Parthenolide

Parthenolide at a Glance

Parthenolide is a germacranolide sesquiterpene lactone — the principal bioactive of feverfew (Tanacetum parthenium), the compound feverfew products are standardised to, and the best-studied member of a chemically reactive family that runs right through the Asteraceae. It sits in the leaf’s glandular trichomes at roughly 0.2–0.5% of dry weight, where it can account for as much as 85% of the plant’s total sesquiterpene lactone content ^{28,29Reference 28Pareek A et al. · 2011Systematic reviewFeverfew (Tanacetum parthenium L.): a systematic reviewView study →Reference 29Kashkooe A et al. · 2024ReviewExploring the phytochemistry, signaling pathways, and mechanisms of action of Tanacetum parthenium (L.) Sch.Bip. — a comprehensive literature reviewView study →}.

Two things make it genuinely interesting. It is a covalent NF-κB inhibitor with named target residues — it alkylates cysteine-179 of IKKβ and cysteine-38 of the p65 subunit, shutting down the inflammatory transcription programme at two points ^{5,7Reference 5Kwok BH et al. · 2001In vitroThe anti-inflammatory natural product parthenolide from the medicinal herb feverfew directly binds to and inhibits IκB kinase — in vitroView study →Reference 7García-Piñeres AJ et al. · 2001In vitroCysteine 38 in p65/NF-κB plays a crucial role in DNA binding inhibition by sesquiterpene lactones — in vitroView study →}. And it was the first small molecule shown to kill leukaemia stem cells selectively, sparing normal haematopoietic cells in the same assay — a finding that launched a whole medicinal-chemistry programme ^{11,4Reference 11Guzman ML et al. · 2005In vitroThe sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells — in vitro / animal modelView study →Reference 4Ghantous A et al. · 2013ReviewParthenolide: from plant shoots to cancer roots — reviewView study →}.

Two things temper all of it. The reactive group that does the work — the α-methylene-γ-lactone — is shared by hundreds of sesquiterpene lactones, so “inhibits NF-κB in vitro” says very little about parthenolide specifically ^{8Reference 8Rüngeler P et al. · 1999In vitroInhibition of transcription factor NF-κB by sesquiterpene lactones: a proposed molecular mechanism of action — in vitroView study →}. And parthenolide is barely bioavailable: the only formal human pharmacokinetic study, giving up to 4 mg/day orally, could not detect it in plasma at all ^{15Reference 15Curry EA 3rd et al. · 2004Clinical trialPhase I dose escalation trial of feverfew with standardized doses of parthenolide in patients with cancer — clinical trialView study →}. Everything downstream of that fact — including feverfew’s migraine reputation — has to be read with it in mind.

The Reactive Warhead — and Why It Is a Class Property

Parthenolide’s chemistry is an electrophile. The exocyclic α-methylene on its γ-lactone ring is a Michael acceptor: it reacts with the thiol of an accessible cysteine and forms a covalent adduct. Parthenolide carries a second electrophilic centre as well, an epoxide across the ten-membered ring ^{29Reference 29Kashkooe A et al. · 2024ReviewExploring the phytochemistry, signaling pathways, and mechanisms of action of Tanacetum parthenium (L.) Sch.Bip. — a comprehensive literature reviewView study →}. That is the whole mechanism, and it explains the breadth of the target list.

It is also almost entirely a class property. When 28 sesquiterpene lactones were screened against NF-κB, most of the potent inhibitors turned out to be the ones bearing two reactive centres — an α-methylene-γ-lactone plus an α,β-unsaturated carbonyl — and the proposed mechanism (cross-linking Cys38 in the DNA-binding loop with Cys120 nearby) applied to the family, not to any one member ^{8Reference 8Rüngeler P et al. · 1999In vitroInhibition of transcription factor NF-κB by sesquiterpene lactones: a proposed molecular mechanism of action — in vitroView study →}. The same dose-by-reactivity relationship shows up on the other side of the redox ledger: sesquiterpene lactones from feverfew and Calea urticifolia activate the Nrf2/ARE antioxidant response in proportion to how many α,β-unsaturated carbonyl groups each molecule carries, with the triply-reactive compound the most potent ^{10Reference 10Umemura K et al. · 2008In vitroPreconditioning by sesquiterpene lactone enhances H2O2-induced Nrf2/ARE activation — in vitroView study →}. Reactivity, not identity, is the variable.

Three consequences follow, and they set the reading frame for everything below.

• “Inhibits NF-κB in vitro” is close to uninformative about a specific lactone. In the one head-to-head that matters here, costunolide isolated from Magnolia grandiflora was a more potent NF-κB inhibitor than parthenolide from the same plant ^{22Reference 22Koo TH et al. · 2001In vitroA sesquiterpene lactone, costunolide, from Magnolia grandiflora inhibits NF-κB by targeting IκB phosphorylation — in vitroView study →}.
• Selectivity is expected to be poor. A promiscuous thiol alkylator hits Keap1, glutathione, tubulin, caspases and much else besides NF-κB ^{3Reference 3Freund RRA et al. · 2020ReviewAdvances in chemistry and bioactivity of parthenolide — reviewView study →}. Where parthenolide does show selectivity — the leukaemia-stem-cell work — that is the surprising result, not the default.
• The warhead is also the allergen. The same electrophilicity that alkylates a signalling protein alkylates skin proteins and creates a hapten, which is why parthenolide is a registered contact-allergy patch-test reagent (see Toxicity & Safety) ^{33,36Reference 33Paulsen E · 2020ObservationalCompositae sensitization in Danish children and adolescents — cross-sectional patch-test studyView study →Reference 36ClinicalTrials.gov NCT00133341 · 2005Clinical trialClinical evaluation of the 3 allergens methyldibromoglutaronitrile, parthenolide and gold sodium thiosulphate for T.R.U.EView study →}.

