INDEX

Feverfew

(Source: SaluGenecists, Inc.)

Summary

Feverfew, which looks similar to chamomile, is a perennial plant with small, daisy-like flowers. It is cultivated in flower gardens throughout Europe and the United States. The leaf, both with and without the stem, collected when the plant is in flower, is the part used medicinally. It is usually freeze-dried or air-dried and given as a capsule or tablet.

At least 39 constituents of feverfew have been identified; however, controversy continues as to which constituents are responsible for feverfew\’s pharmacological effects. Although the sesquiterpene lactone parthenolide was widely believed to be the active constituent, recent research has suggested that there may be other important active ingredients. The flowering herb also contains essential oils (including chrysanthenyl acetate), flavonoids, monoterpenes and polyacetylene compounds. Melatonin has also been detected.

Experimental studies have confirmed that feverfew has activity similar to common non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin. Extracts of feverfew have been shown to inhibit the release of arachidonic acid from cell membranes as well as the synthesis of compounds which promote inflammation, including inflammatory prostaglandins, leukotrienes, thromboxanes, lactones and tanetin, a lipophilic flavonol.

In addition to its extensive anti-inflammatory properties, feverfew also exerts other physiological effects including the inhibition of platelet aggregation and secretion of allergic mediators, e.g., histamine and serotonin. Its parthenolide component has been shown to produce a tonic effect on vascular smooth muscle, inhibiting the contraction of smooth muscle normally caused by serotonin and phenylephrine. Feverfew constituents have also been shown to have antimicrobial activity and other immune-supporting effects.

Feverfews use in the prevention and treatment of migraine headache is the only condition for which confirmed scientific documentation exists at the present time. Feverfew also has a long history of use for fever, menstrual irregularities, arthritis, psoriasis, allergies, asthma, dyspepsia including indigestion and flatulence, as a general intestinal stimulant and tonic, and to expel worms and intestinal parasites.

Feverfew has been used by large numbers of people for hundreds of years without reports of toxicity and no toxic reactions were reported in patients taking feverfew in a 6 month migraine study. Physical contact with the herb may cause adverse reactions as some sensitive individuals may develop dermatitis from external contact or aphthous ulcerations from chewing on the leaves. Feverfew is contraindicated during pregnancy and for individuals with known hypersensitivity to members of the Compositae family such as ragweed, chrysanthemums, marigolds and daisies. While there are no known drug/nutrient/herb interactions for feverfew, concomitant use of feverfew with herbs that affect platelet aggregation, such as garlic and gingko, or anticoagulant drugs, such as warfarin, could theoretically increase risk of bleeding in some people. Additionally, owing to their effects on prostaglandins, NSAIDs might decrease the effectiveness of feverfew.

Typical dosage varies depending upon the form being used and the health care application for which it is being used.

Key Constituents

  • Feverfew\’s primary active chemicals are its sesquiterpene lactones, which contain an alpha-methylene-gamma-lactone group: in particular those of the germacranolide type, including parthenolide (0.06-0.6%) and 3-beta-hydroxy parthenolide; the guaianolide type and others containing chlorine. The postflowering leaves can contain up to four times as much parthenolide as the preflowering leaves.
  • The flowering herb also contains 0.02-0.07% essential oils (including Chrysanthenyl acetate L-camphor, L-borneol, terpenes, and miscellaneous esters), flavonoids, monoterpenes, and polyacetylene compounds.
  • Melatonin has also been detected In feverfew leaf samples and a commercial preparation (1.37-2.45g/g).

The leaf is the part of feverfew that contains its active components. At least 39 constituents of feverfew have been identified; however, controversy continues as to which constituents are responsible for feverfew\’s pharmacological effects.

The sesquiterpene lactone, parthenolide, was widely believed to be the active constituent, and at least 0.2% parthenolide is thought to be required for efficacy. However, in a Dutch study, an alcoholic extract of feverfew standardized to 0.35% parthenolide was found ineffective for preventing migraine, suggesting that parthenolide may not be the only important active ingredient and that other constituents are necessary for migraine prevention.

Chrysanthenyl acetate, an essential oil of feverfew, has been suggested as one active component in the prevention of migraine. Chrysanthenyl acetate inhibits prostaglandin synthetase and might have analgesic properties.

Historical Use

Feverfew has been used for centuries as a febrifuge to treat colds and febrile diseases, and for the treatment of migraines and arthritis. Eclectic physicians used feverfew as a gastrointestinal tonic, to increase appetite, improve digestion, secretion, and to cleanse the kidneys. Other historical uses of feverfew have been in the treatment of anemia, earache, dysmenorrhea, dyspepsia, trauma, and intestinal parasites. It has also been used as an abortifacient, and in gardens to control noxious pests (its pyrethrin component is an effective insecticide and herbicide).

