Benefits
Monthly headache attack frequency in daily-use trials
In the largest placebo-controlled trial, in adults with migraine, a CO2 extract lowered attacks by 1.9 a month versus 1.3 with placebo, a small difference, while attack intensity and duration did not differ. A maker-funded dose-finding trial and a 9-month extract trial found no overall effect; smaller leaf trials were positive. A Cochrane review rates the evidence low quality.
Parthenolide action on a cell signaling enzyme in lab studies
In laboratory experiments, parthenolide, the main studied compound in feverfew, binds directly to and blocks IKK-beta, an enzyme that switches on the NF-κB signaling pathway. In a 6-week placebo-controlled trial, oral dried feverfew leaf did not differ from placebo on blood markers or symptom scores, so this lab effect has not been shown to translate to people.
Platelet activity in laboratory studies
In test-tube studies with human blood cells, feverfew extract and parthenolide reduced platelet clumping and the release of serotonin from platelets, and leaf extracts reduced eicosanoid production by white blood cells. These were laboratory findings; their relevance to oral use in people is not established.
Mechanism of action
Parthenolide binding to IKK-beta
Parthenolide binds directly to IkappaB kinase beta (IKK-beta), the enzyme that activates NF-κB signaling. Mutating cysteine 179 in the enzyme's activation loop abolished this sensitivity, and the activity depends on the alpha-methylene gamma-lactone group that parthenolide shares with related sesquiterpene lactones. Shown in laboratory studies.
Platelet serotonin secretion and aggregation
In vitro, feverfew extract and parthenolide had similar inhibitory effects on serotonin (5-HT) secretion from human platelets and on platelet aggregation triggered by several stimulants, suggesting parthenolide or similar compounds account for the extract's platelet effects.
Eicosanoid synthesis in white blood cells
Feverfew leaf extracts inhibited production of thromboxane B2 and leukotriene B4 by rat and human white blood cells in the laboratory, through both sesquiterpene lactones and other components of the leaf.
Clinical trials
Randomized, double-blind, placebo-controlled, multicenter, parallel-group trial of MIG-99 feverfew CO2 extract, 6.25 mg three times daily, for 16 weeks after a 4-week baseline. Primary endpoint: attacks per 28 days in treatment months 2 and 3 versus baseline. Supported by the extract's manufacturer, per the Cochrane review. (Diener et al. 2005, Cephalalgia)
Adults with migraine by International Headache Society criteria; 170 analyzed for efficacy (89 MIG-99, 81 placebo).
From a baseline of 4.76 attacks a month, attacks fell by 1.9 with MIG-99 and by 1.3 with placebo (P = 0.0456), a between-group difference of about 0.6 attacks a month. Responder odds ratio 3.4 (P = 0.0049). A Cochrane review reports no significant differences in attack intensity or duration. Possibly related adverse events 8.4% versus 10.2%.
Randomized, double-blind, multicenter, placebo-controlled trial with an adaptive design comparing three MIG-99 doses (2.08, 6.25 and 18.75 mg three times daily) with placebo for 12 weeks. Supported by the extract's manufacturer, per the Cochrane review. (Pfaffenrath et al. 2002, Cephalalgia)
147 adults with migraine with or without aura.
No statistically significant difference from placebo on the primary outcome (attacks in the last 28 days) or secondary outcomes in the whole study population. Only a predefined subgroup of 49 patients with at least four baseline attacks improved (6.25 mg dose: minus 1.8 versus minus 0.3 attacks per 28 days, P = 0.02). Adverse events similar across groups.
Randomized, double-blind, placebo-controlled crossover trial after a one-month single-blind placebo run-in: one capsule of dried feverfew leaves daily (mean capsule weight 82 mg per the Cochrane review) or placebo for four months each. (Murphy et al. 1988, Lancet)
72 volunteers with migraine; 59 with complete data.
Feverfew periods had fewer and less severe attacks and less vomiting than placebo periods; duration of individual attacks did not change. No serious side effects.
Double-blind, placebo-controlled trial in people already eating fresh feverfew leaves daily, randomized to freeze-dried feverfew capsules or placebo. (Johnson et al. 1985, Br Med J (Clin Res Ed))
17 people with migraine who already ate fresh feverfew leaves daily (8 feverfew, 9 placebo).
The placebo group, who in effect stopped feverfew, had a significant increase in headache frequency and severity, nausea and vomiting; the feverfew group showed no change.
Randomized, double-blind, placebo-controlled crossover trial lasting 9 months: one capsule a day of dried alcoholic feverfew extract containing 0.5 mg parthenolide (143 mg capsule per the Cochrane review) or placebo. (De Weerdt et al. 1996, Phytomedicine)
50 adults with migraine who had not used feverfew before; 44 completed.
Both treatment periods had the same number of attacks; no preventive effect was shown for this preparation.
Randomized, double-blind, placebo-controlled trial of dried chopped feverfew (70 to 86 mg) or placebo once daily for six weeks in women with rheumatoid arthritis; outcomes included symptom scores, grip strength, C reactive protein and other blood markers. (Pattrick et al. 1989, Ann Rheum Dis)
41 women with a symptomatic autoimmune condition; 40 analyzed (20 per group).
No important differences between groups in any clinical or laboratory measure over six weeks.