Alprazolam

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

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

Summary sheet: Alprazolam
Alprazolam
Alprazolam.svg
Chemical Nomenclature
Common names Xanax, Alprazolam
Substitutive name Alprazolam
Systematic name 8-Chloro-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine
Class Membership
Psychoactive class Depressant
Chemical class Benzodiazepine
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
Threshold 0.10 mg
Light 0.25 - 0.5 mg
Common 0.5 - 1.5 mg
Strong 1.5 - 2 mg
Heavy 2 - 3 mg +
Duration
Total 5 - 8 hours
Onset 20 - 40 minutes
Peak 1 - 2 hours
Offset 2 - 6 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


Alprazolam (also known as Xanax) is a depressant substance of the benzodiazepine class. Its characteristic effects include anxiety suppression, sedation, disinhibition, and muscle relaxation.[2]

Like other benzodiazepines, alprazolam binds to specific sites on the GABAA receptor.[3] It is commonly used for the medical treatment of panic disorder, generalized anxiety disorder (GAD), or social anxiety disorder (SAD).[4]

Alprazolam has a fast onset of action and symptomatic relief. Ninety percent of peak effects are achieved within the first hour of using in preparation for panic disorder and full peak effects are achieved in 1.5 and 1.6 hours respectively.[5][6] Peak benefits achieved for generalized anxiety disorder (GAD) may take up to a week.[7]

The sudden discontinuation of benzodiazepines can be potentially dangerous or life-threatening for individuals using regularly for extended periods of time, sometimes resulting in seizures or death.[8] 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.[9]

Xanax (Alprazolam) 2 mg tri-score tablets

Chemistry

Alprazolam is a drug of the benzodiazepine class. Benzodiazepine drugs contain a benzene ring fused to a diazepine ring, which is a seven membered ring with the two nitrogen constituents located at R1 and R4. The benzyl ring of alprazolam is substituted at R8 with a chlorine group. Further, the diazepine ring is bonded at R5 to a phenyl ring. Alprazolam also contains a 1-methylated triazole ring fused to and incorporating R1 and R2 of its diazepine ring. Alprazolam belongs to a class of benzodiazepines containing this fused triazole ring, called triazolobenzodiazepines, distinguished by the suffix "-zolam".

Alprazolam is substituted with a phenyl group at position 6, with a chlorine atom at position 8 and with a methyl group at position 1. It is an analogue of triazolam, the difference between them being the absence of a chlorine atom in the 'ortho' position of the phenyl ring. It is soluble in alcohol and insoluble in water.

Pharmacology

Benzodiazepines 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.[10] Alprazolam is a positive allosteric modulator of the gamma-aminobutyric acid (GABA) type A receptor. As this site is the most prolific inhibitory receptor set within the brain, its modulation results in the sedating (or calming effects) of alprazolam on the nervous system. The anticonvulsant properties of benzodiazepines may be, in part or entirely, due to binding to voltage-dependent sodium channels rather than benzodiazepine receptors.[11]

Alprazolam causes a marked suppression of the hypothalamic pituitary-adrenal axis. Administration of alprazolam has been demonstrated to elicit an increase in striatal dopamine concentrations.[12] This results in effects including reduced anxiety, muscle relaxant, antidepressant and anticonvulsant activity. he GABA chemical and receptor system mediates inhibitory or calming effects of alprazolam on the nervous system. Binding of alprazolam to the GABAA receptor, a chloride ion channel, enhances the effects of GABA, a neurotransmitter. When GABA binds the GABAA receptor the channel opens and chloride enters the cell which makes it more resistant to depolarisation. Therefore, alprazolam has a depressant effect on synaptic transmission to reduce anxiety.[13]

The GABAA receptor is made up of 5 subunits out of a possible 19, and GABAA receptors made up of different combinations of subunits have different properties, different locations within the brain, and, importantly, different activities with regard to benzodiazepines. Alprazolam and other triazolobenzodiazepines such as triazolam that have a triazole ring fused to their diazepine ring appear to have antidepressant properties.[14] This is perhaps due to the similarities shared with tricyclic antidepressants, as they have two benzene rings fused to a diazepine ring. Alprazolam causes a marked suppression of the hypothalamic-pituitary-adrenal axis. The therapeutic properties of alprazolam are similar to other benzodiazepines and include anxiolytic, anticonvulsant, muscle relaxant, hypnotic and amnesic; however, it is used mainly as an anxiolytic.

