Caffeic acid

Caffeic Acid: A Comprehensive Reference

1. Identity: Chemical and Botanical Profile

Chemical Names and Classification

Caffeic acid (3,4-dihydroxy-cinnamic acid) is an organic compound and a potent antioxidant. It is also known by the synonyms 3,4-dihydroxycinnamic acid; 3-(3,4-dihydroxyphenyl)-2-propenoic acid; and 3,4-dihydroxybenzeneacrylic acid. Its molecular formula is C₉H₈O₄, with a relative molecular weight of 180.16 Da. Caffeic acid is a yellow, solid chemical compound that is structurally classified as a hydroxycinnamic acid, and the molecule consists of both phenolic and acrylic functional groups. It has a structure consisting of a benzene ring (an aromatic ring) with two hydroxyl groups at the 3,4 position and a carboxylic acid group at the 9 position attached to it.

Caffeic acid is a polyphenol, classified as a hydroxycinnamic acid (HCA) and a secondary metabolite in lignin biosynthesis, which occurs in almost all plants, specifically in coffee, thyme, sage, and olive plants. It is chemically unrelated to caffeine; instead, the shared name is related to its presence in coffee. Caffeic acid exists in cis and trans forms, with the trans isomer being the predominant naturally occurring form.

Caffeic acid [(E)-3-(3,4-dihydroxyphenyl)prop-2-enoic acid] is a white amorphous powder with a molecular mass of 180.16 g/mol. In its pure form it appears as yellow prisms or plates when crystallized from water; it is sparingly soluble in cold water but very soluble in hot water and cold ethanol.

Biosynthesis

Caffeic acid is biosynthesized in plant tissues via the endogenous shikimate pathway, which is responsible for the production of aromatic amino acids from glucose. Phenylalanine is a precursor for the synthesis of caffeic acid. Caffeic acid is found in all plants as an intermediate in the biosynthesis of lignin, a naturally occurring complex carbohydrate representing the principal components of biomass and its residues. It is the precursor to ferulic acid, coniferyl alcohol, and sinapyl alcohol, all of which are significant building blocks in lignin. The transformation to ferulic acid is catalyzed by the enzyme caffeate O-methyltransferase.

Natural Sources

Caffeic acid is found in all plants as an intermediate in the biosynthesis of lignin. It is the main hydroxycinnamic acid present in the human diet, with the highest content being found in blueberries, kiwis, plums, cherries, and apples, although also present in cereals, carrots, salad, eggplants, cabbage, artichoke, and coffee. Caffeic acid can be found in many products consumed daily, such as coffee beans, green tea, tomatoes, potatoes, artichokes, carrots, lettuces, dark plums, cherries, gooseberries, blackcurrants, grapes, and herbs (basil, rosemary, oregano).

Caffeic acid is also abundant in blueberry, raspberry, blackberry, Portuguese crowberry, and strawberry purées, where it is formed by the hydrolysis of caffeoylquinic acids (CQAs) and conjugated glycosides during the puréeing process. Caffeic acid has also been identified in wood smoke condensates and in the bee product propolis, presumably from resin gathered from caffeic acid-containing plants. Propolis is a resinous mixture created by honeybees from different botanical sources, and it is a natural product that has been used in folk medicine for many centuries.

Caffeic acid, one of the most common phenolic acids, frequently occurs in fruits, grains, and dietary supplements for human consumption as simple esters with quinic acid or saccharides and is also found in traditional Chinese herbs. Caffeic acid derivatives occur as major water-soluble components of Salvia miltiorrhiza (danshen), including caffeic acid monomers and a wide variety of oligomers. Rosmarinic acid and salvianolic acids occur as the major caffeic acid derivatives (polyphenolic acids) in Chinese Salvia species.

Key Derivatives and Related Compounds

Caffeic acid and its derivative caffeic acid phenethyl ester (CAPE) are produced in many kinds of plants. CAPE is lipophilic, with a molecular mass of 284.31 g/mol, and is one of the most studied natural derivatives of caffeic acid. CAPE is a central active component of propolis from honeybee hives. Its lipophilicity allows it to cross the blood-brain barrier in rats. Other notable derivatives include rosmarinic acid (a caffeic acid ester with 3,4-dihydroxyphenyllactic acid, abundant in Rosmarinus officinalis and other Lamiaceae), chlorogenic acid (a caffeic acid ester with quinic acid, the dominant polyphenol in coffee), and the synthetic analogue caffeic acid phenethyl amide (CAPA).

