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Feverfew

Scientific Name(s): Tanacetum parthenium (L.) Schulz-Bip.
Common Name(s): Altamisa, Bachelor's button, Chamomile grande, Chrysanthemum atricaire, European feverfew, Feather-fully, Featherfew, Featherfoil, Febrifuge plant, Feddygen fenyw, Feverfew, Flirtroot, Grande chamomile, Midsummer daisy, Mutterkraut, Nosebleed, Santa Maria, Vetter-voo, Wild chamomile, Wild quinine

Medically reviewed by Drugs.com. Last updated on Aug 22, 2023.

Clinical Overview

Use

Feverfew is primarily known for use in prophylaxis of migraine headaches and associated nausea and vomiting; however, evidence regarding this use is inconclusive.

Dosing

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.

Contraindications

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

Pregnancy/Lactation

Avoid use. Adverse effects have been documented. 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.

Interactions

None well documented. Potential drug interactions may occur with coadministration of agents or herbs with anticoagulant/antiplatelet properties, nonsteroidal anti-inflammatory agents, salicylates, or thrombolytic agents.

Adverse Reactions

Patients withdrawn from feverfew may experience an effect often known as "post-feverfew syndrome." Handling fresh feverfew leaves may cause allergic contact dermatitis. Swelling of the lips, tongue, and oral mucosa, in addition to mouth ulceration, have been reported with feverfew use. GI effects, such as abdominal pain, nausea, vomiting, diarrhea, indigestion, and flatulence, may also occur.

Toxicology

No studies of chronic toxicity have been performed. The safety of long-term use has not been established.

Scientific Family

Botany

Native to the Balkan Peninsula, feverfew is now found in Australia, Europe, China, Japan, and North Africa. In the mid-19th century, feverfew was introduced in the United States. The plant grows along roadsides, fields, waste areas, and the borders of woods from eastern Canada to Maryland and westward to Missouri. Feverfew is a short, bushy, aromatic perennial that grows 0.3 to 1 m in height. Its yellow-green leaves are usually less than 8 cm in length, almost hairless, and pinnate-bipinnate (chrysanthemum-like). Its yellow tubular florets bloom from July to October and are approximately 2 cm in diameter; they resemble those of chamomile (Matricaria chamomilla), with which they are sometimes confused, and have a single layer of 10 to 20 white outer-ray florets.(Chavez 1999, Freeman 2009, Jain 1999, van Wyk 2004)

Historically, the plant has been placed into 5 different genera; therefore, some controversy exists as to which genus the plant belongs. Former botanical names include Chrysanthemum parthenium (L.) Bernh., Leucanthemum parthenium (L.) Gren. and Godr., Pyrethrum parthenium (L.) Bernh., and Matricaria parthenium (L.).(Awang 1989, Chavez 1999) Feverfew is a member of the daisy (Asteraceae) family, which includes aster, chamomile, chrysanthemum, ragweed, sunflower, tansy, and yarrow.

History

The feverfew herb has a long history of use in traditional and folk medicine, especially among Greek and early European herbalists. 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 derive from use in treating menstrual cramps in young girls, because the word parthenos means "virgin" in the Greek language. It is possible the common English name feverfew was derived from a feathery plant known as featherfew.(Chavez 1999, van Wyk 2004)

The first century Greek physician Dioscorides used feverfew as an antipyretic. Feverfew also was known as "medieval aspirin" or the "aspirin" of the 17th century. In 1633, the plant was recommended for use in treatment of headaches in Gerard's Herbal.(Blumenthal 2003, Chavez 1999, Freeman 2009, Setty 2005)

The plant has been used to treat arthritis, asthma, constipation, dermatitis, earache, fever, headache, inflammatory conditions, insect bites, labor, menstrual disorders, potential miscarriage, psoriasis, spasms, stomachache, swelling, tinnitus, toothache, vertigo, and worms. Feverfew also has 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.(Chavez 1999, Jain 1999, Pareek 2011, Pittler 2004, Setty 2005, Sumner 1992)

