Citizendia

gamma-Hydroxybutyric acid
Systematic (IUPAC) name
4-Hydroxybutanoic acid
Identifiers
CAS number 591-81-1
ATC code N01AX11
PubChem 3037032
DrugBank ?
Chemical data
Formula C4H8O3 
Mol. mass 104. IUPAC Nomenclature is a system of naming Chemical compounds and of describing the science of Chemistry in general CAS registry numbers are unique numerical identifiers for Chemical compounds Polymers biological sequences mixtures and Alloys They are also referred to The Anatomical Therapeutic Chemical Classification System is used for the classification of drugs It is controlled by the WHO Collaborating Centre for Drug A section of the Anatomical Therapeutic Chemical Classification System. PubChem is a Database of chemical Molecules The system is maintained by the National Center for Biotechnology Information (NCBI a component The DrugBank database available at the University of Alberta is a unique Bioinformatics and Cheminformatics resource that combines detailed drug (i A chemical formula is a way of expressing information about the Atoms that constitute a particular Chemical compound, and how the relationship between those atoms changes Carbon (kɑɹbən is a Chemical element with the symbol C and its Atomic number is 6 Hydrogen (ˈhaɪdrədʒən is the Chemical element with Atomic number 1 Oxygen (from the Greek roots ὀξύς (oxys (acid literally "sharp" from the taste of acids and -γενής (-genēs (producer literally begetteris the The molecular mass (abbreviated m of a substance, more commonly referred to as molecular weight and abbreviated as MW, is the Mass of one 10 g/mol (GHB)
126. 09 g/mol (sodium salt)
142. 19 g/mol (potassium salt)
Synonyms γ-Hydroxybutyric acid
gamma-Hydroxybutyrate
GHB
Pharmacokinetic data
Bioavailability 25% (oral)
Metabolism 95%, mainly Hepatic, also in blood and tissues
Half life 30 - 60 minutes
Excretion 5%, renal
Therapeutic considerations
Pregnancy cat.

B
Legal status

Prohibited (S9)(AU) Schedule III(CA) Class C(UK) Class B (NZ), Schedule I and III (US)
Routes Usually oral; intravenous

gamma-Hydroxybutyric acid (4-hydroxybutanoic acid, C4H8O3), commonly abbreviated GHB, is a naturally-occurring substance found in the central nervous system, wine, beef, small citrus fruits, and almost all animals in small amounts. This article deals with the general meaning of the term "synonym" In Pharmacology, bioavailability is used to describe the fraction of an administered Dose of unchanged drug that reaches the Systemic circulation, one of Drug metabolism is the Metabolism of drugs, their Biochemical modification or degradation usually through specialized enzymatic systems The liver is a vital organ in the human body and is present in Vertebrates and some other animals The biological half-life of a substance is the time it takes for a substance (drug radioactive nuclide or other to lose half of its pharmacologic physiologic or radiologic activity Excretion is the process of eliminating waste products of Metabolism and other non-useful materials The kidneys are complicated organs that have numerous biological roles The pregnancy category of a pharmaceutical agent is an assessment of the risk of fetal injury due to the pharmaceutical if it is used as directed by the mother during The regulation of therapeutic goods, that is drugs and therapeutic devices, varies by jurisdiction The Standard for the Uniform Scheduling of Drugs and Poisons, abbreviated SUSDP, is a document used in the regulation of drugs and poisons in Australia. For a topic outline on this subject see List of basic Australia topics. The Controlled Drugs and Substances Act is Canada 's federal drug control statute Country to "Dominion of Canada" or "Canadian Federation" or anything else please read the Talk Page The Misuse of Drugs Act 1971 (c38 is an Act of Parliament, by which the United Kingdom aims to control the possession and supply of numerous drugs The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom, the UK or Britain,is a Sovereign state located New Zealand is an Island country in the south-western Pacific Ocean comprising two main landmasses (the North Island and the South Island The Controlled Substances Act ( CSA) was enacted into law by the Congress of the United States as Title II of the Comprehensive Drug Abuse Prevention and Control The United States of America —commonly referred to as the In Pharmacology and Toxicology, a route Intravenous therapy or IV therapy is the giving of Liquid substances directly into a Vein. Metabolomics is the "systematic study of the unique chemical fingerprints that specific cellular processes leave behind" - specifically the study of their small-molecule metabolite In Vertebrates the central nervous system ( CNS) is the part of the Nervous system which is enclosed in the Meninges. [1] It is also a neuroprotective therapeutic nutrient that is confusingly categorized as an illegal drug in a number of countries. The term neuroprotection refers to mechanisms within the Nervous system which protect Neurons from Apoptosis or Degeneration, for example following Medication, also referred to as medicine, can be loosely defined as any substance intended for use in the diagnosis cure mitigation treatment or prevention of disease The illegal drug trade or drug trafficking is a global Black market consisting of the cultivation manufacture distribution and sale of illegal Drugs [2] It is currently regulated in the US and sold by Jazz Pharmaceuticals under the name Xyrem. This article describes the status of Xyrem as a prescription drug [3]

Historically, GHB has been used in a medical setting as a general anesthetic, to treat conditions such as insomnia, clinical depression, narcolepsy, and alcoholism, and to improve athletic performance. [4] It is also used illegally under the street names Juice, Liquid Ecstasy, Fantasy, Georgia Homeboy, Grevious Bodily Harm, and simply G In Northern Ireland it is often called Get Her bucked, although mainly said by teenagers, this is a derogatory term which can be seen as offensive, it is commonly used as either an intoxicant or as a date rape drug. The illegal drug trade or drug trafficking is a global Black market consisting of the cultivation manufacture distribution and sale of illegal Drugs Date rape drug refers to any drug that can be used to assist in the commission of a Sexual assault ( Date rape) GHB is naturally produced in the human body's cells and is structurally related to the ketone body beta-hydroxybutyrate. Ketone bodies are three water-soluble compounds that are produced as by-products when Fatty acids are broken down for energy in the Liver and beta -Hydroxybutyric acid ( beta -hydroxybutyrate or 3-hydroxybutyric acid is a Ketone body. As a supplement/drug, it is used most commonly in the form of a salt. [5] GHB is also produced as a result of fermentation, and so is found in small quantities in some beers and wines.

