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{{BioPsy}}
 
{{BioPsy}}
   
:''[[GHB]] redirects here. ''
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{{drugbox | Watchedfields = changed
{{lowercase|gamma-Hydroxybutyric acid}}
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| verifiedrevid = 311402204
{{drugbox |
 
 
| image = 4-hydroxybutanoic-acid.png
 
| image = 4-hydroxybutanoic-acid.png
| image2= GHB3d.png
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| image2= GHB-3D-balls.png
 
| width = 200
 
| width = 200
| imagename = ''gamma''-Hydroxybutyric acid
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| imagename = γ-Hydroxybutyric acid
 
| IUPAC_name = 4-Hydroxybutanoic acid
 
| IUPAC_name = 4-Hydroxybutanoic acid
| synonyms = γ-Hydroxybutyric acid<br>''gamma''-Hydroxybutyrate<br>GHB
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| synonyms = γ-Hydroxybutyric acid<br>&gamma;-Hydroxybutyrate<br>GHB
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| CASNo_Ref = {{cascite}}
 
| CAS_number = 591-81-1
 
| CAS_number = 591-81-1
 
| ATC_prefix = N01
 
| ATC_prefix = N01
 
| ATC_suffix = AX11
 
| ATC_suffix = AX11
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| ATC_supplemental = {{ATC|N07|XX04}}
 
| PubChem = 3037032
 
| PubChem = 3037032
| DrugBank = ?
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| ChemSpiderID = 9984
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| DrugBank = DB01440
 
| C = 4 | H = 8 | O = 3
 
| C = 4 | H = 8 | O = 3
 
| molecular_weight = 104.10 g/mol (GHB)<br>126.09 g/mol (sodium salt)<br>142.19 g/mol (potassium salt)
 
| molecular_weight = 104.10 g/mol (GHB)<br>126.09 g/mol (sodium salt)<br>142.19 g/mol (potassium salt)
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| bioavailability = 25% (oral)
 
| bioavailability = 25% (oral)
 
| metabolism = 95%, mainly [[Hepatic]], also in blood and tissues
 
| metabolism = 95%, mainly [[Hepatic]], also in blood and tissues
| elimination_half-life = 30 - 60 minutes
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| elimination_half-life = 30–60 minutes
 
| excretion = 5%, [[Kidney|renal]]
 
| excretion = 5%, [[Kidney|renal]]
 
| pregnancy_category = B
 
| pregnancy_category = B
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| legal_CA = Schedule III
 
| legal_CA = Schedule III
 
| legal_UK = Class C
 
| legal_UK = Class C
| legal_status = Class B ([[New Zealand|NZ]]), [[Controlled Substances Act|Schedule I and III]] ([[United States|US]])
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| legal_status = Class B ([[New Zealand|NZ]]), [[Controlled Substances Act|Schedule I and III]] (US)
 
| routes_of_administration = Usually oral; [[Intravenous therapy|intravenous]]
 
| routes_of_administration = Usually oral; [[Intravenous therapy|intravenous]]
 
}}
 
}}
   
'''''gamma''-Hydroxybutyric acid''' (4-hydroxybutanoic acid, C<sub>4</sub>H<sub>8</sub>O<sub>3</sub>), commonly abbreviated '''GHB''', is a [[metabolomics|naturally-occurring]] substance found in the [[central nervous system]], wine, beef, small citrus fruits, and almost all animals in small amounts.<ref name="Choc_to_Morph">{{cite book |last=Weil |first=Andrew |authorlink=Andrew Weil |coauthors=Winifred Rosen |title= From Chocolate to Morphine|edition=2nd edition |year= 1993|publisher= Houghton Mifflin Company|location=Boston/New York|language=English|isbn= 0-395-66079-3|pages= 77|chapter= Depressants|}}</ref> It is also a [[neuroprotective]] [[medication|therapeutic drug]] that is [[illegal drug|illegal]] in a number of countries.<ref name="erowidGHBlaw">[http://erowid.org/chemicals/ghb/ghb_law.shtml Erowid GHB Vault : Legal Status<!-- Bot generated title -->]</ref> It is currently regulated in the US and sold by Jazz Pharmaceuticals under the name [[Xyrem]].<ref>[http://stocks.us.reuters.com/stocks/fullDescription.asp?rpc=66&symbol=JAZZ.O Jazz Pharmaceuticals Inc (JAZZ.O) Full Description | Stocks | Reuters.com<!-- Bot generated title -->]</ref>
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'''γ-Hydroxybutyric acid''' ('''GHB'''), also known as '''4-hydroxybutanoic acid''' and '''sodium oxybate'''<ref>[http://www.nlm.nih.gov/medlineplus/druginfo/meds/a605032.html Sodium Oxybate: MedlinePlus Drug Information]</ref>, is a naturally-occurring substance found in the [[central nervous system]], wine, beef, small citrus fruits, and almost all animals in small amounts.<ref name="Choc_to_Morph">{{cite book |last=Weil |first=Andrew |authorlink=Andrew Weil |coauthors=Winifred Rosen |title= From Chocolate to Morphine|edition=2nd |year= 1993|publisher= Houghton Mifflin Company|location=Boston/New York|isbn= 0-395-66079-3|page= 77|chapter= Depressants}}</ref> It is also a [[neuroprotective]] [[medication|therapeutic nutrient]] {{Citation needed|date=November 2009}} that is categorized as an [[illegal drug]] in many countries.<ref name="erowidGHBlaw">[http://erowid.org/chemicals/ghb/ghb_law.shtml Erowid GHB Vault : Legal Status<!-- Bot generated title -->].</ref> It is currently regulated in the US. GHB as the [[sodium]] salt, known as sodium oxybate, is sold by Jazz Pharmaceuticals under the name [[Xyrem]]<ref>[http://stocks.us.reuters.com/stocks/fullDescription.asp?rpc=66&symbol=JAZZ.O Jazz Pharmaceuticals Inc (JAZZ.O) Full Description | Stocks | Reuters.com<!-- Bot generated title -->].</ref> to treat [[cataplexy]] and excessive daytime sleepiness in patients with [[narcolepsy]].
   
Historically, GHB has been used in a medical setting as a general anesthetic, to treat conditions such as insomnia, clinical depression, narcolepsy, and alcoholism, and to improve athletic performance.<ref name="emedicineonGHB">{{cite web | title = Toxicity, Gamma-Hydroxybutyrate | date = [[January 8]], [[2007]] | author = Theodore I Benzer | url = http://www.emedicine.com/emerg/topic848.htm | publisher = [[eMedicine]]}}</ref> It is also used [[illegal drugs|illegally]] under the street names ''Juice'', ''Liquid Ecstasy'', ''Fantasy'', '''''G'''eorgia '''H'''ome'''b'''oy'', and simply ''G'', either as an intoxicant or as a [[date rape drug]]. GHB is naturally produced in the human body's cells and is structurally related to the [[ketone body]] [[beta-hydroxybutyrate]]. As a drug, it is used most commonly in the form of a salt.<ref>e.g., '''sodium gamma-hydroxybutyrate''' (Na.GHB, '''sodium oxybate''') or potassium gamma-hydroxybutyrate (K.GHB)</ref> GHB is also produced as a result of fermentation, and so is found in small quantities in some beers and wines.
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GHB has been used in a medical setting as a general anesthetic, to treat conditions such as insomnia, clinical depression, narcolepsy, and [[alcoholism]], and to improve athletic performance.<ref name="emedicineonGHB">{{cite web | title = Toxicity, Gamma-Hydroxybutyrate | date = 8 January 2007 | author = Theodore I Benzer | url = http://www.emedicine.com/emerg/topic848.htm | publisher = [[eMedicine]]}}</ref> It is also used as an intoxicant ([[illegal drugs|illegally]] in many jurisdictions) or as a [[date rape drug]].<ref name="dea-daterape"/> GHB is naturally produced in the human body's cells and is structurally related to the [[ketone body]] [[beta-hydroxybutyrate]]. As a supplement/drug, it is used most commonly in the form of a salt.<ref>e.g., '''sodium gamma-hydroxybutyrate''' (Na.GHB, '''sodium oxybate''') or potassium gamma-hydroxybutyrate (K.GHB).</ref> GHB is also produced as a result of fermentation, and so is found in small quantities in some beers and wines. [[Succinic semialdehyde dehydrogenase deficiency]] is a disease that causes GHB to accumulate in the blood.
   
 
== History ==
 
== History ==
Synthesis of the chemical GHB was first reported in 1874 by Alexander Saytzeff,<ref>Alexander Saytzeff (1874): Ueber die Reduction des Succinylchlorids. Liebigs Annalen der Chemie. 171: 258-290. {{DOI|10.1002/jlac.18741710216}}</ref> but the first major research into its use in humans was conducted in the early 1960s by Dr. [[Henri Laborit]] to use in studying the neurotransmitter [[GABA]].{{Fact|date=February 2007}} It quickly found a wide range of uses due to its minimal side-effects and short duration of action, the only difficulties being the narrow safe dosage range and the dangers presented by its combination with [[alcohol]] and other [[central nervous system]] depressants.
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Synthesis of the chemical GHB was first reported in 1874 by [[Alexander Mikhaylovich Zaytsev|Alexander Zaytsev]],<ref>{{cite journal | author = Alexander Saytzeff | year = 1874 | title = Über die Reduction des Succinylchlorids | journal = [[Liebigs Annalen der Chemie]] | volume = 171 | pages = 258–290 | language = German | doi = 10.1002/jlac.18741710216}}</ref> but the first major research into its use in humans was conducted in the early 1960s by Dr. [[Henri Laborit]] to use in studying the neurotransmitter [[GABA receptor|GABA]].<ref> {{cite journal | author = H. Laborit, J.M. Jouany, J. Gerald, F. Fabiani | year = 1960 | title = Generalities concernant l’etude experimentale de l’emploi clinique du gamma hydroxybutyrate de Na | journal = Aggressologie | volume = 1 | page =407 | language = French| pmid = 13758011}}</ref> It quickly found a wide range of uses due to its minimal side-effects and short duration of action, the only difficulties being the narrow therapeutic dosage range (despite an unusually high [[LD50]]) and the dangers presented by its combination with [[alcohol]] and other [[central nervous system]] depressants.
   
GHB was widely used in France, Italy, and other European countries for several decades as a sleeping agent and an anesthetic in childbirth, but problems with its abuse potential and development of newer drugs have led to a decrease in legitimate medical use of GHB in recent times. The only common medical applications for GHB today are in the treatment of [[narcolepsy]] and more rarely alcoholism. In the typical scenario, GHB has been synthesized from [[gamma-Butyrolactone|''gamma''-butyrolactone]] (GBL) by adding [[sodium hydroxide]] (lye) in [[ethanol]] or water. As of late, GBL has become controlled and more circuitous routes have to be taken, such as those starting with [[tetrahydrofuran]] (THF).
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GHB was widely used in France, Italy, and other European countries for several decades as a sleeping agent and an anesthetic in childbirth, but problems with its abuse potential and development of newer drugs have led to a decrease in legitimate medical use of GHB in recent times. The only common medical applications for GHB today are in the treatment of [[narcolepsy]] and more rarely alcoholism. In the typical scenario, GHB has been synthesized from [[gamma-Butyrolactone|&gamma;-butyrolactone]] (GBL) by adding [[sodium hydroxide]] (lye) in [[ethanol]] or water. As of late, GBL has become controlled and more circuitous routes have to be taken, such as those starting with [[tetrahydrofuran]] (THF).
   
A popular children's toy, [[Bindeez]] (also known as Aqua Dots, in the United States), produced by Melbourne company Moose, was banned in Australia in early November 2007 when it was discovered that [[1,4-Butanediol|1,4-butanediol]] (1,4-B), which is [[metabolism|metabolized]] into GHB, had been substituted for the non-toxic plasticiser [[1,5-Pentanediol|1,5-pentanediol]] in the bead manufacturing process. Three young children were hospitalized as a result of ingesting a large number of the beads, and the toy was recalled.<ref>{{Cite news
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A popular children's toy, [[Bindeez]] (also known as Aqua Dots, in the United States), produced by Melbourne company Moose, was banned in Australia in early November 2007 when it was discovered that [[1,4-Butanediol|1,4-butanediol]] (1,4-B), which is [[metabolism|metabolized]] into GHB, had been substituted for the non-toxic plasticiser [[1,5-Pentanediol|1,5-pentanediol]] in the bead manufacturing process. Three young children were hospitalized as a result of ingesting a large number of the beads, and the toy was recalled.<ref>{{Cite news
 
| author = Michael Perry, James Pomfret, Roger Crabb
 
| author = Michael Perry, James Pomfret, Roger Crabb
 
| title = Australia bans China-made toy on toxic drug risk
 
| title = Australia bans China-made toy on toxic drug risk
| date = Nov 7, 2007
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| date = 7 November 2007
 
| publisher = [[Reuter]]
 
| publisher = [[Reuter]]
 
| url = http://www.reuters.com/article/worldNews/idUSSYD2129620071107
 
| url = http://www.reuters.com/article/worldNews/idUSSYD2129620071107
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== Pharmacology ==
 
== Pharmacology ==
GHB has at least two distinct binding sites<ref>[http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=15567424&ordinalpos=25&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum Gamma-hydroxybutyric acid (GHB) and gamma-aminobut...[Neuropharmacology. 2004&#93; - PubMed Result<!-- Bot generated title -->]</ref> in the [[central nervous system]]. GHB is an agonist at the newly-characterized [[GHB receptor]], which is [[inhibitory]],<ref>[http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T4P-3XRY8R1-J&_user=6304637&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000069652&_version=1&_urlVersion=0&_userid=6304637&md5=a5a75f0ed71f53cdf5a9fa86477d119c]</ref> <ref name="mechanism">[http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=15745703&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum [A mechanism for gamma-hydroxybutyrate (GHB) as a ...[Med Sci (Paris). 2005&#93; - PubMed Result<!-- Bot generated title -->]</ref> and it is a weak agonist at the [[GABA receptor|GABA<sub>B</sub>]] receptor, which is also [[inhibitory]].<ref name="mechanism" /> GHB is a naturally occurring substance which acts in a similar fashion to some [[neurotransmitters]] in the mammalian brain.<ref>[http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=15047976&ordinalpos=11&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum Gamma-hydrobutyric acid (GHB) and its chemical mod...[Pol J Pharmacol. 2004 Jan-Feb&#93; - PubMed Result<!-- Bot generated title -->]</ref> GHB is probably synthesized from GABA in GABAergic [[neurons]], and released when the neurons fire.<ref name="mechanism" />
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GHB has at least two distinct binding sites<ref>{{cite journal |author=Wu Y, Ali S, Ahmadian G, ''et al.'' |title=Gamma-hydroxybutyric acid (GHB) and gamma-aminobutyric acidB receptor (GABABR) binding sites are distinctive from one another: molecular evidence |journal=[[Neuropharmacology]] |volume=47 |issue=8 |pages=1146–56 |year=2004 |month=December |pmid=15567424 |doi=10.1016/j.neuropharm.2004.08.019 |url=}}</ref> in the [[central nervous system]]. GHB is an [[agonist]] at the newly-characterized [[GHB receptor]], which is [[excitatory postsynaptic potential|excitatory]],<ref>{{cite journal | doi = 10.1016/S0006-2952(99)00265-8 | title = γ-hydroxybutyrate receptor function studied by the modulation of nitric oxide synthase activity in rat frontal cortex punches | year = 1999 | author = Cash, C | journal = Biochemical Pharmacology | volume = 58 | page = 1815 }}</ref><ref name="mechanism">{{cite journal |author=Maitre M, Humbert JP, Kemmel V, Aunis D, Andriamampandry C |title=[A mechanism for gamma-hydroxybutyrate (GHB) as a drug and a substance of abuse] |language=French |journal=[[Med Sci (Paris)]] |volume=21 |issue=3 |pages=284–9 |year=2005 |month=March |pmid=15745703 |doi= |url=http://www.edk.fr/reserve/revues/ms_papier/e-docs/00/00/06/F7/document_article.md}}</ref> and it is a weak agonist at the [[GABA receptor|GABA<sub>B</sub>]] receptor, which is [[inhibitory]].<ref name="mechanism" /> GHB is a naturally-occurring substance that acts in a similar fashion to some [[neurotransmitters]] in the mammalian brain.<ref>{{cite journal |author=Waszkielewicz A, Bojarski J |title=Gamma-hydrobutyric acid (GHB) and its chemical modifications: a review of the GHBergic system |journal=[[Pol J Pharmacol]] |volume=56 |issue=1 |pages=43–9 |year=2004 |pmid=15047976 |doi= |url=http://www.if-pan.krakow.pl/pjp/pdf/2004/1_43.pdf|format=PDF}}</ref> GHB is probably synthesized from GABA in GABAergic [[neurons]], and released when the neurons fire.<ref name="mechanism" />
   