In Central and South America, feverfew plant has been used to treat a variety of disorders. 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.(Chavez 1999) In Danish folk medicine, feverfew is used as an antiepileptic.(Jäger 2009) The leaves are ingested fresh or dried, with a typical daily dosage of 2 to 3 leaves. The bitter taste is often offset by the addition of sweeteners. Feverfew also has been planted around houses to purify the air because of its strong, lasting odor; a tincture of its blossoms is used as an insect repellent and balm for bites.(Reader's Digest 1986) Feverfew has also been used as an antidote for opium overdose.(Duke 1985)

Chemistry

The chemistry of feverfew is well defined. The most important biologically active principles are sesquiterpene lactones, principally parthenolide. Parthenolide is found in the superficial leaf glands (0.2% to 0.5%), but not in the stems, and comprises up to 85% of the total sesquiterpene content.(Awang 1989, Bohlmann 1982, Chavez 1999, Jin 2007) Factors such as seed origin geographical location, stage of plant growth at harvest, plant parts used, and duration and condition of storage can all affect parthenolide content.(Blumenthal 2003) A study revealed that degradation of parthenolide in a feverfew solution follows a first-order reaction. It was also discovered that parthenolide was stable when the environmental pH was between 5 and 7 but unstable at a pH of 3 or less. The effects of temperature on the degradation of parthenolide were also measured. The content remained constant after 6 months of storage in a refrigerator. However, at 25°C (80°F), feverfew slowly degraded after 3 months, with decomposition occurring after 1 or 2 months if stored at 40°C (104°F) or higher. Increases in humidity were also associated with increased degradation of parthenolide.(Jin 2007)

Flavonoids

The following flavonoids have been isolated: 6-hydroxykaempferol 3,6-dimethyl ether, 6-hydroxykaempferol 3,6,4′-trimethyl ether (tanetin), quercetagetin 3,6-dimethyl ether, quercetagetin 3,6,3′-trimethyl ether (accompanied by isomeric 3,6,4′-trimethyl ether), apigenin (also apigenin 7-glucuronide), luteolin (also luteolin 7-glucuronide), chrysoeriol, santin, jaceidin, and centaureidin.(Hobbs 1989, Long 2003, Williams 1995, Williams 1999, Williams 1999)

Sesquiterpene lactones

More than 30 sesquiterpene lactones have been identified in feverfew. In general, there are 5 different types of sesquiterpene lactones, which may be classified by chemical ring structures. Feverfew contains eudesmanolides, germacranolides, and guaianolides. Parthenolide is a germacranolide.(Chavez 1999)

Researchers have also isolated the following sesquiterpene lactones: artecanin, artemorin, balchanin, canin, costunolide, 10-epicanin, epoxyartemorin, 1-beta-hydroxyarbusculin, 3-beta-hydroxycostunolide, 8-alpha-hydroxyestagiatin, 8-beta-hydroxyreynosinn, 3-beta-hydroxyparthenolide, manolialide, reynosin, santamarine, secotanaparthenolide A, secotanaparthenolide B, tanaparthin-alpha-peroxide, and 3,4-beta-epoxy-8-deoxycumambrin B.(Setty 2005) Other members of this class have been isolated and possess spasmolytic activity, perhaps through inhibition of the influx of extracellular calcium into vascular smooth muscle cells.(Begley 1989, Chavez 1999, Groenewegen 1986, Milbrodt 1997)

Volatile oils

Twenty-three compounds, representing 90% or more of the volatile oils, have been identified from feverfew. The primary components include camphor (56.9%), camphene (12.7%), rho-cymene (5.2%), and bornyl acetate (4.6%). Other components identified include tricylene, alpha-thujene, alpha-pinene, beta-pinene, alpha-phellandrene, alpha-terpinene, gamma-terpinene, chrysantheone, pinocarvone, borneol, terpinen-4-ol, rho-cymen-8-ol, alpha-terpineol, myrtenal, carvacrol, eugenol, trans-myrtenol acetate, isobornyl 2-methyl butanoate, and caryophyllene oxide.(Akpulat 2005)

Other chemical constituents

The coumarin isofraxidin and an isofraxidin drimenyl ether named 9-epipectachol B have been isolated from the roots of the plant, as well as (2-glyceryl)-0-coniferaldehyde.(Kisiel 1997, Sy 1999)

