Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Alprazolam: Difference between pages

{{Short description|Benzodiazepine medication}}

{{Redirect-multi|2|Xanax|Xanny|the Billie Eilish song|Xanny (song)|other uses}}

{{Use dmy dates|date=January 2024}}

{{Cs1 config|name-list-style=vanc|display-authors=6}}

{{Good article}}

{{Infobox drug

| Watchedfields = changed

| verifiedrevid = 477164519

| image = Alprazolam structure.svg

| width = 135

| alt =

| image2 = Alprazolam ball-and-stick model.png

| alt2 =

| caption = <!-- Clinical data -->

| pronounce = {{IPAc-en|æ|l|'|p|r|æ|z|ə|l|æ|m}} or {{IPAc-en|æ|l|'|p|r|eɪ|z|ə|l|æ|m}}

| tradename = Xanax, others

| DailyMedID = Alprazolam

| pregnancy_AU = C

| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Alprazolam Use During Pregnancy | website=Drugs.com | date=4 May 2020 | url=https://www.drugs.com/pregnancy/alprazolam.html | access-date=8 June 2020 | archive-date=20 June 2020 | archive-url=https://web.archive.org/web/20200620184047/https://www.drugs.com/pregnancy/alprazolam.html | url-status=live }}</ref><ref>{{cite web | title=Prescribing medicines in pregnancy database | website=Therapeutic Goods Administration (TGA) | date=21 June 2022 | url=https://www.tga.gov.au/products/medicines/find-information-about-medicine/prescribing-medicines-pregnancy-database | access-date=17 June 2024 | archive-date=2 March 2023 | archive-url=https://web.archive.org/web/20230302112837/https://www.tga.gov.au/products/medicines/find-information-about-medicine/prescribing-medicines-pregnancy-database | url-status=live }}</ref>

| pregnancy_category =

| dependency_liability = Very High<ref name=Ait2018/>

| addiction_liability = High<ref name="Ait2018" />

| routes_of_administration = [[Oral administration|By mouth]]

| class = [[Benzodiazepine]]

| ATC_prefix = N05

| ATC_suffix = BA12

| ATC_supplemental = <!-- Legal status -->

| legal_AU = S8

| legal_AU_comment = <ref>{{cite web | title=Therapeutic Goods (Poisons Standard—June 2024) Instrument 2024 | website=Federal Register of Legislation | date=30 May 2024 | url=https://www.legislation.gov.au/F2024L00589/latest/text | access-date=17 June 2024}}</ref>

| legal_BR = B1<!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->

| legal_BR_comment =

| legal_CA = Schedule IV

| legal_CA_comment = Targeted (CDSA IV)<ref>{{cite web | title=Xanax Product information | website=[[Health Canada]] | date=20 April 2023 | url=https://health-products.canada.ca/dpd-bdpp/info?lang=eng&code=4471 | access-date=17 June 2024}}</ref>

| legal_DE = Anlage III

| legal_DE_comment = (in doses higher than {{nowrap|1 mg}})

| legal_NZ = <!-- Class A, B, C -->

| legal_NZ_comment =

| legal_UK_comment = /&nbsp;Class C<ref name="Xanax UK SmPC">{{cite web | title=Xanax Summary of Product Characteristics (SmPC) | website=(emc) | date=28 July 2023 | url=https://www.medicines.org.uk/emc/product/1657/smpc | access-date=20 November 2023}}</ref><ref name="misuse of drugs legislation">{{cite web | title=List of most commonly encountered drugs currently controlled under the misuse of drugs legislation | website=GOV.UK | date=20 October 2016 | url=https://www.gov.uk/government/publications/controlled-drugs-list--2/list-of-most-commonly-encountered-drugs-currently-controlled-under-the-misuse-of-drugs-legislation | access-date=20 November 2023 | archive-date=8 December 2019 | archive-url=https://web.archive.org/web/20191208222115/https://www.gov.uk/government/publications/controlled-drugs-list--2/list-of-most-commonly-encountered-drugs-currently-controlled-under-the-misuse-of-drugs-legislation | url-status=live }}</ref>

| legal_US_comment = <ref name="Xanax FDA label">{{cite web | title=Xanax- alprazolam tablet | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=388e249d-b9b6-44c3-9f8f-880eced0239f | access-date=19 February 2021 | archive-date=17 January 2021 | archive-url=https://web.archive.org/web/20210117223138/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=388e249d-b9b6-44c3-9f8f-880eced0239f | url-status=live }}</ref><ref name="Xanax XR FDA label">{{cite web | title=Xanax XR- alprazolam tablet, extended-release | website=DailyMed | date=12 March 2021 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=aa58fff3-c297-49be-838b-599c32ad9835 | access-date=2 June 2022 | archive-date=17 April 2021 | archive-url=https://web.archive.org/web/20210417013226/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=aa58fff3-c297-49be-838b-599c32ad9835 | url-status=live }}</ref><ref>{{cite web | title=Xanax XR- alprazolam tablet, extended-release | website=DailyMed | date=12 April 2023 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c8990714-c2f5-4b0c-9f1c-91d77156d962 | access-date=17 June 2024}}</ref>

| legal_EU = Rx-only

| legal_EU_comment = <ref>{{Cite web|url=https://www.ema.europa.eu/en/documents/psusa/alprazolam-list-nationally-authorised-medicinal-products-psusa00000109202203_en.pdf|title=List of nationally authorised medicinal products}}</ref>

| legal_UN = P IV

| legal_UN_comment =

| legal_status = Rx-only

<!--Pharmacokinetic data-->

| = %

| metabolism = [[Liver]], via [[ P450 3A4]]

| metabolites = * α-hydroxyalprazolam

* 4-hydroxyalprazolam

| onset = 30~60 minutes<ref name=Lill2016>{{cite book |vauthors=Lilley LL, Snyder JS, Collins SR |title=Pharmacology for Canadian Health Care Practice |date=2016 |publisher=Elsevier Health Sciences |isbn=9781771720663 |page=329 |url=https://books.google.com/books?id=dNgoDwAAQBAJ&pg=PA329 |access-date=13 September 2020 |archive-date=10 May 2022 |archive-url=https://web.archive.org/web/20220510111235/https://books.google.com/books?id=dNgoDwAAQBAJ&pg=PA329 |url-status=live }}</ref>

| elimination_half-life = {{plainlist|

*Instant-release:

*11~13 hours<ref name=AHFS2018/>

*Extended-release:

*11~16 hours<ref name=AHFS2018/>}}

| duration_of_action = {{plainlist|

*Instant-release:

*6 hours<ref name=Lill2016/>

*Extended-release:

*11.3 hours}}

| excretion = [[Kidney]]

<!--Identifiers-->

| =

| IUPHAR_ligand = 7111

| NIAID_ChemDB =

| PDB_ligand =

| synonyms = <!-- Chemical and physical data -->

| IUPAC_name = 8-Chloro-1-methyl-6-phenyl-4''H''-[1,2,4]triazolo[4,3-a] [1,4]benzodiazepine

| C = 17

| H = 13

| Cl = 1

| N = 4

| SMILES = Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2

| StdInChI_comment =

| density =

| density_notes =

| melting_point =

| melting_high =

| melting_notes =

| boiling_point =

| boiling_notes =

| solubility =

| sol_units =

| specific_rotation =

<!-- Definition and medical uses -->

'''Alprazolam''', sold under the brand name '''Xanax''' among others, is a fast-acting, potent [[tranquilizer]] of moderate duration within the [[triazolobenzodiazepine]] group of chemicals called [[benzodiazepine]]s.<ref>{{cite book |vauthors=Goldberg R |title=Drugs Across the Spectrum |date=2009 |publisher=Cengage Learning |isbn=9781111782009 |page=195 |url=https://books.google.com/books?id=EZlsCgAAQBAJ&pg=PA195 |access-date=24 August 2017 |archive-date=4 June 2020 |archive-url=https://web.archive.org/web/20200604135538/https://books.google.com/books?id=EZlsCgAAQBAJ&pg=PA195%2F |url-status=live }}</ref> Alprazolam is most commonly prescribed in the management of [[anxiety disorder]]s, especially [[panic disorder]] and [[generalized anxiety disorder]] (GAD).<ref name="Xanax FDA label" /> Other uses include the treatment of [[Chemotherapy-induced nausea and vomiting|chemotherapy-induced nausea]], together with other treatments.<ref name="AHFS2018" /> GAD improvement occurs generally within a week.<ref name="Verster2004">{{cite journal | vauthors = Verster JC, Volkerts ER | title = Clinical pharmacology, clinical efficacy, and behavioral toxicity of alprazolam: a review of the literature | journal = CNS Drug Reviews | volume = 10 | issue = 1 | pages = 45–76 | year = 2004 | pmid = 14978513 | pmc = 6741717 | doi = 10.1111/j.1527-3458.2004.tb00003.x }}</ref><ref>{{cite book |veditors=Tampi RR, Muralee S, Weder ND, Penland H |title=Comprehensive Review of Psychiatry |year=2008 |publisher=Wolters Kluwer/ Lippincott Williams & Wilkins Health |location=Philadelphia, PA |isbn=978-0-7817-7176-4 |page=226 |url=https://books.google.com/books?id=AANMupaUs6UC&pg=PA226 |access-date=13 March 2016 |archive-date=19 March 2017 |archive-url=https://web.archive.org/web/20170319063132/https://books.google.com/books?id=AANMupaUs6UC&pg=PA226 |url-status=live }}</ref> Alprazolam is generally taken [[oral administration|orally]].<ref name="AHFS2018">{{cite web |author1=American Society of Health-System Pharmacists |title=Alprazolam Monograph for Professionals |url=https://www.drugs.com/monograph/alprazolam.html |website=Drugs.com |access-date=25 October 2018 |date=13 November 2017 |archive-date=7 December 2010 |archive-url=https://web.archive.org/web/20101207030717/https://www.drugs.com/monograph/alprazolam.html |url-status=live }}</ref>

<!-- Side effects and mechanism -->

Common side effects include [[sleepiness]], [[Depression (mood)|depression]], [[Reduced affect display|suppressed emotions]], mild to severe [[Ataxia|decreases in motor skills]], [[Hiccup|hiccups]], dulling or declining of [[cognition]], decreased [[alertness]], [[xerostomia|dry mouth]] (mildly), [[Bradycardia|decreased heart rate]], [[CNS depression|suppression]] of [[central nervous system]] activity, impairment of judgment (usually in higher than therapeutic doses), marginal to severe decreases in memory formation, decreased ability to [[Information processing (psychology)|process new information]], as well as partial to complete [[anterograde amnesia]],<ref>{{cite journal | vauthors = Chowdhury ZS, Morshed MM, Shahriar M, Bhuiyan MA, Islam SM, Bin Sayeed MS | title = The Effect of Chronic Alprazolam Intake on Memory, Attention, and Psychomotor Performance in Healthy Human Male Volunteers | journal = Behavioural Neurology | volume = 2016 | pages = 3730940 | date = 2016 | pmid = 27462136 | pmc = 4947648 | doi = 10.1155/2016/3730940 | doi-access = free | title-link = doi }}</ref> depending on dosage.<ref name=AHFS2018/> Some of the sedation and drowsiness may improve within a few days.<ref name=Pav10>{{cite book |vauthors=Pavuluri MN, Janicak PG, Marder SR |title=Principles and Practice of Psychopharmacotherapy |year=2010 |publisher=Wolters Kluwer Health/ Lippincott Williams & Wilkins |location=Philadelphia, PA |isbn=978-1-60547-565-3 |page=535 |url=https://books.google.com/books?id=_ePK9wwcQUMC&pg=PA535 |edition=5th |access-date=13 March 2016 |archive-date=17 July 2020 |archive-url=https://web.archive.org/web/20200717220547/https://books.google.com/books?id=_ePK9wwcQUMC&pg=PA535 |url-status=live }}</ref>