If taken orally, GABA itself would not cross the [[blood-brain-barrier]], nor would a high concentration actually reach the GABA receptors once in the brain. Since GABA is naturally synthesized in the brain, a higher than normal concentration would be quickly metabolized.<ref>[http://www.bio.net/bionet/mm/neur-sci/1999-May/038337.html OTC GABA and the Blood-Brain Barrier<!-- Bot generated title -->]</ref>
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GHB induces the accumulation of either a derivative of [3H]-tryptophan or [3H]-tryptophan itself in the extracellular space, possibly by increasing tryptophan transport across the blood-brain barrier. The blood content of certain neutral amino-acids, including tryptophan, is also increased by peripheral GHB administration. GHB-induced stimulation of tissue serotonin turnover may be due to an increase in tryptophan transport to the brain and in its uptake by serotonergic cells. As the serotonergic system may be involved in the regulation of sleep, mood, and anxiety, the stimulation of this system by high doses of GHB may be involved in certain neuropharmacological events induced by GHB administration.
   
However, at pharmacological doses, GHB reaches much higher concentrations in the brain and activates GABA<sub>B</sub> receptors, which are primarily responsible for its sedative effects.<ref>[http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&uid=16129424&cmd=showdetailview Drosophila GABA(B) receptors are involved in behav...[Eur J Pharmacol. 2005&#93; - PubMed Result<!-- Bot generated title -->]</ref> GHB's sedative effects are blocked by GABA<sub>B</sub> antagonists.
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If taken orally, GABA itself very poorly crosses the [[blood-brain-barrier]], nor do high concentrations very effectively reach the GABA receptors once inside the brain. Since GABA is naturally synthesized in the brain, a higher-than-normal concentration would be quickly metabolized.<ref>[http://www.bio.net/bionet/mm/neur-sci/1999-May/038337.html OTC GABA and the Blood-Brain Barrier<!-- Bot generated title -->].</ref>
   
The role of the GHB receptor in the behavioural effects induced by GHB is more complex. GHB receptors are densely expressed in many areas of the brain, including the cortex and hippocampus, and these are the receptors that GHB displays the highest affinity for. There has been somewhat limited research into the GHB receptor - however, there is evidence that activation of the GHB receptor in some brain areas results in the release of [[glutamate]] - the principle excitatory neurotransmitter.<ref>[http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=14535954&ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum Selective gamma-hydroxybutyric acid receptor ligan...[J Neurochem. 2003&#93; - PubMed Result<!-- Bot generated title -->]</ref> Drugs which selectively activate the GHB receptor cause [[absence seizures]] in high doses, as do GHB and GABA(B) agonists.<ref>[http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=7791129&ordinalpos=5&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum Presynaptic gamma-hydroxybutyric acid (GHB) and ga...[J Pharmacol Exp Ther. 1995&#93; - PubMed Result<!-- Bot generated title -->]</ref>
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However, at pharmacological doses, GHB reaches much higher concentrations in the brain and activates GABA<sub>B</sub> receptors, which are primarily responsible for its sedative effects.<ref>{{cite journal |author=Dimitrijevic N, Dzitoyeva S, Satta R, Imbesi M, Yildiz S, Manev H |title=Drosophila GABA(B) receptors are involved in behavioral effects of gamma-hydroxybutyric acid (GHB) |journal=[[Eur. J. Pharmacol.]] |volume=519 |issue=3 |pages=246–52 |year=2005 |month=September |pmid=16129424 |doi=10.1016/j.ejphar.2005.07.016 |url=}}</ref> GHB's sedative effects are blocked by GABA<sub>B</sub> antagonists.
   
Activation of both the GHB receptor and GABA(B) is responsible for the addictive profile of GHB. GHB's effect on dopamine release is biphasic,<ref>[http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=1847191&ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum Extracellular events induced by gamma-hydroxybutyr...[J Neurochem. 1991&#93; - PubMed Result<!-- Bot generated title -->]</ref> low concentrations stimulate dopamine release via the GHB receptor.<ref>[http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=2173754&ordinalpos=9&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum A specific gamma-hydroxybutyrate receptor ligand p...[J Pharmacol Exp Ther. 1990&#93; - PubMed Result<!-- Bot generated title -->]</ref> Higher concentrations inhibit dopamine release via GABA(B) receptors as do other GABA(B) agonists such as [[baclofen]] and [[phenibut]].<ref>[http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=8549640&ordinalpos=15&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum Tonic GABA-ergic modulation of striatal dopamine r...[Eur J Pharmacol. 1995&#93; - PubMed Result<!-- Bot generated title -->]</ref> After the initial phase of inhibition, dopamine release is then increased via the GHB receptor. Both the inhibition and increase of dopamine release by GHB are inhibited by opioid antagonists such as [[naloxone]] and [[naltrexone]]. Dynorphin may play a role in the inhibition of dopamine release via [[kappa opioid receptor]]s.<ref>[http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=2691926&ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum Gammahydroxybutyrate: an endogenous regulator of e...[Neurosci Biobehav Rev. 1989&#93; - PubMed Result<!-- Bot generated title -->]</ref>
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The role of the GHB receptor in the behavioural effects induced by GHB is more complex. GHB receptors are densely expressed in many areas of the brain, including the cortex and hippocampus, and these are the receptors that GHB displays the highest affinity for. There has been somewhat limited research into the GHB receptor; however, there is evidence that activation of the GHB receptor in some brain areas results in the release of [[glutamate]], the principle excitatory neurotransmitter.<ref name = "nsngtu">{{cite journal |author=Castelli MP, Ferraro L, Mocci I, ''et al.'' |title=Selective gamma-hydroxybutyric acid receptor ligands increase extracellular glutamate in the hippocampus, but fail to activate G protein and to produce the sedative/hypnotic effect of gamma-hydroxybutyric acid |journal=[[J. Neurochem.]] |volume=87 |issue=3 |pages=722–32 |year=2003 |month=November |pmid=14535954 |doi= 10.1046/j.1471-4159.2003.02037.x|url=}}</ref> Drugs that selectively activate the GHB receptor cause [[absence seizures]] in high doses, as do GHB and GABA(B) agonists.<ref>{{cite journal |author=Banerjee PK, Snead OC |title=Presynaptic gamma-hydroxybutyric acid (GHB) and gamma-aminobutyric acidB (GABAB) receptor-mediated release of GABA and glutamate (GLU) in rat thalamic ventrobasal nucleus (VB): a possible mechanism for the generation of absence-like seizures induced by GHB |journal=[[J. Pharmacol. Exp. Ther.]] |volume=273 |issue=3 |pages=1534–43 |year=1995 |month=June |pmid=7791129 |doi= |url=http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=7791129}}</ref>
   
This explains the paradoxical mix of sedative and stimulatory properties of GHB, as well as the so-called "rebound" effect, experienced by individuals using GHB as a sleeping agent, where they awake suddenly after several hours of GHB-induced deep sleep. That is to say, that over time, the concentration of GHB in the system decreases below the threshold for significant GABA<sub>B</sub> receptor activation and activates predominantly the GHB receptor, leading to wakefulness.
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Activation of both the GHB receptor and GABA(B) is responsible for the addictive profile of GHB. GHB's effect on dopamine release is biphasic,<ref>{{cite journal |author=Hechler V, Gobaille S, Bourguignon JJ, Maitre M |title=Extracellular events induced by gamma-hydroxybutyrate in striatum: a microdialysis study |journal=[[J. Neurochem.]] |volume=56 |issue=3 |pages=938–44 |year=1991 |month=March |pmid=1847191 |doi= 10.1111/j.1471-4159.1991.tb02012.x|url=}}</ref> low concentrations stimulate dopamine release via the GHB receptor.<ref>{{cite journal |author=Maitre M, Hechler V, Vayer P, ''et al.'' |title=A specific gamma-hydroxybutyrate receptor ligand possesses both antagonistic and anticonvulsant properties |journal=[[J. Pharmacol. Exp. Ther.]] |volume=255 |issue=2 |pages=657–63 |year=1990 |month=November |pmid=2173754 |doi= |url=http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=2173754}}</ref> Higher concentrations inhibit dopamine release via GABA(B) receptors as do other GABA(B) agonists such as [[baclofen]] and [[phenibut]].<ref>{{cite journal |author=Smolders I, De Klippel N, Sarre S, Ebinger G, Michotte Y |title=Tonic GABA-ergic modulation of striatal dopamine release studied by in vivo microdialysis in the freely moving rat |journal=[[Eur. J. Pharmacol.]] |volume=284 |issue=1-2 |pages=83–91 |year=1995 |month=September |pmid=8549640 |doi= 10.1016/0014-2999(95)00369-V|url=}}</ref> After the initial phase of inhibition, dopamine release is then increased via the GHB receptor. Both the inhibition and increase of dopamine release by GHB are inhibited by opioid antagonists such as [[naloxone]] and [[naltrexone]]. Dynorphin may play a role in the inhibition of dopamine release via [[kappa opioid receptor]]s.<ref>{{cite journal |author=Mamelak M |title=Gammahydroxybutyrate: an endogenous regulator of energy metabolism |journal=[[Neurosci Biobehav Rev]] |volume=13 |issue=4 |pages=187–98 |year=1989 |pmid=2691926 |doi= 10.1016/S0149-7634(89)80053-3|url=}}</ref>
   
Recently, analogs of GHB, such as [[4-hydroxy-4-methylpentanoic acid]] have been synthesised and tested on animals, in order to gain a better understanding of GHB's mode of action.<ref>[http://jpet.aspetjournals.org/cgi/content/full/305/2/675 A Tertiary Alcohol Analog of gamma -Hydroxybutyric Acid as a Specific gamma -Hydroxybutyric Acid Receptor Ligand - Wu et al. 305 (2): 675 - Journal of Pharmacology And Experimental Therapeutics<!-- Bot generated title -->]</ref> Analogues of GHB such as 3-methyl-GHB, 4-methyl-GHB and 4-phenyl-GHB have been shown to produce similar effects to GHB in some animal studies, but these compounds are even less well researched than GHB itself. Of these analogues, only 4-methyl-GHB (gamma-hydroxyvaleric acid, GHV) and its prodrug form [[gamma-valerolactone]] (GVL) have been reported as drugs of abuse in humans, and on the available evidence seem to be less potent but more toxic than GHB, with a particular tendency to cause nausea and vomiting.
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This explains the paradoxical mix of sedative and stimulatory properties of GHB, as well as the so-called "rebound" effect, experienced by individuals using GHB as a sleeping agent, wherein they awake suddenly after several hours of GHB-induced deep sleep. That is to say that, over time, the concentration of GHB in the system decreases below the threshold for significant GABA<sub>B</sub> receptor activation and activates predominantly the GHB receptor, leading to wakefulness.
   
Other prodrug ester forms of GHB have also rarely been encountered by law enforcement, including 1,4-diacetoxybutane, methyl-4-acetoxybutanoate and ethyl-4-acetoxybutanoate, but these are generally covered by analogue laws in jurisdictions where GHB is illegal, and little is known about them beyond their presumably delayed onset and longer duration of action. The intermediate compound 4-hydroxybutaldehyde is also a prodrug for GHB, however as with all aldehydes this compound is caustic and is strong-smelling and foul-tasting; actual use of this compound as an intoxicant is likely to be unpleasant and result in severe nausea and vomiting.
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Recently, analogs of GHB, such as [[4-hydroxy-4-methylpentanoic acid]] have been synthesised and tested on animals, in order to gain a better understanding of GHB's mode of action.<ref>{{cite journal | url = http://jpet.aspetjournals.org/cgi/content/full/305/2/675 | title = A Tertiary Alcohol Analog of gamma-Hydroxybutyric Acid as a Specific gamma -Hydroxybutyric Acid Receptor Ligand | doi = 10.1124/jpet.102.046797 | year = 2003 | author = Wu, H. | journal = Journal of Pharmacology and Experimental Therapeutics | volume = 305 | page = 675 | pmid = 12606613}}</ref> Analogues of GHB such as 3-methyl-GHB, 4-methyl-GHB and 4-phenyl-GHB have been shown to produce similar effects to GHB in some animal studies, but these compounds are even less well researched than GHB itself. Of these analogues, only 4-methyl-GHB (γ-hydroxyvaleric acid, GHV) and its prodrug form [[gamma-valerolactone]] (GVL) have been reported as drugs of abuse in humans, and on the available evidence seem to be less potent but more toxic than GHB, with a particular tendency to cause nausea and vomiting.
   
[[Image:GHB metab path.png]]
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Other prodrug ester forms of GHB have also rarely been encountered by law enforcement, including 1,4-diacetoxybutane, methyl-4-acetoxybutanoate, and ethyl-4-acetoxybutanoate, but these are, in general, covered by analogue laws in jurisdictions where GHB is illegal, and little is known about them beyond their delayed onset and longer duration of action. The intermediate compound 4-hydroxybutaldehyde is also a prodrug for GHB; however, as with all aldehydes this compound is caustic and is strong-smelling and foul-tasting; actual use of this compound as an intoxicant is likely to be unpleasant and result in severe nausea and vomiting.
   
Also note that both of the metabolic breakdown pathways shown for GHB can run in either direction, depending on the concentrations of the substances involved, so the body can make its own GHB either from GABA or from succinic semialdehyde. Under normal physiological conditions, the concentration of GHB in the body is rather low, and the pathways would run in the reverse direction to what is shown here to produce endogenous GHB. However, when GHB is consumed for medical or recreational purposes its concentration in the body is much higher than normal, which changes the enzyme kinetics so that these pathways operate to metabolise GHB rather than producing it.
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[[Image:GHB metab path.png|thumb|center|839px|Metabolic pathway of GHB.]]
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Also note that both of the metabolic breakdown pathways shown for GHB can run in either direction, depending on the concentrations of the substances involved, so the body can make its own GHB either from GABA or from succinic semialdehyde. Under normal physiological conditions, the concentration of GHB in the body is rather low, and the pathways would run in the reverse direction to what is shown here to produce endogenous GHB. However, when GHB is consumed for [[recreational drug use|recreational]] or health promotion purposes, its concentration in the body is much higher than normal, which changes the enzyme kinetics so that these pathways operate to metabolise GHB rather than producing it.
   
