www.nejm.org june
`
`30, 2005
`
`2721
`
`The New England Journal of Medicine
`
`AMN1019
`IPR of Patent No. 8,772,306
`
`

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`
` new england journal
`The
`
` medicine
`of
`
`Table 1. Molecular Mechanisms and Physiological Consequences of Ingestion of GHB.*
`
` receptors)
`
`B
`
`Variable
`Molecular mechanisms
`Altered dopamine release (mediated by GABA
`Increased serotonin turnover
`Increased level of acetylcholine
`Increased level of dynorphin A
`Increased level of 3'-5' cyclic guanosine monophosphate in brain
`
`Altered activity of adenyl cyclase
`(mediated by GHB receptors)
`G-protein activation (mediated by GHB receptors)
`Decreased glucose use in brain
`Reduced mitogen-activated phosphorylation of protein kinase in brain
`(mediated by GABA
` receptors)
`B
`Altered presynaptic release of GABA and glutamate (mediated by GHB
`receptors and GABA
` receptors)
`B
`Decreased binding to NMDA receptors
`Increased plasma concentration of neurosteroids (mediated by GABA
`receptors)
`Physiological consequences
`
` receptors)
`Hypothermia
`(mediated by GABA
`B
`
` receptors)
`Hypertension
`(mediated by GABA
`B
`
` receptors)
`Tachycardia
`(mediated by GHB receptors and GABA
`B
`
`Increased activity of renal sympathetic nerves
`(mediated by GABA
`receptors)
`Decreased minute ventilation
`
`Decreased intestinal motility
`receptors)
`(mediated by GABA
`B
`EEG and behavioral changes, including absence-like seizures and slow-
`wave sleep, depending on the dose (mediated by GHB receptors and
`GABA
` receptors)
`B
`Impaired spatial learning
`Increased protection against neurotoxicity
`
`
`
`B
`
`
`
`B
`
`References
`
`11
`
`Howard and Banerjee
`12
`Gobaille et al.
`13
`Sethy et al.
`14
`Maitre
`14
`Maitre
`15
`Snead
`15
`Snead
`Kuschinsky et al.
`17
`Ren and Mody
`
`16
`
`Hu et al.,
`
`18
`
` Ferraro et al.
`
`19
`
`20
`Sircar and Basak
`21
`Barbaccia et al.
`
`22
`Quéva et al.
`23
`Hicks et al.
`23
`Hicks et al.
`23
`Hicks et al.
`
`24
`
`Hedner et al.
`25
`Carai et al.
`26
`Snead,
` Van Cauter et al.
`
`27
`
`20
`Sircar and Basak
`28
`Ottani et al.,
`Yosunkaya et al.,
`30
`Guney et al.
`
`29
`
`* Parenthetical data regarding mediation indicate whether the effects cited are due to an effect of GHB on GHB receptors
`or GABA
` receptors. When no mechanism is indicated, there are no data regarding mediation. GHB denotes
`-hydroxy-
`g
`B
`N
`butyric acid, GABA
`receptor,
`-aminobutyric acid type B receptor, GABA
`-aminobutyric acid, NMDA
`-methyl-
`-aspartate,
`g
`g
`B
`D
`and EEG electroencephalography.
`
`18
`function to inhibit the release of GABA.
` Despite
`data showing that GHB may be biologically active
`in its own right, compelling evidence suggests that
`most of the physiologic and pharmacologic effects
`of systemically administered GHB are mediated by
`the GABA
` receptor (Table 1).
`B
`
`gaba receptors
`GABA is ubiquitous in the brain and can activate li-
`gand-gated ion channels — GABA type A (GABA
`)
`A
`and GABA type C (GABA
`) receptors — as well as
`C
` receptors. Activation of the GABA
` receptor
`GABA
`B
`A
`results in the influx of chloride ions and the gener-
`ation of a fast inhibitory postsynaptic potential (Fig.
`41
`2).
