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Cascara Sagrada

Glossary, HerbsSuccess Chemistry Staff

Cascara Sagrada Rhamnus purshiana De Candolle is the largest species of


Occasionally growing up to 15 m in height;

however, it is more commonly a large shrub or small

tree (5–10 m) (1–5). Rhamnus purshiana is native to the Pacific

Northwest United States and south western Canada

(1–5). Rhamnus is the generic name for buckthorn, and

the species name, purshiana, was given in honor of the

German botanist Friedrich Pursh (4). The crude drug consists

of the dried bark of the tree, which is officially known

as Cascara or cascara sagrada, Spanish for “sacred bark”

(1–4). The dried aged bark of the tree has been used by Native

Americans for centuries as a laxative. It was accepted

into medical practice in the United States in 1877 as a commonly

used laxative and was the principal ingredient in

many over-the-counter (OTC) laxative products. Cascara

was first listed in the U.S. Pharmacopeia (USP) in 1890 as

a laxative mild enough for use in treating the elderly and

children. Products that were official in the USP included

cascara sagrada extract, fluid extract, aromatic fluid extract,

and tablets. In 2002, the U.S. Food and Drug Administration

issued a final rule concerning the status of cascara

sagrada (including casanthranol, cascara fluid extract aromatic,

cascara sagrada bark, cascara sagrada extract, and

cascara sagrada fluid extract) in OTC drug products (5).

The final rule stated that cascara sagrada in OTC drug

products is not generally recognized as safe and effective

or is misbranded (6).



General Description

The shrub or small tree of R. purshiana De Candolle has

elliptical leaves, greenish flowers, and black berries. It

ranges in height from 4.5 to 15mand has a reddish-brown

bark (4). Most of the commercial production comes from

Oregon,Washington, and southern British Columbia. The

bark is collected in spring (April/May) and early summer

by stripping from wild trees scattered throughout the

native forests. It is removed by making longitudinal incisions

and peeling off sections, which tend to roll into large

quills. Trees are also felled and the bark is removed from

the larger branches. The bark is then air dried, with the

inner surface protected from the sun in order to preserve

its yellow color. The dried bark is allowed to mature for

1 or 2 years before use in commercial preparations (4). The

fresh bark contains chemical constituents that act as a gastrointestinal

(GI) irritant and emetic; thus, the bark must

be aged for at least 1 year prior to human use. Cascara

bark and its preparations have been used for centuries by

the Pacific Northwest Native Americans, as well as the

European settlers, and cascara preparations are now used

worldwide as a laxative (5).

Commercial preparations of cascara (Cortex Rhamni

Purshianae) consist of the dried, whole, or fragmented

bark of R. purshiana. The bark and its preparations are

official in the pharmacopoeias of many countries (1,7–9).

Cascara was first listed in the USP in 1890 as a laxative.

The official listing of cascara in USP 25 (9) defined it as

the dried bark (at least 1-year old) of R. purshiana, yielding

not less than 7% of total hydroxyanthracene derivatives

calculated as cascaroside A on a dried basis. Not less than

60% of the total hydroxyanthracene derivatives consist of

cascarosides, calculated as cascaroside A (9).



The chemistry of cascara has been extensively investigated

and numerous quinoid constituents are reported

to be present in the bark (1). Much of the chemical and

pharmacological research on cascara was performed over

50 years ago, and anthraquinone glycosides were established

as the active constituents of the bark (5). Hydroxyanthracene

glycosides make up 6% to 9% of the bark,

of which 70% to 90% is C-10 glycosides, with aloins A

and B and desoxy aloins A and B (= chrysalis) accounting

for 10% to 30% (1). The cascarosides A and B and

cascarosides C and D are diastereoisomeric pairs derived

from 8--O-glucosides of aloin A and B and 8-O-glucosyl-

11-deoxy loin, respectively, and constitute 60% to 70%

of the total glycosides (1). Hydrolysis of the cascarosides

cleaves the O-glycosidic bonds to yield aloins (barbaloin

and chrysaloin). The cascarosides are not bitter, whereas

most of their hydrolysis products (the aloins) are very

bitter. Both the USP and the European Pharmacopoeia

recognize the cascarosides and aloins as the active constituents

of cascara and have chemical assay procedures

for determining these glycosides (7–9).

Other major hydroxyanthracene glycosides include

the hydroxy anthraquinones chrysophanol-8-O-glucoside

and aloe-emodin-8-O-glucoside at a concentration of 10%

to 20% (10). In the fresh bark, anthraquinones are present

in the reduced form and are converted by oxidation to their

corresponding parent anthraquinone glycosides during

drying and storage (3).

Dosage Forms and Dose

Cascara sagrada is available as extracts, fluidextracts, and

tablets (9).

