and so do not worsen cns depression as much as might be expected. 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. any ghb/gbl overdose is a medical emergency and should be cared for by appropriately trained personnel. a newer synthetic drug sch-50911, which acts as a selective gabab antagonist, quickly reverses ghb overdose in mice. 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 nature of clinical trials of ghb and the lack of medical indemnity coverage inherent in using an untested treatment for a life-threatening overdose. detection of use ghb may be quantitated in blood or plasma to confirm a diagnosis of poisoning in hospitalized patients, to provide evidence in an impaired driving, or to assist in a medicolegal death investigation. blood or plasma ghb concentrations are usually in a range of 50–250 mg/l in persons receiving the drug therapeutically (during general anesthesia), 30–100 mg/l in those arrested for impaired driving, 50–500 mg/l in acutely intoxicated patients and 100–1000 mg/l in victims of fatal overdosage. urine is often the preferred specimen for routine drug abuse monitoring purposes. both γ-butyrolactone (gbl) and 1,4-butanediol are converted to ghb in the body. in january 2016, it was announced scientists had developed a way to detect ghb, among other things, in saliva. endogenous production cells produce ghb by reduction of succinic semialdehyde via succinic semialdehyde reductase (ssr). this enzyme appears to be induced by camp levels, 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. 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. 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. 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. the benzamide antipsychotics—amisulpride, nemonapride, etc.—have been shown to bind to these ghb-activated receptors in vivo. 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. in spite of its demonstrated neurotoxicity, (see relevant section, above), ghb has neuroprotective properties, and has been found to protect cells from hypoxia. 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, in particular fruit wines. the amount found in wine is pharmacologically insignificant and not sufficient to produce psychoactive effects. pharmacology ghb has at least two distinct binding sites in the central nervous system. ghb acts as an agonist at the inhibitory ghb receptor and as a weak agonist at the inhibitory gabab receptor. ghb is a naturally occurring substance that acts in a similar fashion to some neurotransmitters in the mammalian brain. ghb is probably synthesized from gaba in gabaergic neurons, and released when the neurons fire. ghb has been found to activate oxytocinergic neurons in the supraoptic nucleus. if taken orally, gaba itself does not effectively cross the blood–brain barrier. ghb induces the accumulation of either a derivative of tryptophan or tryptophan itself in the extracellular space, possibly by increasing tryptophan transport across the blood–brain barrier. the blood content of certain neutral amino-acids, including tryptophan, is also increased by peripheral ghb administration. ghb-induced stimulation of tissue serotonin turnover may be due to an increase in tryptophan transport to the brain and in its uptake by serotonergic cells. as the serotonergic system may be involved in the regulation of sleep, mood, and anxiety, the stimulation of this system by high doses of ghb may be involved in certain neuropharmacological events induced by ghb administration. however, at therapeutic doses, ghb reaches much higher concentrations in the brain and activates gabab receptors, which are primarily responsible for its sedative effects. 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 principal excitatory neurotransmitter. drugs that selectively activate the ghb receptor cause absence seizures in high doses, as do ghb and gabab agonists. activation of both the ghb receptor and gabab is responsible for the addictive profile of ghb. ghb's effect on dopamine release is biphasic. low concentrations stimulate dopamine release via the ghb receptor. higher concentrations inhibit dopamine release via gabab receptors as do other gabab agonists such as baclofen and phenibut. after an 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. dynorphin may play a role in the inhibition of dopamine release via kappa opioid receptors. 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, wherein 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 (umb68) have been synthesised and tested on animals, in order to gain a better understanding of ghb's mode of action. 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 (γ-hydroxyvaleric acid, ghv) and a prodrug form γ-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. other prodrug ester forms of ghb have also rarely been encountered by law enforcement, including 1,4-butanediol diacetate (bdda/dabd), methyl-4-acetoxybutanoate (mab), and ethyl-4-acetoxybutanoate (eab), but these are, in general, covered by analogue laws in jurisdictions where ghb is illegal, and little is known about them beyond their delayed onset and longer duration of action. the intermediate compound γ-hydroxybutyraldehyde (ghbal) is also a prodrug for ghb; however, as with all aliphatic 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. metabolic pathway of ghb 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 recreational or health promotion purposes, 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. history alexander zaytsev worked on this chemical family and published work on it in 1874. 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.: 11–12 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.: 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.: 27–28 it was also studied to treat alcohol addiction; while the evidence for this use is weak,: 28–29 however sodium oxybate is marketed for this use in italy. ghb and sodium oxybate were also studied for use in narcolepsy from the 1960s onwards.: 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 were found to cause eosinophilia-myalgia syndrome, although eosinophilia-myalgia syndrome is also tied to tryptophan overload. in 2001 tryptophan supplement sales were allowed to resume, and in 2005 the fda ban on tryptophan supplement importation was lifted. 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. the fda issued a warning in november 1990 that sale of ghb was illegal. 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. 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.: 18–25, 28 : 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. legal status ghb sold in italy for therapeutic use in the united states, ghb was placed on schedule i of the controlled substances act in march 2000. however, used in sodium oxybate under an ind or nda from the us fda, it is considered a schedule iii substance but with schedule i trafficking penalties, one of several drugs that are listed in multiple schedules. on 20 march 2001, the un commission on narcotic drugs placed ghb in schedule iv of the 1971 convention on psychotropic substances. in the uk ghb was made a class c drug in june 2003. in october 2013 the acmd recommended upgrading it from schedule iv to schedule ii in line with un recommendations. their report concluded that the minimal use of xyrem in the uk meant that prescribers would be minimally inconvenienced by the rescheduling. this advice was followed and ghb was moved to schedule 2 on 7 january 2015. in hong kong, ghb is regulated under schedule 1 of hong kong's chapter 134 dangerous drugs ordinance. 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 hk$10,000. the penalty for trafficking or manufacturing the substance is a hk$150,000 fine and life imprisonment. possession of the substance for consumption without license from the department of health is illegal with a hk$100,000 fine or five years of jail time.