What is specific to parthenolide is the combination: a named residue on a named kinase ^{5Reference 5Kwok BH et al. · 2001In vitroThe anti-inflammatory natural product parthenolide from the medicinal herb feverfew directly binds to and inhibits IκB kinase — in vitroView study →}, demonstrated in-vivo activity where its saturated analogue has none ^{21Reference 21Feltenstein MW et al. · 2004AnimalAnti-inflammatory and anti-hyperalgesic effects of sesquiterpene lactones from Magnolia and Bear’s foot — animal modelView study →}, and a cellular selectivity window in leukaemia that no other lactone has matched ^{11Reference 11Guzman ML et al. · 2005In vitroThe sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells — in vitro / animal modelView study →}.

Parthenolide vs. Feverfew’s Migraine Record

Feverfew’s whole reputation is migraine prophylaxis, and parthenolide is the compound that reputation is standardised on. The gap between those two statements is the most important thing here — because no controlled trial has ever tested isolated parthenolide for migraine.

What the human evidence actually is. Six double-blind placebo-controlled trials of feverfew monopreparations (561 patients) were captured by Cochrane, which could not pool them and rated the evidence low quality. The largest rigorous trial — a stable supercritical-CO₂ extract, MIG-99, at 6.25 mg three times daily for 16 weeks — cut migraine frequency by 1.9 attacks/month against 1.3 on placebo, a difference of about 0.6 attacks per month, with no significant effect on attack intensity or duration ^{24,25Reference 24Wider B et al. · 2015Systematic reviewFeverfew for preventing migraine — systematic reviewView study →Reference 25Diener HC et al. · 2005RCTEfficacy and safety of 6.25 mg t.i.d. feverfew CO2-extract (MIG-99) in migraine prevention — a randomized, double-blind, multicentre, placebo-controlled studyView study →}. The preceding dose-ranging trial of the same extract failed on its primary endpoint and reached significance only in a small pre-defined subgroup ^{26Reference 26Pfaffenrath V et al. · 2002RCTThe efficacy and safety of Tanacetum parthenium (feverfew) in migraine prophylaxis — a double-blind, multicentre, randomized placebo-controlled dose-response studyView study →}. Every one of these studies dosed the plant.

Why the marker was chosen. Parthenolide became the standardisation marker on the strength of an in-vitro bioassay, not a clinical dose-response: in 1992 Heptinstall’s group showed that physicochemical parthenolide measurements tracked a platelet-antisecretory bioassay across authenticated and commercial feverfew, that commercial products varied wildly (in some, parthenolide was undetectable), and concluded that manufacturers should therefore standardise to it ^{17Reference 17Heptinstall S et al. · 1992In vitroParthenolide content and bioactivity of feverfew (Tanacetum parthenium (L.) Schultz-Bip.): estimation of commercial and authenticated feverfew products — in vitroView study →}. That is a quality-control argument. It was never a demonstration that parthenolide is the active principle.

Three lines of evidence sit awkwardly with the marker hypothesis.

1. The exposure arithmetic does not work. In the only formal human PK study, oral parthenolide at 4 mg/day — administered as feverfew tablets to cancer patients — produced no detectable plasma concentration (limit of detection 0.5 ng/mL) ^{15Reference 15Curry EA 3rd et al. · 2004Clinical trialPhase I dose escalation trial of feverfew with standardized doses of parthenolide in patients with cancer — clinical trialView study →}. A standardised 50–125 mg leaf capsule at a ≥0.2% marker specification delivers a fraction of a milligram, an order of magnitude below the dose that was already undetectable. Whatever migraine prophylaxis is, it is hard to attribute to systemic parthenolide.
2. Feverfew’s own authors hedge. The systematic literature is explicit that the active principles “probably include one or more of the sesquiterpene lactones,” and that lipophilic compounds other than parthenolide carry part of the anti-inflammatory activity ^{28Reference 28Pareek A et al. · 2011Systematic reviewFeverfew (Tanacetum parthenium L.): a systematic reviewView study →} — a role the herb’s methylated flavonols (tanetin, santin, jaceidin, apigenin, luteolin) plainly contribute to.
3. Feverfew keeps working without it — for a different endpoint. A deliberately parthenolide-depleted feverfew extract, made for cosmetics precisely to remove the sensitiser, retained free-radical-scavenging and anti-inflammatory activity, reduced UV-induced DNA damage in vivo, and cut UV erythema versus placebo in a clinical study ^{31,32Reference 31Martin K et al. · 2008Clinical trialParthenolide-depleted feverfew (Tanacetum parthenium) protects skin from UV irradiation and external aggression — in vitro / animal model / clinical studyView study →Reference 32Rodriguez KJ et al. · 2013In vitroA purified feverfew extract protects from oxidative damage by inducing DNA repair in skin cells via a PI3-kinase-dependent Nrf2/ARE pathway — in vitroView study →}. This does not show parthenolide is irrelevant to migraine — the endpoint is topical photoprotection, not headache — but it does show that feverfew’s bioactivity is not a synonym for its parthenolide content.

A note on a common misreading. MIG-99, the CO₂ extract that produced the best migraine result, is not parthenolide-depleted — Cochrane describes it as having a standardised and constant parthenolide concentration, and its virtue was reproducibility, not removal ^{24Reference 24Wider B et al. · 2015Systematic reviewFeverfew for preventing migraine — systematic reviewView study →}. The parthenolide-depleted preparation is the separate topical cosmetic ingredient described above ^{31Reference 31Martin K et al. · 2008Clinical trialParthenolide-depleted feverfew (Tanacetum parthenium) protects skin from UV irradiation and external aggression — in vitro / animal model / clinical studyView study →}. The honest gap is not “the depleted extract won”; it is that the molecule has never been tested on its own for this indication, and its measured systemic exposure is nil.

