Butterbur

Scientific Name(s): Petasites frigidus (L.) Fr., Petasites hybridus (L.) G. Gaertner, Meyer and Scherb., Petasites japonicus Siebold & Zucc. Maxim.
Common Name(s): Arctic sweet coltsfoot (P. frigidus), Blatterdock, Bog rhubarb, Bogshorns, Butter-dock, Butterbur, Butterfly dock, Coltsfoot, Exwort, Fuki, Japanese butterbur, Japanese sweet coltsfoot (P. japonicus), Pestilence-wort (P. hybridus), Pestwurz

Medically reviewed by Drugs.com. Last updated on Oct 1, 2022.

Clinical Overview

Use

Limited clinical trials of variable methodological quality suggest a possible place in therapy for butterbur in prophylaxis of migraine, as well as in management of intermittent (seasonal) allergic rhinitis. However, recommendations are based on weak clinical efficacy data, and long-term safety of butterbur has not been established. Only commercial preparations that are certified not to contain toxic pyrrolizidine alkaloids should be used.

Dosing

Guideline recommendations regarding butterbur use in migraine prophylaxis and management of allergic rhinitis are conflicting, and clinical trials demonstrate weak clinical efficacy or were of variable methodological quality. Only commercial preparations that do not contain hepatotoxic pyrrolizidine alkaloids should be used. Studies in special populations, such as those with renal or hepatic function impairment, are not available. Long-term safety of butterbur use has not been established.

Contraindications

Avoid use in hepatic impairment. Limited animal studies suggest butterbur's chemical constituents may exert cardiovascular effects.

Pregnancy/Lactation

Avoid use. Preparations may contain hepatotoxic pyrrolizidine alkaloids with carcinogenic and mutagenic activities.

Interactions

None well documented.

Adverse Reactions

There is a low potential for side effects. GI symptoms, including nausea, flatulence, and belching, are the most common documented adverse reactions. Allergies, including anaphylaxis, have been reported.

Toxicology

Preparations may contain pyrrolizidine alkaloids with carcinogenic and mutagenic potential; commercial products typically are certified as pyrrolizidine alkaloid free ("PA free"); however, levels of active petasins as well as toxic alkaloids have been found to be highly variable and incongruent with product labeling. Possible hepatotoxicity has been reported.

Scientific Family

• Asteraceae (Aster)

Botany

Butterbur is a perennial shrub native to Europe that commonly grows in wet, marshy ground or on sandbars near streams. Its distinctive pink-lilac flowers grow on large spikes that appear in spring before its large, downy leaves emerge. P. japonicus is commonly grown and consumed in Japan.(Aydin 2013, USDA 2022)

Although butterbur is sometimes considered synonymous with Tussilago farfara (both share the common name "coltsfoot"), the two plants should not be confused. Butterbur and coltsfoot are detailed separately (see Coltsfoot monograph).

History

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. The name butterbur relates to the use of the leaves to wrap butter during warm weather. During the Middle Ages, butterbur leaves and roots were used to treat cough, plague, and fever. P. japonicus is a common vegetable in Japan and Taiwan; 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.(Aydin 2013, Duke 2002)

A CO₂ extract of P. hybridus leaves (Ze 339, standardized to petasins 8 mg) is currently licensed in Switzerland and other countries for the treatment of allergic rhinitis.(Urda 2022) Known by the brand name Tesalin, Ze 339 was changed from prescription-only to nonprescription status in 2018.(Forsch 2020)

Chemistry

Butterbur contains senecionine and other toxic pyrrolizidine alkaloids in the leaf and root; a competitive immunoassay has been developed for the determination of alkaloid content. High-performance liquid chromatography (HPLC) analyses of both plant parts indicate that, on average, alkaloid levels are lower in leaves than in roots.(Aydin 2013, Duke 2022, Duke 2022, Duke 2002)

