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Revision as of 11:18, 6 March 2012 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Saving copy of the {{drugbox}} taken from revid 480474758 of page Botulinum_toxin for the Chem/Drugbox validation project (updated: 'ChemSpiderID', 'DrugBank').  Latest revision as of 03:23, 15 November 2024 edit Artoria2e5 (talk | contribs)Extended confirmed users, IP block exemptions34,180 edits →Mechanism of action: ''Clostridium'' neurotoxins 
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{{Short description|Neurotoxic protein produced by Clostridium botulinum}}
{{ambox | text = This page contains a copy of the infobox ({{tl|drugbox}}) taken from revid of page ] with values updated to verified values.}}
{{Use dmy dates|date=April 2024}}
{{drugbox
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Infobox drug
| verifiedrevid = 480475821
| Verifiedfields = changed | Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 477313756
| drug_name = Botulinum toxin A
| image = Botulinum toxin 3BTA.png | image = Botulinum toxin 3BTA.png
| width =
| image_source = Cartoon representation of Botulinum toxin. ] entry {{PDBe|3BTA}}
| alt =
| caption = ] of tertiary structure of ''BotA'' ({{UniProt|P0DPI1}}). ] entry {{PDBe|3BTA}}.


<!--Clinical data--> <!-- Clinical data -->
| pronounce =
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --
| tradename = Botox, Myobloc, Jeuveau, others
| pregnancy_US = <!-- A / B / C / D / X -->
| Drugs.com = {{ubl|
| legal_AU = <!-- Unscheduled / S2 / S4 / S8 -->
abobotulinumtoxinA {{drugs.com|monograph|abobotulinumtoxina}}|
| legal_UK = <!-- GSL / P / POM / CD -->
daxibotulinumtoxinA {{drugs.com|monograph|daxibotulinumtoxina}}|
| legal_US = <!-- OTC / Rx-only --> Rx-Only
incobotulinumtoxinA {{drugs.com|monograph|incobotulinumtoxina}}|
| routes_of_administration = IM (approved),SC, intradermal, into glands
onabotulinumtoxinA {{drugs.com|monograph|onabotulinumtoxina}}|

prabotulinumtoxinA {{drugs.com|monograph|prabotulinumtoxina-xvfs}}|
<!--Identifiers-->
rimabotulinumtoxinB {{drugs.com|monograph|rimabotulinumtoxinb.html}}
| CAS_number_Ref = {{cascite|correct|??}}
}}
| CAS_number = 93384-43-1
| MedlinePlus = a619021
| DailyMedID = Botulinum toxin
| pregnancy_AU = B3
| pregnancy_AU_comment = <ref name="Letybo APMDS" /><ref name="Nuceiva APMDS" /><ref name="Relfydess APMDS" />
| pregnancy_category =
| routes_of_administration = ], ], ]
| class =
| ATC_prefix = M03 | ATC_prefix = M03
| ATC_suffix = AX01 | ATC_suffix = AX01
| ATC_supplemental =
| PubChem = 5485225
| biosimilars = abobotulinumtoxinA, daxibotulinumtoxinA, daxibotulinumtoxinA-lanm, evabotulinumtoxinA, incobotulinumtoxinA, letibotulinumtoxinA, letibotulinumtoxinA-wlbg,<ref name="Letybo FDA label" /> onabotulinumtoxinA, prabotulinumtoxinA, relabotulinumtoxinA, rimabotulinumtoxinB

<!-- Legal status -->
| legal_AU = S4
| legal_AU_comment = <ref name="Letybo APMDS" /><ref name="Nuceiva APMDS">{{cite web | title=Nuceiva | website=Therapeutic Goods Administration (TGA) | date=10 February 2023 | url=https://www.tga.gov.au/resources/auspmd/nuceiva | access-date=8 April 2023}}</ref><ref>{{cite web | title=Nuceiva (PPD Australia Pty Ltd) | website=Therapeutic Goods Administration (TGA) | date=16 February 2023 | url=https://www.tga.gov.au/resources/prescription-medicines-registrations/nuceiva-ppd-australia-pty-ltd | access-date=8 April 2023 | archive-date=18 March 2023 | archive-url=https://web.archive.org/web/20230318023528/https://www.tga.gov.au/resources/prescription-medicines-registrations/nuceiva-ppd-australia-pty-ltd | url-status=live }}</ref><ref>{{cite web | title=Nuceiva prabotulinumtoxinA 100 Units Powder for Solution for Injection vial (381094) | website=Therapeutic Goods Administration (TGA) | date=26 January 2023 | url=https://www.tga.gov.au/resources/artg/381094 | access-date=8 April 2023 | archive-date=8 April 2023 | archive-url=https://web.archive.org/web/20230408041216/https://www.tga.gov.au/resources/artg/381094 | url-status=live }}</ref><ref>{{cite web | title=Prescription medicines: registration of new chemical entities in Australia, 2014 | website=Therapeutic Goods Administration (TGA) | date=21 June 2022 | url=https://www.tga.gov.au/resources/resource/guidance/prescription-medicines-registration-new-chemical-entities-australia-2014 | access-date=10 April 2023 | archive-date=10 April 2023 | archive-url=https://web.archive.org/web/20230410065838/https://www.tga.gov.au/resources/resource/guidance/prescription-medicines-registration-new-chemical-entities-australia-2014 | url-status=live }}</ref><ref>{{Cite web |url=https://www.tga.gov.au/resources/auspar/auspar-letybo |title=AusPAR: Letybo &#124; Therapeutic Goods Administration (TGA) |access-date=31 March 2024 |archive-date=31 March 2024 |archive-url=https://web.archive.org/web/20240331043040/https://www.tga.gov.au/resources/auspar/auspar-letybo |url-status=live }}</ref><ref name="Relfydess APMDS">{{cite web | title=Relfydess (relabotulinumtoxinA, purified Botulinum toxin type A) | website=Therapeutic Goods Administration (TGA) | date=30 July 2024 | url=https://www.tga.gov.au/resources/auspmd/relfydess-relabotulinumtoxina-purified-botulinum-toxin-type | access-date=12 October 2024}}</ref>
| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->
| legal_BR_comment =
| legal_CA = Rx-only
| legal_CA_comment = /{{nbsp}}Schedule D<ref>{{cite web | title=Regulatory Decision Summary - Botox | website=Health Canada | date=23 October 2014 | url=https://hpr-rps.hres.ca/reg-content/regulatory-decision-summary-detail.php?lang=en&linkID=RDS00792 | access-date=12 June 2022 | archive-date=12 June 2022 | archive-url=https://web.archive.org/web/20220612064147/https://hpr-rps.hres.ca/reg-content/regulatory-decision-summary-detail.php?lang=en&linkID=RDS00792 | url-status=live }}</ref><ref>{{Cite web|url=https://hpr-rps.hres.ca/reg-content/regulatory-decision-summary-detail.php?lang=en&linkID=RDS00405|archive-url=https://web.archive.org/web/20220607080128/https://hpr-rps.hres.ca/reg-content/regulatory-decision-summary-detail.php?lang=en&linkID=RDS00405|url-status=live|title=Regulatory Decision Summary - Nuceiva |date=23 October 2014|archive-date=7 June 2022|website=Health Canada|access-date=11 June 2022}}</ref><ref>{{cite web | title=Regulatory Decision Summary for Xeomin | website=Drug and Health Products Portal | date=15 March 2022 | url=https://dhpp.hpfb-dgpsa.ca/review-documents/resource/RDS1709049767533 | access-date=1 April 2024}}</ref><ref>{{cite web | title=Regulatory Decision Summary for Botox | website=Drug and Health Products Portal | date=7 February 2024 | url=https://dhpp.hpfb-dgpsa.ca/review-documents/resource/RDS1708464933703 | access-date=2 April 2024 | archive-date=2 April 2024 | archive-url=https://web.archive.org/web/20240402033454/https://dhpp.hpfb-dgpsa.ca/review-documents/resource/RDS1708464933703 | url-status=live }}</ref><ref>{{cite web | title=Health Canada New Drug Authorizations: 2016 Highlights | website=] | date=14 March 2017 | url=https://www.canada.ca/en/health-canada/services/publications/drugs-health-products/health-canada-new-drug-authorizations-2016-highlights.html | access-date=7 April 2024 | archive-date=7 April 2024 | archive-url=https://web.archive.org/web/20240407045431/https://www.canada.ca/en/health-canada/services/publications/drugs-health-products/health-canada-new-drug-authorizations-2016-highlights.html | url-status=live }}</ref>
| legal_DE = <!-- Anlage I, II, III or Unscheduled -->
| legal_DE_comment =
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment =
| legal_UK = POM
| legal_UK_comment = <ref>{{cite web | title=Azzalure - Summary of Product Characteristics (SmPC) | website=(emc) | date=16 August 2022 | url=https://www.medicines.org.uk/emc/product/6584/smpc | access-date=18 December 2022 | archive-date=18 December 2022 | archive-url=https://web.archive.org/web/20221218024754/https://www.medicines.org.uk/emc/product/6584/smpc | url-status=live }}</ref><ref>{{cite web | title=Alluzience, 200 Speywood units/ml, solution for injection - Summary of Product Characteristics (SmPC) | website=(emc) | date=2 October 2022 | url=https://www.medicines.org.uk/emc/product/13798/smpc | access-date=18 December 2022 | archive-date=18 December 2022 | archive-url=https://web.archive.org/web/20221218024756/https://www.medicines.org.uk/emc/product/13798/smpc | url-status=live }}</ref><ref>{{cite web | title=Letybo 50 units powder for solution for injection - Summary of Product Characteristics (SmPC) | website=(emc) | date=10 May 2022 | url=https://www.medicines.org.uk/emc/product/13707/smpc | access-date=18 December 2022 | archive-date=18 December 2022 | archive-url=https://web.archive.org/web/20221218024749/https://www.medicines.org.uk/emc/product/13707/smpc | url-status=live }}</ref><ref>{{cite web | title=Xeomin 50 units powder for solution for injection - Summary of Product Characteristics (SmPC) | website=(emc) | date=28 July 2022 | url=https://www.medicines.org.uk/emc/product/4609/smpc | access-date=18 December 2022 | archive-date=18 December 2022 | archive-url=https://web.archive.org/web/20221218024747/https://www.medicines.org.uk/emc/product/4609/smpc | url-status=live }}</ref>
| legal_US = Rx-only
| legal_US_comment = <ref name="Botox FDA label">{{cite web | title=Botox- onabotulinumtoxina injection, powder, lyophilized, for solution | website=DailyMed | date=30 July 2021 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=33d066a9-34ff-4a1a-b38b-d10983df3300 | access-date=12 June 2022 | archive-date=2 June 2022 | archive-url=https://web.archive.org/web/20220602233512/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=33d066a9-34ff-4a1a-b38b-d10983df3300 | url-status=live }}</ref><ref>{{cite web | title=Botox Cosmetic- onabotulinumtoxina injection, powder, lyophilized, for solution | website=DailyMed | date=9 February 2021 | url=https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=485d9b71-6881-42c5-a620-a4360c7192ab | access-date=18 December 2022 | archive-date=18 December 2022 | archive-url=https://web.archive.org/web/20221218022735/https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=485d9b71-6881-42c5-a620-a4360c7192ab | url-status=live }}</ref><ref name="Myobloc FDA label">{{cite web | title=Myobloc- rimabotulinumtoxinb injection, solution | website=DailyMed | date=22 March 2021 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=675cb354-9d13-482e-8ac2-22f709c58b4f | access-date=12 June 2022 | archive-date=2 June 2022 | archive-url=https://web.archive.org/web/20220602233512/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=675cb354-9d13-482e-8ac2-22f709c58b4f | url-status=live }}</ref><ref>{{cite web | title=Dysport- botulinum toxin type a injection, powder, lyophilized, for solution | website=DailyMed | date=28 February 2022 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=71313a04-1349-4c26-b840-a39e4a3ddaed | access-date=12 June 2022 | archive-date=2 June 2022 | archive-url=https://web.archive.org/web/20220602233513/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=71313a04-1349-4c26-b840-a39e4a3ddaed | url-status=live }}</ref><ref name="Daxxify FDA label">{{cite web | title=Daxxify- botulinum toxin type a injection, powder, lyophilized, for solution | website=DailyMed | date=19 September 2022 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3aaa6e14-a3f7-4fb2-b9f9-d3a9c3ae1f74 | access-date=27 September 2022 | archive-date=28 September 2022 | archive-url=https://web.archive.org/web/20220928041736/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3aaa6e14-a3f7-4fb2-b9f9-d3a9c3ae1f74 | url-status=live }}</ref><ref name="Letybo FDA label">{{cite web | title=Letybo- letibotulinumtoxina-wlbg injection, powder, lyophilized, for solution | website=DailyMed | date=5 August 2024 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=910e5d0e-4d0b-4de8-8e2d-97879a044181 | access-date=5 September 2024}}</ref>
| legal_EU = Rx-only
| legal_EU_comment =
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment =
| legal_status = <!-- For countries not listed above -->

<!-- Pharmacokinetic data -->
| bioavailability =
| protein_bound =
| metabolism =
| metabolites =
| onset =
| elimination_half-life =
| duration_of_action =
| excretion =

<!-- Identifiers -->
| index_label = Botulinum toxin A
| index2_label = Botulinum toxin B
| CAS_number_Ref = {{cascite|changed|CAS}}
| CAS_number = 93384-43-1
| CAS_number2 = 93384-43-2
| CAS_supplemental =
| PubChem =
| IUPHAR_ligand =
| DrugBank_Ref = {{drugbankcite|changed|drugbank}} | DrugBank_Ref = {{drugbankcite|changed|drugbank}}
| DrugBank = DB00042 | DrugBank = DB00083
| DrugBank2 = DB00042
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = NA
| ChemSpiderID = none
| C=6760 | H=10447 | N=1743 | O=2010 | S=32
| UNII_Ref = {{fdacite|correct|FDA}}
| molecular_weight = 149.322,3223 ]
| UNII = E211KPY694
| UNII2_Ref = {{fdacite|correct|FDA}}
| UNII2 = 0Y70779M1F
| KEGG = D00783
| KEGG2 = D08957
<!-- | KEGG3 = D00783 -->
| ChEBI =
| ChEMBL =
| NIAID_ChemDB =
| PDB_ligand =
| synonyms = BoNT, botox

<!-- Chemical and physical data -->
| C=6760 | H=10447 | N=1743 | O=2010 | S=32
}} }}

{{Infobox enzyme
| Name = Bontoxilysin
| EC_number = 3.4.24.69
| GO_code = 0006508
| width =
| caption =
}}

