Review of the traditional uses, phytochemistry, pharmacology and toxicology of giant fennel (Ferula communis L. subsp. communis)

Document Type: Review Article


Biotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran


Ferula communis L., subsp. communis, namely giant fennel, has extensively been used in traditional medicine for a wide range of ailments. Fresh plant materials, crude extracts and isolated components of F. communis showed a wide spectrum of in vitro and in vivo pharmacological properties including antidiabetic, antimicrobial, antiproliferative, and cytotoxic activities. The present paper, reviews the traditional uses, botany, phytochemistry, pharmacology and toxicology of F. communis in order to reveal its therapeutic potential and future research opportunities. A bibliographic literature search was conducted in different scientific databases and search engines including Scopus, Cochrane Library, Embase, Google Scholar, Pubmed, SciFinder, and Web of science. Phytochemical studies have led to the isolation of different compounds such as sesquiterpenes from F. communis. This plant has two different chemotypes, the poisonous and non-poisonous chemotypes. Each chemotype is endowed with various constituents and different activities. The poisonous chemotype exhibits anticoagulant and cytotoxic activities with sesquiterpene coumarins as major constituents, while the non-poisonous one exhibits estrogenic and cytotoxic effects with daucane sesquiterpene esters as the main compounds. In addition, although various pharmacological properties have been reported for F. communis, anti-microbial activities of the plant have been investigated in most studies. Studies revealed that F. communis exhibits different biological activities, and contains various bioactive compounds. Although, antibacterial and cytotoxic activities are the two main pharmacological effects of this plant, further studies should focus on the mechanisms underlying these actions, as well as on those biological activities that have been reported traditionally.


1. Iranshahi M, Amin GR, Jalalizadeh H, Shafiee A. New germacrane derivative from Ferula persica Willd. var. latisecta Chamberlain. Pharm Biol 2003; 41:431-433.

2. Iranshahi M, Ghiadi M, Sahebkar A, Rahimi A, Bassarello C, Piacente S, et al. Badrakemonin, a new eremophilane-type sesquiterpene from the roots of Ferula badrakema Kos.-Pol. Iran J Pharm Res 2009; 8:275-279.

3. Iranshahi M, Rezaee R, Sahebkar A, Bassarello C, Piacente S, Pizza C. Sesquiterpene coumarins from the fruits of Ferula badrakema. Pharm Biol 2009; 47:344-347.

4. Iranshahi M, Kalateghi F, Sahebkar A, Sardashti A, Schneider B. New sesquiterpene coumarins from the roots Ferula flabelliloba. Pharm Biol 2010; 48:217-220.

5. Iranshahi M, Masullo M, Asili A, Hamedzadeh A, Jahanbin B, Festa M, et al. Sesquiterpene coumarins from Ferula gumosa. J Nat Prod 2010; 73:1958-1962.

6. Kasaian J, Iranshahy M, Masullo M, Piacente S, Ebrahimi F, Iranshahi M. Sesquiterpene lactones from Ferula oopoda and their cytotoxic properties. J Asian Nat Prod Res 2014; 16:248-253.

7. Iranshahi M, Amin G, Amini M, Shafiee A. Sulfur containing derivatives from Ferula persica var.  latisecta. Phytochemistry 2003; 63:965-966.

8. Iranshahi M,  Amin G, Salehi Sourmaghi MH, Shafiee A, Hadjiakhoondi A. Sulphur containing compounds in the essential oil of Ferula persica Willd. var. persica. Flavour Frag J 2006; 21:260-261.

9. Iranshahi M, Hassanzadeh-Khayyat MH, Fazly Bazzaz BS, Sabeti Z, Enayati F. High content of polysulphides in the volatile oil of Ferula latisecta Rech. F. et Aell. fruits and antimicrobial activity of the oil. J Essent Oil Res 2008; 20:183-185.

10. Iranshahi M. A review of volatile sulfur-containing compounds from terrestrial plants: biosynthesis, distribution and analytical methods. J Essent Oil Res 2012; 24:393-434.

11. Appendino G, Tagliapietra S, Gariboldi P, Mario Nano G, Picci V. ω-Oxygenated prenylated coumarins from Ferula communis. Phytochemistry 1988; 27:3619-3624.