What It's Used For

The pharmacology divides cleanly: a well-characterised covalent mechanism and a striking leukaemia-stem-cell result on one side, and on the other a near-total absence of human efficacy data for the isolate.

Evidence by IndicationStrength of support · Beta

Support is an experimental score — weighted by study type (human > animal > in vitro) and volume. A beta, not a validated metric. Because there are almost no human efficacy data for the isolated molecule, every score here is capped by design; the plant’s migraine trials are not counted as parthenolide evidence.

01Anti-inflammatoryPromising48%Residue-level NF-κB mechanism ^{5,7Reference 5Kwok BH et al. · 2001In vitroThe anti-inflammatory natural product parthenolide from the medicinal herb feverfew directly binds to and inhibits IκB kinase — in vitroView study →Reference 7García-Piñeres AJ et al. · 2001In vitroCysteine 38 in p65/NF-κB plays a crucial role in DNA binding inhibition by sesquiterpene lactones — in vitroView study →} plus in-vivo rat carrageenan activity for the isolate, absent in its saturated analogue ^{21Reference 21Feltenstein MW et al. · 2004AnimalAnti-inflammatory and anti-hyperalgesic effects of sesquiterpene lactones from Magnolia and Bear’s foot — animal modelView study →}

02Leukaemia stem-cell apoptosisPromising45%Replicated primary-cell and xenograft work on the isolate; carried forward by the DMAPT analogue ^{11,12,14Reference 11Guzman ML et al. · 2005In vitroThe sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells — in vitro / animal modelView study →Reference 12Guzman ML et al. · 2007In vitroAn orally bioavailable parthenolide analog selectively eradicates acute myelogenous leukemia stem and progenitor cells — in vitro / animal modelView study →Reference 14Hewamana S et al. · 2008In vitroThe novel nuclear factor-κB inhibitor LC-1 is equipotent in poor prognostic subsets of chronic lymphocytic leukemia and shows strong synergy with fludarabine — in vitroView study →}

03Antiplatelet / antisecretoryShaky34%Human platelet and leucocyte granule-secretion assays; the basis for the standardisation bioassay ^{17,18Reference 17Heptinstall S et al. · 1992In vitroParthenolide content and bioactivity of feverfew (Tanacetum parthenium (L.) Schultz-Bip.): estimation of commercial and authenticated feverfew products — in vitroView study →Reference 18Heptinstall S et al. · 1985In vitroExtracts of feverfew inhibit granule secretion in blood platelets and polymorphonuclear leucocytes — in vitroView study →}

04Migraine prophylaxisShaky30%Six trials of the plant, Cochrane-rated low quality; zero trials of the isolate, and nil measured systemic exposure ^{15,24,25Reference 15Curry EA 3rd et al. · 2004Clinical trialPhase I dose escalation trial of feverfew with standardized doses of parthenolide in patients with cancer — clinical trialView study →Reference 24Wider B et al. · 2015Systematic reviewFeverfew for preventing migraine — systematic reviewView study →Reference 25Diener HC et al. · 2005RCTEfficacy and safety of 6.25 mg t.i.d. feverfew CO2-extract (MIG-99) in migraine prevention — a randomized, double-blind, multicentre, placebo-controlled studyView study →}

05Antiallergic / mast-cell stabilisationShaky28%Rat mast-cell histamine release and murine passive cutaneous anaphylaxis ^{19Reference 19Hayes NA · 1987AnimalThe activity of compounds extracted from feverfew on histamine release from rat mast cells — animal modelView study →}

06CNS axon regenerationShaky24%One strong recent rodent programme via microtubule detyrosination, delivered as DMAPT ^{16Reference 16Leibinger M et al. · 2023AnimalInhibition of microtubule detyrosination by parthenolide facilitates functional CNS axon regeneration — animal model. eLife. https://pubmed.ncbi.nlm.nih.gov/37846146/View study →}

How Parthenolide Works

Every mechanism below traces back to the same electrophilic chemistry; what differs is which thiol gets hit and in what cell.

A Unifying Interpretation

One reaction explains the list. Parthenolide is a bifunctional electrophile that forms covalent adducts with accessible cysteine thiols; NF-κB happens to present two unusually reactive and functionally critical ones, in IKKβ and in p65’s DNA-binding loop ^{5,7Reference 5Kwok BH et al. · 2001In vitroThe anti-inflammatory natural product parthenolide from the medicinal herb feverfew directly binds to and inhibits IκB kinase — in vitroView study →Reference 7García-Piñeres AJ et al. · 2001In vitroCysteine 38 in p65/NF-κB plays a crucial role in DNA binding inhibition by sesquiterpene lactones — in vitroView study →}. Cells with an already-strained redox buffer — which leukaemia stem cells are — hit their threshold first, which is the most economical account of the selectivity window ^{11Reference 11Guzman ML et al. · 2005In vitroThe sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells — in vitro / animal modelView study →}. The Nrf2/ARE induction is the same chemistry read from the cell’s defensive side ^{10Reference 10Umemura K et al. · 2008In vitroPreconditioning by sesquiterpene lactone enhances H2O2-induced Nrf2/ARE activation — in vitroView study →}. And the contact allergy is the same chemistry read from the immune system’s side. A single reactive group, four different-looking literatures.

The corollary is the caution that runs through all of it: a mechanism this generic is easy to demonstrate and hard to make selective, and dosing enough parthenolide to alkylate a target in a person has never been achieved.

Pharmacokinetics

This section is load-bearing — it reframes every in-vitro potency figure above.

