Frangula (Frangula alnus / Rhamnus frangula): A Comprehensive Reference
1. Identity and Botanical Description
1.1 Nomenclature and Taxonomy
Frangula alnus Mill., commonly known as alder buckthorn, glossy buckthorn, or breaking buckthorn, is a tall deciduous shrub in the family Rhamnaceae. The plant carries two widely used scientific names that are treated as synonyms across regulatory and pharmacopoeial literature: the herbal drug, by definition, consists of the dried, whole or fragmented bark of the stems and branches of Rhamnus frangula L. (Frangula alnus Miller). Unlike other "buckthorns," alder buckthorn does not have thorns. Additional vernacular names include black alder, alder dogwood, and glossy buckthorn.
It is native to Europe, northernmost Africa, and western Asia, from Ireland and Great Britain north to the 68th parallel in Scandinavia, east to central Siberia and Xinjiang in western China, and south to northern Morocco, Turkey, and the Alborz in Iran and the Caucasus Mountains. It is also introduced and naturalised in eastern North America.
1.2 Botanical Description
Alder buckthorn is a non-spiny deciduous shrub, growing to 3–6 m (10–20 ft), occasionally to 7 m (23 ft) tall. The shrub grows in western Asia, Europe, and northernmost Africa; its bark is dark, with a bright lemon-yellow inner bark, and is the main economic part of the plant. Leaves are alternate and have smooth wavy edges; flowers are produced from May to June and are hermaphrodite and pollinated by insects; small black fruits containing seeds ripen from September to November.
1.3 The Medicinal Part
The part used medicinally is the dried bark collected from the young trunk and moderately-sized branches in early summer, kept at least one year before being used. It is stripped from the branches and dried either on sunny days, out of doors, in half-shade, or by artificial heat, on shelves or trays, in a warm, well-ventilated room. The mandatory aging and drying step is pharmacologically significant: the presence of anthranols in fresh bark, potentially irritating to the intestines, makes the drying and aging process essential, during which these compounds oxidize into therapeutically active and well-tolerated anthraquinones. Dried, seasoned bark from one to two years old alone should be used, as the freshly stripped bark acts as an irritant poison on the gastro-intestinal canal.
1.4 Common Preparations and Dosage Forms
The EMA's HMPC conclusions cover frangula bark preparations obtained by drying and comminuting the bark; the dried comminuted bark may also be put in a solvent (such as ethanol) to dissolve compounds and form an extract. Herbal medicines containing these preparations are standardised based on hydroxyanthracene derivatives and are usually available as herbal tea to be drunk and in solid and liquid forms to be taken by mouth. Additional forms described in the phytotherapy literature include: herbal teas and decoctions (the most traditional and accessible form); nebulized dry extracts available in tablets or capsules, with precise dosing of active ingredients; mother tinctures (liquid alcohol-based preparations); and powders, to be taken in wafers or mixed with other vehicles.
2. Traditional and Historical Use
2.1 Europe
Frangula bark has been treasured since medieval times as a natural remedy, most notably serving as a gentle yet effective laxative. Healers and herbalists would dry and age the bark, as fresh bark can be too harsh, to harness its properties. Buckthorn bark has been used medicinally since at least the 1600s, when it was listed in the London Pharmacopeia, a primary medical reference of its era.
Although most herbs have had a wide variety of traditional uses, later refined to a single or a few proven benefits, buckthorn bark throughout its history has been consistently used to relieve one ailment: constipation and its by-products (hemorrhoids and anal irritation). Historical European texts also attributed broader "purifying" properties to frangula bark: the use of frangula bark as a laxative is mentioned in nearly all major historical references. Due to its laxative properties, the herbal substance was also used as a detoxifier for the blood and other viscera (liver, gallbladder, and spleen). In former times, such purification was often the first step to treat a variety of diseases; such a procedure is now considered obsolete.
Historical sources refer to frangula bark as a "cheap and effective laxative," and it was also indicated as effective for complaints of haemorrhoids and for liver diseases, as a decoction often together with sodium sulphate. Rarely, the external use of the fresh bark is also mentioned in older texts, though this use never became mainstream.
2.2 North America (Related Species)
The dried bark of cascara (Frangula purshiana, formerly Rhamnus purshiana), a closely related species, was used as a laxative in folk medicine by the indigenous peoples of the Pacific Northwest, and later worldwide in conventional medicine until 2002. Commercially, it is called "cascara sagrada" ('sacred bark' in Spanish), and following its introduction to formal U.S. medicine in 1877, it replaced the berries of R. catharticus as the favored laxative.
3. Key Constituents and Active Compounds
3.1 Anthraquinone Glycosides (Primary Active Constituents)
Glucofrangulin A and B are the main constituents of frangula bark with known therapeutic activity, and they belong to the anthraquinone O-glycosides. Studies with the main characteristic constituents frangula-emodin derivatives, such as glucofrangulins A and B and frangulins A, B, and C, are central to the monograph evidence base. The European Pharmacopoeia quantifies the active content of the bark with reference to glucofrangulin A (C₂₇H₃₀O₁₄; Mr 578.5). The bark (and to a lesser extent the fruit) has been used as a laxative, due to its 3–7% anthraquinone content.
The main active constituents are hydroxyanthraquinone glycosides including emodin, frangulin, iso-emodin, aloe-emodin, and chrysophanol. Emodin was subsequently named "Frangula emodin," and later "Rheum emodin," due to its occurrence in Frangula alnus (now known as Rhamnus frangula) and Rheum emodi.
3.2 Other Constituents
In addition to anthraquinones, the bark also contains naphthoquinones and traces of peptide alkaloids like frangulanin, along with bitter substances, arachidic acid, and rhamnoxanthin. Alder buckthorn is high in anthraquinone glycosides, while resins, tannins, and lipids make up the bulk of the bark's other ingredients. Polyphenolic analysis of F. alnus leaves has revealed several additional compounds including p-coumaric acid, rosmarinic acid, chlorogenic acid, ferulic acid, quercitrin, rutoside, quercetin, and trifolin.
4. Established Mechanisms of Action
4.1 Pharmacokinetic Activation
Anthraquinones such as frangula are inactive glycosides that, when ingested, pass unabsorbed and unchanged down the small intestine and are hydrolyzed by colonic bacterial glycosidases to yield active molecules. These active metabolites increase the transport of electrolytes into the colonic lumen and stimulate myenteric plexuses to increase intestinal motility. The anthraquinones typically induce defecation six to eight hours after oral dosing.
4.2 Dual Mechanism of Laxative Action
The mechanism of action is attributable to two different actions: first, there is an increase in colonic motility leading to a reduction of transit time in the colon, which is usually slowed down in patients affected by constipation. Secondly, frangula anthraquinones influence the secretion process by inhibiting the absorption of water and electrolytes in colonic epithelial cells, increasing the resistance of tight junctions, and stimulating the secretion of water and electrolytes (Na⁺ and Cl⁻) into the colon lumen.
Anthraquinone laxatives inhibit the absorption of water and sodium in the colon by inhibiting the activities of Na⁺-K⁺-ATPase of colonic epithelial cells. Another mechanism involves anthracene-induced downregulation of AQP8 expression in the colon epithelium, thus retaining water in the colonic cavity. In addition to increasing the water content of the stool to soften it, anthraquinones can directly stimulate the plexus of the colonic myenteric nerve and facilitate colon peristalsis activity.
Anthraquinone glycosides travel to the large bowel where bacterial action forms anthrone aglycones, the true active forms. The laxative effect on the gut is largely a local one; systemic absorption is limited. Two distinct mechanisms are in force: a modification of intestinal motility and an accumulation of fluid in the intestinal lumen. Experiments in animals and humans have shown that the introduction of anthrones into the colon quickly induces vigorous peristaltic movements.
5. Scientific Evidence by Area of Use
5.1 Constipation (Primary Evidence Base)
Nature and Strength of Evidence
The HMPC conclusions on the use of frangula bark medicines for occasional constipation are based on "well-established use." This means that there are bibliographic data providing scientific evidence of their effectiveness and safety when used in this way, covering a period of at least 10 years in the EU. However, this designation reflects a specific regulatory pathway, not the same level of evidence as prospective randomised controlled trials. There are no well-designed investigations available that evaluate the herbal substance alone — not in combination with other laxatives — in a representative study population. Also, there are no well-designed non-experimental descriptive studies with mono-preparations of frangula bark available. The evidence for medicinal use is obtained from pharmacological data, experts' reports and opinions, and extensive clinical experience.
Human Pharmacological Data
As reported in the EMA plant monograph, the administration in humans of an aqueous suspension containing the equivalent of 12 mg of anthraquinone derivatives (glucofrangulin and frangulin) had a laxative effect within the following 6 to 24 hours. In the literature, there are no clinical studies exclusively relating to the administration of frangula extracts but only in combination with other active ingredients.
Combination Product Studies
Fotiades et al. (1976) investigated the efficacy of Laxariston® in the treatment of constipation. Three grams of this preparation contained 0.9 g methylcellulose, 0.3 g frangula bark (13.5 mg hydroxyanthracene derivatives), 0.3 g senna leaves (7.5 mg hydroxyanthracene derivatives), 0.15 g rhubarb root (6.75 mg hydroxyanthracene derivatives), and 0.015 g Achillea extract. From the results of the study carried out on patients with arthritis, those who had undergone abdominal surgery, or those with functional constipation, the product had a very positive efficacy in 77% of patients with good tolerance. Another study evaluated the same product in 95 pregnant women suffering from constipation, with an ameliorative result in 55 women of the treated group with a low percentage of side effects. It is worth noting that 3 g of Laxariston® contained 27.75 mg hydroxyanthracene derivatives, of which nearly 50% derived from frangula bark, suggesting a substantial contribution to efficacy from this constituent.
Animal Data Supporting Laxative Use
Administration of a methanolic extract of frangula bark (17.5% anthranoid glycosides calculated as 1,8-dihydroxyanthraquinone-glycoside) in mice resulted in a dose-dependent decrease of intestinal transit time. After oral administration of 50 mg/kg body weight, defecation took place after 4 hours in 20% of the mice; after oral administration of 100 mg/kg body weight in 40% of the mice.
Overall Evidence Assessment
There are only limited clinical data available for frangula bark as a standalone preparation. The EMA concluded that short-term use in the case of occasional constipation can be regarded as safe. However, pharmacovigilance actions for anthranoid-containing laxatives must be maintained because further investigations are needed regarding the carcinogenic potential of these substances. Overall, the evidence for the laxative indication is pharmacologically plausible and supported by extensive historical use and regulatory acceptance, but robust randomised controlled trials on frangula bark as a mono-preparation are lacking.
5.2 Antibacterial and Antibiofilm Activity
Evidence here is exclusively preclinical (in vitro). Studies have revealed that bark extracts of F. alnus have strong antibacterial activities against Staphylococcus aureus. A study investigating the antibiofilm activity of F. alnus ethyl-acetate extract toward S. aureus ATCC strains and clinical isolates found, via GCxGC-MS and LC-MS/MS analysis, that the extract was rich in phenols, flavonoids, emodin, catechin, and ester 4-ethoxy benzoic acid as dominant components. Research examined the inhibitory effect of F. alnus extracts and emodin on S. aureus biofilm matrix components including exopolysaccharides and eDNA; it was demonstrated that both substances significantly reduced the production of exopolysaccharides and the amount of eDNA, and decreased the number of persister cells in the studied strains and isolates. These findings are in vitro only, and no human clinical data exist in this area.
Frangula has demonstrated antimicrobial, antifungal, and insecticidal properties, which extend its use beyond medicinal applications to agricultural practices, though again this evidence base remains preclinical.
5.3 Antiviral Activity
Preclinical data only. The constituent emodin, an anthraquinone derivative, has been shown to inhibit replication of the herpes simplex virus, an effect comparable to acyclovir in laboratory settings. Inactivation of enveloped viruses by anthraquinones extracted from plants has been reported in antimicrobial research, though translation to human clinical outcomes has not been established for frangula-derived preparations specifically.
5.4 Antioxidant Activity
F. alnus has shown strong antioxidant effects attributed to the polyphenolic composition of leaves and reduction of reactive oxygen species (ROS) accumulation. The bark extract possesses moderate antioxidant capacity (44.6%, 46.8%, and 2.25 mmol Fe²⁺/g measured by DPPH, ABTS, and FRAP assay, respectively), which can be related to relatively high phenolic content (116.07 mg/g). These findings are from in vitro assays and do not represent human clinical evidence.
5.5 Antiproliferative and Cytotoxic Activity
F. alnus leaf extracts have shown cytotoxic effects against Jurkat, MCF-7, HeLa, and HT-29 cancer cell lines using MTT and flow cytometry assays. Emodin demonstrates versatile antimicrobial functions, both in vitro and in vivo, and exhibits cytotoxicity towards various cancer cells, including breast, liver, lung, ovarian, prostate, tongue, and pancreatic cancer cells, through the induction of cell cycle arrest. In vitro experiments with various constituents of frangula bark also demonstrate platelet-inhibiting and antiproliferative effects. All of this evidence is preclinical; no human clinical trials have evaluated frangula bark preparations for cancer or antiproliferative indications.