12. Fraigui O, Lamnaouer D, Faouzi MYA. Acute toxicity of ferulenol, a 4-hydroxycoumarin isolated from Ferula communis L. Vet Hum Toxicol 2002; 44:5-7.

13. Arnoldi L, Ballero M, Fuzzati N, Maxia A, Mercalli E, Pagni L. HPLC-DAD-MS identification of bioactive secondary metabolites from Ferula communis roots. Fitoterapia 2004; 75:342-354.

14. Appendino G, Cravotto G, Sterner O, Ballero M. Oxygenated sesquiterpenoids from a nonpoisonous sardinian chemotype of giant fennel (Ferula communis). J Nat Prod 2001; 64:393-395.

15. Gunther RT. The Greek Herbal of Dioscortdes. New York: Hafner; 1959.

16. Heywood VH. The Biology and Chemistry of the Umbellifercre. London: Academic Press; 1972.p.1247-1249.

17. Collenette S. An Illustrated Guide to the Flowers of Saudi Arabia. London:Scorpion Publishing Ltd; 1985.

18. Bnouham M, Mekhfi H, Legssyer A, Ziyyat A. Medicinal plants used in the treatment of diabetes in Morocco. Int J Diabetes Metabol 2002; 10:33-50.

19. Dioscorides. DE MATERIA MEDICA. South Africa: AIBIDIS PRESS; 2000.p. 468.

20. Valle MG, Appending G, Nano GM, Picci V. Prenylated coumarins and sesquiterpenoids from Ferula communis. Phytochemistry 1986; 26:253-256.

21. Miski M, Mabry TJ. Daucane esters from Ferula communis subsp. communis. Phytochemistry 1985; 24:1735-1741.

22. Miski M, Jakupovic J. Cyclic farnesyl-coumarin and farnesyl-chromone derivatives from Ferula communis subsp. communis. Phytochemistry 1990; 29:1995-1998.

23. Valle MG, Appendino G, Nano GM, Picci V. Prenylated coumarins and sesquiterpenoids from Ferula communis. Phytochemistry 1986; 26:253-256.

24. Appendino G, Tagliapietra S, Nano GM, Picci V. Ferprenin, a prenylated coumarin from Ferula communis. Phytochemistry 1988; 27:944-946.

25. Lamnaouer D, Bodo B, Martin MT, Molho D. Ferulenol and ω-hydroxyferulenol, toxic coumarins from Ferula communis var. genuina. Phytochemistry 1987; 26:1613-1615.

26. Appendino G, Tagliapietra S, Paglino L, Nano GM, Monti D, Ppicci V. Sesquiterpenoid esters from the fruits of Ferula communis. Phytochemistry 1990; 29:1481-1484.

27. Abd El-Razek MH, Ohta S, Hirata T. Terpenoid coumarins of the genus Ferula. Heterocycles 2003; 60:689–716.

28. Iranshahi M, Amanolahi F, Schneider B. New sesquiterpene coumarin from the roots of Ferula latisecta. Avicenna J Phytomed 2012; 2:133-138.

29. Nazari ZE, Iranshahi M. Biologically active sesquiterpene coumarins from Ferula species. Phytother Res 2011; 25:315-323.

30. Carboni S, Malaguzzi V, Marsili A. Ferulenol a new coumarin derivative from Ferula communis. Tetrahedron Lett 1964; 5:2783-2786.

31. Mamoci E, Cavoski I, Simeone V, Mondelli D, Al-Bitar L, Caboni P. Chemical composition and in vitro activity of plant extracts from Ferula communis and Dittrichia viscosa against postharvest fungi. Molecules 2011; 16:2609-2625.

32. Lamnaouer D, Fraigui O, Martin MT, Gallard JF, Bodo B. Structure of isoferprenin, a 4-hydroxycoumarin derivative from Ferula communis var. genuina. J Nat Prod 1991; 54:576-578.

33. Appendino G, Tagliapietra S, Crarotto G, Nano GM. Structure and synthesis of a prenylated acetophene from Ferula communis. Gaz Chem Ital 1989; 119:385±388.

34. Pinar M, Rodriguez B. A new coumarin from Ferula loscosii and the correct structure of coladonin. Phytochemistry 1977; 16:1987-1989.

35. Abu-Gabal NS, Edris FM, Abu Mustafa EA. Further investigation on Ferula communis grown in Saudi Arabia. Egypt J Chem 2008; 51:107-114.

