IngredientsHederacoside C is a triterpenoid saponin with hederagenin as its aglycone part. Its formal IUPAC-derived name is 3β-[[2-O-(6-deoxy-α-L-mannopyranosyl)-α-L-arabinopyranosyl]oxy]-23-hydroxy-olean-12-en-28-oic acid, O-6-deoxy-α-L-mannopyranosyl-(1→4α)-O-β-D-glucopyranosyl-(1→6)-β-D-glucopyranosyl ester; its CAS registry number is 14216-03-6, and it bears the synonyms Hederasaponin C and Kalopanaxsaponin B. Its molecular formula is C₅₉H₉₆O₂₆, with a molecular weight of 1221.4 g/mol.
The compound is a bidesmosidic (bisglycoside) triterpenoid saponin built on an oleanane scaffold. While hederagenin provides the foundational triterpenoid scaffold, the addition of sugar moieties, as seen in Hederacoside C (HDC), significantly enhances water solubility and modulates target interactions.
Hedera helix L., commonly referred to as common ivy, is a woody species in the Araliaceae family. It is native to most of Europe and parts of western Asia, and grows as a clinging evergreen vine on tree trunks, walls, and fences in gardens, waste spaces, and wild habitats.
Hedera helix is an evergreen perennial plant that blooms from September to November in the northern hemisphere and is naturally grown or cultivated around the world. Its leaves are rich in saponins (e.g., hederacoside C) and phenolic compounds (chlorogenic acid, 3,5-caffeoylquinic acid, rutin, hyperoside, etc.) and they have medical importance.
Hederacoside C, a triterpenoid saponin found in Hedera helix, is considered the most important compound in relation to the plant's therapeutic efficacy. It is the principal and quantitatively dominant saponin among several related hederasaponins present in the leaves. The content ratios of the hederasaponins (C:B:D:E:F:G:H:I) are about 1000:70:45:10:40:15:6:5, confirming hederacoside C's position as the overwhelmingly predominant saponin. Saponins in powdered dried leaves of Hedera helix have been measured at a concentration of 21.83 mg/g for hederacoside C, 0.41 mg/g for alpha-hederin, and 0.02 mg/g for hederagenin.
Beyond Hedera helix, hederacoside C (under the synonym Kalopanaxsaponin B) has also been identified in other species of the Araliaceae family. It has been isolated from the stem bark of Kalopanax pictus.
In both traditional and commercial use, hederacoside C is not isolated as a standalone ingredient but is encountered primarily as the principal active marker compound of standardized Hedera helix leaf (herbal drug name: Hederae folium) dry and liquid extracts. Ivy leaf preparations are obtained as dry, liquid, and soft extracts by putting the plant material in a solvent (such as ethanol) to dissolve compounds and form a liquid extract; the solvent is then partially or completely evaporated to obtain a soft or dry extract.
The ethanol concentration for the extraction of the ivy leaves is 60% (m/m) in the preparation of the dry extract, while 62.4% (m/m) (= 70% V/V) for the liquid extract. On an industrial scale, hederacoside C is typically extracted from ivy leaf using a 30%–60% v/v ethanol-water mixture.
Hedera helix comes with several formulations, including tablets, liquids, and topical ointments. Pharmaceutical products containing standardized extract of ivy leaves are commonly sold over-the-counter as an expectorant for relieving respiratory tract infections. Standardization of the raw drug is governed by the European Pharmacopoeia: Hederae folium are the whole or cut, dried leaves of Hedera helix L., with a minimum content specification of 3.0% of hederacoside C (C₅₉H₉₆O₂₆; Mr 1221).
Commercial extracts are also standardized to higher hederacoside C concentrations depending on the product. For example, one standardized raw material of Hedera helix leaves is specified to contain 14.8% of hederacoside C. Another commercial extract is described as standardized to 10% hederacoside C.
Ivy (Hedera helix L.) leaves have been used in traditional medicine for centuries. Hedera helix's story in herbal lore stretches back to classical antiquity. The Greek physician Dioscorides (Materia Medica, 1st century AD) mentioned "Hedera" as a remedy for coughs and dropsy, and praised decoctions of ivy leaves for loosening phlegm.
In the past, the leaves and berries were taken orally as an expectorant to treat cough and bronchitis. In 1597, the British herbalist John Gerard recommended water infused with ivy leaves as a wash for sore or watering eyes.
