Podophyllum

Other Names

AindriAmerican MandrakeAmerican PodophyllumAnapodophyllum peltatumBa Jiao LianBankakariBantrapushiBehenCitron SauvageCitronnierDevil's AppleDuck's FootDysosmaFuss-blattwurzelGiriparpatGround LemonGwai KouHimalayan MayappleHog AppleIndian AppleIndian MayappleIndian PodophyllumIpécacuanha de la CarolineKakhriLaghu PatraLemon AppleMandrakeMay AppleMayappleOl mo sePa Giao LianPecaPied de CanardPodofilloPodófiloPodofiloPodophyllePodophylle à Feuilles PeltéesPodophylle en BouclierPodophylle IndienPodophylle PeltéPodophylli RhizomaPodophyllinPodophyllum callicarpumPodophyllum emodiPodophyllum hexandrumPodophyllum montanumPodophyllum peltatumPodophyllum RootPomme de MaiRaccoon BerryRhizome de PodophyllumSinopodophyllum emodiSinopodophyllum hexandrumUmbrella LeafUmbrella PlantVegetable CalomelVegetable MercuryWild JalapWild LemonWild Mandrake

Synopsis

Podophyllum: A Comprehensive Reference

1. Identity and Botanical Description

Podophyllum is the collective pharmacognostic designation for the dried rhizomes and roots of two principal species: Podophyllum peltatum Linnaeus (American mayapple) and Podophyllum hexandrum Royle — also known as Sinopodophyllum hexandrum (Royle) T.S. Ying — the Himalayan or Indian mayapple. Podophyllum consists of the dried rhizomes and roots of Podophyllum peltatum Linn., belonging to the family Berberidaceae. The name itself is derived etymologically from the Greek: podos (a foot) and phyllon (a leaf), referring to the resemblance of the leaves to a duck's foot.

Podophyllum peltatum is a North American herbaceous perennial plant in the family Berberidaceae, with common names including mayapple, American mandrake, wild mandrake, and ground lemon. Mayapples are woodland plants, typically growing in colonies derived from a single root. 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.

Podophyllum peltatum is indigenous to the eastern part of the United States and Canada, and grows wildly in Virginia, North Carolina, Kentucky, Indiana, and Tennessee. It is a perennial herb which grows wildly in moist and shady places.

Podophyllum hexandrum Royle (syn. P. emodi Wall. ex-Hook f. Thomas), belonging to the Berberidaceae family, is a medicinal plant of great importance. It is commonly known as Indian May apple or Himalayan May Apple. It is mentioned by the name Bantrapushi in Ayurveda and is also known by other names like Bankakari and Giriparpat (India), Laghu Patra (Nepal), and Kakhri (Pakistan). P. hexandrum is distributed from Indian Himalayas to Bhutan, Pakistan, Afghanistan, Nepal, Taiwan, and China; in Pakistan it is found in the Himalayan zone, Gilgit, Chitral, and Azad Kashmir regions at 2,000 to 4,000 m altitude.

The broader tribe Podophylleae encompasses additional species. Currently there are four genera — Podophyllum, Sinopodophyllum, Diphylleia, and Dysosma — with 13 species in the tribe Podophylleae.

Common Names and Synonyms

Podophyllum peltatum — mayapple, mandrake, raccoon berry, wild lemon
Podophyllum hexandrum — Indian May apple, Himalayan May Apple; known as Bantrapushi or Bankakari in Ayurveda
Podophyllum Rhizome, May-apple Root, Wild Mandrake

Common Preparations and Forms

Podophyllin (Podophyllum Resin): Podophyllum rhizomes contain 2–8% resinous material termed as podophyllin. This crude resin is the traditional pharmaceutical form.
Purified podophyllotoxin (Podofilox): Podophyllotoxin (PPT) is the active ingredient in Podofilox, a medical cream used to treat genital warts and molluscum contagiosum.
Standardized solution and cream: Available as 0.5% topical solution or 0.15% cream for patient self-application, or as 25% podophyllin resin in compound tincture of benzoin applied by a clinician.
Semisynthetic pharmaceutical derivatives: Podophyllotoxin is the precursor of two antineoplastic agents, etoposide and teniposide, and of other analogs useful as antiviral agents.
Posalfilin: Posalfilin is a drug containing podophyllin and salicylic acid that is used to treat the plantar wart.

