Nobiletin

• Anti-inflammatory
• Neuroprotective
• Metabolic regulation
• Anticancer

• Cardiovascular protection
• Hepatoprotective
• Antioxidant
• Circadian rhythm regulation
• Cognitive enhancement

Nobiletin, a hexamethoxyflavone primarily found in citrus peels, exerts its diverse biological effects through multiple molecular pathways. One of nobiletin’s most distinctive mechanisms is its ability to modulate circadian rhythms by directly activating RORα and RORγ nuclear receptors, which regulate core clock genes including BMAL1 and CLOCK. This circadian regulation has far-reaching effects on metabolism, inflammation, and cellular homeostasis. In metabolic regulation, nobiletin activates AMP-activated protein kinase (AMPK), a master regulator of cellular energy homeostasis.

AMPK activation leads to increased glucose uptake, enhanced fatty acid oxidation, and reduced lipogenesis. Nobiletin also activates peroxisome proliferator-activated receptor alpha (PPARα) and PPARγ, further improving lipid metabolism and insulin sensitivity. Additionally, it enhances adiponectin production and reduces leptin resistance, contributing to improved metabolic homeostasis. As an anti-inflammatory agent, nobiletin inhibits the nuclear factor-kappa B (NF-κB) signaling pathway by preventing IκB kinase (IKK) activation and subsequent nuclear translocation of NF-κB, thereby reducing the expression of pro-inflammatory genes.

It suppresses the production of inflammatory cytokines including tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6), while inhibiting cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression. Nobiletin also modulates the mitogen-activated protein kinase (MAPK) pathway, including p38, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK), further contributing to its anti-inflammatory properties. In the central nervous system, nobiletin exhibits neuroprotective effects through multiple mechanisms. It activates the cAMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) signaling pathway, promoting neuronal survival, synaptic plasticity, and neurogenesis.

Nobiletin also enhances the phosphatidylinositol 3-kinase (PI3K)/Akt/glycogen synthase kinase-3β (GSK-3β) pathway, which protects neurons from apoptosis and promotes cell survival. In models of neurodegenerative diseases, nobiletin reduces amyloid-β and tau protein aggregation while promoting their clearance, which may explain its potential benefits for Alzheimer’s disease. It also protects dopaminergic neurons through activation of the SIRT1/FoxO3a pathway, which regulates autophagy, mitochondrial dynamics, and biogenesis, potentially benefiting Parkinson’s disease. In cancer cells, nobiletin demonstrates multiple anticancer mechanisms.

It induces apoptosis through both intrinsic (mitochondrial) and extrinsic (death receptor) pathways by modulating the expression of Bcl-2 family proteins, activating caspases, and promoting cytochrome c release. Nobiletin inhibits cancer cell proliferation by arresting the cell cycle at G1 or G2/M phases through regulation of cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors such as p21 and p27. It also suppresses cancer cell migration and invasion by inhibiting matrix metalloproteinases (MMPs) and epithelial-mesenchymal transition (EMT). Additionally, nobiletin has been shown to inhibit angiogenesis by reducing vascular endothelial growth factor (VEGF) expression and signaling.

The antioxidant properties of nobiletin are primarily attributed to its ability to indirectly enhance endogenous antioxidant defense systems rather than direct radical scavenging. Unlike hydroxylated flavonoids, nobiletin’s methoxy groups limit its direct radical scavenging capacity. Instead, it activates the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, leading to increased expression of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and heme oxygenase-1 (HO-1). In the cardiovascular system, nobiletin demonstrates protective effects by improving endothelial function, reducing platelet aggregation, and modulating lipid metabolism.

It inhibits platelet activation and aggregation by affecting calcium mobilization and thromboxane A2 production. Nobiletin also improves lipid profiles by enhancing reverse cholesterol transport and inhibiting cholesterol synthesis through modulation of key enzymes like HMG-CoA reductase. The highly methoxylated structure of nobiletin contributes to its lipophilicity and ability to penetrate cell membranes, including the blood-brain barrier, which enhances its intracellular effects and potentially its therapeutic efficacy in neurological conditions. However, this same characteristic limits its water solubility and oral bioavailability, necessitating various formulation strategies to enhance its absorption and therapeutic potential.

