Feverfew

Feverfew (Featherfew) is a herb from the family of Asteraceae (the daisy family) with the true botanical name of Tanacetum parthenium (genus and species, respectively); It derives its common name of Feverfew from the latin word febrifugia meaning fever reducer, and the alternate name of Featherfew is so due to its feathery leaves.^[4] Feverfew is sometimes also referred to as Chrysanthemum, Matricaria, Pyrenthrum, or Leucanthemum parthenium (due to the plant being placed into 5 different genera in the past, usually Matricaria) with some other common names being wild chamomile, mutterroot, midsummer daisy, nosebleed or parthenolide/parthenium.^[4] It is native to the Balkan Peninsula but spread into North Africa and Eastern Asia. Some sources call Feverfew 'Medieval Aspirin' or the aspirin of the 18th century.^[4][5]

Historical usage of the plant includes it being used for treatment of arthritis, asthma, constipation, dermatitis, earache, fever, headache, inflammatory conditions, insect bites, labor, menstrual disorders, potential miscarriage, psoriasis, spasms, stomach ache, swelling, tinnitus, toothache, vertigo, worms, and for the treatment of cough and cold. Its most common historical usage is as an antipyretic (fever reducers) from which its most well known name is derived.^[4] Traditional preparation of the herb includes just eating 2-3 fresh leaves, although it is usually consumed with something sweet due to the leaves being bitter.^[4]

Traditionally used for, well, a lot; mostly to fight fevers but apparently does a lot of other treatments that are related to inflammation and pain

The components of Feverfew are as listed below:

• The sesquiterpene Parthenolide (of the germacranolide class) at 0.2-0.5% total weight of the leaves, but not present in the stem, and totalling up to 85% of total sesquiterpenes in Feverfew^[4]

• Other sesquiterpene compounds of the eudesmanolide, germacranolide, and guaianolide classes^[4]

• Methylated and hydroxylated flavonoids, mostly based off the structure of kaempferol, quercetin and apigenin^[4] Apigenin is approximately 0.5% of the aerial parts by dry weight^[6]

• Other flavonoids such as tanetin, chrysoeriol, santin, luteolin, jaceidin, and centaureidin^[4]

• Melatonin at 1010.6-1120ng/g in hot water extracts and 1803.4-2086.9ng/g in 50% methanol extracts (varies depending on how it is measured)^[7] mostly in the leaves^[8]

• Volatile oils, mostly camphor (56.9%) and camphene (12.7%)^[4]

• The coumarin isofraxidin and its ether, 9-epipectachol B^[9]

• (2-glyceryl)-O-coniferaldehyde^[10]

Mostly due to Parthenolide and its related sequesterpenes, which are seen as the active ingredients; although the flavonoids (in general) seem to contribute. Volatile oils contribute mostly to the smell of feverfew

The active components of Feverfew are currently seen as the sequesterpenes, namely Parthenolide. Below are the structures of Parthenolide and three other common sequesterpenes in Feverfew along some unique bioflavonoid compounds.

Feverfew products appear to have a degree of hygroscopicity (water attracting).^[11]

Feverfew, particularily parthenolide, appear to be indirect serotonin antagonists. Due to them interfering with the serotonin releasing properties of D-amphetamine and fenfluramine but not serotonin itself (replicated elsewhere^[12]), it is suspected that parthenolide may act at the level of inhibiting synaptic release of serotonin.^[13][4] When rats are fed 20mg/kg Feverfew with 11.7mcg Parthenolide (500mcg Parthenolide human dose) for 30 days, the contractile response in the intestinal tract in response to serotonin was significantly attenuated in correlation with the Parthenolide content, and also reduced contractions in response to pilocarpine and histamine.^[12]

An ethanolic extract of fresh Feverfew leaves was found to have affinity for the GABA(A)-benzodiazepine binding site, which was attributed to the apigenin content at 0.5% of the dry weight of the leaves.^[6] The IC₅₀ value of this reaction was 11.93uM, which is slightly higher than previous estimates of 8uM,^[14] 4uM,^[15] and 3uM.^[16]

