Quercetin

• Anti-inflammatory effects
• Antioxidant protection
• Senolytic activity (when combined with other compounds)

• Immune support
• Cardiovascular health
• Allergy relief
• Exercise recovery

Quercetin is a flavonoid polyphenol that exerts its biological effects through multiple mechanisms, primarily involving antioxidant, anti-inflammatory, and cell signaling pathways. Its diverse mechanisms contribute to its wide range of potential health benefits, from immune support to cardiovascular protection.

Direct Radical Scavenging: Quercetin acts as a direct antioxidant by donating hydrogen atoms to neutralize reactive oxygen species (ROS) and free radicals. Its chemical structure, particularly the presence of hydroxyl groups and a conjugated π system, enables it to stabilize free radicals by forming relatively stable quercetin radicals.

Metal Chelation: Forms complexes with transition metals like iron and copper, preventing them from participating in reactions that generate reactive oxygen species (Fenton reaction).

Enhancement Of Endogenous Antioxidants: Upregulates endogenous antioxidant defenses by activating nuclear factor erythroid 2-related factor 2 (Nrf2), which increases the expression of antioxidant enzymes including superoxide dismutase (SOD), catalase, and glutathione peroxidase.

Protection Of Antioxidant Networks: Helps regenerate other antioxidants like vitamin E and works synergistically with vitamin C in antioxidant networks.

Nf Kb Inhibition: Suppresses the nuclear factor kappa B (NF-κB) signaling pathway, a master regulator of inflammatory responses, by inhibiting IκB kinase (IKK) activity and preventing the nuclear translocation of NF-κB.

Cytokine Modulation: Reduces the production of pro-inflammatory cytokines including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6).

Enzyme Inhibition: Inhibits cyclooxygenase (COX) enzymes, particularly COX-2, which are responsible for the production of inflammatory prostaglandins., Inhibits lipoxygenase (LOX) enzymes, reducing the production of leukotrienes, which are mediators of inflammatory responses., Inhibits phospholipase A2 (PLA2), an enzyme that releases arachidonic acid from membrane phospholipids, thereby reducing the substrate availability for both COX and LOX pathways.

Mapk Pathway Modulation: Modulates mitogen-activated protein kinase (MAPK) signaling pathways, including p38 MAPK, JNK, and ERK, which are involved in inflammatory responses and cellular stress.

Mast Cell Stabilization: Inhibits mast cell degranulation and the release of histamine and other inflammatory mediators, contributing to its anti-allergy effects.

T Cell Effects: Modulates T-cell function by affecting T-cell proliferation, differentiation, and cytokine production, potentially balancing immune responses.

Dendritic Cell Modulation: Affects dendritic cell maturation and function, influencing antigen presentation and subsequent immune responses.

Neutrophil Function: Modulates neutrophil activity, including migration, oxidative burst, and neutrophil extracellular trap (NET) formation.

Mechanism Overview: When combined with certain compounds like dasatinib, quercetin exhibits senolytic properties (the ability to selectively eliminate senescent cells).

Bcl Family Modulation: Targets anti-apoptotic Bcl-2 family proteins (particularly Bcl-xL) that are upregulated in senescent cells, making these cells more susceptible to apoptosis.

Pi3k Akt Pathway: Inhibits the PI3K/AKT pathway, which is involved in senescent cell survival.

Senescent Cell Specificity: Preferentially affects senescent cells due to their altered metabolic state and increased susceptibility to certain forms of cell death compared to normal cells.

Endothelial Function: Improves endothelial function by increasing nitric oxide (NO) production through enhanced endothelial nitric oxide synthase (eNOS) activity and by protecting NO from degradation by reactive oxygen species.

Blood Pressure Effects: May help reduce blood pressure through multiple mechanisms, including improved endothelial function, calcium channel modulation, and angiotensin-converting enzyme (ACE) inhibition.

Lipid Metabolism: Affects lipid metabolism by modulating enzymes involved in cholesterol synthesis and transport, potentially helping to maintain healthy cholesterol levels.

