Celandine

Metadata

Approved Indications

Commission E (Germany)

• Approved indication: Spastic discomfort of the gastrointestinal tract and bile ducts (“Spasmen im Bereich des Gastrointestinaltraktes und der Gallenwege”)
• Originally approved with daily doses corresponding to 12-30 mg total alkaloids calculated as chelidonine
• Following hepatotoxicity reports, the BfArM restricted the maximum daily dose to 2.5 mg total alkaloids (calculated as chelidonine) and required warning labels regarding liver injury
• Products exceeding 2.5 mg total alkaloids per daily dose were withdrawn from the German market

ESCOP

• No ESCOP monograph has been published for greater celandine

EMA/HMPC

• The HMPC conducted a full assessment of Chelidonium majus L., herba (EMA/HMPC/369801/2009)
• No EU herbal monograph was adopted — neither as “well-established use” nor as “traditional use”
• The HMPC concluded that the benefit-risk balance was negative, given the hepatotoxicity signal and the limited clinical evidence of therapeutic benefit
• A public statement was issued instead of a monograph (EMA/HMPC/743927/2010)

Agreement/Disagreement Analysis

This herb illustrates a significant divergence between historical Commission E approval and modern European regulatory assessment. Commission E approved celandine in the 1980s-1990s based on pharmacological data and traditional use, but accumulating hepatotoxicity case reports led to BfArM dose restrictions and ultimately to the EMA’s refusal to adopt a monograph. The trajectory parallels butterbur — Commission E approval followed by safety-driven regulatory reversal — though celandine’s efficacy evidence was always weaker than butterbur’s.

Conditions Treated

Primary Indications

• Biliary dyskinesia: Spastic complaints of the bile ducts with colicky upper abdominal pain
• Functional dyspepsia: Upper abdominal discomfort with sensation of fullness, bloating, nausea, and flatulence
• Spastic gastrointestinal complaints: Cramping pain in the GI tract

Secondary Indications

• Choleretic support (stimulation of bile production and flow)
• Component of multi-herb formulations for functional GI disorders (e.g., STW 5/Iberogast)

Traditional/Historical Uses

• Topical use for warts (“Warzenkraut”): The fresh yellow-orange latex (sap) has been applied topically to warts, corns, and skin conditions for centuries; this is the most persistent folk use across European traditions
• Eye conditions: The name “Chelidonium” derives from the Greek “chelidon” (swallow), based on the ancient belief — recorded by Dioscorides and Pliny — that swallows used the plant’s juice to sharpen the eyesight of their young
• Traditionally used in European folk medicine for jaundice, liver complaints, and as a purgative
• In homeopathy, Chelidonium majus is used for right-sided liver and biliary complaints (a prominent constitutional remedy)

Mechanism of Action

Isoquinoline Alkaloid Profile

Greater celandine contains over 94 identified alkaloids belonging to several structural classes. The pharmacologically most important include:

• Chelidonine (benzophenanthridine): The principal alkaloid and marker compound; exhibits papaverine-like musculotropic spasmolytic activity on smooth muscle; induces caspase-dependent apoptosis in cell lines; inhibits CYP3A4 and glutathione-S-transferase (GST)
• Sanguinarine (benzophenanthridine): Antimicrobial activity including anti-MRSA effects (MIC 1.56-3.12 mcg/mL); disrupts cytoplasmic membranes; potent inhibitor of IL-1beta secretion; pro-apoptotic
• Chelerythrine (benzophenanthridine): Protein kinase C inhibitor; time- and concentration-dependent irreversible inactivator of CYP3A4 through modification of Cysteine-239; anti-inflammatory
• Berberine (protoberberine): Stimulates biliary contraction (cholecystokinetic); anti-inflammatory; decreases TNF-alpha secretion; antimicrobial
• Coptisine (protoberberine): Competitive antagonist at smooth muscle receptors; spasmolytic; contributes to choleretic effect
• Protopine (protopine-type): Non-competitive smooth muscle antagonist; papaverine-like spasmolytic activity

Spasmolytic Mechanism

The primary pharmacological rationale for celandine’s use in biliary complaints is its spasmolytic activity, which closely resembles the musculotropic mechanism of papaverine:

