Caffeic Acid

• Antioxidant protection
• Anti-inflammatory
• Neuroprotection
• Cardiovascular support

• Anticancer properties
• Antimicrobial activity
• Hepatoprotection
• Blood glucose regulation
• Skin protection
• Immunomodulation

Caffeic acid exerts its diverse biological effects through multiple mechanisms at the molecular level. As a potent antioxidant, caffeic acid effectively neutralizes free radicals through direct scavenging of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Its unique chemical structure, featuring a catechol group (two adjacent hydroxyl groups on the aromatic ring) and an extended side chain with a conjugated double bond, allows it to form a resonance-stabilized phenoxy radical that accounts for its potent antioxidant activity. The catechol moiety is particularly effective at donating hydrogen atoms to neutralize free radicals, while the extended conjugation helps stabilize the resulting caffeic acid radical.

Beyond direct radical scavenging, caffeic acid enhances the body’s endogenous antioxidant defenses by activating the Nrf2 (Nuclear factor erythroid 2-related factor 2) signaling pathway. This activation leads to increased expression of antioxidant enzymes such as glutathione S-transferase (GST), NAD(P)H:quinone oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). Caffeic acid exhibits strong anti-inflammatory properties by inhibiting the NF-κB (nuclear factor kappa B) signaling pathway, a master regulator of inflammatory responses. It suppresses the phosphorylation and degradation of IκB (inhibitor of kappa B), preventing the nuclear translocation of NF-κB and subsequent expression of pro-inflammatory genes.

Caffeic acid also inhibits the production of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6). Additionally, it suppresses the activity of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), thereby reducing the production of prostaglandins and nitric oxide that contribute to inflammation. In the cardiovascular system, caffeic acid improves endothelial function by enhancing nitric oxide (NO) production through increased expression and activity of endothelial nitric oxide synthase (eNOS). It also reduces lipid peroxidation in blood vessels and inhibits platelet aggregation, contributing to its cardioprotective effects.

Caffeic acid positively influences lipid metabolism by inhibiting HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis, and by promoting cholesterol efflux from cells. For metabolic health, caffeic acid enhances insulin sensitivity by activating the insulin receptor substrate-1 (IRS-1)/phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, which increases glucose uptake in tissues. It also inhibits key enzymes involved in carbohydrate metabolism, such as α-amylase and α-glucosidase, slowing glucose absorption and reducing postprandial glucose spikes. In the brain, caffeic acid crosses the blood-brain barrier and exerts neuroprotective effects by reducing oxidative stress, inhibiting microglial activation, and preventing neuronal apoptosis.

It modulates several neurotransmitter systems and promotes the expression of neurotrophic factors like brain-derived neurotrophic factor (BDNF). Caffeic acid demonstrates anticancer potential through multiple mechanisms, including cell cycle arrest, induction of apoptosis in cancer cells, inhibition of angiogenesis, and modulation of various signaling pathways involved in cell proliferation and survival. It also inhibits matrix metalloproteinases (MMPs), which are involved in tumor invasion and metastasis. Caffeic acid phenethyl ester (CAPE), a derivative of caffeic acid, has shown particularly strong anticancer and immunomodulatory properties.

For liver protection, caffeic acid enhances the activity of phase II detoxification enzymes, facilitating the elimination of toxins and reducing oxidative stress in hepatocytes. It also inhibits lipid peroxidation in liver cell membranes and prevents mitochondrial dysfunction, which are key factors in various liver diseases. Caffeic acid exhibits antimicrobial properties by disrupting bacterial cell membranes, inhibiting bacterial enzymes, and interfering with quorum sensing mechanisms. It has shown activity against various bacteria, fungi, and viruses, including herpes simplex virus and HIV.

For skin health, caffeic acid provides photoprotection by absorbing UV radiation and neutralizing UV-induced free radicals. It also inhibits matrix metalloproteinases that degrade collagen and elastin, thereby helping to maintain skin structural integrity and potentially reducing signs of aging.

The optimal dosage range for caffeic acid supplements is not well-established in humans due to limited clinical trials. Based on preclinical studies and the limited human research available, dosages typically range from 25-250 mg per day. For general antioxidant support and preventive benefits, 25-100 mg daily is commonly suggested. Higher doses (100-250 mg) have been used in animal studies targeting specific health conditions, but human equivalent doses require further validation.

Most people obtain caffeic acid primarily through dietary sources rather than supplements, with average dietary intake estimated at 5-30 mg per day from coffee, fruits, and vegetables.

Caffeic acid has moderate oral bioavailability, estimated at approximately 20-30% in humans based on limited studies. The absorption occurs primarily in the small intestine through both passive diffusion and active transport mechanisms involving monocarboxylic acid transporters (MCTs). Free caffeic acid is absorbed more readily than its bound forms found in foods. In plants and foods, caffeic acid often exists as esters (particularly chlorogenic acid, which is an ester of caffeic acid and quinic acid), which must be hydrolyzed by intestinal esterases before absorption.

