Mayapple

Other Names

American MandrakeAnapodophyllum canadenseAnapodophyllum canadense moriniAnapodophyllum peltatumDevil's AppleDuck's FootGround LemonHog AppleIndian AppleIndian Apple RootLemon AppleMandrakeMay ApplePodophyllum callicarpumPodophyllum montanumPodophyllum peltatumPodophyllum peltatum f. aphyllumPodophyllum peltatum f. biltmoreanumPodophyllum peltatum f. callicarpumPodophyllum peltatum f. deamiiPodophyllum peltatum var. annulareRaccoonberryUmbrella LeafUmbrella PlantVegetable CalomelVegetable MercuryWild LemonWild Mandrake

Synopsis

Mayapple (Podophyllum peltatum): A Comprehensive Reference

1. Identity, Botanical Classification, and Natural Source

Podophyllum peltatum is a North American herbaceous perennial plant in the family Berberidaceae. Its common names include mayapple, American mandrake, wild mandrake, and ground lemon. Additional vernacular names recorded in the botanical and ethnobotanical literature include raccoonberry, hog apple, devil's apple, duck's foot, Indian apple, wild lemon, and vegetable mercury.

The plant was formally named by Linnaeus; Podophyllum translates, somewhat cryptically, as "foot leaf," while the species epithet peltatum refers to the way petioles join at the middle of the leaf blade rather than at its margin. Current taxonomy recognizes just a single species in the genus Podophyllum; several Asian species formerly classified in Podophyllum now constitute the genera Dysosma and Sinopodophyllum.

The geographic range of Podophyllum peltatum is largely congruent with the boundaries of the eastern deciduous forest. It occurs from New England west through the Great Lakes and south to forested eastern Texas, and is infrequent along the Gulf Coast. Mayapples are woodland plants, typically growing in colonies derived from a single root.

Morphology

The stems grow to 30–40 cm tall, with palmately lobed umbrella-like leaves up to 20–40 cm in diameter with 3–9 shallowly to deeply cut lobes. The plants produce several stems from a creeping underground rhizome; some stems bear a single leaf and do not produce any flower or fruit, while flowering stems produce a pair or more leaves with 1–8 flowers in the axil between the apical leaves. The flowers are white, yellow, or red, 2–6 cm in diameter with 6–9 petals, and mature into a green, yellow, or red fleshy fruit 2–5 cm long.

The upright stems grow from a shallow, creeping, branched underground rhizome, composed of many thick dark or reddish-brown tubers connected by fleshy fibers and downward-spreading roots at the nodes.

Medicinal Part and Common Preparations

As defined in pharmacognosy references, "podophyllum" in the pharmaceutical sense consists of the dried rhizomes and roots of Podophyllum peltatum Linn., belonging to family Berberidaceae, known as American Mandrake or May-apple root. The rhizomes contain 2–8% of a resinous material termed podophyllin. The dried rhizome and root, the alcohol-extracted resin (podophyllin), and the isolated purified compound podophyllotoxin are the principal forms used medicinally. Each flower gives way to an edible, fleshy, greenish fruit that turns golden when ripe and may be used to make preserves and jellies. Leaves and roots are poisonous, however.

2. Traditional and Historical Use

Indigenous North American Use

Mayapple has been used by Indigenous Americans as an emetic, cathartic, and anthelmintic agent; the rhizome was used for a variety of medicinal purposes, originally by indigenous inhabitants and later by other settlers. Native American tribes used it to treat snake bites and warts, to induce vomiting, to destroy parasitic worms, and even as a suicidal agent. Native Americans used Podophyllum for a wide variety of medicinal purposes and as an insecticide.

Samuel Champlain noted Huron tribes eating the fruit in 1616, and shortly thereafter the plant was collected and cultivated in gardens in Europe. As early as 1731, Mark Catesby described the medicinal use of American mayapple root in his Natural History of the Carolinas.

