A Review on Citrullus colocynthis Schrad.: From Traditional Iranian Medicine to Modern Phytotherapy

Abstract

Citrullus colocynthis Schrad. is an annual plant that grows in the south, center, and east areas of Iran. It is recognized by different pharmacologic activities in traditional Iranian medicine (TIM) (i.e., purgative, anti-inflammatory, antidiabetic, analgesic, hair growth-promoting, abortifacient, and antiepileptic. Some of these activities were confirmed in modern phytotherapy. Adverse events such as colic, diarrhea, hematochezia, nephrosis, and vomiting and narrow therapeutic index cause herbalists to use this plant cautiously. If some points about this plant in TIM are considered, it may be possible to produce more tolerable preparations from this plant. In this article, all aspects of this plant in TIM are reviewed; also, the medicinal properties declared for this plant in TIM are compared with those showed in modern phytotherapy. In addition, opinions of TIM and modern phytotherapy about safety and acceptable dosage of this plant are discussed.

Full text

A Review on Citrullus colocynthis Schrad.:
From Traditional Iranian Medicine to Modern Phytotherapy
Roja Rahimi, PharmD, PhD(cand),
1
Gholamreza Amin, PharmD, PhD,
1,2
and Mohammad Reza Shams Ardekani, PharmD, PhD
1,2
Abstract
Citrullus colocynthis Schrad. is an annual plant that grows in the south, center, and east areas of Iran. It is
recognized by different pharmacologic activities in traditional Iranian medicine (TIM) (i.e., purgative, anti-
inflammatory, antidiabetic, analgesic, hair growth–promoting, abortifacient, and antiepileptic. Some of these
activities were confirmed in modern phytotherapy. Adverse events such as colic, diarrhea, hematochezia, ne-
phrosis, and vomiting and narrow therapeutic index cause herbalists to use this plant cautiously. If some points
about this plant in TIM are considered, it may be possible to produce more tolerable preparations from this
plant. In this article, all aspects of this plant in TIM are reviewed; also, the medicinal properties declared for this
plant in TIM are compared with those showed in modern phytotherapy. In addition, opinions of TIM and
modern phytotherapy about safety and acceptable dosage of this plant are discussed.
Introduction
Citrullus colocynthis Schrad. from the family Cu-
curbitaceae is an ancient medicine believed to be the wild
gourd of the Old Testament. Its extremely bitter tastes and its
violent purgative properties were well known to the ancient
Greek and Roman physicians.
1
Its popular common names in
English are bitter apple, bitter cucumber, colocynth, and bitter
gourd.
2
It is also a well-known medicinal plant in traditional
Iranian medicine (TIM) and is used alone or in compounds for
many medicinal purposes. It is distributed mainly in Asia and
Africa. It is found in the southwest (Khouzestan, Fars),
southeast (Kerman, Bandarabbas, Balouchestan), central
(Yazd), and eastern parts (Lout desert) of Iran.
3
The names
mentioned in traditional Iranian manuscripts for C. colocynthis
are kabast,
4,5
Sharang (bitter thing),
6
Khiar Talkh (bitter cu-
cumber), Kharboze talkhak (bitter melon),
5
Kharboze roubah (fox
melon), Hanzal,Hindavane Aboujahl (Aboujahl’s melon), Alg-
ham (bitter thing), and Kousht.
7
Many of these names imply the
extremely bitterness of this plant.
Botanical Characteristics
C. colocynthis is an annual plant resembling the common
watermelon. The stems are herbaceous and beset with rough
hairs; the leaves stand alternately on long petioles. They are
triangular, manycleft, variously sinuated, obtuse, hairy, a
fine green on the upper surface, and rough and pale un-
derneath. Its flowers are yellow, appearing singly at axils of
leaves; its fruit is globular, the size of an orange, yellow and
smooth, which when ripe contains within it a hard coria-
ceous rind, and a white spongy pulp enclosing many ovate
compressed white or brownish seeds (Fig. 1).
8
The fruit is
very bitter. In TIM it is believed that if there is only one fruit
on the plant, this fruit is very poisonous and it should not be
used because it is extremely toxic.
4,6
Constituents
The pulp contains a bitter compound called colocynthin, a
resin called colocynthein, colocynthetin, pectin, and gum.
The seed contains fixed oil and albuminoids.
9
Temperament
The principles of TIM are based on quadratic elements.
These four elements are air, fire, water, and soil and each one
has their specific quality: air is hot and moist, fire is hot and
dry, water is cold and moist, and soil is cold and dry. Fol-
lowers of this doctrine believe that the entire world is made
from quadratic elements and the differences and diversities
between objects are attributed to different ratios of these four
elements used in their structures. Thus, every object in the
world has a specific quality based on dominant element(s) in
its structure. This specific quality has been known as tem-
perament (Midzaj).
10,11
Belief about temperament has existed
1
Department of Traditional Pharmacy, Faculty of Traditional Iranian Medicine, Tehran University of Medical Sciences, Tehran, Iran.
2
Department of Pharmacognosy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
THE JOURNAL OF ALTERNATIVE AND COMPLEMENTARY MEDICINE
Volume 18, Number 6, 2012, pp. 551–554
ªMary Ann Liebert, Inc.
DOI: 10.1089/acm.2011.0297
551