Traditional healers have used ivy leaves for various complaints such as bronchitis, whooping cough, arthritis, rheumatism, and dysentery. Historically, ivy leaf extracts have been employed to treat inflammatory bronchial diseases, inflammation, burns, cough, neuralgia, and rheumatism.
In the German Commission E monograph, traditional indications include catarrh of the airways and the symptomatic treatment of chronic inflammatory bronchial diseases. In empirical medicine, uses have included irritable cough, spasmodic cough, adjuvant for pertussis, gout, rheumatism, and scrofula; externally, decoctions were used for parasite infestations such as lice and scabies, as well as for ulcers and burns.
The traditional use of Hedera helix dating back to the 19th century resulted in the whole plant and especially individual phytochemicals, in particular saponins, becoming the main topic of a good deal of research aimed at verifying its biological and pharmacological properties. By 2007, more than 80% of herbal expectorants prescribed in Germany comprised ivy extract and amounted to nearly 2 million prescriptions nationwide.
A number of triterpene saponins have been previously isolated from Hedera helix, including α-hederin, hederasaponin-C, hederacoside-E, and hederacoside-F, in addition to phenolic acids (caffeic, chlorogenic, neochlorogenic, dicaffeoyl-quinic, rosmarinic, dihydroxybenzoic, protocatechuic, and p-coumaric), and flavonoids (quercetin, kaempferol, rutin, isoquercitrin, astragalin, and kaempferol rutinoside).
The active constituents of H. helix include monodesmoside α-hederin, hederacoside B, hederacoside C, and hederacoside D. Hederacoside C (the main component), α-hederin, and the aglycone hederagenin are considered to be the active substances responsible for mucolytic, spasmolytic, bronchodilatory, and antibacterial effects.
A critical pharmacological relationship exists between hederacoside C and α-hederin. The mucolytic and expectorant actions of ivy are based on indirect beta-2 adrenergic effects, and these actions are due to the saponins α-hederin and hederacoside C, the latter of which is metabolized to α-hederin when ingested.
Through the drying process, the saponin α-hederin can form from hederacoside C. By hydrolytic cleavage the saponin glycosides are transformed into the aglycone hederagenin, as well as the toxic (haemolytic) alpha-hederin and beta-hederin.
Hederacoside C is classified as a bisdesmosidic triterpenoid saponin of the oleanane type. The aglycone core, hederagenin, is a pentacyclic triterpenoid bearing a carboxylic acid group at C-28 and hydroxyl groups at C-3 and C-23. While hederagenin provides the foundational triterpenoid scaffold, the addition of sugar moieties, as seen in Hederacoside C (HDC), significantly enhances water solubility and modulates target interactions, improving its efficacy against conditions like osteoarthritis and acute inflammation.
The most extensively investigated mechanism of action pertains to the respiratory system and involves the conversion of hederacoside C to α-hederin in vivo. Mucolytic and expectorant action is based on indirect beta-2 adrenergic effects; this action is a result of saponins alpha-hederin and hederacoside C, the latter of which is metabolized to alpha-hederin when ingested. Alpha-hederin inhibits the intracellular uptake of beta-2 receptors and leads to increased beta-2 adrenergic response of the cell.
This mechanism has been characterized in detail at the molecular level. Preincubation with 1 µM α-hederin for 24 hours clearly led to an inhibition of receptor internalization even after stimulation with 1 µM terbutaline for 20 minutes. Compared to the positive control, similar intracellular vesicles were not observed in α-hederin-treated cells. Using α-hederin-pretreated alveolar type II cells (A549) this inhibition of β₂AR internalization was confirmed.
Importantly, hederacoside C itself does not directly act on β₂-adrenergic receptors. Remarkably, preincubation with hederagenin and hederacoside C, two saponins structurally related to α-hederin, did not influence this regulatory process at a concentration of 1 µM, as shown by live cell imaging studies. This finding is confirmed at the molecular level by work published in Biochemistry: structure-related saponins like hederacoside C and hederagenin did not influence either the binding behavior of β₂AR or the intracellular cAMP level.
Furthermore, testing the influence of α-hederin, hederacoside C, and hederagenin on the contraction and relaxation behaviour of isolated bovine tracheal smooth muscle strips showed that none of the tested compounds altered histamine or methacholine-induced contraction; however, the isoprenaline-induced relaxation of precontracted muscle strips was significantly enhanced when pre-treated with 1 µM of α-hederin for 18 hours. Pre-treatment with hederacoside C or hederagenin had no effect on isoprenaline-induced relaxation.