Three quercetin glucosides (quercetin 3-O-beta-D-glucoside, quercetin 3-O-beta-D-6"-O-acetylglucoside, and rutin) were isolated from flower buds of P. japonicus subsp. gigantea Kitam., along with caffeic acid.(Matsuura 2002)

A large number of sesquiterpenes have been isolated from butterbur, with petasin and related eromophilanes being the most pharmacologically important. The sesquiterpene distribution varies according to plant part, growth season, and plant location. Use of HPLC methods for quantitative determination of petasin has been reported, and the existence of a distinct chemovar with furanoeremophilanes has been noted.(Aydin 2013, Wang 2013)

Petasin is unstable and spontaneously converts to isopetasin(Benemei 2017); rearrangements occur in dry plant materials and in stored extracts. The biosynthesis of petasin has been elucidated. Differences in the sesquiterpene profiles of various European Petasites species have been studied. Other constituents of butterbur include the flavonoid glycosides isoquercitrin and astralagin.(Wang 2013)

Uses and Pharmacology

Only commercial preparations that are certified not to contain toxic pyrrolizidine alkaloids should be used.(Brozek 2010)

Clinical studies have most extensively investigated use in allergic rhinitis and migraine; the availability of clinical trial data regarding these conditions make animal studies largely irrelevant.

Allergic rhinitis

Various aspects of the mechanism of action have been demonstrated in vitro and in vivo. Antigen-induced degranulation in mast cells has been found to be inhibited in vitro by petatewalide B extracted from the leaves of P. japonicus. Anti-inflammatory responses involved in allergies were also observed with petatewalide B via inhibition of iNOS but not COX-2. While accumulation of eosinophils, macrophages, and lymphocytes were inhibited in an asthma mouse model.(Choi 2016)

Clinical data

Several clinical trials using commercial preparations of butterbur have evaluated their efficacy in the management of allergic rhinitis. Subjective and objective data serve as end points and measures of efficacy. However, 3 of the larger trials were sponsored by manufacturers of butterbur extract, and at least 1 study with negative results has been published.(Guo 2007) Mechanisms of action for butterbur in allergic rhinitis may relate more to leukotriene activity rather than an antihistaminic effect, although the standardized extract Ze 339 has been shown to inhibit transcellular histamine transport.(Mettler 2022)

Global Allergy and Asthma European Network Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines (2010) conditionally recommend that butterbur not be used in patients with allergic rhinitis based on the very low–quality evidence of benefit and the high risk of adverse effects.(Brozek 2010)

The American Association of Otolaryngology-Head and Neck Surgery (AAOHNS) clinical practice guideline on allergic rhinitis (2015) states that too few data are available to make recommendations regarding use of butterbur for managing symptoms of allergic rhinitis. Additionally, no recommendations could be made regarding use of herbal therapies in general, based on the panel's limited knowledge of herbal medicines and concerns regarding quality of standardization and safety (low level of confidence in evidence; uncertain evidence quality).(Seidman 2015)

According to consensus opinion among rhinology experts in 2020, butterbur is recommended as an option for adjunctive treatment for allergic rhinitis based on low- to moderate-level evidence of efficacy, low risk for adverse effects, and moderate cost.(Wu 2020) A real-world observational study of the Ze 339 extract in 229 patients demonstrated relief of early-onset allergic symptoms and later inflammatory symptoms. Adverse effects were mild and rare; 3 patients reported GI symptoms, primarily nausea.(Blosa 2021) Efficacy and safety in pediatric patients were examined in a subanalysis of a real-world observational study that compared results of Ze 339 alone and in combination with other medication. Symptoms were reduced similarly in both groups and tolerability was rated high by both patients and physicians, although no specific adverse events were discussed.(Moll 2015)

Anti-inflammatory

Animal and in vitro data

In rat gastric ulceration models, butterbur extract blocked the effects of ethanol and indomethacin.(Brune 1993, Chizzola 2000, Diener 2004) Anti-inflammatory activity of P. hybridus and P. japonicus extracts has also been demonstrated in a hepatic toxicity mouse model(Alhusayan 2020) and in lipocytes and macrophages in vitro, respectively.(Ahn 2020) Inhibition of pro-inflammatory cytokine and chemokine response to viral mimics but not bacteria has been observed with the leaf extract of P. hybridus.(Steiert 2017)

