Celandine

Celandine (Chelidonium majus L.): A Comprehensive Reference

1. Identity and Botanical Description

1.1 Nomenclature and Taxonomy

Greater celandine (Chelidonium majus L.) is a plant species of high pharmacological interest, characterized by a predominance of isoquinoline alkaloids and complemented by emerging classes of bioactive constituents such as lignanamides and polyphenols. It belongs to the family Papaveraceae, and is classified as a short-lived hemicryptophyte. The genus name Chelidonium is monotypic — C. majus is the sole accepted species — and is placed within the subfamily Papaveroideae.

The plant is known under numerous common names across languages and cultures. In English it is most frequently called greater celandine, swallowwort, or tetterwort. In Chinese traditional medicine it is known as bai-qu-cai. It was also historically known as "Devil's Milk," due to its acrid milky juice.

Nomenclatural disambiguation: A common point of confusion is the name "celandine." In some places, "celandine" can also refer to lesser celandine (Ficaria verna), a completely different plant; this article concerns greater celandine (Chelidonium majus), the one with the orange latex. Greater celandine should not be confused with lesser celandine (Ranunculus ficaria), which is in the family Ranunculaceae, and the two plants are unrelated.

1.2 Botanical Description and Distribution

C. majus has up to a 1-metre-high stem, branched and sparsely pubescent. The alternately placed leaves are light bluish at the bottom and green at the top. The basal leaves are long-petioled, with obovated, pinnatosected leaflets with 5–7 lobed segments. The apical leaves are short-petioled, with 3-lobed leaflets. From April to October the plant produces umbellate inflorescences with 2–6 flowers, which have 4 bright yellow petals and two whitish, early-dropping sepals. The fruit is an elongated (3 cm), pod-shaped, multiseeded capsule, dehiscent with two valves. The seeds are shiny, ovate, and dark brown or black, with elaiosomes. The underground part is a short taproot with numerous and elongated lateral roots. The whole plant contains yellow to orange latex. C. majus grows in the lowlands and foothills in leafy forests, in brushwood, parks, gardens, on roadsides, and around buildings.

1.3 Plant Parts Used and Common Preparations

The aerial parts and roots of greater celandine are used in herbalism. The above-ground parts are gathered during the flowering season and dried at high temperatures. The root is harvested in autumn between August and October and dried. The fresh rhizome is also used. Preparations are made from alcoholic and hot aqueous extractions.

Common dosage forms reported in the scientific and regulatory literature include:

• Dried herb: The aerial parts are used for the treatment of dyspeptic complaints, gastrointestinal spasms, and mild gall ailments; extracts of the plant are found in commercial preparations against gastrointestinal disorders.
• Standardized extracts in capsule form: Extracts standardized to a content of 4 mg chelidonine per capsule are recommended to be taken three times per day.
• Fresh latex: The dark yellow-orange sap can be used fresh from the plant by splitting a leaf or stem, and this can be used to treat warts, verrucae, corns, and herpes, or made into an oil or balm for daily application.
• Multi-herb combination preparations: Greater celandine (Chelidonii herba) is one of the eight dried herb components of the proprietary combination product STW-5 (Iberogast), which also contains angelica roots, chamomile flowers, caraway fruit, milk thistle fruit, balm leaves, peppermint leaves, and licorice root, generated using a defined extraction method with fixed amounts of components.
• Semi-synthetic injectable derivative (Ukrain): A possible application in cancer treatment involves Ukrain, a semisynthetic Chelidonium majus derivative consisting of one molecule of thiophosphoric acid conjugated to three molecules of chelidonine.

2. Historical and Traditional Use

2.1 Ancient Greece and Rome

The plant has been used in herbal medicine since Dioscorides and Pliny the Elder's times, in the 1st century AD. As ancient as the Dioscorides era are the first records on using Chelidonium as a remedy for several sicknesses. Inspired by the "signatura rerum" (Doctrine of Signatures) principle and an apparent ancient folk tradition, various indications were given, such as anti-jaundice and cholagogue effects, pain-relieving properties, and — quite often mentioned — ophthalmological problems. Pliny the Elder mentioned it in his Naturalis Historia, while Dioscorides recommended it for treating liver disorders and jaundice in his work De Materia Medica. The Doctrine of Signatures, a historical concept suggesting that a plant's appearance indicates its healing properties, linked celandine's yellow sap to the treatment of jaundice.

