Cantharidin is an odorless, colorless fatty substance of the
terpenoid
The terpenoids, also known as isoprenoids, are a class of naturally occurring organic chemicals derived from the 5-carbon compound isoprene and its derivatives called terpenes, diterpenes, etc. While sometimes used interchangeably with "terpenes" ...
class, which is secreted by many species of
blister beetle
Blister beetles are beetles of the family Meloidae, so called for their defensive secretion of a blistering agent, cantharidin. About 7,500 species are known worldwide. Many are conspicuous and some are aposematically colored, announcing their ...
s. It is a burn agent or a poison in large doses, but preparations containing it were historically used as
aphrodisiac
An aphrodisiac is a substance that increases sexual desire, sexual attraction, sexual pleasure, or sexual behavior. Substances range from a variety of plants, spices, foods, and synthetic chemicals. Natural aphrodisiacs like cannabis or cocain ...
s (
Spanish fly
The Spanish fly (''Lytta vesicatoria'') is an aposematic emerald-green beetle in the blister beetle family (Meloidae). It is distributed across Eurasia.
The species and others in its family were used in traditional apothecary preparatio ...
). 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
A blister agent (or vesicant), is a chemical compound that causes severe skin, eye and mucosal pain and irritation. They are named for their ability to cause severe chemical burns, resulting in painful water blisters on the bodies of those affe ...
(blistering agent), exposure to which can cause severe
chemical burn
A chemical burn occurs when living tissue is exposed to a corrosive substance (such as a strong acid, base or oxidizer) or a cytotoxic agent (such as mustard gas, lewisite or arsine). Chemical burns follow standard burn classification and may c ...
s. Properly dosed and applied, the same properties have also been used therapeutically, for instance for treatment of skin conditions such as
molluscum contagiosum
Molluscum contagiosum (MC), sometimes called water warts, is a viral infection of the skin that results in small raised pink lesions with a dimple in the center. They may become itchy or sore, and occur singularly or in groups. Any area of the sk ...
infection of the skin.
Cantharidin is classified as an
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.
Chemistry
Structure and nomenclature
Cantharidin, from the Greek ''kantharis'', for beetle, is an odorless, colorless
natural product with solubility in various organic solvents, but only slight solubility in water.
Its skeleton is
tricyclic
Tricyclics are chemical compounds that contain three interconnected rings of atoms.
Many compounds have a tricyclic structure, but in pharmacology, the term has traditionally been reserved to describe heterocyclic drugs. Among these are antid ...
, formally, a tricyclo-
2,6">.2.1.02,6ecane skeleton. Its functionalities include a
carboxylic acid anhydride
An organic acid anhydride is an acid anhydride that is an organic compound. An acid anhydride is a compound that has two acyl groups bonded to the same oxygen atom. A common type of organic acid anhydride is a carboxylic anhydride, where the pa ...
(−CO−O−CO−) substructure in one of its rings, as well as a bridging
ether
In organic chemistry, ethers are a class of compounds that contain an ether group—an oxygen atom connected to two alkyl or aryl groups. They have the general formula , where R and R′ represent the alkyl or aryl groups. Ethers can again be c ...
in its
bicyclic
In chemistry, a bicyclic molecule () is a molecule that features two joined rings. Bicyclic structures occur widely, for example in many biologically important molecules like α-thujene and camphor. A bicyclic compound can be carbocyclic (all ...
ring system.
The complete mechanism of the
biosynthesis of cantharidin is unknown. Its framework formally consists of two
isoprene units. However,
feeding studies
Eating (also known as consuming) is the ingestion of food, typically to provide a heterotrophic organism with energy and to allow for growth. Animals and other heterotrophs must eat in order to survive — carnivores eat other animals, he ...
indicate that the biosynthetic process is more complicated and not a simple product of
geranyl pyrophosphate
Geranyl pyrophosphate (GPP), also known as geranyl diphosphate (GDP), is the pyrophosphate ester of the terpenoid geraniol. Its salts are colorless. It is a precursor to many natural products.
Occurrence
GPP is an intermediate in the isopreno ...
or related ten-carbon parent structure as the seeming
monoterpene
Monoterpenes are a class of terpenes that consist of two isoprene units and have the molecular formula C10H16. Monoterpenes may be linear (acyclic) or contain rings (monocyclic and bicyclic). Modified terpenes, such as those containing oxygen func ...
nature would suggest. Instead, there is a
farnesol (15-carbon) precursor from which certain carbon segments are later excised.