Some caffeic acid may also reach the colon, where it can be metabolized by gut microbiota, potentially producing bioactive metabolites with different properties than the parent compound. After absorption, caffeic acid undergoes extensive phase II metabolism in the liver, primarily through glucuronidation, sulfation, and methylation, which affects its bioactivity and distribution in the body.

Liposomal encapsulation: Can increase bioavailability by 2-3 times by protecting caffeic acid from degradation and enhancing cellular uptake, Nanoparticle formulations: May increase bioavailability by up to 3-4 times through improved solubility and cellular penetration, Co-administration with piperine (black pepper extract): Can inhibit glucuronidation and increase bioavailability by approximately 30-60%, Phytosomal complexes: Binding caffeic acid with phospholipids can enhance absorption by 2-3 times, Esterification: Caffeic acid phenethyl ester (CAPE) and other esters may have improved stability and absorption profiles, Taking with a small amount of healthy fats: May enhance absorption of caffeic acid, Consuming with other antioxidants: Synergistic effects have been observed when combined with other antioxidants like vitamin C, vitamin E, or other phenolic compounds, Microemulsion delivery systems: Can improve solubility and stability, potentially enhancing bioavailability, Consuming with probiotics: May enhance metabolism by gut microbiota, potentially increasing the production of bioactive metabolites

For optimal absorption, caffeic acid supplements are best taken on an empty stomach, 30 minutes before meals or 2 hours after meals. However, if gastrointestinal discomfort occurs, it can be taken with food, preferably with a small amount of healthy fat to enhance absorption. For cardiovascular benefits, taking caffeic acid in the morning may be beneficial as it can help improve endothelial function throughout the day. For antioxidant and anti-inflammatory effects, consistent daily dosing is more important than specific timing.

When used for neuroprotection, some research suggests that morning administration may be preferable, though evidence is limited. For blood glucose management, taking caffeic acid 15-30 minutes before meals may help reduce post-prandial glucose spikes. When used for photoprotection, oral supplements should be taken consistently for at least 4-6 weeks to build up protective effects, while topical applications are most effective when applied in the morning under sunscreen. The half-life of caffeic acid in the body is relatively short (estimated at 1-2 hours), so divided doses throughout the day may provide more consistent benefits for certain conditions.

For those consuming caffeic acid primarily through coffee, morning consumption aligns with natural circadian rhythms and may provide optimal benefits, though the caffeine content should be considered for those sensitive to its effects.

• Gastrointestinal discomfort (mild nausea, stomach upset)
• Headache (rare)
• Skin irritation (with topical applications in sensitive individuals)
• Allergic reactions (rare, more common in individuals with allergies to plants containing caffeic acid)
• Sleep disturbances (rare, particularly when taken in the evening)
• Temporary increase in liver enzymes (rare, at very high doses)
• Potential pro-oxidant effects at very high doses (theoretical concern based on in vitro studies)

• Known hypersensitivity or allergy to caffeic acid or plants high in caffeic acid
• Pregnancy and breastfeeding (due to insufficient safety data)
• Bleeding disorders (theoretical concern due to potential antiplatelet effects)
• Scheduled surgery (discontinue 2 weeks before due to potential antiplatelet effects)
• Hormone-sensitive conditions (theoretical concern due to potential weak estrogenic effects)
• Severe liver or kidney disease (use with caution due to limited research)
• Iron deficiency anemia (high doses may reduce iron absorption)

• Anticoagulant and antiplatelet medications (may enhance blood-thinning effects)
• Antihypertensive drugs (may enhance blood pressure-lowering effects)
• Antidiabetic medications (may enhance blood glucose-lowering effects)
• Hepatotoxic drugs (theoretical concern for additive effects at very high doses)
• Drugs metabolized by cytochrome P450 enzymes (potential for mild interactions)
• Iron supplements (may reduce absorption if taken simultaneously)
• Sedative medications (potential additive effects)
• Estrogen-containing medications (theoretical interaction due to potential weak estrogenic effects)
• Immunosuppressants (potential interaction due to immunomodulatory effects)

No official upper limit has been established. Most preclinical studies have used doses equivalent to 250-500 mg daily in humans without significant adverse effects. However, for long-term use, doses above 250 mg daily are not recommended without medical supervision due to limited long-term safety data. For topical applications, concentrations up to 5% have been used safely in cosmetic formulations, though most products use 0.5-3% concentration.