• Chelidonine, protopine, and coptisine antagonize BaCl2-stimulated and carbachol-stimulated contractions of isolated guinea pig ileum
• The mechanism involves non-competitive smooth muscle relaxation independent of cholinergic receptors
• This activity is relevant to the relaxation of bile duct smooth muscle, relieving biliary spasm and facilitating bile flow

Choleretic and Cholecystokinetic Effects

• Berberine stimulates gallbladder contraction (cholecystokinetic effect)
• Celandine extracts increase bile production by approximately 20% in perfusion models
• Combined spasmolytic and choleretic actions provide the pharmacological basis for the biliary dyskinesia indication

Additional Pharmacological Activities

• Anti-inflammatory: Multiple alkaloids decrease TNF-alpha and IL-1beta in human neutrophils in a concentration-dependent manner
• MAO inhibition: Berberine, sanguinarine, and chelidonine are irreversible inhibitors of rat liver mitochondrial monoamine oxidase (serotonin and tyramine substrates)
• Antimicrobial: Sanguinarine and chelerythrine show activity against gram-positive bacteria including MRSA
• Cytotoxic/antimitotic: Chelidonine induces G2/M cell cycle arrest; sanguinarine and chelerythrine induce apoptosis in various cancer cell lines (preclinical data only)

Clinical Evidence Summary

Ritter 1993 — Functional Dyspepsia RCT

• Design: Randomized, double-blind, placebo-controlled
• Population: n = 60 patients with functional epigastric complaints
• Intervention: Greater celandine tablets (6 tablets/day; each tablet containing 66-167.2 mg dry extract; total daily dose equivalent to ~24 mg total alkaloids as chelidonine) vs. placebo for 6 weeks
• Primary outcome: Significant decrease in dyspeptic symptoms (cramp-like GI pain, sensation of fullness, bloating, nausea) in the celandine group vs. placebo
• Result: 60% of celandine patients improved or became symptom-free vs. 27% in the placebo group (physician assessment)
• Limitation: Small sample size; the alkaloid dose used (24 mg/day) substantially exceeds the current BfArM-restricted maximum of 2.5 mg/day
• Note: This trial is frequently cited in Commission E and pharmacological reviews, but the dose used is no longer considered safe

Kupke et al. 1991 — Cholagogum F Nattermann (Combination Product)

• Design: Prospective, multicenter, placebo-controlled, double-blind pilot study
• Population: n = 76 patients (39 active, 37 placebo) with upper abdominal pain due to biliary dyskinesia
• Intervention: Cholagogum F Nattermann (dried extracts of Chelidonium majus + Curcuma/turmeric) vs. placebo for 3 weeks
• Primary outcome: Reduction of colicky and dull upper abdominal pain was more rapid during the first treatment week with Cholagogum F vs. placebo
• Result: Statistically significant improvement in colicky pain; no significant difference for secondary symptoms (nausea, vomiting, meteorism)
• Limitation: Combination product — effects cannot be attributed to celandine alone; small sample size; pilot study
• PMID: 10495621 (published report by Kupke et al.)

STW 5 (Iberogast) — Indirect Evidence

• Greater celandine is one of nine herbal components in STW 5 (Iberogast), which has strong clinical evidence for functional dyspepsia and IBS from multiple RCTs
• However, STW 5-II is a related formulation that omits celandine (and two other herbs) and shows comparable efficacy, suggesting celandine may not be an essential component
• The contribution of celandine to STW 5’s overall effect cannot be isolated from the combination

Ukrain — The Cancer Controversy

• Ukrain (NSC-631570) is a semi-synthetic compound consisting of one molecule of thiophosphoric acid conjugated to three molecules of chelidonine, administered intravenously
• Seven RCTs have been published, all reporting positive results for various cancers (pancreatic, colorectal, breast)
• Systematic review (Ernst & Schmidt, 2005; PMID: 15992697): Found that all trials reported exclusively positive results, which is statistically implausible and suggests publication bias; methodological quality was poor; manufacturer involvement was present in most studies; no independent replications exist
• Conclusion: There is no solid scientific basis for the rational use of Ukrain in cancer treatment; the Ukrain literature represents a cautionary example of manufacturer-driven publication bias in alternative oncology
• Ukrain is not relevant to the oral herbal use of celandine preparations

Safety Profile

Hepatotoxicity — The Central Safety Concern

Greater celandine hepatotoxicity is the defining safety issue for this herb and has fundamentally altered its regulatory status in Europe.

