Petasinas

Petasines: A Comprehensive Reference

1. Identity and Botanical Origin

1.1 Nomenclature and Classification

Petasines (also written as petasins) are a group of sesquiterpene ester compounds that serve as the principal pharmacologically active constituents of the genus Petasites, most notably the species Petasites hybridus (L.) G.Gaertn., B.Mey. & Scherb. Petasin — the prototypical member — is a natural chemical compound classified as a sesquiterpene and is specifically the ester of petasol and angelic acid. Petasins as a class are defined as sesquiterpenes, that is, esters of petasol and angelic acid.

Petasin was isolated from Petasites hybridus (L.) Compositae. It has been of particular biosynthetic interest because it possesses the eremophilane carbon skeleton, which cannot be directly derived by the Biogenetic Isoprene Rule proposed by Ruzicka. It has been suggested that eremophilanes are derived from the eudesmane skeleton by a methyl shift across the ring junction.

The botanical name Petasites is derived from the Greek word petasos, a type of broad-brimmed hat worn by shepherds, referring to the plant's broad, downy leaves.

1.2 Source Plant

Petasites hybridus, also known as the butterbur, is a herbaceous perennial flowering plant in the family Asteraceae that is native to Europe and northern Asia. It has long rhizomes and large leaves, which develop after flowering and can reach up to 60 cm in diameter, grows up to 3 feet in height, and is native to Europe and present as an introduced species in North America and West and North Asia. It is common on riverbanks, in wet meadows and in other damp and shady locations.

The genus Petasites belongs to the daisy family (Asteraceae) and includes about 19 known species, each adapted to different corners of the world, from riverbanks in Europe to marshy forests across North America and Asia. Petasites japonicus, known as bog rhubarb or giant butterbur, has been used for its therapeutic effect on allergy and asthma in Korea and European countries, whereas Petasites tricholobus, distributed widely in southwest and northwest China, has been used for the treatment of palsy, hypertension, coughs, and snake-bite. Petasites hybridus is medicinally the most widely used species due to its two sesquiterpenes, petasin and isopetasin.

1.3 Plant Parts Used and Distribution of Petasines

The concentration of petasines and their derivatives — specifically isopetasin, neopetasin, S-petasin, iso-S-petasin, and neo-S-petasin — varies across plant parts but is generally higher in the plant's rhizomes and roots. In evidence-based phytotherapy, extracts from leaves and rhizomes are applied for different indications. While leaf extracts are administered to treat allergic rhinitis symptoms, rhizome extracts are utilized, among other uses, in the management of gastrointestinal spasms and migraines.

1.4 Individual Petasine Compounds

The main active substances of P. hybridus (common butterbur) include petasin and its isomers — isopetasin and neopetasin — and S-petasin (a methylthio derivative of petasin) and its isomers, iso-S-petasin and neo-S-petasin. Only the petasin chemotype is considered suitable for pharmaceutical purposes.

Petasin is unstable and spontaneously converts to isopetasin; rearrangements occur in dry plant materials and in stored extracts. Other constituents of butterbur include the flavonoid glycosides isoquercitrin and astragalin.

1.5 Common Preparations and Standardized Extracts

All major randomized controlled trials have contained the proprietary extract Petadolex, derived from the underground parts of Petasites hybridus and standardized to contain a minimum of 15% petasins and practically free of toxic pyrrolizidine alkaloids (content below 0.088 ppm). Petadolex® is specified to ≥15% petasin — the active ingredient of butterbur — and was introduced in Germany in 1972 and in the US in 1998.

A second major extract, Ze 339, is prepared from the leaves of P. hybridus rather than the rhizome. Ze 339 is a CO₂ extract prepared from the leaves of the plant. Ze 339 was approved by the Swiss government agency Swissmedic as an anti-allergic drug (Tesalin; Zeller AG, Romanshorn, Switzerland) to treat seasonal allergic rhinitis.

The following variables critically impact the properties of a butterbur extract and differ considerably between products: variety of species (petasin chemotype or furan chemotype), plant part (whole plant, leaves, or roots), cultivation versus wild collection, extraction solvent, and extraction procedure.

Thanks to extraction with supercritical CO₂, the concentrations of the potentially hepatotoxic and carcinogenic pyrrolizidine alkaloids in the best-characterized extracts lie below detection limits.