European Settler and Early American Medical Use

Linnaeus gave the plant its official scientific name, Podophyllum peltatum, in his 1753 publication Species Plantarum. American Indians and colonists used podophyllum resin as a cathartic and anthelmintic, an antidote for snake bite, and as a poison. The first report in medical literature was in 1731 by Catesby.

The United States Pharmacopeia has listed Podophyllum peltatum as a purgative and anthelmintic since its founding in 1820. Specifically, the dried rhizome and roots appeared on the USP from 1820 to 1841 and again from 1955 to the 1970s, with the resin on the USP from 1863 to 1942 and again from 1955 into the 1970s.

Eclectic Medicine

The introduction of podophyllin to the medical profession by Prof. John King, who first prepared it and indicated its therapy, marks an epoch in the history of Eclectic medicine. Podophyllum was one of the earliest favorites of that school of practice. Eclectic physicians considered it one of the most stimulating and powerful alteratives available. It was held to act strongly on the liver and intestines as a potent cholagogue, stimulating peristalsis significantly, and was used to relieve atonic constipation, hepatic congestion, dyspepsia, and gallbladder dysfunction.

Podophyllin, the crude resin obtained from the rhizomes and roots, was subsequently employed as a purgative, but usage declined until 1942, when podophyllin was recommended for the treatment of venereal warts. At some point, the mayapple resin extracted from the rhizome was considered one of the most powerful laxatives available, and it was even sold commercially (Carter's Little Liver Pills in the early 1900s), but because of toxicity this use was discontinued.

Mid-20th-Century Pharmaceutical History

By the mid-19th century, topical use of podophyllin to treat malignant growths was recognized. In 1942, a paper was published on the successful use of Podophyllum peltatum to treat genital warts; since then, studies have shown that it can also be used to treat psoriasis and as an antineoplastic and antiviral agent. The Food and Drug Administration approved the topical use of podophyllum resin for the treatment of condyloma acuminatum in 1990.

3. Key Constituents and Active Compounds

The Podophyllin Resin Complex

The resin prepared from the dried rhizome and roots of Podophyllum peltatum contains podophyllotoxin, α-peltatin, and β-peltatin. The peltatins are present only in the American podophyllum. Extensive chemical investigation of Podophyllum species has revealed the presence of a resin called podophyllin, which contains several lignans with pharmacological properties. These include podophyllotoxin, epipodophyllotoxin, podophyllotoxone, flavonoids such as quercetin, quercetin-3-glycoside, 4-demethylpodophyllotoxin, podophyllotoxin glucoside, 4-dimethylpodophyllotoxin glucoside, kaempferol, kaempferol-3-glucoside, deoxypodophyllotoxin, picropodophyllotoxin, isopicropodophyllone, 4-methyl deoxypodophyllotoxin, α-peltatin, and β-peltatin.

Podophyllotoxin: The Primary Active Lignan

Podophyllotoxin is a nonalkaloid toxin lignan extracted from the roots and rhizomes of Podophyllum species, with important antineoplastic and antiviral properties. It is characterized by its molecular formula C₂₂H₂₂O₈ and antimitotic activity through inhibition of tubulin polymerization, which disrupts microtubule formation and cell division.

Indian podophyllum (P. emodi) is preferred to American podophyllum (P. peltatum) as a commercial source because it gives more resin richer in podophyllotoxin. The content of podophyllotoxin is about 4.3% of dry weight in P. emodi against 0.25% in P. peltatum. An extraction process based on rehydration of powdered tissues of P. peltatum prior to extraction with organic solvent, allowing endogenous β-glucosidases to hydrolyze lignans, can increase the yield of podophyllotoxin of rhizomes and leaves to about 5.2% of dry weight. The leaves of P. peltatum are notably a rich source of podophyllotoxin, storing lignans as glucopyranosides.

Flavonoids and Other Constituents

The rhizome also contains flavonoids including kaempferol, quercetin, and their glycosides. Other compounds identified include desmethyl podophyllotoxin, desoxypodophyllotoxin, podophyllotoxone, the flavonoid quercetin, and starch.