Case Report Evidence

• Benninger et al. (1999): Reported 10 cases of acute hepatitis in patients taking greater celandine preparations for gastric and biliary disorders; injury ranged from mild to severe with marked cholestasis in 5 patients; no liver failure occurred. Published in Gastroenterology. PMID: 10535888
• Stickel et al. (2003): Additional case report of acute hepatitis induced by greater celandine with positive rechallenge (recurrence upon re-exposure), published in Scandinavian Journal of Gastroenterology
• Moro et al. (2009): Review of literature and report of a new case of hepatitis from greater celandine. PMID: 19397968
• Numerous additional case reports from Germany, Austria, Switzerland, Spain, and Korea have been published; notably, no cases have been reported from the United States or the Americas (LiverTox, NCBI)

BfArM Regulatory Assessment

• The German BfArM received 48 spontaneous reports of liver injury attributed to greater celandine
• 14 cases were judged well-documented; 30 were poorly documented but sufficient for assessment
• BfArM’s ad hoc causality assessment found causality probable (16 cases) or possible (6 cases) in all 22 formally assessed reports
• Regulatory action: BfArM restricted the maximum daily alkaloid dose to 2.5 mg (calculated as chelidonine), down from the originally approved 12-30 mg/day; mandatory warning labels were required; higher-dose products were withdrawn from the market

Teschke Re-Analysis (2011)

• Teschke et al. (2011) re-evaluated the same 22 BfArM spontaneous reports using the liver-specific, quantitative CIOMS/RUCAM (Roussel Uclaf Causality Assessment Method) scale. PMID: 21893153
• Results: Highly probable (n=2), probable (n=6), possible (n=10), unlikely (n=1), excluded (n=3)
• This represented a substantial downgrading from BfArM’s original assessment, with 3 cases now excluded and 1 unlikely
• Conclusion: Greater celandine hepatotoxicity exists as a distinct form of herb-induced liver injury, but due to poor data quality, the causal association is “less strong than hitherto assumed”
• Published in Regulatory Toxicology and Pharmacology

Clinical Characteristics of Liver Injury

• Pattern: Hepatocellular (resembling acute viral hepatitis on histology, with lymphocytic infiltrates and spotty necrosis)
• Latency: Typically 1-6 months (mean onset of symptoms ~30 days; mean onset of jaundice ~36 days)
• Demographics: Female predominance; average age 56 years
• Severity: Moderate to marked ALT elevations (up to ~2900 U/L reported); hyperbilirubinemia (8-12 mg/dL); marked cholestasis in some cases
• Outcome: All documented cases resolved after discontinuation, typically within 2-6 months; no fatal cases or liver transplantation have been described
• Rechallenge: Positive rechallenge (recurrence upon re-exposure) has been documented in several cases — rechallenge should be avoided
• Mechanism: Appears to be idiosyncratic (not dose-dependent); none of the individual alkaloids has been specifically identified as hepatotoxic in isolation; immunoallergic features are uncommon
• LiverTox likelihood score: B (uncommon but likely cause of clinically apparent liver injury)

EMA/HMPC Outcome

• The HMPC assessed the totality of evidence and concluded that the benefit-risk ratio of herbal products containing greater celandine is negative
• No EU herbal monograph was adopted (neither well-established use nor traditional use)
• This is one of the few herbs for which the EMA explicitly declined to issue a monograph on safety grounds

Parallel to Butterbur

The celandine hepatotoxicity story closely parallels the butterbur (Petasites hybridus) situation:

• Both herbs received Commission E approval
• Both subsequently generated hepatotoxicity signals from spontaneous reports
• Both led to BfArM regulatory intervention (market withdrawal for butterbur; dose restriction for celandine)
• Both had their causality reassessed, with some questioning the strength of the evidence
• In both cases, the EMA/HMPC declined to adopt a standard monograph
• The key difference: butterbur had strong RCT efficacy data (AAN Level A for migraine), while celandine’s clinical evidence was always limited