[[Benzodiazepine withdrawal syndrome|Benzodiazepine withdrawal]] symptoms may occur if use is suddenly decreased.<ref name=AHFS2018 /><ref name="Verster2004" />

<!-- History and culture -->

Alprazolam was invented by Jackson Hester Jr. at the [[Upjohn|Upjohn Company]]<ref>{{cite web | last=Ainsworth | first=Susan J. | title=Hester Dies At 80 | website=Chemical & Engineering News | date=9 December 2013 | url=https://cen.acs.org/articles/91/i49/Hester-Dies-80.html | access-date=21 April 2024}}</ref> and patented in 1971 and approved for medical use in the United States in 1981.<ref name=AHFS2018/><ref name=Fis2006>{{cite book |vauthors=Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=536 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA536 |access-date=13 September 2020 |archive-date=28 August 2021 |archive-url=https://web.archive.org/web/20210828082144/https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA536 |url-status=live }}</ref> Alprazolam is a [[Controlled Substances Act#Schedule IV controlled substances|Schedule IV]] controlled substance and is a common drug of abuse.<ref name=Ait2018>{{cite journal | vauthors = Ait-Daoud N, Hamby AS, Sharma S, Blevins D | title = A Review of Alprazolam Use, Misuse, and Withdrawal | journal = Journal of Addiction Medicine | volume = 12 | issue = 1 | pages = 4–10 | date = 2018 | pmid = 28777203 | pmc = 5846112 | doi = 10.1097/ADM.0000000000000350 }}</ref><ref>{{cite book |vauthors=Malamed SF |title=Sedation: A Guide to Patient Management |date=2009 |publisher=Elsevier Health Sciences |isbn=978-0323075961 |page=105 |url=https://books.google.com/books?id=Abp9ci5-n1wC&pg=PA105 |access-date=13 September 2020 |archive-date=10 May 2022 |archive-url=https://web.archive.org/web/20220510111235/https://books.google.com/books?id=Abp9ci5-n1wC&pg=PA105 |url-status=live }}</ref> It is available as a [[generic medication]].<ref name="Xanax FDA label" /> In 2022, it was the 41st most commonly prescribed medication in the United States, with more than 14{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2022 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=30 August 2024 | archive-date=30 August 2024 | archive-url=https://web.archive.org/web/20240830202410/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Alprazolam Drug Usage Statistics, United States, 2013 - 2022 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Alprazolam | access-date = 30 August 2024 }}</ref>

==Medical uses==

[[File:Boites d'alprazolam444.jpg|thumb|Alprazolam pills in boxes, as sold in [[France]]; both the original [[Pfizer]] brand product Xanax and various [[Generic drug|generic forms]] of alprazolam are depicted here.]]

[[File:Xanax 2 mg.jpg|thumb|A prescription bottle of Xanax]]

Alprazolam is used in the management of [[anxiety disorder]]s and [[nausea]] due to [[chemotherapy]].<ref name="AHFS2018" /> Alprazolam is [[indicated]] for the treatment of [[generalized anxiety disorder]] (GAD) and [[panic disorder]] with or without [[agoraphobia]] in adults.<ref name="Xanax FDA label" />

===Panic disorder===

Alprazolam is effective in the relief of moderate to severe [[anxiety]] and [[panic attack]]s.<ref name="Xanax FDA label" /> In [[Australia]], alprazolam is not recommended for the treatment of [[panic disorder]] because of concerns regarding [[Drug tolerance|tolerance]], [[Substance dependence|dependence]], and [[Substance abuse|abuse]].<ref name= Moy2012>{{cite journal | vauthors = Moylan S, Giorlando F, Nordfjærn T, Berk M | title = The role of alprazolam for the treatment of panic disorder in Australia | journal = The Australian and New Zealand Journal of Psychiatry | volume = 46 | issue = 3 | pages = 212–24 | date = March 2012 | pmid = 22391278 | doi = 10.1177/0004867411432074 | s2cid = 11006795 | url = http://www.barglow.com/moylan2012alprazolam.pdf | access-date = 27 October 2012 | archive-date = 22 April 2017 | archive-url = https://web.archive.org/web/20170422062457/http://www.barglow.com/moylan2012alprazolam.pdf | url-status = live }}</ref> Most evidence shows that the benefits of alprazolam in treating panic disorder last only four to ten weeks. However, people with panic disorder have been treated on an open basis for up to eight months without apparent loss of benefit.<ref name="Xanax FDA label" />

Alprazolam is recommended by the World Federation of Societies of Biological Psychiatry (WFSBP) for treatment-resistant cases of panic disorder where there is no history of tolerance or dependence.<ref>{{cite journal | vauthors = Bandelow B, Zohar J, Hollander E, Kasper S, Möller HJ | title = World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and posttraumatic stress disorders | journal = The World Journal of Biological Psychiatry | volume = 3 | issue = 4 | pages = 171–99 | date = October 2002 | pmid = 12516310 | doi = 10.3109/15622970209150621 | doi-access = free | title-link = doi }}</ref>

A 2023 [[meta-analysis]] of published and unpublished FDA-submitted regulatory trials of alprazolam extended-release for panic disorder found that only one of five clinical trials showed a positive efficacy outcome (20%), while the rest were negative and did not demonstrate effectiveness.<ref name="pmid37853797">{{cite journal | vauthors = Ahn-Horst RY, Turner EH | title = Unpublished trials of alprazolam XR and their influence on its apparent efficacy for panic disorder | journal = Psychol Med | volume = 54| issue = 5| pages = 1026–1033 | date = October 2023 | pmid = 37853797 | doi = 10.1017/S0033291723002830 | url = | doi-access = free | title-link = doi }}</ref> In the published literature, three trials were published conveying a positive outcome (100%), but of these, only one was positive and the other two were considered to have been inappropriately spun as positive.<ref name="pmid37853797" /> The [[effect size]] ([[Hedges's g]]) of alprazolam for the treatment of panic disorder based on the five clinical trials was 0.33 (a small effect) and based on the published trials was 0.47 (a moderate effect), equating to an increase of 0.14 or 42%.<ref name="pmid37853797" /> The authors concluded that [[publication bias]] substantially inflated the effectiveness of alprazolam for panic disorder.<ref name="pmid37853797" />

===Anxiety disorders===

[[Anxiety]] associated with [[Major depressive disorder|depression]] is responsive to alprazolam. Clinical studies have shown that the effectiveness is limited to four months for [[anxiety disorder]]s.<ref name="Xanax FDA label" /> However, the research into [[antidepressant]] properties of alprazolam is poor and has only assessed its short-term effects against depression.<ref name="van Marwijk-2012">{{cite journal | vauthors = van Marwijk H, Allick G, Wegman F, Bax A, Riphagen II | title = Alprazolam for depression | journal = The Cochrane Database of Systematic Reviews | volume = 2012 | issue = 7 | pages = CD007139 | date = July 2012 | pmid = 22786504 | pmc = 6769182 | doi = 10.1002/14651858.CD007139.pub2 | url = http://dare.ubvu.vu.nl/bitstream/handle/1871/48567/300660.pdf?sequence=1 | veditors = van Marwijk H | access-date = 18 July 2017 | archive-date = 11 August 2017 | archive-url = https://web.archive.org/web/20170811142853/http://dare.ubvu.vu.nl/bitstream/handle/1871/48567/300660.pdf?sequence=1 | url-status = live }}</ref> In one study, some long term, high-dosage users of alprazolam developed reversible depression.<ref>{{cite journal | vauthors = Lydiard RB, Laraia MT, Ballenger JC, Howell EF | title = Emergence of depressive symptoms in patients receiving alprazolam for panic disorder | journal = The American Journal of Psychiatry | volume = 144 | issue = 5 | pages = 664–5 | date = May 1987 | pmid = 3578580 | doi = 10.1176/ajp.144.5.664 }}</ref>

In the US, alprazolam is [[indicated]] for the treatment of [[generalized anxiety disorder]] and [[panic disorder]] with or without [[agoraphobia]].<ref name="Xanax FDA label" /><ref name="Xanax XR FDA label" />

In the UK, alprazolam is indicated for short-term symptomatic treatment of anxiety in adults.<ref name="Xanax UK SmPC" />

===Chemotherapy-induced nausea and vomiting===

Alprazolam may be used in combination with other medications for [[chemotherapy-induced nausea and vomiting]].<ref name=AHFS2018/>

==Contraindications==

Benzodiazepines require special precaution if used in children and in alcohol- or drug-dependent individuals. Particular care should be taken in pregnant or elderly people, people with [[substance use disorder]] history, particularly [[alcohol dependence]], and people with [[comorbid]] [[mental disorder|psychiatric disorders]].<ref>{{cite journal | vauthors = Authier N, Balayssac D, Sautereau M, Zangarelli A, Courty P, Somogyi AA, Vennat B, Llorca PM, Eschalier A | title = Benzodiazepine dependence: focus on withdrawal syndrome | journal = Annales Pharmaceutiques Françaises | volume = 67 | issue = 6 | pages = 408–13 | date = November 2009 | pmid = 19900604 | doi = 10.1016/j.pharma.2009.07.001}}</ref>

Alprazolam should be avoided or carefully monitored by medical professionals in individuals with [[myasthenia gravis]], acute narrow-angle [[glaucoma]], severe liver deficiencies such as [[cirrhosis]], severe [[sleep apnea]], pre-existing respiratory depression, marked [[neuromuscular]] [[respiratory]], acute [[pulmonary insufficiency]], chronic [[psychosis]], [[hypersensitivity]], [[allergy]] to alprazolam or other benzodiazepines, and [[borderline personality disorder]], where it may induce [[suicidality]] and [[episodic dyscontrol syndrome|dyscontrol]].<ref name=bnf>{{cite web |url=http://www.bnf.org/bnf/bnf/current/3173.htm |archive-url=https://archive.today/20120720173716/http://www.bnf.org/bnf/bnf/current/3173.htm |url-status=dead |archive-date=20 July 2012 |title=Alprazolam |access-date=3 August 2007 |year=2007 |publisher=British National Formulary}}</ref><ref name=hori>{{cite journal | vauthors = Hori A | title = Pharmacotherapy for personality disorders | journal = Psychiatry and Clinical Neurosciences | volume = 52 | issue = 1 | pages = 13–9 | date = February 1998 | pmid = 9682928 | doi = 10.1111/j.1440-1819.1998.tb00967.x | doi-access = | title-link = doi | s2cid = 26667425 }}</ref><ref>{{cite journal | vauthors = Gardner DL, Cowdry RW | title = Alprazolam-induced dyscontrol in borderline personality disorder | journal = The American Journal of Psychiatry | volume = 142 | issue = 1 | pages = 98–100 | date = January 1985 | pmid = 2857071 | doi = 10.1176/ajp.142.1.98 }}</ref>

Like all [[central nervous system]] [[depressant]]s, alprazolam in larger-than-normal doses can cause significant deterioration in [[alertness]] and increase [[drowsiness]], especially in those unaccustomed to the drug's effects.<ref>{{cite journal | vauthors = Kozená L, Frantik E, Horváth M | title = Vigilance impairment after a single dose of benzodiazepines | journal = Psychopharmacology | volume = 119 | issue = 1 | pages = 39–45 | date = May 1995 | pmid = 7675948 | doi = 10.1007/BF02246052 | s2cid = 2618084 }}</ref>

==Side effects==

[[File:Side effects of alprazolam.svg|thumb|[[Side effect]]s from alprazolam]]