2. Traditional and Historical Use

Native American and Early North American Use

Linnaeus gave the plant its official scientific name, Podophyllum peltatum, in his 1753 publication Species Plantarum. A perennial herb native to moist woodland edges from southern New England south to Georgia and west to Texas, mayapple became popular not just for its beautiful flower, edible fruit, and horticultural novelty, but also for the medicinal properties of its root.

Mayapple has been used by Indigenous Americans as an emetic, cathartic, and anthelmintic agent. The rhizome of the mayapple has been used for a variety of medicinal purposes, originally by indigenous inhabitants and later by other settlers. Samuel Champlain noted Huron tribes eating the fruit in 1616, and shortly thereafter it 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.

The drug has long been used by the North American Indians as a vermifuge and emetic, and was introduced into the 1864 Pharmacopoeia. Podophyllin, a crude resin obtained from the rhizomes and roots, was subsequently employed as a purgative, but usage declined until in 1942 podophyllin was recommended for the treatment of venereal warts. Since then, extensive research has led to an appreciation of podophyllum's antitumour properties and the development of successful anticancer agents.

Some pharmaceuticals were originally discovered in the course of investigations of botanicals that were used by Native Americans for medicinal purposes. Examples are taxol, obtained from Taxus brevifolia (Pacific yew tree), and etoposide phosphate, a derivative of podophyllotoxin, which is a constituent of Podophyllum peltatum (May apple or American mandrake). Both are currently used for the treatment of various malignancies.

Ayurvedic and Himalayan Traditions (Podophyllum hexandrum)

Podophyllum hexandrum has been described as a divine drug in the Indian traditional system of medicine, the Ayurveda, and has also been used in the traditional Chinese system of medicine for the treatment of a number of ailments. It was known as Aindri (a divine drug) in ancient times; its name in Hindi and Ayurveda is bantrapushi or Giriparpat.

It has been reported to be used through the ages and in modern times as an intestinal purgative and emetic, salve for infected and necrotic wounds, and inhibitor of tumor growth. The rhizome of the plant contains a resin, known generally and commercially as Indian Podophyllum Resin, which can be processed to extract podophyllotoxin or podophyllin, a neurotoxin.

In Unani medicine the plant species has been used to treat various ailments like constipation, fever, jaundice, liver disorders, syphilis, and diseases of lymph glands. The podophyllotoxin extract has been documented for its use as a laxative, and as a remedy for various medical complications such as gonorrhea, tuberculosis, menstrual disorders, psoriasis, dropsy, cough, syphilis, and venereal warts.

Conservation Status

Ever-increasing demand for the drug in modern medicine, coupled with its existing use in the traditional system of medicine, has resulted in ruthless uprooting of the underground parts of the plant leading to intense collection and the lack of organized cultivation. Consequently, P. hexandrum has been declared an endangered species. It is categorized as a globally rare plant in the IUCN Red List.

3. Key Constituents and Active Compounds

Lignan Profile

Podophyllum rhizomes contain 2–8% resinous material termed podophyllin. The major constituents of podophyllum resin are the lignan derivatives characterized as podophyllotoxin, α-peltatin, and β-peltatin. The lignans are found in the form of glycosides and also as their free aglycones. It also contains desmethylpodophyllotoxin, desoxypodophyllotoxin, podophyllotoxone, a flavonoid quercetin, and starch.

Peltatins are present only in the American Podophyllum. Podophyllin contains approximately 16 chemicals including podophyllotoxin, alpha- and beta-peltatin, desoxypodophyllotoxin, and quercetin.

Podophyllotoxin: Primary Active Compound

Podophyllotoxin (PPT) is an aryltetralin lignan primarily found in the rhizomes of Sinopodophyllum hexandrum and Podophyllum peltatum. It is a crystalline polycyclic compound with an empirical formula C₂₂H₂₂O₈ and a molecular weight of 414.41 m/z. Podophyllotoxin was first isolated from Podophyllum peltatum by Podwyssotzki in 1884 as crystals, and its structure was elucidated until 1930. Its correct structure was definitively assigned in 1951.