<!-- Definition and medical uses -->
'''Botulinum toxin''', or '''botulinum neurotoxin''' (commonly called '''botox'''), is a ] ] produced by the ] '']'' and related species.<ref name="Montecucco2005">{{cite journal | vauthors = Montecucco C, Molgó J | title = Botulinal neurotoxins: revival of an old killer | journal = Current Opinion in Pharmacology | volume = 5 | issue = 3 | pages = 274–279 | date = June 2005 | pmid = 15907915 | doi = 10.1016/j.coph.2004.12.006 }}</ref> It prevents the release of the ] ] from ] endings at the ], thus causing ].<ref>{{cite journal | vauthors = Figgitt DP, Noble S | title = Botulinum toxin B: a review of its therapeutic potential in the management of cervical dystonia | journal = Drugs | volume = 62 | issue = 4 | pages = 705–722 | date = 2002 | pmid = 11893235 | doi = 10.2165/00003495-200262040-00011 | s2cid = 46981635 }}</ref> The toxin causes the disease ].<ref name=Shukla2004/> The toxin is also used commercially for medical and cosmetic purposes.<ref name="pmid33776040" /><ref name="Al-Ghamdi" /> Botulinum toxin is an acetylcholine release inhibitor and a neuromuscular blocking agent.<ref name="Letybo FDA label" /><ref name="Daxxify FDA label" />

The seven main types of botulinum toxin are named types A to G (A, B, C1, C2, D, E, F and G).<ref name="pmid33776040">{{cite journal | vauthors = Janes LE, Connor LM, Moradi A, Alghoul M | title = Current Use of Cosmetic Toxins to Improve Facial Aesthetics | journal = Plastic and Reconstructive Surgery | volume = 147 | issue = 4 | pages = 644e–657e | date = April 2021 | pmid = 33776040 | doi = 10.1097/PRS.0000000000007762 | s2cid = 232408799 }}</ref><ref name="pmid16417591">{{cite journal | vauthors = Rosales RL, Bigalke H, Dressler D | title = Pharmacology of botulinum toxin: differences between type A preparations | journal = European Journal of Neurology | volume = 13 | issue = Suppl 1 | pages = 2–10 | date = February 2006 | pmid = 16417591 | doi = 10.1111/j.1468-1331.2006.01438.x | s2cid = 32387953 }}</ref> New types are occasionally found.<ref name=BotX>{{cite web |title=Botulism toxin X: Time to update the textbooks, thanks to genomic sequencing |url=https://answers.childrenshospital.org/botulinum-toxin-x-discovered/ |publisher=Boston Children's Hospital |access-date=28 October 2019 |date=7 August 2017 |archive-date=14 September 2021 |archive-url=https://web.archive.org/web/20210914040619/https://answers.childrenshospital.org/botulinum-toxin-x-discovered/ |url-status=live }}</ref><ref name=BotH>{{cite web |title=Study: Novel botulinum toxin less dangerous than thought |url=https://www.cidrap.umn.edu/news-perspective/2015/06/study-novel-botulinum-toxin-less-dangerous-thought |website=CIDRAP |publisher=University of Minnesota |access-date=28 October 2019 |date=17 June 2015 |archive-date=28 October 2019 |archive-url=https://web.archive.org/web/20191028181916/http://www.cidrap.umn.edu/news-perspective/2015/06/study-novel-botulinum-toxin-less-dangerous-thought |url-status=live }}</ref> Types A and B are capable of causing disease in humans, and are also used commercially and medically.<ref name=Farag2020>{{cite journal | vauthors = Farag SM, Mohammed MO, El-Sobky TA, ElKadery NA, ElZohiery AK | title = Botulinum Toxin A Injection in Treatment of Upper Limb Spasticity in Children with Cerebral Palsy: A Systematic Review of Randomized Controlled Trials | journal = JBJS Reviews | volume = 8 | issue = 3 | pages = e0119 | date = March 2020 | pmid = 32224633 | pmc = 7161716 | doi = 10.2106/JBJS.RVW.19.00119 | doi-access = free | title-link = doi }}</ref><ref name=Blumetti2019>{{cite journal | vauthors = Blumetti FC, Belloti JC, Tamaoki MJ, Pinto JA | title = Botulinum toxin type A in the treatment of lower limb spasticity in children with cerebral palsy | journal = The Cochrane Database of Systematic Reviews | volume = 2019 | issue = 10 | pages = CD001408 | date = October 2019 | pmid = 31591703 | pmc = 6779591 | doi = 10.1002/14651858.CD001408.pub2 }}</ref><ref>{{cite web |author1=American Society of Health-System Pharmacists |title=OnabotulinumtoxinA (Botulinum Toxin Type A) Monograph for Professionals |url=https://www.drugs.com/monograph/onabotulinumtoxina.html |website=drugs.com |access-date=4 March 2015 |date=27 October 2011 |archive-date=6 September 2015 |archive-url=https://web.archive.org/web/20150906194001/http://www.drugs.com/monograph/onabotulinumtoxina.html |url-status=live }}</ref> Types C–G are less common; types E and F can cause disease in humans, while the other types cause disease in other animals.<ref name="WHO2018" />

<!-- Side effects -->
Botulinum toxins are among the most potent toxins known to science.<ref>{{cite journal | vauthors = Košenina S, Masuyer G, Zhang S, Dong M, Stenmark P | title = Crystal structure of the catalytic domain of the Weissella oryzae botulinum-like toxin | journal = FEBS Letters | volume = 593 | issue = 12 | pages = 1403–1410 | date = June 2019 | pmid = 31111466 | doi = 10.1002/1873-3468.13446 | doi-access = free | title-link = doi }}</ref><ref>{{Cite journal |date=November 2010 |title=Botulinum toxin: Bioweapon & magic drug |journal=Indian Journal of Medical Research |pmc=3028942 |volume=132 |issue=5 |pages=489–503 |pmid=21149997 | vauthors = Dhaked RK, Singh MK, Singh P, Gupta P }}</ref> Intoxication can occur naturally as a result of either wound or intestinal infection or by ingesting formed toxin in food. The estimated human ] of type A toxin is 1.3–2.1{{nbsp}}]/kg ] or ], 10–13{{nbsp}}ng/kg when inhaled, or 1000{{nbsp}}ng/kg when taken by mouth.<ref name="Arnon">{{cite journal | vauthors = Arnon SS, Schechter R, Inglesby TV, Henderson DA, Bartlett JG, Ascher MS, Eitzen E, Fine AD, Hauer J, Layton M, Lillibridge S, Osterholm MT, O'Toole T, Parker G, Perl TM, Russell PK, Swerdlow DL, Tonat K | title = Botulinum toxin as a biological weapon: medical and public health management | journal = JAMA | volume = 285 | issue = 8 | pages = 1059–1070 | date = February 2001 | pmid = 11209178 | doi = 10.1001/jama.285.8.1059 }}</ref>

==Medical uses==
Botulinum toxin is used to treat a number of therapeutic indications, many of which are not part of the approved drug label.<ref name="Al-Ghamdi">{{Cite journal |vauthors=Al-Ghamdi AS, Alghanemy N, Joharji H, Al-Qahtani D, Alghamdi H |date=January 2015 |title=Botulinum toxin: Non cosmetic and off-label dermatological uses |journal=Journal of Dermatology & Dermatologic Surgery |volume=19 |issue=1 |pages=1–8 |doi=10.1016/j.jdds.2014.06.002 | doi-access=free | title-link=doi }}</ref>

===Muscle spasticity===
Botulinum toxin is used to treat a number of disorders characterized by overactive muscle movement, including ],<ref name=Farag2020/><ref name=Blumetti2019/> post-stroke ],<ref>{{cite journal | vauthors = Ozcakir S, Sivrioglu K | title = Botulinum toxin in poststroke spasticity | journal = Clinical Medicine & Research | volume = 5 | issue = 2 | pages = 132–138 | date = June 2007 | pmid = 17607049 | pmc = 1905930 | doi = 10.3121/cmr.2007.716 }}</ref> post-spinal cord injury spasticity,<ref>{{cite journal | vauthors = Yan X, Lan J, Liu Y, Miao J | title = Efficacy and Safety of Botulinum Toxin Type A in Spasticity Caused by Spinal Cord Injury: A Randomized, Controlled Trial | journal = Medical Science Monitor | volume = 24 | pages = 8160–8171 | date = November 2018 | pmid = 30423587 | pmc = 6243868 | doi = 10.12659/MSM.911296 }}</ref> ] of the head and neck,<ref>{{cite web |url=https://www.mayoclinic.org/diseases-conditions/cervical-dystonia/symptoms-causes/syc-20354123 |title=Cervical dystonia - Symptoms and causes |publisher=Mayo Clinic |date=28 January 2014 |access-date=14 October 2015 |archive-date=12 December 2018 |archive-url=https://web.archive.org/web/20181212142423/https://www.mayoclinic.org/diseases-conditions/cervical-dystonia/symptoms-causes/syc-20354123 |url-status=live }}</ref> ],<ref name=Shukla2004>{{cite journal | vauthors = Shukla HD, Sharma SK | title = Clostridium botulinum: a bug with beauty and weapon | journal = Critical Reviews in Microbiology | volume = 31 | issue = 1 | pages = 11–18 | year = 2005 | pmid = 15839401 | doi = 10.1080/10408410590912952 | s2cid = 2855356 }}</ref> ],<ref>{{cite journal | vauthors = Pacik PT | title = Botox treatment for vaginismus | journal = Plastic and Reconstructive Surgery | volume = 124 | issue = 6 | pages = 455e–456e | date = December 2009 | pmid = 19952618 | doi = 10.1097/PRS.0b013e3181bf7f11 | doi-access = free }}</ref> limbs, jaw, and ].<ref name="Primary">{{cite journal | vauthors = Felber ES | title = Botulinum toxin in primary care medicine | journal = The Journal of the American Osteopathic Association | volume = 106 | issue = 10 | pages = 609–614 | date = October 2006 | pmid = 17122031 | doi = | s2cid = 245177279 }}</ref> Similarly, botulinum toxin is used to relax the clenching of muscles, including those of the ],<ref name=achalasia>{{cite journal | vauthors = Stavropoulos SN, Friedel D, Modayil R, Iqbal S, Grendell JH | title = Endoscopic approaches to treatment of achalasia | journal = Therapeutic Advances in Gastroenterology | volume = 6 | issue = 2 | pages = 115–135 | date = March 2013 | pmid = 23503707 | pmc = 3589133 | doi = 10.1177/1756283X12468039 }}</ref> ],<ref name=Bruxism>{{cite journal | vauthors = Long H, Liao Z, Wang Y, Liao L, Lai W | title = Efficacy of botulinum toxins on bruxism: an evidence-based review | journal = International Dental Journal | volume = 62 | issue = 1 | pages = 1–5 | date = February 2012 | pmid = 22251031 | doi = 10.1111/j.1875-595X.2011.00085.x | pmc = 9374973 | doi-access = free | title-link = doi }}</ref> ] and ],<ref name="multiple">{{cite journal | vauthors = Mangera A, Andersson KE, Apostolidis A, Chapple C, Dasgupta P, Giannantoni A, Gravas S, Madersbacher S | title = Contemporary management of lower urinary tract disease with botulinum toxin A: a systematic review of botox (onabotulinumtoxinA) and dysport (abobotulinumtoxinA) | journal = European Urology | volume = 60 | issue = 4 | pages = 784–795 | date = October 2011 | pmid = 21782318 | doi = 10.1016/j.eururo.2011.07.001 }}</ref> or clenching of the anus which can exacerbate ].<ref>{{cite journal | vauthors = Villalba H, Villalba S, Abbas MA | title = Anal fissure: a common cause of anal pain | journal = The Permanente Journal | volume = 11 | issue = 4 | pages = 62–65 | date = 2007 | pmid = 21412485 | pmc = 3048443 | doi = 10.7812/tpp/07-072 }}</ref> Botulinum toxin appears to be effective for ] ].<ref>{{cite journal | vauthors = Duthie JB, Vincent M, Herbison GP, Wilson DI, Wilson D | title = Botulinum toxin injections for adults with overactive bladder syndrome | journal = The Cochrane Database of Systematic Reviews | issue = 12 | pages = CD005493 | date = December 2011 | pmid = 22161392 | doi = 10.1002/14651858.CD005493.pub3 | veditors = Duthie JB }}</ref>

===Other muscle disorders===
], otherwise known as improper eye alignment, is caused by imbalances in the actions of muscles that rotate the eyes. This condition can sometimes be relieved by weakening a muscle that pulls too strongly, or pulls against one that has been weakened by disease or trauma. Muscles weakened by toxin injection recover from paralysis after several months, so injection might seem to need to be repeated, but muscles adapt to the lengths at which they are chronically held,<ref>{{cite journal | vauthors = Scott AB | title = Change of eye muscle sarcomeres according to eye position | journal = Journal of Pediatric Ophthalmology and Strabismus | volume = 31 | issue = 2 | pages = 85–88 | year = 1994 | pmid = 8014792 | doi = 10.3928/0191-3913-19940301-05 }}</ref> so that if a paralyzed muscle is stretched by its antagonist, it grows longer, while the antagonist shortens, yielding a permanent effect.<ref>{{cite book |vauthors=Simpson L |url=https://books.google.com/books?id=fIwBX6oBDCMC&q=strabismus%20paralyzed%20muscle%20is%20stretched%20the%20antagonist%20shortens%20permanent&pg=PA400 |title=Botulinum Neurotoxin and Tetanus Toxin |date=2 December 2012 |publisher=Elsevier |isbn=978-0-323-14160-4 |access-date=1 October 2020 |archive-date=28 August 2021 |archive-url=https://web.archive.org/web/20210828010046/https://books.google.com/books?id=fIwBX6oBDCMC&q=strabismus+paralyzed+muscle+is+stretched+the+antagonist+shortens+permanent&pg=PA400 |url-status=live }}</ref>

In January 2014, botulinum toxin was approved by UK's ] for treatment of restricted ankle motion due to lower-limb spasticity associated with stroke in adults.<ref name="DDD" /><ref>{{cite web |url=https://www.thepharmaletter.com/article/uk-s-mhra-approves-botox-for-treatment-of-ankle-disability-in-stroke-survivors |title=UK's MHRA approves Botox for treatment of ankle disability in stroke survivors |website=The Pharma Letter |access-date=16 March 2020 |archive-date=27 July 2020 |archive-url=https://web.archive.org/web/20200727033634/https://www.thepharmaletter.com/article/uk-s-mhra-approves-botox-for-treatment-of-ankle-disability-in-stroke-survivors |url-status=live }}</ref>

