Tanacetum (Chrysanthemum) parthenium, belonging to the family Compositae and most commonly called feverfew, is an aromatic perennial herb with yellowish-green chrysanthemum-like leaves and small daisy-like flowers that bloom in July and August. The name feverfew is thought to have arisen from its earlier name featherfew, referring to the plant’s feather-like leaves. The name changed because it was associated with treating fevers.¹ The plant grows prolifically in gardens and other open spaces and has been naturalized throughout a large part of Europe. Feverfew has been introduced into this country and is now a popular plant grown for both ornamental and medicinal purposes. Throughout history feverfew has been used to treat many conditions including fever, headache, menstrual difficulties, stomachache, toothache, and insect bites. Within the past 15 years, feverfew has mainly been used to treat migraine headaches. It is also often used to treat arthritis and inflammatory diseases such as psoriasis. There is clinical evidence for its efficacy, and recent basic research has investigated the pharmacological mechanisms underlying its therapeutic effects.

Chemical Composition

The most well-studied and abundant group of active compounds in feverfew are the sesquiterpene lactones. Of these lactones, parthenolide is the most prominent. These low-molecular-weight lactones are believed to be produced by superficial leaf glands. They are colorless, bitter-tasting lipophilic compounds present in a number of species in the Compositae family. Other sesquiterpene lactones include 3-b-hydroxyparthenolide, seco-tanaparthenolide A, canin, artecanin, and balchanin.² Many of the pharmacological effects of feverfew extracts are attributed to the sesquiterpene lactones, especially parthenolide. Volatile oils contained in feverfew include pinene, bornyl acetate, angelate, costic acid, farnesine, and spiroketal enol ethers. The lipophilic flavonols tanetin and quercetagetin and water-soluble flavone glycosides apigenin 7-glucuronide, luteolin 7-glucuronide, luteolin 7-glucoside and chrysoeriol 7-glucuronide are also present in feverfew leaves.³

Clinical Investigations

Migraine Headache: Feverfew’s clinical efficacy in treating migraine headaches is well-substantiated. The first well-documented report of feverfew’s effectiveness was a survey conducted by the City of London Migraine Clinic in 1983.⁴

Johnson and colleagues surveyed 270 migraine sufferers who were self-treating their headaches by chewing several feverfew leaves daily. More than 70% of respondents reported a decrease in frequency and severity of attacks. These observations prompted the clinic to conduct a controlled study of feverfew’s ability to prevent migraine. A double-blind, placebo-controlled trial was conducted with 17 patients who were already taking fresh leaves daily for their migraines. Nine patients were switched to a placebo and subsequently experienced a significant increase in the frequency and severity of their headaches.⁵ Those remaining on feverfew showed no increase in headaches.

A much larger study was done a few years later at University Hospital in Nottingham, U.K.⁶ In this report, published in the British medical journal Lancet, migraine prophylaxis was assessed in a 4-month, randomized, double-blind, placebo-controlled crossover study. Patients treated with dried feverfew leaf powder in capsules equivalent to two medium sized leaves experienced a 24% reduction in the number and severity of headaches as well as a significant reduction in nausea and vomiting accompanying the attacks. These well-publicized studies, along with feverfew’s success in treating migraine, are largely responsible for this herb’s current popularity. Feverfew appears to work best on classic migraine associated with sensitivity to light.⁷

Arthritis: Feverfew has pharmacological inhibitory effects on prostaglandin (PG) biosynthesis and various components of the inflammatory response, thus has been widely used to treat the pain and inflammation of arthritis. A double-blind, placebo-controlled study was carried out in Nottingham, U.K. in 1989 to test the efficacy of feverfew in treating the symptoms of rheumatoid arthritis.⁷ Forty-one female patients were given either dried leaf capsules (70–80 mg) or a placebo once a day for six weeks. No relief from pain or joint stiffness was seen in the feverfew treatment group. Although this study yielded negative results for rheumatoid arthritis, feverfew may be more effective in osteoarthritis or in less severe soft tissue inflammatory conditions; additional studies on clinical efficacy are needed.

