Γ-Hydroxybutyric acid

{{main|Sodium oxybate}}

GHB is used for medical purposes in the treatment of narcolepsy{{cite journal |vauthors = Mayer G |title = The use of sodium oxybate to treat narcolepsy |journal = Expert Review of Neurotherapeutics |volume = 12 |issue = 5 |pages = 519–29 |date = May 2012 |pmid = 22550980 |doi = 10.1586/ern.12.42 |s2cid = 43706704 }} and, more rarely, alcohol dependence,{{cite journal |vauthors = Caputo F, Mirijello A, Cibin M, Mosti A, Ceccanti M, Domenicali M, Bernardi M, Maremmani I, Addolorato G |title = Novel strategies to treat alcohol dependence with sodium oxybate according to clinical practice |journal = European Review for Medical and Pharmacological Sciences |volume = 19 |issue = 7 |pages = 1315–20 |date = April 2015 |pmid = 25912595 }}{{cite journal |vauthors = Keating GM |title = Sodium oxybate: a review of its use in alcohol withdrawal syndrome and in the maintenance of abstinence in alcohol dependence | journal = Clinical Drug Investigation |volume = 34 |issue = 1 |pages = 63–80 | date = January 2014 |pmid = 24307430 |doi = 10.1007/s40261-013-0158-x |s2cid = 2056246}} although there remains uncertainty about its efficacy relative to other pharmacotherapies for alcohol dependence.{{cite journal |vauthors = Leone MA, Vigna-Taglianti F, Avanzi G, Brambilla R, Faggiano F |title = Gamma-hydroxybutyrate (GHB) for treatment of alcohol withdrawal and prevention of relapses |journal = The Cochrane Database of Systematic Reviews |issue = 2 | pages = CD006266 |date = February 2010 |pmid = 20166080 |doi = 10.1002/14651858.CD006266.pub2 |collaboration = Cochrane Drugs and Alcohol Group |quote= There is insufficient randomised evidence to be confident of a difference between GHB and placebo, or to determine reliably if GHB is more or less effective than other drugs for the treatment of alcohol {{sic|?|withdrawl}} or the prevention of relapses.}} The authors of a 2010 Cochrane review{{Cite journal |url=https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD006266.pub2/full |title=cochranelibrary.com |date=2010 |doi=10.1002/14651858.CD006266.pub2 |pmid=20166080 |access-date=23 January 2023 |archive-date=5 November 2022 |archive-url=https://web.archive.org/web/20221105110933/https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD006266.pub2/full |url-status=live |journal=The Cochrane Database of Systematic Reviews |issue=2 |pages=CD006266 | vauthors = Leone MA, Vigna-Taglianti F, Avanzi G, Brambilla R, Faggiano F }} concluded that "GHB appears better than NTX and disulfiram in maintaining abstinence and preventing craving in the medium term (3 to 12 months)". It is sometimes used off-label for the treatment of fibromyalgia.{{cite journal |vauthors = Calandre EP, Rico-Villademoros F, Slim M |title = An update on pharmacotherapy for the treatment of fibromyalgia |journal = Expert Opinion on Pharmacotherapy |volume = 16 |issue = 9 |pages = 1347–68 |date = June 2015 |pmid = 26001183 |doi=10.1517/14656566.2015.1047343 |s2cid = 24246355}}{{cite journal |vauthors = Staud R |title = Sodium oxybate for the treatment of fibromyalgia |journal = Expert Opinion on Pharmacotherapy |volume = 12 |issue = 11 |pages = 1789–98 |date = August 2011 |pmid = 21679091 |doi=10.1517/14656566.2011.589836 |s2cid = 33026097 }} GHB is the active ingredient of the prescription medication sodium oxybate (Xyrem). Sodium oxybate is approved by the U.S. Food and Drug Administration for the treatment of cataplexy associated with narcolepsy{{Cite web |url=http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2002/21196ltr.pdf |archive-url=https://web.archive.org/web/20121017094123/http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2002/21196ltr.pdf |archive-date=17 October 2012 |url-status=live |title=FDA Approval Letter for Xyrem; Indication: Cataplexy associated with narcolepsy; 17 July 2002 |access-date=6 March 2022}} and excessive daytime sleepiness (EDS) associated with narcolepsy.{{Cite web |url=http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2005/021196s005ltr.pdf |archive-url=https://web.archive.org/web/20121017094134/http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2005/021196s005ltr.pdf |archive-date=17 October 2012 |url-status=live |title=FDA Approval Letter for Xyrem; Indication: EDS (Excessive Daytime Sleepiness) associated with narcolepsy; 18 November 2005 |access-date=6 March 2022}}

GHB has been shown to reliably increase slow-wave sleep{{cite journal |vauthors = Scrima L, Hartman PG, Johnson FH, Thomas EE, Hiller FC |title = The effects of gamma-hydroxybutyrate on the sleep of narcolepsy patients: a double-blind study |journal = Sleep |volume = 13 |issue = 6 |pages = 479–90 |date = December 1990 |pmid = 2281247 |doi = 10.1093/sleep/13.6.479 |doi-access = free }}{{cite journal |vauthors = Scrima L, Johnson FH, Hiller FC |title = Long-Term Effect of Gamma-Hydroxybutyrate on Sleep in Narcolepsy Patients |journal=Sleep Research |year=1991 |volume=20 |pages=330}}{{cite journal |vauthors = Van Cauter E, Plat L, Scharf MB, Leproult R, Cespedes S, L'Hermite-Balériaux M, Copinschi G |title = Simultaneous stimulation of slow-wave sleep and growth hormone secretion by gamma-hydroxybutyrate in normal young Men |journal = The Journal of Clinical Investigation |volume = 100 |issue = 3 |pages = 745–53 |date = August 1997 |pmid = 9239423 |pmc = 508244 |doi = 10.1172/JCI119587 }} and decrease the tendency for REM sleep in modified multiple sleep latency tests.{{cite journal |vauthors = Scrima L, Shander D |title = Letter to Editor on article: Re: Narcolepsy Review (Aldrich MS: 8-9-91) |journal = The New England Journal of Medicine |volume = 324 |issue = 4 |pages = 270–72 |date = January 1991 |pmid = 1985252 |doi = 10.1056/nejm199101243240416 }}

The FDA-approved labeling for sodium oxybate{{cite web |title = FDA Approved Labeling Text: Xyrem® (sodium oxybate) oral solution |date = 18 November 2005 |url = https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021196s005lbl.pdf |publisher = U.S. Food and Drug Administration |access-date = 23 April 2021 |archive-date = 24 January 2022 |archive-url = https://web.archive.org/web/20220124165753/https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021196s005lbl.pdf |url-status = live }} suggests no evidence GHB has teratogenic, carcinogenic or hepatotoxic properties. Its favorable safety profile relative to ethanol may explain why GHB continues to be investigated as a candidate for alcohol substitution.{{cite journal |vauthors = Guiraud J, Addolorato G, Aubin HJ, Batel P, de Bejczy A, Caputo F, Goudriaan AE, Gual A, Lesch O, Maremmani I, Perney P, Poulnais R, Raffaillac Q, Soderpalm B, Spanagel R, Walter H, van den Brink W |title = Treating alcohol dependence with an abuse and misuse deterrent formulation of sodium oxybate: Results of a randomised, double-blind, placebo-controlled study |journal = European Neuropsychopharmacology |volume = 52 |issue = |pages = 18–30 |date = July 2021 |pmid = 34237655 |doi=10.1016/j.euroneuro.2021.06.003 |doi-access = free|hdl = 11392/2483205 |hdl-access = free }}

GHB is a central nervous system depressant used as an intoxicant.{{cite journal | vauthors = Schep LJ, Knudsen K, Slaughter RJ, Vale JA, Mégarbane B | title = The clinical toxicology of γ-hydroxybutyrate, γ-butyrolactone and 1,4-butanediol | journal = Clinical Toxicology | volume = 50 | issue = 6 | pages = 458–70 | date = July 2012 | pmid = 22746383 | doi = 10.3109/15563650.2012.702218 | s2cid = 19697449 }} It has many street names. Its effects have been described as comparable with ethanol (alcohol) and MDMA use, such as euphoria, disinhibition, enhanced libido and empathogenic states. A review comparing ethanol to GHB concluded that the dangers of the two drugs were similar.{{cite journal | vauthors = Sellman JD, Robinson GM, Beasley R | title = Should ethanol be scheduled as a drug of high risk to public health? | journal = Journal of Psychopharmacology | volume = 23 | issue = 1 | pages = 94–100 | date = January 2009 | pmid = 18583435 | doi = 10.1177/0269881108091596 }} At higher doses, GHB may induce nausea, dizziness, drowsiness, agitation, visual disturbances, depressed breathing, amnesia, unconsciousness, and death. One potential cause of death from GHB consumption is polydrug toxicity. Co-administration with other CNS depressants such as alcohol or benzodiazepines can result in an additive effect (potentiation), as they all bind to gamma-aminobutyric acid (or "GABA") receptor sites. The effects of GHB can last from 1.5 to 4 hours, or longer if large doses have been consumed.{{cite journal | vauthors = 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 = 263–69 | date = April 2000 | pmid = 10869868 | doi = 10.1016/S0741-8329(99)00090-7 }} Consuming GHB with alcohol can cause respiratory arrest and vomiting in combination with unarousable sleep, which can lead to death.{{cite journal | vauthors = Thai D, Dyer JE, Benowitz NL, Haller CA | title = Gamma-hydroxybutyrate and ethanol effects and interactions in humans | journal = Journal of Clinical Psychopharmacology | volume = 26 | issue = 5 | pages = 524–29 | date = October 2006 | pmid = 16974199 | pmc = 2766839 | doi = 10.1097/01.jcp.0000237944.57893.28 }}[http://www.erowid.org/chemicals/ghb/ghb_health.shtml "The Vaults Of Erowid"] {{Webarchive|url=https://web.archive.org/web/20151122183546/https://www.erowid.org/chemicals/ghb/ghb_health.shtml |date=22 November 2015 }}. Erowid.org (18 March 2009). Retrieved on 27 September 2012.

