This communication includes the results of botanical, chemical and pharmacological investigations on the Saudi Arabian variant of khat (Catha edulis). Some differences in the botanical characteristics concerning the serration of leaves, sizes of pericyclic and wood fibres and vein islet number etc. have been observed. The chemical study revealed the presence of many alkaloids including cathine which seems to be the most prominent. It was found comparatively rich in flavonoids. The steam volatile constituents were also studied. The pharmacological studies on the crude material fed in the diet and on the alcoholic extracts showed central and cardiac stimulant effects„ hypertensive, smooth muscle relaxant and a protective effects on experimentally induced gastric ulcers.
Khat (Catha edulis Forsk, Family Celastraceae) also known as gat, chat, tschat, mira etc. usually consists of the leaves and young shoots of this plant. The dried leaves are known as Arabian or Abyssinian tea. It is an ancient plant which grows wild or is cultivated in Eastern Africa, Southern Arabia, Yemen, Ethiopia, Kenya, Madagascar, Somalia and Tanzania. The fresh leaves and tops are customarily chewed in these areas to attain a state of euphoria and stimulation (Nelhans, 1974).
The consumption of khat has considerably increased in the recent years leading to serious social and economic problems. Some countries have therefore declared its consumption as illegal and imposed heavy penalties for its abuse. Recently, World Health Organization has also classified khat as a drug of abuse which can produce mild to moderate psychic dependence but little, if any, physical dependence and tolerance (Nahas, 1981).
Khat has been subjected to many investigations concerning its botanical, chemical and pharmacological aspects and it has been reported that there are some differences in the characteristics and constituents of this plant from different sources. These variations may be due to the cultivation of this plant over the centuries under different ecological conditions as well as to local traditions of cultivation and harvesting.
As no specific and detailed study has been carried out on the Saudi Arabian variant of Catha edulis, the present investigation has been undertaken to study its botanical, chemical and pharmacological aspects and provide a comparative data with the khat of other sources.
Different samples of fresh plant materials (leaves and young shoots) collected from FEFA area of Southern part of Saudi Arabia were used for the macro and microscopic studies.
Macroscopy: The branches are green in colour, glabrous and cylinderical with some what flattened tips and dilated nodes. They bear opposite and decussate or alternate leaves at the nodes. The leaves often bear stepules at the nodes. The leaves are simple and measure 3.5 - 8 cm long and 1-4 cm wide at the widest part. They have short, round patioles which are about 3-7 cm long. In fresh condition the leaves are bright green, when dry they are dark green in colour. The lamina is oval lanceolate in shape with smooth and glabrous surfaces. The apex is acute or some time acuminate and the base is symmetric. The margin is serrate with the exception of small portion near the base which is entire. The serration increases towards the apex and terminates in characteristic short glandular teeth (Fig. 1 AB). The glandular teeths are about 70-130-195 long and 70-122-175 wide and bend towards the midrib. The midilb is projected on both side being more prominent on the lower. Nearly 8-14 pairs of lateral veins leave the midrib at an acute angle and bend upwards nearer the margin. The venation is pinnately recticulate. The leaves have anastomose venation nearer the margin (Fig. 1 AB). It has slight characteristic odour and a mild astringent taste.
Microscopy: Free hand sections of leaves, petioles and branches were prepared. The sections were examined using the following reagents: (1) Phloroglucinol, HC1. (2) Iodine water N/50, (3) Sudan III, (4) Million's Reagent, (5) Ferric chloride solution 5%, (6) 50% v/v glycerine solution and (7) Ruthenium red solution. All diagrams pertaining the microscopy were drawn with the help of projection microscope.
1. The Leaf
A transverse section of the leaf through midrib exhibits the following characteristics (Fig. 1 & 2).
1.1 Lamina (Fig. 1 C)
1:1a Upper Epidermis
The upper epidermis consists of a single layer of polygonal cells with a fairly thick and smooth cuticle. The outer walls of the cells are thickened with cellulose and the anticlinal walls are wavy. The cells measure 7 - 14 - 20 in length, 7 - 12 - 18 in width. The trichomes and stomata are absent (Fig. 1 D.E.).