` There is little evidence to support the hypoth-
`esis that GHB interacts with the ionotropic GABA
`A
`42
`receptor.
`The GABA
` receptor mediates a slow inhibitory
`B
`postsynaptic potential. Effector mechanisms asso-
` receptor include signaling
`ciated with the GABA
`B
`through the action of the adenylate cyclase system
`
`and activation of calcium channels and G-protein–
`coupled, inwardly rectifying potassium channels.
`The GABA
` receptor is a heterodimer composed of
`B
`receptor 1 and receptor 2 subunits. The GABA
` re-
`B
`ceptor is transported from the interior of the cell to
`the cell surface by the receptor 2 subunit. Postsyn-
`aptic GABA
` receptors are coupled to G-protein–
`B
`coupled, inwardly rectifying potassium channels.
`Presynaptic GABA
` receptors are subdivided into
`B
`those that control the release of GABA (autorecep-
`tors) and those that inhibit the release of all other
`neurotransmitters (heteroreceptors). GABA
` recep-
`B
`tors mediate their presynaptic effects through volt-
`age-dependent inhibition of high-voltage–activat-
`43
`ed calcium channels (Fig. 2).
`
` receptors
`ghb and gaba
`b
`Because of the structural similarity of GHB to GABA
`-like effects of GHB,
`and the pharmacologic GABA
`B
`the question of whether the GHB receptor and the
`GABA
` receptor are the same has been raised, and
`B
`
`2722
`
`n engl j med
`
`352;26
`
`www.nejm.org june
`
`30
`
`,
`
`2005
`
`The New England Journal of Medicine
`
`AMN1019
`IPR of Patent No. 8,772,306
`
`

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`drug therapy
`
`1,4-Butanediol
`
`Alcohol dehydrogenase
`
`g-Butyrolactone
`
`g-Hydroxybutyraldehyde
`
`Serum lactonase
`
`a-Ketoglutarate
`
`D-2-Hydroxyglutarate
`transhydrogenase
`
`D-2-Hydroxyglutaric acid
`
`Unknown
`isomerase
`
`Succinic
`semialdehyde
`
`L-2-Hydroxyglutarate
`
`Uncharacterized reaction
`
`2-Carbon
`condensation?
`
`4,5-Dihydroxyhexanoate
`
`CO2 + H2O
`
`GHB
`
`Fatty
`acid
`b-oxidation
`spiral
`
`Succinic
`semialdehyde
`reductase
`
`b-Oxidation
`(keto and hydroxy
`acids; glycollate)?
`
`Succinic
`semialdehyde
`dehydrogenase
`
`Aldehyde dehydrogenase
`
`Homocarnosine
`
`Carnosinase
`
`GHB
`dehydrogenase
`
`GABA
`
`GABA
`transaminase
`
`Succinic
`semialdehyde
`
`Blocked in
`deficiency of
`succinic
`semialdehyde
`dehydrogenase
`
`Succinate
`
`Krebs
`cycle
`
`-Butyrolactone and 1,4-Butanediol.
`Figure 1. Putative Metabolic Interrelationship of GHB with g
`The most important synthetic pathway for
`-hydroxybutyric acid (GHB) entails conversion of
`-aminobutyric acid
`g
`g
`(GABA) to succinic semialdehyde by mitochondrial GABA transaminase, followed by reduction of succinic semialdehyde
`to GHB by cytosolic succinic semialdehyde reductase. Mitochondrial succinic semialdehyde dehydrogenase, converting
`succinic semialdehyde to succinate, couples neurotransmitter metabolism to mitochondrial energy production. This is
`the enzyme missing in clinical and experimental deficiency of succinic semialdehyde dehydrogenase. A minor pathway
`for GHB production involves partial oxidation of 1,4-butanediol. Systemically administered
`-butyrolactone is converted
`g
`by a circulating lactonase to GHB. This lactonase is not present in brain tissue. The most significant catabolic pathway
`+
`-linked succinic semialdehyde reduc-
`for GHB degradation is the oxidation of GHB to succinic semialdehyde by NADP
`tase. The resultant succinic semialdehyde undergoes further metabolism to either GABA or succinate. A mitochondrial
`+
`NADP
`-independent transhydrogenase is capable of metabolizing GHB to succinic semialdehyde with the production of
`d
`l
`-2-hydroxyglutaric acid from
`-2-hydroxyglutarate and an end product of 4,5-dihydroxyhexanoate. There is disagree-
`ment as to whether there is significant metabolism of GHB through a
`-oxidation scheme.