2. Traditional and Historical Use

2.1 European Folk Medicine

Herbal preparations of P. hybridus have been practiced in traditional medicine in Europe for over 900 years, for the treatment of a broad spectrum of human ailments. Butterbur has historically been used for a variety of health issues such as pain, headache, anxiety, cough, fever, and gastrointestinal and urinary tract conditions. It has also been used topically to improve wound healing.

Leaves of Petasites hybridus were used in Austrian and Czech traditional medicine internally (as tea or cold maceration in ethanol) and externally (as compresses or maceration in vinegar) for treatment of infections, fever, flu, colds, hay fever, and allergies.

Extracts from leaves and rhizomes of P. hybridus were used to treat spasms of the gastrointestinal tract and asthma due to its spasmolytic activities in the late Middle Ages. During the Middle Ages, butterbur leaves and roots were used to treat cough, plague, and fever. In medieval Europe, people burned butterbur roots to try to ward off the plague, giving it names like "plague root" and "pestilence herb."

2.2 Use in Other Traditions

Butterbur is a herbaceous plant belonging to the Asteraceae that has been used in folk medicine in Asia and America for the treatment of many illnesses such as fever, respiratory diseases, spasms, and pain. In Japan and Taiwan, P. japonicus is a common vegetable; the baked flower bud is used in traditional medicine as an expectorant or in the treatment of asthma. Other traditional uses include the treatment of gastric ulcer and bee stings.

2.3 Traditional Preparations

Traditional preparations of butterbur included teas, cold macerations in ethanol, and compresses. The plant's large leaves — which can measure up to 60 cm across — were also used practically. The name "butterbur" is attributed to the traditional use of its large leaves to wrap butter in warm weather. Modern pharmaceutical preparations — CO₂ extracts and standardized tablets — represent a significant departure from traditional preparations in terms of the removal of toxic pyrrolizidine alkaloids and standardization of petasine content.

3. Key Constituents and Phytochemistry

3.1 Primary Petasine Compounds

Plants of the genus Petasites contain large amounts of active compounds such as sesquiterpene esters, sesquiterpene lactones, and pyrrolizidine alkaloids. Pyrrolizidine alkaloids are toxic, while some of the sesquiterpene esters and sesquiterpene lactones have medicinal properties.

Primarily petasin and isopetasin sesquiterpene esters are considered as the most valuable pharmaceutical components in Petasites plants. The petasine composition of rhizome extracts comprises isopetasin, neopetasin, and petasin.

The extract is primarily composed of sesquiterpene esters, mainly of the petasin and the furanopetasin chemotype, and constitutes a mixture of petasin, isopetasin, neopetasin as well as furanoeremophilanes and eremophilanlactones.

3.2 S-Petasin and Methylthio Derivatives

S-petasin is a sulfur-containing methylthio derivative of petasin. Research has shown that triacylglycerol levels are reduced by S-petasin in oleic acid-induced HepG2 cells. Western blot assay revealed that S-petasin stimulated phosphorylation of AMPKα and ACCα. S-petasin was further shown to inhibit lipogenesis and enhance triacylglycerol turnover by downregulation of FAS and SCD-1 and upregulation of ATGL and HSL through the AMPK signaling-dependent regulation of transcriptional factors FKHR and SREBP-1. This in vitro study indicated that S-petasin has potential as a candidate compound for NAFLD (non-alcoholic fatty liver disease) therapy.

3.3 Co-occurring Constituents

The essential oil of the rhizomes of Petasites hybridus has been investigated by gas chromatography, mass spectrometry, and NMR techniques. Two sesquiterpene hydrocarbons, petasitene and pethybrene, have been identified. In addition to sesquiterpene esters, the rhizome and roots also contain toxic pyrrolizidine alkaloids.

Petasites hybridus contains senecionine and other toxic pyrrolizidine alkaloids in its leaves and roots. Also present are the sesquiterpene esters — petasin, isopetasin, and neopetasin.

4. Established Mechanisms of Action

4.1 Inhibition of Leukotriene Biosynthesis

The anti-inflammatory activity of Petasites hybridus extracts is attributed to its sesquiterpene ester components, such as petasin and isopetasin. Butterbur decreases the production of the inflammatory mediators prostaglandin E2 (PGE2), leukotriene B4 (LTB4), and cysteinyl-leukotrienes (LTs) in animal and human cellular systems, as well as in purified enzyme preparations.