Contents

History

Synthesis of the chemical GHB was first reported in 1874 by Alexander Saytzeff,[6] but the first major research into its use in humans was conducted in the early 1960s by Dr. Henri Laborit to use in studying the neurotransmitter GABA. Henri Laborit ( November 21, 1914 - May 18, 1995) was a French physician writer and philosopher Gamma-aminobutyric acid (GABA is the chief inhibitory Neurotransmitter in the Mammalian Central nervous system. It quickly found a wide range of uses due to its minimal side-effects and short duration of action, the only difficulties being the narrow therapeutic dosage range (despite an unusually high LD50) and the dangers presented by its combination with alcohol and other central nervous system depressants. In Chemistry, an alcohol is any Organic compound in which a Hydroxyl group ( - O[[hydrogen H]]) is bound to a Carbon In Vertebrates the central nervous system ( CNS) is the part of the Nervous system which is enclosed in the Meninges.

GHB was widely used in France, Italy, and other European countries for several decades as a sleeping agent and an anesthetic in childbirth, but problems with its abuse potential and development of newer drugs have led to a decrease in legitimate medical use of GHB in recent times. The only common medical applications for GHB today are in the treatment of narcolepsy and more rarely alcoholism. Narcolepsy is a Neurological condition most characterized by Excessive Daytime Sleepiness (EDS in which a person falls asleep during the day at inappropriate In the typical scenario, GHB has been synthesized from gamma-butyrolactone (GBL) by adding sodium hydroxide (lye) in ethanol or water. gamma -Butyrolactone (γ-butyrolactone or GBL is a Hygroscopic colorless oily liquid with a weak characteristic Odor and is soluble in water Sodium hydroxide ( Na[[hydroxide OH]]) also known as Lye, caustic soda and (incorrectly according to IUPAC nomenclature As of late, GBL has become controlled and more circuitous routes have to be taken, such as those starting with tetrahydrofuran (THF). "THF" redirects here For other uses see THF (disambiguation.

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. Bindeez (also marketed as Aqua Dots, Beados, AquaBeads/アクアビーズ, and Pixos) are a children's Toy that was awarded Australian Metabolism is the set of Chemical reactions that occur in living Organisms in order to maintain Life. Three young children were hospitalized as a result of ingesting a large number of the beads, and the toy was recalled. [7]

Pharmacology

GHB has at least two distinct binding sites[8] in the central nervous system. In Vertebrates the central nervous system ( CNS) is the part of the Nervous system which is enclosed in the Meninges. GHB is an agonist at the newly-characterized GHB receptor, which is inhibitory,[9] [10] and it is a weak agonist at the GABAB receptor, which is also inhibitory. Gamma-hydroxybutyrate receptor or GHB receptor is a receptor that binds Gamma-Hydroxybutyric acid. An Inhibitory Postsynaptic Potential (commonly abbreviated as IPSP) is the change in membrane voltage of a postsynaptic Neuron which results from synaptic The GABA receptors are a class of receptors that respond to the Neurotransmitter γ-aminobutyric acid (GABA the chief inhibitory neurotransmitter in An Inhibitory Postsynaptic Potential (commonly abbreviated as IPSP) is the change in membrane voltage of a postsynaptic Neuron which results from synaptic [10] GHB is a naturally occurring substance which acts in a similar fashion to some neurotransmitters in the mammalian brain. See Chemical synapse for an introduction to concepts and terminology used in this article [11] GHB is probably synthesized from GABA in GABAergic neurons, and released when the neurons fire. Neurons (ˈnjuːɹɒn also known as neurones and nerve cells) are responsive cells in the Nervous system that process and transmit information [10]

If taken orally, GABA itself very poorly crosses the blood-brain-barrier, nor do high concentrations very effectively reach the GABA receptors once inside the brain. The blood-brain barrier (BBB is a metabolic or cellular structure in the Central nervous system (CNS that restricts the passage of various chemical substances and microscopic Since GABA is naturally synthesized in the brain, a higher than normal concentration would be quickly metabolized. [12]

However, at pharmacological doses, GHB reaches much higher concentrations in the brain and activates GABAB receptors, which are primarily responsible for its sedative effects. [13] GHB's sedative effects are blocked by GABAB antagonists.

The role of the GHB receptor in the behavioural effects induced by GHB is more complex. GHB receptors are densely expressed in many areas of the brain, including the cortex and hippocampus, and these are the receptors that GHB displays the highest affinity for. There has been somewhat limited research into the GHB receptor - however, there is evidence that activation of the GHB receptor in some brain areas results in the release of glutamate - the principle excitatory neurotransmitter. Glutamic acid (abbreviated as Glu or E) is one of the 20 Alpha Amino acids It is not among the human Essential amino acids Its [14] Drugs which selectively activate the GHB receptor cause absence seizures in high doses, as do GHB and GABA(B) agonists. Absence seizures are one of several kinds of Seizures These seizures are sometimes referred to as petit mal seizures (from the French for "little illness" [15]

