Etizolam

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Fatal overdose may occur when thienodiazepines are combined with other depressants such as opiates, benzodiazepines, barbiturates, gabapentinoids, alcohol or other GABAergic substances.[1]

It is strongly discouraged to combine these substances, particularly in common to heavy doses.

Summary sheet: Etizolam
Etizolam
Etizolam.svg
Chemical Nomenclature
Common names Etizolam, Etilaam, Etizest, Depas
Substitutive name Etizolam
Systematic name 4-(2-Chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine
Class Membership
Psychoactive class Depressant
Chemical class Thienodiazepine / Thienotriazolodiazepine
Routes of Administration

WARNING: Always start with lower doses due to differences between individual body weight, tolerance, metabolism, and personal sensitivity. See responsible use section.



⇣ Oral
Dosage
Bioavailability 93%[citation needed]
Threshold 0.2 mg
Light 0.5 - 1 mg
Common 1 - 2 mg
Strong 2 - 5 mg
Heavy 5 mg +
Duration
Total 5 - 7 hours
Onset 15 - 30 minutes
Come up 30 - 60 minutes
Peak 2 - 3 hours
Offset 1.5 - 2.5 hours
After effects 6 - 24 hours









DISCLAIMER: PW's dosage information is gathered from users and resources for educational purposes only. It is not a recommendation and should be verified with other sources for accuracy.

Interactions


Etizolam (also known as Etilaam, Etizest, Depas, and many others) is a novel depressant substance of the thienodiazepine class. Etizolam is chemically related to benzodiazepines and acts by binding to GABA receptors in the brain.

Etizolam is not commonly prescribed. It has been sold as a research chemical online and is commonly used as a substitute for pharmaceutical benzodiazepines like alprazolam (Xanax) or diazepam (Valium). Etizolam is commonly found in pellet or pill form, laid on blotter paper, dissolved in propylene glycol or as a pure powder.

Subjective effects include anxiety suppression, disinhibition, muscle relaxation, sedation, and euphoria. Etizolam is commonly administered orally and sublingually due to the high bioavailability of these routes.

As with benzodiazepines, the sudden discontinuation of thienodiazepines can be dangerous or even life-threatening for long-term or heavy users. As a result, individuals who are physically dependent on this substance are advised to taper their dose by gradually lowering the amount taken each day over a prolonged period of time instead of stopping use abruptly.[2]

Due to its high abuse and addiction potential, it is highly advised to use proper harm reduction practices if using this substance.[citation needed]

History and culture

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Etizolam first appeared on the online research chemical market in 2011. Since then its popularity has steadily increased. This likely owes itself to both its low cost and its abundance, and the highly dependence-forming and addictive nature that it shares with recreationally-used benzodiazepines.[3]

Etizolam differs from most other research chemicals in that it is approved and actively prescribed as a medical treatment for anxiety in many countries around the world, commonly under brand names like Etilaam and Etizest. Its origins as a medical drug are unclear, although medical papers citing its use in the treatment of anxiety have been documented as early as the 1990s.[4]

Chemistry

Etizolam is a structural relative of benzodiazepines, whereby the benzene ring has been replaced by a thiophene ring, classifying it as a thienodiazepine. Thiophene is a five membered aromatic ring with one sulfur atom. Etizolam contains a thiophene ring fused to a diazepine ring, which is a seven membered ring with the two nitrogen constituents located at R1 and R4. This forms the thienodiazepine core of etizolam. An ethyl chain is bound to this bicyclic structure at R7. Additionally, a R2' chlorine-substituted phenyl ring is bound to this structure at R5.

Etizolam also contains a methylated triazole ring fused to and incorporating R1 and R2 of its diazepine ring. Etizolam shares this fused triazole ring substitution with certain benzodiazepine drugs, called triazolobenzodiazepines, distinguished by the suffix "-zolam".

Pharmacology

Thienodiazepines produce a variety of effects by binding to the benzodiazepine binding site (formerly referred to as the BZD receptor) at the GABA-A receptor complex, magnifying the efficicacy and effects of the neurotransmitter gamma aminobutyric acid (GABA) by increasing its ability to bind more readily to its own receptors.[5] This is known as positive allosteric modulation.[6] As this site is the most prolific inhibitory receptor set within the brain, its modulation results in the sedating (or calming effects) of etizolam on the nervous system.