Parthenolide has been implicated in being antagonistic to Cocaine (the illegal drug of abuse), as Parthenolide has been demonstrated to inhibit cocaine-induced locomotion in planarians (worms used in research)^[17] and also negated withdrawal.^[18] A study has been conducted in rats injected with 0.125 or 0.25mg/kg bodyweight Parthenolide against 1mg/kg Cocaine demonstrated that parthenolide was able to work against Cocaine's reduction of Ventral Tegmental Area brain activity when injected prior to Cocaine, and worked against Cocaine's inhibitory affect on bursting activity in these neurons.^[19]

When tested in migroglia cells, parthenolide caused a dose-dependent anti-inflammatory response to LPS (a pro-inflammatory agent used in research) secondary to a reduction of NF-kB translocation. When measuring the release of pro-inflammatory cytokines, TNF-α was reduced by 54% and IL-6 by 98% at 5uM concentration.^[20]

The most common modern usage of Feverfew is in combating migraines and headaches, and several human interventions have been conducted at this point in time.

One study using a liquid sublingual (placed under the tongue) mixture of ginger and Feverfew as in persons with migraines for greater than 1 year with or without aura with 2-6 migraines per month found that using the combination as treatment (to be taken when a migraine was about to occur, as assessed by headache) that over a month long period the severity of headaches was lesser with the combination supplement (1.41 on a scale of 1-3 relative to placebo's 1.67) and was associated with decreased pain 2 hours after treatment rather than a slight increase or stability seen in placebo.^[2] 16% of placebo said to be pain-free at 2 hours whereas 32% of treatment reported the same.^[2] On a battery of measures related to migraines, treatment was significantly more effective at suppressing 'pulsating' and 'nausea' at the onset of the migraine and 2 hours later retained these benefits but also became more effective than placebo at reducing sensitivity to light and sound as well as reducing how much migraines 'worsen with activity'. No influence on vomiting or how 'one-sided' the migraine was were seen.^[2] Sublinguial combination therapy of ginger and Feverfew has been seen elsewhere,^[21] but had a smaller sample and was open-label without control; lesser quality compared to the aforementioned study.^[21]

Sublingual combination therapy of ginger and feverfew appears to be effective as a treatment for migraines, taken at migraine onset for rapid relief. Minimal studies, however, with invested interest (no manipulation of results appear to exist, however)

One using a thrice daily carbon dioxide extract of Feverfew at 6.25mg thrice a day (MIG-99 brand name at 18.25mg total, high parthenolide content) noted that over 4 months in persons suffering from migraines with or without aura with 3-6 migraines a month for at least a year and 4-6 migraines during the 28 day run-in phase that treatment of Feverfew resulted in fever attacks during weeks 5-12 (-39.5%, -27% in placebo) with no furthering beneficial results between weeks 12 and 28, although consistently outperforming placebo henceforth.^[22] There was no significant difference between treatment and placebo when measured after the first 4 weeks, however.^[22]

This same extract (MIG-99) was used previously in a study with similar design, where benefits over placebo were not demonstrated.^[23] Subgroup analysis showing that Feverfew was significantly effective only in those with high migraine frequency prompted the aforementioned study,^[22] and the combination suggests that Feverfew may not be significantly beneficial for minor headaches and migraines any more than placebo but be significantly effective for those with worse intensity and frequency.

Another (independent) study was conducted pairing white willow bark (the natural source of aspirin precursor, salicyclic acid) with Feverfew and noted up to 57.2-61.7% reduced attack frequency and 38.7-62.6% attack intensity (first numbers measured at 6 weeks, latter at 12) relative to baseline, but had no control group and thus the results seen were treatment combined with placebo.^[3] This study, however, noted that prolonged usage of Feverfew had no furthering influence on attack frequency but continued to reduce intensity up to 12 weeks which was the last recorded measurement.^[3]

Finally, one study using Feverfew in isolation still noted decreases in migraine intensity and frequency over 2 months of treatment (trial was four months in length, but groups switched half-way through with no warning in a cross-over design with no wash-out period).^[24] The treatment was 70-84mg of crushed fresh leaves, put into capsules, and significant reductions were seen in nausea/vomiting as well as migraine frequency with a trend towards reduced intensity and no affect on migraine duration.^[24]