Activation of both the GHB receptor and GABA(B) is responsible for the addictive profile of GHB. GHB's effect on dopamine release is biphasic,[16] low concentrations stimulate dopamine release via the GHB receptor. [17] Higher concentrations inhibit dopamine release via GABA(B) receptors as do other GABA(B) agonists such as baclofen and phenibut. Baclofen (brand names Kemstro and Lioresal) is a derivative of gamma-aminobutyric acid (GABA primarily used to treat Spasticity. Beta-phenyl-gamma-aminobutyric acid, better known as Phenibut or less commonly Fenibut or Phenybut, is natural derivative of the relaxing neurotransmitter [18] After the initial phase of inhibition, dopamine release is then increased via the GHB receptor. Both the inhibition and increase of dopamine release by GHB are inhibited by opioid antagonists such as naloxone and naltrexone. Naloxone is a drug used to counter the effects of Opioid overdose, for example Heroin or Morphine overdose Naltrexone is an Opioid receptor antagonist used primarily in the management of Alcohol dependence and Opioid dependence. Dynorphin may play a role in the inhibition of dopamine release via kappa opioid receptors. The κ-Opioid receptor is a type of Opioid receptor which binds the peptide opioid Dynorphin as the primary Endogenous ligand. [19]

This explains the paradoxical mix of sedative and stimulatory properties of GHB, as well as the so-called "rebound" effect, experienced by individuals using GHB as a sleeping agent, where they awake suddenly after several hours of GHB-induced deep sleep. That is to say, that over time, the concentration of GHB in the system decreases below the threshold for significant GABAB receptor activation and activates predominantly the GHB receptor, leading to wakefulness.

Recently, analogs of 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. 4-Hydroxy-4-methylpentanoic acid (UMB68 is an organic molecule similar in structure to the drug GHB. [20] Analogues of GHB such as 3-methyl-GHB, 4-methyl-GHB and 4-phenyl-GHB have been shown to produce similar effects to GHB in some animal studies, but these compounds are even less well researched than GHB itself. Of these analogues, only 4-methyl-GHB (gamma-hydroxyvaleric acid, GHV) and its prodrug form gamma-valerolactone (GVL) have been reported as drugs of abuse in humans, and on the available evidence seem to be less potent but more toxic than GHB, with a particular tendency to cause nausea and vomiting. gamma-Valerolactone is a Lactone chemically related to Gamma-butyrolactone.

Other prodrug ester forms of GHB have also rarely been encountered by law enforcement, including 1,4-diacetoxybutane, methyl-4-acetoxybutanoate and ethyl-4-acetoxybutanoate, but these are generally covered by analogue laws in jurisdictions where GHB is illegal, and little is known about them beyond their presumably delayed onset and longer duration of action. The intermediate compound 4-hydroxybutaldehyde is also a prodrug for GHB, however as with all aldehydes this compound is caustic and is strong-smelling and foul-tasting; actual use of this compound as an intoxicant is likely to be unpleasant and result in severe nausea and vomiting.

Image:GHB metab path.png

Also note that both of the metabolic breakdown pathways shown for GHB can run in either direction, depending on the concentrations of the substances involved, so the body can make its own GHB either from GABA or from succinic semialdehyde. Under normal physiological conditions, the concentration of GHB in the body is rather low, and the pathways would run in the reverse direction to what is shown here to produce endogenous GHB. However, when GHB is consumed for health promotion purposes (or abusively) its concentration in the body is much higher than normal, which changes the enzyme kinetics so that these pathways operate to metabolise GHB rather than producing it.

Medical uses

GHB has been used historically as a general anesthetic in the 1960s,[4] as a hypnotic in the treatment of insomnia, to treat depression, and to improve athletic performance. Anesthesia, or anaesthesia (see spelling differences; from Greek grc αν- an-, "without" and grc αἲσθησις For the state of mind see Hypnosis. Hypnotic drugs induce Sleep (which differentiates them from the Sedative Insomnia is a symptom of a sleeping disorder characterized by persistent difficulty falling asleep or staying asleep despite the opportunity Major depressive disorder, also known as major depression, unipolar depression, unipolar disorder, clinical depression, or simply depression 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. Alcoholism is a term with multiple and sometimes conflicting definitions [21] 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. Cataplexy is a medical condition which often affects people who have Narcolepsy, a disorder whose principal signsare EDS (Excessive Daytime Sleepiness sleep attacks sleep Narcolepsy is a Neurological condition most characterized by Excessive Daytime Sleepiness (EDS in which a person falls asleep during the day at inappropriate [22]

When GHB is used in its sodium or potassium salt form, a significant quantity of excess sodium or potassium may be consumed, which should be taken into consideration by people with heart conditions, hypertension or compromised renal function. The bioavailability of sodium GHB is considerably reduced when it is consumed with food, and so it is advised to wait at least two hours after eating before consuming the dose. In Pharmacology, bioavailability is used to describe the fraction of an administered Dose of unchanged drug that reaches the Systemic circulation, one of Because of its strong sedative effects, patients should not drive or operate heavy machinery for at least six hours after taking sodium GHB.