Platelet Aggregation: Inhibits platelet aggregation and thrombus formation, contributing to cardiovascular health.

Glucose Metabolism: Influences glucose metabolism by affecting glucose transporters (particularly GLUT4), insulin signaling pathways, and enzymes involved in glucose metabolism.

Ampk Activation: Activates AMP-activated protein kinase (AMPK), a key regulator of cellular energy homeostasis that promotes glucose uptake, fatty acid oxidation, and mitochondrial biogenesis.

Adipocyte Function: Modulates adipocyte differentiation, lipid accumulation, and adipokine production, potentially contributing to metabolic health.

Kinase Inhibition: Acts as a broad-spectrum kinase inhibitor, affecting various protein kinases involved in cell signaling, including PI3K, Akt, and multiple tyrosine kinases.

Sirtuin Activation: May activate sirtuins, particularly SIRT1, which are NAD+-dependent deacetylases involved in cellular stress responses, metabolism, and aging.

Autophagy Modulation: Influences autophagy processes, which are important for cellular quality control and adaptation to stress.

Epigenetic Effects: Affects epigenetic mechanisms, including histone modifications and DNA methylation, potentially influencing gene expression patterns.

Absorption Limitations: Standard quercetin has poor oral bioavailability (typically less than 10%) due to limited absorption and extensive first-pass metabolism.

Metabolic Transformation: Undergoes significant metabolism, including glucuronidation, sulfation, and methylation, primarily in the intestine and liver.

Active Metabolites: Some quercetin metabolites retain biological activity and may contribute to its overall effects.

Tissue Distribution: Quercetin and its metabolites can accumulate in various tissues, with higher concentrations typically found in the lungs, kidneys, liver, and intestines.

NF-κB signaling pathway components, Nrf2-ARE pathway, MAPK signaling cascade proteins, PI3K/Akt pathway components, Cyclooxygenase (COX) enzymes, Lipoxygenase (LOX) enzymes, Phospholipase A2 (PLA2), Mast cell mediator release mechanisms, Bcl-2 family proteins, Protein kinases (various), SIRT1 and other sirtuins, Endothelial nitric oxide synthase (eNOS), AMPK pathway components, Glucose transporters (particularly GLUT4), Epigenetic modifiers (histone deacetylases, DNA methyltransferases)

500-1000 mg daily

With Meals: Best taken with meals containing fat to improve absorption

Divided Doses: For doses above 500 mg, dividing into 2-3 doses throughout the day may improve tolerance and effectiveness

Consistency: Regular daily use is typically more effective than intermittent use for most applications

Standard Quercetin: 500-1000 mg daily

Quercetin Phytosome: 250-500 mg daily (enhanced absorption may allow for lower doses)

Emiq: 50-100 mg daily (significantly enhanced absorption allows for lower doses)

Liposomal Quercetin: 250-500 mg daily (enhanced absorption may allow for lower doses)

Pregnancy Lactation: Not recommended due to insufficient safety data

Renal Impairment: Lower doses recommended; consult healthcare provider

Hepatic Impairment: Lower doses recommended; consult healthcare provider

Athletes: 500-1000 mg daily, with potential benefit from timing around exercise sessions

Low (less than 10% in standard form)

Poor Water Solubility: Quercetin has limited water solubility, which restricts its dissolution in the gastrointestinal tract

Extensive Metabolism: Undergoes significant first-pass metabolism in the intestinal wall and liver

P Glycoprotein Efflux: May be subject to efflux by P-glycoprotein transporters in the intestine

Molecular Size: Relatively large molecular size limits passive diffusion across cell membranes

With Meals: Best taken with meals containing fat to improve absorption

Consistency: Regular daily use maintains more consistent blood levels

Specific Timing: For allergy relief, taking in the morning may provide daytime symptom relief; for exercise recovery, taking before and after exercise may be optimal

Absorption Site: Primarily absorbed in the small intestine

Peak Plasma Time: Standard forms: 4-7 hours; Enhanced forms: 0.5-2 hours

Half Life: 3.5-28 hours, depending on the form and individual metabolism

Metabolism: Extensively metabolized via glucuronidation, sulfation, and methylation

