Parthenium (Tanacetum parthenium, Feverfew): A Comprehensive Reference
1. Identity and Botanical Classification
1.1 Accepted Nomenclature and Synonyms
Tanacetum parthenium, known as feverfew, is a flowering plant in the daisy family, Asteraceae. It may be grown as an ornament, and may be identified by its synonyms, Chrysanthemum parthenium and Pyrethrum parthenium. Additional synonyms used historically and in the literature include Matricaria parthenium and Leucanthemum parthenium. By its common names, the plant is known as featherfew, feverfew, bachelor's button, and midsummer daisy, and is a member of the Asteraceae family found in Australia, Europe, China, Japan, and North Africa.
Feverfew (also known as European feverfew) is different from American feverfew (Parthenium integrifolium), a plant native to the eastern United States. The two plants should not be confused; the present article concerns exclusively Tanacetum parthenium.
1.2 Botanical Description
It is a perennial plant that reaches a height of 30–80 cm, with short, fine hairs on the stem and ovate, greenish-yellow, pinnate leaves. The flower heads at the tops of the shoots, with white ligulate flowers and yellow tubular flowers, measure up to 2 cm in diameter. All parts of the plant have a characteristic strong and pleasant spicy scent.
Native from South-East Europe to Asia, it grows in mountain scrub, rocky slopes, waste places and gardens. Having its origin in the Balkans region, it is now distributed worldwide. It spreads rapidly by seed, and will cover a wide area after a few years.
1.3 Etymology
The name feverfew is a corruption of the word febrifuge, signifying its fever-dispelling properties.
1.4 Common Preparations and Dosage Forms
The pharmacological material is the herb, collected during the flowering stage, from June to September. Commercial preparations include fresh leaf, freeze-dried leaf, and air-dried leaf given as capsules or tablets. The leaves are ingested fresh or dried, with a typical daily dosage of 2 to 3 leaves. Standardized dry-leaf capsules, CO₂ extracts, tinctures, and topical formulations (including parthenolide-depleted purified extracts for cosmetic use) are available commercially.
The parthenolide content of commercially available feverfew supplements varies substantially (by more than 40-fold) despite labeling claims of "standardization." This variability complicates direct comparisons across clinical studies.
2. Traditional and Historical Use
2.1 Ancient Mediterranean Use
Tanacetum parthenium 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, with the feverfew herb having a long history of use in traditional and folk medicine, especially among Greek and early European herbalists. Noted by Dioscorides in the 1st century AD, it was used to treat many different ailments including migraine, fever, rheumatism, menstrual and digestive problems, and psoriasis.
2.2 European Folk and Herbal Traditions
Traditionally, people have used feverfew for a variety of purposes, including respiratory disorders, gastrointestinal disorders, menstrual disorders, kidney disease, liver disease, tinnitus, earache, fever, infertility, and anemia. Feverfew has also been used for psoriasis, allergies, asthma, tinnitus, dizziness, nausea, and vomiting. Feverfew has also been used as an abortifacient, as an insecticide (possibly due to monoterpenes), and for treating coughs and colds; traditionally, the herb has been used as an antipyretic, from which its common name is derived. In Danish folk medicine, feverfew is used as an antiepileptic.
2.3 Central and South American Use
The Kallaway Indians of the Andes mountains value it for treating colic, kidney pain, morning sickness, and stomachache. Costa Ricans use a decoction of the herb as a digestive aid, a cardiotonic, an emmenagogue, and as an enema for worms. In Mexico, it is used as an antispasmodic and as a tonic to regulate menstruation. In Venezuela, it is used for treating earaches.
2.4 Regulatory Recognition of Traditional Use
Canada's Health Protection Branch granted a Drug Identification Number (DIN) for a British feverfew (T. parthenium) product, allowing the manufacturer, Herbal Laboratories Ltd, Ottawa, Canada, to claim that this nonprescription drug prevents migraine headaches. The agency recommends a daily dosage of 125 mg of a dried feverfew leaf preparation from authenticated T. parthenium containing at least parthenolide 0.2% for the prevention of migraine.
3. Key Chemical Constituents
3.1 Sesquiterpene Lactones
The most extensively studied classes of phytochemicals found in feverfew include sesquiterpene lactones and flavonoids; additionally, other compounds present in the plant belong to phytosterols, triterpenoids, fatty acids, phenolic acids, and essential oils. Feverfew is especially rich in sesquiterpene lactones, with over 30 distinct types identified in the plant.