 
== Medical uses ==
 
== Medical uses ==
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GHB has been used as a general [[anesthetic]] in the 1960s,<ref name="emedicineonGHB"/> as a [[hypnotic]] in the treatment of [[insomnia]], to treat [[Clinical depression|depression]], and to improve athletic performance. In Italy, under the trade name Alcover (ATC code N07BB), GHB is used in the treatment of [[alcoholism]] (50 to 100 milligrams per kilogram per day, in 3 or more divided doses), both for acute [[alcohol withdrawal]] and medium- to long-term detoxification.<ref>An author/scientist Gian Luigi Gessa has been researching alcoholism and the effects of various drugs to persons afflicted with said disease for the past ten years. His studies in 1998 note that GHB, as a pharmaceutical aid, can be much less toxic and much more effective than the leading pharmaceutical compound ([[disulfiram]]).</ref> In the United States, the [[Food and Drug Administration]] permits the use of GHB under the trade name Xyrem to reduce the number of [[cataplexy]] attacks and excessive daytime sleepiness in patients with [[narcolepsy]].<ref>In clinical trials Xyrem significantly reduced cataplexy attacks at a dose of 6000–9000 mg per night. This is around three times the dose used recreationally, but almost all narcolepsy patients in the clinical trials were already stabilized on CNS stimulants such as [[modafinil]]; in patients not prescribed modafinil, this dosage could be dangerous and should be reduced appropriately. Also, the prescribing information for Xyrem states that patients should take the dose immediately before going to bed, and then a second dose 3–4 hours later. The maximum dose taken at one time should not exceed 4500 mg. Patients with hepatic insufficiency (compromised liver function) have slower clearance of GHB and require reduced doses, typically half the normal dose. Xyrem oral solution is standardised to 500 mg Na.GHB/1 mL water, buffered to pH 7.5 with malic acid.</ref>
GHB has been used historically as a general [[anesthetic]] in the 1960s,<ref name="emedicineonGHB"/> as a [[hypnotic]] in the treatment of [[insomnia]], to treat [[Clinical depression|depression]], and to improve athletic performance. In Italy, under the trade name Alcover (ATC code N07BB), GHB is used in the treatment of [[alcoholism]] (50 to 100 milligrams per kilogram per day, in 3 or more divided doses), both for acute alcohol withdrawal and medium to long-term detoxification.{{Fact|date=February 2007}} <ref>An author/scientist Gian Luigi Gessa has been researching alcoholism and the effects of various drugs to persons afflicted with said disease for the past ten years. His studies in 1998 note that GHB, as a pharmaceutical aid, can be much less toxic and much more effective than the leading pharmaceutical compound ([[disulfiram]]).{{Fact|date=February 2007}}</ref> In the United States, the [[Food and Drug Administration]] permits the use of GHB under the trade name Xyrem to reduce the number of [[cataplexy]] attacks in patients with [[narcolepsy]].<ref>In clinical trials Xyrem significantly reduced cataplexy attacks at a dose of 6000–9000mg per night. This is around three times the dose used recreationally, but almost all narcolepsy patients in the clinical trials were already stabilized on CNS stimulants such as [[modafinil]]; in patients not prescribed modafinil, this dosage could be dangerous and should be reduced appropriately. Also the prescribing information for Xyrem states that patients should take the dose immediately before going to bed, and then a second dose 3–4 hours later. The maximum dose taken at one time should not exceed 4500 mg. Patients with hepatic insufficiency (compromised liver function) have slower clearance of GHB and require reduced doses, typically half the normal dose. Xyrem oral solution is standardised to 500 mg Na.GHB / 1 mL water, buffered to pH 7.5 with malic acid. </ref>
 
   
 
When GHB is used in its sodium or potassium salt form, a significant quantity of excess sodium or potassium may be consumed, which should be taken into consideration by people with heart conditions, hypertension or compromised renal function. The [[bioavailability]] of sodium GHB is considerably reduced when it is consumed with food, and so it is advised to wait at least two hours after eating before consuming the dose. Because of its strong sedative effects, patients should not drive or operate heavy machinery for at least six hours after taking sodium GHB.
 
When GHB is used in its sodium or potassium salt form, a significant quantity of excess sodium or potassium may be consumed, which should be taken into consideration by people with heart conditions, hypertension or compromised renal function. The [[bioavailability]] of sodium GHB is considerably reduced when it is consumed with food, and so it is advised to wait at least two hours after eating before consuming the dose. Because of its strong sedative effects, patients should not drive or operate heavy machinery for at least six hours after taking sodium GHB.
   
Adverse effects from Xyrem in clinical trials included: headache, nausea, dizziness, [[nasopharyngitis]], [[somnolence]], vomiting, [[urinary incontinence]], confusion, [[dyspnea]], [[hypoesthesia]], [[paresthesia]], [[tremor]], [[Vertigo (medical)|vertigo]], and blurred vision. Out of the 717 patients and 182 healthy volunteers who took part in the trials (899 total), two of them died from drug overdoses, although only one of these involved GHB.<ref>[http://www.biopsychiatry.com/ghb/xyrem.pdf Xyrem drug data sheet]</ref>
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Adverse effects from Xyrem in clinical trials included: headache, nausea, dizziness, [[nasopharyngitis]], [[somnolence]], vomiting, [[urinary incontinence]], confusion, [[dyspnea]], [[hypoesthesia]], [[paresthesia]], [[tremor]], [[Vertigo (medical)|vertigo]], and blurred vision. Out of the 717 patients and 182 healthy volunteers who took part in the trials (899 total), two of them died from drug overdoses, although only one of these involved GHB.<ref>[http://www.biopsychiatry.com/ghb/xyrem.pdf Xyrem drug data sheet].</ref>
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  +
In January 2008, Jazz Pharmaceuticals completed enrollment in the second Phase III trial for a modified version of sodium oxybate for use by people with [[Fibromyalgia]], whose sufferers endure much pain and difficulty with sleep.<ref>http://www.reuters.com/finance/stocks/companyProfile?rpc=66&symbol=JAZZ.O</ref><ref>http://investor.jazzpharma.com/phoenix.zhtml?c=210227&p=irol-newsArticle&id=1243912</ref>
   
== Non-medical use==
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The company completed one of the Phase III clinical trials in September 2008.<ref>http://www.prohealth.com/library/showarticle.cfm?libid=13910</ref> It expects to submit a New Drug Application to the US Federal Drug Administration (FDA) before the end of 2009 for JZP-6, for use in treating Fibromyalgia.
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== Non-medical use ==
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{{Refimprovesect|date=August 2008}}
 
[[Image:Gamma-hydroxybutyrate.jpg|thumb|gamma-hydroxybutyrate powder]]
 
[[Image:Gamma-hydroxybutyrate.jpg|thumb|gamma-hydroxybutyrate powder]]
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Do not add street names below without references that they are in common use.
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GHB is a CNS [[depressant]] used as an [[intoxicant]]. It has many [[Street name (disambiguation)|street names]], including "Georgie Home Boy", "Liquid Ecstasy", "Liquid X", and "Liquid G", as well as "Fantasy" and the reordered [[initialism]] [[Grievous bodily harm|GBH]]. At recreational doses, GHB can cause a state of [[Euphoria (emotion)|euphoria]], increased enjoyment of movement and music, increased [[libido]], increased sociability and [[intoxication]]. At higher doses, GHB may induce [[nausea]], [[dizziness]], [[drowsiness]], [[Psychomotor agitation|agitation]], visual disturbances, depressed [[breath]]ing, [[amnesia]], [[unconsciousness]], and death. The effects of GHB can last from 1.5 to 3 hours, or even longer if large doses have been consumed or if it is mixed with alcohol. {{Citation needed|date=January 2009}}
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GHB is a CNS [[depressant]] used as an [[intoxicant]]. It has many street names, including Liquid Ecstasy and Liquid X. At recreational doses, GHB can cause a state of [[Euphoria (emotion)|euphoria]], increased enjoyment of movement and music, increased [[libido]], increased sociability and [[intoxication]]. At higher doses, GHB may induce [[nausea]], [[dizziness]], [[drowsiness]], [[agitation]], visual disturbances, depressed [[breath]]ing, [[amnesia]], [[unconsciousness]], and death. The effects of GHB can last from 1.5 to 3 hours, or even longer if large doses have been consumed or if it is mixed with alcohol.
 
   
In general, the doses used recreationally are between 500 mg and 3000 mg, corresponding to approximately 0.5–3 mL of liquid if the concentration is 1 gram / 1 mL (which is not always the case). When used as a recreational drug, GHB may be found as the sodium or potassium salt, which is a white crystalline powder, or as GHB salt dissolved in water to form a clear solution - generally at a concentration of 1 gram / 1 mL and so is twice the strength of the Xyrem solution sold legally for medical use. The sodium salt of GHB has a thin, very salty, chemical taste.{{Fact|date=November 2007}}
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In general, the doses used recreationally are between 500&nbsp;mg and 3000&nbsp;mg. When used as a recreational drug, GHB may be found as the sodium or potassium salt, which is a white crystalline powder, or as GHB salt dissolved in water to form a clear solution. The sodium salt of GHB has a thin, very salty, chemical taste.{{Citation needed|date=November 2007}}. Other salt forms such as calcium GHB and magnesium GHB have also been reported, but the sodium salt is by far the most common.
   
GHB salt dissolved in water is potentially dangerous, as the concentration of GHB may not be known, and so the actual dose of GHB being consumed can be difficult to judge accurately. Since GHB sold for recreational use is subject to no standardisation it can be impossible to verify the actual concentration of GHB solution bought on the illicit market. Other salt forms such as calcium GHB and magnesium GHB have also been reported, but the sodium salt is by far the most common.
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Some chemicals convert to GHB in the stomach and blood. GBL, or [[gamma-Butyrolactone|''gamma''-butyrolactone]], is one such [[prodrug]]. Other prodrugs include [[1,4-Butanediol|1,4-butanediol]]. There may be additional toxicity concerns with these precursors. 1,4-B and GBL are normally found as pure liquids, although they may be mixed with other more harmful solvents when intended for industrial use, e.g., as [[paint stripper]] or varnish thinner.
   
Some chemicals convert to GHB in the stomach and blood. GBL, or [[gamma-Butyrolactone|''gamma''-butyrolactone]], is one such [[prodrug]]. Other prodrugs include [[1,4-Butanediol|1,4-butanediol]]. There may be additional toxicity concerns with these precursors. 1,4-B and GBL are normally found as pure liquids, although they may be mixed with other more harmful solvents when intended for industrial use, e.g., as [[paint stripper]] or varnish thinner.
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GHB can be produced in clandestine labs, and it is claimed that most of the GHB used in the U.S. is illegally manufactured within its borders. While available as a prescription for [[sleep disorder]]s in some other countries, GHB was banned (in the U.S.) by the FDA in 1990. However, on 17 July 2002, GHB was approved for treatment of cataplexy, often associated with narcolepsy. GHB is "colourless and odorless".<ref name="jones">{{cite journal | author = Jones, C. | title = Suspicious death related to gamma-hydroxybutyrate (GHB) toxicity (2001) | doi = 10.1054/jcfm.2001.0473 | year = 2001 | journal = Journal of Clinical Forensic Medicine | volume = 8 | page = 74}}</ref>
   
GHB can be produced in clandestine labs, and it is claimed that most of the GHB used in the US is illegally manufactured within its borders. While available as a prescription for sleep disorders in some other countries, GHB was banned (in the U.S.) by the FDA in 1990 because of the dangers associated with its use. However, on [[July 17]], [[2002]] GHB was approved for treatment of cataplexy, often associated with narcolepsy. GHB is "colourless and odorless".<ref name="jones">Jones, C. Suspicious death related to gamma-hydroxybutyrate (GHB) toxicity (2001), Journal of Clinical Forensic Medicine Volume 8, Issue 2, June 2001, Pages 74-76.</ref>
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=== Drug ===
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==== Club scene or "rave" ====
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Since the 1970s [[disco|club scene]], [[discotheque|club-goers]] have used a range of drugs to enhance their experience on the dance floor such as amyl nitrite "[[poppers]]" and [[cocaine]]. In the [[1990]]s, newer "club drugs" became popular, such as [[ketamine]] and "designer" phenethylamines designed to circumvent contemporary drug laws, "ecstasy" ([[3,4-methylenedioxymethamphetamine|chemically MDMA, 3,4-methylenedioxy methamphetamine, or 3,4-methylenedioxy methyl alpha-methyl phenethylamine]]) and [[2C-I]] (chemically [[2,5-dimethoxy-4-iodophenethylamine]]) being prominent examples. When the laws "catch up" to certain drugs, clandestine chemists manufacture another drug, designed to affect the user in the same way as the now-banned drug. Since most of these drugs are [[congener|congeners]] of the banned drugs, the [[Federal Analogue Act]] was introduced to ban these substances proactively, based on the proclivity of a said chemical to mimic either the structure or the effects of the banned drug.
   
===As a club scene or "rave" drug===
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Like these other "club drugs," GHB is taken because users feel that it enhances the experience of being in a club or at a party; small doses of GHB are thought to act as a stimulant and [[aphrodisiac]]. GHB is sometimes referred to as ''liquid ecstasy'', ''liquid X'', or ''liquid E'' due to its tendency to produce euphoria and sociability and its use in the dance party scene. When GHB was banned, several "designer drugs" were made to replicate its effects - [[GBL]] and [[1,4-butanediol]], all of which [[drug metabolism|metabolized]] into GHB ''in vivo'' and are now banned.<ref>Mary Klein, Frances Kramer, "Rave drugs: Pharmacological considerations", ''AANA Journal'', Vol. 72 (2004), 61–67.</ref><ref> </ref> Despite this nickname, GHB is not related to "Ecstasy," either chemically or in affect upon the user.
{{Refimprovesect|date=July 2007}}
 
   
Since the 1970s [[disco|club scene]], [[discotheque|club-goers]] have used a range of drugs to enhance their experience on the dance floor such as amyl nitrite "[[poppers]]" and [[cocaine]]; in the 1990s, newer "club drugs" became popular, such as [[ketamine]] and Ecstasy ([[MDMA]]). Like these other "club drugs," GHB is taken because users feel that it enhances the experience of being in a club or at a party; GHB is sometimes referred to as ''liquid ecstasy'' due to its tendency to produce euphoria and sociability and its use in the dance party scene.
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==== Date rape ====
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The drug has been identified as a [[date rape drug]],<ref name="dea-daterape">[http://www.usdoj.gov/dea/ongoing/daterapep.html GHB, GBL and 1,4BD as Date Rape Drugs<!-- Bot generated title -->].</ref> much the same way as [[Alcoholic beverage|alcohol]] and potent [[benzodiazepines]], often known colloquially as "[[Rohypnol]]," the trade name of a certain potent benzodiazepine, [[flunitrazepam]]. (It should be noted that several other vastly more common benzodiazepines are as potent or more potent than Rohypnol - [[Xanax]], [[Ativan]], [[Klonopin]], [[Halcion]] [the most potent of all benzodiazepines], and [[Estazolam]].) It has a [[salt]]y taste, but as it is colourless and odorless,<ref name="jones"/> it has been described as "very easy to add to drinks"<ref name="jones"/> that mask the flavor. GHB has been used in cases of drug-related sexual assault, usually when the victim is vulnerable due to intoxication with a sedative, generally alcohol.<ref>{{cite journal |author=ElSohly MA, Salamone SJ |title=Prevalence of drugs used in cases of alleged sexual assault |journal=J Anal Toxicol |volume=23 |issue=3 |pages=141–6 |year=1999 |pmid=10369321 |doi= |url=}}</ref> However it is difficult to establish how often GHB is used to facilitate rape as it is difficult to detect in a urine sample after a day, and many victims may not recall the rape until some time after this.<ref>[http://www.udel.edu/wellspring/SOS/drugs.htm S.O.S. - Date Rape Drugs<!-- Bot generated title -->].</ref><ref>[http://www.independent.co.uk/news/world/europe/labs-making-daterape-drug-raided-863938.html "Labs making date-rape drug raided"], ''The Independent World'', 10 July 2008.</ref> However cases of GHB being used as a date rape drug is quite rare, see the [[Date_rape_drug#Mistaken_Self-Diagnosis|date rape drug]] article for more information.
   