In July 2016, the US ] (FDA) approved abobotulinumtoxinA (Dysport) for injection for the treatment of lower-limb spasticity in pediatric patients two years of age and older.<ref>{{cite web |title=FDA Approved Drug Products – Dysport |publisher=U.S. ] (FDA) |url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=125274 |archive-url=https://web.archive.org/web/20161108054053/https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=125274 |archive-date=8 November 2016 |url-status=live |access-date=7 November 2016}} {{PD-notice}}</ref><ref>{{cite journal | vauthors = Pavone V, Testa G, Restivo DA, Cannavò L, Condorelli G, Portinaro NM, Sessa G | title = Botulinum Toxin Treatment for Limb Spasticity in Childhood Cerebral Palsy | journal = Frontiers in Pharmacology | volume = 7 | pages = 29 | date = 19 February 2016 | pmid = 26924985 | pmc = 4759702 | doi = 10.3389/fphar.2016.00029 | doi-access = free | title-link = doi }}</ref> AbobotulinumtoxinA is the first and only FDA-approved botulinum toxin for the treatment of pediatric lower limb spasticity.<ref>{{cite journal | vauthors = Syed YY | title = AbobotulinumtoxinA: A Review in Pediatric Lower Limb Spasticity | journal = Paediatric Drugs | volume = 19 | issue = 4 | pages = 367–373 | date = August 2017 | pmid = 28623614 | doi = 10.1007/s40272-017-0242-4 | s2cid = 24857218 }}</ref> In the US, the ] the text of the labels of prescription medicines and for which medical conditions the drug manufacturer may sell the drug. However, prescribers may freely prescribe them for any condition they wish, also known as ].<ref>{{cite journal | vauthors = Wittich CM, Burkle CM, Lanier WL | title = Ten common questions (and their answers) about off-label drug use | journal = Mayo Clinic Proceedings | volume = 87 | issue = 10 | pages = 982–990 | date = October 2012 | pmid = 22877654 | pmc = 3538391 | doi = 10.1016/j.mayocp.2012.04.017 }}</ref> Botulinum toxins have been used off-label for several pediatric conditions, including ].<ref name="Ocampo_2012" />

===Excessive sweating===
AbobotulinumtoxinA has been approved for the treatment of axillary ], which cannot be managed by topical agents.<ref name="Primary"/><ref name="Eisenach JH, Atkinson JL, Fealey RD. 657–666">{{cite journal | vauthors = Eisenach JH, Atkinson JL, Fealey RD | title = Hyperhidrosis: evolving therapies for a well-established phenomenon | journal = Mayo Clinic Proceedings | volume = 80 | issue = 5 | pages = 657–666 | date = May 2005 | pmid = 15887434 | doi = 10.4065/80.5.657 | doi-access = free | title-link = doi }}</ref>

===Migraine===
In 2010, the FDA approved ] botulinum toxin injections for ] ] of ] ] ].<ref>{{cite news |title=FDA Approves Botox to Treat Chronic Migraines |url=http://www.webmd.com/migraines-headaches/news/20101018/fda-approves-botox-to-treat-chronic-migraines#1 |access-date=12 May 2017 |work=WebMD |archive-date=5 May 2017 |archive-url=https://web.archive.org/web/20170505183032/http://www.webmd.com/migraines-headaches/news/20101018/fda-approves-botox-to-treat-chronic-migraines#1 |url-status=live }}</ref> However, the use of botulinum toxin injections for episodic migraine has not been approved by the FDA.<ref>{{Cite journal |date=2011 |title=HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use BOTOX® safely and effectively. See full prescribing information for BOTOX. |url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/103000s5236lbl.pdf |journal=Accessdata.fda.gov |access-date=27 April 2024 |archive-date=16 February 2024 |archive-url=https://web.archive.org/web/20240216083806/https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/103000s5236lbl.pdf |url-status=live }}</ref>

===Cosmetic uses===
]
In cosmetic applications, botulinum toxin is considered relatively safe and effective<ref>{{cite journal | vauthors = Satriyasa BK | title = Botulinum toxin (Botox) A for reducing the appearance of facial wrinkles: a literature review of clinical use and pharmacological aspect | journal = Clinical, Cosmetic and Investigational Dermatology | volume = 12 | pages = 223–228 | date = 10 April 2019 | pmid = 31114283 | pmc = 6489637 | doi = 10.2147/CCID.S202919 | doi-access = free }}</ref> for reduction of facial ], especially in the uppermost third of the face.<ref name=Small2014>{{cite journal | vauthors = Small R | title = Botulinum toxin injection for facial wrinkles | journal = American Family Physician | volume = 90 | issue = 3 | pages = 168–175 | date = August 2014 | pmid = 25077722 }}</ref> Commercial forms are marketed under the brand names Botox Cosmetic/Vistabel from ], Dysport/Azzalure from ] and ], Xeomin/Bocouture from Merz, Jeuveau/Nuceiva from Evolus, manufactured by ] in South Korea.<ref name="Krause_2019" /> The effects of botulinum toxin injections for ]r lines ('11's lines' between the eyes) typically last two to four months and in some cases, product-dependent, with some patients experiencing a longer duration of effect of up to six months or longer.<ref name="Small2014" /> Injection of botulinum toxin into the muscles under facial wrinkles causes relaxation of those muscles, resulting in the smoothing of the overlying skin.<ref name=Small2014/> Smoothing of wrinkles is usually visible three to five days after injection, with maximum effect typically a week following injection.<ref name=Small2014/> Muscles can be treated repeatedly to maintain the smoothed appearance.<ref name=Small2014/>

DaxibotulinumtoxinA (Daxxify) was approved for medical use in the United States in September 2022.<ref name="Daxxify FDA label" /><ref name="Daxxify FDA snapshot" /> It is indicated for the temporary improvement in the appearance of moderate to severe glabellar lines (wrinkles between the eyebrows).<ref name="Daxxify FDA label" /><ref name="Daxxify FDA snapshot">{{cite web | title=Drug Trials Snapshot: Daxxify | website=U.S. ] (FDA) | date=7 September 2022 | url=https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshot-daxxify | access-date=23 March 2024 | archive-date=1 February 2024 | archive-url=https://web.archive.org/web/20240201162717/https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshot-daxxify | url-status=live }} {{PD-notice}}</ref><ref>{{cite press release | title=Revance Announces FDA Approval of Daxxify (DaxibotulinumtoxinA-lanm) for Injection, the First and Only Peptide-Formulated Neuromodulator With Long-Lasting Results | publisher=Revance | via=Business Wire | date=8 September 2022 | url=https://www.businesswire.com/news/home/20220908005320/en/Revance-Announces-FDA-Approval-of-DAXXIFY%E2%84%A2-DaxibotulinumtoxinA-lanm-for-Injection-the-First-and-Only-Peptide-Formulated-Neuromodulator-With-Long-Lasting-Results | access-date=24 September 2022 | archive-date=10 September 2022 | archive-url=https://web.archive.org/web/20220910163940/https://www.businesswire.com/news/home/20220908005320/en/Revance-Announces-FDA-Approval-of-DAXXIFY%E2%84%A2-DaxibotulinumtoxinA-lanm-for-Injection-the-First-and-Only-Peptide-Formulated-Neuromodulator-With-Long-Lasting-Results/ | url-status=live }}</ref> DaxibotulinumtoxinA is an acetylcholine release inhibitor and neuromuscular blocking agent.<ref name="Daxxify FDA label" /> The FDA approved daxibotulinumtoxinA based on evidence from two clinical trials (Studies GL-1 and GL-2), of 609 adults with moderate to severe glabellar lines.<ref name="Daxxify FDA snapshot" /> The trials were conducted at 30 sites in the United States and Canada.<ref name="Daxxify FDA snapshot" /> Both trials enrolled participants 18 to 75 years old with moderate to severe glabellar lines.<ref name="Daxxify FDA snapshot" /> Participants received a single intramuscular injection of daxibotulinumtoxinA or placebo at five sites within the muscles between the eyebrows.<ref name="Daxxify FDA snapshot" /> The most common side effects of daxibotulinumtoxinA are headache, drooping eyelids, and weakness of facial muscles.<ref name="Daxxify FDA snapshot" />

LetibotulinumtoxinA (Letybo) was approved for medical use in the United States in February 2024.<ref name="Letybo FDA label" /><ref name="Letybo FDA snapshot">{{cite web | title=Drug Trials Snapshots: Letybo | website=U.S. ] (FDA) | date=29 February 2024 | url=https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-letybo | access-date=23 March 2024 | archive-date=23 March 2024 | archive-url=https://web.archive.org/web/20240323195046/https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-letybo | url-status=live }} {{PD-notice}}</ref> It is indicated to temporarily improve the appearance of moderate-to-severe glabellar lines.<ref name="Letybo FDA label" /><ref>{{cite web | title=Novel Drug Approvals for 2024 | website=U.S. ] (FDA) | date=29 April 2024 | url=https://www.fda.gov/drugs/novel-drug-approvals-fda/novel-drug-approvals-2024 | access-date=30 April 2024 | archive-date=30 April 2024 | archive-url=https://web.archive.org/web/20240430031024/https://www.fda.gov/drugs/novel-drug-approvals-fda/novel-drug-approvals-2024 | url-status=live }}</ref> The FDA approved letibotulinumtoxinA based on evidence from three clinical trials (BLESS I , BLESS II , and BLESS III ) of 1,271 participants with moderate to severe wrinkles between the eyebrows for efficacy and safety assessment.<ref name="Letybo FDA snapshot" /> These trials were conducted at 31 sites in the United States and the European Union.<ref name="Letybo FDA snapshot" /> All three trials enrolled participants 18 to 75 years old with moderate to severe glabellar lines (wrinkles between the eyebrows).<ref name="Letybo FDA snapshot" /> Participants received a single intramuscular injection of letibotulinumtoxinA or placebo at five sites within the muscles between the eyebrows.<ref name="Letybo FDA snapshot" /> The most common side effects of letibotulinumtoxinA are headache, drooping of eyelid and brow, and twitching of eyelid.<ref name="Letybo FDA snapshot" />

===Other===
Botulinum toxin is also used to treat disorders of hyperactive nerves including excessive sweating,<ref name="Eisenach JH, Atkinson JL, Fealey RD. 657–666"/> ],<ref>{{cite journal | vauthors = Mittal SO, Safarpour D, Jabbari B | title = Botulinum Toxin Treatment of Neuropathic Pain | journal = Seminars in Neurology | volume = 36 | issue = 1 | pages = 73–83 | date = February 2016 | pmid = 26866499 | doi = 10.1055/s-0036-1571953 | s2cid = 41120474 }}</ref> and some ] symptoms.<ref name="Primary"/> In addition to these uses, botulinum toxin is being evaluated for use in treating ].<ref>{{cite journal | vauthors = Charles PD | title = Botulinum neurotoxin serotype A: a clinical update on non-cosmetic uses | journal = American Journal of Health-System Pharmacy | volume = 61 | issue = 22 Suppl 6 | pages = S11–S23 | date = November 2004 | pmid = 15598005 | doi = 10.1093/ajhp/61.suppl_6.S11 | doi-access = free }}</ref> Studies show that botulinum toxin may be injected into arthritic shoulder joints to reduce chronic pain and improve range of motion.<ref>{{cite journal | vauthors = Singh JA, Fitzgerald PM | title = Botulinum toxin for shoulder pain | journal = The Cochrane Database of Systematic Reviews | issue = 9 | pages = CD008271 | date = September 2010 | pmid = 20824874 | doi = 10.1002/14651858.cd008271.pub2 }}</ref> The use of botulinum toxin A in children with ] is safe in the upper and lower limb muscles.<ref name="Farag2020" /><ref name="Blumetti2019" />

==Side effects==
While botulinum toxin is generally considered safe in a clinical setting, serious side effects from its use can occur. Most commonly, botulinum toxin can be injected into the wrong muscle group or with time spread from the injection site, causing temporary paralysis of unintended muscles.<ref name="pmid20418969"/>

Side effects from cosmetic use generally result from unintended paralysis of facial muscles. These include partial facial paralysis, muscle weakness, and ]. Side effects are not limited to direct paralysis, however, and can also include headaches, flu-like symptoms, and allergic reactions.<ref name="Coté_2005"/> Just as cosmetic treatments only last a number of months, paralysis side effects can have the same durations.<ref>{{cite journal | vauthors = Witmanowski H, Błochowiak K | title = The whole truth about botulinum toxin - a review | journal = Postepy Dermatologii I Alergologii | volume = 37 | issue = 6 | pages = 853–861 | date = December 2020 | pmid = 33603602 | doi = 10.5114/ada.2019.82795 | pmc = 7874868 }}</ref> At least in some cases, these effects are reported to dissipate in the weeks after treatment.<ref>{{cite journal | vauthors = Witmanowski H, Błochowiak K | title = The whole truth about botulinum toxin - a review | journal = Postepy Dermatologii I Alergologii | volume = 37 | issue = 6 | pages = 853–861 | date = December 2020 | pmid = 33603602 | pmc = 7874868 | doi = 10.5114/ada.2019.82795 }}</ref> Bruising at the site of injection is not a side effect of the toxin, but rather of the mode of administration, and is reported as preventable if the clinician applies pressure to the injection site; when it occurs, it is reported in specific cases to last 7–11 days.<ref>{{cite journal | vauthors = Hamman MS, Goldman MP | title = Minimizing bruising following fillers and other cosmetic injectables | journal = The Journal of Clinical and Aesthetic Dermatology | volume = 6 | issue = 8 | pages = 16–18 | date = August 2013 | pmid = 24003345 | pmc = 3760599 }}</ref> When injecting the masseter muscle of the jaw, loss of muscle function can result in a loss or reduction of power to chew solid foods.<ref name="Coté_2005" /> With continued high doses, the muscles can atrophy or lose strength; research has shown that those muscles rebuild after a break from Botox.<ref>{{cite news | vauthors = Schiffer J |date=8 April 2021 |title=How Barely-There Botox Became the Norm |work=The New York Times |url=https://www.nytimes.com/2021/04/08/style/self-care-how-barely-there-botox-became-the-norm.html |archive-url=https://ghostarchive.org/archive/20211228/https://www.nytimes.com/2021/04/08/style/self-care-how-barely-there-botox-became-the-norm.html |archive-date=28 December 2021 |url-access=limited |access-date=23 November 2021 |issn=0362-4331 |url-status=live}}</ref>

Side effects from therapeutic use can be much more varied depending on the location of injection and the dose of toxin injected. In general, side effects from therapeutic use can be more serious than those that arise during cosmetic use. These can arise from paralysis of critical muscle groups and can include ], ], and in some cases, seizures, respiratory arrest, and death.<ref name="Coté_2005" /> Additionally, side effects common in cosmetic use are also common in therapeutic use, including trouble swallowing, muscle weakness, allergic reactions, and flu-like syndromes.<ref name="Coté_2005">{{cite journal | vauthors = Coté TR, Mohan AK, Polder JA, Walton MK, Braun MM | title = Botulinum toxin type A injections: adverse events reported to the US Food and Drug Administration in therapeutic and cosmetic cases | journal = Journal of the American Academy of Dermatology | volume = 53 | issue = 3 | pages = 407–415 | date = September 2005 | pmid = 16112345 | doi = 10.1016/j.jaad.2005.06.011 | url = https://zenodo.org/record/1259075 | access-date = 29 December 2021 | archive-date = 23 May 2022 | archive-url = https://web.archive.org/web/20220523173847/https://zenodo.org/record/1259075 | url-status = live }}</ref>