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. Parthenolide, a germacranolide, is the major sesquiterpene lactone of this plant, composed of up to 85% of the total sesquiterpene. Extracts of Tanacetum parthenium contain various volatile oils having mono- and/or sesquiterpene components, flavonoids, tannins, and pyrethrin, as well as terpenoids of the family of sesquiterpene lactones known as germacranolides, guaianolides and eudesmanolides. These latter compounds include parthenolide, 3-β-hydroxy-parthenolide, costunolide, 3-β-hydroxy-costunolide, artemorin, 8-α-hydroxy-estafiatin and chrysanthemonin.
Parthenolide is a sesquiterpene lactone derived from leaves of the medicinal plant feverfew (Tanacetum parthenium); it contains an α-methylene-γ-lactone ring and epoxide group, which are able to interact with nucleophilic sites of biological molecules. This structural feature underlies much of its pharmacological reactivity.
3.2 Flavonoids and Phenolic Acids
T. parthenium (L.) contains many sesquiterpene lactones, with higher concentration of parthenolide, lipophilic and polar flavonoids in the leaves and the flower heads. Flavonoids identified include tanetin, quercetin, apigenin, luteolin, chrysoeriol, santin, and centaureidin. Results of HPLC showed that the major polyphenol compounds present in the hydroethanolic extracts from various parts of T. parthenium were 3,5-dicaffeoyl-quinic acid, chlorogenic acid, and 3,4-dicaffeoyl-quinic acid. Chrysanthenone and α-thujone were the dominant volatile compounds in the essential oil from the flowers, while camphor, trans-chrysanthenyl acetate, and camphene were predominant in the essential oil from the leaves and herb.
Tanacetum parthenium is rich in bioactive compounds, namely sesquiterpene lactones, flavonoids, and volatile oils; sesquiterpene lactones possess anti-migraine activity, while phenolic compounds possess anti-inflammatory and antioxidant action.
3.3 Volatile Oils
Volatile substances contained in the essential oil of feverfew include monoterpenes, such as camphor, camphene, ester derivatives of chrysanthenol, verbenol, and borneol, as well as sesquiterpene hydrocarbons such as germacrene D and β-farnesene. The flowering herb also contains 0.02% to 0.07% volatile oils (L-camphor, L-borneol, terpenes, and miscellaneous esters), and various compounds in the volatile oil have shown pharmacologic activity.
3.4 Other Constituents
The plant also contains a high percentage of sterols and triterpenes in the roots. A link between the relatively high concentration of melatonin in different feverfew varieties and a decrease in melatonin excretion during migraine attacks has been suggested. Fresh or dried leaves have been found to contain significantly more melatonin than commercially prepared standardized feverfew tablets.
4. Mechanisms of Action
4.1 NF-κB Inhibition
Parthenolide, a naturally occurring sesquiterpene lactone derived from feverfew (Tanacetum parthenium), exhibits exceptional anti-cancer and anti-inflammatory properties, making it a prominent candidate for further studies and drug development. Parthenolide shows strong NF-κB- and STAT-inhibition-mediated transcriptional suppression of pro-apoptotic genes, and acts both at the transcriptional level and by direct inhibition of associated kinases (IKK-β). Parthenolide can stimulate apoptotic pathways through the inhibition of NF-κB, activation of p53, and increase in reactive oxygen species.
4.2 Platelet Aggregation and Serotonin Inhibition
Extracts of feverfew (Tanacetum parthenium) inhibited secretory activity in blood platelets and polymorphonuclear leucocytes (PMNs). Release of serotonin from platelets induced by various aggregating agents (adenosine diphosphate, adrenaline, sodium arachidonate, collagen, and U46619) was inhibited. Platelet aggregation was consistently inhibited but thromboxane synthesis was not.
Researchers have demonstrated that parthenolide noncompetitively inhibited serotonin (5-HT)-mediated spasmogenic response of indirect-acting 5-HT agonists in isolated rat stomach fundus preparation. Parthenolide noncompetitively antagonized the contractions elicited by the serotonergic drugs fenfluramine and dextroamphetamine on the fundal tissue. The mechanism of action associated with parthenolide does not involve the inhibition of 5-HT2 receptors directly, but rather occurs at the level of 5-HT stored in vesicles of the intramural neurons of fundal tissue.
