The Blister Beetle and Cantharidin

Richard Haynes

Epicauta pennsylvanica, a black blister beetle described in my previous article ("The Blister Beetle," The Citizen Scientist, 23 September 2005), synthesizes cantharidin (Figs. 1 and 2), a very powerful toxin and a potent blistering agent. The toxicity of cantharidin (human LD 50 ~ 0.5 mg/kg) is similar to that of strychnine. The complete biosynthesis mechanism remains unknown. (We will return to this further in this article.)

Figure 1. Cantharidin: 2,3-dimethyl 1-7- oxabicyclo [2,2,1] heptane-2,3-dicarboxylic anhydride.

Figure 2. Three-D model of cantharidin (C = green, O = red and H = gray).

From ancient times until relatively recently, it was employed as a therapeutic drug. In addition, it has a black history as the reputed aphrodisiac powder “Spanish fly,” obtained from the beetle Lytta vesicatoria (Greek lytta = rage; Latin vesica = blister). This metallic green colored blister beetle is commonly found throughout the Mediterranean, Europe and Russia (Fig. 3).

Figure 3. Spanish fly (Lytta vesicatoria).

Recorded uses of “Spanish fly” begin with the Greeks, though certainly this beetle and others of its family were known long before they wrote of it. In Greek and, later, Roman times, these small, beautiful beetles were plucked early in the morning from the leaves and branches of trees such as olive, ash or elder and shrubs such as privet, lilac and honeysuckle. The collectors wore facial coverings and gloves to protect themselves as they shook the beetles on to cloths placed on the ground. The beetles, which contain up to 5% (of body weight) cantharidin each, were killed with vinegar, then dried and carefully crushed into a powder that contained bright green metallic particles. This crude powder was often administered as a therapeutic drug but it also had a reputation, albeit a mythical one, as a potent aphrodisiac.

Medical uses of cantharidin date to at least Hippocrates (ca. 460 – 377 BC). Cantharidin was given to pregnant women as an aborting agent. It was also administered as a diuretic and to alleviate epilepsy, asthma, rabies and sterility. The First Century Greek physician Dioscorides extolled its use as a vesicant for fever patients by suggesting that the resulting skin blisters would “draw the toxins out of the body.” However, as recently as 2003, a four-year-old Canadian child went into toxic shock syndrome within 24 hours of having a cantharidin ointment applied to his chest as a cosmetic treatment for molluscum contagiosum, a poxvirus infection. Left untreated, this infection typically disappears with time. Fortunately, the child received emergency hospital care and survived.

Cantharidin's so-called pharmaceutical properties were popular worldwide until the early twentieth century, when tests showed little beneficial and many deleterious effects, including death. Currently, it may be occasionally applied in collodion solution to treat benign warts, though in the U.S. the FDA bans cantharidin and cantharidin preparations.

The Greeks, and especially the Romans, believed in the aphrodisiac qualities of crude cantharidin for it was much used by the wealthy and powerful, with many deaths probably resulting. Lucretius (ca. 99-55 BC), the Roman poet and philosopher, is said to have died insane from the effects of such a love potion given him by his wife.

In 1772, the infamous Marquis de Sade (1740-1814) was convicted by a French court in absentia for giving chocolates containing Spanish fly to a number of young prostitutes, at least one of whom died. Warned, he fled the country, thus escaping the guillotine.

Spanish fly's (cantharidin) reputation as an aphrodisiac comes from the irritating, burning sensation in the genitourinary tract when it is taken in small doses. In females, genital heat and irritation occurs. Violent and painful uterine contractions may take place, often with bloody urine and the possibility of abortion in pregnancies. In the male, priapism develops and sometimes satyriasis. This swelling of the genital organs is extremely painful. Frequent urination occurs not long after a small amount has been taken. Depending upon the amount ingested, genital gangrene may result. Often, the amount of this deadly chemical required to bring about such sensations is very close to the lethal dose, which is the equivalent of a few dried beetles.

Cantharidin poisoning affects the body in various gruesome ways. The most common symptoms are nausea, abdominal pain, bloody diarrhea, blistering of the throat and esophageal linings and kidney necrosis. There follows pain in the loins, an intense urge to void urine but only slow drops pass. In 24 hours or less convulsions and death occurs.

There is no antidote for cantharidin poisoning and bodily function maintenance is all that is available.