[[Sedative]] drugs, including alprazolam, have been associated with an increased risk of death.<ref>{{cite journal | vauthors = Kripke DF | title = Mortality Risk of Hypnotics: Strengths and Limits of Evidence | journal = Drug Safety | volume = 39 | issue = 2 | pages = 93–107 | date = February 2016 | pmid = 26563222 | doi = 10.1007/s40264-015-0362-0 | s2cid = 7946506 | url = https://escholarship.org/content/qt08d9f3d5/qt08d9f3d5.pdf?t=nz1gjv | doi-access = free | title-link = doi | access-date = 29 August 2019 | archive-date = 14 March 2020 | archive-url = https://web.archive.org/web/20200314025805/https://escholarship.org/content/qt08d9f3d5/qt08d9f3d5.pdf?t=nz1gjv | url-status = live }}</ref>

Possible [[side effects]] include:

* [[Anterograde amnesia]]<ref name=Barbee95/>

* [[attention|Concentration]] problems

* [[Ataxia]]

* [[Dysarthria]]<ref>{{cite journal | vauthors = Cassano GB, Toni C, Petracca A, Deltito J, Benkert O, Curtis G, Hippius H, Maier W, Shera D, Klerman G | title = Adverse effects associated with the short-term treatment of panic disorder with imipramine, alprazolam or placebo | journal = European Neuropsychopharmacology | volume = 4 | issue = 1 | pages = 47–53 | date = March 1994 | pmid = 8204996 | doi = 10.1016/0924-977X(94)90314-X | url = https://deepblue.lib.umich.edu/bitstream/handle/2027.42/31721/0000659.pdf | hdl = 2027.42/31721 | s2cid = 14557358 | hdl-access = free | access-date = 18 July 2017 | archive-date = 20 February 2020 | archive-url = https://web.archive.org/web/20200220201013/https://deepblue.lib.umich.edu/bitstream/handle/2027.42/31721/0000659.pdf | url-status = live }}</ref>

* [[Disinhibition]]<ref name="Michel L, Lang JP 2003 479–85">{{cite journal|vauthors=Michel L, Lang JP|year=2003|title=[Benzodiazepines and forensic aspects]|trans-title=Benzodiazepines and Forensic Aspects|url=https://europepmc.org/article/med/15029082|journal=L'Encephale|language=fr|volume=29|issue=6|pages=479–85|pmid=15029082|access-date=31 December 2020|archive-date=2 June 2022|archive-url=https://web.archive.org/web/20220602200027/https://europepmc.org/js/chunk-087ebf1c.0d65fdb7.js|url-status=live}}</ref>

* [[Somnolence|Drowsiness]], [[dizziness]], [[lightheadedness]], [[fatigue]], [[ataxia]], and [[vertigo]]<ref name=drftb>{{cite journal | vauthors = Rawson NS, Rawson MJ | title = Acute adverse event signalling scheme using the Saskatchewan Administrative health care utilization datafiles: results for two benzodiazepines | journal = Canadian Journal of Clinical Pharmacology | volume = 6 | issue = 3 | pages = 159–66 | year = 1999 | pmid = 10495368 }}</ref><ref name="acmirttoadom">{{cite web |url=https://www.medicinenet.com/alprazolam/article.htm |title=Alprazolam – Complete Medical Information Regarding This Treatment of Anxiety Disorders |publisher=MedicineNet |website=Medicinenet.com |access-date=2 August 2007 |archive-date=9 March 2019 |archive-url=https://web.archive.org/web/20190309191305/https://www.medicinenet.com/alprazolam/article.htm |url-status=live }}</ref>

* [[Xerostomia|Dry mouth]] (infrequent)<ref>{{cite journal | vauthors = Elie R, Lamontagne Y | title = Alprazolam and diazepam in the treatment of generalized anxiety | journal = Journal of Clinical Psychopharmacology | volume = 4 | issue = 3 | pages = 125–9 | date = June 1984 | pmid = 6145726 | doi = 10.1097/00004714-198406000-00002 | s2cid = 735484 }}</ref>

* [[Hallucination]]s (rare)<ref name=ase/>

* [[Jaundice]] (very rare)<ref>{{cite journal | vauthors = Noyes R, DuPont RL, Pecknold JC, Rifkin A, Rubin RT, Swinson RP, Ballenger JC, Burrows GD | title = Alprazolam in panic disorder and agoraphobia: results from a multicenter trial. II. Patient acceptance, side effects, and safety | journal = Archives of General Psychiatry | volume = 45 | issue = 5 | pages = 423–8 | date = May 1988 | pmid = 3358644 | doi = 10.1001/archpsyc.1988.01800290037005 }}</ref>

* [[Seizure]] (less common)<ref>{{cite web|url=https://www.mayoclinic.org/drugs-supplements/alprazolam-oral-route/proper-use/drg-20061040?p=1|date=1 May 2019|title=Side Effects|work=[[Mayo Clinic]]|access-date=22 May 2019|archive-date=28 November 2020|archive-url=https://web.archive.org/web/20201128234437/https://www.mayoclinic.org/drugs-supplements/alprazolam-oral-route/proper-use/drg-20061040?p=1|url-status=live}}</ref>

* [[Rash|Skin rash]]

* [[Hypoventilation|Respiratory depression]]

* [[Constipation]]<ref name="drftb" /><ref name="acmirttoadom" />

* [[Suicidal ideation]] or [[suicide]]<ref name=Dobb2017>{{cite journal | vauthors = Dodds TJ | title = Prescribed Benzodiazepines and Suicide Risk: A Review of the Literature | journal = The Primary Care Companion for CNS Disorders | volume = 19 | issue = 2 | date = March 2017 | pmid = 28257172 | doi = 10.4088/PCC.16r02037 | doi-access = free | title-link = doi }}</ref>

* [[Urinary retention]] (infrequent)<ref name=ase>{{cite web |url=https://www.drugs.com/alprazolam.html |title=Alprazolam Side Effects, Interactions and Information |access-date=2 August 2007 |website=Drugs.com |archive-url=https://web.archive.org/web/20070819005943/http://www.drugs.com/alprazolam.html |archive-date=19 August 2007 |url-status=live}}</ref>

*[[Muscle weakness]]{{medical citation needed|date=August 2023}}

In September 2020, the U.S. [[Food and Drug Administration]] (FDA) required that [[boxed warning]]s for all benzodiazepine medications be updated to describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class.<ref>{{cite web | title=FDA expands Boxed Warning to improve safe use of benzodiazepine drug | website=U.S. [[Food and Drug Administration]] (FDA) | date=23 September 2020 | url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-requiring-boxed-warning-updated-improve-safe-use-benzodiazepine-drug-class | access-date=23 September 2020 | archive-date=24 September 2020 | archive-url=https://web.archive.org/web/20200924002523/https://www.fda.gov/drugs/drug-safety-and-availability/fda-requiring-boxed-warning-updated-improve-safe-use-benzodiazepine-drug-class | url-status=live }} {{PD-notice}}</ref>

===Paradoxical reactions===

Although unusual, the following [[paradoxical reaction]]s have been shown to occur:

* [[Aggression]]<ref>{{cite journal | vauthors = Rapaport M, Braff DL | title = Alprazolam and hostility | journal = The American Journal of Psychiatry | volume = 142 | issue = 1 | pages = 146a–146 | date = January 1985 | pmid = 2857070 | doi = 10.1176/ajp.142.1.146a }}</ref>

* [[Mania]], [[psychomotor agitation|agitation]], [[Attention deficit hyperactivity disorder|hyperactivity]], and [[Psychomotor agitation|restlessness]]<ref>{{cite journal | vauthors = Arana GW, Pearlman C, Shader RI | title = Alprazolam-induced mania: two clinical cases | journal = The American Journal of Psychiatry | volume = 142 | issue = 3 | pages = 368–9 | date = March 1985 | pmid = 2857534 | doi = 10.1176/ajp.142.3.368 }}</ref><ref>{{cite journal | vauthors = Strahan A, Rosenthal J, Kaswan M, Winston A | title = Three case reports of acute paroxysmal excitement associated with alprazolam treatment | journal = The American Journal of Psychiatry | volume = 142 | issue = 7 | pages = 859–61 | date = July 1985 | pmid = 2861755 | doi = 10.1176/ajp.142.7.859 | citeseerx = 10.1.1.461.6316 }}</ref><ref>{{cite journal | vauthors = Reddy J, Khanna S, Anand U, Banerjee A | title = Alprazolam-induced hypomania | journal = The Australian and New Zealand Journal of Psychiatry | volume = 30 | issue = 4 | pages = 550–2 | date = August 1996 | pmid = 8887708 | doi = 10.3109/00048679609065031 | citeseerx = 10.1.1.941.5119 | s2cid = 38542776 }}</ref>

* [[Rage (emotion)|Rage]] and hostility<ref name="Michel L, Lang JP 2003 479–85"/>

* [[Fasciculation|Twitches]] and [[tremor]]<ref>{{cite journal | vauthors = Béchir M, Schwegler K, Chenevard R, Binggeli C, Caduff C, Büchi S, Buddeberg C, Lüscher TF, Noll G | title = Anxiolytic therapy with alprazolam increases muscle sympathetic activity in patients with panic disorders | journal = Autonomic Neuroscience | volume = 134 | issue = 1–2 | pages = 69–73 | date = July 2007 | pmid = 17363337 | doi = 10.1016/j.autneu.2007.01.007 | s2cid = 44980758 }}</ref>

===Food and drug interactions===

Alprazolam is primarily [[metabolised|metabolized]] via [[CYP3A4]].<ref name="Otani-2003">{{cite journal | vauthors = Otani K | title = [Cytochrome P450 3A4 and Benzodiazepines] | language = ja | journal = Seishin Shinkeigaku Zasshi = Psychiatria et Neurologia Japonica | volume = 105 | issue = 5 | pages = 631–42 | year = 2003 | pmid = 12875231 }}</ref> Combining CYP3A4 inhibitors such as [[cimetidine]], [[erythromycin]], [[norfluoxetine]], [[fluvoxamine]], [[itraconazole]], [[ketoconazole]], [[nefazodone]], [[propoxyphene]], and [[ritonavir]] delay the [[hepatic]] clearance of alprazolam, which may result in its accumulation<ref>{{cite journal | vauthors = Dresser GK, Spence JD, Bailey DG | title = Pharmacokinetic-pharmacodymic consequences and clinical relevance of cytochrome P450 3A4 inhibition | journal = Clinical Pharmacokinetics | volume = 38 | issue = 1 | pages = 41–57 | date = January 2000 | pmid = 10668858 | doi = 10.2165/00003088-200038010-00003 | s2cid = 37743328 }}</ref> and increased severity of its side effects.<ref name=cpoati>{{cite journal | vauthors = Greenblatt DJ, Wright CE | title = Clinical pharmacokinetics of alprazolam. Therapeutic implications | journal = Clinical Pharmacokinetics | volume = 24 | issue = 6 | pages = 453–71 | date = June 1993 | pmid = 8513649 | doi = 10.2165/00003088-199324060-00003 | s2cid = 46252882 }}</ref><ref>{{cite journal | vauthors = Wang JS, DeVane CL | title = Pharmacokinetics and drug interactions of the sedative hypnotics | journal = Psychopharmacology Bulletin | volume = 37 | issue = 1 | pages = 10–29 | year = 2003 | doi = 10.1007/BF01990373 | pmid = 14561946 | s2cid = 1543185 | url = http://www.medworksmedia.com/psychopharmbulletin/pdf/12/010-029_PB%20W03_Wang_final.pdf | archive-url = https://web.archive.org/web/20070709230745/http://www.medworksmedia.com/psychopharmbulletin/pdf/12/010-029_PB%20W03_Wang_final.pdf | archive-date = 9 July 2007 }}</ref>