2.2 Medieval Europe

In medieval herbals, celandine was often associated with magical properties, such as restoring sight or breaking prison locks. It has been listed in pharmacopeias and sold in pharmacies in parallel to the spontaneous collection by people seeking drugs against gastrointestinal disorders, cancer, infections, but especially against warts and any skin protuberances. Greater celandine was considered one of the best remedies for hepatic disorders, biliary catarrh, hepatic congestion, splenic congestion, jaundice, obstruction of the bile ducts, throbbing pain in the right hypochondrium, and pain extending beneath the right scapula. Actions on the liver were extended to bilious headaches, migraines, supraorbital neuralgia, bilious dyspepsia with headache, liver-coughs, and other gastric or intestinal disturbances due to faulty liver action.

This use for hepatic disorders was repeated in many pharmacopeias around the world throughout history. Ingestion of the herb for the liver and gallbladder remains the main indication for internal use in modern herbal medicine practice. One of the main traditional uses was to drop the juice into the eyes, combined with milk to soften the sharpness of the pure juice.

2.3 Central and Eastern European Folk Medicine

Central and Eastern European folk medicine has always used this herb extensively. In this region, the plant is known under many unique vernacular names, especially in Slavonic languages, associated or not with the old Greek relation to "chelidon" — the swallow.

In folk medicine experience in Europe, C. majus is used to treat skin diseases in many areas, such as removing warts, and it has significant effects on skin wounds, scabies, ulcers, and skin eruptions. It is a traditional folk remedy against warts in France, German-speaking countries, Hungary, and the UK.

2.4 Traditional Chinese Medicine

C. majus is widely used in traditional Chinese medicine. In traditional Chinese medicine, the plant was used to improve blood circulation. Its aerial parts are used for the treatment of dyspeptic complaints, gastrointestinal spasms, and mild gall ailments, both in traditional Chinese as well as Western herbal medicine. First recorded in the Salvation Materia Medica, Chelidonium majus L. is now included in both the European and Chinese Pharmacopoeia.

2.5 Traditional Indications Not Confirmed by Modern Research

Traditional indications that have not been confirmed by modern research include diuretic, anti-edema, expectorant and antitussive, pulmonary, and ophthalmological diseases. Such claims about Chelidonium majus have not been verified according to the modern evidence-based approach, and no data on rigorous testing toward such properties actually exist in the literature.

3. Key Constituents and Active Compounds

3.1 Isoquinoline Alkaloids (Primary Bioactive Class)

The major pharmacologically relevant components, most of which were first isolated over a century ago, are isoquinoline alkaloids — berberine, chelerythrine, chelidonine, coptisine, and sanguinarine. The most abundant specialized metabolites produced in aerial and underground parts of the plant are isoquinoline alkaloids, mostly derivatives of benzophenanthridine (chelidonine, chelerythrine, sanguinarine), protoberberine (berberine, coptisine, stylopine), and protopine (protopine, allocryptopine).

The major alkaloid subclasses and their principal representatives are:

• Benzophenanthridines: Chelidonine, sanguinarine, chelerythrine, norchelidonine, homochelidonine, hemochelidonine. The main alkaloid present in both the herb and root is coptisine.
• Protoberberines: Berberine, coptisine, stylopine. Berberine is an isoquinoline-based alkaloid found in greater celandine (Chelidonium majus), among other plants.
• Protopine alkaloids: Protopine, allocryptopine.
• Aporphine alkaloids have also been identified in the biosynthetic profile. Advances in analytical chemistry have refined our understanding of its complex alkaloid biosynthetic pathways, from shikimate precursors through multiple structural subclasses, including protoberberine, benzophenanthridine, aporphine, and protopine alkaloids.

Leaf extracts may contain up to 20 alkaloids, including benzophenanthridines, protoberberines, and hydroxycinnamic acid derivatives. More than 50 alkaloids have been isolated from this plant.

3.2 Non-Alkaloid Constituents

In addition to isoquinoline alkaloids and lignanamides, greater celandine also contains polyphenols, including chelidonic acid and ferulic acid, as well as caffeic acid derivatives. Caffeic acid derivatives, such as caffeoylmalic acid, are also present. The characteristic latex also contains proteolytic enzymes and the phytocystatin chelidostatin, a cysteine protease inhibitor.