Physiological Effects

Anti-inflammatory

Feverfew’s long folk history of use in the treatment of inflammatory conditions such as fever, arthritis, and migraine is validated by experimental studies that confirm activity similar to common non-steroidal anti-inflammatory agents (NSAIDs), such as aspirin. In experimental studies, extracts of feverfew have been shown to inhibit the synthesis of compounds which promote inflammation, including inflammatory prostaglandins, leukotrienes, and thromboxanes.

In one study, parthenolide inhibited cyclooxygenase (the enzyme that converts arachidonic acid to prostaglandins) in vitro. The alpha-methylene-gamma-lactone group, specifically, parthenolide also inhibited the expression of inducible cyclooxygenase and proinflammatory cytokines in macrophages. In other studies, aqueous extracts of whole plant and leaf inhibited prostaglandin biosynthesis but did not inhibit cyclooxygenase. Other studies suggest that sesquiterpene lactones, including parthenolide, inhibit the release of arachidonic acid from membrane phospholipid stores rather than its conversion via cyclooxygenase into thromboxane B2. Chloroform extract of feverfew also inhibited uptake and liberation of arachidonic acid into or from platelet membrane phospholipids. Feverfew\’s inhibition of ararchidonic acid release at the initial stage of synthesis is an action more like that of cortisone than NSAIDs.

Multiple active components in feverfew appear to be responsible for these effects. Chloroform extracts of feverfew produced a dose-dependent inhibition of the generation of thromboxane B2 and leukotriene B4 by stimulated leukocytes, and this inhibition was due to the activity of other lactones as well as sesquiterpene lactones. Pharmacological tests also indicate that tanetin, a new lipophilic flavonol isolated from feverfew, also inhibits the generation of proinflammatory eicosanoids and may therefore contribute to feverfew\’s anti-inflammatory activity.

Anti-secretory activity in platelets

Feverfew also has beneficial effects on blood platelet behavior including ihibition of both platelet aggregation and the biosynthesis of inflammatory prostaglandins and arachidonic acid products, and the secretion of allergic mediators, e.g., histamine and serotonin. Feverfew has also been shown to inhibit the release of serotonin from platelets induced by aggregating agents. Feverfew\’s pattern of effects on ploatelets is different from that seen with other inhibitors of platelet aggregation and the effect on polymorphs is more pronounced than that obtained by very high concentrations of NSAIDS. In one study, aqueous extract of feverfew did not inhibit aggregation induced by arachidonic acid, but did inhibit platelet phospholipase A2, suggesting its antiplatelet actions are due to a phospholipase inhibitor that prevents the release of arachidonic acid.

In another study, eleven fractions obtained from chloroform extract of feverfew demonstrated antisecretory activity, while two did not. All active fractions contained compounds with an alpha-methylene-gamma-lactone group.

While in patients taking feverfew, platelets aggregated normally to ADP and thrombin, the aggregation response to serotonin was greatly reduced, implying that while normal clotting mechanisms remain intact, feverfew breaks the biochemical chain of events leading to a migraine.

Feverfew extract was shown to inhibit the activity of polymorphonuclear leucocytes in vitro via blockade of cellular sulphydryl groups. Parthenolide was clearly an important agent, but was not the sole determinant of these effects. It is suggested that the activity of responsible compounds was a result of inhibition of protein kinase C or subsequent events in polymorphonuclear leucocyte activation in vitro.

Chloroform extract of feverfew dose-dependently inhibited histamine release induced by stimulating rat peritoneal mast cdells through an IgE-anti-IgE reaction. The data suggest that feverfew\’s action is different from the inhibition of mast cells caused by cromoglycate and quercitin. Additionally, feverfew extract does not inhibit histamine release by interfering with oxidative phosphorylation.

Inhibition of smooth muscle contraction

Parthenolide has been shown to produce a tonic effect on vascular smooth muscle. Extracts of fresh feverfew (but not chloroform extracts) have been shown to cause a dose- and time-dependent inhibition of the contractile responses of isolated smooth tissue to receptor-acting agonists such as serotonin and phenylephrine. Chloroform extracts of feverfew and parthenolide have inhibited smooth muscle contraction in isolated tissue in a time-dependent, irreversible manner, but the inhibition required the presence of the alpha-methylene-gamma-lactone group. Inhibitory effects are non-specific and may result from interference with postreceptor contractile mechanisms. Their irreversible nature implies a long-lasting toxic effect on tissue.

Anti-microbial activity

Eudesamanolides isolated from feverfew demonstrated antribacterial activity towards Stap. Aureus, E. coli and Salmonella spp. Parthenolide inhibited the growth of Gram-positive bacteria, yeasts and filamentous fungi in vitro.

