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GHB: Difference between revisions
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==Pharmacology== | ==Pharmacology== | ||
GHB has at least two distinct binding sites<ref>{{cite journal | vauthors=((Mamelak, M.)) | journal=Neuroscience & Biobehavioral Reviews | title=Gammahydroxybutyrate: An endogenous regulator of energy metabolism | volume=13 | issue=4 | pages=187–198 | date=1 December 1989 | url=https://www.sciencedirect.com/science/article/pii/S0149763489800533 | issn=0149-7634 | doi=10.1016/S0149-7634(89)80053-3}}</ref> in the central nervous system. GHB is an [[agonist]] at the newly characterized GHB receptor, which is excitatory.<ref>{{cite journal | vauthors=((Wu, Y.)), ((Ali, S.)), ((Ahmadian, G.)), ((Liu, C. C.)), ((Wang, Y. T.)), ((Gibson, K. M.)), ((Calver, A. R.)), ((Francis, J.)), ((Pangalos, M. N.)), ((Carter Snead, O.)) | journal=Neuropharmacology | title=γ-Hydroxybutyric acid (GHB) and γ-aminobutyric acidB receptor (GABABR) binding sites are distinctive from one another: molecular evidence | volume=47 | issue=8 | pages=1146–1156 | date=1 December 2004 | url=https://www.sciencedirect.com/science/article/pii/S0028390804002527 | issn=0028-3908 | doi=10.1016/j.neuropharm.2004.08.019}}</ref><ref name="Maitre2005">{{cite journal | vauthors=((Maitre, M.)), ((Humbert, J.-P.)), ((Kemmel, V.)), ((Aunis, D.)), ((Andriamampandry, C.)) | journal=médecine/sciences | title=Mécanismes d’action d’un médicament détourné : le γ-hydroxybutyrate | volume=21 | issue=3 | pages=284–289 | date=1 March 2005 | url=https://www.medecinesciences.org/articles/medsci/abs/2005/03/medsci2005213p284/medsci2005213p284.html | issn=0767-0974 | doi=10.1051/medsci/2005213284}}</ref> It is also a weak [[agonist]] at the [[GABA]]<sub>B</sub> receptor, which is inhibitory.<ref name="Maitre2005"/> | GHB has at least two distinct binding sites<ref>{{cite journal | vauthors=((Mamelak, M.)) | journal=Neuroscience & Biobehavioral Reviews | title=Gammahydroxybutyrate: An endogenous regulator of energy metabolism | volume=13 | issue=4 | pages=187–198 | date=1 December 1989 | url=https://www.sciencedirect.com/science/article/pii/S0149763489800533 | issn=0149-7634 | doi=10.1016/S0149-7634(89)80053-3}}</ref> in the central nervous system. GHB is an [[agonist]] at the newly characterized GHB receptor, which is excitatory.<ref>{{cite journal | vauthors=((Wu, Y.)), ((Ali, S.)), ((Ahmadian, G.)), ((Liu, C. C.)), ((Wang, Y. T.)), ((Gibson, K. M.)), ((Calver, A. R.)), ((Francis, J.)), ((Pangalos, M. N.)), ((Carter Snead, O.)) | journal=Neuropharmacology | title=γ-Hydroxybutyric acid (GHB) and γ-aminobutyric acidB receptor (GABABR) binding sites are distinctive from one another: molecular evidence | volume=47 | issue=8 | pages=1146–1156 | date=1 December 2004 | url=https://www.sciencedirect.com/science/article/pii/S0028390804002527 | issn=0028-3908 | doi=10.1016/j.neuropharm.2004.08.019}}</ref><ref name="Maitre2005">{{cite journal | vauthors=((Maitre, M.)), ((Humbert, J.-P.)), ((Kemmel, V.)), ((Aunis, D.)), ((Andriamampandry, C.)) | journal=médecine/sciences | title=Mécanismes d’action d’un médicament détourné : le γ-hydroxybutyrate | volume=21 | issue=3 | pages=284–289 | date=1 March 2005 | url=https://www.medecinesciences.org/articles/medsci/abs/2005/03/medsci2005213p284/medsci2005213p284.html | issn=0767-0974 | doi=10.1051/medsci/2005213284}}</ref> It is also a weak [[agonist]] at the [[GABA]]<sub>B</sub> receptor, which is inhibitory.<ref name="Maitre2005" /> | ||
However, at therapeutic doses, GHB reaches much higher concentrations in the brain and activates [[GABA]]<sub>B</sub> receptors, which are primarily responsible for its sedative effects.<ref name="Dimitrijevic2005">{{cite journal | vauthors=((Dimitrijevic, N.)), ((Dzitoyeva, S.)), ((Satta, R.)), ((Imbesi, M.)), ((Yildiz, S.)), ((Manev, H.)) | journal=European Journal of Pharmacology | title=Drosophila GABAB receptors are involved in behavioral effects of γ-hydroxybutyric acid (GHB) | volume=519 | issue=3 | pages=246–252 | date=20 September 2005 | url=https://www.sciencedirect.com/science/article/pii/S0014299905007442 | issn=0014-2999 | doi=10.1016/j.ejphar.2005.07.016}}</ref> GHB's sedative effects are blocked by GABA<sub>B</sub> [[antagonists]]. As the [[GABA]] system is the most prolific inhibitory receptor set within the brain, its modulation results in the [[sedating]] (or [[anxiety suppression|calming effects]]) of GHB on the nervous system. While research into the GHB receptor is limited, there is evidence that activation of the GHB receptor in some brain areas results in the release of [[glutamate]], the principal excitatory neurotransmitter.<ref name="Castelli2003">{{cite journal | vauthors=((Castelli, M. P.)), ((Ferraro, L.)), ((Mocci, I.)), ((Carta, F.)), ((Carai, M. A. M.)), ((Antonelli, T.)), ((Tanganelli, S.)), ((Cignarella, G.)), ((Gessa, G. L.)) | journal=Journal of Neurochemistry | title=Selective γ-hydroxybutyric acid receptor ligands increase extracellular glutamate in the hippocampus, but fail to activate G protein and to produce the sedative/hypnotic effect of γ-hydroxybutyric acid: γ-Hydroxybutyric analogues on glutamate levels | volume=87 | issue=3 | pages=722–732 | date=19 September 2003 | url=http://doi.wiley.com/10.1046/j.1471-4159.2003.02037.x | issn=00223042 | doi=10.1046/j.1471-4159.2003.02037.x}}</ref> Drugs that selectively activate the GHB receptor cause absence seizures in high doses, as do GHB and [[GABA]]<sub>B</sub> agonists.<ref name="Castelli2003"/> | However, at therapeutic doses, GHB reaches much higher concentrations in the brain and activates [[GABA]]<sub>B</sub> receptors, which are primarily responsible for its sedative effects.<ref name="Dimitrijevic2005">{{cite journal | vauthors=((Dimitrijevic, N.)), ((Dzitoyeva, S.)), ((Satta, R.)), ((Imbesi, M.)), ((Yildiz, S.)), ((Manev, H.)) | journal=European Journal of Pharmacology | title=Drosophila GABAB receptors are involved in behavioral effects of γ-hydroxybutyric acid (GHB) | volume=519 | issue=3 | pages=246–252 | date=20 September 2005 | url=https://www.sciencedirect.com/science/article/pii/S0014299905007442 | issn=0014-2999 | doi=10.1016/j.ejphar.2005.07.016}}</ref> GHB's sedative effects are blocked by GABA<sub>B</sub> [[antagonists]]. As the [[GABA]] system is the most prolific inhibitory receptor set within the brain, its modulation results in the [[sedating]] (or [[anxiety suppression|calming effects]]) of GHB on the nervous system. While research into the GHB receptor is limited, there is evidence that activation of the GHB receptor in some brain areas results in the release of [[glutamate]], the principal excitatory neurotransmitter.<ref name="Castelli2003">{{cite journal | vauthors=((Castelli, M. P.)), ((Ferraro, L.)), ((Mocci, I.)), ((Carta, F.)), ((Carai, M. A. M.)), ((Antonelli, T.)), ((Tanganelli, S.)), ((Cignarella, G.)), ((Gessa, G. L.)) | journal=Journal of Neurochemistry | title=Selective γ-hydroxybutyric acid receptor ligands increase extracellular glutamate in the hippocampus, but fail to activate G protein and to produce the sedative/hypnotic effect of γ-hydroxybutyric acid: γ-Hydroxybutyric analogues on glutamate levels | volume=87 | issue=3 | pages=722–732 | date=19 September 2003 | url=http://doi.wiley.com/10.1046/j.1471-4159.2003.02037.x | issn=00223042 | doi=10.1046/j.1471-4159.2003.02037.x}}</ref> Drugs that selectively activate the GHB receptor cause absence seizures in high doses, as do GHB and [[GABA]]<sub>B</sub> agonists.<ref name="Castelli2003" /> | ||
Activation of both the GHB receptor and [[GABA]]<sub>B</sub> is responsible for the addictive profile of GHB. GHB's effect on [[dopamine]] release is biphasic.<ref name="Dimitrijevic2005"/> This means that while low concentrations stimulate [[dopamine]] release via the GHB receptor,<ref>{{cite journal | vauthors=((Maitre, M.)), ((Hechler, V.)), ((Vayer, P.)), ((Gobaille, S.)), ((Cash, C. D.)), ((Schmitt, M.)), ((Bourguignon, J. J.)) | journal=The Journal of Pharmacology and Experimental Therapeutics | title=A specific gamma-hydroxybutyrate receptor ligand possesses both antagonistic and anticonvulsant properties | volume=255 | issue=2 | pages=657–663 | date= November 1990 | issn=0022-3565}}</ref> higher concentrations inhibit [[dopamine]] release via [[GABA]]<sub>B</sub> receptors.<ref>{{cite journal | vauthors=((Smolders, I.)), ((De Klippel, N.)), ((Sarre, S.)), ((Ebinger, G.)), ((Michotte, Y.)) | journal=European Journal of Pharmacology | title=Tonic GABA-ergic modulation of striatal dopamine release studied by in vivo microdialysis in the freely moving rat | volume=284 | issue=1 | pages=83–91 | date=15 September 1995 | url=https://www.sciencedirect.com/science/article/pii/001429999500369V | issn=0014-2999 | doi=10.1016/0014-2999(95)00369-V}}</ref> After an initial phase of inhibition, [[dopamine]] release is then increased via the GHB receptor. | Activation of both the GHB receptor and [[GABA]]<sub>B</sub> is responsible for the addictive profile of GHB. GHB's effect on [[dopamine]] release is biphasic.<ref name="Dimitrijevic2005" /> This means that while low concentrations stimulate [[dopamine]] release via the GHB receptor,<ref>{{cite journal | vauthors=((Maitre, M.)), ((Hechler, V.)), ((Vayer, P.)), ((Gobaille, S.)), ((Cash, C. D.)), ((Schmitt, M.)), ((Bourguignon, J. J.)) | journal=The Journal of Pharmacology and Experimental Therapeutics | title=A specific gamma-hydroxybutyrate receptor ligand possesses both antagonistic and anticonvulsant properties | volume=255 | issue=2 | pages=657–663 | date= November 1990 | issn=0022-3565}}</ref> higher concentrations inhibit [[dopamine]] release via [[GABA]]<sub>B</sub> receptors.<ref>{{cite journal | vauthors=((Smolders, I.)), ((De Klippel, N.)), ((Sarre, S.)), ((Ebinger, G.)), ((Michotte, Y.)) | journal=European Journal of Pharmacology | title=Tonic GABA-ergic modulation of striatal dopamine release studied by in vivo microdialysis in the freely moving rat | volume=284 | issue=1 | pages=83–91 | date=15 September 1995 | url=https://www.sciencedirect.com/science/article/pii/001429999500369V | issn=0014-2999 | doi=10.1016/0014-2999(95)00369-V}}</ref> After an initial phase of inhibition, [[dopamine]] release is then increased via the GHB receptor. | ||
GHB induces the accumulation of either a derivative of tryptophan or [[tryptophan]] itself, possibly by increasing tryptophan transport across the blood–brain barrier. | GHB induces the accumulation of either a derivative of tryptophan or [[tryptophan]] itself, possibly by increasing tryptophan transport across the blood–brain barrier. GHB-induced stimulation may be due to this increase in tryptophan transport to the brain and in its uptake by serotonergic cells. As the [[Serotonin|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. | ||
These findings may explain the paradoxical mix of sedative and stimulatory properties of GHB as well as the so-called "rebound" effect reported by individuals using GHB as a sleeping agent wherein they awake suddenly after several hours of GHB-induced deep sleep. Over time, the concentration of GHB in the system decreases below the threshold for significant [[GABA]]<sub>B</sub> receptor activation and activates predominantly the GHB receptor, leading to wakefulness. | These findings may explain the paradoxical mix of sedative and stimulatory properties of GHB as well as the so-called "rebound" effect reported by individuals using GHB as a sleeping agent wherein they awake suddenly after several hours of GHB-induced deep sleep. Over time, the concentration of GHB in the system decreases below the threshold for significant [[GABA]]<sub>B</sub> receptor activation and activates predominantly the GHB receptor, leading to wakefulness. | ||
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One study found that repeated administration of GHB to rats for 15 days drastically reduced the number of neurons and non-neuronal cells within the hippocampus and in the prefrontal cortex. With doses of 10 mg/kg of GHB, they were decreased by 61% in the hippocampus region and 32% in the prefrontal cortex, and with 100 mg/kg, they were decreased by 38% and 9%, respectively. This paper demonstrates contradicting effects on neuronal loss, with lower doses (10 mg/kg) producing the most neurotoxicity, and higher doses (100 mg/kg) producing less. | One study found that repeated administration of GHB to rats for 15 days drastically reduced the number of neurons and non-neuronal cells within the hippocampus and in the prefrontal cortex. With doses of 10 mg/kg of GHB, they were decreased by 61% in the hippocampus region and 32% in the prefrontal cortex, and with 100 mg/kg, they were decreased by 38% and 9%, respectively. This paper demonstrates contradicting effects on neuronal loss, with lower doses (10 mg/kg) producing the most neurotoxicity, and higher doses (100 mg/kg) producing less. | ||
In spite of its demonstrated neurotoxicity, GHB has neuroprotective properties, and has been found to protect cells from hypoxia. <ref>Ottani A, Saltini S, Bartiromo M, Zaffe D, Renzo Botticelli A, Ferrari A, et al. (October 2003). "Effect of gamma-hydroxybutyrate in two rat models of focal cerebral damage". ''Brain Research''. '''986''' (1–2): 181–90. [[wikipedia:Digital_object_identifier|doi]]:[https://doi.org/10.1016%2FS0006-8993%2803%2903252-9 10.1016/S0006-8993(03)03252-9] [https://en.wikipedia.org/wiki/PMID_(identifier) PMID] [https://pubmed.ncbi.nlm.nih.gov/12965243/ 12965243] [https://en.wikipedia.org/wiki/S2CID_(identifier) S2CID] [https://api.semanticscholar.org/CorpusID:54374774 54374774]</ref> | |||
===Overdose=== | ===Overdose=== | ||
To avoid a possible overdose of GHB, it is important to start with a low dose and work your way up slowly by increasing the dosage in small increments. While a common recreational dose is 3g, a dose of 5g - 10g can result in convulsions, unconsciousness and vomiting. [[toxicity::Doses above 10 grams are associated with a risk of death]].<ref name="ErowidGHBVault"/> One must also factor in the added difficulty of knowing the purity of the product (among other problems like its hygroscopy may lower the concentration of GHB in one solution, which is the form which is commonly bought and sold in the illicit market). This makes it hard for even the experienced user to dose properly.<ref>https://www.erowid.org/chemicals/ghb/ghb_health.shtml</ref> | To avoid a possible overdose of GHB, it is important to start with a low dose and work your way up slowly by increasing the dosage in small increments. While a common recreational dose is 3g, a dose of 5g - 10g can result in convulsions, unconsciousness and vomiting. [[toxicity::Doses above 10 grams are associated with a risk of death]].<ref name="ErowidGHBVault" /> One must also factor in the added difficulty of knowing the purity of the product (among other problems like its hygroscopy may lower the concentration of GHB in one solution, which is the form which is commonly bought and sold in the illicit market). This makes it hard for even the experienced user to dose properly.<ref>https://www.erowid.org/chemicals/ghb/ghb_health.shtml</ref> | ||
===Tolerance and addiction potential=== | ===Tolerance and addiction potential=== | ||
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*'''Norway:''' GHB is considered a narcotic and is only available by prescription under the trade name Xyrem.{{citation needed}} | *'''Norway:''' GHB is considered a narcotic and is only available by prescription under the trade name Xyrem.{{citation needed}} | ||
*'''Switzerland:''' GHB is a controlled substance specifically named under Verzeichnis A. Medicinal use is permitted.<ref>{{cite web|url=https://www.admin.ch/opc/de/classified-compilation/20101220/index.html|title=Verordnung des EDI über die Verzeichnisse der Betäubungsmittel, psychotropen Stoffe, Vorläuferstoffe und Hilfschemikalien|publisher=Bundeskanzlei [Federal Chancellery of Switzerland]|access-date=January 1, 2020|language=de}}</ref> | *'''Switzerland:''' GHB is a controlled substance specifically named under Verzeichnis A. Medicinal use is permitted.<ref>{{cite web|url=https://www.admin.ch/opc/de/classified-compilation/20101220/index.html|title=Verordnung des EDI über die Verzeichnisse der Betäubungsmittel, psychotropen Stoffe, Vorläuferstoffe und Hilfschemikalien|publisher=Bundeskanzlei [Federal Chancellery of Switzerland]|access-date=January 1, 2020|language=de}}</ref> | ||
*'''United Kingdom:''' GHB was made a Class C drug in June 2003.{{citation needed}} | *'''United Kingdom:''' GHB was made a Class C drug in June 2003.{{citation needed}} | ||
*'''United States:''' GHB was placed on Schedule I of the Controlled Substances Act in March 2000. However, when sold as sodium oxybate, it is considered a Schedule III substance but with Schedule I trafficking penalties.<ref>{{Citation | year=2010 | title=Laws | url=http://web.archive.org/web/20100116121252/http://www.projectghb.org/laws.htm}}</ref> It is one of several drugs that are listed in multiple schedules. | *'''United States:''' GHB was placed on Schedule I of the Controlled Substances Act in March 2000. However, when sold as sodium oxybate, it is considered a Schedule III substance but with Schedule I trafficking penalties.<ref>{{Citation | year=2010 | title=Laws | url=http://web.archive.org/web/20100116121252/http://www.projectghb.org/laws.htm}}</ref> It is one of several drugs that are listed in multiple schedules. | ||