The latex's wart-removing property is attributed to its proteolytic enzymes. Enzymes included in the latex — like extracellular peroxidases, DNases, and lectin-like-active glycoproteins — can also exhibit antimicrobial activity.

3.3 Alkaloid Content by Plant Part

Research has shown that roots contained a higher number and amounts of alkaloids in comparison to aerial parts. The biological effects of the principal constituents of the plant are different and often quite antagonistic. As their representation varies in the course of vegetation, the efficacy of summary preparations changes in dependence on the prevailing substance in the preparation.

4. Mechanisms of Action

4.1 Antispasmodic and Spasmolytic Mechanisms

The antispasmodic activity of greater celandine is primarily attributed to its alkaloid compounds, including chelidonine, berberine, and coptisine. This antispasmodic activity has been demonstrated in whole herb extracts of greater celandine, as well as individually extracted alkaloid constituents in vitro and in vivo animal studies. These alkaloids exert a muscle-relaxing effect by inhibiting the contraction of smooth muscle via inhibiting calcium influx into the muscle cells, which reduces muscle contractions and alleviates spasms.

Two ethanolic dry extracts from the herb with a defined content of chelidonine, protopine, and coptisine, and the alkaloids themselves, were studied in three different antispasmodic test models on isolated ileum of guinea-pigs. In the BaCl₂-stimulated ileum, chelidonine and protopine exhibited the known papaverine-like musculotropic action, whereas coptisine was ineffective in this model. Both extracts were active with 53.5% and 49.0% relaxation at 5 × 10⁻⁴ g/ml. The carbachol and electric-field-stimulated contractions were antagonized by all three alkaloids.

These results indicate that the anti-spasmodic effects of the herb comprise both musculotropic and neurotropic mechanisms. The specific chemical compound responsible for the antispasmodic activity of greater celandine is, however, unknown.

4.2 Choleretic and Cholecystokinetic Mechanisms

Comparison of guinea pig and rat reactions to C. majus tincture suggested a cholecystokinetic mechanism of action, attributed to the stimulation of smooth musculature by berberine. Studies using isolated rat livers indicated that, alongside the earlier-reported cholecystokinetic action, an increase of bile production also contributes to the final outcome. The activity was not very high, reaching a 20% increase by perfusion with C. majus extract. The activity of the alkaloid and polyphenol fractions separately were only about half of that, suggesting an additive action of the complex mixture of all active constituents.

4.3 Anti-Inflammatory Mechanisms

Pharmacological testing revealed that several alkaloid compounds exhibited moderate inhibitory activity against nitric oxide production in lipopolysaccharide (LPS)-stimulated BV-2 macrophage cells, suggesting notable anti-inflammatory potential. Additionally, anti-inflammatory screening of sanguinarine, chelerythrine, and a quaternary benzophenanthridine fraction was conducted in carrageenan-induced rat paw oedema assays. Sanguinarine is particularly toxic with an LD₅₀ of 18 mg per kg body weight (IP in rats).

4.4 Anticancer Mechanisms (Preclinical)

Previous research has suggested that the anti-tumor effects of C. majus extract are likely due to chelidonine, chelerythrine, sanguinarine, and berberine. Sanguinarine induces apoptosis in a variety of cancer cells but does not exert an apoptotic effect on normal cells, and hence it has the potential to be developed as an anticancer drug. A mechanism of telomerase inhibition by stabilization of telomeric G-quadruplex structures has been studied for several natural isoquinoline alkaloids including berberine, chelerythrine, chelidonine, sanguinarine, and papaverine. Strong inhibitory effects of chelerythrine, sanguinarine, and berberine on telomerase activity were observed and concluded to be most likely via substrate sequestration. These isoquinoline alkaloids exhibited strong interaction with telomeric sequence G-quadruplex, whereas chelidonine and papaverine had no significant interaction with the telomeric quadruplex, but strongly inhibited telomerase at the transcription level of hTERT.

4.5 Antimicrobial Mechanisms

Sanguinarine disrupts the cytoplasmic membrane, causing cell lysis, and is effective against MRSA, with MIC values between 3.12 μg/mL and 1.56 μg/mL. Berberine was effective against Gram-negative bacteria — Vibrio cholerae and E. coli — where it damaged bacterial fimbria, thereby inhibiting adhesion to the mucosal surface. Chelidocystatines protect the plant against pests and are among the components of the latex which presumably contribute to the removal of warts resulting from human papillomavirus infection.

