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Metizolam: Difference between revisions
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'''Metizolam''' (also known as '''Desmethyletizolam''') is a synthetic [[psychoactive class::depressant]] of the [[chemical class::thienodiazepine]] chemical class that reportedly produces [[etizolam]]-like effects such as [[anxiety suppression]], [[disinhibition]], [[sedation]], [[muscle relaxation]] and [[memory suppression]] when [[Routes of administration|administered]]. It is half as potent and has a 60% longer half-life than etizolam.{{citation needed}} | '''Metizolam''' (also known as '''Desmethyletizolam''') is a synthetic [[psychoactive class::depressant]] of the [[chemical class::thienodiazepine]] chemical class that reportedly produces [[etizolam]]-like effects such as [[anxiety suppression]], [[disinhibition]], [[sedation]], [[muscle relaxation]] and [[memory suppression]] when [[Routes of administration|administered]]. It is half as potent and has a 60% longer half-life than etizolam.{{citation needed}} | ||
This compound was patented in 1995 by a Japanese company as a medication for treating anxiety.<ref>Heteroaromaten mit anellierten Siebenringen, III. Umwandlung von Thienotriazolooxazepinen in Diazepine | https:// | This compound was patented in 1995 by a Japanese company as a medication for treating anxiety.<ref>{{cite journal | vauthors=((Weber, K.-H.)), ((Bauer, A.)), ((Langbein, A.)), ((Daniel, H.)) | journal=Justus Liebigs Annalen der Chemie | title=Heteroaromaten mit anellierten Siebenringen, III. Umwandlung von Thienotriazolooxazepinen in Diazepine | volume=1978 | issue=8 | pages=1257–1265 | date=20 September 1978 | url=https://onlinelibrary.wiley.com/doi/10.1002/jlac.197819780806 | issn=00754617 | doi=10.1002/jlac.197819780806}}</ref><ref>{{Citation | vauthors=((Nakanishi, M.)), ((Tahara, T.)), ((Araki, K.)), ((Shiroki, M.)) | title=Triazolothienodiazepine compounds | url=https://patents.google.com/patent/US3904641/en}}</ref><ref>{{Citation | vauthors=((Kitajima, H.)), ((Ehara, S.)), ((Sato, H.)), ((Moriwaki, M.)), ((Onishi, K.)) | title=Thienylazole compound and thienotriazolodiazepine compound | url=https://patents.google.com/patent/CA2191756A1/en}}</ref> Despite this, it has little to no history of human usage prior to its release as a grey area [[research chemical]] by online vendors in September 2015.{{citation needed}} | ||
Similar to [[benzodiazepines]], [[Thienodiazepine#Discontinuation|the sudden discontinuation of thienodiazepines]] can be potentially dangerous or life-threatening for individuals using regularly for extended periods of time, sometimes resulting in seizures or death. It is highly recommended to [[taper]] one's dose by gradually lowering the amount taken each day for a prolonged period of time instead of stopping abruptly.<ref>Canadian | Similar to [[benzodiazepines]], [[Thienodiazepine#Discontinuation|the sudden discontinuation of thienodiazepines]] can be potentially dangerous or life-threatening for individuals using regularly for extended periods of time, sometimes resulting in seizures or death. It is highly recommended to [[taper]] one's dose by gradually lowering the amount taken each day for a prolonged period of time instead of stopping abruptly.<ref>{{cite journal | vauthors=((Kahan, M.)), ((Wilson, L.)), ((Mailis-Gagnon, A.)), ((Srivastava, A.)) | journal=Canadian Family Physician | title=Canadian guideline for safe and effective use of opioids for chronic noncancer pain. Appendix B-6: Benzodiazepine Tapering | volume=57 | issue=11 | pages=1269–1276 | date= November 2011 | url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3215603/ | issn=0008-350X}}</ref> | ||
==Chemistry== | ==Chemistry== | ||
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==Pharmacology== | ==Pharmacology== | ||
