Apigenin

Pharmacology & Research

Apigenin is a dietary flavone — the flavone sibling of luteolin (apigenin plus a B-ring 3′-hydroxyl is luteolin) and the 3-deoxy analogue of the flavonol kaempferol. Its popular reputation, the “chamomile before bed” calm, rests on an inference rather than a trial: there is no randomised controlled trial of isolated apigenin for any human outcome. The anxiety and sleep evidence comes from whole chamomile extract (standardised to ~1.2% apigenin), and apigenin is only the presumed active because it binds the GABA-A benzodiazepine site in vitro — a mechanism that turns out to be genuinely mixed ^{13,14Reference 13Viola H et al. · 1995Apigenin, a component of Matricaria recutita flowers, is a central benzodiazepine-receptor ligand with anxiolytic effectsView study →Reference 14Avallone R et al. · 2000Pharmacological profile of apigenin, a flavonoid isolated from Matricaria chamomilla (benzodiazepine-site binding but reduced Cl⁻ current and no anxiolysis alone)View study →}. Everything else (anticancer, anti-inflammatory, metabolic) is cell-culture and animal work, undercut further by apigenin’s poor bioavailability: oral doses reach only low-nanomolar plasma levels, ~100–1000× below the concentrations used in those studies ^{17,18Reference 17Meyer H et al. · 2006Bioavailability of apigenin from apiin-rich parsley in humansView study →Reference 18Borges G et al. · 2022Absorption, distribution, metabolism and excretion of apigenin and its glycosides in healthy male adultsView study →}.

1. Anxiety (as chamomile extract)

Apigenin’s most-cited human benefit — and it is a chamomile benefit. A randomised, double-blind, placebo-controlled trial of oral chamomile extract in 57 patients with mild-to-moderate generalised anxiety disorder (GAD) showed a significant reduction in anxiety (HAM-A) over 8 weeks ^{1Reference 1Amsterdam JD et al. · 2009RCTA randomised, double-blind, placebo-controlled trial of oral Matricaria recutita (chamomile) extract therapy for generalised anxiety disorderView study →}. A larger long-term design followed 179 GAD outpatients on open-label chamomile, then randomised responders to continuation versus placebo; chamomile was safe and reduced relapse, though the relapse-prevention difference did not reach significance ^{2Reference 2Mao JJ et al. · 2016RCTLong-term chamomile (Matricaria chamomilla L.) treatment for generalised anxiety disorder — a randomised clinical trialView study →}. A companion study found salivary-cortisol changes during chamomile therapy ^{3Reference 3Keefe JR et al. · 2018An exploratory study of salivary cortisol changes during chamomile extract therapy of moderate to severe generalised anxiety disorderView study →}.

Gap: these are RCTs of whole chamomile extract, not isolated apigenin — the active ingredient is inferred. The trials are modest in size and dominated by a single research group, and there are zero isolated-apigenin anxiety trials ^{1,2Reference 1Amsterdam JD et al. · 2009RCTA randomised, double-blind, placebo-controlled trial of oral Matricaria recutita (chamomile) extract therapy for generalised anxiety disorderView study →Reference 2Mao JJ et al. · 2016RCTLong-term chamomile (Matricaria chamomilla L.) treatment for generalised anxiety disorder — a randomised clinical trialView study →}.

2. Sleep quality (as chamomile extract)

Genuinely mixed, and again a chamomile question. A placebo-controlled pilot in 34 adults with chronic primary insomnia (chamomile extract, 28 days) found no significant difference on any sleep measure ^{4Reference 4Zick SM et al. · 2011RCTPreliminary examination of the efficacy and safety of a standardised chamomile extract for chronic primary insomnia — a randomised placebo-controlled pilot studyView study →}. A separate trial in 60 elderly nursing-home residents did find improved sleep quality versus placebo ^{5Reference 5Adib-Hajbaghery M · 2017Clinical trialThe effects of chamomile extract on sleep quality among elderly people — a clinical trialView study →}, and a systematic review concluded chamomile appears helpful for sleep quality and GAD but noted weak evidence for primary insomnia specifically ^{6Reference 6Hieu TH et al. · 2019Meta-analysisTherapeutic efficacy and safety of chamomile for state anxiety, generalised anxiety disorder, insomnia, and sleep quality — a systematic review and meta-analysisView study →}.