Adverse effects from Xyrem in clinical trials included: headache, nausea, dizziness, nasopharyngitis, somnolence, vomiting, urinary incontinence, confusion, dyspnea, hypoesthesia, paresthesia, tremor, vertigo, and blurred vision. Acute viral nasopharyngitis or acute coryza, usually known as the common cold, is a highly contagious viral Infectious disease of the Somnolence (or " drowsiness " is a state of near- Sleep, a strong desire for sleep or sleeping for unusually long periods (c Urinary incontinence ( UI) is any involuntary leakage of Urine. Dyspnea or dyspnoea (pronounced disp-nee-ah, IPA /dɪsp'niə/ from Latin dyspnoea, from Greek dyspnoia from Hypoesthesia refers to a reduced sense of Touch or sensation or a partial loss of sensitivity to sensory stimuli. Paresthesia (pron /ˌpɛɹɪsˈθiʒə/ paraesthesia in British English, pron Tremor is an unintentional somewhat rhythmic muscle movement involving to-and-from movements (oscillations of one or more parts of the body Vertigo (from the Latin vertere, to turn and the suffix -igo, a condition i Out of the 717 patients and 182 healthy volunteers who took part in the trials (899 total), two of them died from drug overdoses, although only one of these involved GHB. [23]

Non-medical use

gamma-hydroxybutyrate powder
gamma-hydroxybutyrate powder

GHB is a CNS depressant used as an intoxicant. Depressant is a chemical agent that diminishes the function or activity of a specific part of the body (see also Sedative) A psychoactive drug or psychotropic substance is a Chemical substance that acts primarily upon the Central nervous system where it alters Brain It has many street names, including Liquid Ecstasy and Liquid X. At recreational doses, GHB can cause a state of euphoria, increased enjoyment of movement and music, increased libido, increased sociability and intoxication. Euphoria is a medically recognized emotional state related to Pleasure and Happiness. Libido in its common usage means Sexual desire however more technical definitions such as those found in the work of Carl Jung, are more general referring to libido Intoxication is the state of being affected by one or more psychoactive drugs. At higher doses, GHB may induce nausea, dizziness, drowsiness, agitation, visual disturbances, depressed breathing, amnesia, unconsciousness, and death. Nausea ( Latin: Nausea, Greek:, " Sea-sickness " also called wamble) is the sensation of unease and discomfort Many different terms are often used to describe what is collectively known as dizziness. Somnolence (or " drowsiness " is a state of near- Sleep, a strong desire for sleep or sleeping for unusually long periods (c Breathing takes Oxygen in and Carbon dioxide out of the body Aerobic Organisms require oxygen to create energy via respiration, in Amnesia (from Greek) is a condition in which Memory is disturbed See also Unconscious mind. Unconsciousness, more appropriately referred to as loss of Consciousness or lack of consciousness is The effects of GHB can last from 1. 5 to 3 hours, or even longer if large doses have been consumed or if it is mixed with alcohol.

In general, the doses used recreationally are between 500 mg and 3000 mg, corresponding to approximately 0. 5–3 mL of liquid if the concentration is 1 gram / 1 mL (which is not always the case). When used as a recreational drug, GHB may be found as the sodium or potassium salt, which is a white crystalline powder, or as GHB salt dissolved in water to form a clear solution - generally at a concentration of 1 gram / 1 mL and so is twice the strength of the Xyrem solution sold legally for medical use. The sodium salt of GHB has a thin, very salty, chemical taste.

GHB salt dissolved in water is potentially dangerous, as the concentration of GHB may not be known, and so the actual dose of GHB being consumed can be difficult to judge accurately. Since GHB sold for recreational use is subject to no standardisation it can be impossible to verify the actual concentration of GHB solution bought on the illicit market. 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 chemicals convert to GHB in the stomach and blood. GBL, or gamma-butyrolactone, is one such prodrug. gamma -Butyrolactone (γ-butyrolactone or GBL is a Hygroscopic colorless oily liquid with a weak characteristic Odor and is soluble in water A prodrug is a pharmacological substance ( drug) that is administered in an inactive (or significantly less active form Other prodrugs include 1,4-butanediol. There may be additional toxicity concerns with these precursors. 1,4-B and GBL are normally found as pure liquids, although they may be mixed with other more harmful solvents when intended for industrial use, e. g. , as paint stripper or varnish thinner. Paint stripper, or paint remover, is the generic name given to Solvent mixtures designed to remove Paint and other finishes and also to clean the underlying

GHB can be produced in clandestine labs, and it is claimed that most of the GHB used in the US is illegally manufactured within its borders. While available as a prescription for sleep disorders in some other countries, GHB was banned (in the U. A sleep disorder (somnipathy is a medical disorder of the Sleep patterns of a person or animal S. ) by the FDA in 1990 because of the dangers associated with its use. However, on July 17, 2002 GHB was approved for treatment of cataplexy, often associated with narcolepsy. Events 180 - Twelve inhabitants of Scillium in North Africa are executed for being Christians See also 2002 (disambiguation Year 2002 ( MMII) was a Common year starting on Tuesday of the Gregorian calendar. GHB is "colourless and odorless". [24]

As a club scene or "rave" drug

Since the 1970s club scene, club-goers have used a range of drugs to enhance their experience on the dance floor such as amyl nitrite "poppers" and cocaine; in the 1990s, newer "club drugs" became popular, such as ketamine and Ecstasy (MDMA). Disco is a Genre of dance-oriented music whose origins are hard to define A discothèque, diskoˈtɛk̚ compare the Spanish "discoteca" is an Entertainment venue or Club with recorded music played by "Discaires" Poppers is the Street term for various Alkyl nitrites taken for recreational purposes through direct inhalation, particularly Amyl nitrite Cocaine ( benzoylmethyl ecgonine) is a Crystalline Tropane Alkaloid that is obtained from the leaves of the Coca plant Ketamine is a drug for use in human and veterinary medicine developed by Parke-Davis (today a part of Pfizer) in 1962 MDMA ( 34-methylenedioxy- N -methylamphetamine) most commonly known today by the street name Ecstasy (often abbreviated E, X, Like these other "club drugs," GHB is taken because users feel that it enhances the experience of being in a club or at a party; GHB is sometimes referred to as liquid ecstasy due to its tendency to produce euphoria and sociability and its use in the dance party scene.