Several laboratories have characterized petasins (petasin, isopetasin, and neopetasin) isolated from extracts of butterbur as pharmacologically active components which inhibit leukotriene synthesis in leukocytes. The molecular mechanisms by which petasins abrogate inflammatory effector cell functions have, at least partially, been identified. In vitro studies revealed that petasins may have several intracellular targets and that this may depend on the stereoisomer used.

Bickel et al. reported that isopetasin — but not petasin — inhibited leukotriene biosynthesis in stimulated peritoneal macrophages of inbred NMRI mice, while other investigators found petasin, isopetasin, and neopetasin to inhibit leukotriene synthesis in diverse cellular systems.

4.2 Calcium Channel Antagonism

Petasites inhibit the opening of L-type voltage-gated calcium channels, decreasing vasoconstriction of vessels and excitation of neurons. Wang et al. hypothesized that petasins act as direct antagonists of voltage-gated Ca²⁺-channels (VGCCs) in vascular smooth muscle cells. Petasin blocks intracellular calcium influx into neutrophils and eosinophils and inhibits leukotriene biosynthesis. Additionally, the calcium-antagonistic properties of petasins were proven in aortic ring preparations from rats.

4.3 COX-2 Inhibition

The herb's active components — including petasin and isopetasin — have been found to exhibit anti-inflammatory effects through the inhibition of COX-2, leading to decreased leukotriene synthesis and prostaglandin E2 release. Butterbur inhibits cyclooxygenase-2 (COX-2) activity. This inhibition is independent of the petasin and isopetasin content, suggesting that the therapeutic effect on cyclooxygenase inhibition may not result from a single constituent of the extract alone.

4.4 TRPA1 and TRPV1 Receptor Channel Modulation

Using calcium imaging and patch clamp recordings, Benemei et al. found that isopetasin activates TRPA1 channels leading to excitation of neuropeptide-containing nociceptors, which finally results in heterologous desensitization and reduced neurogenic inflammation. They proposed that this mechanism may account for the anti-migraine action of butterbur.

Earlier findings of TRPA1 receptor channels being involved in the site of action of petasin and isopetasin were confirmed. Furthermore, researchers suggest an important inhibitory effect on TRPV1 receptor channels and assume a cooperative action between the two TRP receptors. These mechanisms may contribute to the migraine prophylactic effect of petasins.

Butterbur root extract with its active ingredients petasin and isopetasin has been used in the prophylactic treatment of migraine for years, and calcitonin gene-related peptide (CGRP) is known as a biomarker and promoting factor of migraine. Investigators set out to examine the impact of petasins on the CGRP release from trigeminal afferents induced by activation of the calcium-conducting transient receptor potential channels TRPA1 and TRPV1.

4.5 Mitochondrial Complex I Inhibition

Mitochondrial electron transport chain complex I (ETCC1) is an essential core of cancer metabolism. From a plant extract screening, petasin (PT) was identified as a highly potent ETCC1 inhibitor with a chemical structure distinct from conventional inhibitors. PT had at least 1,700 times higher activity than that of metformin or phenformin and induced cytotoxicity against a broad spectrum of tumor types. PT administration also induced prominent growth inhibition in multiple syngeneic and xenograft mouse models in vivo.

4.6 Phosphodiesterase Inhibition

S-petasin concentration-dependently inhibited PDE3 and PDE4 activities with IC₅₀ values of 25.5 μM and 17.5 μM respectively. According to Lineweaver-Burk analysis, S-petasin competitively inhibited PDE3 and PDE4 activities. These results for S-petasin at least partially explain why Petasites formosanus is used as a folk medicine to treat asthma in Taiwan.

4.7 Spasmolytic Effects

The petasines, as the main components of butterbur, inhibit the synthesis of leukotrienes and decrease the intracellular concentration of calcium, which explains the anti-inflammatory and spasmolytic properties of extracts of butterbur. Results confirm petasins as active spasmolytic compounds of P. hybridus rhizome extracts, and demonstrate that the total content of petasins determines the spasmolytic effects, regardless of the individual composition of the different petasins.

