Hispidulin

Pharmacology & Research

Hispidulin is a methoxyflavone — literally 6-methoxyapigenin — of sage, yerba santa and mugwort, first noted among the yerba-santa chemopreventive flavones in a 1992 screen ^{1Reference 1Liu YL et al. · 1992Isolation of potential cancer-chemopreventive agents from Eriodictyon californicumView study →}. What makes it worth its own page, unusually for a thin flavone, is a genuine, well-characterised CNS mechanism: it is a positive allosteric ligand at the benzodiazepine site of GABA-A receptors and it crosses the blood-brain barrier, giving a real (rodent) basis for anticonvulsant/anxiolytic activity ^{2,3Reference 2Kavvadias D et al. · 2004The flavone hispidulin, a benzodiazepine-receptor ligand with positive allosteric properties, traverses the blood-brain barrier and exhibits anticonvulsive effectsView study →Reference 3Kavvadias D et al. · 2003Constituents of sage (Salvia officinalis) with in-vitro affinity to human brain benzodiazepine receptorView study →}. Everything else — a broad anticancer literature, anti-inflammatory and bone signals — is the classic “flavone hits everything” pattern: many single-cell-line studies, scattered mechanisms, no depth, and no trial of the isolate.

1. Neuro (GABA-A benzodiazepine site)

Hispidulin’s distinctive claim. Isolated from sage as a human-brain benzodiazepine-receptor binder ^{3Reference 3Kavvadias D et al. · 2003Constituents of sage (Salvia officinalis) with in-vitro affinity to human brain benzodiazepine receptorView study →}, it is a positive allosteric modulator that gives oral/i.p. anticonvulsive protection in seizure models and — importantly — was directly shown to cross the blood-brain barrier ^{2Reference 2Kavvadias D et al. · 2004The flavone hispidulin, a benzodiazepine-receptor ligand with positive allosteric properties, traverses the blood-brain barrier and exhibits anticonvulsive effectsView study →}; a separate line shows activity at α6-subunit-containing cerebellar GABA-A receptors, attenuating methamphetamine-induced hyperlocomotion ^{4Reference 4Liu YC et al. · 2016Hispidulin alleviated methamphetamine-induced hyperlocomotion by acting at α6-subunit-containing GABA-A receptors in the cerebellumView study →}.

Gap: all rodent/in-vitro, with no human anxiolytic or anticonvulsant data for the isolate and unresolved α6-vs-classic-benzodiazepine-site selectivity ^{2,4Reference 2Kavvadias D et al. · 2004The flavone hispidulin, a benzodiazepine-receptor ligand with positive allosteric properties, traverses the blood-brain barrier and exhibits anticonvulsive effectsView study →Reference 4Liu YC et al. · 2016Hispidulin alleviated methamphetamine-induced hyperlocomotion by acting at α6-subunit-containing GABA-A receptors in the cerebellumView study →}.

2. Anticancer

Hispidulin sensitises ovarian cancer cells to TRAIL via AMPK activation (blocking Mcl-1 translation) ^{5Reference 5Yang JM et al. · 2010Hispidulin sensitises human ovarian cancer cells to TRAIL-induced apoptosis by AMPK activation blocking Mcl-1 translationView study →}, inhibits gallbladder cancer via HIF-1α ^{6Reference 6Gao H et al. · 2015Hispidulin inhibits proliferation and enhances chemosensitivity of gallbladder cancer cells by targeting HIF-1αView study →} and suppresses pancreatic-tumour angiogenesis via VEGFR2/PI3K/Akt/mTOR ^{7Reference 7He L et al. · 2011Hispidulin suppresses the angiogenesis and growth of human pancreatic cancer by targeting VEGFR2-mediated PI3K/Akt/mTOR signallingView study →}, with a 2020 review cataloguing the wider apoptosis/STAT3/NF-κB literature ^{8Reference 8Liu K et al. · 2020ReviewHispidulin: a promising flavonoid with diverse anti-cancer properties (review)View study →}.

Gap: the classic “flavone hits everything” pattern — scattered mechanisms, single labs per tumour, no isolate trials, and effective concentrations far above achievable plasma levels ^{8Reference 8Liu K et al. · 2020ReviewHispidulin: a promising flavonoid with diverse anti-cancer properties (review)View study →}.

3. Anti-inflammatory

Hispidulin suppresses Akt/NF-κB/STAT3 in LPS-activated BV2 microglia ^{9Reference 92020Hispidulin inhibits neuroinflammation in LPS-activated BV2 microglia by attenuating Akt, NF-κB and STAT3View study →} and alleviates imiquimod psoriasis-like skin inflammation by reducing Th1/Th17 populations ^{10Reference 102020Hispidulin alleviates imiquimod-induced psoriasis-like skin inflammation by inhibiting splenic Th1/Th17 populations and keratinocyte activationView study →}.