Uses and Pharmacology

Feverfew extracts are not only potent inhibitors of serotonin release from platelets but also of polymorphonuclear leukocyte granules, providing a possible connection to the claimed benefit of feverfew in migraines and arthritis.(Awang 1989, Chavez 1999, Heptinstall 1985, Heptinstall 1987, Heptinstall 1988, Krause 1990, Kwok 2001, Voyno-Yasenetskaya 1988) Extracts from fresh feverfew leaves have demonstrated inhibition of smooth muscle spasms by blocking open potassium channels.(Barsby 1992, Barsby 1993, Barsby 1993) Parthenolide has demonstrated effects on smooth muscles via noncompetitive inhibition of serotonin (5-hydroxytriptamine [5-HT])–mediated spasmogenic response in isolated rat stomach(Béjar 1996) and inhibition of the proliferation of vascular smooth muscle cells via cell cycle arrest.(Weng 2009)

Antiepileptic activity

In vitro data

Feverfew may have a potential role as an antiepileptic agent. Specifically, an ethanolic extract of T. parthenium had high affinity for the gamma-aminobutyric acid (GABAA)-benzodiazepine site. The flavonoid apigenin was isolated and may be responsible for these effects.(Jäger 2009)

Anti-inflammatory activity

A proposed mechanism of action involves parthenolide inhibition of the nuclear factor kappa B (NF-kappaB) pathway by blocking I-kappaB kinase beta (IKK-beta), an activator of NF-kappaB.(Kwok 2001, Sur 2009) The IKK-beta complex plays an important role in proinflammatory cytokine-mediated signaling. Additionally, a component of essential oil, trans-chrysanthenyl acetate, is a known inhibitor of prostaglandin synthetase and may contribute to anti-inflammatory effects, especially when used for the treatment of migraine headaches.(Awang 2009) Feverfew was also shown to inhibit histamine release from rat peritoneal mast cells, possibly via mediation of calcium influx.(Hayes 1987)

In vitro data

Chloroform leaf extracts, rich in sesquiterpene lactones, irreversibly inhibit production of inflammatory prostaglandins in rat and human leukocytes. Lipophilic compounds other than parthenolide may be associated with anti-inflammatory activity, particularly through reductions in human neutrophil oxidative burst activity.(Brown 1997, Collier 1980, Jin 2007) Results suggest that feverfew's inhibition of prostaglandin synthesis differs in mechanism from that of salicylates.(Heptinstall 1985, Loecshe 1988, Makheja 1981, Williams 1995, Williams 1999) These mechanisms include inhibition of phospholipase A2 in platelets,(Makheja 1982, Pugh 1988, Sur 2009) as well as inhibition of the activity of the proinflammatory enzymes 5-lipoxygenase, phosphodiesterase-3, and phosphodiesterase-4; and inhibition of the release of the proinflammatory mediators nitric oxide, prostaglandin E2, and tissue necrosis factor alpha (TNF-alpha) from macrophages and TNF-alpha, interleukin 2 (IL-2), interferon (IFN)-gamma, and IL-4 from human peripheral blood mononuclear cells.(Sur 2009) Additionally, a cytotoxic effect has been observed.(O'Neill 1987)

Approximately 400 genes in human monocytic THP-1 cells were identified that were consistently regulated by feverfew extracts. Of these, 245 were up-regulated genes and 155 were down-regulated genes. Most of the identified genes were involved in cellular metabolism, including regulation of metabolism and alcohol, nucleotide, and lipid metabolism. Cells pretreated with feverfew extracts demonstrated a reduction in lipopolysaccharide-mediated TNF-alpha release in a dose-dependent manner.(Chen 2009)

Clinical data

In a 6-week double-blind, randomized, placebo-controlled trial, 41 women with rheumatoid arthritis received placebo or feverfew 70 to 86 mg. Of 15 parameters tested, only grip strength improved significantly (P=0.04) in the feverfew group compared with the placebo group. However, the dose of feverfew in this study may have been too low, and the parthenolide content was not standardized. 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-alpha, and interferon-gamma.(Pattrick 1989, Piela-Smith 2001, Setty 2005)