Common Dosage Forms and Preparations

Caffeic acid is available in several forms as a dietary supplement and pharmaceutical:

• Oral tablets: Caffeic acid tablets are used clinically in China and have been studied in thrombocytopenia. In clinical trials, patients took caffeic acid tablets orally at 300 mg three times per day for up to 12 consecutive weeks.
• Propolis extracts: Caffeic acid is present in many food sources, including coffee drinks, blueberries, apples, and cider, and also in several medications of popular use, mainly those based on propolis.
• Nanoformulations and novel delivery: Various approaches, including nanoformulations, lipophilic derivatives, and absorption enhancers, are being explored to address bioavailability issues.
• Dietary intake through food: The most common source of caffeic acid exposure is through consumption of coffee, fruits, and vegetables.

2. Traditional and Historical Use

General Ethnopharmacological Background

Caffeic acid has not historically been isolated and administered as a pure chemical. Rather, it has been an active constituent of a broad range of plant medicines used across cultures, with practitioners unknowingly harnessing its biological properties. Caffeic acid-rich plants (e.g., Echinacea, Salvia, Rosmarinus, and bee propolis) were traditionally employed for their tonic, antimicrobial, and anti-inflammatory properties.

Caffeic acid is one of the major active components in many traditional Chinese medicines. It is one of the most common phenolic acids found in traditional Chinese herbs and occurs as major water-soluble components of Salvia miltiorrhiza (danshen), including caffeic acid monomers and a wide variety of oligomers. Danshen has been used in traditional Chinese medicine for centuries as a cardiovascular tonic, circulatory aid, and treatment for chest pain and menstrual disorders.

Propolis in Traditional Medicine

Propolis, one of the richest natural sources of caffeic acid and CAPE, has been used in folk medicine across many cultures for centuries. Historically, caffeic acid-rich plants, including coffee, propolis, and various medicinal herbs, were utilized for their antioxidant, antimicrobial, anti-inflammatory, and wound-healing properties. Propolis was employed in ancient Egypt for embalming, used by Greek and Roman physicians for wound care, and has featured prominently in folk medicine traditions across Europe, the Middle East, and South America.

Echinacea and North American Traditions

Modern immunology research reveals mechanisms supporting traditional uses: echinacea phytochemicals, particularly alkylamides, caffeic acid derivatives, and polysaccharides, modulate both innate and adaptive immune responses, enhancing natural killer cell activity and increasing production of immune signaling molecules. Echinacea species, which contain significant amounts of caffeic acid derivatives including echinacoside and cichoric acid, were used by Native American tribes for infections, pain, and toothache, and became major medicines in 19th-century American botanical practice.

Mediterranean and European Herbal Traditions

Sage (Salvia officinalis), rosemary (Rosmarinus officinalis), thyme (Thymus vulgaris), and olive (Olea europaea) — all rich in caffeic acid and its derivatives — have deep roots in Mediterranean herbal medicine. Caffeic acid-rich plants such as Salvia and Rosmarinus were employed for their tonic, antimicrobial, and anti-inflammatory properties. Sage was used in European folk medicine as an antiseptic and digestive aid; rosemary as an antispasmodic and circulatory stimulant; and thyme preparations as antimicrobial agents in wound healing.

First Formal Identification

Caffeic acid was first identified by Hlasiwetz in 1867 as a breakdown product of caffetannic acid. Scientific isolation and characterization of caffeic acid as a distinct compound thus dates to the mid-19th century, after which systematic pharmacological investigation gradually commenced.

3. Key Constituents, Active Compounds, and Mechanisms of Action

Antioxidant Mechanisms

Caffeic acid plays a key role in scavenging reactive oxygen species (ROS) generated in energy metabolism, and is also responsible for maintaining normal levels of nitric oxide (NO) within cells. Caffeic acid was able to prevent hydroxyl radical formation promoted by the classical Fenton reaction, and in addition to its ability to prevent hydroxyl radical formation, caffeic acid demonstrated a great inhibition of membrane lipid peroxidation.