Extracts of feverfew inhibit platelet 5-HT secretion via neutralization of sulfhydryl groups inside or outside the cell. The sesquiterpenes in feverfew contain the alpha-methylenebutyrolactone unit capable of reacting with sulfhydryl groups. Compounds that contain sulfhydryl groups such as cysteine and N-(2-mercaptopropionyl)glycine prevented the inhibition of platelet behaviour by feverfew. Feverfew and parthenolide dramatically reduced the number of acid-soluble sulfhydryl groups in platelets, an effect which occurred at concentrations similar to those that inhibited platelet secretory activity.
4.3 Inhibition of Prostaglandin Synthesis and Phospholipase Activity
Proposed mechanisms for feverfew in the treatment of headache include the inhibitions of prostaglandin biosynthesis, phospholipase A, nuclear factor kappa B (NF-κB), NO synthesis, and platelet aggregation. Parthenolide inhibits prostaglandin synthetase in vitro and seems to possess analgesic properties.
4.4 Anti-inflammatory Cytokine Inhibition
Anti-inflammatory properties of feverfew include inhibition of proinflammatory cytokine (tumor necrosis factor α [TNFα], interferon-γ [INF-γ], interleukin-2 [IL-2], IL-4) release, decrease in nuclear factor κB (NF-κB) mediated gene transcription, inhibition of neutrophil chemotaxis, and inhibition of adhesion molecule expression.
4.5 Reactive Oxygen Species and Apoptotic Pathways
Parthenolide-induced ROS-mediated apoptosis of tumor cells occurs via the intrinsic apoptotic signaling pathway. The mechanism of cell killing was via parthenolide-induced generation of reactive oxygen species, resulting in turn in a proapoptotic Bax conformational change, release of mitochondrial cytochrome c and caspase activation. Parthenolide also decreased nuclear levels of the antiapoptotic transcription factor nuclear factor-kappa B.
4.6 Granule Secretion in Leukocytes
Feverfew extracts are not only potent inhibitors of serotonin release from platelets but also of polymorphonuclear leukocyte granules, providing a possible connection between the claimed benefit of feverfew in migraines and arthritis.
4.7 Histamine Release Inhibition
A chloroform extract of feverfew inhibited histamine release from rat peritoneal mast cells in a different manner from established mast cell inhibitors, such as cromoglycate and quercetin. The exact mechanism of action has not been determined but may be mediated by entry of calcium into mast cells.
4.8 Limitations in Mechanistic Understanding
A definitive chemical link between the aetiology of migraine and parthenolide or any other of the feverfew constituents has still not been established. Given the diversity of feverfew's pharmacological activity, parthenolide may not be the sole active principle; the plant is rich in sesquiterpene lactones, the principal one being parthenolide, but the active constituent remains incompletely appreciated.
5. Scientific Evidence by Area of Use
5.1 Migraine Prevention
Clinical background: Feverfew (Tanacetum parthenium L.) extract is a herbal remedy which has been used for preventing attacks of migraine.
Cochrane review (2004): Five trials were identified that assessed the efficacy of feverfew (taken as an oral preparation) compared with placebo. Results from these trials were mixed and did not convincingly establish that feverfew is more effective than placebo for preventing migraine. The reviewers' conclusion was that "there is insufficient evidence from randomised, double-blind trials to suggest an effect of feverfew over and above placebo for preventing migraine."
Cochrane review update (2015): Since the last version of this 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.
Study-level details: Three trials reporting positive effects of feverfew are all of small sample size (17 to 60 participants), while two rigorous trials (n = 50, 147) did not find significant differences between feverfew and placebo. There was no difference in how severe the pain was or how long it lasted. For the secondary outcome measures of intensity and duration of migraine attacks, incidence and severity of nausea and vomiting, and global assessment, no statistically significant differences were reported.
NCCIH position (2020): Some studies in people have looked into feverfew's use as a remedy for migraine headache; for instance, a 2020 review looked at 7 studies of feverfew for migraine, which included a total of 634 participants.
Proposed antimigraine mechanism: Feverfew may produce an antimigraine effect in a manner similar to methysergide maleate (Sansert), a known 5-HT antagonist.
Instability of preparations: As clinical trials of feverfew for the prevention of migraine attacks published in the 1980s and 1990s produced inconsistent results, wide variations in the strength of the parthenolides and differences in the stability of feverfew preparations were suggested as explanations.
Evidence strength: Overall, the evidence for feverfew in migraine prevention is rated as low quality by the 2015 Cochrane review, with mixed and inconclusive findings from the totality of RCTs conducted to date.
