Feverfew

Metadata

Approved Indications

Commission E (Germany)

• Approved indication: Migraine prophylaxis
• The Commission E issued a positive monograph for feverfew herb for the prevention of migraine headaches
• Based on clinical safety data and controlled studies suggesting prophylactic efficacy

ESCOP

• The ESCOP monograph (2003, 2nd edition) lists feverfew for the prevention of migraine headaches
• Recommended daily dose: 50-250 mg of dried feverfew leaf containing at least 0.2% parthenolide
• Clinical safety data concluded no major safety problems; rare gastrointestinal complaints and allergic skin reactions noted

EMA/HMPC

• The HMPC published an assessment report on Tanacetum parthenium (L.) Schultz Bip., herba (EMA/HMPC/587579/2009, Revision 1)
• Traditional use only: The HMPC concluded that feverfew herb preparations can be used for the prevention of migraine based on long-standing traditional use, after serious conditions have been excluded by a doctor
• The HMPC did not grant “well-established use” status, as clinical studies were considered insufficient due to small sample sizes and methodological shortcomings
• Monograph covers preparations obtained by drying and powdering the above-ground parts of the plant

Agreement/Disagreement Analysis

There is a notable gradient of regulatory endorsement for feverfew across authorities. The German Commission E and ESCOP both positively recognize feverfew for migraine prophylaxis based on available clinical evidence. The EMA/HMPC takes a more cautious stance, classifying feverfew under “traditional use” rather than “well-established use,” indicating that while long-standing use is acknowledged, the clinical trial evidence is not considered robust enough for the higher tier. The AAN/AHS (2012) classified the specific standardized extract MIG-99 as “probably effective” (Level B) — a nuanced position that acknowledges efficacy evidence for a particular preparation while leaving the broader question of feverfew preparations open. This regulatory heterogeneity reflects the genuine complexity of the evidence base: positive results in some trials, negative results in others, and significant variability in preparations tested.

Conditions Treated

Primary Indication: Migraine Prophylaxis

• Prevention of migraine attacks (with or without aura)
• Reduction in frequency, severity, and associated symptoms (nausea, vomiting)
• Evidence level: Moderate (Commission E approved; AAN Level B for MIG-99; Cochrane “low quality evidence”)

Secondary Indications (Traditional/Preliminary Evidence)

• Fever: Traditional use as an antipyretic (the common name “feverfew” derives from the Latin febrifugia, meaning “fever reducer”)
• Arthritis and inflammatory conditions: In vitro anti-inflammatory activity documented; limited clinical evidence
• Menstrual pain: Traditional use; no controlled clinical trials
• Toothache: Historical folk use; no modern evidence

Historical and Folk Uses

• Used since antiquity by Dioscorides and in medieval herbalism
• Traditional indications included fever, headache, menstrual irregularities, arthritis, and digestive complaints
• The 17th-century herbalist John Parkinson recommended it for “all paines of the head”

Mechanism of Action

Key Active Compounds

• Parthenolide: The principal sesquiterpene lactone (0.2-0.5% in leaves); considered the primary bioactive constituent
  • Contains an alpha-methylene-gamma-butyrolactone ring and an epoxide moiety, both critical for biological activity
  • Concentrated in superficial leaf glands; absent from stems
  • Comprises up to 85% of total sesquiterpene lactone content
• Other sesquiterpene lactones: 3-beta-hydroxyparthenolide, costunolide, reynosin, and others
• Flavonoids: Tanetin (a lipophilic flavonol), apigenin, luteolin
• Volatile oils: Trans-chrysanthenyl acetate (a prostaglandin synthetase inhibitor), camphor, camphene

Pharmacological Mechanisms

1. Serotonin Release Inhibition

• Parthenolide inhibits the release of serotonin (5-HT) from platelets induced by aggregating agents (ADP, adrenaline, collagen, thromboxane mimetics)
• The mechanism involves interaction with protein kinase C (PKC) and neutralization of sulfhydryl groups on platelet membrane proteins
• This anti-serotonergic effect is relevant to migraine pathophysiology, where platelet serotonin release during the headache phase contributes to vasoactive changes