In response to the occurrence of these side effects, in 2008, the FDA notified the public of the potential dangers of the botulinum toxin as a therapeutic. Namely, the toxin can spread to areas distant from the site of injection and paralyze unintended muscle groups, especially when used for treating muscle spasticity in children treated for cerebral palsy.<ref name=FDA08>{{cite web |url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2008/ucm116857.htm |title=FDA Notifies Public of Adverse Reactions Linked to Botox Use |publisher=U.S. ] (FDA) |access-date=6 May 2012 |date=8 February 2008 |archive-url=https://web.archive.org/web/20120302084857/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2008/ucm116857.htm |archive-date=2 March 2012 |url-status=dead}} {{PD-notice}}</ref> In 2009, the FDA announced that boxed warnings would be added to available botulinum toxin products, warning of their ability to spread from the injection site.<ref name=FDA09/><ref>{{cite press release | title=FDA Gives Update on Botulinum Toxin Safety Warnings; Established Names of Drugs Changed | publisher=U.S. ] (FDA) | date=3 August 2009 | url=http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2009/ucm175013.htm | archive-url=https://web.archive.org/web/20150924140939/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2009/ucm175013.htm | archive-date=24 September 2015 | url-status=dead | access-date=18 December 2022}}</ref><ref>{{cite web | title=Update of Safety Review of OnabotulinumtoxinA (marketed as Botox/Botox Cosmetic), AbobotulinumtoxinA (marketed as Dysport) and RimabotulinumtoxinB (marketed as Myobloc) | publisher=U.S. ] (FDA) | date=3 August 2009 | url=http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm174959.htm | archive-url=https://web.archive.org/web/20150701032216/http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm174959.htm | archive-date=1 July 2015 | url-status=dead | access-date=18 December 2022}}</ref><ref>{{cite web | title=Follow-up to the February 8, 2008, Early Communication about an Ongoing Safety Review of Botox and Botox Cosmetic (Botulinum toxin Type A) and Myobloc (Botulinum toxin Type B) | publisher=U.S. ] (FDA) | date=8 February 2008 | url=http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm143819.htm | archive-url=https://web.archive.org/web/20150602084706/http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm143819.htm | archive-date=2 June 2015 | url-status=dead | access-date=18 December 2022}}</ref> However, the clinical use of botulinum toxin A in cerebral palsy children has been proven to be safe with minimal side effects.<ref name=Farag2020/><ref name=Blumetti2019/> Additionally, the FDA announced name changes to several botulinum toxin products, to emphasize that the products are not interchangeable and require different doses for proper use. Botox and Botox Cosmetic were given the generic name of onabotulinumtoxinA, Myobloc as rimabotulinumtoxinB, and Dysport retained its generic name of abobotulinumtoxinA.<ref name="FDA Botulinum" /><ref name="FDA09">{{cite web |url=https://www.pharmaceuticalonline.com/doc/fda-gives-update-on-botulinum-toxin-safety-0001 |title=FDA Gives Update on Botulinum Toxin Safety Warnings; Established Names of Drugs Changed |date=4 August 2009 |website=Pharmaceutical Online |access-date=16 July 2019 |archive-date=6 July 2019 |archive-url=https://web.archive.org/web/20190706132201/https://www.pharmaceuticalonline.com/doc/fda-gives-update-on-botulinum-toxin-safety-0001 |url-status=live }}</ref> In conjunction with this, the FDA issued a communication to health care professionals reiterating the new drug names and the approved uses for each.<ref name=FDA09hc/> A similar warning was issued by ] in 2009, warning that botulinum toxin products can spread to other parts of the body.<ref>{{cite news |url=https://www.cbc.ca/news/science/botox-chemical-may-spread-health-canada-confirms-1.786237 |work=CBC News |title=Botox chemical may spread, Health Canada confirms |date=13 January 2009 |url-status=live |archive-url=https://web.archive.org/web/20090221144310/http://www.cbc.ca/consumer/story/2009/01/13/botox.html |archive-date=21 February 2009}}</ref>

==Role in disease==
{{Main|Botulism}}

Botulinum toxin produced by ''Clostridium botulinum'' (an anaerobic, gram-positive bacterium) is the cause of botulism.<ref name=Shukla2004/> Humans most commonly ingest the toxin from eating improperly canned foods in which ''C.&nbsp;botulinum'' has grown. However, the toxin can also be introduced through an infected wound. In infants, the bacteria can sometimes grow in the intestines and produce botulinum toxin within the intestine and can cause a condition known as ].<ref>{{cite web |url=https://www.cdc.gov/botulism/definition.html |title=Kinds of Botulism |publisher=U.S. ] (CDC) |access-date=4 October 2016 |archive-date=5 October 2016 |archive-url=https://web.archive.org/web/20161005195008/http://www.cdc.gov/botulism/definition.html |url-status=live }}</ref> In all cases, the toxin can then spread, blocking nerves and muscle function. In severe cases, the toxin can block nerves controlling the respiratory system or heart, resulting in death.<ref name=Montecucco2005/>

<!--Diagnosis & Treatment-->
Botulism can be difficult to diagnose, as it may appear similar to diseases such as ], ], and ]. Other tests, such as brain scan and spinal fluid examination, may help to rule out other causes. If the symptoms of botulism are diagnosed early, various treatments can be administered. In an effort to remove contaminated food that remains in the gut, enemas or induced vomiting may be used.<ref name=CDCTreat>{{cite web |url=https://www.cdc.gov/botulism/testing-treatment.html |access-date=5 October 2016 |title=Botulism – Diagnosis and Treatment |publisher=U.S. ] (CDC) |archive-date=5 October 2016 |archive-url=https://web.archive.org/web/20161005200323/http://www.cdc.gov/botulism/testing-treatment.html |url-status=live }}</ref> For wound infections, infected material may be removed surgically.<ref name=CDCTreat/> Botulinum antitoxin is available and may be used to prevent the worsening of symptoms, though it will not reverse existing nerve damage. In severe cases, mechanical respiration may be used to support people with respiratory failure.<ref name=CDCTreat/> The nerve damage heals over time, generally over weeks to months.<ref>{{Cite web |title=Botulism - Diagnosis and treatment |url=https://www.mayoclinic.org/diseases-conditions/botulism/diagnosis-treatment/drc-20370266 |access-date=1 November 2023 |website=Mayo Clinic |archive-date=1 November 2023 |archive-url=https://web.archive.org/web/20231101010856/https://www.mayoclinic.org/diseases-conditions/botulism/diagnosis-treatment/drc-20370266 |url-status=live }}</ref> With proper treatment, the case fatality rate for botulinum poisoning can be greatly reduced.<ref name=CDCTreat/>

Two preparations of botulinum antitoxins are available for treatment of botulism. Trivalent (serotypes A, B, E) botulinum ] is derived from equine sources using whole ]. The second antitoxin is ] (serotypes A, B, C, D, E, F, G), which is derived from equine antibodies that have been altered to make them less immunogenic. This antitoxin is effective against all main strains of botulism.<ref>{{cite journal | vauthors = Barash JR, Arnon SS | title = A novel strain of Clostridium botulinum that produces type B and type H botulinum toxins | journal = The Journal of Infectious Diseases | volume = 209 | issue = 2 | pages = 183–191 | date = January 2014 | pmid = 24106296 | doi = 10.1093/infdis/jit449 | doi-access = | title-link = doi }}</ref><ref name=BotH/>

==Mechanism of action==
] (''TeNT''), toxins acting inside the axon terminal<ref name=Barr2005>{{cite journal | vauthors = Barr JR, Moura H, Boyer AE, Woolfitt AR, Kalb SR, Pavlopoulos A, McWilliams LG, Schmidt JG, Martinez RA, Ashley DL | title = Botulinum neurotoxin detection and differentiation by mass spectrometry | journal = Emerging Infectious Diseases | volume = 11 | issue = 10 | pages = 1578–1583 | date = October 2005 | pmid = 16318699 | pmc = 3366733 | doi = 10.3201/eid1110.041279 }}</ref>]]

Botulinum toxin exerts its effect by cleaving key proteins required for nerve activation. First, the toxin binds specifically to presynaptic surface of ] that use the neurotransmitter ]. Once bound to the nerve terminal, the neuron ] the toxin into a ] by receptor-mediated ].<ref name=Dressler05>{{cite journal | vauthors = Dressler D, Saberi FA, Barbosa ER | title = Botulinum toxin: mechanisms of action | journal = Arquivos de Neuro-Psiquiatria | volume = 63 | issue = 1 | pages = 180–185 | date = March 2005 | pmid = 15830090 | doi = 10.1159/000083259 | s2cid = 16307223 | title-link = doi | doi-access = free }}</ref> As the vesicle moves farther into the cell, it acidifies, activating a portion of the toxin that triggers it to push across the vesicle membrane and into the cell ].<ref name=Montecucco2005/> Botulinum neurotoxins recognize distinct classes of receptors simultaneously (]s, ] and ]).<ref name="pmid30388027">{{cite journal | vauthors = Dong M, Masuyer G, Stenmark P | title = Botulinum and Tetanus Neurotoxins | journal = Annual Review of Biochemistry | volume = 88 | issue = 1 | pages = 811–837 | date = June 2019 | pmid = 30388027 | pmc = 7539302 | doi = 10.1146/annurev-biochem-013118-111654 }}</ref> Once inside the cytoplasm, the toxin cleaves ] (proteins that mediate vesicle fusion, with their target membrane bound compartments) meaning that the acetylcholine vesicles cannot bind to the intracellular cell membrane,<ref name=Dressler05/> preventing the cell from releasing vesicles of neurotransmitter. This stops nerve signaling, leading to ].<ref name=Montecucco2005/><ref name="pmid30388027" />

The toxin itself is released from the bacterium as a single chain, then becomes activated when cleaved by its own proteases.<ref name="Primary"/> The active form consists of a two-chain ] composed of a 100-] heavy chain ] joined via ] to a 50-kDa light chain polypeptide.<ref name=Bowlin11/> The heavy chain contains domains with several functions; it has the domain responsible for binding specifically to ] nerve terminals, as well as the domain responsible for mediating translocation of the light chain into the cell cytoplasm as the vacuole acidifies.<ref name=Montecucco2005/><ref name=Bowlin11/> The light chain is a M27-family zinc ] and is the active part of the toxin. It is translocated into the host cell cytoplasm where it cleaves the host protein ], a member of the SNARE protein family, which is responsible for ]. The cleaved SNAP-25 cannot mediate fusion of vesicles with the host cell membrane, thus preventing the release of the ] acetylcholine from axon endings.<ref name=Montecucco2005/> This blockage is slowly reversed as the toxin loses activity and the SNARE proteins are slowly regenerated by the affected cell.<ref name=Montecucco2005/>

The seven toxin serotypes (A–G) are traditionally separated by their antigenicity. They have different tertiary structures and sequence differences.<ref name=Bowlin11/><ref name="Genetic Diversity">{{cite book | vauthors = Hill KK, Smith TJ | title = Botulinum Neurotoxins | chapter = Genetic diversity within Clostridium botulinum serotypes, botulinum neurotoxin gene clusters and toxin subtypes | series = Current Topics in Microbiology and Immunology | volume = 364 | pages = 1–20 | date = 2013 | pmid = 23239346 | doi = 10.1007/978-3-642-33570-9_1 | publisher = Springer | isbn = 978-3-642-33569-3 | veditors = Rummel A, Binz T }}</ref> While the different toxin types all target members of the SNARE family, different toxin types target different SNARE family members.<ref name=Barr2005/> The A, B, and E serotypes cause human botulism, with the activities of types A and B enduring longest ''in vivo'' (from several weeks to months).<ref name=Bowlin11/> Existing toxin types can recombine to create "hybrid" (mosaic, chimeric) types. Examples include BoNT/CD, BoNT/DC, and BoNT/FA, with the first letter indicating the light chain type and the latter indicating the heavy chain type.<ref name="pmid30347838">{{cite journal | vauthors = Davies JR, Liu SM, Acharya KR | title = Variations in the Botulinum Neurotoxin Binding Domain and the Potential for Novel Therapeutics | journal = Toxins | volume = 10 | issue = 10 | pages = 421 | date = October 2018 | pmid = 30347838 | pmc = 6215321 | doi = 10.3390/toxins10100421 | doi-access = free | title-link = doi }}</ref> BoNT/FA received considerable attention under the name "BoNT/H", as it was mistakenly thought it could not be neutralized by any existing antitoxin.<ref name=BotH/>

Botulinum toxins are closely related to ]. The two are collectively known as ] and the light chain is classified by ] as family M27.<ref>{{cite web | url = https://www.ebi.ac.uk/merops/cgi-bin/famsum?family=M27 | title = Family M27 | work = MEROPS Peptidase Database }}</ref> ''Clostridium'' neurotoxins belong in the wider family of ]s, which also includes ] and ]. Nonclassical types include BoNT/X ({{UniProt|P0DPK1}}), which is toxic in mice and possibly in humans;<ref name=BotX/> a BoNT/J ({{UniProt|A0A242DI27}}) found in cow '']'';<ref>{{cite journal | vauthors = Brunt J, Carter AT, Stringer SC, Peck MW | title = Identification of a novel botulinum neurotoxin gene cluster in Enterococcus | journal = FEBS Letters | volume = 592 | issue = 3 | pages = 310–317 | date = February 2018 | pmid = 29323697 | pmc = 5838542 | doi = 10.1002/1873-3468.12969 | doi-access = free | title-link = doi }}</ref> and a BoNT/Wo ({{UniProt|A0A069CUU9}}) found in the rice-colonizing '']''.<ref name="pmid30347838"/>

==History==

===Initial descriptions and discovery of ''Clostridium botulinum''===
One of the earliest recorded outbreaks of foodborne botulism occurred in 1793 in the village of ] in what is now ], Germany. Thirteen people became sick and six died after eating pork stomach filled with ], a local delicacy. Additional cases of fatal food poisoning in ] led the authorities to issue a public warning against consuming smoked blood sausages in 1802 and to collect case reports of "sausage poisoning".<ref name="Erbguth 2004">{{cite journal | vauthors = Erbguth FJ | title = Historical notes on botulism, Clostridium botulinum, botulinum toxin, and the idea of the therapeutic use of the toxin | journal = Movement Disorders | volume = 19 | issue = Supplement 8 | pages = S2–S6 | date = March 2004 | pmid = 15027048 | doi = 10.1002/mds.20003 | s2cid = 8190807 }}</ref> Between 1817 and 1822, the German physician ] published the first complete description of the symptoms of botulism, based on extensive clinical observations and animal experiments. He concluded that the toxin develops in bad sausages under anaerobic conditions, is a biological substance, acts on the nervous system, and is lethal even in small amounts.<ref name="Erbguth 2004"/> Kerner hypothesized that this "sausage toxin" could be used to treat a variety of diseases caused by an overactive nervous system, making him the first to suggest that it could be used therapeutically.<ref name="Erbguth 1999">{{cite journal | vauthors = Erbguth FJ, Naumann M | title = Historical aspects of botulinum toxin: Justinus Kerner (1786-1862) and the "sausage poison" | journal = Neurology | volume = 53 | issue = 8 | pages = 1850–1853 | date = November 1999 | pmid = 10563638 | doi = 10.1212/wnl.53.8.1850 | s2cid = 46559225 }}</ref> In 1870, the German physician Müller coined the term ''botulism'' to describe the disease caused by sausage poisoning, from the Latin word {{Lang|la|botulus}}, meaning 'sausage'.<ref name="Erbguth 1999"/>