Giving alprazolam, as compared to lorazepam, has been demonstrated to elicit a statistically significant increase in extracellular dopamine D1 and D2 concentrations in the striatum.[15]

Subjective effects

The general head space of alprazolam is described by many as one of intense sedation, relaxation, anxiety suppression and decreased inhibition.

Disclaimer: The effects listed below cite the Subjective Effect Index (SEI), a research literature based on anecdotal reports and the personal experiences of PsychonautWiki contributors. As a result, they should be regarded with a healthy degree of skepticism. It is 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 much more likely with higher doses and may include addiction, serious injury, or death.

Physical effects
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Visual effects
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Paradoxical effects
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Cognitive effects
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After effects
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Experience reports

Anecdotal reports which describe the effects of this compound within our experience index include:

Additional experience reports can be found here:

Toxicity and harm potential

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This toxicity and harm potential section is a stub.

As a result, it may contain incomplete or even dangerously wrong information. You can help by expanding upon or correcting it.
Note: Always conduct independent research and use harm reduction practices if using this substance.

Radar plot showing relative physical harm, social harm, and dependence of benzodiazepines in comparison to other drugs.[21]

Alprazolam has a low toxicity relative to dose.[22] However, it is potentially lethal when mixed with depressants like alcohol or opioids.

It is strongly recommended that one use harm reduction practices when using this substance.

The acute oral LD50 in rats is 331–2171 mg/kg. Other experiments in animals have indicated that cardiopulmonary collapse can occur following massive intravenous doses of alprazolam.

Dependence and abuse potential

Alprazolam is extremely physically and psychologically addictive.

Tolerance will develop to the sedative-hypnotic effects within a couple of days of continuous use.[23] 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.

Alprazolam presents cross-tolerance with all benzodiazepines, meaning that after its consumption all benzodiazepines will have a reduced effect.

Overdose

Benzodiazepine overdose may occur with extremely high doses or, more commonly, when it is taken with other depressants. This risk is especially present with other GABAergic depressants, such as barbiturates and alcohol, since they work in a similar fashion but bind to distinct sites on the GABAA receptor, resulting in significant cross-potentiation.[citation needed]

Benzodiazepine overdose is a medical emergency that may lead to a coma, permanent brain injury or death if not treated promptly. Symptoms may include severe slurred speech, confusion, delusions, respiratory depression, and non-responsiveness. The user might seem like they are sleepwalking. The user is also more susceptible to consume more of the same or another substance due to their impaired judgement, which is typically not seen with other substances during overdose.

Benzodiazepine overdoses may be treated effectively in a hospital environment, with generally favorable outcomes. Care is primarily supportive in nature, although overdoses are sometimes treated with flumazenil, a GABAA antagonist[24] or additional procedures such as adrenaline injections if other substances are involved.[citation needed]

Discontinuation

Benzodiazepine discontinuation is notoriously difficult; it is potentially life-threatening for individuals using regularly to discontinue use without tapering their dose over a period of weeks. There is an increased risk of high blood pressure, seizures, and death.[25] Substances which lower the seizure threshold such as tramadol should be avoided during withdrawal.[citation needed] Abrupt discontinuation also causes rebound stimulation which presents as anxiety, insomnia and restlessness.[citation needed]

If one wishes to discontinue after a period of regular use, it is safest to reduce the dose each day by a very small amount for a couple of weeks until close to abstinence. If using a short half-life benzodiazepine such as alprazolam or etizolam, a longer acting variety such as diazepam or clonazepam can be substituted. Symptoms may still be present, but their severity will be reduced significantly.

For more information on tapering from benzodiazepines in a controlled manner, please see this guide. Small quantities of alcohol can also help to reduce the symptoms, but otherwise cannot be used as an effective tapering agent.

The duration and severity of withdrawal symptoms depend on a number of factors including the half-life of the substance used, tolerance and the duration of abuse. Major symptoms will usually start within just a few days after discontinuation and persist for around a week for shorter lasting benzodiazepines. Benzodiazepines with longer half-lives will exhibit withdrawal symptoms with a slow onset and extended duration.[citation needed]

Dangerous interactions

Although many psychoactive substances are reasonably safe to use on their own, they can suddenly become dangerous or even life-threatening when combined with other substances. The following list includes some known dangerous combinations (although it is not guaranteed to include all of them). Independent research (e.g. Google, DuckDuckGo) should always be conducted to ensure that a combination of two or more substances is safe to consume. Some of the listed interactions have been sourced from TripSit.