These antioxidant effects are attributed to caffeic acid's ability to modulate several pathways, such as inhibiting NF-κB, STAT3, and ERK1/2, thereby reducing inflammatory responses, and activating the Nrf2/ARE pathway to enhance antioxidant cell defenses. The Nrf2 (nuclear factor erythroid 2-related factor 2) pathway is a master regulator of cellular antioxidant responses. NRF2 is a transcription factor that regulates the cellular response to oxidative stress and affects the expression of superoxide dismutase and HO-1.

Anti-inflammatory Mechanisms

The anti-inflammatory effect of caffeic acid and its derivative CAPE may be mediated through the inhibition of NF-κB activation. NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a central transcription factor controlling expression of pro-inflammatory cytokines. Caffeic acid is a selective inhibitor for leukotriene biosynthesis, having been demonstrated to inhibit the 5-lipoxygenase pathway responsible for leukotriene production. CAPE (caffeic acid phenethyl ester) exerts its antioxidative effects through the Nrf2-mediated HO-1 pathway and its anti-inflammatory effects through NF-κB inhibition.

Anticancer Mechanisms

Caffeic acid acts on the angiogenesis of cancer cells through decreasing JNK-1 phosphorylation and reducing HIF-1α activation, causing a decline of vascularization mediated by vascular endothelial growth factor; and it may act on tumor cells by repressing MMP-2 and MMP-9 expressions, which in turn inhibits the activation of NF-κB, thus reducing cancer invasiveness and growth. Its anticancer effects are linked to modulation of cell signaling pathways, together with angiogenesis, cell cycle, apoptosis, and the PI3K/Akt pathway.

Neuroprotective Mechanisms

Caffeic acid significantly attenuated cerebral ischemic injury and resisted ferroptosis both in vivo and in vitro. The regulation of Nrf2 by caffeic acid initiated the transcription of downstream target genes, which were shown to be anti-inflammatory, antioxidative and antiferroptotic. Caffeic acid has emerged as a promising neuroprotective candidate due to its antioxidant, anti-inflammatory, and enzyme-inhibitory properties. Research has demonstrated that caffeic acid can inhibit acetylcholinesterase and beta-secretase (BACE-1), enzymes implicated in Alzheimer's disease pathology, and can inhibit amyloid-β aggregation in preclinical models.

Cardiovascular Mechanisms

Caffeic acid, CAPE, and the synthetic caffeic acid phenethyl amide (CAPA) exhibit vasorelaxant activity by acting on the endothelial and vascular smooth muscle cells. Their antioxidant, anti-inflammatory, and anti-angiogenic properties contribute to an important anti-atherosclerotic effect, and protect tissues against ischemia/reperfusion injuries and the cellular dysfunction caused by different physico-chemical agents.

Metabolic and Antidiabetic Mechanisms

Caffeic acid holds strong potential for use in metabolic syndrome management by its anti-obesity, antidiabetic, hypolipidemic, and hypotensive activities. In animal and cell-based studies, caffeic acid has been shown to inhibit alpha-glucosidase and alpha-amylase (enzymes that digest carbohydrates), reduce hepatic glucose output via suppression of gluconeogenic enzymes, and improve insulin sensitivity through anti-inflammatory and antioxidant actions.

Antimicrobial Mechanisms

In vitro and in vivo experiments have proven numerous physiological effects of caffeic acid, including antibacterial and antiviral activities. Caffeic acid's antimicrobial activity is attributed in part to its ability to disrupt bacterial cell membranes and inhibit essential microbial enzymes. It has demonstrated activity against both Gram-positive and Gram-negative bacteria, as well as against certain fungi including Candida species.

Hematological Mechanisms

Caffeic acid has been approved as a tablet formulation in China for thrombocytopenia. Its hematological effects include stimulation of platelet production (thrombopoiesis), promotion of bone marrow hematopoiesis, and inhibition of platelet destruction. The mechanism is thought to involve stimulation of megakaryocyte differentiation and reduction of immunologically mediated platelet clearance.

4. Pharmacokinetics and Bioavailability

Absorption

Caffeic acid is characterized by relatively low oral bioavailability, primarily resulting from extensive presystemic metabolism occurring in intestinal mucosa and liver, where it undergoes rapid conjugation through glucuronidation, sulfation, and methylation. Caffeic acid demonstrated poor permeability across Caco-2 cells, which contributes to its restricted intestinal absorption as well as low oral bioavailability in rats. Caffeic acid conjugates are absorbed rapidly after being eaten, reaching a maximum concentration after 1–2 hours.