Distribution and availability
The level of cantharidin in blister beetles can be quite variable. Among blister beetles of the genus ''
Epicauta
''Epicauta'' is a genus of beetles in the blister beetle family, Meloidae. The genus was first scientifically described in 1834 by Pierre François Marie Auguste Dejean. ''Epicauta'' is distributed nearly worldwide, with species native to all con ...
'' in
Colorado
Colorado (, other variants) is a state in the Mountain West subregion of the Western United States. It encompasses most of the Southern Rocky Mountains, as well as the northeastern portion of the Colorado Plateau and the western edge of t ...
, ''E. pennsylvanica'' contains about 0.2 mg, ''E. maculata'' contains 0.7 mg, and ''E. immaculata'' contains 4.8 mg per beetle; males also contain higher levels than females.
Males of ''
Berberomeloe majalis
''Berberomeloe majalis'', the red-striped oil beetle, is an insect in the genus '' Berberomeloe'', in the family of Blister Beetles. It is native to the western Mediterranean Basin.
Description
It has a typical length around 5 cm (2 in.) ...
'' 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 in
haemolymph
Hemolymph, or haemolymph, is a fluid, analogous to the blood in vertebrates, that circulates in the interior of the arthropod (invertebrate) body, remaining in direct contact with the animal's tissues. It is composed of a fluid plasma in which ...
is also higher in males (80.9 ± 106.5 µg/g) than in females (20.0 ± 41.5 µg/g).
History
Aphrodisiac preparations
Preparations made from
blistering beetles have been used since ancient times as an
aphrodisiac
An aphrodisiac is a substance that increases sexual desire, sexual attraction, sexual pleasure, or sexual behavior. Substances range from a variety of plants, spices, foods, and synthetic chemicals. Natural aphrodisiacs like cannabis or cocain ...
, possibly because their physical effects were perceived to mimic those of sexual arousal, and because they can cause prolonged erection or
priapism
Priapism is a condition in which a penis remains erect for hours in the absence of stimulation or after stimulation has ended. There are three types: ischemic (low-flow), nonischemic (high-flow), and recurrent ischemic (intermittent). Most cases ...
in men.
[Peter V. Taberner, ''Aphrodisiacs: The Science and the Myth'', Springer Science & Business Media, 2012, pp.100ff] 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
Publius Cornelius Tacitus, known simply as Tacitus ( , ; – ), was a Roman historian and politician. Tacitus is widely regarded as one of the greatest Roman historiography, Roman historians by modern scholars.
The surviving portions of his t ...
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).
* The German emperor
Henry IV (1050–1106) is said to have consumed cantharides.
* The French surgeon
Ambroise Paré
Ambroise Paré (c. 1510 – 20 December 1590) was a French barber surgeon who served in that role for kings Henry II, Francis II, Charles IX and Henry III. He is considered one of the fathers of surgery and modern forensic pathology and a p ...
(1510–1590) described a case in 1572 of a man suffering from "the most frightful
satyriasis
Hypersexuality is extremely frequent or suddenly increased libido. It is controversial whether it should be included as a clinical diagnosis used by mental healthcare professionals. Nymphomania and satyriasis were terms previously used for the c ...
" after taking a potion composed of
nettles and a cantharid extract.
This is perhaps the same man of whom Paré relates that a
courtesan
Courtesan, in modern usage, is a euphemism for a "kept" mistress or prostitute, particularly one with wealthy, powerful, or influential clients. The term historically referred to a courtier, a person who attended the court of a monarch or other ...
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. The same Paré also cites the case of a priest who died of
hematuria
Hematuria or haematuria is defined as the presence of blood or red blood cells in the urine. “Gross hematuria” occurs when urine appears red, brown, or tea-colored due to the presence of blood. Hematuria may also be subtle and only detectable w ...
after swallowing a dose of cantharides which he intended to fortify his sex drive.
[ Augustin Cabanès]
''Remèdes d'autrefois''
Paris: A. Maloine, 1910, p. 498ff.
* 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.
* The French sorceress
Catherine Monvoisin
Catherine Monvoisin, or Montvoisin, née ''Deshayes'', known as "La Voisin" (c. 1640 – 22 February 1680), was a French fortune teller, commissioned poisoner, and professional provider of alleged sorcery. She was the head of a network of fo ...