36. Iranshahi M, Amin G, Shafiee A. A New Coumarin from Ferula persica. Pharm Biol 2004; 42:440-442.

37. Iranshahi M, Shahverdi AR, Mirjani R, Amin G, Shafiee A. Umbelliprenin from Ferula persica roots inhibits the red pigment production in Serratia marcescens. Z Natur forsch C 2004; 59:506-508.

38. Miski M, Mabry TJ. Fercolide, a type of sesquiterpene lactone from Ferula communis subsp. communis and the correct structure of vaginatin. Phytochemistry 1986; 25:1673-1675.

39. Lamnaouer D, Martin MT, Molho D, Bodo B. Isolation of daucane esters from Ferula communis var. brevifolia. Phytochemistry 1989; 28:2711-2716.

40. Al-Yahya MA, Muhammad I, Mirza HH, El-Feraly FS. Antibacterial constituents from the rhizomes of Ferula communis. Phytother Res 1998; 12:335-339.

41. Sahebkar A, Iranshahi M. Volatile constituents of the genus Ferula (Apiaceae): A review. J Essent Oil Bear Pl 2011; 14:504-531.

42. Sahebkar A, Iranshahi M. Biological activities of essential oils from the genus Ferula (Apiaceae). Asian Biomed 2010; 4:835-847.

43. Ferrari B, Tomi F, Casanova J. Composition and chemical variability of Ferula communis essential oil from Corsica. Flavour Frag J 2005; 20:180-185.

44. Marongiu B, Piras A, Porcedda S. Comparative analysis of the oil and supercritical CO2 extract of Ferula communis L. J Essent Oil Res 2005; 17:150-152.

45. Manolakou S, Tzakou O, Yannitsaros A. Volatile constituents of Ferula communis L. subsp. communis growing spontaneously in Greece. Record Nat Prod 2013; 7:54-58.

46. Maggi F, Lucarini D, Tirillini B, Sagratini G, Papa F, Vittori S. Chemical analysis of the essential oil of Ferula glauca L. (Apiaceae) growing in Marche (central Italy). Biochem Syst Ecol 2009; 37:432-441.

47. Miski M, Mabry TJ, Bohlmann F. Fercoperol, an unusual cyclic-endoperoxynerolidol derivative from Ferula communis subsp. communis. J Nat Prod 1986; 49:916-918.

48. De Pascual Teresa J, Villaseco MA, Hernandez JM. Complex acetylenes from the roots of Ferula communis. Planta Med 1986; 6:458-462.

49. Unasho A, Geyid A, Melaku A, Debela A, Mekasha A, Girma S, et al. Investigation of antibacterial activities of Albizia gummifera and Ferula communis on Streptococcus pneumoniae and Streptoccus pyogenes. Ethiop Med J 2009; 47:25-32.

50. Mossa JS, El-Feraly FS, Muhammad I. Antimycobacterial constituents from Juniperus procera, Ferula communis and Plumbago zeylanica and their in vitro synergistic activity with isonicotinic acid hydrazide. Phytother Res 2004; 18:934-937.

51. Mamoci E, Cavoski I, Andres MF, Díaz CE, Gonzalez-Coloma A. Chemical characterization of the aphid antifeedant extracts from Dittrichia viscosa and Ferula communis. Biochem Syst Ecol 2012; 43:101-107.

52. Bruneton J. Toxic plants dangerous to human and animals. Paris: Lavoiser publishing Inc; 1999.

53. Rubiolo P, Matteodo M, Riccio G, Ballero M, Christen P, Fleury-Souverain S, et al. Analytical discrimination of poisonous and nonpoisonous chemotypes of giant fennel (Ferula communis L.) through their biologically active and volatile fractions. J Agr Food Chem 2006; 54:7556-7563.

54. Carta A. Ferulosis; isolation of the substance with hypoprothrombinemizing action from the galbanum of Ferula communis. La ferulosi; l'isolamento della sostanza and azione ipoprotrombinemizzante dal galbano della Ferula communis. Boll Soc Ital Biol Sper 1951; 27:690-693.