not only in TIM but also in many other traditional medical
theories, including Unani (Greek), Arabic, Roman, Indian,
European, and Chinese traditional medicines.
12
Plants also
are not an exception to this rule and have their own tem-
peraments. In a recent study, it has been shown that there is
a significant relationship between the temperament of plants
and their major chemical constituents.
13
Based on this theory,
C. colocynthis is called to have a hot and dry nature.
4,14
Medicinal Parts
The main medicinal part of the plant is the fruit pulp, and
it is better to remove this pulp from the fruit when it is
administered, because after the pulp is taken out of the fruit
its potency is decreased over time
4
and lost after 2 years.
7,15
When it remains in the fruit, the pulp keeps its potency for
about 4 years.
4,7,15
Other medicinal parts of plant are the
seed, leaf, and root.
15
Pharmacologic Activities
Information from TIM
Pulp has been known to be a potent phlegmatic purga-
tive.
4,15
This means that it can expel phlegmatic humor from
organs, vessels, and pores of the body and discharge it by
defecation.
7
It is useful for arthritis by expelling phlegmatic
humor from joints.
6
Even if it is rubbed on a painful knee, the
pain is relieved.
2
It is beneficial for sciatica and gout.
4,6
When
used in an enema is useful for colic, sciatica, backache, and
paralysis.
7,15
The oil of C. colocynthis made by boiling its pulp
with sesame or olive oil is externally used for ear pains,
tinnitus, toothache, and hair loss.
6,7,15
Ingestion of about 3.5 g
of this oil is phlegmatic purgative and vermifuge.
7,15
The
seed of C. colocynthis is purgative and emetic. The leaf of
C. colocynthis is melancholic purgative and used for melan-
cholia and epilepsy.
4,15
External use of its leaf is useful for
inflammation and bleeding.
6,15
The root is a potent antidote
for scorpion and snail bites.
14
The most popular traditional
use of C. colocynthis seeds and fruits in Iran is as an antidi-
abetic medication. Most of herbal medicine sellers in Iran
know C. colocynthis as a useful medication for diabetes. An-
other medicinal use of this plant declared by herbal medicine
sellers is for fever. For this purpose, feet are washed by
decoction of its fruit.
Information from modern phytotherapy
It has been shown that aqueous extracts of different parts
of C. colocynthis including seeds, fruit, root, and stem have
analgesic and anti-inflammatory activities in mice and rats
without inducing acute toxicity. The most potent activity
was observed from extract of immature fruits followed by
seeds.
16
Topical use of fruit extract has been shown prom-
ising hair growth–promoting activity in androgen-induced
alopecia of mice. The treatment was also successful in
bringing a greater number of hair follicles into the anagenic
phase than the standard finasteride.
17
In a study, the differential effects of diets enriched with
C. colocynthis oil (extracted from seeds), sunflower oil, or olive
oil were evaluated on the pancreatic b-cell mass in strepto-
zotocin (STZ)–induced diabetes in rats. After 2 months, hy-
perglycemia and insulin resistance were significantly less
pronounced in the rats fed a C. colocynthis oil-enriched diet
compared with other rat groups. Pancreatic b-cell mass re-
mained lower in the STZ-induced diabetic rats fed with
olive oil- and sunflower oil-enriched diets compared with
the C. colocynthis group.
18
It has been shown that different
C. colocynthis seed extracts have an insulinotropic effect
and significantly stimulated insulin secretion, which could
at least partly explain their antidiabetic activities.
19
Results
of a study done on Wistar rats showed that the extract of
C. colocynthis fruit dose-dependently reduced the blood
glucose level in STZ-induced diabetic rats but did not have
significant effect on normal blood glucose.
20
A 2-month randomized, double-blind, placebo-controlled
clinical trial was conducted in 50 patients with type 2 dia-
betes in Iran. Two (2) groups of 25 each under standard
antidiabetic therapy received 100 mg C. colocynthis fruit
capsules or placebos 3 times a day for 2 months, respectively.
The results showed a significant decrease in HbA1c and
fasting blood glucose levels in C. colocynthis–treated patients.
Other serological parameters levels including total choles-
terol, low-density lipoprotein, high-density lipoprotein, tri-
glycerides, aspartate transaminase, alanine transaminase,
alkaline phosphatase, urea, and creatinine levels in both of
the groups did not change significantly. No notable gastro-
intestinal side-effect was observed in either group.
21
Although the mentioned study rejects the hypolipidemic
effect of C. colocynthis, two studies have demonstrated ben-
eficial effects of it in this case. After 4-month administration
of ethanolic extract of C. colocynthis pulp to hyperlipidemic
rabbits, the increased cholesterol levels were brought to
normal. Similarly, phospholipids and triglycerides levels also
were observed to be reduced.
22
Another study on nondia-
betic hyperlipidemic patients showed that a daily intake of
300 mg/day of powdered seeds of C. colocynthis for 6 weeks
can lower the triglyceride and cholesterol concentration
FIG. 1. Dried fruit of Citrullus colo-
cynthis.
552 RAHIMI ET AL.