Well-controlled clinical trials investigating feverfew’s effectiveness in treating other diseases are presently lacking. Although many cases of successful treatment with feverfew have been documented over the years, such evidence is anecdotal. Until rigorously conducted clinical studies are undertaken, many of feverfew’s claims will remain unsubstantiated, and most of the medical community will continue to be skeptical.

Pharmacological Effects

Since the early 1980s there have been many studies of the mechanism of action of various components in feverfew extracts. A number of these U.K.-based studies focused on feverfew’s effects on blood platelets, leukocytes, and vascular smooth muscle cells.

Platelet Aggregation: In studies on platelet aggregation, feverfew extracts inhibited ADP, thrombin, and collagen-induced aggregation of human blood platelets in vitro.⁸ However, aggregation induced by arachidonic acid was unaffected. These results were confirmed by Heptinstall and colleagues in a series of studies conducted from 1987–90.^9-11

In these studies, sesquiterpene lactones potently blocked human blood platelet aggregation as well as the secretion of the intracellular granular contents of the platelets.¹⁰ The sesquiterpene lactones contain an a-methylbutyrolactone unit as part of their structure, which is capable of blocking cellular sulfhydryl (SH) groups. This results in disulfide-linked polymers of cytoskeletal proteins and likely disrupts membrane-cytoskeletal proteins important in platelet aggregation and secretory functions.⁹ Feverfew extracts were also shown to inhibit the interaction of platelets with collagen substrates.¹² This interaction involves the initial attachment of platelets, followed by spreading and formation of thrombi-like aggregates. These observations suggested that feverfew has potential as an antithrombotic drug.¹³

In a similar in vitro study, feverfew extracts inhibited the attachment of human monocytes to cell culture plates.¹⁴ In addition to blocking platelet aggregation, feverfew also inhibited the secretion of granular contents such as ADP and serotonin. Crude feverfew extracts and isolated parthenolide blocked serotonin (5-HT) secretion from platelets when stimulated by a variety of platelet activating agents.¹¹ Similar inhibitory effects of feverfew on other secretory processes have been demonstrated, e.g., mast cell release of histamine¹⁵ and secretory activity of neurophils stimulated by a variety of agents.¹⁶

The ability of feverfew to prevent vasoconstriction could explain its effectiveness in migraine treatment.

Inflammatory Pathway: Investigators working at Miles Laboratories were first to recognize the similar effects of feverfew and aspirin in treating pain and inflammation.¹⁷ Because acetylsalicylate works to inhibit PG biosynthesis, the researchers speculated that feverfew could also interfere with the PG synthetic pathway. Using an aqueous extract made from the aboveground parts of the feverfew plant, they noted an 88% inhibition of PG production. However, the cyclooxygenation of arachidonic acid was not affected as it is in the first step in PG biosynthesis with aspirin. Makheja and Bailey confirmed this initial observation by demonstrating that in human platelets thromboxane B₂ synthesis from exogenously added arachidonic acid was not affected by feverfew.¹⁸ These investigators concluded that the inhibition was at the level of phospholipase A₂ and the generation of precursor arachidonic acid. These results were further validated in similar studies using rat peritoneal leukocytes and human polymorphonuclear leukocytes.¹⁹ The formation of arachidonate metabolites was inhibited by extracts of feverfew in a concentration-dependent manner but not via inhibition of the cyclooxygenase pathway. Consistent with these results is the finding that feverfew extracts were shown to directly inhibit phospholipase A₂ in a noncompetitive manner.²⁰ A recent study demonstrated a potent inhibitory effect of sesquiterpene lactones on macrophage production and release of proinflammatory cytokines, such as TNF-a and IL-1.²¹

Vascular Smooth Muscle Contraction: Several studies have shown that feverfew extracts have important effects on vascular smooth muscle contraction. Chloroform extracts of fresh feverfew produced a progressive and time-dependent inhibition of rabbit aortic smooth muscle contraction.²² Contraction stimulated by serotonin, phenylephrine, and angiotensin II was inhibited, indicating a nonspecific, most likely post-receptor site of action. The inhibition was also irreversible, implying a long-lasting toxic effect on the smooth muscle tissue. In a later study parthenolide was shown to be responsible for this inhibitory response.²³

Surprisingly, chloroform extracts of dried leaf of feverfew, the form typically available in health food stores in Britian, contained little or no parthenolide. As expected, this form does not inhibit smooth muscle contraction; in contrast, it elicits a potent reversible sustained contraction. It was postulated that the sesquiterpene lactones may have decomposed during prolonged storage or due to reactions with thiols or other nucleophilic centers in intrinsic proteins. A followup study by this group found that an unknown nonsesquiterpene lactone component from feverfew extracts specifically blocks a voltage-dependent potassium channel in vascular smooth muscle cells.²⁴ This inhibition of voltage-dependent potassium channels would increase the excitability of the vascular smooth muscle and could potentiate the effects of vasoconstrictive stimuli.