Antimicrobial activity

In vitro data

Parthenolide inhibited the growth of gram-positive bacteria, yeast, and filamentous fungi.(Chavez 1999) A hydroalcoholic extract of feverfew inhibited the growth of Leishmania amazonesis at an inhibitory concentration (IC50) of 29 mcg/mL, while a dichloromethane fraction inhibited growth at an IC50 of 3.6 mcg/mL. Parthenolide has also inhibited Mycobacterium tuberculosis and Mycobacterium avium at minimum inhibitory concentrations of 16 and 64 mcg/mL, respectively.(Tiuman 2005)

Antioxidant effects

Feverfew parthenolide-free extract is suggested to have antioxidant and anti-inflammatory activities. Specifically, its antioxidant effects have been demonstrated through inhibition of smoke and ultraviolet-induced DNA damage; apoptosis; and scavenging of free radicals.(Ditre 2008)

Animal and in vitro data

Both feverfew extract and a synthetic parthenolide demonstrated protective effects against oxidative and other damage from radiation treatment in mice.(Pooja 2021) A parthenolide-depleted formulation of feverfew was assessed for its antioxidant effects on primary normal human keratinocytes and dermal fibroblasts. It possessed more radical scavenging activity against a large range of oxygen-reactive species, including oxygen, hydroxyl, peroxynitrate, and ferric radicals, compared with ascorbic acid. Specifically, it had a 5-fold greater radical scavenging activity for oxygen and hydroxyl and 3-fold greater activity for ferric radicals compared with ascorbic acid. In the presence of cigarette smoke, parthenolide-depleted feverfew protected the keratinocyte against the production of cigarette smoke–induced oxygen reactive species.(Martin 2008) Thus feverfew, specifically products depleted of parthenolide for the avoidance of skin reactions, may be beneficial for its antioxidant effects.

Cancer

Mechanisms of action are poorly understood but may include (1) cytotoxic action associated with interruption of DNA replication by the highly reactive lactone ring, epoxide, and methylene groups of parthenolide through inhibition of thymidine incorporation into DNA; or (2) oxidative stress, intracellular thiol depletion, endoplasmic reticulum stress, caspase activation, and mitochondrial dysfunction.(Chavez 1999, Zhang 2004, Zhang 2004) A mechanism study in lung cancer cells suggests parthenolide works through modulation of insulinlike growth factor 1 receptor (IGF-1R)–mediated PI3K/Akt/FoxO3alpha signaling.(Sun 2020)

In vitro data

Parthenolide has been investigated for use in the treatment of leukemia. Specifically, parthenolide inhibits NF-kappaB, a nuclear factor that plays a vital role in cell survival, and selectively destroys the leukemic cells to cause apoptosis in primary human acute myeloid leukemia (AML) cells and in blast crisis chronic myeloid leukemia (CML) cells.(Guzman 2005, Jordan 2007) Parthenolide targeted AML progenitor and leukemic stem cells in a nonobese diabetic/severe combined immunodeficient xenograft mouse model.(Guzman 2005) In addition, another study of cell lines from patients diagnosed with pre–B-cell acute lymphoblastic leukemia (ALL) containing the chromosomal translocation t(4;11)(q21;q23) and from those without the translocation determined that parthenolide was able to induce apoptosis accompanied by mitochondrial dysfunction. Cells with the chromosomal translocation were more sensitive to parthenolide than those without. Parthenolide also enhanced the production of nitric oxide and superoxide anion in all ALL cells.(Zunino 2007)

Parthenolide and similar lactones displayed anticancer activity against several human cancer cell lines, including human fibroblasts, human laryngeal carcinoma, human cells transformed with simian virus 40, human epidermoid cancer of the nasopharynx, human melanoma, and anti–Epstein-Barr early antigen activity. Additionally, an ethanolic extract of feverfew inhibited the growth of 2 human breast cancer lines, human glioblastoma cell lines, and 1 human cervical cancer cell line. Of all the constituents of feverfew tested, parthenolide demonstrated the greatest inhibitory effect.(Wu 2006) Another in vitro study demonstrated that parthenolide was effective at inhibiting the proliferation of human lung carcinoma, human medulloblastoma, human colon adenocarcinoma, and human umbilical vein endothelial cells.(Parada-Turska 2007) Results from another study suggest that parthenolide given in combination with hyperthermia (ie, heat) may increase thermosensitization of human lung adenocarcinoma cells via induction of apoptosis or cell cycle arrest through inhibition of NF-kappaB activation.(Hayashi 2010) One study documents how parthenolide may influence and enhance the effectiveness of paclitaxel.(Anderson 2008, Barsby 1993, Chavez 1999, Collier 1980, Kapadia 2002, Lesiak 2010, Miglietta 2004, O'Neill 1987, Ross 1999)

