Feverfew

Feverfew (Tanacetum parthenium): A Comprehensive Reference

1. Identity

Botanical and Chemical Names

Feverfew's accepted botanical name is Tanacetum parthenium. It is also known under a wide range of synonyms and common names, including Chrysanthemum parthenium, Leucanthemum parthenium, Matricaria parthenium, Pyrethrum parthenium, featherfew, altamisa, bachelor's button, featherfoil, febrifuge plant, midsummer daisy, Santa Maria, wild chamomile, wild quinine, mutterkraut, and MIG-99, among others. Feverfew (also known as European feverfew) is distinct from American feverfew (Parthenium integrifolium), a plant native to the eastern United States.

Taxonomy and Natural Source

Feverfew (Tanacetum parthenium) is a member of the daisy family (Asteraceae) and is a short, bushy perennial. Its yellow-green leaves and yellow flowers resemble those of chamomile, for which it is sometimes confused. The flowers bloom from July to October. Feverfew is a perennial plant with leaves that look like those of chrysanthemum and flowers that look like daisies. It is native to parts of western Asia and the Balkans, but now grows throughout the world. More specifically, it is native to the Balkan Peninsula and is now found in Australia, Europe, China, Japan, and North Africa. In the mid-19th century, feverfew was introduced in the United States.

Parts Used and Common Forms

The leaves are used in medicinal preparations. Feverfew supplements are available fresh, freeze-dried, or dried and can be purchased in capsule, tablet, or liquid extract forms. The common name "feverfew" derives from the Latin febrifugia, meaning fever reducer, though its modern research focus is firmly on migraine prevention. In traditional European practice, fresh leaves were sometimes chewed directly, a practice now discouraged due to mouth irritation risk.

2. Traditional and Historical Use

Ancient Greece

The ancient Greeks called the herb Parthenium, supposedly because it was used medicinally to save the life of someone who had fallen from the Parthenon during its construction in the fifth century BC. The name may also derive from use in treating menstrual cramps in young girls, because the word parthenos means "virgin" in the Greek language. The first-century Greek physician Dioscorides used feverfew as an antipyretic. Dioscorides also recommended it to warm the body and calm inflammation, especially for joint issues or period discomfort.

Medieval and Early European Herbalism

Feverfew is a medicinal plant traditionally used for the treatment of fevers, migraine headaches, rheumatoid arthritis, stomach aches, toothaches, insect bites, infertility, and problems with menstruation and labor during childbirth. The herb has a long history of use in traditional and folk medicine, especially among Greek and early European herbalists. During medieval times, healers placed feverfew inside cushions to help with headaches while brewing potent infusions that lowered fevers and cleared impurities. In Wales, doctors gave it to stimulate womb activity when menstruation was late or labor became painful. By the 1600s, this plant had become the top choice against severe head pain — individuals often consumed raw foliage each day to stop attacks before they started.

In 1633, the plant was recommended for use in treatment of headaches in Gerard's Herbal. Recognition of feverfew's effectiveness in the prevention and treatment of migraine headache can also 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."

Broader Traditional Applications

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. It has additionally been used for psoriasis, allergies, asthma, tinnitus, dizziness, nausea, and vomiting. Traditional purposes recorded by NCCIH include use for respiratory disorders, gastrointestinal disorders, menstrual disorders, kidney disease, liver disease, tinnitus, earache, fever, infertility, and anemia.

Modern Revival

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. This personal account reportedly triggered wider interest in the United Kingdom, leading to formal clinical investigation. Feverfew has enjoyed a revival over the past several decades due to approval of its use for treatment of migraine by both the Canadian and British governments.

3. Key Constituents and Active Compounds

Sesquiterpene Lactones

Parthenolide is found in the superficial leaf glands (0.2%–0.5%), but not in the stems, and comprises up to 85% of the total sesquiterpene content. More than 30 sesquiterpene lactones have been identified in feverfew. Among its bioactive compounds, parthenolide stands out as the most potent, categorized as a germacranolide-type sesquiterpene lactone, and has been extensively studied in multiple investigations.

Authenticated Tanacetum parthenium grown in the UK contained a high level of parthenolide in leaves, flowering tops and seeds but a low level in stalks and roots. The level of parthenolide in powdered leaf material fell during storage. Commercial feverfew products varied widely in their parthenolide content, and in some products parthenolide was not detected. The parthenolide content of commercially available feverfew supplements varies substantially — by more than 40-fold — despite labeling claims of "standardization."