2. NF-kB Pathway Inhibition

• Parthenolide directly binds to and inhibits IkB kinase beta (IKKbeta), preventing degradation of IkBalpha and thus blocking nuclear translocation and activation of NF-kB
• This produces broad anti-inflammatory effects including suppression of pro-inflammatory cytokines (TNF-alpha, IL-1beta, IL-6), adhesion molecules, and inducible enzymes (COX-2, iNOS)

3. TRPA1 Channel Modulation

• More recent research (Materazzi et al., 2013) identified TRPA1 as a key target for the antimigraine effect
• Parthenolide acts as a partial agonist at TRPA1, initially activating then desensitizing the channel
• This desensitization inhibits CGRP (calcitonin gene-related peptide) release from trigeminal neurons and CGRP-mediated meningeal vasodilation
• CGRP is a central mediator in migraine pathophysiology and the target of modern anti-CGRP monoclonal antibodies (erenumab, fremanezumab)

4. Arachidonic Acid Cascade Inhibition

• Parthenolide inhibits the release of arachidonic acid from membrane phospholipids (distinct from the NSAID mechanism, which inhibits cyclooxygenase downstream)
• This upstream inhibition reduces production of pro-inflammatory prostaglandins, leukotrienes, and thromboxanes
• Trans-chrysanthenyl acetate from the essential oil independently inhibits prostaglandin synthetase

5. Platelet Aggregation Inhibition

• Feverfew extracts inhibit platelet aggregation through sulfhydryl group neutralization and inhibition of phospholipase A2
• This contributes to the overall anti-inflammatory and potentially antithrombotic profile

Clinical Evidence Summary

Key Randomized Controlled Trials

Johnson et al. (1985) — First Prophylactic Trial

• Design: Randomized, double-blind, placebo-controlled
• n = 17 (migraine patients who had been self-medicating with feverfew)
• Intervention: Freeze-dried feverfew capsules vs. placebo
• Duration: Crossover design, 6 months
• Result: Patients switched to placebo experienced a significant increase in migraine frequency and severity (“post-feverfew syndrome”), supporting prophylactic efficacy
• Significance: First controlled evidence of prophylactic effect; small sample limits generalizability
• PMID: 3929876

Murphy et al. (1988) — Lancet Crossover Trial

• Design: Randomized, double-blind, placebo-controlled, crossover
• n = 72 (60 completed; 59 analyzed)
• Intervention: Dried feverfew leaves (one capsule daily, approx. 82 mg) vs. placebo for 4 months per arm
• Result: Treatment with feverfew was associated with significant reduction in mean number and severity of migraine attacks and degree of vomiting; visual analogue scores showed significant improvement
• Significance: Largest early trial; published in The Lancet; established clinical credibility
• PMID: 2899663

De Weerdt et al. (1996) — Negative Trial

• Design: Randomized, double-blind, placebo-controlled, crossover
• n = 50 (44 completed)
• Intervention: Dried alcoholic extract of feverfew (0.5 mg parthenolide per capsule) vs. placebo for 9 months
• Result: No significant difference between feverfew and placebo groups in migraine frequency
• Significance: Important negative trial; patients had not previously used feverfew (unlike earlier positive trials); different extract preparation may explain discrepancy
• Published: Phytomedicine 1996;3:225-30

Pfaffenrath et al. (2002) — MIG-99 Dose-Response Study

• Design: Randomized, double-blind, placebo-controlled, dose-response (adaptive design)
• n = 147 (IHS-defined migraine)
• Intervention: MIG-99 (CO2 extract of feverfew) at 2.08, 6.25, or 18.75 mg t.i.d. vs. placebo for 12 weeks
• Result: In the overall ITT population, no statistically significant difference was found. However, in the predefined confirmatory subgroup of patients with >= 4 attacks at baseline (n=49), migraine frequency decreased dose-dependently (P=0.001); the 6.25 mg t.i.d. dose showed the greatest reduction (-1.8 +/- 1.5 attacks/28 days vs. -0.3 +/- 1.9 for placebo, P=0.02)
• Significance: Identified the optimal MIG-99 dose (6.25 mg t.i.d.); positive result limited to a subgroup analysis
• PMID: 12230594

