View source for Gamma-Hydroxybutyric acid

{{DISPLAYTITLE:''Gamma''-Hydroxybutyric acid}}
{{drugbox | Watchedfields = changed
| verifiedrevid = 311402204
| image = 4-hydroxybutanoic-acid.png
| image2= GHB-3D-balls.png
| width = 200
| imagename  = &gamma;-Hydroxybutyric acid
| IUPAC_name = 4-Hydroxybutanoic acid
| synonyms = γ-Hydroxybutyric acid<br>&gamma;-Hydroxybutyrate<br>GHB
| CASNo_Ref = {{cascite}}
| CAS_number = 591-81-1
| ATC_prefix = N01
| ATC_suffix = AX11
| ATC_supplemental = {{ATC|N07|XX04}}
| PubChem = 3037032
| ChemSpiderID = 9984
| DrugBank = DB01440
| 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)
| SMILES = OCCCC(=O)O
| bioavailability = 25% (oral)
| metabolism = 95%, mainly [[Hepatic]], also in blood and tissues
| elimination_half-life = 30–60 minutes
| excretion = 5%, [[Kidney|renal]]
| pregnancy_category = B
| legal_AU = S9
| legal_CA = Schedule III
| legal_UK = Class C
| legal_status = Class B ([[New Zealand|NZ]]), [[Controlled Substances Act|Schedule I and III]] (US)
| routes_of_administration = Usually oral; [[Intravenous therapy|intravenous]]
}}

'''γ-Hydroxybutyric acid''' ('''GHB'''), also known as '''4-hydroxybutanoic acid''' and '''sodium oxybate''',<ref>{{cite web|url=http://www.nlm.nih.gov/medlineplus/druginfo/meds/a605032.html |title=Sodium Oxybate: MedlinePlus Drug Information |publisher=Nlm.nih.gov |date=2010-07-28 |accessdate=2010-08-01}}</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 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 Australia, Canada, most of Europe and 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]]. The same company is also investigating the drug for use as a [[fibromyalgia]] treatment.<ref>http://online.wsj.com/article/SB10001424052748703649004575437340141238552.html</ref>

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 ==
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]]){{Citation needed|date=June 2010}} 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. In the [[Netherlands]], GHB could be bought as aphrodisiac and euphoriant in a [[smartshop]] for several years, until several incidents caused it to become regulated which no longer made it possible to buy it at smartshops. 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 in many countries 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
 | author = Michael Perry, James Pomfret, Roger Crabb
 | title = Australia bans China-made toy on toxic drug risk
 | date = 7 November 2007
 | publisher = [[Reuter]]
 | url = http://www.reuters.com/article/worldNews/idUSSYD2129620071107
}}</ref>

== Pharmacology ==
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" />

GHB induces the accumulation of either a derivative of tryptophan or 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 does not effectively cross the [[blood-brain-barrier]].<ref>{{cite journal |author=Kuriyama K, Sze PY |title=Blood-brain barrier to H3-gamma-aminobutyric acid in normal and amino oxyacetic acid-treated animals |journal=Neuropharmacology |volume=10 |issue=1 |pages=103–8 |year=1971 |month=January |pmid=5569303 |doi= 10.1016/0028-3908(71)90013-X|url=}}</ref> 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>

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.

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 principal 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>

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 an 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>

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.

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 | last2 = Zink | first2 = N | last3 = Carter | first3 = LP | last4 = Mehta | first4 = AK | last5 = Hernandez | first5 = RJ | last6 = Ticku | first6 = MK | last7 = Lamb | first7 = R | last8 = France | first8 = CP | last9 = Coop | first9 = A | issue = 2}}</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.

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.

[[File:GHB metabolic pathway.svg|thumb|center|600px|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 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 use ==
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>

GHB is the active ingredient in a [[prescription medication]] called [[Xyrem]] (sodium oxybate) oral solution.  Xyrem is approved by the [[U.S. Food and Drug Administration]] (FDA) for the treatment of [[cataplexy]] associated with [[narcolepsy]] <ref>{{cite web|url= http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2002/21196ltr.pdf |title= FDA Approval Letter for Xyrem; Indication: Cataplexy associated with narcolepsy; 17 Jul 2002}}</ref> and [[Excessive daytime sleepiness|Excessive Daytime Sleepiness]] (EDS) associated with [[narcolepsy]] .<ref>{{cite web|url= http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2005/021196s005ltr.pdf |title= FDA Approval Letter for Xyrem; Indication: EDS (Excessive Daytime Sleepiness) associated with narcolepsy; 18 Nov 2005}}</ref>
The [[American Academy of Sleep Medicine]] (AASM) recommends Xyrem as a standard of care for the treatment of [[cataplexy]], daytime sleepiness, and disrupted sleep due to narcolepsy in its Practice Parameters for the Treatment of Narcolepsy and other Hypersomnias of Central Origin.  These recommendations are based upon careful review of the medical literature, and the designation “standard” of care “reflects a high degree of clinical certainty” based on strong empirical evidence.<ref>{{cite web|url= http://www.aasmnet.org/Resources/PracticeParameters/PP_narcolepsy.pdf |title= Practice Parameters for the Treatment of Narcolepsy and other Hypersomnias of Central Origin (Morgenthaler et al. Sleep. 2007;30:1705)}}</ref>