Gap: whole-chamomile trials with population-dependent results — negative in true insomniacs, positive only in the elderly — small samples throughout, and no isolated-apigenin sleep data at all ^{4,6Reference 4Zick SM et al. · 2011RCTPreliminary examination of the efficacy and safety of a standardised chamomile extract for chronic primary insomnia — a randomised placebo-controlled pilot studyView study →Reference 6Hieu TH et al. · 2019Meta-analysisTherapeutic efficacy and safety of chamomile for state anxiety, generalised anxiety disorder, insomnia, and sleep quality — a systematic review and meta-analysisView study →}.

3. Anticancer, anti-inflammatory & metabolic

Mechanistically rich, entirely preclinical, plus some dietary epidemiology. Apigenin induces apoptosis and cell-cycle arrest and suppresses PI3K/Akt/mTOR and NF-κB across many cancer cell lines and rodent models ^{9,10,12Reference 9Shukla S · 2010Apigenin — a promising molecule for cancer preventionView study →Reference 10Rahmani AH et al. · 2022The potential role of apigenin in cancer prevention and treatmentView study →Reference 12Shukla S et al. · 2015AnimalApigenin blocks IKKα activation and suppresses prostate cancer progression (NF-κB suppression in TRAMP mice)View study →}, and blocks LPS-induced cytokine release in macrophages ^{11Reference 11Zhang X et al. · 2014Flavonoid apigenin inhibits lipopolysaccharide-induced inflammatory response through multiple mechanisms in macrophagesView study →}. On the population side, higher dietary flavone/apigenin intake was associated with lower ovarian-cancer risk in a large cohort ^{7Reference 7Gates MA et al. · 2007A prospective study of dietary flavonoid intake and incidence of epithelial ovarian cancerView study →} and, in a meta-analysis, possibly lower rectal-cancer risk ^{8Reference 8Chang H et al. · 2018Meta-analysisDietary flavonoids and the risk of colorectal cancer — an updated meta-analysis of epidemiological studiesView study →}.

Gap: no human interventional trial of apigenin for any of these — the anticancer/anti-inflammatory data are cell and animal only, and the epidemiology measures flavone-rich diets (confounded by vegetable intake), not the isolate. Apigenin’s poor bioavailability makes reaching in-vitro-active concentrations in people doubtful ^{11,17Reference 11Zhang X et al. · 2014Flavonoid apigenin inhibits lipopolysaccharide-induced inflammatory response through multiple mechanisms in macrophagesView study →Reference 17Meyer H et al. · 2006Bioavailability of apigenin from apiin-rich parsley in humansView study →}.

Mechanisms

Target / pathway	Nature of evidence	Relevant to
GABA-A benzodiazepine-site ligand (Ki ~4 µM)	in vitro + animal behaviour — mixed (agonist / antagonist / inverse-agonist reports)	anxiety, sleep
NF-κB / IKK suppression (↓ IL-6, IL-1β, TNF; NLRP3 disruption)	in vitro + animal	anti-inflammatory, anticancer
CDK inhibition / cell-cycle arrest + intrinsic apoptosis	in vitro + animal	anticancer
Nrf2 / PI3K-Akt-mTOR & MAPK modulation	in vitro + animal	metabolic, neuroprotective, anticancer
MAO / monoamine modulation	in vitro	anxiety (adjunct)

The GABA-A story deserves a flag: some rodent work shows anxiolysis without sedation, other work reports inverse-agonist/proconvulsant effects and no anxiolysis, with both flumazenil-sensitive and -insensitive components ^{13,14,15Reference 13Viola H et al. · 1995Apigenin, a component of Matricaria recutita flowers, is a central benzodiazepine-receptor ligand with anxiolytic effectsView study →Reference 14Avallone R et al. · 2000Pharmacological profile of apigenin, a flavonoid isolated from Matricaria chamomilla (benzodiazepine-site binding but reduced Cl⁻ current and no anxiolysis alone)View study →Reference 15Campbell EL et al. · 2004The dietary flavonoids apigenin and (−)-epigallocatechin gallate enhance the positive modulation by diazepam of the activation by GABA of recombinant GABA-A receptorsView study →}. The mechanism is real but not clean — and, like the others, mostly demonstrated at micromolar concentrations the bloodstream doesn’t reach.