(known as "La Voisin", c. 1640–1680) is recorded in the 1670s as having prepared a love charm made from
Spanish fly
The Spanish fly (''Lytta vesicatoria'') is an aposematic emerald-green beetle in the blister beetle family (Meloidae). It is distributed across Eurasia.
The species and others in its family were used in traditional apothecary preparatio ...
mixed with dried mole's blood and bat's blood.
* Aphrodisiac sweets which probably contained cantharides were circulated in
libertine circles in the 1700s in France. They were multicolored tablets nicknamed "pastilles de Richelieu" after the
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
Louis XV (15 February 1710 – 10 May 1774), known as Louis the Beloved (french: le Bien-Aimé), was King of France from 1 September 1715 until his death in 1774. He succeeded his great-grandfather Louis XIV at the age of five. Until he reache ...
.
* The French writer Donatien Alphonse François — notoriously known as the
Marquis de Sade (1740–1814) — is said to have given
aniseed
Anise (; '), also called aniseed or rarely anix is a flowering plant in the family Apiaceae native to Eurasia.
The flavor and aroma of its seeds have similarities with some other spices and herbs, such as star anise, fennel, licorice, and t ...
-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
Sodomy () or buggery (British English) is generally anal or oral sex between people, or sexual activity between a person and a non-human animal ( bestiality), but it may also mean any non- procreative sexual activity. Originally, the term ''sodo ...
), but was later reprieved on appeal.
[Schaeffer, Neil (2000). ''The Marquis de Sade: A Life'', Cambridge, MA, USA: Harvard University Press, p. 58.]
Non-aphrodisiac uses
* The Spanish clergyman
Juan de Horozco y Covarrubias (
es) (c. 1540–1610) reported the use of blister beetles as a
poison
Poison is a chemical substance that has a detrimental effect to life. The term is used in a wide range of scientific fields and industries, where it is often specifically defined. It may also be applied colloquially or figuratively, with a broa ...
as well as an aphrodisiac.
* Preparations of dried blister beetles were at one time used as a treatment for
smallpox
Smallpox was an infectious disease caused by variola virus (often called smallpox virus) which belongs to the genus Orthopoxvirus. The last naturally occurring case was diagnosed in October 1977, and the World Health Organization (WHO) c ...
. As late as 1892
Andrew Taylor Still
Andrew Taylor Still, DO (August 6, 1828 – December 12, 1917) was the founder of osteopathic medicine. He was also a physician and surgeon, author, inventor and Kansas territorial and state legislator. He was one of the founders of Baker Univers ...
, the founder of
osteopathy
Osteopathy () is a type of alternative medicine that emphasizes physical manipulation of the body's muscle tissue and bones. Practitioners of osteopathy are referred to as osteopaths.
Osteopathic manipulation is the core set of techniques in ...
, recommended inhaling a tincture of cantharidin as an effective preventative and treatment for smallpox, decrying
vaccination
Vaccination is the administration of a vaccine to help the immune system develop immunity from a disease. Vaccines contain a microorganism or virus in a weakened, live or killed state, or proteins or toxins from the organism. In stimulating ...
.
Pharmaco-chemical isolation
Cantharidin was first isolated as a chemically pure substance in 1810 by
Pierre Robiquet
Pierre Jean Robiquet (13 January 1780 – 29 April 1840) was a French chemist. He laid founding work in identifying amino acids, the fundamental building blocks of proteins. He did this through recognizing the first of them, asparagine, in 1806 ...
, a French chemist then living in Paris. Robiquet isolated cantharidin as the active ingredient in pharmacological preparations of ''
Lytta vesicatoria
The Spanish fly (''Lytta vesicatoria'') is an aposematic emerald-green beetle in the blister beetle family (Meloidae). It is distributed across Eurasia.
The species and others in its family were used in traditional apothecary preparation ...
'', a.k.a. "
Spanish fly
The Spanish fly (''Lytta vesicatoria'') is an aposematic emerald-green beetle in the blister beetle family (Meloidae). It is distributed across Eurasia.
The species and others in its family were used in traditional apothecary preparatio ...
", a species of
blister beetle
Blister beetles are beetles of the family Meloidae, so called for their defensive secretion of a blistering agent, cantharidin. About 7,500 species are known worldwide. Many are conspicuous and some are aposematically colored, announcing their ...