Other Phytochemicals

Phytochemicals found in feverfew also include camphor and the flavonoids luteolin and apigenin. Other potentially active constituents include flavonoid glycosides and pinenes. Monoterpenes in the plant may exert insecticidal activity, and alpha-pinene derivatives may possess sedative and mild tranquilizing effects.

Standardization

Since therapeutic efficacy has only been demonstrated for preparations of feverfew that contain parthenolide, it has been suggested that manufacturers of feverfew products should use measurements of parthenolide as a means of standardization and quality control. Canada's Health Protection Branch recommends a daily dosage of 125 mg of a dried feverfew leaf preparation from authenticated T. parthenium containing at least 0.2% parthenolide for the prevention of migraine.

4. Mechanisms of Action

NF-κB Inhibition and Anti-Inflammatory Action

The best-known mechanisms of parthenolide are the inhibition of nuclear factor-κB (NF-κB) activity via inhibitor-κB kinase and the induction of oxidative stress. The anti-inflammatory properties of feverfew have been primarily attributed to its capacity to inhibit NF-κB, resulting in a reduction in pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF-α). Extracts of the plant also inhibit the release of enzymes from white cells found in inflamed joints, and a similar anti-inflammatory effect may occur in the skin, providing a rationale for the traditional use of feverfew in psoriasis.

Platelet Activity and Serotonin

Extracts of feverfew inhibit platelet aggregation and the platelet release reaction. The active components are believed to be sesquiterpene lactones such as parthenolide. Evidence indicates that inhibition of platelet behavior is via neutralization of sulphydryl groups either inside or outside the cell. Parthenolide has been shown to decrease serotonin release from activated platelets, therefore showing potential as an anti-platelet therapy. In addition to its extensive anti-inflammatory properties, feverfew also exerts 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.

Arachidonic Acid Pathway

Feverfew appears to act by inhibiting formation of prostaglandins in the arachidonic acid pathway, inhibiting serotonin and histamine secretion, preventing platelet aggregation, and reducing vascular response to vasoactive amines. Feverfew also inhibits prostaglandin synthesis and the release of arachidonic acid. This action may explain its historical use for inflammatory conditions such as arthritis.

Relevance to Migraine Pathophysiology

The combination of feverfew's inhibitory effects on blood platelet aggregation, inflammatory processes, and smooth muscle contraction are likely responsible for feverfew's therapeutic effect in the prevention and treatment of migraine headaches. In patients taking feverfew, platelets aggregated normally to ADP and thrombin; however, 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.

Synovial Fibroblasts and Rheumatoid Arthritis Pathways

Human synovial fibroblasts express an intracellular adhesion molecule-1 (ICAM-1) that has been implicated in the pathogenesis of rheumatoid arthritis. Feverfew extracts or purified parthenolide inhibited the increased expression of ICAM-1 on human synovial fibroblasts by cytokines IL-1, TNF-α, and interferon-γ.

5. Scientific Evidence by Area of Use

Migraine Prevention

Overview of Clinical Trials

Results from prior trials are not uniformly convincing: three trials reporting positive effects of feverfew are all of small sample size (17 to 60 participants), while two more rigorous trials (n = 50 and n = 147) did not find significant differences between feverfew and placebo. A newer and larger study was added to the Cochrane review, and it showed that feverfew reduced migraine frequency by a little more than half a migraine (0.6) per month compared to placebo. There was no statistically significant difference in how severe the pain was, or how long it lasted.

Cochrane Review Conclusions

Overall the results from the six included trials are mixed and provide low-quality evidence. With the addition of the most recent and largest rigorous study, a difference in effect between feverfew and placebo of 0.6 attacks per month was reported. This adds some positive evidence to the mixed and inconclusive findings of the previous review. However, this constitutes low-quality evidence, which needs to be confirmed in larger rigorous trials with stable feverfew extracts and clearly defined migraine populations before firm conclusions can be drawn.

Earlier Positive Trials

In one of the earliest trials, 17 patients who ate fresh leaves of feverfew daily as prophylaxis against migraine participated in a double-blind placebo-controlled trial: eight patients received capsules containing freeze-dried feverfew powder and nine received placebo. Those who received placebo had a significant increase in the frequency and severity of headache, nausea, and vomiting with the emergence of untoward effects during the early months of treatment. The group given capsules of feverfew showed no change in the frequency or severity of symptoms of migraine. This provided evidence that feverfew taken prophylactically prevents attacks of migraine.