Pharmacokinetics

Apigenin is a textbook “great in a dish, disappointing in a body” flavone. The aglycone is highly lipophilic and nearly water-insoluble, and in plants it is stored as glycosides — apiin (apigenin-7-apiosylglucoside, the parsley/celery form) and apigenin-7-O-glucoside (the chamomile marker) — whose sugar sets where absorption happens: chamomile’s glucoside peaks earlier (upper-GI) than parsley’s apiosylglucoside, which waits for colonic bacteria ^{18Reference 18Borges G et al. · 2022Absorption, distribution, metabolism and excretion of apigenin and its glycosides in healthy male adultsView study →}. In the cleanest human study, an apiin-rich parsley dose gave a mean peak plasma apigenin of only 127 nmol/L at ~7 h, with just ~0.2% of the dose recovered in urine and inter-individual variability roughly two-thirds of the mean ^{17Reference 17Meyer H et al. · 2006Bioavailability of apigenin from apiin-rich parsley in humansView study →}. What little is absorbed is heavily conjugated, so the circulating species are apigenin glucuronides and sulfates, not the free aglycone ^{18Reference 18Borges G et al. · 2022Absorption, distribution, metabolism and excretion of apigenin and its glycosides in healthy male adultsView study →}.

This is the load-bearing caveat: most mechanistic studies use 5–100 µM applied to cells, while achievable human plasma sits in the low-to-mid nanomolar range — roughly 100–1000× lower, and mostly as inactive conjugates ^{17,19Reference 17Meyer H et al. · 2006Bioavailability of apigenin from apiin-rich parsley in humansView study →Reference 19DeRango-Adem EF · 2021Does oral apigenin have real potential for a therapeutic effect in the context of human gastrointestinal and other cancers? Frontiers in Pharmacology, 12, 681477. https://pubmed.ncbi.nlm.nih.gov/34084146/View study →}. Much of the current formulation research (nanoparticles, phospholipid complexes) exists specifically to close that gap ^{19Reference 19DeRango-Adem EF · 2021Does oral apigenin have real potential for a therapeutic effect in the context of human gastrointestinal and other cancers? Frontiers in Pharmacology, 12, 681477. https://pubmed.ncbi.nlm.nih.gov/34084146/View study →}. The honest read: apigenin’s vivid in-vitro pharmacology is hypothesis-generating, not what a capsule delivers to tissue.

Clinical trials

Apigenin has no completed trial as an isolated molecule. Its human evidence is entirely trials of whole chamomile extract (anxiety, sleep) plus dietary-flavone epidemiology; the rest is preclinical.

Efficacy trials (isolate)	Whole-chamomile trials	Dietary epidemiology	Preclinical
None	Several (anxiety, sleep)	Cohorts (flavone intake)	Extensive

Last checked: July 2026.

Monoamine oxidase (MAO) inhibition

Apigenin is also reported as an in-vitro monoamine-oxidase inhibitor (with sub-micromolar MAO-A potency in some isolated-enzyme assays), one of several flavonoid MAO inhibitors ^{16Reference 16Salehi B et al. · 2019The therapeutic potential of apigeninView study →}. As with the others the activity is modest next to the β-carbolines and, given apigenin’s very low systemic and brain exposure, is best read as an in-vitro property rather than a clinical effect. See the natural MAO inhibitors guide for the comparison.