[[Imipramine]] and [[desipramine]] have been reported to increase an average of 31% and 20% respectively by the [[concomitant drug|concomitant]] administration of alprazolam tablets.<ref name="Xanax FDA label" /> [[Combined oral contraceptive pill]]s reduce the clearance of alprazolam, which may lead to increased plasma levels of alprazolam and accumulation.<ref>{{cite journal | vauthors = Back DJ, Orme ML | title = Pharmacokinetic drug interactions with oral contraceptives | journal = Clinical Pharmacokinetics | volume = 18 | issue = 6 | pages = 472–84 | date = June 1990 | pmid = 2191822 | doi = 10.2165/00003088-199018060-00004 | s2cid = 32523973 }}</ref>

[[alcohol (drug)|Alcohol]] is one of the most common interactions; alcohol and alprazolam taken in combination have a [[synergistic]] effect on one another, which can cause severe sedation, behavioral changes, and intoxication. The more alcohol and alprazolam taken, the worse the interaction.<ref name="Michel L, Lang JP 2003 479–85"/> Combination of alprazolam with the herb [[kava]] can result in the development of a semi-[[coma]]tose state.<ref>{{cite journal|vauthors=Izzo AA, Ernst E|year=2001|title=Interactions between herbal medicines and prescribed drugs: a systematic review|url=https://link.springer.com/article/10.2165/00003495-200161150-00002|journal=Drugs|volume=61|issue=15|pages=2163–75|doi=10.2165/00003495-200161150-00002|pmid=11772128|s2cid=46983699|access-date=31 December 2020|archive-date=25 May 2021|archive-url=https://web.archive.org/web/20210525182102/https://link.springer.com/article/10.2165%2F00003495-200161150-00002|url-status=live}}</ref> Plants in the genus ''[[Hypericum]]'', including [[St. John's wort]], conversely can lower the plasma levels of alprazolam and reduce its therapeutic effect.<ref>{{cite journal | vauthors = Izzo AA | title = Drug interactions with St. John's Wort (Hypericum perforatum): a review of the clinical evidence | journal = International Journal of Clinical Pharmacology and Therapeutics | volume = 42 | issue = 3 | pages = 139–48 | date = March 2004 | pmid = 15049433 | doi = 10.5414/CPP42139 }}</ref><ref>{{cite journal | vauthors = Madabushi R, Frank B, Drewelow B, Derendorf H, Butterweck V | title = Hyperforin in St. John's wort drug interactions | journal = European Journal of Clinical Pharmacology | volume = 62 | issue = 3 | pages = 225–33 | date = March 2006 | pmid = 16477470 | doi = 10.1007/s00228-006-0096-0 | s2cid = 22510479 }}</ref><ref>{{cite journal | vauthors = Izzo AA, Ernst E | title = Interactions between herbal medicines and prescribed drugs: an updated systematic review | journal = Drugs | volume = 69 | issue = 13 | pages = 1777–98 | year = 2009 | pmid = 19719333 | doi = 10.2165/11317010-000000000-00000 | s2cid = 25720882 }}</ref>

===Pregnancy and breastfeeding===

Benzodiazepines cross the [[placenta]], enter the [[fetus]], and are also excreted in [[breast milk]].<ref name="Xanax FDA label" />

The use of alprazolam during [[pregnancy]] is associated with [[congenital abnormalities]],<ref name="Xanax FDA label" /><ref>{{cite journal | vauthors = Oo CY, Kuhn RJ, Desai N, Wright CE, McNamara PJ | title = Pharmacokinetics in lactating women: prediction of alprazolam transfer into milk | journal = British Journal of Clinical Pharmacology | volume = 40 | issue = 3 | pages = 231–6 | date = September 1995 | pmid = 8527284 | pmc = 1365102 | doi = 10.1111/j.1365-2125.1995.tb05778.x }}</ref> and use in the last trimester may cause fetal [[drug dependence]] and [[withdrawal symptoms]] in the post-natal period as well as neonatal flaccidity and respiratory problems.<ref>{{cite journal | vauthors = Iqbal MM, Sobhan T, Ryals T | title = Effects of commonly used benzodiazepines on the fetus, the neonate, and the nursing infant | journal = Psychiatric Services | volume = 53 | issue = 1 | pages = 39–49 | date = January 2002 | pmid = 11773648 | doi = 10.1176/appi.ps.53.1.39 | url = https://e-lactancia.org/media/papers/2013/12/beanzodiacepinaBF-2002.pdf | access-date = 18 July 2017 | archive-date = 26 March 2018 | archive-url = https://web.archive.org/web/20180326141422/http://e-lactancia.org/media/papers/2013/12/beanzodiacepinaBF-2002.pdf | url-status = live }}</ref><ref>{{cite journal | vauthors = García-Algar O, López-Vílchez MA, Martín I, Mur A, Pellegrini M, Pacifici R, Rossi S, Pichini S | title = Confirmation of gestational exposure to alprazolam by analysis of biological matrices in a newborn with neonatal sepsis | journal = Clinical Toxicology | volume = 45 | issue = 3 | pages = 295–8 | year = 2007 | pmid = 17453885 | doi = 10.1080/15563650601072191 | s2cid = 2155435 }}</ref> However, in long-term users of benzodiazepines, abrupt discontinuation due to concerns of [[teratogenesis]] has a high risk of causing extreme withdrawal symptoms and a severe [[rebound effect]] of the underlying [[mental health disorder]]. [[Spontaneous abortions]] may also result from abrupt withdrawal of psychotropic medications, including benzodiazepines.<ref>{{cite journal | vauthors = Einarson A, Selby P, Koren G | title = Abrupt discontinuation of psychotropic drugs during pregnancy: fear of teratogenic risk and impact of counselling | journal = Journal of Psychiatry & Neuroscience | volume = 26 | issue = 1 | pages = 44–8 | date = January 2001 | pmid = 11212593 | pmc = 1408034 }}</ref>

===Overdose===

{{Main|Benzodiazepine overdose}}

[[File:Xanax 0.25, 0.5 & 1 mg.jpg|thumb|Xanax 0.25 mg. (top row), 0.5 mg. (middle row), and 1 mg. (bottom row) tablets]]

The maximum recommended daily dose is 10 milligrams per day.<ref name="Xanax FDA label" />

Overdoses of alprazolam can be mild to severe depending on the quantity ingested and if other drugs are taken in combination.<ref>{{cite journal | vauthors = Isbister GK, O'Regan L, Sibbritt D, Whyte IM | title = Alprazolam is relatively more toxic than other benzodiazepines in overdose | journal = British Journal of Clinical Pharmacology | volume = 58 | issue = 1 | pages = 88–95 | date = July 2004 | pmid = 15206998 | pmc = 1884537 | doi = 10.1111/j.1365-2125.2004.02089.x | doi-access = free | title-link = doi }}</ref>

Alprazolam overdoses cause excess [[central nervous system]] (CNS) depression.<ref name=ase/>

===Dependence and withdrawal===

{{See also|Benzodiazepine dependence|Benzodiazepine withdrawal syndrome}}

The potential for misuse among those taking it for medical reasons is controversial, with some expert reviews stating that the risk is low and similar to that of other benzodiazepine drugs.<ref name= "APAguide">{{cite book |doi=10.1176/appi.books.9780890423905.154688 |title=APA Practice Guideline for the Treatment of Patients With Panic Disorder |volume=1 |edition=2nd |author=Work Group on Panic Disorder |date=January 2009 |url=https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/panicdisorder.pdf |isbn=978-0-89042-385-1 |access-date=25 October 2018 |archive-date=7 June 2019 |archive-url=https://web.archive.org/web/20190607004900/http://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/panicdisorder.pdf |url-status=live }}</ref> Others state that there is a substantial risk of misuse and dependence in both patients and non-medical users and that the short half-life and rapid onset of action may increase the risk of misuse.<ref name=AHFS2018/><ref name=Moy2012/> Compared to the large number of prescriptions, relatively few individuals increase their dose on their own initiative or engage in [[drug-seeking behavior]].<ref name= DEAbrief>{{cite web |url=https://www.justice.gov/dea/concern/b.html |archive-url=https://web.archive.org/web/20090312084246/http://www.justice.gov/dea/concern/b.html |archive-date=12 March 2009 |access-date=1 October 2011 |title=DEA Brief Benzodiazepines |quote=Given the millions of prescriptions written for benzodiazepines (about 100 million in 1999), relatively few individuals increase their dose on their own initiative or engage in drug-seeking behavior.}}</ref>

Alprazolam, like other benzodiazepines, binds to specific sites on the GABA_A ([[γ-Aminobutyric acid|gamma-aminobutyric acid]]) receptor. When bound to these sites, which are referred to as benzodiazepine receptors, it modulates the effect of GABA_A receptors and, thus, of GABAergic neurons.<ref name=":0" />{{Unreliable medical source|date=April 2024}} Long-term use causes adaptive changes in the benzodiazepine receptors, making them less sensitive to stimulation and thus making the drugs less potent.<ref name=":1">{{cite book| vauthors = Stahl SM |url=https://www.worldcat.org/oclc/43051626|title=Essential psychopharmacology: neuroscientific basis and practical application|date=June 2000|publisher=Cambridge University Press|isbn=0-521-64154-3|edition=2nd|location=Cambridge, United Kingdom|pages=501–502|oclc=43051626}}</ref>

[[Drug withdrawal|Withdrawal]] and [[rebound symptoms]] commonly occur and necessitate a gradual reduction in dosage to minimize withdrawal effects when discontinuing.<ref name=Verster2004/>

Not all withdrawal effects are evidence of true dependence or withdrawal. Recurrence of symptoms such as anxiety may simply indicate that the drug was having its expected anti-anxiety effect and that, in the absence of the drug, the symptom has returned to pretreatment levels. If the symptoms are more severe or frequent, the person may be experiencing a [[rebound effect]] due to the removal of the drug. Either of these can occur without the person actually being drug dependent.<ref name=":1" />

Alprazolam and other benzodiazepines may also cause the development of [[physical dependence]], [[drug tolerance|tolerance]], and [[benzodiazepine withdrawal symptoms]] during rapid dose reduction or cessation of therapy after long-term treatment.<ref>{{cite journal | vauthors = Juergens SM, Morse RM | title = Alprazolam dependence in seven patients | journal = The American Journal of Psychiatry | volume = 145 | issue = 5 | pages = 625–7 | date = May 1988 | pmid = 3258735 | doi = 10.1176/ajp.145.5.625 }}</ref><ref>{{cite journal | vauthors = Klein E | title = The role of extended-release benzodiazepines in the treatment of anxiety: a risk-benefit evaluation with a focus on extended-release alprazolam | journal = The Journal of Clinical Psychiatry | volume = 63 | issue = Suppl 14 | pages = 27–33 | year = 2002 | pmid = 12562116 | url = https://www.psychiatrist.com/jcp/role-extended-release-benzodiazepines-treatment-anxiety/ | url-access = registration | access-date = 18 July 2017 | archive-date = 29 August 2017 | archive-url = https://web.archive.org/web/20170829114249/http://www.psychiatrist.com/JCP/article/Pages/2002/v63s14/v63s1406.aspx | url-status = live }}</ref> There is a higher chance of withdrawal reactions if the drug is administered in a higher dosage than recommended, or if a person stops taking the medication altogether without slowly allowing the body to adjust to a lower-dosage regimen.<ref name="Ashton manual">{{cite web |url=https://www.benzo.org.uk/manual/ |title=The Ashton Manual – Benzodiazepines: How They Work and How to Withdraw |access-date=31 October 2008 |vauthors=Ashton H |date=August 2002 |publisher=Benzo.org.uk |archive-date=14 September 2008 |archive-url=https://web.archive.org/web/20080914131610/http://www.benzo.org.uk/manual/ |url-status=live }}</ref><ref>{{cite journal | vauthors = Closser MH, Brower KJ | title = Treatment of alprazolam withdrawal with chlordiazepoxide substitution and taper | journal = Journal of Substance Abuse Treatment | volume = 11 | issue = 4 | pages = 319–23 | year = 1994 | pmid = 7966502 | doi = 10.1016/0740-5472(94)90042-6 | url = https://deepblue.lib.umich.edu/bitstream/handle/2027.42/31476/0000398.pdf?sequence=1&isAllowed=y | hdl = 2027.42/31476 | hdl-access = free | access-date = 18 July 2017 | archive-date = 29 June 2020 | archive-url = https://web.archive.org/web/20200629224131/https://deepblue.lib.umich.edu/bitstream/handle/2027.42/31476/0000398.pdf?sequence=1&isAllowed=y | url-status = live }}</ref>