Parthenolide is poorly water-soluble and poorly bioavailable, and this is not a theoretical concern. In the only formal human pharmacokinetic study, patients with cancer took feverfew (Tanacet) as a daily oral tablet in 28-day cycles at escalating doses of 1, 2, 3 and 4 mg of parthenolide. Solid-phase extraction and mass spectrometry were used to measure plasma parthenolide, with a limit of detection of 0.5 ng/mL. At every dose level, including 4 mg/day, there was no detectable concentration in plasma, and the pharmacokinetic analysis could not be completed at all. The authors concluded that purified parthenolide would be needed to administer higher doses ^{15Reference 15Curry EA 3rd et al. · 2004Clinical trialPhase I dose escalation trial of feverfew with standardized doses of parthenolide in patients with cancer — clinical trialView study →}.

Set that against the concentrations at which the interesting biology happens — low-micromolar LD₅₀ values in primary leukaemia cells ^{13Reference 13Neelakantan S et al. · 2009In vitroAminoparthenolides as novel anti-leukemic agents: discovery of the NF-κB inhibitor, DMAPT (LC-1) — in vitroView study →} — and the arithmetic is brutal: the in-vitro potency is real, and the systemic exposure from any realistic oral botanical dose is below the detection limit, several orders of magnitude short.

The consequences shaped the entire field:

• Solubility drove analogue development. Reacting parthenolide with dimethylamine gives a Michael adduct that can be converted to a water-soluble fumarate salt — DMAPT — with dramatically improved solubility and roughly 70% oral bioavailability in animals ^{12,13Reference 12Guzman ML et al. · 2007In vitroAn orally bioavailable parthenolide analog selectively eradicates acute myelogenous leukemia stem and progenitor cells — in vitro / animal modelView study →Reference 13Neelakantan S et al. · 2009In vitroAminoparthenolides as novel anti-leukemic agents: discovery of the NF-κB inhibitor, DMAPT (LC-1) — in vitroView study →}. Every in-vivo systemic result of the last two decades runs through that analogue, not the parent.
• Local and topical exposure is a different question. Skin contact with parthenolide does not require systemic absorption to matter — sensitisation is a local event, which is why the contact-allergy story is clinically real while the systemic pharmacology is not.

No human half-life, clearance, volume of distribution, metabolite profile or absolute oral bioavailability figure for parthenolide is established, because the concentrations were never measurable. Metabolism is presumed to be dominated by rapid conjugation of the electrophilic centre with glutathione and other thiols — the same reaction that produces its pharmacology — but this is inference from the chemistry, not measured human ADME ^{3Reference 3Freund RRA et al. · 2020ReviewAdvances in chemistry and bioactivity of parthenolide — reviewView study →}.

From Parthenolide to DMAPT (LC-1)

Keep these two molecules separate; the literature frequently does not.

Parthenolide is the natural product. It kills leukaemia stem cells in vitro and in xenografts ^{11Reference 11Guzman ML et al. · 2005In vitroThe sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells — in vitro / animal modelView study →}, and it cannot be dosed into a person at a level anyone has measured ^{15Reference 15Curry EA 3rd et al. · 2004Clinical trialPhase I dose escalation trial of feverfew with standardized doses of parthenolide in patients with cancer — clinical trialView study →}.

DMAPT — dimethylamino-parthenolide, also called LC-1 — is a synthetic analogue made by adding dimethylamine across the α-methylene of the lactone and taking the fumarate salt. It was selected from a series of aminoparthenolides screened for anti-leukaemic activity, several of which killed >90% of primary AML cells at 10 µM with low-micromolar LD₅₀ values ^{13Reference 13Neelakantan S et al. · 2009In vitroAminoparthenolides as novel anti-leukemic agents: discovery of the NF-κB inhibitor, DMAPT (LC-1) — in vitroView study →}. DMAPT induces rapid death of primary human leukaemia stem cells from both myeloid and lymphoid leukaemias, works through oxidative stress, NF-κB inhibition and p53 activation, and — the point of the exercise — has approximately 70% oral bioavailability, with in-vivo activity demonstrated in mouse xenografts and in spontaneous canine leukaemias ^{12Reference 12Guzman ML et al. · 2007In vitroAn orally bioavailable parthenolide analog selectively eradicates acute myelogenous leukemia stem and progenitor cells — in vitro / animal modelView study →}. In CLL it was equipotent across prognostic subsets and strongly synergistic with fludarabine ^{14Reference 14Hewamana S et al. · 2008In vitroThe novel nuclear factor-κB inhibitor LC-1 is equipotent in poor prognostic subsets of chronic lymphocytic leukemia and shows strong synergy with fludarabine — in vitroView study →}. More recently, systemic DMAPT was the agent used to deliver parthenolide’s microtubule effect to the injured rodent CNS ^{16Reference 16Leibinger M et al. · 2023AnimalInhibition of microtubule detyrosination by parthenolide facilitates functional CNS axon regeneration — animal model. eLife. https://pubmed.ncbi.nlm.nih.gov/37846146/View study →}.

Where it stands. The CLL work in 2008 was published explicitly “in view of imminent first-in-man study of LC-1 in Cardiff” ^{14Reference 14Hewamana S et al. · 2008In vitroThe novel nuclear factor-κB inhibitor LC-1 is equipotent in poor prognostic subsets of chronic lymphocytic leukemia and shows strong synergy with fludarabine — in vitroView study →}, and a 2013 review described parthenolide-derived agents as being tested in cancer clinical trials ^{4Reference 4Ghantous A et al. · 2013ReviewParthenolide: from plant shoots to cancer roots — reviewView study →}. No results from that first-in-man study appear in the peer-reviewed literature, and a search of ClinicalTrials.gov in July 2026 returns no registered DMAPT or LC-1 study. The honest status is: a well-motivated analogue that reached early human study more than fifteen years ago, with no published human efficacy or safety outcome.