As a date rape drug

The drug has been referred to in the media as a date rape drug, in much the same way as alcohol and Rohypnol. Date rape drug refers to any drug that can be used to assist in the commission of a Sexual assault ( Date rape) Flunitrazepam (ˌfluːnaɪˈtræzəpæm is a highly potent Hypnotic drug with powerful Sedative, Anxiolytic, Amnestic, and Skeletal As it is colourless and odorless,[24] it has been described as "very easy to add to drinks". [24] GHB has been used in cases of drug-related sexual assault, usually when the victim is vulnerable due to intoxication with a sedative, generally alcohol and as such are less likely to notice a strange taste to his or her drink. [25] However it is 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 not recall the rape until some time after this. [26] GHB, produced as a sodium salt (sodium oxybate), may provide a noticeable salty character to the drink, although individual sensitivity to the taste of salt varies[27]. GHB can also be produced as different salts, some of which may not have a taste as distinctive as the sodium salt (e. g. , magnesium oxybate), or much less commonly in the unstable free-acid form. [28]

Use by bodybuilders

Some athletes and bodybuilders also use GHB, as GHB has been shown to elevate human growth hormone in vivo. [29] The growth hormone elevating effects of GHB are mediated through muscarinic acetylcholine receptors and can be prevented by prior administration of pirenzepine, a muscarinic acetylcholine receptor blocking agent. [30]

As certain succinate salts have been shown to elevate growth hormone in vitro[31], being GHB is metabolized into succinate some people have suggested this may play a role in the growth hormone elevations from GHB. Succinic acid ( IUPAC Systematic name: butanedioic acid; historically known as spirit of amber) is a Dicarboxylic acid. In vitro ( Latin: within the glass refers to the technique of performing a given experiment in a controlled environment outside of a living Organism There is however currently no evidence to show that succinate plays any role in the growth hormone elevations from GHB.

Endogenous production by the body

Cells produce GHB by reduction of succinic semialdehyde. Succinic semialdehyde is a GABA analogue See also Succinic semialdehyde dehydrogenase deficiency 4-aminobutyrate This enzyme appears to be induced by cAMP levels[32], meaning substances that elevate cAMP, such as forskolin and vinpocetine, may increase GHB synthesis and release. Forskolin is a Labdane Diterpene that is produced by the Indian Coleus plant ( Coleus forskohlii) Vinpocetine (brand names Cavinton, Intelectol; chemical name ethyl apovincaminate) is a semisynthetic derivative alkaloid of Vincamine (sometimes 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. Succinic semialdehyde dehydrogenase deficiency (SSADHD also known as 4-hydoxybutyric aciduria or gamma-hydoxybutyric aciduria, is a rare Autosomal Succinic semialdehyde dehydrogenase deficiency (SSADHD also known as 4-hydoxybutyric aciduria or gamma-hydoxybutyric aciduria, is a rare Autosomal Urine is a liquid waste product of the body secreted by the Kidneys by a process of filtration from Blood and Excreted through the Urethra. Cerebrospinal fluid ( CSF) Liquor cerebrospinalis, is a clear Bodily fluid that occupies the Subarachnoid space and the Ventricular system [33]

The precise function of GHB in the body is not clear. It is known however that the brain expresses a large amount of receptors that are activated by GHB. [34] These receptors are excitatory and not responsible for the sedative effects of GHB - they have been shown to elevate the principle excitatory neurotransmitter - glutamate. Glutamic acid (abbreviated as Glu or E) is one of the 20 Alpha Amino acids It is not among the human Essential amino acids Its [14] The benzamide antipsychotics - amisulpride, sulpiride - have been shown to bind to this receptor in vivo[35]. Amisulpride (brand-name Solian) is an Antipsychotic drug sold by Sanofi-Aventis. Sulpiride (sold as Meresa, Sulpirid Ratiopharm, Sulpirid Neuraxpharm, Bosnyl, Dogmatil, Eglonyl, Sulpiryd Other antipsychotics were tested and were not found to have an affinity for this receptor.

It is a precursor to GABA, glutamate and glycine in certain brain areas. Gamma-aminobutyric acid (GABA is the chief inhibitory Neurotransmitter in the Mammalian Central nervous system. Glutamic acid (abbreviated as Glu or E) is one of the 20 Alpha Amino acids It is not among the human Essential amino acids Its Glycine (abbreviated as Gly or G) is the Organic compound with the formula NH2CH2COOH [36]

GHB has neuroprotective properties and has been found to protects cells from hypoxia. Chronic Hypoxia is a pathological condition in which the body as a whole ( generalized hypoxia) or region of the body ( tissue hypoxia) is deprived of adequate [37]

As a natural fermentation by-product

GHB is also produced as a result of fermentation and so is found in small quantities in some beers and wines, particularly fruit wines. However, the amount of GHB found in wine is insignificant and not sufficient to produce any effects. [38]

Dangers

As with pure alcohol, the dose-response curve of GHB 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. The Dose-response relationship describes the change in effect on an Organism caused by differing levels of Exposure (or Doses to a Stressor (usually Legal GHB comes in standardized doses and is free from contaminants, so it is much safer (cf. legal alcohol vs. bathtub gin). Bathtub gin refers to any style of homemade spirit made in amateur conditions Also, like pure alcohol, small doses of GHB are considered safe, but high doses can cause unconsciousness, convulsions, vomiting, suppression of the gag reflex, respiratory depression and death. See also Unconscious mind. Unconsciousness, more appropriately referred to as loss of Consciousness or lack of consciousness is An epileptic seizure is caused by excessive and/or hypersynchronous electrical Neuronal activity and is usually self-limiting Vomiting (also called throwing up, emesis) is the forceful expulsion of the contents of one's Stomach through the Mouth and sometimes the The pharyngeal reflex or gag reflex is a Reflex contraction of the back of the throat evoked by touching the Soft palate, that prevents something from In Medicine, hypoventilation (also known as respiratory depression) occurs when ventilation is inadequate ( hypo means "below" to perform needed Death is the termination of the biological functions that define living Organisms It refers both to a specific 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. Depressant is a chemical agent that diminishes the function or activity of a specific part of the body (see also Sedative) The benzodiazepines (pronounced, often abbreviated to "benzos") are a class of Psychoactive drugs with varying Hypnotic g. , diazepam), barbiturates, and others. Diazepam (daɪˈæzɨpæm first marketed as Valium by Hoffmann-La Roche, is a Benzodiazepine derivative Drug. Barbiturates are drugs that act as central nervous system Depressants and by virtue of this they produce a wide spectrum of effects from mild Sedation

