Apigenin
1. Identity and Chemical Characterization
Apigenin (4′,5,7-trihydroxyflavone) is a flavone compound found in many plants that is the aglycone of several naturally occurring glycosides. It belongs to the flavone structural class and has the molecular formula C15H10O5. Apigenin has a low molecular weight (MW 270.24), forming yellow needles in pure form, is practically insoluble in water, moderately soluble in hot alcohol, and soluble in dilute potassium hydroxide and dimethyl sulfoxide. It is a yellow crystalline solid that has historically been used to dye wool.
The flavone sub-class of flavonoids is characterized by a C2–C3 double bond, unsubstituted C3 carbon, and a C4 ketone oxidation. Apigenin is biosynthetically derived from the general phenylpropanoid pathway and the flavone synthesis pathway. Apigenin also exists as a dimer, biapigenin, mainly isolated from the buds and flowers of Hypericum perforatum.
In nature, apigenin is most commonly found in glycosidic form. In nature, apigenin is commonly found as a 7-O-glucoside, 6-C-glucoside, or 8-C-glucoside, which is enzymatically metabolized to free apigenin prior to intestinal absorption. The naturally occurring glycosides formed by the combination of apigenin with sugars include: apiin (apigenin 7-O-apioglucoside), isolated from parsley and celery, and apigetrin (apigenin 7-glucoside), found in dandelion coffee.
CAS Number and Regulatory Status
Apigenin carries the CAS registry number 520-36-5. Apigenin is a flavonoid of low toxicity and multiple beneficial bioactivities. It is commercially available as a dietary supplement ingredient in many countries and is generally derived from botanical extraction, primarily from chamomile flowers (Matricaria chamomilla) and celery (Apium graveolens).
2. Natural Sources and Botanical Origins
Apigenin is present principally as glycosylated in significant amounts in vegetables (parsley, celery, onions), fruits (oranges), herbs (chamomile, thyme, oregano, basil), and plant-based beverages (tea, beer, and wine). Flavonoids comprise a class of naturally occurring phytochemicals in almost all plant tissues, where they protect plants from harmful sunlight radiation, defend against pathogens and herbivory, regulate plant metabolism, and serve as visual attractors for pollinators.
Apigenin is particularly abundant in the flowers of chamomile plants, constituting 68% of total flavonoids. Dried parsley can contain about 45 mg apigenin per gram, and the apigenin content of fresh parsley is reportedly 215 mg per 100 grams, which is much higher than the next highest food source. Chamomile is one of the richest natural sources of apigenin (840 mg per 100 g dry weight), while chamomile herbal infusions (where dried flower is infused into water) contain 0.8–1.2% apigenin, mostly in the form of apigenin-7-O-glucoside.
Chamomile, with its scientific name Matricaria chamomilla L., also known as German chamomile, is an aromatic plant belonging to the Asteraceae family. Chamomile, parsley, and celery represent important sources of apigenin both for daily human intake and for the industrial extraction of this flavone.
A summary of the most concentrated food sources includes:
- Parsley, celery, spices such as rosemary, oregano, thyme, basil and coriander, chamomile, cloves, lemon balm, artichokes and spinach, peppermint, red wine, and licorice.
Commercial Forms and Preparations
Chamomile extract, parsley, and celery (Apium graveolens) are the main botanical sources of bulk apigenin used in supplement formulas. Apigenin is commercially available in several forms:
- Standardized botanical extracts: Chamomile flower extract standardized to a defined percentage of apigenin (e.g., 1.2%, 3%) is commonly used in capsule or tablet formulations.
- Isolated aglycone powder: High-purity (e.g., 98%) apigenin can be extracted from celery or synthesized, and is encapsulated for supplemental use.
- Herbal teas: Chamomile tea represents the most traditional and widespread dietary form of apigenin consumption.
- Advanced delivery systems: Improved bioavailability of oral dosage forms has been evaluated using apigenin-loaded water-in-oil-in-water emulsions, tested via in vitro simulations of digestion confirming that the carriers enable delivery of bioactive compounds while minimizing degradation. Emerging technologies to enhance apigenin oral delivery include nanoparticles, also using surfactants for enhanced drug solubility.