In clinical trials Xyrem significantly reduced cataplexy attacks at a dose of 6000–9000&nbsp;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&nbsp;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&nbsp;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.

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>

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>{{cite web|url=http://www.reuters.com/finance/stocks/companyProfile?rpc=66&symbol=JAZZ.O |title=Reuters.com |publisher=Reuters.com |date= |accessdate=2010-08-01}}</ref><ref>{{cite web|url=http://investor.jazzpharma.com/phoenix.zhtml?c=210227&p=irol-newsArticle&id=1243912 |title=JazzPharma - Investors - News Release |publisher=Investor.jazzpharma.com |date= |accessdate=2010-08-01}}</ref>

The company completed one of the Phase III clinical trials in September 2008.<ref>{{cite web|url=http://www.prohealth.com/library/showarticle.cfm?libid=13910 |title=65-center trial of sodium oxybate for fibromyalgia pain completed; second phase III trial still recruiting in US and UK |publisher=Prohealth.com |date=2008-09-11 |accessdate=2010-08-01}}</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.

== Non-medical use ==
{{Ref improve section|date=August 2008}}
[[Image:Gamma-hydroxybutyrate.jpg|thumb|gamma-hydroxybutyrate powder]]
<!-- Do not add street names below without references that they are in common use.
Otherwise they will be removed immediately. Wikipedia is not a dictionary, a jargon guide, or a collection of local trivia. -->
GHB is a CNS [[depressant]] used as an [[intoxicant]]. It has many [[Street name (disambiguation)|street names]], including "Georgia Home Boy", "Liquid Ecstasy", "Liquid X", and "Liquid G", as well as "Fantasy" and the reordered [[initialism]] [[Grievous bodily harm|GBH]]. Its effects have been described anecdotally as comparable to [[alcohol]] and [[MDMA|ecstasy]] use, such as [[Euphoria (emotion)|euphoria]], disinhibition, enhanced sensuality and empathogenesis. 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.<ref name=GALL1>{{cite journal |author=Galloway GP, Frederick-Osborne SL, Seymour R, Contini SE, Smith DE |title=Abuse and therapeutic potential of gamma-hydroxybutyric acid |journal=Alcohol |volume=20 |issue=3 |pages=263–9 |year=2000 |month=April |pmid=10869868 |doi= 10.1016/S0741-8329(99)00090-7|url=}}</ref>

In general, the doses used recreationally are between 500&nbsp;mg and 3,000&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 salty taste.<ref name=GALL1/> 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 stream. 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.

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 | pmid = 15274975 | issue = 2}}</ref>

=== Drug ===
==== Club scene or "rave" ====
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]]s of the banned drugs, the [[Federal Analogue Act]] was introduced in the US 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.<ref>Mary Klein, Frances Kramer, "Rave drugs: Pharmacological considerations", ''AANA Journal'', Vol. 72 (2004), 61–67.</ref> Despite this nickname, GHB has entirely separate chemical and pharmacological modes of action compared to ecstasy.

==== Date rape ====
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 hypnotic benzodiazepine, [[flunitrazepam]]. 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 are quite rare, see the [[Date rape drug#Mistaken Self-Diagnosis|date rape drug]] article for more information.

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>{{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 | pmid = 16566766 | issue = 2}}</ref>

=== Bodybuilding ===
[[File:Dangerous dietary supplements.gif|thumb|right|300px|FDA warning against products containing GHB and its prodrugs.]]
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>{{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 | last2 = Spangelos | first2 = B | last3 = Hagiwara | first3 = Y | last4 = Hagiwara | first4 = H | last5 = Ueyama | first5 = H | last6 = Goldstein | first6 = A}}</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 ===
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>National Organization for Rare Disorders. [http://www.rarediseases.org/search/rdbdetail_abstract.html?disname=Succinic%20Semialdehyde%20Dehydrogenase%20Deficiency  Succinic Semialdehyde Dehydrogenase Deficiency]. Retrieved 6 March 2010.</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>{{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 = 17| issue =  12| doi = 10.1096/fj.02-0846fje| pmid = 12958178 | pages = 1691–3}}</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.