Contraindications

• Pre-existing liver disease: Any hepatic impairment is a contraindication given the idiosyncratic hepatotoxicity risk
• Bile duct obstruction: Choleretic activity may exacerbate mechanical obstruction; contraindicated in choledocholithiasis and biliary obstruction
• Acute cholecystitis: Stimulation of bile flow is contraindicated during acute biliary inflammation
• Pregnancy: Contraindicated (Category X); the alkaloid profile includes compounds with uterotonic and cytotoxic properties; chelidonine and protopine have been shown to affect uterine contractility in perfusion models
• Lactation: Insufficient safety data; avoid use
• Children: No data; not recommended under 12 years

Drug Interactions

• CYP3A4 substrates: Chelidonine and chelerythrine inhibit CYP3A4 in a dose-dependent manner; chelerythrine is an irreversible inactivator of CYP3A4 through covalent modification of Cysteine-239. Drugs with narrow therapeutic indices metabolized by CYP3A4 (e.g., cyclosporine, tacrolimus, certain statins, some calcium channel blockers) may have increased plasma levels
• Hepatotoxic drugs: Additive hepatotoxicity risk when combined with other potentially hepatotoxic agents (acetaminophen at high doses, methotrexate, statins, azole antifungals, isoniazid)
• Anticoagulants: No direct clinical interaction data, but the CYP3A4 inhibition potential warrants caution with drugs that rely on CYP3A4 for metabolism
• P-glycoprotein substrates: Chelidonine has been shown to modulate multidrug resistance (MDR) and inhibit P-glycoprotein activity in cancer cell lines; clinical significance is uncertain but theoretical interactions with P-gp substrates (digoxin, dabigatran) cannot be excluded
• MAO inhibitors: Celandine alkaloids inhibit monoamine oxidase; theoretical interaction with MAOIs, SSRIs, or tyramine-rich foods, though clinical significance at therapeutic herb doses is not established

Side Effects

• Common (at therapeutic doses): Mild nausea, GI discomfort
• Uncommon: Contact dermatitis from handling fresh plant material (the orange latex is irritating)
• Rare: Hepatocellular liver injury (see hepatotoxicity section above)
• Topical use: The fresh latex can cause skin irritation, burns, and allergic contact dermatitis; oral mucosal contact should be avoided

Pregnancy/Lactation

• Contraindicated in pregnancy (Category X): Chelidonine and protopine affect uterine smooth muscle contractility; the alkaloid profile includes cytotoxic compounds; no human pregnancy safety data exists
• Avoid during lactation: Alkaloid excretion into breast milk is probable but not studied; insufficient safety data

Clinical Dosage

Current Restricted Dose (Post-BfArM Intervention)

• Maximum daily dose: Preparations equivalent to 2.5 mg total alkaloids calculated as chelidonine
• This represents a substantial reduction from the originally Commission E-approved range of 12-30 mg total alkaloids/day
• At 2.5 mg/day, the clinical efficacy demonstrated in the Ritter 1993 trial (which used ~24 mg/day) cannot be expected

Historical/Traditional Doses (Pre-Restriction)

• Dried herb (infusion): 1.2-3.6 g daily
• Fluid extract (1:1, 25% ethanol): 1-2 mL, three times daily
• Dry extract (DER 4-7:1): 100-200 mg, three times daily
• Tincture (1:5, 45% ethanol): 1-2 mL, three times daily

Topical Use (Warts)

• Fresh plant latex applied directly to warts 2-3 times daily
• Traditional use; not subject to the same dose restrictions as internal use
• Avoid contact with healthy surrounding skin and mucous membranes

Key Products (Historical)

• Chelidonium-containing products (Germany): Various monoproducts formerly available at higher doses; now restricted or withdrawn
• STW 5 (Iberogast): Multi-herb combination containing celandine as one of nine components; celandine content per dose is very low; the product has an independent and extensive safety database
• Cholagogum F Nattermann: Combination of celandine + turmeric extract for biliary complaints [NEEDS-RESEARCH: current market availability]
• Ukrain (injectable): Semi-synthetic thiophosphoric acid derivative of chelidonine; not a herbal product in the traditional sense; not approved in most jurisdictions