significantly.
23
It has been demonstrated in a recent study
that different parts of C. colocynthis possess antibacterial
(against Escherichia coli,Pseudomonas aeruginosa,Staphylo-
coccus aureus, and Enterococcus faecalis) and antifungal
(against some Candida species) properties.
24
The fruit of
C. colocynthis has shown antioxidant and free-radical scav-
enging capacity.
25,26
C. colocynthis extract in concentrations
higher than 10 lg/mL was shown to inhibit lipid peroxida-
tion and reactive oxygen species production.
27
Cucurbitacin
glucosides extracted from C. colocynthis leaves have shown
growth-inhibitory activity on human breast cancer cells.
28
In addition, whole extract from C. colocynthis has a dose-
dependent cytotoxicity effect on human larynx carcinoma.
29
Dosage
The acceptable dosage of C. colocynthis fruit in TIM is from
0.6 to 1.75 g per day.
15
In modern phytotherapy, 0.1–0.4 g/
day is allowed to be administered. The acceptable dosage for
other parts of the plant is 120–300 mg up to 600 mg/day of
seed and 0.2 to 0.4 g/day of root powder.
30
The difference
between TIM and modern phytotherapy in acceptable dos-
age may be due to administering fruit with its correctives
such as Arabic gum, gum tragacanth, and myrrh gum in
TIM. These correctives reduce adverse events of fruit and
allow the administration of larger doses. Its substitutes, if it is
not available, are equal weight of Ricinus communis L. seed
and a third of its weight in Peganum harmala L. seed.
7
Adverse Events, Precautions, and Contraindications
C. colocynthis is harmful for patients with a hot nature. The
most important characteristics of people with a hot nature
are feeling hot more than normal in a hot condition, getting
warm easily in a cold condition, warm fingertips in a normal
condition, preferring cold drinks, not easily standing hunger,
having enough energy, suffering from eye aches and head-
aches, having a sudden hot feeling in a normal condition,
and having blood hypertension.
12
C. colocynthis causes
headache, abdominal cramps, and nausea in very cold
weather and dysentery and inflammation in very hot
weather.
15
Therefore, it should not be administered during
summer and winter.
7
Toxic dosage of C. colocynthis reported
in modern phytotherapy is 600–1000 mg and may cause co-
lic, diarrhea, hematochezia, nephrosis, and vomiting. Lethal
doses ( ‡2 g) may cause convulsions, paralysis, and possibly
death caused by circulatory collapse.
30
In 1989, three exam-
ples of toxic acute colitis were reported, which occurred after
ingestion of C. colocynthis. The prominent clinical features
were dysenteric diarrhea, colonoscopic changes including
congestion and hyperemia of the mucosa with abundant
exudates, but no ulceration or pseudopolyp formation. These
pathologic features disappeared within 14 days in all three
cases.
31
Herbal medicine sellers also are aware of adverse
events of C. colocynthis and do not prescribe this medication
for more than 2 months. The most reported adverse events
by these sellers are diarrhea, inaction of intestine, and liver
impairment. In a recent study, C. colocynthis extract was
found to be free of hepatotoxic effects in concentrations up to
100 lg/mL incubation mixture from liver slices.
27
However,
another study on rat liver showed that alcoholic extract of
C. colocynthis in concentration above 100 mg/kg can have
toxic effects on liver cells, which may induce hepatocyte
necrosis and liver fibrosis.
32
The daily use of 0.25 g of C. co-
locynthis fruit/kg for 42 days was not fatal to sheep and
caused slight diarrhea, catarrhal enteritis, centrilobular hepa-
tocellular fatty change, and degeneration of the renal tubular
cells.
33
In case of poisoning, stomach evacuation is recom-
mended followed by administration of tincture of opium,
followed by stimulating and mucilaginous beverages.
