Feverfew

• How It Works

  Feverfew may benefit patients with migraine headaches.

  One or more compounds found in feverfew are thought to prevent migraines. One such compound, parthenolide, was found to block the formation of inflammatory proteins. A feverfew extract was shown to reduce the number of migraine attacks and also decrease the mild headache that occurs before a migraine attack.

  Feverfew also showed anticancer effects in lab studies. Human studies are needed.

• Purported Uses
  • To prevent migraine headaches
    Some clinical trials support this use. Post-feverfew withdrawal syndrome (consisting of muscle stiffness, anxiety, headaches, nausea, and vomiting) can occur after patients discontinue using this herb.
  • To treat arthritis
    Although compounds in feverfew show anti-inflammatory activity in the laboratory, a clinical trial did not support this use.
  • To relieve painful and heavy menstruation
    No scientific evidence supports this use.
  • To treat psoriasis
    Although compounds in feverfew show anti-inflammatory activity in the laboratory, human data are lacking.
• Do Not Take If

  You are allergic to ragweed, chrysanthemums, marigolds, or other members of the Compositae family.
  You are taking Cytochrome P450 3A4 substrate drugs: Feverfew may increase the risk of side effects of these drugs.
  You are taking anticoagulant/antiplatelet drugs: Feverfew may increase the risk of bleeding.

• Side Effects
  • Stomach upset
  • Red, itchy rash
  • Mouth ulcerations when chewing fresh feverfew leaves
  • Withdrawal symptoms (post-feverfew syndrome): May occur when patients stop taking feverfew after a long period of time. These include muscle stiffness, anxiety, moderate pain, headache, nausea, and vomiting.
• Scientific Name

  Tanacetum parthenium

• Clinical Summary

  Feverfew is a plant that belongs to the daisy/sunflower family of flowering plants. It is widely used in traditional medicine for the treatment of fevers, migraine headaches, rheumatoid arthritis, stomach ache, toothache, insect bites and infertility.

  Although much of its activity is attributed to the compound parthenolide, a parthenolide-free extract of feverfew demonstrated free radical-scavenging properties, affording protection against UV-induced sun damage ⁽¹⁾. Feverfew extracts also possess antiprotozoal ⁽²⁾, antibacterial ⁽³⁾, anti-inflammatory ^(1) (4), and antioxidant ⁽⁵⁾ properties.

  In clinical trials, a feverfew extract reduced the frequency of migraine attacks ⁽⁶⁾ and a feverfew/ginger formulation prevented mild headache before the onset of moderate to severe headache in patients with migraine ⁽⁷⁾. In another study, a combination of feverfew and acupuncture treatments led to greater improvements in quality of life in women with migraine, compared with feverfew or acupuncture alone ⁽⁸⁾. Despite anti-inflammatory benefits, a clinical trial did not find benefit for patients with rheumatoid arthritis ⁽⁹⁾.

  Parthenolide from feverfew has demonstrated anticancer effects in vitro ^{(10) (11) (12) (13) (14) (15) (16) (17)}. A phase I clinical study involving cancer patients showed that up to 4 mg of parthenolide was well tolerated; however, parthenolide could not be detected in the plasma ⁽¹⁸⁾. Consequently, a synthetic analog dimethylamino-parthenolide (DMAPT), a more hydrophilic form of parthenolide, with greater bioavailability was identified. Oral administration of DMAPT has been found to be safe and resulted in increased plasma concentrations in an animal model ⁽¹⁹⁾. More studies are warranted.

• Purported Uses
  • Arthritis
  • Dysmenorrhea
  • Migraine prophylaxis
  • Psoriasis
• Mechanism of Action

  The sesquiterpene lactones, particularly parthenolide, are the active constituents responsible for feverfew’s beneficial effects. Parthenolide attenuates activation of the NF-kappa B complex to block transcription of inflammatory proteins ⁽²¹⁾. The inhibition of this pathway also leads to decreased platelet activity ⁽²²⁾. Other mechanisms that produce antiplatelet activity by parthenolide include sulfhydryl group alterations, changes in protein kinase C interactions, and arachidonic acid metabolism ^{(22) (23) (24)}. The flavonol content also has anti-inflammatory effects ^(25) (26).

  In vitro studies suggest various activities induced by parthenolide can produce antiproliferative effects. In colorectal cancer cells, it suppresses angiogenesis by reducing VEGF and VEGF-receptor expression. ⁽¹⁰⁾ In cervical and breast cancer cell lines, parthenolide modulates apoptosis-regulating gene expression ⁽¹¹⁾ and activates both apoptosis pathway and AMPK-autophagy survival pathway through ROS generation ⁽¹²⁾. In glioblastoma cells, it induces caspase 3/7-mediated apoptosis independent of NF-kappa B suppression ⁽²⁷⁾. Parthenolide sensitizes the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) leading to apoptosis via activation of both caspases 8 and 3 in hepatocellular carcinoma cells ⁽¹⁷⁾.