55. Lamnaouer D. Anticoagulant activity of coumarins from Ferula communis L. Therapie 1999; 54:747-751.

56. Tagliapietra S, Aragno M, Ugazio G, Nano GM. Experimental studies on the toxicity of some compounds isolated from Ferula communis in the rat. Res Commun Chem Pathol Pharmacol 1989; 66:333-336.

57. Alzweiri M, Al-Shudeifat M, Al-Khaldi K, Al-Hiari Y, Afifi FU. Acetylated ferulenol-oxy-ferulenol as a proposed marker for fresh Ferula toxicity: A metabolomic approach. J Liq Chromatogr Relat Technol 2015; 38:283-288.

58. Lahouel M, Zini R, Zellagui A, Rhouati S, Carrupt P-A, Morin D. Ferulenol specifically inhibits succinate ubiquinone reductase at the level of the ubiquinone cycle. Biochem Biophys Res Commun 2007; 355:252-257.

59. Monti M, Pinotti M, Appendino G, Dallocchio F, Bellini T, Antognoni F, et al. Characterization of anti-coagulant properties of prenylated coumarin ferulenol. Biochim Biophys Acta 2007; 1770:1437-1440.

60. Tligui N, Ruth GR, Felice LJ. Plasma ferulenol concentration and activity of clotting factors in sheep with Ferula communis variety brevifolia intoxication. Am J Vet Res 1994; 55:1564-1569.

61. Bocca C, Gabriel L, Bozzo F, Miglietta A. Microtubule-interacting activity and cytotoxicity of the prenylated coumarin ferulenol. Planta Med 2002; 68:1135-1137.

62. Poli F, Appendino G, Sacchetti G, Ballero M, Maggiano N, Ranelletti FO. Antiproliferative effects of daucane esters from Ferula communis and F. arrigonii on human colon cancer cell lines. Phytother Res 2005; 19:152-157.

63. Macho A, Blanco-Molina M, Spagliardi P, Appendino G, Bremner P, Heinrich M, et al. Calcium ionophoretic and apoptotic effects of ferutinin in the human Jurkat T-cell line. Biochem Pharmacol 2004; 68:875-883.

64. Dall'Acqua S, Linardi MA, Maggi F, Nicoletti M, Petitto V, Innocenti G, et al. Natural daucane sesquiterpenes with antiproliferative and proapoptotic activity against human tumor cells. Bioorg Med Chem 2011; 19:5876-5885.

65. Dall’Acqua S, Linardi MA, Bortolozzi R, Clauser M, Marzocchini S, Maggi F, et al. Natural daucane esters induces apoptosis in leukaemic cells through ROS production. Phytochemistry 2014; 108:147–156.

66. GliszczyƄska ABrodelius PE. Sesquiterpene coumarins. Phytochem Rev 2012; 11:77-96.

67. Saidkhodzhaev AI, Nikonov GK. The structure of ferutinin. Chem Nat Compd 1975; 9:25-26.

68. Zamaraeva MV, Hagelgans AI, Abramov AY, Ternovsky VI, Merzlyak PG, Tashmukhamedov BA, et al. Ionophoretic properties of ferutinin. Cell Calcium 1997; 22:235-241.

69. Abramov AY, Zamaraeva MV, Hagelgans AI, Azimov RR, Krasilnikov OV. Influence of plant terpenoids on the permeability of mitochondria and lipid bilayers. Biochim Biophys Acta 2001; 1512:98-110.

70. Zamaraeva M, Charishnikova O, Saidkhodjaev A, Isidorov V, Granosik M, Rózalski M, et al. Calcium mobilization by the plant estrogen ferutinin does not induce blood platelet aggregation. Pharmacol Rep 2010; 62:1117-1126.

71. Macho A, Blanco-Molina M, Spagliardi P, Appendino G, Bremner P, Heinrich M, et al. Calcium ionophoretic and apoptotic effects of ferutinin in the human Jurkat T-cell line. Biochem Pharmacol 2004; 68:875-883.

72. Matin MM, Nakhaeizadeh H, Bahrami AR, Iranshahi M, Arghiani N, Rassouli FB. Ferutinin, an apoptosis inducing terpenoid from Ferula ovina. Asian Pac J Cancer Prev 2014; 15:2123-2128.

73. Ferretti M, Cavani F, Manni P, Carnevale G, Bertoni L, Zavatti M, et al. Ferutinin dose-dependent effects on uterus and mammary gland in ovariectomized rats. Histol Histopathol 2014; 29:1027-1037.