===As a date rape drug===
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GHB, produced as a sodium salt (sodium oxybate, [[Jazz Pharmaceuticals|Jazz Pharmaceuticals']] Xyrem), may provide a noticeable salty character to the drink, although individual sensitivity to the taste of salt varies.<ref>{{cite journal |author=Pangborn RM, Pecore SD |title=Taste perception of sodium chloride in relation to dietary intake of salt |journal=[[Am. J. Clin. Nutr.]] |volume=35 |issue=3 |pages=510–20 |year=1982 |month=March |pmid=7064902 |doi= |url=http://www.ajcn.org/cgi/pmidlookup?view=long&pmid=7064902}}</ref> GHB can also be produced as different salts, some of which may not have a taste as distinctive as the sodium salt (e.g., magnesium oxybate), or much less commonly in the unstable free-acid form.<ref>{{cite journal | doi = 10.1111/j.1556-4029.2006.00074.x | title = GHB Free Acid: II. Isolation and Spectroscopic Characterization for Forensic Analysis | year = 2006 | author = Witkowski, Mark R.; Ciolino, Laura A.; De Francesco, James V. | journal = Journal of Forensic Sciences | volume = 51 | page = 330}}</ref>
The drug has been referred to in the media as a [[date rape drug]], in much the same way as [[Alcoholic beverage|alcohol]] and [[Rohypnol]]. As it is colourless and odorless,<ref name="jones"/> it has been described as "very easy to add to drinks".<ref name="jones"/> GHB has been used in many cases of drug-related sexual assault, usually when the victim is vulnerable due to intoxication with a sedative, generally alcohol or more rarely cannabis, and as such are less likely to notice a strange taste to his or her drink.<ref>[http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=10369321&ordinalpos=27&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum Prevalence of drugs used in cases of alleged sexua...[J Anal Toxicol. 1999 May-Jun&#93; - PubMed Result<!-- Bot generated title -->]</ref> However it is difficult to establish how often GHB is used to facilitate rape as it is difficult to detect in a urine sample after a day, and many victims may not recall the rape until some time after this.<ref>[http://www.udel.edu/wellspring/SOS/drugs.htm S.O.S. - Date Rape Drugs<!-- Bot generated title -->]</ref> GHB produced as a sodium salt (sodium oxybate) may provide a noticeable salty character to the drink, although individual sensitivity to the taste of salt varies<ref>[http://www.ajcn.org/cgi/content/abstract/35/3/510 Taste perception of sodium chloride in relation to dietary intake of salt - Pangborn and Pecore 35 (3): 510 - American Journal of Clinical Nutrition<!-- Bot generated title -->]</ref>. GHB can also be produced as different salts, some of which may not have a taste as distinctive as the sodium salt (e.g., magnesium oxybate), or much less commonly in the unstable free-acid form.<ref>[http://www.blackwell-synergy.com/doi/abs/10.1111/j.1556-4029.2006.00074.x?journalCode=jfo Blackwell Synergy - J Forensic Sci, Volume 51 Issue 2 Page 330-339, March 2006 (Article Abstract)<!-- Bot generated title -->]</ref>
 
   
===Use by bodybuilders===
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=== Bodybuilding ===
Some athletes and bodybuilders also use GHB, as GHB has been shown to elevate human growth hormone in vivo.<ref>[http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=9373886&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus Different control mechanisms of growth hormone (GH...[Psychoneuroendocrinology. 1997&#93; - PubMed Result<!-- Bot generated title -->]</ref>
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[[File:Dangerous dietary supplements.gif|thumb|right|300px|FDA warning against products containing GHB and its prodrugs.]]
The growth hormone elevating effects of GHB are mediated through muscarinic acetylcholine receptors and can be prevented by prior administration of pirenzepine, a muscarinic acetylcholine receptor blocking agent.<ref>{{cite web|title=Muscarinic cholinergic mediation of the GH response to gamma-hydroxybutyric acid: neuroendocrine evidence in normal and parkinsonian subjects|url=http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6TBX-3XWJKG7-6&_user=10&_coverDate=02%2F29%2F2000&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=e5444781501a8528283aaba4bf91bc30}} </ref>
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Some athletes and bodybuilders also use GHB, as GHB has been shown to elevate [[human growth hormone]] [[in vivo]].<ref>{{cite journal | doi = 10.1016/S0306-4530(97)00055-3 | title = Different control mechanisms of growth hormone (GH) secretion between γ-amino- and γ-hydroxy-butyric acid: neuroendocrine evidence in parkinson's disease | author = Riccardo Volpi, Paolo Chiodera, Paolo Caffarra, Augusto Scaglioni, Antonella Saccani and Vittorio Coiro | journal = [[Psychoneuroendocrinology]] | volume = 22 | issue = 7 | year = 1997 | pages =531–538}}</ref> The growth hormone elevating effects of GHB are mediated through [[muscarinic acetylcholine receptors]] and can be prevented by prior administration of pirenzepine, a muscarinic acetylcholine receptor blocking agent.<ref>{{cite journal |title=Muscarinic cholinergic mediation of the GH response to gamma-hydroxybutyric acid: neuroendocrine evidence in normal and parkinsonian subjects | doi = 10.1016/S0306-4530(99)00048-7 |year=2000 |author=Volpi, R |journal=Psychoneuroendocrinology |volume=25 |page=179}}</ref>
   
As certain [[succinate]] salts have been shown to elevate growth hormone [[in vitro]]<ref>[http://www.nature.com/npp/journal/v11/n4/abs/1380135a.html Alpha-Tocopherol Succinate, But Not Alpha-Tocopherol Or Other Vitamin E Analogs Stimulates Prolactin And Growth Hormone Release From Rat Anterior Pituitary Cells in vitro<!-- Bot generated title -->]</ref>, being GHB is metabolized into succinate some people have suggested this may play a role in the growth hormone elevations from GHB. There is however currently no evidence to show that succinate plays any role in the growth hormone elevations from GHB.
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As certain [[succinate]] salts have been shown to elevate growth hormone [[in vitro]],<ref>{{cite journal | doi = 10.1016/0955-2863(95)00044-Z | title = Alpha-Tocopherol Succinate, But Not Alpha-Tocopherol Or Other Vitamin E Analogs Stimulates Prolactin And Growth Hormone Release From Rat Anterior Pituitary Cells in vitro | year = 1995 | author = Badamchian, M | journal = The Journal of Nutritional Biochemistry | volume = 6 | page = 340}}</ref> and because GHB is metabolized into succinate some people have suggested this may play a role in the growth hormone elevations from GHB. There is however currently no evidence to show that succinate plays any role in the growth hormone elevations from GHB.
   
 
=== Endogenous production by the body ===
 
=== Endogenous production by the body ===
Cells produce GHB by reduction of [[succinic semialdehyde]]. This enzyme appears to be induced by cAMP levels<ref>[http://lib.bioinfo.pl/pmid:9692734 Neurochemical and electrophysiological evidence for the existence of a functional gamma-hydroxybutyrate system in NCB-20 neurons<!-- Bot generated title -->]</ref>, meaning substances that elevate cAMP, such as [[forskolin]] and [[vinpocetine]], may increase GHB synthesis and release. People with the disorder known as [[succinic semialdehyde dehydrogenase deficiency]], also known as [[gamma-hydroxybutyric aciduria]], have elevated levels of GHB in their [[urine]], blood plasma and [[cerebrospinal fluid]].<ref>[http://www.rarediseases.org/search/rdbdetail_abstract.html?disname=Succinic%20Semialdehyde%20Dehydrogenase%20Deficiency Rarediseases.org]</ref>
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Cells produce GHB by reduction of [[succinic semialdehyde]] via the enzyme succinic semialdehyde dehydrogenase. This enzyme appears to be induced by cAMP levels,<ref>{{cite journal |author=Kemmel V, Taleb O, Perard A, ''et al.'' |title=Neurochemical and electrophysiological evidence for the existence of a functional gamma-hydroxybutyrate system in NCB-20 neurons |journal=[[Neuroscience]] |volume=86 |issue=3 |pages=989–1000 |year=1998 |month=October |pmid=9692734 |doi=10.1016/S0306-4522(98)00085-2 }}</ref> meaning substances that elevate cAMP, such as [[forskolin]] and [[vinpocetine]], may increase GHB synthesis and release. People with the disorder known as [[succinic semialdehyde dehydrogenase deficiency]], also known as [[gamma-hydroxybutyric aciduria]], have elevated levels of GHB in their [[urine]], blood plasma and [[cerebrospinal fluid]].<ref>[http://www.rarediseases.org/search/rdbdetail_abstract.html?disname=Succinic%20Semialdehyde%20Dehydrogenase%20Deficiency Rarediseases.org].</ref>
   
The precise function of GHB in the body is not clear. It is known however that the brain expresses a large amount of receptors that are activated by GHB.<ref>[http://www.fasebj.org/cgi/content/full/17/12/1691 Cloning and characterization of a rat brain receptor that binds the endogenous neuromodulator {gamma}-hydroxybutyrate (GHB) - ANDRIAMAMPANDRY et al. 17 (12): 1691 - The FASEB Journal<!-- Bot generated title -->]</ref> These receptors are excitatory and not responsible for the sedative effects of GHB - they have been shown to elevate the principle excitatory neurotransmitter - [[glutamate]].<ref>[http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=14535954&ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum Selective gamma-hydroxybutyric acid receptor ligan...[J Neurochem. 2003&#93; - PubMed Result<!-- Bot generated title -->]</ref>
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The precise function of GHB in the body is not clear. It is known, however, that the brain expresses a large amount of receptors that are activated by GHB.<ref>{{cite journal | author = C. Andriamampandry, O. Taleb, S. Viry, C. Muller, J. P. Humbert, S. Gobaille, D. Aunis and M. Maitre | title = Cloning and characterization of a rat brain receptor that binds the endogenous neuromodulator &gamma;-hydroxybutyrate | journal = [[The FASEB Journal]] | year = 2003 | volume = | issue = | doi = 10.1096/fj.02-0846fje| pmid = 12958178}}</ref> These receptors are excitatory and not responsible for the sedative effects of GHB - they have been shown to elevate the principle excitatory neurotransmitter—[[glutamate]].<ref name = "nsngtu"/> The benzamide antipsychotics—[[amisulpride]], [[sulpiride]]—have been shown to bind to this receptor in vivo.<ref>{{cite journal |author=Maitre M, Ratomponirina C, Gobaille S, Hodé Y, Hechler V |title=Displacement of [3H] gamma-hydroxybutyrate binding by benzamide neuroleptics and prochlorperazine but not by other antipsychotics |journal=[[Eur. J. Pharmacol.]] |volume=256 |issue=2 |pages=211–4 |year=1994 |month=April |pmid=7914168 |doi= 10.1016/0014-2999(94)90248-8|url=}}</ref> Other antipsychotics were tested and were not found to have an affinity for this receptor.
The benzamide antipsychotics - [[amisulpride]], [[sulpiride]] - have been shown to bind to this receptor in vivo<ref>[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7914168&dopt=Abstract Displacement of [3H&#93; gamma-hydroxybutyrate binding...[Eur J Pharmacol. 1994&#93; - PubMed Result<!-- Bot generated title -->]</ref>. Other antipsychotics were tested and were not found to have an affinity for this receptor.
 
   
It is a precursor to [[GABA]], [[glutamate]] and [[glycine]] in certain brain areas.<ref>[http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=10381791&ordinalpos=13&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum gamma-Hydroxybutyrate modulates synthesis and extr...[J Pharmacol Exp Ther. 1999&#93; - PubMed Result<!-- Bot generated title -->]</ref>
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It is a precursor to [[GABA]], [[glutamate]], and [[glycine]] in certain brain areas.<ref>{{cite journal |author=Gobaille S, Hechler V, Andriamampandry C, Kemmel V, Maitre M |title=gamma-Hydroxybutyrate modulates synthesis and extracellular concentration of gamma-aminobutyric acid in discrete rat brain regions in vivo |journal=[[J. Pharmacol. Exp. Ther.]] |volume=290 |issue=1 |pages=303–9 |year=1999 |month=July |pmid=10381791 |doi= |url=http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=10381791}}</ref>
   
GHB has neuroprotective properties and has been found to protects cells from [[hypoxia (medical)|hypoxia]].<ref>[http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=12965243&ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum Effect of gamma-hydroxybutyrate in two rat models ...[Brain Res. 2003&#93; - PubMed Result<!-- Bot generated title -->]</ref>
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GHB has neuroprotective properties and has been found to protect cells from [[hypoxia (medical)|hypoxia]].<ref>{{cite journal |author=Ottani A, Saltini S, Bartiromo M, ''et al.'' |title=Effect of gamma-hydroxybutyrate in two rat models of focal cerebral damage |journal=[[Brain Res.]] |volume=986 |issue=1–2 |pages=181–90 |year=2003 |month=October |pmid=12965243 |doi=10.1016/S0006-8993(03)03252-9 }}</ref>
   
=== As a natural fermentation by-product ===
+
=== Natural fermentation by-product ===
GHB is also produced as a result of fermentation and so is found in small quantities in some beers and wines, particularly fruit wines. However, the amount of GHB found in wine is insignificant and not sufficient to produce any effects. <ref> Elliott S, Burgess V. The presence of gamma-hydroxybutyric acid (GHB) and gamma-butyrolactone (GBL) in alcoholic and non-alcoholic beverages. Forensic Science International. 2005 July 16;151(2-3):289-92. </ref>
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GHB is also produced as a result of fermentation and so is found in small quantities in some beers and wines, in particular fruit wines. However, the amount of GHB found in wine is insignificant and not sufficient to produce any effects.<ref>Elliott S, Burgess V. "The presence of gamma-hydroxybutyric acid (GHB) and gamma-butyrolactone (GBL) in alcoholic and non-alcoholic beverages". ''Forensic Science International''. 2005 July 16;151(2–3):289–92.</ref>
   
 
== Dangers ==
 
== Dangers ==
As with pure alcohol, the [[Dose-response relationship|dose-response curve]] of GHB is very steep, and "proper" dosing of illegal GHB can be difficult since it often comes as a salt dissolved in water, and the actual amount of GHB and/or other additives per "capful" can vary. Legal GHB comes in standardized doses and is free from contaminants, so it is much safer (cf. legal alcohol vs. [[bathtub gin]]). Also, like pure alcohol, small doses of GHB are considered safe, but high doses can cause [[unconsciousness]], [[convulsions]], [[vomiting]], suppression of the [[gag reflex]], [[hypoventilation|respiratory depression]] and [[death]]. These effects vary between persons and are dose-dependent. Synergy of its sedative effects are seen when combined with other [[Depressant|CNS depressants]] such as alcohol, [[benzodiazepine]]s (e.g., [[diazepam]]), [[barbiturate]]s, and others.
+
{{Refimprovesect|date=August 2008}}
   
Another complication is the difference in [[pharmacokinetics]] between GHB and its two prodrugs, 1,4-B and GBL. 1,4-B is converted into GHB in the body by two enzymes [[alcohol dehydrogenase]] and [[aldehyde dehydrogenase]], which gives it a delayed onset of effects and a longer duration of action. GHB is then further metabolised, again by alcohol dehydrogenase and aldehyde dehydrogenase, into the inactive [[succinate]].
+
=== Dose response curve ===
  +
As with pure alcohol, the [[Dose-response relationship|dose-response curve]] of GHB is very steep, and "proper" dosing of illegal GHB can be difficult since it often comes as a salt dissolved in water, and the actual amount of GHB and/or other additives per "capful" can vary. Legal GHB comes in standardized doses and is free from contaminants, so it is much safer (cf. legal alcohol vs. [[bathtub gin]]). Also, like pure alcohol, small doses of GHB are considered safe, but high doses can cause [[unconsciousness]], [[convulsions]], [[vomiting]], suppression of the [[gag reflex]], [[hypoventilation|respiratory depression]], and [[death]]. These effects vary between persons and are dose-dependent. Synergy of its sedative effects are seen when combined with other [[Depressant|CNS depressants]] such as alcohol, [[benzodiazepine]]s (e.g., [[diazepam]]), [[barbiturate]]s, and others.
   
