Butterbur

February 2007

Three accepted species: Petasites frigidus (L.) Fr., Petasites hybridus (L.) Gaertner, Meyer and Scherb., and Petasites japonicus . Family: Asteraceae (Aster)

Blatterdock , bog rhubarb , bogshorns , butter-dock , butterbur , butterfly dock , coltsfoot , exwort , fuki (Japanese), pestilence-wort , pestwurz (German), Petadolex , Petaforce , Tesalin , ZE339

Uses

Commercial preparations derived from butterbur include Petadolex (available in the United States since 1997), Tesalin , and Petaforce . A few small clinical trials (some open label) have shown some benefit in the treatment of migraines and allergic rhinitis.

Dosing

Trials in migraine, allergic rhinitis, and asthma have used butterbur extracts in dosages ranging from 50 to 75 mg twice daily. Tesalin 16 to 32 mg in divided doses has been used in allergic rhinitis. Trials have included subjects 6 years of age and older.

Contraindications

Consider the use of butterbur-containing preparations in congestive heart failure a relative contraindication because of negative chronotropic effects demonstrated in animal experiments.

Pregnancy/Lactation

Contraindicated. Preparations may contain liver toxins with carcinogenic and mutagenic potential.

Interactions

None well documented.

Adverse Reactions

GI symptoms comprise the majority of reported adverse reactions. Inhibition of testosterone production has been reported.

Toxicology

Pyrrolizidine alkaloids found in butterbur are known liver toxins with carcinogenic and mutagenic potential. Commercial dosage forms must be free of hepatotoxic pyrrolizidine alkaloids.

Butterbur is a perennial shrub native to Europe that has very large, downy leaves. It commonly grows in wet, marshy ground or on sandbars near streams. The distinctive pink-lilac flowers grow on large spikes and appear before the leaves in spring. P. japonicus is commonly grown and consumed in Japan. ^1, , ²

The generic name petasites is derived from the Greek word petasus , a type of broad-brimmed hat worn by shepherds, referring to the broad, downy leaves. The name butterbur relates to the use of the leaves to wrap butter. During the Middle Ages, butterbur leaves and roots were used to treat cough, plague, and fever.

P. japonicus is a common vegetable in Japan; 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

Butterbur contains senecionine and other toxic pyrrolizidine alkaloids in the leaf and root; a competitive immunoassay has been developed for determination of alkaloid content. High-performance liquid chromatography (HPLC) analyses of both plant parts indicate that, on average, leaves have lower alkaloid levels than roots. ^4, , ⁵

A large number of sesquiterpenes have been isolated from butterbur, with petasin and related eromophilanes being the most pharmacologically important. ^6, , ^7, , ^8, , ^9, , ^10, The sesquiterpene distribution varies according to plant part, growth season, and plant location. ^5, , ^11, , ^12, HPLC methods for quantitative determination of petasin have been reported, ^13, , ^14, and the existence of a distinct chemovar with furanoeremophilanes has been noted. The petasin series of compounds is unstable in storage, with rearrangements occurring in dry plant materials and in stored extracts. The biosynthesis of petasin has been elucidated. ^15, Differences in sesquiterpene profiles of various European petasites species have been studied. ^16, Other constituents of butterbur include the flavonoid glycosides isoquercitrin and astralagin. ¹⁷

Allergic rhinitis Several clinical trials have been conducted on commercial preparations of butterbur to evaluate their efficacy in the management of allergic rhinitis. Both subjective and objective data serve as end points and measures of efficacy. ^18, , ^19, , ^20, , ^21, , ^22, , ^23, , ^24, , ²⁵

Efficacy over placebo has been demonstrated, and equivalence to fexofenadine 180 mg and cetirizine 10 mg has been shown. Dosages used in these trials range from Tesalin 16 to 32 mg (in divided doses) and Petadolex 100 mg in adults, with durations of 7 to 14 days.