• Contraindications

  Individuals allergic to ragweed, chrysanthemums, marigolds, or other members of the Compositae family may have cross-sensitivity to feverfew.

• Adverse Reactions

  Common: Minor gastrointestinal distress; oral ulcerations from chewing fresh feverfew leaves; airborne contact dermatitis ⁽²⁸⁾; exacerbated dermatitis following use of a moisturizer containing feverfew ⁽²⁹⁾.

  Withdrawal symptoms: Muscle stiffness, anxiety, and moderate pain usually occur following cessation of long-term use of feverfew (referred to as the post-feverfew syndrome) ⁽²⁵⁾.

• Herb-Drug Interactions

  Cytochrome P450 3A4 substrates: Feverfew inhibits CYP1A2/2C8/2C9/2C19/2D6 and 3A4, and can affect the intracellular concentration of drugs metabolized by these enzymes ⁽³⁰⁾.

  Anticoagulants/antiplatelets: The active constituent in feverfew inhibits platelet activity and may have additive effects ^{(22) (23) (24) (31)}.

• References

  1. Martin K, Sur R, Liebel F, et al. Parthenolide-depleted feverfew (Tanacetum parthenium) protects skin from UV irradiation and external aggression. Arch Dermatol Res. Feb 2008;300(2):69-80. doi: 10.1007/s00403-007-0818-x

  2. Izumi E, Morello LG, Ueda-Nakamura T, et al. Trypanosoma cruzi: antiprotozoal activity of parthenolide obtained from Tanacetum parthenium (L.) Schultz Bip. (Asteraceae, Compositae) against epimastigote and amastigote forms. Exp Parasitol. Mar 2008;118(3):324-330. doi: 10.1016/j.exppara.2007.08.015

  3. Mohsenzadeh F, Chehregani A, Amiri H. Chemical composition, antibacterial activity and cytotoxicity of essential oils of Tanacetum parthenium in different developmental stages. Pharm Biol. Sep 2011;49(9):920-926. doi: 10.3109/13880209.2011.556650

  4. Mathema VB, Koh YS, Thakuri BC, et al. Parthenolide, a sesquiterpene lactone, expresses multiple anti-cancer and anti-inflammatory activities. Inflammation. Apr 2012;35(2):560-565. doi: 10.1007/s10753-011-9346-0

  5. Wu C, Chen F, Wang X, et al. Identification of antioxidant phenolic compounds in feverfew (Tanacetum parthenium) by HPLC-ESI-MS/MS and NMR. Phytochem Anal. Sep-Oct 2007;18(5):401-410. doi: 10.1002/pca.995

  6. Diener HC, Pfaffenrath V, Schnitker J, et al. Efficacy and safety of 6.25 mg t.i.d. feverfew CO2-extract (MIG-99) in migraine prevention – A randomized, double-blind, multicentre, placebo-controlled study. Cephalalgia. Nov 2005;25(11):1031-1041. doi: 10.1111/j.1468-2982.2005.00950.x

  7. Cady RK, Goldstein J, Nett R, et al. A double-blind placebo-controlled pilot study of sublingual feverfew and ginger (LipiGesic M) in the treatment of migraine. Headache. Jul-Aug 2011;51(7):1078-1086. doi: 10.1111/j.1526-4610.2011.01910.x

  8. Ferro EC, Biagini AP, da Silva IE, et al. The combined effect of acupuncture and Tanacetum parthenium on quality of life in women with headache: randomised study. Acupunct Med. Dec 2012;30(4):252-257. doi: 10.1136/acupmed-2012-010195

  9. Pattrick M, Heptinstall S, Doherty M. Feverfew in rheumatoid arthritis: a double blind, placebo controlled study. Ann Rheum Dis. Jul 1989;48(7):547-549.

  10. Kim SL, Lee ST, Trang KT, et al. Parthenolide exerts inhibitory effects on angiogenesis through the downregulation of VEGF/VEGFRs in colorectal cancer. Int J Mol Med. May 2014;33(5):1261-1267. doi: 10.3892/ijmm.2014.1669

  11. Al-Fatlawi AA, Al-Fatlawi AA, Irshad M, et al. Effect of parthenolide on growth and apoptosis regulatory genes of human cancer cell lines. Pharm Biol. Jan 2015;53(1):104-109. doi: 10.3109/13880209.2014.911919

  12. Lu C, Wang W, Jia Y, et al. Inhibition of AMPK/autophagy potentiates parthenolide-induced apoptosis in human breast cancer cells. J Cell Biochem. Aug 2014;115(8):1458-1466. doi: 10.1002/jcb.24808