  • Stimulants - It can be dangerous to combine depressants with stimulants due to the risk of accidental excessive intoxication. Stimulants mask the sedative effect of depressants, which is the main factor most people use to gauge their level of intoxication. Once the stimulant effects wear off, the effects of the depressant will significantly increase, leading to intensified disinhibition, motor control loss, and dangerous black-out states. This combination can also potentially result in severe dehydration if one's fluid intake is not closely monitored. If choosing to combine these substances, one should strictly limit themselves to a pre-set schedule of dosing only a certain amount per hour until a maximum threshold has been reached.

Legal status

Internationally, alprazolam is included under the United Nations Convention on Psychotropic Substances as Schedule IV.[26]

  • Australia: Alprazolam was originally a Schedule 4 (prescription only) medication; however, as of January 2014, it will become a Schedule 8 medication, subjecting it to more rigorous prescribing requirements.[27]
  • Austria: Alprazolam is legal for medical use under the AMG (Arzneimittelgesetz Österreich) and illegal when sold or possessed without a prescription under the SMG (Suchtmittelgesetz Österreich).[citation needed]
  • Germany: Alprazolam is controlled under Anlage III BtMG (Narcotics Act, Schedule III) as of August 1, 1986.[28] It can only be prescribed on a narcotic prescription form, except preparations which contain up to 1 mg triazolam in each dosage form.[29]
  • Ireland: Alprazolam is a Schedule 4 medicine.[30]
  • Italy: Alprazolam is a schedule IV drug (Tabella 4) of the "Testo unico sulla droga (D.P.R. 309/90)". When prescribed for medical use it falls under Pharmaceuticals section B and E (Tabella medicinali sezione B ed E).[31][32]
  • Russia: In Russia, since 2013, alprazolam is a Schedule III controlled substance.[33]
  • Sweden: Alprazolam is a prescription drug in List IV (Schedule 4) under the Narcotics Drugs Act (1968).[34]
  • Switzerland: Alprazolam is a controlled substance specifically named under Verzeichnis B. Medicinal use is permitted.[35]
  • Turkey: Alprazolam is a 'green prescription' only substance[36] and illegal when sold or possessed without a prescription.[citation needed]
  • The Netherlands: Alprazolam is a List 2 substance of the Opium Law and is available for prescription.[citation needed]
  • United Kingdom: Alprazolam is classified as a controlled drug and listed under Schedule IV, Part I (CD Benz POM) of the Misuse of Drugs Regulations 2001, allowing possession with a valid prescription. The Misuse of Drugs Act 1971 makes it illegal to possess the drug without a prescription and, for such purposes, it is classified as a Class C drug.[37]
  • United States: Alprazolam is a prescription medication assigned to Schedule IV of the Controlled Substances Act by the DEA.[38]

See also

External links

Further reading

  • The Ashton Manual - Useful information on safe withdrawal from long-term benzodiazepine use and dependence