Only one study currently provides evidence against Feverfew, suggesting that 25mg Riboflavin (a B-vitamin) used as placebo was equally effective as combination therapy of Feverfew (100mg at 0.7% parthenolide), Magnesium (300mg with equal parts oxide and citrate), and Riboflavin (400mg).^[1] Over 3 months, the amount of persons that recorded a 50% reduction or greater in migraine frequency was similar in both groups although both groups did report significant improvements from baseline. This study has been criticized elsewhere^[25] as the high placebo response (44%) was unbecoming of an adequately powered trial and that the dose of feverfew, paired with a lack of data on sourcing and quality, undermines the quality of the intervention.^[25]

Some results that effects of Feverfew against placebo occur mostly after 4 weeks in time, improve in the ability to reduce the frequency and intensity of migraines up to 12 weeks, and then maintain benefits henceforth. Reductions of both frequency and intensity have been seen, and mixed yet minimal results on migraine duration (may only apply to sublingual)

Three interventions^[2][3][22] have used branded Feverfew products, whereas the following were sponsored by the provider of the products.^[22][3] No authors declared a conflict of interest, but in one study the company was involved in the study design.^[22] Of all human interventions, no clinically relevant side effects were demonstrated that differed from placebo. The study using sublinguial delivery did not more mouth numbing associated with treatment than placebo.^[2]

Overall, though, meta-analysis of the data appears to be difficult due to the heterogenity of the experiments above.^[26]

Overall, there are plenty of studies on Feverfew and Migraine but when the studies that use other compounds (White willow bark, ginger) are excluded and company interventions are taken into account, the body of evidence is diminished somewhat. There is still considerable evidence that Feverfew outperforms placebo for persons with high migraine frequency (3-6 monthly) but it is questionable for lesser frequencies

Feverfew, via the active ingredient Parthenolide, appears to be a potent inhibitor of NF-kB activation by inhibiting an upstream signalling molecule, Iκβ kinase, and preventing its complex (IKKβ) from signalling NF-kB,^[27] which has also been observed in liver cells^[28] colon cells,^[29] and migroglia (brain cells).^[20] When Feverfew is tested without Parthenolide, the other compounds in feverfew fail to inhibit NF-kB activation to any degree of efficacy.^[30] Thus, parthenolide per se appears to be able to prevent nuclear activation of NF-kB and intervene downstream of pro-inflammatory events.

Alternate mechanisms involve inhibiting prostaglandin synthesis. Although Feverfew shows no efficacy at intervening in the first step of prostaglandin synthesis (cyclooxygenation of arachidonic acid by COX enzymes) but intervenes elsewhere to prevent prostaglandin accumulation.^[31] These mechansism of action appeared to be secondary not to parthenolide, but to fat-soluble sequesterpines also found in the leaves and stem (with the stem containing more).^[32][33] When looking at individual molecules possessing this ability, Tanetin becomes of interest although sequeterpene lactones in general seem to possess bioactivty.^[4]

An in vitro test noted that platelet aggregation induced by ADP, collagen, or thrombin was completely abolished with a water extract of feverfew, and acted prior to arachidonic acid (as addition of arachidonic acid to the medium continued to produce pro-inflammatory prostaglandins), suggesting components possess phospholipase inhibition properties.^[34] This inhibition potential has been noted elsewhere.^[35][36]

Appears to work against prostaglandin synthesis, but at the stages immediately before and somewhat after where Aspirin targets (the COX enzymes). Additionally, may generally prevent inflammatory signalling from the nucleus via NF-kB which is attributable wholly to parthenolide

A supercritical CO₂ extraction of Feverfew was able to inhibit nitric oxide release from macrophages stimulated by LPS, and in a dose-dependent manner inhibited NO release significantly at 1ug/mL concentration, back to baseline levels at 5ug/mL, and reduced NO release to below control (no LPS stimulation) levels at 10ug/mL or above.^[37] Concentrations of 10ug/mL were also able to completely abolish TNF-α release from macrophages, and although mRNA of eNOS and iNOS were unaffected their protein expression was reduced with Feverfew.^[37]

