A Review of the Neuropharmacological Properties of Khat[1]

8/8/2019 A Review of the Neuropharmacological Properties of Khat[1]

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Review article

A review of the neuropharmacological properties of khat

Anteneh M. Feyissa, John P. Kelly

Department of Pharmacology and Therapeutics, NUI Galway, Galway, Ireland

Received 5 October 2007; received in revised form 21 December 2007; accepted 23 December 2007

Available online 17 January 2008

Abstract

Background: The psychostimulant khat (Catha edulis Forsk), is a herbal drug cultivated and chewed as a recreational and socializing drug in EastAfrica and the Arabian Peninsula for centuries. Due to increasing air transportation and the loosening of customs restrictions, it is now readily

available in the Western Countries mainly used by immigrants from khat growing areas causing a concern to policy-makers.

Objective: We conducted this review to further gain an insight to the neuropharmacological effects of khat.

Methodology: PubMed search engine with key terms khat or qat or mirra orqaad/jaad or cathinone was used to obtain articles relevant to

khat chewing. In total 284 English written articles published from 1959 to 2007 were screened.

Results: Most of the studies focused on cathinone, the postulated active psychostimulant alkaloid in khat. There were few studies which

investigated the entire plant extract in either in vitro or animal studies. In the majority of the studies it was reported that both cathinone and

cathine, another psychoactive constituent, have actions that are similar to those of amphetamine.

Conclusions: It seems that the well investigated khat alkaloids have many features similar to amphetamines; however there is a need for a more

thorough examination of khat itself in well designed in vitro, animal and human studies with a range of comparator drugs before confirming the

claim that khat is a natural amphetamine.

2008 Elsevier Inc. All rights reserved.

Keywords: Cathinone; Dopamine; Khat; Neuropharmacology; Psychosis

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1148

1.1. Prevalence of use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1148

1.2. Legal considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1149

2. Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1149

3. Analysis of active constituents of khat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1149

3.1. Active constituents of khat leaf . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1149

3.2. Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1150

3.3. Detection of khat alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1152

4. Neuropharmacology of khat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11524.1. Psychological sequelae of chewing khat. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1153

4.1.1. Psychosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1153

4.1.2. Aggression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1154

4.1.3. Mood disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1154

4.1.4. Addiction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1154

4.1.5. Khat-induced neurotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1155

Available online at www.sciencedirect.com

Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 11471166www.elsevier.com/locate/pnpbp

Abbreviations: AUC, area under the curve; DOPAC, Dihydroxyphenylacetic acid; DRL, Differential reinforcement of low rates; GCMS, Gas chromatography

Mass spectrometry; HAD, Hospital Anxiety and Depression Scale; 5-HIAA, 5-hydroxyindoleacetic acid; 5-HT, 5-hydroxytryptamine; IL, Intromission Latency; IP,

Intraperitoneal; MAO, Monoamine-oxidase; MDMA, 3, 4-methylenedioxy-N-methylamphetamine; ML, Mounting latency; 6-OHDA, 6-hydroxy dopamine. Corresponding author.

E-mail address: [email protected] (J.P. Kelly).

0278-5846/$ - see front matter 2008 Elsevier Inc. All rights reserved.doi:10.1016/j.pnpbp.2007.12.033
mailto:[email protected]://dx.doi.org/10.1016/j.pnpbp.2007.12.033http://dx.doi.org/10.1016/j.pnpbp.2007.12.033mailto:[email protected]


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4.2. Behavioural studies in animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1155

4.2.1. Motor activity and stereotyped behaviour. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1156

4.2.2. Analgesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1158

4.2.3. Feeding behaviour. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1158

4.2.4. Sexual behaviour . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1158

4.2.5. Cathinone in animal models of addiction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1159

4.3. Khat and neurochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11605. Algorithms of laboratory/preclinical studies on khat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1161

6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1162

7. Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1162

Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1163

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1163

1. Introduction

Khat, Catha edulis Forsk, is an evergreen shrub or treefound growing wild or cultivated in the east of a region

extending from Southern Africa to the Arabian Peninsula

(Krikorian, 1984). The habit of khat chewing has prevailed for

centuries in this part of the world, being cited in certain ancient

texts, including the Old Testament (Cox and Rampes, 2003).

The earliest scientific report on khat in the West was in the

eighteenth century when the botanist Peter Forskal identified

the plant in Yemen and called it C. edulis. There are several

names for the plant, depending on its origin: tchatEthiopia,

qatYemen (Alem et al., 1999), qaad/jaadSomalia (Elmi,

1983), miraaKenya (Patel, 2000), mairungiUganda

(Ihunwo et al., 2004), MuhuloTanzania, HagigatHebrew

(Bentur et al., 2007), cat, catha, gat, tohai, and muraa(Fasanmade et al., 2007). The dried leaves of khat are

known as Abyssinian tea or Arabian tea (WHO, 2006).

These many names attest to the widespread and presumably

fairly old knowledge ofC. edulis by native peoples of eastern

and Southeastern Africa (Krikorian, 1984). However, the most

common name is khat (Alem et al., 1999).