Another complication is the difference in pharmacokinetics between GHB and its two prodrugs, 1,4-B and GBL. Pharmacokinetics (in Greek: “pharmacon” meaning drug and “kinetikos” meaning putting in motion the study of time dependency sometimes abbreviated as “PK” is a 1,4-B is converted into GHB in the body by two enzymes alcohol dehydrogenase and aldehyde dehydrogenase, which gives it a delayed onset of effects and a longer duration of action. Alcohol dehydrogenase (ADH is an enzyme discovered in the mid-1960s in Drosophila melanogaster. Aldehyde dehydrogenases, EC 1213, are a group of Enzymes that Catalyse the Oxidation (dehydrogenation of Aldehydes Mitochrondrial GHB is then further metabolised, again by alcohol dehydrogenase and aldehyde dehydrogenase, into the inactive succinate. Succinic acid ( IUPAC Systematic name: butanedioic acid; historically known as spirit of amber) is a Dicarboxylic acid.

If alcohol has also been consumed this can saturate the dehydrogenase enzymes and so delays the conversion of 1,4-B into GHB, meaning that 1,4-B takes much longer to take effect and people may re-dose thinking it hasn't done anything, leading to an accidental overdose later on once it finally takes effect. 1,4-B itself can also contribute to the enzyme saturation, so, when alcohol and 1,4-B are consumed together, it produces a complex and somewhat unpredictable interaction between the varying levels of alcohol, 1,4-B and GHB present in the body. Alcohol also makes the GHB last longer in the body by competing for dehydrogenase enzymes, and hence delaying the conversion of GHB into succinate.

The other precursor GBL is rapidly converted into GHB by lactamase enzymes found in the blood. Beta-lactamases are Enzymes ( produced by some bacteria and are responsible for their resistance to Beta-lactam antibiotics like Penicillins GBL is more lipophilic (fat soluble) than GHB, and so is absorbed faster and has higher bioavailability; the paradox is that this can mean that GBL has a faster onset of effects than GHB itself, even though it is a prodrug. A prodrug is a pharmacological substance ( drug) that is administered in an inactive (or significantly less active form The levels of lactamase enzyme can vary between individuals, and GBL is not active in its own right, so people who have never tried GBL before may have delayed or fewer effects than expected; however, once someone has taken GBL a few times, the production of lactamase enzymes is increased and he/she will feel the effects like normal.

Because of these pharmacokinetic differences, 1,4-B tends to be slightly less potent, slower to take effect but longer-acting than GHB, whereas GBL tends to be more potent and faster-acting than GHB, and has around the same duration.

Alcohol worsens both CNS depression and vomiting, so combining alcohol with GHB or its precursors can be particularly dangerous. Another factor to be considered is that people who drink alcohol regularly tend to induce expression of their dehydrogenase enzymes, and thus have higher levels of these enzymes than people that do not drink alcohol regularly; this means that regular alcohol drinkers will both convert 1,4-B into GHB more rapidly and also break down GHB into succinate faster than people that do not drink alcohol. This multitude of different factors can make the interactions between 1,4-B, GHB and alcohol very complicated and highly variable between different individuals.

Death while using GHB is most likely 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[39] 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. The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom, the UK or Britain,is a Sovereign state located [40]

Treatment of overdose

Overdose of GHB can be difficult to treat because of its multiple effects on the body. [41][42][4] 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 can induce bradycardia and consequent heart failure. In Medicine, hypoventilation (also known as respiratory depression) occurs when ventilation is inadequate ( hypo means "below" to perform needed Bradycardia, as applied to adult medicine is defined as a resting Heart rate of under 60 beats per minute though it is seldom symptomatic until the rate drops below 50 beat/min Because of the faster and more complete absorption of GBL relative to GHB, its dose-response curve is steeper, and overdoses of GBL tend to be more dangerous and problematic than overdoses involving only GHB or 1,4-B.

As well as causing these depressant effects, GHB overdose also often produces twitches or convulsions, especially when combined with stimulants such as amphetamines. Amphetamine, and related drugs such as Methamphetamine are a group of drugs that act by increasing levels of Norepinephrine, Serotonin, and Dopamine Also GHB tends to cause nausea and vomiting, particularly when combined with alcohol; so a patient may be simultaneously unconscious, vomiting, and convulsing.

The most likely risk of death from GHB overdose is inhalation of vomit while unconscious. This risk can be minimised by laying the patient down in the recovery position. The recovery position or more technically known as the lateral recumbent position is a First aid technique recommended for assisting people who are unconscious People are most likely to vomit as they become unconscious, and as they wake up. This is best managed in a hospital setting, but, if the patient is not in a hospital, it is very important that someone stays with the patient until he/she becomes fully unconscious, to keep the patient in the recovery position and to check how deeply unconscious the he/she becomes.

Then someone needs to stay with the patient in order to keep monitoring pulse and breathing rate. Finally, someone must stay with the patient until he fully wakes up. This is important, because people tend to become conscious enough to roll onto their backs just before they start to vomit again, but often while they are still too deeply unconscious to protect their own airway. This makes the period while people are waking up particularly dangerous.