Both the National Cancer Institute (NCI) and the National Center for Complementary and Integrative Health (NCCIH) recognise the importance of evidence-based complementary medicine modalities, but further development of emodin as an anti-cancer agent is hindered by uncertainties surrounding its potential toxicity.
5.6 Platelet Aggregation Inhibition
Reference lists associated with the EMA assessment of frangula bark include data on frangulin B as an antagonist of collagen-induced platelet aggregation and adhesion, isolated from Rhamnus formosana. This observation is in vitro only.
6. Body Systems and Health Areas Associated with Frangula
- Gastrointestinal system: The primary and best-supported indication. The bark is widely used in traditional as well as modern medicine as a laxative.
- Cardiovascular system (indirect, risk context): Hypokalemia, occurring as the effect of long-term laxative use, potentiates the action of cardiac glycosides and interacts with antiarrhythmic drugs.
- Immune / antimicrobial: Preclinical interest in antibacterial effects against staphylococcal species, particularly in the context of biofilm formation.
- Oncology (preclinical only): In vitro cytotoxic effects have been characterised for emodin and leaf polyphenols against multiple cancer cell lines; no clinical translation exists.
- Skin (historical/topical): The high levels of hydroxy-benzoic acids and flavanols in alder buckthorn bark have been considered for use against staphylococcal local infections.
7. Dosage Forms and Reported Dosages
7.1 EMA / HMPC Recommendations (Well-Established Use)
The recommended dosage as a laxative for adults, elderly, and adolescents over 12 years (20–30 mg hydroxyanthracene derivatives once daily at night) is supported by experts' opinions and by clinical investigations with other hydroxyanthracene-containing laxatives, notably preparations of senna and aloes.
The duration of use is limited to a maximum of one week (for short-term use in cases of occasional constipation) to address potential adverse effects of long-term misuse and the potential genotoxicity and carcinogenicity of anthraquinones and derivatives.
Contraindications listed in the EMA monograph include patients with known hypersensitivity to frangula, intestinal obstruction and stenosis, atony, appendicitis, inflammatory colon diseases (e.g., Crohn's disease, ulcerative colitis), abdominal pain of unknown origin, and severe dehydration states with water and electrolyte depletion.
The HMPC concluded that these frangula bark preparations can be used short-term for occasional constipation. Frangula bark medicines should only be used in adults and adolescents over the age of 12 years and should not be taken for longer than one week.
7.2 ESCOP Monograph Dosage
The ESCOP monograph "Frangulae cortex" also recommends 20–30 mg hydroxyanthracene derivatives. After consideration of the toxicological data, the patient should be informed that the correct individual dose is the smallest required to produce a comfortable soft-formed motion. It is therefore preferable to recommend a larger range of 10–30 mg hydroxyanthracene derivatives.
7.3 Traditional Preparations
For constipation, 0.5–2.5 g of alder buckthorn dried bark is taken directly in capsules or as a decoction at night. As a tincture, 0.5–2.5 ml is administered at bedtime for constipation.
Frangula bark preparations should only be used if a therapeutic effect cannot be achieved by a change of diet or the administration of bulk-forming agents (Commission E, 1993).
8. Safety Considerations and Drug Interactions
8.1 Adverse Effects of Short-Term Use
Frangula bark may produce abdominal pain and spasm and passage of liquid stools, in particular in patients with irritable colon. However, these symptoms may also occur generally as a consequence of individual overdosage, and in such cases dose reduction is necessary. Hypersensitivity reactions including pruritus, urticaria, and local or generalised exanthema may also occur.
8.2 Adverse Effects of Chronic or Excessive Use
Long-term use can result in electrolyte disturbances and in atony and dilatation of the colon. Chronic use may lead to disorders in water equilibrium and electrolyte metabolism and may result in albuminuria and haematuria. Furthermore, chronic use may cause pigmentation of the intestinal mucosa (pseudomelanosis coli).
Anthraquinones cause apoptosis of colonic epithelial cells, which are then phagocytosed by macrophages and appear as a lipofuscin-like pigment that darkens the colonic mucosa, a condition termed pseudomelanosis coli. Whether anthraquinone laxatives given over the long term cause adverse functional or structural changes in the intestine is controversial. Pseudomelanosis coli is usually found after a minimum of 9–12 months of regular stimulant laxative use. Discontinuing laxative use usually leads to the resolution of melanosis coli, and it is not associated with an increased risk of colon cancer in current evidence, although melanosis coli may be associated with a higher incidence of colonic non-adenoma polyps and low-grade adenomas; thus, follow-up colonoscopy should be considered in patients with this condition.