If alcohol has also been consumed this can saturate the dehydrogenase enzymes and so delays the conversion of 1,4-B into GHB, meaning that 1,4-B takes much longer to take effect and people may re-dose thinking it hasn't done anything, leading to an accidental overdose later on once it finally takes effect. 1,4-B itself can also contribute to the enzyme saturation, so, when alcohol and 1,4-B are consumed together, it produces a complex and somewhat unpredictable interaction between the varying levels of alcohol, 1,4-B and GHB present in the body. Alcohol also makes the GHB last longer in the body by competing for dehydrogenase enzymes, and hence delaying the conversion of GHB into succinate.
+
=== Combination with alcohol ===
  +
Alcohol worsens both CNS depression and vomiting, so combining alcohol with GHB or its precursors can be particularly dangerous. Another factor to be considered is that people who drink alcohol regularly tend to induce expression of their dehydrogenase enzymes, and thus have higher levels of these enzymes than people that do not drink alcohol regularly; this means that regular alcohol drinkers will both convert 1,4-B into GHB more rapidly and also break down GHB into succinate faster than people that do not drink alcohol. This multitude of different factors can make the interactions between 1,4-B, GHB and alcohol very complicated and highly variable between different individuals.
   
The other precursor GBL is rapidly converted into GHB by [[Beta-lactamase|lactamase]] enzymes found in the blood. GBL is more lipophilic (fat soluble) than GHB, and so is absorbed faster and has higher bioavailability; the paradox is that this can mean that GBL has a faster onset of effects than GHB itself, even though it is a [[prodrug]]. The levels of lactamase enzyme can vary between individuals, and GBL is not active in its own right, so people who have never tried GBL before may have delayed or fewer effects than expected; however, once someone has taken GBL a few times, the production of lactamase enzymes is increased and he/she will feel the effects like normal.
+
Death while using GHB is most likely when it is combined with alcohol or other depressant drugs; however, an overdose of GHB alone may be lethal. A review of the details of 194 deaths attributed to or related to GHB over a ten-year period<ref>[http://www.aafs.org/pdf/Seattleabstracts06.pdf Zvosec et al. American Academy of Forensic Science in Seattle, 2006]</ref> found that most were from respiratory depression caused by interaction with alcohol or other drugs; several were from choking on vomit and asphyxiating; remaining causes of death included motor vehicle and other accidents. The review included 70 cases in which high levels of GHB were found post-mortem without concomitant ingestion of other drugs or alcohol.
   
Because of these pharmacokinetic differences, 1,4-B tends to be slightly less potent, slower to take effect but longer-acting than GHB, whereas GBL tends to be more potent and faster-acting than GHB, and has around the same duration.
+
If alcohol has also been consumed this can saturate the dehydrogenase enzymes and so delays the conversion of 1,4-B into GHB, meaning that 1,4-B takes much longer to take effect and people may re-dose thinking it has not done anything, leading to an accidental overdose later on once it finally takes effect. 1,4-B itself can also contribute to the enzyme saturation, so, when alcohol and 1,4-B are consumed together, it produces a complex and somewhat unpredictable interaction between the varying levels of alcohol, 1,4-B and GHB present in the body. Alcohol also makes the GHB last longer in the body by competing for dehydrogenase enzymes, and hence delaying the conversion of GHB into succinate.
   
Alcohol worsens both CNS depression and vomiting, so combining alcohol with GHB or its precursors can be particularly dangerous. Another factor to be considered is that people who drink alcohol regularly tend to induce expression of their dehydrogenase enzymes, and thus have higher levels of these enzymes than people that do not drink alcohol regularly; this means that regular alcohol drinkers will both convert 1,4-B into GHB more rapidly and also break down GHB into succinate faster than people that do not drink alcohol. This multitude of different factors can make the interactions between 1,4-B, GHB and alcohol very complicated and highly variable between different individuals.
+
=== Other combinations ===
  +
Another complication is the difference in [[pharmacokinetics]] between GHB and its two prodrugs, 1,4-B and GBL. 1,4-B is converted into GHB in the body by two enzymes [[alcohol dehydrogenase]] and [[aldehyde dehydrogenase]], which gives it a delayed onset of effects and a longer duration of action. GHB is then further metabolised, again by alcohol dehydrogenase and aldehyde dehydrogenase, into the inactive [[succinate]].
   
Death while using GHB is most likely when it is combined with alcohol or other depressant drugs; however, as with all substances, an overdose of GHB alone may be lethal. A review of the details of 194 deaths attributed to or related to GHB over a ten-year period<ref>Zvosec et al. American Academy of Forensic Science in Seattle, 2006 [http://www.aafs.org/pdf/Seattleabstracts06.pdf]</ref> found that most were from respiratory depression caused by interaction with alcohol or other drugs; several were from choking on vomit and asphyxiating; remaining causes of death included motor vehicle and other accidents. The review included 70 cases where high levels of GHB were found post-mortem without concomitant ingestion of other drugs or alcohol.
+
The other precursor GBL is rapidly converted into GHB by [[Beta-lactamase|lactamase]] enzymes found in the blood. GBL is more lipophilic (fat soluble) than GHB, and so is absorbed faster and has higher bioavailability; the paradox is that this can mean that GBL has a faster onset of effects than GHB itself, even though it is a [[prodrug]]. The levels of lactamase enzyme can vary between individuals, and GBL is not active in its own right, so people who have never tried GBL before may have delayed or fewer effects than expected; however, once someone has taken GBL a few times, the production of lactamase enzymes is increased and he/she will feel the effects like a regular user.
   
Determining conclusively whether someone's death was caused by GHB is very difficult because a lab test will always detect the presence of some GHB in the human body, and levels of GHB can vary in the same individual depending on what part of the body is tested. GHB is a naturally-occurring substance that is always present in everyone, but little research has been done on what levels are normal in what parts of the body at what times.
+
Because of these pharmacokinetic differences, 1,4-B tends to be slightly less potent, slower to take effect but longer-acting than GHB, whereas GBL tends to be more potent and faster-acting than GHB, and has around the same duration.
   
There have been no systematic studies into the effects of GHB if taken chronically in humans, and hence whether prolonged use of GHB causes any bodily harm remains unknown. A [[United Kingdom|UK]] parliamentary committee commissioned report found the use of GHB to be less dangerous than tobacco and alcohol in social harms, physical harm and addiction.<ref>Science and Technology Committee Report (page 176), 2006). [http://news.bbc.co.uk/1/shared/bsp/hi/pdfs/31_07_06_drugsreport.pdf]</ref>
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=== Death and other harmful effects ===
  +
GHB use is conclusively associated with death, as documented by many reports, including one in which 3 deaths were associated with Xyrem use (pharmaceutical GHB, or "Sodium Oxybate"),<ref>(Zvosec DL, Smith SW, Hall BJ. Three deaths associated with use of Xyrem�. Sleep Med 2009;10:490–3.)</ref>. Because rodents are particularly resistant to death from GHB, many have assumed that GHB is equally safe in humans. The fact that clinical effects of GHB occur at approximately 1/10th the dose in humans as in rodents is evidence that GHB is much more toxic in humans than in rodents. One large series documents 226 deaths attributed to GHB; this will be published in the American Journal of Emergency Medicine this year.<ref>Zvosec DL, Smith SW, Porrata T, Strobl AQ, Dyer JE. Case series of 226 gamma-hydroxybutyrate-associated deaths: lethal toxicity and trauma. Am J Emerg Med In Press.</ref> A preliminary report of this case series, with 194 deaths, was presented at the American Academy of Forensic Science. <ref>Zvosec DL et al. Gamma Hydroxybutyrate (GHB)-Related Deaths: Review of 194 Cases. Proceedings of the American Academy of Forensic Sciences, February 2006; Volume XII, page 359. URL link: http://www.aafs.org/pdf/Seattleabstracts06.pdf.</ref> In this series, death records were reviewed for toxicology, autopsy findings, and history. Of 226 deaths included, 213 suffered cardiorespiratory arrest and 13 suffered fatal accidents. Seventy-one deaths (34%) had no co-intoxicants. Postmortem blood GHB was 18-4400mg/L (median=347) in deaths negative for co-intoxicants.
   
=== Treatment of overdose ===
+
GHB is produced in the body in very small amounts, and blood levels may climb after death to levels in the range of 30-50 mg/L. <ref>Zvosec DL. Smith SW. Response to Editorial: “Xyrem safety: The debate continues”. Sleep Medicine 2010; 11:105-109.</ref> Levels higher than this are found in GHB deaths. Levels lower than this may be due to GHB or to postmortem endogenous elevations. Only careful attention to historical details, and analysis of other body fluids (e.g., vitreous) can determine for with any certainly whether measurable levels below 30-50 mg/L are exogenous or endogenous.
Overdose of GHB can be difficult to treat because of its multiple effects on the body.<ref name="allenalsalim">{{cite journal | author = Allen, L. | coauthors = Alsalim, W. | date = [[2006-04-01]] | title = Gammahydroxybutyrate overdose and physostigmine | journal = [[Emergency Medicine Journal]] | volume = 23 | issue = 4 | pages = 300 | doi = 10.1136/emj.2006.035139 }}</ref><ref name="intubationtreatment">{{cite journal | author = Michael, H. | coauthors = Harrison, M. | date = [[2005-01-01]] | title = Endotracheal intubation in &gamma;-hydroxybutyric acid intoxication and overdose | journal = [[Emergency Medicine Journal]] | volume = 22 | issue = 1 | pages = 43 | doi = 10.1136/emj.2004.021154 }}</ref><ref name="emedicineonGHB"/> GHB tends to cause rapid unconsciousness at doses above 3500 mg, with single doses over 7000 mg often causing life-threatening [[respiratory depression]], and higher doses still can induce [[bradycardia]] and consequent heart failure. Because of the faster and more complete absorption of GBL relative to GHB, its dose-response curve is steeper, and overdoses of GBL tend to be more dangerous and problematic than overdoses involving only GHB or 1,4-B.
 
   
As well as causing these depressant effects, GHB overdose also often produces twitches or convulsions, especially when combined with stimulants such as [[amphetamines]]. Also GHB tends to cause nausea and vomiting, particularly when combined with alcohol; so a patient may be simultaneously unconscious, vomiting, and convulsing.
+
There have been no systematic studies into the effects of GHB if taken chronically in humans, and hence whether prolonged use of GHB causes any bodily harm remains unknown. A UK parliamentary committee commissioned report found the use of GHB to be less dangerous than tobacco and alcohol in social harms, physical harm and addiction.<ref>[http://news.bbc.co.uk/1/shared/bsp/hi/pdfs/31_07_06_drugsreport.pdf Science and Technology Committee Report (p. 176), 2006)]</ref>
   
Overdoses wherein the patient has consumed GHB along with both alcohol and amphetamine-based stimulants are often particularly problematic; the stimulants may cause the patient to slip in and out of consciousness and he/she may be confused and combative, fighting off medical staff while half-awake before lapsing back into unconsciousness again. Care should be taken when attempting to sweep foreign bodies out of the mouth of a patient that presents with a suspected GHB overdose. The patient may bite very hard, and sometimes will not let go.{{Fact|date=November 2007}}
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=== Treatment of overdose ===
  +
{{Refimprovesect|date=August 2008}}
  +
Overdose of GHB can be difficult to treat because of its multiple effects on the body.<ref name="emedicineonGHB"/><ref name="allenalsalim">{{cite journal | author = Allen, L. | coauthors = Alsalim, W. | date = 1 April 2006 | title = Gammahydroxybutyrate overdose and physostigmine | journal = [[Emergency Medicine Journal]] | volume = 23 | issue = 4 | page = 300 | doi = 10.1136/emj.2006.035139 | year = 2006 | pmid = 16549578}}</ref><ref name="intubationtreatment">{{cite journal | author = Michael, H. | coauthors = Harrison, M. | date = 1 January 2005 | title = Endotracheal intubation in &gamma;-hydroxybutyric acid intoxication and overdose | journal = [[Emergency Medicine Journal]] | volume = 22 | issue = 1 | page = 43 | doi = 10.1136/emj.2004.021154 | year = 2005 | pmid = 15611542}}</ref> GHB tends to cause rapid unconsciousness at doses above 3500&nbsp;mg, with single doses over 7000&nbsp;mg often causing life-threatening [[respiratory depression]], and higher doses still inducing [[bradycardia]] and [[cardiac arrest]]. Other side-effects include [[convulsions]] (especially when combined with [[stimulants]]), and nausea/vomiting (especially when combined with [[Alcoholic beverage|alcohol]]).
   
The most likely risk of death from GHB overdose is inhalation of vomit while unconscious. This risk can be minimised by laying the patient down in the [[recovery position]]. People are most likely to vomit as they become unconscious, and as they wake up. This is best managed in a hospital setting, but, if the patient is not in a hospital, it is very important that someone stays with the patient until he/she becomes fully unconscious, to keep the patient in the recovery position and to check how deeply unconscious the he/she becomes.
+
The greatest life threat due to GHB overdose (with or without other substances) is respiratory arrest.<ref name="GHBdeath">Zvosec, DL, Smith, SW, Porrata, T, et al. Preventable deaths from Gamma hydroxybutyrate ingestion (Abstract). Ann Emerg Med 2006; 48:S75</ref> Other relatively common causes of death due to GHB ingestion include [[Pulmonary aspiration|aspiration]] of vomitus, positional asphyxia, and trauma sustained while intoxicated (e.g., motor vehicle accidents while driving under the influence of GHB).<ref name="GHBdeath">Zvosec, DL, Smith, SW, Porrata, T, et al. Preventable deaths from Gamma hydroxybutyrate ingestion (Abstract). Ann Emerg Med 2006; 48:S75</ref> The risk of aspiration pneumonia and positional asphyxia risk can be reduced by laying the patient down in the [[recovery position]]. People are most likely to vomit as they become unconscious, and as they wake up. GHB overdose is a medical emergency and assessment in an emergency department is needed.
 