Clinical data

Parthenolide has been investigated in clinical studies for a therapeutic role in cancer.(Ghantous 2013)

CNS effects

Alpha-pinene derivatives may possess sedative and mild tranquilizing effects.(Pareek 2011)

Animal data

In a study in mice, an aqueous extract of T. parthenium was found to have both anxiolytic and antidepressant effects at doses of 1 mg/kg, 5 mg/kg, and 10 mg/kg, but not at 20 mg/kg and 40 mg/kg doses. Results on several tests were similar to the comparator diazepam. The study suggested a mechanism related to action at the GABAA receptor.(Cárdenas 2017)

A 40 mg/kg dose significantly reduced neuropathic pain in a constriction injury−induced neuropathy model in rats. A significant dose-response curve was noted, but lower doses were not effective.(Safakhah 2018)

Cystic fibrosis

In cystic fibrosis, there is an excessive inflammatory response due to the dysregulated production of proinflammatory cytokines, including TNF-alpha, IL-1beta, IL-6, and IL-8. These cytokines are dependent on the transcription factor NF-kappaB for secretion. Phosphorylation of its inhibitor, I-kappaB, by the enzyme IKK leads to the activation of NF-kappaB, which ultimately facilitates the transcription of NF-kappaB–dependent genes.(Saadane 2007)

Animal and in vitro data

In vitro data suggest that parthenolide inhibits IKK and can directly inactivate NF-kappaB. In an in vitro model, the effects of pretreatment with parthenolide on 2 cell lines with defective and normal cystic fibrosis transmembrane conductance regulator (CFTR) were assessed. Pretreatment with parthenolide inhibited IL-8 production associated with IKK activity inhibition and ultimately inhibition of NF-kappaB translocation to the nucleus. Another study evaluated parthenolide's effects in an in vivo model using CFTR knockout mice. Parthenolide inhibited the degradation of I-kappaB and NF-kappaB activation. In addition, parthenolide decreased cytokine production and polymorphonuclear influx into the lung.(Saadane 2007)

Dermatological activity

Clinical data

Feverfew-containing products may be beneficial for treating dermatological conditions such as rosacea and atopic dermatitis.(Eichenfield 2007, Wu 2008) Specifically, a parthenolide-free extract of feverfew demonstrated anti-inflammatory and antioxidant effects when used topically. In a 3-week study, 31 women 25 to 62 years of age with a history of sensitive skin and/or atopic dermatitis topically applied a facial moisturizer containing a parthenolide-free feverfew extract. The product significantly improved erythema, overall irritation, and tactile roughness as noted by the participants and investigators (P<0.05).(Eichenfield 2007)

Migraine prevention

The potential action of feverfew in migraine prevention does not appear to be limited to a single mechanism. Plant extracts affect a wide variety of physiologic pathways. Some of these mechanisms have been discussed previously, including inhibition of prostaglandin synthesis, decrease of vascular smooth muscle spasm, and blockage of platelet granule secretion. Feverfew may produce an antimigraine effect in a manner similar to methysergide maleate (Sansert [discontinued product]), a known 5-HT antagonist.(Tyler 1987)

Clinical data

A great deal of interest has focused on the activity of feverfew in the treatment and prevention of migraine headaches.(Feverfew 1985) The first modern, public account of its use as prophylaxis for migraine appeared in a 1978 article in the British health magazine Prevention about a patient with severe migraine headaches since 16 years of age. At age 68, she began using 3 leaves of feverfew daily, and after 10 months, her headaches ceased completely.(Hobbs 1990)