Subjective effects

Anecdotal reports suggest that in terms of its relative potency, 1 mg of etizolam is approximately equivalent to 0.5 mg of alprazolam (Xanax), 0.5 mg of clonazepam (Klonopin), or 10 mg of diazepam (Valium). It is often compared to a less potent and sedating version of alprazolam in terms of the speed of its onset, total duration, and recreational effect.

Disclaimer: The effects listed below cite the Subjective Effect Index (SEI), an open research literature based on anecdotal user reports and the personal analyses of PsychonautWiki contributors. As a result, they should be viewed with a healthy degree of skepticism.

It is also worth noting that these effects will not necessarily occur in a predictable or reliable manner, although higher doses are more liable to induce the full spectrum of effects. Likewise, adverse effects become increasingly likely with higher doses and may include addiction, severe injury, or death ☠.

Physical effects
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Paradoxical effects
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  • 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%).[7][8] These paradoxical effects occur with greater frequency in recreational abusers, individuals with mental disorders, children, and patients on high-dosage regimes.[9][10] Although not formally studied, thienodiazepines are assumed to share this risk.

Cognitive effects
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After effects
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Experience reports

There are currently anecdotal reports which describe the effects of this compound within our experience index.

. Additional experience reports can be found here:

Toxicity and harm potential

Blepharospasms (twitching eyelid) can occur with long-term use.[11] Rarely, erythema annulare centrifugum skin lesions have also been reported.[12]
Further information: Research chemicals § Toxicity and harm potential

Etizolam likely has a low toxicity relative to dose.[13] However, it is potentially lethal when mixed with depressants like alcohol or opioids.

It is strongly recommended that one use harm reduction practices such as volumetric dosing when using this substance.

Tolerance and addiction potential

Like most benzodiazepines, etizolam is considered to be highly addictive with a high potential for abuse.

In one study in which multiple doses of either etizolam or lorazepam were administered to rat neurons, tolerance to the anticonvulsant effects of lorazepam but not to etizolam was observed.[14] Etizolam therefore has a reduced liability to induce tolerance, and dependence when compared with classic benzodiazepines.[14]

Tolerance will, however, develop to the sedative-hypnotic effects within a couple of days of continuous use. After cessation, the tolerance returns to baseline in 7 - 14 days. However, in certain cases this may take significantly longer in a manner which is proportional to the duration and intensity of one's long-term usage.

Thienodiazepine discontinuation is notoriously difficult and potentially life-threatening for heavy or long-term users. There is an increased risk of seizure following discontinuation of thienodiazepines. Withdrawal symptoms or rebound symptoms may occur after ceasing usage abruptly following a few weeks or longer of steady dosing, and may necessitate a gradual dose reduction. For more information on tapering from thienodiazepines in a controlled manner, please see this guide. Substances which lower the seizure threshold such as tramadol should be avoided during withdrawal.

Etizolam presents cross-tolerance with all benzodiazepines and thienodiazepines, meaning that after its consumption all benzo and thienodiazepines will have a reduced effect.

Overdose

Thienodiazepine overdose may occur when taken in extremely heavy quantities or concurrently with other depressants. This is particularly dangerous with other GABAergic depressants such as barbiturates and alcohol since they work in a similar fashion, but bind to distinct allosteric sites on the GABAA receptor, thus their effects potentiate one another. Thienodiazepine increase the frequency in which the chlorine ion pore opens on the GABAA 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[15]. 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, 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 GABAA antagonist[16]. However, care is primarily supportive in nature.

Dangerous interactions

Warning: Many psychoactive substances that are reasonably safe to use on their own can suddenly become dangerous and even life-threatening when combined with certain other substances. The following list provides some known dangerous interactions (although it is not guaranteed to include all of them).

Always conduct independent research (e.g. Google, DuckDuckGo, PubMed) to ensure that a combination of two or more substances is safe to consume. Some of the listed interactions have been sourced from TripSit.

  • Depressants (1,4-Butanediol, 2-methyl-2-butanol, alcohol, barbiturates, GHB/GBL, methaqualone, opioids) - This combination can result in dangerous or even fatal levels of respiratory depression. These substances potentiate the muscle relaxation, sedation and amnesia caused by one another and can lead to unexpected loss of consciousness at high doses. There is also an increased risk of vomiting during unconsciousness and death from the resulting suffocation. If this occurs, users should attempt to fall asleep in the recovery position or have a friend move them into it.
  • Dissociatives - This combination can result in an increased risk of vomiting during unconsciousness and death from the resulting suffocation. If this occurs, users should attempt to fall asleep in the recovery position or have a friend move them into it.
  • Stimulants - It is dangerous to combine thienzodiazepines with stimulants due to the risk of excessive intoxication. Stimulants mask the sedative effect of thienzodiazepines, which is the main factor most people consider when determining their level of intoxication. Once the stimulant wears off, the effects of thienzodiazepines will be significantly increased, leading to intensified disinhibition. If combined, one should strictly limit themselves to only dose a certain amount of thienzodiazepines per hour. This combination can also potentially result in severe dehydration if hydration is not monitored.