A study of human bioavailability after red wine consumption provides direct evidence of oral absorption: five healthy male participants consumed 100, 200, and 300 mL of red wine providing approximately 0.9, 1.8, and 2.7 mg of caffeic acid, correspondingly. Plasma samples were collected over a 300-minute period. Both plasma caffeic acid levels and antioxidant activity were dose-dependent, and the Cmax was reached at about 60 minutes after red wine intake. The findings advocate that caffeic acid is bioavailable in humans and may contribute to the antioxidant capacity of plasma.

Distribution and Blood-Brain Barrier Penetration

Once absorbed, caffeic acid shows broad distribution across tissues, including potential to penetrate the blood–brain barrier; however, most systemic exposure is due to its metabolites rather than parent compound. Research has confirmed the presence of caffeic acid in human cerebrospinal fluid, providing evidence that dietary polyphenols can cross the blood-brain barrier in humans, though the hydrophilic nature and moderate molecular weight of caffeic acid restrict its BBB permeability. The proven anti-neurodegenerative properties of caffeic acid in vivo are limited due to its poor solubility, which limits bioavailability.

Metabolism and Excretion

Once absorbed, caffeic acid undergoes extensive metabolic transformations in the liver and kidneys. Excretion primarily occurs through urine in conjugated forms, and its relatively short half-life restricts prolonged systemic activity. A minor fraction of caffeic acid is metabolized in the intestinal wall and secreted back into the gut lumen in the form of ferulic acid. Caffeic acid and its methylated metabolites have been observed in plasma and urine in rats and human subjects after the digestion of chlorogenic acid. Additionally, gut microbiota play a role in the anaerobic metabolism of caffeic acid, transforming it into phenylpropionic acid derivatives.

Caffeic acid's absorption is affected by dietary matrix and composition of gut microbiota, resulting in substantial interindividual variability in pharmacokinetics.

Bioavailability Enhancement Strategies

Various approaches, including nanoformulations, lipophilic derivatives, and absorption enhancers, are being explored to address bioavailability issues. CAPE, the phenethyl ester of caffeic acid, has greater lipophilicity (logP 3.2–13.8) compared to caffeic acid itself, which improves membrane permeability and facilitates BBB penetration. However, the rapid metabolism of CAPE by esterase leads to its low bioavailability.

5. Scientific Evidence by Area of Use

5.1 Hematology: Thrombocytopenia and Myelosuppression

This represents the area with the strongest, most clinically developed human evidence for caffeic acid. Caffeic acid tablets are an approved pharmaceutical in China for treatment of thrombocytopenia.

Multicenter clinical trial (human evidence): A clinical study determined the efficacy and safety of oral caffeic acid tablets in management of primary immune thrombocytopenia (ITP). One hundred and three ITP patients with platelet count >10×10⁹/L and no serious bleeding symptoms from three centers were enrolled. Patients were divided into group A (PLT <30×10⁹/L) and group B (PLT ≥30×10⁹/L). Patients in both groups took caffeic acid tablets orally at 300 mg three times per day for 12 consecutive weeks. In group A, the overall response rate was 51.0% (26/51). Caffeic acid was effective in patients with ITP with few and mild adverse effects.

Systematic review and meta-analysis: A systematic review searched multiple databases and 35 publications with an overall 2,533 patients were included. The results showed that caffeic acid tablets were effective in the treatment of thrombocytopenia with a statistically significant difference [relative risk ratio (RR) = 1.24, 95% CI (1.17, 1.31), P < .00001] and in increasing platelet counts [SMD = 1.50, 95% CI (1.09, 1.91), P < .00001], white blood cell count [SMD = 1.08, 95% CI (0.77, 1.39), P < .00001], and neutrophil count [SMD = 0.73, 95% CI (0.19, 1.28), P = .009], and caffeic acid reduced myelosuppression [RR = 0.19, 95% CI (0.1, 0.37), P < .00001] and adverse effects [RR = 0.75, 95% CI (0.58, 0.96), P = .02].

Caffeic acid can effectively improve the clinical outcome of patients with thrombocytopenia with a good safety profile and is worth promoting. However, due to the low quality and small sample size of the included literature, a larger sample size and more standardized, high-quality studies are needed to validate these results.