5. Scientific Evidence by Area of Use

5.1 Functional Dyspepsia and Gastrointestinal Spasms

For centuries, celandine has been used to treat gastrointestinal complaints, dyspepsia, and gallbladder disease. The oral use of greater celandine as an antispasmodic is approved by the German Commission E.

The strongest clinical evidence for celandine in functional dyspepsia comes from the multi-herb product STW-5 (Iberogast), in which celandine is one of nine components. STW-5 is a fixed combination of nine herbal extracts — Iberis amara, peppermint, caraway, chamomile, licorice, lemon balm, angelica, celandine, and milk thistle — with multimodal actions including fundic relaxation/accommodation, antispasmodic effects, and sensory modulation. The usual dose is 20 drops (~1 mL) three times daily before meals.

Some research suggests that taking STW-5 (Iberogast) by mouth for 4 weeks reduces the severity of acid reflux, stomach pain, cramping, nausea, and vomiting. However, because celandine is only one of nine ingredients in this preparation, the contribution of celandine alone cannot be isolated from these results. Greater celandine was traditionally used for liver and gallbladder complaints, loss of appetite, and gastroenteritis. None of these indications is supported by direct trial evidence as a monotherapy.

No human studies have been done that substantiate the benefits of celandine alone in these conditions or define its safety, tolerability, and adverse effects.

Evidence strength: Preliminary and indirect. Evidence for gastrointestinal benefits is largely derived from animal/preclinical studies and from multi-herb combination products in which the contribution of celandine cannot be disaggregated. No adequate monotherapy randomized controlled trials (RCTs) in humans are available.

5.2 Biliary Dyskinesia and Bile Disorders

Some early research suggests that taking a specific extract containing greater celandine and turmeric (Cholagogum F Nattermann) by mouth reduces pain in patients with a bile disorder called biliary dyskinesia. This study involved a combination product, not celandine as a sole agent. The preclinical evidence for choleretic activity is noted above, with the caveat that observed effects in isolated perfused rat liver models reached only a 20% increase in bile flow.

Evidence strength: Preliminary, from combination product studies; preclinical models only for isolated plant. No high-quality human RCTs for celandine monotherapy in biliary disorders are available.

5.3 Warts and Topical Skin Conditions

Celandine is a traditional folk remedy against warts in France, German-speaking countries, Hungary, and the UK, and is used in the preparation of a range of off-the-shelf treatments for warts and skin conditions. The latex's wart-removing property is attributed to its proteolytic enzymes.

In vitro, the fresh sap and isolated alkaloid constituents have demonstrated activity against adenoviruses and herpes simplex virus type I (HSV-1), which is the virus responsible for cold sores.

In Europe, the plant was known primarily as a remedy for plantar warts (verruca) — and is still used today in various preparations for this purpose.

Evidence strength: The topical use for warts has longstanding traditional backing and some in-vitro mechanistic plausibility (proteolytic enzymes, antiviral alkaloids). However, rigorous controlled clinical trials specifically on celandine-only topical preparations for warts are lacking in the peer-reviewed literature. Anecdotal and in-vitro evidence predominates.

5.4 Anticancer Applications — Ukrain

Ukrain is an anticancer drug based on the extract of the plant Chelidonium majus L. Numerous pre-clinical and clinical investigations seem to suggest that Ukrain is pharmacologically active and clinically effective. A systematic review searched seven electronic databases for all relevant randomised clinical trials; data were extracted and validated, tabulated, and summarised narratively; methodological quality was assessed with the Jadad score. Seven trials met the inclusion criteria. Without exception, their findings suggest that Ukrain has curative effects on a range of cancers. However, the methodological quality of most studies was poor. In addition, the interpretation of several trials was impeded by other problems. The data from randomised clinical trials suggest Ukrain has potential as an anticancer drug.