Clinical Trials

Parthenolide itself has one completed therapeutic human study — a phase I dose-escalation of feverfew-delivered parthenolide in cancer patients, which established tolerability up to 4 mg/day and non-detectability in plasma ^{15Reference 15Curry EA 3rd et al. · 2004Clinical trialPhase I dose escalation trial of feverfew with standardized doses of parthenolide in patients with cancer — clinical trialView study →}. Everything else registered under the compound’s name is diagnostic: parthenolide is a patch-test allergen, and the trials that exist are dose-response studies to fix its concentration in the T.R.U.E. Test allergen panel ^{36Reference 36ClinicalTrials.gov NCT00133341 · 2005Clinical trialClinical evaluation of the 3 allergens methyldibromoglutaronitrile, parthenolide and gold sodium thiosulphate for T.R.U.EView study →}.

There are no efficacy trials of isolated parthenolide for any indication, and no registered trial of DMAPT/LC-1. Feverfew’s six migraine trials belong to the plant ^{24Reference 24Wider B et al. · 2015Systematic reviewFeverfew for preventing migraine — systematic reviewView study →}.

Last checked: July 2026.

Isolate vs. Plant Studies

The split here is unusually clean, and it runs the opposite way to most compound pages.

The mechanistic and preclinical evidence is overwhelmingly the isolate. The IKKβ and p65 alkylation studies ^{5,6,7,9Reference 5Kwok BH et al. · 2001In vitroThe anti-inflammatory natural product parthenolide from the medicinal herb feverfew directly binds to and inhibits IκB kinase — in vitroView study →Reference 6Hehner SP et al. · 1999In vitroThe antiinflammatory sesquiterpene lactone parthenolide inhibits NF-κB by targeting the IκB kinase complex — in vitroView study →Reference 7García-Piñeres AJ et al. · 2001In vitroCysteine 38 in p65/NF-κB plays a crucial role in DNA binding inhibition by sesquiterpene lactones — in vitroView study →Reference 9García-Piñeres AJ et al. · 2004In vitroRole of cysteine residues of p65/NF-κB on the inhibition by the sesquiterpene lactone parthenolide and N-ethyl maleimide, and on its transactivating potential — in vitroView study →}, the 28-lactone NF-κB structure–activity screen ^{8Reference 8Rüngeler P et al. · 1999In vitroInhibition of transcription factor NF-κB by sesquiterpene lactones: a proposed molecular mechanism of action — in vitroView study →}, the leukaemia stem-cell apoptosis and xenograft work ^{11Reference 11Guzman ML et al. · 2005In vitroThe sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells — in vitro / animal modelView study →}, the LC-1 CLL series ^{14Reference 14Hewamana S et al. · 2008In vitroThe novel nuclear factor-κB inhibitor LC-1 is equipotent in poor prognostic subsets of chronic lymphocytic leukemia and shows strong synergy with fludarabine — in vitroView study →}, the rat carrageenan comparison against 11,13-dihydroparthenolide ^{21Reference 21Feltenstein MW et al. · 2004AnimalAnti-inflammatory and anti-hyperalgesic effects of sesquiterpene lactones from Magnolia and Bear’s foot — animal modelView study →} and the microtubule/axon-regeneration programme ^{16Reference 16Leibinger M et al. · 2023AnimalInhibition of microtubule detyrosination by parthenolide facilitates functional CNS axon regeneration — animal model. eLife. https://pubmed.ncbi.nlm.nih.gov/37846146/View study →} all test purified compound. As a mechanism base for a single molecule, that is a real strength — it is not borrowed from the plant.

The human evidence is entirely the plant, and it is modest. Six placebo-controlled migraine trials of feverfew monopreparations, unpoolable and rated low quality ^{24,25,26Reference 24Wider B et al. · 2015Systematic reviewFeverfew for preventing migraine — systematic reviewView study →Reference 25Diener HC et al. · 2005RCTEfficacy and safety of 6.25 mg t.i.d. feverfew CO2-extract (MIG-99) in migraine prevention — a randomized, double-blind, multicentre, placebo-controlled studyView study →Reference 26Pfaffenrath V et al. · 2002RCTThe efficacy and safety of Tanacetum parthenium (feverfew) in migraine prophylaxis — a double-blind, multicentre, randomized placebo-controlled dose-response studyView study →}; one null rheumatoid-arthritis trial of dried feverfew ^{27Reference 27Pattrick M et al. · 1989RCTFeverfew in rheumatoid arthritis: a double-blind, placebo-controlled study — randomised controlled trialView study →}; and, for the topical side, clinical work on a parthenolide-depleted feverfew extract, which by construction says nothing about the molecule ^{31Reference 31Martin K et al. · 2008Clinical trialParthenolide-depleted feverfew (Tanacetum parthenium) protects skin from UV irradiation and external aggression — in vitro / animal model / clinical studyView study →}. The single human study of parthenolide as a measured entity found it undetectable ^{15Reference 15Curry EA 3rd et al. · 2004Clinical trialPhase I dose escalation trial of feverfew with standardized doses of parthenolide in patients with cancer — clinical trialView study →}.

The transferability caveat therefore points both directions. Feverfew’s clinical record cannot be credited to parthenolide, because the molecule has never been isolated in a trial and is not measurably absorbed. And parthenolide’s preclinical record cannot be credited to feverfew, because those effects require concentrations no botanical preparation delivers. The two literatures are about the same chemical and almost nothing else in common.