5. Scientific Evidence by Area of Use

5.1 Migraine Prevention

Clinical Evidence

Migraine prophylaxis is the area with the strongest accumulated human clinical evidence for petasines. A randomized, group-parallel, placebo-controlled, double-blind clinical study was carried out with a special CO₂ extract from the rhizome of Petasites hybridus. Following a four-week run-in phase, 60 patients received either Petadolex or placebo at a dosage of two capsules (each capsule containing 25 mg) twice daily over 12 weeks. Outcome variables included the frequency, intensity, and duration of migraine attacks and accompanying symptoms. The frequency of migraine attacks decreased by a maximum of 60% compared to the baseline, and this reduction was statistically significant (p < 0.05) compared to placebo.

A larger three-arm, parallel-group, randomized trial compared Petasites extract 75 mg twice daily, Petasites extract 50 mg twice daily, or placebo twice daily in 245 patients with migraine. The proportion of patients with a ≥50% reduction in attack frequency after 4 months was 68% for patients in the Petasites extract 75-mg arm and 49% for the placebo arm (p < 0.05). Results were also significant in favor of the 75 mg dose at 1, 2, and 3 months.

The authors concluded that Petasites extract 75 mg twice daily is more effective than placebo and is well tolerated as a preventive therapy for migraine, whereas Petasites 50 mg twice daily was not significantly more effective than placebo on the primary study endpoints.

A single adult study at 50 mg twice daily also yielded positive results: a group of 33 adult subjects given a dose of 50 mg twice daily demonstrated a decrease in migraine frequency from a baseline of 3.4 per month to 1.8 per month after 12 weeks of treatment (p=0.0024).

Systematic Reviews and Guideline Assessment

A systematic review assessed the effectiveness of Petasites hybridus in the prophylaxis of migraine and concluded that there is moderate evidence in support of the effectiveness for 3–4 months of daily treatment with 150 mg Petasites. However, this conclusion may not be reliable given the small number of identified trials.

Based on these trials, the American Headache Society gave the herb a level A recommendation and declared it effective in preventing migraine headaches. The Complementary Migraine Guidelines of the AAN also mentioned butterbur as a level A recommendation for the prevention of chronic episodic migraine; however, these guidelines have since been retired.

In randomized, double-blinded and placebo-controlled trials with Petadolex®, migraine attack frequency was reduced significantly at 150 mg/day, and no relevant abnormal liver function was reported.

Evidence Strength Assessment

The overall evidence for migraine prophylaxis is the strongest area for petasines. Multiple randomized controlled trials using the standardized Petadolex extract demonstrated efficacy at 75 mg twice daily. However, the evidence base is limited in scale — the trials enrolled relatively small numbers of patients — and the AAN guideline that had conferred a Level A recommendation was subsequently retired in the context of emerging safety concerns about hepatotoxicity. Although some preliminary studies indicate that butterbur may reduce the frequency of migraine headaches in adults and children, clinical neurology associations do not recommend it because of concerns of possible liver toxicity.

5.2 Allergic Rhinitis

Clinical Evidence

Six randomized controlled trials studied Petasites hybridus (butterbur) extract for allergic rhinitis (AR) and suggest that P. hybridus is superior to placebo or similarly effective compared with non-sedative antihistamines for intermittent AR.

The leaf extract Ze 339 has been the primary vehicle for the allergic rhinitis indication. In vitro studies suggested that an extract of Petasites hybridus (Ze 339) blocks leukotriene synthesis in monocytes and granulocytes. Petasins are considered to be the pharmacologically active fraction within Ze 339. Patients suffering from allergic rhinitis received three times a day two tablets of Ze 339 standardized to 8 mg petasins within a time period of 1 week. After 5 days of treatment, Ze 339 significantly improved primary endpoints, which were day- and night-time nasal symptoms.

Nasal resistance measured by rhinomanometry gradually decreased as a consequence of Ze 339 treatment, reaching normal levels after 5 days.

In an open clinical trial in patients suffering from allergic rhinitis, a reduction of leukotriene and histamine levels in nasal fluids was associated with the butterbur extract administration.

A larger observational study with Ze 339 in Switzerland found: Data from 226 patients were collected during three documented visits. The mean study duration was 63 days, with 75% of patients being treated for at least 4 weeks. Of the patients, 58.5% started with Ze 339 monotherapy and 41.5% received other antiallergic and/or sympathomimetic drugs. In both groups, the allergic total symptom score and the inflammatory total symptom scores were significantly (p < 0.001) reduced, and the scores for quality of life were improved.