In the United States, caffeic acid is not approved as a drug but is generally recognized as safe (GRAS) as a food component naturally present in many common foods, particularly coffee and fruits. As a dietary supplement ingredient, it falls under the Dietary Supplement Health and Education Act (DSHEA) of 1994, which means manufacturers cannot make specific disease treatment claims but can make structure/function claims about its effects on normal body functions. For cosmetic use, caffeic acid is approved as a skin conditioning agent and antioxidant. The FDA does not require pre-market approval for dietary supplements containing caffeic acid, but manufacturers are responsible for ensuring safety and accurate labeling.

Caffeic acid phenethyl ester (CAPE), a derivative of caffeic acid found in propolis, is also regulated as a dietary supplement ingredient in the US.

Eu: In the European Union, caffeic acid is recognized as a natural food component and is permitted in food supplements under the Food Supplements Directive (2002/46/EC). It must comply with general food safety regulations. Novel food authorization may be required for certain applications or extraction methods. For cosmetic use, it is listed in the European Inventory of Cosmetic Ingredients as an antioxidant and skin conditioning agent. The European Food Safety Authority (EFSA) has not issued specific health claims for caffeic acid.

Canada: Health Canada permits caffeic acid in natural health products (NHPs) with appropriate safety data. It is listed in the Natural Health Products Ingredients Database (NHPID) with antioxidant and skin conditioning roles. Product license applications must include quality, safety, and efficacy information. As with the US, it is more commonly found as part of plant extracts rather than as an isolated compound.

Australia: The Therapeutic Goods Administration (TGA) permits caffeic acid in listed complementary medicines. It is included in the Australian Inventory of Chemical Substances (AICS) and permitted for use in cosmetics and personal care products. Specific therapeutic claims require higher levels of evidence and registration as a registered medicine.

Japan: In Japan, caffeic acid is approved as a food component and is also permitted in quasi-drug formulations for skin conditioning and antioxidant properties. The Ministry of Health, Labour and Welfare regulates its use in various applications.

China: The National Medical Products Administration (NMPA) permits caffeic acid in both cosmetic formulations and health food products with appropriate registration. Traditional Chinese Medicine formulations containing caffeic acid-rich herbs have separate regulatory pathways.

India: The Food Safety and Standards Authority of India (FSSAI) recognizes caffeic acid as a natural food component. For use in Ayurvedic and traditional formulations, it falls under AYUSH regulations when present in natural herbal extracts.

Medium

For standard caffeic acid supplements (25-100 mg daily): $0.30-$1.00 per day. For higher potency supplements (100-250 mg daily): $0.75-$2.50 per day. Enhanced delivery forms (liposomal, phytosomal): $1.50-$4.00 per day. Topical formulations: $1.00-$5.00 per daily application, depending on concentration and additional ingredients. Caffeic acid phenethyl ester (CAPE) supplements: $1.50-$4.00 per day.

Caffeic acid offers good value for its cost, particularly when considering its multiple health benefits. For general antioxidant support, more cost-effective alternatives exist (such as vitamin C), but caffeic acid’s unique mechanisms and potential specific benefits for cardiovascular, neurological, and metabolic health may justify the cost for certain health goals. The best value is typically found in products that contain caffeic acid as part of a broader spectrum of phenolic compounds from natural extracts, such as those from coffee, propolis, or fruit sources. These provide not only caffeic acid but also complementary compounds that may work synergistically.

Enhanced delivery systems significantly increase cost but may provide better value through improved bioavailability, especially for individuals with absorption issues or those seeking specific therapeutic effects. For skin health and photoprotection, topical formulations that combine caffeic acid with other antioxidants like vitamins C and E offer good value despite higher upfront costs, as they provide scientifically validated benefits that may reduce the need for more expensive cosmetic procedures. Caffeic acid phenethyl ester (CAPE) supplements, while more expensive than basic caffeic acid, may offer superior value for specific applications such as immune support and targeted anti-inflammatory effects based on research findings. Consumers should be cautious of very low-priced products claiming to contain pure caffeic acid, which may contain lower purity or potency than claimed.

Similarly, extremely high-priced products often reflect marketing rather than superior quality. For most health applications, moderate price point products from reputable manufacturers offer the best balance of quality and value. Food sources of caffeic acid (such as coffee, fruits, and vegetables) provide the most cost-effective way to obtain this compound, though in lower concentrations than supplements. Incorporating these foods into the diet is generally the most economical approach to obtaining the benefits of caffeic acid.

Pure caffeic acid powder typically has a shelf life of 1-2 years

when properly stored. Capsules and tablets generally have a shelf life of 1-2 years. Liquid formulations and topical products containing caffeic acid usually have shorter shelf lives of 6-12 months after opening due to increased vulnerability to oxidation. Caffeic acid phenethyl ester (CAPE) and other ester derivatives generally have improved stability compared to free caffeic acid, with shelf lives of 2-3 years

when properly stored.

Store in a cool, dry place away from direct sunlight and heat sources. Ideal temperature range is 15-25°C (59-77°F). Keep container tightly closed when not in use to prevent moisture absorption. For topical products, refrigeration after opening may extend stability.