Its Role in Plants

Parthenolide is a defence metabolite, and its anatomy says so. It is stored in the glandular trichomes on the leaf surface — the plant’s first point of contact with microbes and herbivores — and is largely absent from stalks and roots ^{17,23,28Reference 17Heptinstall S et al. · 1992In vitroParthenolide content and bioactivity of feverfew (Tanacetum parthenium (L.) Schultz-Bip.): estimation of commercial and authenticated feverfew products — in vitroView study →Reference 23Blakeman JP · 1979In vitroAntimicrobial properties and possible rôle in host–pathogen interactions of parthenolide, a sesquiterpene lactone isolated from glands of Chrysanthemum parthenium — in vitroView study →Reference 28Pareek A et al. · 2011Systematic reviewFeverfew (Tanacetum parthenium L.): a systematic reviewView study →}. The classic study isolating it from those glands found it antimicrobial, and framed its role in terms of host–pathogen interaction at the leaf surface ^{23Reference 23Blakeman JP · 1979In vitroAntimicrobial properties and possible rôle in host–pathogen interactions of parthenolide, a sesquiterpene lactone isolated from glands of Chrysanthemum parthenium — in vitroView study →}. Concentrating a reactive electrophile in surface glands, where it can alkylate an attacker’s proteins on contact without exposing the plant’s own cytoplasm, is an elegant solution and a familiar Asteraceae strategy.

Biosynthetically it is a germacranolide: a sesquiterpene skeleton built from farnesyl diphosphate, cyclised to the ten-membered germacrane ring, lactonised, and finally epoxidised — with costunolide as the immediate germacranolide precursor from which the 4,5-epoxide is formed ^{3Reference 3Freund RRA et al. · 2020ReviewAdvances in chemistry and bioactivity of parthenolide — reviewView study →}. The rest of feverfew’s lactone suite — artecanin, canin and the guaianolides — represents further rearrangement of the same skeleton.

Content is strongly modulated by genetics and conditions: parthenolide levels in T. parthenium span an order of magnitude across chemotypes and harvests, and fall during storage of powdered leaf material ^{17Reference 17Heptinstall S et al. · 1992In vitroParthenolide content and bioactivity of feverfew (Tanacetum parthenium (L.) Schultz-Bip.): estimation of commercial and authenticated feverfew products — in vitroView study →}.

Prevalence in Nature

Parthenolide is best regarded as a feverfew marker with a scattered wider distribution, not a ubiquitous plant metabolite. Its documented occurrence:

Source	Plant part	Reported parthenolide content
Feverfew (Tanacetum parthenium)	leaf glandular trichomes	~0.2–0.5% dry wt; up to ~85% of total sesquiterpene lactones 28Reference 28Pareek A et al. · 2011Systematic reviewFeverfew (Tanacetum parthenium L.): a systematic reviewView study →
Feverfew (Tanacetum parthenium)	flowering tops, seeds	high, qualitatively; low in stalks and roots 17Reference 17Heptinstall S et al. · 1992In vitroParthenolide content and bioactivity of feverfew (Tanacetum parthenium (L.) Schultz-Bip.): estimation of commercial and authenticated feverfew products — in vitroView study →
Southern magnolia (Magnolia grandiflora)	plant material	present, quantity not established 21,22Reference 21Feltenstein MW et al. · 2004AnimalAnti-inflammatory and anti-hyperalgesic effects of sesquiterpene lactones from Magnolia and Bear’s foot — animal modelView study →Reference 22Koo TH et al. · 2001In vitroA sesquiterpene lactone, costunolide, from Magnolia grandiflora inhibits NF-κB by targeting IκB phosphorylation — in vitroView study →

Two things are worth stating plainly. First, the concentration data are thin. Beyond feverfew leaf, published figures are qualitative; even within feverfew, commercial products have been found to vary from the specification down to no detectable parthenolide at all ^{17Reference 17Heptinstall S et al. · 1992In vitroParthenolide content and bioactivity of feverfew (Tanacetum parthenium (L.) Schultz-Bip.): estimation of commercial and authenticated feverfew products — in vitroView study →}. Second, the Magnolia grandiflora occurrence is a genuine outlier — parthenolide is otherwise an Asteraceae story, and M. grandiflora is a Magnoliaceae — and it is where the compound was co-isolated alongside costunolide for the comparative NF-κB work ^{22Reference 22Koo TH et al. · 2001In vitroA sesquiterpene lactone, costunolide, from Magnolia grandiflora inhibits NF-κB by targeting IκB phosphorylation — in vitroView study →} and the rat anti-inflammatory study ^{21Reference 21Feltenstein MW et al. · 2004AnimalAnti-inflammatory and anti-hyperalgesic effects of sesquiterpene lactones from Magnolia and Bear’s foot — animal modelView study →}. Reports of parthenolide in other Tanacetum and Chrysanthemum species exist but are not well quantified.

Discovery & Synthesis

First isolation. Parthenolide was isolated from feverfew — then classified as Chrysanthemum parthenium, which is where the name comes from — by Šorm’s terpene group in Prague, who published its constitution in 1961 as part of their long On terpenes series ^{1Reference 1Souček M et al. · 1961On terpenesView study →}. The initial assignment did not survive: Govindachari, Joshi and Kamat published a revised structure in 1964 and the full germacranolide structure paper in Tetrahedron in 1965 ^{2Reference 2Govindachari TR et al. · 1965Structure of parthenolideView study →}. Its ecological role at the leaf surface was characterised in 1979, when it was isolated directly from the leaf glands and shown to be antimicrobial ^{23Reference 23Blakeman JP · 1979In vitroAntimicrobial properties and possible rôle in host–pathogen interactions of parthenolide, a sesquiterpene lactone isolated from glands of Chrysanthemum parthenium — in vitroView study →}.