1.1b Mesophyll (Fig. 1 C)
The mesophyll is dorsiventral and it is clearly differentiated into palisade and spongy mesophyll. The palisade consists of two rows of thin walled, compactly arranged
cylinderical cells. The cells are about 20 - 31 - 42 in
length and 7 - 14 - 20 in width. The cells of the inner
row are usually shorter and wider than the cells of the upper row. The palisade ratio is 3 - 5 - 7.
The spongy mesophyll consists of 11 - 16 rows of losely packed spongy parenchyma cells which measure 17 - 29 - 42 in diameter. Many of them contain cluster crystalls or—calcium oxalate and yellowish brown tanniferrous substance which stain greenish black with ferric chloride solution, orange red with Sudan III and brown with dilute Iodine.
1.1c Lower Epidermis (Fig. 1d)
The lower epidermis consists of a single layer of polygonal cells which are thickened in a similar manner to those of
the upper epidermis. The cells are about 7 - 12 - 18 by
10 - 12 - 14 . The anticlinal walls are slightly wavy.
The epidermis is covered with thick and smooth cuticle. Some of the cells contain cluster of calcium oxalate. Anomocytic stomata are abundant. The stomata are oval in shape and measure 13 - 16 - 22 by 10 - 14 - 18 . No trichomes are present. The-g"tomatal Index is 10 to 12.
1.2 Midrib (Fig. 2)
The upper and lower epidermises are similar to that of the lamina.
The palisade of the lamina is discontinuous over the midrib. The cortex contains two zones of collenchymatous cells, one adjacent to each epidermis. Each zone is composed of 1 - 3 layers of rounded collenchymatous cells which measure 3 - 10.5 - 18 in diameter. The remainder of the cortex consias of several layers of thin walled parenchyma cells. The cells are large, isodiametric and are about 14 - 42 - 70 in diameter. Many of them contain dark brown tanniferrous substances and calcium oxalate clusters. The tanniferrous tissues stain with ferric chloride solution, Sudan III and
Iodine solution. The clusters are about 4 - 12 - 18 in
The meristele is well marked and more characteristic. It consists of crescent shaped xylem surrounded by thin walled phloem and batches of pericyclic fibres on the outer side. The xylem consists of radially arranged lignified vessels which exhibit spiral, reticulate and rarely pitted thickening and are about 3 - 19 - 35 diameter. Accompanying the vessels are few tracheas and wood parenchyma cells. The wood fibres are rare. The tracheids are about 25 - 500 in length and 7 - 25 in width.
The phloem is composed of compactly arranged thick walled phloem parenchyma cells, sieve tube, companion cells and some small tanniferrous cells. Many of the phloem parenchyma cells contain clusters of calcium oxalate. No phloem fibres are present. The pericycle consists of batches of thick walled, slightly lignified fibres some of which are characteristically branched at the end. They are very large and are about 400
to more than 2000 in length and 7 - 10 - 14 in width.
2. The Petiole
A transverse section of the petiole appears more or less circular in outline. It is composed of epidermis and cortex with a crescent shaped vascular bundle (Fig. 3A & B)
The epidermis consists of a single layer of polygonal cells with straight anticlinal walls and covered with smooth cuticle.
The cells measure 7 - 16 - 25 in length and 7 - 12 - 18
in width. The stomate are rare and they are anomocytic. Trichomes are absent.
Adjacent to the epidermis, the cortex contains 1 - 2 rows of collenchyma cells which are about 10 - 28 - 35 in diameter. The remainder of the cortex is composerof several layers of parenchyma cells. The cells are isodiametric and are about 17 - 44 - 70 in diameter. Some of them are tanniferrous cells which stain with Ferric Chloride, Sudan III and Iodine solution. A large number of them contain clusters of calcium oxalate which are about 4 - 42 in diameter.
2.3 Vascular Bundle
The vascular bundle is characteristic and similar to that of midrib. It is composed of sylem vessels, wood, fibres, tracheids and wood parenchyma cells. The vessels are about
13 - 16 - 30 in diameter and exhibit spiral, reticulate and pitted thickenings. The tracheides are similar to that in
midrib. The wood fibres are lignified, slightly pitted and
are tapering at the ends. They are about 200 - 700 in
length and 7 - 14 in width. The wood parenchyma cells are also lignified and pitted.