Optimal dosage ranges for nobiletin in humans have not been well established through clinical trials. Most studies use citrus peel extracts standardized to contain specific percentages of polymethoxyflavones (PMFs), including nobiletin. Based on preclinical studies and limited human research, typical daily doses range from 50-200 mg of nobiletin or 500-2000 mg of standardized citrus peel extract containing 5-10% PMFs. Animal studies showing metabolic and neuroprotective benefits have used doses equivalent to approximately 100-300 mg/day in humans

when adjusted for body surface area.

Nobiletin has poor oral bioavailability, estimated at approximately 1-5% in animal studies, primarily due to its extremely low water solubility (less than 10 μg/mL), extensive first-pass metabolism in the liver, and efflux by P-glycoprotein transporters in the intestine.

Despite its lipophilic nature, which theoretically should enhance membrane permeability, the poor aqueous solubility significantly limits its dissolution in the gastrointestinal tract and subsequent absorption. Once absorbed, nobiletin undergoes extensive metabolism, primarily through demethylation and conjugation reactions, forming various metabolites including 3′-demethylnobiletin, 4′-demethylnobiletin, and multiple hydroxylated derivatives.

These metabolites may contribute significantly to nobiletin’s biological activities, as some have shown equal or greater potency than the parent compound in certain assays.

Nanoemulsion formulations – can increase bioavailability by 5-20 fold by improving solubility and enhancing intestinal permeability, Liposomal encapsulation – protects nobiletin from degradation and enhances cellular uptake, Self-emulsifying drug delivery systems (SEDDS) – improve dissolution and absorption in the gastrointestinal tract, Phospholipid complexation – enhances lipid solubility and membrane permeability, Microemulsions – provide a stable delivery system with enhanced solubility, Solid lipid nanoparticles – offer controlled release and improved stability, Combination with piperine – inhibits P-glycoprotein efflux and intestinal metabolism, Co-administration with medium-chain triglycerides or other lipids – enhances solubility and lymphatic transport, Cyclodextrin inclusion complexes – improve aqueous solubility while maintaining stability, Solid dispersion techniques – enhance dissolution rate and solubility

Nobiletin is best absorbed when taken with meals containing fat, which can enhance solubility and stimulate bile secretion, improving dissolution and absorption. The presence of other citrus flavonoids may enhance nobiletin’s bioavailability through competitive inhibition of metabolic enzymes or transporters. For metabolic conditions and circadian rhythm regulation, evening dosing (approximately 1-2 hours before bedtime) may be more effective due to nobiletin’s effects on circadian clock genes and metabolic pathways that are particularly active during the night-time phase. For neuroprotective and cognitive effects, consistent daily dosing is important, with some evidence suggesting that morning dosing may be beneficial for cognitive enhancement during the day.

Enhanced formulations like nanoemulsions or liposomes may have different optimal timing recommendations based on their specific pharmacokinetic profiles, but generally follow the same principles of taking with food and considering circadian timing for specific conditions. Taking divided doses throughout the day may maintain more consistent blood levels due to nobiletin’s relatively short half-life (approximately 3-6 hours in animal studies).

• Gastrointestinal discomfort (mild to moderate)
• Nausea (uncommon)
• Diarrhea (uncommon)
• Headache (rare)
• Dizziness (rare)
• Potential sleep disturbances if taken late at night due to circadian rhythm effects
• Allergic reactions (rare)
• Mild drowsiness or alertness changes (due to effects on central nervous system)

• Pregnancy and breastfeeding (due to insufficient safety data)
• Scheduled surgery (discontinue 2 weeks before due to potential anticoagulant effects)
• Bleeding disorders (due to antiplatelet activity)
• Hormone-sensitive conditions (due to potential effects on hormone metabolism)
• Individuals taking medications metabolized by CYP450 enzymes (due to potential interactions)
• Individuals with severe liver or kidney disease (due to limited data on metabolism and excretion in these populations)
• Individuals with circadian rhythm disorders or sleep disorders (may require careful timing and monitoring)

