Podophyllum peltatum L. (May-apple)

English Common Names

May-apple, May apple, mayapple, American mandrake (not to be confused with the European mandrake, Mandragora officinarum L., a European plant used throughout history for medicines and potions), mandrake, wild mandrake, Devil's apple, Indian apple, ground-lemon (ground lemon), hog-apple, wild citron, wild lemon, yellow berry, duck's foot, raccoon berry, wild jalap, umbrella plant, vegetable calomel, vegetable mercury.

"Calomel" is mercurous chloride, which was used medicinally in early times; the names "vegetable calomel" and "vegetable mercury" reflect use of May-apple for the same medicinal purposes (Acorus calamus, treated in this work, has been referred to as "sweet calomel").

French Common Names

Citron sauvage, citronnier, ipécacuanha de la Caroline, pied de canard, podophylle pelté, podophylle à feuilles peltées, podophylle en bouclier, pomme de mai.

Morphology

An unusual perennial herb up to 60 cm tall, May-apple has one to three umbrella-shaped and deeply lobed leaves. The stems are produced from branched underground rhizomes about 6 mm thick and sometimes as long as a meter. These rhizomes are dark or reddish-brown, subcylindrical, with stem and leaf scars above and root scars below. They are yellowish-white internally, faintly odorous, and bitterly acrid in taste.

Generally in non-botanical literature for May-apple, the term "root" is applied collectively to the harvested rhizome and its attached roots. The solitary, waxy-white, nodding flowers are 2 to 4 cm across. Plants with pink flowers and maroon or red fruits (forma deamii Raymond) also appear rarely.

Flowering occurs in May in the north and the yellow, oval or roundish, mucilaginous, pulpy fruit, 2 to 4 cm across, ripens in July and August, turning from green to yellow.

The fruit is disagreeably scented when immature but considered pleasantly fragrant when ripe by most, and with an odd subacid, faintly strawberry flavour. Some people, however, find the ripe fruit nauseous, and as noted below the unripe fruit is poisonous. Rarely, plants may have a cluster of fruits (forma polycarpum Clute).

Classification and Geography

May-apple occurs throughout the eastern United States from southern New England to southern Minnesota south to eastern Texas and northern Florida. In Canada it is found throughout much of southern Ontario south of the Canadian Shield. It is frequent over much of its Ontario range.

In Quebec it is rare and occurs mostly along the upper St. Lawrence River. Quebec has designated the species as threatened, and in the province it may not be collected or destroyed, or possessed outside of its natural habitat, under penalty of substantial fines. Most of the few known populations in Quebec may have been introduced by North American Indians.

May-apple has persisted at various points where it has been introduced north of the natural range limit shown on the accompanying map, such as in the Gatineau Hills north of Ottawa and in Nova Scotia.

May-apple is one of several eastern North American plants that have very close relatives in eastern Asia. The similarity between the deciduous forests of eastern Asia and eastern North America, along with other evidence, suggests that a temperate deciduous forest, the arcto-tertiary flora, formed a continuous band around the northern hemisphere 15 to 20 million years ago.

This band was later fragmented by climatic cooling, uplift of mountains with isolation and rainshadow effects, and continental glaciations, the two major remaining fragments surviving in eastern Asia and eastern North America. At least four Asian species have been recognized.

The most important medicinal Asian relative is the Himalayan May-apple, Podophyllum hexandrum Royle (= P. emodi Wall.), a plant with shiny mottled leaves, erect, conspicuous and often pink flowers, red fruits, and a clumped instead of spreading habit. Another Asian species, P. pleianthum Hance, is also used medicinally.

Distribution Map

Ecology

May-apple occurs in moist, shady, deciduous, rich woodlands, forest edges, thickets and marshy meadows and ditches.

Moths and bumblebees are the likely pollinators. Canadian researchers have reported that the flowers do not produce nectar and that fruit and seed set is greater where May-apple plants grow close to flowering wood betony (Pedicularis canadensis L.) which produces nectar prolifically. The wood betony is a so-called "magnet species," attracting pollinators and thus facilitating the pollination of flowers of other species growing near it. May-apple fruit is eaten and dispersed by mammals, birds, and Eastern box turtles.

Medicinal Uses

North American Indians used May-apple as a purifying medicine to expel parasitic worms, and in the treatment of certain cancers, such as tumourous skin growths. A brew of powdered May-apple was employed as a laxative (the purgative action is very strong). The powder was also applied as a poultice to get rid of warts.

Settlers came to use May-apple for a variety of illnesses, including typhoid fever, cholera, dysentery, hepatitis, rheumatism, kidney, bladder and prostate problems, and venereal diseases.

In 1885 Canadian pioneer botanist Catharine Parr Traill reported that most Canadian physicians were using May-apple root in the treatment of complaints of the liver. This use persisted many years, for example in the well known Carter's liver pills.

The root of May-apple is the source of the powdered mixture of resins referred to pharmaceutically as Resina Podophylli -- resin of podophyllum or simply podophyllum. Highest activity occurs in the rhizomes just after the foliage is shed, and again in the early spring.