Cascara Sagrada

one-half dose in the morning and at bedtime) of standardized

preparations is 20 to 30 mg of hydroxyanthracene

derivatives calculated as cascaroside A (dried aged bark,

0.25–1 g) (1). Do not exceed the recommended dose and do

not use this dose for more than 1 to 2 weeks continuously.




While there are no specific data describing the carcinogenicity

or mutagenicity for cascara sagrada, there are

data available for emodin, one of the naturally occurring

anthraquinones present in cascara (11–18). There are

several studies reporting genotoxic and mutagenic effects

both in vitro and in vivo for emodin and its derivatives,

causing them to be classified as potential carcinogens (12–

18). In vitro, the toxicity of 1,8-dihydroxyanthraquinone,

such as emodin, may involve redox cycling between the

quinone and the semiquinone radical generating reactive

oxygen species (ROS), resulting in lipid peroxidation, protein

damage, and DNA oxidation (16,19,20). For example,

treatment of Reuber hepatoma and fibroblast Balb/3T3

cells with various anthraquinones resulted in the formation

of 8-oxo-dG (16). In addition, concentrations of 50 M

aloe–emodin increased DNA damage as measured by

the single-cell gel electrophoresis assay (COMET assay)

(21). Aloe–emodin and other anthraquinones also dose

dependently induced tk-mutations and micronuclei in

mouse lymphoma L5178Y cells and inhibited topoisomerase

II–mediated decatenation in a DNA decatenation

assay 21,22). The authors suggested that anthraquinones

bind noncovalently to DNA and inhibit the catalytic function

of topoisomerase II, which can lead to DNA breakage

by competing with the DNA binding site of the enzyme

23). It is also possible that anthraquinones can covalently

bind to DNA as observed with other quinones, such as p benzoquinone

(24,25). Binding of anthraquinones toDNA

might also facilitate DNA oxidation due to their high potency

of generating ROS. Besides the above-mentioned

effects of redox cycling by anthraquinones, it is also reported

that production of ROS by emodin can cause an

immunosuppressive effect in human mononuclear cells

and might result in apoptosis in A549 cells in vitro 19).

In vivo toxicology was assessed by the National Toxicology

Program and published in 2001 (11). Reports that

1,8-dihydroxyanthraquinone caused tumors in the GI tract

of rats led to the investigation of emodin in rodents, as

this compound is structurally similar and was reported

to be mutagenic in bacteria. The acute and chronic toxicities

of emodin were investigated in rodents exposed to

emodin in feed for 16 days, 14 weeks, or 2 years. In the

16-day study, rodents were fed diets containing average

daily doses equivalent to 50, 170, 480, 1400, or 3700 mg/kg

body weight for males and 50, 160, 460, 1250, or 2000

mg/kg body weight for females. The results showed that

the mean body weights of males and females exposed

to 480 mg/kg or greater were significantly lower than

those of the controls. Macroscopic lesions were observed

in the gallbladder and kidney of rats exposed to the highest

doses of 1400 or 3700 mg/kg. In the 14-week study,

rats were fed diets containing approximately 20, 40, 80,

170, or 300 mg/kg for males and females. Mean body

weights of males exposed to 170 mg/kg or greater and

females exposed to 80 mg/kg or greater were significantly

lower than those of the controls. In rats exposed to 170 or

300 mg/kg of emodin, increases in platelet counts and

decreases in total serum protein and albumin concentrations

were observed. Relative kidney weights of rats exposed

to 80 mg/kg or greater and relative lung and liver

weights of rats exposed to 40mg/kgor greater were significantly

increased compared to the control groups. The incidences

and severities of nephropathy were increased in

males and females exposed to 40 mg/kg or greater. In the

chronic toxicity study (2 years), groups of 65 male and 65

female rats were fed diets containing emodin at an equivalent

to average daily doses of approximately 110, 320, or

1000 mg/kg to males and 120, 370, or 1100 mg/kg to

females for 105 weeks. Survival of exposed males and females

was similar to that of the controls. There were negative

trends in the incidences of mononuclear cell leukemia

in both male and female rats and incidence of leukemia in

the group fed 1000 mg/kg was significantly decreased.

At the 12-month interim evaluation, nephropathy was

slightly higher (11).

In terms of genetic toxicology, emodin was mutagenic

in Salmonella typhimurium strain TA100 in the

presence of S9 activation; however, no mutagenicity was

detected in strain TA98, with or without S9 (11). Chromosomal

aberrations were induced in cultured Chinese

hamster ovary cells treated with emodin, with or without

metabolic activation by S9. In the rat bone marrow

micronucleus test, administration of emodin by three intraperitoneal

injections gave negative results. Results of

acute-exposure (intraperitoneal injection) micronucleus

tests in bone marrow and peripheral blood erythrocytes of

male and female mice were also negative. In a peripheral

blood micronucleus test on mice from the 14-week study,

negative results were seen in male mice, but a weak positive

response was observed in similarly exposed females.

