Article: Gamma-Hydroxybutyric acid

Gamma-Hydroxybutyric acid
Systematic (IUPAC) name
4-Hydroxybutanoic acid
Identifiers
CAS number	591-81-1
ATC code	??
PubChem	3037032
DrugBank	?
Chemical data
Formula	C4H8O3
Mol. weight	104.11
Pharmacokinetic data
Bioavailability	?
Metabolism	?
Half life	?
Excretion	?
Therapeutic considerations
Pregnancy cat.	?
Legal status	Schedule I (USA); Class C (UK)
Routes	Usually Oral; IV

GHB redirects here. See also Great Highland Bagpipe.

gamma-Hydroxybutyric acid (4-hydroxybutanoic acid, C₄H₈O₃) is both a drug and a naturally occurring substance found in the central nervous system where it might act as a neurotransmitter, as well as in other organs such as the liver, kidneys, heart and bones. GHB is structurally related to the ketone body beta-hydroxybutyrate. As a drug it is used most commonly in the form of a salt like sodium gamma-hydroxybutyrate (Na-GHB, sodium oxybate) or potassium gamma-hydroxybutyrate (K-GHB). The drug is often viewed as a date rape drug and is often referred to as liquid ecstasy despite its unrelated effects.

Uses

Endogenous

Cells produce GHB by reduction of succinic semialdaehyde. People with the disorder known as succinic semialdehyde dehydrogenase deficiency, also known as gamma-hydroxybutyric aciduria, have elevated levels of GHB in their urine, blood plasma and cerebrospinal fluid[1].

The precise function of GHB in the body is not clear. It is an immediate precursor to GABA, a neurotransmitter which regulates awakeness, physical activity and sleep. As GABA cannot cross the blood-brain barrier, GHB obtained from food may be used for converting to GABA. GHB protects cells from oxygen starvation, which might explain presence of the compound in vital organs. GHB was also found to have neuroprotective capabilities.

Medical

It has been used as a general anesthetic, and a hypnotic in the treatment of insomnia. GHB has also been used to treat clinical depression, and improve athletic performance. In the United States, the Food and Drug Administration permits the use of GHB under the trade name Xyrem to reduce the number of cataplexy attacks in patients with narcolepsy. In Italy, under the trade name Alcover (ATC code N07BB), GHB is used in the treatment of alcoholism (50 to 100 milligrams per kilogram per day, in 3 or more divided doses), both for acute alcohol withdrawal and medium to long term detoxification. An author/scientist by the name of Gian Luigi Gessa has been researching alcoholism and the effects of various drugs to persons afflicted with said disease for the past ten years. His studies in 1998 note that GHB, as a pharmaceutical aid, can be much less toxic and much more effective than the leading pharmaceutical compound (disulfiram).

Recreational

Gamma-hydroxybutyrate powder

GHB is an intoxicant. It has many street names, including G, Juice, Liquid Ecstasy, and Gamma-OH (see list of street names of drugs).

In the United States it was placed on Schedule I of the Controlled Substances Act in March of 2000 although when sold as Xyrem it is considered schedule III making it the only drug to simultaneously occupy two different schedules[2][3]. On March 20, 2001, the Commission on Narcotic Drugs placed GHB in Schedule IV of the 1971 Convention on Psychotropic Substances[4]. In the UK it was made a class C drug in June 2003.

The sodium salt of GHB has a thin, very salty, chemical taste. At low doses, GHB can cause a state of euphoria, increased sociality and intoxication. This kind of use is particularly common at rave parties. At higher doses, GHB may induce nausea, dizziness, drowsiness, agitation, bizarre behavior visual disturbances, depressed breathing, amnesia and unconsciousness. The effects of GHB can last from 1.5 to 3 hours.

Some chemicals convert to GHB in the stomach and blood. GBL, or gamma-butyrolactone, is one such precursor. The dose of GHB is difficult to judge when in liquid form because the concentration of GHB may not known.

Other precursors include 1,4-butanediol. There may be additional toxicity concerns with these precursors.

Mode of action

The action of GHB has yet to be fully elucidated. GHB clearly has at least two sites of action, stimulating the newly characterized and aptly named "GHB receptor" as well as the GABA_B. GHB, if it is indeed a neurotransmitter, will only reach concentrations high enough to act at the GHB receptor, as it only has weak affinity for the GABA_B. However, during recreational usage, GHB can reach very high concentrations in the brain, relative to basal levels, and can act at the GABA_B receptor [5]. GHBs action at the GABA_B is probably responsible for its sedative effects. GHB-mediated GABA_B receptor stimulation inhibits dopamine release as well as causes the release of natural sedative neurosteroids (like all other GABA_B agonists e.g. Baclofen). In animals GHBs sedative effects can be stopped by GABA_B antagonists (blockers).