Chronic ingested overdoses of anthranoid-containing medicinal products may lead to toxic hepatitis.
8.3 Genotoxicity and Carcinogenicity Concerns
Several anthranoid derivatives (notably the aglycones aloe-emodin, chrysophanol, emodin, and physicon) are genotoxic in bacterial and/or mammalian test systems. The EMA's own monograph acknowledges: studies with emodin (a constituent of frangula bark preparations) revealed effects on oestrus cycle length and nephropathy in mice. Several hydroxyl anthracene derivatives were mutagenic and genotoxic in several in vitro test systems; however, this was not proven in in vivo systems. In long-term carcinogenicity studies, effects on kidneys and colon/caecum were reported.
The EFSA Panel on Food Additives and Nutrient Sources (ANS) was asked to deliver a scientific opinion on the safety of hydroxyanthracene derivatives. Hydroxyanthracene derivatives are naturally occurring in different botanical species and used in food to improve bowel function. The Panel reviewed available scientific data on genotoxic and carcinogenic effects, and noted that emodin, aloe-emodin, and the structurally related substance danthron have shown evidence of in vitro genotoxicity.
A published study investigated frangula bark extract and its active component emodin in human peripheral blood lymphocytes. Bark extract at 500 μg/ml produced cell death and DNA damage, while emodin induced cell death and DNA damage at 150 μg/ml and 200 μg/ml, respectively, and an increase of ROS was observed at 25 μg/ml. The results suggest that both the bark extract and emodin are cyto/genotoxic to human peripheral blood lymphocytes and that oxidative stress is involved in the mechanism of their toxicity. These are in vitro findings at concentrations that may not reflect typical clinical exposure.
The group of anthraquinone-containing laxatives is known to cause melanosis coli and their possible role has also been suggested in the development of colorectal adenomas and cancer. However, the overall evidence on cancer risk from clinical use remains inconclusive. The EMA has maintained pharmacovigilance requirements for this class of herbal substances.
8.4 Drug Interactions
Hypokalemia occurring as the effect of long-term laxative drug use potentiates the action of cardiac glycosides and interacts with antiarrhythmic drugs. Use with other drugs inducing hypokalemia (e.g., diuretics, adrenocorticosteroids, and licorice root) may accelerate electrolyte imbalance.
Another mechanism involved is the increase in rate of intestinal transit, resulting in a decrease of intestinally absorbed drugs. This pharmacokinetic interaction is relevant to any co-administered oral medication.
With long-term use, there is enhancement of the effect of cardiac glycosides, influence on antiarrhythmic drugs, and increase in potassium losses when combined with adrenal steroids, thiazide diuretics, and licorice root.
The WHO monograph states that F. alnus bark and other laxatives containing anthraquinone glycosides should not be used continuously for longer than 1–2 weeks, because of the possible electrolyte imbalance (hypokalaemia). Hypokalaemia could be aggravated by concomitant use of other medicinal products that induce the imbalance, such as diuretics.
8.5 Pregnancy and Lactation
The use during lactation is contraindicated because after administration of anthranoids, active metabolites such as rhein were excreted in breast milk in small amounts. The WHO recommends that use during pregnancy or lactation is contraindicated, except under medical supervision, after evaluating benefits and risks. Their use is contraindicated in children under 10 years old.
8.6 Fresh Bark Toxicity
Intoxication with fresh frangula bark causes colics, and the fresh bark specifically causes vomiting. This is mechanistically attributed to the presence of anthranols and other irritant compounds that are converted to the therapeutically active forms only through the mandatory aging and drying process.
9. Regulatory and Pharmacopoeial Status
Frangula bark is covered by European Pharmacopoeia monographs, specifically "Frangula bark" (Ph. Eur. 9:0025) and "Standardised Frangula bark dry extract" (Ph. Eur. 9:1214). The World Health Organization (WHO) has published monographs on safety, efficacy, and quality control of Aloe, Cassia, Frangula, and Cascara for their use as medicinal plants. In these monographs, it is recommended that products containing anthraquinone glycosides should not be used for longer than 1–2 weeks, due to the possible incidence of serious adverse events such as electrolyte imbalance. ESCOP has also published a full monograph ("Frangulae cortex"), and Germany's Commission E has addressed the herb within its monograph system.
In 2013, the European Food Safety Authority (EFSA) raised concerns regarding the prolonged use of hydroxyanthracene derivative-containing laxatives, highlighting the potential risks of electrolyte imbalances, bowel dysfunction, and dependence.
References
Go back