In the 1970s a “James Bond”- like case featured cantharidin as the poison agent. A Bulgarian diplomat was assassinated in London near Trafalgar Square as he boarded a bus. He was stuck in an ankle with the sharp tip of an umbrella wielded by an unknown assailant. The unfortunate diplomat, believing it to be an accident, at first did not seek medical help. Asking for assistance too late, he rapidly sickened and died. An autopsy revealed the remains of a tiny cantharidin pill embedded in his flesh.

In the 1970s and 1980s, the Republic of South Africa (RSA) had cantharidin secretly produced allegedly “to contaminate targeted enemies,” as it is phrased in the literature (3). At least one case of poisoning by cantharidin was documented. In 1990 RSA President F. W. De Klerk banned any further work on such lethal agents.

The high toxicity level of cantharidin appears to be based on its powerful ability to bind to the enzyme protein phosphatase 2A (PP2A) and inhibiting its action. PP2A is a major intracellular protein phosphatase that regulates many components of growth and metabolic activities in the cell. Thus, cantharidin interrupts one of the most important regulatory elements of cellular signal transduction.

The biosynthesis of cantharidin appears to take place through a naturally occurring alcohol farnesol, though another possibility is in vivo synthesis beginning with mevalonic acid (4).

Figure 4. Farnesol, a linear sesquiterpene alcohol

Figure 5. Farnesol , 3-4 Model

(C = green, O = red and H = gray).

Oil soluble farnesol is prevalent in nature and may be extracted from a number of plants such as citronella, tuberose, ambrette, cyclamen and others. Having a delicate, pleasant fragrance, this alcohol is used in perfumery. As we have seen, blister beetles are voracious plant grazers and may acquire farnesol by ingestion. If this is so, it is not too difficult to visualize an internal synthesis somewhat like that of Fig. 6. (Any/all rearrangement steps are not known.) Beginning with farnesol three bonds are cleaved and oxygen is added.

Figure 6. Possible in vivo synthesis of cantharidin from farnesol (5).

In 1810, cantharidin was isolated from beetles in its crystalline form by Pierre-Jean Robiquet (1780-1840), a French chemist (who also isolated codeine from opium in 1832). He named the compound Kantharos (Greek), which means beetle. It is an odorless, colorless, crystalline solid with a melting point of 218°C. The stereochemistry of cantharidin was not shown until the early 1940s. It was successfully synthesized in the 1950s by the Belgium-American chemist, Gilbert Stork, starting with furan and dimethyl maleate. This classical synthesis required an eleven step procedure (steps not shown in Fig. 7).

Figure 7. Stork synthesis of cantharidin requires 11 steps (5).

After Stork, a few other workers synthesized cantharidin. However, it was not until University of California, Berkeley, chemist W. G. Dauben reported his successful results in 1976, that the procedure was reduced to two steps (Fig. 8). Dauben, a proponent of pressure reactions, utilized 15 kbar of pressure and hydrogen with nickel as the catalyst, to synthesize cantharidin.

Figure 8. Synthesis of cantharidin in only two steps.

Cantharidin in two steps! This was a huge improvement over eleven steps. However, the little blister beetle still achieves the same result without pressure, most likely with very few steps. How does he do it? Enzymes? Catalyst? We don't know. Perhaps in the future the complete in vivo synthesis will be clarified.

In the meantime, research reportedly continues in China with cantharidin in cancer treatment as some promise in that direction has apparently been seen. Drs. Thomas Eisner and James Carrel (4) have shown that the toxicity of cantharidin makes it a potentially useful biological control agent.

References

2. J. M. Langley, et al., Canadian Family Physician 49, 887-889, 2003.

3. http://www.nti.org/e_research/profiles/safrica/chemical/2440_3605.html

4. Thomas Eisner, For Love of Insects, Belknap, Harvard University, 2003.

5. J. P McCormack, J. E. Carrel and J. P. Doom, J. American Chemical. Society , 8071-8074, 1986.

6. Gerard Dupuis and Nicole Berlund, Cantharidin: Origin and Synthesis, Lycée Fridherbe, Lille, Fr.

Additional Reading

Arthur V. Evans, Charles L. Bellamy, Lisa Charles Watson, An Inordinate Fondness for Beetles, University of California Press, Berkeley, 1996.

Rick Imes, The Practical Entomologist, Fireside Book, Simon & Schuster, Inc., 1992.

Richard E. White, Beetles, Peterson Field Guides, Houghton Mifflin, 1983.