The expectorant action via a separate pathway has also been characterized: the expectorant activity of saponins in general is thought to be mediated by the gastric mucosa, with reflex stimulation of the bronchial mucous glands via parasympathetic pathways.
The spasmolytic potential of hederacoside C has been quantified relative to other ivy constituents. The antispasmodic activity of a dry extract of Hedera helix (6:1, extraction solvent 30% ethanol) standardized on papaverine (papaverine equivalent value, PE) was studied in in-vitro tests on isolated guinea pig ileum. A spasmolytic activity equivalent to that of 1 mg papaverine was exerted by 169 mg of hederacoside C, 18 mg of α-hederin, and 21 mg of their aglycone hederagenin; 7 mg of kaempferol; and 18 mg of quercetin. This demonstrates that hederacoside C is substantially less potent as a spasmolytic agent than the co-occurring α-hederin, reinforcing its role as a prodrug precursor rather than a primary directly acting agent.
The anti-inflammatory potential of the hederagenin family is robust, primarily attributed to its capacity to suppress master inflammatory regulators like NF-κB and MAPKs, which are foundational signaling cascades known to modulate inflammatory responses and drive the pathogenesis of various inflammatory diseases. Hederacoside C mediates inflammation by inhibiting activation of MAPK/NF-κB and its downstream signaling pathway, and has anti-inflammatory and antibacterial activity.
In LPS-stimulated macrophage models, hederacoside C reduces TNF-alpha, IL-1beta, IL-6, COX-2, and nitric oxide synthase (NOS) levels in a concentration-dependent manner and IL-1 receptor-associated kinase-1 (IRAK1) activity in isolated mouse peritoneal macrophages stimulated by LPS when used at concentrations ranging from 5 to 10 µM.
Hederacoside C is also an inhibitor of acetylcholinesterase (AChE), with an IC₅₀ of 31.3 µM.
Thanks to the well-studied status of ivy and the positive assessment of the European Committee on Herbal Medicinal Products, ivy extracts can be used as an active pharmaceutical ingredient in medicinal products in the category "well-established use" in Europe. The HMPC concluded that ivy leaf preparations can be used as an expectorant for productive (chesty) coughs. Ivy leaf medicines should only be used in adults, adolescents, and children from the age of 2 years.
As a medicinal plant, H. helix has been approved by the German Commission E due to its antispasmodic, spasmolytic, antimicrobial, anti-inflammatory, anthelmintic, antioxidative, antitumor, and antileishmanial activities.
The clinical evidence base for ivy leaf preparations (standardized to hederacoside C) has been evaluated in two major systematic reviews.
An initial 2011 systematic review (NCBI Bookshelf / DARE) identified ten eligible studies reporting on 17,463 subjects. Studies were heterogeneous in design and conduct; 2 were RCTs. Three studies evaluated a combination of ivy and thyme, while 7 studies investigated monopreparations of ivy. Only one RCT (n = 360) investigating an ivy/thyme combination used a placebo control and showed statistically significant superiority in reducing the frequency and duration of cough. The 2011 review concluded that evidence was inconclusive due to lack of methodologically robust data.
An updated systematic review published in 2021 in the European Journal of Clinical Pharmacology (PMC8275562) searched MEDLINE, EMBASE, the Cochrane Library, and clinical trial registries from December 2009 to January 2020. Randomized controlled trials (RCTs), controlled clinical trials (CCTs), and observational studies (OSs) investigating ivy leaf mono- or combination preparations were included; in total, six RCTs, 1 CCT, and 4 OSs were identified. All studies concluded that ivy leaf extract is an effective and safe option for the treatment of cough due to URTIs and bronchitis, and three RCTs reported a more rapid reduction in cough severity and/or frequency under ivy leaf treatment.
However, the reviewers also stated that the clinical significance of these effects appears to be minimal. No serious adverse effects were reported. The overall quality of reporting was low and the risk of bias was high.
Two double-blinded RCTs compared an ivy mono-preparation to placebo in 390 adults over 7 days. Cough severity was measured by the Bronchitis Severity Scale (BSS) and Visual Analog Scale (VAS) and cough frequency by the Verbal Category Descriptive (VCD) scale. Statistically significant differences in BSS, VAS, and VCD improvement favoring ivy treatment were reported by treatment day 3.