Podophyllotoxins are not only found in typical species such as Podophyllum peltatum L. and Podophyllum emodi Wall., but can also be found in other genera, including Sinopodophyllum, Diphylleia, and Dysosma (Berberidaceae), Polygala (Polygalaceae), Anthriscus (Apiaceae), Linum (Linaceae), Juniperus, Callitris and Thujopsis (Cupressaceae), and others. Hitherto, more than ninety podophyllotoxins have been identified.

Flavonoids and Other Compounds

Prenylated flavonoids, flavonoid glycosides, and labdane diterpenes are isolated from the fruits of Sinopodophyllum hexandrum. Quercetin and kaempferol are more abundant in samples from certain geographic regions, while podophyllotoxin and lignan production is favored in others. There are approximately 43 chemical constituents including 26 lignans, 9 flavonoids, and 8 other constituents identified across the 12 species studied in the tribe.

4. Mechanisms of Action

Microtubule Inhibition

Podophyllotoxin's pharmacological effects have been recognized to involve inhibiting microtubule assembly by blocking the colchicine binding site, thereby exhibiting inhibition of microtubule protein polymerization and inducing G2/M blockade. PPT and its derivatives are known to bind to the β-subunit colchicine structural domain of tubulin. This binding inhibits the polymerization of tubulin, thereby preventing the formation of the prophase spindle during mitosis.

Topoisomerase II Inhibition

At the molecular mechanism level, PTOX and its derivatives exhibit significant anticancer effects by inhibiting tubulin and DNA topoisomerase II, respectively, leading to cell cycle arrest and DNA breakage. PPT has inhibited topoisomerase II enzyme, arrested the cell cycle at G2 phase, caused DNA damage, and induced apoptosis by direct inhibition of protein tyrosine kinase.

Importantly, the two mechanisms are structurally separable. As a consequence of structural changes, the mechanism of cytotoxic action of etoposide changes with respect to podophyllotoxin. The natural product binds to the colchicine site on the β-subunit of tubulin in the interface of α- and β-monomers, leading to the inhibition of tubulin polymerization; etoposide, by contrast, inhibits the enzyme topoisomerase II, intervening in the cell cycle at an earlier stage of replication but also blocking cell cycle at the mitotic stage.

Antiviral Activity

Podophyllotoxin possesses a large number of medical applications, as it inhibits replication of both cellular and viral DNA by binding necessary enzymes. This underlies its clinical utility in treating HPV-associated warts topically, where its anti-proliferative action on virally infected keratinocytes drives wart regression.

Effects on Mitochondria and Cellular Respiration

Podophyllin is neurotoxic; the exact mechanism of action on the nervous system is not fully understood, but may be related to its toxic effects on cell respiration. Podophyllin has a direct toxic effect on mitochondria, reducing the activity of electron transport enzymes, cytochrome oxidase, and succinoxidase. Podophyllin's teratogenic effects and anticancer activity are thought to be related to its toxic effects on cell division and nucleic acid synthesis.

5. Scientific Evidence by Area of Use

5.1 External Genital and Anal Warts (Condyloma Acuminata)

This is the most extensively studied and best-supported clinical application of podophyllum-derived compounds. Both crude podophyllin resin and purified podophyllotoxin have been evaluated in multiple randomized controlled trials (RCTs).

Podophyllin resin (25%) — clinician-applied: Podocon-25® is composed of Podophyllin (Podophyllum Resin, American) 25% in benzoin tincture, indicated for the removal of soft genital (venereal) warts (condylomata acuminata). However, its use in this form requires strict physician supervision due to significant local and systemic toxicity risks.

Purified podophyllotoxin 0.5% solution and 0.15% cream — self-applied: A landmark RCT provided high-quality comparative evidence. The 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, in 358 immunocompetent men and women with genital warts of 3 months' duration or less. 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. Self-treatment of anogenital warts with podophyllotoxin showed greater efficacy and cost-effectiveness than clinic-based treatment with podophyllin.