Evidence Strength Assessment

Since the last version of the Cochrane review, one larger rigorous study has been included, reporting a difference in effect between feverfew and placebo of 0.6 attacks per month. This adds some positive evidence to the mixed and inconclusive findings of the previous review. However, this constitutes low-quality evidence, which needs to be confirmed in larger rigorous trials with stable feverfew extracts and clearly defined migraine populations before firm conclusions can be drawn. In clinical studies, a feverfew extract reduced the frequency and pain intensity of migraine attacks; a formulation containing feverfew was reported useful in decreasing the duration of aura; and a feverfew/ginger formula prevented mild headache before the onset of moderate to severe headache in patients with migraine.

Rheumatoid Arthritis

Forty-one female patients with symptomatic rheumatoid arthritis received either dried chopped feverfew (70–86 mg) or placebo capsules once daily for six weeks. Allocation was random and not known by patient or observer. Of 15 parameters tested, only grip strength improved significantly (P = 0.04) in the feverfew group compared with the placebo group. Although the double-blind, placebo-controlled study of 40 patients demonstrated no apparent benefit from oral feverfew in rheumatoid arthritis, the dosage used was small (70–86 mg 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 is yet to be determined.

Inflammatory compounds released by white blood cells and platelets are significant contributing factors to the inflammation and cellular damage seen in rheumatoid arthritis. Feverfew's 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 feverfew's other anti-inflammatory effects, indicates that feverfew could greatly reduce inflammation in rheumatoid arthritis — but confirmatory clinical trials are lacking.

Anticancer Research (Preclinical)

The anticancer potential of parthenolide has attracted significant research attention. Parthenolide and its more water-soluble synthetic derivative, dimethylamino-parthenolide (DMAPT), have been subjects of many preclinical in vitro and in vivo studies performed on cancer cells from hematological malignancies and solid tumors. Parthenolide selectively ablates myeloid leukemia cells at an IC50 of 2.5 μM and causes apoptosis in primary human AML cells and blast crisis CML cells. It has been shown that parthenolide is cytotoxic to hepatoma cells and leukemia cells while sparing normal liver cells and hematopoietic cells, suggesting that the cytotoxic effect of parthenolide may be selective for tumor cells.

Despite its deciphered anticancer potential and mechanisms of action in pre-clinical experiments, the clinical application of parthenolide remains hindered because of disadvantages including weak aqueous solubility, low oral bioavailability, and relative instability. The water-soluble analogue DMAPT has advanced into the first phase of a clinical trial for the treatment of acute myeloid leukemia (AML). Feverfew also showed anticancer effects in lab studies; however, human studies are needed. All anticancer evidence to date is preclinical and cannot be applied to clinical practice without further investigation.

Psoriasis, Skin Conditions, and Other Uses

Although much of its activity is attributed to the compound parthenolide, a parthenolide-free extract of feverfew has demonstrated free radical-scavenging properties, affording protection against UV-induced sun damage. Feverfew extracts also possess antiprotozoal, antibacterial, anti-inflammatory, and antioxidant properties. Feverfew is currently promoted for migraine headaches, blood vessel relaxation, minor pain (especially tension headaches), and joint support. Topically (applied to the skin), feverfew is promoted to provide relief from itching and skin irritation. Clinical evidence for these additional topical and systemic uses is either absent or too limited to draw conclusions.

6. Body Systems Associated with Feverfew

• Neurological / Cephalic: Migraine headache prevention and tension headache management are the primary modern indications for feverfew.
• Cardiovascular / Hematological: Feverfew exerts inhibition of platelet aggregation and secretion of allergic mediators, e.g., histamine and serotonin.
• Musculoskeletal / Inflammatory: Feverfew is associated with alleviating pain from migraines, osteoarthritis, rheumatoid arthritis, and menstrual cramps.
• Gastrointestinal: Feverfew has a history of use for dyspepsia including indigestion and flatulence, and as a general intestinal stimulant and tonic.
• Reproductive / Menstrual: Traditional use included treatment of infertility and problems with menstruation and labor during childbirth.
• Dermatological: Extracts of the plant inhibit the release of enzymes from white cells found in inflamed joints, and a similar anti-inflammatory effect may occur in the skin, providing a rationale for the traditional use of feverfew in psoriasis.
• Oncological (research context only): The anticancer potential of parthenolide has attracted great attention, though all evidence remains preclinical.

7. Dosage Forms and Reported Dosages

Available Forms

Feverfew supplements are available fresh, freeze-dried, or dried and can be purchased in capsule, tablet, or liquid extract forms.