74. Arghiani N, Matin MM, Bahrami AR, Iranshahi M, Sazgarnia A, Rassouli FB. Investigating anticancer properties of the sesquiterpene ferutinin on colon carcinoma cells, in vitro and in vivo. Life Sci 2014; 109:87-94.

75. Appendino G, Spagliardi P, Cravotto G, Pocock V, Milligan S. Daucane Phytoestrogens:  A Structure−Activity Study. J Nat Prod 2002; 65:1612-1615.

76. Gao M, Wong SY, Lau PM, Kong SK. Ferutinin induces in vitro eryptosis/erythroptosis in human erythrocytes through membrane permeabilization and calcium influx. Chem Res Toxicol 2013; 26:1218-1228.

77. Fu SW, Zeng GF, Zong SH, Zhang ZY, Zou B, Fang Y,   et al. Systematic review and meta-analysis of the bone protective effect of phytoestrogens on osteoporosis in ovariectomized rats. Nutr Res 2014; 34:467-477.

78. Ferretti M, Bertoni L, Cavani F, Zavatti M, Resca E, Carnevale G, et al. Influence of ferutinin on bone metabolism in ovariectomized rats. II: Role in recovering osteoporosis. J Anat 2010; 217:48-56.

79. Cavani F, Ferretti M, Carnevale G, Bertoni L, Zavatti M, Palumbo C. Effects of different doses of ferutinin on bone formation/resorption in ovariectomized rats. J Bone Miner Metab 2012; 30:619-629.

80. Zavatti M, Resca E, Bertoni L, Maraldi T, Guida M, Carnevale G, et al. Ferutinin promotes proliferation and osteoblastic differentiation in human amniotic fluid and dental pulp stem cells. Life Sci 2013; 92:993-1003.

81. Geroushi A, Auzi AA, Elhwuegi AS, Elzawam F, Elsherif A, Nahar L, et al. Antiinflammatory sesquiterpenes from the root oil of Ferula hermonis. Phytother Res 2011; 25:774-777.

82. Abourashed EA, Galal AM, Shibl AM. Antimycobacterial activity of ferutinin alone and in combination with antitubercular drugs against a rapidly growing surrogate of Mycobacterium tuberculosis. Nat Prod Res 2011; 25:1142-1149.

83. Al-Ja'Fari AH, Vila R, Freixa B, Costa J, Cañigueral S. Antifungal compounds from the rhizome and roots of Ferula hermonis. Phytother Res 2013; 27:911-915.

84. Zanoli P, Rivasi M, Zavatti M, Brusiani F, Vezzalini F, Baraldi M. Activity of single components of Ferula hermonis on male rat sexual behavior. Int J Impot Res 2005; 17:513-518.

85. Zavatti M, Montanari C, Zanoli P. Role of ferutinin in the impairment of female sexual function induced by Ferula hermonis. Physiol Behav 2006; 89:656-661.

86. Zanoli P, Zavatti M, Geminiani E, Corsi L, Baraldi M. The phytoestrogen ferutinin affects female                   sexual behavior modulating ERα expression in the hypothalamus. Behav Brain Res 2009; 199:283-287.

87. Al-Mughrabi KI, Aburjai TA. Fungitoxic activity of root extracts from Ferula harmonis. Phytopathol Mediterr 2003; 42:141-148.

88. Appendino G, Tagliapietra S, Nano GM, Picci V. An anti-platelet acetylene from the leaves of Ferula communis. Fitoterapia 1993; 64:179.

89. Lamnaouer D. Anticoagulant activity of the coumarins of Ferula communis L. Activite anticoagulante des coumarines de Ferula communis L. Therapie 1999; 54:747-751.

90. Appendino G, Mercalli E, Fuzzati N, Arnoldi L, Stavri M, Gibbons S, et al. Antimycobacterial coumarins from the Sardinian giant fennel (Ferula communis). J Nat Prod 2004; 67:2108-2110.

91. Lahouel M, Zini R, Zellagui A, Rhouati S, Carrupt PA, Morin D. Ferulenol specifically inhibits succinate ubiquinone reductase at the level of the ubiquinone cycle. Biochem Biophys Res Commun 2007; 355:252-257.