IngredientsCichoric acid was first isolated and identified in 1958, while working on the leaves of chicory (Cichorium intybus L.) plants; it was identified as a phenolic compound that is a tartaric acid ester of two caffeic acids (a hydroxycinnamic acid), and was proposed to be named chicoric acid.
Other common names for chicoric acid are cichoric acid and dicaffeoyltartaric acid. Chicoric acid is a hydroxycinnamic acid, an organic compound of the phenylpropanoid class, occurring in a variety of plant species. It is a derivative of both caffeic acid and tartaric acid.
The compound's IUPAC name is (2R,3R)-2,3-bis[[(E)-3-(3,4-dihydroxyphenyl)prop-2-enoyl]oxy]butanedioic acid. It is also known as L-chicoric acid, (-)-chicoric acid, and by the CAS numbers 70831-56-0 and 6537-80-0. It has a role as a HIV-1 integrase inhibitor and a geroprotector.
Chicoric acid is widely distributed in dicotyledons of Angiospermae, namely Asteraceae, Lamiaceae, Rosaceae, Alismataceae, Cucurbitaceae, and others.
To date, plants from at least 63 genera and species have been found to contain chicoric acid. Since its first discovery in chicory, chicoric acid has been charted in many plant families, including those of seagrass, horsetail, fern, lettuce, and basil.
The most commercially and pharmacologically significant sources include:
Two genera within the Cichorioideae and Asteroideae sub-families of the Asteraceae are well-known for their chicoric acid production (e.g., Cichorium, Echinacea), yet chicoric acid has not been detected in other genera within these plant sub-families.
Cichoric acid is encountered in commerce primarily as a constituent of plant-derived preparations rather than as a pure isolated compound. The aerial parts of Echinacea purpurea contain alkylamides (isobutylamides), caffeic acid derivatives (mostly cichoric acid and caftaric acid), flavonoids, and polysaccharides. Roots also contain caffeic acid derivatives (cichoric acid and caftaric acid) and alkylamides.
As a suitable marker for the distinction of Echinacea species, it is often assayed using RP-HPLC and thin layer chromatography (TLC) methods. Current quality standard monographs in the USP for E. purpurea aerial parts and roots provide a TLC identification method, with the presence of cichoric acid and the absence of echinacoside as indicators.
Cichoric acid-containing preparations include: dried plant material (aerial parts, roots), standardized liquid and solid extracts of E. purpurea, tinctures, capsules, tablets, and pressed juice preparations. In experimental settings, CA has been formulated into a metered dose inhaler (MDI), allowing the drug to target the site of action for respiratory applications.
Echinacea was first widely used by several North American Indian tribes against various conditions such as wounds, burns, insect bites, headaches, stomach cramps, coughs, and measles. Echinacea was used by many different Native American tribes, including the Cheyenne, Choctaw, Dakota, Delaware, Fox, Kiowa, Ponca, Sioux, and Winnebago. They applied it to wounds to promote healing and prevent infection, thanks to its antimicrobial qualities, and valued it for its ability to bolster the immune system, helping to ward off colds, flu, and other respiratory ailments.
By 1921, Echinacea — specifically the root of E. angustifolia — was by far the most popular treatment prescribed by Eclectic physicians. The Eclectics used Echinacea for about 50 years, which is a relatively short time in the context of traditional use.
Cichorium originated in ancient Rome and Greece and was distributed in the Mediterranean and Southwest Asia. Of the eight total species, three exist in China. C. intybus, a perennial herb of Cichorium, was cultivated as a high-grade vegetable in the 19th century, and can be cooked into lettuce and used for health care.
Chicoric acid has been widely used in medicines, nutritional supplements, and health foods due to its promising pharmacological effects in regulating glucose and lipid metabolism; anti-inflammatory, antioxidant, and anti-aging properties, and against digestive system diseases.
Though chicoric acid was first identified in 1958, it was largely ignored until recent popular media coverage cited potential health-beneficial properties from consuming food and dietary supplements containing this compound. Echinacea purpurea (L.) Moench, the main plant material of chicoric acid, has a 400-year history of use in Europe and America.
It is important to distinguish historical use of the whole plant (notably Echinacea and chicory) from scientific evidence attributing specific effects to cichoric acid as an isolated compound. Traditional preparation and use predate the isolation of cichoric acid; attribution of traditional therapeutic activity specifically to cichoric acid is a retrospective chemical interpretation.