• Anticoagulant and antiplatelet medications (may enhance bleeding risk due to nobiletin’s antiplatelet effects)
• Cytochrome P450 substrates (may affect metabolism of drugs metabolized by CYP1A2, CYP2C9, CYP2D6, and CYP3A4)
• P-glycoprotein substrates (may alter drug transport and absorption)
• Calcium channel blockers (potential for additive effects on calcium signaling)
• Antihypertensive medications (may enhance blood pressure-lowering effects)
• Statins (potential for increased bioavailability and risk of side effects)
• Immunosuppressants (may interfere with therapeutic effects through immunomodulatory actions)
• Antidiabetic medications (may enhance blood glucose-lowering effects)
• Sedatives and CNS depressants (potential for additive effects on central nervous system)
• Medications affecting circadian rhythm (potential for complex interactions with sleep-wake cycle regulation)

Due to limited human clinical data, a definitive upper limit has not been established. Based on animal toxicity studies, doses up to 200-300 mg/kg body weight have been used without significant adverse effects, suggesting a relatively high safety margin. For human supplementation, doses exceeding 300 mg of nobiletin or 3000 mg of standardized citrus peel extract daily are not recommended without medical supervision due to potential drug interactions and limited long-term safety data.

Nobiletin itself is not approved as a drug by the FDA and is not commonly available as an isolated supplement. Citrus peel extracts containing nobiletin are regulated as dietary supplements under the Dietary Supplement Health and Education Act (DSHEA) of 1994. Manufacturers cannot make specific disease treatment claims but may make general structure/function claims with appropriate disclaimers. The FDA has not evaluated the safety or efficacy of nobiletin specifically.

Nobiletin is generally recognized as safe (GRAS) as a component of citrus fruits and their extracts when used in food applications.

Eu: In the European Union, nobiletin is not approved as a medicinal product. Citrus peel extracts containing nobiletin may be sold as food supplements, subject to the general food safety regulations. The European Food Safety Authority (EFSA) has not issued specific health claims for nobiletin or citrus peel extracts. Some EU member states may have their own regulations regarding traditional herbal medicinal products containing citrus extracts. Nobiletin is permitted as a food flavoring component derived from natural sources.

Canada: Health Canada regulates citrus peel extracts containing nobiletin as Natural Health Products (NHPs). Several citrus extract products have been issued Natural Product Numbers (NPNs), allowing them to be sold with specific health claims related to traditional use. Isolated nobiletin is not specifically approved as a standalone ingredient. Health Canada permits nobiletin as a component of citrus flavoring agents in food products.

Australia: The Therapeutic Goods Administration (TGA) regulates citrus peel extracts as complementary medicines. Several products containing these extracts are listed on the Australian Register of Therapeutic Goods (ARTG). Traditional use claims are permitted with appropriate evidence of traditional use. Nobiletin as an isolated compound is not specifically regulated. Food Standards Australia New Zealand (FSANZ) permits nobiletin as a component of natural flavoring substances derived from citrus.

China: Dried citrus peel (Chen Pi) is officially listed in the Chinese Pharmacopoeia as a traditional Chinese medicine. Various formulations containing citrus peel are approved for specific indications based on traditional use and modern research. Nobiletin as an isolated compound is primarily used in research rather than as an approved therapeutic agent. The National Medical Products Administration (NMPA) has not approved any medications with nobiletin as the primary active ingredient.

Japan: Citrus peel is included in several Kampo medicine formulations approved by the Ministry of Health, Labour and Welfare for specific indications. Nobiletin as an isolated compound is not specifically regulated for therapeutic use. The Japanese Ministry of Health, Labour and Welfare permits nobiletin as a natural component of food flavorings derived from citrus. There is growing research interest in Japan regarding nobiletin’s potential applications in neurodegenerative diseases and metabolic disorders.