An earlier clinical trial in China examined a cohort of 74 patients treated with 0.5% podophyllotoxin-ethanolic solution. The study reported 75 cases of genital warts treated with highly purified podophyllotoxin; all volunteers were diagnosed according to typical skin lesions, comprising 48 males and 26 females with a mean age of 28.4 years. The average duration of disease was 4.4 months. All lesions were treated with 0.5% podophyllotoxin-ethanolic solution topically twice per day for 3 successive days. The treatment was repeated if any warts persisted, but not more than 3 therapies in total were applied. The results showed an overall cure rate of 86.5% and an effectiveness rate (more than 50% lesions disappeared) of 96.15%.

A female-specific RCT comparing 0.5% podophyllotoxin cream against 20% podophyllin solution found substantial differences: the total frequency of warts eradicated was 94% with podophyllotoxin and 74% with podophyllin solution (P < 0.001).

A published integrated safety assessment reviewing multiple trials concluded that topical application of podophyllin solution can no longer be recommended due to its low efficacy and gross toxicity. Self-treatment with 0.15–0.5% purified podophyllotoxin preparations, applied twice daily for 3 days, is now advocated as the alternative first-line therapy of choice. In light of overwhelming safety and efficacy data in favor of podophyllotoxin-derived products, it is concluded that podophyllin preparations have no place in the modern treatment portfolio for anogenital warts.

A meta-analysis including 13 RCTs with 1,716 patients found that podophyllotoxin nanogel can improve the cure rate of patients with condyloma acuminatum (pooled OR=1.76).

Overall evidence strength for genital warts: Strong; multiple RCTs and meta-analyses support the efficacy of purified podophyllotoxin (podofilox). Regulatory agencies in numerous countries have approved podofilox for this indication. PPT is on the World Health Organization's List of Essential Medicines.

5.2 Anticancer Applications via Semisynthetic Derivatives (Etoposide and Teniposide)

Given the antimitotic properties of podophyllin, investigators at Sandoz Pharmaceuticals synthesized a series of podophyllotoxin derivatives in search of safe and effective antineoplastic drugs in the 1950s. A series of aldehyde condensation products of the nonpurified root of the Indian Podophyllum plant resulted in synthesis of the glucoside derivative of 4′-demethylepipodophyllotoxin, which had antitumour activity. Their extensive work led to 60 compounds, two of which showed increased antineoplastic activity — etoposide (developed in 1966) and teniposide (synthesized in 1967).

Etoposide and teniposide were selected for clinical trials in 1967 and 1971, respectively. Clinical investigations showed that they had significant antitumour activity with low toxicity in acute myeloid leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lung cancer (both small cell and non-small cell), gastric cancer, breast cancer, and ovarian cancer.

Etoposide: Etoposide, sold under the brand name Vepesid among others, is a chemotherapy medication used for the treatment of a number of types of cancer including testicular cancer, lung cancer, lymphoma, leukemia, neuroblastoma, and ovarian cancer. Etoposide was approved for medical use in the United States in 1983 and is on the World Health Organization's List of Essential Medicines. It became the drug of first choice for the treatment of many malignancies such as testicular and small cell lung cancer. Etoposide's systemic application was shown to induce a complete response in up to 25% of previously treated patients with acute nonlymphocytic leukemia.

Teniposide: Teniposide is chemically similar to etoposide, distinguished only by a thienyl group, whereas etoposide has a methyl group. It is mainly used to treat Hodgkin's lymphoma, acute lymphocytic leukemia, bladder cancer, and immature neuroblastoma.

Mayapple can be used topically as an escharotic in removing warts, and two of its derivatives, etoposide and teniposide, have shown promise in treating some cancers. Etoposide is among the World Health Organisation's list of essential medicines and it is derived from podophyllotoxin.

Overall evidence strength for cancer derivatives: Very strong for etoposide and teniposide as established, approved oncology agents, supported by decades of phase III clinical trial data. These are conventional pharmaceuticals, not dietary supplements. The parent compound podophyllotoxin itself is not approved for systemic cancer treatment due to unacceptable toxicity at therapeutically required doses.