In 1992, Romach and colleagues reported that dose escalation is not a characteristic of long-term alprazolam users and that the majority of long-term alprazolam users change their initial pattern of regular use to one of symptom control only when required.<ref>{{cite journal | vauthors = Romach MK, Somer GR, Sobell LC, Sobell MB, Kaplan HL, Sellers EM | title = Characteristics of long-term alprazolam users in the community | journal = Journal of Clinical Psychopharmacology | volume = 12 | issue = 5 | pages = 316–321 | date = October 1992 | pmid = 1479048 | doi = 10.1097/00004714-199210000-00004 | s2cid = 7738529 }}</ref>

Some common symptoms of alprazolam discontinuation include [[malaise]], weakness, [[insomnia]], [[tachycardia]], lightheadedness, and dizziness.<ref>{{cite journal | vauthors = Fyer AJ, Liebowitz MR, Gorman JM, Campeas R, [[Adeera Levin|Levin A]], Davies SO, Goetz D, Klein DF | title = Discontinuation of alprazolam treatment in panic patients | journal = The American Journal of Psychiatry | volume = 144 | issue = 3 | pages = 303–8 | date = March 1987 | pmid = 3826428 | doi = 10.1176/ajp.144.3.303 | url = https://www.benzo.org.uk/alprazolam.htm | access-date = 10 December 2008 | archive-date = 1 November 2019 | archive-url = https://web.archive.org/web/20191101080725/https://www.benzo.org.uk/alprazolam.htm | url-status = live }}</ref>

Those taking more than 4&nbsp;mg per day have an increased potential for dependence. This medication may cause withdrawal symptoms upon abrupt withdrawal or rapid tapering, which in some cases have been known to cause seizures, as well as marked [[delirium]] similar to that produced by the [[anticholinergic]] tropane alkaloids of Datura ([[hyoscine hydrobromide|scopolamine]] and [[atropine]]).<ref>{{cite journal | vauthors = Breier A, Charney DS, Nelson JC | title = Seizures induced by abrupt discontinuation of alprazolam | journal = The American Journal of Psychiatry | volume = 141 | issue = 12 | pages = 1606–7 | date = December 1984 | pmid = 6150649 | doi = 10.1176/ajp.141.12.1606 }}</ref><ref>{{cite journal | vauthors = Noyes R, Perry PJ, Crowe RR, Coryell WH, Clancy J, Yamada T, Gabel J | title = Seizures following the withdrawal of alprazolam | journal = The Journal of Nervous and Mental Disease | volume = 174 | issue = 1 | pages = 50–2 | date = January 1986 | pmid = 2867122 | doi = 10.1097/00005053-198601000-00009 }}</ref><ref>{{cite journal | vauthors = Levy AB | title = Delirium and seizures due to abrupt alprazolam withdrawal: case report | journal = The Journal of Clinical Psychiatry | volume = 45 | issue = 1 | pages = 38–9 | date = January 1984 | pmid = 6141159 }}</ref> The discontinuation of this medication may also cause rebound anxiety.{{medical citation needed|date=August 2023}}

In a 1983 study, only 5% of patients who abruptly ceased taking long-acting benzodiazepines after less than eight months demonstrated withdrawal symptoms, but 43% who had been taking them for more than eight months did. With alprazolam, a short-acting benzodiazepine, taken for eight weeks, 65% of patients experienced significant rebound anxiety. To some degree, these older benzodiazepines are self-tapering.<ref name="Schatzberg">{{cite book |vauthors=Schatzberg A, DeBattista C |url=https://books.google.com/books?id=D3zz1NCm3qcC&pg=391 |title=Manual of Clinical Psychopharmacology |publisher=American Psychiatric Pub. |year=2003 |location=Washington, DC |page=391 |isbn=978-1-58562-209-2 |access-date=22 January 2014 |archive-date=26 June 2014 |archive-url=https://web.archive.org/web/20140626214152/http://books.google.com/books?id=D3zz1NCm3qcC&pg=391 |url-status=live }}</ref>

The benzodiazepines [[diazepam]] and [[oxazepam]] have been found to produce fewer withdrawal reactions than alprazolam, [[temazepam]], or [[lorazepam]]. Factors that determine the risk of [[substance dependence|psychological dependence]] or [[physical dependence]] and the severity of the [[benzodiazepine withdrawal symptoms]] during dose reduction of alprazolam include: dosage used, length of use, frequency of dosing, personality characteristics of the individual, previous use of cross-dependent/cross-tolerant drugs (alcohol or other sedative-hypnotic drugs), current use of cross-dependent/-tolerant drugs, use of other short-acting, high-potency benzodiazepines,<ref name="wolf1991">{{cite journal | vauthors = Wolf B, Griffiths RR | title = Physical dependence on benzodiazepines: differences within the class | journal = Drug and Alcohol Dependence | volume = 29 | issue = 2 | pages = 153–6 | date = December 1991 | pmid = 1686752 | doi = 10.1016/0376-8716(91)90044-Y | doi-access = free | title-link = doi }}</ref><ref>{{cite journal | vauthors = Higgitt A, Fonagy P, Lader M | title = The natural history of tolerance to the benzodiazepines | journal = Psychological Medicine. Monograph Supplement | volume = 13 | pages = 1–55 | year = 1988 | pmid = 2908516 | doi = 10.1017/S0264180100000412 | s2cid = 38037200 }}</ref> and method of discontinuation.<ref name="Ashton manual"/>

==Pharmacology==

[[File:6huo GABAA-Rezeptorstruktur.png|thumb|Alprazolam binds at the α1β3γ2 [[GABAA receptor]].

Alprazolam with red space-filling [[carbon]] atoms. γ2 receptor subunit in mint green. The α1' subunit is hidden.<ref name="Masiulis_2019">{{cite journal | vauthors = Masiulis S, Desai R, Uchański T, Serna Martin I, Laverty D, Karia D, Malinauskas T, Zivanov J, Pardon E, Kotecha A, Steyaert J, Miller KW, Aricescu AR | title = GABA_A receptor signalling mechanisms revealed by structural pharmacology | journal = Nature | volume = 565 | issue = 7740 | pages = 454–459 | date = January 2019 | pmid = 30602790 | pmc = 6370056 | doi = 10.1038/s41586-018-0832-5 | bibcode = 2019Natur.565..454M }}</ref>]]

Alprazolam is a [[GABAA receptor positive allosteric modulators|GABA_A receptor positive allosteric modulator]].<ref name=":0">{{cite web |title=Alprazolam |url=https://thedrugclassroom.com/video/alprazolam/ |website=The Drug Classroom |access-date=21 January 2019 |archive-date=22 January 2019 |archive-url=https://web.archive.org/web/20190122094609/https://thedrugclassroom.com/video/alprazolam/ |url-status=live }}</ref>{{Unreliable medical source|date=April 2024}} When it binds to the receptor, effects of [[GABA]] are enhanced, leading to inhibition of neurons in the brain. This results in effects including reduced anxiety, muscle relaxant, and anticonvulsant activity.<ref>{{cite journal | vauthors = Huybrechts I | title = The pharmacology of alprazolam: a review | journal = Clinical Therapeutics | volume = 13 | issue = 1 | pages = 100–117 | date = 1991 | pmid = 2029716 }}</ref> The activity of alprazolam in the central nervous system is dose-dependent.<ref name="Xanax FDA label" />

===Mechanism of action===

Alprazolam is classed as a high-potency [[triazolobenzodiazepine]]:<ref>{{cite journal |vauthors=Skelton KH, Nemeroff CB, Owens MJ |title=Spontaneous withdrawal from the triazolobenzodiazepine alprazolam increases cortical corticotropin-releasing factor mRNA expression |journal=The Journal of Neuroscience |volume=24 |issue=42 |pages=9303–9312 |date=October 2004 |pmid=15496666 |pmc=6730084 |doi=10.1523/JNEUROSCI.1737-04.2004 |doi-access=free | title-link = doi }}</ref><ref>{{cite journal |vauthors=Chouinard G |title=Issues in the clinical use of benzodiazepines: potency, withdrawal, and rebound |journal=The Journal of Clinical Psychiatry |volume=65 |issue=Suppl 5 |pages=7–12 |year=2004 |pmid=15078112 |url=https://www.psychiatrist.com/pcc/issues-clinical-benzodiazepines-potency-withdrawal/ |url-access=registration |access-date=18 July 2017 |archive-date=29 August 2017 |archive-url=https://web.archive.org/web/20170829052925/http://www.psychiatrist.com/JCP/article/Pages/2004/v65s05/v65s0502.aspx |url-status=live }}</ref> a benzodiazepine with a [[1,2,4-Triazole|triazole ring]] attached to its structure. As a benzodiazepine, alprazolam produces a variety of therapeutic and adverse effects by binding to the [[GABA A receptor|GABA_A]] benzodiazepine receptor site and modulating its function; [[GABA receptor]]s are the most prolific inhibitory receptor within the brain. The GABA chemical and receptor system mediates the inhibitory or calming effects of alprazolam on the nervous system. The binding of alprazolam to the GABA_A receptor, a chloride ion channel, enhances the effects of GABA, a [[neurotransmitter]]. When GABA binds the GABA_A 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.<ref>{{cite book|title=Top 100 Drugs: Clinical Pharmacology and Practical Prescribing|vauthors=Andrew H, Lonsdale D, Burrage D, Baker E |isbn=9780702055164|location=Edinburgh|oclc=864676781|year=2014}}</ref><ref>{{cite journal |vauthors=Huybrechts I |title=The pharmacology of alprazolam: a review |journal=Clinical Therapeutics |volume=13 |issue=1 |pages=100–117 |date=January 1991 |pmid=2029716}}</ref>

The GABA_A receptor is made up of 5 subunits out of a possible 19, and GABA_A 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.<ref name="Barbee95">{{cite journal |vauthors=Barbee JG |title=Memory, benzodiazepines, and anxiety: integration of theoretical and clinical perspectives |journal=The Journal of Clinical Psychiatry |volume=54 |issue=Suppl |pages=86–97; discussion 98–101 |date=October 1993 |pmid=8262893}}</ref><ref>{{cite journal |vauthors=White G, Gurley DA |title=Alpha subunits influence Zn block of gamma 2 containing GABAA receptor currents |journal=NeuroReport |volume=6 |issue=3 |pages=461–464 |date=February 1995 |pmid=7766843 |doi=10.1097/00001756-199502000-00014}}</ref> This is perhaps due to the similarities shared with [[tricyclic antidepressant]]s, 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]]<ref>{{cite journal |vauthors=Arvat E, Giordano R, Grottoli S, Ghigo E |title=Benzodiazepines and anterior pituitary function |journal=Journal of Endocrinological Investigation |volume=25 |issue=8 |pages=735–47 |date=September 2002 |pmid=12240908 |doi=10.1007/bf03345110 |s2cid=32002501}}</ref> and [[Amnesia|amnesic]]; however, it is used mainly as an anxiolytic.<ref>{{cite web |author-link=United States National Library of Medicine |title=PubChem Compound Summary for CID 2118, Alprazolam |url=https://pubchem.ncbi.nlm.nih.gov/compound/2118 |url-status=live |archive-url=https://web.archive.org/web/20231219033646/https://pubchem.ncbi.nlm.nih.gov/compound/Alprazolam |archive-date=19 December 2023 |access-date=19 December 2023 |website=PubChem }}</ref>