Antioxidant

In vitro data

The active chemical components of butterbur, including several dicaffeoylquinic acids, have demonstrated antioxidant effects in in vitro experiments.(Cui 2005, Kim 2018, Lin 2004, Matsuura 2002, Oh 2005, Park 2010, Sok 2006)

Antiviral effects

In vitro data

An extract of P. hybridus leaves (standardized to petasins 8 mg) licensed in Switzerland and other countries to treat allergic rhinitis was assessed in vitro for its effect on SARS-CoV-2 virus replication. Potent antiviral effects against the Wuhan variant were demonstrated by the extract as well as its active components isopetasin and neopetasin, with mean inhibitory concentration (IC₅₀) values ranging from 0.12 to 1.2 mcg/mL. The reference drug remdesivir exhibited an IC₅₀ of 2.37 mcg/mL. The high value of the selectivity index for the butterbur extract (200) indicated a better efficacy and safety ratio than isopetasin (80), neopetasin (50), or remdesivir (21.1). The butterbur extract and isopetasin exhibited antiviral activity against the Delta variant that was comparable to their activity against the Wuhan variant.(Urda 2022)

Asthma

Insight into the mechanism of action was demonstrated by the inhibition of the accumulation of eosinophils, macrophages, and lymphocytes in an asthma mouse model.(Choi 2016)

Animal data

Studies of Petasites extracts in rodents have shown a decrease in airway hyperresponsiveness, including inhibition of eosinophil infiltration and mucus hypersecretion, as well as relaxation of tracheal tissues. Decreases in circulating levels of histamine and leukotrienes were also observed.(Brattström 2010, Lee 2011, Lee 2013, Shih 2011, Zhang 2011)

Clinical data

There are limited clinical trials evaluating the efficacy of butterbur extracts in asthma. In one small trial (N=16), butterbur 50 mg/day taken for 1 week improved bronchial hyperresponsiveness (primary outcome).(Lee 2004) A reduction in asthma attacks was reported in another open-design trial after subjects were administered butterbur root 150 mg/day.(Danesch 2004)

Cancer

Animal and in vitro data

Methanol extracts of the leaves of P. japonicus were antimutagenic in human cancer and rat liver cell lines,(Kang 2010) while the root extract inhibited proliferation in a dose-dependent manner in hepatocarcinoma cells in vitro and in mice.(Kim 2015)

Cardiac effects

Animal and in vitro data

The active chemical component petasin has been investigated for reported hypotensive effects. In in vitro experiments and rat studies, both the S- and iso-S forms of petasin exerted a negative chronotropic effect on cardiac tissue. Reduced rates of atrial firing and a dose-dependent bradycardiac effect have been demonstrated. At the cellular level, blockade of the calcium channels was suggested, but the mechanism of action has not been established.(Esberg 2003, Wang 2004, Wang 2010, Wang 2001, Wang 2002)

CNS effects

Animal data

In Alzheimer disease mouse models, butterbur leaf extract (P. japonicus) prevented amyloid-beta plaque-induced oxidative stress in the dentate gyrus (associated with learning and memory), exhibited neuroprotection in the hippocampus, and improved amyloid-beta plaque-induced synaptic degeneration markers. Memory deficits observed in untreated controls were also significantly improved in the butterbur group.(Kim 2018)

Clinical data

Addition of butterbur extract to a 3-herb preparation showed superior efficacy to the 3-herb preparation alone regarding primary (anxiety and depression scale scores) and secondary parameters in a randomized, placebo-controlled, pharmacoclinical trial in patients with somatoform disorders (N=182).(Melzer 2009)

Glycemic effects

Animal data

Petasin modulated glucose metabolism in a study of mice.(Adachi 2014)