3. Traditional and Historical Use
For centuries, apigenin-containing plant preparations have been used in traditional medicines to treat diseases that have an inflammatory and/or degenerative component. The historical record of use centers principally on chamomile, which is the most apigenin-rich plant accessible in everyday preparations.
Several ancient cultures have documented chamomile's use, including Roman, Greek, Egyptian, and other civilizations. The Egyptians used chamomile for treating anxiety and to treat fevers associated with malaria. Ancient Greek physicians prescribed chamomile for nervous stomach, headaches, and colic.
Chamomile is included in the pharmacopoeias of at least 26 countries, including the United Kingdom, Belgium, and Germany. It is one of the most popular herbal remedies worldwide, being used to treat nervous indigestion, upset stomach, gastric ulcers, and colic. It is also widely used to promote relaxation and sleep. Topically, it is used to treat a variety of acute and chronic inflammatory skin disorders.
In traditional Chinese medicine, plants containing apigenin have been used historically as therapeutic agents against inflammation, infections, and various diseases.
Apigenin-containing preparations have been used in folk medicines for centuries as a way to treat anxiety and inflammation. While ancient populations were using chamomile herbal infusions empirically (based only on experience and observation), today we know that chamomile's medicinal properties stem from its high enrichment in terpenoids and flavonoids.
It is important to note that traditional uses are associated with whole plant preparations (particularly chamomile tea), in which apigenin is one of many active constituents. German chamomile flowers contain 0.24%–1.9% volatile oil, made up of a variety of compounds; the principal terpenoids are α-bisabolol and chamazulene. Thus, traditional outcomes cannot be attributed exclusively to apigenin.
4. Key Constituents, Active Compounds, and Mechanisms of Action
4.1 Anti-Inflammatory Mechanisms
The anti-inflammatory properties of apigenin are mediated by several signaling mechanisms. Several studies have shown that apigenin inhibits nuclear factor-kappa B (NF-κB) activation, a transcription factor responsible for regulating inflammatory reactions. Apigenin has been shown to suppress Toll-like receptor 4 (TLR4) signaling and the associated activation of downstream inflammatory pathways. Studies have shown that apigenin downregulates TLR4 expression in lipopolysaccharide (LPS) models, which leads to the activation of inflammatory signaling pathways such as NF-κB and MAPKs.
4.2 Antioxidant Mechanisms
Apigenin has been reported to act as a free-radical scavenger with antioxidant, anti-inflammatory, anti-mutagenic, anti-hyperglycemic, and antiviral effects. In addition, apigenin has been shown to increase the activities of intracellular glutathione reductase (GSH) and superoxide dismutase (SOD), enhancing the endogenous defense against oxidative stress.
4.3 GABAergic and Central Nervous System Mechanisms
In vitro, apigenin binds competitively to the benzodiazepine site on GABAA receptors, though there exist conflicting findings regarding how apigenin interacts with this site. Apigenin interacts with GABA receptors, enhancing inhibitory neurotransmission. It blocks acetylcholinesterase and increases acetylcholine availability. Apigenin impacts the serotonergic system by binding to serotonin receptors and affecting serotonin transporter activity and acts as a monoamine oxidase inhibitor, increasing levels of monoamines in the brain. Apigenin has been shown to increase 5-HT levels, decrease 5-HT turnover, and prevent dopamine changes.
Apigenin improved ERK/CREB/BDNF signaling, which contributed to long-term potentiation and memory function, and also attenuated hippocampal cholinergic deficit and improved acetylcholine levels, which are important for cholinergic neurotransmission and required for memory function.
4.4 Anticancer Signaling Pathways
Apigenin was reported to suppress various human cancers in vitro and in vivo by multiple biological effects, such as triggering cell apoptosis and autophagy, inducing cell cycle arrest, suppressing cell migration and invasion, and stimulating an immune response. The signaling pathways modulated by apigenin include the PI3K/AKT, MAPK/ERK, JAK/STAT, NF-κB, and Wnt/β-catenin pathways.
Apigenin is a potent inhibitor of several protein tyrosine kinases, including epidermal growth factor receptor and Src tyrosine kinase.