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 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>

=== 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, 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>

== Adverse effects ==
{{Ref improve section|date=August 2008}}

=== Combination with alcohol ===
In humans, GHB has been shown to inhibit the elimination rate of alcohol. This may explain the respiratory arrest that has been reported after ingestion of both drugs.<ref>{{cite journal |author=Poldrugo F, Addolorato G |title=The role of gamma-hydroxybutyric acid in the treatment of alcoholism: from animal to clinical studies |journal=Alcohol Alcohol. |volume=34 |issue=1 |pages=15–24 |year=1999 |pmid=10075397 |doi= |url=}}</ref> A review of the details of 194 deaths attributed to or related to GHB over a ten-year period found that most were from respiratory depression caused by interaction with alcohol or other drugs.<ref>[http://web.archive.org/web/20071203005230/http://www.aafs.org/pdf/Seattleabstracts06.pdf Zvosec et al. American Academy of Forensic Science in Seattle, 2006]</ref>

=== Reported deaths ===
One report has suggested that Xyrem (pharmaceutical GHB, or "Sodium Oxybate") overdose may be fatal, based on deaths of three patients who had been prescribed the drug.<ref>{{cite pmid|19269893}}</ref> However, for two of the three cases, post-mortem GHB concentrations were 141 and 110&nbsp;mg/L, which is within the expected range of concentrations for GHB after death, and the third case was a patient with a history of intentional drug overdose.<ref>{{cite journal |author=Feldman NT |title=Xyrem safety: the debate continues |journal=Sleep Med. |volume=10 |issue=4 |pages=405–6 |year=2009 |month=April |pmid=19332385 |doi=10.1016/j.sleep.2009.02.002 |url=}}</ref>

One publication has investigated 226 deaths attributed to GHB.<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>  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 18–4400&nbsp;mg/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&nbsp;mg/L.<ref>{{cite pmid|19959395}}</ref> Levels higher than this are found in GHB deaths. Levels lower than this may be due to GHB or to postmortem endogenous elevations.

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>{{cite web|url=http://news.bbc.co.uk/1/shared/bsp/hi/pdfs/31_07_06_drugsreport.pdf |title=Microsoft Word - HC1031.doc |format=PDF |date= |accessdate=2010-08-01}}</ref>

=== Treatment of overdose ===
{{Ref improve section|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 | pmid = 16549578 | pmc = 2579509}}</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 | pmid = 15611542 | pmc = 1726538}}</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 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"/> 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.

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.{{Citation needed|date=March 2010}}

Most stimulants are not effective at counteracting the unconsciousness from GHB.{{Citation needed|date=August 2008}}

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 | pmid = 15940094 }}</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.{{Or|date=March 2010}}

===Detection of use===
GHB may be quantitated in blood or plasma to confirm a diagnosis of poisoning in hospitalized patients, provide evidence in an impaired driving arrest or to assist in a medicolegal death investigation. Blood or plasma GHB concentrations are usually in a range of 50–250&nbsp;mg/L in persons receiving the drug therapeutically (during general anesthesia), 30–100&nbsp;mg/L in those arrested for impaired driving, 50–500&nbsp;mg/L in acutely intoxicated patients and 100–1000&nbsp;mg/L in victims of fatal overdosage. Urine is often the preferred specimen for routine drug abuse monitoring purposes. Both [[gamma-butyrolactone]] (GBL) and [[1,4-butanediol]] are converted to GHB in the body.<ref>Couper FJ, Thatcher JE, Logan BK. Suspected GHB overdoses in the emergency department. J. Anal. Toxicol. 28: 481-484, 2004.</ref><ref>Marinetti LJ, Isenschmid DS, Hepler BR, Kanluen S. Analysis of GHB and 4-methyl-GHB in postmortem matrices after long-term storage. J. Anal. Toxicol. 29: 41-47, 2005.</ref><ref>R. Baselt, ''Disposition of Toxic Drugs and Chemicals in Man'', 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 680-684.</ref>