Recreational doses of 1–2 g generally provide a feeling of euphoria, and larger doses create deleterious effects such as reduced motor function and drowsiness.{{cite journal | vauthors = Busardò FP, Jones AW | title = GHB pharmacology and toxicology: acute intoxication, concentrations in blood and urine in forensic cases and treatment of the withdrawal syndrome | journal = Current Neuropharmacology | volume = 13 | issue = 1 | pages = 47–70 | date = January 2015 | pmid = 26074743 | pmc = 4462042 | doi = 10.2174/1570159X13666141210215423 }} The sodium salt of GHB has a salty taste. Other salt forms such as calcium GHB and magnesium GHB have also been reported,{{cite patent |country= US |number= 4393236 |title= Production of nonhygroscopic salts of 4-hydroxybutyric acid |inventor= Klosa, Joseph |gdate= 12 July 1983 }} but the sodium salt is by far the most common.

Some prodrugs, such as γ-butyrolactone (GBL), convert to GHB in the stomach and bloodstream. Other prodrugs exist, such as 1,4-butanediol (1,4-B).{{Cite web|work=PubChem|title=1,4-Butanediol|url=https://pubchem.ncbi.nlm.nih.gov/compound/8064|access-date=15 January 2021|publisher=U.S National Library of Medicine|archive-date=1 February 2021|archive-url=https://web.archive.org/web/20210201111223/https://pubchem.ncbi.nlm.nih.gov/compound/8064|url-status=live}} GBL and 1,4-B are normally found as pure liquids, but they can be mixed with other more harmful solvents when intended for industrial use (e.g. as paint stripper or varnish thinner).{{cn|date=February 2024}}

GHB can be manufactured with little knowledge of chemistry, as it involves the mixing of its two precursors, GBL and an alkali hydroxide such as sodium hydroxide, to form the GHB salt. Due to the ease of manufacture and the availability of its precursors, it is not usually produced in illicit laboratories like other synthetic drugs, but in private homes by low-level producers.{{cite journal | vauthors = Kapoor P, Deshmukh R, Kukreja I | title = GHB acid: A rage or reprive | journal = Journal of Advanced Pharmaceutical Technology & Research | volume = 4 | issue = 4 | pages = 173–178 | date = October 2013 | pmid = 24350046 | pmc = 3853692 | doi = 10.4103/2231-4040.121410 | doi-access = free }}

GHB is colourless and odourless.{{cite journal | vauthors = Jones C | title = Suspicious death related to gamma-hydroxybutyrate (GHB) toxicity | journal = Journal of Clinical Forensic Medicine | volume = 8 | issue = 2 | pages = 74–76 | date = June 2001 | pmid = 15274975 | doi = 10.1054/jcfm.2001.0473 }}

GHB has been used as a club drug, apparently starting in the 1990s, as small doses of GHB can act as a euphoriant and are believed to be aphrodisiac.{{cite journal | vauthors = Kam PC, Yoong FF | title = Gamma-hydroxybutyric acid: an emerging recreational drug | journal = Anaesthesia | volume = 53 | issue = 12 | pages = 1195–98 | date = December 1998 | pmid = 10193223 | doi = 10.1046/j.1365-2044.1998.00603.x | doi-access=free | quote = In the UK, GHB has been available in the night clubs around London since 1994... }}{{cite journal | vauthors = Carter LP, Pardi D, Gorsline J, Griffiths RR | title = Illicit gamma-hydroxybutyrate (GHB) and pharmaceutical sodium oxybate (Xyrem): differences in characteristics and misuse | journal = Drug and Alcohol Dependence | volume = 104 | issue = 1–2 | pages = 1–10 | date = September 2009 | pmid = 19493637 | pmc = 2713368 | doi = 10.1016/j.drugalcdep.2009.04.012 }} Slang terms for GHB include liquid ecstasy, lollipops, liquid X or liquid E due to its tendency to produce euphoria and sociability and its use in the dance party scene.{{cite journal | vauthors = Klein M, Kramer F | title = Rave drugs: pharmacological considerations | journal = AANA Journal | volume = 72 | issue = 1 | pages = 61–67 | date = February 2004 | pmid = 15098519 }}

Some athletes have been know to use GHB, or its analogs, due to marketing claims the drug as an anabolic agent. However, no such evidence exists to suggest links between the use of GHB and muscle development or performance improvement.

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GHB became known to the general public as a date-rape drug by the late 1990s.{{cite web | url = http://www.usdoj.gov/dea/ongoing/daterapep.html | title = GHB, GBL and 1,4BD as Date Rape Drugs | access-date = 10 May 2012 | author = US Drug Enforcement Administration | archive-url = https://web.archive.org/web/20120510151441/http://www.justice.gov/dea//ongoing/daterapep.html | archive-date = 10 May 2012}}{{cite news|agency=The Associated Press|title=Warning on Risk of 'Party Drug' Chemicals|url=https://www.nytimes.com/1999/05/12/us/warning-on-risk-of-party-drug-chemicals.html|work=The New York Times|date=12 May 1999|access-date=16 April 2018|archive-date=6 April 2023|archive-url=https://web.archive.org/web/20230406044951/https://www.nytimes.com/1999/05/12/us/warning-on-risk-of-party-drug-chemicals.html|url-status=live}} GHB is colourless and odorless and has been described as "very easy to add to drinks". When consumed, the victim will quickly feel groggy and sleepy and may become unconscious. Upon recovery they may have an impaired ability to recall events that have occurred during the period of intoxication. In these situations evidence and the identification of the perpetrator of the rape is often difficult.{{cite journal | vauthors = Németh Z, Kun B, Demetrovics Z | title = The involvement of gamma-hydroxybutyrate in reported sexual assaults: a systematic review | journal = Journal of Psychopharmacology | volume = 24 | issue = 9 | pages = 1281–7 | date = September 2010 | pmid = 20488831 | doi = 10.1177/0269881110363315 | s2cid = 25496192 }}{{cite journal | vauthors = ElSohly MA, Salamone SJ | title = Prevalence of drugs used in cases of alleged sexual assault | journal = Journal of Analytical Toxicology | volume = 23 | issue = 3 | pages = 141–6 | year = 1999 | pmid = 10369321 | doi = 10.1093/jat/23.3.141 | doi-access = free }}

It is also 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 only recall the rape some time after its occurrence; however, a 2006 study suggested that there was "no evidence to suggest widespread date rape drug use" in the UK, and that less than 2% of cases involved GHB, while 17% involved cocaine,{{cite web | url=http://www.24dash.com/news/health/2006-11-16-No-evidence-to-suggest-widespread-date-rape-drug-use | archive-url=https://web.archive.org/web/20090108174731/http://www.24dash.com/news/Health/2006-11-16-No-evidence-to-suggest-widespread-date-rape-drug-use | url-status=dead | archive-date=8 January 2009 | title=No evidence to suggest widespread date rape drug use' | date=16 November 2006 | access-date=8 April 2014 }}{{cite news | url=http://news.bbc.co.uk/1/hi/uk/6152646.stm | title=Date-rape drugs 'not widespread' | work=BBC News | date=16 November 2006 | access-date=8 April 2014 | archive-date=20 May 2007 | archive-url=https://web.archive.org/web/20070520122215/http://news.bbc.co.uk/1/hi/uk/6152646.stm | url-status=live }} and a survey in the Netherlands published in 2010 found that the proportion of drug-related rapes where GHB was used appeared to be greatly overestimated by the media.[https://web.archive.org/web/20081007071413/http://www.udel.edu/wellspring/SOS/drugs.htm Alcohol and other popular Date Rape Drugs]. udel.edu{{cite web | url = https://www.independent.co.uk/news/world/europe/labs-making-daterape-drug-raided-863938.html | title = Labs making date-rape drug raided | archive-url = https://web.archive.org/web/20150925190920/http://www.independent.co.uk/news/world/europe/labs-making-daterape-drug-raided-863938.html | archive-date=25 September 2015 | work = The Independent | date = 10 July 2008 }} More recently, a study in Western Australia reviewed the pre-hospital context given in medical records around emergency department presentations with analytical confirmation of GHB exposure. This study found that most cases reported daily dosing and subsequent accidental overdose rather than their presentation being associated with date-rape.{{cite journal | vauthors = Smith JL, Greene S, McCutcheon D, Weber C, Kotkis E, Soderstrom J, Douglas B, Lenton S, Grigg J, Dessauer P, Ezard N, Fatovich DM | title = A multicentre case series of analytically confirmed gamma-hydroxybutyrate intoxications in Western Australian emergency departments: Pre-hospital circumstances, co-detections and clinical outcomes | journal = Drug and Alcohol Review | date = March 2024 | volume = 43 | issue = 4 | pages = 984–996 | pmid = 38426636 | doi = 10.1111/dar.13830 | doi-access = free }}