Despite numerous reports on beneficial effects of Ukrain in preclinical investigations, case reports, and non-randomized as well as randomized clinical trials, up to now there is no solid scientific basis for a rational use of Ukrain in cancer treatment. The suggested selective antitumour activity of Ukrain remains controversial. Moreover, a systematic review of published clinical trial data revealed that most of the clinical data do not meet stringent criteria for randomized clinical studies, and methodological limitations — including small sample size and poor or unknown method of randomisation — actually prevent final conclusions on the putative value of Ukrain for the treatment of cancer patients.

Chelidonium is used to make Ukrain, a drug that has been promoted for the treatment of cancer and viral infections but is not known to be effective.

Evidence strength: Weak and methodologically compromised. Although individual RCTs exist, the systematic review of these seven trials identified pervasive quality problems, precluding firm clinical conclusions. Ukrain is not approved by the US FDA, EMA, or other major regulatory bodies as a cancer treatment.

5.5 Antimicrobial Activity

Chelidonium majus extracts exhibit antimicrobial activity due to the complex alkaloid composition. Research evaluated the antimicrobial potential of extracts from wild plants and in vitro cultures, as well as seven major individual alkaloids. Roots contained a higher number and amounts of alkaloids in comparison to aerial parts. All tested plant extracts manifested antimicrobial activity related to different chemical structures of the alkaloids. Chelerythrine was the most effective against P. aeruginosa (MIC at 1.9 mg/L), while sanguinarine was most effective against S. aureus (MIC at 1.9 mg/L). Strong antifungal activity was observed against C. albicans when chelerythrine, chelidonine, and aerial-part extracts were used.

8-hydroxydihydrosanguinarine and 8-hydroxydihydrochelerythrine, isolated from C. majus, have shown significant inhibition against MRSA strains, with minimal inhibitory concentrations/minimal bactericidal concentrations (MIC/MBC) of MRSA strains ranging from 0.49–15.63/1.95–62.50 μg/mL.

Evidence strength: These findings are exclusively in vitro (cell/bacterial cultures) and in vivo preclinical (animal) models. No controlled human clinical trials demonstrating antimicrobial efficacy of celandine preparations have been identified. Results should not be extrapolated to clinical utility without further evidence.

5.6 Anti-Inflammatory Activity

The major constituents of C. majus are isoquinoline alkaloids — namely chelidonine, protopine, chelerythrine, sanguinarine, berberine, and coptisine — alongside flavonoids and phenolic acids. Its crude extracts and purified compounds are involved in a wide range of biological activities, exhibiting anti-inflammatory, anti-microbial, immunomodulatory, anti-tumor, choleretic, hepatoprotective, and analgesic effects.

Evidence strength: Predominantly preclinical (in vitro and animal). No dedicated human clinical trials on celandine's anti-inflammatory effect as a primary endpoint have been identified in the peer-reviewed literature.

5.7 Sedative and Analgesic Properties

The main alkaloid from this plant, chelidonine, has antispasmodic, weak central analgesic, and papaverine-like effects. Celandine also acts as a mild sedative and has been used to treat asthma, bronchitis, and whooping cough.

Evidence strength: Mechanistic plausibility from preclinical data, with no controlled human trials identified for these specific indications.

6. Body Systems Associated with Celandine

Reported biological activities include anticancer, antioxidant, anti-inflammatory, antimicrobial, antiviral, and immunomodulatory effects. Based on the reviewed literature, the principal body systems with which celandine research has been associated are:

• Hepatobiliary system: Choleretic, cholecystokinetic, and hepatoprotective activity (preclinical); historically the primary therapeutic target area.
• Gastrointestinal system: Antispasmodic, spasmolytic, and prokinetic activity; used in functional dyspepsia and IBS.
• Integumentary system (skin): Topical wart removal, antiviral and proteolytic action via fresh latex.
• Immune and oncological system: Immunomodulatory effects (preclinical and Ukrain studies); anticancer preclinical research.
• Central nervous system: Mild sedative and analgesic properties attributed to chelidonine.
• Antimicrobial: In vitro activity against bacterial and fungal pathogens.

7. Dosage Forms and Reported Dosages

The following dosages appear specifically in referenced scientific or regulatory sources:

• Extracts standardized to a content of 4 mg chelidonine per capsule are recommended to be taken three times per day.
• For the multi-herb preparation STW-5 (Iberogast), the usual dose is 20 drops (~1 mL) three times daily before meals.
• In the Ukrain clinical trials in cancer patients, 10 mg was given intravenously every three days.
• Large oral doses can irritate the gastrointestinal tract, and excessive use for long periods should be avoided because of the risk of hepatotoxic effects, including severe hepatitis, severe cholestasis, and fibrosis.