Elimination: Primarily excreted in urine as metabolites

Choose enhanced bioavailability forms when possible, particularly for therapeutic applications, Take with meals containing some fat to improve absorption, Consider combination with vitamin C for synergistic effects, For standard forms, dividing the daily dose may improve overall absorption, Be aware that higher doses of standard quercetin may not proportionally increase blood levels due to absorption limitations

Quercetin has a generally favorable safety profile when used at recommended doses. It has been consumed as part of the human diet for thousands of years in fruits and vegetables, and as a supplement for several decades. Most adverse effects are mild and transient, though some drug interactions and specific contraindications should be considered.

• [“Headache (mild, transient)”,”Tingling or numbness (particularly in extremities)”,”Mild digestive discomfort (nausea, bloating, or upset stomach)”]
• [“Kidney stress at very high doses (primarily in individuals with pre-existing kidney issues)”,”Mild allergic reactions (skin rash, itching)”,”Sleep disturbances when taken late in the day (in sensitive individuals)”]
• [“Hypotension (in individuals taking blood pressure medications)”,”Hypoglycemia (in individuals taking diabetes medications)”,”Elevated liver enzymes (at very high doses)”]

Established Limit: No official upper limit has been established by regulatory authorities

Research Safety: Doses up to 1000 mg daily appear safe for most adults in clinical studies

High Dose Concerns: Doses above 1200 mg daily have limited safety data and may increase the risk of side effects

Long Term Safety: Long-term safety data beyond 12 weeks is limited, though no major concerns have emerged from existing research

Children: Not typically recommended for children without medical supervision; insufficient safety data

Elderly: Generally safe; may need to consider potential drug interactions due to higher likelihood of polypharmacy

Kidney Impairment: Use with caution; lower doses recommended due to potential renal stress at high doses

Liver Impairment: Use with caution; may affect metabolism of quercetin and increase risk of interactions

Recommended Tests: No specific laboratory monitoring is required for most individuals

Monitoring In High Risk: Those with kidney disease, on multiple medications, or taking high doses may benefit from periodic kidney and liver function tests

Signs To Watch: Unusual bleeding or bruising, significant digestive distress, signs of allergic reaction

Standard Quercetin: Generally safe at recommended doses; most safety data is based on this form

Enhanced Bioavailability Forms: May require lower doses due to increased absorption; safety profile appears similar to standard forms

Combination Products: Consider potential additive effects or interactions with other ingredients

Limited long-term safety data beyond 12 weeks of continuous use, Insufficient data on safety during pregnancy and lactation, Limited research on potential hormonal effects at high doses, Incomplete understanding of all potential drug interactions

Quercetin occupies different regulatory positions across global markets, generally classified as a dietary or food supplement rather than a pharmaceutical. Its regulatory status is influenced by its long history of consumption as a natural component of foods, its established safety profile, and the growing body of research supporting various health benefits.

Classification: Dietary supplement under the Dietary Supplement Health and Education Act (DSHEA) of 1994

Regulatory Authority: Food and Drug Administration (FDA)

Market Access: Freely available without prescription; sold in health food stores, pharmacies, online retailers, and some grocery stores

Permitted Claims: Permitted with appropriate disclaimer (e.g., ‘supports immune health’, ‘helps maintain cardiovascular function’), Prohibited without drug approval (e.g., cannot claim to treat, cure, or prevent any disease), Products must carry the standard dietary supplement disclaimer: ‘These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.’