`b
`
`data have been conflicting on this point. However,
`the results of recent studies, taken in conjunction
`with older data, suggest that the GHB receptor and
`22,44,45
`the GABA
` receptor are separate and distinct.
`B
`GHB binds to the GHB receptor and the GABA
`B
`receptor with high affinity and low affinity, respec-
`14,15
` suggest that
`tively. Available biochemical data
`the intrinsic neurobiologic activity of GHB is medi-
`ated through the GHB receptor. However, many of
`the pharmacologic, clinical, behavioral, and toxico-
`logic effects of exogenously administered GHB (Ta-
`ble 1) appear to be mediated through the GABA
`B
`receptor, where GHB may act both directly, as a
`45,46
`partial GABA
` receptor agonist,
` and indirect-
`B
`
`ly, on the GABA
` receptor, through GHB-derived
`B
`47
`GABA.
` The micromolar concentrations of GHB
`that are normally present in mammalian brain
`31
`tissue
` can activate GHB receptors but are insuf-
` receptors, for which GHB
`ficient to activate GABA
`B
`has a weak affinity. However, the supraphysiolog-
`ic (i.e., millimolar) concentrations of GHB that
`4
`result from systemic administration
` of this com-
`pound have been shown to compete for binding
`35,48
`sites at the GABA
` receptor,
` activate recombi-
`B
`45,49
`nant GABA
` receptor heterodimers,
` and have
`B
`an electrophysiological effect that is blocked by
` receptor antagonist but not by a
`a specific GABA
`B
`46,50
`GHB antagonist.
`
`n engl j med
`
`352;26
`
`www.nejm.org june
`
`30, 2005
`
`2723
`
`The New England Journal of Medicine
`
`AMN1019
`IPR of Patent No. 8,772,306
`
`

`
`The new england journal of medicine
`
`
`
`
`
`
`
`
`
`
`Exogenous GHB
`from abuse
`or addiction
`
`Presynaptic neuron
`
`Glutamate
`
`GHB-derived
`GABA
`
`GHBR
`
`GABA
`
`Endogenous
`GHB
`
`GABABR
`
` Ca2+
`channel
`
`Exogenous GHB
`
`GHB-derived
`GABA
`
`GHBR
`
`GABAAR
`Cl¡ channel
`
`GHBR
`
`GABAAR
`Cl¡ channel
`
`K+
`channel
`
`GABABR
`
`Endoplasmic
`reticulum
`
`Postsynaptic neuron
`
`Figure 2. Synthesis and Release of GHB and GABA at Synapses.
`The diagram shows the presynaptic and postsynaptic effects of endogenously
`released g-hydroxybutyric acid (GHB) (as indicated by dashed arrows) and
`g-aminobutyric acid (GABA) (as indicated by solid arrows) and the effects of
`the exogenously administered GHB, as in abuse and addiction. GABA is synthe-
`sized from glutamate in inhibitory neurons and in turn gives rise to GHB.