Systematic Review Conclusions

There is encouraging evidence suggesting that P. hybridus may be an effective herbal treatment for seasonal (intermittent) AR. The most frequently studied plant in phytotherapy reviews of seasonal allergic rhinitis was Petasites hybridus (butterbur), showing beneficial effects on immunological parameters, subjective symptoms, and nasal airflow.

Evidence Strength Assessment

Although there have been studies of butterbur root or leaf extracts as possible therapies for symptoms of hay fever (allergic rhinitis), the results were insufficient to determine effectiveness and safety. While multiple RCTs and systematic reviews show encouraging signals — particularly for Ze 339 in intermittent allergic rhinitis — overall regulatory confidence and guideline endorsement remain limited.

5.3 Asthma

Preclinical and Limited Clinical Evidence

Petatewalide B, a derivative of Petasites, has been found to exhibit anti-allergic activities. Specifically, the compound inhibits the activation of β-hexosaminidase in RBL-2H3 mast cells. Petatewalide B also inhibits nitric oxide synthase, which decreases nitric oxide production in mouse peritoneal macrophages. The compound also decreases the concentration of eosinophils, macrophages, and lymphocytes in mouse bronchoalveolar lavage fluid.

S-petasin from Petasites formosanus has been studied in animal models of asthma. S-petasin (10–30 μmol/kg, administered subcutaneously) dose-dependently and significantly attenuated the enhanced pause value induced by methacholine in sensitized and challenged mice. It also significantly suppressed the increases in total inflammatory cells, lymphocytes, neutrophils, eosinophils, and levels of cytokines including IL-2, IL-4 and IL-5, TNF-α, and IFN-γ in bronchoalveolar lavage fluid. In addition, S-petasin dose-dependently and significantly attenuated total and OVA-specific immunoglobulin E (IgE) levels in the serum and BALF.

Asthmatic patients were shown to benefit from butterbur's anti-inflammatory activity whilst on steroids. However, formal controlled clinical trials in asthma are absent from the published record, and the evidence remains at the preclinical and preliminary open-label stage.

Evidence Strength Assessment

There is no established evidence that butterbur is useful for treating bronchitis, urinary tract infections, asthma, or other such disorders based on controlled human trials. The mechanistic rationale is plausible given petasines' anti-inflammatory and spasmolytic properties, but human evidence is insufficient to characterize efficacy.

5.4 Gastrointestinal and Urogenital Spasms

Modern indications under investigation include the prophylaxis of migraine and tension headache, as well as spasms of the urogenital tract, gastrointestinal tract, and bile duct. Butterbur has been reported to be used in urinary tract spasms and in treating patients with irritable bladder.

A pre-clinical study showed that ethanolic extracts of butterbur blocked ethanol-induced gastric damage and reduced ulcerations of the small intestine caused by indometacin in rats. Human controlled trials in these indications are lacking; most evidence comes from animal models and traditional use reports.

5.5 Anticancer Research

Petasines, particularly petasin and its sulfur-containing analogues, have attracted interest in oncological research. These findings are exclusively preclinical and should be understood as hypothesis-generating rather than clinically applicable.

From a plant extract screening, petasin was identified as a highly potent mitochondrial electron transport chain complex I (ETCC1) inhibitor with a chemical structure distinct from conventional inhibitors. It had at least 1,700 times higher activity than that of metformin or phenformin and induced cytotoxicity against a broad spectrum of tumor types. Administration also induced prominent growth inhibition in multiple syngeneic and xenograft mouse models in vivo.

In colorectal cancer cell lines, petasin elevated expression of caspase-3 and caspase-9 and decreased Bcl-2 protein — all consistent with induction of apoptosis in SW-620 cells. Petasin also suppressed the expression of MMP-3 and MMP-9, suggesting that the anticancer effects of petasin may be partly due to the inactivation of the Akt/mTOR signaling pathway.