Diener et al. (2005) — MIG-99 Phase III Confirmatory Trial

• Design: Randomized, double-blind, placebo-controlled, multicentre, parallel-group
• n = 170 ITT (MIG-99 n=89; placebo n=81)
• Intervention: MIG-99 6.25 mg t.i.d. (18.75 mg/day) vs. placebo for 16 weeks
• Result: Migraine frequency decreased from 4.76 by 1.9 attacks/month in MIG-99 group vs. 1.3 in placebo (P=0.046); responder rate (>= 50% reduction) 30.3% vs. 17.3% (P=0.047); significant improvements in migraine days and global assessment by patients and investigators
• Significance: Confirmatory Phase III trial; provided the primary evidence for the AAN Level B classification
• PMID: 16232154

Systematic Reviews and Meta-Analyses

Cochrane Review (Wider et al., 2015)

• Included 6 studies with 561 participants
• Concluded: “There is low quality evidence from a single, clinically and methodologically sound trial that a specific feverfew extract (MIG-99) is effective in the prevention of migraine. Other studies were small, of questionable quality, and showed mixed results”
• The results need to be confirmed in larger, rigorous trials with stable feverfew extracts
• PMID: 25892430

AAN/AHS Guideline (2012)

• Classified MIG-99 as Level B: Probably Effective for migraine prevention in adults
• Based on one positive Class I trial (Diener 2005), one positive Class II trial (Pfaffenrath 2002), and one negative Class II trial (De Weerdt 1996)
• Published in Neurology 2012;78:1346-1353
• PMID: 22529203

Safety Profile

Contraindications

• Pregnancy: Contraindicated. Feverfew has historically been used as an emmenagogue and abortifacient. Parthenolide may stimulate uterine contractions. Animal studies have not established safety in pregnancy
• Allergy to Asteraceae (Compositae): Patients with known hypersensitivity to plants in the daisy family (chamomile, ragweed, chrysanthemum, marigold, etc.) should avoid feverfew due to risk of cross-reactivity and allergic contact dermatitis
• Children under 12: Insufficient safety data; not recommended
• Pre-surgical: Discontinue at least 2 weeks before planned surgery or dental procedures due to antiplatelet effects

Drug Interactions

• Anticoagulants (warfarin, heparin, DOACs): Feverfew inhibits platelet aggregation and may potentiate anticoagulant effects, increasing bleeding risk. Monitor for signs of excessive bleeding; INR monitoring recommended with warfarin
• Antiplatelet agents (aspirin, clopidogrel): Additive antiplatelet effects; increased risk of bruising and bleeding
• NSAIDs: Theoretical additive effects on arachidonic acid metabolism; feverfew may alter prostaglandin synthesis through a different mechanism than NSAIDs
• CYP substrate drugs: In vitro evidence suggests feverfew may inhibit certain drug-metabolizing liver enzymes, potentially increasing blood levels of CYP substrates; clinical significance uncertain
• Other antimigraine medications (triptans, ergotamines): Caution advised with concurrent use; potential for serotonergic interactions though clinical significance not established

Side Effects

• Common (up to 18% of users):
  • Mouth ulceration (11% in long-term users who chew raw leaves; less frequent with capsule formulations)
  • Loss of taste
  • Lip and tongue swelling (with raw leaf use)
• Uncommon:
  • Gastrointestinal complaints (nausea, abdominal pain, bloating, flatulence, diarrhea)
  • Allergic skin reactions (contact dermatitis)
• Rare:
  • Headache (paradoxical)
  • Dizziness
• Post-Feverfew Syndrome: Described in long-term users who abruptly discontinue; characterized by rebound headaches, insomnia, anxiety, fatigue, joint pain, and muscle stiffness. Gradual tapering is recommended rather than abrupt cessation
• Overall: In controlled clinical trials, the adverse event profile of standardized extracts (MIG-99) was comparable to placebo. No serious adverse events have been reported in clinical trials

Pregnancy and Lactation

• Pregnancy Category X: Contraindicated throughout pregnancy. Feverfew has a historical reputation as an emmenagogue and uterotonic agent. Parthenolide may stimulate uterine smooth muscle. No adequate human pregnancy studies exist
• Lactation: Insufficient data; avoid use during breastfeeding as a precaution. It is unknown whether parthenolide or other active constituents are excreted in breast milk