Giving alprazolam, as compared to [[lorazepam]], has been demonstrated to elicit a statistically significant increase in extracellular [[dopamine]] [[dopamine receptor D1|D1]] and [[dopamine receptor D2|D2]] concentrations in the [[striatum]].<ref>{{cite journal |vauthors=Bentué-Ferrer D, Reymann JM, Tribut O, Allain H, Vasar E, Bourin M |title=Role of dopaminergic and serotonergic systems on behavioral stimulatory effects of low-dose alprazolam and lorazepam |journal=European Neuropsychopharmacology |volume=11 |issue=1 |pages=41–50 |date=February 2001 |pmid=11226811 |doi=10.1016/S0924-977X(00)00137-1 |s2cid=24653686}}</ref><ref>{{cite journal |vauthors=Giardino L, Zanni M, Pozza M, Bettelli C, Covelli V |title=Dopamine receptors in the striatum of rats exposed to repeated restraint stress and alprazolam treatment |journal=European Journal of Pharmacology |volume=344 |issue=2–3 |pages=143–7 |date=March 1998 |pmid=9600648 |doi=10.1016/s0014-2999(97)01608-7}}</ref>

===Pharmacokinetics===

[[File:Alprazolam metabolism.svg|thumb|Alprazolam metabolized into 4-hydroxyalprazolam (top) and α-hydroxyalprazolam (bottom)]]

Alprazolam is taken orally, and is absorbed well – 80% of alprazolam binds to [[blood proteins|proteins in the serum]] (the majority binding to [[albumin]]). The concentration of alprazolam peaks after one to two hours.<ref name="Xanax FDA label" />

Alprazolam is metabolized in the liver, mostly by the [[cytochrome]] enzyme [[CYP3A4]]. Two major metabolites are produced: 4-hydroxyalprazolam and α-hydroxyalprazolam, as well as an inactive [[benzophenone]]. The low concentrations and low potencies of 4-hydroxyalprazolam and α-hydroxyalprazolam indicate that they have little to no contribution to the effects of alprazolam.<ref name="Xanax FDA label" />

The metabolites and some unmetabolized alprazolam are filtered out by the kidneys and are excreted in the urine.<ref name="Xanax FDA label" />

==Chemistry==

===Physical properties===

Alprazolam is a [[triazole]] and [[benzodiazepine]] derivative 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.<ref name=SED>{{cite book| vauthors = Ruben V, Hruby V |title=Synthesis of Essential Drugs |year=2006 | pages = 76–77 | edition = 1 | publisher=[[Elsevier]] Science | isbn = 9780444521668}}</ref> It is slightly soluble in [[chloroform]], soluble in [[Alcohol (chemistry)|alcohol]], slightly soluble in [[acetone]] and insoluble in water.<ref name=merck>{{cite book | vauthors = O'Neil MJ, Smith A, Heckelman PE, Budavari S | date = 2013 | title = The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals |publisher=Merck |location=Whitehouse Station, N.J. |isbn= 978-1-84973-670-1 |edition= Fifteenth | page = 58 }}</ref> It has a [[melting point]] of {{convert|228|-|229.5|C|F K}}.<ref name=merck/><ref name="Patent3">{{cite patent | country = US | number = 3709898 | url = https://patents.google.com/patent/US3709898A/en?oq=3.709.898+ | title = Process for the production of triazolobenzodiazepines and intermediates | inventor = Hester JJ | assign1 = Upjohn Company | gdate = 9 January 1973 | postscript = . }} {{Webarchive|url=https://web.archive.org/web/20200221210103/https://patents.google.com/patent/US3709898A/en%3Foq%3D3.709.898%2B |date=21 February 2020 }} {{cite web |url=https://patents.google.com/patent/US3709898A/en%3Foq%3D3.709.898%2B |title=Process for the production of triazolobenzodiazepines and intermediates |access-date=2 June 2022 |archive-date=21 February 2020 |archive-url=https://web.archive.org/web/20200221210103/https://patents.google.com/patent/US3709898A/en%3Foq%3D3.709.898%2B }}</ref>

===Synthesis===

For the synthesis of alprazolam the same method can be used as for [[triazolam]], excepting that it starts from 2-amino-5-chlorobenzophenone.<ref name="Patent">{{cite patent | url = https://patents.google.com/patent/US3987052 | country = US | number = 3987052 | title = 6-Phenyl-4H-s-triazolo(4,3-a)(1,4)benzodiazepines | assign1 = Upjohn Company | inventor = Hester Jr JB | gdate = 19 October 1976 }} {{Webarchive|url=https://web.archive.org/web/20200220232745/https://patents.google.com/patent/US3987052 |date=20 February 2020 }} {{cite web |url=https://patents.google.com/patent/US3987052 |title=6-Phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepines |access-date=21 February 2020 |archive-date=20 February 2020 |archive-url=https://web.archive.org/web/20200220232745/https://patents.google.com/patent/US3987052 }}</ref> However, an alternative easier synthesis starting with 2,6-dichloro-4-phenylquinoline has been suggested, in which it reacts with [[hydrazine]] giving 6-chloro-2-hydrazino-4-phenylquinoline. Boiling the mixture with [[triethyl orthoacetate]] results in cyclization with the formation of the [[triazole]] ring. The product undergoes oxidative degradation in the presence of [[periodate]] and [[ruthenium dioxide]] in [[acetone]] solution, giving 2-[4-(3'-methyl-1,2,4-triazolo)]-5-chlorobenzophenone. Oxy-methylation with [[formaldehyde]] results in a product that is treated with phosphorus tribromide when 2-[4-(3'-methyl-5'-bromomethyl-1,2,4-triazolo)]-5-chlorobenzophenone is obtained. By substituting the [[bromine]] atom with an amino group conferred by ammonia, it forms [[alprazolam triazolobenzophenone]], following which an intramolecular heterocyclization takes place to obtain alprazolam.<ref name=SED/><ref name=Synthesis>{{cite journal|vauthors=Walser, A, Zenchoff G |title=Quinazolines and 1,4-benzodiazepines. 81. s-Triazolo[4,3-a][1,4]benzodiazepines by oxidative cyclization of hydrazones |year=1977 | volume = 20 | issue = 12 |pages = 1694–1697 | journal = Journal of Medicinal Chemistry |doi = 10.1021/jm00222a035 |pmid=592339 }}</ref><ref name="Patent3"/>

===Detection===

Quantification of alprazolam in blood and plasma samples may be necessary to confirm a diagnosis of intoxication in hospitalized patients, or to provide evidence in the case of crimes e.g., impaired driving arrest, or to assist in a thorough forensic investigation, e.g., in a [[medical jurisprudence|medicolegal]] death investigation. Blood or plasma alprazolam concentrations are usually in a range of 10–100 μg/L in persons receiving the drug therapeutically, 100–300 μg/L in those arrested for impaired driving, and 300–2,000 μg/L in victims of acute overdosage. Most of the commercial [[immunoassays]] used for the benzodiazepine class of drugs cross-react with alprazolam, but confirmation and quantitative determination are usually done by [[chromatographic]] techniques.<ref>{{cite book |vauthors= Baselt R |title=Disposition of Toxic Drugs and Chemicals in Man |edition=9th |publisher=Biomedical Publications |location=Seal Beach, CA |year=2011 |pages=45–48 |isbn=978-0-9626523-8-7}}</ref>

==Dosage forms==

Alprazolam regular release and [[Orally disintegrating tablet|orally disintegrating tablets]] are available as 0.25&nbsp;mg, 0.5&nbsp;mg, 1&nbsp;mg, and 2&nbsp;mg tablets.<ref name="Xanax FDA label" /> Extended-release tablets are available as 0.5&nbsp;mg, 1&nbsp;mg, 2&nbsp;mg, and 3&nbsp;mg tablets.<ref name="Xanax XR FDA label" /> Liquid alprazolam is available in a 1&nbsp;mg/mL oral concentrate.<ref>{{cite web | title=ALPRAZOLAM solution, concentrate | website=DailyMed | date=17 January 2023 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b945ac6f-796e-41ef-85e9-61007e4a4e9a | access-date=17 June 2024 | archive-date=3 March 2024 | archive-url=https://web.archive.org/web/20240303180713/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b945ac6f-796e-41ef-85e9-61007e4a4e9a | url-status=live }}</ref>

==Legal status==

Alprazolam has varied legal status depending on jurisdiction:

* In the United States, alprazolam is a prescription drug and is assigned to [[Controlled Substances Act#Schedule IV controlled substances|Schedule IV]] of the [[Controlled Substances Act]] by the [[Drug Enforcement Administration]] (DEA).<ref>{{cite web |url=http://www.usdoj.gov/dea/pubs/scheduling.html |title=DEA, Drug Scheduling |publisher=[[Drug Enforcement Administration]] |access-date=31 October 2008 |archive-url=https://web.archive.org/web/20081104023502/http://www.usdoj.gov/dea/pubs/scheduling.html |archive-date=4 November 2008 |url-status=dead}}</ref>

* Under the UK drug misuse classification system, alprazolam is a [[Drugs controlled by the UK Misuse of Drugs Act|Class C]] drug.<ref name="misuse of drugs legislation" /><ref>{{cite web |url=https://www.legislation.gov.uk/ukpga/1971/38/schedules |title=Misuse of Drugs Act 1971 (c. 38) |year=1991 |publisher=The UK Statute Law database |access-date=2 August 2007 |archive-date=27 November 2010 |archive-url=https://web.archive.org/web/20101127183256/http://www.statutelaw.gov.uk/content.aspx?LegType=All+Primary&PageNumber=56&NavFrom=2&parentActiveTextDocId=1367412&activetextdocid=1367464 |url-status=live }}</ref> In the UK, alprazolam is not available on the [[National Health Service]] (NHS) and can only be obtained on a private prescription.<ref name=BNF60>{{cite book |title=British National Formulary (BNF 60) |date=September 2010 |publisher=[[BMJ Group]] and RPS Publishing |location=United Kingdom |isbn=978-0-85369-931-6 |page=212 |chapter=4.1.2: Anxiolytics |author=[[British Medical Association]], [[Royal Pharmaceutical Society of Great Britain]]|title-link=British National Formulary }}</ref>

* In Ireland, alprazolam is a Schedule 4 medicine.<ref>{{cite web |title=Misuse of Drugs (Amendment) Regulations |year=1993 |url=http://www.irishstatutebook.ie/1993/en/si/0342.html |work=Irish Statute Book |publisher=Office of the Attorney General |access-date=7 September 2009 |archive-date=30 January 2015 |archive-url=https://web.archive.org/web/20150130123136/http://www.irishstatutebook.ie/1993/en/si/0342.html |url-status=live }}</ref>

* In Sweden, alprazolam is a prescription drug in List IV (Schedule 4) under the Narcotics Drugs Act (1968).<ref>{{cite web |url=http://www.lakemedelsverket.se/upload/lvfs/konsoliderade/LVFS_2011_10_konsoliderad_tom_2012_6.pdf |title=Läkemedelsverkets föreskrifter (LVFS 2011:10) om förteckningar över narkotika |trans-title=Medical Products Agency on the lists of drugs |date=October 2011 |publisher=[[Läkemedelsverket]] |location=Sweden |language=sv |access-date=6 August 2012 |archive-date=16 May 2013 |archive-url=https://web.archive.org/web/20130516030119/http://www.lakemedelsverket.se/upload/lvfs/konsoliderade/LVFS_2011_10_konsoliderad_tom_2012_6.pdf |url-status=dead }}</ref>