Avoid storing near strong-smelling substances as caffeic acid may absorb odors. For powder forms, use a desiccant in the container if the original packaging doesn’t include one. Caffeic acid is more stable under slightly acidic conditions (pH 4-6) than under neutral or basic conditions, so formulations with appropriate pH buffering may have extended stability. For maximum stability, store caffeic acid products in an inert atmosphere (e.g., nitrogen-flushed containers) when possible.

Exposure to light (especially UV light) accelerates oxidation, High temperatures (above 30°C/86°F) significantly reduce stability, Moisture and humidity promote hydrolysis and degradation, Alkaline pH conditions (pH > 7) increase degradation rate, Presence of metal ions (particularly iron and copper) catalyzes oxidation, Oxygen exposure leads to oxidative degradation, Microbial contamination can occur in liquid formulations without proper preservatives, Repeated freeze-thaw cycles accelerate degradation, For topical formulations, incompatible ingredients may reduce stability, Enzymatic degradation can occur in some formulations, Caffeic acid may undergo isomerization from the trans to cis form under certain conditions, particularly when exposed to UV light, which can reduce its biological activity, In solution, caffeic acid can polymerize over time, especially in the presence of oxidizing agents

Synthesis Methods

Natural Sources

Quality Considerations

Caffeic acid has a rich history of indirect traditional use, primarily through the consumption of plants and foods that naturally contain high levels of this compound. While caffeic acid itself was not specifically identified or isolated until the early 20th century, many traditional medicinal plants rich in this compound have been used for centuries across different cultures. Coffee, one of the richest sources of caffeic acid, has been consumed for its stimulating and medicinal properties since at least the 15th century in the Arabian Peninsula, before spreading globally. Traditional Arabic and Ethiopian medicine recognized coffee’s ability to enhance alertness, improve digestion, and reduce inflammation, effects that we now know are partly attributable to its caffeic acid content.

In traditional European herbal medicine, plants rich in caffeic acid such as sage, thyme, and rosemary were used for their antiseptic, digestive, and respiratory benefits. These herbs were often prepared as teas, tinctures, or poultices for various ailments. The antimicrobial and anti-inflammatory properties now attributed to caffeic acid align with these traditional applications. In Traditional Chinese Medicine (TCM), herbs containing caffeic acid like honeysuckle (Lonicera japonica) and chrysanthemum were used to clear heat, reduce inflammation, and treat infections.

These plants were often included in formulations for febrile conditions, skin disorders, and respiratory infections. In Ayurvedic medicine, plants containing caffeic acid such as holy basil (Tulsi) were revered for their adaptogenic, anti-inflammatory, and immune-enhancing properties. Tulsi remains an important herb in Ayurvedic practice for stress reduction, respiratory health, and overall wellness. Propolis, a resinous substance produced by bees that contains high levels of caffeic acid and its derivatives (particularly CAPE), has been used medicinally across many cultures for thousands of years.

Ancient Egyptians, Greeks, and Romans all recognized propolis for its healing properties, using it for wound treatment, infection prevention, and immune support. Native American healing traditions utilized various berries and herbs containing caffeic acid for their medicinal properties. These were often used for pain relief, wound healing, and as general tonics. The modern scientific interest in caffeic acid began in the early 20th century when it was first isolated and characterized, but significant research into its health benefits only gained momentum in the 1980s and 1990s with the growing interest in plant phenolics and antioxidants.

The discovery of caffeic acid phenethyl ester (CAPE) as a bioactive component of propolis in the 1980s further accelerated research, particularly in the areas of cancer prevention and treatment. In contemporary food science, caffeic acid has been recognized as an important bioactive compound in coffee, fruits, and vegetables. The bitter taste associated with some of these foods is partly attributed to caffeic acid and its derivatives, particularly chlorogenic acid. Today, caffeic acid is recognized as a multifunctional compound with applications spanning from food preservation to cosmetic formulations and health supplements, representing a bridge between traditional plant-based healing and modern evidence-based approaches to health and wellness.

No comprehensive meta-analyses specifically on caffeic acid interventions have been published to date. Most evidence comes from individual preclinical studies, in vitro research, and limited human trials., Several systematic reviews have included caffeic acid as part of broader analyses of phenolic compounds and their health effects, particularly in the context of dietary antioxidants and coffee consumption.

Investigation of caffeic acid derivatives for neuroprotective effects in models of Alzheimer’s disease, Evaluation of caffeic acid phenethyl ester (CAPE) for anti-inflammatory effects in patients with inflammatory conditions, Topical formulations containing caffeic acid for photoprotection and skin aging, Caffeic acid as a complementary approach for managing metabolic syndrome components, Combination therapy of caffeic acid with standard treatments for various cancers