30
For preventing adverse events, it is recommended in TIM
to administer equal weights of starch, Arabic gum, myrrh
gum, or gum tragacanth.
4,7
In addition, it should be ground
carefully until it is completely powdered, because if there is
any unground particle present, it can cause inflammation of
the gastrointestinal tract.
6
It is also harmful for slender
people, and it should be administered with fruit juice for
these people.
15
C. colocynthis is abortifacient; thus, it is contraindicated
during pregnancy.
15
A recent study has indicated that 12
weeks exposure of female rats to C. colocynthis causes adverse
effects on the reproductive system and fertility.
34
Reversible
antifertility effects of ethanolic extract of C. Colocynthis fruit
was demonstrated in male albino rats.
35
Conclusions
C. colocynthis has different pharmacologic activities. Some
of pharmacologic properties declared for this plant in TIM
are confirmed by different studies done in modern phy-
totherapy. Among these properties, antidiabetic activity of
the fruit and seed of this plant is very popular in TIM, and
although some in vivo and clinical trials in modern phy-
totherapy confirm this activity, there are not any approved
products from this herb in Iran. Moreover, some herbal
sellers administer it illegally especially for diabetes. Con-
sidering the points recommended in TIM such as using
C. colocynthis with correctives and grinding well, it may be
possible to produce a more safe and tolerable product from
this plant. The other pharmacologic properties of C. colo-
cynthis mentioned in TIM and confirmed by modern research
include analgesic, anti-inflammatory, abortifacient, purga-
tive, and hair growth–promoting activities. Two (2) clinical
trials were found for this plant; one confirmed antidiabetic
properties of 100 mg fruit 3 times a day for 2 months in
patients with type 2 diabetes,
21
and another confirmed hy-
polipidemic activity of 300 mg per day of seed for 6 weeks in
patients with hyperlipidemia.
23
No serious adverse events
were reported from these two studies.
The toxic range in modern phytotherapy (600–1000 mg)
has overlap with therapeutic dosage in TIM (600–1750 mg).
This overlap as discussed above may be due to using the
fruit of C. colocynthis with its correctives in TIM. Moreover,
TIM is a holistic therapeutic system, and the nature of the
patient is considered before treatment. With regard to TIM,
the most adverse events of this plant are seen in people with
a hot nature, and it is preferred not to administer this plant in
them, whereas in modern medicine the nature of patients is
not considered for treatment. It is emphasized again that it is
contraindicated during pregnancy because it is abortifacient.
Diseases that have been mentioned for treatment with
C. colocynthis in TIM but that have not evaluated in modern
phytotherapy until now include sciatica, paralysis, asthma,
chronic cough, tinnitus, epilepsy, elephantiasis, and scorpion
and snail bites. Since serious adverse events have been
BITTER APPLE USE IN TIM 553

reported from this plant, it is not recommended that it be
used before doing further studies on its possible adverse
events, in order to assess more precisely the risk–benefit ratio
of this plant and to judge conclusively about its clinical use.
Considering points in TIM such as use with correctives and
taking into account the nature of patients may be useful in
reducing adverse events of C. colocynthis.
Disclosure Statement
No financial conflicts exist.
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Address correspondence to:
Roja Rahimi, PharmD, PhD(cand)
Department of Traditional Pharmacy
Faculty of Traditional Iranian Medicine
Tehran University of Medical Sciences
Tehran 1417653761
Iran
E-mail: rojarahimi@gmail.com
554 RAHIMI ET AL.