Cantharidin is an odorless, colorless fatty substance of theterpenoid class, which is secreted by many species ofblister beetles.[a] Its main current use in pharmacology is treatingmolluscum contagiosum andwarts topically.[2] It is a burn agent,poisonous in large doses. It has been historically used as anaphrodisiac (in potions sold under the name "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 potentvesicant (blistering agent), exposure to which can cause severechemical burns. Properly dosed and applied, the same properties have also been used therapeutically, for instance, for treatment of skin conditions, such asmolluscum contagiosum infection of the skin.
Cantharidin is classified as anextremely hazardous substance in theUnited States, and is subject to strict reporting requirements by facilities that produce, store, or use it in significant quantities.[3]
Cantharidin, from the Greekkantharis, for beetle,[4] is an odorless, colorlessnatural product with solubility in various organic solvents,[specify] but only slight solubility in water.[5] Its skeleton istricyclic, formally, a tricyclo-[5.2.1.02,6]decane skeleton. Its functionalities include acarboxylic acid anhydride (−CO−O−CO−) substructure in one of its rings, as well as a bridgingether in itsbicyclic ring system.
The level of cantharidin in blister beetles can be quite variable. Among blister beetles of the genusEpicauta inColorado,E. pennsylvanica contains about 0.2 mg,E. maculata contains 0.7 mg, andE. immaculata contains 4.8 mg per beetle; males also contain higher levels than females.[6]
Males ofBerberomeloe majalis have higher level of cantharidin per beetle: 64.22 ± 51.28 mg/g (dry weight) and 9.10 ± 12.64 mg/g (d. w.). Cantharidin content inhaemolymph is also higher in males (80.9 ± 106.5 μg/g) than in females (20.0 ± 41.5 μg/g).[7]
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 aDiels-Alder cycloaddition reaction to form the six-membered ring.[8][9][10] The starting material often utilizes a furan as the diene, giving the formation of a bicyclic ring.
Most total syntheses of cantharidin start with a Diels-Alder reaction.
The complete mechanism of thebiosynthesis of cantharidin is unknown. Its framework formally consists of twoisoprene units.[11] However,feeding studies indicate that the biosynthetic process is more complicated, and not a simple product ofgeranyl pyrophosphate or related ten-carbon parent structure, as the seemingmonoterpene nature would suggest. Instead, there is afarnesol (15-carbon) precursor from which certain carbon segments are later excised.[12]
Biosynthesis from farnesol — bonds to be formed and major atoms to be added are inblue; while bonds to be broken and atoms/structural segments to be removed are inred.
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 byRNA interference methods. Themevalonate pathway (MVA pathway) is responsible for producingisoprenoids in many organisms, including farnesol.[13] 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.[14]
Preparations made fromblister beetles (particularly "Spanish fly") have been used since ancient times as anaphrodisiac, possibly because their physical effects were perceived to mimic those of sexual arousal,[15] and because they can cause prolonged erection orpriapism in men.[16] These preparations were known ascantharides, from the Greek word for "beetle".[citation needed]
Examples of such use found in historical sources include:
The ancient Roman historianTacitus relates that a cantharid preparation was used by the empressLivia, wife ofAugustus Caesar, to entice members of the imperial family or dinner guests to commit sexual indiscretions (thus, providing her information to hold over them).[17]
The German emperorHenry IV (1050–1106) is said to have consumed cantharides.[18]
The French surgeonAmbroise Paré (1510–1590) described a case in 1572 of a man suffering from "the most frightfulsatyriasis" after taking a potion composed ofnettles and a cantharid extract.[19] This is perhaps the same man of whom Paré relates that acourtesan 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 ofhematuria after swallowing a dose of cantharides, which he intended to fortify his sex drive.[20]
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.[20]
The French sorceressCatherine Monvoisin (known as "La Voisin," c. 1640–1680) was recorded in the 1670s as having prepared a love charm made from Spanish fly mixed with dried mole's blood and bat's blood.[21]
Aphrodisiac sweets presumably laced with cantharides were circulated withinlibertine circles during the 1700s in France. They were multicolored tablets nicknamed "pastilles de Richelieu," after theMaréchal de Richelieu, a notorious libertine (not to be confused with his great-uncle, theCardinal Richelieu) who procured sexual encounters for KingLouis XV.[20][22]
The French writer Donatien Alphonse François — notoriously known as theMarquis de Sade (1740–1814) — is said to have givenaniseed-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 ofsodomy), but was later reprieved on appeal.[23][24]
Preparations of dried blister beetles were at one time used as a treatment forsmallpox.[26] As late as 1892,Andrew Taylor Still, the founder ofosteopathy, recommended inhaling atincture of cantharidin as an effective preventative and treatment for smallpox, decryingvaccination.[27]
Japaneseninja used blister beetles combined with arsenic to create a noxious gas.[28][29]
Cantharidin was first isolated as a chemically pure substance in 1810 byPierre Robiquet,[30] a French chemist then living inParis. Robiquet isolated cantharidin as the active ingredient in pharmacological preparations ofLytta vesicatoria (Spanish fly), a species ofblister 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 atroom temperature. He demonstrated that it was the active principle responsible for the aggressivelyblistering 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 asstrychnine.[31]