Mechanisms of action for butterbur in allergic rhinitis relate to a role in leukotriene activity rather than an antihistaminic effect. ^3, , ^18, , ²⁵

Asthma There are limited trials evaluating the efficacy of butterbur extracts in asthma. One small trial (N = 16) found improvement in the primary outcome of bronchial hyper-responsiveness with Petaforce 50 mg for 1 week. ²⁶ A reduction in asthma attacks was reported in another open-design trial after subjects were administered Petadolex 150 mg. ²⁷

Migraine Three clinical trials have evaluated the efficacy of a butterbur extract ( Petadolex ) for the prevention of migraines, all recording a decrease in the number of migraine attacks per month. A number of responders in these trials achieved at least a 50% reduction in attacks. ^28, , ^29, , ^30, , ^31, , ³² Dosages of Petadolex ranging from 50 mg twice daily ^28, , ^29, , ^33, to 75 mg twice daily ^30, were used in these trials for periods of 3 to 5 months. One of the trials, an open-label design, included children 6 to 9 years of age and adolescents up to 17 years of age. ³⁰

Other effects

Antibacterial Triterpenoids extracted from butterbur rhizome demonstrated in vitro activity against Bacillus subtilis equivalent to chloramphenicol, but showed no activity against Escherichia coli or Staphylococcus aureus . ³⁴

Anti-inflammatory In rat gastric ulceration models, butterbur extract blocked the effects of ethanol and indomethacin. ^28, , ^35, , ³⁶

Antioxidant In vitro experiments conducted to explain the active chemical components of butterbur have demonstrated its antioxidant effect. ^37, , ^38, , ^39, , ^40, , ⁴¹

Cardiac The active chemical component, petasin, has been investigated for reported hypotensive effects. Petasin (both the s- and iso-s- forms) has, in both in vitro experiments and in rat studies, exerted a negative chronotropic effect on cardiac tissue. A reduced rate in atrial firing and a dose-dependent bradycardiac effect were demonstrated. At the cellular level, blockade of the calcium channels was suggested, but the mechanism of action was not established. ^42, , ^43, , ^44, , ⁴⁵ Clinical trials are lacking.

Commercial extracts of butterbur, free of pyrrolizidine, have been used in clinical trials. Trials in migraine and asthma have used Petadolex 50 to 75 mg twice daily. ^23, , ^27, , ^28, , ^29, , ³⁰ Tesalin 16 to 32 mg in divided doses has been used in allergic rhinitis. ^18, , ^19, , ^20, , ^21, , ^22, , ^23, , ²⁴ Trials included subjects 6 years of age and older. Studies in special populations, such as renal or hepatic function impairment, are not available.

Use is contraindicated. Preparations may contain liver toxins with carcinogenic and mutagenic potential. ^2, , ⁴⁶

None well documented. A theoretical interaction with calcium channel antagonists and inotropic drugs exists. ^43, , ⁴⁴

Few adverse reactions have been reported in clinical trials; however, these trials have been of short duration (maximum, 4 to 5 months). The majority of documented symptoms are GI in nature. ^3, , ^20, , ^21, , ^24, Inhibition of testosterone production has been demonstrated by butterbur extracts in animal experiments. ^29, Liver function was unaffected in a 2-week trial of a commercial (pyrrolizidine-free) preparation, but the trial was not large enough to establish harm. ²⁴

Pyrrolizidine alkaloids are liver toxins with carcinogenic and mutagenic potential. ^2, , ^3, , ^4, , ³⁶ Commercial butterbur preparations utilize an extraction process to remove the pyrrolizidine content.

1. USDA, NRCS. The PLANTS Database . (http://plants.usda.gov, October 2006). National Plant Data Center, Baton Rouge, LA 70874-4490 USA.

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3. Shimoda H , Tanaka J , Yamada E , Morikawa T , Kasajima N , Yoshikawa M . Anti type I allergic property of Japanese butterbur extract and its mast cell degranulation inhibitory ingredients. J Agric Food Chem . 2006;54:2915-2920. PubMed

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11. Debrunner B, Neuenschwander M. Sesquiterpenes of Petasites hybridus (L.) G.M. et Sch.: influence of locations and seasons on sesquiterpene distribution. Pharm Acta HeIv . 1995;70:315-323.

