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Dept. a/Pharmacology, Faculty a/Medicine & Health Sciences, Sana 'a University.
*Dept. 0/ Pharmacology, Faculty a/Pharmacy, Khartoum University ,Sudan.
Summary:
""
Al-Adhal, A. A.
Yemen
The aim of this study is to investigate the effect
of Medical
(Catha Journal,
edu/is on some
Vol. 4, NO.1, October 2001 39~49
biochemical parameters on short and long-term basis.
YMJ
Fresh Khat in Sub-Acute
a dose of 20 grams/kilogram,
wasof
given
to three
groups
of rabbits
toxicity studies
Catha
edulis
(Khat)
AL-ADHAL,
A. and
A., aMOHAMMED,
O.Y.'
(nine each), for one, two,
and three weeks,
fourth group was left
as a control,
"SAEED, N.S.*, GANEM, N.S
and in another trial fresh Khat was given in three doses 20, 30 and 40
gram/kilogram to three groups of rabbits (six each), for six months, and a fourth
group was left as a control. The results were as follows: fasting blood sugar (FBS),
triglyceride (TG), GOT, and GPT were increased in both trials. The CBC which
was measured only in the second trial showed that Khat lowered hemoglobin,
WBCs, and lymphocytes while it increased neutrophils. The Khat treated groups
showed lowered body weights in the second (six months) tria1. The heart weight
relative to the body weight was increased in the first trial, while this result was not
seen in the second trial.
.
INTRODUCTION
middle and lower sections are also
Khat is a natural stimulant from the used. Other names by which Khat is Catha EduIi.l'
For.l'k plant, family; known include: Qat, Kat, Chat, Kut-es
Celastraceae, found in the flowering Salihin, Mirra, Tohai, Tschat, Catha,
I
evergreen tree or large shrub which Qaut, Abssynian Tea, African Tea, and
grows in East Africa and Southern African Salad. Kutes-Salihin (Arabic)
Arabia (1). It grows wild at altitudes of means a diet to help pious people to
] 500-2000 meters above sea level (2). stay awake at night for praying. That
I
j
i
It reaches height from 10 feet to 20 feet made some western authors to name
and its - scrawny leaves resemble Khat (incorrectly) as an addictive drug
withered basil. Fresh Khat leaves are of Islam (3). Khat leaves contain
r
I
crimson-brown and glossy but become psychoactIve ingredients known as
I
Jyellow-green
Corresponding Author.
as they
age. They also cathinone, which is structurally and
AI-Adhal A.A. Faculty of Medicine & Health Sciences
Sana'a
emit University
a strong smel1. The most favored chemically
similar to d-amphetamine;
part of the leaves are
the young
and
cathine,
milder form
Yemen
Medicalshoots
Journal,
Vol.
4, No. I,a October
200] of S~.thil)one.
near the top of the plant. However,
leaves and stems at the
t
Fresh leaves contain both ingredients;
those left unrefrigerated beyond 48
hours would contain only cathine,
which explains user's preference for
fresh leaves (4).There appear to be a
number of different varieties of the
plant differing in khatamine content
between 0.1 % (Yemen, Madagascar)
and 0.5% (Kenya).
On a dry basis the leaves contain about
1.0%
of
(+)norpseudoephedrine
(cathine), and for many years this was
thought to be the principle responsible
for the stimulant effect of the drug. In
1975 another
phenylpropane,
(- )-a
aminopropiophenone (cathinone), was
isolated at UN laboratories and is
considered to be the principal CNS
stimulant of the fresh plant (5). The Sisomer is more active than the other
enamiomer (6). (-)-cathinone has
phannacological properties analogous
to
those
of
(+)amphetamine,
possessing a similar potency and the
same mechanism of action. Many
other
components
(alkaloids.
sesquiterpenes, triterpenes, flavonoids,
numerous acids as esters), including an
essential oil containing about 40
components, have been characterized
(7). Khat is also very rich in Ascorbic
acid which is an excellent antidote to
amphetaminetype compounds (8).