Since its discovery by Europeans, this poisonous plant has had many medicinal uses, especially internally as a digestive medicine, but also externally in treatment of sores and skin problems. Of particular interest is the fact that both the North American and the Asian May-apple contain anti-cancer agents.

At present, extracts of May-apple are used in topical medications for genital warts and some skin cancers.

Toxicity

The roots as well as the unripe fruit, seeds and leaves can be fatally poisonous. Recorded symptoms include vomiting, diarrhea, dizziness, headache, bloating, lowered blood pressure, hallucinations, loss of reflexes, confusion, and stupor.

Grazing animals avoid the plant because of its bitterness, but pigs have died after eating May-apple shoots.

May-apple should not be used during pregnancy, as it is teratogenic and can cause abortion (even topical application has caused minor fetal anomalies).

May-apple extract is sometimes applied to cervical warts, and can cause the development of atypical epithelial cells; a false positive PAP smear has been recorded 6 months after such topical application.

Extreme caution is recommended in the handling of May-apple. Fragments of root flicked into the eye during grinding can cause extreme swelling, internal bleeding, severe pain and temporary loss of sight. Even handling the rhizomes can cause dermatitis, and there are recorded cases of death following topical application.

May-apple is too toxic to attempt self-medication. May-apple is sold through mail-order nursery catalogues, and the potential danger of handling the plant is not always made clear.

Chemistry

Podophyllotoxins are called aliphatic alkaloids, which are functionally and structurally similar to alkaloids, with multiple rings, but lack nitrogen. These active principles are in the unripe fruit, the leaves and stem, and especially in the rhizome and roots. The rhizome and roots contain 3.5 to 6% of a resinous mixture, podophyllum resin or podophyllin.

Podophyllin, like the drug colchicine, arrests cell division through an effect on RNA and DNA synthesis during interphase, a property useful in treating cancer. Podophyllin also is responsible for the laxative effects of May-apple. The resin contains lignan glycosides, including about 20% podophyllotoxin, 10% alpha-peltatin and 5% beta-peltatin. These have anticancer and purgative properties. Podophyllotin blocks the release of iodine from the thyroid gland and the release of catecholamines from the adrenal medulla.

Synthetic and semisynthetic variations of the podophyllotoxin, known as epipodophyllotoxins, have been employed as anticancer agents; the most active are the drugs Teniposide and Etopiside (also known as Vepeside) from the cultivated Asian species, which are widely used to treat cancers.

Non-medicinal Uses

Although Harvard botanist Asa Gray described the fruit as "eaten by pigs and boys," most current books on edible wild plants report an agreeable taste. It must be remembered that the unripe fruits are not only bitter, but poisonous. The fully ripe fruits are claimed to make excellent jellies and marmalades. Drinks made by admixture with lemonade or Madeira wine are locally popular. The eminent student of medicinal plants James A. Duke coined the following ditty:

"Toxicologists may deem it an error,
To imbibe of May-apple Madeira.
But if the list was complete
Of the toxins we eat,
Perhaps we would all die of terror."

Agricultural and Commercial Aspects

In 1990 the market for drugs from May-apple was worth over 100 million dollars. Both the Eurasian and the North American May-apples are an important source of anti-cancer drugs, on a par with Madagascar periwinkle and species of yew.

May-apple is currently an ingredient of prescription drugs sold in the United States and is used in at least seven Canadian drug products. The supply is obtained exclusively from material collected in the wild, mostly in Indiana, Kentucky, North Carolina, Tennessee, and Virginia. The roots are collected in the autumn and dried. Several hundred tonnes are collected annually for both domestic and international markets.

Since the demand is increasing, harvesting from the wild is laborious, and drug content of wild plants is variable, it has been suggested that high-yielding clones be identified and cultivated. Although seed germination presents problems, the plants are readily grown from root divisions.

Myths, Legends, Tales, Folklore, and Interesting Facts

• May-apple sometimes forms circles of plants (fairy rings) like some mushrooms and ferns.
• E.M. Frieders (cited in World Wide Web Links, below) wrote: "The small edible fruits are lemon-shaped and are yellowish in color (so why mayapple and not maylemon, I ask?)."

Selected References

• Bedows, E., and Hatfield, G.M. 1982. An investigation of the antiviral activity of Podophyllum peltatum. J. Nat. Prod. 45: 725-729.
  
  
• Bennet, R.G., and Grist, W.J. 1985. Nasal papillomas: sucessful treatment with podophyllin. South. Med. J. 78: 224-225.
  
  
• Bhadula, S.K., Singh, A., Lata, H., Kuniyal, C.P., and Purohit, A.N. 1996. Genetic resources of Podophyllum hexandrum Royle, an endangered medicinal species from Garhwal, Himalaya, India. Plant Genet. Resourc. Newsl. 106: 26-29.
  
  
• Chandler, R.F. 1990. Podophyllum. Can. Pharm. J. 123: 330-331, 333.
  
  
• Chatterjee, R. 1952. Indian Podophyllum. Econ. Bot. 6: 342-354.
  