  13. Yip-Schneider MT, Nakshatri H, Sweeney CJ, et al. Parthenolide and sulindac cooperate to mediate growth suppression and inhibit the nuclear factor-kappa B pathway in pancreatic carcinoma cells. Mol Cancer Ther. Apr 2005;4(4):587-594. doi: 10.1158/1535-7163.MCT-04-0215

  14. Zhang S, Ong CN, Shen HM. Involvement of proapoptotic Bcl-2 family members in parthenolide-induced mitochondrial dysfunction and apoptosis. Cancer Lett. Aug 10 2004;211(2):175-188. doi: 10.1016/j.canlet.2004.03.033

  15. Parada-Turska J, Paduch R, Majdan M, et al. Antiproliferative activity of parthenolide against three human cancer cell lines and human umbilical vein endothelial cells. Pharmacol Rep. Mar-Apr 2007;59(2):233-237.

  16. Lesiak K, Koprowska K, Zalesna I, et al. Parthenolide, a sesquiterpene lactone from the medical herb feverfew, shows anticancer activity against human melanoma cells in vitro. Melanoma Res. Feb 2010;20(1):21-34. doi: 10.1097/CMR.0b013e328333bbe4

  17. Carlisi D, D’Anneo A, Angileri L, et al. Parthenolide sensitizes hepatocellular carcinoma cells to TRAIL by inducing the expression of death receptors through inhibition of STAT3 activation. J Cell Physiol. Jun 2011;226(6):1632-1641. doi: 10.1002/jcp.22494

  18. Curry EA, 3rd, Murry DJ, Yoder C, et al. Phase I dose escalation trial of feverfew with standardized doses of parthenolide in patients with cancer. Invest New Drugs. Aug 2004;22(3):299-305. doi: 10.1023/B:DRUG.0000026256.38560.be

  19. Guzman ML, Rossi RM, Neelakantan S, et al. An orally bioavailable parthenolide analog selectively eradicates acute myelogenous leukemia stem and progenitor cells. Blood. Dec 15 2007;110(13):4427-4435. doi: 10.1182/blood-2007-05-090621

  20. Pareek A, Suthar M, Rathore GS, et al. Feverfew (Tanacetum parthenium L.): A systematic review. Pharmacogn Rev. Jan 2011;5(9):103-110. doi: 10.4103/0973-7847.79105

  21. Reuter U, Chiarugi A, Bolay H, et al. Nuclear factor-kappaB as a molecular target for migraine therapy. Ann Neurol. Apr 2002;51(4):507-516.

  22. Sahler J, Bernard JJ, Spinelli SL, et al. The feverfew plant-derived compound, parthenolide enhances platelet production and attenuates platelet activation through NF-kappaB inhibition. Thromb Res. May 2011;127(5):426-434. doi: 10.1016/j.thromres.2010.12.013

  23. Groenewegen WA, Heptinstall S. A comparison of the effects of an extract of feverfew and parthenolide, a component of feverfew, on human platelet activity in-vitro. J Pharm Pharmacol. Aug 1990;42(8):553-557.

  24. Heptinstall S, White A, Williamson L, et al. Extracts of feverfew inhibit granule secretion in blood platelets and polymorphonuclear leucocytes. Lancet. May 11 1985;1(8437):1071-1074.

  25. Johnson ES, Kadam NP, Hylands DM, et al. Efficacy of feverfew as prophylactic treatment of migraine. Br Med J (Clin Res Ed). Aug 31 1985;291(6495):569-573.

  26. Williams CA, Hoult JR, Harborne JB, et al. A biologically active lipophilic flavonol from Tanacetum parthenium. Phytochemistry. Jan 1995;38(1):267-270.

  27. Anderson KN, Bejcek BE. Parthenolide induces apoptosis in glioblastomas without affecting NF-kappaB. J Pharmacol Sci. Feb 2008;106(2):318-320.

  28. Paulsen E, Christensen LP, Andersen KE. Compositae dermatitis from airborne parthenolide. Br J Dermatol. Mar 2007;156(3):510-515. doi: 10.1111/j.1365-2133.2006.07674.x

  29. Killoran CE, Crawford GH, Pedvis-Leftick A. Two cases of compositae dermatitis exacerbated by moisturizer containing feverfew. Dermatitis. Dec 2007;18(4):225-229.

  30. Unger M, Frank A. Simultaneous determination of the inhibitory potency of herbal extracts on the activity of six major cytochrome P450 enzymes using liquid chromatography/mass spectrometry and automated online extraction. Rapid Commun Mass Spectrom. 2004;18(19):2273-2281. doi: 10.1002/rcm.1621

  31. Collins SC, Dufresne RG, Jr. Dietary supplements in the setting of mohs surgery. Dermatol Surg. Jun 2002;28(6):447-452.

  32. Murphy JJ, Heptinstall S, Mitchell JR. Randomised double-blind placebo-controlled trial of feverfew in migraine prevention. Lancet. Jul 23 1988;2(8604):189-192.