4-hydroxybutanoic acid (GHB or γ-Hydroxybutyric acid) – is a natural neurotransmitter of the central nervous system and also a psychoactive substance, which has depressive, sedative and euphorogenic properties. This substance has been known since the end of 19th century, but the first pooled study was published by Henri Laborti at the beginning of 1960, which consisted of the study of GABA receptors in an attempt to create an analogue of a total inhibitory neurotransmitter, which could pass through the blood-brain barrier. In May 1990 GHB was presented as a dietary supplement and was sold to bodybuilders as a weight control tool and as a sleeping drug, and also as L-tryptophan replacement. In November 1990 FDA published a statement warning regarding illegal status of GHB realization. In 2001, this substance was listed in Schedule IV of the 1971 Convention and was put under international control by the United Nations Commission on Narcotic Drugs. 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. GHB can also be formed as a result of fermentation, that is why it can be detected in small amounts in some kinds of beer and vine, fruit vine in particular. The amount of the substance present in vine is pharmacologically insignificant to induce psychoactive effects.
GHB is usually used in the form of a salt like sodium γ-hydroxybutyrate (NaGHB, sodium oxybate, or Xyrem) or potassium γ-hydroxybutyrate. The substance has a molecular formula C4H8O3, molecular weight 104.11 g/mol for acid, and 126.09 g/mol for salt solution. It has a melting point of 145-146 °C. The substance is well-soluble in water, alcohol and ether. The boiling point is about 180 °C, log Kow=(-0,40) при 25 °C, Hydroxyl radical reaction rate constant = 7.0X10-12 cu cm/molecule-sec at 25 °C. GHB is a naturally occurring short-chained fatty acid found in mammalian tissue. GHB is a hydroxycarboxylic acid, whose salts are also known as oxybates in pharmacy. GHB and GBL are subject to interconversion in aqueous media. GBL is converted to GHB via hydrolysis, whereas GHB is converted to GBL via intramolecular esterification, depending on solution pH and temperature. The salts of GHB are odourless and partly hygroscopic. Sodium oxybate has a distinctive salty taste. The synthesis process of GHB was first reported in 1874 by Alexander Zaytsev. According to the standard algorithm, GHB was synthesized from γ- butyrolactone (GBL) by adding sodium hydroxide to ethanol or water. Recently GHB has been under control in some countries, that is why more complicated ways of synthesis are used, e.g. starting from tetrahydrofuran (THF). GHB is synthesized in illegal laboratories by a number of various methods, for example, by transforming GBL into GHB at an alkaline pH. It requires adding sodium chloride or potassium chloride. There are a number of dangerous factors, which are associated with this reaction, particularly because this reaction is an exothermic one, and GBL is highly flammable. Moreover, commercially available household or industrial products, used for synthesis, are not intended for consumption and contain other potentially toxic substances, including heavy metals and other organic solvents, like acetone and tolyol. Use of these products as reagents can lead to serious toxicity, if the resulting product is impure.
Pharmacokinetics and pharmacodynamics.
GHB can pass through brain-blood barrier and synthesized in vivo as a product of GABA metabolism after GBL or 1,4-BD administration. This substance is metabolized through citric acid cycle with the formation of carbon dioxide and water. It can also activate the pentose phosphate pathway. GHB is absorbed and metabolized rapidly, half life period in plasma is about 20 minutes (following 12.5 mg/kg oral dose) and it has a steep curve "dose-response". In 1969 Roth and Giarman discovered that [3H]GABA turns into [3H]GHB through the formation of amber semi-aldehyde (intermediate compound) in brain tissue. This was confirmed by Anderson et al. The transformation is mediated by enzymes GABA aminotransferase and amber semi-aldehyde reductase. In human and pig brain this enzyme is dimeric (MR between 82,000 and 110,000 Da), while in rat and cattle brain it is present as monomeric protein. The enzyme is also localized in mitochondria, so it was assumed that mitochondria are the original place of GHB synthesis, with subsequent transfer to the cytosol. GHB is also synthesized after administration of γ-butyrolactone (GBL). GBL to GHB hydrolysis is mediated by lactonase in vivo. In whole blood of rats half-life of GBL is only one minute, moreover, serum is more active than plasma. It was found that the rat liver has significant activity of lactonase. However, it is absent in human cerebrospinal fluid. Muscle tissue can bind most of the starting GBL dose, delaying its transformation into GHB and increasing duration of action. Also, 1,4-BD is rapidly metabolized in GHB in natural conditions in a reaction, mediated by alcohol dehydrogenase (ADH).