Evidence strength: Moderate — positive clinical signal from multiple trials and a meta-analysis, but most underlying studies are of moderate quality, and many originate from a single country (China), limiting generalizability.

5.2 Antioxidant and Anti-inflammatory Effects

Caffeic acid notably protects cells and tissues from oxidative stress and inflammation, highlighting its therapeutic role in the management of pathogenesis. The antioxidant activity of caffeic acid has been extensively demonstrated across cell-based and animal studies.

Strong evidence of the ability of caffeic acid to reverse metabolic syndrome effects through the reduction in inflammatory markers such as TNFα coupled with reduced oxidative stress parameters has guided researchers to more proteomic and metabolomic approaches.

Evidence strength: Robust at the preclinical level (in vitro and animal models), with mechanistic clarity around NF-κB suppression and Nrf2 activation; direct human clinical evidence is limited and primarily indirect (i.e., through dietary epidemiology of caffeic acid-containing foods like coffee).

5.3 Cardiovascular Health

Caffeic acid and its derivatives have shown a very high potential for treating and preventing cardiovascular diseases in preclinical studies. Their antioxidant, anti-inflammatory, and anti-angiogenic properties contribute to an important anti-atherosclerotic effect, and protect tissues against ischemia/reperfusion injuries.

Animal and cell-based models have demonstrated that caffeic acid can reduce low-density lipoprotein oxidation, attenuate foam cell formation, reduce platelet aggregation, and exhibit vasorelaxant activity. Caffeic acid has revealed a good safety profile in a phase 1 clinical trial (NCT02050334).

There is an obvious shortage of in vivo studies to further explore these compounds' potential in vascular physiology. Nevertheless, their favorable pharmacokinetic profile and overall lack of toxicity make these compounds suitable for clinical studies.

Evidence strength: Preliminary to moderate — strong mechanistic evidence in preclinical models; no large randomized human cardiovascular outcome trials have been conducted specifically with caffeic acid.

5.4 Cancer Biology

The consumption of caffeic acid has been linked to a reduced risk of certain cancers, mitigation of chemotherapy and radiotherapy-induced toxicity, and reversal of resistance to first-line chemotherapeutic agents — though this evidence is primarily preclinical.

Caffeic acid can affect cancer cells alone or in combination with anticancer drugs, which could decrease the anticancer drug dose or help prevent or overcome resistance against those drugs.

Phase 1 human safety trial: One clinical trial (NCT02050334), titled "CC100: Safety and Tolerability of Single Doses", involved 18 participants aged 18 to 65. They were administered caffeic acid at a maximum concentration of 24 mg/kg. The findings indicated that caffeic acid did not lead to severe adverse effects; the main reported adverse effects were back pain and headache. However, the trial outcomes have not been published.

Evidence strength: Weak to preliminary in humans — the mechanistic and preclinical evidence is extensive, but controlled human anticancer trials are largely absent. Current evidence does not support caffeic acid as an established anticancer therapeutic in human oncology.

5.5 Neuroprotection and Alzheimer's Disease

Alzheimer's disease (AD) is a complex neurodegenerative disorder marked by cholinergic deficits, oxidative stress, amyloid-β aggregation, and tau hyperphosphorylation. Caffeic acid, a naturally occurring hydroxycinnamic acid, has emerged as a promising neuroprotective candidate due to its antioxidant, anti-inflammatory, and enzyme-inhibitory properties.

In animal models, caffeic acid has been shown to reduce amyloid-β plaque burden, inhibit acetylcholinesterase activity, reduce neuroinflammation, and improve cognitive performance in tests of spatial memory. Caffeic acid inhibits oxidative stress-mediated neuronal death in rat brain by regulating ferroptosis via the Nrf2 signaling pathway.

The hydrophilic nature and moderate molecular weight of caffeic acid further restrict its permeability across the blood–brain barrier (BBB), a significant challenge in translating these neuroprotective findings to human clinical outcomes.

Evidence strength: Preliminary — evidence is almost entirely from in vitro and rodent models. No human clinical trials in neurological conditions have been completed and reported.

5.6 Metabolic Syndrome, Obesity, and Diabetes

Caffeic acid holds strong potential to be used in metabolic syndrome management by its anti-obesity, antidiabetic, hypolipidemic, and hypotensive activities. Preclinical studies have demonstrated that caffeic acid can reduce fasting blood glucose, improve insulin sensitivity, reduce fat accumulation in adipose tissue, and lower serum triglycerides and cholesterol in animal models.