Gap: preclinical only, and shared with most dietary flavones — not distinctive ^{9,10Reference 92020Hispidulin inhibits neuroinflammation in LPS-activated BV2 microglia by attenuating Akt, NF-κB and STAT3View study →Reference 102020Hispidulin alleviates imiquimod-induced psoriasis-like skin inflammation by inhibiting splenic Th1/Th17 populations and keratinocyte activationView study →}.

4. Bone

Hispidulin attenuates bone resorption and osteoclast differentiation via suppression of RANKL-induced NF-κB and NFATc1 ^{11Reference 11Nepal M et al. · 2013Hispidulin attenuates bone resorption and osteoclastogenesis via the RANKL-induced NF-κB and NFATc1 pathwaysView study →}.

Gap: essentially a single isolate study, with no in-vivo bone-density confirmation for hispidulin alone ^{11Reference 11Nepal M et al. · 2013Hispidulin attenuates bone resorption and osteoclastogenesis via the RANKL-induced NF-κB and NFATc1 pathwaysView study →}.

Mechanisms

Target / pathway	Effect	Relevant to
GABA-A benzodiazepine site	positive allosteric modulation (binding + potentiation)	anticonvulsant / anxiolytic
GABA-A α6-subunit (cerebellar)	modulation → ↓ methamphetamine hyperlocomotion	CNS / behavioural
Blood-brain barrier	crosses it (measured)	enables the CNS mechanism
AMPK; HIF-1α; VEGFR2/PI3K-Akt-mTOR	activated; downregulated; inhibited	anticancer (various lines)
NF-κB / STAT3 / Akt	suppressed	anti-(neuro)inflammatory
RANKL → NF-κB / NFATc1	suppressed	bone resorption

Pharmacokinetics

Hispidulin (4’,5,7-trihydroxy-6-methoxyflavone; often stored in plants as the 7-O-glucoside homoplantaginin) has low oral bioavailability, typical of flavone aglycones — extensive phase-II glucuronidation/sulfation and rapid clearance, with low, short-lived plasma exposure in rat studies ^{12Reference 122014AnimalLC-MS/MS determination and pharmacokinetic study of seven flavonoids (including hispidulin) in rat plasma after oral Cirsium japonicum extractView study →}, and the glucoside shows poor, hydrolysis-dependent oral handling ^{13Reference 132016AnimalPharmacokinetics of homoplantaginin (hispidulin-7-O-glucoside) in rats after intravenous, intraperitoneal and oral administrationView study →}. The notable exception is the CNS: hispidulin crosses the blood-brain barrier (directly measured) ^{2Reference 2Kavvadias D et al. · 2004The flavone hispidulin, a benzodiazepine-receptor ligand with positive allosteric properties, traverses the blood-brain barrier and exhibits anticonvulsive effectsView study →}, which is what makes its central GABA-A mechanism plausible despite modest systemic levels. The large gap between µM in-vitro potencies and achievable free plasma levels is the main translational caveat for the non-CNS claims.

Clinical trials

There are no randomised or controlled human trials of isolated hispidulin for any indication; human-relevant claims are inferred from rodent and cell-culture data plus whole-plant preparations in which hispidulin is one constituent.

Last checked: July 2026.

Toxicity & Safety

Hispidulin is a low-toxicity, widespread dietary/medicinal flavone (sage, yerba santa, mugwort, Grindelia, snow lotus), consumed for centuries within culinary and herbal plants with no signal of acute toxicity in the preclinical literature. There are no isolate human safety data, and standard flavone caveats apply (theoretical CYP/UGT interaction from heavy conjugation). One mechanistic caution deserves a flag despite the low overall rating: because hispidulin is a genuine benzodiazepine-site GABA-A modulator that reaches the brain ^{2Reference 2Kavvadias D et al. · 2004The flavone hispidulin, a benzodiazepine-receptor ligand with positive allosteric properties, traverses the blood-brain barrier and exhibits anticonvulsive effectsView study →}, additive CNS depression with benzodiazepines, alcohol or other sedatives is biologically plausible and untested.

Pregnancy & lactation

Avoid. There are no reproductive-safety data for the isolate, and a CNS-penetrant GABA-A benzodiazepine-site modulator with additional anti-osteoclast/NF-κB activity has an unacceptable unknown profile in pregnancy and lactation — and some botanical sources (mugwort/Artemisia) carry their own traditional pregnancy contraindications.

Dosage

There is no established human dose for isolated hispidulin — no isolate trials exist, so any figure would be extrapolation. Intake occurs incidentally via sage, yerba santa, mugwort and other herbs; no therapeutic dose should be stated.

References