Early studies in the 1980s consisting of small sample sizes generally showed positive results. A study in 8 patients treated with feverfew and 9 placebo-control patients found that fewer headaches were reported by patients taking feverfew for up to 6 months. Patients in both groups had self-medicated with feverfew for several years before enrolling in the study. The incidence of headaches remained constant in those receiving feverfew for the trial but increased almost 3-fold in patients who switched to placebo (P<0.02).(Johnson 1985) The abrupt discontinuation of feverfew caused incapacitating headaches in some patients. Nausea and vomiting were reduced in patients taking feverfew; however, the statistical analysis has been questioned.(Johnson 1985, Waller 1985) These results were confirmed in a placebo-controlled study in 72 patients with migraine, in which treatment with feverfew was associated with a reduction in mean number and severity of attacks and in degree of vomiting.(Murphy 1988) On the basis of their research, investigators predicted that feverfew may be useful not only for classical migraine and cluster headaches, but also for premenstrual, menstrual, and other headaches, although studies evaluating these uses have not been conducted.(Hobbs 1990)

A study published in 1982 at the City of London Migraine Clinic revealed that experimental observations may not be clinically relevant to migraine patients taking feverfew. Ten patients who had taken extracts of the plant for up to 8 years to control migraine headaches were evaluated for physiologic changes that may have been related to the plant. The platelets of all treated patients aggregated characteristically to ADP and thrombin similarly to those of control patients. However, aggregation in response to serotonin was greatly attenuated in the feverfew users.(Biggs 1982)

The clinical efficacy and safety of 3 dosage regimens of a carbon dioxide (CO2) feverfew extract, each given 3 times daily, were compared with placebo in a 2002 double-blind, multicenter, randomized, controlled trial in patients with migraine with or without aura (N=147) according to International Headache Society criteria. The primary end point was the total number of migraine attacks during the last 28 days of treatment compared with the 4-week baseline period. Secondary end points were total and average duration and intensity of migraine attacks, and number of days with accompanying migraine symptoms. No statistically significant effects were seen for primary or secondary end points. Furthermore, a dose-response relationship was not observed. Subgroup analysis of 49 patients with at least 4 migraine attacks during the baseline period showed a significant effect with the 6.25 mg three times daily dose compared with placebo (P=0.02).(Pfaffenrath 2002) Following this study, a 2005 randomized, double-blind, placebo-controlled, multicenter, parallel-group study assessed the efficacy of a feverfew CO2 extract (MIG-99) in 170 patients (intention-to-treat) with migraine headaches. Patients were randomized to receive feverfew CO2 extract 6.25 mg 3 times daily or placebo for 16 weeks. At weeks 5 through 12, migraine frequency declined from 4.8 attacks to 2.9 attacks (−1.9±0.2) in patients treated with feverfew compared with 3.5 attacks (−1.3±0.2) with placebo. The number of migraine attacks per 28 days was less in the feverfew group.(Diener 2005)

In a 2012 10-week randomized, double-blind, controlled study involving 69 women with migraine without aura, observed substantial mean reductions in pain with feverfew 150 mg/day were similar to those with acupuncture twice a week. Overall quality of life was significantly better in the acupuncture group versus the feverfew group (P<0.05), whereas the combination of the 2 treatments was significantly better than either alone for almost all outcome measures.(Ferro 2012, Lopresti 2020)

In a Cochrane review evaluating the clinical efficacy and safety of feverfew monopreparations versus placebo for preventing migraine, a total of 5 randomized, placebo-controlled, double-blind trials (N=343) met inclusion criteria. Results from the meta-analysis reported insufficient evidence to conclude whether feverfew was superior to placebo in reducing the frequency and severity of migraine attacks, incidence and severity of nausea and vomiting, and global assessment of efficacy in patients with migraine headaches. Dosage forms varied in the trials, and thus may have impacted the results. Three trials used dried powdered feverfew leaf extract at 50 to 100 mg/day for 8 to 24 weeks; one 4-month crossover trial used an alcoholic feverfew extract at 143 mg/day for 8 weeks; and 1 trial used a CO2 extract (2.08 mg vs 6.25 mg vs 18.75 mg 3 times daily for 12 weeks). The 2 studies of highest methodological quality used the dried alcoholic and CO2 extracts and reported no benefit, while the studies of lower methodological quality used the dried powdered leaf extract and reported a favorable response. In the 4-month crossover trial, fewer symptomatic medications were used during the feverfew phase.(Lopresti 2020, Pittler 2004) The addition of one new study (n=218) in the 2015 updated review added limited positive evidence to the current inconclusive evidence and reported 0.6 fewer attacks per month with feverfew compared with placebo.(Wider 2015)

