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.[9][10] The substance is also used illicitly for various reasons, including as a performance-enhancing drug, date rape drug, and as a recreational drug.[11]
"GHB" redirects here. For other uses, see GHB (disambiguation).Clinical data
High[3]
- AU: S8 (Controlled drug)
- BR: Class B1 (Psychoactive drugs)[4]
- CA: Schedule I
- DE: Prescription only (Anlage III for higher doses)
- NZ: Class B
- UK: Class B
- US: Schedule I / Schedule III (Xywav and Xyrem)[5][6]
- UN: Psychotropic Schedule II
- EU: List I (Netherlands)
25% (oral)
Within 5–15 minutes[7]
30–60 minutes
C4H8O3
104.105 g·mol−1
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.[12]
Succinic semialdehyde dehydrogenase deficiency is a disease that causes GHB to accumulate in the blood.
Endogenous production[edit]
Cells produce GHB by reduction of succinic semialdehyde via succinic semialdehyde reductase (SSR). This enzyme appears to be induced by cAMP levels,[83] 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.[84] 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.[85]
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.[86] 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.[87] The benzamide antipsychotics—amisulpride, nemonapride, etc.—have been shown to bind to these GHB-activated receptors in vivo.[88] 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.[89]
In spite of its demonstrated neurotoxicity, (see relevant section, above), GHB has neuroprotective properties, and has been found to protect cells from hypoxia.[90]
History[edit]
Alexander Zaytsev worked on this chemical family and published work on it in 1874.[115][116] 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.[117]: 11–12 [118] 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.[117]: 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.[117]: 27–28 It was also studied to treat alcohol addiction; while the evidence for this use is weak,[117]: 28–29 however sodium oxybate is marketed for this use in Italy.[119]
GHB and sodium oxybate were also studied for use in narcolepsy from the 1960s onwards.[117]: 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[120] were found to cause eosinophilia-myalgia syndrome, although eosinophilia-myalgia syndrome is also tied to tryptophan overload.[121] In 2001 tryptophan supplement sales were allowed to resume, and in 2005 the FDA ban on tryptophan supplement importation was lifted.[122] 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.[123][124] The FDA issued a warning in November 1990 that sale of GHB was illegal.[123] 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.[125][126][127]
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.[117]: 18–25, 28 [128]: 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.[129]