Among the isolated alkaloids are the
cathadulins, with molecular weights
range from 600 to 1200 (9).
Protocol for the first trial
1- Rabbits were grouped into 4
groups:
group 1 (control), 2, 3, and 4.
2- Nine rabbits were allocated for
each gn;>up, and their weights were
recorded.
3- Fresh Khat of the Saoti type was
given in a dose of 20
gram/kilogram of animal weight
Yemen Medical Jouma], Vol. 4, No. I, October
J
39
200]
'--r~'
for one, two and three weeks to
groups 2, 3 and 4 respectively. The
control group was kept without
Khat.
4- This dose was given at 8 am, and
before handing food)o make sure
that Khat was consurrfed.
5- Green fodder was.: given as a
standard food during the trial.
6- All groups were kept in the same
environment, under the same
conditions and were fed the same
food.
7- At the end of the study the animals
were weighed and killed and their
blood samples were examined.
8- The hearts, livers, and kidneys
were separated and weighed.
9- Blood sugar, cholesterol, GOT,
GPT, alkaline phosphatase, urea
and creatinine were also
measured.
Protocol for the second trial
1- Rabbits were grouped into 4
groups; group I; control 2, 3, and 4,
2- Six rabbits were allocated for each/'
group, and their weights were
recorded.
3- Fresh Khat of the Saoti type was
given in doses of 20, 30 and 40
gram/kilogram of animal weight for
six months to groups 2, 3 and 4
respectively. The control group was
kept without Khat.
4- This dose was given at 8 am, and
before handing food to make sure
that Khat was consumed.
5- Green fodder was given as a
standard food during the trial.
6- All groups were kept in the same
environment, under the same
conditions
and were fed the same food.
7- At the end of the study the animals
were weighed and killed and their
blood samples were examined.
~.
Ai-Adhal, A. A.
Sub-Acute toxicity studies of Catha edu/is
Figure (3) Mean values ofHb in rabbits in the control group, and after
20, 30
and 40mg/kg Khat respectively
Figure (5) Mean values of fasting blood sugar (FBS) in rabbits in the control
group, and after 20, 30 and 40mg/kg Khat for 6 m~nths respectively
.,.
I 'I
L~-Iobi"1
A. .
~I
"
Group 1
ICFBS
I
Group 2
Group 3
Group 4
,1
. .,
if
L
P value < 0.05
Figure (4) Mean values ofWBCs in rabbits in the control group, and after 20, 30
and 40mg/kg Khat for 6 months
Group 1
Group 2
Group 3
Group 4
P value < 0.05
Figure (6) Mean values of triglyceride (TG) in rabbits in the control group, and
after 20, 30 and 40mg/kg Khat for 6 months.
8000
7000
6000
5000
4000
lawsc
I
3000
2000
ICTG
1000
I
0
Group 1 . Group 2 Group 3 Group 4
P value = 0.056
.",
Group 1 Group 2 Group 3 Group 4
P value < 0.05
Yemen Medical Joumal, Vol. 4, No. I, October 2001
43
Yemen Medical Journal, Vol. 4, No.1, October 2001
-.
AI-Adhal, A. A.
Sub-Acute toxicity studies of Catha edu/is
Figure (7) Mean values of sGOT & sGPT in rabbits in the control group, and
after 20, 30 and 40mg/kg Khat for 6 months
Figure (9) increase in body wt in rabbits in the control group, and after 20, 30
and 40mg/kg Khat for 6 months respectively
60
50
D.OOT
..OPT
Group 1
Group 2
Group 3
Group 4
Group 1
P value < 0.05
Figure (8) Mean values of alkaline phosphatase (Alk. P.) in rabbits in the
control group, and after 20, 30 and 40mg/kg Khat for 6 months respectively.
195'm
190.pb
185 180
175t:Jf.
170 165
Group 2
P value < 0.05
Figure (10) The effect of20mg/kg/day Khat in 3 groups ofrabbits (9 each) on
the heart weight relative to the body weight after 1,2 and 3 weeks, group 2,3
and 4 respectively, group 1 is control
.