During the course of reviewing this subject, a substantial gap was identified in which the wealth of knowledge about caffeic acid is limited to findings in animal models or cell lines. Further studies in the form of a clinical trial or a population cohort study would further strengthen the beneficial effect of caffeic acid on metabolic syndrome.

Evidence strength: Weak in humans — rich preclinical evidence, but no adequately powered human randomized controlled trials have been completed. Epidemiological associations via coffee consumption exist but are confounded by caffeine and other bioactive compounds.

5.7 Antimicrobial Effects

In vitro and in vivo experiments have proven antimicrobial activities of caffeic acid and its derivatives, including antibacterial and antiviral activities. Caffeic acid has demonstrated inhibitory activity against a range of bacteria including Staphylococcus aureus, Escherichia coli, Helicobacter pylori, and against fungi such as Candida albicans. Antiviral properties have been observed against HIV, influenza, and herpes viruses in cell culture studies.

Evidence strength: Weak — primarily in vitro data. There are no published human clinical trials of caffeic acid as an antimicrobial or antiviral agent.

5.8 Hepatoprotection

The hepatoprotective effects of caffeic acid are reported through in vitro and in vivo studies. Animal models have shown that caffeic acid can reduce liver enzyme elevations, decrease hepatic lipid peroxidation, and suppress inflammatory signaling in models of chemically induced liver injury, non-alcoholic fatty liver disease, and hepatic fibrosis.

Evidence strength: Preliminary — animal and cell-line data only; no human clinical trials focused specifically on caffeic acid's hepatoprotective effects have been published.

6. Body Systems and Health Associations

Based on preclinical and, to a more limited extent, clinical research, caffeic acid has been associated with effects on multiple physiological systems:

• Hematological system: Promotion of platelet and leukocyte production; reduction of chemotherapy-induced myelosuppression. This is the most clinically developed area.
• Cardiovascular system: Antioxidant protection of vascular endothelium, anti-atherosclerotic activity, vasorelaxation, and protection from ischemia-reperfusion injury.
• Central nervous system: Neuroprotection against oxidative and inflammatory damage; inhibition of amyloid-β aggregation and acetylcholinesterase; potential role in Alzheimer's disease and cerebral ischemia.
• Metabolic/endocrine system: Antidiabetic activity through inhibition of carbohydrate-digesting enzymes, improvement of insulin sensitivity, anti-obesity effects.
• Hepatic system: Protection against chemically induced liver injury and oxidative hepatocellular damage.
• Immune system: Immunomodulatory effects; support of innate immune responses in the context of caffeic acid-containing extracts (e.g., echinacea, propolis).
• Musculoskeletal system: Preclinical evidence for protection of cartilage integrity and reduction of inflammation in osteoarthritis models via NRF2/HO-1 and NF-κB pathways.
• Gastrointestinal system: Potential mucosal protective effects and modulation of gut microbiota.
• Oncological context: Preclinical evidence for antiproliferative, pro-apoptotic, and anti-angiogenic activity across multiple cancer cell lines.

7. Dosage Forms and Reported Dosages

The following dosage information is sourced directly from published studies and should not be extrapolated as recommendations:

• Thrombocytopenia (human clinical trial): Patients took caffeic acid tablets orally at 300 mg three times per day for 12 consecutive weeks.
• Thrombocytopenia combined with dexamethasone (multicenter RCT): Participants received caffeic acid tablets given orally at a dose of 900 mg per day for 3 consecutive months.
• Phase 1 safety trial (human): Trial NCT02050334 involved 18 participants aged 18 to 65, administered caffeic acid at a maximum concentration of 24 mg/kg.
• Animal model (preclinical, Parkinson's disease model): Caffeic acid at 10 mg/kg raised motor function activity scores compared to the rotenone group and a lower-dose (2.5 mg/kg) group.
• Animal pharmacokinetics: The pharmacokinetics of caffeic acid were investigated in rabbits using three different doses: 5, 10, and 25 mg/kg.
• Dietary exposure from red wine (human bioavailability study): Five healthy male participants consumed 100, 200, and 300 mL of red wine, providing approximately 0.9, 1.8, and 2.7 mg of caffeic acid, correspondingly.

