Cantharidin

Cantharidin¹ is a tricyclic alkaloid that contains anhydride and ether groups. It is a virulent toxin produced by blister beetles of the family Meloidae, mostly in the genus Epicauta.

An early mention of cantharidin in the chemical literature came in an 1878 article by British physician/chemist Alexander Wynter Blyth, who determined the sublimation temperatures of some alkaloids and similar compounds. (Cantharidin sublimes at 110 °C under 12-Torr pressure.) Twenty years later, physician Francis Whitaker Tunnicliffe at St. Bartholomew’s Hospital (London) described cantharidin as a “vascular tonic” (vesicant, or blister former) for treating tuberculosis and lupus.

It was not until 1953 that the presence of cantharidin in blister beetles was documented. Taiwanese chemist Hung-Yuan Hsu reported that the content of the molecule in the Formosan blister beetle (genus Maloe) was 0.97%. In a more complete analysis in 1967, Wilbert G. Walter and John F. Cole at the University of Mississippi (Oxford) described the isolation of the active principle of the North American blister beetle Epicauta pestifera and their determination that it was cantharidin.

Hundreds of articles in subsequent years described the toxic nature of cantharidin. It does, however, have a few medical uses, mainly as a topical treatment for warts, but also as an abortifacient (abortion inducer) and a veterinary diuretic. Notoriously, it is also the active ingredient in “Spanish fly” an ancient, risky, and not always effective aphrodisiac.

In 2001, Lisa Moed, Tor A. Shwayder, and Mary Wu Chang* at New York University School of Medicine (New York City) wrote an extensive review titled “Cantharidin Revisited: A Blistering Defense of an Ancient Medicine”. In their section on cantharidin’s history with the US Food and Drug Administration (FDA), they noted that the drug was first registered in the 1950s, when the agency did not require efficacy data. After a 1962 amendment to the original FDA act of 1938 required efficacy data , the agency took cantharidin off the market because no data had been submitted. (In July 2023, long after the review was published, FDA reinstated cantharidin as a topical for treating molluscum contagiosum [“water warts”].)

Chang et al.’s 2001 defense of cantharidin was that it is a safe drug when properly used. They cited a 1995 article by Stefan Herzig, Martin Tepel, and co-workers at University Hospital Eppendorf (Hamburg, Germany), who reported that the compound, a phosphatase inhibitor, acts as a vasoconstrictor and positive inotrope (muscle strengthener) in guinea pigs and in vitro in human cardiac tissue. Based on these results, they conjectured that less toxic derivatives of cantharidin could be therapies for treating human cardiac failure.

1. Scifinderⁿ: 4,7-epoxyisobenzofuran-1,3-dione, hexahydro-3a,7a-dimethyl-, (3aR,4S,7R,7aS)-rel-.