4. Mechanisms of Action

Podophyllotoxin Itself: Antimitotic via Tubulin Inhibition

By itself, (−)-podophyllotoxin inhibits microtubule assembly, thus leading to cell cycle arrest. The compound's pharmacological mechanism involves binding to tubulin, preventing its assembly into microtubules essential for mitosis, thereby inducing cell cycle arrest in the G2/M phase and apoptosis. Podophyllin is a cytotoxic agent used topically in the treatment of genital warts; it arrests mitosis in metaphase, an effect it shares with other cytotoxic agents such as the vinca alkaloids.

Semisynthetic Derivatives (Etoposide and Teniposide): Topoisomerase II Inhibition

Etoposide and teniposide were shown not to be inhibitors of microtubule assembly, which suggested that their antitumor properties were due to another mechanism of action — via their interaction with DNA and inhibition of DNA topoisomerase II. The primary action mode of the epipodophyllotoxins is to inhibit the catalytic activity of topoisomerase II by stabilizing the covalent topoisomerase II–DNA cleavable complex, causing DNA strand breaks and eventually leading to cell death.

Etoposide, a semi-synthetic derivative of podophyllotoxin, exerts anticancer effects by inhibiting topoisomerase II, an enzyme essential for DNA replication and cell division. By stabilizing the enzyme–DNA complex, etoposide induces DNA strand breaks, promoting apoptosis in rapidly dividing cancer cells. Etoposide and teniposide are phase-specific cytotoxic drugs acting in the late S and early G2 phases of the cell cycle.

Cathartic and Gastrointestinal Mechanism

When taken by mouth, podophyllin has a drastic laxative action and produces violent peristalsis. It acts strongly on the liver and intestines and is a potent cholagogue, stimulating peristalsis significantly; it was traditionally used to relieve atonic constipation, hepatic congestion, dyspepsia, and gallbladder dysfunction.

5. Scientific Evidence by Area of Use

5.1 Topical Treatment of Genital Warts (Condyloma Acuminata)

Podophyllotoxin (PPT, C₂₂H₂₂O₈) is an arylnaphthalene lignan present in podophyllin, a resin generated by the genus Podophyllum, a member of the Berberidaceae family. In 1820, PPT was included in the US Pharmacopoeia due to its biological activities, and it is considered the most plentiful and effective constituent isolated from podophyllin. It has been used in dermatology with a long history; in particular, 0.5% podophyllotoxin tincture was identified as a first-line drug for genital wart treatment by the US FDA.

Key clinical evidence: A randomized controlled trial evaluated the efficacy and cost-effectiveness of self-applied podophyllotoxin 0.5% solution and podophyllotoxin 0.15% cream, compared to clinic-applied 25% podophyllin in the treatment of genital warts over 4 weeks, conducted in 358 immunocompetent men and women with genital warts of 3 months' duration or less. In the principal analysis, both podophyllotoxin solution (OR 2.93, 95% CI 1.56 to 5.50) and podophyllotoxin cream (OR 1.97, 95% CI 1.04 to 3.70) were associated with significantly increased odds of remission of all warts compared to podophyllin. Local side effects were seen in 24% of subjects, and recurrence of warts within 12 weeks of study entry occurred in 43% of all initially cleared subjects, without statistically significant differences between treatment groups.

Podophyllotoxin (podofilox, Condylox) is an FDA-approved drug; podophyllotoxin may be more effective than podophyllum resin and is less toxic. Applying podophyllum resin (podophyllin) as a 10% to 25% suspension in tincture of benzoin or as a 2% to 4% gel directly to the affected area is effective for the removal of warts caused by human papillomavirus. The evidence base for topical podophyllotoxin in genital warts is strong, consisting of multiple randomized controlled trials; the crude podophyllin resin is considered less well-standardized and more variable in composition. The American source of podophyllin normally contains one-fourth the amount of podophyllotoxin as the Indian source.