Medium to high

Isolated nobiletin is rarely available commercially for supplementation and is primarily sold as a research chemical at prices ranging from $200-$500 per 100 mg, making

it prohibitively expensive for regular supplementation. Standardized citrus peel extracts containing nobiletin along with other polymethoxyflavones typically cost $0.50-$2.00 per day for basic extracts and $2.00-$5.00 per day for premium, highly standardized formulations. Enhanced delivery systems such as nanoemulsions or liposomal formulations generally cost $3.00-$8.00 per day.

The cost-effectiveness of nobiletin must be evaluated in the context of citrus peel extracts, as isolated nobiletin is not practically available for regular supplementation due to its high cost and limited commercial availability. Citrus peel extracts offer reasonable value for their metabolic, neuroprotective, and anti-inflammatory benefits, with the therapeutic effects resulting from the combined action of multiple polymethoxyflavones including nobiletin, tangeretin, and sinensetin. Basic citrus peel extracts provide good value for general health maintenance and mild inflammatory conditions. However, their effectiveness is limited by poor bioavailability of the active compounds.

Premium extracts with standardized polymethoxyflavone content provide more consistent results but at a higher price point. For metabolic conditions, nobiletin’s unique ability to modulate circadian rhythms and improve insulin sensitivity may offer significant value compared to other supplements or pharmaceutical interventions, particularly when considering its favorable side effect profile. For neurodegenerative conditions, nobiletin’s ability to cross the blood-brain barrier and its multiple neuroprotective mechanisms may provide good value even at higher price points, especially given the limited effective interventions currently available for conditions like Alzheimer’s disease. Enhanced delivery formulations such as nanoemulsions, liposomes, or SEDDS offer the best therapeutic potential due to significantly improved bioavailability (5-20 fold increase), potentially justifying their higher cost for specific health conditions.

When comparing the cost-effectiveness of citrus peel extracts to other botanical supplements with similar indications, they generally offer competitive value, particularly when the broad spectrum of biological activities and unique circadian regulatory effects are considered. For research purposes, the high cost of pure nobiletin is justified for controlled studies investigating its specific mechanisms and effects.

Pure nobiletin is relatively stable compared to hydroxylated flavonoids due to its hexamethoxylated structure, which reduces its susceptibility to oxidation.

When properly stored, isolated nobiletin may maintain stability for 2-3 years. Standardized citrus peel extracts containing nobiletin typically have a shelf life of 2 years from the date of manufacture. Enhanced delivery formulations such as nanoemulsions or liposomes generally have shorter shelf lives of 1-2 years, depending on the specific formulation and preservative system.

Store in a cool, dry place away from direct sunlight in airtight, opaque containers. Refrigeration is recommended for liquid formulations and can extend shelf life of extracts containing nobiletin. Protect from moisture, heat, oxygen, and light exposure, which can accelerate degradation. For research-grade pure nobiletin, storage under inert gas (nitrogen or argon) at -20°C is recommended for maximum stability.

Enhanced delivery formulations may have specific storage requirements provided by the manufacturer, which should be followed carefully to maintain stability and potency. Avoid repeated freeze-thaw cycles, particularly for liquid formulations, as this can destabilize the product.

Exposure to UV light and sunlight – causes photodegradation, though less rapidly than hydroxylated flavonoids, High temperatures (above 30°C) – accelerates decomposition and may cause demethylation, Moisture – can promote hydrolysis and microbial growth, particularly in liquid formulations, Oxygen exposure – leads to oxidation, though the methoxy groups provide some protection compared to hydroxyl groups, pH extremes – nobiletin is most stable at slightly acidic to neutral pH (5-7), Metal ions (particularly iron and copper) – can catalyze oxidation reactions, Enzymatic activity – may occur in improperly processed plant extracts, Incompatible excipients in formulations – certain preservatives or other ingredients may interact negatively with nobiletin, Repeated freeze-thaw cycles – can destabilize enhanced delivery formulations such as nanoemulsions or liposomes

Synthesis Methods

Natural Sources

Quality Considerations

Nobiletin itself was not identified or isolated until the modern era, but it is a constituent of citrus peels, which have been used in traditional medicine systems for centuries. While the specific contribution of nobiletin to the traditional uses of citrus peels was unknown to ancient practitioners, it is now recognized as one of the key bioactive compounds in these historically important medicinal materials. In Traditional Chinese Medicine (TCM), dried citrus peels, known as ‘Chen Pi’ (primarily from Citrus reticulata), have been used for over 2,000 years. They were classified as herbs that regulate qi (vital energy), dispel dampness, and resolve phlegm.