. 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
Colloquially, "room temperature" is a range of air temperatures that most people prefer for indoor settings. It feels comfortable to a person when they are wearing typical indoor clothing. Human comfort can extend beyond this range depending on ...
. He demonstrated that it was the active principle responsible for the aggressively
blistering properties of the coating of the eggs of the blister beetle, and established as well that cantharidin had toxic properties comparable in degree to those of the most virulent poisons known in the 19th century, such as
strychnine.
Other uses of the pharmacological isolate
* Diluted solutions of cantharidin can be used as a
topical
A topical medication is a medication that is applied to a particular place on or in the body. Most often topical medication means application to body surfaces such as the skin or mucous membranes to treat ailments via a large range of classes ...
medication to remove
wart
Warts are typically small, rough, hard growths that are similar in color to the rest of the skin. They typically do not result in other symptoms, except when on the bottom of the feet, where they may be painful. While they usually occur on the ...
s
and
tattoo
A tattoo is a form of body modification made by inserting tattoo ink, dyes, and/or pigments, either indelible or temporary, into the dermis layer of the skin to form a design. Tattoo artists create these designs using several Process of tatt ...
s and to treat the small
papules
A papule is a small, well-defined bump in the skin. It may have a rounded, pointed or flat top, and may have a dip. It can appear with a stalk, be thread-like or look warty. It can be soft or firm and its surface may be rough or smooth. Some h ...
of ''
molluscum contagiosum
Molluscum contagiosum (MC), sometimes called water warts, is a viral infection of the skin that results in small raised pink lesions with a dimple in the center. They may become itchy or sore, and occur singularly or in groups. Any area of the sk ...
''.
* In
Santería
Santería (), also known as Regla de Ocha, Regla Lucumí, or Lucumí, is an African diaspora religions, African diasporic religion that developed in Cuba during the late 19th century. It arose through a process of syncretism between the tradit ...
rituals, cantharides are used in
incense
Incense is aromatic biotic material that releases fragrant smoke when burnt. The term is used for either the material or the aroma. Incense is used for aesthetic reasons, religious worship, aromatherapy, meditation, and ceremony. It may also b ...
.
Veterinary issues
Poisoning from cantharidin is a significant veterinary concern, especially in horses by ''Epicauta'' species; species infesting feedstocks depend on region—e.g., ''Epicauta pennsylvanica'' (black blisterbeetle) 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.
[ Beetles feed on ]weed
A weed is a plant considered undesirable in a particular situation, "a plant in the wrong place", or a plant growing where it is not wanted.Harlan, J. R., & deWet, J. M. (1965). Some thoughts about weeds. ''Economic botany'', ''19''(1), 16-24. ...
s and occasionally move into crop fields used to produce livestock feeds (e.g., alfalfa
Alfalfa () (''Medicago sativa''), also called lucerne, is a perennial flowering plant in the legume family Fabaceae. It is cultivated as an important forage crop in many countries around the world. It is used for grazing, hay, and silage, as w ...
), where they are found to cluster and find their way into baled hay, e.g., a single flake (4-5 in. section) may have several hundred insects, or none at all.[ Horses are very sensitive to the cantharidin produced by beetle infestations: the 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.
]Great bustard
The great bustard (''Otis tarda'') is a bird in the bustard family, the only member of the genus ''Otis''. It breeds in open grasslands and farmland from northern Morocco, South and Central Europe, to temperate Central and East Asia. European po ...
s, a strongly polygynous bird species, 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. Great bustards may eat toxic blister beetle
Blister beetles are beetles of the family Meloidae, so called for their defensive secretion of a blistering agent, cantharidin. About 7,500 species are known worldwide. Many are conspicuous and some are aposematically colored, announcing their ...
s of the genus ''Meloe
The blister beetle genus ''Meloe'' is a large, widespread group commonly referred to as oil beetles. They are known as "oil beetles" because they release oily droplets of hemolymph from their joints when disturbed; this contains cantharidin, a ...
'' to increase the sexual arousal of males.
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.