`Both GHB and GABA are released on depolarization of the GABA-releasing
`(GABAergic) neuron. GABA, in forms that are either endogenous or derived
`from exogenously administered GHB, acts on GABAA and GABAB receptors
`(GABAAR and GABABR, respectively). GABAA receptors are ionotropic and,
`when activated by GABA, cause fast postsynaptic inhibition by the efflux of
`chloride ions (Cl¡). GABAB receptors are metabotropic and, when activated by
`either GABA or high concentrations of GHB, induce slow postsynaptic inhibi-
`tion by activating potassium (K+) currents. Presynaptic GABAB autoreceptors
`— when activated by GHB, GABA, or both — reduce the release of GABA by
`suppressing the influx of calcium (Ca2+). Both endogenous and exogenous
`forms of GHB have a dual action on the GHB receptor (GHBR) and the
`GABAB receptor. GHB that binds with high affinity to the presynaptic GHB re-
`ceptor decreases the release of GABA; GHB that binds to a low-affinity site on
`the GABAB receptor increases activation of cell-surface receptors by inhibiting
`constitutive and agonist-induced endocytosis. The result is enhancement of
`GHB function mediated by GABAB receptors, with a greater effect on presyn-
`aptic inhibition than on postsynaptic inhibition. Adapted from Owens and
`Kreigstein.40
`
`In addition to being a weak partial agonist of the
`GABAB receptor, GHB may also activate the GABAB
`receptor indirectly, through its conversion to GABA
`(Fig. 2). This hypothesis could explain the inordi-
`nately high concentration of GHB required to pro-
`duce GABAB-receptor–mediated effects, since high
`micromolar to low millimolar concentrations of
`GHB are required to produce enough GHB-derived
`GABA to activate GABAB receptors.47 Furthermore,
`recent data suggest that GHB-derived GABA acti-
`vates the GABAB receptor and induces endocytosis
`of the GABAB receptor, whereas GHB itself oppos-
`es this process and, acting at the GABAB receptor,
`causes the GABAB receptor to be retained on the cell
`surface, thus prolonging the functionality of the re-
`ceptor.51
`Thus, experimental evidence to date suggests
`that the high concentrations of GHB in brain tissue
`that would be predicted to accrue from exogenous
`administration of this compound4 — as occurs in
`the clinical scenarios of GHB intoxication, addic-
`tion, and abuse — may exert their protean pharma-
`cologic, toxicologic, and behavioral effects primar-
`ily through mechanisms mediated by the GABAB
`receptor (Fig. 2).
`
`toxicity, abuse, addiction,
`and withdrawal
`
`ghb toxicity
`GHB has a half-life of 20 to 30 minutes, plasma lev-
`els peak about 40 minutes after oral ingestion, and
`the compound can be detected in urine for up to 12
`hours.52 GHB has a narrow margin of safety. Doses
`of 20 to 30 mg per kilogram of body weight lead to
`euphoria and memory loss, as well as to drowsiness
`and sleep. However, coma may result when twice
`this dose (or more) is administered.53 In some se-
`ries, GHB was the second most common drug de-
`tected in the serum of young people presenting with
`drug-induced coma, just behind cocaine.54
`The clinical hallmark of GHB overdose is rapid
`onset of profound coma, myoclonus, respiratory de-
`pression, hypoventilation, and bradycardia. These
`signs persist for an unusually short time, given the
`depth of the coma.53 The usual rapid and uneventful
`recovery from GHB intoxication can create a false
`sense of security in the GHB user.55 The level of con-
`sciousness in patients with GHB-induced coma
`does not correlate with the serum level of GHB.56
`GHB intoxication should be considered in any pa-
`
`2724
`
`n engl j med
`
`352;26
`
`www.nejm.org june
`
`30
`
`, 2005
`
`The New England Journal of Medicine
`
`AMN1019
`IPR of Patent No. 8,772,306
`
`

`
`drug therapy
`
`tient, particularly any young man, who presents with
`rapid onset of coma of unknown cause when head
`trauma, metabolic disorders, central nervous sys-
`tem infection, and increased intracranial pressure
`have been ruled out.