60
50
40
IDAIk.
p.1
ID"'~"'"bod'_I'" I
20r.. 10
Group 2
Group 3
Group 4
0
Group 1 Group 2 Group 3 Group 4
P value < 0.05
'. "
<.
P value < 0.05
'L
Sub-Acute toxicity studies of Catha edulis
AI-Adhal, A. A.
r
,.
ri i
I
i
I
I
I
I
'
i
from the 'vascular bed to lymphoid
tissue (20, 29).
The explanation of the significant
d<::crease in hemoglobin caused by
Khat may be due to the inhibition of de
novo RNA synthesis (3'0), where RNA
is required for the synthesis of globin
the component of hemoglobin. In both
the 3 weeks- and the six months trials,
results showed increase in the body
weight in all groups the Khat treated
and non- Khat treated animals.
However, the increase in body weight
showed a dose-dependent reduction
with Khat in the second trial, the
means increase in body weight after
six months were 58.6 :f: 0.32%, 51.3
:r.
0.6%,48.8::1:0.37% and 40:f: 0.4]% in
the control group, group 2, group 3 and
group 4 respectively. The last three
groups are given 20, 30, and 40 gram
fresh Khat per kg body weight
respectively.
This may be due to the anorectic effect
of Khat. The anorectic effect of
cathinone starts at 16 mg/kg (3]), this
is found in ] 6 grams of fresh Khat
(Trease and Evans, 1996). The
anorectic effect is thought to be
mediated through opiate mechanism
(32), which is not antagonized by
pizotifen as seen in our study.
Indeed, I recommend another study to
be done using an opioid antagonist to
investigate its effect on the anorectic
effect of Khat.
some authors that Khat chewing may
be associated with hepatitis (23, 24,
25). The high contents of Tannins in
Khat may be responsible for this
detrimental effect on the liver (26). On
the other hand" alkaline phosphatase,
which reflects bone disease and
obstructive jaundice (I 8) was not
increased byKhat. .
The decrease in triglycerides produced
by Khat can be explained by its
sympathomimetic acti~n which favors
lipolysis and this action is mediated
through stimulation of 83receptors
(27). The stimulation of 83receptors,
as other B3 receptors results in
activation of adenyl cyclase, and
increase conversion of A TP to c-AMP
(20). The adrenocortical action of Khat
also contributes to the dosedependent
decrease in the blood triglyceride level
seen in our study (28), Blood urea in
the animal study was insignificantly
increased this may be due to the
decrease in the urinary flow rate seen
in the clinical study.
In the complete blood count (CBC),
the most important results were
significant decrease in WBCs and
hemoglobin by ] 8% and] 1.5%
respectively. The decrease in the
WBCs lies in the lymphocytes, while
neutrophils
were
significantly
increased by 39.1 %. These result can
be explained by knowing that Khat
may have stimulating effects on the
adrenocortical function in animals
(28). Glucocorticoids increase the
concentration of neutrophils, and
decrease
the
concentration
of
lymphocytes, monocytes, eosinophils
. and basophils. The increase in
~ neutrophils is due both to the increase
influx into the blood from the bone
marrow and decreased migration from
the blood vessels. The. reduction in
circulating lymphocytes and other
cells is the result of their movements
Many studies, in animals showed a
dose-dependent decrease in body
weight, with chronic administration of
Khat, but these occurred in doses
range
from
50-200'
~
mg
Khatamines/Kg (33, 34). The heart
weight relative to the body'weight is
significautly decreased 'by Khat in the
first trial (the three-weeks trial), while
this effect is not seen in the
;
Yemen Medical Journal, Vol. 4, No. I, October 2001
47
six-month trial. The decrease in the
heart weight relative to the body
weight in the three-weeks trial may be
explained
by
the
..increased
contractility of the myocardium
caused by the sympathetic effect of
Khat mediated by B-receptors. Finany,
the disappearance of this increase can
be interpreted by the tolerance
developed to the sympathetic effects of
Khat (35).
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" -.
,.
Yemen Medical Journal, Vol. 4, No, I, October 2001
49