In 1895 ], a Belgian microbiologist, discovered what is now called ''Clostridium botulinum'' and confirmed that a toxin produced by the bacteria causes botulism.<ref name="Monheit 2017">{{cite journal | vauthors = Monheit GD, Pickett A | title = AbobotulinumtoxinA: A 25-Year History | journal = Aesthetic Surgery Journal | volume = 37 | issue = suppl_1 | pages = S4–S11 | date = May 2017 | pmid = 28388718 | pmc = 5434488 | doi = 10.1093/asj/sjw284 }}</ref> On 14 December 1895, there was a large outbreak of botulism in the Belgian village of ] that occurred at a funeral where people ate pickled and smoked ham; three of them died. By examining the contaminated ham and performing autopsies on the people who died after eating it, van Ermengem isolated an anaerobic microorganism that he called ''Bacillus botulinus''.<ref name="Erbguth 2004"/> He also performed experiments on animals with ham extracts, isolated bacterial cultures, and toxins extracts from the bacteria. From these he concluded that the bacteria themselves do not cause foodborne botulism, but rather produce a toxin that causes the disease after it is ingested.<ref>{{cite journal | vauthors = Pellett S | title = Learning from the past: historical aspects of bacterial toxins as pharmaceuticals | journal = Current Opinion in Microbiology | volume = 15 | issue = 3 | pages = 292–299 | date = June 2012 | pmid = 22651975 | doi = 10.1016/j.mib.2012.05.005 }}</ref> As a result of Kerner's and van Ermengem's research, it was thought that only contaminated meat or fish could cause botulism. This idea was refuted in 1904 when a botulism outbreak occurred in ], Germany, because of canned white beans. In 1910, the German microbiologist J. Leuchs published a paper showing that the outbreaks in Ellezelles and Darmstadt were caused by different strains of ''Bacillus botulinus'' and that the toxins were serologically distinct.<ref name="Erbguth 2004"/> In 1917, ''Bacillus botulinus'' was renamed ''Clostridium botulinum'', as it was decided that term ''Bacillus'' should only refer to a group of aerobic microorganisms, while ''Clostridium'' would be only used to describe a group of anaerobic microorganisms.<ref name="Monheit 2017"/> In 1919, ] used toxin-antitoxin reactions to identify two strains of ''Clostridium botulinum'', which she designated A and B.<ref name="Monheit 2017"/>

===Food canning===
{{more citations needed section|date=August 2018}}

Over the next three decades, 1895–1925, as food canning was approaching a billion-dollar-a-year industry, botulism was becoming a public health hazard. ], a Swiss-American veterinary scientist, created a center at the Hooper Foundation in San Francisco, where he developed techniques for growing the organism and extracting the toxin, and conversely, for preventing organism growth and toxin production, and inactivating the toxin by heating. The California canning industry was thereby preserved.<ref>{{cite web |date=24 June 2022 |title=Home Canning and Botulism |url=https://www.cdc.gov/foodsafety/communication/home-canning-and-botulism.html |access-date=3 August 2022 |archive-date=2 August 2022 |archive-url=https://web.archive.org/web/20220802021326/https://www.cdc.gov/foodsafety/communication/home-canning-and-botulism.html |url-status=live }}</ref>

===World War II===
With the outbreak of World War II, weaponization of botulinum toxin was investigated at ] in Maryland. Carl Lamanna and James Duff<ref>{{cite journal | vauthors = Lamanna C, McELROY OE, Eklund HW | title = The purification and crystallization of Clostridium botulinum type A toxin | journal = Science | volume = 103 | issue = 2681 | pages = 613–614 | date = May 1946 | pmid = 21026141 | doi = 10.1126/science.103.2681.613 | bibcode = 1946Sci...103..613L }}</ref> developed the concentration and crystallization techniques that Edward J. Schantz used to create the first clinical product. When the Army's ] was disbanded, Schantz moved to the Food Research Institute in Wisconsin, where he manufactured toxin for experimental use and provided it to the academic community.

The mechanism of botulinum toxin action – blocking the release of the neurotransmitter acetylcholine from nerve endings – was elucidated in the mid-20th century,<ref>{{cite journal | vauthors = Burgen AS, Dickens F, Zatman LJ | title = The action of botulinum toxin on the neuro-muscular junction | journal = The Journal of Physiology | volume = 109 | issue = 1–2 | pages = 10–24 | date = August 1949 | pmid = 15394302 | pmc = 1392572 | doi = 10.1113/jphysiol.1949.sp004364 }}</ref> and remains an important research topic. Nearly all toxin treatments are based on this effect in various body tissues.

===Strabismus===
Ophthalmologists specializing in eye muscle disorders (]) had developed the method of EMG-guided injection (using the ], the electrical signal from an activated muscle, to guide injection) of local anesthetics as a diagnostic technique for evaluating an individual muscle's contribution to an eye movement.<ref>{{cite journal | vauthors = Magoon E, Cruciger M, Scott AB, Jampolsky A | title = Diagnostic injection of Xylocaine into extraocular muscles | journal = Ophthalmology | volume = 89 | issue = 5 | pages = 489–491 | date = May 1982 | pmid = 7099568 | doi = 10.1016/s0161-6420(82)34764-8 }}</ref> Because ] frequently needed repeating, a search was undertaken for non-surgical, injection treatments using various anesthetics, alcohols, enzymes, enzyme blockers, and snake neurotoxins. Finally, inspired by ]'s work with chicks at Johns Hopkins,<ref>{{cite journal | vauthors = Drachman DB | title = Atrophy of Skeletal Muscle in Chick Embryos Treated with Botulinum Toxin | journal = Science | volume = 145 | issue = 3633 | pages = 719–721 | date = August 1964 | pmid = 14163805 | doi = 10.1126/science.145.3633.719 | s2cid = 43093912 | bibcode = 1964Sci...145..719D }}</ref> ] and colleagues injected botulinum toxin into monkey extraocular muscles.<ref name="Scott_1973">{{cite journal | vauthors = Scott AB, Rosenbaum A, Collins CC | title = Pharmacologic weakening of extraocular muscles | journal = Investigative Ophthalmology | volume = 12 | issue = 12 | pages = 924–927 | date = December 1973 | pmid = 4203467 }}</ref> The result was remarkable; a few picograms induced paralysis that was confined to the target muscle, long in duration, and without side effects.

After working out techniques for freeze-drying, buffering with ], and assuring sterility, potency, and safety, Scott applied to the FDA for investigational drug use, and began manufacturing botulinum type A neurotoxin in his San Francisco lab. He injected the first strabismus patients in 1977, reported its clinical utility in 1980,<ref>{{cite journal | vauthors = Scott AB | title = Botulinum toxin injection into extraocular muscles as an alternative to strabismus surgery | journal = Ophthalmology | volume = 87 | issue = 10 | pages = 1044–1049 | date = October 1980 | pmid = 7243198 | doi = 10.1016/s0161-6420(80)35127-0 | s2cid = 27341687 }}</ref> and had soon trained hundreds of ophthalmologists in EMG-guided injection of the drug he named Oculinum ("eye aligner").

In 1986, Oculinum Inc, Scott's micromanufacturer and distributor of botulinum toxin, was unable to obtain product liability insurance, and could no longer supply the drug. As supplies became exhausted, people who had come to rely on periodic injections became desperate. For four months, as liability issues were resolved, American blepharospasm patients traveled to Canadian eye centers for their injections.<ref name="Boffey_1986" />

Based on data from thousands of people collected by 240 investigators, Oculinum Inc (which was soon acquired by Allergan) received FDA approval in 1989 to market Oculinum for clinical use in the United States to treat adult strabismus and ]. Allergan then began using the trademark Botox.<ref name=alg/> This original approval was granted under the ].<ref name="pmid20036435">{{cite journal | vauthors = Wellman-Labadie O, Zhou Y | title = The US Orphan Drug Act: rare disease research stimulator or commercial opportunity? | journal = Health Policy | volume = 95 | issue = 2–3 | pages = 216–228 | date = May 2010 | pmid = 20036435 | doi = 10.1016/j.healthpol.2009.12.001 }}</ref>

===Cosmetics===
]
The effect of botulinum toxin type-A on reducing and eliminating forehead wrinkles was first described and published by Richard Clark, MD, a plastic surgeon from Sacramento, California. In 1987 Clark was challenged with eliminating the disfigurement caused by only the right side of the forehead muscles functioning after the left side of the forehead was paralyzed during a facelift procedure. This patient had desired to look better from her facelift, but was experiencing bizarre unilateral right forehead eyebrow elevation while the left eyebrow drooped, and she constantly demonstrated deep expressive right forehead wrinkles while the left side was perfectly smooth due to the paralysis. Clark was aware that Botulinum toxin was safely being used to treat babies with strabismus and he requested and was granted FDA approval to experiment with Botulinum toxin to paralyze the moving and wrinkling normal functioning right forehead muscles to make both sides of the forehead appear the same. This study and case report of the cosmetic use of Botulinum toxin to treat a cosmetic complication of a cosmetic surgery was the first report on the specific treatment of wrinkles and was published in the journal ''Plastic and Reconstructive Surgery'' in 1989.<ref name="Clark_1989" /> Editors of the journal of the American Society of Plastic Surgeons have clearly stated "the first described use of the toxin in aesthetic circumstances was by Clark and Berris in 1989."<ref name="Rohrich_2003">{{cite journal | vauthors = Rohrich RJ, Janis JE, Fagien S, Stuzin JM | title = The cosmetic use of botulinum toxin | journal = Plastic and Reconstructive Surgery | volume = 112 | issue = 5 Suppl | pages = 177S–188S | date = October 2003 | pmid = 14504502 | doi = 10.1097/01.prs.0000082208.37239.5b }}</ref>

Also in 1987, Jean and Alastair Carruthers, both doctors in ], observed that blepharospasm patients who received injections around the eyes and upper face also enjoyed diminished facial glabellar lines ("frown lines" between the eyebrows). Alastair Carruthers reported that others at the time also noticed these effects and discussed the cosmetic potential of botulinum toxin.<ref name="Carruthers A 2003">{{cite journal | vauthors = Carruthers A | title = History of the clinical use of botulinum toxin A and B | journal = Clinics in Dermatology | volume = 21 | issue = 6 | pages = 469–472 | date = Nov–Dec 2003 | pmid = 14759577 | doi = 10.1016/j.clindermatol.2003.11.003 }}</ref> Unlike other investigators, the Carruthers did more than just talk about the possibility of using botulinum toxin cosmetically. They conducted a clinical study on otherwise normal individuals whose only concern was their eyebrow furrow. They performed their study between 1987 and 1989 and presented their results at the 1990 annual meeting of the American Society for Dermatologic Surgery. Their findings were subsequently published in 1992.<ref name="Carruthers JD 19922">{{cite journal | vauthors = Carruthers JD, Carruthers JA | title = Treatment of glabellar frown lines with C. botulinum-A exotoxin | journal = The Journal of Dermatologic Surgery and Oncology | volume = 18 | issue = 1 | pages = 17–21 | date = January 1992 | pmid = 1740562 | doi = 10.1111/j.1524-4725.1992.tb03295.x }}</ref>

===Chronic pain===

] reported in 2000 that people who had cosmetic injections around the face reported relief from chronic headache.<ref>{{cite journal | vauthors = Binder WJ, Brin MF, Blitzer A, Schoenrock LD, Pogoda JM | title = Botulinum toxin type A (Botox) for treatment of migraine headaches: an open-label study | journal = Otolaryngology–Head and Neck Surgery | volume = 123 | issue = 6 | pages = 669–676 | date = December 2000 | pmid = 11112955 | doi = 10.1067/mhn.2000.110960 | s2cid = 24406607 }}</ref> This was initially thought to be an indirect effect of reduced muscle tension, but the toxin is now known to inhibit release of peripheral nociceptive neurotransmitters, suppressing the central pain processing systems responsible for ] headache.<ref>{{cite journal | vauthors = Jackson JL, Kuriyama A, Hayashino Y | title = Botulinum toxin A for prophylactic treatment of migraine and tension headaches in adults: a meta-analysis | journal = JAMA | volume = 307 | issue = 16 | pages = 1736–1745 | date = April 2012 | pmid = 22535858 | doi = 10.1001/jama.2012.505 }}</ref><ref>{{cite journal | vauthors = Ramachandran R, Yaksh TL | title = Therapeutic use of botulinum toxin in migraine: mechanisms of action | journal = British Journal of Pharmacology | volume = 171 | issue = 18 | pages = 4177–4192 | date = September 2014 | pmid = 24819339 | pmc = 4241086 | doi = 10.1111/bph.12763 }}</ref>

==Society and culture==

===Economics===
{{Update|date=October 2017}}

{{As of|2018}}, botulinum toxin injections are the most common cosmetic operation, with 7.4 million procedures in the United States, according to the ].<ref>{{cite web |url=https://www.plasticsurgery.org/news/press-releases/new-plastic-surgery-statistics-reveal-trends-toward-body-enhancement |title=New plastic surgery statistics reveal trends toward body enhancement |date=11 March 2019 |website=Plastic Surgery |archive-url=https://web.archive.org/web/20190312062815/https://www.plasticsurgery.org/news/press-releases/new-plastic-surgery-statistics-reveal-trends-toward-body-enhancement |archive-date=12 March 2019}}</ref>

The global market for botulinum toxin products, driven by their cosmetic applications, was forecast to reach $2.9 billion by 2018. The facial aesthetics market, of which they are a component, was forecast to reach $4.7 billion ($2 billion in the US) in the same timeframe.<ref>{{cite web |url=http://www.companiesandmarkets.com/News/Healthcare-and-Medical/The-global-botox-market-forecast-to-reach-2-9-billion-by-2018/NI2991 |title=The global botox market forecast to reach $2.9 billion by 2018 |date=10 May 2012 |access-date=5 October 2012 |vauthors=Chapman L |archive-url=https://web.archive.org/web/20120806230249/http://www.companiesandmarkets.com/News/Healthcare-and-Medical/The-global-botox-market-forecast-to-reach-2-9-billion-by-2018/NI2991 |archive-date=6 August 2012 |url-status=dead}}</ref>