The relevance of the GHB receptor in the behavioural effects induced by GHB is more controversial. It seems hard to believe that the GHB receptor is not important when it is densely expressed in many areas of the brain, including the cortex, as well as it being the high affinity site of GHB action. There is limited research into GHB receptor. However, evidence shows that it causes the release of glutamate, which should be stimulatory. It does not seem, however, that the GHB receptor explains either GHB's sedative or rewarding/addictive properties.

One can propose a scheme where high doses of GHB are sedative through its action at the GABA_B receptor, while a lower dose is somehow stimulatory. This may explain the so-called "rebound" effect, experienced by individuals using GHB as a sleeping agent, where they awake after several hours of GHB-induced sleep. That is to say, that over time, the concentration of GHB in the system decreases (because of metabolism) below a threshold for stimulating GABA_B receptor function, and simply stimulates the GHB receptor, leading to wakefulness.

Dangers

The dose-response curve is very steep, and proper dosing of GHB is difficult since it often comes as a salt dissolved in water, and the actual amount of GHB per "capful" can vary. While small doses of GHB are considered safe, high doses can cause unconsciousness, convulsions, vomiting, suppression of the gag reflex and breathing, or death. These effects vary between persons and are dose dependent. Synergy of its sedative effects are seen when combined with other CNS depressants such as alcohol, benzodiazepines (e.g. Valium), barbiturates, and others. Contrary to widespread belief, GHB may be lethal when ingested alone. At the American Acadamy of Forensic Science in Seattle, in 2006, Zvosec et al. reported 208 deaths due to GHB, most from respiratory depression and some from choking on vomit and asphyxiating; 70 of these deaths were due to GHB only (proven to have no co-intoxicants), with GHB toxic blood levels in many of these cases < 100 mg/Liter. All but one was self-administered. Death while using GHB is more likely in combination with alcohol or other depressant drugs. The toxic dose of GHB in rodents is approximately 10-fold higher than in humans; correspondingly, the LD50 of GHB in rodents, which is estimated to be between 1100mg/kg and 2000mg/kg, is much higher than in humans[6]. This discrepancy has led to dangerous misconceptions about the lethal potential of GHB.

An Australian coroner in Sydney has ruled that cruise ship passenger, Mrs Dianne Brimble, was gang raped on the Pacific Sky after being given a GHB overdose that resulted in her death. Photographs of Mrs Brimble taken during the ordeal show the level of the drug in her system was so high it caused her to froth at the mouth.^[1]

There have been no long-term studies into the effects of GHB if taken chronically, and hence whether prolonged use of GHB causes any bodily harm (aside from addiction) remains unknown.

Addiction

GHB is physically addictive and may also result in psychological addiction. Physical dependence develops when GHB is taken on a regular basis (i.e. every 2-4 hours for multiple consecutive days or weeks). Withdrawal effects may include hallucinations, insomnia, anxiety, tremors, sweating, edginess, chest pain and tightness, muscle and bone aches, sensitivity to external stimuli (sound, light, touch), dysphoria, and mental dullness. These side effects will subside after 2 - 21 days depending on usage. Although there have been reported fatalities due to GHB withdrawal, reports are inconclusive and further research is needed. Unlike alcohol, there is no firm data that chronic use of GHB causes permanent damage to the body. In rats, no organ or brain damage was observed after chronic administration of GHB [7].

History

GHB was first synthesized in the early 1960s by Dr. Henri Laborit to use in studying the neurotransmitter GABA.^{[citation needed]} It quickly found a wide range of uses due to its minimal side effects and controlled action, the only difficulties being the narrow safe dosage range and the dangers presented by its combination with alcohol and other CNS depressants.

Typically GHB has been synthesized from GBL (Gamma-butyrolactone) by adding sodium hydroxide (lye) in ethanol or water. As of late, GBL has become controlled and more circuitous routes have to be taken such as those starting with THF (tetrahydrofuran).

GHB in popular culture

In the Murder In A Flash episode of CSI: Miami one of the victims, an 18 year-old boy, is found to have died from GHB intoxication. GHB is also named as "the date-rape drug" by one of the investigators who also relates the information that males often take the drug to get high. In the matter of the GHB-related death however, the victim had received the GHB without noticing it.

In episode 21 "A Trip to the Dentist" of season 1 of Veronica Mars, Veronica discovers that she had been given GHB at a party, although it was accidental. This party is referenced throughout season one and is a major conflict for the character.

An episode of Law and Order: Special Victims Unit involves a woman who was drugged by GHB by a vengeful colleague in hopes of the woman being raped.