The most important substances in the immunostimulating activity of E. purpurea include polysaccharides, caffeic acid derivatives (cichoric acid), alkamides, and glycoproteins. It is not yet fully clear which individual substances are primarily responsible for activity.
Cichoric acid was originally isolated from E. purpurea and is found in much higher concentrations in this species compared with E. angustifolia and E. pallida. However, E. angustifolia and E. pallida have higher amounts of other types of caffeic acid derivatives. These differences are not thought to have much clinical significance; rather, they may prove valuable in quick chemical differentiation of species.
The cichoric acid content of Echinacea purpurea cultivated in Iran is approximately 1.50 ± 0.65% (w/w), which is comparable with cichoric acid content in native plants. The amount of chicoric acid differs significantly in different regions and in different areas of the same plant.
Cichoric acid (CA) is one of the polyphenol compounds with strong antioxidant capacities. It also exhibits free radical scavenger properties, antiviral and phagocyte promoting activity, and anti-inflammatory, antiatherosclerotic, and antidiabetic properties. The antioxidant activity of CA was found to be comparable with that of rosmarinic acid.
Cichoric acid isolated from Echinacea purpurea activated phagocytic cells both in vitro and in vivo. CA has immunostimulatory properties, promoting phagocyte activity in vitro and in vivo.
Literature data indicate its immunostimulatory and antiviral activity, and the capacity of stimulating the effect of phagocytosis in vitro and in vivo. In addition, CA inhibits hyaluronidase activity, which is a key enzyme in the course of bacterial infection.
The human immunodeficiency virus (HIV) integrase (IN) must covalently join the viral cDNA into a host chromosome for productive HIV infection. L-chicoric acid (L-CA) is a potent inhibitor of IN in vitro and inhibits integration and entry. Using recombinant HIV IN, steady-state kinetic analyses with L-CA were consistent with a noncompetitive or irreversible mechanism of inhibition.
Using recombinant HIV IN, steady-state kinetic analyses with L-CA were consistent with a noncompetitive or irreversible mechanism of inhibition. These data demonstrate that L-CA is a noncompetitive but reversible inhibitor of IN in vitro and of HIV integration in vivo.
CA stimulated glucosamine-mediated glucose uptake by stimulating translocation of the glucose transporter 2. Moreover, the production of reactive oxygen species, the expression of COX-2 and iNOS, and the mRNA levels of TNF-α and IL-6 were attenuated. Furthermore, CA was verified to promote glucose uptake and inhibit inflammation through PI3K/Akt, NF-κB, and MAPK signaling pathways in HepG2 cells.
CA protects against IL-1β-induced inflammatory responses and cartilage degradation in chondrocytes. In this study, CA blocked the formation of inflammatory intermediates and decreased the activity of cartilage matrix catabolic enzymes like ADAMTS5 and MMPs. The degradation of collagen-II and aggrecan in chondrocytes induced by IL-1β, NF-κB activity, and the activation of the JNK pathway were also prevented by CA.
One study reported that chicoric acid promoted glucose uptake in L6 muscle cells. More recently, another study revealed that chicoric acid regulated glucose homeostasis, stimulated the AMPKα pathway, and reversed insulin resistance in HepG2 cells.
Cichoric acid, a plant-based nutraceutical extracted from Echinacea purpurea and other edible plants and vegetables, exhibits multiple biological functions, including antioxidant and hypoglycemic effects.
Chicoric acid, through potent binding at the allosteric site, has been shown to inhibit allosterically protein tyrosine phosphatase PTP1B. PTP1B is a known negative regulator of insulin receptor signaling, and its inhibition is considered a validated target for insulin sensitization in type 2 diabetes research.
The activity of CA against herpes simplex virus has been demonstrated. CA has been evaluated for hepatoprotective and anti-hepatitis B virus properties from Cichorium intybus leaves in cell culture (Biol Pharm Bull, 2014).
Chicoric acid is purportedly one of the numerous active ingredients (alongside alkamides, other caffeic acid derivatives, polysaccharides, and glycoproteins) associated with human health benefits from E. purpurea dietary supplements.
Cichoric acid, polysaccharides, and alkylamides are potentially effective in stimulating an in vivo, non-specific immune response in normal rats, and cichoric acid (at doses of 30 or 100 mg/kg daily for a period in mice) increased the resistance of splenic lymphocytes to apoptosis.