Then someone needs to stay with the patient in order to keep monitoring pulse and breathing rate. Finally, someone must stay with the patient until he fully wakes up. This is important, because people tend to become conscious enough to roll onto their backs just before they start to vomit again, but often while they are still too deeply unconscious to protect their own airway. This makes the period while people are waking up particularly dangerous.
 
   
  +
=== Treatment ===
 
Convulsions from GHB can be treated with [[diazepam]] or [[lorazepam]], even though these are also CNS depressants they are GABA<sub>A</sub> agonists, whereas GHB is primarily a GABA<sub>B</sub> agonist, so the benzodiazepines do not worsen CNS depression as much as might be expected.
 
Convulsions from GHB can be treated with [[diazepam]] or [[lorazepam]], even though these are also CNS depressants they are GABA<sub>A</sub> agonists, whereas GHB is primarily a GABA<sub>B</sub> agonist, so the benzodiazepines do not worsen CNS depression as much as might be expected.
   
Most stimulants are not effective at counteracting the unconsciousness from GHB, but intravenous injection of cholinergic drugs such as [[arecoline]], [[neostigmine]], and [[physostigmine]] can quickly reverse the effects of the GHB and cause rapid awakening; this can be dangerous, however, as these drugs lower the convulsion threshold and so can make convulsions worse. For this reason, these drugs are seldom used in most countries, although, in France and Italy where there is a much longer history of medical use of GHB, physostigmine treatment for GHB overdose is more common.
+
Most stimulants are not effective at counteracting the unconsciousness from GHB.{{Citation needed|date=August 2008}}
 
The best treatment of a more serious GHB overdose is co-administration of lorazepam with physostigmine, and the dose of both drugs must be carefully titrated to avoid worsening either the CNS depression or the convulsions. Overdoses with larger quantities of GHB or more particularly GBL (generally 10,000mg or more) can stop both heart and breathing.
 
   
It can be very dangerous to look after someone who is unconscious as a result of drug overdose if the attending party does not have proper medical training. When an individual presents with a suspected GHB overdose and is unconscious, the first priority should be to check their pulse and breathing. If the patient is taking less than 8 breaths per minute, and if his/her pulse is less than 60 a minute (both numbers are for adults), then the appropriate course of action is call an ambulance. CPR must not be used while the patient is still breathing and has a heart beat as this may cause considerable damage.
+
Because of the faster and more complete absorption of GBL relative to GHB, its dose-response curve is steeper, and overdoses of GBL tend to be more dangerous and problematic than overdoses involving only GHB or 1,4-B. Any GHB/GBL overdose is a [[medical emergency]] and should be cared for by appropriately trained personnel.
   
A newer synthetic drug [[SCH-50911]], which acts as a selective GABA<sub>B</sub> antagonist, quickly reverses GHB overdose in mice.<ref name="mousetreatment">{{cite journal | author = Carai, M.A.M. | coauthors = Colombo, G.; Gessa, G.L. | year = 2005 | title = Resuscitative Effect of a &gamma;-Aminobutyric Acid B Receptor Antagonist on &gamma;-Hydroxybutyric Acid Mortality in Mice | journal = Annals of Emergency Medicine | volume = 45 | issue = 6 | pages = 614-619 | doi = 10.1016/j.annemergmed.2004.12.013 }}</ref> However this treatment has yet to be tried in humans, and it is unlikely that it will be researched for this purpose in humans due to the illegal and unethical nature of clinical trials of GHB, and the lack of medical indemnity coverage inherent in using an untested treatment for a life-threatening overdose.
+
A newer synthetic drug [[SCH-50911]], which acts as a selective GABA<sub>B</sub> antagonist, quickly reverses GHB overdose in mice.<ref name="mousetreatment">{{cite journal | author = Carai, M.A.M. | coauthors = Colombo, G.; Gessa, G.L. | year = 2005 | title = Resuscitative Effect of a &gamma;-Aminobutyric Acid B Receptor Antagonist on &gamma;-Hydroxybutyric Acid Mortality in Mice | journal = Annals of Emergency Medicine | volume = 45 | issue = 6 | pages = 614–619 | doi = 10.1016/j.annemergmed.2004.12.013 }}</ref> However this treatment has yet to be tried in humans, and it is unlikely that it will be researched for this purpose in humans due to the illegal nature of clinical trials of GHB, and the lack of medical indemnity coverage inherent in using an untested treatment for a life-threatening overdose.
   
 
== Addiction ==
 
== Addiction ==
GHB can be physically addictive and may result in [[psychological addiction]]. Physical dependence develops when GHB is taken on a regular basis (i.e., every 2-4 hours for multiple consecutive days or weeks). [[Withdrawal]] effects may include [[insomnia]], restlessness, [[anxiety]], [[tremor]]s, sweating, loss of appetite, edginess, [[tachycardia]], chest pain and tightness, muscle and bone aches, sensitivity to external stimuli (sound, light, touch), [[dysphoria]], and mental dullness. These side-effects will subside after 2 - 21 days, depending on frequency of usage and the size of the doses used. In particularly severe cases, withdrawal from GHB may cause symptoms similar to acute withdrawal from alcohol or barbiturates ([[delirium tremens]]) and can cause convulsions and hallucinations.
 
   
Although there have been reported fatalities due to GHB withdrawal, reports are inconclusive and further research is needed. Unlike [[ethanol|alcohol]], there is no firm data that chronic use of GHB causes permanent damage to the body. In rats, no organ or brain damage was observed after chronic administration of GBL (a precursor to GHB).<ref>{{Citation
+
{{Refimprovesect|date=August 2008}}
| author = National Toxicology Program
 
| title =Toxicology and Carcinogenesis Studies of g-Butyrolactone (CAS No. 96-48-0) in F344/N Rats and B6C3F1 Mice (Gavage Studies)
 
| year = March 1992
 
| pages =
 
| place =
 
| work = NTP Study Reports
 
| publisher = Department of Health and Human Services, NIH
 
| url = http://ntp.niehs.nih.gov/index.cfm?objectid=07097962-0CEC-4EFA-62E349AF22EB2E9D}}</ref>
 
   
== Legal status ==
+
GHB can be physically addictive and may result in [[psychological addiction]]. Physical dependence develops when GHB is taken on a regular basis (i.e., every 2–4 hours for multiple consecutive days or weeks). [[Withdrawal]] effects may include [[insomnia]], restlessness, [[anxiety]], [[tremor]]s, sweating, loss of appetite, edginess, [[tachycardia]], chest pain and tightness, muscle and bone aches, sensitivity to external stimuli (sound, light, touch), [[dysphoria]], and mental dullness. These side-effects will subside after 2 – 21 days, depending on frequency of usage and the size of the doses used. In particularly severe cases, withdrawal from GHB may cause symptoms similar to acute withdrawal from alcohol or barbiturates ([[delirium tremens]]) and can cause convulsions and hallucinations.
   
In [[Hong Kong]], GHB is regulated under Schedule 1 of [[Hong Kong|Hong Kong's]] Chapter 134 ''Dangerous Drugs Ordinance''. It can only be used legally by health professionals and for university research purposes. The substance can be given by pharmacists under a prescription. Anyone who supplies the substance without prescription can be fined $10000 (HKD). The penalty for trafficking or manufacturing the substance is a $5,000,000 ([[Hong Kong dollar|HKD]]) fine and life imprisonment. Possession of the substance for consumption without license from the Department of Health is illegal with a $1,000,000 (HKD) fine and/or 7 years of jail time.
+
Although there have been reported fatalities due to GHB withdrawal, reports are inconclusive and further research is needed. Unlike [[ethanol|alcohol]], there is no firm data that chronic use of GHB causes permanent damage to the body. In rats, no organ or brain damage was observed after chronic administration of GBL (a precursor to GHB).<ref>{{Citation
  +
| author = National Toxicology Program
  +
| title =Toxicology and Carcinogenesis Studies of g-Butyrolactone (CAS No. 96-48-0) in F344/N Rats and B6C3F1 Mice (Gavage Studies)
  +
| year = March 1992
  +
| pages =
  +
| place =
  +
| work = NTP Study Reports
  +
| publisher = Department of Health and Human Services, NIH
  +
| url = http://ntp.niehs.nih.gov/index.cfm?objectid=07097962-0CEC-4EFA-62E349AF22EB2E9D}}</ref>
   
In the United States it was placed on Schedule I of the [[Controlled Substances Act]] in March 2000 although when sold as [[Xyrem]] it is considered Schedule III, one of several drugs which is listed in multiple schedules.<ref>[http://www.projectghb.org/laws.htm ProjectGHB.org]</ref><ref name="erowidGHBlaw" /> On [[March 20]], [[2001]], the [[Commission on Narcotic Drugs]] placed GHB in Schedule IV of the 1971 [[Convention on Psychotropic Substances]].<ref>[http://www.whitehousedrugpolicy.gov/publications/factsht/gamma/ Whitehousedrugpolicy.org]</ref> In the UK it was made a class C drug in June 2003.
+
== Withdrawal ==
  +
Withdrawal from GHB can be a life-threatening condition. Treatment with [[benzodiazepines]] can be used, although extremely high doses may be required (e.g. > 100 mg/d of diazepam). With the exception of [[baclofen]], other treatments are often ineffective. Evidence shows that [[baclofen]] is the most effective drug for GHB withdrawal. GHB and baclofen are agonists for the GABAb receptor.<ref>{{cite journal | journal = Neurocrit Care | date = 12 February 2008 | title = Baclofen and Gamma-Hydroxybutyrate Withdrawal | author = Letourneau JL, | coauthors = Hagg DS, Smith SM | pmid =18266111 | doi = 10.1007/s12028-008-9062-2 | publisher = Humana Press Inc | url = http://www.springerlink.com/content/mp06r2652678r742/ | volume = 8 | page = 430}}</ref>
   
In New Zealand and Australia, GHB, 1,4-B and GBL are all Class B illegal drugs, along with any possible esters, ethers and aldehydes. GABA itself is also listed as an illegal drug in these jurisdictions which seems unusual given its failure to cross the blood-brain barrier, but there was a perception among legislators that all known analogues should be covered as far as this was possible. Attempts to circumvent the illegal status of GHB have led to the sale of derivatives such as 4-methyl-GHB (gamma-hydroxyvaleric acid, GHV) and its prodrug form gamma-valerolactone (GVL), but these are also covered under the law by virtue of their being "substantially similar" to GHB or GBL and; so importation, sale, possession and use of these compounds is also considered to be illegal.
+
== Legal status ==
+
In the United States, it was placed on Schedule I of the [[Controlled Substances Act]] in March 2000. However, when sold as [[Xyrem]], it is considered Schedule III, one of several drugs that are listed in multiple schedules.<ref name="erowidGHBlaw" /><ref>[http://www.projectghb.org/laws.htm ProjectGHB.org]</ref> On 20 March 2001, the [[Commission on Narcotic Drugs]] placed GHB in Schedule IV of the 1971 [[Convention on Psychotropic Substances]].<ref>[http://www.whitehousedrugpolicy.gov/publications/factsht/gamma/ Whitehousedrugpolicy.org].</ref> In the UK it was made a class C drug in June 2003.
== GHB in popular culture ==
 
{{Trivia|date=December 2007}}
 
In the "[[Murder In A Flash (CSI episode)|Murder In A Flash]]" episode of ''[[CSI: Miami]]'', one of the victims, an 18-year-old boy, is found to have died from GHB intoxication. GHB is also named as "the date-rape drug" by one of the investigators, who also relates the information that males often take the drug to get high. In the matter of the GHB-related death, however, the victim had received the GHB without noticing it.
 
 
In the ''[[NCIS (TV series)|NCIS]]'' episode "[[Twisted Sister (NCIS episode)|Twisted Sister]]" GHB was used to drug Sarah McGee, Special Agent Timothy McGee's sister, into thinking that she committed a murder as a cover-up. A classmate, whom she despises, drugged her by adding it to her peanut butter.
 
 
In the pilot episode of ''[[Veronica Mars]]'', Veronica tells us she was raped at a party when she was sixteen. At the end of episode 20, "M.A.D.", of season 1, Veronica discovers that she had been given GHB at the party and investigates that night in the following episode, "A Trip to the Dentist". This party is referenced throughout season one and is a major conflict for the character, which was revisited in the final episode of season 2 when she finally learned exactly what happened that night. Season 3 of ''[[Veronica Mars]]'' centers around the main character's freshman year at Hearst College, where she investigates a string of GHB-related rapes on campus.
 
 
An episode of ''[[Law and Order: Special Victims Unit]]'' involves a woman who is drugged with GHB by a vengeful colleague in hopes that the woman will be raped. In the ''[[Law & Order]]'' episode "Fools for Love," one of the victim's deaths is attributed to choking on vomit from a GHB overdose administered by her rapist/killer.
 
 
The television series ''[[The West Wing]]'' featured GHB in a multi-episode story during the conclusion of season 4 and the beginning of season 5. The president's daughter consumes GHB that had been slipped into an alcoholic beverage without her knowledge, and, as she feels the effects of the drug, her boyfriend implies that she has consumed ecstasy. Later, she is kidnapped from a nightclub bathroom while barely or not conscious, setting off a massive manhunt. The president is told later by an FBI agent that the drug is created by mixing degreasing solvent and drain cleaner, and he finishes the agent's sentence by acknowledging he is aware the drug is known as a date-rape drug.
 
 
The French activist and psychoanalytic theorist [[Félix Guattari]] used GHB recreationally in the early 1970s, see ''[[The Anti-Oedipus Papers]]'' (2006:308,326)
 
 
Near the end of the second season of the television series ''[[Everwood]]'', leading character Amy Abbott is pressured into consuming a low dose of GHB dissolved in water with her then-boyfriend, allegedly-recovered addict Tommy Callahan. In a misguided effort to keep her from accidentally overdosing, he consumes most of the drugs before giving her the remainder, thus overdosing himself. Upon realizing he was unresponsive, Amy called her doctor father to come to his rescue, and, while they succeeded in saving Tommy's life, this encounter with the controlled substance ended their relationship.
 
 
An episode of the fifth series of ''[[Spooks]]'' shows Ros using a refined form of the drug to incapacitate targets for intelligence gathering.
 
 
In the third episode of the American version of [[Queer as Folk (North American TV series)|''Queer as Folk'']], the character Ted falls into a coma after being given a large dose of GHB by a date he brings home.
 
   
In the popular funk song "Party Song" by [[Brady's Bunch]], GHB is referenced in a clever line: "A to the B to the C to the D to the E to the F to the GHB." The song also references "Hangin' out with my Georgia Homeboy."
+
In Hong Kong, GHB is regulated under Schedule 1 of [[Hong Kong|Hong Kong's]] Chapter 134 ''Dangerous Drugs Ordinance''. It can only be used legally by health professionals and for university research purposes. The substance can be given by pharmacists under a prescription. Anyone who supplies the substance without prescription can be fined [[Hong Kong dollar|HK$]]10000. The penalty for trafficking or manufacturing the substance is a HK$5,000,000 fine and life imprisonment. Possession of the substance for consumption without license from the Department of Health is illegal with a HK$1,000,000 fine and/or 7 years of jail time.
   