`Death from an overdose of GHB may occur as a
`result of respiratory compromise, aspiration, posi-
`tional asphyxia, or pulmonary edema,53,57,58 as well
`as traumatic injury or accident, possibly due to the
`abrupt loss of consciousness induced by GHB.53,59
`Well over half of all patients who present with GHB
`intoxication have abused other drugs as well.60,61
`Chief among these drugs is ethanol, which is syner-
`gistic with GHB in the induction of respiratory de-
`pression and hypotension62 and thus increases
`the risk of an adverse outcome with an overdose
`of GHB.
`The management of GHB intoxication in a pa-
`tient who is spontaneously breathing is primarily
`supportive and includes stabilization of the airway,
`establishment of intravenous access, oxygen sup-
`plementation, and administration of atropine for
`persistent bradycardia.53,63,64 Intubation is rarely
`indicated but should be performed in the presence
`of marked hypoventilation, hypoxemia, or mucosal
`ulcerations or in the absence of the gag response.53
`Mucosal ulcerations are of concern because illicit
`forms of GHB are often made from g-butyrolactone
`and sodium hydroxide, an extremely basic mixture
`that causes mucosal burns. Aspiration of this mix-
`ture into the lungs can lead to serious pulmonary
`complications.57
`There are no specific antidotes to GHB, nor is
`there a role for naloxone or flumazenil in the rever-
`sal of GHB-induced coma.65 Activated charcoal is
`not indicated because of the very short half-life of
`GHB and the risk of aspiration.53 Although phy-
`sostigmine has been used to reverse the clinical
`signs of GHB intoxication, there is insufficient evi-
`dence to recommend its use in the treatment of GHB
`toxicity.66 A patient who has recovered within six
`hours after the onset of symptoms can be dis-
`charged, because GHB has a relatively short half-life,
`and patients usually have a rapid and uneventful re-
`covery from an overdose of GHB. Before discharge,
`the cause of the GHB toxicity should be determined
`— in other words, did the overdose occur acciden-
`tally during a one-time recreational use, or did it oc-
`cur in the context of repeated GHB abuse? Discharge
`plans should be made accordingly, to provide the pa-
`tient with assistance in dealing with the issues that
`led to the GHB overdose. This strategy is particular-
`
`ly important in the avoidance of GHB withdrawal if
`chronic GHB abuse led to the overdose. Any patient
`with a recovery time that is longer than six hours
`should be admitted to the hospital.
`
`ghb abuse
`Since the early 1990s, GHB and its prodrugs, g-buty-
`rolactone and 1,4-butanediol, have been used and
`abused by bodybuilders67 because these com-
`pounds were reported to stimulate the production
`of growth hormone (Table 2).27 Like g-butyrolac-
`tone, 1,4-butanediol has behavioral and toxic ef-
`fects caused primarily by its metabolism to GHB by
`an alcohol dehydrogenase.72,73 However, the diol
`itself carries inherent toxicity and is particularly
`dangerous when used in conjunction with ethanol,
`which enhances its toxicity, probably because of
`competition of the two compounds for alcohol de-
`hydrogenase.74
`By the late 1990s, GHB had become a popular
`club drug and had gained substantial notoriety both
`as a major recreational drug of abuse55,62,68 and as
`a “date rape” drug.75 Subsequently, data on the
`addictive properties of these compounds began to
`emerge.59 In 1990, the Food and Drug Administra-
`tion had banned the sale of nonprescription GHB;
`in 2000, the agency classified it as a Schedule I sub-