Clinical Dosage

Key Dosing Principles

1. Standardization matters: Products should contain a minimum of 0.2% parthenolide; commercial products vary up to 150-fold in parthenolide content
2. Onset of effect: Beneficial effects may not be apparent for 4-6 weeks; clinical trials typically lasted 12-16 weeks
3. Do not chew raw leaves: This traditional method causes mouth ulceration in up to 11% of users; encapsulated dried leaf or standardized extracts are preferred
4. Taper on discontinuation: Abrupt cessation after long-term use may trigger post-feverfew syndrome; gradual dose reduction recommended
5. CO2 extract (MIG-99): The specific CO2-extracted preparation has the strongest clinical evidence; results may not be generalizable to all feverfew products

Sources

• Johnson ES, Kadam NP, Hylands DM, Hylands PJ. Efficacy of feverfew as prophylactic treatment of migraine. BMJ. 1985;291(6495):569-573. PMID: 3929876
• Murphy JJ, Heptinstall S, Mitchell JRA. Randomised double-blind placebo-controlled trial of feverfew in migraine prevention. Lancet. 1988;2(8604):189-192. PMID: 2899663
• De Weerdt CJ, Bootsma HPR, Hendriks H. Herbal medicines in migraine prevention: randomized double-blind placebo-controlled crossover trial of a feverfew preparation. Phytomedicine. 1996;3:225-230.
• Pfaffenrath V, Diener HC, Fischer M, Friede M, Henneicke-von Zepelin HH. The efficacy and safety of Tanacetum parthenium (feverfew) in migraine prophylaxis — a double-blind, multicentre, randomized placebo-controlled dose-response study. Cephalalgia. 2002;22(7):523-532. PMID: 12230594
• Diener HC, Pfaffenrath V, Schnitker J, Friede M, Henneicke-von Zepelin HH. 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. 2005;25(11):1031-1041. PMID: 16232154
• Wider B, Pittler MH, Ernst E. Feverfew for preventing migraine. Cochrane Database Syst Rev. 2015;(4):CD002286. PMID: 25892430
• Holland S, Silberstein SD, Freitag F, et al. Evidence-based guideline update: NSAIDs and other complementary treatments for episodic migraine prevention in adults. Neurology. 2012;78(17):1346-1353. PMID: 22529203
• Materazzi S, Benemei S, Fusi C, et al. Parthenolide inhibits nociception and neurogenic vasodilatation in the trigeminovascular system by targeting the TRPA1 channel. Pain. 2013;154(12):2750-2758. PMID: 23933184
• Kwok BH, Koh B, Ndubuisi MI, Elofsson M, Bhatt DK, Bhatt RK, Bhatt RK, Crews CM. The anti-inflammatory natural product parthenolide from the medicinal herb feverfew directly binds to and inhibits IkappaB kinase. Chem Biol. 2001;8(8):759-766.
• Heptinstall S, White A, Williamson L, Mitchell JR. Extracts of feverfew inhibit granule secretion in blood platelets and polymorphonuclear leucocytes. Lancet. 1985;1(8437):1071-1074. PMID: 2860288
• ESCOP Monographs. Tanaceti parthenii herba (Feverfew). 2nd ed. Stuttgart: Thieme; 2003.
• EMA/HMPC. Assessment report on Tanacetum parthenium (L.) Schultz Bip., herba. Revision 1. EMA/HMPC/587579/2009.
• German Commission E Monograph: Tanaceti parthenii herba. Published in Blumenthal M et al., eds. The Complete German Commission E Monographs. Austin: American Botanical Council; 1998.

Connections

• Butterbur: The other major herbal migraine prophylactic; butterbur (Petadolex) had AAN Level A evidence but was withdrawn from the German market due to pyrrolizidine alkaloid hepatotoxicity concerns. Feverfew and butterbur represent contrasting cases: butterbur has stronger efficacy evidence but greater safety concerns, while feverfew has a better safety profile but weaker clinical evidence
• Willow Bark: Both are traditional European analgesic/anti-inflammatory herbs with Commission E approval; willow bark is used for musculoskeletal pain rather than migraine
• Ginger: Sometimes used acutely for migraine-associated nausea; a 2014 RCT compared ginger powder to sumatriptan for acute migraine treatment, complementing feverfew’s prophylactic role
• CGRP pathway connection: Feverfew’s parthenolide inhibits CGRP release via TRPA1 desensitization, mechanistically linking it to the newest class of prescription migraine drugs (erenumab, fremanezumab, galcanezumab)