No consensus standardized oral dosage for celandine as a monotherapy has been established through controlled clinical trials. Existing dosage recommendations reflect traditional phytotherapeutic practices and the standardized extract used in early clinical investigations rather than rigorously validated human pharmacokinetic data.

8. Safety Considerations and Interactions

8.1 Hepatotoxicity — The Primary Safety Signal

Several cases of acute cholestatic hepatitis apparently related to the use of greater celandine have been reported in the published literature. Liver injury typically arises after 1 to 6 months of use, with jaundice and moderate to marked elevations in serum aminotransferase levels. The pattern of injury is usually hepatocellular and the clinical presentation and liver histology resemble acute viral hepatitis. Immunoallergic features are uncommon, but autoantibodies may be present in low to moderate levels in many cases. The clinical syndrome rarely resembles autoimmune hepatitis and usually resolves rapidly once the botanical is discontinued.

Toxic liver injury due to greater celandine has been assumed in patients originating from various European countries. Based on regulatory and liver-unspecific ad hoc causality assessments in 22 spontaneous cases in Germany, causality levels for greater celandine were considered probable in 16 and possible in 6 cases. Upon applying the liver-specific CIOMS scale, causality for greater celandine was found highly probable in 2 cases, probable in 6, possible in 10, unlikely in 1, and excluded in 3.

Greater celandine, a potent herb often used in alternative medicine, has significant hepatotoxic potential. A mechanism for Chelidonium majus-induced hepatotoxicity has not been established.

Animal experimental studies found that the fresh plant can cause acute toxicity due to the latex. Drying of the plant considerably reduces the toxicity. The use of therapeutic doses is considered safe due to the low quantity of alkaloids in the plant preparations.

Recent reports of severe hepatotoxicity associated with the use of STW-5 (Iberogast) are possibly related to greater celandine, one of the extracts used in this formulation.

Both patients in one case series fully recovered after the withdrawal of greater celandine. These cases add to the existing database about the potential hepatotoxicity of drugs containing greater celandine and raise the question whether the approval of this drug should be re-evaluated in the light of lacking evidence for a therapeutic benefit.

8.2 Hemolytic Anemia

Hemolytic anemia has been reported after the oral use of a celandine extract; there was intravascular hemolysis, renal insufficiency, liver cytolysis, and thrombocytopenia; a direct antiglobulin test was positive.

8.3 Gastrointestinal Irritation

Large doses can irritate the gastrointestinal tract.

8.4 Toxicity of Specific Constituents

Some herbal chemicals in medicinal plants of traditional and modern medicine carry the risk of herb-induced liver injury (HILI) with a severe or potentially lethal clinical course, and the requirement of a liver transplant. A recent study suggested that human hepatocytes seemed to be more sensitive to Chelidonium extracts than canine, rat, and monkey hepatocytes. This differential sensitivity has direct implications for interpreting animal toxicology data.

8.5 Regulatory Status and Contraindications

An excessive use for long periods should be avoided because of the risk of hepatotoxic effects, including severe hepatitis, severe cholestasis, and fibrosis. Discontinuation of herbal use is mandatory at the time when herb-induced liver injury is first suspected as a diagnosis.

The sap contains protease (protein-dissolving) enzymes that destroy malignant viruses, and therefore topical application should be restricted to the affected area and not used on broken skin or wounds.

8.6 Pregnancy and Special Populations

The EMA's assessment report and the NIH LiverTox database note that no adequate safety data in pregnant women are available. Given its alkaloid content and documented hepatotoxic potential, use during pregnancy is not supported by evidence.

8.7 Drug Interactions

Sanguinarine is particularly toxic with an LD₅₀ of 18 mg per kg body weight (IP in rats). Theoretical pharmacodynamic interactions exist with hepatotoxic drugs due to the additive liver-injury potential documented in case reports. Berberine, a major constituent, is known to inhibit certain cytochrome P450 enzymes (particularly CYP3A4 and CYP2D6) in vitro — an effect documented for isolated berberine in other contexts — potentially affecting the metabolism of concomitant medications, although specific interaction studies with whole celandine preparations are not available in the reviewed literature.

References

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