There have been several high-profile cases of GHB as a date-rape drug that received national attention in the United States. In early 1999, a 15-year-old girl, Samantha Reid of Rockwood, Michigan, died from GHB poisoning. Reid's death inspired the legislation titled the "Hillory J. Farias and Samantha Reid Date-Rape Drug Prohibition Act of 2000". This is the law that made GHB a Schedule 1 controlled substance.{{cite web | vauthors = Martin JH | date = 16 January 2009 | url = http://www.thenewsherald.com/articles/2009/01/16/news/doc4970e3f098507043714937.txt | title = Remembering Samantha Reid: 10th anniversary of teen's GHB death | archive-url = https://web.archive.org/web/20160304093819/http://www.thenewsherald.com/articles/2009/01/16/news/doc4970e3f098507043714937.txt | archive-date=4 March 2016 | work = thenewsherald.com | access-date = 27 September 2012 }} In the United Kingdom, British serial killer Stephen Port administered GHB to his victims by adding it to drinks given to them, raping them, and murdering four of them in his flat in Barking, East London.{{cite news |url=https://www.bbc.co.uk/news/uk-england-38077859 |title=Stephen Port: Serial killer guilty of murdering four men |work=BBC News |date=23 November 2016}}

GHB can be detected in hair.{{cite journal | vauthors = Kintz P, Cirimele V, Jamey C, Ludes B | title = Testing for GHB in hair by GC/MS/MS after a single exposure. Application to document sexual assault | journal = Journal of Forensic Sciences | volume = 48 | issue = 1 | pages = 195–200 | date = January 2003 | pmid = 12570228 | doi = 10.1520/JFS2002209| url = http://www.hawaii.edu/hivandaids/Testing_for_GHB_in_Hair_by_GCMSMS_After_a_Single_Exposure_Doc_Sexual_Assault.pdf | archive-url = https://web.archive.org/web/20121224171516/http://www.hawaii.edu/hivandaids/Testing_for_GHB_in_Hair_by_GCMSMS_After_a_Single_Exposure_Doc_Sexual_Assault.pdf | archive-date=24 December 2012 }} Hair testing can be a useful tool in court cases or for the victim's own information.{{Cite web| title = Drink Speaks the Truth: Forensic Investigation of Drug Facilitated Sexual Assaults| url = http://www.forensicmag.com/articles/2013/06/drink-speaks-truth-forensic-investigation-drug-facilitated-sexual-assaults| date = 20 June 2013| access-date = 24 July 2014| archive-date = 14 March 2016| archive-url = https://web.archive.org/web/20160314222003/http://www.forensicmag.com/articles/2013/06/drink-speaks-truth-forensic-investigation-drug-facilitated-sexual-assaults| url-status = live}} Most over-the-counter urine test kits test only for date-rape drugs that are benzodiazepines, which GHB is not. To detect GHB in urine, the sample must be taken within four hours of GHB ingestion, and cannot be tested at home.{{cite journal | url=https://www.gtfch.org/cms/images/stories/media/tb/tb2015/Lott_et_al_2015.pdf |archive-url=https://web.archive.org/web/20160304082734/https://www.gtfch.org/cms/images/stories/media/tb/tb2015/Lott_et_al_2015.pdf |archive-date=4 March 2016 |url-status=live | title=Measurement of exogenous gamma-hydroxybutyric acid (GHB) in urine using isotope ratio mass spectrometry (IRMS) | vauthors = Lott S, Piper T, Mehling LM, Spottke A, Maas A, Thevis M, Madea B, Hess C | journal=Toxichem Krimtech | year=2015 | volume=82 | pages=264}}

File:HarmCausedByDrugsTable.svg study ranking various drugs (legal and illegal) based on statements by drug-harm experts. GHB was found to be the ninth overall most dangerous drug.{{cite journal | vauthors = Nutt DJ, King LA, Phillips LD | title = Drug harms in the UK: a multicriteria decision analysis | journal = Lancet | volume = 376 | issue = 9752 | pages = 1558–1565 | date = November 2010 | pmid = 21036393 | doi = 10.1016/S0140-6736(10)61462-6 | s2cid = 5667719 | citeseerx = 10.1.1.690.1283 }}]]

In humans, GHB has been shown to reduce the elimination rate (thus increasing the elimination {{em|time}}) of alcohol. This may explain the respiratory arrest that has been reported after ingestion of both drugs.{{cite journal | vauthors = Poldrugo F, Addolorato G | title = The role of gamma-hydroxybutyric acid in the treatment of alcoholism: from animal to clinical studies | journal = Alcohol and Alcoholism | volume = 34 | issue = 1 | pages = 15–24 | year = 1999 | pmid = 10075397 | doi = 10.1093/alcalc/34.1.15 | doi-access = free }} 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.Zvosec et al. [https://web.archive.org/web/20071203005230/http://www.aafs.org/pdf/Seattleabstracts06.pdf Proceedings of the American Academy of Forensic Science in Seattle, 2006]. Web.archive.org (3 December 2007). Retrieved on 24 December 2011.

One publication has investigated 226 deaths attributed to GHB.{{cite journal | vauthors = Zvosec DL, Smith SW, Porrata T, Strobl AQ, Dyer JE | title = Case series of 226 γ-hydroxybutyrate-associated deaths: lethal toxicity and trauma | journal = The American Journal of Emergency Medicine | volume = 29 | issue = 3 | pages = 319–32 | date = March 2011 | pmid = 20825811 | doi = 10.1016/j.ajem.2009.11.008 }} Of the 226 deaths included, 213 had a cardiorespiratory arrest and 13 had fatal accidents. Seventy-one of these deaths (34%) had no co-intoxicants. Postmortem blood GHB was 18–4400 mg/L (median=347) in deaths negative for co-intoxicants.

One report has suggested that sodium oxybate overdose might be fatal, based on deaths of three patients who had been prescribed the drug.{{cite journal | vauthors = Zvosec DL, Smith SW, Hall BJ | title = Three deaths associated with use of Xyrem | journal = Sleep Medicine | volume = 10 | issue = 4 | pages = 490–93 | date = April 2009 | pmid = 19269893 | doi = 10.1016/j.sleep.2009.01.005 }} However, for two of the three cases, post-mortem GHB concentrations were 141 and 110 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.{{cite journal | vauthors = Feldman NT | title = Xyrem safety: the debate continues | journal = Sleep Medicine | volume = 10 | issue = 4 | pages = 405–06 | date = April 2009 | pmid = 19332385 | doi = 10.1016/j.sleep.2009.02.002 }} The toxicity of GHB has been an issue in criminal trials, as in the death of Felicia Tang, where the defense argued that death was due to GHB, not murder.

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.{{cite journal | vauthors = Zvosec DL, Smith SW | title = Response to Editorial: "Xyrem safety: The debate continues" | journal = Sleep Medicine | volume = 11 | issue = 1 | pages = 108; author reply 108–09 | date = January 2010 | pmid = 19959395 | doi = 10.1016/j.sleep.2009.08.004 }} Levels higher than this are found in GHB deaths. Levels lower than this may be due to GHB or to postmortem endogenous elevations.