Feverfew appears to inhibit aggregation of platelets via its parthenolide content. Platelets and Megakaryocytes contain NF-kB^[38] and their activating complexes,^[39] and this NF-kB activation is inhibited by Parthenolide in vitro.^[40] In general, anti-platelet effects have been noted with both Feverfew and Parthenolide previously^[41][42][43] which may, ultimately, be secondary to less expresison of the adhesion factors CD62P and CD40L, as assessed by collagen tests.^[40]

NF-kB is not the only mechanism of action for Parthenolide's anti-platelet functions, however. Interactions with PKC have been noted^[43] as well as alterations of arachidonic metabolism (preventing uptake and release of arachidonic acid from platelet membranes^[44]) and sequestering sulfhydryl groups.^[42][45]

Parthenolide has the ability to reduce platelet aggregation in response to pro-inflammatory and collagen-induced stimuli, and may be useful as a preventative medicine to limit blood clotting. This, however, also inherently carries possible adverse interactions with anti-blood clotting medication

This inhibition of NF-kB in platelets and Megakaryocytes can enhance the proliferation of platelets despite inhibiting their aggregation. Parthenolide enhanced platelet production from Megakaryoblastic cell lines Meg01 and MO7E at 5uM (MO7E, nonsignificant) and 10uM (significantly in both cell lines) when incubated for 24 hours.^[40] Isolated primary mouse and human megakaryocytes both showed a more platelet producing phenotype after incubation with parthenolide, and this increase was secondary to NF-kB activation.^[40] These platelets were deemed function due to morphology and collagen-activation.^[40]

Parthenolide appears to proliferate platelets as well as prevent their aggregation

Lactone sequesterpene compounds from Feverfew have been demonstrated to active genetic transcription of the anti-oxidant response element (ARE) secondary to Nrf2, with the guaianolide class being the most potent (due to the presence of an α-methylene-γ-lactone moiety).^[46] This activation of the ARE via Nrf2 is due to pathenolide (most researched sequesterpene) being a pro-oxidative molecule, and many studies that measure glutathione (an anti-oxidant in cells that is depleted in response to oxidation) depletion of glutathione is observed after incubation with partheolide^[47] and prevention of this depletion (via buffering glutathone levels with N-AC) prolongs cell life of cancer cells.^[48] However, parthenolide-induced apoptosis has also been correlated with catalase activity, suggesitng lipid peroxidation plays a role.^[49]

Another component of the anti-cancer effects of Feverfew is the inhibition of NF-kB and reduction of inflammatory signalling (discussed more in the Immunity and Inflammation section) due to activation of NF-kB (inflammationn) strengthing most cells, including cancer cells, to intentional cell death.^[50] In general, when a cell is preventing from having NF-kB translocate to the nucleus (occurs after 'activation') they tend to become prone to cellular death and are chemosensitized, with anti-cancer drugs becoming more effective.^[47][51][52]

Finally, Parthenolide is implicated in suppressing STAT (signal transducer and activator of transcription) activation. In some cancer cells (skin,^[53] colorectal,^[54] liver,^[55] breast,^[56] as well as prostate and leukemia^[57][58][59]), this family of signalling proteins are more likely to be hyperactive and exert more cytoprotective effects to the cell and prolong survival via Bcl-x2 and Survivin (evidence by STAT3).^[60] Parthenolide has also been found to suppress translocation of JNK (resulting in a pro-apoptic effect in this study) and reduce p38 activation.^[61]

The efficacy of Parthenolide as an anti-cancer agent appears to be through a two-pronged ability to invoke cellular death (via oxidative stress) and prevent the cancer cell from preserving its own life by inhibiting NF-kB, STATs, and p38

Interestingly, Parthenolide in normal cells appears to be cytoprotective via JNK inhibition^[61] and when the cell is subject to oxidative stress the addition of parthenolide appears to also protect cell integrity.^[48][49][62] When comparing the susceptability of leukemia cells to normal hematopeoic cells, it was found that the cancer cells were approximately 10 times as likely to get destroyed in response to Parthenolide.^[63] It should be noted that cytotoxicity in normal cells can still be forced at a concentration high enough, however.