Synthesis. The germacrane ring’s conformational flexibility makes parthenolide a non-trivial synthetic target, and total synthesis has never been commercially relevant. The practical routes are isolation from feverfew — the compound is available in ample amounts from the plant ^{3Reference 3Freund RRA et al. · 2020ReviewAdvances in chemistry and bioactivity of parthenolide — reviewView study →} — and semisynthesis from costunolide, its immediate biosynthetic precursor, by epoxidation. Modern chemistry has concentrated not on making parthenolide but on derivatising it: the aminoparthenolide series that produced DMAPT is a Michael addition to the natural product ^{13Reference 13Neelakantan S et al. · 2009In vitroAminoparthenolides as novel anti-leukemic agents: discovery of the NF-κB inhibitor, DMAPT (LC-1) — in vitroView study →}, and reviews of the field are organised around bioactivity-driven derivatisation and chemical-probe development rather than de-novo construction ^{3Reference 3Freund RRA et al. · 2020ReviewAdvances in chemistry and bioactivity of parthenolide — reviewView study →}.

Patents: not yet researched.

Toxicity & Safety

Parthenolide is a reactive electrophile, and its safety profile is exactly what that predicts: low acute toxicity at the trace levels a botanical delivers, a real and well-documented contact-sensitisation hazard, and essentially no isolate toxicology at pharmacologically active doses because those doses have never been achieved in a person.

Contact Dermatitis & the Asteraceae Story

This is the dominant clinical safety fact, and it is a class phenomenon — sesquiterpene lactones are the cause of allergic contact dermatitis to the Compositae/Asteraceae family, and parthenolide is one of the standard reagents used to detect it ^{34Reference 34Punchihewa N et al. · 2022ObservationalAllergic contact dermatitis to Compositae: an Australian case series — retrospective observational studyView study →}. It is a component of the sesquiterpene lactone (SL) mix screening allergen and is registered in its own right in the T.R.U.E. Test panel, where a phase II dose-response study was run purely to establish the right diagnostic concentration ^{36Reference 36ClinicalTrials.gov NCT00133341 · 2005Clinical trialClinical evaluation of the 3 allergens methyldibromoglutaronitrile, parthenolide and gold sodium thiosulphate for T.R.U.EView study →}. Reviews describe it flatly as a strong contact allergen ^{29Reference 29Kashkooe A et al. · 2024ReviewExploring the phytochemistry, signaling pathways, and mechanisms of action of Tanacetum parthenium (L.) Sch.Bip. — a comprehensive literature reviewView study →}.

Prevalence, from patch-test series:

• Danish children and adolescents: 1.8% of consecutive eczema patients under 18 were SL-mix/parthenolide positive in 1995–2006; in the 2007–2019 series, 3% of 388 children tested were Compositae-sensitised, with 2.8% positive to SL mix ^{33Reference 33Paulsen E · 2020ObservationalCompositae sensitization in Danish children and adolescents — cross-sectional patch-test studyView study →}.
• Australian adults: 44 of 3,679 patch-tested patients (1.2%) reacted to Compositae, with SL mix simultaneously positive in 42% of the relevant cases. Most relevant cases came from direct plant handling — gardeners — but nearly a third came from personal-care products, all in women, with facial involvement significant ^{34Reference 34Punchihewa N et al. · 2022ObservationalAllergic contact dermatitis to Compositae: an Australian case series — retrospective observational studyView study →}.
• Feverfew-containing moisturisers have been reported to exacerbate established Compositae dermatitis ^{35Reference 35Killoran CE et al. · 2007Case reportTwo cases of compositae dermatitis exacerbated by moisturizer containing feverfew — case reportView study →} — which is precisely why cosmetic feverfew is sold parthenolide-depleted, a preparation described as free of sensitisation potential ^{31Reference 31Martin K et al. · 2008Clinical trialParthenolide-depleted feverfew (Tanacetum parthenium) protects skin from UV irradiation and external aggression — in vitro / animal model / clinical studyView study →}.

Cross-reactivity within the family means a person sensitised to one Asteraceae plant may react to ragweed, chrysanthemum, daisy, arnica, chamomile or marigold. Airborne exposure to plant debris is a documented route, which is why the face is disproportionately affected ^{34Reference 34Punchihewa N et al. · 2022ObservationalAllergic contact dermatitis to Compositae: an Australian case series — retrospective observational studyView study →}.

Oral & Mucosal Effects

In the six controlled feverfew trials, adverse events were mild and transient, most commonly gastrointestinal complaints and mouth ulcers, with no major safety concerns identified ^{24Reference 24Wider B et al. · 2015Systematic reviewFeverfew for preventing migraine — systematic reviewView study →}. Mouth ulceration and oral inflammation from chewing fresh feverfew leaf is a well-documented effect and is attributed to direct mucosal contact with the lactones. The phase I oncology study found feverfew delivering up to 4 mg/day of parthenolide well tolerated with no dose-limiting toxicity, and the maximum tolerated dose was not reached ^{15Reference 15Curry EA 3rd et al. · 2004Clinical trialPhase I dose escalation trial of feverfew with standardized doses of parthenolide in patients with cancer — clinical trialView study →} — but note that this is a tolerability finding at a dose that produced no measurable systemic exposure, so it is not evidence that pharmacologically active parthenolide levels would be safe.

Bleeding & Drug Interactions

Parthenolide inhibits granule secretion and serotonin release from platelets ^{17,18Reference 17Heptinstall S et al. · 1992In vitroParthenolide content and bioactivity of feverfew (Tanacetum parthenium (L.) Schultz-Bip.): estimation of commercial and authenticated feverfew products — in vitroView study →Reference 18Heptinstall S et al. · 1985In vitroExtracts of feverfew inhibit granule secretion in blood platelets and polymorphonuclear leucocytes — in vitroView study →}, which gives a mechanistically plausible antiplatelet effect and a theoretical additive risk with aspirin, warfarin, clopidogrel and other anticoagulant or antiplatelet drugs. This is inference from pharmacology, not a measured clinical interaction: no dedicated human drug-interaction or CYP450 study of parthenolide was identified, and no isoform-level inhibition or induction data are available. As a general precaution the herb literature advises discontinuing feverfew before surgery. Absence of interaction reports here reflects absence of study, not demonstrated safety.