In multiple studies, GHB has been found to impair spatial memory, working memory, learning and memory in rats with chronic ad{{shy}}min{{shy}}is{{shy}}tra{{shy}}tion.{{cite journal | vauthors = 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 = 701–08 | date = December 2004 | pmid = 15582677 | doi = 10.1016/j.pbb.2004.09.022 | s2cid = 31736568 }}{{cite journal | vauthors = García FB, Pedraza C, Arias JL, Navarro JF | title = [Effects of subchronic administration of gammahydroxybutyrate (GHB) on spatial working memory in rats] | language = es | journal = Psicothema | volume = 18 | issue = 3 | pages = 519–24 | date = August 2006 | pmid = 17296081 }}{{cite journal | vauthors = 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 = 1 | pages = 386–89 | date = October 2008 | pmid = 18991885 | doi = 10.1196/annals.1432.044 | bibcode = 2008NYASA1139..386S | s2cid = 1823886 }} These effects are associated with decreased NMDA receptor expression in the cerebral cortex and possibly other areas as well. In addition, the neu{{shy}}ro{{shy}}tox{{shy}}icity appears to be caused by oxidative stress.{{cite journal | vauthors = Sgaravatti AM, Sgarbi MB, Testa CG, Durigon K, Pederzolli CD, Prestes CC, Wyse AT, Wannmacher CM, Wajner M, Dutra-Filho CS | title = Gamma-hydroxybutyric acid induces oxidative stress in cerebral cortex of young rats | journal = Neurochemistry International | volume = 50 | issue = 3 | pages = 564–70 | date = February 2007 | pmid = 17197055 | doi = 10.1016/j.neuint.2006.11.007 | s2cid = 43049617 }}{{cite journal | vauthors = Sgaravatti AM, Magnusson AS, Oliveira AS, Mescka CP, Zanin F, Sgarbi MB, Pederzolli CD, Wyse AT, Wannmacher CM, Wajner M, Dutra-Filho CS | 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 | date = June 2009 | pmid = 19296210 | doi = 10.1007/s11011-009-9136-7 | s2cid = 13460935 }}

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.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[https://web.archive.org/web/20100223062656/http://www.time.com/time/interactive/0,31813,1640235,00.html Addiction and the Brain]. Time

Rats forced to consume massive doses of GHB will intermittently prefer GHB solution to water.{{cite journal | vauthors = Colombo G, Agabio R, Balaklievskaia N, Diaz G, Lobina C, Reali R, Gessa GL | title = Oral self-administration of gamma-hydroxybutyric acid in the rat | journal = European Journal of Pharmacology | volume = 285 | issue = 1 | pages = 103–07 | date = October 1995 | pmid = 8846805 | doi = 10.1016/0014-2999(95)00493-5 }}{{cite web | url = http://www.lycaeum.org/~ghbfaq/dangerous.html | title = Is GHB toxic? Addictive? Dangerous? | archive-url = https://web.archive.org/web/20110127050233/http://www.lycaeum.org/~ghbfaq/dangerous.html | archive-date=27 January 2011 | work = lycaeum.org }}

GHB has also been associated with a withdrawal syndrome of insomnia, anxiety, and tremor that usually resolves within three to twenty-one days.{{cite journal | vauthors = Galloway GP, Frederick SL, Staggers FE, Gonzales M, Stalcup SA, Smith DE | title = Gamma-hydroxybutyrate: an emerging drug of abuse that causes physical dependence | journal = Addiction | volume = 92 | issue = 1 | pages = 89–96 | date = January 1997 | pmid = 9060200 | doi = 10.1111/j.1360-0443.1997.tb03640.x }}{{cite web |url=https://www.ualberta.ca/~csps/JPPS4(2)/M.Okun/GHB.htm |title=GHB: An Important Pharmacologic and Clinical Update |publisher=Ualberta.ca |access-date=1 August 2010 |archive-date=4 March 2016 |archive-url=https://web.archive.org/web/20160304115225/http://www.ualberta.ca/~csps/JPPS4(2)/M.Okun/GHB.htm |url-status=live }} The withdrawal syndrome can be severe producing acute delirium and may require hospitalization in an intensive care unit for management. Management of GHB dependence involves considering the person's age, comorbidity and the pharmacological pathways of GHB.{{cite journal | vauthors = Santos C, Olmedo RE | title = Sedative-Hypnotic Drug Withdrawal Syndrome: Recognition And Treatment | journal = Emergency Medicine Practice | volume = 19 | issue = 3 | pages = 1–20 | date = March 2017 | pmid = 28186869 }} The mainstay of treatment for severe withdrawal is supportive care and benzodiazepines for control of acute delirium, but larger doses are often required compared to acute delirium of other causes (e.g. > 100 mg/d of diazepam). Baclofen has been suggested as an alternative or adjunct to benzodiazepines based on anecdotal evidence and some animal data.{{cite journal | vauthors = LeTourneau JL, Hagg DS, Smith SM | title = Baclofen and gamma-hydroxybutyrate withdrawal | journal = Neurocritical Care | volume = 8 | issue = 3 | pages = 430–33 | year = 2008 | pmid = 18266111 | pmc = 2630388 | doi = 10.1007/s12028-008-9062-2 }} However, there is less experience with the use of baclofen for GHB withdrawal, and additional research in humans is needed. Baclofen was first suggested as an adjunct because benzodiazepines do not affect GABA_B receptors and therefore have no cross-tolerance with GHB while baclofen, which works via GABA_B receptors, is cross-tolerant with GHB and may be more effective in alleviating withdrawal effects of GHB.{{cite journal | vauthors = Carter LP, Koek W, France CP | title = Behavioral analyses of GHB: receptor mechanisms | journal = Pharmacology & Therapeutics | volume = 121 | issue = 1 | pages = 100–14 | date = January 2009 | pmid = 19010351 | pmc = 2631377 | doi = 10.1016/j.pharmthera.2008.10.003 }}

GHB withdrawal is not widely discussed in textbooks and some psychiatrists, general practitioners, and even hospital emergency physicians may not be familiar with this withdrawal syndrome.{{cite journal | vauthors = van Noorden MS, van Dongen LC, Zitman FG, Vergouwen TA | title = Gamma-hydroxybutyrate withdrawal syndrome: dangerous but not well-known | journal = General Hospital Psychiatry | volume = 31 | issue = 4 | pages = 394–96 | year = 2009 | pmid = 19555805 | doi = 10.1016/j.genhosppsych.2008.11.001 }}

Overdose of GHB can sometimes be difficult to treat because of its multiple effects on the body.{{cite journal | vauthors = Allen L, Alsalim W | title = Best evidence topic report. Gammahydroxybutyrate overdose and physostigmine | journal = Emergency Medicine Journal | volume = 23 | issue = 4 | pages = 300–01 | date = April 2006 | pmid = 16549578 | pmc = 2579509 | doi = 10.1136/emj.2006.035139 }}{{cite journal | vauthors = Michael H, Harrison M | title = Best evidence topic report: endotracheal intubation in gamma-hydroxybutyric acid intoxication and overdose | journal = Emergency Medicine Journal | volume = 22 | issue = 1 | pages = 43 | date = January 2005 | pmid = 15611542 | pmc = 1726538 | doi = 10.1136/emj.2004.021154 }} 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 threat to life due to GHB overdose (with or without other substances) is respiratory arrest.{{cite journal | vauthors = Morse BL, Vijay N, Morris ME | title = γ-Hydroxybutyrate (GHB)-induced respiratory depression: combined receptor-transporter inhibition therapy for treatment in GHB overdose | journal = Molecular Pharmacology | volume = 82 | issue = 2 | pages = 226–235 | date = August 2012 | pmid = 22561075 | pmc = 3400846 | doi = 10.1124/mol.112.078154 }} 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).{{cite journal | vauthors = Zvosec DL, Smith SW, Porrata T, Strobl AQ, Dyer JE | title = Case series of 226 γ-hydroxybutyrate-associated deaths: lethal toxicity and trauma | journal = The American Journal of Emergency Medicine | volume = 29 | issue = 3 | pages = 319–332 | date = March 2011 | pmid = 20825811 | doi = 10.1016/j.ajem.2009.11.008 }} 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. It is important to keep the victim awake and moving; the victim must not be left alone due to the risk of death through vomiting. Frequently the victim will be in a good mood but this does not mean the victim is not in danger. GHB overdose is a medical emergency and immediate assessment in an emergency department is needed.

Convulsions from GHB can be treated with the benzodiazepines diazepam or lorazepam. Even though these benzodiazepines are also CNS depressants, they primarily modulate GABA_A receptors whereas GHB is primarily a GABA_B receptor agonist, and so do not worsen CNS depression as much as might be expected.{{cite book |vauthors=Allen MJ, Sabir S, Sharma S |chapter=GABA Receptor |date=2022 |chapter-url=http://www.ncbi.nlm.nih.gov/books/NBK526124/ |title=StatPearls |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=30252380 |access-date=21 October 2022 |archive-date=1 December 2022 |archive-url=https://web.archive.org/web/20221201103049/https://www.ncbi.nlm.nih.gov/books/NBK526124/ |url-status=live }}

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_B antagonist, quickly reverses GHB overdose in mice.{{cite journal | vauthors = Carai MA, Colombo G, Gessa GL | 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 = 614–19 | date = June 2005 | pmid = 15940094 | doi = 10.1016/j.annemergmed.2004.12.013 }} 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.