It is assumed that GHB is metabolized through the formation of amber acid and citric acid cycle (TCA cycle/Krebs cycle), eventually producing carbon dioxide and water. GHB “directs” glucose-6-phosphate (G6P) to the pentose phosphate pathway (produces ribose for nucleic acid synthesis and NADPH). In acidic environment GHB can turn into lactone, GBL, and this process was used for gas chromatographic analysis of the substance. GBL wasn’t detected in plasma or urine, that is why it is assumed that in natural conditions this transformation doesn`t occur. GHB is rapidly absorbed in humans, concentration peak (Cmax) is reached in 20-60 minutes after administration (tmax = 20-60 min). As doses increase, a significant increase of tmax is observed with a slight change in the peak plasma concentration (Сmax). After administration of a dose of 12.5 mg/kg, elimination half-life was 20 minutes. Only 2-5% was excreted in urine unchanged. In a double-blind, randomized, cross-controlled trial “dose-response” it was revealed that mean peak concentrations of GHB in plasma were 79.1, 83.1, 113.5 and 130.1 mg/L after oral administrations of 40, 50, 60 and 72 mg/kg, respectively. Physiological and subjective effects, caused by GHB were dose-dependant, and also dependent on GHB concentration in plasma. After administration of 1,4-BD at a dose of 25 mg/kg maximum plasma concentration was 45.6 mg/l and was reached in 39.4 minutes since intake of 1,4-BD with elimination half-life, on average, of 32 minutes.
As it was mentioned earlier, GHB was first synthesized in 1960 in an attempt to study the effects of GABA and butyric acid and to synthesize a compound, which could prevent oxidation and could pass blood-brain barrier. Later, Bessman and Fishbein found out that GHB is an endogenous compound, which exists as a GABA metabolite. In the course of these studies, GHB was isolated from both rat and human brain. A lot of studies were carried out on its effects on various neurotransmitter systems. Even though these studies produced different results, the main data indicates the fact that GHB predominantly affects the dopaminergic system. Also, there can be concomitant increase in endogenous opioids release, for example, dynorphine. At relatively high doses of GHB, ACh level increases in certain areas of the brain. In works of Gessa GHB was administered to rabbits intravenously, and to rats intraperitoneally (from 250 to 2000 mg/kg). Results of the study showed that there was a slight increase in 5-HT and NA and also a significant increase in DA level in brain tissue (mainly in the caudate nucleus). Maximum increase in DA concentration was registered after 1-2 hours after administration of 2000 mg/kg with a subsequent gradual decline. DOPA causes a more significant increase of initial DA concentration in rat brain, and GHB causes a more stable increase. Joint administraton of these substances (DOPA 50 mg/kg i.v. and GHB 2000 mg/kg i.p.) causes further increase. GHB doesn't affect DOPA-decarboxylase. In view of the above, it can be concluded that GHB, apparently, is not a MAO inductor. GHB also indirectly reduces NDMA-receptor expression in the cortex, which determines its potential neurotoxicity, which causes spatial memory impairment with long-term use. As for the DA concentration in synapse change curve with GHB use, initially there is inhibition of DA release in synapse, and increase in DA production in neurons as well. Then, there is a dose-dependent stimulation of DA release. GHB doesn't have affinity to GABA receptors. In studies on GHB effects on specific GABA receptor, by means of NCS-382 it was determined that the highest concentration of GHB binding sites was in olfactory bulbs, hippocampus and cerebral cortex. The receptor itself is associated with the family of Gi- and Go-proteins. When it is activated, there is an increase in spontaneous excitation in the neurons of the prefrontal cortex. Considering the fact that NCS-382 suppresses this effect, it can be assumed that GHB binds to GHB-specific receptor, causing this response. Considering that DA slows prefrontal neuron activity, it can be assumed that GHB reduces DA levels, preventing inhibition of exicitation of prefrontal cortex neurons. In studies using CGP-35348, it was revealed that GABA receptor activation with GHB leads to hyperpolarization. Na-dependant transporter of GHB was discovered to eliminate it from synaptic cleft after the neuron release.
As for neuroendocrine properties of GHB, it is known that it significantly increases prolactine and growth hormone levels. Considering that DA suppresses prolactine production, there is GHB mediated decrease in DA levels, and the assumption is made that growth hormone increase is not directly connected to the inhibition. On the other hand, 5-HT stimulates prolactine and growth hormone secretion in rats and humans, that is why GHB can induce prolactine and growth hormone release by alteration of 5-HT release from nerve terminals. Also, GHB has a direct effect on neurons of hyppothalamus and stimulates the secretion of GH-releasing hormone. Slow-wave and rapid-eye- movement (REM) sleep, induced by GHB, is considered a period, when GH production is the highest. GHB also increases the threshold of pressure receptor sensitivity, without directly affecting chemoreceptors. It also has a strong hepatic and renal vasodilating effect, which indicates the fact that GHB has "anti-shock activity". In recent studies, it has been established that this substance doesn't have any negative effects while under anesthesia even in the absence of adequate neuroleptanalgesic premedication. However, sometimes there is a progressive hypertensive episode and a decrease in the amplitude of the T-wave (which is associated with a decrease in the level of potassium in the blood serum). It is proved in an experiment that GHB decreases cholesterol levels in blood. The results of GHB research in terms of its influence on electric activity by electroencephalogram (EEG) showed, that GHB use causes obvious epileptiform changes in the EEG (in animals), which are not observed in studies on human volunteers. Moreover, GHB controls convulsions, induced by chemical substances (ammonium chloride, strychnine, cardiazol and isoniazid). Based on behavioral and electroencephalographic criteria, it was determined that sleep, induced by GHB, is described as indistinguishable from natural sleep unlike coma, in which the 1-2-3-4-REM phases of sleep are disturbed. GHB enhances 3-4 stages (delta/slow-wave sleep), which are followed by REM-sleep. Sleep effects, enhanced by GHB, disappear in 3-4 hours at normal doses, without any side effects.