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13. Siegenthaler P, Neuenschwander M. Analytic investigations of sesquiterpenes of Petasites albus (L.) Gaertn. Pharm Acta HeIv . 1996;71:345-353.

14. Siegenthaler P, Neuenschwander M. Sesquiterpenes from Petasites hybridus ( Furanopetasin chemovar ): separation, isolation and quantitation of compounds from fresh plant extracts. Pharm Acta HeIv . 1997;72:57-67. PubMed

15. Brooks CJ, Keates RA. Biosynthesis of petasin in Petasites hybridus . Phytochemistry . 1972;11:3235-3245.

16. Novotny L, et al. Chemotaxonomy of some European Petasites species. Phytochemistry . 1966;5:1281-1287.

17. Schwendimann JM, Tabacchi R, Jacot-Guillarmod A. Identification of the phenolic compounds in the leaves of Homogyne alpina , Petasites albus , Petasites hybridus , and Adenostyles alliariae . HeIv Chim Acta . 1974;57:552-557.

18. Gex-Collet C, Imhof L, Brattström A, Pichler WJ, Helbling A. The butterbur extract petasin has no effect on skin test reactivity induced by different stimuli: a randomized, double-blind crossover study using histamine, codeine, methacholine, and aeroallergen solutions. J Investig Allergol Clin Immunol . 2006;16:156-161. PubMed

19. Schapowal A; Study Group. Treating intermittent allergic rhinitis: a prospective, randomized, placebo and antihistamine-controlled study of Butterbur extract Ze 339. Phytother Res . 2005;19:530-537. PubMed

20. Schapowal A; Petasites Study Group. Randomised controlled trial of butterbur and cetirizine for treating seasonal allergic rhinitis. BMJ . 2002;324:144-146. PubMed

21. Schapowal A; Petasites Study Group. Butterbur Ze339 for the treatment of intermittent allergic rhinitis: dose-dependent efficacy in a prospective, randomized, double-blind, placebo-controlled study. Arch Otolaryngol Head Neck Surg . 2004;130:1381-1386. PubMed

22. Lee DK, Gray RD, Robb FM, Fujihara S, Lipworth BJ. A placebo-controlled evaluation of butterbur and fexofenadine on objective and subjective outcomes in perennial allergic rhinitis. Clin Exp Allergy . 2004;34:646-649. PubMed

23. Lee DK, Carstairs IJ, Haggart K, Jackson CM, Currie GP, Lipworth BJ. Butterbur, a herbal remedy, attenuates adenosine monophosphate induced nasal responsiveness in seasonal allergic rhinitis. Clin Exp Allergy . 2003;33:882-886. PubMed

24. Brattstrom A. A newly developed extract (Ze 339) from butterbur ( Petasites hybridus L.) is clinically efficient in allergic rhinitis (hay fever). Phytomedicine . 2003;10(suppl 4):50-52.

25. Thomet OA, Schapowal A, Heinisch VW, Wiesmann UN, Simon HU. Anti-inflammatory activity of an extract of Petasites hybridus in allergic rhinitis. Int Immunopharmacol . 2002;2:997-1006. PubMed

26. Lee DK, Haggart K, Robb FM, Lipworth BJ. Butterbur, a herbal remedy, confers complementary anti-inflammatory activity in asthmatic patients receiving inhaled corticosteroids. Clin Exp Allergy . 2004;34:110-114.

27. Danesch UC. Petasites hybridus (Butterbur root) extract in the treatment of asthma—an open trial. Altern Med Rev . 2004;9:54-62. PubMed

28. Diener HC, Rahlfs VW, Danesch U. The first placebo-controlled trial of a special butterbur root extract for the prevention of migraine: reanalysis of efficacy criteria. Eur Neurol . 2004;51:89-97.