Legal status

Internationally, etizolam was added to the UN Convention on Psychotropic Substances as a Schedule IV controlled substance in March 2020.[17][18]

  • Australia: Schedule 4 issued by the Office of Drug Control, in accordance with Regulation 5 of the Customs (Prohibited Imports) Regulations 1956. Does not state it is Schedule 4 in Poison Standard October 2020[19], but it may fall under the analog act for deschloroetizolam. License and permit are required for import/export.
  • Austria: Etizolam is illegal to possess, produce, supply, or import since 2012[20] under the NPSG (Neue Psychoaktive Substanzen Gesetz). However, offenders with no intent to distribute will likely not have to face a charge.[21]
  • Brazil: Since March 23, 2021, due to ANVISA's Resolution RDC nº 473[22], possession, production and sale is illegal as it is listed on Portaria SVS/MS nº 344[23].
  • Canada: Etizolam appears to be captured under section 18 of the CDSA's Schedule VI as "Benzodiazepines, salts thereof and their derivatives"
  • Germany: Etizolam is controlled under Anlage III BtMG (Narcotics Act, Schedule III)[24] as of July 17, 2013.[25] It can only be prescribed on a narcotic prescription form.[26]
  • Japan: Etizolam is controlled by Japan by the Narcotics and Psychotropics Control Law, which makes it illegal to possess, sell, or manufacture it without a prescription.[27]
  • Poland: Etizolam is a NPS class drug in Poland, making it illegal to possess or distribute.[28]
  • Russia: In Russia, since 2017, etizolam is a Schedule III controlled substance.[29]
  • Switzerland: Etizolam is a controlled substance specifically named under Verzeichnis B. Medicinal use is permitted.[30]
  • Turkey: Etizolam is a classed as drug and is illegal to possess, produce, supply, or import.[31] [32]
  • The Netherlands: Etizolam is a List 2 substance of the Opium Law, making it illegal.[33]
  • United Kingdom: As of May 31st, 2017, etizolam is a Class C substance in the United Kingdom, making it illegal to possess, produce, or supply.[34]
  • United States: Etizolam was temporarily scheduled on January 23rd, 2023 by the DEA, making Etizolam a Schedule I controlled substance [35]. Prior to its temporary scheduling, some state legislatures have passed laws prohibiting it in their jurisdictions. As of July 2019, etizolam is a controlled substance in the following states: Alabama[36], Arkansas[37], Florida[38], Georgia[39], Louisiana, Mississippi[40], Texas,[citation needed] South Carolina[41] and Virginia[42], Indiana[43], and Ohio[citation needed].
  • Arizona: In 2018, The State Of Arizona Legislature has listed Etizolam as a controlled substance under House Bill 2033[44]
  • Arkansas: In August 2014, the state of Arkansas listed etizolam as a Schedule I substance under its substance scheduling guidelines.[45]
  • North Carolina: On March 22, 2017, the General Assembly of North Carolina enacted an addendum to the North Carolina Controlled Substances Act including etizolam as a Schedule I substance.
  • Texas: On Jun 9, 2017, the state of Texas listed etizolam as a Penalty Group 3 substance with HB 2671.[46] Contrary to some online reports and conflicting information with the overall Texas controlled substance list website, etizolam became a penalty group 3 substance with the passage of this bill.