* In the Netherlands, alprazolam is a List 2 substance of the [[Opium Law]] and is available for prescription.{{cn|date=April 2024}}

* In Germany, alprazolam can be prescribed normally in doses up to 1&nbsp;mg. Higher doses are scheduled as [[Anlage III]] drugs and require a [[special prescription form]].{{cn|date=April 2024}}

* In Australia, alprazolam, as of February 2014, is a Schedule 8 medication.<ref>{{cite web |title=Alprazolam to be rescheduled from next year |year=2013 |url=http://www.australiandoctor.com.au/news/latest-news/alprazolam-to-be-rescheduled-from-next-year |url-access=subscription |access-date=8 November 2013 |archive-date=27 March 2014 |archive-url=https://web.archive.org/web/20140327070853/http://www.australiandoctor.com.au/news/latest-news/alprazolam-to-be-rescheduled-from-next-year |url-status=dead }}</ref><ref>{{cite web | title=2.6 Flubromazolam | website=Therapeutic Goods Administration (TGA) | date=3 February 2016 | url=https://www.tga.gov.au/book-page/26-flubromazolam | access-date=2 June 2022 | archive-date=17 May 2018 | archive-url=https://web.archive.org/web/20180517015854/http://www.tga.gov.au/book-page/26-flubromazolam | url-status=live }}</ref><ref>{{cite web | title=Up-scheduling of alprazolam from Schedule 4 to Schedule 8 | website=NSW Health Pharmaceutical services | date=2 June 2022 | url=https://www.health.nsw.gov.au/pharmaceutical/Pages/alprazolam-upscheduling.aspx | access-date=2 June 2022 | archive-date=25 March 2022 | archive-url=https://web.archive.org/web/20220325175600/https://www.health.nsw.gov.au/pharmaceutical/Pages/alprazolam-upscheduling.aspx | url-status=live }}</ref>

* In the Philippines, alprazolam is legally classified as a "dangerous drug" under the [[Comprehensive Dangerous Drugs Act of 2002]], along with other schedule drugs listed in the [[Convention on Psychotropic Substances|1971 Convention on Psychotropic Substances]].<ref>{{cite web |title=Comprehensive Dangerous Drugs Act of 2002 |url=https://www.lawphil.net/statutes/repacts/ra2002/ra_9165_2002.html |website=The LawPhil Project |access-date=17 August 2018 |date=2002 |archive-date=15 September 2018 |archive-url=https://web.archive.org/web/20180915112956/http://lawphil.net/statutes/repacts/ra2002/ra_9165_2002.html |url-status=live }}</ref> The importation of dangerous drugs including alprazolam, requires authorization from the [[Philippine Drug Enforcement Agency]].<ref>{{cite news |title=BOC seizes regulated and prohibited drugs at NAIA |url=http://www.gmanetwork.com/news/money/economy/540792/boc-seizes-regulated-and-prohibited-drugs-at-naia/story/ |access-date=17 August 2018 |work=GMA News |date=15 October 2015 |archive-date=27 June 2020 |archive-url=https://web.archive.org/web/20200627092725/https://www.gmanetwork.com/news/money/economy/540792/boc-seizes-regulated-and-prohibited-drugs-at-naia/story/ |url-status=live }}</ref>

Internationally, alprazolam is included under the United Nations [[Convention on Psychotropic Substances]] as Schedule IV.<ref>{{cite web|url=http://www.incb.org/pdf/e/list/green.pdf |title=List of Psychotropic Substances under International Control |access-date=7 December 2008 |publisher=International Narcotics Control Board |date=August 2003 |archive-url=https://web.archive.org/web/20081217053452/http://www.incb.org/pdf/e/list/green.pdf |archive-date=17 December 2008 |url-status=dead}}</ref>

==Availability==

In December 2013, in anticipation of the rescheduling of alprazolam to Schedule 8 in Australia, Pfizer Australia announced they would be discontinuing the Xanax brand in Australia as it was no longer commercially viable.<ref>{{cite web |url=http://www.shpa.org.au/lib/pdf/manuf_alerts/xanax_discontinuation_oct2013.pdf |archive-url=https://web.archive.org/web/20140204153214/http://www.shpa.org.au/lib/pdf/manuf_alerts/xanax_discontinuation_oct2013.pdf |url-status=dead |archive-date=4 February 2014 |title=Discontinuation of Xanax |publisher=Pfizer Australia}}</ref>

==Recreational use==

{{Further|Benzodiazepine use disorder}}

There is a risk of misuse and dependence in both patients and [[Recreational drug use|non-medical users]] of alprazolam; alprazolam's high affinity binding, high potency, and rapid onset increase its abuse potential. The [[physical dependence]] and [[Drug withdrawal|withdrawal syndrome]] of alprazolam also add to its [[Addiction|addictive nature]]. In the small subgroup of individuals who escalate their doses, there is usually a history of [[Alcohol abuse|alcohol]] or other [[substance use disorder]]s.<ref name=Moy2012/>

Despite this, most prescribed alprazolam users do not use their medication recreationally, and the long-term use of benzodiazepines does not generally correlate with the need for dose escalation.<ref>{{cite journal | vauthors = Soumerai SB, Simoni-Wastila L, Singer C, Mah C, Gao X, Salzman C, Ross-Degnan D | title = Lack of relationship between long-term use of benzodiazepines and escalation to high dosages | journal = Psychiatric Services | volume = 54 | issue = 7 | pages = 1006–11 | date = July 2003 | pmid = 12851438 | doi = 10.1176/appi.ps.54.7.1006 | doi-access = | title-link = doi }}</ref> However, based on US findings from the Treatment Episode Data Set (TEDS), an annual compilation of patient characteristics in substance abuse treatment facilities in the United States, admissions due to "primary tranquilizer" (including, but not limited to, benzodiazepine-type) drug use increased 79% from 1992 to 2002, suggesting that misuse of benzodiazepines may be on the rise.<ref>{{cite journal | vauthors = Licata SC, Rowlett JK | title = Abuse and dependence liability of benzodiazepine-type drugs: GABA(A) receptor modulation and beyond | journal = Pharmacology Biochemistry and Behavior | volume = 90 | issue = 1 | pages = 74–89 | date = July 2008 | pmid = 18295321 | pmc = 2453238 | doi = 10.1016/j.pbb.2008.01.001 }}</ref>

The [[Centers for Disease Control and Prevention]] (CDC) reported an 89 percent increase in emergency room visits nationwide related to nonmedical benzodiazepine use between 2004 and 2008.<ref>{{cite journal | title = Emergency department visits involving nonmedical use of selected prescription drugs - United States, 2004-2008 | journal = MMWR. Morbidity and Mortality Weekly Report | volume = 59 | issue = 23 | pages = 705–9 | date = June 2010 | pmid = 20559200 | url = https://www.cdc.gov/mmwr/pdf/wk/mm5923.pdf | author-link = Centers for Disease Control and Prevention | author1 = Centers for Disease Control and Prevention (CDC) | access-date = 21 April 2024 | archive-date = 17 June 2024 | archive-url = https://web.archive.org/web/20240617060502/https://www.cdc.gov/mmwr/pdf/wk/mm5923.pdf | url-status = live }}</ref><ref>{{cite news |vauthors=Goodnough A |date=14 September 2011 |url=https://www.nytimes.com/2011/09/14/us/in-louisville-a-centers-doctors-cut-off-xanax-prescriptions.html |title=Abuse of Xanax Leads a Clinic to Halt Supply |newspaper=[[The New York Times]] |access-date=26 February 2017 |archive-date=24 February 2017 |archive-url=https://web.archive.org/web/20170224043511/http://www.nytimes.com/2011/09/14/us/in-louisville-a-centers-doctors-cut-off-xanax-prescriptions.html |url-status=live }}</ref>

Alprazolam is one of the most commonly prescribed and misused benzodiazepines in the United States.<ref name=APPT>{{cite book | vauthors = Galanter M |title=The American Psychiatric Publishing Textbook of Substance Abuse Treatment |year=2008 |publisher=American Psychiatric Publishing |url=https://books.google.com/books?id=6wdJgejlQzYC&pg=PA222 |edition=4th |isbn=978-1-58562-276-4 |page=222 |access-date=22 January 2014}}</ref><ref name= dawn2neodredv>{{cite web |url=http://www.samhsa.gov/data/DAWN/files/ED2006/DAWN2k6ED.pdf |title=Drug Abuse Warning Network, 2006: National Estimates of Drug-Related Emergency Department Visits |access-date=13 February 2012 |work=U.S. Department of Health and Human Services |year=2006 |publisher=[[Substance Abuse and Mental Health Services Administration]] |archive-url=https://web.archive.org/web/20120312194735/http://www.samhsa.gov/data/DAWN/files/ED2006/DAWN2k6ED.pdf |archive-date=12 March 2012 |url-status=dead }}</ref> A large-scale nationwide [[Federal government of the United States|U.S. government]] study conducted by the [[Substance Abuse and Mental Health Services Administration]] concluded that, in the US, benzodiazepines are recreationally the most frequently used pharmaceuticals due to their widespread availability, accounting for 35% of all drug-related visits to hospital [[Emergency department|emergency]] and [[urgent care facilities]]. Men and women are equally likely to use benzodiazepines recreationally. The report found that alprazolam is the most common benzodiazepine for recreational use, followed by [[clonazepam]], [[lorazepam]], and [[diazepam]]. The number of emergency department visits due to benzodiazepines increased by 36% between 2004 and 2006.<ref name="dawn2neodredv"/>

{{cquote|Regarding the significant increases detected, it is worthwhile to consider that the number of pharmaceuticals dispensed for legitimate therapeutic uses may be increasing over time, and DAWN estimates are not adjusted to take such increases into account. Nor do DAWN estimates take into account the increases in the population or ED use between 2004 and 2006.<ref name="dawn2neodredv"/>}}

Those at particularly high risk for misuse and dependence are people with a history of alcoholism or drug abuse and/or dependence<ref>{{cite journal | vauthors = Ballenger JC | title = Psychopharmacology of the anxiety disorders | journal = The Psychiatric Clinics of North America | volume = 7 | issue = 4 | pages = 757–71 | date = December 1984 | pmid = 6151647 | doi = 10.1016/S0193-953X(18)30728-7 }}</ref><ref>{{cite journal | vauthors = Ciraulo DA, Barnhill JG, Greenblatt DJ, Shader RI, Ciraulo AM, Tarmey MF, Molloy MA, Foti ME | title = Abuse liability and clinical pharmacokinetics of alprazolam in alcoholic men | journal = The Journal of Clinical Psychiatry | volume = 49 | issue = 9 | pages = 333–7 | date = September 1988 | pmid = 3417618 }}</ref> and people with [[borderline personality disorder]].<ref>{{cite journal | vauthors = Vorma H, Naukkarinen HH, Sarna SJ, Kuoppasalmi KI | title = Predictors of benzodiazepine discontinuation in subjects manifesting complicated dependence | journal = Substance Use & Misuse | volume = 40 | issue = 4 | pages = 499–510 | year = 2005 | pmid = 15830732 | doi = 10.1081/JA-200052433 | s2cid = 1366333 }}</ref>