The vessels are surrounded by phloem which is composed of phloem paranchuma cells, sieve tissue and companion cells. A few of them are tanniferrous cells. Abundant clusters of calcium oxalate are present. No phloem fibres are present. The pericyclic fibres are similar to that of midrib.
3. The Stem
A transverse section of the stem is somewhat rounded in outline and consists of an epidermis followed by cortex, pericycle, continuous ring of vascular tissue and pith (Fig.4).
The epidermis is composed of a single layer of moderately thick walled rectangular parenchyma cells with straight anticlinal wall. A thick and smooth cuticle is deposited on the outer side
side of the epidermis. The cells measure 10 - 18 - 25 in
length and 10 - 14 - 18 in width in tranverse section. Anomocytic type TA' stomata are rarely present.
The cortex consists of 1 - 3 layers of collenchymatous cells in the outer region. The cells are about 10 - 12 - 14 in diameter. The remainder of the cortex is composed of parenchymatuous cells which are isodiametric and are about
14 - 32 - 50 in diameter. Some of them are tanniferrous
cells. The tanniferrous cells are dark brown in colour and stain with ferric chloride, Sudan III and Iodine solution. A large number of parenchyma cells contain cluster crystalls of calcium oxalate which measure 10 - 14 - 18 in diameter. No endodermis is present.
The pericycle is well marked and consists of a complete ring of fibres which are interrupted by thin walled parenchyma cells. The fibres are slightly lignified and resemble the fibres of midrib and petiole.
The phloem is composed of compactly arranged thin walled phloem parenchyma cells, sieve tissue, companion cells and smaller tanniferrous cells. The cells are about 7 - 11 - 14 in diameter. Small cluster crystalls of calcium oxalate are abundant in the phloem region. Phloem fibres are absent.
In between phloem and xylem there is cambium which is composed of few layers radially arranged thin walled cambial cells.
The xylem consists of continuous ring of lignified tissues, which are composed of xylem vessels, xylem fibres, tracheids wood parenchyma cells and medullary rays.
The medullary rays are uniseriat and consist of slightly lignified rectangular parenchyma cells. The vessels exhibit pitted recticulate and spiral thickening. The tracheids are lignified and pitted and are about 250 - 600 in length and 7 - 25 in width. The wood fibres have lignified and slightly pitted walls
with tapering ends. They are about 200 - 800 in length
and 7 - 15 in width. The xylem parenchyma are rectangular, pitted and lignified.
The pith is elongated and consists of large rounded parenchyma cells which measure 15 - 70 in diameter. The tanniferrous cells and calcium oxalate clusters are abundant. The clusters are about
10 - 40 in diameter. No starch grains are present. ''
5. The Powder of khat
The powder of khat is greenish yellow in colour. It has slight, characteristic odour and astringent taste. It exhibits the following microscopical features (Fig. 3c and Fig. 4c).:
1. Fragments of lamina showing recticulate venation.
2. Fragments of upper epidermis with wavy anticlinal walls.
3. Fragments of upper epidermis with palisade cells.
4. Fragments of lower epidermis with anomocytic stomata.
5. Fragments of slightly lignified pericyclic fibres.
6. Fragments of pericyclic fibres often branched at the end.
7. Tracheids and wood fibres with lignified walls and elongated oval piths.
8. Fragments of vessels spiral, pitted and recticulate.
9. Thin walled parenchyma cells with cluster crystals of calcium oxalate and dark brown cell contents (tanniferrous cells).
10. Lignified and pitted xylem parenchyma.
11. Free cluster crystals of calcium oxalate.
In conclusion, it is observed from study that the khat grown in Saudi Arabia resembles the khat grown in other countries.
The following slight differences are noticed in this study.
a) The serration of the leaves ends in well marked dark brownish glandular projection which are bending towards the midrib. The glands stain brownish with ferric chloride, Sudan III and Iodine solution.
b) The paricyclic fibres, wood fibres and tracheids are of slightly different sizes.
c) There are also some slight variations regarding the vein islet number, palisade ratio and stomatal index (Table I).