Migraine Headache: The pharmacological effects of feverfew extracts on platelet aggregation and secretion, leukocyte and macrophage function, and vascular smooth muscle contraction are consistent with its reported efficacy in migraine treatment. Evidence supports an association between migraines and vascular system instability. Migraines are characterized by excessive intracranial arterial constriction followed by rebound dilation of the extracranial blood vessels.²⁵

Drugs that act to constrict these extracranial vessels give relief in migraine. Feverfew’s ability to block the voltage-dependent potassium channel resulting in vasoconstriction could explain its effectiveness in migraine treatment. Alternatively, the direct inhibition of vascular smooth muscle contraction by parthenolide could decrease the initial excessive intracranial arterial constriction which triggers the rebound vasodilation. Platelet aggregation and release of serotonin may also play a role in the pathogenesis of migraine. Feverfew’s inhibition of these functions would, therefore, be expected to prevent some of the vascular responses triggered by serotonin. According to the neurogenic theory of migraine perivascular sensory afferents of the trigeminal nerve are triggered, prompting the release of neuropeptides. These neuropeptides in turn promote the release inflammatory substances which lead to an inflammatory response involving vasodilation of the meningeal blood vessels. Feverfew’s ability to inhibit PG synthesis and the secretion of many inflammatory cytokines from neutrophils and macrophages as well as inhibiting histamine release from mast cells could also explain in part its effectiveness in treating migraines.

Toxicity and Adverse Side Effects

In general there have been no reports of any serious adverse effects from taking feverfew, especially at doses recommended for migraine prophylaxis. The main side effects encountered are mouth ulceration from chewing the fresh leaves and some reports of abdominal pain.⁵ Contact dermatitis (likely due to the sesquiterpene lactone content) has been reported in certain hypersensitive individuals,²⁶ as well as cross-sensitivity to other plants in the Compositae family. Feverfew’s inhibition of PG synthesis and platelet aggregation and its potential antithrombic effects indicate that those with clotting disorders or on anticoagulant medication should consult a physician before taking it. Since no systematic long-term toxicology studies have been conducted, young children or pregnant or lactating women should not take feverfew. (One study carried out in Poland showed chromosomal damage and cytotoxic effects in HeLa cells exposed to sesquiterpene lactones.²⁷) At subtoxic concentrations cells arrested in interphase but did not die. These effects point to feverfew’s potential for having both antitumor activity and harmful effects on the cells. In 1988, however, Anderson and colleagues looked for evidence of mutagenicity in lymphocytes from 30 patients taking feverfew daily for 11 months,²⁸ but found no evidence of chromosomal aberrations.

Dosage Forms and Recommended Use

Feverfew is commonly taken orally either as fresh leaves or in tablets or capsules containing 25–500 mg of dried leaf powder. The sesquiterpene lactones in feverfew are extremely bitter and are best consumed with food. A tea can also be prepared from dried or fresh leaves. A typical dose in treating migraine is two or three small leaves a day. Johnson and colleagues gave 50 mg/day of dried leaves in capsules once a day for six months in their clinical trials for migraine prophylaxis.⁵ Optimal doses for therapeutic benefits have not yet been determined.

There is also concern about the variable potency of commercially available products. When assayed for their ability to inhibit platelet secretory activity and compared to fresh leaves, different products showed a wide variation.¹¹ Many contained very little active ingredient. These findings could be due to the variation in content of parthenolide at different stages of growth of the plant or a problem in the extraction or in the stability of the sesquiterpene lactones. A difference has also been found between dried and fresh leaf preparations with opposing effects seen in extracts made from either fresh or dried leaves.²³

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