5.2 Rheumatoid Arthritis
One study showed no apparent benefit from oral feverfew in rheumatoid arthritis. This was a double-blind, placebo-controlled trial (Pattrick, Heptinstall & Doherty, Ann Rheum Dis, 1989). Therefore, the benefit of feverfew in rheumatoid arthritis has yet to be determined. Despite the plausibility of an anti-inflammatory effect based on in vitro and ex vivo studies—inflammatory compounds released by white blood cells and platelets are significant contributing factors to the inflammation and cellular damage seen in rheumatoid arthritis, and feverfew's inhibition of the release of inflammatory particles has been demonstrated to be much greater than that achieved by NSAIDs like aspirin—human clinical data remain insufficient to support this indication.
Evidence strength: Insufficient — a single negative RCT and no confirmatory trials.
5.3 Cancer and Leukemia (Preclinical)
Overview: Parthenolide (PN) has been shown to inhibit NF-κB signaling and other pro-survival signaling pathways, induce apoptosis, and reduce a subpopulation of cancer stem-like cells in several cancers.
Leukemia stem cells: The in vitro actions of the sesquiterpene lactone parthenolide on cells isolated from patients with chronic lymphocytic leukemia (CLL) showed that the median LD₅₀ for parthenolide was 6.2 μM (n=78). Chronic lymphocytic leukemia cells were more sensitive towards parthenolide than were normal T lymphocytes or CD34⁺ haematopoietic progenitor cells. Research into acute myelogenous leukemia (AML) stem cells has shown selective apoptosis induction, with parthenolide and a parthenolide analog, dimethylamino-parthenolide, having been shown to be effective against leukemic cells while sparing normal hematopoietic stem cells (HSCs).
Drug resistance: Parthenolide, which is a specific NF-κB inhibitor, effectively eliminated drug-resistant leukemia stem cells and enhanced the sensitivity of K562/ADM cells to doxorubicin-induced apoptosis by down-regulating NF-κB pathway-mediated P-glycoprotein expression.
Melanoma: Cell death accompanied by mitochondrial membrane depolarization and caspase-3 activation was observed as the result of parthenolide application. Melanoma cells from the vertical growth phase and melanocytes were less susceptible to parthenolide-induced cell death than metastatic cells when drug concentration was at least 6 μmol/L.
Bioavailability limitation: Parthenolide's lack of solubility in water, and thus bioavailability, limits its potential as a drug. Research into synthetic analogs with improved bioavailability (e.g., dimethylaminoparthenolide, DMAPT) is ongoing.
Evidence strength: Preclinical only — extensive in vitro and some animal data exist, but no published human clinical trials of parthenolide or feverfew for cancer have been identified in the peer-reviewed literature.
5.4 Topical Anti-inflammatory and Skin Applications
Newly developed purified feverfew extract (Feverfew PFE) retains the anti-inflammatory properties of feverfew with minimal skin sensitization. The anti-inflammatory properties of feverfew, as assessed by inhibition of TNFα release, seem to be far superior to other botanicals including teas (green, black, white), echinacea, licorice extract, chamomile, and aloe vera. In a 4-week, controlled, full-face clinical trial of 35 women… (the full trial results are referenced but not available to quote in detail). Topically (applied to the skin), feverfew is promoted to provide relief from itching and skin irritation. The hydroethanolic extracts from different parts of T. parthenium plants were shown to have a potent protective effect on skin cells.
Evidence strength: Preliminary — small controlled clinical trials exist for topical purified extracts, particularly for skin redness and irritation; data are limited and further large-scale trials are needed.
5.5 Antimicrobial Activity
Parthenolide inhibited the growth of gram-positive bacteria, yeast, and filamentous fungi. The herb extract had the highest content of condensed tannins and terpenoids and exhibited the most effective antimicrobial properties against 12 bacterial and fungal strains (in vitro).
Evidence strength: In vitro only — no human clinical trials identified.
6. Body Systems and Health Areas of Association
- Neurological / Headache: Primary contemporary use; prevention of migraine attacks via serotonin and prostaglandin modulation.
- Musculoskeletal / Inflammatory: Traditional use for rheumatoid arthritis and pain conditions, though clinical evidence for benefit in rheumatoid arthritis is lacking.
- Hematological / Cardiovascular: Inhibition of platelet aggregation and secretion of allergic mediators, including 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.
- Immune / Mast Cells: Inhibition of histamine release from mast cells and degranulation of polymorphonuclear leukocytes.