The following general, basic characteristics are helpful in the identification of khat:
1. Oval-lanceolate serrate leaf.
2. Dark reddish brown glandular teeth at the ends of serration.
3. Recticulate and anastomose venation.
4. Anomocyctic stoma.
5. Crescent shaped lignified vascular bundle.
6. Slightly lignified pericyclic fibres branched at the end.
7. Epidermis with cluster crystals of calcium oxalate.
8. Tanniferrous cells.
Phytochemical screening of the plant revealed the presence of many constituents viz, volatile components, flavonoids, sterols and/or triterpenes, tannins, together with alkaloids.
1. Study of volatile components:
About no g powdered khat was water distilled for 4-5 hours. The distillate was salted out by saturating with sodium chloride and extracted with ether (3x500 m1). The ether extract was filtered over anhydrous sodium sulfate and distilled off under reduced pressure. A yellowish oily residue was left representing the aroma of khat. It was examined by TLC on silica gel G plates using different developing systems viz 10% ethyl acetate in n. hexane and other systems used for the study of alkaloids and located under UV using different chromogenic reagents viz ninhydrine, Dragendorff's and 1% w/v vanilin in sulfuric acid reagents. The results shoed that none of the volatile constituents gave positive reaction with Dragendorff's or ninhydrine reagents; with 1% vanilin sulfuric, however, only 6 spots could be revealed (Rf 0.69, 0.5, 0.22, 0.17, 0.13 and 0.09) the major one was with the highest Rf. It was also analyzed by GLC whereby numerous peaks could be obtained (Fig.5). Comparing the resolved peaks with those of the available authentic samples, only some of the general volatile oil constituents could be tentatively identified. Complete analysis of this part by GC/MS and GC/IR is in progress.
2. Study of Lipids
The petroleum ether extract (10 g) was dissolved in 5% alcoholic potassium hydroxide (500 ml) and refluxed for 4 hours. Solution was concentrated under reduced pressure and diluted with water and the unsaponifiable matter was extracted with ether (3x500 ml). The organic solvent was washed with water and filtered over anhydrous sodium sulfate and distilled off under reduced pressure to give about 3g of a solid residue (unsaponifiable). The mother liquor was rendered acidic with HC1 and similarly extracted with with ether. After removal of ether under reduced pressure about 6 g of a viscous greenish residue was left (saponifiable).
2.a Study of Unsaponifiable Matter:
One and half g of this matter was chromatographed on about 50 g silica gel Merck 1870-230 mesh) and eluted successively with n-hexane; n-hexane containing increasing amounts of ethyl acetate; ethyl acetate-methanol and finally with
methanol. 25 ml fractions were collected. By TLC using different solvent systems and different spray reagents similar fractions were pooled together and solvent removed under reduced pressure.
Fractions 26-33 and 61-70 gave 10 mg and 25 mg of white neels, m.p. 225° and 100°C respectively. The IR, NMR and UV analysis showed their hydrocarbon nature. Further work to collect more material for 13C-NMR analysis is continued with the aim of their full structure elucidation. The other fractions showed mixture of components, none of which could be isolated in a pure form.
The GLC analysis of the pet. ether extract and unsaponifiable matter (Fig. 6), on the other hand, and comparing with a
standard mixture of sterols resulted in identification of
some sterols in the lipid fraction of khat viz. sitosterol
and some others as shown in the Fig.6.
2b. Study of Saponifiable Matter: (Fatty acids)
About 1.5 g of the saponifiable matter was methylated by dissolving in 50m1 absolute methanol containing few drops of conc. H2SO4. The mixture was refluxed on a boiling water bath for 4 hours; solvent removed under reduced pressure, diluted with water and extracted with ether (3x100 ml). The ether extract was dehydrated and distilled off. The residue representing the methyl esters of fatty acids was analyzed by GLC and the results were compared with those of standards analyzed under the same operating conditions. The results are compiled in Table III.