4.5 NAD+/CD38 Axis
Apigenin has been characterized as an inhibitor of the NAD+ase CD38. Pharmacological inhibition of CD38 by apigenin results in higher intracellular NAD+ levels, and treatment of cell cultures with apigenin decreases global acetylation as well as the acetylation of p53 and RelA-p65. Many studies have shown that high levels of CD38 and low levels of NAD+ are associated with aging, immunity, metabolic health, and cancer development. Given the biological significance of NAD+ and its regulator CD38, the discovery of apigenin not only as an inhibitor of CD38 (thereby increasing levels of NAD+ and decreasing levels of cADPR and ADPR) but also as a broadly-acting molecule with effects on sleep and aging holds therapeutic potential in humans.
4.6 Metabolism of Apigenin
After ingestion of plant material, glucoside forms of apigenin are enzymatically metabolized in vivo into free apigenin (the aglycone form) and subsequently absorbed. Apigenin undergoes phase I metabolism via CYP1A2, and to a lesser extent CYP3A4, generating the 3′-hydroxylated product luteolin. Flavonoids as a sub-class are poorly bioavailable from the diet due to their low water solubility, chemical instability, and rapid metabolism in the body. As a BCS class II drug, apigenin is characterized by relatively low solubility and high permeability in the intestine, which leads to extremely low bioavailability.
5. Scientific Evidence by Area of Use
5.1 Anxiety and Mood
Clinical evidence (chamomile extract as a proxy for apigenin): The most robust human data in this area derive from clinical trials using standardized chamomile extract, with apigenin as one of its principal active ingredients. Apigenin's therapeutic potential is underscored by human clinical studies using chamomile extract, which contains apigenin as an active ingredient. Collectively, chamomile extract has been reported to alleviate anxiety, improve mood, and relieve pain.
A randomized, long-term clinical trial of the application of 500 mg three times per day of chamomile extract in the treatment of generalized anxiety disorder (GAD) was conducted, administered to eligible participants with a DSM-IV Axis-I diagnosis of GAD for 12 weeks of open-label therapy. Studies on anxiety are more encouraging: 1,500 mg daily of chamomile extract for eight weeks reduced anxiety symptoms in patients with generalized anxiety disorder, and doses of 220 to 1,100 mg improved depression and mood scores.
A systematic review analyzed the effects of oral chamomile on anxiety from 10 clinical trials, with apigenin being one of chamomile's principal active compounds. Oral chamomile's anxiolytic efficacy was evaluated in patients with generalized anxiety disorder (moderate to severe), primary insomnia, cancer, menopause, menstrual-related mood disorders, and dysmenorrhea. Most clinical trials used chamomile capsules with dosages ranging from 250 mg to 2 g daily; in others, the intervention consisted of one or two cups of chamomile tea daily. The duration of clinical trials ranged from two to 26 weeks.
Important caveat: Many of these studies utilize chamomile extract, which is often about 1% apigenin by mass (0.8–1.2%) and in which apigenin is a bioactive ingredient. It is difficult to be certain whether the effects observed from chamomile extract in these studies are solely due to apigenin, other components of chamomile, or a combination of both. No clinical trials examining isolated apigenin for anxiety in humans have been identified in the literature.
5.2 Sleep
Clinical studies assessing apigenin's potential effects on sleep are promising, albeit limited. One study testing the effects of 270 mg of chamomile extract versus placebo twice per day for 28 days in patients with primary insomnia observed a trend toward improvement in daytime functioning, though it did not reach statistical significance. Another trial assessed the impact of chamomile extract versus placebo for eight weeks in patients with depression with or without anxiety. Subjects took a single 220 mg capsule daily in the first week and gradually increased to five capsules (1,100 mg) per day for the last four weeks. The authors observed significant reductions in depression and mood scores.
A randomized trial found that drinking chamomile tea for two weeks after childbirth significantly improved sleep efficiency and postnatal depression. A cross-sectional study in a large adult cohort found that lower dietary apigenin intake correlated with worse sleep quality.