== Neurotoxicity ==

In multiple studies, GHB has been found to impair [[spatial memory|spatial]] and [[working memory|working]] [[learning]] and [[memory]] in rats with chronic administration.<ref name="pmid15582677">{{cite journal | author = Sircar R, Basak A | title = Adolescent gamma-hydroxybutyric acid exposure decreases cortical N-methyl-D-aspartate receptor and impairs spatial learning | journal = Pharmacology, Biochemistry, and Behavior | volume = 79 | issue = 4 | pages = 701–8 | year = 2004 | month = December | pmid = 15582677 | doi = 10.1016/j.pbb.2004.09.022 | url = http://linkinghub.elsevier.com/retrieve/pii/S0091-3057(04)00320-X}}</ref><ref name="pmid17296081">{{cite journal | author = García FB, Pedraza C, Arias JL, Navarro JF | title = [Effects of subchronic administration of gammahydroxybutyrate (GHB) on spatial working memory in rats] | language = Spanish; Castilian | journal = Psicothema | volume = 18 | issue = 3 | pages = 519–24 | year = 2006 | month = August | pmid = 17296081 | doi = | url = }}</ref><ref name="pmid18991885">{{cite journal | author = Sircar R, Basak A, Sircar D | title = Gamma-hydroxybutyric acid-induced cognitive deficits in the female adolescent rat | journal = Annals of the New York Academy of Sciences | volume = 1139 | issue = | pages = 386–9 | year = 2008 | month = October | pmid = 18991885 | doi = 10.1196/annals.1432.044 | url = http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0077-8923&date=2008&volume=1139&spage=386}}</ref><ref name="pmid19288974">{{cite journal | author = Pedraza C, García FB, Navarro JF | title = Neurotoxic effects induced by gammahydroxybutyric acid (GHB) in male rats | journal = The International Journal of Neuropsychopharmacology / Official Scientific Journal of the Collegium Internationale Neuropsychopharmacologicum (CINP) | volume = 12 | issue = 9 | pages = 1165–77 | year = 2009 | month = October | pmid = 19288974 | doi = 10.1017/S1461145709000157 | url = http://journals.cambridge.org/abstract_S1461145709000157}}</ref> These effects are associated with decreased [[NMDA receptor]] expression in the [[cerebral cortex]] and possibly other areas as well.<ref name="pmid15582677"/>

Pedraza et al. (2009) found that repeated administration of GHB to rats for 15 days ''drastically'' reduced the number of neurons and non-neuronal cells in the CA1 region of the [[hippocampus]] and in the [[prefrontal cortex]]. With doses of 10&nbsp;mg/kg of GHB, they were decreased by 61% in the CA1 region and 32% in the prefrontal cortex, and with 100&nbsp;mg/kg, they were decreased by 38% and 9%, respectively. It is interesting to note that GHB has biphasic effects on neuronal loss, with lower doses (10&nbsp;mg/kg) producing the most neurotoxicity, and higher doses (100&nbsp;mg/kg) producing less.

Pretreatment with [[NCS-382]], a [[GHB receptor]] [[receptor antagonist|antagonist]], prevents both learning/memory deficits and neuronal loss in GHB-treated animals, suggesting that GHB's neurotoxic actions are mediated via activation of the [[GHB receptor]].<ref name="pmid19288974"/> In addition, the neurotoxicity appears to be caused by [[oxidative stress]].<ref name="pmid19288974"/><ref name="pmid17197055">{{cite journal | author = Sgaravatti AM, Sgarbi MB, Testa CG, ''et al.'' | title = Gamma-hydroxybutyric acid induces oxidative stress in cerebral cortex of young rats | journal = Neurochemistry International | volume = 50 | issue = 3 | pages = 564–70 | year = 2007 | month = February | pmid = 17197055 | doi = 10.1016/j.neuint.2006.11.007 | url = http://linkinghub.elsevier.com/retrieve/pii/S0197-0186(06)00335-4}}</ref><ref name="pmid19296210">{{cite journal | author = Sgaravatti AM, Magnusson AS, Oliveira AS, ''et al.'' | title = Effects of 1,4-butanediol administration on oxidative stress in rat brain: study of the neurotoxicity of gamma-hydroxybutyric acid in vivo | journal = Metabolic Brain Disease | volume = 24 | issue = 2 | pages = 271–82 | year = 2009 | month = June | isbn = 1101100991367 | pmid = 19296210 | doi = 10.1007/s11011-009-9136-7}}</ref>