The results of these investigations show no evidence

of carcinogenic activity of emodin in male F344/N rats

in the two-year study. There was equivocal evidence of

carcinogenic activity of emodin in female F344/N rats and

male B6C3F1 mice. There was no such evidence in female

B6C3F1 mice exposed to 312, 625, or 1250 ppm (11).

Other investigations of the carcinogenic potential of

cascara have been carried out in rodents. In one study,

the effects of the laxative bisacodyl (4.3 and 43 mg/kg)

and cascara (140 and 420 mg/kg) on the induction of

azoxymethane (AOM)-induced aberrant crypt foci (ACF)

and tumors in rats were investigated (26). Animals were

treated with AOM and laxatives (alone or in combination)

for 13 weeks. The results demonstrated that bisacodyl (4.3

and 43 mg/kg), given alone, did not induce the development

of colonic ACF and tumors. However, bisacodyl

(4.3 mg/kg) coupled with AOM increased the number of

crypts per focus but not the number of tumors. Bisacodyl

(43 mg/kg) significantly increased the number of crypts

per focus and tumors. Cascara (140 and 420 mg/kg)

did not induce the development of colonic ACF and tumors

and did not modify the number of AOM-induced

ACF and tumors (27). Results from another study were

similar. Dietary exposure to high doses of these glycosides

for 56 successive days did not induce the appearance

of ACF or increase in incidence of ACF induced by

126 Soni and Mahady

1,2-dimethylhydrazine (DMH). However, in rats treated

with both DMH and the highest dose of glycosides, the

average number of aberrant crypts per focus, considered

a consistent predictor of tumor outcome, was higher than

that in rats given DMH alone (26).



Laxative Effects

Cascara sagrada is an anthraquinone laxative and is

used for short-term treatment of occasional constipation

(1,28,29). The laxative effects of cascara are primarily due

to the anthraquinone glycosides, the cascarosides A–D

(1,5). Other anthranoid derivatives that may be active include

emodin anthrone-6-O-rhamnoside (franguloside),

and physcion and chrysophanol in glycosidic and aglycone

forms (30,31). Anthraquinone laxatives are prodrugs

in that after oral administration, the hydroxyanthracene

glycosides are poorly absorbed in the small intestine, but

are hydrolyzed in the colon by intestinal bacteria to form

pharmacologically active metabolites, which are partly absorbed

there (28,30); this acts as a stimulant and irritant to

the GI tract (29).

The mechanism of action of cascara is similar to that

of senna in that the action is twofold: (i) stimulation of

colonic motility, resulting in augmented propulsion, and

accelerated colonic transit (which reduces fluid absorption

fromthe fecal mass); and (ii) an increase in the paracellular

permeability across the colonic mucosa, probably due to

an inhibition of Na+, K+-adenosine triphosphatase or an

inhibition of chloride channels (30,32), which results in an

increase in the water content in the large intestine (29,32).

The laxative effect of cascara is generally not observed

before 6 to 8 hours after oral administration. The hydroxyanthracene

glycosides are excreted predominantly in the

feces but are excreted to some extent in urine as well,

producing an orange color; anthrones and anthranols also

pass into breast milk (30).

Anthraquinone laxatives may produce an excessive

laxative effect and abdominal pain. The major symptoms

of overdose are gripes and severe diarrhea, with consequent

losses of fluid and electrolytes (29). Treatment

should be supported with generous amounts of fluid.

Electrolytes should be monitored, particularly potassium.

This is especially important in children and the elderly.

Renal excretion of the compounds may cause abnormal

coloration of urine (yellow–brown to reddish depending

on the pH of the urine). Large doses may cause nephritis.

Melanotic pigmentation of the colonic mucosa (pseudomelanosis

coli) has been observed in individuals who

abuse anthraquinone laxatives. Pigmentation is usually

benign and reverses within 4 to 12 months of discontinuation

of the products (29).

Contraindications and Precautions

Patients should be warned that certain constituents of cascara

sagrada are excreted by the kidney and may color

the urine (harmless). Rectal bleeding or failure to have a

bowel movement after the use of a laxative may indicate

a serious condition. Laxatives containing anthraquinone

glycosides should not be used for periods longer than 1 to

2 weeks (29). Decreased intestinal transit time may result

in reduced absorption of orally administered drugs (1).

