cascarósido

Cascarosides: A Comprehensive Reference

1. Identity: Botanical Source, Chemical Names, and Common Forms

Botanical Source and Nomenclature

Cascaroside is a naturally occurring compound found primarily in cascara sagrada (Rhamnus purshiana), a plant historically used by Native American tribes as a traditional remedy for digestive complaints. The plant is also known by its updated taxonomic designation Frangula purshiana. Common names include cascara, cascara buckthorn, cascara sagrada, bearberry, and, in Chinook Jargon, chittem stick and chitticum stick; the species belongs to the family Rhamnaceae and is native to western North America from southern British Columbia south to central California, and eastward to northwestern Montana.

In Spanish, cascara sagrada means "sacred bark," a designation reflecting both its ceremonial reverence and its powerful medicinal properties. The plant is a large shrub or small tree 4.5–12 m (15–39 ft) tall, with a trunk 20–50 cm in diameter. The tree is also cultivated in North America and Kenya.

Chemical Classification

The active ingredients, cascarosides A and B, belong to a group of compounds known as anthraquinone glycosides, which are credited with cascara's well-known laxative effects. Anthraquinones usually occur in plants as glycosides; for example, the sennosides from senna (Cassia species) are O-glycosides, and the aloins from Aloe are C-glycosides. The cascarosides from cascara (Rhamnus purshiana) are unusual molecules in that they are C,O-glycosides, having one glucose linked to a central anthrone via a carbon atom and a second glucose linked via oxygen.

The four primary glycosides — cascarosides A, B, C, and D — contain both O- and C-glycosidic linkages that are chemically designated as the C-10 isomers of the 8-O-beta-D-glucopyranosides of aloin and chrysophanol. Electron-impact and field desorption mass spectrometry, together with NMR and circular dichroism spectroscopy, were used to confirm that cascarosides A and B are C-10 isomers of 8-O-(β-D-glucopyranosyl) barbaloin. More specifically, cascarosides A and B are glycosides of barbaloin, while cascarosides C and D are glycosides of chrysaloin (deoxy-barbaloin).

Two additional analogous glycosides, cascarosides E and F, derived from emodin, were later isolated. Cascaroside A carries the molecular formula C₂₇H₃₂O₁₄ (PubChem CID 442727), and in the case of C-O-glycosides (cascarosides), the additional glycosidic linkage makes them more water-soluble and produces a higher pharmacological effect.

Co-occurring Constituents in the Bark

The active laxative constituents of cascara include at least 6% to 9% anthracene derivatives, which exist as normal O-glycosides and C-glycosides. A number of dianthrones are also present, including emodin, chrysophanol, and the heterodianthrones, as well as palmidin A, B, and C. The free anthraquinones are likely formed in the leaves and stored in the bark, mainly as C-glycosides, with older bark containing the highest concentration. Cascara also contains other nonlaxative compounds such as rhamnol, linoleic acid, myristic acid, syringic acid, resins, fat, starch, glucose, and malic and tannic acid.

In cascara, the phytochemical profile is marked by cascaroside A, aloin A, and aloin B, with emodin and traces of aloe-emodin. The British Pharmacopoeia (BP) and European Pharmacopoeia (EP) require the bark to contain not less than 8.0% of hydroxyanthracene glycosides, of which not less than 60% consists of cascarosides, calculated as cascaroside A.

Preparation and Forms

The bark is collected in the spring or early summer, when it easily peels from the tree. Once stripped from the tree, the bark must be aged for several months, because fresh-cut, dried bark causes vomiting and violent diarrhea. The bark should be aged for at least one year prior to use in medicinal preparations, to lose its gripping properties. The British Pharmacopoeia specifies that collection must be made at least one year before the bark is used, as fresh bark contains an emetic principle. Alternatively, the fresh bark may be artificially aged by heat or aeration.

Cascara sagrada is prepared in both liquid and solid forms. It is commonly found in teas, tinctures, capsules, and herbal laxative blends. The cascarosides have a sweet and more pleasant taste than the aloins.

2. Traditional and Historical Use

Indigenous North American Traditions

Cascara sagrada is Spanish for "sacred bark" and was used for centuries by Native Americans as a laxative. Cascara sagrada was used traditionally by Native American tribes, such as the Salish and Chinook, for its laxative, digestive, and purgative properties. They prepared it as a decoction for treating constipation and gastrointestinal discomfort.