Essential oil obtained from feverfew flowers showed bacteriocidal and fungicidal activity against most of the 27 organisms tested using agar diffusion and broth dilution. Extracts of feverfew tested similarly also showed activity against Stap. Aureus, Strep. haemolyticus, Sarcina flava and E. coli. Gram-positive species, fungi and dermatophytes were much more sensitive than Gram-negative species.

Other

Other pharmacological effects of feverfew include the cytostatic effect of compounds containing an alpha-methylene-gamma-lactone group on tumor cell growth.

Feverfew extract and parthenolide were cytotoxic (after incubation for 48-72 hours) to mitogen-induced human peripheral blood mononuclear cell proliferation and cytokine-mediated responses. If feverfew is cytotoxic in vivo to lymphocytes or macrophages that are overactive, this might explain its pain relieving effects in rhematoid arthritis.

The sesquiterpene lactone costunolide, which is structurally close to parthenolide, exhibts a strong inhibition of nitric oxide synthase vivonitric oxide synthase inhibitor has been found to significantly reduce the severity of migraine headache.

Typical Use

Feverfews use in the prevention and treatment of migraine headache is the only condition for which confirmed scientific documentation exists at the present time.

Feverfew also has a long history of use for fever, menstrual irregularities, arthritis, psoriasis, allergies, asthma, dyspepsia including indigestion and flatulence, as a general intestinal stimulant and tonic, and to expel worms and intestinal parasites.

Migraine

The combination of feverfew\’s inhibitory effects on blood platelet aggregation, inflammatory processes and smooth muscle contraction are likely responsible for feverfews therapeutic effect in the prevention and treatment of migraine headaches.

Recognition of feverfew\’s effectiveness in the prevention and treatment of migraine headache can be traced back to physician John Hill\’s reference to the herb in his book, The Family Herbal, in which he noted, \”In the worst headache this herb exceeds whatever else is known.\” In 1973, at the suggestion of a friend, Mrs. Anne Jenkins in Wales began taking 3 fresh leaves of feverfew a day to try to rid herself of severe, recurrent migraines. After 10 months, Mrs. Jenkins\’ migraines completely ceased and did not recur as long as she kept taking feverfew.

Word spread, finally attracting the interest of Dr. Steward Johnson, a migraine specialist, who in 1983, began a survey in Britian, which found that 72% of those surveyed (253 with true migraine, many of whom had been unresponsive to orthodox medicine), had experienced a significant decrease in the frequency and/or intensity of their attacks after eating feverfew daily for prolonged periods. In addition, 78% of the 23 people suffering from tension headaches found that feverfew reduced headache frequency and severity. Of the 242 patients who recorded the frequency, 33% no longer had attacks, and 76% had fewer migraines each month compared to before taking feverfew. Associated nausea and vomiting decreased or disappeared. When attacks did occur, conventional painkillers (e.g., aspirin) were more effective, and feverfew users experienced no adverse reactions with their orthodox medications. Lastly, many patients also suffering from arthritis found these symptoms also somewhat relieved by feverfew.

The survey revealed some side effects in a small percentage of users including mouth ulcers or inflammation, but, in contrast, a percentage of other users experienced improved digestion, a sense of well being and improved sleep. These results prompted two double-blind clinical investigations of feverfew\’s preventive and therapeutic effects in the treatment of migraine.

The first study, conducted at the London Migraine Clinic, evaluated 17 patients who reported being helped by feverfew and had been self-medicating with raw feverfew every day for at least 3 months. Those patients given placebo (who therefore stopped using feverfew) experienced a significant increase in the frequency and severity of headache, nausea, and vomiting during the 6 months of the study, while patients taking feverfew showed no change in the frequency or severity of their symptoms. Two patients in the placebo group who had been in complete remission during self-treatment with feverfew leaves developed recurrence of incapacitating migraine and had to withdraw from the study. Renewed remission of symptoms in both patients occurred after self-treatment with feverfew was resumed. Another important finding of this study was that long-term users of feverfew were normal in terms of the large number of biochemical and hematological parameters evaluated.

The results of the second study, which was performed at the University of Nottingham a few years later, clearly demonstrated that feverfew effectively reduced the number and severity of migraine attacks. In this study, 59 patients were randomly allocated to receive either one capsule of dried feverfew leaves (82 mg) daily or placebo. After 4 months, patients were switched to the other treatment for another 4 months. Treatment with feverfew was associated with a reduction in the mean number and severity of attacks and in the degree of vomiting; however, duration of attacks, once commenced, was unaltered.

