Journal of Ethnopa-ology, 2.3 (1988) 291- 298 Elsevier Scientific Publishers Ireland Ltd.

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ACUTE EFFECTS OF A KHAT EXTRACT ON THE RAT ELECTROENCEPHALOGRAM

MOSTAFA SALEH*, HAMDY MEKKAWY and FATHY EL-KOMY

Department of Zoology, Faculty of Science, Al Azhw University, Na.w City, and the National Center for Sociological and Criminological Research, Cairo (Egypt)

(Accepted April 7, 1988)

Summary

Rats chronically implanted with cortical screw electrodes were treated with three different oral doses of a Khat extract and the EEG recorded for 5 h. Several abnormalities in EEG patterns were observed, particularly after the administration of the largest dose (400 mg/kg). Spectral analysis of EEG showed a significant shift of frequencies towards faster, lower voltage activ- ity following administration of the two smaller doses (50 and 100 mg/kg), reflecting a stimulant effect of the extract. The highest degree of cortical activation was observed following administration of the smallest dose. With the largest dose, an initial activation was followed by a state of EEG depres- sion characterized by a high percentage of slow, high voltage waves. It is concluded that Khat extract in small doses has a stimulant effect on the rat brain, but with larger doses induces a state of depression.

Introduction

Khat (Cutha edulis Forsk.) is habitually used in southern Arabia and East Africa as a stimulant. Alles et al. (19611 and Halbach (19721 have described the subjective symptoms of central stimulation following the chewing of khat leaves. Alkaloids extracted from khat have been shown to elicit stereotyped behavior (Berardelli et al., 1980; Zelger et al., 1980; Valtertio and Kalix, 19821, to induce increased spontaneous motor activity (WHO Advisory Group, 1980; Valterio and Kalix, 19821, and to alter EEG patterns (Berardelli, 19801. Reviewing the literature on the pharmacology of khat, Kalix and Braenden (19851 concluded that ( - lcathinone and ( + lnorpseudoephedrine are responsible for the stimulating effects of khat on the central nervous system, with the former alkaloid being more potent than the latter one.

*Present address: Department of Biology, University of Bahrain, P.O. Box 1082 Bahrain, Arabian Gulf.

0378-8741/88/$03.15 0 1988 Elsevier Scientific Publishers Ireland Ltd. PublishedandPrintedinIreland

Although numerous studies have investigated the pharmacological effects of single chemicals found in khat, only a few have dealt with the effects of whole plant material, as normally taken by users, or of the com- plex mixture of chemicals found in its extracts (Alles et al., 1961; Nabil et al., 1986). Moreover, despite the often reported central stimulating effects of khat or its active components, the effects on the brain have received rela- tively limited attention (Bunney and Aghajanian, 1976; WHO Advisory Group, 1980; Zelger and Carlini, 1981; Wagner et al., 1982; Mereu et al., 1983). Except for one report (Berardelli et al., 19801, briefly describing qualitative changes in EEG following administration of cathinone in the rat, the effects of khat, its extracts or active individual components on the brain have never been investigated in electroencephalographic terms. The present report provides a detailed analysis of the effects of three different doses of an extract of khat, taken orally, on electroencephalographic patterns in the awake rat.

Experimental

Forty adult male Wistar rats (200-250 g body wt) were divided into four equal groups. Three groups were treated with khat extract, each receiving one of three designated doses, and one group served as a control. The ani- mals were housed individually and food (Purina) and water were available ad libitum.

Surgical implantation of EEG electrodes was performed under sodium pentobarbital anesthesia (42 mg/kg i.p.1 and semi-sterile conditions. Cortical screw electrodes were bilaterally implanted in the skull so that one pair was in contact with the frontal cortex and another with the occipital cortex. A single screw implanted in the nasal bone served as a reference electrode. The animal was allowed at least 1 week to recover from surgery prior to any treatment or recording.

Khat leaves were obtained from plants grown at the Botanical Gardens of the Ministry of Agriculture in Qanater, Egypt. The fresh leaves were extracted using a chloroformldiethyl ether mixture (1:3) according to the method of Alles et al. (1961) resulting in a total alkaloid yield of 0.1%. Three doses of 50, 100 and 400 mg extract per kg body weight were used. The extract dose, suspended in a 1:l Tween80Lsaline mixture was administered using a stomach tube in a volume of 0.2-0.4 ml. Control animals underwent exactly the same treatment as experimental animals but received 0.3 ml of the TweenSOlsaline vehicle.

For EEG recording, the animal was placed in a small plastic cage and connected to freely movable recording leads. The animal was habituated to the recording procedure several times before the actual recording was carried out. On the recording day, each animal was allowed 30 min to become accus- tomed to the recording situation before a sample EEG was recorded, and then the extract or the control solution was administered. Each animal was

left in the recording cage and an EEG record of 15-20 min was made every hour for 5 h following the treatment.

EEG records were visually screened to identify any abnormal activity patterns. Spectral analysis was then carried out manually on 10, randomly selected, 10-s segments of EEG records from each hourly record of each rat. Results of this analysis were expressed as percentage of each of the stand- ard EEG rhythms in the record. The amplitude of waves of the predominant EEG activity was also measured in ten, l-s segments for each hourly record of each rat.

Differences among animal groups were assessed by analysis of variance and Student’s t-test. Statistical significance was reached when P < 0.05.