5.3 Plantar Warts and Other Cutaneous Warts

Podophyllotoxin or podophyllin is used as a purgative and as a cytostatic. Posalfilin is a drug containing podophyllin and salicylic acid that is used to treat the plantar wart. Clinical evidence specific to plantar warts is more limited than for genital warts; the combination preparation with salicylic acid has been used in clinical practice, but large-scale RCT data specifically for this formulation and indication are less robust compared to the genital wart literature.

5.4 Antiviral Activity Beyond HPV

Podophyllotoxin is the precursor of two antineoplastic agents, etoposide and teniposide, and of other analogs useful as antiviral agents. Emerging evidence suggests that PPT has potential therapeutic applications beyond its well-documented role in mitotic spindle inhibition, particularly as an anti-leishmaniasis agent. Leishmaniasis, a parasitic zoonotic disease, could benefit from PPT's ability to disrupt microtubule formation, presenting a novel mechanism of action when used alongside traditional anti-inflammatory topical treatments. This prospect is supported by promising findings showing that PPT, at a concentration of 200 µg/mL, exhibited 83% lethality against Leishmania major promastigotes 48 hours post-cultivation. These findings remain preclinical and require further investigation before clinical conclusions can be drawn.

5.5 Radioprotection

Podophyllum hexandrum and its derived bioactive constituents have the potential to become novel radioprotective agents. This area of investigation is largely preclinical and animal-based at this stage; human clinical evidence is absent.

5.6 Hairy Oral Leukoplakia

People use the podophyllum resin (podophyllin) for the removal of warts, including plantar warts and genital warts, and corns. It is also used for white patches on the tongue in people with weakened immune systems (hairy leukoplakia), and other conditions, but there is no good scientific evidence to support these other uses.

6. Body Systems and Health Areas of Association

Integumentary system (skin and mucous membranes): Primary site of topical application; anti-wart activity via cytotoxic destruction of HPV-infected cells.
Oncology (via derivatives): Podophyllotoxin has a variety of medical applications including as antiviral and antitumor agents. The antitumor agents include etoposide and teniposide, used in various chemotherapies including lung cancer, lymphomas, and genital tumors.
Gastrointestinal system: When taken by mouth, it has a drastic laxative action and produces violent peristalsis. Historically used as a cathartic and purgative.
Hepatobiliary system: Historically used as a cholagogue and liver stimulant in Ayurvedic practice. Also used as a hepatic stimulant and purgative in Ayurvedic medicines.
Parasitology/Infectious disease: Mayapple has been used by Indigenous Americans as an emetic, cathartic, and anthelmintic agent.
Nervous system (toxicological relevance): Podophyllin toxicity can result from topical, oral, intralesional, or intramuscular exposure, with systemic effects including psychosis, altered consciousness, peripheral neuropathy, and autonomic disturbances such as gastrointestinal paresis and urinary retention. Neuropathy is characterized by slowly progressive sensory loss, paresthesias, muscle weakness, and diminished deep tendon reflexes, predominantly affecting distal limbs in a length-dependent pattern.

7. Dosage Forms and Reported Dosages

Topical Podophyllin Resin (Physician-Applied)

A small amount of Podophyllum resin 10–25% in compound tincture of benzoin should be applied to each wart and allowed to air dry before the treated area comes into contact with clothing. Overapplication or failure to air dry can result in local irritation caused by spread of the compound to adjacent areas. The preparation should be thoroughly washed off 1–4 hours after application to reduce local irritation. As podophyllin is a powerful caustic and severe irritant, it is recommended the first application be left in contact for only a short time (30–40 minutes) to determine patient response.

Purified Podophyllotoxin (Patient Self-Applied)

A concentration of 0.5% podophyllotoxin is used for self-treatment of anogenital warts, applied twice daily for 3 consecutive days per week for 4 weeks. A 0.15% cream formulation is also available, applied by the same cyclic protocol. Self-treatment with 0.15–0.5% purified podophyllotoxin preparations, applied twice daily for 3 days, is now advocated as the alternative first-line therapy of choice.

Podofilox 0.5% Solution (FDA-Labeled)

Per the FDA-approved product labeling (DailyMed), Podofilox 0.5% Solution is indicated for the topical treatment of external genital warts (Condyloma acuminatum) and is not indicated in the treatment of perianal or mucous membrane warts.