Poisoning byEpicauta 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; andE. occidentalis, temexia, and vittata species (striped blister beetles) in the U.S. southwest—where the concentrations of the agent in each can vary substantially.[5] Beetles feed onweeds, and occasionally move into crop fields used to produce livestock feeds (e.g.,alfalfa), where they are found to cluster and find their way intobaled hay, e.g., a single flake (4–5 in. section[36]) may have several hundred insects, or none at all.[5] Horses are very sensitive to the cantharidin produced by beetle infestations: theLD50 for horses is roughly 1 mg/kg of the horse's body weight. Horses may be accidentally poisoned when fed bales of fodder with blister beetles in them.[37]
Great bustards, a stronglypolygynous bird species,[38] 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.[39][40] Great bustards may eat toxicblister beetles of the genusMeloe to increase the sexual arousal of males.[41]
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.[42] However, this references unregulated sources of cantharidin.[43] In July 2023, the US FDA approved a topical formulation of cantharidin (Ycanth) for the treatment ofmolluscum contagiosum.[2]
Wheningested by humans, theLD50 is unknown, but fatal doses have been recorded between 10 mg and 65 mg.[44] The median lethal dose appears to be around 1 mg/kg[45] but individuals have survived after consuming oral doses as high as 175 mg.[46] Ingesting cantharidin can initially cause severe damage to the lining of thegastrointestinal andurinary tracts, and may also cause permanentrenal damage. Symptoms of cantharidin poisoning includehematuria, abdominal pain, and (rarely)priapism.[43]
The extreme toxicity of cantharidin makes any use as an aphrodisiac highly dangerous.[47][48] As a result, it is illegal to sell (or use) cantharidin or preparations containing it without a prescription in many countries.[42]
This sectionis missing information about toxicological mechanism when ingested. Please expand the section to include this information. Further details may exist on thetalk page.(September 2022)
Topical cantharidin is absorbed by the lipid membranes ofepidermal cells, causing the release ofserine proteases,enzymes that break thepeptide bonds in proteins. This causes the disintegration ofdesmosomal plaques, cellular structures involved in cell-to-cell adhesion, leading to detachment of thetonofilaments 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.[49][50]
VP-102, an experimental drug-device combination that includes cantharidin delivered via a single-use applicator, was studied for the treatment ofmolluscum contagiosum,common warts, andgenital warts.[51] 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.[2]
Theliver, primarily responsible for metabolism and detoxification, often becomes damaged in cases of cantharidin poisoning. Thehepatotoxicity of cantharidin arises from its inhibition of hepatocyte proliferation pathways, the promotion of hepatocyteapoptosis orautophagy, and increased inflammation.[52] 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.[52] Cantharidin has a 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.
Cantharidin appears to have some effect in the topical treatment ofcutaneous leishmaniasis in animal models.[53] 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.[54][55][56]Laboratory studies with cultured tumor cells suggest that this activity may be the result ofPP2A inhibition.[57][58]
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.[52] Cantharidin's general lack of target specificity in cancer cells and toxic effects towards healthy cells are limiting for clinical oncological applications.
^Capinera JL, Gardner DR, Stermitz FR (1985). "Cantharidin Levels in Blister Beetles (Coleoptera: Meloidae) Associated with Alfalfa in Colorado".Journal of Economic Entomology.78 (5):1052–1055.doi:10.1093/jee/78.5.1052.
^Bravo C, Mas-Peinado P, Bautista LM, Blanco G, Alonso JC, García-París M (2017). "Cantharidin is conserved across phylogeographic lineages and present in both morphs of IberianBerberomeloe blister beetles (Coleoptera, Meloidae)".Zoological Journal of the Linnean Society.180 (4):790–804.doi:10.1093/zoolinnean/zlw016.hdl:10261/153832.
^Dauben WG, Kessel CR, Takemura KH (15 October 1980). "Simple, efficient total synthesis of cantharidin via a high-pressure Diels-Alder reaction".Journal of the American Chemical Society.102 (22):6893–6894.Bibcode:1980JAChS.102.6893D.doi:10.1021/ja00542a060.
^"In-nin V" [Hidden Infiltration V].Bansenshukai [The Book of Ninja]. Vol. 15. Translated by Cummins A, Yoshie M. Watkins Publishing. 2013.ISBN978-1-78028-493-4.
^abKarras DJ, Farrell SE, Harrigan RA, Henretig FM, Gealt L (September 1996). "Poisoning from "Spanish fly" (cantharidin)".The American Journal of Emergency Medicine.14 (5):478–483.doi:10.1016/S0735-6757(96)90158-8.PMID8765116.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.
^abBinder R (May 1979). "Malpractice--in dermatology".Cutis.23 (5):663–666.PMID456036.
^Sandroni P (October 2001). "Aphrodisiacs past and present: a historical review".Clinical Autonomic Research.11 (5):303–307.doi:10.1007/BF02332975.PMID11758796.S2CID32348540.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.
^Bertaux B, Prost C, Heslan M, Dubertret L (February 1988). "Cantharide acantholysis: endogenous protease activation leading to desmosomal plaque dissolution".The British Journal of Dermatology.118 (2):157–165.doi:10.1111/j.1365-2133.1988.tb01769.x.PMID3279999.S2CID45714898.
^Zhang C, Peng Y, Wang F, Tan X, Liu N, Fan S, et al. (December 2010). "A synthetic cantharidin analog for the enhancement of doxorubicin suppression of stem cell-derived aggressive sarcoma".Biomaterials.31 (36):9535–9543.doi:10.1016/j.biomaterials.2010.08.059.PMID20875681.