The [[poly-drug use]] of powerful depressant drugs poses the highest level of health concerns due to a significant increase in the likelihood of experiencing an [[Drug overdose|overdose]], which may cause fatal [[respiratory depression]].<ref>{{cite journal | vauthors = Walker BM, Ettenberg A | title = The effects of alprazolam on conditioned place preferences produced by intravenous heroin | journal = Pharmacology Biochemistry and Behavior | volume = 75 | issue = 1 | pages = 75–80 | date = April 2003 | pmid = 12759115 | doi = 10.1016/S0091-3057(03)00043-1 | s2cid = 23137094 }}</ref><ref>{{cite web |url=http://www.odadas.state.oh.us/WebManager/UltimateEditorInclude/UserFiles/WebDocuments/Planning/Jan05ExecSummry.pdf |archive-url=https://web.archive.org/web/20110807100011/http://www.odadas.state.oh.us/WebManager/UltimateEditorInclude/UserFiles/WebDocuments/Planning/Jan05ExecSummry.pdf |url-status=dead |archive-date=7 August 2011 |title=OSAM-O-GRAM Highlights of Statewide Drug Use Trends |access-date=10 December 2008 |publisher=Wright State University and the University of Akron |date=January 2008 |location=Ohio, US}}</ref>

A 1990 study found that diazepam has a higher misuse potential relative to many other benzodiazepines and that some data suggest that alprazolam and lorazepam resemble diazepam in this respect.<ref name="griffiths1990">{{cite journal | vauthors = Griffiths RR, Wolf B | title = Relative abuse liability of different benzodiazepines in drug abusers | journal = Journal of Clinical Psychopharmacology | volume = 10 | issue = 4 | pages = 237–43 | date = August 1990 | pmid = 1981067 | doi = 10.1097/00004714-199008000-00002 | s2cid = 28209526 }}</ref>

Anecdotally, injection of alprazolam has been reported, causing dangerous damage to blood vessels, closure of blood vessels ([[embolization]]), and decay of muscle tissue ([[rhabdomyolysis]]).<ref>{{cite journal | vauthors = Wang EC, Chew FS | title = MR Findings of Alprazolam Injection into the Femoral Artery with Microembolization and Rhabdomyolysis | journal = Radiology Case Reports | volume = 1 | issue = 3 | pages = 99–102 | year = 2006 | pmid = 27298694 | pmc = 4891562 | doi = 10.2484/rcr.v1i3.33 | doi-access = free | title-link = doi }}</ref> Alprazolam is not very soluble in water; when crushed in water, it does not fully [[solubility|dissolve]] (40&nbsp;μg/ml of [[properties of water|H₂O]] at pH 7).<ref name="DB00404 Alprazolam">{{cite web |url=http://redpoll.pharmacy.ualberta.ca/drugbank/cgi-bin/getCard.cgi?CARD=APRD00280 |title=DB00404 (Alprazolam) |publisher=DrugBank |location=Canada |date=26 June 2008 |access-date=12 July 2011 |archive-url=https://web.archive.org/web/20080129100402/http://redpoll.pharmacy.ualberta.ca/drugbank/cgi-bin/getCard.cgi?CARD=APRD00280 |archive-date=29 January 2008 |url-status=live}}</ref> There are also reports of alprazolam being [[insufflation (medicine)|snorted]].<ref>{{cite journal | vauthors = Sheehan MF, Sheehan DV, Torres A, Coppola A, Francis E | title = Snorting benzodiazepines | journal = The American Journal of Drug and Alcohol Abuse | volume = 17 | issue = 4 | pages = 457–68 | year = 1991 | pmid = 1684083 | doi = 10.3109/00952999109001605 }}</ref> Due to the low weight of a dose, alprazolam, in one case, was distributed on [[Blotting paper#Drugs|blotter paper]] in a manner similar to LSD.<ref>{{cite web |url=https://www.justice.gov/dea/programs/forensicsci/microgram/mg0508/mg0508.html |archive-url=https://web.archive.org/web/20080521082459/http://www.justice.gov/dea/programs/forensicsci/microgram/mg0508/mg0508.html |archive-date=21 May 2008 |type=Microgram Bulletin |date=May 2008 |title=Intelligence Alert – Xanax Blotter Paper in Bartlesville, Oklahoma |publisher=US Drug Enforcement Administration}}</ref>

Misuse of alprazolam and other benzodiazepines has been shown to cause [[cognitive impairment]].<ref name="The Effect of Chronic Alprazolam In">{{cite journal | vauthors = Chowdhury ZS, Morshed MM, Shahriar M, Bhuiyan MA, Islam SM, Bin Sayeed MS | title = The Effect of Chronic Alprazolam Intake on Memory, Attention, and Psychomotor Performance in Healthy Human Male Volunteers | journal = Behavioural Neurology | volume = 2016 | pages = 3730940 | year = 2016 | pmid = 27462136 | pmc = 4947648 | doi = 10.1155/2016/3730940 | doi-access = free | title-link = doi }}</ref> Alprazolam has typically caused [[anterograde amnesia]] effects (inability to recall new events), but a study conducted on mice by the Department of Pharmaceutical Sciences and Drug Research at [[Punjabi University]] has also determined that alprazolam can produce retrograde amnesic effects (inability to remember events occurring before amnesia). One 2016 study found that "chronic administration of alprazolam affects memory but attentive and psychomotor performance remained unaffected".<ref>{{cite journal | vauthors = Chowdhury ZS, Morshed MM, Shahriar M, Bhuiyan MA, Islam SM, Bin Sayeed MS | title = The Effect of Chronic Alprazolam Intake on Memory, Attention, and Psychomotor Performance in Healthy Human Male Volunteers | journal = Behavioural Neurology | volume = 2016 | pages = 3730940 | date = 2016 | pmid = 27462136 | pmc = 4947648 | doi = 10.1155/2016/3730940 | doi-access = free | title-link = doi }}</ref>

A 2016 randomized controlled trial stated that "overall, long-term benzodiazepine users may not be in their full cognitive state upon withdrawal".<ref name="The Effect of Chronic Alprazolam In"/> Similarly, a 2017 meta-analysis concluded that "a range of neuropsychological functions are impaired as a result of long-term benzodiazepine use, and that these are likely to persist even following withdrawal".<ref>{{cite journal | vauthors = Crowe SF, Stranks EK | title = The Residual Medium and Long-term Cognitive Effects of Benzodiazepine Use: An Updated Meta-analysis | journal = Archives of Clinical Neuropsychology | volume = 33 | issue = 7 | pages = 901–911 | date = November 2018 | pmid = 29244060 | doi = 10.1093/arclin/acx120 | doi-access = free | title-link = doi }}</ref>

===Slang terms===

Slang terms for alprazolam vary by geographic location. Some of the more common terms are modified versions of the trade name "Xanax", such as Xannies (or Xanies) and the phonetic equivalent of Zannies;<ref>{{cite book|vauthors=Mesibov G|title=Outer Strength, Inner Strength|date=2004|publisher=Xulon Press|isbn=9781594675041|page=213|quote=Some people sell Xanax on the street for ten or fifteen dollars a pill. They call them Xannies.|url=https://books.google.com/books?id=uUb_lkQQ24kC&pg=PA213|access-date=18 July 2017|archive-date=26 April 2021|archive-url=https://web.archive.org/web/20210426222507/https://books.google.com/books?id=uUb_lkQQ24kC&pg=PA213|url-status=live}}</ref><ref>{{cite book|vauthors=Curry M|title=Dancing with the Devil: How Puff Burned the Bad Boys of Hip-hop|date=2009|publisher=NewMark Books|isbn=9780615276502|page=120|quote=Puff would get so wired sometimes – his favorites were weed, ecstasy and xannies (Xanax) – that he wouldn't realize that he was speeding.|url=https://books.google.com/books?id=bqz8X2HFcP0C&pg=PA120|access-date=18 July 2017|archive-date=27 April 2021|archive-url=https://web.archive.org/web/20210427092903/https://books.google.com/books?id=bqz8X2HFcP0C&pg=PA120|url-status=live}}</ref> references to their drug classes, such as benzos or downers; or remark upon their shape or color (most commonly a straight, perforated tablet or an oval-shaped pill): bars, ladders, Xanbars, Xans, Z-bars, handlebars, beans, footballs, planks, poles, sticks, blues, or blue footballs.<ref>{{cite web|url=https://axisresidentialtreatment.com/xanax-addiction/street-terms/ |title=Street Names for Xanax |website=Axis Residential Treatment |author=<!--not given--> |access-date=14 February 2014 |archive-url=https://web.archive.org/web/20140222144858/http://www.axisresidentialtreatment.com/xanax-addiction/street-terms/ |archive-date=22 February 2014}}</ref><ref>{{cite web |url=http://www.alprazolamaddictionhelp.com/street-names-for-alprazolam |website=Alprazolamaddictionhelp.com |title=Street Names for Alprazolam |author=<!--not given--> |access-date=14 February 2014 |archive-date=22 February 2014 |archive-url=https://web.archive.org/web/20140222011837/http://www.alprazolamaddictionhelp.com/street-names-for-alprazolam |url-status=dead }}</ref><ref>{{cite web |url= https://www.fda.gov/Drugs/DrugSafety/ucm518473.htm |website= U.S. [[Food and Drug Administration]] (FDA) |year= 2017 |author= FDA |title= Both opioids and benzodiazepines depress the central nervous system (CNS). FDA Drug Safety Communication: FDA warns about serious risks and death when combining opioid pain or cough medicines with benzodiazepines; requires its strongest warning |access-date= 15 October 2017 |id= ("Additional Information for Patients > bullet 5") |quote= Do not take opioid pain medicines with benzodiazepines or other medicines that depress the CNS without discussing it with your health Do not take opioid pain medicines with benzodiazepines or other medicines that depress the CNS without discussing it with your health care professional. Do not take opioid cough medicines with benzodiazepines or other medicines that depress the CNS professional. Do not take opioid cough medicines with benzodiazepines or other medicines that depress the CNS |archive-date= 1 November 2017 |archive-url= https://web.archive.org/web/20171101170452/https://www.fda.gov/Drugs/DrugSafety/ucm518473.htm |url-status= live }}</ref><ref name="MPR Xanax Slang">{{cite web |title=Xanax (Alprazolam) Drug Slang/Code Words |url=https://www.empr.com/home/drug-slang-code-words/xanax-alprazolam-drug-slang-code-words/ |website=MPR |date=2 August 2017 |access-date=17 March 2019 |archive-date=14 December 2019 |archive-url=https://web.archive.org/web/20191214023324/https://www.empr.com/home/drug-slang-code-words/xanax-alprazolam-drug-slang-code-words/ |url-status=live }}</ref>

==In popular culture==

*''Take Your Pills: Xanax'', a 2022 [[Netflix]] documentary, provides an overview of the drug's history and usage.<ref>{{cite web |vauthors=Carroll L |title=New Netflix documentary calls out Xanax overuse: What doctors want you to know |url=https://www.today.com/health/mind-body/take-your-pills-xanax-netflix-rcna60645 |website=Today |access-date=12 December 2022 |date=8 December 2022 |archive-date=12 December 2022 |archive-url=https://web.archive.org/web/20221212182607/https://www.today.com/health/mind-body/take-your-pills-xanax-netflix-rcna60645 |url-status=live }}</ref><ref>{{cite web | last=Villarreal | first=Ryan | title=Everything You Need to Know About 'Take Your Pills: Xanax' | website=Netflix Tudum | date=20 September 2023 | url=https://www.netflix.com/tudum/articles/take-your-pills-xanax-release-date-trailer | access-date=17 June 2024}}</ref>

== References ==

{{Reflist}}

== External links ==

{{Commons category}}

{{Anxiolytics}}

{{Benzodiazepines}}

{{GABAA receptor positive modulators}}

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[[Category:Anxiolytics]]

[[Category:Chloroarenes]]

[[Category:Deaths attributed to Xanax overdose| ]]

[[Category:Drugs developed by Pfizer]]

[[Category:GABAA receptor positive allosteric modulators]]

[[Category:Hallucinogen antidotes]]

[[Category:Triazolobenzodiazepines]]

[[Category:Wikipedia medicine articles ready to translate]]