The dried bark of cascara was used as a laxative in folk medicine by the indigenous peoples of the Pacific Northwest, and later worldwide in conventional medicines until 2002. Commercially, it is called "cascara sagrada" ('sacred bark' in Spanish), while in the local trade language Chinook Jargon it is known as "chittem bark" or "chitticum bark."

Introduction to Western Medicine

In traditional medicine, cascara was used as a laxative by American Indians and immigrants to America. R. purshiana itself was not described officially until 1805 and was not introduced into medicine until 1877. The berries of the European counterpart (European buckthorn, Rhamnus frangula) were described in the London Pharmacopoeia of 1650.

Native Americans were able to introduce European settlers to many valuable herbs, including cascara sagrada, among others such as black cohosh, echinacea, goldenseal, and slippery elm. Following its introduction to formal U.S. medicine in 1877, cascara replaced the berries of R. catharticus as the favored laxative.

Throughout the late 19th and early 20th centuries, cascara sagrada and its derivatives, including cascaroside, became accepted ingredients in over-the-counter laxative preparations in Europe and North America. It was introduced to Western medicine in the late 1800s, quickly becoming a primary botanical laxative in the U.S. Pharmacopeia and a common over-the-counter remedy for constipation through the mid-20th century. The historical interest in using cascara damaged native cascara populations during the 1900s due to overharvesting.

Traditional Preparations

Early herbalists and healers would often steep the dried bark in water to create a decoction, which was then used to relieve constipation, promote regular bowel movements, and support overall colon health. Early pharmaceutical preparations included fluid extracts. As documented in an 1878 report preserved in a PMC archive, cascara sagrado was described as "a most admirable remedy in habitual constipation, certainly superior to any article" previously used, and was prescribed as the fluid extract.

3. Key Constituents and Established Mechanisms of Action

Primary Active Constituents: The Cascarosides

The major constituents are cascarosides that stimulate the large intestine and produce a laxative effect. Cascarosides A and B are the major principles that act on the large intestine to induce peristalsis and evacuation. As prodrugs, the main compounds responsible for their laxative activity are the aglycones of the glycoside derivatives of anthracene. These glycosides function as prodrugs, which after metabolism in the colon by bacterial glycosidases create poorly absorbed compounds that have a laxative effect.

Mechanism of Action

The active laxative components in cascara are anthraquinone derivatives and their glucosides, referred to as cascarosides. They appear to act locally as an irritant to the colon, promoting peristalsis and stool evacuation. Anthraquinones also inhibit reabsorption of electrolytes and water from the colon.

More specifically, anthraglycosides produce an active secretion of water and electrolytes within the lumen of the small intestine and inhibit their absorption from the large intestine, causing an increase in bowel content volume and strengthening of intestinal dilatation pressure to stimulate peristalsis.

The mechanism of action may be by direct stimulation of peristaltic activity or possibly via irritation of the intestinal mucosa and endothelial cells. The mechanisms of action are firstly an influence on the motility of the large intestine — stimulation of peristaltic contractions and inhibition of local contractions — resulting in accelerated transit.

Cascaroside B exerts its mode of action through the stimulation of peristalsis in the colon. This activity is facilitated by the irritation of the intestinal mucosa, resulting from the biotransformation of the cascaroside into its active form by gut flora.

In anthracene laxatives, hydroxylation of C-1 and C-8 is essential for activity. Glycosylation is also important — the sugar moiety serves to transport the aglycone to the site of action in the large intestine. Aglycones are not active in animals: after ingestion they are absorbed in the stomach and never reach the colon to produce a local effect.

Defecation takes place after a delay of 8–10 hours due to the time taken for transport to the colon and metabolization into the active compound.

Pharmacokinetics

Cascarosides are largely inactive until they are metabolized by colonic bacteria, which cleave the glycosidic bonds to release the pharmacologically active aglycone (anthrone). Anthraquinones are absorbed mainly in the intestines. The absorption rates of free anthraquinones are faster than those of their conjugated glycosides because of the higher liposolubility.

The metabolic pathways of anthraquinones include hydrolysis, glycuronidation, sulfation, methylation/demethylation, hydroxylation/dehydroxylation, oxidation/reduction (hydrogenation), acetylation, and esterification by intestinal flora and liver metabolic enzymes, among which hydrolysis, glycuronidation, and sulfation are dominant. After absorption, the anthranoids are transformed mainly to their corresponding glucuronide and sulfate derivatives, which appear in urine and bile.