`stance.76 However, illicit forms of GHB remain
`available under a number of names, such as G, liq-
`uid ecstasy, grievous bodily harm, Georgia home
`boy, liquid X, soap, easy lay, salty water, scoop, cher-
`ry meth, and nitro.53,69 In addition, g-butyrolactone
`and 1,4-butanediol are still available for purchase
`on the Internet, where they are advertised for mood
`enhancement, sleep induction, and bodybuilding.77
`The abuse of GHB and its congeners, g-butyro-
`lactone and 1,4-butanediol, probably stems from
`the euphoria, disinhibition, and heightened sexual
`awareness said to be experienced after administra-
`tion of the drug.69 The psychic effects of GHB have
`been likened to those of ethanol in combination
`with reduced anxiety, feelings of euphoria, enhanced
`sensuality, and emotional warmth.53 The resultant
`dreamy, altered sensorium accompanying the use
`of GHB has made it popular among attendees of
`so-called circuit parties77 or “raves”.60 Raves, all-
`night dance parties attended by large numbers of
`young people, are characterized by clandestine ven-
`ues, hypnotic electronic music, and the liberal use
`of drugs, among them GHB.78 Circuit parties differ
`from raves in that they are usually attended by men
`who are either bisexual or homosexual.77 When
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`Table 2. Clinical Aspects of GHB Overdose, Abuse, Addiction, and Withdrawal.*
`
`Feature
`
`Overdose
`
`Comments
`
`References
`Couper et al.,56 Chin et al.,63
`Mokhlesi et al.65
`
`Clinical characteristics Men with history of drug overdose, substance abuse, or psychiatric illness
`Profound coma of rapid onset associated with myoclonus, hypoventilation, brady-
`cardia, and miosis
`Clinical symptoms indistinguishable from overdose of benzodiazepine or ethanol
`Respiratory depression worse when ingested with ethanol
`Usually rapid and uneventful recovery
`Difficult to diagnose because of nonspecific nature of symptoms, rapid disappear-
`ance of GHB from urine and blood, and failure of routine screens to detect GHB
`Supportive treatment with stabilization of the airway, intravenous access, oxygen
`supplementation, and atropine for persistent bradycardia
`No specific antidote
`No indication for activated charcoal, naloxone, or flumazenil
`Little evidence for efficacy of physostigmine
`Intubate for serious hypoventilation, absence of the gag reflex, hypoxemia, or pres-
`ence of mucosal ulcerations
`
`Treatment
`
`Abuse
`
`Clinical characteristics
`
`Treatment
`Addiction
`
`Clinical characteristics
`
`Treatment
`Withdrawal
`
`Clinical characteristics
`
`Treatment
`
`Increased prevalence in young men
`Club drug used at raves and circuit parties
`Abused in conjunction with ethanol, cocaine, and “ecstasy”
`Taken for euphoria, disinhibition, and heightened sexual awareness
`None
`
`Rarely occurs in occasional users
`Occurs in bodybuilders and those using GHB for anxiety and insomnia
`Frequent and increased dosing prompted by rebound insomnia
`Use of drug every 2 to 4 hr around the clock
`None
`
`Increased prevalence in men
`History of bodybuilding, anxiety, or insomnia
`Use of drug every 2 to 4 hr around the clock
`Onset of symptoms 1 to 6 hr after last dose
`Tremor, autonomic dysfunction, anxiety, delirium
`Symptoms lasting up to 2 wk, possibly recurring in episodic fashion
`Supportive care; correction of imbalance in fluids, glucose level, and electrolytes
`Physical restraint possibly required
`Sedation with high-dose benzodiazepines
`No indication for antipsychotic or anticonvulsant drugs
`
`* GHB denotes g-hydroxybutyric acid.