References

  1. Risks of Combining Depressants (Tripsit) | https://tripsit.me/combining-depressants/
  2. Benzodiazepine Metabolism: An Analytical Perspective" (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/18855614
  3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4303399/
  4. FDA approved labeling for Xanax revision 08/23/2011 | http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/018276s045lbl.pdf
  5. Pharmacokinetics and Pharmacodynamics of Alprazolam after Oral and IV Administration (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/6152055
  6. The Speed of Onset of Action of Alprazolam-XR Compared to Alprazolam-CT in Panic Disorder (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/17514187
  7. Clinical Pharmacology, Clinical Efficacy, and Behavioral Toxicity of Alprazolam: A Review of the Literature | http://onlinelibrary.wiley.com/doi/10.1111/j.1527-3458.2004.tb00003.x/pdf
  8. A fatal case of benzodiazepine withdrawal. (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/19465812
  9. Canadian Guideline for Safe and Effective Use of Opioids for Chronic Non-Cancer Pain - Appendix B-6: Benzodiazepine Tapering | http://nationalpaincentre.mcmaster.ca/opioid/cgop_b_app_b06.html
  10. Benzodiazepine interactions with GABA receptors (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/6147796
  11. Benzodiazepines, but not beta carbolines, limit high frequency repetitive firing of action potentials of spinal cord neurons in cell culture. (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/2450203
  12. Role of dopaminergic and serotonergic systems on behavioral stimulatory effects of low-dose alprazolam and lorazepam (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/11226811
  13. Andrew, Hitchings (2014). Top 100 drugs : clinical pharmacology and practical prescribing. Lonsdale, Dagan,, Burrage, Daniel,, Baker, Emma. Edinburgh. ISBN 9780702055164. OCLC 864676781.
  14. Barbee JG (October 1993). "Memory, benzodiazepines, and anxiety: integration of theoretical and clinical perspectives". The Journal of Clinical Psychiatry. 54 Suppl (Suppl): 86–97, discussion 98–101. PMID 8262893.
  15. Bentué-Ferrer D, Reymann JM, Tribut O, Allain H, Vasar E, Bourin M (February 2001). "Role of dopaminergic and serotonergic systems on behavioral stimulatory effects of low-dose alprazolam and lorazepam". European Neuropsychopharmacology. 11 (1): 41–50. doi:10.1016/S0924-977X(00)00137-1. PMID 11226811. S2CID 24653686.
  16. http://www.ncbi.nlm.nih.gov/pubmed/18922233 | Saïas T, Gallarda T | Paradoxical aggressive reactions to benzodiazepine use: a review
  17. Paton C | Benzodiazepines and disinhibition: a review | Psychiatr Bull R Coll Psychiatr | http://pb.rcpsych.org/cgi/reprint/26/12/460.pdf
  18. Bond AJ | Drug-induced behavioral disinhibition: incidence, mechanisms, and therapeutic implications | CNS Drugs
  19. Drummer OH | Benzodiazepines—effects on human performance and behavior | Forensic Sci Rev
  20. Goyal, Sarita. "Drugs and Dreams." Indian Journal of Clinical Practice (n.d.): n. pag. Web. | http://medind.nic.in/iaa/t13/i3/iaat13i3p624.pdf
  21. Development of a rational scale to assess the harm of drugs of potential misuse (ScienceDirect) | http://www.sciencedirect.com/science/article/pii/S0140673607604644
  22. Benzodiazepine metabolism: an analytical perspective (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/18855614
  23. Principles and Practice of Psychopharmacotherapy | http://books.google.com/books?id=_ePK9wwcQUMC&pg=PA535
  24. Amrein, R., Leishman, B., Bentzinger, C., & Roncari, G. (1987). Flumazenil in benzodiazepine antagonism. Medical Toxicology and Adverse Drug Experience, 2(6), 411-429. PMID: 8306565
  25. A fatal case of benzodiazepine withdrawal. (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/19465812
  26. List of Psychotropic Substances under International Control | http://www.incb.org/documents/Psychotropics/green_lists/Green_list_ENG_2014_85222_GHB.pdf
  27. Alprazolam to be rescheduled from next year | http://www.australiandoctor.com.au/news/latest-news/alprazolam-to-be-rescheduled-from-next-year
  28. "Zweite Verordnung zur Änderung betäubungsmittelrechtlicher Vorschriften" (PDF) (in German). Bundesanzeiger Verlag. Retrieved December 26, 2019. 
  29. "Anlage III BtMG" (in German). Bundesministerium der Justiz und für Verbraucherschutz. Retrieved December 26, 2019. 
  30. Misuse Of Drugs (Amendment) Regulations | http://www.irishstatutebook.ie/1993/en/si/0342.html
  31. Tabella IV Sostanze stupefacenti http://www.salute.gov.it/imgs/C_17_pagineAree_3729_listaFile_itemName_3_file.pdf
  32. Tabella Medicinali D.P.R. 309/90 http://www.salute.gov.it/imgs/C_17_pagineAree_3729_listaFile_itemName_4_file.xls
  33. Постановление Правительства РФ от 04.02.2013 N 78 | https://www.consultant.ru/cons/cgi/online.cgi?req=doc&base=LAW&n=141744&dst=100005&date=02.12.2019
  34. "Läkemedelsverkets föreskrifter (LVFS 2011:10) om förteckningar över narkotika" [Medical Products Agency on the lists of drugs] | http://www.lakemedelsverket.se/upload/lvfs/konsoliderade/LVFS_2011_10_konsoliderad_tom_2012_6.pdf
  35. "Verordnung des EDI über die Verzeichnisse der Betäubungsmittel, psychotropen Stoffe, Vorläuferstoffe und Hilfschemikalien" (in German). Bundeskanzlei [Federal Chancellery of Switzerland]. Retrieved January 1, 2020. 
  36. YEŞİL REÇETEYE TABİ İLAÇLAR | https://www.titck.gov.tr/storage/Archive/2019/contentFile/01.04.2019%20SKRS%20Ye%C5%9Fil%20Re%C3%A7eteli%20%C4%B0la%C3%A7lar%20Aktif%20SON%20-%20G%C3%9CNCEL_58b1ff4a-2e1c-4867-bad7-eec855d6162a.pdf
  37. https://www.gov.uk/government/publications/controlled-drugs-list
  38. DEA, Drug Scheduling | http://www.deadiversion.usdoj.gov/schedules/index.html