gamma-hydroxybutyric acid gamma-hydroxybutyric acid gamma-hydroxybutyric acid (or γ-hydroxybutyric acid (ghb), also known as 4-hydroxybutanoic acid) is a naturally occurring neurotransmitter and a depressant drug. it is a precursor to gaba, glutamate, and glycine in certain brain areas. it acts on the ghb receptor and is a weak agonist at the gabab receptor. ghb has been used in the medical setting as a general anesthetic and as treatment for cataplexy, narcolepsy, and alcoholism. it is also used illegally as an intoxicant, as an athletic-performance enhancer, as a date-rape drug, and as a recreational drug. γ-hydroxybutyric acidclinical dataother namesγ-hydroxybutyric acidγ-hydroxybutyrateghbfishiesroutes ofadministrationby mouth, intravenousatc coden01ax11 (who) n07xx04 (who)legal statuslegal status au: s8 (controlled drug) ca: schedule i de: prescription only (anlage iii for higher doses) nz: class b uk: class c us: schedule i / schedule iii(xywav and xyrem) eu: list i (netherlands) pharmacokinetic databioavailability25% (oral)metabolism95%, mainly liver, also in blood and tissuesonset of actionwithin 5–15 minuteselimination half-life30–60 minutesexcretion5%, kidneyidentifiers iupac name 4-hydroxybutanoic acid cas number591-81-1 ypubchem cid3037032iuphar/bps4711drugbankdb01440 ychemspider9984 yunii30iw36w5b2keggc00989 ychebichebi:30830 ychemblchembl1342 ycomptox dashboard (epa)dtxsid2074740 echa infocard100.218.519 chemical and physical dataformulac4h8o3molar mass104.105 g·mol−13d model (jsmol)interactive image smiles o=c(o)ccco inchi inchi=1s/c4h8o3/c5-3-1-2-4(6)7/h5h,1-3h2,(h,6,7) ykey:sjzrecivhvdyjc-uhfffaoysa-n y (verify) it is commonly used in the form of a salt, such as sodium γ-hydroxybutyrate (naghb, sodium oxybate, or xyrem) or potassium γ-hydroxybutyrate (kghb, potassium oxybate). ghb is also produced as a result of fermentation, and is found in small quantities in some beers and wines, beef, and small citrus fruits. succinic semialdehyde dehydrogenase deficiency is a disease that causes ghb to accumulate in the blood. medical use main article: sodium oxybate ghb is used for medical purposes in the treatment of narcolepsy and, more rarely, alcohol dependence, although there remains uncertainty about its efficacy relative to other pharmacotherapies for alcohol dependence. the authors of a 2010 cochrane review 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. 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 and excessive daytime sleepiness (eds) associated with narcolepsy. ghb has been shown to reliably increase slow-wave sleep and decrease the tendency for rem sleep in modified multiple sleep latency tests. the fda approved labeling for sodium oxybate 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. recreational use ghb powder delphic analysis of harm assessment for 20 popular recreational drugs (conducted by david nutt and his colleagues at university of bristol in 2007) ranks (in decreasing order of harmfulness) ghb 15th in dependence, 19th in physical harm, and 14th in social harm. ghb is a central nervous system depressant used as an intoxicant. 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. 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. consuming ghb with alcohol can cause respiratory arrest and vomiting in combination with unarousable sleep, which can lead to death. 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. the sodium salt of ghb has a salty taste. 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 prodrugs, such as γ-butyrolactone (gbl), convert to ghb in the stomach and blood stream. other prodrugs exist, such as 1,4-butanediol (1,4-b). 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). 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. ghb is colourless and odourless. a 2006 report commissioned by a uk parliamentary committee found the use of ghb to be less dangerous than tobacco and alcohol in physical harm, dependence and social harms. party use 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. 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. sports and athletics some athletes have used ghb or its analogs because of being marketed as anabolic agents, although there is no evidence that it builds muscle or improves performance. usage as a date-rape drug fda warning against products containing ghb and its prodrugs ghb became known to the general public as a date-rape drug by the late 1990s. 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. 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, and a survey in the netherlands published in 2010 found that the proportion of drug-related rape where ghb was used appeared to be greatly overestimated by the media. 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. the british serial killer stephen port administered ghb to his victims. ghb can be detected in hair. hair testing can be a useful tool in court cases or for the victim's own information. most over-the-counter urine test kits test only for date-rape drugs that are benzodiazepines, and ghb is not a benzodiazepine. to detect ghb in urine, the sample must be taken within four hours of ghb ingestion, and cannot be tested at home. adverse effects combination with alcohol in humans, ghb has been shown to reduce the elimination rate of alcohol. this may explain the respiratory arrest that has been reported after ingestion of both drugs. 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. deaths one publication has investigated 226 deaths attributed to ghb. of 226 deaths included, 213 had a cardiorespiratory arrest and 13 had fatal accidents. 71 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. 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. 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. levels higher than this are found in ghb deaths. levels lower than this may be due to ghb or to postmortem endogenous elevations. neurotoxicity in multiple studies, ghb has been found to impair spatial memory, working memory, learning and memory in rats with chronic administration. these effects are associated with decreased nmda receptor expression in the cerebral cortex and possibly other areas as well. in addition, the neurotoxicity appears to be caused by oxidative stress. addiction 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. rats forced to consume massive doses of ghb will intermittently prefer ghb solution to water. withdrawal ghb has also been associated with a withdrawal syndrome of insomnia, anxiety, and tremor that usually resolves within three to twenty-one days. 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. 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. 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 gabab receptors and therefore have no cross-tolerance with ghb while baclofen, which works via gabab receptors, is cross-tolerant with ghb and may be more effective in alleviating withdrawal effects of ghb. 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. overdose overdose of ghb can sometimes be difficult to treat because of its multiple effects on the body. ghb tends to cause rapid unconsciousness at doses above 3500 mg, with single doses over 7000 mg often causing life-threatening respiratory depression, and higher doses still inducing bradycardia and cardiac arrest. other side-effects include convulsions (especially when combined with stimulants), and nausea/vomiting (especially when combined with alcohol). the greatest life threat due to ghb overdose (with or without other substances) is respiratory arrest. 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). 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 gabaa receptors whereas ghb is primarily a gabab receptor agonist,