See also

External links

Literature

  • Sanna, E., Pau, D., Tuveri, F., Massa, F., Maciocco, E., Acquas, C., ... & Biggio, G. (1999). Molecular and neurochemical evaluation of the effects of etizolam on GABAA receptors under normal and stress conditions. Arzneimittelforschung, 49(02), 88-95. https://doi.org/10.1055/s-0031-1300366
  • Altamura, A. C., Moliterno, D., Paletta, S., Maffini, M., Mauri, M. C., & Bareggi, S. (2013). Understanding the pharmacokinetics of anxiolytic drugs. Expert Opinion on Drug Metabolism & Toxicology, 9(4), 423-440. https://doi.org/10.1517/17425255.2013.759209
  • Fracasso, C., Confalonieri, S., Garattini, S., & Caccia, S. (1991). Single and multiple dose pharmacokinetics of etizolam in healthy subjects. European Journal of Clinical Pharmacology, 40(2), 181-185. https://doi.org/10.1007/BF00280074

References

  1. ↑ Risks of Combining Depressants - TripSit 
  2. ↑ Kahan, M., Wilson, L., Mailis-Gagnon, A., Srivastava, A. (November 2011). "Canadian guideline for safe and effective use of opioids for chronic noncancer pain. Appendix B-6: Benzodiazepine Tapering". Canadian Family Physician. 57 (11): 1269–1276. ISSN 0008-350X. 
  3. ↑ Etizolam - TripSit wiki, retrieved 11 May 2017 
  4. ↑ Sanna, E., Pau, D., Tuveri, F., Massa, F., Maciocco, E., Acquas, C., Floris, C., Fontana, S., Maira, G., Biggio, G. (28 December 2011). "Molecular and Neurochemical Evaluation of the Effects of Etizolam on GABAA Receptors under Normal and Stress Conditions". Arzneimittelforschung. 49 (02): 88–95. doi:10.1055/s-0031-1300366. ISSN 0004-4172. 
  5. ↑ Haefely, W. (29 June 1984). "Benzodiazepine interactions with GABA receptors". Neuroscience Letters. 47 (3): 201–206. doi:10.1016/0304-3940(84)90514-7. ISSN 0304-3940. 
  6. ↑ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3684331/#s2title
  7. ↑ Saïas, T., Gallarda, T. (September 2008). "[Paradoxical aggressive reactions to benzodiazepine use: a review]". L’Encephale. 34 (4): 330–336. doi:10.1016/j.encep.2007.05.005. ISSN 0013-7006. 
  8. ↑ Paton, C. (December 2002). "Benzodiazepines and disinhibition: a review". Psychiatric Bulletin. 26 (12): 460–462. doi:10.1192/pb.26.12.460. ISSN 0955-6036. 
  9. ↑ Bond, A. J. (1 January 1998). "Drug- Induced Behavioural Disinhibition". CNS Drugs. 9 (1): 41–57. doi:10.2165/00023210-199809010-00005. ISSN 1179-1934. 
  10. ↑ Drummer, O. H. (February 2002). "Benzodiazepines - Effects on Human Performance and Behavior". Forensic Science Review. 14 (1–2): 1–14. ISSN 1042-7201. 
  11. ↑ Wakakura, M., Tsubouchi, T., Inouye, J. (March 2004). "Etizolam and benzodiazepine induced blepharospasm". Journal of Neurology, Neurosurgery, and Psychiatry. 75 (3): 506–507. doi:10.1136/jnnp.2003.019869. ISSN 0022-3050. 
  12. ↑ Kuroda, K., Yabunami, H., Hisanaga, Y. (January 2002). "Etizolam-induced superficial erythema annulare centrifugum". Clinical and Experimental Dermatology. 27 (1): 34–36. doi:10.1046/j.0307-6938.2001.00943.x. ISSN 0307-6938. 
  13. ↑ Mandrioli, R., Mercolini, L., Raggi, M. A. (October 2008). "Benzodiazepine metabolism: an analytical perspective". Current Drug Metabolism. 9 (8): 827–844. doi:10.2174/138920008786049258. ISSN 1389-2002. 
  14. ↑ 14.0 14.1 Sanna, E., Busonero, F., Talani, G., Mostallino, M. C., Mura, M. L., Pisu, M. G., Maciocco, E., Serra, M., Biggio, G. (5 September 2005). "Low tolerance and dependence liabilities of etizolam: molecular, functional, and pharmacological correlates". European Journal of Pharmacology. 519 (1–2): 31–42. doi:10.1016/j.ejphar.2005.06.047. ISSN 0014-2999. 
  15. ↑ Twyman, R. E., Rogers, C. J., Macdonald, R. L. (March 1989). "Differential regulation of gamma-aminobutyric acid receptor channels by diazepam and phenobarbital". Annals of Neurology. 25 (3): 213–220. doi:10.1002/ana.410250302. ISSN 0364-5134. 