A prospective, open, non-interventional study conducted at 25 medical practices throughout Switzerland compared ivy leaf cough syrup (EA 575®) to acetylcysteine (ACC). The study was intended to gain further data on the application of a cough syrup containing ivy leaf extract EA 575® by evaluating its efficacy and safety in children and adults with symptoms of acute bronchitis. The study showed that both preparations are effective and safe in the treatment of bronchitis, and the EA 575® preparation showed to be effective in children and adults independent of the indication or concomitant disease, and can therefore be used as an alternative to the synthetic ACC preparation.
Extract from ivy leaf at 50 mg/kg body weight dose-dependently inhibited bronchoconstriction induced by inhalation of ovalbumin (57% inhibition, p = 0.01) or platelet activating factor (43% inhibition, p = 0.03). This is preclinical (animal) data and does not directly constitute clinical proof of efficacy.
The respiratory evidence base for hederacoside C-containing ivy preparations is moderate. Multiple RCTs and observational studies support efficacy and safety for acute productive cough; however, systematic reviewers consistently note that study quality is variable, risk of bias is high, and the clinical magnitude of benefit is modest. The EMA/HMPC classification of "well-established use" is the most authoritative regulatory endorsement available.
Preclinical evidence indicates that hederacoside C may have protective effects in inflammatory bowel conditions. In a study published in Acta Pharmacologica Sinica (2023), in the context of inflammatory bowel disease, hederacoside C was found to ameliorate colitis not just by inhibiting cytokines, but also by downregulating S100A9, a key protein in neutrophil degranulation, thereby helping to repair the intestinal barrier.
Animal model data showed that hederacoside C (0.625, 1.25, and 2.5 mg/kg, intraperitoneally injected for 7 consecutive days) can alleviate TNBS-induced enteritis. This evidence is preclinical (animal and in vitro only); no human clinical trials specifically investigating hederacoside C in inflammatory bowel disease have been identified in the literature.
Preclinical in vitro research has examined hederacoside C's potential in cartilage and joint disease. Hederacoside C (HDC), a natural compound extracted from the leaves of Hedera helix with inflammation modulatory properties, was investigated for its latent mechanism in alleviating osteoarthritis in vitro. The results showed that HDC pretreatment suppressed the advanced glycation end-products (AGEs)-induced over-regulation of reactive oxygen species (ROS) level and inflammatory factors. HDC also downregulated the degradation of extracellular matrix (ECM) induced by AGEs. Mechanistically, HDC suppressed the NF-κB signaling pathway in chondrocytes. This study indicated HDC may be a new potential therapeutic option in osteoarthritis.
This evidence is entirely preclinical and has not been validated in human trials.
Hederacoside C has been studied in animal and cell models of bacterial infection. Hederacoside C (5, 10, 50 mg/kg, intraperitoneally injected for 3 consecutive times for 8 hours) can attenuate the breast lesions caused by Staphylococcus aureus. Mechanistically, results of ELISA, western blot, and qRT-PCR indicated that HDC significantly inhibited the expressions of IL-6, IL-1β, and TNF-α and enhanced IL-10 by downregulating and upregulating their relevant genes, respectively, in a model of Staphylococcus aureus-induced mastitis. All existing antibacterial evidence is preclinical.
Hederacoside C (0.02 mg/kg) reduces carrageenan-induced hind paw edema by 37% compared to vehicle control in a rat model of acute inflammation. Hederacoside C (5 mg/kg, i.p.) reduces serum levels of TNF-alpha and IL-1beta in LPS-challenged mice by 60 and 65%, respectively.
A 2025 review in Molecules (PMC12388280) noted that a foundational study demonstrated potent inhibition of inflammatory mediators in LPS-stimulated macrophages; however, it is important to note that this in vitro model does not fully replicate the complex cellular and signaling environment of chronic inflammatory diseases like osteoarthritis, necessitating validation in more advanced models.
Hederacoside C (0.5–5 µg) inhibits mutagenicity induced by aflatoxin B1 in Salmonella typhimurium agar cultures from 21 to 67%. This is in vitro data only and its clinical relevance is unknown.
Based on available evidence, hederacoside C and its parent plant Hedera helix are associated with the following body systems and health areas:
Ivy leaf preparations are obtained as dry, liquid, and soft extracts by putting the plant material in a solvent (such as ethanol) to dissolve compounds and form a liquid extract. Hedera helix comes with several formulations including tablets, liquids, and topical ointments.