[[Thienzodiazepines]] produce a variety of effects by binding to the benzodiazepine receptor site and magnifying the efficiency and effects of the [[neurotransmitter]] gamma aminobutyric acid ([[GABA]]) by acting on its receptors.<ref>Benzodiazepine interactions with GABA receptors | [[Thienzodiazepines]] produce a variety of effects by binding to the benzodiazepine receptor site and magnifying the efficiency and effects of the [[neurotransmitter]] gamma aminobutyric acid ([[GABA]]) by acting on its receptors.<ref>{{cite journal | vauthors=((Haefely, W.)) | journal=Neuroscience Letters | title=Benzodiazepine interactions with GABA receptors | volume=47 | issue=3 | pages=201–206 | date=29 June 1984 | issn=0304-3940 | doi=10.1016/0304-3940(84)90514-7}}</ref> As this site is the most prolific inhibitory receptor set within the brain, its modulation results in the [[sedating]] (or [[anxiety suppression|calming effects]]) of metizolam on the nervous system. | ||
Metizolam is absorbed fairly rapidly, with peak plasma levels achieved between 30 minutes and 2 hours. It has a mean elimination half life of about 3.4 hours. Metizolam acts as a full agonist at the benzodiazepine/GABAa receptor to produce its range of therapeutic and adverse effects. | Metizolam is absorbed fairly rapidly, with peak plasma levels achieved between 30 minutes and 2 hours. It has a mean elimination half life of about 3.4 hours. Metizolam acts as a full agonist at the benzodiazepine/GABAa receptor to produce its range of therapeutic and adverse effects. | ||
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===Overdose=== | ===Overdose=== | ||
Thienodiazepine overdose may occur when a [[thienodiazepine]] is taken in extremely heavy quantities or concurrently with other depressants. This is particularly dangerous with other GABAergic depressants such as [[barbiturate |barbiturates]] and [[alcohol]] since they work in a similar fashion, but bind to distinct allosteric sites on the GABA<sub>A</sub> receptor. Thus their effects potentiate one another. Thienodiazepines increase the frequency in which the chlorine ion pore opens on the GABA<sub>A</sub> receptor while barbiturates increase the duration in which they are open, meaning when both are consumed, the ion pore will open more frequently and stay open longer.<ref>Twyman, R. E., Rogers, C. J., | Thienodiazepine overdose may occur when a [[thienodiazepine]] is taken in extremely heavy quantities or concurrently with other depressants. This is particularly dangerous with other GABAergic depressants such as [[barbiturate |barbiturates]] and [[alcohol]] since they work in a similar fashion, but bind to distinct allosteric sites on the GABA<sub>A</sub> receptor. Thus their effects potentiate one another. Thienodiazepines increase the frequency in which the chlorine ion pore opens on the GABA<sub>A</sub> receptor while barbiturates increase the duration in which they are open, meaning when both are consumed, the ion pore will open more frequently and stay open longer.<ref>{{cite journal | vauthors=((Twyman, R. E.)), ((Rogers, C. J.)), ((Macdonald, R. L.)) | journal=Annals of Neurology | title=Differential regulation of γ‐aminobutyric acid receptor channels by diazepam and phenobarbital | volume=25 | issue=3 | pages=213–220 | date= March 1989 | url=https://onlinelibrary.wiley.com/doi/10.1002/ana.410250302 | issn=0364-5134 | doi=10.1002/ana.410250302}}</ref> Thienodiazepine overdose is a medical emergency that may lead to a coma, permanent brain injury or death if not treated promptly and properly. | ||
Symptoms of a thienodiazepine overdose may include severe [[thought deceleration]], [[language suppression|slurred speech]], [[confusion]], [[delusions]], [[respiratory depression]], coma or death. Thienodiazepine overdoses may be treated effectively in a hospital environment, with generally favorable outcomes. Thienodiazepine overdoses are sometimes treated with [[flumazenil]], a GABA<sub>A</sub> antagonist,<ref> | Symptoms of a thienodiazepine overdose may include severe [[thought deceleration]], [[language suppression|slurred speech]], [[confusion]], [[delusions]], [[respiratory depression]], coma or death. Thienodiazepine overdoses may be treated effectively in a hospital environment, with generally favorable outcomes. Thienodiazepine overdoses are sometimes treated with [[flumazenil]], a GABA<sub>A</sub> antagonist,<ref>{{cite journal | vauthors=((Hoffman, E. J.)), ((Warren, E. W.)) | journal=Clinical Pharmacy | title=Flumazenil: a benzodiazepine antagonist | volume=12 | issue=9 | pages=641–656; quiz 699–701 | date= September 1993 | issn=0278-2677}}</ref> however care is primarily supportive in nature. | ||
===Paradoxical effects=== | ===Paradoxical effects=== | ||
Paradoxical reactions to [[benzodiazepines]] such as increased seizures (in epileptics), aggression, increased anxiety, violent behavior, loss of impulse control, irritability and suicidal behavior sometimes occur (although they are rare in the general population, with an incidence rate below 1%).<ref>Mancuso, C. E., Tanzi, M. G., | Paradoxical reactions to [[benzodiazepines]] such as increased seizures (in epileptics), aggression, increased anxiety, violent behavior, loss of impulse control, irritability and suicidal behavior sometimes occur (although they are rare in the general population, with an incidence rate below 1%).<ref>{{cite journal | vauthors=((Mancuso, C. E.)), ((Tanzi, M. G.)), ((Gabay, M.)) | journal=Pharmacotherapy | title=Paradoxical Reactions to Benzodiazepines: Literature Review and Treatment Options | volume=24 | issue=9 | pages=1177–1185 | date= September 2004 | url=http://doi.wiley.com/10.1592/phco.24.13.1177.38089 | issn=0277-0008 | doi=10.1592/phco.24.13.1177.38089}}</ref><ref>{{cite journal | vauthors=((Paton, C.)) | journal=Psychiatric Bulletin | title=Benzodiazepines and disinhibition: a review | volume=26 | issue=12 | pages=460–462 | date= December 2002 | url=https://www.cambridge.org/core/product/identifier/S0955603600001240/type/journal_article | issn=0955-6036 | doi=10.1192/pb.26.12.460}}</ref> | ||
These paradoxical effects occur with greater frequency in recreational abusers, individuals with mental disorders, children, and patients on high-dosage regimes.<ref>Bond, A. J. | These paradoxical effects occur with greater frequency in recreational abusers, individuals with mental disorders, children, and patients on high-dosage regimes.<ref>{{cite journal | vauthors=((Bond, A. J.)) | journal=CNS Drugs | title=Drug-Induced Behavioural Disinhibition: Incidence, Mechanisms and Therapeutic Implications | volume=9 | issue=1 | pages=41–57 | date= 1998 | url=http://link.springer.com/10.2165/00023210-199809010-00005 | issn=1172-7047 | doi=10.2165/00023210-199809010-00005}}</ref><ref>{{cite journal | vauthors=((Drummer, O. H.)) | journal=Forensic Science Review | title=Benzodiazepines - Effects on Human Performance and Behavior | volume=14 | issue=1–2 | pages=1–14 | date= February 2002 | issn=1042-7201}}</ref> Due to the close structural and pharmacological similarities they share, it is likely that these same risks apply to [[thienodiazepines]] as well. | ||
==Preparation methods== | ==Preparation methods== | ||
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Metizolam is currently a grey area compound within most parts of the world. This means that it is not known to be specifically illegal within any country, but people may still be charged for its possession under certain circumstances such as under analogue laws and with intent to sell or consume. | Metizolam is currently a grey area compound within most parts of the world. This means that it is not known to be specifically illegal within any country, but people may still be charged for its possession under certain circumstances such as under analogue laws and with intent to sell or consume. | ||
*'''Canada''': All benzodiazepines are Schedule IV controlled substances in Canada.<ref> | *'''Canada''': All benzodiazepines are Schedule IV controlled substances in Canada.<ref>{{Citation | vauthors=((Branch, L. S.)) | year=2022 | title=Consolidated federal laws of Canada, Controlled Drugs and Substances Act | url=https://laws-lois.justice.gc.ca/eng/acts/C-38.8/page-15.html}}</ref> | ||
*'''Germany''': Metizolam is controlled under the NpSG (''New Psychoactive Substances Act'')<ref>{{cite web|url=https://www.gesetze-im-internet.de/npsg/anlage.html|title=Anlage NpSG|publisher=Bundesministerium der Justiz und für Verbraucherschutz|access-date=December 10, 2019|language=de}}</ref> as of July 18, 2019.<ref>{{cite web|url=http://www.bgbl.de/xaver/bgbl/start.xav?startbk=Bundesanzeiger_BGBl&jumpTo=bgbl119s1083.pdf|title=Verordnung zur Änderung der Anlage des Neue-psychoaktive-Stoffe-Gesetzes und von Anlagen des Betäubungsmittelgesetzes|publisher=Bundesanzeiger Verlag|work=Bundesgesetzblatt Jahrgang 2019 Teil I Nr. 27|publication-date=July 17, 2019|access-date=December 28, 2019|language=de}}</ref> Production and import with the aim to place it on the market, administration to another person and trading is punishable. Possession is illegal but not penalized.<ref>{{cite web|url=https://www.gesetze-im-internet.de/npsg/__4.html|title=§ 4 NpSG|publisher=Bundesministerium der Justiz und für Verbraucherschutz|access-date=December 10, 2019|language=de}}</ref> | *'''Germany''': Metizolam is controlled under the NpSG (''New Psychoactive Substances Act'')<ref>{{cite web|url=https://www.gesetze-im-internet.de/npsg/anlage.html|title=Anlage NpSG|publisher=Bundesministerium der Justiz und für Verbraucherschutz|access-date=December 10, 2019|language=de}}</ref> as of July 18, 2019.<ref>{{cite web|url=http://www.bgbl.de/xaver/bgbl/start.xav?startbk=Bundesanzeiger_BGBl&jumpTo=bgbl119s1083.pdf|title=Verordnung zur Änderung der Anlage des Neue-psychoaktive-Stoffe-Gesetzes und von Anlagen des Betäubungsmittelgesetzes|publisher=Bundesanzeiger Verlag|work=Bundesgesetzblatt Jahrgang 2019 Teil I Nr. 27|publication-date=July 17, 2019|access-date=December 28, 2019|language=de}}</ref> Production and import with the aim to place it on the market, administration to another person and trading is punishable. Possession is illegal but not penalized.<ref>{{cite web|url=https://www.gesetze-im-internet.de/npsg/__4.html|title=§ 4 NpSG|publisher=Bundesministerium der Justiz und für Verbraucherschutz|access-date=December 10, 2019|language=de}}</ref> | ||
*'''Sweden''': Following its sale as a [[designer drug]], metizolam was made illegal in Sweden on January 26, 2016.<ref>(in Swedish) Folkhälsomyndigheten. | https://www.folkhalsomyndigheten.se/nyheter-och-press/nyhetsarkiv/2016/januari/31-nya-substanser-klassas-som-narkotika-eller-halsofarlig-vara/</ref> | *'''Sweden''': Following its sale as a [[designer drug]], metizolam was made illegal in Sweden on January 26, 2016.<ref>(in Swedish) Folkhälsomyndigheten. | https://www.folkhalsomyndigheten.se/nyheter-och-press/nyhetsarkiv/2016/januari/31-nya-substanser-klassas-som-narkotika-eller-halsofarlig-vara/</ref> | ||
*'''Switzerland''': Metizolam is a controlled substance specifically named under Verzeichnis E.<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''': Metizolam is a controlled substance specifically named under Verzeichnis E.<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> | ||
*'''Turkey:''' Metizolam is a classed as drug and is illegal to possess, produce, supply, or import.<ref>{{cite web|title=Karar Sayısı: 2016/9019|url=https://resmigazete.gov.tr/eskiler/2016/08/20160803-15.pdf|publication-date=June 22, 2016|date=June 22, 2016|work=Resmî Gazete, Sayı: 29790|language=tr}}</ref> | *'''Turkey:''' Metizolam is a classed as drug and is illegal to possess, produce, supply, or import.<ref>{{cite web|title=Karar Sayısı: 2016/9019|url=https://resmigazete.gov.tr/eskiler/2016/08/20160803-15.pdf|publication-date=June 22, 2016|date=June 22, 2016|work=Resmî Gazete, Sayı: 29790|language=tr}}</ref> | ||
*'''United Kingdom''': It is illegal to produce, supply, or import this drug under the Psychoactive Substance Act, which came into effect on May 26, 2016.<ref>Psychoactive Substances Act 2016 | *'''United Kingdom''': It is illegal to produce, supply, or import this drug under the Psychoactive Substance Act, which came into effect on May 26, 2016.<ref>{{Citation | title=Psychoactive Substances Act 2016 | url=https://www.legislation.gov.uk/ukpga/2016/2/contents/enacted}}</ref> | ||
==See also== | ==See also== | ||