Monitoring Recommendations

• If celandine preparations are used, baseline liver function tests (ALT, AST, bilirubin, ALP) should be obtained before starting treatment
• Repeat LFTs at 4 weeks and at any time symptoms of hepatitis develop (fatigue, nausea, dark urine, jaundice, right upper quadrant pain)
• Discontinue immediately if transaminases exceed 2x upper limit of normal
• Maximum treatment duration of 4 weeks is recommended; prolonged use increases hepatotoxicity risk

Sources

• Benninger J, Schneider HT, Schuppan D, Kirchner T, Hahn EG. Acute hepatitis induced by greater celandine (Chelidonium majus). Gastroenterology. 1999;117(5):1234-7. PMID: 10535888
• Teschke R, Glass X, Schulze J. Herbal hepatotoxicity by Greater Celandine (Chelidonium majus): causality assessment of 22 spontaneous reports. Regul Toxicol Pharmacol. 2011;61(3):282-91. PMID: 21893153
• Gilca M, Gaman L, Panait E, Stoian I, Atanasiu V. Chelidonium majus — an integrative review: traditional knowledge versus modern findings. Forsch Komplementmed. 2010;17(5):241-8. PMID: 20980763
• Zielinska S, Jezierska-Domaradzka A, Wojciak-Kosior M, et al. Greater Celandine’s Ups and Downs — 21 Centuries of Medicinal Uses of Chelidonium majus From the Viewpoint of Today’s Pharmacology. Front Pharmacol. 2018;9:299. PMID: 29623040
• Li Q, Wang M, Zhu M, et al. Alkaloids in Chelidonium majus L: a review of its phytochemistry, pharmacology and toxicology. Front Pharmacol. 2024;15:1440979. PMID: 39239653
• Marinelli E, Ferreo M, Ferrante C, et al. Hepatotoxicity induced by greater celandine (Chelidonium majus L.): a review of the literature. Eur Rev Med Pharmacol Sci. 2017;21(1 Suppl):46-52. PMID: 28379595
• Moro PA, Cassetti F, Giugliano G, et al. Hepatitis from Greater celandine (Chelidonium majus L.): Review of literature and report of a new case. J Ethnopharmacol. 2009;124(2):328-32. PMID: 19397968
• Ernst E, Schmidt K. Ukrain — a new cancer cure? A systematic review of randomised clinical trials. BMC Cancer. 2005;5:69. PMID: 15992697
• EMA/HMPC Assessment Report on Chelidonium majus L., herba (EMA/HMPC/369801/2009)
• EMA/HMPC Public Statement on Chelidonium majus L., herba (EMA/HMPC/743927/2010)
• Commission E Monograph: Chelidonii herba (Schöllkraut)
• LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Greater Celandine. NCBI Bookshelf NBK548684
• Kupke D, von Hagens H, Bulitta M, Ritter R. The effect of chelidonium- and turmeric root extract on upper abdominal pain due to functional disorders of the biliary system. Results from a placebo-controlled double-blind study. PMID: 10495621

Connections

• Related to Artichoke and Boldo as choleretic/hepatobiliary remedies in European phytotherapy; artichoke has a much more favorable safety profile and stronger evidence base for similar indications
• Compare with Milk Thistle as a hepatobiliary herb; milk thistle is hepatoprotective (silymarin) while celandine is potentially hepatotoxic — representing opposite ends of the liver safety spectrum within the same therapeutic category
• Part of the STW 5/Iberogast multi-herb combination for functional dyspepsia, where the celandine component is present at very low doses alongside eight other botanical extracts
• The hepatotoxicity regulatory trajectory closely parallels Butterbur: both received Commission E approval, generated hepatotoxicity signals, and experienced regulatory reversal — though butterbur had stronger efficacy evidence (AAN Level A for migraine)
• Compare with Wormwood as another bitter/choleretic herb with dose-dependent toxicity concerns (thujone in wormwood vs. isoquinoline alkaloids in celandine)
• The berberine alkaloid content connects celandine to Berberine-containing plants (goldenseal, Oregon grape), though celandine is not a significant clinical source of berberine