Canada's Health Protection Branch granted a Drug Identification Number for a British feverfew (T. parthenium) product, allowing the manufacturer (Herbal Laboratories, Ltd.) 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 parthenolide at least 0.2% for the prevention of migraine.(Awang 1983, Pareek 2011)

The American Academy of Neurology and the American Headache Society Quality Standards Report lists CO2 feverfew extract as probably effective (level B) for migraine prevention.(AAN/AHS [Holland 2012]) Other guidelines have been published discussing a place in therapy for feverfew in the treatment and prevention of migraines.(D'Andrea 2014, Rajapakse 2016)

Dosing

Products containing feverfew are not recommended for use in children younger than 2 years.(Freeman 2009)

Parthenolide content of 21 feverfew products was found to vary 150-fold (0.02 to 3 mg).(Nelson 2002) Feverfew-containing products are not strictly regulated by the U.S. Food and Drug Administration.

Migraine prevention

An optimal dose of feverfew has not been established. Dried leaf preparation dosages ranging from 50 to 150 mg/day for various treatment durations have been evaluated in clinical trials.(Lopresti 2020, Pittler 2004, Wider 2015) Feverfew supplements for migraine prevention may also be available as CO2 extracts.(Pareek 2011, Wider 2015)

Canada's Health Protection Branch recommends a daily dosage of 125 mg of a dried feverfew leaf preparation from authenticated T. parthenium containing parthenolide at least 0.2% for the prevention of migraine(Awang 1993, Pareek 2011); however, this compound has not been confirmed as a major active principle for migraine.

Patients may prefer to take feverfew with food because of its bitter taste. Beneficial effects may be noted within 4 to 6 weeks after initiation with feverfew. Upon discontinuation of feverfew, the dose should be gradually tapered to avoid the emergence of withdrawal symptoms. Feverfew should be stored in a cool, dry, dark environment to protect the parthenolide content.(Blumenthal 2003, Heptinstall 1988)

Pregnancy / Lactation

Avoid use. Adverse effects have been documented. Feverfew may promote menstruation and is known to possess emmenagogic activity (ejection of the placenta and fetal membranes) and may induce abortion,(Brinker 1998, Ernst 2002, Newall 1996, Yao 2006) In a rat model, 5 pregnant rats received feverfew 839 mg/kg/day on either gestational days 1 through 8 or days 8 through 15. Fetal weights in those exposed to feverfew on gestational days 8 through 15 were lower compared with the ethanol control group; this result is possibly due to an increased frequency of runts in treated litters.(Palevitch 1997)

Interactions

Agents with antiplatelet properties: Herbs (anticoagulant/antiplatelet properties) may enhance the adverse/toxic effect of agents with antiplatelet properties. Bleeding may occur. Consider therapy modification.(Mousa 2010, Spolarich 2007, Stanger 2012, Ulbricht 2008)

Anticoagulants: Herbs (anticoagulant/antiplatelet properties) may enhance the adverse/toxic effect of anticoagulants. Bleeding may occur. Consider therapy modification.(Fan 2017, Heck 2000, Izzat 1998, Jiang 2005, Krüth 2004, Lambert 2001, Mousa 2010, Shi 2012, Spolarich 2007, Stanger 2012, Tsai 2013, Ulbricht 2008, Vaes 2000, Wang 2015)

Herbs (anticoagulant/antiplatelet properties): May enhance the adverse/toxic effect of other herbs (anticoagulant/antiplatelet properties). Bleeding may occur. Consider therapy modification.(Mousa 2010, Spolarich 2007, Stanger 2012, Ulbricht 2008)

Nonsteroidal anti-inflammatory agents: Herbs (anticoagulant/antiplatelet properties) may enhance the adverse/toxic effect of nonsteroidal anti-inflammatory agents. Bleeding may occur. Consider therapy modification.(Mousa 2010, Spolarich 2007, Stanger 2012, Ulbricht 2008)