5.2 Anticancer Applications via Semisynthetic Derivatives (Etoposide, Teniposide)

The PTOX derivatives etoposide (VP-16) and teniposide (VM-26) have been approved by the US Food and Drug Administration (FDA) for cancer treatment. Etoposide is among the World Health Organization's list of essential medicines and is derived from podophyllotoxin. Podophyllotoxin is semisynthetically converted to etoposide, which is mainly used for the treatment of lung and testicular cancer.

Due to its ability to selectively target tumor cells with high proliferative indices, etoposide has become a cornerstone of lung cancer treatment regimens, particularly in combination therapies. Extensive studies have revealed that PTOX derivatives can induce cell cycle G2/M arrest and DNA/RNA breaks by targeting tubulin and topoisomerase II, respectively. Numerous PTOX derivatives have been developed to address the major limitations of PTOX, such as systemic toxicity, drug resistance, and low bioavailability.

It is important to note that the well-characterized anticancer evidence base applies to the semisynthetic pharmaceutical derivatives etoposide and teniposide — not to crude mayapple extract or podophyllin itself. The parent compound podophyllotoxin was found to be too toxic for systemic clinical use, which drove the development of these derivatives.

5.3 Oral Hairy Leukoplakia

Podophyllum has been used topically to treat genital warts and hairy leukoplakia; however, clinical data are limited and toxicity of components limits use.

Clinical evidence: Nine patients with oral hairy leukoplakia seen at the Oral Medicine Clinic, University of California San Francisco, were offered treatment with podophyllum resin 25% solution. Topical therapy with podophyllum resin 25% solution usually achieves resolution after one or two applications, though treatments may temporarily cause local pain, discomfort, and alteration of taste. Podophyllum resin has cellular cytotoxic effects, but its mechanism of action in resolving oral hairy leukoplakia has not been elucidated. As with antiviral therapy, oral hairy leukoplakia often recurs several weeks after successful podophyllin therapy.

A randomized clinical trial compared the efficiency of topical applications of podophyllin resin (25%) versus podophyllin resin (25%) combined with acyclovir cream (5%) in the treatment of oral hairy leukoplakia. Forty-six OHL lesions were treated, with applications performed weekly. All 24 lesions from the combination group presented total clinical resolution while 4 lesions from the podophyllin-alone group did not. The podophyllin-alone group required up to 25 weekly applications while the combination group required up to 18. Evidence for this indication is rated as preliminary and limited by small sample sizes and the absence of placebo-controlled trials.

5.4 Purgative and Gastrointestinal Use

Podophyllum resin has been used as a drastic purgative and as a hydragogue cathartic. This use is now considered unsafe due to toxicity. Use as a cathartic or purgative is considered unsafe. Toxicity precludes home use of podophyllum; products for oral use have been withdrawn from the market for various safety reasons.

5.5 Antiviral Activity

The podophyllotoxin extract has been documented for its use as a remedy for various medical complications, including gonorrhea, tuberculosis, menstrual disorders, psoriasis, syphilis, and venereal warts. The podophyllotoxin family is now confirmed to elicit various curative properties, including mitotoxic, antimicrobial, anti-inflammatory, antispasmogenic, hypolipidemic, immunosuppressive, antioxidative, analgesic, and cathartic activities. However, most of this evidence is preclinical; direct antiviral effects in clinical settings remain inadequately studied via controlled trials.

6. Body Systems and Health Areas Associated with Mayapple

Dermatology and integument: Treatment of genital warts (condyloma acuminata), plantar warts, and other papillomavirus-related lesions; oral hairy leukoplakia; historically, psoriasis and skin ulcers.
Oncology: Via semisynthetic derivatives etoposide and teniposide — lung cancer, testicular cancer, lymphomas, and other neoplasms. Well-known for its use in the treatment of non-Hodgkin's lymphoma, lung cancer, and genital tumors.
Gastrointestinal system: Historical cathartic, purgative, cholagogue, and anthelmintic uses.
Hepatic system: Eclectic physicians categorized it as a liver stimulant and hepatic alterative.
Immunology/Infectious disease: Historical use for snake bite, antiparasitic applications, and antiviral properties.