Convulsions from GHB can be treated with diazepam or lorazepam, even though these are also CNS depressants they are GABAA agonists, whereas GHB is primarily a GABAB agonist, so the benzodiazepines do not worsen CNS depression as much as might be expected. Diazepam (daɪˈæzɨpæm first marketed as Valium by Hoffmann-La Roche, is a Benzodiazepine derivative Drug. Lorazepam (also known by its brand name Ativan or Temesta) is a Benzodiazepine drug with short to medium duration of action

Most stimulants are not effective at counteracting the unconsciousness from GHB, but intravenous injection of cholinergic drugs such as arecoline, neostigmine, and physostigmine can quickly reverse the effects of the GHB and cause rapid awakening; this can be dangerous, however, as these drugs lower the convulsion threshold and so can make convulsions worse. Arecoline is an Alkaloid -type natural product found in the Areca nut, the fruit of the areca palm ( Areca catechu) Neostigmine is a Parasympathomimetic, specifically a reversible Cholinesterase inhibitor. Physostigmine (also known as eserine from éséré West African name for the Calabar bean is a Parasympathomimetic, specifically a reversible Cholinesterase For this reason, these drugs are seldom used in most countries, although, in France and Italy where there is a much longer history of medical use of GHB, physostigmine treatment for GHB overdose is more common.

The best treatment of a more serious GHB overdose is co-administration of lorazepam with physostigmine, and the dose of both drugs must be carefully titrated to avoid worsening either the CNS depression or the convulsions. Overdoses with larger quantities of GHB or more particularly GBL (generally 10,000mg or more) can stop both heart and breathing.

It can be very dangerous to look after someone who is unconscious as a result of drug overdose if the attending party does not have proper medical training. When an individual presents with a suspected GHB overdose and is unconscious, the first priority should be to check their pulse and breathing. If the patient is taking less than 8 breaths per minute, and if his/her pulse is less than 60 a minute (both numbers are for adults), then the appropriate course of action is call an ambulance. CPR must not be used while the patient is still breathing and has a heart beat as this may cause considerable damage.

A newer synthetic drug SCH-50911, which acts as a selective GABAB antagonist, quickly reverses GHB overdose in mice. SCH-50911 is a selective GABAB antagonist developed by Schering-Plough Corporation [43] However this treatment has yet to be tried in humans, and it is unlikely that it will be researched for this purpose in humans due to the illegal and unethical nature of clinical trials of GHB, and the lack of medical indemnity coverage inherent in using an untested treatment for a life-threatening overdose.

Addiction

GHB can be physically addictive and may result in psychological addiction. The term " addiction " is used in many contexts to describe an obsession compulsion or excessive Physical dependence or psychological dependence such as 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 insomnia, restlessness, anxiety, tremors, sweating, loss of appetite, edginess, tachycardia, chest pain and tightness, muscle and bone aches, sensitivity to external stimuli (sound, light, touch), dysphoria, and mental dullness. Withdrawal, also known as withdrawal/abstinence syndrome, refers to the characteristic signs and symptoms that appear when a drug that causes Physical dependence is Insomnia is a symptom of a sleeping disorder characterized by persistent difficulty falling asleep or staying asleep despite the opportunity Anxiety is a physiological and psychological state characterized by Cognitive, Somatic, Emotional and Behavioral components Tremor is an unintentional somewhat rhythmic muscle movement involving to-and-from movements (oscillations of one or more parts of the body Dysphoria (from Greek δύσφορος (dysphoros from δυσ- difficult and φέρω to bear is generally characterized as an unpleasant or uncomfortable mood such as sadness These side-effects will subside after 2 - 21 days, depending on frequency of usage and the size of the doses used. In particularly severe cases, withdrawal from GHB may cause symptoms similar to acute withdrawal from alcohol or barbiturates (delirium tremens) and can cause convulsions and hallucinations. Delirium tremens (colloquially the DTs, " the horrors " " the fear "" the shakes "" jazz hands ""

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). [44]

Withdrawal

Withdrawal from GHB can be a life threatening condition. Treatment with benzodiazepines and other treatments is often ineffective. The benzodiazepines (pronounced, often abbreviated to "benzos") are a class of Psychoactive drugs with varying Hypnotic Evidence shows that baclofen is the most effective drug for GHB withdrawal. Baclofen (brand names Kemstro and Lioresal) is a derivative of gamma-aminobutyric acid (GABA primarily used to treat Spasticity. GHB and baclofen are agonists for the GABAb receptor. [45]

Legal status

In Hong Kong, GHB is regulated under Schedule 1 of Hong Kong's Chapter 134 Dangerous Drugs Ordinance. Hong Kong ( officially the Hong Kong Special Administrative Region, is a territory located on China 's south coast on the Pearl River Delta, and borders Hong Kong ( officially the Hong Kong Special Administrative Region, is a territory located on China 's south coast on the Pearl River Delta, and borders It can only be used legally by health professionals and for university research purposes. The substance can be given by pharmacists under a prescription. Anyone who supplies the substance without prescription can be fined $10000 (HKD). The penalty for trafficking or manufacturing the substance is a $5,000,000 (HKD) fine and life imprisonment. Possession of the substance for consumption without license from the Department of Health is illegal with a $1,000,000 (HKD) fine and/or 7 years of jail time.