Parthenolide appears to favor destruction of cancer cells, indicating either increased susceptability of cancer cells to death by Parthenolide or decreased Parthenolide-induced protective effects

A mechanism of fibrosis therapy includes inducing cell death (apoptosis) in hepatic stellate cells (HSCs), as evidenced by mechanisms of clearance^[64][65] and experimental augmentation of these cells reducing fibrosis.^[66] Parthenolide has been investigated for its roles in fibrosis,^[28] and parthenolide shows anti-proliferative and pro-apoptotic effects in isolated rat HSCs, with its cytotoxicity affecting both regular liver cells but significantly more toxic to stellate cells at tested (2.5-20uM) concentrations.^[28] The mechanisms seem to be via pro-oxidative stress and anti-inflammatory effects, and oral ingestion of 2 or 4mg/kg parthenolide to rats acted to normalize liver fibrosis and body weight in fibrotic rats and corrected serum liver enzymes measured (ALT, AST).^[28]

A topical solution containing 0.5%, 0.75%, and 1% Feverfew was able to prevent reddening of the skin even after the feverfew was depleted of the active pathenolide, suggesting other sequesterpenes or flavonoids contributed to the observed effects.^[30] The aforementioned concentrations, when put into a test against methyl nicotinate (used to redden the skin via inflammatory prostaglandin release) Feverfew inhibited erythema by 27.6%, 39.1%, and 68.3% while the positive control of 3% Ibuprofen inhibited at a potency of 38.4%, suggesting topical Feverfew has more anti-inflammatory efficacy against erythema than Ibuprofen on a per weight basis.^[30] This study was conducted in persons confirmed to not have Feverfew allegies.

The other non-parthenolide compounds appear to prevent topical allergic reactions when applied prior to the allergic response, although parthenolide depleted Feverfew may be needed

Parthenium dermatitis is an allergic reaction to Parthenium Hysterophorus, a plant in the Compositae family alongside Feverfew.^[67] This plant and this condition are currently the leading cause of contact dermatitis in India,^[68] where the plant was introduced accidentally in a 1956 wheat shipment from the USA.^[67] In some bad cases, airborne exposure (to growing plants rather than supplements) to Parthenium Hysterophorus results in near whole-body erythroderma.^[67]

Parthenium Hysterophorus causes many of these reactions through Parthenolide. Due to the parthenolide content of Feverfew (Tanacetum parthenium), these reactions do apply to Feverfew topical usage. Case studies do arise where Feverfew is added to cosmetics and elicits allergic topical responses.^[69]

A parthenolide-depleted Feverfew cream has been developed for cosmetic usage,^[30] but persons with known Feverfew hypersensitivty may still experience reactions, as a study which confirmed less than 0.51ng/mL found allergic reactions in four out of seven (57%) persons.^[70]

An allergic skin reaction does exist with Parthenolide and Feverfew, and even Feverfew-depleted products may contain enough Feverfew to elicit a response in persons with severe allergies

Traditional usage of Feverfew has been contradinctied in pregnant and expecting women, as well as breastfeeding women. Currently, only one animal study has been conducted on the matter which suggested that a further test was needed.^[71] This study noted used an ethanolic extract of Feverfew (839mg/kg, 1.4% Parthenolide; 58.7 times the recommended human dose) which does confound the results due to the adverse effects of alcohol on the fetus, but found no significant differences between Feverfew and water during gestational days of 1-8 while Feverfew attenuated maternal weight gain during gestational days 8-15.^[71]

No adverse effects on fertility were noted, and a trend to increased implantation losses at conception was noted but not significant (due to the low sample size, could have been an outlier),^[71] increased placental weight was noted after birth with Feverfew relative to water, but not to the degree of the active control alcohol.^[71] When conducting an in vitro test, however, all embryos were destroyed after 4ul/mL incubation with Feverfew solution for 26 hours.

Very limited evidence on the interactions of Pregnancy and Feverfew, but Feverfew has the potential for adverse side effects on the fetus. These 'potentials' are done with a high dose of oral feverfew and even then are less than alcohol