It is argued that therapy with anthrone C-glycosides (present in cascara) or dianthrone O-glycosides (present in senna) is preferable to therapy with anthraquinones, as the anthranoid moiety of the former seems to be substantially less readily absorbed from the gastrointestinal tract. Anthraquinones are widely distributed throughout the body, mainly in blood-flow-rich organs and tissues such as blood, intestines, stomach, liver, lung, kidney, and fat.

The laxative effect on the gut is largely a local one; systemic absorption is limited. The main excretion routes for anthraquinones are the kidney, rectum, and gallbladder.

Structure–Activity Considerations

In the case of C-O-glycosides (cascarosides), the additional glycosidic linkage makes them more water-soluble and produces a higher pharmacological effect. The glycosylated cascarosides demonstrate lower cytotoxicity compared with their aglycone counterparts. This suggests that while the core anthraquinone structure can interact with cellular components to initiate apoptosis, the addition of glucose units mitigates this effect.

4. Scientific Evidence by Area of Use

4.1 Constipation and Bowel Regularity

Constipation relief is the primary and best-documented indication for cascarosides. The evidence for the pharmacological class (anthraquinone laxatives) is well-established, though specific high-quality randomized controlled trials isolating cascarosides are limited.

Cascara sagrada is an herbal medication used for centuries as a laxative, which is now available in the United States without prescription for short-term treatment of constipation. Cascara is typically an extract from the dried, aged bark of Rhamnus purshiana, a species of buckthorn tree or shrub native to North America.

Scientific research has explored the mechanism of action of cascaroside, revealing that it stimulates peristalsis in the colon, thereby promoting bowel movements. Several small-scale clinical studies and animal trials have shown that cascaroside-containing extracts can effectively relieve constipation and support regularity. One example of early formal clinical documentation is a 1982 Italian clinical experience (Marchesi et al., G.Clin.Med. 1982) examining a preparation containing cascara sagrada and boldo in the therapy of simple constipation in the elderly.

The British Pharmacopoeia and European Pharmacopoeia acknowledge the bark's laxative efficacy, and they require the bark to contain not less than 8.0% of hydroxyanthracene glycosides, of which not less than 60% consists of cascarosides, calculated as cascaroside A, underscoring the recognition of cascarosides as the pharmacologically relevant fraction.

Evidence strength: The overall body of modern clinical evidence on cascaroside's efficacy and safety is limited. Larger, well-controlled studies are needed to confirm its benefits and clarify optimal dosing for various populations.

4.2 Colon Cleansing Prior to Procedures

Cascara-containing preparations have been studied in the context of colonoscopy preparation. A large clinical study (Fork et al., Gastrointest Radiol 1982) examined colon cleansing regimens and included cascara among the agents assessed in a series of 1,200 patients, documenting its use as a bowel-preparation agent. The specifics of outcomes are not fully publicly accessible from abstract data alone.

Cascara is used for the relief of constipation and hemorrhoids and as a rectoanal postoperative treatment.

4.3 Cancer-Related Laboratory Research (Preclinical Only)

The co-occurring compounds in the cascara bark, particularly emodin and aloe-emodin, have been the subject of preclinical oncology research. This research is not related to the cascarosides themselves as discrete molecules, but to free anthraquinone aglycones present in the same plant.

In vitro studies suggest that emodin has hepatoprotective, neuroprotective, anti-osteoporotic, and chemopreventive effects. Emodin also enhances the cytotoxic effects of some chemotherapeutic agents. However, human studies have not been conducted to confirm these effects.

In animal models, dietary aloe-emodin prevented colorectal cancer tumor development in an Apc-deficient mouse model and also reduced the number of colorectal tumors in a colitis-related colon carcinogenesis model. Emodin has been demonstrated to inhibit cancer cell proliferation, migration, and invasion, reduce cell viability, and induce cell cycle arrest and apoptosis, with some mechanisms identified including promoting reactive oxygen species production and downregulating CXCR4 and VEGFR2 expression and STAT3 activation.

Laboratory studies show some promise for cascara's use in cancer and liver disease, but human studies are needed. A component of cascara, aloe-emodin, is the main focus of this research.

Evidence strength: All oncology evidence is preclinical (in vitro or animal model). No human trials have been conducted. These findings should not be extrapolated to clinical use.

