Gamma-Hydroxybutyric acid

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.

Uses

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.

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 anaesthetic, 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

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

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. On March 20, 2001, the Commission on Narcotic Drugs placed GHB in Schedule IV of the 1971 Convention on Psychotropic Substances. 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 libido, 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 precursor. The dose of GHB is difficult to judge when in liquid form because the concentration of GHB may not be 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 characterised and aptly named "GHB receptor" as well as the GABAB. 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 GABAB. However, during recreational usage, GHB can reach very high concentrations in the brain, relative to basal levels, and can act at the GABAB receptor. GHBs action at the GABAB is probably responsible for its sedative effects. GHB-mediated GABAB receptor stimulation inhibits dopamine release as well as causes the release of natural sedative neurosteroids (like all other GABAB agonists eg. Baclofen). In animals GHBs sedative effects can be stopped by GABAB 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 GABAB 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 GABAB receptor function, and simply stimulates the GHB receptor, leading to wakefulness.

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 (eg. Valium), barbiturates, and others.

Death while using GHB is possible when it is combined with alcohol or other depressant drugs but, 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  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

Addiction

GHB can be physically addictive and may result in psychological addiction. Physical dependence develops when GHB is taken on a regular basis (ie. 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).

History

GHB was first synthesized in the early 1960s by Dr. Henri Laborit to use in studying the neurotransmitter GABA. 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).

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