  16. ↑ Hoffman, E. J., Warren, E. W. (September 1993). "Flumazenil: a benzodiazepine antagonist". Clinical Pharmacy. 12 (9): 641–656; quiz 699–701. ISSN 0278-2677. 
  17. ↑ "WHO: World Health Organization recommends 12 NPS for scheduling". December 2019. Retrieved October 16, 2020. 
  18. ↑ "CND accepts all WHO recommendations on the control of several psychoactive substances from the 42nd ECDD meeting". World Health Organization (WHO). March 18, 2020. Retrieved October 16, 2020. 
  19. ↑ Health, Poisons Standard October 2020 
  20. ↑ "Neue Psychoaktive Substanzen" (in German). Bundeskriminalamt Österreich. Retrieved February 17, 2022. 
  21. ↑ "NPSG" (in German). Bundeskriminalamt Österreich. Retrieved February 17, 2022. 
  22. ↑ "Resolução de diretoria colegiada - RDC Nº 473" (in Portuguese). Retrieved May 20, 2021. 
  23. ↑ "Portaria SVS/MS nº 344 - Lista de substâncias sujeitas a controle especial no Brasil" (in Portuguese). Retrieved May 20, 2021. 
  24. ↑ "Anlage III BtMG" (in German). Bundesministerium der Justiz und für Verbraucherschutz. Retrieved December 19, 2019. 
  25. ↑ "Siebenundzwanzigste Verordnung zur Änderung betäubungsmittelrechtlicher Vorschriften" (in German). Bundesanzeiger Verlag. Retrieved December 19, 2019. 
  26. ↑ "§ 8 BtMVV" (in German). Bundesministerium der Justiz und für Verbraucherschutz. Retrieved December 19, 2019. 
  27. ↑ "新たに３物質を向精神薬に指定します" (in Japanese). 厚生労働省 [Ministry of Health, Labour and Welfare (MHLW)]. Retrieved March 28, 2021. 
  28. ↑ "Rozporządzenie Ministra zdrowia z dnia 21 sierpnia 2019 r. zmieniające rozporządzenie w sprawie wykazu substancji psychotropowych, środków odurzających oraz nowych substancji psychoaktywnych" (PDF) (in Polish). 
  29. ↑ Постановление Правительства РФ от 12.07.2017 N 827 “О внесении изменений в некоторые акты Правительства Российской Федерации в связи с совершенствованием контроля за оборотом наркотических средств и психотропных веществ” - КонсультантПлюс 
  30. ↑ "Verordnung des EDI über die Verzeichnisse der Betäubungsmittel, psychotropen Stoffe, Vorläuferstoffe und Hilfschemikalien" (in German). Bundeskanzlei [Federal Chancellery of Switzerland]. Retrieved January 1, 2020. 
  31. ↑ Başbakanlık Mevzuatı Geliştirme ve Yayın Genel Müdürlüğü 
  32. ↑ https://resmigazete.gov.tr/eskiler/2014/01/20140125-3-1.pdf
  33. ↑ Opiumwet, Lijst II (Dutch), 2023 
  34. ↑ The Misuse of Drugs (Amendment) (England, Wales and Scotland) Regulations 2017 | http://www.tihs.org.uk/timeline/resources/2017-631.pdf
  35. ↑ Schedules of Controlled Substances: Temporary Placement of Etizolam, Flualprazolam, Clonazolam, Flubromazolam, and Diclazepam in Schedule I | https://www.federalregister.gov/documents/2022/12/23/2022-27278/schedules-of-controlled-substances-temporary-placement-of-etizolam-flualprazolam-clonazolam
  36. ↑ Alabama Code Title 20. Food, Drugs, and Cosmetics § 20-2-23 
  37. ↑ http://www.healthy.arkansas.gov/aboutadh/rulesregs/controlled_substances_list.pdf
  38. ↑ Statutes & Constitution :View Statutes : Online Sunshine 
  39. ↑ http://www.namsdl.org/library/946E60B2-ABB3-24A6-F087859B3EA48EC1/
  40. ↑ HB1231 (As Sent to Governor) - 2014 Regular Session 
  41. ↑ Controlled Substance Schedule, SCDHEC 
  42. ↑ 18VAC110-20-322. Placement of chemicals in Schedule I. 
  43. ↑ Ellington’s bill banning two deadly drugs could soon be law, State of Indiana House of Representatives 
  44. ↑ HB2033 - 531R - H Ver 
  45. ↑ http://www.healthy.arkansas.gov/aboutADH/RulesRegs/ControlledSubstanceListSummary.pdf
  46. ↑ https://capitol.texas.gov/tlodocs/85R/billtext/pdf/HB02671S.pdf


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