One study revealed that exposure to S-petasin and iso-S-petasin isolated from common butterbur elicits high cytotoxicity and apoptotic cell death responses through caspase activation and cytochrome c release in prostate cancer cells. Further, isopetasin and S-isopetasin extracted from Petasites formosanus have been shown to act as multidrug resistance inhibitors by targeting P-glycoprotein and suppressing the proliferation of multidrug-resistant cancer cells.

In breast cancer cell lines, butterbur extract caused a dose-dependent selective reduction in viability with a concomitant increase in apoptosis. The highest cytotoxicity was observed in MDA-MB-231 cells (IC50 – 520 μg/mL), followed by the MCF-7 cancer cell line (IC50 – 865 μg/mL). At the same time, the extract exhibited very low cytotoxicity to the non-tumorigenic L929 cell line.

Evidence Strength Assessment

All anticancer evidence for petasines is at the preclinical stage — in vitro cell culture experiments and animal models. A 2021 study reported that petasin can inhibit tumor growth and metastasis in an animal model of cancer. No human clinical trials in oncology indications have been reported in the peer-reviewed literature.

5.6 Neuroprotection and Alzheimer's Disease

Studies have found that butterbur may potentially be effective in treating Alzheimer's disease due to its neuroprotective effect. However, only studies involving in vitro and in vivo models have been performed.

Derivatives of Petasites have been found to have antioxidant activity; DPPH free radical-scavenging value and ferric ion reducing potential were both increased. In one study examining the cognitive effects of butterbur, the herb significantly decreased levels of reactive oxygen species (ROS) and increased the viability of HT22 mouse neuronal cells exposed to Aβ plaques.

Several experimental studies have confirmed the potential of petasins to be neuroprotective. However, all evidence remains at the preclinical stage with no controlled human trials published.

6. Body Systems and Health Areas of Association

Based on the accumulated research literature, petasines are associated with the following body systems and health areas:

• Neurological system: Migraine prophylaxis through CGRP inhibition, TRPA1/TRPV1 desensitization, and voltage-gated calcium channel blockade.
• Immune and allergic system: Allergic rhinitis through leukotriene and histamine pathway inhibition; mast cell stabilization; eosinophil regulation.
• Respiratory system: Antispasmodic action on bronchial smooth muscle; preclinical evidence in asthma models.
• Gastrointestinal system: Spasmolytic effects on gastrointestinal smooth muscle; preclinical gastroprotective effects.
• Urogenital system: Historically reported use for urinary tract spasms and irritable bladder.
• Oncology: Preclinical evidence of ETCC1 inhibition, apoptosis induction, and anti-metastatic activity across multiple tumor types.
• Central nervous system / neuroprotection: Preclinical antioxidant and anti-amyloid activity relevant to neurodegeneration.
• Metabolic (hepatic lipid metabolism): S-petasin preclinical evidence in NAFLD models via AMPK pathway.

7. Dosage Forms and Clinically Studied Dosages

7.1 Forms

Petasines are available commercially in several standardized supplement and medicinal product forms, including soft gel capsules, tablets, and CO₂ extracts. Typically, doses are taken 2 to 3 times daily with meals.

7.2 Dosages Used in Clinical Studies

Migraine Prophylaxis (Petadolex® — rhizome extract)

• One trial administered 60 patients Petadolex at a dosage of two capsules (each capsule containing 25 mg) twice daily over 12 weeks. This amounts to 100 mg/day.
• A three-arm randomized trial compared Petasites extract 75 mg twice daily, Petasites extract 50 mg twice daily, and placebo in 245 patients over 4 months.
• In randomized, double-blinded, and placebo-controlled trials, migraine attack frequency was reduced significantly at 150 mg/day.
• In a pediatric study, patients aged 6–9 years received 50–75 mg/day and those aged 10–17 years received 100 mg/day; in months 3–4, non-responders increased the dose to 75 mg/day (6–9 years of age) or 150 mg/day (10–17 years of age).

Allergic Rhinitis (Ze 339 — leaf extract)

• Patients suffering from allergic rhinitis received three times a day two tablets of Ze 339 standardized to 8 mg petasins within a time period of 1 week. This amounts to 24 mg petasins per day.

7.3 Standardization

The Petadolex extract is standardized to contain a minimum of 15% petasins and is practically free of toxic pyrrolizidine alkaloids, with content below 0.088 ppm.