From the results cited in Table III. it is clear that lipid fraction of khat is rich in fatty acids. Of the identified esters, hexanoate, heptanoate and octanoate are the most prominent.
3. STUDY OF ALKALOIDS.
Screening of the different extractives revealed the presence of many alkaloids, being much in the chloroform and methanol extracts.
The nonaqueous titration of the total alkaloids revealed a total percentage of about 0.2% calculated as cathine.
For the study of the individual alkaloids, the methanolic extract was used. It was diluted with water, rendered alkaline with sodium hydroxide and extracted several times with chloroform. TLC study of the concentrated chloroform extract revealed on locating with ninhydrine reagent a major spot which on isolation and analysis proved to be cathine. On locating with Dragendorff's reagent, many other spots were revealed of which one was prominent and expected to be Cathinone.*
3a. Isolation and Characterization of Alkaloids.
Two kg powdered material was macerated with methanol (3.5 L) over 2 days. The solvent was removed under reduced pressure and the residue diluted with water (1.5 L). The solution was successively extracted with benzene, chloroform and ethyl acetate. Each solvent was concentrated under reduced pressure and examined by TLC. The benzene extracted material was taken by 5% HC1, rendered alkaline with ammonia and extracted with chloroform (3x100 ml). A yellow powdered material was left on removal of the solvent under reduced pressure. TLC study of this material is shown in Table IV.
** Standard samples (Cathedulins K1, K2, K4) supplied through the courtesy of Prof. K. Szendrei, Dept. of Pharmacognosy, University Medical School,
H - 6701, Szeged, Hungary
The chloroform and mother liquid showed nearly the same qualitative pattern concerning those of alkaloids. The rich quantity of these alkaloids were isolated after basification of the mother liquid with NaOH, responds to ninhydrine reagent and are expected to be of the phenyl alkylamine group.TLC analysis showed 6 spots by ninhydrine of which the major one was proved to be cathine (Rf 0.36) and the next prominent alkaloid was detected with Dragendorff's reagent and expected to be cathinone as referred to the published data on the Rf values in the same solvent system (9). On the hand, this fraction was analyzed by GLC and showed a corresponding number of peaks. The result of TLC study and GLC analysis are summarized in Table V. and Fig. 7. respectively.
3b. Isolation of Cathine.
Two kg powdered plant were extracted by percolation with slightly acidified ethanol. The acidic alcoholic solution showed positive presence of alkaloids. It was concentrated under reduced pressure, diluted with water and rendered alkaline with sodium hydroxide and completely extracted with chloroform (alkalinization with ammonia resulted into heavy emulsion formation). On distillation of chloroform under reduced pressure, a yellowish residue was obtained, when recrystallized it gave cathine, confirmed by m.p.(178°C), NMR (CDC1 3):0.99 (3 Hd, CH3), 2.3 (3 HS, NH2, OH) 2.95 (1HP, CH). 4.15 (1Hd, O-CH), 7.21 (5HS, C6H5)
IR max (nujol film) 3260 cm -1, 3340 cm -1, (NH, OH).
(i) GLC Analysis of Cathine
The isolated compound which was proved to be cathine was analyzed by GLC.
A standard calibration curve was constructed and this was used for the quantitative assay of cathine in different extractives of khat.
(ii) Microcrystal Identification of Cathine
This was carried out with the aim of finding out a micro and specific method for its detection. 0.1$ solution. of cathine hydrochloride was used and the different alkaloidal precipitants were tried. Kraut's reagent gave a very characteristic rod shape crystals of different shape than those obtained with ephedrine.
It was found interesting that when Kraut's reagent was applied on the crude fraction, it was found rich in cathine but also contained other alkaloids as different shapes of crystals could be detected (Fig. 9.); the isolation and characterization of the corresponding alkaloids is in progress.
4. Study of Flavonoids
The mother liquid of the methanol extract before alkalinisation and extraction of alkaloids, was extracted with ethyl acetate. The solvent was removed under reduced pressure where a yellow powdered product was obtained. This gave positive results for flavonoids. TLC study showed the presence of 5 flavonoids as shown in Table VI.