Results

Figure 1 shows electroencephalograms recorded from frontal and occipital cortical areas of rats before and after treatment with khat extract or control solution. Before treatment, the EEG appeared mostly arrhythmic with intermittent short trains of irregular activity within the theta (3-8 Hz) and alpha (9- 12 Hz) frequency bands against a background of beta (< 12 Hz) activity. EEG tracings of rats treated with the control solution did not show any detectable deviation from the pretreatment pattern (Fig. 1Al.

The orally administered extract generally began to show effects 30 min to 1 h following administration. All animals remained awake throughout the recording session. A shift of EEG activity towards low voltage, faster activ- ity was seen in all records 1 h after extract administration and continued for up to the end of the 5-h recording session. These records were characterized by irregular, low voltage. activity extending across all EEG frequency bands, with beta dominating the records. This cortical activation was most evident in the EEG of the occipital area, particularly following treatment with the two smaller doses of the extract (Fig. lB, 10 With the largest dose, EEG activation was noticeable only during the first 2 or 3 h following extract administration (Fig. 1Dl. In all records, intermittent high voltage, slow activ- ity, mostly within the delta rhythm frequency range, appeared more fre- quently following extract administration. With the largest extract dose, these slow waves became highly abundant, particularly in records of the occipital cortical area (Fig. 1Dl. Paroxysmal wave complexes, ultraslow waves, spindles and sharp waves were also seen occasionally after adminis- tration of the large dose (Fig. 1Dl. Considerable individual variation occurred in responses to the largest dose. In 6 of the 10 rats receiving the 400 mg/kg dose, continuous trains of high voltage, slow activity, mostly within the delta band (superimposed on low voltage beta activity), dominated the EEG for up to 4 h following the administration of that dose (Fig. lD1. Spectral analysis of the data revealed the shifting of dominant EEG activity from theta to the faster beta frequency bands. A significant increase in beta index (0~ of beta activity in the record) was detected in EEGs of both frontal and occipi-

Fig. 1. Electroencephalograms of frontal (f) and occipital (0) cortical areas of a control rat (A) and rats treated withSO( 100~C)and400(D~mgofkhatextract~gorally,recordedimmediatelybefore~Otime~ and1,2.3.4and5hfo~owingtreatment.Calibrationl~~V,Ims.

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tal areas of all treated rats along with a significant drop in the index of the slower theta rhythm (Fig. 21. The increase in beta index was greater in the occipital cortex than in the frontal cortex and with the smallest extract dose more than with the largest dose. With the two smaller doses, the beta index remained significantly higher than its control value till the end of the record- ing period of 5 h. With the largest dose, the significant increase in beta index lasted for only 2-3 h following extract administration. Except for a significant, but transient, increase in alpha index of the occipital area 1 h following administration of the smallest dose, no significant change in that index in any of the records was observed.

No significant change in the delta index of the occipital cortical area was observed following treatment with the two smaller doses. With the largest dose of the extract, however, a highly significant increase in delta index was seen in the occipital area 1 h following the treatment. In the frontal area, the increase in delta index appeared 2 h after extract administration. The delta index of both cortical areas remained significantly higher than normal for the rest of the recording session.

The shift of EEG activities towards the faster frequencies was accompa- nied by a significant drop in the voltage of the dominant activity (Fig. 31. This drop in the amplitude was largely associated with the shifting of the

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Fig. 3. Changes in the amplitude of dominant EEG activity of frontal (A) and occipital (Bbcortical areas of control rats (0) and rats treated with 50 ( l 1. 100 (0) and 400 (A) mg khat extract/kg orally. Bars repre- sent 1PS.E.M.

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dominant activity from theta to beta frequency bands. However, the ampli- tude of the dominant waves, within the beta frequency band, continued to drop in both occipital and frontal EEGs for 5 h following treatment with the smallest dose.

Discussion

Psychological correlates of central stimulation induced by the chewing of khat have been described by Alles et al. (19611, Margetts (19671, Halbach (19721 and Kalix and Braenden (19851. The results of the present investiga- tion show a stimulant effect of orally administered khat extract on the rat cerebral cortex as manifested by a shifting of the cortical EEG activity to lower voltage, higher frequency patterns. Maximum cortical stimulation was obtained with the smallest dose of the extract (50 mg/kgl but became less pronounced or completely disappeared with the two larger doses. Similar dose-response patterns have been reported in the effects of a similar khat extract on a number of cardiac parameters (Nabil et al., 19861 and in cathi- none-induced hypermobility (Valterio and Kalix, 19821. Berardelli et al. (19801, using a series of i.p. doses of (-lcathinone, reported only moderate EEG activation with the smaller doses and “epileptic activity without an activation patterns” with the larger doses.

The results of the present study also show that although the largest dose initially resulted in a mild-cortical activation, signs of cortical depression were later observed in all animals to varying degrees. Individual differences among animals in that respect are probably due to differences in the rate of absorption of the active components of the extract. In some animals, high voltage, slow waves became so prevalent in the EEG that the effect of the dose was clearly that of cortical depression rather than stimulation. The depressant effect of large doses of khat has been also reported by Margetts (19671 and Nabil et al. (19861. A similar pattern of effect has been reported by Kalix and Braenden (19851 who described how users in a khat chewing session would progress from a state of stimulation and excitation to that of depression and a feeling of depletion as more and more khat was consumed.

The unusually high percentage of abnormal EEG patterns in animals treated with the extract and the severity of the depression observed in some animals, suggests some kind of adverse effect of khat on the central nervous system.

References

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Berardelli, A., Capocaccia, L., Pacitti, C., Tancredi, V., Quinteri. F. and Elmi. A. (1980) Behav- ioral and EEG effects induced by an amphetamine-like substance (cathinone) in rats. Pharma- cological Research Communications 12.959-954.

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