In animal models, apigenin positively impacts both sleep and longevity. For example, apigenin improves learning and memory in older mice, reduces tumor proliferation in a mouse xenograft model of triple-negative breast cancer, and induces sedative effects in mice and rats. The overall human evidence for apigenin specifically (versus chamomile extract broadly) on sleep remains preliminary and indirect.
5.3 Neuroprotection and Cognitive Function
Apigenin may induce muscle relaxation and sedation depending on the dose, and it is also active as an antioxidant, anti-inflammatory, anti-amyloidogenic, neuroprotective, and cognition-enhancing substance with interesting potential in the treatment/prevention of Alzheimer's disease. With regards to neuroprotection, apigenin has been recognized as a promising agent for the amelioration of Alzheimer's disease by relieving amyloid-β burden, suppressing the amyloidogenic process, reducing oxidative stress, and reversing the ERK/CREB/BDNF pathway.
In a clinical study, cognitive functions in people with Alzheimer's disease after administration of a preparation containing apigenin over an extended period of time were improved. However, the broader body of evidence for apigenin's neuroprotective effects in humans remains at an early stage, with most data derived from preclinical (animal and cell) models.
The antidepressive and antianxiolytic effects of apigenin in preclinical research are related to the inhibition of inflammatory markers (TNF-α, IL-6, IL-1β, iNOS, and COX-2) and NF-κB activation; the modulation of monoamine, dopamine, and serotonin levels; the normalization of HPA axis alterations; and downregulation of the cAMP pathway.
5.4 Anticancer Activity
In the 1980s, apigenin was proposed to interfere with the process of carcinogenesis. Since then, more and more evidence has demonstrated its anticancer efficacy, both in vitro and in vivo. Apigenin has been reported to induce cell growth arrest and apoptotic induction by modulating multiple cell signaling pathways in a wider range of human tumors including those of the breast, lung, liver, skin, blood, colon, prostate, pancreatic, cervical, oral, and stomach.
Specific preclinical findings include:
- In HCT116 human colon cancer cells, apigenin inhibited cell proliferation by inducing G2/M phase arrest. This flavone also suppressed the expression of cyclin B1 and its activating partners Cdc2 and Cdc25c, whereas the expression of cell-cycle inhibitors, such as p53 and p21, was increased.
- In human prostate carcinoma cells, apigenin treatment resulted in G1 arrest and a marked decrease in the protein expression of cyclin D1, -D2, and -E and their activating partners CDK-2, -4, and -6.
- Apigenin has been shown to suppress angiogenesis in melanoma and carcinoma of the breast, skin, and colon.
- Total animal studies presented anti-metastatic effects of apigenin using experimental models, with mechanisms involving modulations of epithelial-mesenchymal transition (EMT), matrix metalloproteinases (MMPs), angiogenesis, and various metastasis-related signaling pathways.
Evidence strength and human data: Human clinical trials examining the effect of supplementation of apigenin on disease prevention have not been conducted, although there is considerable potential for apigenin to be developed as a cancer chemopreventive agent. Researchers have also discussed combinatorial strategies to enhance the anti-cancer effect of apigenin on various cancers and its use as an adjuvant chemotherapeutic agent to overcome cancer drug resistance or to alleviate adverse effects of chemotherapy. The anticancer evidence for apigenin in humans remains preclinical; no phase II or phase III trials demonstrating clinical benefit in cancer have been published.
5.5 Cardiovascular System
Apigenin possesses a wide range of biological properties that exert antioxidant, anti-inflammatory, anticancer, and antibacterial effects. These effects have been reported to be beneficial in the treatment of atherosclerosis, stroke, hypertension, ischemia/reperfusion-induced myocardial injury, and diabetic cardiomyopathy, and provide protection against drug-induced cardiotoxicity.
The neuroprotective and cardioprotective effects of apigenin in vivo have been studied in detail using experimental models of stroke, such as middle cerebral artery occlusion (MCAO) and bilateral common carotid artery occlusion (BCCAO) models of cerebral ischemia. Apigenin has been reported to reduce low-density lipoprotein and cholesterol levels in preclinical models. All of these findings are from preclinical (animal) models; controlled human trials specifically on apigenin's cardiovascular effects are lacking.