====US market====
In 2020, 4,401,536 botulinum toxin Type A procedures were administered.<ref>{{cite web |title=2020 National Plastic Surgery Statistics: Cosmetic Surgical Procedures |url=https://www.plasticsurgery.org/documents/News/Statistics/2020/plastic-surgery-statistics-report-2020.pdf |publisher=American Society of Plastic Surgeons |access-date=22 May 2021 |archive-date=23 June 2021 |archive-url=https://web.archive.org/web/20210623232536/https://www.plasticsurgery.org/documents/News/Statistics/2020/plastic-surgery-statistics-report-2020.pdf |url-status=live }}</ref> In 2019 the botulinum toxin market made US$3.19 billion.<ref name="FBI">{{cite web |title=Botulinum Toxin Market |url=https://www.fortunebusinessinsights.com/industry-reports/botulinum-toxin-market-100996 |work=Fortune Business Insights |access-date=22 May 2021 |archive-date=27 June 2021 |archive-url=https://web.archive.org/web/20210627192718/https://www.fortunebusinessinsights.com/industry-reports/botulinum-toxin-market-100996 |url-status=live }}</ref>

====Botox cost====
Botox cost is generally determined by the number of units administered (avg. $10–30 per unit) or by the area ($200–1000) and depends on expertise of a physician, clinic location, number of units, and treatment complexity.<ref>{{Cite web |title=How Much Does Botox Cost |url=https://www.cosmeticassociation.org/cosmetic-procedures/botox/how-much-does-botox-cost/ |access-date=13 March 2013 |website=American Cosmetic Association |archive-date=13 March 2023 |archive-url=https://web.archive.org/web/20230313122938/https://www.cosmeticassociation.org/cosmetic-procedures/botox/how-much-does-botox-cost/ |url-status=live }}</ref>

====Insurance====
In the US, botox for medical purposes is usually covered by insurance if deemed medically necessary by a doctor and covers a plethora of medical problems including overactive bladder (OAB), urinary incontinence due to neurologic conditions, headaches and migraines, TMJ, spasticity in adults, cervical dystonia in adults, severe axillary hyperhidrosis (or other areas of the body), blepharospasm, upper or lower limb spasticity.<ref>{{cite web |title=Medicare Guidelines for Botox Treatments |url=https://www.medicarefaq.com/faqs/medicare-coverage-for-botox-treatments |work=MedicareFAQ.com |date=27 September 2021 |access-date=22 May 2021 |archive-date=23 May 2021 |archive-url=https://web.archive.org/web/20210523024145/https://www.medicarefaq.com/faqs/medicare-coverage-for-botox-treatments/ |url-status=live }}</ref><ref>{{cite web |title=BOTOX (onabotulinumtoxinA) for injection, for intramuscular, intradetrusor, or intradermal use |work=Highlights of Prescribing Information |url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/103000s5302lbl.pdf |publisher=U.S. ] (FDA) |access-date=22 May 2021 |archive-date=28 March 2021 |archive-url=https://web.archive.org/web/20210328131433/https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/103000s5302lbl.pdf |url-status=live }}</ref>

====Hyperhidrosis====
Botox for excessive sweating is FDA approved.<ref name="pmid20418969">{{cite journal | vauthors = Nigam PK, Nigam A | title = Botulinum toxin | journal = Indian Journal of Dermatology | volume = 55 | issue = 1 | pages = 8–14 | date = 2010 | pmid = 20418969 | pmc = 2856357 | doi = 10.4103/0019-5154.60343 | doi-access = free }}</ref>

====Cosmetic====
Standard areas for aesthetics botox injections include facial and other areas that can form fine lines and wrinkles due to every day muscle contractions and/or facial expressions such as smiling, frowning, squinting, and raising eyebrows. These areas include the glabellar region between the eyebrows, horizontal lines on the forehead, crow's feet around the eyes, and even circular bands that form around the neck secondary to platysmal hyperactivity.<ref>{{cite web |title=Botox Procedures: What is Botox & How Does it Work |url=https://www.facialesthetics.org/botox-procedures-2/ |work=The American Academy of Facial Esthetics |access-date=22 May 2021 |archive-date=22 May 2021 |archive-url=https://web.archive.org/web/20210522010411/https://www.facialesthetics.org/botox-procedures-2/ |url-status=live }}</ref>

===Bioterrorism===
Botulinum toxin has been recognized as a potential agent for use in ].<ref>{{cite web |vauthors=Koirala J, Basnet S |date=14 July 2004 |title=Botulism, Botulinum Toxin, and Bioterrorism: Review and Update |work=] |publisher=Cliggott Publishing |url=http://www.medscape.com/viewarticle/482812 |access-date=14 July 2010 |url-status=dead |archive-url=https://web.archive.org/web/20110601225033/http://www.medscape.com/viewarticle/482812 |archive-date=1 June 2011}}</ref> It can be absorbed through the eyes, mucous membranes, respiratory tract, and non-intact skin.<ref>{{cite web |url=https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/clostridium-botulinum.html |title=Pathogen Safety Data Sheets: Infectious Substances – ''Clostridium botulinum'' |author=Public Health Agency of Canada |date=19 April 2011 |access-date=24 January 2022 |archive-date=24 January 2022 |archive-url=https://web.archive.org/web/20220124011913/https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/clostridium-botulinum.html |url-status=live }}</ref>
The effects of botulinum toxin are different from those of nerve agents involved insofar in that botulism symptoms develop relatively slowly (over several days), while nerve agent effects are generally much more rapid. Evidence suggests that nerve exposure (simulated by injection of ] and ]) will increase mortality by enhancing botulinum toxin's mechanism of toxicity.<ref>{{cite book |vauthors=Fleisher LA, Roizen MF, Roizen J |url=https://books.google.com/books?id=RSQmDwAAQBAJ&q=nerve+exposure++will+increase+mortality+by+enhancing+botulinum+toxin's&pg=PA56 |title=Essence of Anesthesia Practice E-Book |date=31 May 2017 |publisher=Elsevier Health Sciences |isbn=978-0-323-39541-0 |access-date=10 June 2022 |archive-date=11 November 2021 |archive-url=https://web.archive.org/web/20211111023438/https://books.google.com/books?id=RSQmDwAAQBAJ&q=nerve+exposure++will+increase+mortality+by+enhancing+botulinum+toxin%27s&pg=PA56 |url-status=live }}</ref>
With regard to detection, protocols using ] detection equipment (such as M-8 paper or the ICAM) will not indicate a "positive" when samples containing botulinum toxin are tested.<ref>{{cite web |url=https://www.wmddetectorselector.army.mil/PDFs/328.pdf |title=M8 Paper |author=<!--Not stated--> |date=<!--Not stated--> |publisher=U.S. Army |access-date=16 September 2020 |quote="M8 paper is a chemically-treated, dye-impregnated paper used to detect liquid substances for the presence of V- and G-type nerve agents and H- and L-type blister agents." |archive-date=23 October 2020 |archive-url=https://web.archive.org/web/20201023152924/https://www.wmddetectorselector.army.mil/PDFs/328.pdf |url-status=live }}</ref> To confirm a diagnosis of botulinum toxin poisoning, therapeutically or to provide evidence in death investigations, botulinum toxin may be quantitated by immunoassay of human biological fluids; serum levels of 12–24 mouse LD<sub>50</sub> units per milliliter have been detected in poisoned people.<ref>{{cite book |author=Baselt RC |title=Disposition of toxic drugs and chemicals in man |year=2014 |publisher=Biomedical Publications |location=Seal Beach, Ca. |isbn=978-0-9626523-9-4 |pages=260–61}}</ref>

During the early 1980s, German and French newspapers reported that the police had raided a ] gang safe house in Paris and had found a makeshift laboratory that contained flasks full of '']'', which makes botulinum toxin. Their reports were later found to be incorrect; no such lab was ever found.<ref>{{cite book |vauthors=McAdams D, Kornblet S |veditors=Pilch RF, Zilinskas RA |title=Encyclopedia of Bioterrorism Defense |year=2011 |publisher=Wiley-Liss |isbn=978-0-471-68678-1 |chapter=Baader-Meinhof Group (OR Baader-Meinhof Gang |pages=1–2 |doi=10.1002/0471686786.ebd0012.pub2}}</ref>

===Brand names===
{{Globalize|article|USA|2name=the United States|date=April 2017}}

Commercial forms are marketed under the brand names Botox (onabotulinumtoxinA),<ref name="Botox FDA label" /><ref name="FDA Botulinum">{{cite web | title=OnabotulinumtoxinA (marketed as Botox/Botox Cosmetic), AbobotulinumtoxinA (marketed as Dysport) and RimabotulinumtoxinB (marketed as Myobloc) Information | publisher=U.S. ] (FDA) | date=3 November 2018 | url=https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/onabotulinumtoxina-marketed-botoxbotox-cosmetic-abobotulinumtoxina-marketed-dysport-and | access-date=18 December 2022 | archive-date=18 December 2022 | archive-url=https://web.archive.org/web/20221218020508/https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/onabotulinumtoxina-marketed-botoxbotox-cosmetic-abobotulinumtoxina-marketed-dysport-and | url-status=live }}</ref><ref>{{cite web | title=Botulinum Toxin Type A Product Approval Information - Licensing Action 4/12/02 | publisher=U.S. ] (FDA) | date=9 February 2009 | url=https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/ucm080509.htm | archive-url=https://web.archive.org/web/20170113111252/https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/ucm080509.htm | archive-date=13 January 2017 | url-status=dead | access-date=18 December 2022}}</ref> Dysport/Azzalure (abobotulinumtoxinA),<ref name="FDA Botulinum" /><ref>{{cite web |title=Drug Approval Package: Dysport (abobotulinumtoxin) NDA #125274s000 |publisher=U.S. ] (FDA) |date=17 August 2011 |url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/125274s000_dysport_toc.cfm |access-date=23 November 2019 |archive-date=24 November 2019 |archive-url=https://web.archive.org/web/20191124011534/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/125274s000_dysport_toc.cfm |url-status=live }}</ref> Letybo (letibotulinumtoxinA),<ref name="Letybo FDA label" /><ref name="Letybo APMDS">{{Cite web |url=https://www.tga.gov.au/resources/auspmd/letybo |title=Letybo &#124; Therapeutic Goods Administration (TGA) |access-date=18 December 2022 |archive-date=18 December 2022 |archive-url=https://web.archive.org/web/20221218020505/https://www.tga.gov.au/resources/auspmd/letybo |url-status=live }}</ref><ref>{{cite press release | title=Hugel's 'Letybo' First in Korea to Obtain Marketing Approval from Australia | website=Hugel | via=PR Newswire | date=24 November 2022 | url=https://www.prnewswire.com/news-releases/hugels-letybo-first-in-korea-to-obtain-marketing-approval-from-australia-301686683.html | access-date=18 December 2022 | archive-date=18 December 2022 | archive-url=https://web.archive.org/web/20221218020505/https://www.prnewswire.com/news-releases/hugels-letybo-first-in-korea-to-obtain-marketing-approval-from-australia-301686683.html | url-status=live }}</ref> Myobloc (rimabotulinumtoxinB),<ref name="Myobloc FDA label" /><ref name="FDA Botulinum" /> Xeomin/Bocouture (incobotulinumtoxinA),<ref>{{cite web |title=Drug Approval Package: Xeomin (incobotulinumtoxinA) Injection NDA #125360 |publisher=U.S. ] (FDA) |date=24 December 1999 |url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/125360s0000TOC.cfm |access-date=23 November 2019 |archive-date=27 July 2020 |archive-url=https://web.archive.org/web/20200727030043/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/125360s0000TOC.cfm |url-status=live }}</ref> and Jeuveau (prabotulinumtoxinA).<ref>{{cite web |title=Drug Approval Package: Jeuveau |publisher=U.S. ] (FDA) |date=5 March 2019 |url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/761085Orig1s000TOC.cfm |access-date=22 November 2019 |url-status=live |archive-url=https://web.archive.org/web/20191123073132/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/761085Orig1s000TOC.cfm |archive-date=23 November 2019}} {{PD-notice}}</ref><ref name="Krause_2019">{{cite web |url=https://www.refinery29.com/en-us/jeuveau-newtox-injections-for-wrinkles |title=Jeuveau, The Most Affordable Wrinkle Injectable |vauthors=Krause R |date=10 June 2019 |website=refinery29.com |access-date=9 July 2019 |archive-date=18 March 2021 |archive-url=https://web.archive.org/web/20210318023749/https://www.refinery29.com/en-us/jeuveau-newtox-injections-for-wrinkles |url-status=live }}</ref>

Botulinum toxin A is sold under the brand names Jeuveau, Botox, and Xeomin. Botulinum toxin B is sold under the brand name Myobloc.<ref name="Myobloc FDA label" />

In the United States, botulinum toxin products are manufactured by a variety of companies, for both therapeutic and cosmetic use. A US supplier reported in its company materials in 2011 that it could "supply the world's requirements for 25 ] approved by Government agencies around the world" with less than one gram of raw botulinum toxin.<ref>{{cite web |url=http://www.allergan.com/assets/pdf/2011AnnualReport.pdf |title=2011 Allergan Annual Report |publisher=] |access-date=3 May 2012 |archive-date=15 November 2012 |archive-url=https://web.archive.org/web/20121115061406/http://www.allergan.com/assets/pdf/2011AnnualReport.pdf |url-status=live }} See PDF p. 7.</ref> Myobloc or Neurobloc, a botulinum toxin type B product, is produced by Solstice Neurosciences, a subsidiary of US WorldMeds. AbobotulinumtoxinA), a therapeutic formulation of the type A toxin manufactured by ] in the United Kingdom, is licensed for the treatment of focal dystonias and certain cosmetic uses in the US and other countries.<ref name=FDA09hc>{{cite web |title=Information for Healthcare Professionals: OnabotulinumtoxinA (marketed as Botox/Botox Cosmetic), AbobotulinumtoxinA (marketed as Dysport) and RimabotulinumtoxinB (marketed as Myobloc) |publisher=U.S. ] (FDA) |date=13 September 2015 |url=https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm174949.htm |archive-url=https://web.archive.org/web/20150913185039/https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm174949.htm |archive-date=13 September 2015 |url-status=dead |access-date=1 September 2015}} {{PD-notice}}</ref> LetibotulinumtoxinA (Letybo) was approved for medical use in the United States in February 2024.<ref name="Letybo FDA label" />

Besides the three primary US manufacturers, numerous other botulinum toxin producers are known. Xeomin, manufactured in Germany by ], is also available for both therapeutic and cosmetic use in the US.<ref name="Available Neurotoxins">{{cite journal | vauthors = Walker TJ, Dayan SH | title = Comparison and overview of currently available neurotoxins | journal = The Journal of Clinical and Aesthetic Dermatology | volume = 7 | issue = 2 | pages = 31–39 | date = February 2014 | pmid = 24587850 | pmc = 3935649 }}</ref> Lanzhou Institute of Biological Products in China manufactures a botulinum toxin type-A product; as of 2014, it was the only botulinum toxin type-A approved in China.<ref name="Available Neurotoxins" /> Botulinum toxin type-A is also sold as Lantox and Prosigne on the global market.<ref>{{cite web |title=Botulinum Toxin Type A |publisher=Hugh Source (International) Limited |url=http://www.btxa.com/ |access-date=14 July 2010 |archive-date=24 July 2008 |archive-url=https://web.archive.org/web/20080724102749/http://www.btxa.com/ |url-status=live }}</ref> Neuronox, a botulinum toxin type-A product, was introduced by Medy-Tox of South Korea in 2009.<ref>{{cite news |vauthors=Petrou I |date=Spring 2009 |title=Medy-Tox Introduces Neuronox to the Botulinum Toxin Arena |newspaper=The European Aesthetic Guide |url=http://www.miinews.com/pdf/MedyTox_Ed_EAGsp09v2_022809.pdf |access-date=9 December 2009 |archive-url=https://web.archive.org/web/20130320010107/http://www.miinews.com/pdf/MedyTox_Ed_EAGsp09v2_022809.pdf |archive-date=20 March 2013 |url-status=dead}}</ref>

===Toxin production===
Botulism toxins are produced by bacteria of the genus ''Clostridium,'' namely ''C.&nbsp;botulinum'', '']'', '']'' and ''],''<ref>{{cite journal | vauthors = Schantz EJ, Johnson EA | title = Properties and use of botulinum toxin and other microbial neurotoxins in medicine | journal = Microbiological Reviews | volume = 56 | issue = 1 | pages = 80–99 | date = March 1992 | pmid = 1579114 | pmc = 372855 | doi = 10.1128/MMBR.56.1.80-99.1992 }}</ref> which are widely distributed, including in soil and dust. Also, the bacteria can be found inside homes on floors, carpet, and countertops even after cleaning.<ref name=CDC2018Gen>{{cite web|title=About Botulism |url=https://www.cdc.gov/botulism/general.html|date=9 October 2018|website=U.S. ] (CDC) |access-date=13 May 2020|archive-date=27 April 2020|archive-url=https://web.archive.org/web/20200427164333/https://www.cdc.gov/botulism/general.html|url-status=live}}</ref> Complicating the problem is that the taxonomy for ''C.&nbsp;botulinum'' remains chaotic. The toxin has likely been ] across lineages, contributing to the multi-species pattern seen today.<ref>{{cite journal | vauthors = Poulain B, Popoff MR | title = Why Are Botulinum Neurotoxin-Producing Bacteria So Diverse and Botulinum Neurotoxins So Toxic? | journal = Toxins | volume = 11 | issue = 1 | pages = 34 | date = January 2019 | pmid = 30641949 | pmc = 6357194 | doi = 10.3390/toxins11010034| doi-access = free }}</ref><ref>{{cite journal | vauthors = Hill KK, Xie G, Foley BT, Smith TJ, Munk AC, Bruce D, Smith LA, Brettin TS, Detter JC | title = Recombination and insertion events involving the botulinum neurotoxin complex genes in Clostridium botulinum types A, B, E and F and Clostridium butyricum type E strains | journal = BMC Biology | volume = 7 | issue = 1 | pages = 66 | date = October 2009 | pmid = 19804621 | pmc = 2764570 | doi = 10.1186/1741-7007-7-66 | doi-access = free }}</ref>

Food-borne botulism results, indirectly, from ingestion of food contaminated with ''Clostridium'' spores, where exposure to an ] allows the spores to germinate, after which the bacteria can multiply and produce toxin.<ref name=CDC2018Gen/> Critically, ingestion of toxin rather than spores or vegetative bacteria causes ].<ref name=CDC2018Gen/> Botulism is nevertheless known to be transmitted through canned foods not cooked correctly before canning or after can opening, so is preventable.<ref name=CDC2018Gen/> Infant botulism arising from consumption of honey or any other food that can carry these spores can be prevented by eliminating these foods from diets of children less than 12 months old.<ref>{{cite web |title=Botulism |website=U.S. ] (CDC) |date=19 August 2019 |url=https://www.cdc.gov/botulism/ |access-date=28 August 2019 |archive-date=3 August 2016 |archive-url=https://web.archive.org/web/20160803091921/http://www.cdc.gov/botulism/ |url-status=live }}</ref>

===Organism and toxin susceptibilities===
{{Expand section|1=modern content and referencing on antibiotic susceptibilities |small=no|date=February 2015}}

Proper refrigeration at temperatures below {{convert|4.4|C|F}} slows the growth of ''C.&nbsp;botulinum''.<ref>{{Cite web |date=29 March 2011 |title=Clostridium botulinum Toxin Formation |url=https://www.fda.gov/files/food/published/Fish-and-Fishery-Products-Hazards-and-Controls-Guidance-Chapter-13-Download.pdf |access-date=12 March 2023 |website=U.S. ] (FDA) |page=246 |archive-date=8 February 2021 |archive-url=https://web.archive.org/web/20210208183813/https://www.fda.gov/files/food/published/Fish-and-Fishery-Products-Hazards-and-Controls-Guidance-Chapter-13-Download.pdf |url-status=live }}</ref> The organism is also susceptible to high salt, high oxygen, and low pH levels.<ref name="WHO2018" />{{failed verification|date=December 2022}} The toxin itself is rapidly destroyed by heat, such as in thorough cooking.<ref>{{cite journal | vauthors = Licciardello JJ, Nickerson JT, Ribich CA, Goldblith SA | title = Thermal inactivation of type E botulinum toxin | journal = Applied Microbiology | volume = 15 | issue = 2 | pages = 249–256 | date = March 1967 | pmid = 5339838 | pmc = 546888 | doi = 10.1128/AEM.15.2.249-256.1967 }}</ref> The spores that produce the toxin are heat-tolerant and will survive boiling water for an extended period of time.<ref>{{cite journal | vauthors = Setlow P | title = I will survive: DNA protection in bacterial spores | journal = Trends in Microbiology | volume = 15 | issue = 4 | pages = 172–180 | date = April 2007 | pmid = 17336071 | doi = 10.1016/j.tim.2007.02.004 }}</ref>

The botulinum toxin is ] and thus deactivated at temperatures greater than {{convert|85|C|F}} for five minutes.<ref name="WHO2018">{{cite web |title=Fact sheets - Botulism |url=https://www.who.int/news-room/fact-sheets/detail/botulism |work=World Health Organization |access-date=23 March 2019 |date=10 January 2018 |archive-date=23 March 2019 |archive-url=https://web.archive.org/web/20190323162924/https://www.who.int/news-room/fact-sheets/detail/botulism |url-status=live }}</ref> As a zinc ] (see below), the toxin's activity is also susceptible, post-exposure, to ] by ], e.g., zinc-coordinating ]s.<ref name=Bowlin11>{{cite journal | vauthors = Li B, Peet NP, Butler MM, Burnett JC, Moir DT, Bowlin TL | title = Small molecule inhibitors as countermeasures for botulinum neurotoxin intoxication | journal = Molecules | volume = 16 | issue = 1 | pages = 202–220 | date = December 2010 | pmid = 21193845 | pmc = 6259422 | doi = 10.3390/molecules16010202 | doi-access = free | title-link = doi }}</ref><ref name=Janda0911>{{cite journal | vauthors = Capková K, Salzameda NT, Janda KD | title = Investigations into small molecule non-peptidic inhibitors of the botulinum neurotoxins | journal = Toxicon | volume = 54 | issue = 5 | pages = 575–582 | date = October 2009 | pmid = 19327377 | pmc = 2730986 | doi = 10.1016/j.toxicon.2009.03.016 | bibcode = 2009Txcn...54..575C }}</ref>

==Research==

===Blepharospasm and strabismus===
{{See also|Botulinum toxin therapy of strabismus}}

University-based ophthalmologists in the US and Canada further refined the use of botulinum toxin as a therapeutic agent. By 1985, a scientific protocol of injection sites and dosage had been empirically determined for treatment of ] and strabismus.<ref>{{cite journal | vauthors = Flanders M, Tischler A, Wise J, Williams F, Beneish R, Auger N | title = Injection of type A botulinum toxin into extraocular muscles for correction of strabismus | journal = Canadian Journal of Ophthalmology. Journal Canadien d'Ophtalmologie | volume = 22 | issue = 4 | pages = 212–217 | date = June 1987 | pmid = 3607594 }}</ref> Side effects in treatment of this condition were deemed to be rare, mild and treatable.<ref>{{cite journal | vauthors = | title = Botulinum toxin therapy of eye muscle disorders. Safety and effectiveness. American Academy of Ophthalmology | journal = Ophthalmology | volume = Suppl | issue = Suppl 37-41 | pages = 37–41 | date = September 1989 | pmid = 2779991 | doi = 10.1016/s0161-6420(89)32989-7 }}</ref> The beneficial effects of the injection lasted only four to six months. Thus, blepharospasm patients required re-injection two or three times a year.<ref>{{cite journal | vauthors = Hellman A, Torres-Russotto D | title = Botulinum toxin in the management of blepharospasm: current evidence and recent developments | journal = Therapeutic Advances in Neurological Disorders | volume = 8 | issue = 2 | pages = 82–91 | date = March 2015 | pmid = 25922620 | pmc = 4356659 | doi = 10.1177/1756285614557475 }}</ref>

In 1986, Scott's micromanufacturer and distributor of Botox was no longer able to supply the drug because of an inability to obtain product liability insurance. People became desperate, as supplies of Botox were gradually consumed, forcing him to abandon people who would have been due for their next injection. For a period of four months, American blepharospasm patients had to arrange to have their injections performed by participating doctors at Canadian eye centers until the liability issues could be resolved.<ref name="Boffey_1986">{{Cite news |vauthors=Boffey PM |date=14 October 1986 |title=Loss Of Drug Relegates Many To Blindness Again |work=] |url=https://www.nytimes.com/1986/10/14/science/loss-of-drug-relegates-many-to-blindness-again.html |access-date=14 July 2010 |archive-date=26 January 2011 |archive-url=https://web.archive.org/web/20110126045116/http://www.nytimes.com/1986/10/14/science/loss-of-drug-relegates-many-to-blindness-again.html |url-status=live }}</ref>

In December 1989, Botox was approved by the US FDA for the treatment of strabismus, blepharospasm, and ] in people over 12 years old.<ref name=alg>{{cite web |date=30 April 2009 |title=Re: Docket No. FDA-2008-P-0061 |publisher=U.S. ] (FDA) |url=https://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/UCM143989.pdf |access-date=26 July 2010 |archive-url=https://web.archive.org/web/20100706104512/https://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/UCM143989.pdf |archive-date=6 July 2010 |url-status=dead}} {{PD-notice}}</ref>

In the case of treatment of ] in people younger than 12 years of age, several studies have yielded differing results.<ref name="Ocampo_2012">{{cite web |vauthors=Ocampo VV, Foster CS |url=http://emedicine.medscape.com/article/1198876-treatment#showall |title=Infantile Esotropia Treatment & Management |publisher=] |date=30 May 2012 |access-date=6 April 2014 |archive-date=28 November 2014 |archive-url=https://web.archive.org/web/20141128091146/http://emedicine.medscape.com/article/1198876-treatment#showall |url-status=live }}</ref><ref>{{cite journal | vauthors = Koudsie S, Coste-Verdier V, Paya C, Chan H, Andrebe C, Pechmeja J, Leoni S, Korobelnik JF | title = | journal = Journal Français d'Ophtalmologie | volume = 44 | issue = 4 | pages = 509–518 | date = April 2021 | pmid = 33632627 | doi = 10.1016/j.jfo.2020.07.023 | s2cid = 232058260 }}</ref>

===Cosmetic===<!-- Much of this is already covered under history – should be merged/removed -->

The effect of botulinum toxin type-A on reducing and eliminating forehead wrinkles was first described and published by Richard Clark, MD, a plastic surgeon from Sacramento, California. In 1987 Clark was challenged with eliminating the disfigurement caused by only the right side of the forehead muscles functioning after the left side of the forehead was paralyzed during a facelift procedure. This patient had desired to look better from her facelift, but was experiencing bizarre unilateral right forehead eyebrow elevation while the left eyebrow drooped and she emoted with deep expressive right forehead wrinkles while the left side was perfectly smooth due to the paralysis. Clark was aware that botulinum toxin was safely being used to treat babies with strabismus and he requested and was granted FDA approval to experiment with botulinum toxin to paralyze the moving and wrinkling normal functioning right forehead muscles to make both sides of the forehead appear the same. This study and case report on the cosmetic use of botulinum toxin to treat a cosmetic complication of a cosmetic surgery was the first report on the specific treatment of wrinkles and was published in the journal ''Plastic and Reconstructive Surgery'' in 1989.<ref name="Clark_1989">{{cite journal | vauthors = Clark RP, Berris CE | title = Botulinum toxin: a treatment for facial asymmetry caused by facial nerve paralysis | journal = Plastic and Reconstructive Surgery | volume = 84 | issue = 2 | pages = 353–355 | date = August 1989 | pmid = 2748749 | doi = 10.1097/01.prs.0000205566.47797.8d }}</ref> Editors of the journal of the American Society of Plastic Surgeons have clearly stated "the first described use of the toxin in aesthetic circumstances was by Clark and Berris in 1989."<ref name="Rohrich_2003" />

J. D. and J. A. Carruthers also studied and reported in 1992 the use of botulinum toxin type-A as a cosmetic treatment. They conducted a study of participants whose only concern was their glabellar forehead wrinkle or furrow. Study participants were otherwise normal. Sixteen of seventeen participants available for follow-up demonstrated a cosmetic improvement. This study was reported at a meeting in 1991. The study for the treatment of ]r frown lines was published in 1992.<ref name="Carruthers JD 19922" /> This result was subsequently confirmed by other groups (Brin, and the Columbia University group under Monte Keen<ref name="Keen_1994">{{cite journal | vauthors = Keen M, Kopelman JE, Aviv JE, Binder W, Brin M, Blitzer A | title = Botulinum toxin A: a novel method to remove periorbital wrinkles | journal = Facial Plastic Surgery | volume = 10 | issue = 2 | pages = 141–146 | date = April 1994 | pmid = 7995530 | doi = 10.1055/s-2008-1064563 | s2cid = 29006338 }}</ref>). The FDA announced regulatory approval of botulinum toxin type A (Botox Cosmetic) to temporarily improve the appearance of moderate-to-severe frown lines between the eyebrows (glabellar lines) in 2002 after extensive clinical trials.<ref>{{cite web |date=29 October 2009 |title=Botulinum Toxin Type A Product Approval Information – Licensing Action 4/12/02 |publisher=U.S. ] (FDA) |url=https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/ucm080509.htm |access-date=26 July 2010 |archive-url=https://web.archive.org/web/20100308063343/https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/ucm080509.htm |archive-date=8 March 2010 |url-status=dead}} {{PD-notice}}</ref> Well before this, the cosmetic use of botulinum toxin type A became widespread.<ref>{{cite journal |doi=10.1509/jm.10.0406 |title=How Doppelgänger Brand Images Influence the Market Creation Process: Longitudinal Insights from the Rise of Botox Cosmetic |year=2012 |vauthors=Giesler M |journal=Journal of Marketing |volume=76 |issue=6 |pages=55–68 |s2cid=167319134}}</ref> The results of Botox Cosmetic can last up to four months and may vary with each patient.<ref>{{cite web |date=22 January 2014 |title=Botox Cosmetic (onabotulinumtoxinA) Product Information |publisher=] |url=http://www.botox.com/ |access-date=1 March 2018 |archive-date=21 July 2021 |archive-url=https://web.archive.org/web/20210721001858/https://www.botox.com/ |url-status=live }}</ref> The US ] (FDA) approved an alternative product-safety testing method in response to increasing public concern that ] testing was required for each batch sold in the market.<ref name="Allergan_2011">{{cite web |date=24 June 2011 |title=Allergan Receives FDA Approval for First-of-Its-Kind, Fully in vitro, Cell-Based Assay for Botox and Botox Cosmetic (onabotulinumtoxinA) |publisher=Allergan |url=http://agn.client.shareholder.com/releasedetail.cfm?ReleaseID=587234 |access-date=26 June 2011 |url-status=dead |archive-url=https://web.archive.org/web/20110626185759/http://agn.client.shareholder.com/releasedetail.cfm?ReleaseID=587234 |archive-date=26 June 2011}}</ref><ref name="The Washington Post_2008">{{cite news |date=12 April 2008 |title=In U.S., Few Alternatives To Testing On Animals |newspaper=] |url=https://www.washingtonpost.com/wp-dyn/content/article/2008/04/11/AR2008041103733.html |access-date=26 June 2011 |archive-date=12 November 2012 |archive-url=https://web.archive.org/web/20121112163835/http://www.washingtonpost.com/wp-dyn/content/article/2008/04/11/AR2008041103733.html |url-status=live }}</ref>

Botulinum toxin type-A has also been used in the treatment of ] smiles;<ref name="pmid25654058">{{cite journal | vauthors = Nayyar P, Kumar P, Nayyar PV, Singh A | title = BOTOX: Broadening the Horizon of Dentistry | journal = Journal of Clinical and Diagnostic Research | volume = 8 | issue = 12 | pages = ZE25–ZE29 | date = December 2014 | pmid = 25654058 | pmc = 4316364 | doi = 10.7860/JCDR/2014/11624.5341 }}</ref> the material is injected into the hyperactive muscles of upper lip, which causes a reduction in the upward movement of lip thus resulting in a smile with a less exposure of ].<ref name="pmid19123705">{{cite journal | vauthors = Hwang WS, Hur MS, Hu KS, Song WC, Koh KS, Baik HS, Kim ST, Kim HJ, Lee KJ | title = Surface anatomy of the lip elevator muscles for the treatment of gummy smile using botulinum toxin | journal = The Angle Orthodontist | volume = 79 | issue = 1 | pages = 70–77 | date = January 2009 | pmid = 19123705 | doi = 10.2319/091407-437.1 | doi-access = free | title-link = doi }}</ref> Botox is usually injected in the three lip elevator muscles that converge on the lateral side of the ala of the nose; the ] (LLS), the ] (LLSAN), and the ] (ZMi).<ref name="pmid20529632">{{cite journal | vauthors = Gracco A, Tracey S | title = Botox and the gummy smile | journal = Progress in Orthodontics | volume = 11 | issue = 1 | pages = 76–82 | date = May 2010 | pmid = 20529632 | doi = 10.1016/j.pio.2010.04.004 }}</ref><ref name="pmid21093661">{{cite journal | vauthors = Mazzuco R, Hexsel D | title = Gummy smile and botulinum toxin: a new approach based on the gingival exposure area | journal = Journal of the American Academy of Dermatology | volume = 63 | issue = 6 | pages = 1042–1051 | date = December 2010 | pmid = 21093661 | doi = 10.1016/j.jaad.2010.02.053 }}</ref>

===Upper motor neuron syndrome===
Botulinum toxin type-A is now a common treatment for muscles affected by the ] syndrome (UMNS), such as ],<ref name=Farag2020/> for muscles with an impaired ability to effectively ]. Muscles affected by UMNS frequently are limited by ], loss of ], decreased movement control, and hypertonicity (including ]). In January 2014, Botulinum toxin was approved by UK's ] (MHRA) for the treatment of ankle disability due to lower limb spasticity associated with stroke in adults.<ref name="DDD">{{cite web | url = http://www.dddmag.com/news/2014/02/uk-approves-new-botox-use?et_cid=3751256&et_rid=657808477&type=cta | title = UK Approves New Botox Use | archive-url = https://web.archive.org/web/20140222135115/http://www.dddmag.com/news/2014/02/uk-approves-new-botox-use?et_cid=3751256&et_rid=657808477&type=cta | archive-date=22 February 2014 | date = February 2014 | work = Drug Discovery and Development }}</ref> Joint motion may be restricted by severe muscle imbalance related to the syndrome, when some muscles are markedly hypertonic, and lack effective active lengthening. Injecting an overactive muscle to decrease its level of contraction can allow improved reciprocal motion, so improved ability to move and exercise.<ref name=Farag2020/>

===Sialorrhea===
] is a condition where oral secretions are unable to be eliminated, causing pooling of saliva in the mouth. This condition can be caused by various neurological syndromes such as ], intellectual disability, and cerebral palsy. Injection of botulinum toxin type-A into salivary glands is useful in reducing the secretions.<ref>{{cite journal | vauthors = Khan WU, Campisi P, Nadarajah S, Shakur YA, Khan N, Semenuk D, McCann C, Roske L, McConney-Ellis S, Joseph M, Parra D, Amaral J, John P, Temple M, Connolly B | title = Botulinum toxin A for treatment of sialorrhea in children: an effective, minimally invasive approach | journal = Archives of Otolaryngology–Head & Neck Surgery | volume = 137 | issue = 4 | pages = 339–344 | date = April 2011 | pmid = 21242533 | doi = 10.1001/archoto.2010.240 | doi-access = free | title-link = doi }}</ref>

===Cervical dystonia===
Botulinum toxin type-A is used to treat ], but it can become ineffective after a time. Botulinum toxin type B received FDA approval for treatment of cervical ] in December 2000. Brand names for botulinum toxin type-B include Myobloc in the United States and Neurobloc in the European Union.<ref name="Available Neurotoxins" />

===Chronic migraine===
{{See also|Migraine treatment#Botulinum Toxin (Botox)}}

Onabotulinumtoxin A (trade name Botox) received FDA approval for treatment of chronic ]s on 15 October 2010. The toxin is injected into the head and neck to treat these chronic headaches. Approval followed evidence presented to the agency from two studies funded by Allergan showing a very slight improvement in incidence of chronic migraines for those with migraines undergoing the Botox treatment.<ref name=FDA10>{{cite press release |title=FDA approves Botox to treat chronic migraine |publisher=U.S. ] (FDA) |date=19 October 2010 |url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm229782.htm |archive-url=https://web.archive.org/web/20101019002022/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm229782.htm |archive-date=19 October 2010 |url-status=dead |access-date=23 November 2019}} {{PD-notice}}</ref><ref>{{Cite news |vauthors=Watkins T |date=15 October 2010 |title=FDA approves Botox as migraine preventative |newspaper=] |url=http://us.cnn.com/2010/HEALTH/10/15/migraines.botox/index.html |access-date=16 October 2010 |archive-date=27 July 2020 |archive-url=https://web.archive.org/web/20200727025543/http://us.cnn.com/2010/HEALTH/10/15/migraines.botox/index.html |url-status=live }}</ref>

Since then, several randomized control trials have shown botulinum toxin type A to improve headache symptoms and quality of life when used prophylactically for participants with chronic ]<ref>{{cite journal | vauthors = Dodick DW, Turkel CC, DeGryse RE, Aurora SK, Silberstein SD, Lipton RB, Diener HC, Brin MF | title = OnabotulinumtoxinA for treatment of chronic migraine: pooled results from the double-blind, randomized, placebo-controlled phases of the PREEMPT clinical program | journal = Headache | volume = 50 | issue = 6 | pages = 921–936 | date = June 2010 | pmid = 20487038 | doi = 10.1111/j.1526-4610.2010.01678.x | s2cid = 9621285 }}</ref> who exhibit headache characteristics consistent with: pressure perceived from outside source, shorter total duration of chronic migraines (<30 years), "detoxification" of participants with coexisting chronic daily headache due to medication overuse, and no current history of other preventive headache medications.<ref>{{cite journal | vauthors = Ashkenazi A | title = Botulinum toxin type a for chronic migraine | journal = Current Neurology and Neuroscience Reports | volume = 10 | issue = 2 | pages = 140–146 | date = March 2010 | pmid = 20425239 | doi = 10.1007/s11910-010-0087-5 | s2cid = 32191932 }}</ref>

===Depression===
{{See also|List of investigational antidepressants}}

A few small trials have found benefits in people with ].<ref>{{cite journal | vauthors = Magid M, Keeling BH, Reichenberg JS | title = Neurotoxins: Expanding Uses of Neuromodulators in Medicine--Major Depressive Disorder | journal = Plastic and Reconstructive Surgery | volume = 136 | issue = 5 Suppl | pages = 111S–119S | date = November 2015 | pmid = 26441090 | doi = 10.1097/PRS.0000000000001733 | s2cid = 24196194 }}</ref><ref name="AdisInsight" /><ref name="Ceolato-Martin_2024">{{Cite journal | vauthors = Ceolato-Martin C, Chevallier-Collins C, Clément JP, Charles E, Lacroix A, Ranoux D |date=January 2024 | veditors = Ai S |title=OnabotulinumtoxinA in Resistant Depression: A Randomized Trial Comparing Two Facial Injection Sites (OnaDEP Study) |journal=Depression and Anxiety |language=en |volume=2024 |issue=1 |doi=10.1155/2024/1177925 |doi-access=free |issn=1091-4269}}</ref> A 2021 meta-analysis supports the usefulness of botox in unipolar depression, but finds significant heterogenity among the findings.<ref>{{cite journal | vauthors = Arnone D, Galadari H, Rodgers CJ, Östlundh L, Aziz KA, Stip E, Young AH | title = Efficacy of onabotulinumtoxinA in the treatment of unipolar major depression: Systematic review, meta-analysis and meta-regression analyses of double-blind randomised controlled trials | journal = Journal of Psychopharmacology | volume = 35 | issue = 8 | pages = 910–918 | date = August 2021 | pmid = 33719696 | pmc = 8366169 | doi = 10.1177/0269881121991827 }}</ref> The main hypothesis for its action is based on the ].<ref>{{cite journal | vauthors = Finzi E, Rosenthal NE | title = Treatment of depression with onabotulinumtoxinA: a randomized, double-blind, placebo controlled trial | journal = Journal of Psychiatric Research | volume = 52 | pages = 1–6 | date = May 2014 | pmid = 24345483 | doi = 10.1016/j.jpsychires.2013.11.006 }}</ref> Another hypothesis involves a connection between the facial muscle and specific brain regions in animals, but additional evidence is required to support or disprove this theory.<ref name="Ceolato-Martin_2024" />

===Premature ejaculation===
{{See also|List of investigational sexual dysfunction drugs}}

The drug for the treatment of ] has been under development since August 2013, and is in ] trials.<ref name="AdisInsight">{{Cite web |url=http://adisinsight.springer.com/drugs/800008810 |title=Onabotulinum toxin A - Allergan - AdisInsight |access-date=5 September 2017 |archive-date=30 October 2017 |archive-url=https://web.archive.org/web/20171030223633/http://adisinsight.springer.com/drugs/800008810 |url-status=live }}</ref><ref>{{ClinicalTrialsGov|NCT01917006|An Exploratory Study of the Safety and Efficacy of Botox for the Treatment of Premature Ejaculation}}</ref>

== References ==
{{notelist}}
{{Reflist}}

== Further reading ==
* {{cite journal | vauthors = Carruthers JD, Fagien S, Joseph JH, Humphrey SD, Biesman BS, Gallagher CJ, Liu Y, Rubio RG | title = DaxibotulinumtoxinA for Injection for the Treatment of Glabellar Lines: Results from Each of Two Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 3 Studies (SAKURA 1 and SAKURA 2) | journal = Plastic and Reconstructive Surgery | volume = 145 | issue = 1 | pages = 45–58 | date = January 2020 | pmid = 31609882 | pmc = 6940025 | doi = 10.1097/PRS.0000000000006327 | doi-access = free | title-link = doi }}
* {{cite journal | vauthors = Solish N, Carruthers J, Kaufman J, Rubio RG, Gross TM, Gallagher CJ | title = Overview of DaxibotulinumtoxinA for Injection: A Novel Formulation of Botulinum Toxin Type A | journal = Drugs | volume = 81 | issue = 18 | pages = 2091–2101 | date = December 2021 | pmid = 34787840 | pmc = 8648634 | doi = 10.1007/s40265-021-01631-w | doi-access = free | title-link = doi }}

== External links ==
* {{PDBe-KB2|P0DPI1|Botulinum neurotoxin type A}}
* {{PDBe-KB2|P10844|Botulinum neurotoxin type B}}
* {{PDBe-KB2|A0A0X1KH89|Bontoxilysin A}}
* {{cite web |title=AbobotulinumtoxinA Injection |website=MedlinePlus |url=https://medlineplus.gov/druginfo/meds/a609035.html}}
* {{cite web |title=IncobotulinumtoxinA Injection |website=MedlinePlus |url=https://medlineplus.gov/druginfo/meds/a611008.html}}
* {{cite web |title=OnabotulinumtoxinA Injection |website=MedlinePlus |url=https://medlineplus.gov/druginfo/meds/a608013.html}}
* {{cite web |title=PrabotulinumtoxinA-xvfs Injection |website=MedlinePlus |url=https://medlineplus.gov/druginfo/meds/a619021.html}}
* {{cite web |title=RimabotulinumtoxinB Injection |website=MedlinePlus |url=https://medlineplus.gov/druginfo/meds/a608014.html}}

{{Muscle relaxants}}
{{Toxins}}
{{Acetylcholine metabolism and transport modulators}}
{{Cosmetics}}
{{Metalloendopeptidases}}
{{Enzymes}}
{{Portal bar|Biology|border=no|Medicine}}
{{Authority control}}

{{DEFAULTSORT:Botulinum Toxin}}
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