7. Dosage Forms and Dosages Reported in Sources

For genital warts caused by the human papillomavirus: a 0.5% podophyllotoxin gel is applied twice daily for three days in a row and repeated for two to four cycles. Podophyllotoxin is a chemical taken from podophyllum.

Podophyllum resin applied as a 10% to 25% suspension in tincture of benzoin, or as a 2% to 4% gel, directly to the affected area has been reported for the removal of HPV warts.

Topical preparations of podophyllum require professional application and must be rinsed off after 1 to 4 hours.

Topical therapy with podophyllum resin 25% solution for oral hairy leukoplakia usually achieves resolution after one or two applications.

In clinical trial settings for oral hairy leukoplakia, 25% podophyllin resin was used topically, applied weekly.

In the context of the semisynthetic derivative etoposide for oncology, dosing is conducted under physician supervision and established pharmaceutical protocols. These dosages are entirely distinct from any dietary supplement use of the crude plant.

8. Safety Considerations

General Toxicity Profile

The remainder of the plant (beyond the ripe fruit) contains podophyllotoxin, a potent toxin that renders it poisonous, causing severe gastrointestinal distress, dermatitis, and potential neurotoxicity if ingested. All parts of the plant, except the fruit, contain podophyllotoxin, which is highly toxic if consumed.

Fatalities have occurred following the ingestion or topical application of podophyllum. Clinical signs appear within 12 hours and include altered mental state, tachypnea, peripheral neuropathy, nausea, hypotension, vomiting, and fever. Muscle paralysis with respiratory failure, renal failure, hallucinations, and seizures have also been reported.

Neurological Toxicity

Intoxications with podophyllin have resulted in peripheral neurological side-effects such as autonomic neuropathy, sensorimotor peripheral neuropathy, and acute ataxic sensory neuronopathy. Ingestion of large doses can result in severe neuropathic toxicity.

Topical Use Hazards

When applied topically, podophyllin is a strong irritant to the skin and mucous membranes and can lead to poisoning because of systemic absorption. Topical application may cause skin irritation and chemical burns. Application to the inside of the mouth may cause transient burning, unpleasant taste, and pain.

Oral Use and Product Withdrawal

Toxicity precludes home use of podophyllum resin derived from P. peltatum and P. hexandrum; products for oral use have been withdrawn from the market for various safety reasons. The clinical practicality of podophyllotoxin was largely hampered by undesirable secondary effects such as gastrointestinal toxicity, neurotoxicity, hair loss, and bone marrow suppression, which led to the development of less-toxic derivatives or analogues.

Pregnancy and Lactation

The oral and local use of the resin should be avoided during pregnancy, as this has been associated with teratogenicity and fetal death. Birth defects, fetal death, and stillbirth have been associated with the use of podophyllum during pregnancy. Excretion into breast milk and effects on breastfeeding infants are unknown; use during breastfeeding should be avoided.

Chronic Use

Chronic use of mayapple as a cathartic has been associated with hypokalemia and metabolic acidosis.

Drug Interactions

No well-documented drug interactions with podophyllum have been established in the sources reviewed. The toxicity profile of the plant is nevertheless severe enough to make any concurrent use with other medications requiring medical supervision.

Confusion with European Mandrake

Podophyllum peltatum should not be confused with the European or Mediterranean Mandrake, Mandragora officinarum, which has anticholinergic properties. Mistaken identity between the two has been documented in case reports.

Regulatory Status

In clinical applications, podophyllotoxin itself, marketed as podofilox (0.5% topical solution or gel), received FDA approval in 1990 and 1997 for treating external genital warts. The Food and Drug Administration approved the topical use of podophyllum resin for the treatment of condyloma acuminatum in 1990. Oral dietary supplement use of crude mayapple or its resin is not approved by the FDA, and oral products have been withdrawn from the market.

References

Health Conditions

Health conditions that Mayapple may help support.

No conditions available.

Body Systems

Body systems that Mayapple may help support.

No body systems available.