== Addiction ==

Although there have been reported fatalities due to GHB withdrawal, reports are inconclusive and further research is needed.<ref name="autogenerated1997">Galloway GP, Frederick SL, Staggers FE, Gonzales M, Stalcup SA, Smith DE. Gamma-hydroxybutyrate: an emerging drug of abuse that causes physical dependence. Addiction. 1997;92(1):89-96.</ref> Addiction occurs when repeated drug use disrupts the normal balance of brain circuits that control rewards, memory and cognition, ultimately leading to compulsive drug taking.<ref>Department of Health and Human Services, SAMHSA Office of Applied Studies 2005 National Survey on Drug Use and Health (ages 12 years and up); American Heart Association; Johns Hopkins University study, Principles of Addiction Medicine; Psychology Today; National Gambling Impact Commission Study; National Council on Problem Gambling; Illinois Institute for Addiction Recovery; Society for Advancement of Sexual Health; All Psych Journal</ref><ref><Time Health & Science: Addiction and the Brain=http://www.time.com/time/interactive/0,31813,1640235,00.html></ref>

Colombo reports that rats forced to consume massive doses of GHB will intermittently prefer GHB solution to water, but notes that "no rat showed any sign of withdrawal when GHB was finally removed at the end of the 20-week period" or during periods of voluntary abstinence.<ref>Colombo, Giancarlo; Agabio, Roberta. "Oral self-administration of gamma-hydroxybutyric acid in the rat". European Journal of Pharmacology. 1995. 285(1). 103-107. RT 120 E 4.</ref><ref><Is GHB toxic? Addictive? Dangerous?=http://www.lycaeum.org/~ghbfaq/dangerous.html></ref>

== Withdrawal ==
GHB has also been associated with a withdrawal syndrome of insomnia, anxiety, and tremor that usually resolves within three to twelve days.<ref name="autogenerated1997"/><ref name=J Pharm Pharmaceut Sci (www.ualberta.ca/~csps)>{{cite web|url=http://www.ualberta.ca/~csps/JPPS4(2)/M.Okun/GHB.htm |title=GHB: An Important Pharmacologic and Clinical Update |publisher=Ualberta.ca |date= |accessdate=2010-08-01}}</ref> Treatment with [[benzodiazepines]] can be used, although extremely high doses may be required (e.g. > 100&nbsp;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 | issue = 3 | pmc = 2630388}}</ref>  GHB withdrawal is not widely discussed in text books and as a result most psychiatrists are not familiar with this withdrawal syndrome.<ref name="van Noorden-">{{Cite journal | last1 = van Noorden | first1 = MS. | last2 = van Dongen | first2 = LC. | last3 = Zitman | first3 = FG. | last4 = Vergouwen | first4 = TA. | title = Gamma-hydroxybutyrate withdrawal syndrome: dangerous but not well-known. | journal = Gen Hosp Psychiatry | volume = 31 | issue = 4 | pages = 394–6 | month = | year = 2009| doi = 10.1016/j.genhosppsych.2008.11.001 | pmid = 19555805 }}</ref>

== 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]{{Dead link|date=August 2010}}</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.

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 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<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 in Switzerland,<ref name="Kompendium Xyrem">{{cite web |url=http://www.kompendium.ch/MonographieTxt.aspx?lang=de&MonType=fi |title=Xyrem untersteht dem Bundesgesetz über die Betäubungsmittel und die psychotropen Stoffe |work= |accessdate=}}</ref> GHB is considered a narcotic and is only available by prescription under the trade name Xyrem (Union Chimique Belge S.A.).

== 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 ==
{{Reflist|2}}

== 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]
* [[Erowid]] [http://www.erowid.org/chemicals/ghb/ 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.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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[[cs:GHB]]
[[da:GHB]]
[[de:4-Hydroxybutansäure]]
[[es:Ácido γ-hidroxibutírico]]
[[eu:GHB]]
[[fa:گاما-هیدروکسی‌بوتیریک اسید]]
[[fr:Acide gamma-hydroxybutyrique]]
[[ko:감마 하이드록시뷰티린산]]
[[is:Smjörsýra]]
[[it:Gamma-idrossibutirrato]]
[[he:GHB]]
[[lv:Oksisviestskābe]]
[[lt:GHB]]
[[hu:GHB]]
[[ms:GHB]]
[[nl:4-hydroxybutaanzuur]]
[[ja:Γ-ヒドロキシ酪酸]]
[[no:GHB]]
[[nn:GHB]]
[[pl:Kwas 4-hydroksybutanowy]]
[[pt:Ácido gama-hidroxibutírico]]
[[ru:Натрия оксибутират]]
[[simple:Gamma-Hydroxybutyric acid]]
[[sl:Gama-hidroksibutirat]]
[[sr:GHB]]
[[fi:Gammahydroksivoihappo]]
[[sv:GHB]]
[[zh:Γ-羟基丁酸]]
[[Category:2Fix]]