Pharmaceutical Derivatives

Etoposide and teniposide are administered under medical supervision at dose regimens specific to each cancer indication and chemotherapy protocol; they are outside the scope of dietary supplement dosing and are not self-administered.

8. Safety Considerations and Interactions

Systemic Toxicity Profile

Podophyllin toxicity can result from topical, oral, intralesional, or intramuscular exposure, with systemic effects including psychosis, altered consciousness, peripheral neuropathy, and autonomic disturbances such as gastrointestinal paresis and urinary retention.

Podophyllin resin is a topical agent used to treat condylomata acuminata, and systemic toxicity has resulted from both topical exposure and oral ingestion, with fatal outcomes reported after ingestion of as little as 350 mg of podophyllin. The first fatal case after oral administration was reported in 1890.

A documented case report illustrates the severity of topical toxicity: coma requiring respiratory support, and major neurologic complications as well as hematologic and hepatic toxicity, were observed in a patient following topical podophyllin application. Therapy with charcoal hemoperfusion resulted in resolution of the acute toxicity, leaving a peripheral neuropathy which had not completely resolved after 4 months.

Neurotoxicity

Adverse effects on the nervous system may occur following topical application of podophyllum; these are usually delayed in onset and prolonged in duration. Cerebral toxicity (manifested by altered sensorium ranging from mild confusion to coma) may occur following topical application of podophyllum and continue for 7 to 10 days, during which the electroencephalogram (EEG) may show generalized slowing.

The delay of onset of symptoms in several case reports may suggest that the metabolites of podophyllotoxin are more toxic than podophyllotoxin itself.

Factors Increasing Risk of Systemic Absorption

The risk of systemic toxicity may be increased when podophyllum is applied to friable, bleeding, or recently biopsied warts, or when the medication is inadvertently applied to normal skin or mucous membranes surrounding the affected area.

Hematologic and Organ Toxicity

Neurotoxicity is the most serious effect along with bone marrow depression, gastrointestinal irritation, and hepatic and renal dysfunction. Management of podophyllin toxicity is mainly symptomatic, and no specific antidote exists. Activated charcoal is recommended for gastric lavage after recent ingestion.

Gastrointestinal Toxicity

In large doses, Podophyllum can cause violent emesis and catharsis, gastritis and enteritis, which can potentially be fatal.

Oral Use: Prohibition

The internal use of Podophyllum is no longer advised because of its toxicity. It is listed by the FDA as an unsafe herb.

Pregnancy and Reproductive Toxicity

Podophyllin and podophyllotoxin are embryocidal in animals and humans, and pregnancy is an absolute contraindication. The oral and local use of the resin should be avoided during pregnancy, as this has been associated with teratogenicity and fetal death. The safety of podophyllin during pregnancy has not been established, and its use is contraindicated in pregnant women.

Management of Poisoning

Management of podophyllin toxicity is mainly symptomatic, and no specific antidote exists. Activated charcoal is recommended for gastric lavage after recent ingestion. Intensive management of ventilation and circulation, accompanied by monitoring for above-mentioned complications, is required. Hemoperfusion should be used for severe systemic poisoning since it has been shown to be effective in reducing the plasma fraction of podophyllum toxin and other active metabolites.

Instability and Variability of Crude Preparations

Podophyllin resin preparations differ in the concentration of active components and contaminants, and their shelf life and stability are unknown. This variability is a key reason why purified podophyllotoxin preparations have largely supplanted crude podophyllin resin in clinical practice.

Drug Interactions

No pharmacokinetic drug–drug interactions with podophyllum or podophyllin are well-characterized in the peer-reviewed literature for topical use at recommended doses. The systemic semisynthetic derivatives (etoposide, teniposide) carry well-documented interactions relevant to oncological prescribing, including interactions with anticoagulants, cyclosporine, and other chemotherapy agents, but these are outside the scope of the parent botanical used as a supplement or topical agent.

References

Health Conditions

Health conditions that Podophyllum may help support.

No conditions available.

Body Systems

Body systems that Podophyllum may help support.

No body systems available.