GHB may be quantitated in blood or plasma to confirm a diagnosis of poisoning in hospitalized patients, to provide evidence in an impaired driving, or to assist in a medicolegal death investigation. Blood or plasma GHB concentrations are usually in a range of 50–250 mg/L in persons receiving the drug therapeutically (during general anesthesia), 30–100 mg/L in those arrested for impaired driving, 50–500 mg/L in acutely intoxicated patients and 100–1000 mg/L in victims of fatal overdosage. Urine is often the preferred specimen for routine drug abuse monitoring purposes. Both γ-butyrolactone (GBL) and 1,4-butanediol are converted to GHB in the body.{{cite journal | vauthors = Couper FJ, Thatcher JE, Logan BK | title = Suspected GHB overdoses in the emergency department | journal = Journal of Analytical Toxicology | volume = 28 | issue = 6 | pages = 481–84 | date = September 2004 | pmid = 15516299 | doi = 10.1093/jat/28.6.481 | doi-access = free }}{{cite journal | vauthors = Marinetti LJ, Isenschmid DS, Hepler BR, Kanluen S | title = Analysis of GHB and 4-methyl-GHB in postmortem matrices after long-term storage | journal = Journal of Analytical Toxicology | volume = 29 | issue = 1 | pages = 41–47 | year = 2005 | pmid = 15808012 | doi = 10.1093/jat/29.1.41 | doi-access = free }}R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 680–84.

In January 2016, it was announced scientists had developed a way to detect GHB, among other things, in saliva.{{cite news|url=http://www.bbc.co.uk/newsbeat/article/35262515/new-spit-test-for-date-rape-drug-developed-in-the-uk|title=New spit test for 'date rape' drug developed in the UK|work=BBC News|date=August 2016|access-date=9 January 2016|archive-date=8 November 2020|archive-url=https://web.archive.org/web/20201108135545/http://www.bbc.co.uk/newsbeat/article/35262515/new-spit-test-for-date-rape-drug-developed-in-the-uk|url-status=live}}

Cells produce GHB by reduction of succinic semialdehyde via succinic semialdehyde reductase (SSR). This enzyme appears to be induced by cAMP levels,{{cite journal | vauthors = Kemmel V, Taleb O, Perard A, Andriamampandry C, Siffert JC, Mark J, Maitre M | 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 | date = October 1998 | pmid = 9692734 | doi = 10.1016/S0306-4522(98)00085-2 | s2cid = 21001043 }} meaning substances that elevate cAMP, such as forskolin and vinpocetine, may increase GHB synthesis and release. Conversely, endogeneous GHB production in those taking valproic acid will be inhibited via inhibition of the conversion from succinic acid semialdehyde to GHB.{{cite book | vauthors = Löscher W | author-link1 = Wolfgang Löscher | chapter = Valproic Acid: Mechanism of Action | chapter-url = https://books.google.com/books?id=HAOY0qG-vAYC&q=vpa+inhibition+of+ssa+to+GHB&pg=PA774 | veditors = Levy RH, Mattson RH, Meldrum BS, Perucca E | title = Antiepileptic drugs | date = 2002 | publisher = Lippincott Williams & Wilkins | location = Philadelphia | isbn = 978-0-7817-2321-3 | edition = 5th | page = 774 | access-date = 16 August 2021 | archive-date = 18 August 2023 | archive-url = https://web.archive.org/web/20230818072407/https://books.google.com/books?id=HAOY0qG-vAYC&q=vpa+inhibition+of+ssa+to+GHB&pg=PA774 | url-status = live }} People with the disorder known as succinic semialdehyde dehydrogenase deficiency, also known as γ-hydroxybutyric aciduria, have elevated levels of GHB in their urine, blood plasma and cerebrospinal fluid.National Organization for Rare Disorders. [http://www.rarediseases.org/search/rdbdetail_abstract.html?disname=Succinic%20Semialdehyde%20Dehydrogenase%20Deficiency Succinic Semialdehyde Dehydrogenase Deficiency] {{Webarchive|url=https://web.archive.org/web/20230406000025/http://rarediseases.org/search/rdbdetail_abstract.html?disname=Succinic%20Semialdehyde%20Dehydrogenase%20Deficiency |date=6 April 2023 }}. Retrieved 6 March 2010.

The precise function of GHB in the body is not clear. It is known, however, that the brain expresses a large number of receptors that are activated by GHB.{{cite journal | vauthors = Andriamampandry C, Taleb O, Viry S, Muller C, Humbert JP, Gobaille S, Aunis D, Maitre M | s2cid = 489179 | title = Cloning and characterization of a rat brain receptor that binds the endogenous neuromodulator gamma-hydroxybutyrate (GHB) | journal = FASEB Journal | volume = 17 | issue = 12 | pages = 1691–93 | date = September 2003 | pmid = 12958178 | doi = 10.1096/fj.02-0846fje | doi-access = free }} These receptors are excitatory, however, and therefore not responsible for the sedative effects of GHB; they have been shown to elevate the principal excitatory neurotransmitter, glutamate. The benzamide antipsychotics—amisulpride, nemonapride, etc.—have been shown to bind to these GHB-activated receptors in vivo.{{cite journal | vauthors = 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 = European Journal of Pharmacology | volume = 256 | issue = 2 | pages = 211–14 | date = April 1994 | pmid = 7914168 | doi = 10.1016/0014-2999(94)90248-8 }} Other antipsychotics were tested and were not found to have an affinity for this receptor.

GHB is a precursor to GABA, glutamate, and glycine in certain brain areas.{{cite journal | vauthors = 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 = The Journal of Pharmacology and Experimental Therapeutics | volume = 290 | issue = 1 | pages = 303–09 | date = July 1999 | doi = 10.1016/S0022-3565(24)34899-2 | pmid = 10381791 }}

In spite of its demonstrated neurotoxicity, (see relevant section, above), GHB has neuroprotective properties, and has been found to protect cells from hypoxia.{{cite journal | vauthors = Ottani A, Saltini S, Bartiromo M, Zaffe D, Renzo Botticelli A, Ferrari A, Bertolini A, Genedani S | title = Effect of gamma-hydroxybutyrate in two rat models of focal cerebral damage | journal = Brain Research | volume = 986 | issue = 1–2 | pages = 181–90 | date = October 2003 | pmid = 12965243 | doi = 10.1016/S0006-8993(03)03252-9 | s2cid = 54374774 }}

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. The amount found in wine is pharmacologically insignificant and not sufficient to produce psychoactive effects.{{cite journal | vauthors = Elliott S, Burgess V | title = The presence of gamma-hydroxybutyric acid (GHB) and gamma-butyrolactone (GBL) in alcoholic and non-alcoholic beverages | journal = Forensic Science International | volume = 151 | issue = 2–3 | pages = 289–92 | date = July 2005 | pmid = 15939164 | doi = 10.1016/j.forsciint.2005.02.014 }}

GHB has at least two distinct binding sites in the central nervous system.{{cite journal | vauthors = Wu Y, Ali S, Ahmadian G, Liu CC, Wang YT, Gibson KM, Calver AR, Francis J, Pangalos MN, Carter Snead O | 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 | date = December 2004 | pmid = 15567424 | doi = 10.1016/j.neuropharm.2004.08.019 | s2cid = 54233206 }} GHB acts as an agonist at the inhibitory GHB receptor{{cite journal | vauthors = Cash CD, Gobaille S, Kemmel V, Andriamampandry C, Maitre M | title = Gamma-hydroxybutyrate receptor function studied by the modulation of nitric oxide synthase activity in rat frontal cortex punches | journal = Biochemical Pharmacology | volume = 58 | issue = 11 | pages = 1815–19 | date = December 1999 | pmid = 10571257 | doi = 10.1016/S0006-2952(99)00265-8 }}{{cite journal | vauthors = 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 = fr | journal = Médecine/Sciences | volume = 21 | issue = 3 | pages = 284–89 | date = March 2005 | pmid = 15745703 | doi = 10.1051/medsci/2005213284 | doi-access = free }} and as a weak agonist at the inhibitory GABA_B receptor. GHB is a naturally occurring substance that acts in a similar fashion to some neurotransmitters in the mammalian brain.{{cite journal | vauthors = Waszkielewicz A, Bojarski J | title = Gamma-hydrobutyric acid (GHB) and its chemical modifications: a review of the GHBergic system | journal = Polish Journal of Pharmacology | volume = 56 | issue = 1 | pages = 43–49 | year = 2004 | pmid = 15047976 | url = http://www.if-pan.krakow.pl/pjp/pdf/2004/1_43.pdf | access-date = 3 June 2008 | archive-date = 6 August 2021 | archive-url = https://web.archive.org/web/20210806054129/http://if-pan.krakow.pl/pjp/pdf/2004/1_43.pdf | url-status = live }} GHB is probably synthesized from GABA in GABAergic neurons, and released when the neurons fire.