`
`Van Sassenbroeck
`et al.,60 Kam and Yoong,68
`McDonough et al.69
`
`Teter and Guthrie,55
`Freese et al.59
`
`McDonough et al.,69 Tarabar
`and Nelson,70 Anderson
`and Dyer71
`
`used at raves and circuit parties, GHB frequently
`is ingested along with other illicit drugs, most com-
`monly ethanol, methylenedioxymethamphetamine
`(MDMA, or “ecstasy”), or cocaine.60 The abuse of
`GHB at raves and other party settings appears to
`be far more prevalent among men than among
`women.61,69,79
`GHB poses a serious risk for persons who are in-
`
`fected with the human immunodeficiency virus who
`are taking protease inhibitors, since these com-
`pounds alter the metabolism of GHB through their
`interaction with the cytochrome P-450 system. The
`result is that even small doses of GHB in the pres-
`ence of these compounds may lead to the classic
`signs of GHB overdose (i.e., coma and respiratory
`compromise).80,81
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`drug therapy
`
`ghb addiction
`GHB is highly addictive.76 Occasional users of the
`drug may be at risk for rape, overdose, or death,
`given the settings in which occasional use occurs,
`but occasional users are unlikely to become addict-
`ed. Frequent users who take GHB as an antidepres-
`sant or for sleep, weight loss, or the enhancement
`of bodybuilding are far more likely to become ad-
`dicted.59 Some GHB users describe rebound insom-
`nia or alertness occurring after two or three hours
`of sleep, an effect that often leads them to take ad-
`ditional doses to return to sleep. Thus, such users
`may ultimately escalate the dosage to one dose ev-
`ery two to four hours, around the clock.82 GHB us-
`ers typically do not see GHB as a drug because of
`assurances they find in publications and on the In-
`ternet that it is a “safe” and “natural” product.83
`Therefore, the GHB user may ignore warnings from
`friends and family who may comment about in-
`creasingly bizarre behavior; users also generally fail
`to recognize their incipient addiction until with-
`drawal ensues.84
`Protocols for the treatment of GHB addiction
`and systematic detoxification have not been pub-
`lished, to our knowledge. However, it would make
`sense to consider the use of baclofen, a GABAB re-
`ceptor agonist, for such therapy, since this com-
`pound appears to be effective in reducing the need
`for addictive drugs in animal models of GHB addic-
`tion as well as cocaine, heroin, and ethanol addic-
`tion.85,86
`
`ghb withdrawal
`Frequent ingestion of GHB can be associated with
`severe, potentially life-threatening withdrawal
`symptoms, necessitating vigorous clinical manage-
`ment, preferably in an inpatient setting.62,69,82 Al-
`though occasional users of GHB may have a mild
`withdrawal syndrome when the drug is discontin-
`ued, those who have been taking GHB every one
`to three hours can have severe symptoms similar
`to those of withdrawal from ethanol or benzodi-
`azepine.70 In dependent persons, withdrawal symp-
`toms may start within one to six hours after ces-
`sation of the drug.69 Although most withdrawal
`symptoms occur in those who have taken the drug
`every one to three hours, such symptoms have also
`been noted in persons who have used the drug
`every eight hours. In contrast, cessation of GHB pre-
`scribed in the context of once-daily dosing for nar-
`colepsy usually does not lead to withdrawal symp-
`toms.70
`
`The minimum daily dose of GHB that is asso-
`ciated with withdrawal is reported to be 18 g; for
`g-butyrolactone, it is 10 g.54 However, the major
`caveat concerning these data is the lack of quality
`and quantity controls with respect to the ingestion
`of GHB. Since most patients who present with GHB
`toxicity or withdrawal have purchased the drug ille-
`gally, the purity and size of the described “capful”
`or “teaspoon” doses are quite variable, ranging
`from 500 mg to 5 g per dose.59 As in other forms of
`addiction and abuse, most patients who present in
`GHB withdrawal are male.69 Most of them have
`been taking GHB for less than two years, and about
`75 percent have been using GHB, rather than pre-
`cursors such as g-butyrolactone.54
`GHB withdrawal symptoms may be mild on pre-
`sentation, but they may increase in intensity and
`severity over hours or days and culminate in deliri-
`um or frank psychosis. The most common features
`of withdrawal are tremor, tachycardia, restlessness,
`insomnia, anxiety, nausea, and vomiting. Delirium,
`often with diaphoresis and hypertension, occurs in
`people with severe dependence.59,69 Death from
`GHB withdrawal caused by pulmonary edema has
`been reported.69
`Symptoms of withdrawal from GHB may last up
`to two weeks. In addition to the acute GHB with-
`drawal syndrome, a prolonged withdrawal state
`lasting from three to six months and characterized
`by dysphoria, anxiety, memory problems, and in-
`somnia has been reported.87 A person with protract-
`ed or untreated symptoms of GHB withdrawal may
`abuse either alcohol or benzodiazepines in an at-
`tempt to relieve anxiety and insomnia.
