Flavonoid
Apigenin
Emerging EvidenceThe sedative and anxiolytic mechanism is well described preclinically and apigenin is the compound behind chamomile's reputation, but controlled human trials of isolated apigenin are scarce - hence Emerging rather than a higher rating. The nearest human evidence is for whole chamomile extract, which contains apigenin among many other compounds. For sleep it is weak: 34 adults with chronic primary insomnia who took 270 mg twice daily for 28 days showed no significant difference from placebo on any sleep-diary measure (Zick 2011). For anxiety it is modest: in 57 outpatients with mild-to-moderate generalised anxiety disorder, eight weeks of extract reduced Hamilton anxiety scores slightly more than placebo (p=0.047; Amsterdam 2009), and in a longer trial 1,500 mg a day kept symptoms lower over 26 weeks but did not significantly reduce relapse (Mao 2016). The 50 mg listed here is a common product strength, not a dose taken from a controlled sleep trial. Compared with L-theanine and magnesium glycinate — its two partners in the Deep Sleep stack — apigenin has the thinnest human evidence and the most drug interactions. Verdict: an optional last addition for sleep, best tried alone so you can tell whether it does anything, and one to clear with a pharmacist if you take any prescription medicine.
Recommended Dose
50 mg daily
Timing
30 min before bed
Mechanism of Action
Apigenin is a flavone found in chamomile flowers and parsley. It was isolated from chamomile as a ligand of the brain's benzodiazepine receptor: it displaced the benzodiazepine flunitrazepam from its binding site (Ki 4 µM) without acting on muscarinic or adrenergic receptors, and in mice it reduced anxiety-like behaviour without sedation at benzodiazepine-like doses, with mild sedation only at ten times that dose (Viola 1995). It also inhibits CD38, the main NAD+-consuming enzyme, and raised NAD+ in cell culture and in obese mice (Escande 2013) — the reason it turns up in longevity stacks — though that has not been shown in people. Absorption is the catch: taken as the pure compound, metabolites equal to only about 0.5% of the dose appeared in urine over 24 hours, against 34% for the glycoside form in chamomile tea (Borges 2022).
Side Effects & Safety
Well-tolerated. Mild sedation intended. Theoretical concerns about muscle relaxation at very high doses. May interact with sedatives. In the chamomile-extract trials, adverse events did not differ from placebo (Zick 2011; Amsterdam 2009; Mao 2016).
Do not use / talk to a doctor first
- Taking any narrow-therapeutic-index drug cleared by CYP3A4, without checking with a pharmacist
- Scheduled surgery or a general anaesthetic, given the sedative effect and CYP involvement in anaesthetic clearance
Interactions
Drugs cleared by CYP3A4
Apigenin reversibly inhibits CYP3A4, which clears a large share of prescription medicines - statins, many benzodiazepines, several immunosuppressants and calcium-channel blockers among them. Inhibition raises the drug's levels. This is the interaction that matters most on this page
Source: Saric Mustapic 2018, Molecules (PMID 30301254)
Drugs cleared by CYP1A2
Apigenin is a potent CYP1A2 inhibitor. Caffeine, theophylline, clozapine and olanzapine are cleared this way
Source: Shimada 2010, J Biochem Mol Toxicol (PMID 20806393)
P-glycoprotein substrates
Apigenin inhibits P-glycoprotein, which can raise absorption of drugs that rely on it for efflux. Demonstrated in animal pharmacokinetic work with imatinib and dasatinib
Source: PMC3863468; PMC9964503 - animal pharmacokinetics
Sedatives, benzodiazepines and alcohol
Additive sedation - apigenin acts at benzodiazepine binding sites, and the mild sedation is the intended effect here
Source: mechanistic
Pregnancy & breastfeeding
Not adequately studied as an isolated supplement in pregnancy or breastfeeding. Not recommended without medical advice.
Who should avoid / see a doctor
Anyone taking prescription medication should check with a pharmacist first. This is the one compound on this page whose main risk is not its own toxicity but what it does to OTHER drugs: apigenin inhibits CYP3A4, CYP1A2, CYP2A6 and P-glycoprotein, and CYP3A4 alone handles clearance of a large fraction of prescription medicines. Most of that evidence is in vitro or in animals, which makes the size of the effect in people uncertain - not the direction.
Synergies
Used in These Stacks
See Apigenin inside a full protocol — the stack pages cover when and why to combine it.
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References
- 1.Saric Mustapic 2018, Molecules — Apigenin showed reversible inhibition of CYP3A4 among tested flavonoid aglycones. (in vitro)
- 2.Shimada 2010, Journal of Biochemical and Molecular Toxicology — Apigenin is a potent inhibitor of human CYP1A2, by a mechanism distinct from genistein's. (in vitro)
- 3.Flavonoid aglycones and CYP activity, PMC6749521 — Effects of flavonoid aglycones on CYP1A2, CYP2A6, CYP2C8 and CYP2D6 activity. (in vitro)
- 4.Viola 1995, Planta Med — Apigenin isolated from Matricaria recutita (chamomile) competitively inhibited flunitrazepam binding at central benzodiazepine receptors (Ki 4 µM), with no effect on muscarinic, alpha-1 adrenergic or GABA-A muscimol binding; anxiolytic in mice in the elevated plus-maze without sedation or muscle relaxation, mild sedation at a 10-fold dose, no anticonvulsant action. (binding studies and mice)
- 5.Escande 2013, Diabetes — Apigenin and quercetin inhibit CD38, the primary mammalian NAD+ase; apigenin raised intracellular NAD+ in cell culture and, given to obese mice, increased NAD+ and improved aspects of glucose and lipid homeostasis. (cell and mouse work)
- 6.Borges 2022, Free Radic Biol Med — Healthy men: apigenin per se was poorly absorbed, with urinary metabolites equal to 0.5% of intake over 24 h; apigenin glycosides from a parsley drink gave 11.2% and from chamomile tea 34% urinary recovery.
- 7.Zick 2011, BMC Complement Altern Med — 34 adults with DSM-IV chronic primary insomnia, randomised double-blind pilot: chamomile extract 270 mg twice daily for 28 days produced no significant differences from placebo in any sleep-diary measure; adverse events similar to placebo. (whole chamomile extract, not isolated apigenin)
- 8.Amsterdam 2009, J Clin Psychopharmacol — 57 outpatients with mild-to-moderate generalised anxiety disorder, randomised double-blind, 8 weeks: chamomile extract reduced total HAM-A scores more than placebo (p=0.047); adverse events not different between groups. (whole chamomile extract)
- 9.Mao 2016, Phytomedicine — 179 adults with moderate-to-severe GAD took open-label chamomile extract 1,500 mg/day for 12 weeks; 93 responders were randomised to 26 weeks of chamomile or placebo. Relapse 15.2% vs 25.5% (HR 0.52, p=0.16, not significant); GAD symptoms stayed significantly lower on chamomile; similar low adverse-event rates. (whole chamomile extract)