8. Safety Considerations and Known Interactions

8.1 Pyrrolizidine Alkaloids: The Principal Toxicological Concern

One major area of safety concern is pyrrolizidine alkaloids (PAs), which are commonly found in the butterbur plant. These substances can cause hepatotoxicity, lung toxicity, carcinogenesis, and thrombosis. Plants used for pharmaceutical purposes, and especially the preparations made from these plants, should ideally contain high amounts of petasin/isopetasin, and, most importantly, low amounts of pyrrolizidine alkaloids.

Analysis of 21 commercially available dietary supplements showed that 7 products contained pyrrolizidine alkaloids; 5 of the 7 products containing toxic alkaloids had no detectable level of the pharmacologically active petasins. Only 7 of the 21 dietary supplement products tested contained petasins within the limits claimed on the label plus no toxic pyrrolizidine alkaloids.

8.2 Hepatotoxicity Reports

Postmarketing pharmacovigilance between 1992 and 2006 revealed 40 cases of increased liver enzymes and possible hepatotoxicity with P. hybridus extracts, including 9 cases of acute hepatitis and 2 cases of liver failure.

While most herbal-induced liver injury (HILI) patients presented mild serum biochemistry changes (<3 ULN, dose range 50 to 225 mg/day; treatment duration 4–730 days), nine developed severe HILI (average time-to-onset 103 days, ALT-range 3–153; AST 2–104-fold ULN).

However, causality assessment of the most studied extract yielded a more nuanced picture. The RUCAM (Roussel Uclaf Causality Assessment Method) test found no probable relationship between the butterbur root extract Petadolex® and cases of serious liver injury. Two cases of non-serious reversible liver enzyme elevations were rated as probably related to Petadolex®.

A no-observable-adverse-effect-level at 15-fold of the maximal clinical dose was established for rats. At supratherapeutic doses, i.e., 45–90-fold the maximal clinical dose, bile duct hyperplasia was observed, and mechanistic studies revealed regulations of solute carriers to likely account for bile duct proliferations. Liver function tests performed in cultures of primary human hepatocytes did not evidence hepatotoxicity at therapeutic butterbur levels. In randomized, double-blinded, and placebo-controlled trials with Petadolex®, no relevant abnormal liver function was reported.

The hepatotoxicity risk of root extracts led to the withdrawal of the marketing authorization of medicinal products containing the root extract in Switzerland in 2004.

8.3 Adverse Events in Clinical Trials

The most frequently reported adverse reactions in clinical trials considered possibly related to treatment were mild gastrointestinal events, predominantly burping. In the Ze 339 observational study, only three mild gastrointestinal adverse events occurred.

Approved preparations are associated with known negative side effects including gastrointestinal problems, nausea, headache, drowsiness, and halitosis.

8.4 Extract Quality and Regulatory Issues

Many butterbur extracts or even drug powders are marketed in various countries, especially in the United States; however, those extracts are not comparable to each other. Similar to biopharmaceutical products, the manufacturing process critically determines the properties of the butterbur extract.

Published results of Petadolex are not transferable to any other butterbur extract. Although used over centuries in traditional medicine to treat various disorders, there are no approved medical uses, but it is sold as a dietary supplement.

8.5 Allergy Risk

Petasites hybridus is a member of the family Asteraceae. Individuals with known sensitivity to plants in this family (including ragweed, chrysanthemums, marigolds, and daisies) may be at elevated risk of cross-reactive allergic responses, though specific clinical data on cross-reactivity frequency are limited.

8.6 Known Drug Interactions

Asthmatic patients were shown to benefit from butterbur's anti-inflammatory activity whilst on steroids, suggesting some degree of complementary pharmacological activity. Liver function tests were performed in cultures of primary human hepatocytes with migraine co-medications and did not evidence hepatotoxicity at therapeutic butterbur levels. No significant pharmacokinetic drug interactions with petasines have been established in formal human studies to date.

8.7 Special Populations

Concerns about the potential toxic effects of pyrrolizidine alkaloids in butterbur limit its use in human and animal studies. Specifically, PAs are known to be genotoxic and potentially teratogenic, making products not certified PA-free inappropriate during pregnancy or in pediatric populations except under specialist guidance. Use of uncharacterized (non-PA-certified) preparations carries the greatest risk.

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• Wikipedia: Petasites hybridus (referenced for botanical context and regulatory status)