  
• Couillard, L., and Forest, G. 1998. Espèces menacées au Québec - Le podophylle pelté. Gouvernement du Québec, Ministère de l'Environnement et de la Faune, Direction de la conservation et du patrimoine écologique, Québec. 4 pp.
  
  
• Demaggio, A.E., and Wilson, C.L. 1986. Floral structure and organogenesis in Podophyllum peltatum (Berberidaceae). Am. J. Bot. 73: 21-32.
  
  
• Duke, J.A. 1983. The marvelous mayapple. Bot. Grower (Newsl.) 1(1): 3-4.
  
  
• Ernst, W.R. 1964. The genera of Berberidaceae, Lardizabalaceae, and Menispermaceae in the southeastern United States. J. Arnold Arbor. 45: 1-35.
  
  
• Fisher, AA. 1981. Severe systemic and local reactions to topical podophyllum resin. Cutis 28: 233.
  
  
• Geber, M.A., De-Kroon, H., and Watson, M.A. 1997. Organ preformation in mayapple as a mechanism for historical effects on demography. J. Ecol. 85: 211-223.
  
  
• George, L.O. 1997. Podophyllum. In Flora of North America north of Mexico, Vol. 3. Edited by Flora of North America Editorial Committee. Oxford University Press, New York, NY. pp. 287-288.
  
  
• Graham, N.A., and Chandler, R.F. 1990. Herbal medicine - Podophyllum. Can. Pharm. J. 123: 330-333.
  
  
• Jackson, D.E., and Dewick, P.M. 1984. Aryltetralin lignans from Podophyllum hexandrum and Podophyllum peltatum. J. Phytochem. 23: 1147-1152.
  
  
• Kelly, M.G., and Hartwell, J.L. 1954. The biological effects and the chemical composition of podophylloton. A review. J. Nat. Cancer Inst. 14: 967-1010.
  
  
• Krochmal, A., Wilkins, L.,Van Lear, D., and Chien, M. 1974. Mayapple, Podophyllum peltatum L. USDA Forest Service Research Paper NE-296. U.S. Department of Agriculture, Upper Darby, PA. 9 pp.
  
  
• Kroon, H., Whigham, D.F., and Watson, M.A. 1991. Developmental ecology of mayapple: effects of rhizome severing, fertilization and timing of shoot senescence. Ecology 5: 360-368.
  
  
• Kutney, J.P., Arimoto, M., Hewitt, G.M., Jarvis, T.C., and Sakata, K. 1991. Studies with plant cell cultures of Podophyllum peltatum L. I. Production of podophyllotoxin, deoxypodophyllotoxin, podophyllotoxin, and 4'-demethylpodophyllotoxin. Heterocycles (Tokyo) 32: 2305-2309.
  
  
• Laverty, T.L. 1992. Plant interactions for pollinator visits: a test of the magnet species effect. Oecologia 89: 502-508.
  
  
• Laverty, T.M., and Plowright, R.C. 1986. Fruit and seed set in mayapple (Podophyllum peltatum): influence of intraspecific factors and local enhancement near Pedicularis canadensis. Can. J. Bot. 66: 173-178.
  
  
• McFarland, M.F., III, and McFarland, J. 1981. Accidental ingestion of Podophyllum. Clin. Toxicol. 18: 973-977.
  
  
• Meijer, W. 1974. Podophyllum peltatum -- May Apple a potential new cash-crop plant of Eastern North America. Econ. Bot. 28: 68-72.
  
  
• Miller, R. 1985. Podophyllin. Int. J. Dermatol. 24: 491-498.
  
  
• Montgomery, F.H. 1965. Poisonous fruits. Federation of Ontario Naturalists, Edward Gardens, Don Mills, ON. 24 pp.
  
  
• Rosenstein, G., Rosenstein, H., Freeman, M., and Weston, N. 1976. Podophyllum -- a dangerous laxative. Pediatrics 57: 419-421.
  
  
• Rust, R.W., and Roth, R.R. 1979. Seed production and seedling establishment in the mayapple, Podophyllum peltatum L. Am. Midl. Nat. 105: 51-60.
  
  
• Sadowska, A., Wiweger, M., Lata, B., and Obidoska, G. 1997. In vitro propagation of Podophyllum peltatum L. by the cultures of embrya and divided embrya. Biol. Plant. 39: 331-336.
  
  
• Sohn, J.J., and Policansky, D. 1977. The cost of reproduction in the mayapple Podophyllum peltatum (Berberidaceae). Ecology 58: 1366-1374.
  
  
• Taylor, C., and Taylor, J. 1964. Podophyllum peltatum f. Deamii from Bryan County, Oklahoma. Rhodora 66: 167.
  
  
• Von Krogh, G. 1981. Podophyllotoxin for condyloma acuminatum eradication. Acta Derm. Venereol. 98 (Suppl.):1-48
  
  
• Whisler, S.L., and Snow, A.A. 1992. Potential for the loss of self-incompatibility in pollen-limited populations of mayapple (Podophyllum peltatum). Am. J. Bot. 79: 1273-1278.