What Has Not Been Assessed

Isolate-level genotoxicity, repeat-dose, carcinogenicity and reproductive toxicology for parthenolide were not identified in this search. Reactive Michael acceptors are non-selective by nature and cytotoxic to normal cells at high concentration — the leukaemia work’s selectivity window is a relative sparing, not an absence of toxicity ^{11Reference 11Guzman ML et al. · 2005In vitroThe sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells — in vitro / animal modelView study →}. Feverfew as a herb carries a traditional emmenagogue/abortifacient reputation and a pregnancy contraindication, but no controlled reproductive data exist for the isolated molecule; pregnancy and lactation are decided on the feverfew monograph, where intake is decided, and no molecule-level verdict is issued here.

Safety at a Glance

⚠️ Moderate toxicityDaisy-family allergyDrug interactions

• A strong contact allergen. Parthenolide is a standard patch-test reagent for Asteraceae/Compositae allergy and a component of the sesquiterpene-lactone mix; roughly 1–3% of patch-tested populations react ^{33,34,36Reference 33Paulsen E · 2020ObservationalCompositae sensitization in Danish children and adolescents — cross-sectional patch-test studyView study →Reference 34Punchihewa N et al. · 2022ObservationalAllergic contact dermatitis to Compositae: an Australian case series — retrospective observational studyView study →Reference 36ClinicalTrials.gov NCT00133341 · 2005Clinical trialClinical evaluation of the 3 allergens methyldibromoglutaronitrile, parthenolide and gold sodium thiosulphate for T.R.U.EView study →}.
• Cross-reacts across the daisy family. Sensitisation to ragweed, chrysanthemum, arnica, chamomile or marigold predicts reaction; airborne plant debris is a real exposure route, and the face is disproportionately affected ^{34,35Reference 34Punchihewa N et al. · 2022ObservationalAllergic contact dermatitis to Compositae: an Australian case series — retrospective observational studyView study →Reference 35Killoran CE et al. · 2007Case reportTwo cases of compositae dermatitis exacerbated by moisturizer containing feverfew — case reportView study →}.
• Theoretical bleeding risk. Inhibits platelet granule and serotonin release in vitro, so it may add to anticoagulants and antiplatelet drugs — mechanistic inference, never measured clinically ^{17,18Reference 17Heptinstall S et al. · 1992In vitroParthenolide content and bioactivity of feverfew (Tanacetum parthenium (L.) Schultz-Bip.): estimation of commercial and authenticated feverfew products — in vitroView study →Reference 18Heptinstall S et al. · 1985In vitroExtracts of feverfew inhibit granule secretion in blood platelets and polymorphonuclear leucocytes — in vitroView study →}.
• Mouth ulceration and GI upset are the common real-world effects, from direct mucosal contact rather than systemic action ^{24Reference 24Wider B et al. · 2015Systematic reviewFeverfew for preventing migraine — systematic reviewView study →}.
• Reactive electrophile, non-selective by design. Its cellular selectivity is relative, and no isolate genotoxicity, repeat-dose or reproductive toxicology was identified.
• Tolerability at botanical doses is good. Up to 4 mg/day orally was well tolerated with no dose-limiting toxicity — but at that dose it was also undetectable in plasma, so this is not a clearance for active systemic levels ^{15Reference 15Curry EA 3rd et al. · 2004Clinical trialPhase I dose escalation trial of feverfew with standardized doses of parthenolide in patients with cancer — clinical trialView study →}.

Dosage

There is no established human dose for isolated parthenolide, and no product supplies it as an isolate. The figures below are what has been studied, and they are stated for reference only.

Two things to carry away. The rodent and in-vitro figures are not convertible to human oral dosing — the compound’s problem is precisely that oral administration does not produce measurable plasma levels ^{15Reference 15Curry EA 3rd et al. · 2004Clinical trialPhase I dose escalation trial of feverfew with standardized doses of parthenolide in patients with cancer — clinical trialView study →}. And any product you can buy is feverfew, not parthenolide: the marker percentage on the label describes the plant material’s composition, not a delivered systemic dose.

These are doses studied in research and are not a personal recommendation.

References

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31. Martin K, Sur R, Liebel F, et al. (2008). Parthenolide-depleted feverfew (Tanacetum parthenium) protects skin from UV irradiation and external aggression — in vitro / animal model / clinical study. Archives of Dermatological Research. https://pubmed.ncbi.nlm.nih.gov/18071724/
32. Rodriguez KJ, Wong HK, Oddos T, Southall M. (2013). A purified feverfew extract protects from oxidative damage by inducing DNA repair in skin cells via a PI3-kinase-dependent Nrf2/ARE pathway — in vitro. Journal of Dermatological Science. https://pubmed.ncbi.nlm.nih.gov/24035441/
33. Paulsen E, Andersen KE. (2020). Compositae sensitization in Danish children and adolescents — cross-sectional patch-test study. Contact Dermatitis. https://pubmed.ncbi.nlm.nih.gov/32542786/
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35. Killoran CE, Crawford GH, Pedvis-Leftick A. (2007). Two cases of compositae dermatitis exacerbated by moisturizer containing feverfew — case report. Dermatitis. https://pubmed.ncbi.nlm.nih.gov/18021604/
36. ClinicalTrials.gov NCT00133341. (2005). Clinical evaluation of the 3 allergens methyldibromoglutaronitrile, parthenolide and gold sodium thiosulphate for T.R.U.E. Test Panel 3 — a phase II clinical trial, dose-response study. https://clinicaltrials.gov/study/NCT00133341

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