Isolate vs. Plant Studies

Apigenin is a case study in mistaking a herb for its molecule. The human evidence is chamomile, not apigenin: the anxiety and sleep RCTs test a standardised whole extract, and apigenin is the presumed active only by mechanistic inference ^{1,14Reference 1Amsterdam JD et al. · 2009RCTA randomised, double-blind, placebo-controlled trial of oral Matricaria recutita (chamomile) extract therapy for generalised anxiety disorderView study →Reference 14Avallone R et al. · 2000Pharmacological profile of apigenin, a flavonoid isolated from Matricaria chamomilla (benzodiazepine-site binding but reduced Cl⁻ current and no anxiolysis alone)View study →}. In plants it is a glycoside, not the aglycone (apiin, cosmosiin), which absorbs differently and is what a “apigenin-containing” herb actually delivers ^{18Reference 18Borges G et al. · 2022Absorption, distribution, metabolism and excretion of apigenin and its glycosides in healthy male adultsView study →}. And several repo “apigenin” findings are really distinct C-glycosides — vitexin (apigenin-8-C-glucoside) and isovitexin (apigenin-6-C-glucoside) are separate molecules with their own pharmacology, and in one chickweed study the C-glycosides were inactive antioxidants while other flavones were active — so attributing that to “apigenin” would be wrong. Across the database apigenin is named in the flavonoid fraction of many herbs — chamomile, holy basil, passionflower, dandelion, hyssop — usually as a whole-extract contributor without an apigenin-specific assay. The single most apigenin-specific pharmacology finding actually complicates the sleep story: injected alone, isolated apigenin bound the benzodiazepine site but reduced GABA-A currents and produced no anxiolytic, myorelaxant or anticonvulsant effect ^{14Reference 14Avallone R et al. · 2000Pharmacological profile of apigenin, a flavonoid isolated from Matricaria chamomilla (benzodiazepine-site binding but reduced Cl⁻ current and no anxiolysis alone)View study →}. Read the calm as a chamomile-extract effect, not a demonstrated property of the molecule.

Prevalence in Nature

Apigenin is one of the most widely distributed dietary flavones, across the Apiaceae (parsley, celery, celery seed), Asteraceae (chamomile) and Lamiaceae (thyme, oregano), plus scattered fruits and leafy vegetables ^{26Reference 26U.S et al. · 2013U.S. Department of Agriculture, Agricultural Research Service. USDA Database for the Flavonoid Content of Selected Foods, Release 3.1 (2013) — apigenin, mg/100 g. https://www.ars.usda.gov/ARSUserFiles/80400525/Data/Flav/Flav3-1.pdfView study →}. It is almost never present as the free aglycone — it accumulates as glycosides: apiin (apigenin-7-O-apiosylglucoside) in parsley and celery, apigenin-7-O-glucoside (cosmosiin, the chamomile marker), and C-glycosides such as vitexin and isovitexin. Food databases report aglycone-equivalents after hydrolysis, so a listed “apigenin” figure sums free plus bound forms.

The dominant quantitative caveat is drying. Dried parsley (~4,504 mg/100 g) dwarfs every other food — roughly 20× fresh parsley and ~230× fresh celery — but that is a desiccation artefact (drying concentrates, it doesn’t create the compound), so it is held here in prose rather than on the chart. Fresh parsley (~216 mg/100 g) is still by far the richest common fresh source, with celery seed, vine (Malabar) spinach, chamomile flowers, Chinese celery, kumquat and celery hearts forming the tiers below it ^{25,26Reference 25Xie XY et al. · 2014Simultaneous determination of eight flavonoids in the flowers of Matricaria chamomilla by HPLC (apigenin 0.54–0.62 mg/g dried flower)View study →Reference 26U.S et al. · 2013U.S. Department of Agriculture, Agricultural Research Service. USDA Database for the Flavonoid Content of Selected Foods, Release 3.1 (2013) — apigenin, mg/100 g. https://www.ars.usda.gov/ARSUserFiles/80400525/Data/Flav/Flav3-1.pdfView study →}. Chamomile tea and dried oregano/thyme deliver only modest amounts.

Biosynthetically apigenin is a core flavone: naringenin is oxidised to apigenin by flavone synthase — the soluble FNS I (a dioxygenase, characteristic of Apiaceae like parsley) or the membrane P450 FNS II ^{24Reference 24Martens S · 2005Flavones and flavone synthasesView study →}. It carries no B-ring 3′-hydroxyl, so flavonoid 3′-hydroxylase acting on apigenin gives luteolin — apigenin is luteolin’s des-3′-OH sibling, and the flavone analogue of the flavonol kaempferol (which differs only by a 3-OH). There is essentially no non-plant source: animals don’t make it, and gut microbiota deglycosylate and degrade it (they can even reduce luteolin to apigenin) rather than synthesise it, so diet is the only meaningful source.