Quality Requirements: Must be manufactured in compliance with dietary supplement Good Manufacturing Practices (21 CFR Part 111), Serious adverse events must be reported to the FDA, Must comply with dietary supplement labeling regulations including Supplement Facts panel

New Dietary Ingredient Status: Not considered a New Dietary Ingredient (NDI) due to its presence in the food supply before October 15, 1994

Gras Status: Generally Recognized As Safe (GRAS) for certain food uses, though this applies to food applications rather than supplement uses

Classification: Food supplement under Directive 2002/46/EC

Regulatory Authority: European Food Safety Authority (EFSA) provides scientific opinions; European Commission and individual member states implement regulations

Market Access: Available without prescription throughout the EU, though specific regulations may vary by member state

Novel Food Status: Not considered a Novel Food due to significant history of consumption before May 15, 1997

Health Claims: No authorized health claims under Regulation (EC) No 1924/2006 as of 2023, Several applications for health claims have been submitted but not approved due to insufficient evidence according to EFSA standards, General, non-specific claims (e.g., ‘supports wellbeing’) may be used in some contexts if accompanied by an authorized specific health claim

Maximum Levels: No EU-wide maximum levels established; some member states have established national guidance

Member State Variations: While EU regulations provide an overarching framework, implementation and enforcement vary by member state, Some member states have established recommended maximum levels or specific quality requirements

Post Brexit Status: Regulated similarly to pre-Brexit, but with potential for divergence from EU regulations over time

Classification: Food supplement

Regulatory Authority: Food Standards Agency (FSA) and Medicines and Healthcare products Regulatory Agency (MHRA)

Health Claims: Currently follows the EU health claims register, with no approved claims for quercetin

Market Access: Freely available without prescription

Classification: Natural Health Product (NHP)

Regulatory Authority: Health Canada, specifically the Natural and Non-prescription Health Products Directorate (NNHPD)

Product License: Requires pre-market approval and product license (Natural Product Number or NPN), Manufacturers must submit safety, efficacy, and quality evidence to obtain an NPN

Permitted Claims: Health Canada has approved certain claims for quercetin based on its Monograph, including ‘Provides antioxidants’ and ‘Used in Herbal Medicine as a capillary/blood vessel protectant’, Claims require supporting evidence proportional to the risk level of the claim

Quality Requirements: Must meet specifications outlined in the Natural Health Products Regulations for identity, purity, potency, and contaminants

Classification: Listed Complementary Medicine

Regulatory Authority: Therapeutic Goods Administration (TGA)

Listing Process: Must be listed on the Australian Register of Therapeutic Goods (ARTG) and receive an AUST L number, Sponsors self-certify the safety, quality, and limited efficacy claims; TGA conducts post-market compliance reviews

Permitted Claims: Limited to general health maintenance claims and traditional uses; cannot reference serious diseases

Quality Requirements: Must comply with the requirements of the Therapeutic Goods Act and relevant quality standards

Classification Options: May be sold as a general food supplement without specific health claims, Some quercetin products qualify under the Foods with Function Claims (FFC) system introduced in 2015

Regulatory Authority: Ministry of Health, Labour and Welfare (MHLW) and Consumer Affairs Agency (CAA)

Emiq Status: Enzymatically Modified Isoquercitrin (EMIQ) has specific regulatory recognition in Japan and has been approved for certain functional claims

Market Status: Widely available; Japan has been at the forefront of developing enhanced bioavailability forms of quercetin

Classification Options: May be registered as a ‘Health Food’ with specific function claims, May be sold as a general food supplement without specific health claims

Regulatory Authority: National Medical Products Administration (NMPA) and State Administration for Market Regulation (SAMR)

Registration Process: Health Food registration requires extensive safety and efficacy data, Approved Health Foods receive the ‘Blue Hat’ symbol

Market Reality: Growing domestic production of quercetin supplements, Significant sales through cross-border e-commerce channels, which operate under different regulatory frameworks

Codex Alimentarius: Codex guidelines provide some international framework but do not specifically address quercetin, No specific Codex standards addressing quercetin or similar flavonoid supplements

Mutual Recognition: Limited mutual recognition of quercetin supplement approvals between countries; manufacturers typically need to comply with each region’s regulations separately

Quercetin demonstrates synergistic relationships with several compounds that can enhance its bioavailability, potentiate its effects, or complement its mechanisms of action. Understanding these synergies can help optimize quercetin supplementation strategies for specific health goals.