GHB has been found to activate oxytocinergic neurons in the supraoptic nucleus.{{cite journal | vauthors = McGregor IS, Callaghan PD, Hunt GE | title = From ultrasocial to antisocial: a role for oxytocin in the acute reinforcing effects and long-term adverse consequences of drug use? | journal = British Journal of Pharmacology | volume = 154 | issue = 2 | pages = 358–68 | date = May 2008 | pmid = 18475254 | pmc = 2442436 | doi = 10.1038/bjp.2008.132 }}

If taken orally, GABA itself does not effectively cross the blood–brain barrier.{{cite journal | vauthors = 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 = 103–08 | date = January 1971 | pmid = 5569303 | doi = 10.1016/0028-3908(71)90013-X }}

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.{{cite journal | vauthors = Gobaille S, Schleef C, Hechler V, Viry S, Aunis D, Maitre M | title = Gamma-hydroxybutyrate increases tryptophan availability and potentiates serotonin turnover in rat brain | journal = Life Sciences | volume = 70 | issue = 18 | pages = 2101–2112 | date = March 2002 | pmid = 12002803 | doi = 10.1016/s0024-3205(01)01526-0 }} 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.{{cite journal | vauthors = Hedner T, Lundborg P | title = Effect of gammahydroxybutyric acid on serotonin synthesis, concentration and metabolism in the developing rat brain | journal = Journal of Neural Transmission | volume = 57 | issue = 1–2 | pages = 39–48 | date = 1983 | pmid = 6194255 | doi = 10.1007/BF01250046 | s2cid = 9471705 }} 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.{{cite journal | vauthors = Pardi D, Black J | title = gamma-Hydroxybutyrate/sodium oxybate: neurobiology, and impact on sleep and wakefulness | journal = CNS Drugs | volume = 20 | issue = 12 | pages = 993–1018 | date = 2006 | pmid = 17140279 | doi = 10.2165/00023210-200620120-00004 | s2cid = 72211254 }}

However, at therapeutic doses, GHB reaches much higher concentrations in the brain and activates GABA_B receptors, which are primarily responsible for its sedative effects.{{cite journal | vauthors = 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 = European Journal of Pharmacology | volume = 519 | issue = 3 | pages = 246–252 | date = September 2005 | pmid = 16129424 | doi = 10.1016/j.ejphar.2005.07.016 }} GHB's sedative effects are blocked by GABA_B antagonists.{{cite journal | vauthors = Pistis M, Muntoni AL, Pillolla G, Perra S, Cignarella G, Melis M, Gessa GL | title = Gamma-hydroxybutyric acid (GHB) and the mesoaccumbens reward circuit: evidence for GABA(B) receptor-mediated effects | journal = Neuroscience | volume = 131 | issue = 2 | pages = 465–474 | date = 2005 | pmid = 15708487 | doi = 10.1016/j.neuroscience.2004.11.021 | s2cid = 54342374 }}

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.{{cite journal | vauthors = Castelli MP, Ferraro L, Mocci I, Carta F, Carai MA, Antonelli T, Tanganelli S, Cignarella G, Gessa GL | 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 = Journal of Neurochemistry | volume = 87 | issue = 3 | pages = 722–732 | date = November 2003 | pmid = 14535954 | doi = 10.1046/j.1471-4159.2003.02037.x | s2cid = 82175813 }}{{cite journal | vauthors = Kamal RM, van Noorden MS, Franzek E, Dijkstra BA, Loonen AJ, De Jong CA | title = The Neurobiological Mechanisms of Gamma-Hydroxybutyrate Dependence and Withdrawal and Their Clinical Relevance: A Review | language = english | journal = Neuropsychobiology | volume = 73 | issue = 2 | pages = 65–80 | date = 2016 | pmid = 27003176 | doi = 10.1159/000443173 | s2cid = 33389634 | doi-access = free | hdl = 2066/158441 | hdl-access = free }} Drugs that selectively activate the GHB receptor cause absence seizures in high doses, as do GHB and GABA_B agonists.{{cite journal | vauthors = 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 = The Journal of Pharmacology and Experimental Therapeutics | volume = 273 | issue = 3 | pages = 1534–1543 | date = June 1995 | doi = 10.1016/S0022-3565(25)09686-7 | pmid = 7791129 }}

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.{{cite journal | vauthors = Hechler V, Gobaille S, Bourguignon JJ, Maitre M | title = Extracellular events induced by gamma-hydroxybutyrate in striatum: a microdialysis study | journal = Journal of Neurochemistry | volume = 56 | issue = 3 | pages = 938–944 | date = March 1991 | pmid = 1847191 | doi = 10.1111/j.1471-4159.1991.tb02012.x | s2cid = 86392963 }} Low concentrations stimulate dopamine release via the GHB receptor.{{cite journal | vauthors = Maitre M, Hechler V, Vayer P, Gobaille S, Cash CD, Schmitt M, Bourguignon JJ | title = A specific gamma-hydroxybutyrate receptor ligand possesses both antagonistic and anticonvulsant properties | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 255 | issue = 2 | pages = 657–663 | date = November 1990 | doi = 10.1016/S0022-3565(25)23017-8 | pmid = 2173754 }}{{cite journal | vauthors = Míguez I, Aldegunde M, Duran R, Veira JA | title = Effect of low doses of gamma-hydroxybutyric acid on serotonin, noradrenaline, and dopamine concentrations in rat brain areas | journal = Neurochemical Research | volume = 13 | issue = 6 | pages = 531–533 | date = June 1988 | pmid = 2457177 | doi = 10.1007/BF00973292 | s2cid = 27073926 }} Higher concentrations inhibit dopamine release via GABA_B receptors as do other GABA_B agonists such as baclofen and phenibut.{{cite journal | vauthors = 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 = European Journal of Pharmacology | volume = 284 | issue = 1–2 | pages = 83–91 | date = September 1995 | pmid = 8549640 | doi = 10.1016/0014-2999(95)00369-V }} 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 receptors.{{cite journal | vauthors = Mamelak M | title = Gammahydroxybutyrate: an endogenous regulator of energy metabolism | journal = Neuroscience and Biobehavioral Reviews | volume = 13 | issue = 4 | pages = 187–198 | year = 1989 | pmid = 2691926 | doi = 10.1016/S0149-7634(89)80053-3 | s2cid = 20217078 }}

This explains the paradoxical mix of sedative and stimulatory properties of GHB,{{cite journal | vauthors = Oliveto A, Gentry WB, Pruzinsky R, Gonsai K, Kosten TR, Martell B, Poling J | title = Behavioral effects of gamma-hydroxybutyrate in humans | journal = Behavioural Pharmacology | volume = 21 | issue = 4 | pages = 332–342 | date = July 2010 | pmid = 20526195 | pmc = 2911496 | doi = 10.1097/FBP.0b013e32833b3397 }} 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_B receptor activation and activates predominantly the GHB receptor, leading to wakefulness.

Recently, analogs of GHB, such as 4-hydroxy-4-methylpentanoic acid (UMB68) have been synthesised and tested on animals, in order to gain a better understanding of GHB's mode of action.{{cite journal | vauthors = Wu H, Zink N, Carter LP, Mehta AK, Hernandez RJ, Ticku MK, Lamb R, France CP, Coop A | title = A tertiary alcohol analog of gamma-hydroxybutyric acid as a specific gamma-hydroxybutyric acid receptor ligand | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 305 | issue = 2 | pages = 675–79 | date = May 2003 | pmid = 12606613 | doi = 10.1124/jpet.102.046797 | s2cid = 86191608 }} 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 a prodrug form γ-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-butanediol diacetate (BDDA/DABD), methyl-4-acetoxybutanoate (MAB), and ethyl-4-acetoxybutanoate (EAB), 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 γ-hydroxybutyraldehyde (GHBAL) is also a prodrug for GHB; however, as with all aliphatic 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

Only a minor portion (1–5%) of the administered GHB dose is excreted unchanged in the urine. Studies have shown that the maximum concentration of GHB in urine appears within 1 hour and rapidly declines thereafter. The vast majority (95–98%) undergoes extensive metabolism in the liver. GHB is broken down through a series of enzymatic pathways. The primary route involves conversion to succinic semialdehyde (SSA) by either GHB dehydrogenase (ADH) or GHB transhydrogenase. SSA is further oxidized by succinic semialdehyde dehydrogenase (SSADH) to succinic acid, which enters the Krebs cycle and is ultimately converted into carbon dioxide and water.{{cite journal |vauthors=Felmlee MA, Morse BL, Morris ME |title=γ-Hydroxybutyric Acid: Pharmacokinetics, Pharmacodynamics, and Toxicology |journal=The AAPS Journal |volume=23 |issue=1 |pages=22 |date=January 2021 |pmid=33417072 |pmc=8098080 |doi=10.1208/s12248-020-00543-z}}{{cite journal |vauthors=Taxon ES, Halbers LP, Parsons SM |title=Kinetics aspects of Gamma-hydroxybutyrate dehydrogenase |journal= Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics|volume=1868 |issue=5 |pages=140376 |date=May 2020 |pmid=31981617 |doi=10.1016/j.bbapap.2020.140376|doi-access=free }}{{cite journal |vauthors=Kamal RM, van Noorden MS, Franzek E, Dijkstra BA, Loonen AJ, De Jong CA |title=The Neurobiological Mechanisms of Gamma-Hydroxybutyrate Dependence and Withdrawal and Their Clinical Relevance: A Review |journal=Neuropsychobiology |volume=73 |issue=2 |pages=65–80 |date=March 2016 |pmid=27003176 |doi=10.1159/000443173|hdl=2066/158441 |hdl-access=free }}

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.