Discovery & Synthesis

The name comes straight from the plant: apigenin is derived from Apium, the botanical genus of celery and parsley (Apiaceae), reflecting its abundance there. The lineage runs through its glycoside — apiin (the apigenin-apiosylglucoside) was among the earliest flavonoid glycosides described, reported in 1843 from parsley/celery, with the branched sugar apiose characterised later. A single, confidently attributed “first isolation of the free apigenin aglycone” is not reliably documented, so it should not be asserted — what is safe to say is that the name honours Apium and the parent glycoside apiin was isolated from parsley/celery in 1843.

Structurally apigenin is 4′,5,7-trihydroxyflavone — a flavone (2-phenylchromen-4-one) hydroxylated at 5, 7 and 4′. Add a 3′-OH and it becomes luteolin; add a 3-OH (on the C-ring) and you have the flavonol kaempferol — apigenin sits at the centre of that little family. Commercially it is obtained by extraction and purification from plant material (parsley, celery/celery seed, and especially chamomile flowers), typically by hydrolysing the natural glycosides to liberate the aglycone; although apigenin is readily made by classical flavone synthesis, total synthesis is not the commercial route.

Patents: not yet researched (future patent-loop pass).

Toxicity & Safety

Apigenin is a common dietary flavone — eaten daily in parsley, celery and chamomile — and at dietary levels has a long record of low toxicity. The honest limitation is that there is very little controlled human safety data on isolated, supplemental apigenin; safety at concentrated supplement doses (often 50–100+ mg, far above dietary intake) is inferred, not established, and its poor absorption is not a demonstrated guarantee.

The interaction signals are mostly in-vitro and, because achievable plasma is nanomolar, of uncertain clinical weight — but worth noting for concentrated supplements. Apigenin is a competitive inhibitor of CYP2C9 (IC50 ~4–8 µM, e.g. losartan/diclofenac probes) ^{20Reference 20Wang X et al. · 2016In vitroInhibitory effect of apigenin on losartan metabolism and CYP2C9 activity in vitroView study →} and inhibits CYP3A4 ^{21Reference 21Kondža M et al. · 2021Characterisation of the CYP3A4 enzyme inhibition potential of selected flavonoidsView study →}, raising a theoretical concern for CYP2C9 substrates (warfarin, some NSAIDs) and CYP3A4 substrates — most plausibly at the gut wall. It modulates P-glycoprotein in vitro ^{22Reference 22Bai J et al. · 2019In vitroInhibitory effects of flavonoids on P-glycoprotein in vitro and in vivo — food/herb–drug interactions and structure–activity relationshipsView study →}. It is a weak phytoestrogen, acting as a partial estrogen-receptor agonist in vivo (with some ERβ preference), a basis for caution in hormone-sensitive conditions ^{23Reference 23Yao L et al. · 2021AnimalApigenin acts as a partial agonist action at estrogen receptors in vivoView study →}. And because it binds the GABA-A benzodiazepine site ^{13Reference 13Viola H et al. · 1995Apigenin, a component of Matricaria recutita flowers, is a central benzodiazepine-receptor ligand with anxiolytic effectsView study →}, there is a theoretical risk of additive CNS depression with benzodiazepines, alcohol or other sedatives — the one interaction most relevant to the “apigenin for sleep” use.

Dosage

There is no evidence-based dose of isolated apigenin, because no trial has tested it. The popular ~50 mg/day “sleep/longevity” regimen is extrapolated from chamomile-extract trials, cell/animal data and folklore — not from any human trial of the molecule. Where chamomile itself is dosed for anxiety it is a standardised extract (~1.2% apigenin, ~220–1500 mg/day of extract), which is a chamomile dose, not an apigenin dose ^{1,2Reference 1Amsterdam JD et al. · 2009RCTA randomised, double-blind, placebo-controlled trial of oral Matricaria recutita (chamomile) extract therapy for generalised anxiety disorderView study →Reference 2Mao JJ et al. · 2016RCTLong-term chamomile (Matricaria chamomilla L.) treatment for generalised anxiety disorder — a randomised clinical trialView study →}.

These are descriptive, not a recommendation — no dose of isolated apigenin has been shown to do anything in a human trial. Anyone considering a supplement should note the sedative, CYP and estrogenic signals above and seek professional guidance.

References