Clinical trials specifically examining synergistic combinations for various health outcomes, Optimization of dosing ratios for different synergistic combinations, Investigation of novel combinations based on emerging mechanistic insights, Development of enhanced delivery systems for synergistic combinations, Long-term safety and efficacy studies of common combinations

Standard Quercetin: Typically 2-3 years when properly stored in original, sealed container

Enhanced Formulations: Generally 1-2 years for liposomal and phytosome forms due to potential phospholipid oxidation

Liquid Formulations: Usually 1-2 years unopened; 1-3 months after opening if refrigerated

Factors Affecting Shelf Life: Manufacturing quality, packaging type, storage conditions, presence of stabilizers or antioxidants in the formulation

Temperature: Store at room temperature (15-25°C or 59-77°F); avoid temperature extremes

Light Exposure: Protect from direct light, especially sunlight and UV exposure; amber containers provide some protection

Moisture: Keep in dry conditions; use containers with desiccants when possible

Air Exposure: Minimize exposure to air; keep containers tightly closed when not in use

Special Formulations: Liposomal and liquid formulations may benefit from refrigeration after opening; follow manufacturer’s specific recommendations

Accelerated Stability: Testing at elevated temperature and humidity (e.g., 40°C/75% RH) to predict long-term stability

Real Time Stability: Storage under recommended conditions with periodic testing to confirm shelf life

Photostability: Exposure to defined light conditions to assess light sensitivity

Freeze Thaw Stability: Particularly important for liquid formulations that might be exposed to temperature variations

Purchase sizes that will be used within a reasonable timeframe to minimize storage duration, Keep containers tightly closed when not in use, Store away from direct light, heat sources, and areas of high humidity (avoid bathroom storage), Consider refrigeration for opened liposomal and liquid formulations, Look for packaging with moisture and oxygen protection features, Discard products that show significant changes in appearance, odor, or texture, Pay attention to expiration dates, particularly for enhanced bioavailability formulations

Synthesis Methods

Natural Sources

Quality Considerations

Typical Forms

Absorption Enhanced Forms

Testing Methods

Supplier Considerations

Quercetin has been indirectly consumed throughout human history as a component of medicinal plants and foods. While not identified as a specific compound until the 19th century, many traditional herbal remedies that were later found to contain high levels of quercetin have been used for centuries across various cultures for their medicinal properties.

Emerging Applications: Potential to become recognized as one of the first evidence-based senolytic compounds for addressing age-related conditions, May be remembered for its role during the COVID-19 pandemic and subsequent viral research, Likely to be incorporated into personalized nutrition protocols based on individual genetic and metabolic profiles

Research Frontiers: Continued innovation in bioavailability enhancement and targeted delivery, Development of evidence-based synergistic combinations for specific health applications, Identification of responder phenotypes and appropriate biomarkers for personalized use

Historical Significance: Quercetin represents an important case study in the bridge between traditional herbal medicine and modern nutritional science, demonstrating how ancient wisdom can be validated and refined through scientific investigation.

Quercetin has a moderate level of scientific evidence supporting various health benefits. While there is strong mechanistic evidence from in vitro and animal studies, human clinical trials are more limited in number, size, and duration. The strongest evidence exists for immune support, anti-inflammatory effects, and certain aspects of cardiovascular health.

Many studies use standard quercetin with poor bioavailability; results may underestimate potential benefits of enhanced absorption forms, Significant heterogeneity in study designs, populations, dosages, and outcome measures makes comparison difficult, Limited long-term studies (most are 8-12 weeks or shorter), Many studies have small sample sizes, Publication bias may exist, with negative studies less likely to be published, Mechanistic studies in cell cultures and animals may not translate directly to human benefits

Larger, longer-term clinical trials with enhanced bioavailability forms, Studies directly comparing different quercetin formulations, Research on optimal dosing and timing for specific applications, Investigation of synergistic combinations (e.g., with vitamin C, zinc, or other flavonoids), Further exploration of senolytic effects in humans, particularly for age-related conditions, Studies in special populations (elderly, athletes, individuals with specific health conditions)