5.6 Musculoskeletal and Pain
The safety and efficacy of apigenin-rich chamomile oil for treating knee osteoarthritis were examined in a randomized controlled clinical trial. Patients with knee osteoarthritis who applied topical chamomile oil for three weeks saw a significant decline in their need for analgesics (acetaminophen), which improved their mobility.
In a crossover double-blind clinical trial with 100 patients, using a chamomile preparation containing 0.233 mg/g of apigenin and 4.48 µL/mL of chamazulene, 38 patients in the drug-placebo group and 34 patients in the placebo-drug group (a total of 72 patients per protocol) completed the process. According to results, using chamomile oleogel on the patients after 30 minutes caused significant decreases in pain, nausea, vomiting, photophobia, and phonophobia.
5.7 Metabolic and Anti-Diabetic Effects
Apigenin is a flavonoid with antioxidant, anti-inflammatory, and anti-apoptotic activity, and its potential effects on cardiometabolic diseases have been investigated in vivo and in vitro. CD38 plays a crucial role in mitochondrial oxidative stress by reducing the NAD+/NADH ratio and Sirt3 activity in the kidneys of type 2 diabetic rats. The NAD+/NADH ratio and mitochondrial anti-oxidative properties mediated by Sirt3 activation are restored by apigenin, leading to the amelioration of diabetes-induced renal injury. These findings are from animal models. Human data on apigenin for diabetes management are not yet available.
5.8 Antimicrobial and Gut Microbiota
Since apigenin is widely distributed in food items, and a diet high in flavonoids has been reported with many beneficial health effects, an estimation of the daily intake of apigenin could be useful in the correct interpretation of the relationship between health outcomes and apigenin. Preclinical evidence suggests apigenin exerts antimicrobial effects and influences gut microbiota composition, but these findings have not been replicated or confirmed in rigorous human clinical trials.
6. Body Systems and Health Areas of Association
- Central Nervous System: Anxiolytic and sedative effects (via GABAergic modulation); antidepressant activity (via serotonin/dopamine/BDNF pathways); neuroprotection in neurodegenerative disease models.
- Oncology: Anti-proliferative, pro-apoptotic, anti-angiogenic, and anti-metastatic activity across a broad range of cancer types in preclinical models.
- Cardiovascular System: Anti-atherosclerotic, antihypertensive, and cardioprotective effects in animal models.
- Metabolic Health: Anti-diabetic effects in preclinical models; CD38 inhibition raising cellular NAD+.
- Musculoskeletal/Pain: Anti-inflammatory and analgesic-sparing effects demonstrated in limited human clinical trials using chamomile (topical and oral).
- Immune System: Modulation of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β); suppression of NF-κB and TLR4 pathways.
- Skin: Antioxidant and anti-inflammatory effects relevant to dermatological use; inhibition of UV-induced MMP-1 expression demonstrated in cell models.
- Gastrointestinal: Traditional use for digestion; antimicrobial effects on gut microbiota in preclinical research.
7. Dosage Forms and Dosages Reported in Studies
There is no established standard clinical dosage for isolated apigenin, as most human trials have used chamomile extracts standardized to varying apigenin content. The following dosages are as reported in the cited literature:
- 270 mg of chamomile extract versus placebo twice per day (540 mg/day total) for 28 days was tested in patients with primary insomnia.
- One trial administered chamomile extract versus placebo for eight weeks in patients with depression: a single 220 mg capsule daily in the first week, gradually increased to five capsules (1,100 mg) per day for the last four weeks.
- A clinical trial used 500 mg of chamomile extract three times per day for GAD.
- Most clinical trials used chamomile capsules with dosages ranging from 250 mg to 2 g daily.
- In preclinical animal studies: Doses of 20 mg/kg and 40 mg/kg of apigenin were used in depressed mice.
Regarding bioavailability and formulation considerations: Apigenin, a bioactive flavonoid with promising therapeutic potential, suffers from poor water solubility, which limits its bioavailability. In vivo study showed that an apigenin mesoporous silica nanoparticle solid dispersion had an area under the curve 8.32 times higher than that of raw apigenin, indicating that the bioavailability of the dispersion was greatly improved.
8. Safety Considerations and Drug Interactions
8.1 General Safety Profile
Apigenin is a flavonoid of low toxicity and multiple beneficial bioactivities. Chamomile has generally regarded-as-safe (GRAS) status in the United States, primarily because of its long history of diverse traditional use. However, rare allergic reactions have been documented.
8.2 Allergic Reactions
Chamomile is not wind-pollinated and therefore is not associated with allergic rhinitis. However, rare cases of cross-reactivity between chamomile pollen and wind-borne pollens of other plants in the Asteraceae have been documented, or may be caused by adulteration by "dog chamomile" (Anthemis cotula). Individuals with known Asteraceae/Compositae family plant allergies should exercise particular caution.
8.3 CYP Enzyme Interactions
The flavonoid chemical structure makes these small molecules potent inhibitors of CYP1A1, CYP1A2, and CYP1B1. Apigenin is also a potent inhibitor of CYP1A2 and CYP2C9. Studies have indicated that apigenin is an inhibitor of CYP1A2, CYP2C9, and CYP3A4. This implicates apigenin in potential drug interactions with a number of chemotherapies and medications used in the supportive care of cancer. If this flavone were to be taken in conjunction with any one of the interacting substrates, this would lead to decreased metabolism and potentially supratherapeutic or toxic plasma levels.
Apigenin possesses the ability to inhibit P-gp and CYP3A4, and thus it may be involved in drug–drug interactions.
In vivo pharmacokinetic data demonstrate that apigenin pretreatment has the potential to drastically change the pharmacokinetics of dasatinib (a narrow-therapeutic-index anticancer drug), escalating systemic bioavailability. Therefore, concomitant consumption of apigenin-containing food or traditional herbs with dasatinib may cause serious life-threatening drug interactions, and more systematic clinical study on herb–drug interactions is required.
8.4 Sedation and CNS Effects
Since apigenin interacts with GABA-A receptors, it may cause mild sedation or drowsiness, particularly if taken in high doses or before activities requiring alertness. In mice, apigenin helped reduce anxiety but did not produce sedation like some medications that interact with the same GABA receptors; however, when given very high doses of apigenin, it caused mild sedation, making the mice less active.
8.5 Gastrointestinal Effects
Some individuals may experience stomach discomfort, bloating, or nausea, especially when taking concentrated supplements on an empty stomach. If these symptoms occur, taking apigenin with a light meal or snack may reduce stomach irritation.
8.6 Pregnancy and Special Populations
There is limited information regarding pregnancy and breastfeeding in the scientific and traditional literature. Chamomile consumption may pose risks in certain populations, such as pregnant women and individuals taking anticoagulants.
8.7 Lack of Clear Clinical Guidelines
There are currently no clear guidelines for potential apigenin interactions with other medications, nor sound evidence-based justifications for its clinical efficacy in disease situations. Future research and clinical trials are necessary to better understand apigenin's mechanisms of action, refine therapeutic dosing, and confirm its efficacy across various diseases, ultimately facilitating its application in clinical settings.
9. Overall Evidence Assessment
Apigenin has an extensive and growing body of preclinical evidence across multiple disease areas, encompassing cell culture and animal model data. However, the translation of these findings to human clinical outcomes remains incomplete. Apigenin's therapeutic potential is underscored by human clinical studies using chamomile extract, which contains apigenin as an active ingredient. Collectively, chamomile extract has been reported to alleviate anxiety, improve mood, and relieve pain. The most clinically actionable evidence involves chamomile extract preparations for anxiety and mood — areas where several randomized controlled trials have been conducted.
Emerging clinical studies are beginning to affirm apigenin's therapeutic benefits, showing positive effects in treating cancer, cardiovascular diseases, diabetes, neurodegenerative disorders, and inflammatory conditions. Nevertheless, the field is constrained by the absence of large-scale, phase II or phase III trials using isolated, standardized apigenin as the study intervention; by the inherent challenge of attributing outcomes from whole-plant chamomile extracts to apigenin specifically; and by the compound's poor oral bioavailability in conventional formulations.
References
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