Citrus peels were traditionally used to treat digestive disorders, coughs with phlegm, abdominal distension, and nausea. The first documented medicinal use of citrus peels appears in the ancient Chinese pharmacopeia ‘Shennong Bencao Jing’ (Divine Farmer’s Materia Medica), compiled around 200-250 CE. During the Tang Dynasty (618-907 CE), citrus peels were recognized for their ability to ‘break up stagnation’ and improve digestion. The famous physician Sun Simiao included detailed descriptions of citrus peel applications in his work ‘Qianjin Yaofang’ (Thousand Golden Prescriptions).

In the Ming Dynasty (1368-1644 CE), the renowned physician Li Shizhen further documented the medicinal properties of various citrus peels in his monumental work ‘Bencao Gangmu’ (Compendium of Materia Medica), noting their effectiveness for digestive and respiratory conditions. In traditional Japanese Kampo medicine, which evolved from TCM, citrus peels (known as ‘Chinpi’) are components of various formulations used for similar purposes as in Chinese medicine. In traditional European herbal medicine, citrus peels were also valued for their digestive properties and were used to make bitter tonics that stimulated appetite and digestion. They were included in various cordials and digestive bitters from at least the Middle Ages onward.

In the Mediterranean region, citrus peels were incorporated into culinary traditions not only for flavor but also for their perceived health benefits. Nobiletin was first isolated and characterized in the mid-20th century as part of the scientific investigation into the active components of citrus fruits. It was identified as a polymethoxyflavone, a class of compounds that has attracted scientific interest due to their unique biological properties and potential therapeutic applications. Modern scientific interest in nobiletin began to grow in the late 20th and early 21st centuries as research revealed its anti-inflammatory, neuroprotective, and metabolic regulatory properties.

A significant breakthrough in nobiletin research came in the early 2010s when it was discovered to be a potent modulator of circadian rhythms through direct activation of RORα and RORγ nuclear receptors. This finding has opened new avenues for research into nobiletin’s potential applications in metabolic disorders, neurodegenerative diseases, and other conditions with circadian rhythm disruptions. Recent studies have particularly focused on nobiletin’s potential applications in Alzheimer’s disease, Parkinson’s disease, metabolic syndrome, and cancer prevention and treatment. The development of enhanced delivery systems to overcome nobiletin’s poor bioavailability has further expanded its potential therapeutic applications.

Limited meta-analyses specifically on nobiletin; most analyses focus on citrus flavonoids or polymethoxyflavones as a group., A systematic review of polymethoxyflavones (including nobiletin) in neurodegenerative diseases suggested promising neuroprotective potential but highlighted the need for more human clinical trials (Braidy et al., Neural Regeneration Research, 2017)., A comprehensive review of nobiletin’s effects on metabolic disorders concluded that it shows significant promise for treating obesity, insulin resistance, and dyslipidemia, with multiple mechanisms of action identified in preclinical models (Mulvihill et al., Biofactors, 2020).

Several preclinical studies investigating nobiletin’s potential in neurodegenerative diseases, particularly focusing on its neuroprotective properties in Alzheimer’s and Parkinson’s disease models, Research on novel delivery systems to enhance nobiletin’s bioavailability and targeted delivery, Investigations into nobiletin’s potential as a circadian rhythm regulator for metabolic disorders, Studies on the metabolic effects of nobiletin in models of obesity and insulin resistance, Limited early-phase clinical trials evaluating standardized citrus peel extracts containing nobiletin for cognitive function and metabolic parameters