Clinical effects and dosage.
Subjective desirable positive effects of GHB include: psychostimulation at low doses, sedation in higher doses; muscle relaxation; cognitive euphoria comparable to that of cocaine, MDMA and small doses of opioid receptor agonists; the "disinhibition" effect, characterized by the user's tendency to engage in various kinds of "grandiose" actions, risky actions; affected dreams (increase in the duration of visual sleep, brightness and memorability of sleep); increased empathy, attachment and sociability; increased libido and music appreciation; increasing the level of introspection and insight; acceleration of thinking in small doses; visual distortion of perspective (dose-dependent effect), distortion of depth perception; auditory illusions and hallucinations. As for undesirable negative effects, they include: dose-dependent respiratory depression (up to the pathological type of Cheyne-Stokes breathing), dehydration, nausea, vomiting, hypersalivation, functional disorders of the gastrointestinal tract, headache, pupil dilation, spasms and convulsions, vasodilation, ejaculation disorder and orgasm disorder, decreased objective analysis, excitement and anxiety, short-term memory impairment up to amnesia (at high doses, absolute retrograde amnesia), auditory hallucinations. To avoid an overdose in order to prevent the occurrence of side effects, it is recommended to start by minimum dose, gradually increasing it by 10%.
Usually, GHB is used orally or intranasally by inhalation of powdery form of the substance. It is strongly not recommended for intravenous administration in form of a solution. The starting dose, associated with mild perceptible effects, range from 10-15 mg/kg. The user feels empathy, general cognitive load with positive effects, psychostimulation, mood improvement. Medium doses range from 15-20 mg/kg, and the upper bound of medium doses is about 30 mg/kg. Doses of 40 mg/kg and higher are considered as high. They are associated with pronounced side effects. Doses exceeding 60 mg/kg cause transient GHB-associated comatose state, which can last up ton a couple of hours. The time of onset of effects, when administered orally, ranges, on average, from 10 to 20 minutes and reaches its peak at 60 minutes. Total duration of action is about 3 hours. In case of an overdose, with the emergence of drug-induced sleep, it can last up to 6-7 hours depending on the dose. Nowadays, there is a medicament under the name of "Xyrem", which is taken before sleep, titrating the dose depending on the desired effect. It is usually taken at a dose of 4.5 grams half an hour before sleep, dividing the dose by 2.25 grams. GHB is also used for treatment of alcoholism at a dose 5 50-100 mg/kg a day (in 3 or more doses), and also for treatment of alcohol withdrawal.
Special instructions and other.
Studies on GHB toxicity show that it can induce coma, erratic clonic movements, decreased body temperature, hypotension, hallucinations, nausea, vomiting, bradycardia, respiratory depression and apnea. Other psychoactive substances can worsen these toxic effects. Studies on acute toxicity in humans showed that oral administration of GHB at a dose of 10 mg/kg unduced amnesia and hypotention. REM-sleep is caused by doses 20-30 mg/kg, this dose also can induce Cheyne-Stokes breathing. After GHB standard dose of 60 mg/kg, drowsiness occurs after 5 minutes, after that comatose state, which lasts for 1-2 hours then, a sudden awakening. Duration of the coma can be up to 4-6 hours. In studies of Helrich it was revealed that concentration of the substance in plasma, exceeding 260 mg/L, is associated with deep sleep, 52-160 mg/L with light sleep, concentration less than 52 mg/L with wakefulness. A lot of agents were tried against the clinical effects of GHB. Generally accepted medicine for treatment of comatose state (for example, naloxone or flumazenil) weren't effective. Moreover, various anticonvulsant agents (e.g. ethosuximide, sodium valproate, clonazepam, diazepam, L- dopa, phenobarbital) do not have any effect whatsoever, neither do gastric lavage, activated charcoal and other absorbents. That is why GHB toxicity treatment mainly includes supportive and symptomatic measures, sometimes artificial ventilation of the lungs through an intubation tube is used. However, a user usually regains consciousness after about seven hours.
Last edited by a moderator: