Editing Cantharidin

{{Short description|Chemical compound}}
{{Use American English|date=September 2023}}
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'''Cantharidin''' is an odorless, colorless fatty substance of the [[terpenoid]] class, which is secreted by many species of [[blister beetle]]s.{{efn|Including broadly in genus ''[[Epicauta]]'', genus ''[[Berberomeloe]]'', and in species [[Lytta vesicatoria|''Lytta vesicatoria'' (Spanish fly)]]. [[Oedemeridae|False blister beetles]], [[Pyrochroidae|cardinal beetles]], and [[soldier beetles]] also produce cantharidin.}} Its main current use in pharmacology is treating [[molluscum contagiosum]] and [[warts]] topically.<ref name = "FDA_2023">{{cite web | url=https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-first-treatment-molluscum-contagiosum | title=FDA approves first treatment for molluscum contagiosum | work= U.S. Food and Drug Administration | date=24 July 2023 }}</ref> It is a burn agent and [[poison]]ous in large doses, and has been historically used as [[aphrodisiac]]s ([[Lytta vesicatoria|Spanish fly]]). In its natural form, cantharidin is secreted by the male blister beetle, and given to the female as a copulatory gift during mating. Afterwards, the female beetle covers her eggs with it as a defense against predators.

Poisoning from cantharidin is a significant veterinary concern, especially in horses, but it can also be poisonous to humans if taken internally (where the source is usually experimental self-exposure). Externally, cantharidin is a potent [[vesicant]] (blistering agent), exposure to which can cause severe [[chemical burn]]s. Properly dosed and applied, the same properties have also been used therapeutically, for instance, for treatment of skin conditions, such as [[molluscum contagiosum]] infection of the skin.

Cantharidin is classified as an [[List of extremely hazardous substances|extremely hazardous substance]] in the [[United States]], and is subject to strict reporting requirements by facilities that produce, store, or use it in significant quantities.<ref>As defined in Section 302 of the U.S. [[Emergency Planning and Community Right-to-Know Act]] (42 U.S.C. 11002). See {{cite web | url = http://edocket.access.gpo.gov/cfr_2008/julqtr/pdf/40cfr355AppA.pdf | title = 40 C.F.R.: Appendix A to Part 355—The List of Extremely Hazardous Substances and Their Threshold Planning Quantitie | archive-url = https://web.archive.org/web/20120225051612/http://edocket.access.gpo.gov/cfr_2008/julqtr/pdf/40cfr355AppA.pdf | archive-date=25 February 2012 | date = 1 July 2008 | publisher = U.S. Government Printing Office. | access-date = 29 October 2011 }}</ref>

==Chemistry==

===Structure and nomenclature===
Cantharidin, from the Greek ''kantharis'', for beetle,<ref>{{cite book | title = A Dictionary of Entomology | date = 2011 | publisher = CABI | page = 253}}</ref> is an odorless, colorless [[natural product]] with solubility in various organic solvents,{{specify|date=December 2015}} but only slight solubility in water.<ref name = veterinary>{{cite book | vauthors = Schmitz DG | veditors = Aiello SE, Moses MA | year = 2013 | title = The Merck Veterinary Manual | chapter = Overview of Cantharidin Poisoning (Blister Beetle Poisoning) | location = Kenilworth, NJ, USA | publisher = Merck Sharp & Dohme | isbn = 978-0911910612 | chapter-url = https://www.merckvetmanual.com/mvm/toxicology/cantharidin_poisoning/overview_of_cantharidin_poisoning.html | access-date = 14 December 2015 | archive-date = 22 December 2015 | archive-url = https://web.archive.org/web/20151222103819/https://www.merckvetmanual.com/mvm/toxicology/cantharidin_poisoning/overview_of_cantharidin_poisoning.html | url-status = dead }}</ref> Its skeleton is [[tricyclic]], formally, a tricyclo-[5.2.1.0<sup>2,6</sup>]decane skeleton. Its functionalities include a [[Organic acid anhydride|carboxylic acid anhydride]] (−CO−O−CO−) substructure in one of its rings, as well as a bridging [[ether]] in its [[bicyclic]] ring system.

===Distribution and availability===
The level of cantharidin in blister beetles can be quite variable. Among blister beetles of the genus ''[[Epicauta]]'' in [[Colorado]], ''E. pennsylvanica'' contains about 0.2&nbsp;mg, ''E. maculata'' contains 0.7&nbsp;mg, and ''E. immaculata'' contains 4.8&nbsp;mg per beetle; males also contain higher levels than females.<ref>{{cite journal | vauthors = Capinera JL, Gardner DR, Stermitz FR | title = Cantharidin Levels in Blister Beetles (Coleoptera: Meloidae) Associated with Alfalfa in Colorado | journal = Journal of Economic Entomology | year = 1985 | volume = 78 | issue = 5 | pages = 1052–1055 |doi=10.1093/jee/78.5.1052 }}</ref>

Males of ''[[Berberomeloe majalis]]'' have higher level of cantharidin per beetle: 64.22 ± 51.28&nbsp;mg/g (dry weight) and 9.10 ± 12.64&nbsp;mg/g (d. w.). Cantharidin content in [[haemolymph]] is also higher in males (80.9 ± 106.5&nbsp;μg/g) than in females (20.0 ± 41.5&nbsp;μg/g).<ref name=Bravo2017>{{cite journal| vauthors = Bravo C, Mas-Peinado P, Bautista LM, Blanco G, Alonso JC, García-París M |title=Cantharidin is conserved across phylogeographic lineages and present in both morphs of Iberian ''Berberomeloe'' blister beetles (Coleoptera, Meloidae)|journal=Zoological Journal of the Linnean Society|year=2017|volume=180|issue=4|pages=790–804|doi=10.1093/zoolinnean/zlw016|hdl=10261/153832|hdl-access=free}}</ref>

===Laboratory synthesis===
There have been multiple synthetic approaches to achieve cantharidin in the lab. A common strategy employed by different total synthesis methods is to begin with a [[Diels-Alder]] cycloaddition reaction to form the six-membered ring.<ref>{{cite journal | vauthors = Dauben WG, Kessel CR, Takemura KH | title = Simple, efficient total synthesis of cantharidin via a high-pressure Diels-Alder reaction | journal = Journal of the American Chemical Society | volume = 102 | issue = 22 | pages = 6893–6894 | date = 15 October 1980 | doi = 10.1021/ja00542a060 | bibcode = 1980JAChS.102.6893D }}</ref><ref>{{cite web | vauthors = Davidson MG, Eklov BM, Wuts P, Loertscher BM, Schow SR | title = Synthesis of cantharidin | date = 11 April 2019 | url = https://patents.google.com/patent/WO2019070980A2/en | language = en }}</ref><ref>{{cite web | title = Novel green environment-friendly synthesis process of cantharidin | date = 17 May 2017 | url = https://patents.google.com/patent/CN106674248A/en | language = en }}</ref> The starting material often utilizes a furan as the diene, giving the formation of a bicyclic ring. 

[[File:Synthetic Approach to Cantharidin.jpg|thumb|center|415px|Most total syntheses of cantharidin start with a Diels-Alder reaction.]]

===Biosynthesis===
The complete mechanism of the [[biosynthesis]] of cantharidin is unknown. Its framework formally consists of two [[isoprene]] units.<ref>{{cite book | title = Secondary-Metabolite Biosynthesis and Metabolism | veditors = Petroski RJ, McCormick SP | publisher = Springer Science & Business Media | date = 2012 | isbn = 978-0-306-44309-1 }}</ref> However, [[feeding studies]] indicate that the biosynthetic process is more complicated, and not a simple product of [[geranyl pyrophosphate]] or related ten-carbon parent structure, as the seeming [[monoterpene]] nature would suggest. Instead, there is a [[farnesol]] (15-carbon) precursor from which certain carbon segments are later excised.<ref>{{cite journal | vauthors = Jiang M, Lü S, Zhang Y | title = The Potential Organ Involved in Cantharidin Biosynthesis in Epicauta chinensis Laporte (Coleoptera: Meloidae) | journal = Journal of Insect Science | volume = 17 | issue = 2 | pages = 52 | date = January 2017 | pmid = 28423415 | pmc = 5633858 | doi = 10.1093/jisesa/iex021 }}</ref>

[[File:Cantharidin biosynthesis2.png|thumb|center|415 px|Biosynthesis from farnesol ⁠— ⁠bonds to be formed and major atoms to be added are in {{color|blue|blue}}; while bonds to be broken and atoms/structural segments to be removed are in {{color|red|red}}.]]

Biosynthesis utilizing farnesol as a key intermediate is further supported by experiments in which key genes whose transcripts are expected to participate in the biosynthesis pathway were interfered with by [[RNA interference]] methods. The [[mevalonate]] pathway ([[MVA pathway]]) is responsible for producing [[isoprenoids]] in many organisms, including farnesol.<ref>{{cite journal | vauthors = Kaneko M, Togashi N, Hamashima H, Hirohara M, Inoue Y | title = Effect of farnesol on mevalonate pathway of Staphylococcus aureus | journal = The Journal of Antibiotics | volume = 64 | issue = 8 | pages = 547–549 | date = August 2011 | pmid = 21772307 | doi = 10.1038/ja.2011.49 }}</ref>  Interference with two genes that participate in the MVA pathway, methyl farnesoate epoxidase (EcMFE) and juvenile hormone epoxide hydrolase (EcJHEH) inhibited the biosynthesis of cantharidin in male blister beetles.<ref>{{cite journal | vauthors = Jiang M, Lü S, Zhang Y | title = Characterization of Juvenile Hormone Related Genes Regulating Cantharidin Biosynthesis in Epicauta chinensis | journal = Scientific Reports | volume = 7 | issue = 1 | pages = 2308 | date = 23 May 2017 | pmid = 28536442 | pmc = 5442126 | doi = 10.1038/s41598-017-02393-w | bibcode = 2017NatSR...7.2308J }}</ref>

==History==
[[File:Lytta vesicatoria natur.jpg|thumb|left|''Lytta vesicatoria'' (a.k.a "[[Lytta vesicatoria|Spanish fly]]"), a beetle that secretes cantharidin.]]

===Aphrodisiac preparations===
Preparations made from [[blister beetle]]s (particularly "[[Lytta vesicatoria|Spanish fly]]") have been used since ancient times as an [[aphrodisiac]], possibly because their physical effects were perceived to mimic those of sexual arousal,<ref>John L. Capinera, ''Encyclopedia of Entomology, Volume 4'', Springer Science & Business Media, 2008. p.2010</ref> and because they can cause prolonged erection or [[priapism]] in men.<ref name = aph>Peter V. Taberner, ''Aphrodisiacs: The Science and the Myth'', Springer Science & Business Media, 2012, pp.100ff</ref> These preparations were known as ''cantharides'', from the Greek word for "beetle".

Examples of such use found in historical sources include:

* The ancient Roman historian [[Tacitus]] relates that a cantharid preparation was used by the empress [[Livia]], wife of [[Augustus Caesar]], to entice members of the imperial family or dinner guests to commit sexual indiscretions (thus, providing her information to hold over them).<ref>{{cite book|title = Ancient Inventions| vauthors = James P |publisher = Ballantine Books|isbn = 978-0-345-40102-1|year = 1995|page = [https://archive.org/details/ancientinvention00jame/page/177 177]|url = https://archive.org/details/ancientinvention00jame/page/177}}</ref>
* The German emperor [[Henry IV, Holy Roman Emperor|Henry IV]] (1050–1106) is said to have consumed cantharides.<ref>{{cite web | url=http://blogs.scientificamerican.com/guest-blog/2012/03/13/when-sparks-fly-aphrodisiacs-and-the-fruit-fly/ | title=When Sparks Fly: Aphrodisiacs and the Fruit Fly | work=Scientific American | date=13 March 2012 | access-date=18 November 2014 | vauthors=Eplett L | archive-date=29 November 2014 | archive-url=https://web.archive.org/web/20141129060929/http://blogs.scientificamerican.com/guest-blog/2012/03/13/when-sparks-fly-aphrodisiacs-and-the-fruit-fly/ | url-status=live }}</ref>
* The French surgeon [[Ambroise Paré]] (1510–1590) described a case in 1572 of a man suffering from "the most frightful [[hypersexuality|satyriasis]]" after taking a potion composed of [[Urtica dioica|nettles]] and a cantharid extract.<ref name="Milsten_1">{{cite book | vauthors = Milsten R |title=The Sexual Male: Problems and Solutions|publisher=W. W. Norton & Company |year=2000  |isbn=978-0-393-32127-2 |page=170}}</ref> This is perhaps the same man of whom Paré relates that a [[courtesan]] sprinkled a cantharid powder on food she served to him, after which the man experienced "violent priapism" and anal bleeding, of which he later died. Paré also cites the case of a priest who died of [[hematuria]] after swallowing a dose of cantharides, which he intended to fortify his sex drive.<ref name = "Cabanès">{{cite book | author-link1 = Augustin Cabanès | vauthors = Cabanès A | url = https://archive.org/stream/b24878613#page/498/mode/2up | title = Remèdes d'autrefois | location = Paris | publisher = A. Maloine | date =  1910 | page = 498 }}</ref>
* Cantharides were in widespread use among the upper classes in France in the 1600s, despite being a banned substance. Police searches in connection with a rash of poisonings around 1680 turned up many stashes of "bluish flies", which were known to be used in the preparation of aphrodisiac potions.<ref name = "Cabanès"/>
* The French sorceress [[La Voisin|Catherine Monvoisin]] (known as "La Voisin," c. 1640–1680) was recorded in the 1670s as having prepared a love charm made from [[Lytta vesicatoria|Spanish fly]] mixed with dried mole's blood and bat's blood.<ref>Richard Cavendish, ''The Black Arts'' (London: Pan Books, 1969), p. 333.<!--Can someone check the page number on this? It was inherited from a previous inaccurate form of the citation.--></ref>
* Aphrodisiac sweets presumably laced with cantharides were circulated within [[libertine]] circles during the 1700s in France. They were multicolored tablets nicknamed "pastilles de Richelieu," after the [[Armand de Vignerot du Plessis|Maréchal de Richelieu]], a notorious libertine (not to be confused with his great-uncle, the [[Cardinal Richelieu]]) who procured sexual encounters for King [[Louis XV]].<ref name = "Cabanès"/><ref>Jacques Levron, ''Le Maréchal de Richelieu, un libertin fastueux'' (Paris, Perrin, 1971).</ref>
* The French writer Donatien Alphonse François ⁠— ⁠notoriously known as the [[Marquis de Sade]] (1740–1814) ⁠— ⁠is said to have given [[aniseed]]-flavored pastilles laced with Spanish fly to two prostitutes at a pair of orgies in 1772, poisoning and nearly killing them. He was sentenced to death for that (and for the crime of [[sodomy]]), but was later reprieved on appeal.<ref name="isbn0-394-54797-7">{{cite book | vauthors = Ford P, Howell, Michael M |title=The beetle of Aphrodite and other medical mysteries |publisher=Random House |location=New York |year=1985 |isbn=978-0-394-54797-8 |url=https://archive.org/details/beetleofaphrodit00howe }}</ref><ref name = sch>{{cite book | vauthors = Schaeffer N | date = 2000 | title = The Marquis de Sade: A Life | location = Cambridge, MA, USA | publisher = Harvard University Press | page = 58 }}</ref>
{{clear left}}

===Non-aphrodisiac uses===
* The Spanish clergyman [[Juan de Horozco y Covarrubias]] ([[:es:Juan de Horozco y Covarrubias|es]]) (c. 1540–1610) reported the use of blister beetles as a [[poison]] as well as an aphrodisiac.<ref name="Covarrubias_1">{{cite book |title =Tesoros de la lengua castellana o española  | vauthors = Covarrubias-Horozco S |publisher = Universidad de Navarra - Iberoamericana - Vervuert |year = 2006 }}</ref>
* Preparations of dried blister beetles were at one time used as a treatment for [[smallpox]].<ref>{{cite book|vauthors=Closs JF|title=A New Method of Curing the Small-pox ... with a Specimen of Miscellaneous Observations on Medical Subjects; from the Latin ... by a Physician|url=https://books.google.com/books?id=HOtbAAAAcAAJ&pg=PA10|year=1767|publisher=Hawes|access-date=15 April 2017|archive-date=14 January 2023|archive-url=https://web.archive.org/web/20230114162555/https://books.google.com/books?id=HOtbAAAAcAAJ&pg=PA10|url-status=live}} Cantharides referred to throughout the book.</ref> As late as 1892, [[Andrew Taylor Still]], the founder of [[osteopathy]], recommended inhaling a [[tincture]] of cantharidin as an effective preventative and treatment for smallpox, decrying [[vaccination]].<ref>{{cite book | vauthors = Still AT | title = The philosophy and mechanical principles of osteopathy | date = 1892 | chapter = Chapter 12: Smallpox | url = http://www.anatomy4beginners.com/resources/The%20Philosophy%20and%20Mechanical%20Principles%20of%20Osteopathy%20AT%20Still%201902.pdf | archive-url = https://web.archive.org/web/20190714030929/https://anatomy4beginners.com/resources/The%20Philosophy%20and%20Mechanical%20Principles%20of%20Osteopathy%20AT%20Still%201902.pdf | archive-date=14 July 2019 }}</ref>
* Japanese [[ninja]] used blister beetles combined with arsenic to create a noxious gas.<ref name="bansenshukai1">{{cite episode |credits = Glenn C |date = March 29, 2025 |title = Ninja Arts Inspired by the Animal Kingdom | url = https://www3.nhk.or.jp/nhkworld/en/shows/3025200/ |series         = NINJA TRUTH | network = NHK (Japan Broadcasting Corporation) }}</ref><ref name="bansenshukai2">{{cite book |translator-last1 = Cummins | translator-first1 = Antony |translator-first2 = Minami |translator-last2 = Yoshie | year = 2013 | title = Bansenshukai | trans-title = The Book of Ninja | publisher = Watkins Publishing | volume = 15 | chapter = In-nin V | trans-chapter = Hidden Infiltration V | isbn = 9781780284934 }}</ref>

===Pharmaco-chemical isolation===
Cantharidin was first isolated as a chemically pure substance in 1810 by [[Pierre Robiquet]],<ref>{{cite book | vauthors = Wolter H | year = 1995 | title = Kompendium der Tierärztlichen Homöopathie | publisher = Enke | isbn = 978-3432978925 }}</ref> a French chemist then living in [[Paris]]. Robiquet isolated cantharidin as the active ingredient in pharmacological preparations of ''[[Lytta vesicatoria]]'', a.k.a. "[[Lytta vesicatoria|Spanish fly]]", a species of [[blister beetle]]. This was one of the first historical instances of the identification and extraction of a simple active principle from a complex medicine.

Robiquet found cantharidin to be an odorless and colorless solid at [[room temperature]]. He demonstrated that it was the active principle responsible for the aggressively [[blister agent|blistering properties]] of the coating of the eggs of the blister beetle, and additionally established that cantharidin had toxic properties comparable in degree to those of the most virulent poisons known in the 19th century, such as [[strychnine]].<ref>{{cite journal | vauthors = Robiquet PJ | title = Expériences sur les cantharides | journal = Annales de Chimie | year = 1810 | volume = 76 | pages = 302–322 }}</ref>

===Other uses of the pharmacological isolate===
* Diluted solutions of cantharidin can be used as a [[topical]] medication to remove [[wart]]s<ref name="pmid13519856">{{cite journal | vauthors = Epstein WL, Kligman AM | title = Treatment of warts with cantharidin | journal = A.M.A. Archives of Dermatology | volume = 77 | issue = 5 | pages = 508–511 | date = May 1958 | pmid = 13519856 | doi = 10.1001/archderm.1958.01560050014003 }}</ref><ref name="bacelieri">{{cite journal | vauthors = Bacelieri R, Johnson SM | title = Cutaneous warts: an evidence-based approach to therapy | journal = American Family Physician | volume = 72 | issue = 4 | pages = 647–652 | date = August 2005 | pmid = 16127954 | url = http://www.aafp.org/afp/20050815/647.html | access-date = 2 December 2012 | url-status = dead | archive-url = https://web.archive.org/web/20080709031002/http://www.aafp.org/afp/20050815/647.html | archive-date = 9 July 2008 }}</ref> and [[tattoo]]s, and to treat the small [[papules]] of ''[[molluscum contagiosum]]''.<ref>{{cite web | title = Molluscum contagiosum | url = http://www.merck.com/mmpe/sec10/ch122/ch122b.html | date = November 2005 | publisher = Merck Manuals | access-date = 21 October 2007 | archive-date = 18 October 2007 | archive-url = https://web.archive.org/web/20071018055759/http://merck.com/mmpe/sec10/ch122/ch122b.html | url-status = live }}</ref>
* In [[Santería]] rituals, cantharides are used in [[incense]].<ref name="Gonzalez-Wippler_1">{{cite book | vauthors = Gonzalez-Wippler M |title=Santería: The Religion |publisher=Llewellyn Publications |year=2002 |isbn=978-1-56718-329-0 |page=[https://archive.org/details/santerareligio00gonz/page/221 221] |url=https://archive.org/details/santerareligio00gonz/page/221 }}</ref>

==Veterinary issues==
Poisoning by ''Epicauta'' species from cantharidin is a significant veterinary concern, especially in horses; species infesting feedstocks depend on region—e.g., ''Epicauta pennsylvanica'' (black blister beetle) in the U.S. midwest; and ''E. occidentalis, temexia, and vittata'' species (striped blister beetles) in the U.S. southwest—where the concentrations of the agent in each can vary substantially.<ref name = veterinary/> Beetles feed on [[weed]]s, and occasionally move into crop fields used to produce livestock feeds (e.g., [[alfalfa]]), where they are found to cluster and find their way into [[hay bale|baled hay]], e.g., a single flake (4–5 in. section<ref>{{cite book | vauthors = Rockett J, Bosted S | year = 2015 | title = Veterinary Clinical Procedures in Large Animal Practices | publisher = Cengage Learning | isbn = 978-1305537651 | location = Boston, MA, USA | url = https://books.google.com/books?isbn=1305537653 | access-date = 14 December 2015 | page = 65}}</ref>) may have several hundred insects, or none at all.<ref name = veterinary/> Horses are very sensitive to the cantharidin produced by beetle infestations: the {{LD50}} for horses is roughly 1&nbsp;mg/kg of the horse's body weight. Horses may be accidentally poisoned when fed bales of fodder with blister beetles in them.<ref>{{cite web | url = http://www.addl.purdue.edu/newsletters/2006/Fall/EquineCT.htm | title = Blister Beetle Poisoning / Cantharidin toxicosis | access-date = 31 December 2010 | archive-date = 26 June 2010 | archive-url = https://web.archive.org/web/20100626083233/https://www.addl.purdue.edu/newsletters/2006/Fall/EquineCT.htm | url-status = live }}</ref>

[[Great bustard]]s, a strongly [[Polygyny in animals|polygynous]] bird species,<ref>{{cite journal|doi=10.1007/s00265-010-0972-6  |title=Correlates of male mating success in great bustard leks: the effects of age, weight, and display effort |year=2010 | vauthors = Alonso JC, Magaña M, Palacín C, Martín CA |journal=Behavioral Ecology and Sociobiology |volume=64 |issue=10 |pages=1589–1600|bibcode=2010BEcoS..64.1589A |hdl=10261/76985 |s2cid=8741416 }}</ref> are not immune to the toxicity of cantharidin; they become intoxicated after ingesting blister beetles. However, cantharidin has activity also against parasites that infect them.<ref>{{cite journal | vauthors = Bravo C, Bautista LM, García-París M, Blanco G, Alonso JC | title = Males of a strongly polygynous species consume more poisonous food than females | journal = PLOS ONE | volume = 9 | issue = 10 | pages = e111057 | year = 2014 | pmid = 25337911 | pmc = 4206510 | doi = 10.1371/journal.pone.0111057 | bibcode = 2014PLoSO...9k1057B | doi-access = free }}</ref><ref>{{cite journal | vauthors = Sánchez-Barbudo IS, Camarero PR, García-Montijano M, Mateo R | title = Possible cantharidin poisoning of a great bustard (Otis tarda) | journal = Toxicon | volume = 59 | issue = 1 | pages = 100–103 | date = January 2012 | pmid = 22001622 | doi = 10.1016/j.toxicon.2011.10.002 | bibcode = 2012Txcn...59..100S | hdl-access = free | hdl = 10261/143513 }}</ref> Great bustards may eat toxic [[blister beetle]]s of the genus ''[[Meloe]]'' to increase the sexual arousal of males.<ref name=Heneberg2016>{{cite journal | vauthors = Heneberg P |title=On Otis tarda and Marquis de Sade: what motivates male Great Bustards to consume Blister Beetles (Meloidae)?  |year=2016 |journal=Journal of Ornithology |volume=57 |issue=4 |pages=1123–1125  |doi=10.1007/s10336-016-1369-8|bibcode=2016JOrni.157.1123H |s2cid=17325635 }}</ref>

==Human medical issues==

===General risks===
As a blister agent, cantharidin has the potential to cause adverse effects when used medically; for this reason, it has been included in a list of "problem drugs" used by dermatologists and emergency personnel.<ref name="karras-1996">{{cite journal | vauthors = Karras DJ, Farrell SE, Harrigan RA, Henretig FM, Gealt L | title = Poisoning from "Spanish fly" (cantharidin) | journal = The American Journal of Emergency Medicine | volume = 14 | issue = 5 | pages = 478–483 | date = September 1996 | pmid = 8765116 | doi = 10.1016/S0735-6757(96)90158-8 | quote = While most commonly available preparations of Spanish fly contain cantharidin in negligible amounts, if at all, the chemical is available illicitly in concentrations capable of causing severe toxicity. Symptoms of cantharidin poisoning include burning of the mouth, dysphagia, nausea, hematemesis, gross hematuria, and dysuria. Mucosal erosion and hemorrhage is seen in the upper gastrointestinal (GI) tract. Renal dysfunction is common and related to acute tubular necrosis and glomerular destruction. }}</ref> However, this references unregulated sources of cantharidin.<ref name="Binder-1979"> {{cite journal | vauthors = Binder R | title = Malpractice--in dermatology | journal = Cutis | volume = 23 | issue = 5 | pages = 663–666 | date = May 1979 | pmid = 456036 }}</ref> In July 2023, the US FDA approved a topical formulation of cantharidin (Ycanth) for the treatment of [[molluscum contagiosum]].<ref name = "FDA_2023" />

When [[ingestion|ingested]] by humans, the {{LD50}} is unknown, but fatal doses have been 
recorded between 10 mg and 65 mg.<ref>{{cite journal | url=https://jamanetwork.com/journals/jamadermatology/fullarticle/478535 | doi=10.1001/archderm.137.10.1357 | title=Cantharidin Revisited | date=2001 | journal=Archives of Dermatology | volume=137 | issue=10 | pages=1357–1360 | pmid=11594862 | vauthors = Moed L, Shwayder TA, Chang MW }}</ref> The median lethal dose appears to be around 1 mg/kg<ref>{{cite journal | url=https://pubmed.ncbi.nlm.nih.gov/14428136/ | pmid=14428136 | date=1960 | vauthors = Oaks WW, DiTunno JF, Magnani T, Levy HA, Mills LC | title=Cantharidin poisoning | journal=Archives of Internal Medicine | volume=105 | issue=4 | pages=574–582 | doi=10.1001/archinte.1960.00270160072009 }}</ref> but individuals have survived after consuming oral doses as high as 175 mg.<ref>{{cite journal | url=https://pubs.acs.org/doi/10.1021/jf00077a045 | doi=10.1021/jf00077a045 | title=Endothal and cantharidin analogs: Relation of structure to herbicidal activity and mammalian toxicity | date=1987 | journal=Journal of Agricultural and Food Chemistry | volume=35 | issue=5 | pages=823–829 | bibcode=1987JAFC...35..823M | vauthors = Matsuzawa M, Graziano MJ, Casida JE }}</ref> Ingesting cantharidin can initially cause severe damage to the lining of the [[Gastrointestinal tract|gastrointestinal]] and [[Urinary system|urinary tracts]], and may also cause permanent [[renal]] damage. Symptoms of cantharidin poisoning include [[hematuria]], abdominal pain, and (rarely) [[priapism]].<ref name="Binder-1979" />

===Risks of aphrodisiac use===
{{main|Lytta vesicatoria}}
The extreme toxicity of cantharidin makes any use as an aphrodisiac highly dangerous.<ref name=shamloul-2010>{{cite journal | vauthors = Shamloul R | title = Natural aphrodisiacs | journal = The Journal of Sexual Medicine | volume = 7 | issue = 1 Pt 1 | pages = 39–49 | date = January 2010 | pmid = 19796015 | doi = 10.1111/j.1743-6109.2009.01521.x }}</ref><ref name=sandroni-2001>{{cite journal | vauthors = Sandroni P | title = Aphrodisiacs past and present: a historical review | journal = Clinical Autonomic Research | volume = 11 | issue = 5 | pages = 303–307 | date = October 2001 | pmid = 11758796 | doi = 10.1007/BF02332975 | quote = Cantharidin ("Spanish fly") is a chemical with vesicant properties derived from blister beetles, which has been used for millennia as a sexual stimulant by both sexes. Its mode of action is by inhibition of phosphodiesterase and protein phosphatase activity and stimulation of β-receptors, inducing vascular congestion and inflammation. Morbidity from its abuse is significant. The gastrointestinal tract sustains the brunt of toxicity, resulting in fatal hemorrhages. Renal toxicity is a result of its renal excretion, which may lead to acute tubular necrosis. Cardiac effects are most likely due to hemorrhagic shock, but they also can be due to myofibril degeneration, mitochondrial swelling, and pericardial and subendocardial hemorrhages. | s2cid = 32348540 }}</ref>  As a result, it is illegal to sell (or use) cantharidin or preparations containing it without a prescription in many countries.<ref name=karras-1996/>

==Research==

===Mechanism of action===
{{missing information|section|toxicological mechanism when ingested|date=September 2022}}
Topical cantharidin is absorbed by the lipid membranes of [[Epidermis|epidermal cells]], causing the release of [[serine proteases]], [[enzymes]] that break the [[peptide bonds]] in proteins. This causes the disintegration of [[Desmosome|desmosomal plaques]], cellular structures involved in cell-to-cell adhesion, leading to detachment of the [[Tonofibril|tonofilaments]] that hold cells together. The process leads to the loss of cellular connections ([[acantholysis]]), and ultimately results in blistering of the skin. Lesions heal without scarring.<ref name=Moed2001>{{cite journal | vauthors = Moed L, Shwayder TA, Chang MW | title = Cantharidin revisited: a blistering defense of an ancient medicine | journal = Archives of Dermatology | volume = 137 | issue = 10 | pages = 1357–1360 | date = October 2001 | pmid = 11594862 | doi = 10.1001/archderm.137.10.1357 | doi-access = free }}</ref><ref name=Bertaux1988>{{cite journal | vauthors = Bertaux B, Prost C, Heslan M, Dubertret L | title = Cantharide acantholysis: endogenous protease activation leading to desmosomal plaque dissolution | journal = The British Journal of Dermatology | volume = 118 | issue = 2 | pages = 157–165 | date = February 1988 | pmid = 3279999 | doi = 10.1111/j.1365-2133.1988.tb01769.x | s2cid = 45714898 }}</ref>

===Pharmaceutical use===
VP-102, an experimental drug-device combination that includes cantharidin delivered via a single-use applicator, was studied for the treatment of [[molluscum contagiosum]], [[wart|common warts]], and [[genital wart]]s.<ref>{{cite news | url = https://www.drugs.com/nda/vp_102_210528.html | title = Verrica Pharmaceuticals Announces Extension of FDA Review Period of its NDA for VP-102 for the Treatment of Molluscum Contagiosum | date = 28 May 2021 | publisher = [[drugs.com]] | access-date = 24 June 2021 | archive-date = 24 June 2021 | archive-url = https://web.archive.org/web/20210624205303/https://www.drugs.com/nda/vp_102_210528.html | url-status = live }}</ref> The efficacy of cantharidin was formally established for the treatment of molluscum in patients 2 years and older in two double-blind, randomized, placebo-controlled trials.  It is now FDA-approved for the treatment of molluscum contagiousum under the brand name Ycanth and is marketed by Verrica Pharmaceuticals.<ref name = "FDA_2023" />

===Toxicity===
The [[liver]], primarily responsible for metabolism and detoxification, often becomes damaged in cases of cantharidin poisoning. The [[hepatotoxicity]] of cantharidin arises from its inhibition of hepatocyte proliferation pathways, the promotion of hepatocyte [[apoptosis]] or [[autophagy]], and increased inflammation. <ref name="Jin_2023">{{cite journal | vauthors = Jin D, Huang NN, Wei JX | title = Hepatotoxic mechanism of cantharidin: insights and strategies for therapeutic intervention | journal = Frontiers in Pharmacology | volume = 14 | pages = 1201404 | date = 13 June 2023 | pmid = 37383714 | pmc = 10293652 | doi = 10.3389/fphar.2023.1201404 | doi-access = free }}</ref> Many studies have been conducted to elucidate the specific interactions cantharidin has in the liver, that lead to pathology. The poison has been found to inhibit PP1, PP2A (PP = [[protein phosphatase]]), TIL-4 (TIL = [[toll-like receptor]]), NF-KB (NF = [[nuclear factor]]), ERK, and DFF45. Cantharidin promotes TNF-α (TNF = tumor necrosis factor), FASL, ROS, caspase-4, caspase-6, caspase-8, caspase-9, caspase-12, protein kinase R-like ER kinase, inositol-requiring enzyme 1, ATF6 (transcription factor 6), ATF4, BID,BAK, BAX, cyto C, LC3-1, p150, Atg7, P13K Ⅲ, eIF2α, and CHOP pathways.<ref name="Jin_2023" /> Cantharidin has an diverse range of targets in the liver that have been discovered empirically. However, the exact chemical mechanisms by which cantharidin interferes with these structures are unknown.

===Bioactivities===
Cantharidin appears to have some effect in the topical treatment of [[cutaneous leishmaniasis]] in animal models.<ref>{{cite journal | vauthors = Ghaffarifar F | title = Leishmania major: in vitro and in vivo anti-leishmanial effect of cantharidin | journal = Experimental Parasitology | volume = 126 | issue = 2 | pages = 126–129 | date = October 2010 | pmid = 20435039 | doi = 10.1016/j.exppara.2010.04.004 | doi-access = free }}</ref> In addition to topical medical applications, cantharidin and its analogs are of particular interest for oncological applications as they may have toxic activity against cancer cells.<ref>{{cite journal | vauthors = Ratcliffe NA, Mello CB, Garcia ES, Butt TM, Azambuja P | title = Insect natural products and processes: new treatments for human disease | journal = Insect Biochemistry and Molecular Biology | volume = 41 | issue = 10 | pages = 747–769 | date = October 2011 | pmid = 21658450 | doi = 10.1016/j.ibmb.2011.05.007 | bibcode = 2011IBMB...41..747R }}</ref><ref>{{cite journal | vauthors = Chen YN, Cheng CC, Chen JC, Tsauer W, Hsu SL | title = Norcantharidin-induced apoptosis is via the extracellular signal-regulated kinase and c-Jun-NH2-terminal kinase signaling pathways in human hepatoma HepG2 cells | journal = British Journal of Pharmacology | volume = 140 | issue = 3 | pages = 461–470 | date = October 2003 | pmid = 12970086 | pmc = 1574052 | doi = 10.1038/sj.bjp.0705461 }}</ref><ref>{{cite journal | vauthors = Zhang C, Peng Y, Wang F, Tan X, Liu N, Fan S, Wang D, Zhang L, Liu D, Wang T, Wang S, Zhou Y, Su Y, Cheng T, Zhuang Z, Shi C | title = A synthetic cantharidin analog for the enhancement of doxorubicin suppression of stem cell-derived aggressive sarcoma | journal = Biomaterials | volume = 31 | issue = 36 | pages = 9535–9543 | date = December 2010 | pmid = 20875681 | doi = 10.1016/j.biomaterials.2010.08.059 }}</ref>
Laboratory studies with cultured tumor cells suggest that this activity may be the result of [[PP2A]] inhibition.<ref>{{cite journal | vauthors = Dorn DC, Kou CA, Png KJ, Moore MA | title = The effect of cantharidins on leukemic stem cells | journal = International Journal of Cancer | volume = 124 | issue = 9 | pages = 2186–2199 | date = May 2009 | pmid = 19123473 | doi = 10.1002/ijc.24157 | s2cid = 38088568 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Li W, Xie L, Chen Z, Zhu Y, Sun Y, Miao Y, Xu Z, Han X | title = Cantharidin, a potent and selective PP2A inhibitor, induces an oxidative stress-independent growth inhibition of pancreatic cancer cells through G2/M cell-cycle arrest and apoptosis | journal = Cancer Science | volume = 101 | issue = 5 | pages = 1226–1233 | date = May 2010 | pmid = 20331621 | doi = 10.1111/j.1349-7006.2010.01523.x | s2cid = 24345174 | doi-access = free | pmc = 11158714 }}</ref>

Recent research has identified many other pathways in cancer cells that may be interfered with by cantharidin. Generally, cantharidin's anticancer targets include numerous transcription factors, protein kinases, growth factors, and inflammatory cytokines.<ref name="Jin_2023" /> Cantharidin's general lack of target specificity in cancer cells and toxic effects towards healthy cells are limiting for clinical oncological applications.

== Notes ==
{{notelist}}

== References ==
{{reflist}}

== External links ==
* [https://www.faidherbe.org/site/cours/dupuis/canthar4.htm Cantharidin : origin and synthesis] at Lycée Faidherbe de Lille

{{Chemical agents}}
{{Toxins}}
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[[Category:Terpenes and terpenoids]]
[[Category:Phosphatase inhibitors]]
[[Category:Carboxylic anhydrides]]
[[Category:Ethers]]
[[Category:Blister agents]]
[[Category:Insects in culture]]
[[Category:Dermatoxins]]
[[Category:Heterocyclic compounds with 3 rings]]
[[Category:Oxygen heterocycles]]