Hepatoprotective effects

Animal data

Oral administration of butterbur extract (P. hybridus) significantly improved liver function in mice with ovalbumin-induced liver damage. Mechanisms involved reductions in both oxidative stress and inflammatory processes that led to improved histopathological changes (ie, reductions in inflammatory cells and collagenous fiber deposition).(Alhusayan 2020)

Immune system

In vitro data

In vitro studies showed immunomodulatory effects of P. hybridus extracts,(Khaleghi 2014) including inhibition of IL-8 expression and neutrophil chemotaxis by petasin isoforms and an extract from P. hybridus leaves.(Steiert 2017)

Lipids

Animal data

Decreased total cholesterol and low-density lipoproteins have been observed in mice fed high-fat diets and butterbur extracts.(Melzer 2009, Watanabe 2010)

Migraine prophylaxis

The anti-migraine mechanism has been associated with selective desensitization of nociceptors by isopetasin but not angelic acid in animal and in vitro models.(Benemei 2017)

Adults

Clinical data

Previous support for use of butterbur for prevention of episodic migraines in adults by the 2012 American Academy of Neurology and American Headache Society guidelines was withdrawn subsequent to serious concerns over the safety of unregulated manufacturing processes that were not removing toxic pyrrolizidine alkaloids from commercially available products. Additionally, levels of the active moiety, petasins, were found to be highly variable and even lacking in some products.(Avula 2012, Holland 2012, Mauskop 2013)

Previously, the Canadian Headache Society guidelines for migraine prophylaxis (2012) strongly recommended butterbur 75 mg twice daily for migraine prophylaxis in eligible patients based on moderate evidence (controlled trials), noting that the magnitude of benefit may be small, but side effects are minimal.(CHS 2012) Likewise, the European Federation of Neurological Societies guidelines on the treatment of migraines (2009) considered butterbur (petasites) as second-line therapy for migraine prophylaxis based on moderate evidence.(Evers 2009) Meta-analysis suggested that butterbur 50 mg twice daily achieves a 50% reduction in migraine frequency at week 12 (odds ratio, 2.24; 95% CI, 0.64 to 7.81; P=0.2).(Holland 2012)

The safety of long-term use of butterbur has not been established. The maximum duration studied in clinical trials for migraine was 16 weeks.(Holland 2012, Sutherland 2010)

Children

Clinical data

One open-label study evaluating butterbur root extract for migraine prevention was conducted in children and adolescents 6 to 17 years of age.(Pothmann 2005) A second trial (N=58) compared the efficacy of butterbur versus music therapy or placebo; study treatment was administered for 12 weeks. Compared with placebo, a significant reduction in migraine frequency from baseline (primary outcome) was shown for both music therapy and butterbur in the 6-month follow-up per-protocol analysis. In the posttreatment period, the responder rate (ie, occurrence of 50% or more reduction in headache frequency compared with baseline [secondary outcome]) did not differ between placebo and butterbur but was significantly higher with music therapy. After 6 months, there was no significant difference among the 3 treatments regarding responder rate.(Sutherland 2010) Reviews of the data have been published.(Oelkers-Ax 2008, Orr 2014, Utterback 2014) The safety of long-term use of butterbur has not been established.

Obesity

In vitro data

An ethanolic extract of the edible leaves and stalk of P. japonicus reduced biomarkers associated with obesity-induced systemic inflammation in adipocytes and macrophages. Lipid accumulation in adipocytes was also significantly decreased with the extract compared with controls.(Ahn 2020)

Sinusitis

Clinical data

A systematic review of studies of alternative therapies for sinusitis and rhinitis evaluated by a consensus group of rhinology experts (2020) identified no studies of butterbur use for treatment of chronic rhinosinusitis.(Wu 2020)

Dosing

Various commercial preparations are available. Only commercial preparations that do not contain hepatotoxic pyrrolizidine alkaloids should be used.(Brozek 2010) Studies in special populations, such as those with renal or hepatic function impairment, are not available. The safety of long-term use of butterbur has not been established.