In the United States it was placed on Schedule I of the Controlled Substances Act in March 2000 although when sold as Xyrem it is considered Schedule III, one of several drugs which is listed in multiple schedules. The Controlled Substances Act ( CSA) was enacted into law by the Congress of the United States as Title II of the Comprehensive Drug Abuse Prevention and Control This article describes the status of Xyrem as a prescription drug [46][2] On March 20, 2001, the Commission on Narcotic Drugs placed GHB in Schedule IV of the 1971 Convention on Psychotropic Substances. Events 1600 - The Linköping Bloodbath takes place on Maundy Thursday in Linköping, Sweden. Year 2001 ( MMI) was a Common year starting on Monday according to the Gregorian calendar. Commission on Narcotic Drugs is the central drug policy-making body within the United Nations system The Convention on Psychotropic Substances is a United Nations Treaty designed to control Psychoactive drugs such as Amphetamines Barbiturates [47] In the UK it was made a class C drug in June 2003.

In New Zealand and Australia, GHB, 1,4-B and GBL are all Class B illegal drugs, along with any possible esters, ethers and aldehydes. GABA itself is also listed as an illegal drug in these jurisdictions which seems unusual given its failure to cross the blood-brain barrier, but there was a perception among legislators that all known analogues should be covered as far as this was possible. Attempts to circumvent the illegal status of GHB have led to the sale of derivatives such as 4-methyl-GHB (gamma-hydroxyvaleric acid, GHV) and its prodrug form gamma-valerolactone (GVL), but these are also covered under the law by virtue of their being "substantially similar" to GHB or GBL and; so importation, sale, possession and use of these compounds is also considered to be illegal.

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. CSI Miami is a spin-off of the CBS network series. CSI Miami airs new episodes Mondays at 10 PM ET/PT on CBS. 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" GHB was used to drug Sarah McGee, Special Agent Timothy McGee's sister, into thinking that she committed a murder as a cover-up. NCIS, promoted as Navy NCIS in its first season aka Navy NCIS Naval Criminal Investigative Service or NCIS Naval Criminal 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. Veronica Mars is an American television series created by Rob Thomas. 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 what happened that night. 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. Veronica Mars is an American television series created by Rob Thomas.

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. Law & Order Special Victims Unit (also known as Law & Order SVU or simply SVU) is an American Drama In the Law & Order episode "Fools for Love," one of the victim's deaths is attributed to choking on vomit from a GHB overdose administered by her rapist/killer. Law & Order is an American Police procedural and Legal drama television series created by Dick Wolf.

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 had been slipped into an alcoholic beverage without her knowledge, and, as she feels the effects of the drug, her boyfriend implies that 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 1970s, see The Anti-Oedipus Papers (2006:308,326)

Near the end of the second season of the television series Everwood, leading character Amy Abbott is pressured into consuming a low dose of GHB dissolved in water with her then-boyfriend, allegedly-recovered addict Tommy Callahan. Pierre-Félix Guattari ( April 30, 1930 – August 29, 1992) was a French Militant, institutional Psychotherapist Anti-Œdipus (1972 is a book by the French Philosopher Gilles Deleuze and Psychoanalyst Félix Guattari. Everwood was a Prime time television Drama that aired in the United States on The WB. In a misguided effort to keep her from accidentally overdosing, he consumes most of the drugs before giving her the remainder, thus overdosing himself. Upon realizing he was unresponsive, Amy called her doctor father to come to his rescue, and, while they succeeded in saving Tommy's life, this encounter with the controlled substance ended their relationship.

An episode of the fifth series of Spooks shows Ros using a refined form of the drug to incapacitate targets for intelligence gathering. Spooks is a BAFTA award-winning British television drama series produced by the independent production company Kudos for BBC One

In the third episode of the American version of Queer as Folk, the character Ted falls into a coma after being given a large dose of GHB by a date he brings home. Queer as Folk is an American and Canadian Television series co-production produced by Showtime and Temple Street Productions

In the popular funk song "Party Song" by Brady's Bunch, GHB is referenced in a line: "A to the B to the C to the D to the E to the F to the GHB. " The song also references "Hangin' out with my Georgia Homeboy. "

In the song "What's Going On" by Zebrahead, found on their album Playmate of the Year (2000), GHB is referenced as a date rape drug: She takes another sip/ But has no clue of the spike from the G to the H to the B/ She wakes up in the morning/ bruised and raped in the street. Zebrahead is an Orange County California -based punk / rap band which was formed in La Habra, California. Playmate of the Year is Zebrahead 's third studio album and their last on Columbia Records. See also Types of rape The term "date rape" refers to the non-consensual Sexual activity between people who are known to each other either platonically GHB is referred to in the song Shores of California by The Dresden Dolls: And that is why the girl is called a tease / and that is why the guy is called a sleaze / and that's why God made escort agencies / one life to live and mace and GHB. " Shores of California " is the third single by The Dresden Dolls duo taken from the second studio album Yes Virginia The Dresden Dolls are an American musical duo from Boston Massachusetts.

On the Billy Idol album 'Cyberpunk' (1993), on the song 'Then the Night Comes', GHB is mentioned at 2:30 into the song, as follows. Billy Idol (born William Michael Albert Broad, 30 November 1955, Stanmore, Middlesex) is an English rock . . 'I take some GHB, I feel love, joy, And wonderful ringing music, Now, I just got to be me'. Following the album's release, he (Idol) almost died of a GHB overdose in 1994.

In The Anniversary, by Amy Gutman, GHB is referenced as a date rape drug. Amy Gutman (born 1960 is an American novelist Born in Ann Arbor Michigan, she graduated Harvard College magna cum laude, and thereafter became a journalist

Kansas City rapper Tech N9ne mentions GHB use multiple times on the song T9X on the album Absolute Power. Aaron Dontez Yates (born November 8 1971 in Kansas City Missouri) better known by his Stage name Tech N9ne (also Tech N9NE

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External links

The National Institute on Drug Abuse (NIDA is a United States federal-government research institute whose mission is to "lead the Nation in bringing the power of science
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