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 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).
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).
CHEMISTRY AND PREPARATION OF PRODUCTS
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
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).
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
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).
CURRENT REGULATORY STATUS
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
1. Farnsworth NR, Fong HHS, Mahady GB. Cortex Rhamni
Purshianae, WHO Monographs on Selected Medicinal
Plants. Geneva, Switzerland: WHO Publications 2001:2.
2. Gathercoal EN,Wirth EH. Pharmacognosy. Philadelphia: Lea
and Febiger, 1947:411–416.
3. Tyler VE, Bradley LR, Robbers JE. Pharmacognosy, 9th.
Philadelphia: Lea and Febiger, 1988:62–63.
4. Youngken HW. Rhamnaceae (buckthorne family). Textbook
of Pharmacognosy. Philadelphia: The Blakiston Company,
5. Leung AY. Cascara sagrada—New standards are needed.
Drug Cosmet Ind 1977; 12:42.
6. Food and Drug Administration, Department of Health
and Human Services. Status of certain additional over-thecounter
drug category II and III active ingredients. Final rule.
Fed Regist 2002; 67:31125–31127.
7. European Pharmacopoeia, 2nd edn. Strasbourg, France:
Council of Europe, 2002:549.
8. Pharmacop e Fran aise. Paris, France: Adrapharm, 1996: 1–5.
9. The United States Pharmacopeia 25. Rockville, MD: The
United States Pharmacopeia Convention Inc, 2002:281–282.
10. Bruneton J. Pharmacognosy, Phytochemistry, Medicinal
Plants. Paris, France: Lavoisier, 1995:360–361.
11. National Toxicology Program. NTP Toxicology and Carcinogenesis
Studies of EMODIN (CAS NO. 518–82-1) Feed Studies
in F344/N Rats and B6C3F1 Mice. Natl Toxicol Program
Tech Rep Ser 2001; 493:1–278.
12. Masuda T, Ueno Y. Microsomal transformation of emodin
into a direct mutagen. Mutat Res 1984; 125:135–144.
13. Masuda T, Haraikawa K, Morooka N, et al. 2-
Hydroxyemodin, an active metabolite of emodin in the hepatic
microsomes of rats. Mutat Res 1985; 149:327–332.
14. Morita H, Umeda M, Masuda T, et al. Cytotoxic and mutagenic
effects of emodin on cultured mouse carcinoma FM3
A cells. Mutat Res 1988; 204:329–332.
15. Murakami H, Kobayashi J, Masuda T, et al. 2-
Hydroxyemodin, a major hepatic metabolite of emodin in
various animals and its mutagenic activity. Mutat Res 1987;
16. Akuzawa S, Yamaguchi H, Masuda T, et al. Radicalmediated
modification of deoxyguanine and deoxyribose
by luteoskyrin and related anthraquinones. Mutat Res 1992;
17. Krivobok S, Seigle-Murandi F, Steiman R, et al. Mutagenicity
of substituted anthraquinones in the Ames/Salmonella
microsome system. Mutat Res 1992; 279:1–8.
18. Zhang YP, Sussman N, Macina OT, et al. Prediction of the
carcinogenicity of a second group of organic chemicals undergoing
carcinogenicity testing. Environ Health Perspect
1996; 104(suppl. 5):1045–1050.
19. Huang HC, Chang JH, Tung SF, et al. Immunosuppressive
effect of emodin, a free radical generator. Eur J Pharmacol
20. Rahimipour S, Bilkis I, Peron V, et al. Generation of free
radicals by emodic acid and its [D-Lys6]GnRH-conjugate.
Photochem Photobiol 2001; 74:226–236.
21. Mueller SO, Eckert I, Lutz WK, et al. Genotoxicity of the laxative
drug components emodin, aloe-emodin and danthron
in mammalian cells: Topoisomerase II mediated? Mutat Res
22. Mueller SO, Lutz WK, Stopper H. Factors affecting the genotoxic
potency ranking of natural anthraquinones in mammalian
cell culture systems. Mutat Res 1998; 414:125–129.
23. Mueller SO, Stopper H. Characterization of the genotoxicity
of anthraquinones in mammalian cells. Biochim Biophys
Acta 1999; 1428:406–414.
24. Bolton JL, Trush MA, Penning TM, et al. Role of quinones in
toxicology. Chem Res Toxicol 2000; 13:135–160.
25. Levay G, Pongracz K, Bodell WJ. Detection of DNA
adducts in HL-60 cells treated with hydroquinone and
p-benzoquinone by 32P-postlabeling. Carcinogenesis 1991;
26. Mereto E, Ghia M, Brambilla G. Evaluation of the potential
carcinogenic activity of senna and cascara glycosides for the
rat colon. Cancer Lett 1996; 101:79–83.
27. Borrelli F, Mereto E, Capasso F, et al. Effect of bisacodyl and
cascara on growth of aberrant crypt foci and malignant tumors
in the rat colon. Life Sci 2001; 69:1871–1877.
28. Cascara Sagrada Bark. The Complete German Commission E
Monographs. Austin, TX: American Botanical Council, 1998.
29. Goodman and Gilman’s: The Pharmacological Basis of Therapeutics;
9th edn. New York: McGraw-Hill, 2001.
30. Bradley PR. Cascara sagrada. British Herbal Compendium,
Dorset: British Herbal Medicine Association 1992; 1:52–54.
31. Westendorf J. Anthranoid derivatives—Rhamnus species.
Adverse Effects of Herbal Drugs, vol. 2. Heidelberg:
32. deWitte P. Metabolism and pharmacokinetics of the anthranoids.
Pharmacology 1993; 47(suppl. 1):86–97.
33. Lewis JH, Weingold AB. The use of gastrointestinal drugs
during pregnancy and lactation. Am J Gastroenterol 1985;
128 Soni and Mahady
34. Physician’ Desk Reference. Montvale, NJ: Medical Economics
35. Godding EW. Therapeutics of laxative agents with special
reference to the anthraquinones. Pharmacology 1976;
36. Muller-Lissner SA. Adverse effects of laxatives: Facts
and fiction. Pharmacology 1993; 47(suppl. 1):138–
37. Heizer WD. Protein-losing gastroenteropathy and malabsorption
associated with factitious diarrhoea. Ann Intern
Med 1968; 68:839–852.
38. Loew D. Pseudomelanosis coli durch Anthranoide. Z Phytother
39. Patel PM, Selby PJ, Deacon J, et al. Anthraquinone laxatives
and human cancer. Postgrad Med J 1989; 65:216–217.
40. Kune GA. Laxative use not a risk for colorectal cancer: Data
fromthe Melbourne colorectal cancer study.ZGasteroenterol
41. Giavina-Bianchi PF Jr, Castro FF, Machado ML, et al. Occupational
respiratory allergic disease induced by Passiflora alata
and Rhamnus purshiana. Ann Allergy Asthma Immunol 1997;
42. Nadir A, Reddy D, Van Thiel DH. Cascara sagrada-induced
intrahepatic cholestasis causing portal hypertension: Case
report and review of herbal hepatotoxicity. Am J Gastroenterol