In the song "What's Going On" by [[Zebrahead]], found on their album [[Playmate of the Year (album)|Playmate of the Year (2000)]], GHB is referenced as a [[date rape]] drug: She takes another sip/
+
In New Zealand and Australia, GHB, 1,4-B and GBL are all Class B illegal drugs, along with any possible esters, ethers and aldehydes. GABA itself is also listed as an illegal drug in these jurisdictions, which seems unusual given its failure to cross the blood-brain barrier, but there was a perception among legislators that all known analogues should be covered as far as this was possible. Attempts to circumvent the illegal status of GHB have led to the sale of derivatives such as 4-methyl-GHB (gamma-hydroxyvaleric acid, GHV) and its prodrug form gamma-valerolactone (GVL), but these are also covered under the law by virtue of their being "substantially similar" to GHB or GBL and; so importation, sale, possession and use of these compounds is also considered to be illegal.
But has no clue of the spike from the G to the H to the B/ She wakes up in the morning/ bruised and raped in the street. GHB is referred to in the song ''[[Shores of California]]'' by [[The Dresden Dolls]]: ''And that is why the girl is called a tease / and that is why the guy is called a sleaze / and that's why God made escort agencies / one life to live and mace and GHB.''
 
   
On the [[Billy Idol]] album 'Cyberpunk' (1993), on the song 'Then the Night Comes', GHB is mentioned at 2:30 into the song, as follows...'I take some GHB, I feel love, joy, And wonderful ringing music, Now, I just got to be me'. Following the album's release, he (Idol) almost died of a GHB overdose in 1994.
+
In Norway, GHB is considered a narcotic<ref name="urlFOR 30 June 1978 nr 08: Forskrift om narkotika m.v. (Narkotikalisten)">{{cite web |url=http://www.lovdata.no/cgi-wift/ldles?doc=/sf/sf/sf-19780630-0008.html |title=FOR 30 June 1978 nr 08: Forskrift om narkotika m.v. (Narkotikalisten) |work= |accessdate=}}</ref> and is only available by prescription under the trade name Xyrem (Union Chimique Belge S.A.).
   
In ''The Anniversary'', by [[Amy Gutman]], GHB is referenced as a date rape drug.
+
== See also ==
  +
* [[1,4-Butanediol]] (1,4-BD)
  +
* [[gamma-Butyrolactone|''gamma''-Butyrolactone]] (GBL)
  +
* [[gamma-Hydroxyvaleric acid|''gamma''-Hydroxyvaleric acid]] (GHV)
  +
* [[gamma-Valerolactone|''gamma''-Valerolactone]] (GVL)
   
 
== References ==
 
== References ==
{{reflist|2}}
+
{{Reflist|2}}
   
 
== External links ==
 
== External links ==
  +
* [http://ceri.com/feature.htm The Cognitive Enhancement Research Institute - Research findings on GHB and other substances]
 
* [http://www.emcdda.europa.eu/index.cfm?fuseaction=public.Content&nNodeID=431 EMCDDA Report on the risk assessment of GHB in the framework of the joint action on new synthetic drugs]
 
* [http://www.emcdda.europa.eu/index.cfm?fuseaction=public.Content&nNodeID=431 EMCDDA Report on the risk assessment of GHB in the framework of the joint action on new synthetic drugs]
* [http://www.streetdrugs.org/ghb.htm streetdrugs.com]
 
 
* [http://www.erowid.org/chemicals/ghb/ Erowid GHB Vault] (also contains information about addiction and dangers)
 
* [http://www.erowid.org/chemicals/ghb/ Erowid GHB Vault] (also contains information about addiction and dangers)
 
* [http://www.drugabuse.gov/Infofax/RohypnolGHB.html InfoFacts - Rohypnol and GHB] ([[National Institute on Drug Abuse]])
 
* [http://www.drugabuse.gov/Infofax/RohypnolGHB.html InfoFacts - Rohypnol and GHB] ([[National Institute on Drug Abuse]])
 
* [http://www.debernardis.it/medasq.php?z=sodium+oxybate+%5Bmesh%5D+and+alcohol-related+disorders+%5Bmesh%5D&abstract=0&quanti=50&highlight=2&daevidenziare=oxybate+alcohol&dovesiamo=0&azione=Show Pubmed/Medline search on '''sodium oxybate and alcohol-related disorders''']
 
* [http://www.debernardis.it/medasq.php?z=sodium+oxybate+%5Bmesh%5D+and+alcohol-related+disorders+%5Bmesh%5D&abstract=0&quanti=50&highlight=2&daevidenziare=oxybate+alcohol&dovesiamo=0&azione=Show Pubmed/Medline search on '''sodium oxybate and alcohol-related disorders''']
   
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{{Sedatives}}
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{{Other nervous system drugs}}
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{{GABAergics}}
   
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{{DEFAULTSORT:Hydroxybutyric Acid, Gamma-}}
 
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Latest revision as of 19:14, January 3, 2010

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4-hydroxybutanoic-acid
Gamma-Hydroxybutyric acid

4-Hydroxybutanoic acid
IUPAC name
CAS number
591-81-1
ATC code

N01AX11 .

PubChem
3037032
DrugBank
DB01440
Chemical formula {{{chemical_formula}}}
Molecular weight 104.10 g/mol (GHB)
126.09 g/mol (sodium salt)
142.19 g/mol (potassium salt)
Bioavailability 25% (oral)
Metabolism 95%, mainly Hepatic, also in blood and tissues
Elimination half-life 30–60 minutes
Excretion 5%, renal
Pregnancy category B
Legal status Class B (NZ), Schedule I and III (US)
Routes of administration Usually oral; intravenous


γ-Hydroxybutyric acid (GHB), also known as 4-hydroxybutanoic acid and sodium oxybate[1], is a naturally-occurring substance found in the central nervous system, wine, beef, small citrus fruits, and almost all animals in small amounts.[2] It is also a neuroprotective therapeutic nutrient [citation needed] that is categorized as an illegal drug in many countries.[3] It is currently regulated in the US. GHB as the sodium salt, known as sodium oxybate, is sold by Jazz Pharmaceuticals under the name Xyrem[4] to treat cataplexy and excessive daytime sleepiness in patients with narcolepsy.

GHB has been used in a medical setting as a general anesthetic, to treat conditions such as insomnia, clinical depression, narcolepsy, and alcoholism, and to improve athletic performance.[5] It is also used as an intoxicant (illegally in many jurisdictions) or as a date rape drug.[6] GHB is naturally produced in the human body's cells and is structurally related to the ketone body beta-hydroxybutyrate. As a supplement/drug, it is used most commonly in the form of a salt.[7] GHB is also produced as a result of fermentation, and so is found in small quantities in some beers and wines. Succinic semialdehyde dehydrogenase deficiency is a disease that causes GHB to accumulate in the blood.

History Edit

Synthesis of the chemical GHB was first reported in 1874 by Alexander Zaytsev,[8] but the first major research into its use in humans was conducted in the early 1960s by Dr. Henri Laborit to use in studying the neurotransmitter GABA.[9] It quickly found a wide range of uses due to its minimal side-effects and short duration of action, the only difficulties being the narrow therapeutic dosage range (despite an unusually high LD50) and the dangers presented by its combination with alcohol and other central nervous system depressants.

GHB was widely used in France, Italy, and other European countries for several decades as a sleeping agent and an anesthetic in childbirth, but problems with its abuse potential and development of newer drugs have led to a decrease in legitimate medical use of GHB in recent times. The only common medical applications for GHB today are in the treatment of narcolepsy and more rarely alcoholism. In the typical scenario, GHB has been synthesized from γ-butyrolactone (GBL) by adding sodium hydroxide (lye) in ethanol or water. As of late, GBL has become controlled and more circuitous routes have to be taken, such as those starting with tetrahydrofuran (THF).

A popular children's toy, Bindeez (also known as Aqua Dots, in the United States), produced by Melbourne company Moose, was banned in Australia in early November 2007 when it was discovered that 1,4-butanediol (1,4-B), which is metabolized into GHB, had been substituted for the non-toxic plasticiser 1,5-pentanediol in the bead manufacturing process. Three young children were hospitalized as a result of ingesting a large number of the beads, and the toy was recalled.[10]

Pharmacology Edit

GHB has at least two distinct binding sites[11] in the central nervous system. GHB is an agonist at the newly-characterized GHB receptor, which is excitatory,[12][13] and it is a weak agonist at the GABAB receptor, which is inhibitory.[13] GHB is a naturally-occurring substance that acts in a similar fashion to some neurotransmitters in the mammalian brain.[14] GHB is probably synthesized from GABA in GABAergic neurons, and released when the neurons fire.[13]

GHB induces the accumulation of either a derivative of [3H]-tryptophan or [3H]-tryptophan itself in the extracellular space, possibly by increasing tryptophan transport across the blood-brain barrier. The blood content of certain neutral amino-acids, including tryptophan, is also increased by peripheral GHB administration. GHB-induced stimulation of tissue serotonin turnover may be due to an increase in tryptophan transport to the brain and in its uptake by serotonergic cells. As the serotonergic system may be involved in the regulation of sleep, mood, and anxiety, the stimulation of this system by high doses of GHB may be involved in certain neuropharmacological events induced by GHB administration.

If taken orally, GABA itself very poorly crosses the blood-brain-barrier, nor do high concentrations very effectively reach the GABA receptors once inside the brain. Since GABA is naturally synthesized in the brain, a higher-than-normal concentration would be quickly metabolized.[15]

However, at pharmacological doses, GHB reaches much higher concentrations in the brain and activates GABAB receptors, which are primarily responsible for its sedative effects.[16] GHB's sedative effects are blocked by GABAB antagonists.

The role of the GHB receptor in the behavioural effects induced by GHB is more complex. GHB receptors are densely expressed in many areas of the brain, including the cortex and hippocampus, and these are the receptors that GHB displays the highest affinity for. There has been somewhat limited research into the GHB receptor; however, there is evidence that activation of the GHB receptor in some brain areas results in the release of glutamate, the principle excitatory neurotransmitter.[17] Drugs that selectively activate the GHB receptor cause absence seizures in high doses, as do GHB and GABA(B) agonists.[18]

Activation of both the GHB receptor and GABA(B) is responsible for the addictive profile of GHB. GHB's effect on dopamine release is biphasic,[19] low concentrations stimulate dopamine release via the GHB receptor.[20] Higher concentrations inhibit dopamine release via GABA(B) receptors as do other GABA(B) agonists such as baclofen and phenibut.[21] After the initial phase of inhibition, dopamine release is then increased via the GHB receptor. Both the inhibition and increase of dopamine release by GHB are inhibited by opioid antagonists such as naloxone and naltrexone. Dynorphin may play a role in the inhibition of dopamine release via kappa opioid receptors.[22]

This explains the paradoxical mix of sedative and stimulatory properties of GHB, as well as the so-called "rebound" effect, experienced by individuals using GHB as a sleeping agent, wherein they awake suddenly after several hours of GHB-induced deep sleep. That is to say that, over time, the concentration of GHB in the system decreases below the threshold for significant GABAB receptor activation and activates predominantly the GHB receptor, leading to wakefulness.

Recently, analogs of GHB, such as 4-hydroxy-4-methylpentanoic acid have been synthesised and tested on animals, in order to gain a better understanding of GHB's mode of action.[23] Analogues of GHB such as 3-methyl-GHB, 4-methyl-GHB and 4-phenyl-GHB have been shown to produce similar effects to GHB in some animal studies, but these compounds are even less well researched than GHB itself. Of these analogues, only 4-methyl-GHB (γ-hydroxyvaleric acid, GHV) and its prodrug form gamma-valerolactone (GVL) have been reported as drugs of abuse in humans, and on the available evidence seem to be less potent but more toxic than GHB, with a particular tendency to cause nausea and vomiting.

Other prodrug ester forms of GHB have also rarely been encountered by law enforcement, including 1,4-diacetoxybutane, methyl-4-acetoxybutanoate, and ethyl-4-acetoxybutanoate, but these are, in general, covered by analogue laws in jurisdictions where GHB is illegal, and little is known about them beyond their delayed onset and longer duration of action. The intermediate compound 4-hydroxybutaldehyde is also a prodrug for GHB; however, as with all aldehydes this compound is caustic and is strong-smelling and foul-tasting; actual use of this compound as an intoxicant is likely to be unpleasant and result in severe nausea and vomiting.

GHB metab path

Metabolic pathway of GHB.

Also note that both of the metabolic breakdown pathways shown for GHB can run in either direction, depending on the concentrations of the substances involved, so the body can make its own GHB either from GABA or from succinic semialdehyde. Under normal physiological conditions, the concentration of GHB in the body is rather low, and the pathways would run in the reverse direction to what is shown here to produce endogenous GHB. However, when GHB is consumed for recreational or health promotion purposes, its concentration in the body is much higher than normal, which changes the enzyme kinetics so that these pathways operate to metabolise GHB rather than producing it.

Medical uses Edit

GHB has been used as a general anesthetic in the 1960s,[5] as a hypnotic in the treatment of insomnia, to treat depression, and to improve athletic performance. In Italy, under the trade name Alcover (ATC code N07BB), GHB is used in the treatment of alcoholism (50 to 100 milligrams per kilogram per day, in 3 or more divided doses), both for acute alcohol withdrawal and medium- to long-term detoxification.[24] In the United States, the Food and Drug Administration permits the use of GHB under the trade name Xyrem to reduce the number of cataplexy attacks and excessive daytime sleepiness in patients with narcolepsy.[25]

When GHB is used in its sodium or potassium salt form, a significant quantity of excess sodium or potassium may be consumed, which should be taken into consideration by people with heart conditions, hypertension or compromised renal function. The bioavailability of sodium GHB is considerably reduced when it is consumed with food, and so it is advised to wait at least two hours after eating before consuming the dose. Because of its strong sedative effects, patients should not drive or operate heavy machinery for at least six hours after taking sodium GHB.

Adverse effects from Xyrem in clinical trials included: headache, nausea, dizziness, nasopharyngitis, somnolence, vomiting, urinary incontinence, confusion, dyspnea, hypoesthesia, paresthesia, tremor, vertigo, and blurred vision. Out of the 717 patients and 182 healthy volunteers who took part in the trials (899 total), two of them died from drug overdoses, although only one of these involved GHB.[26]

In January 2008, Jazz Pharmaceuticals completed enrollment in the second Phase III trial for a modified version of sodium oxybate for use by people with Fibromyalgia, whose sufferers endure much pain and difficulty with sleep.[27][28]

The company completed one of the Phase III clinical trials in September 2008.[29] It expects to submit a New Drug Application to the US Federal Drug Administration (FDA) before the end of 2009 for JZP-6, for use in treating Fibromyalgia.

Non-medical use Edit

Gamma-hydroxybutyrate

gamma-hydroxybutyrate powder

GHB is a CNS depressant used as an intoxicant. It has many street names, including "Georgie Home Boy", "Liquid Ecstasy", "Liquid X", and "Liquid G", as well as "Fantasy" and the reordered initialism GBH. At recreational doses, GHB can cause a state of euphoria, increased enjoyment of movement and music, increased libido, increased sociability and intoxication. At higher doses, GHB may induce nausea, dizziness, drowsiness, agitation, visual disturbances, depressed breathing, amnesia, unconsciousness, and death. The effects of GHB can last from 1.5 to 3 hours, or even longer if large doses have been consumed or if it is mixed with alcohol. [citation needed]

In general, the doses used recreationally are between 500 mg and 3000 mg. When used as a recreational drug, GHB may be found as the sodium or potassium salt, which is a white crystalline powder, or as GHB salt dissolved in water to form a clear solution. The sodium salt of GHB has a thin, very salty, chemical taste.[citation needed]. Other salt forms such as calcium GHB and magnesium GHB have also been reported, but the sodium salt is by far the most common.