Nonsteroidal anti-inflammatory agents (topical): Herbs (anticoagulant/antiplatelet properties) may enhance the antiplatelet effect of nonsteroidal anti-inflammatory agents (topical). Monitor therapy.(Flector March 2019, Licart May 2020, Pennsaid May 2016, Spolarich 2007, Stanger 2012, Ulbricht 2008)

Salicylates: Herbs (anticoagulant/antiplatelet properties) may enhance the adverse/toxic effect of salicylates. Bleeding may occur. Consider therapy modification.(Mousa 2010, Spolarich 2007, Stanger 2012, Ulbricht 2008)

Thrombolytic agents: Herbs (anticoagulant/antiplatelet properties) may enhance the adverse/toxic effect of thrombolytic agents. Bleeding may occur. Consider therapy modification.(Mousa 2010, Spolarich 2007, Stanger 2012, Ulbricht 2008)

Feverfew drug interactions (more detail)

Adverse Reactions

Adverse reactions in patients administered feverfew 50 mg/day (roughly equivalent to 2 leaves) for 6 months were mild and did not result in discontinuation, with 4 of 8 patients experiencing no adverse effects. Heart rate increased dramatically (by up to 26 beats/minute) in 2 patients. Patients who switched to placebo after taking feverfew for several years experienced a cluster of CNS reactions (eg, fatigue, headaches, insomnia, joint pain, nervousness, poor sleep patterns, stiffness, tension) along with muscle and joint stiffness, often referred to as "post-feverfew syndrome."(Hobbs 1990, Miller 1998)

In a larger series of feverfew users, 18% reported adverse effects, the most serious being mouth ulceration (11%). Feverfew can induce widespread inflammation of the oral mucosa and tongue, often with lip swelling and loss of taste. Dermatitis has been associated with the plant, specifically from handling of the fresh leaves. A case of edematous pruritic erythema contact dermatitis with exudate was reported on the face, neck, and hands of a 45-year-old female florist after handling feverfew. Patch testing was positive for feverfew leaves and flower petals.(Hashimoto 2019) Two case reports describe development of dermatitis soon after use of a facial moisturizer containing feverfew. The first case involved a 45-year-old woman with an eruption on her scalp and face, including the eyelids and behind the ears. The second patient was a 25-year-old woman with an eruption around the eyes. Upon patch testing, both women tested positive to various allergens, including a sesquiterpene lactone mix and the moisturizer, leading to the conclusion that feverfew moisturizer was responsible for the dermatitis.(Feverfew 1985, Hayes 1987, Killoran 2007, Vickers 1985) Other adverse effects have included nausea, vomiting, abdominal pain, diarrhea, indigestion, and flatulence.(Blumenthal 2003)

Toxicology

Because no studies of long-term toxicity have been performed, the safety of feverfew use has not been established. Use is not recommended during pregnancy; the leaves possess potential emmenagogic activity. Feverfew is not recommended during breastfeeding or for use in children.(Awang 1993)

One study evaluated the potential genotoxic effects of long-term feverfew ingestion in 30 individuals with migraine. Analysis of the frequency of chromosomal aberrations and sister chromatid exchanges in circulating lymphocytes from patients who ingested feverfew for 11 months found no unexpected aberrations, suggesting that the plant does not induce chromosomal abnormalities.(Anderson 1988)

Index Terms

References

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This information relates to an herbal, vitamin, mineral or other dietary supplement. This product has not been reviewed by the FDA to determine whether it is safe or effective and is not subject to the quality standards and safety information collection standards that are applicable to most prescription drugs. This information should not be used to decide whether or not to take this product. This information does not endorse this product as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this product. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this product. This information is not specific medical advice and does not replace information you receive from your health care provider. You should talk with your health care provider for complete information about the risks and benefits of using this product.

This product may adversely interact with certain health and medical conditions, other prescription and over-the-counter drugs, foods, or other dietary supplements. This product may be unsafe when used before surgery or other medical procedures. It is important to fully inform your doctor about the herbal, vitamins, mineral or any other supplements you are taking before any kind of surgery or medical procedure. With the exception of certain products that are generally recognized as safe in normal quantities, including use of folic acid and prenatal vitamins during pregnancy, this product has not been sufficiently studied to determine whether it is safe to use during pregnancy or nursing or by persons younger than 2 years of age.

Frequently asked questions

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