Most of the reports available in the literature are based on the physiological and toxicological effects of khat chewing in human beings, or on the pharmacological effects of the pure alkaloids of khat in experimental animals. However, little attention has been paid to study the pharmacology or toxicology of the crude extract of khat, which seems to be a more rational aspects, as the khat chewers ingest not only the pure alkaloids, but also many other chemical compounds present in khat leaves. The present study has been therefore undertaken on the crude ethanolic extract of khat and powdered leaf administered in the diet.
The behavioural studies were carried out in mice weighing 30-35 gms according to the method of Irwin  (10). The ethanolic extract in the dose of 500mg/kg body weight (in single dose) was administered orally. The animals were observed for excitation, tremors, twitches, motor activity, motor coordination, pinna, corneal and righting reflexes and respiratory changes. Motor activity and rectal temperature was recorded every ten minutes after the drug administration over a period of ninety minutes. The effect of the extract on smooth muscle was studied using isolated rabbit duodenum and guinea pig ileum following the method of Ghosh  (11). Studies on skeletal muscles were undertaken using frog's rectus abdominis and rat phrenic nerve diaphragm preparations as described by Bulbring  (13). Cardiovascular studies were carried out on isolated rabbit heart (Langendorff's preparation), and arterial blood pressure of rabbits. ECG lead II was recorded in anaesthelized rats following i.v. administration of the extract. Effect of oral pre-treatment with khat leaves (20% W/W) in diet for two weeks was studied on phenylbutazone and pylorus ligation (Shay rats) induced gastric ulcers in rats according to the methods of [Wilhelmi,1972] (14) and [Shay et al. 1945] (15), respectively. Grading of ulcers was done according to the method of Barret et al.  (16).
The pharmacological studies of khat extract showed increase in the rate and depth of respiration, tremors, twitches and excitability in mice, clonic convulsions were also observed in some of the animals. A significant increase in motor activity was observed in mice treated with extract. Rectal temperature did not show any significant changes, except some mice showing mild hyperthermia. Studies of the ethanol extract on the cardio-vascular system showed a significant positive inotropic and chronotropic activity on isolated heart. The arterial blood pressure was increased following i.v. administration of khat extract. The hypertensive response was blocked by tolazoline hydrochloride. There was a significant decrease in spontaneous movements of rabbit duodenum with a significant smooth muscle relaxation. Inhibition of acetylcholine induced contractions was also observed. Our studies on isolated skeletal muscle showed that the extract in high doses inhibit acetylcholine induced contractions of rectus muscle and electrically induced contractions of rat's diaphragm muscle. The pre-treatment of rats with khat leaves significantly decreased the incidence of ulcers, the volume of gastric contents and gastric acidity in pylorus ligated rats, and significantly protected the gastric mucosal damage induced by phenylbutazone.
The results of experimental studies of khat in Saudi Arabia showed that the ethanolic extract shows significant effect on CNS stimulation and on mild hyperthermia. Increase in arterial blood pressure, heart rate and force of contractions and blockade of hypertensive response by tolazoline hydrochloride suggested sympathomimetic activity of the khat extract. The relaxation of smooth muscle of intestine and inhibition of acetylcholine induced contractions on this muscle, further suggests a sympathomimetic activity of khat.
The studies on isolated skeletal muscles showed slight neuromuscular blocade by khat. The initial increased muscular activity observed in human beings might be due to dominant CNS stimulation. The novel finding observed in our laboratory is the protective effect of khat leaves on experimentally induced gastric ulcers. Luqman  (17) has reported the relied in pain of gastric ulcers in some patients following the chewing of khat leaves. However, most of the earlier workers have reported gastro-intestinal disturbances in chronic khat users [ Halbach 1972, (18) and Hughes 1973 (19) 1. However, the production of gastritis and erosive duodenitis have also been reported by cimetedine which is a well established anti-ulcer drug . [Al-Nakib, 1978 (20) and Fedeli et al. 1978 (21)]. The nature of active principles and mechanism of action of anti-ulcer activity of khat have been further studied and our observations show that the anti-ulcer activity may be present in component(s) of the flavanoid fraction obtained from khat (Al-Meshal et al. 1983).
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