Evidence strength: Immunostimulatory effects of cichoric acid have been demonstrated in vitro and in rodent models. No standalone human randomized controlled trials (RCTs) have been identified specifically testing isolated cichoric acid in human subjects for immune endpoints; most clinical data arise from studies on whole Echinacea preparations where cichoric acid is one component among many. Despite some studies demonstrating benefits no better than that of placebo, Echinacea dietary supplements remain popular, generating $100–200 million in annual sales in the US from 2000 to 2006.
In streptozotocin-induced diabetic C57BL/6J mice and glucosamine-induced HepG2 cells, CA (60 mg kg⁻¹ d⁻¹ in drinking water for 4 weeks) inhibited hepatic injury and chronic inflammation in diabetic mice via antioxidant defence and regulated the balance of gluconeogenesis and glycolysis. CA (100 μM) regulated glucose metabolism and activated antioxidant response in glucosamine-induced HepG2 cells.
Animal diabetes models indicated that CA significantly influenced insulin sensitivity, glucose tolerance, mitochondrial function, and hyperglycemia in obese mice.
These results implied that CA could increase glucose uptake, improve insulin resistance, and attenuate glucosamine-induced inflammation, suggesting that CA is a potential natural nutraceutical with antidiabetic properties and anti-inflammatory effects.
Evidence strength: The antidiabetic evidence for cichoric acid is currently limited to in vitro cell culture studies and animal models (rodents). Further research to fully elucidate the efficacy and safety of chicoric acid for β-cell regeneration as an antidiabetic agent is essential. No human clinical trials specifically testing isolated cichoric acid for glucose regulation have been identified in the available literature.
In 1996, researchers extracted cichoric acid-related compounds from two rare Bolivian plants used as traditional medicinal plants by the Kallawaya tribe. In cell cultures, these compounds were found to be effective HIV integrase inhibitors at low, nontoxic dosages. The researchers then manufactured a synthetic form of cichoric acid called L-cichoric acid. This synthetic form also showed integrase activity.
Cichoric acid is a caffeic acid derivative which has significant anti-respiratory syncytial virus (RSV) effect and low toxicity.
Evidence strength: All antiviral evidence for cichoric acid as an isolated compound — against HIV, HSV, RSV, and hepatitis B — derives from in vitro enzymatic assays, cell culture models, and computational/molecular docking studies. No human clinical trials have evaluated isolated cichoric acid as an antiviral agent.
The anti-proliferative activity has been shown for CA, and anti-cancer activity through inducing apoptosis of human colon cancer cells.
Cichoric acid is defined as a major constituent of Echinacea that inhibits the proliferation of human colon cancer cells in a dose- and time-dependent manner, decreases telomerase activity, and induces apoptosis in these cells.
Newly synthesized cichoric acid–metal complexes have demonstrated anticancer and antimicrobial effects, examined in seven different cell lines including MCF-7, MDA-MB-231, and ZR-75-1 breast cancer cell lines, A375 melanoma cell line, DLD-1 cell line, LN-229 cell line, and FN cell line.
Except for a few preliminary studies, no detailed study on the chemotherapeutic efficacy of chicoric acid against cancer cells has been done.
Evidence strength: All anticancer evidence is in vitro (cell lines). No animal or human clinical studies evaluating cichoric acid as an isolated anticancer agent have been identified in the available peer-reviewed literature.
As noted in the mechanistic section, cichoric acid has demonstrated inhibition of NF-κB, COX-2, iNOS, TNF-α, and IL-6 in cell culture. CA's antioxidant and anti-inflammatory activity has also been investigated using a noise-induced hearing loss model in Wistar rats; results showed its effect by decreasing NF-κB and IL-1β expression and preventing oxidative/nitrosative damage induced by noise in the cochlea.
Evidence strength: Anti-inflammatory evidence is primarily in vitro and in animal models. No human clinical trials specifically using isolated cichoric acid for inflammatory conditions have been identified.
Among the bioactive compounds studied, cichoric acid has been associated with multiple bioactivities, including antioxidant, anti-inflammatory, anti-obesity, and neuroprotective effects. These effects have been documented primarily in preclinical studies.
Evidence strength: Evidence for anti-obesity effects of isolated cichoric acid is currently limited to cell culture and animal model data. No human clinical trials have been identified.