Since these two initial studies, feverfews efficacy in the prevention of migraine headaches has been demonstrated in several controlled studies. However, one 4 month study by a team of Dutch scientists found that the feverfew preparation used (143mg/day of a granulated ethanolic extract of feverfew containing 0.5mg parthenolide and corresponding to about 170mg of original dried herb) did not exert any significant preventive effect on the frequency of migraine attacks. Patients did, however, have a tendency to use less analgesic drugs while using feverfew. The study authors suggested that this result may have been due to the fact that the previous studies in which benefit was noted were conducted in patients who had already found feverfew to be beneficial and had been using the herb for some time, typically 6 months or more. In addition, a dried plant extract preparation was used, whereas the original popularity of feverfew was based on consumption of fresh leaves. Although the preparation contained a known dose of parthenolide, which is thought to be a primary active component, other compounds may also be important.

The mechanisms of action through which feverfew works in the prevention of migraine are not yet fully clarified. Laboratory evidence shows that feverfew extracts inhibit platelet aggregation and inhibit serotonin release from platelets and leucocytes; however, human platelet studies have not found these effects. One possible explanation may be related to the theory that the actively alkylating alpha-methylene-gamma-lactone group (including parthenolide) would be rapidly inactivated via glutathione on entering the bloodstream, but that regeneration of substantial amounts of parthenolide might occur in vivo with cytochrome p-450 enzymes as oxidants, with conversion back to \”free\” parthenolide at the cellular level. This hypothesis is based on observations that sequential treatment of old samples of dried powdered feverfew leaf containing no \”free\” parthenolide with an oxidant and a weak base caused the regeneration of substantial amounts of parthenolide.

Feverfew might also inhibit serum proteases and leukotrienes.

Feverfew also appears to block prostaglandin synthesis by inhibiting phospholipase, thus preventing the release of arachidonic acid.

Preliminary research shows that extracts of fresh feverfew leaves and parthenolide might cause irreversible inhibition of vascular muscle contraction. Chrysanthenyl acetate, an essential oil of feverfew, which inhibits prostaglandin synthetase and might have analgesic properties, has also been suggested as an active factor.

Feverfew also contains melatonin, which might contribute to its pharmacological effect, since migraine attacks have been associated with decreased melatonin excretion. Fresh or dried leaves have been found to contain significantly more melatonin than commercially prepared standardized feverfew tablets.

Rheumatoid arthritis

Inflammatory compounds released by white blood cells and platelets are significant contributing factors to the inflammation and cellular damage seen in rheumatoid arthritis. Feverfews inhibition of the release of inflammatory particles has been demonstrated to be much greater than that achieved by NSAIDs like aspirin. This, especially when combined with feverfews other anti-inflammatory effects, indicates that feverfew could greatly reduce inflammation in rheumatoid arthritis.

Although a double-blind, placebo-controlled study of 40 patients demonstrated no apparent benefit from oral feverfew in rheumatoid arthritis, the dosage used was small (70-86mg dried, chopped feverfew leaf per day), the level of parthenolide was not determined in the product, and patients continued to take NSAIDs, a practice that has been suggested to reduce the efficacy of feverfew. Therefore, the benefit of feverfew in rheumatoid arthritis yet to be determined.

Typical Use

Fresh leaf. Freeze-dried leaf or air-dried leaf given as a capsule or tablet.

Interactions

No known interactions.

Theoretical interactions include the following:

  • Herbs that affect platelet aggregation: Since feverfew affects platelet aggregation, theoretically, concommitant use of feverfew and herbs that affect platelet aggregation, such as garlic and gingko, could increase risk of bleeding in some people.
  • Anticoagulant, antiplatelet drugs: Since feverfew affects platelet aggregation, theoretically, concommitant use of feverfew and these drugs might increase risk of bleeding.
  • NSAIDs: NSAIDs effects on prostaglandins might decrease the effectiveness of feverfew.

Toxicology

Feverfew is an exceptionally non-toxic botanical that has been used by large numbers of people for hundreds of years without reports of toxicity.

Rats fed more than 100 times the human daily dose each day for five weeks, and guinea pigs fed 150 times the human daily dose each day for 7 weeks were identical to control animals, especially in regard to appetite and weight gain.

Parthenolide at concentrations up to 80M was found to be non-mutagenic in a forward mutation assay using Salmonella typhimurium.

No toxic reactions were reported in patients taking feverfew in the 6 month London Migrain Clinic study discussed above, and this herb has been used by large numbers of people for hundreds of years without reports of toxicity.

A study of 30 chronic feverfew users (use over 11 consecutive months) compared to 30 matched non-users found no difference in frequency of chromosomal aberrations nor in frequency of sister chromatid exchanges in circulating peripheral lymphocytes. The mutagenicity of urine from feverfew users was not different from that of non-user migraine patients.

Contraindications

  • Cross-Allergenicity: Individuals with known hypersensitivity to members of the Compositae family, which includes ragweed, chrysanthemums, marigolds, daisies, feverfew and many other herbs, should not take this herb internally.
  • Pregnancy: Feverfew might cause uterine contractions and abortion.