While some older guidelines (Canadian Headache Society 2012 guidelines and European Federation of Neurological Societies 2009 guidelines) supported use of butterbur for migraine prophylaxis, support by the 2012 American Academy of Neurology and American Headache Society guidelines was withdrawn subsequent to serious concerns over the safety of unregulated manufacturing processes that were not removing toxic pyrrolizidine alkaloids from commercially available products. Additionally, levels of the active moiety, petasins, were found to be highly variable and even lacking in some products.(Avula 2012, CHS 2012, Holland 2012, Mauskop 2013)

Although a 2020 consensus opinion among rhinology experts recommends butterbur as an option for adjunctive treatment for allergic rhinitis, published guidelines either recommend against use or state a lack of data to make recommendations.(Brozek 2010, Seidman 2015, Wu 2020)

Pregnancy / Lactation

Avoid use. Preparations may contain hepatotoxic pyrrolizidine alkaloids with carcinogenic and mutagenic potential.(Blumenthal 2000, Ernst 2002)

Interactions

None well documented.(Chen 2012, Ulbricht 2008) Interactions could occur with calcium channel antagonists, inotropic and anticholinergic agents, and inducers of CYP3A4 (eg, St. John's wort, carbamazepine, phenytoin, rifampin), which might result in increased production of toxic metabolites of the alkaloids.

Adverse Reactions

Few adverse reactions have been reported in clinical trials; however, these trials have been of short duration (maximum, 16 weeks). GI symptoms, including nausea, flatulence, and belching, are the most common documented adverse reactions. Headache, dizziness, drowsiness, and fatigue have also been reported, as well as allergy to butterbur or other members of the Aster family.(CHS 2012, Posadzki 2013) Anaphylaxis has been documented in 2 cases, with dyspnea, full-body urticaria, and itching occurring within minutes of consuming Japanese butterbur scape tempura.(Kataoka 2017) Clinical trials have reported mild elevation of liver enzymes with no clinical sequelae.(Sutherland 2010) (See Toxicology.)

Toxicology

Pyrrolizidine alkaloids have carcinogenic and mutagenic potential.(Blumenthal 2000, Duke 2002) In the case of commercial butterbur preparations, an extraction process is used to remove the pyrrolizidine alkaloids content; these products should be labeled as "PA free." Petasin concentrations greater than 37% are toxic.(Sun-Edelstein 2011, Sutherland 2010) The German Federal Health Bureau established regulations that restrict oral exposure to pyrrolizidine alkaloids or their N-oxides to 1 mcg/day (not to exceed 6 weeks’ duration) or 0.1 mcg/day for any duration for nonpregnant, non-lactating adults. However, analysis of 21 commercially available dietary supplements in 2012 showed that 7 products contained pyrrolizidine alkaloids; 6 solid formulations contained 0.1 to 4.48 mcg per dosage form and 1 liquid product contained 8.43 mcg/mL. Typically, doses are taken 2 to 3 times daily with meals. Additionally, 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.(Avula 2012)

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.(Anderson 2009) Clinical trials have reported mild elevation of liver enzymes with no clinical sequelae.(Sutherland 2010)

Acute toxicity studies in rats showed no hepatotoxicity. Dose-related bile duct hyperplasia and increased liver enzymes were observed at 28 days and 6 months, returning to normal after cessation.(Anderson 2009) Examination of in vitro hepatotoxicity using various models demonstrated that toxicity was dependent upon species and differences in cytochrome enzyme activity in the hepatic cells. Human hepatocytes are more tolerant of toxic effects than those in rats or dogs; comparison of effects at increasing concentrations support a lack of hepatotoxicity in clinical use at recommended dosages.(Forsch 2020) Extracts of P. japonicus were not mutagenic in the Ames Salmonella typhimurium test.(Kang 2010) Inhibition of testosterone production has been reported in animal experiments.(Lipton 2004)

Index Terms

• Tussilago farfara

References

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