- Oncology (preclinical): NF-κB-mediated apoptosis in multiple cancer cell types, with particular focus on leukemia stem cells.
- Dermatological: Topical promotion for relief from itching and skin irritation.
- Gastrointestinal: Traditional use includes gastrointestinal disorders.
- Reproductive / Gynaecological: Traditional use includes menstrual disorders.
7. Dosage Forms and Reported Dosages
The following dosages are drawn directly from cited sources and reflect doses used in studies or recommended by regulatory authorities, not general prescriptive guidance:
- 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 parthenolide 0.2% for the prevention of migraine.
- The dose of feverfew for migraine headaches is reported as 100 to 300 mg up to four times daily for 16 weeks from the standard preparation (0.2–0.4% parthenolide), and 6.25 mg three times daily for up to 16 weeks from feverfew supplements with CO₂ extraction. The adult dose of parthenolide was reported as 0.2–0.6 mg for migraine prophylaxis.
- In a published case report, the patient received feverfew 800 mg twice daily for 6 months, then increased to 800 mg three times daily.
Preparation stability matters significantly: wide variations in the strength of the parthenolides and differences in the stability of feverfew preparations were suggested as explanations for inconsistent results in clinical trials.
8. Safety Considerations and Interactions
8.1 Adverse Effects in Clinical Trials
Only mild and transient adverse events, most commonly gastrointestinal complaints and mouth ulcers, were reported in the included trials. Mouth ulcers, contact dermatitis, dysgeusia, and mild gastrointestinal symptoms may occur. Other side effects have included gastrointestinal upset such as mild nausea, vomiting, abdominal pain, diarrhea, and flatulence, which are, fortunately, mild and transient. Feverfew did not appear to affect blood pressure, heart rate, body weight or haematological and biochemical safety parameters in any of the included studies.
8.2 "Post-Feverfew" Withdrawal Syndrome
A possible "post-feverfew" syndrome was observed following withdrawal; symptoms included: anxiety, nervousness, sleep problems, and musculoskeletal aches/pains. Abrupt discontinuation may worsen migraines and cause nervousness and insomnia. Long-term use of feverfew followed by abrupt discontinuation may induce a withdrawal syndrome featuring rebound headaches and muscle and joint pains.
8.3 Oral Mucosal Effects
When the herb is chewed or taken orally it may cause mouth ulcers.
8.4 Allergic Reactions (Compositae/Asteraceae Hypersensitivity)
Feverfew may cause allergic reactions in those allergic to the daisy family, including contact dermatitis or swelling and numbness of the mouth. Feverfew is contraindicated for individuals with known hypersensitivity to members of the Compositae family such as ragweed, chrysanthemums, marigolds and daisies. Parthenolide, which is thought to be the fundamental active ingredient of these extracts, is also responsible for allergic reactions which can sometimes occur following treatment with the extracts of Tanacetum parthenium.
8.5 Antiplatelet and Bleeding Risk
The antiplatelet effect of feverfew may be related to inhibiting ADP, thrombin, and the collagen-induced aggregation of platelets by interfering with cellular phospholipases, preventing the release of arachidonic acid and inhibiting the release of serotonin from platelets. Owing to potential bleeding, feverfew should be discontinued 2 weeks prior to surgery. Although there are no documented cases of feverfew (Tanacetum parthenium) interacting with warfarin in humans, feverfew has been shown to interfere with certain aspects of blood clotting in test tube studies.
8.6 Drug Interactions
Feverfew should be avoided in patients taking other antimigraine medications, nonsteroidal anti-inflammatory drugs (NSAIDs), antiplatelets, or warfarin. Since feverfew affects platelet aggregation, theoretically, concomitant use of feverfew and herbs that affect platelet aggregation, such as garlic and ginkgo, could increase risk of bleeding in some people. Similarly, concomitant use with anticoagulant and antiplatelet drugs might increase risk of bleeding. NSAIDs' effects on prostaglandins might decrease the effectiveness of feverfew.
8.7 Pregnancy and Lactation
Feverfew is contraindicated in pregnant women as it may cause the uterus to contract. Feverfew is not recommended for children or for women who are breastfeeding.
8.8 Standardization Problems
The parthenolide content of commercially available feverfew supplements varies substantially (by more than 40-fold) despite labeling claims of "standardization." This represents a material quality-control concern, since the dose of the principal bioactive constituent cannot be reliably determined from the label alone.
References
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