Gamma-Hydroxybutyric acid

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Gamma-Hydroxybutyric acid
Systematic (IUPAC) name
4-Hydroxybutanoic acid
Identifiers
CAS number	591-81-1
ATC code	N01 AX11
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 represented as a date rape drug, much in the same way as alcohol and rohypnol. It is often referred to as liquid ecstasy despite its unrelated effects.

1 Uses
2 Mode of action
3 Dangers
4 Addiction
5 Legal state
6 History
7 GHB in popular culture
8 References
9 External links

[edit] Uses

[edit] Endogenous

Cells produce GHB by reduction of succinic semialdehyde. 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.

[edit] 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 to 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).

[edit] Recreational

Gamma-hydroxybutyrate powder

GHB is an intoxicant. It has many street names, including G, GB, Juice, Fantasy, Liquid Ecstasy, Liquid X, Gamma-OH and Jungle Juice.

The sodium salt of GHB has a thin, very salty, chemical taste. At low doses, GHB can cause a state of euphoria, increased libido^[2], increased sociality and intoxication. This kind of use is particularly common at rave parties. At higher doses, GHB may induce nausea, dizziness, drowsiness, agitation, 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 prodrug. The dose of GHB is difficult to judge when in liquid form because the concentration of GHB may not be known.

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

[edit] 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.^[3] 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.

Recently, similar molecules to GHB, such as 4-hydroxy-4-methylpentanoic acid have been synthesised and tested on animals, in order to gain a better understanding of GHB's mode of action[[3]].

[edit] Dangers

As with pure alcohol, the dose-response curve is very steep, and proper dosing of illegal GHB can be difficult since it often comes as a salt dissolved in water, and the actual amount of GHB and/or other additives per "capful" can vary. Legal GHB comes in standardized doses and is free from contaminants, so it is much safer (cf. legal alcohol vs. bathtub gin). Also, like pure alcohol, small doses of GHB are considered safe, but high doses can cause unconsciousness, convulsions, vomiting, suppression of the gag reflex and hypoventilation. 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.

Death while using GHB is possible when it is combined with alcohol or other depressant drugs, however as with all substances, an overdose of GHB alone may be lethal. A review of the details of 194 deaths attributed to or related to GHB over a ten year period ^[4] found that most were from respiratory depression caused by interaction with alcohol or other drugs; several were from choking on vomit and asphyxiating; remaining causes of death included motor vehicle and other accidents. The review included 70 cases where high levels of GHB were found post-mortem without concomitant ingestion of other drugs or alcohol.

Determining conclusively whether someone's death was caused by GHB is very difficult because a lab test will always detect the presence of some GHB in the human body, and levels of GHB can vary in the same individual depending on what part of the body is tested. GHB is a naturally occurring substance that is always present in everyone, but little research has been done on what levels are normal in what parts of the body at what times.

There have been no systematic studies into the effects of GHB if taken chronically in humans, and hence whether prolonged use of GHB causes any bodily harm remains unknown. A UK parliamentary committee commissioned report found the use of GHB to be less dangerous than tobacco and alcohol in social harms, physical harm and addiction ^[5].

[edit] Addiction

GHB can be physically addictive and may 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 GBL (a precursor to GHB).^[6]

[edit] Legal state

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.^[7]^[8] On March 20, 2001, the Commission on Narcotic Drugs placed GHB in Schedule IV of the 1971 Convention on Psychotropic Substances.^[9] In the UK it was made a class C drug in June 2003.

[edit] 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).

[edit] 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 the "NCIS" episode "Twisted Sister" GBH was used to drug Sarah McGee, Special Agent Timothy McGee's sister, into thinking that she committed a murder as a cover up. A classmate, whom she despises, drugged her by adding it to her peanut butter.

In the pilot episode of Veronica Mars, Veronica tells us she was raped at a party when she was sixteen. At the end of episode 20, "M.A.D.", of season 1, Veronica discovers that she had been given GHB at the party and investigates that night in the following episode, "A Trip to the Dentist". This party is referenced throughout season one and is a major conflict for the character, which was revisited in the final episode of season 2 when she finally learned exactly who she was raped by that night.

Additionally, the current season 3 of Veronica Mars centers around the main character's freshman year at Hearst College, where she investigates a string of GHB-related rapes on campus.

An episode of Law and Order: Special Victims Unit involves a woman who is drugged with GHB by a vengeful colleague in hopes that the woman will be raped.

The television series The West Wing featured GHB in a multi-episode story during the conclusion of season 4 and the beginning of season 5. The president's daughter consumes GHB that has been slipped into an alcoholic beverage without her knowledge, and as she feels the effects of the drug, her boyfriend implies she has consumed ecstasy. Later, she is kidnapped from a nightclub bathroom while barely or not conscious, setting off a massive manhunt. The president is told later by an FBI agent that the drug is created by mixing degreasing solvent and drain cleaner, and he finishes the agent's sentence by acknowledging he is aware the drug is known as a date-rape drug.

The French activist and psychoanalytic theorist Félix Guattari used GHB recreationally in the early '70's, see The Anti-Oedipus Papers (2006:308,326)

In the movie Syriana, Arash refers to Tehran as the world capital of "liquid MDMA".

An episode of the fifth series of Spooks sees Ros use a refined form of the drug to incapacitate targets for intelligence gathering.