No standardized supplement dosage for caffeic acid has been established by regulatory bodies such as the NIH Office of Dietary Supplements or the European Food Safety Authority (EFSA).

8. Safety Considerations and Notable Interactions

IARC Carcinogenicity Classification

This is a critical and factual safety consideration that distinguishes caffeic acid from most other polyphenols. Caffeic acid is classified by the International Agency for Research on Cancer (IARC) as possibly carcinogenic to humans (Group 2B). This classification is based on animal evidence:

• Caffeic acid was tested for carcinogenicity by oral administration in the diet in one study in mice and one study in rats. In mice, it produced renal-cell adenomas in females and a high incidence of renal tubular-cell hyperplasia in animals of each sex. An increase in the combined incidence of squamous-cell papillomas and carcinomas of the forestomach was seen in male mice, and a high incidence of hyperplasia of the forestomach was seen in both males and females. In rats, it produced squamous-cell papillomas and carcinomas of the forestomach in animals of each sex and a few renal-cell adenomas in males.
• No data were available on the carcinogenicity of caffeic acid to humans.

Important context: the carcinogenic findings were produced at very high dietary doses. Though IARC has classified caffeic acid as a Group 2B carcinogen, coffee consumption seems generally safe within the usual levels of intake and is more likely to benefit health than to harm it. Oral administration of caffeic acid in combination with known carcinogens resulted in enhancing or inhibiting effects depending upon the carcinogen and the time of administration. Humans and experimental animals metabolize caffeic acid to the same metabolites and hydrolyse chlorogenic acid to caffeic acid.

The evidence for caffeic acid being carcinogenic mainly results from caffeic acid/copper-mediated DNA damage in vitro, caffeic acid-evoked gene mutations and chromosomal aberrations in cultured rodent cells, and caffeic acid-induced tumors in animals.

Genotoxicity

Caffeic acid did not induce micronuclei in mice treated in vivo. It produced gene mutation and chromosomal aberrations in cultured rodent cells. It did not induce gene mutation in bacteria. This mixed genotoxicity profile — positive in mammalian cells but negative in the Ames bacterial assay — contributes to the uncertainty around its safety at high doses.

Gastric and Renal Irritation

Caffeic acid can cause epithelial hyperplasia in the forestomach of rats when given 20 g/kg mixed in diet for 4 weeks. It is a GI and kidney irritant. These effects are associated with very high doses used in animal carcinogenicity studies and are not established at levels of typical dietary exposure.

Clinical Adverse Effects in Human Trials

In the phase 1 safety trial, caffeic acid did not lead to severe adverse effects; the main reported adverse effects were back pain and headache. In the multicenter ITP clinical trial, caffeic acid was effective with few and mild adverse effects.

Autoxidation and Pro-oxidant Potential

Caffeic acid is susceptible to autoxidation. Under certain conditions, particularly in the presence of transition metals such as copper and iron, caffeic acid can act as a pro-oxidant rather than an antioxidant, generating reactive quinones and oxygen species that may damage DNA and cellular components. This dual oxidant/antioxidant behavior is concentration- and context-dependent.

Interactions with Iron and Metal Chelation

Caffeic acid's catechol group confers strong metal-chelating properties, enabling it to bind iron and copper ions. This is the basis for both its antioxidant activity (by preventing Fenton-type reactions) and its potential pro-oxidant effects in metal-replete environments. In individuals with iron-deficiency anemia, high consumption of polyphenol-rich foods and beverages containing caffeic acid may theoretically reduce non-heme iron absorption, though this has not been specifically studied for isolated caffeic acid supplementation.

Anticoagulant/Antiplatelet Considerations

In vitro and in vivo experiments have demonstrated antiplatelet activity of caffeic acid. This property, while potentially beneficial in atherosclerosis prevention, could theoretically potentiate the effects of anticoagulant or antiplatelet drugs (e.g., warfarin, aspirin, clopidogrel) if caffeic acid is taken at supplemental doses. No specific human drug interaction studies have been published for isolated caffeic acid.

Long-term Safety and Translation Gaps

Despite strong preclinical support, translation to clinical practice remains limited by issues of bioavailability, metabolism, and long-term safety. Future directions should prioritize mechanistic studies, synergistic drug-combination strategies, and structure–activity relationship optimization to unlock the full therapeutic potential of caffeic acid and its derivatives.

References

• Wikipedia – Caffeic acid
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