Chicoric acid, classified as a hydroxycinnamic acid, has been documented to exhibit a range of health advantages. These include antiviral, antioxidant, anti-inflammatory, obesity-preventing, and neuroprotective effects.
Evidence strength: Neuroprotective effects of cichoric acid are derived from preclinical (in vitro and animal) research. Human clinical evidence is currently lacking.
Literature data indicate the immunostimulatory and antiviral activity of CA, and the capacity of stimulating the effect of phagocytosis in vitro and in vivo. In addition, CA inhibits hyaluronidase activity, which is a key enzyme in the course of bacterial infection.
Research has also explored CA's ability to inhibit YopH, a bacterial virulence factor tyrosine phosphatase expressed by Yersinia species, through binding at two allosteric sites. This work is preclinical.
No established human clinical dosage for isolated cichoric acid has been defined. The following doses appear in the peer-reviewed preclinical literature only:
Cichoric acid functions as a quality marker in Echinacea purpurea products. Cichoric acid is an appropriate marker of the quality of Echinacea purpurea-containing products, because it has immune stimulatory effects and is susceptible to degradation.
Cichoric acid (2R,3R-O-dicaffeoyltartaric acid) is highly susceptible to enzymatic degradation during the preparation of Echinacea purpurea products. Degradation of cichoric acid and other caffeic acid derivatives can be inhibited by antioxidants added to the extraction solvent or in buffered protein extracts saturated with nitrogen.
Inhibitor studies conducted with protein extracts prepared from dried overground parts of E. purpurea revealed that polyphenol oxidases (PPO) but not peroxidases are responsible for the oxidative degradation of exogenous and endogenous caffeic acid derivatives. Cichoric acid was found not to be stable under conditions where oxidative processes could almost be excluded. It was found that an esterase hydrolyzing the ester bonds between tartaric acid and caffeic acid is still active under PPO inhibitory conditions.
CA has low oral bioavailability and poor intestinal absorption, which limits its application. In recent years, research on CA has focused on its pharmacological action, extraction, and purification.
Although cichoric acid reveals many beneficial properties, it should be mentioned that according to the literature, bioavailability of hydroxycinnamic acids is rather low.
Researchers have explored approaches to improve bioavailability: chitosan increased the absorption of CA during a 24-hour period in rats because the relative bioavailability was 174%. Compared to CA without chitosan, the Cmax almost doubled, and the tmax was 180 minutes earlier.
Cichoric acid is a caffeic acid derivative which has significant anti-respiratory syncytial virus effect and low toxicity. There are no published human clinical trials specifically investigating the safety of isolated cichoric acid. Safety data are therefore largely extrapolated from studies on whole Echinacea purpurea preparations and from preclinical models.
Safety is generally assumed from the lack of endemic adverse effects with widespread use of Echinacea. Hypersensitivity has been observed in a few individuals. Evidence for induction and inhibition of metabolic enzymes and transporters suggests potential drug interactions.
Echinacea use should be avoided in individuals with known hypersensitivity to plants of the Asteraceae/Compositae family. Echinacea is also contraindicated in individuals with autoimmune disease, rheumatoid arthritis, systemic lupus erythematosus, leukosis, multiple sclerosis, tuberculosis, and HIV infection.
Echinacea preparations are contraindicated in transplant patients taking immunosuppressants and those with a known allergy to the Asteraceae family. There is conflicting information regarding their use in autoimmune conditions.
Information regarding safety and efficacy in pregnancy and lactation is lacking. Limited clinical evidence, expert opinion, and long-term traditional use suggest that oral Echinacea is safe during pregnancy at typical dosages. Echinacea should be used with caution during lactation.
Specific case reports of interactions are limited, with one report describing an interaction with etoposide. Evidence for induction and inhibition of metabolic enzymes and transporters suggests potential drug interactions for Echinacea preparations broadly, which may include cichoric acid as a constituent.
Because cichoric acid is unstable during processing, the labeled content of Echinacea preparations may not always reflect actual cichoric acid content. The compound is used as a processing quality indicator. This has implications for both efficacy and reproducibility of biological effects observed in research.
An increasing number of publications have reported the beneficial effects of chicoric acid in cell culture and animal studies. However, the field faces significant translational challenges:
Health conditions that Cichoric acid may help support.
Body systems that Cichoric acid may help support.
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