Alexander Zaytsev worked on this chemical family and published work on it in 1874.{{cite book| vauthors = Lewis DE |title=Early Russian organic chemists and their legacy|date=2012|publisher=Springer|isbn=978-3642282195|chapter=Section 4.4.3 Aleksandr Mikhailovich Zaitsev|page=79}}{{Cite journal | year = 1874 | title = Über die Reduction des Succinylchlorids | journal = Liebigs Annalen der Chemie | volume = 171 | pages = 258–90 | language = de | doi = 10.1002/jlac.18741710216 | issue = 2 | vauthors = Saytzeff A | url = https://zenodo.org/record/1427333 | access-date = 30 June 2019 | archive-date = 4 March 2021 | archive-url = https://web.archive.org/web/20210304115852/https://zenodo.org/record/1427333 | url-status = live }} The first extended research into GHB and its use in humans was conducted in the early 1960s by Henri Laborit to use in studying the neurotransmitter GABA.{{cite web|title=Critical review of gamma-hydroxybutyric acid (GHB)|url=https://www.who.int/medicines/areas/quality_safety/4.1GHBcritical_review.pdf |archive-url=https://web.archive.org/web/20140910002840/http://www.who.int/medicines/areas/quality_safety/4.1GHBcritical_review.pdf |archive-date=10 September 2014 |url-status=live|date=2012}}{{rp|11–12}}{{cite journal | vauthors = Laborit H, Jouany JM, Gerard J, Fabiani F | title = [Generalities concerning the experimental study and clinical use of gamma hydroxybutyrate of Na] | language = fr | journal = Agressologie | volume = 1 | pages = 397–406 | date = October 1960 | pmid = 13758011 }} It was studied in a range of uses including obstetric surgery and during childbirth and as an anxiolytic; there were anecdotal reports of it having antidepressant and aphrodisiac effects as well.{{rp|27}} It was also studied as an intravenous anesthetic agent and was marketed for that purpose starting in 1964 in Europe but it was not widely adopted as it caused seizures; as of 2006 that use was still authorized in France and Italy but not widely used.{{rp|27–28}} It was also studied to treat alcohol addiction; while the evidence for this use is weak;{{rp|28–29}} however, sodium oxybate is marketed for this use in Italy.{{cite web|title=Alcover: Riassunto delle Caratteristiche del Prodotto|url=https://farmaci.agenziafarmaco.gov.it/aifa/servlet/PdfDownloadServlet?pdfFileName=footer_000223_027751_RCP.pdf&retry=0&sys=m0b1l3|date=31 March 2017|publisher=Agenzia Italiana del Farmaco|access-date=16 April 2018|archive-date=6 August 2021|archive-url=https://web.archive.org/web/20210806054116/https://farmaci.agenziafarmaco.gov.it/aifa/servlet/PdfDownloadServlet?pdfFileName=footer_000223_027751_RCP.pdf&retry=0&sys=m0b1l3|url-status=dead}} [https://farmaci.agenziafarmaco.gov.it/bancadatifarmaci/farmaco?farmaco=027751 Index page] {{Webarchive|url=https://web.archive.org/web/20210304132532/https://farmaci.agenziafarmaco.gov.it/bancadatifarmaci/farmaco?farmaco=027751 |date=4 March 2021 }}

GHB and sodium oxybate were also studied for use in narcolepsy from the 1960s onwards.{{rp|28}}

In May 1990 GHB was introduced as a dietary supplement and was marketed to body builders, for help with weight control and as a sleep aid, and as a "replacement" for l-tryptophan, which was removed from the market in November 1989 when batches contaminated with trace impurities{{cite journal | vauthors = Ito J, Hosaki Y, Torigoe Y, Sakimoto K | title = Identification of substances formed by decomposition of peak E substance in tryptophan | journal = Food and Chemical Toxicology | volume = 30 | issue = 1 | pages = 71–81 | date = January 1992 | pmid = 1544609 | doi = 10.1016/0278-6915(92)90139-C }} were found to cause eosinophilia–myalgia syndrome, although eosinophilia–myalgia syndrome is also tied to tryptophan overload.{{cite journal | vauthors = Smith MJ, Garrett RH | title = A heretofore undisclosed crux of eosinophilia-myalgia syndrome: compromised histamine degradation | journal = Inflammation Research | volume = 54 | issue = 11 | pages = 435–50 | date = November 2005 | pmid = 16307217 | doi = 10.1007/s00011-005-1380-7 | s2cid = 7785345 }} In 2001 tryptophan supplement sales were allowed to resume, and in 2005 the FDA ban on tryptophan supplement importation was lifted.{{cite book | vauthors = Kapalka GM |title=Nutritional and herbal therapies for children and adolescents : a handbook for mental health clinicians |date=2010 |publisher=Elsevier/AP |isbn=978-0-12-374927-7}} By November 1989 57 cases of illness caused by the GHB supplements had been reported to the Centers for Disease Control and Prevention, with people having taken up to three teaspoons of GHB; there were no deaths but nine people needed care in an intensive care unit.{{cite journal | title = Multistate outbreak of poisonings associated with illicit use of gamma hydroxy butyrate | journal = MMWR. Morbidity and Mortality Weekly Report | volume = 39 | issue = 47 | pages = 861–63 | date = November 1990 | pmid = 2122223 | url = https://www.cdc.gov/mmwr/preview/mmwrhtml/00001847.htm | author1 = Centers for Disease Control (CDC) | access-date = 16 April 2018 | archive-date = 6 June 2021 | archive-url = https://web.archive.org/web/20210606183318/https://www.cdc.gov/mmwr/preview/mmwrhtml/00001847.htm | url-status = live }}{{cite journal | vauthors = Dyer JE | title = gamma-Hydroxybutyrate: a health-food product producing coma and seizurelike activity | journal = The American Journal of Emergency Medicine | volume = 9 | issue = 4 | pages = 321–24 | date = July 1991 | pmid = 2054002 | doi = 10.1016/0735-6757(91)90050-t }} The FDA issued a warning in November 1990 that sale of GHB was illegal. GHB continued to be manufactured and sold illegally and it and analogs were adopted as a club drug and came to be used as a date rape drug, and the DEA made seizures and the FDA reissued warnings several times throughout the 1990s.{{cite book|author1=Institute of Medicine|author2=National Research Council (US) Committee on the Framework for Evaluating the Safety of Dietary Supplements|title=Proposed Framework for Evaluating the Safety of Dietary Supplements: For Comment.|date=2002|publisher=National Academies Press (US)|chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK220875/|chapter=Appendix D: Table of Food and Drug Administration Actions on Dietary Supplements|access-date=16 April 2018|archive-date=29 August 2021|archive-url=https://web.archive.org/web/20210829063758/https://www.ncbi.nlm.nih.gov/books/NBK220875/|url-status=live}}{{cite journal|title=GHB: A Club Drug To Watch|journal=Substance Abuse Treatment Advisory|date=November 2002|volume=2|issue=1|url=https://store.samhsa.gov/shin/content/SMA03-3766/SMA03-3766.pdf|access-date=16 April 2018|archive-url=https://web.archive.org/web/20170801221141/https://store.samhsa.gov/shin/content/SMA03-3766/SMA03-3766.pdf|archive-date=1 August 2017|url-status=dead}}{{cite journal | vauthors = Mason PE, Kerns WP | s2cid = 13325306 | title = Gamma hydroxybutyric acid (GHB) intoxication | journal = Academic Emergency Medicine | volume = 9 | issue = 7 | pages = 730–79 | date = July 2002 | pmid = 12093716 | doi = 10.1197/aemj.9.7.730 | doi-access = free }}

At the same time, research on the use of GHB in the form of sodium oxybate had formalized, as a company called Orphan Medical had filed an investigational new drug application and was running clinical trials with the intention of gaining regulatory approval for use to treat narcolepsy.{{rp|18–25, 28}}{{cite web|title=Transcript: FDA Peripheral and Central Nervous System Drugs Advisory Committee Meeting|url=https://www.fda.gov/ohrms/dockets/ac/01/transcripts/3754t1.txt|publisher=FDA|date=6 June 2001|access-date=16 April 2018|archive-date=16 May 2017|archive-url=https://web.archive.org/web/20170516063446/https://www.fda.gov/ohrms/dockets/ac/01/transcripts/3754t1.txt|url-status=dead}}{{rp|10}}