Dosages Used in Clinical Studies

An optimal dose of feverfew has not been established. For prevention of migraine, dried leaf preparation dosages ranging from 50 to 150 mg/day for various treatment durations have been evaluated in clinical trials. Canada's Health Protection Branch recommends a daily dosage of 125 mg of a dried feverfew leaf preparation from authenticated T. parthenium containing at least 0.2% parthenolide for the prevention of migraine.

Previous RCTs of feverfew in migraine participants which showed encouraging results used doses between 50 and 140 mg of powdered or granulated leaf preparations daily. In the rheumatoid arthritis trial, 41 female patients received either dried chopped feverfew (70–86 mg) or placebo capsules once daily for six weeks. In a 1989 study of women with symptomatic rheumatoid arthritis, the women took dosages of 76 milligrams of dried, powdered feverfew leaf, but acknowledged that 100–125 milligrams was previously suggested as an effective dosage.

For migraine prevention, studies have often used doses ranging from 50 mg to 300 mg of dried feverfew leaf daily; some products are standardized to contain 0.2% to 0.4% parthenolide.

8. Safety Considerations and Drug Interactions

General Safety Profile

Feverfew did not appear to affect blood pressure, heart rate, body weight, or hematological and biochemical safety parameters in any of the included Cochrane-reviewed studies. 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.

Oral and Gastrointestinal Adverse Effects

Feverfew is considered possibly unsafe when fresh leaves are chewed. Chewing unprocessed feverfew leaves can cause mouth sores; swelling of the mouth, tongue, and lips; and loss of taste. Only mild and transient adverse events, most commonly gastrointestinal complaints and mouth ulcers, were reported in the included Cochrane trials. The most commonly reported side effect of feverfew use is the occurrence of mouth sores, primarily associated with chewing feverfew leaves, observed in up to 11% of such users. Less frequently reported side effects include gastrointestinal effects such as diarrhea, nausea, abdominal pain, indigestion, vomiting, and flatulence.

Post-Feverfew Withdrawal Syndrome

Withdrawal symptoms — including muscle stiffness, anxiety, and moderate pain — usually occur following cessation of long-term use of feverfew, a phenomenon referred to as "post-feverfew syndrome." Some users of feverfew have reported that when daily use is stopped suddenly after long periods of use, post-feverfew syndrome occurs (i.e., rebound headaches, anxiety, sleep disturbances, and muscle stiffness or pain) in about 10% of migraine patients who abruptly stop taking feverfew after a long history of daily use.

Pregnancy and Lactation

Do not take feverfew while pregnant because it may affect uterine contractions. Little is known about whether it is safe to use feverfew while breastfeeding. The plant should not be used during pregnancy because the leaves possess emmenagogic activity (ejection of the placenta and fetal membranes) and may induce abortion. Use is not recommended during breastfeeding or in children younger than 2 years.

Allergic Cross-Reactivity

Feverfew is contraindicated in patients allergic to other members of the Asteraceae family, such as aster, chamomile, chrysanthemum, ragweed, sunflower, tansy, and yarrow.

Anticoagulant and Antiplatelet Drug Interactions

Because feverfew might slightly inhibit the activity of blood-clotting cells known as platelets, it should not be combined with strong anticoagulants, such as warfarin (Coumadin) or heparin, except on medical advice. Some evidence suggests that feverfew may inhibit platelet aggregation; however, this has not been demonstrated in humans. Theoretically, feverfew might have additive effects and increase the risk of bleeding when used with anticoagulant or antiplatelet drugs. Due to its potential antiplatelet effects, it is not recommended for use in patients undergoing surgery. Patients with blood clotting disorders should consult their health care provider prior to using products containing feverfew.

NSAID Interactions

Owing to their effects on prostaglandins, NSAIDs might decrease the effectiveness of feverfew. Feverfew might also increase the risk of stomach problems if combined with anti-inflammatory drugs such as aspirin.

Cytochrome P450 Interactions

Feverfew inhibits cytochrome P450 enzymes including CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, and can affect the intracellular concentration of drugs metabolized by these enzymes; however, the clinical relevance of this is not known. There is preliminary evidence that feverfew might inhibit cytochrome P450 1A2 (CYP1A2), though so far this interaction has not been reported in humans. Physicians should watch for an increase in the levels of drugs metabolized by CYP1A2 in patients taking feverfew; some drugs metabolized by this pathway include amitriptyline, haloperidol, ondansetron, propranolol, theophylline, and verapamil.

Alteration of Coagulation Tests

Alteration of coagulation test results and vaginal bleeding has been reported in a 36-year-old woman with migraine after taking feverfew supplements.

References

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