Electrolyte imbalances such as increased loss of potassium

may potentiate the effects of cardiotonic glycosides (e.g.,

digitalis). Existing hypokalemia resulting from long-term

laxative abuse can also potentiate the effects of antiarrhythmic

drugs that affect potassium channels to change

sinus rhythm, such as quinidine. The induction of hypokalemia

by drugs such as thiazide diuretics, adrenocorticosteroids,

or liquorice root may be enhanced, and

electrolyte imbalance may be aggravated (28).

Chronic use (>2 weeks) may cause dependence and

need for increased doses, and an atonic colon with impaired

function (29). It may also lead to pseudomelanosis

coli (harmless) and to an aggravation of constipation with

dependence and possible need for increased dosages.

Chronic abuse with diarrhea and consequent fluid and

electrolyte losses (mainly hypokalemia) may cause albuminuria

and hematuria, and may result in cardiac and

neuromuscular dysfunction (1).

Anthraquinone stimulant laxatives, such as cascara,

should not be administered to patients with intestinal obstruction

and stenosis, atony, severe dehydration states

with water and electrolyte depletion, or chronic constipation

(1,29). Cascara should not be administered to patients

with inflammatory intestinal diseases, such as appendicitis,

Crohn disease, ulcerative colitis, and irritable bowel

syndrome, or in children younger than 12 years (1,29). As

with other stimulant laxatives, cascara is contraindicated

in patients with cramps, colic, hemorrhoids, nephritis, or

any undiagnosed abdominal symptoms such as pain, nausea,

or vomiting (29).

Because of the pronounced action on the large intestine

and insufficient toxicological investigations, products

containing cascara should not be administered to pregnant

women (33,34). Furthermore, anthranoid metabolites are

excreted into breast milk. Thus, cascara should not be used

during lactation, due to insufficient data available to assess

the potential for pharmacological effects in the breast-fed

infant (33).


Adverse Reactions

In single doses, cramp-like discomfort of the GI tract may

occur, which may require a reduction of dosage. Overdose

can lead to colicky abdominal spasms and pain,

as well as the formation of thin, watery stools. Longterm

laxative abuse may lead to electrolyte disturbances

(hypokalemia, hypocalcemia), metabolic acidosis, malabsorption,

weight loss, albuminuria, and hematuria (35,36).

Weakness and orthostatic hypotension may be exacerbated

in elderly patientswhenstimulant laxatives are used

repeatedly. Secondary aldosteronism may occur due to renal

tubular damage after aggravated use. Steatorrhea and

protein-losing gastroenteropathy with hypoalbuminemia

have also been reported in laxative abuse (36). Melanotic

pigmentation of the colonic mucosa (pseudomelanosis

coli) has been observed in individuals taking anthraquinone

laxatives for extended time periods (29,36–

39). The pigmentation is clinically harmless and usually

reversible within 4 to 12 months after the drug is discontinued

(36–40). Conflicting data exist on other toxic effects

such as intestinal–neuronal damage after long-term use

(36). Use of the fresh drug may cause severe vomiting,

Cascara Sagrada 127

with possible spasms (30). Cases of allergic respiratory

diseases after occupational exposure to cascara have been

reported (41). Cascara sagrada is an etiologic agent of IgEmediated

occupational asthma and rhinitis. One case of

cholestatic hepatitis, complicated by portal hypertension,

has been attributed to the ingestion of cascara in one patient

who was also known to abuse alcohol and take a

number of other prescription medications (42).



Prior to June 1998, cascara sagrada was recognized by the

Food and Drug Administration (FDA) as a category I (safe

and effective) OTC preparation (monograph). In 2002, the

U.S. FDA issued a final rule concerning stimulant laxatives

including cascara sagrada (including casanthranol,

cascara fluid extract aromatic, cascara sagrada bark, cascara

sagrada extract, and cascara sagrada fluid extract) in

OTC drug products, stating that they are not generally recognized

as safe and effective or are misbranded (6). This

final rule was based on a decision made by the agency

after it had requested mutagenicity, genotoxicity, and carcinogenicity

data on cascara in 1998. No comments or data

were provided to the FDA for cascara; thus on the basis

the lack of data and information and the failure of any

persons to submit new data from carcinogenicity studies,

the agency has determined that these laxative should be

deemed not generally recognized as safe and effective for

OTC use and has thus reclassified these ingredients to category

II (non monograph) (6). According to the FDA, products

containing aloe and cascara sagrada ingredients must

be reformulated or discontinued; the stimulant laxatives

must therefore be deleted or replaced. Reformulated products

will also need to be relabeled. This final rule is part

of FDA’s ongoing OTC drug product review. However,

these products may still be sold as dietary supplements

under the Dietary Supplements Health and Education Act

of 1994.



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