4.4 Metabolomics and Phytochemical Characterization Research

Natural products containing hydroxyanthracene derivatives (HADs) such as cascara (Rhamnus purshiana), frangula, rhubarb, and senna have long been used for their laxative properties, but also raise safety concerns due to reported genotoxic and carcinogenic potential. Most studies have focused on quantifying HADs, whereas the broader secondary metabolite landscape of these herbal drugs remains underexplored. Modern untargeted metabolomic analyses using UPLC-HRMS/MS techniques have confirmed cascaroside A as the dominant marker compound for R. purshiana, distinguishing it taxonomically and qualitatively from related species.

5. Body Systems and Health Areas

• Large Intestine (Colon): Cascarosides stimulate the large intestine, increasing intestinal motility and contractions to produce a well-documented laxative effect.
• Fluid and Electrolyte Balance: Cascara causes water and electrolytes such as sodium and potassium to be expelled with the feces. This eases bowel passage but can also lead to dangerously low potassium and sodium levels if cascara is used for prolonged periods of time.
• Liver: Cascarosides and related anthraquinones have been associated with hepatic effects, both in terms of rare hepatotoxicity (see Safety section) and — at the preclinical level only — potential hepatoprotective properties of the emodin constituent.
• Gastrointestinal Motility: Cascaroside B may also be of interest for studies focusing on gastrointestinal motility and the pharmacokinetics of glycoside-derived medications.
• Rectoanal Region: Cascara is used for the relief of constipation and hemorrhoids and as a rectoanal postoperative treatment.

6. Dosage Forms and Reported Dosages

Typical doses of cascara are 1 g of the bark, 2 to 6 mL as a fluid extract, or 100 to 300 mg of dried bark extract.

An older pharmaceutical reference source specifies: the usual dose of Cascara sagrada fluid extract is 1 mL; of aromatic fluid extract is 5 mL.

Today, cascara can be found in various dietary supplement forms including capsule, liquid extract, and powder.

With respect to age-related dosing restrictions, cascara is contraindicated in children younger than 10 years.

Regarding duration of use, cascara sagrada should be taken for constipation in the smallest possible dose and should not be taken for longer than one week. The consumption of cascara sagrada in higher doses is not recommended for more than 6 days because it has been associated with the development of hepatitis.

7. Safety Considerations and Interactions

General Safety Profile

Cascara is generally safe and well tolerated, but can cause adverse events including clinically apparent liver injury when used in high doses for longer than recommended periods. Side effects include abdominal cramping and discomfort.

Hepatotoxicity

Liver injury from long-term cascara use is rare and most cases have been self-limited and rapidly reversible upon stopping the laxative. However, severe cases with acute liver failure and development of ascites and portal hypertension have been described.

A documented case: a 48-year-old man developed jaundice 3 days after starting cascara sagrada (bilirubin 11.8 mg/dL, ALT 999 U/L, Alk P 309 U/L, ANA 1:640), developing ascites, but recovering within 3 months of stopping. Liver biopsy revealed moderate portal inflammation with eosinophils and plasma cells and mild portal-portal bridging fibrosis without cirrhosis. Bile duct proliferation and bile stasis were also noted. The patient recovered fully 3 months after discontinuation of cascara. No other cause of hepatotoxicity was identified, and a presumed diagnosis of cascara hepatotoxicity was made.

The pathogenesis of cascara hepatotoxicity is unknown, but it is assumed that anthracene glycosides are involved. The temporal association of ingestion with symptoms and liver biopsy evidence of moderate inflammation with lymphocytes, plasma cells, and eosinophils suggest an immune-mediated process.

Electrolyte Imbalance

Overdose of anthraquinone laxatives results in intestinal pain and severe diarrhea with consequent electrolyte imbalance and dehydration. The primary electrolytes of concern are potassium and sodium. Cascara causes water and electrolytes such as sodium and potassium to be expelled with the feces, which can lead to dangerously low levels if cascara is used for prolonged periods of time.

Melanosis Coli

Melanosis coli is a condition in which macrophages filled with lipofuscin-like pigment are found within the lamina propria or deeper in the wall of the colon. These macrophages may be of such numbers as to impart a brown or black color to the colonic mucosa. Melanosis coli has been associated with increased apoptosis, which is often linked to ingestion of purgatives of the anthracene group (cascara sagrada, aloe, rhubarb, senna, frangula). It is generally accepted that melanosis coli is a benign, reversible condition.

Genotoxicity and Carcinogenicity Concerns

The hydroxyanthraquinones emodin and aloe-emodin gave positive results in genotoxic assays in Salmonella typhimurium, V79-HGPRT, rat hepatocytes, and mouse fibroblasts; however, in another study, such genotoxicity was not observed. The carcinogenicity of emodin has been studied with equivocal results. Regarding cascara and colorectal cancer risk specifically, cascara use is not recommended, but it is unlikely to cause colorectal adenomas or carcinomas, and aloe-emodin and emodin have shown anticancer properties.

Cascara sagrada products are still advertised as slimming or detoxification products; however, considering the potential side effects after chronic use, the intake of this herb for these indications should be restrained. Further in-depth studies concerning the potential genotoxic effects of this bark should give more information about their potential adverse activities.

Contraindications

Cascara is contraindicated in children younger than 10 years; for ileus due to any origin; and for inflammatory diseases of the colon, including ulcerative colitis, irritable bowel syndrome (IBS), and Crohn disease. Emmenagogue and abortifacient effects have been documented. Anthranoid metabolites may also be excreted in breast milk.

Drug and Herbal Interactions

Emodin was found to be highly bound (99.6%) to serum protein, which has implications for potential protein-binding displacement interactions, though these have not been characterized clinically in specific drug-cascaroside interaction studies. Prolonged use leading to electrolyte imbalances (particularly hypokalemia) is a clinically documented concern that could potentiate the effects of cardiac glycosides and antiarrhythmic medications, though this mechanism applies to the broader class of stimulant laxatives and is not specific to cascarosides in isolation.

Regulatory Status

The Food and Drug Administration (FDA) issued a final rule stating that the stimulant laxative ingredients aloe and cascara sagrada (including casanthranol, cascara fluidextract aromatic, cascara sagrada bark, cascara sagrada extract, and cascara sagrada fluidextract) in OTC drug products are not generally recognized as safe and effective or are misbranded. This rule became effective November 5, 2002. The FDA pointed out that there is inadequate data on the toxicity of aloe and cascara sagrada. These products have not been shown to be safe and effective for their intended use.

The agency reclassified these ingredients to category II (nonmonograph) and added them to the list of stimulant laxative ingredients for which the data are inadequate to establish general recognition of safety and effectiveness. Despite regulatory scrutiny, cascara sagrada has since been reclassified by the FDA (for OTC use) due to insufficient safety data for chronic use. However, it remains widely available as an herbal supplement, often included in short-term bowel-cleansing and detox protocols.

References

• NIH LiverTox: Cascara — National Institute of Diabetes and Digestive and Kidney Diseases (NCBI Bookshelf)
• Untargeted Metabolomics for Profiling of Cascara, Senna, Rhubarb, and Frangula Metabolites — PMC/NCBI
• Cascaroside A | C27H32O14 | CID 442727 — PubChem, NIH
• Cascaroside | C27H32O14 | CID 4483732 — PubChem, NIH
• Cascara — ScienceDirect Topics Overview
• Anthraquinone Glycosides — ScienceDirect Topics Overview
• Cascarosides A and B — Journal of Pharmaceutical Sciences (ScienceDirect)
• Cascara Uses, Benefits & Dosage — Drugs.com Natural Products Database
• Cascara — Memorial Sloan Kettering Cancer Center Integrative Medicine
• FDA Final Rule: Status of Certain OTC Drug Category II and III Active Ingredients — Federal Register, May 9, 2002
• Status of Certain Additional OTC Drug Category II and III Active Ingredients. Final Rule — PubMed (Fed Regist. 2002)
• Pharmacokinetics of Anthraquinones from Medicinal Plants — PMC/NCBI
• Botanical Dietary Supplements Gone Bad — PMC/NCBI
• Is Senna Laxative Use Associated to Cathartic Colon, Genotoxicity, or Carcinogenicity? — PMC/NCBI
• Safety of Natural Anthraquinone Emodin: An Assessment in Mice — BMC Pharmacology and Toxicology (Springer)
• Cascara Sagrada-Induced Intrahepatic Cholestasis Causing Portal Hypertension: Case Report — PubMed (Am J Gastroenterol. 2000)
• Constipation and Botanical Medicines: An Overview — ResearchGate
• Frangula purshiana — Wikipedia
• Cascara Sagrada — ScienceDirect Topics (Nursing and Health Professions)
• Can Cascara Sagrada Cause Cancer? — Cancer Therapy Advisor