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.{{cite news | vauthors = Perry M, Pomfret J, Crabb RP | title = Australia bans China-made toy on toxic drug risk | date = 7 November 2007 | work = Reuters | url = https://www.reuters.com/article/worldNews/idUSSYD2129620071107 | access-date = 2 July 2017 | archive-date = 5 April 2023 | archive-url = https://web.archive.org/web/20230405014132/https://www.reuters.com/article/worldNews/idUSSYD2129620071107 | url-status = live }}

File:Alcover 17,5 - Gamma-Hydroxybutyric acid.JPG

In the United States, GHB was placed on Schedule I of the Controlled Substances Act in March 2000. However, used in sodium oxybate under an IND or NDA from the US FDA, it is considered a Schedule III substance but with Schedule I trafficking penalties, one of several drugs that are listed in multiple schedules.{{cite web|title=2000 – Addition of Gamma-Hydroxybutyric Acid to Schedule I|url=https://www.deadiversion.usdoj.gov/fed_regs/rules/2000/fr0313.htm|publisher=US Department of Justice via the Federal Register|date=13 March 2000|access-date=16 April 2018|archive-date=1 May 2021|archive-url=https://web.archive.org/web/20210501154805/https://www.deadiversion.usdoj.gov/fed_regs/rules/2000/fr0313.htm|url-status=dead}}{{cite web|title=William J. Clinton: Statement on Signing the Hillory J. Farias and Samantha Reid Date-Rape Drug Prohibition Act of 2000|url=http://www.presidency.ucsb.edu/ws/index.php?pid=58098|date=18 February 2000|access-date=16 April 2018|archive-date=13 September 2018|archive-url=https://web.archive.org/web/20180913115803/http://www.presidency.ucsb.edu/ws/index.php?pid=58098|url-status=live}}

On 20 March 2001, the UN Commission on Narcotic Drugs placed GHB in Schedule IV of the 1971 Convention on Psychotropic Substances.{{Cite web|url=http://www.whitehousedrugpolicy.gov/publications/factsht/gamma/ |title=Gamma Hydroxybutyrate (GHB) |year=2002 |archive-url=https://web.archive.org/web/20051231122054/http://www.whitehousedrugpolicy.gov/publications/factsht/gamma/ |archive-date=31 December 2005 |access-date=20 November 2016 |url-status=dead }}

In the UK GHB was made a class C drug in June 2003. In October 2013 the ACMD recommended upgrading it from schedule IV to schedule II in line with UN recommendations. Their report concluded that the minimal use of Xyrem in the UK meant that prescribers would be minimally inconvenienced by the rescheduling.{{cite web | url = https://www.gov.uk/government/publications/acmd-advice-on-the-scheduling-of-ghb | title = ACMD advice on the scheduling of GHB | access-date = 23 October 2013 | vauthors = Iversen L | date = 3 October 2013 | format = PDF | publisher = UK Home Office | archive-date = 13 August 2014 | archive-url = https://web.archive.org/web/20140813235435/https://www.gov.uk/government/publications/acmd-advice-on-the-scheduling-of-ghb | url-status = live }} This advice was followed and GHB was moved to schedule 2 on 7 January 2015.{{Cite web |url=https://www.gov.uk/government/publications/circular-0012015-a-change-to-the-misuse-of-drugs-act-1971-control-of-ah-7921-lsd-related-compounds-tryptamines-and-rescheduling-of-ghb/circular-0012015-a-change-to-the-misuse-of-drugs-act-1971-control-of-ah-7921-lsd-related-compounds-tryptamines-and-rescheduling-of-ghb |title=Circular 001/2015: A Change to the Misuse of Drugs Act 1971: control of AH-7921, LSD–related compounds, tryptamines, and rescheduling of GHB |year=2015 |publisher=UK Home Office |access-date=8 May 2017 |archive-date=6 April 2023 |archive-url=https://web.archive.org/web/20230406095103/https://www.gov.uk/government/publications/circular-0012015-a-change-to-the-misuse-of-drugs-act-1971-control-of-ah-7921-lsd-related-compounds-tryptamines-and-rescheduling-of-ghb/circular-0012015-a-change-to-the-misuse-of-drugs-act-1971-control-of-ah-7921-lsd-related-compounds-tryptamines-and-rescheduling-of-ghb |url-status=live }}{{Cite web |url=http://www.legislation.gov.uk/uksi/2014/3277/made |title=The Misuse of Drugs (Amendment No. 3) (England, Wales and Scotland) Regulations 2014 |date=11 December 2014 |publisher=UK Home Office |access-date=8 May 2017 |archive-date=5 August 2023 |archive-url=https://web.archive.org/web/20230805175941/https://www.legislation.gov.uk/uksi/2014/3277/made |url-status=live }} In April 2022 GHB was changed from class C to class B.{{cite web | title = The Misuse of Drugs Act 1971 (Amendment) Order 2022 | url = https://www.legislation.gov.uk/uksi/2022/322/note/made | work = www.legislation.gov.uk | access-date = 15 June 2023 | archive-date = 26 July 2023 | archive-url = https://web.archive.org/web/20230726023326/https://www.legislation.gov.uk/uksi/2022/322/note/made | url-status = live }}

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$10,000. The penalty for trafficking or manufacturing the substance is a HK$150,000 fine and life imprisonment. Possession of the substance for consumption without license from the Department of Health is illegal with a HK$100,000 fine or five years of jail time.

In Canada, GHB has been a Schedule I controlled substance since 6 November 2012 (the same schedule that contains heroin and cocaine). Prior to that date, it was a Schedule III controlled substance (the same schedule that contains amphetamines and LSD).{{cite web |title=Controlled Drugs and Substances Act, SC 1996, c 19 |url=https://www.canlii.org/en/ca/laws/stat/sc-1996-c-19/latest/sc-1996-c-19.html#history |publisher=Canadian Legal Information Institute |access-date=25 November 2018 |archive-date=17 June 2019 |archive-url=https://web.archive.org/web/20190617175124/https://www.canlii.org/en/ca/laws/stat/sc-1996-c-19/latest/sc-1996-c-19.html#history |url-status=live }}

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 (γ-hydroxyvaleric acid, GHV) and its prodrug form γ-valerolactone (GVL), but these are also covered under the law by virtue of their being "substantially similar" to GHB or GBL, so importation, sale, possession and use of these compounds is also considered to be illegal.

In Chile, GHB is a controlled drug under the law {{lang|es|Ley de substancias psicotrópicas y estupefacientes}} (psychotropic substances and narcotics).

In Norway{{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)|language=no|access-date=17 August 2008|archive-date=16 October 2014|archive-url=https://web.archive.org/web/20141016174713/http://www.lovdata.no/cgi-wift/ldles?doc=/sf/sf/sf-19780630-0008.html|url-status=live}} and in Switzerland,[http://www.kompendium.ch/MonographieTxt.aspx?lang=de&MonType=fi] {{dead link|date=October 2017|bot=InternetArchiveBot|fix-attempted=yes}} GHB is considered a narcotic and is only available by prescription under the trade name Xyrem (Union Chimique Belge S.A.).

Sodium oxybate is also used therapeutically in Italy under the brand name Alcover for treatment of alcohol withdrawal and dependence.{{cite journal | vauthors = Haller C, Thai D, Jacob P, Dyer JE | title = GHB urine concentrations after single-dose administration in humans | journal = Journal of Analytical Toxicology | volume = 30 | issue = 6 | pages = 360–64 | year = 2006 | pmid = 16872565 | pmc = 2257868 | doi = 10.1093/jat/30.6.360 }}

• Beta-Hydroxybutyric acid
• γ-Hydroxyvaleric acid (GHV)
• γ-Valerolactone (GVL)
• β-Hydroxy β-methylbutyric acid (HMB)

{{Reflist}}

{{Commons category|GHB}}

• [http://gmd.mpimp-golm.mpg.de/Spectrums/f5bd9fef-a38c-45de-afe5-fce6e5044848.aspx Gamma-hydroxybutyrate MS Spectrum]
• [https://www.euda.europa.eu/publications/risk-assessment/ghb_hu 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)
• [https://web.archive.org/web/20050305152549/http://www.drugabuse.gov/Infofax/RohypnolGHB.html InfoFacts – Rohypnol and GHB] (National Institute on Drug Abuse)

{{Drug use}}

{{Neurotransmitters}}

{{Sedatives}}

{{Euphoriants}}

{{GHBergics}}

{{GABAergics}}

{{Chemical classes of psychoactive drugs}}

{{Authority control}}

{{DEFAULTSORT:Hydroxybutyric Acid, γ-}}

Category:Sedatives

Category:GABAB receptor agonists

Category:GHB receptor agonists

Category:GABA analogues

Category:General anesthetics

Category:Neurotransmitters

Category:Drug culture

Category:Euphoriants

Category:Gamma hydroxy acids

Category:GABA

Category:Glutamate (neurotransmitter)

Category:Drug-facilitated sexual assault