29. Lipton RB, Göbel H, Einhäupl KM, Wilks K, Mauskop A. Petasites hybridus root (butterbur) is an effective preventive treatment for migraine. Neurology . 2004;63:2240-2244. PubMed

30. Pothmann R, Danesch U. Migraine prevention in children and adolescents: results of an open study with a special butterbur root extract. Headache . 2005;45:196-203. PubMed

31. Brown RP, Gerbarg PL. Herbs and nutrients in the treatment of depression, anxiety, insomnia, migraine, and obesity. J Psychiatr Pract . 2001;7:75-91. PubMed

32. Rapoport AM, Bigal ME. Migraine preventive therapy: current and emerging treatment options. Neurol Sci . 2005;26(suppl 2):s111-s120. PubMed

33. Grossman W, Schmidramsl H. An extract of Petasites hybridus is effective in the prophylaxis of migraine. Altern Med Rev . 2001;6:303-310. PubMed

34. Xie WD, Zhang Q, Li PL, Jia ZJ. Two triterpenoids and other constituents from Petasites tricholobus . Phytochemistry . 2005;66:2340-2345. PubMed

35. Brune K, Bickel D, Peskar BA. Gastro-protective effects of extracts of Petasites hybridus : the role of inhibition of peptido-leukotriene synthesis. Planta Med . 1993;59:494-496. PubMed

36. Chizzola R, Ozelsberger B, Langer T. Variability in chemical constituents in Petasites hybridus from Austria. Biochem Syst Ecol . 2000;28:421-432. PubMed

37. Sok DE, Oh SH, Kim YB, Kang HG, Kim MR. Neuroprotection by extract of Petasites japonicus leaves, a traditional vegetable, against oxidative stress in brain of mice challenged with kainic acid. Eur J Nutr . 2006;45:61-69. PubMed

38. Oh SH, Sok DE, Kim MR. Neuroprotective effects of butterbur and rough aster against kainic acid-induced oxidative stress in mice. J Med Food . 2005;8:169-176. PubMed

39. Cui HS, Kim MR, Sok DE. Protection by petaslignolide A, a major neuroprotective compound in the butanol extract of Petasites japonicus leaves, against oxidative damage in the brains of mice challenged with kainic acid. J Agric Food Chem . 2005;53:8526-8532. PubMed

40. Matsuura H, Amano M, Kawabata J, Mizutani J. Isolation and measurement of quercetin glucosides in flower buds of Japanese butterbur ( Petasites japonicus subsp. gigantea Kitam.). Biosci Biotechnol Biochem . 2002;66:1571-1575. PubMed

41. Lin CH, Li CY, Wu TS. A novel phenylpropenoyl sulfonic acid and a new chlorophyll from the leaves of Petasites formosanus KITAMURA. Chem Pharm Bull (Tokyo) . 2004;52:1151-1152. PubMed

42. Wang GJ, Shum AY, Lin YL, et al. Calcium channel blockade in vascular smooth muscle cells: major hypotensive mechanism of S-petasin, a hypotensive sesquiterpene from Petasites formosanus . J Pharmacol Exp Ther . 2001;297:240-246. PubMed

43. Wang GJ, Liao JF, Hintz KK, et al. Calcium-antagonizing activity of S-petasin, a hypotensive sesquiterpene from Petasites formosanus , on inotropic and chronotropic responses in isolated rat atria and cardiac myocytes. Naunyn Schmiedebergs Arch Pharmacol . 2004;369:322-329. PubMed

44. Wang GJ, Wu XC, Lin YL, et al. Ca²⁺ channel blocking effect of iso-S -petasin in rat aortic smooth muscle cells. Eur J Pharmacol . 2002;445:239-245. PubMed

45. Esberg LB, Wang GJ, Lin YL, Ren J. Iso-S -petasin, a hypotensive sesquiterpene from Petasites formosanus , depresses cardiac contraction and intracellular Ca²⁺ transients in adult rat ventricular myocytes. J Pharm Pharmacol . 2003;55:103-107. PubMed

46. Rapoport AM, Bigal ME. Preventive migraine therapy: what is new? Neurol Sci . 2004;25(suppl 3):S177-S185. PubMed