Some chemicals convert to GHB in the stomach and blood. GBL, or gamma-butyrolactone, is one such prodrug. Other prodrugs include 1,4-butanediol. There may be additional toxicity concerns with these precursors. 1,4-B and GBL are normally found as pure liquids, although they may be mixed with other more harmful solvents when intended for industrial use, e.g., as paint stripper or varnish thinner.

GHB can be produced in clandestine labs, and it is claimed that most of the GHB used in the U.S. is illegally manufactured within its borders. While available as a prescription for sleep disorders in some other countries, GHB was banned (in the U.S.) by the FDA in 1990. However, on 17 July 2002, GHB was approved for treatment of cataplexy, often associated with narcolepsy. GHB is "colourless and odorless".[30]

Drug Edit

Club scene or "rave" Edit

Since the 1970s club scene, club-goers have used a range of drugs to enhance their experience on the dance floor such as amyl nitrite "poppers" and cocaine. In the 1990s, newer "club drugs" became popular, such as ketamine and "designer" phenethylamines designed to circumvent contemporary drug laws, "ecstasy" (chemically MDMA, 3,4-methylenedioxy methamphetamine, or 3,4-methylenedioxy methyl alpha-methyl phenethylamine) and 2C-I (chemically 2,5-dimethoxy-4-iodophenethylamine) being prominent examples. When the laws "catch up" to certain drugs, clandestine chemists manufacture another drug, designed to affect the user in the same way as the now-banned drug. Since most of these drugs are congeners of the banned drugs, the Federal Analogue Act was introduced to ban these substances proactively, based on the proclivity of a said chemical to mimic either the structure or the effects of the banned drug.

Like these other "club drugs," GHB is taken because users feel that it enhances the experience of being in a club or at a party; small doses of GHB are thought to act as a stimulant and aphrodisiac. GHB is sometimes referred to as liquid ecstasy, liquid X, or liquid E due to its tendency to produce euphoria and sociability and its use in the dance party scene. When GHB was banned, several "designer drugs" were made to replicate its effects - GBL and 1,4-butanediol, all of which metabolized into GHB in vivo and are now banned.[31][32] Despite this nickname, GHB is not related to "Ecstasy," either chemically or in affect upon the user.

Date rape Edit

The drug has been identified as a date rape drug,[6] much the same way as alcohol and potent benzodiazepines, often known colloquially as "Rohypnol," the trade name of a certain potent benzodiazepine, flunitrazepam. (It should be noted that several other vastly more common benzodiazepines are as potent or more potent than Rohypnol - Xanax, Ativan, Klonopin, Halcion [the most potent of all benzodiazepines], and Estazolam.) It has a salty taste, but as it is colourless and odorless,[30] it has been described as "very easy to add to drinks"[30] that mask the flavor. GHB has been used in cases of drug-related sexual assault, usually when the victim is vulnerable due to intoxication with a sedative, generally alcohol.[33] However it is difficult to establish how often GHB is used to facilitate rape as it is difficult to detect in a urine sample after a day, and many victims may not recall the rape until some time after this.[34][35] However cases of GHB being used as a date rape drug is quite rare, see the date rape drug article for more information.

GHB, produced as a sodium salt (sodium oxybate, Jazz Pharmaceuticals' Xyrem), may provide a noticeable salty character to the drink, although individual sensitivity to the taste of salt varies.[36] GHB can also be produced as different salts, some of which may not have a taste as distinctive as the sodium salt (e.g., magnesium oxybate), or much less commonly in the unstable free-acid form.[37]

Bodybuilding Edit

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Some athletes and bodybuilders also use GHB, as GHB has been shown to elevate human growth hormone in vivo.[38] The growth hormone elevating effects of GHB are mediated through muscarinic acetylcholine receptors and can be prevented by prior administration of pirenzepine, a muscarinic acetylcholine receptor blocking agent.[39]

As certain succinate salts have been shown to elevate growth hormone in vitro,[40] and because GHB is metabolized into succinate some people have suggested this may play a role in the growth hormone elevations from GHB. There is however currently no evidence to show that succinate plays any role in the growth hormone elevations from GHB.

Endogenous production by the body Edit

Cells produce GHB by reduction of succinic semialdehyde via the enzyme succinic semialdehyde dehydrogenase. This enzyme appears to be induced by cAMP levels,[41] meaning substances that elevate cAMP, such as forskolin and vinpocetine, may increase GHB synthesis and release. People with the disorder known as succinic semialdehyde dehydrogenase deficiency, also known as gamma-hydroxybutyric aciduria, have elevated levels of GHB in their urine, blood plasma and cerebrospinal fluid.[42]

The precise function of GHB in the body is not clear. It is known, however, that the brain expresses a large amount of receptors that are activated by GHB.[43] These receptors are excitatory and not responsible for the sedative effects of GHB - they have been shown to elevate the principle excitatory neurotransmitter—glutamate.[17] The benzamide antipsychotics—amisulpride, sulpiride—have been shown to bind to this receptor in vivo.[44] Other antipsychotics were tested and were not found to have an affinity for this receptor.

It is a precursor to GABA, glutamate, and glycine in certain brain areas.[45]

GHB has neuroprotective properties and has been found to protect cells from hypoxia.[46]

Natural fermentation by-product Edit

GHB is also produced as a result of fermentation and so is found in small quantities in some beers and wines, in particular fruit wines. However, the amount of GHB found in wine is insignificant and not sufficient to produce any effects.[47]

Dangers Edit

Dose response curve Edit

As with pure alcohol, the dose-response curve of GHB is very steep, and "proper" dosing of illegal GHB can be difficult since it often comes as a salt dissolved in water, and the actual amount of GHB and/or other additives per "capful" can vary. Legal GHB comes in standardized doses and is free from contaminants, so it is much safer (cf. legal alcohol vs. bathtub gin). Also, like pure alcohol, small doses of GHB are considered safe, but high doses can cause unconsciousness, convulsions, vomiting, suppression of the gag reflex, respiratory depression, and death. These effects vary between persons and are dose-dependent. Synergy of its sedative effects are seen when combined with other CNS depressants such as alcohol, benzodiazepines (e.g., diazepam), barbiturates, and others.

Combination with alcohol Edit

Alcohol worsens both CNS depression and vomiting, so combining alcohol with GHB or its precursors can be particularly dangerous. Another factor to be considered is that people who drink alcohol regularly tend to induce expression of their dehydrogenase enzymes, and thus have higher levels of these enzymes than people that do not drink alcohol regularly; this means that regular alcohol drinkers will both convert 1,4-B into GHB more rapidly and also break down GHB into succinate faster than people that do not drink alcohol. This multitude of different factors can make the interactions between 1,4-B, GHB and alcohol very complicated and highly variable between different individuals.

Death while using GHB is most likely when it is combined with alcohol or other depressant drugs; however, an overdose of GHB alone may be lethal. A review of the details of 194 deaths attributed to or related to GHB over a ten-year period[48] found that most were from respiratory depression caused by interaction with alcohol or other drugs; several were from choking on vomit and asphyxiating; remaining causes of death included motor vehicle and other accidents. The review included 70 cases in which high levels of GHB were found post-mortem without concomitant ingestion of other drugs or alcohol.

If alcohol has also been consumed this can saturate the dehydrogenase enzymes and so delays the conversion of 1,4-B into GHB, meaning that 1,4-B takes much longer to take effect and people may re-dose thinking it has not done anything, leading to an accidental overdose later on once it finally takes effect. 1,4-B itself can also contribute to the enzyme saturation, so, when alcohol and 1,4-B are consumed together, it produces a complex and somewhat unpredictable interaction between the varying levels of alcohol, 1,4-B and GHB present in the body. Alcohol also makes the GHB last longer in the body by competing for dehydrogenase enzymes, and hence delaying the conversion of GHB into succinate.

Other combinations Edit

Another complication is the difference in pharmacokinetics between GHB and its two prodrugs, 1,4-B and GBL. 1,4-B is converted into GHB in the body by two enzymes alcohol dehydrogenase and aldehyde dehydrogenase, which gives it a delayed onset of effects and a longer duration of action. GHB is then further metabolised, again by alcohol dehydrogenase and aldehyde dehydrogenase, into the inactive succinate.

The other precursor GBL is rapidly converted into GHB by lactamase enzymes found in the blood. GBL is more lipophilic (fat soluble) than GHB, and so is absorbed faster and has higher bioavailability; the paradox is that this can mean that GBL has a faster onset of effects than GHB itself, even though it is a prodrug. The levels of lactamase enzyme can vary between individuals, and GBL is not active in its own right, so people who have never tried GBL before may have delayed or fewer effects than expected; however, once someone has taken GBL a few times, the production of lactamase enzymes is increased and he/she will feel the effects like a regular user.

Because of these pharmacokinetic differences, 1,4-B tends to be slightly less potent, slower to take effect but longer-acting than GHB, whereas GBL tends to be more potent and faster-acting than GHB, and has around the same duration.

Death and other harmful effects Edit

GHB use is conclusively associated with death, as documented by many reports, including one in which 3 deaths were associated with Xyrem use (pharmaceutical GHB, or "Sodium Oxybate"),[49]. Because rodents are particularly resistant to death from GHB, many have assumed that GHB is equally safe in humans. The fact that clinical effects of GHB occur at approximately 1/10th the dose in humans as in rodents is evidence that GHB is much more toxic in humans than in rodents. One large series documents 226 deaths attributed to GHB; this will be published in the American Journal of Emergency Medicine this year.[50] A preliminary report of this case series, with 194 deaths, was presented at the American Academy of Forensic Science. [51] In this series, death records were reviewed for toxicology, autopsy findings, and history. Of 226 deaths included, 213 suffered cardiorespiratory arrest and 13 suffered fatal accidents. Seventy-one deaths (34%) had no co-intoxicants. Postmortem blood GHB was 18-4400mg/L (median=347) in deaths negative for co-intoxicants.

GHB is produced in the body in very small amounts, and blood levels may climb after death to levels in the range of 30-50 mg/L. [52] Levels higher than this are found in GHB deaths. Levels lower than this may be due to GHB or to postmortem endogenous elevations. Only careful attention to historical details, and analysis of other body fluids (e.g., vitreous) can determine for with any certainly whether measurable levels below 30-50 mg/L are exogenous or endogenous.

There have been no systematic studies into the effects of GHB if taken chronically in humans, and hence whether prolonged use of GHB causes any bodily harm remains unknown. A UK parliamentary committee commissioned report found the use of GHB to be less dangerous than tobacco and alcohol in social harms, physical harm and addiction.[53]

Treatment of overdose Edit

Overdose of GHB can be difficult to treat because of its multiple effects on the body.[5][54][55] GHB tends to cause rapid unconsciousness at doses above 3500 mg, with single doses over 7000 mg often causing life-threatening respiratory depression, and higher doses still inducing bradycardia and cardiac arrest. Other side-effects include convulsions (especially when combined with stimulants), and nausea/vomiting (especially when combined with alcohol).

The greatest life threat due to GHB overdose (with or without other substances) is respiratory arrest.[56] Other relatively common causes of death due to GHB ingestion include aspiration of vomitus, positional asphyxia, and trauma sustained while intoxicated (e.g., motor vehicle accidents while driving under the influence of GHB).[56] The risk of aspiration pneumonia and positional asphyxia risk can be reduced by laying the patient down in the recovery position. People are most likely to vomit as they become unconscious, and as they wake up. GHB overdose is a medical emergency and assessment in an emergency department is needed.

Treatment Edit

Convulsions from GHB can be treated with diazepam or lorazepam, even though these are also CNS depressants they are GABAA agonists, whereas GHB is primarily a GABAB agonist, so the benzodiazepines do not worsen CNS depression as much as might be expected.

Most stimulants are not effective at counteracting the unconsciousness from GHB.[citation needed]

Because of the faster and more complete absorption of GBL relative to GHB, its dose-response curve is steeper, and overdoses of GBL tend to be more dangerous and problematic than overdoses involving only GHB or 1,4-B. Any GHB/GBL overdose is a medical emergency and should be cared for by appropriately trained personnel.

A newer synthetic drug SCH-50911, which acts as a selective GABAB antagonist, quickly reverses GHB overdose in mice.[57] However this treatment has yet to be tried in humans, and it is unlikely that it will be researched for this purpose in humans due to the illegal nature of clinical trials of GHB, and the lack of medical indemnity coverage inherent in using an untested treatment for a life-threatening overdose.

Addiction Edit

GHB can be physically addictive and may result in psychological addiction. Physical dependence develops when GHB is taken on a regular basis (i.e., every 2–4 hours for multiple consecutive days or weeks). Withdrawal effects may include insomnia, restlessness, anxiety, tremors, sweating, loss of appetite, edginess, tachycardia, chest pain and tightness, muscle and bone aches, sensitivity to external stimuli (sound, light, touch), dysphoria, and mental dullness. These side-effects will subside after 2 – 21 days, depending on frequency of usage and the size of the doses used. In particularly severe cases, withdrawal from GHB may cause symptoms similar to acute withdrawal from alcohol or barbiturates (delirium tremens) and can cause convulsions and hallucinations.

Although there have been reported fatalities due to GHB withdrawal, reports are inconclusive and further research is needed. Unlike alcohol, there is no firm data that chronic use of GHB causes permanent damage to the body. In rats, no organ or brain damage was observed after chronic administration of GBL (a precursor to GHB).[58]

Withdrawal Edit

Withdrawal from GHB can be a life-threatening condition. Treatment with benzodiazepines can be used, although extremely high doses may be required (e.g. > 100 mg/d of diazepam). With the exception of baclofen, other treatments are often ineffective. Evidence shows that baclofen is the most effective drug for GHB withdrawal. GHB and baclofen are agonists for the GABAb receptor.[59]

Legal status Edit

In the United States, it was placed on Schedule I of the Controlled Substances Act in March 2000. However, when sold as Xyrem, it is considered Schedule III, one of several drugs that are listed in multiple schedules.[3][60] On 20 March 2001, the Commission on Narcotic Drugs placed GHB in Schedule IV of the 1971 Convention on Psychotropic Substances.[61] In the UK it was made a class C drug in June 2003.

In Hong Kong, GHB is regulated under Schedule 1 of Hong Kong's Chapter 134 Dangerous Drugs Ordinance. It can only be used legally by health professionals and for university research purposes. The substance can be given by pharmacists under a prescription. Anyone who supplies the substance without prescription can be fined HK$10000. The penalty for trafficking or manufacturing the substance is a HK$5,000,000 fine and life imprisonment. Possession of the substance for consumption without license from the Department of Health is illegal with a HK$1,000,000 fine and/or 7 years of jail time.

In New Zealand and Australia, GHB, 1,4-B and GBL are all Class B illegal drugs, along with any possible esters, ethers and aldehydes. GABA itself is also listed as an illegal drug in these jurisdictions, which seems unusual given its failure to cross the blood-brain barrier, but there was a perception among legislators that all known analogues should be covered as far as this was possible. Attempts to circumvent the illegal status of GHB have led to the sale of derivatives such as 4-methyl-GHB (gamma-hydroxyvaleric acid, GHV) and its prodrug form gamma-valerolactone (GVL), but these are also covered under the law by virtue of their being "substantially similar" to GHB or GBL and; so importation, sale, possession and use of these compounds is also considered to be illegal.

In Norway, GHB is considered a narcotic[62] and is only available by prescription under the trade name Xyrem (Union Chimique Belge S.A.).

See also Edit

References Edit

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