`The mainstay of therapy for GHB withdrawal is
`supportive care and sedation to prevent injury, hy-
`perthermia, and rhabdomyolysis. Physical restraint
`may be required in about one third of patients.69
`Benzodiazepines (either lorazepam or diazepam),
`often in very high doses, are the primary agents used
`to treat GHB withdrawal53,69-71,82 because they have
`a broad therapeutic range, a high threshold for re-
`spiratory depression, and are relatively free of car-
`diovascular complications. Antipsychotic agents are
`not indicated in the management of GHB withdraw-
`al and have the added disadvantage of lowering the
`seizure threshold.70 However, there is no evidence
`that anticonvulsant drugs are effective in the treat-
`ment of GHB withdrawal.70 In withdrawal that is
`refractory to benzodiazepines, pentobarbital ad-
`ministered in the intensive care setting is said to be
`effective.69-71,88 Multiple relapses after GHB detox-
`
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`Normal circumstances
`
`Prefrontal
`cortex
`
`Frontal cortex
`
`Hippocampus
`
`Nucleus
`accumbens
`
`Inhibitory
`GABAergic
`neuron
`
`Inhibited
`dopaminergic
`neuron
`
`Ventral
`tegmental area
`
`Inhibitory
`noradrenergic
`fiber
`
`Locus
`ceruleus
`
`Low
`levels of
`dopamine
`
`Presence of GHB
`
`GHB (–)
`
`(+)
`
`(+)
`
`GHB (–)
`
`Increased
`levels of
`dopamine,
`resulting in
`addiction
`and abuse
`
`Disinhibited
`dopaminergic
`neuron
`
`Figure 3. Mesocorticolimbic Dopaminergic Pathways Putatively Involved
`in the Mechanism of GHB.
`These pathways have been defined in the rat brain96; a similar map for the hu-
`man brain does not exist and can only be extrapolated. The dopaminergic
`neurons in this circuit have their cell bodies in the ventral tegmental area,
`from which they project to the nucleus accumbens, amygdala (not shown),
`and prefrontal cortex. Under normal circumstances, the dopaminergic neu-
`rons in this circuitry are under inhibitory control by both noradrenergic fibers
`from the locus ceruleus and GABAergic neurons in the ventral tegmental
`area. However, in the presence of GHB, which is unable to stimulate postsyn-
`aptic GABAB receptors in the ventral tegmental area,97 there is a preferential
`action at GABAB autoreceptors, with decreased release of GABA and resultant
`disinhibition of dopaminergic neurons in the circuit. This disinhibition is fur-
`ther accentuated by GHB-mediated inhibition of noradrenergic neurons from
`the locus ceruleus.98 The result is increased activity of dopaminergic meso-
`corticolimbic circuitry in the presence of increased levels of GHB in the brain;
`addiction then develops. Minus signs denote inhibition, and plus signs disin-
`hibition. Adapted from Gardner and Lowinson.96
`
`ification in patients who have gone through addic-
`tion and withdrawal are common, as are insomnia,
`depression, and abuse of other drugs.84
`
`ghb-facilitated sexual assault
`GHB has received substantial notoriety during the
`past several years as a date-rape drug — in other
`
`words, a compound used to facilitate sexual assault.
`Low doses of GHB (10 to 20 mg per kilogram) in-
`duce short-term antegrade amnesia, increased libi-
`do, euphoria, suggestibility, and passivity, all of
`which contribute to the use of GHB in sexual as-
`saults.75,89-91 Populations that are at high risk for
`drug-facilita