The European Pharmacopoeia specifies that Hederae folium are the whole or cut, dried leaves of Hedera helix L., with a minimum content of 3.0% of hederacoside C (C₅₉H₉₆O₂₆; Mr 1221). The EMA community herbal monograph records a daily dose of 15–40 mg of hederacoside C for the dry extract forms covered by the monograph.
In pharmacokinetic research conducted in rats, the pharmacokinetics of HDC were studied after intravenous administration of HDC (3, 12.5, and 25 mg/kg) and after oral administration of HDC, Ivy Ex., and AG NPP709 (equivalent to 12.5, 25, and 50 mg/kg HDC).
In the context of animal anti-inflammatory models: hederacoside C at 0.02 mg/kg (i.p.) was studied in carrageenan-induced hind paw edema; and at 5 mg/kg (i.p.) in LPS-challenged mice. In the colitis model, doses of 0.625, 1.25, and 2.5 mg/kg (i.p.) were used for 7 consecutive days. These are animal study doses and are not directly applicable to human use.
For commercially available cough syrups standardized to hederacoside C, one validated syrup provided 0.7 mg hederacoside C per 1 mL of syrup.
A large post-marketing observational study (Fazio et al., 2009, Phytomedicine) assessed the tolerance, safety, and efficacy of Hedera helix extract in inflammatory bronchial diseases under clinical practice conditions in a prospective, open, multicentre post-marketing study in 9,657 patients.
The most frequently reported adverse effects related to English ivy are allergy symptoms, such as allergic contact dermatitis, asthmatic bronchitis, or allergic rhinoconjunctivitis. Gardeners and those with frequent exposure to English ivy may have a high risk of sensitization and should wear appropriate protective clothing.
The most common side effects of English ivy preparations are nausea, vomiting, diarrhea, headache, contact dermatitis, hives, difficulty breathing, or agitation. No serious adverse effects were reported in the systematic review of clinical trials covering ivy leaf preparations for cough.
Contact dermatitis from direct exposure to the fresh plant is well-documented. The leaves can cause severe contact dermatitis in some people. People who have this allergy (strictly a type IV hypersensitivity) are also likely to react to carrots and other members of the Apiaceae, as they contain the same allergen, falcarinol. The raw plant contains falcarinol and related polyacetylenes that may cause contact dermatitis.
Since ivy contains small amounts of emetine, it is not recommended during pregnancy, as this specific alkaloid may increase uterine contractions. A retrospective cohort study specifically investigated the safety of English ivy (Hedera helix) leaf extract during pregnancy with specific reference to hederacoside C and effects on newborns (Alkattan et al., Daru, 2021). English ivy is not recommended in pregnant or breastfeeding women due to a lack of available scientific evidence.
The HMPC concluded that ivy leaf preparations can be used as an expectorant for productive coughs, and that ivy leaf medicines should only be used in adults, adolescents, and children from the age of 2 years.
While hederacoside C itself is the predominant and relatively less toxic form, its hydrolytic product α-hederin carries haemolytic properties. By hydrolytic cleavage the saponin glycosides are transformed into the aglycone hederagenin as well as the toxic (haemolytic) alpha-hederin and beta-hederin. The berries contain saponins that are toxic if ingested in large quantities and can cause gastrointestinal distress.
A study published in Molecules (2017) investigated time-dependent inhibition of CYP2C8 and CYP2C19 by Hedera helix extracts (Rehman et al., Molecules, 2017;22(7)), suggesting that ivy leaf preparations may interact with drugs metabolized by these cytochrome P450 enzymes. This represents a pharmacokinetically plausible interaction that has not yet been evaluated in human clinical studies.
Hederacoside C (HDC) is one of the active ingredients in Hedera helix leaf extract and AG NPP709, a new botanical drug to treat acute respiratory infection and chronic inflammatory bronchitis; however, information regarding its pharmacokinetic properties remains limited. Because the pharmacokinetics of hederacoside C is complex, the microorganisms of the colon can transform and metabolize hederacoside C. This metabolic complexity—involving both hepatic hydrolysis and intestinal microbial biotransformation to α-hederin—is a critical factor in interpreting both efficacy and safety data.
Health conditions that Hederacoside may help support.
Body systems that Hederacoside may help support.
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