Despite being widely used, cantharidin has never been and is not currently FDA approved. It is currently in Phase 3 clinical trials for the treatment of molluscum. However, when compounded properly and applied in the clinic topically by a medical provider familiar with its effects and uses, cantharidin can be safely and effectively used to treat some benign skin lesions like warts and molluscum.[
When ]ingested
Ingestion is the consumption of a substance by an organism. In animals, it normally is accomplished by taking in a substance through the mouth into the gastrointestinal tract, such as through eating or drinking. In single-celled organisms inges ...
by humans, the is around 0.5 mg/kg, with a dose of as little as 10 mg being potentially fatal. Ingesting cantharidin can initially cause severe damage to the lining of the gastrointestinal and urinary tracts, and may also cause permanent renal
The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; bloo ...
damage. Symptoms of cantharidin poisoning include blood in the urine
Hematuria or haematuria is defined as the presence of blood or red blood cells in the urine. “Gross hematuria” occurs when urine appears red, brown, or tea-colored due to the presence of blood. Hematuria may also be subtle and only detectable w ...
, abdominal pain, and rarely prolonged erections.[
]
Risks of aphrodisiac use
The extreme toxicity of cantharidin makes any use as an aphrodisiac highly dangerous. As a result, it is illegal to sell (or use) cantharidin or preparations containing it without a prescription in many countries.[
]
Research
Mechanism of action
Topical cantharidin is absorbed by the lipid membranes of epidermal cells, causing the release of serine proteases
Serine proteases (or serine endopeptidases) are enzymes that cleave peptide bonds in proteins. Serine serves as the nucleophilic amino acid at the (enzyme's) active site.
They are found ubiquitously in both eukaryotes and prokaryotes. Seri ...
, enzymes that break the peptide bonds
In organic chemistry, a peptide bond is an amide type of covalent chemical bond linking two consecutive alpha-amino acids from C1 (carbon number one) of one alpha-amino acid and N2 (nitrogen number two) of another, along a peptide or protein cha ...
in proteins. This causes the disintegration of desmosomal plaques, cellular structures involved in cell-to-cell adhesion, leading to detachment of the tonofilaments that hold cells together. The process leads to the loss of cellular connections (acantholysis
Acantholysis is the loss of intercellular connections, such as desmosomes, resulting in loss of cohesion between keratinocytes,Kumar, Vinay; Fausto, Nelso; Abbas, Abul (2004) ''Robbins & Cotran Pathologic Basis of Disease'' (7th ed.). Saunders. ...
) and ultimately blistering of the skin. Lesions heal without scarring.
Pharmaceutical use
VP-102, an experimental drug-device combination which includes cantharidin delivered via a single-use applicator, is being studied for the treatment of molluscum contagiosum
Molluscum contagiosum (MC), sometimes called water warts, is a viral infection of the skin that results in small raised pink lesions with a dimple in the center. They may become itchy or sore, and occur singularly or in groups. Any area of the sk ...
, common warts
Warts are typically small, rough, hard growths that are similar in color to the rest of the skin. They typically do not result in other symptoms, except when on the bottom of the feet, where they may be painful. While they usually occur on the ...
, and genital wart
Genital warts are a sexually transmitted infection caused by certain types of human papillomavirus (HPV). They are generally pink in color and project out from the surface of the skin. Usually they cause few symptoms, but can occasionally be pai ...
s.
Bioactivities
Cantharidin appears to have some effect in the topical treatment of cutaneous leishmaniasis
Cutaneous leishmaniasis is the most common form of leishmaniasis affecting humans. It is a skin infection caused by a single-celled parasite that is transmitted by the bite of a phlebotomine sand fly. There are about thirty species of '' Leish ...
in animal models. In addition to topical medical applications, cantharidin and its analogues may have activity against cancer cells.
Laboratory studies with cultured tumor cells suggest that this activity may be the result of PP2A
Protein phosphatase 2 (PP2), also known as PP2A, is an enzyme that in humans is encoded by the ''PPP2CA'' gene. The PP2A heterotrimeric protein phosphatase is ubiquitously expressed, accounting for a large fraction of phosphatase activity in eu ...
inhibition.
References
Explanatory notes
Sources
Further reading
* Dupuis, Gérard & Berland, Nicole (2004). "Cantharidin: Origin and synthesis," Lille, FR: Lycée Faidherbe, se
accessed 13 December 2015.
External links
Cantharidin
Cantharidin Revisited: Blistering Defense of an Ancient Medicine
{{Authority control
Terpenes and terpenoids
Phosphatase inhibitors
Carboxylic anhydrides
Ethers
Blister agents
Abortifacients
Insects in culture