Recently published reviews on khat and cathinone focus on

adverse health aspects and have only briefly addressed their

pharmacology (Cox and Rampes, 2003; Al-Hebshi and Skaug,

2005; Al-Habori, 2005), or they investigate whether khat causes

mental disorders in general (Warfa et al., 2007) or how it is

specifically linked to psychosis (Odenwald, 2007). In particular,there is a lack of emphasis on the pharmacokinetics and

behavioural pharmacology of khat. Thus the principal purposes

of this review are to:

a) determine whether khat and its active principles are

comparable to other stimulants such as amphetamines; and

b) to detect gaps in our knowledge of the neuropharmacology

of khat.

To our knowledge, this review is the first in its kind in the

area to critically analyze past literature and to propose

suggestions for further investigation based on the limitations

identified in this review.

1.1. Prevalence of use

Fresh leaves from khat trees are chewed daily by over20 million people on the Arabian Peninsula and East Africa (Saha

and Dollery, 2006; Al-Motarreb et al., 2002). The khat chewing

habit is deeply rooted in the sociocultural traditions of these

countries (Stevenson et al., 1996; Kennedy et al., 1983). Many of

the users originate from countries between Sudan and Madagas-

car and in the southwestern part of the Arabian Peninsula. Khat

use is particularly widespread in Ethiopia, Kenya, Djibouti as well

as Yemen, where its use is socially sanctioned and even pres-

tigious (Kalix, 1990; Belew et al., 2000). Khat is consumed at

parties in combination with smoking cigarettes and drinking tea

and soft drinks (Baron, 1999). The biggest population of chewers

is in Yemen, where the plant is used as a social stimulant (Al-

Motarreb et al., 2002). Recent reports suggest that 8090% of themale adult and 1060% of the female adult population in East

Africa consume khat on a daily basis (Odenwald et al., 2005;

Numan, 2004).

The use of khat has traditionally been confined to the regions

where khat is grown (Yousef et al., 1995; Kalix and Khan, 1984;

Al-Zubairi et al., 2003), because the shoots must be used fresh for

the desired effects (Kite et al., 2003). In recent years, however, the

economic importance and consumption of khat leaves have

increased dramatically (Sawair et al., 2007; Odenwald, 2007).

This change is due to improved road and air transport, which has

allowed a much wider distribution (Mathys and Brenneisen,

1992; Cox and Rampes, 2003). Moreover, the use of the Internethas seen the emergence of several websites which advertise and

sell fresh khat leaves (Toennes and Kauert, 2002; Beyer et al.,

2007; Bentur et al., 2007). In addition, the influx of immigrants

from East Africa and Arabian Peninsula, who continue to use

khat, has resulted in the importation of khat to countries where

these immigrants have settled, including Europe and the United

States (Toennes and Kauert, 2004; Rousseau et al., 1998).In these

immigrant communities, the khat party is an important social

event and is a way for the participants to keep their ethnic identity

(Stevenson et al., 1996; Nencini et al., 1989) and relieve the stress

of living in a foreign country (Griffiths et al., 1997; Bhui et al.,

2006, 2003).In the UK, khat is used by (mainly male) members of

the Somali and Yemeni community (Griffiths et al., 1997;

1148 A.M. Feyissa, J.P. Kelly / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 11471166


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Cunningham, 1998), and the prevalence has been shown to reach

80% in Somali immigrants in London (Griffiths et al., 1997),

whilst in the USA khat use, which gained popularity during the

first Persian Gulfcrisis(Lurie et al., 1994;Giannini et al., 1992),is

most prevalent amongst immigrants from Yemen, Somalia and

Ethiopia (Browne, 1990). Khat use has also been reported in East

Africancommunities in Italy (Nencini et al., 1989), Israel (Graneket al., 1988), Australia (Stevenson et al., 1996), Norway, Holland,

Belgium, German, Switzerland and Canada (Vanwalleghem et al.,

2006; Nielen et al., 2004; Mathys and Brenneisen, 1992; Al-

Motarreb et al., 2002).

1.2. Legal considerations

Khat circulates freely in Yemen, Ethiopia (despite the

Orthodox Tewahdo Church prohibiting its use), Somalia

(though briefly banned during the six months rule of the United

Islamic Courts in Mogadishu in 2006) and some other East

African countries (Widler et al., 1994; Hattab and Angmar-Mnsson, 2000; Alem et al., 1999). Almost every small kiosk in

Addis Ababa, the Ethiopian capital, openly sells khat, and in

small cities and towns all over the country it is brought to

market as produce, where people publicly chew it and offer it to

visitors as a mark of hospitality (Selassie and Gebre, 1996). In

Yemen and Ethiopia there have been attempts to curtail the habit

for social and economic reasons but these have met with little

success (McKee, 1987; Kandela, 2000; Elmi et al., 1987; Elmi,

1983; Drake, 1988). One reason for this is that in Yemen (Al-

Motarreb et al., 2002) and in some parts of Ethiopia it is

consumed by government officials, making its regulation very

difficult.

Although the active alkaloids of khat, namely cathinone andcathine have been labeled as Schedule I and Schedule III

substances respectively by WHO since 1971 (WHO, 2003), its

status in European countries is not uniform (Kalix, 1990). For

example, khat is prohibited in Ireland, France, Switzerland,

Sweden and Norway (Widler et al., 1994; Saha and Dollery,

2006) whilst it is legal in the U.K. and in the Netherlands

(Nielen et al., 2004; Griffiths et al., 1997). Outside of Europe,

it is illegal in the U.S.A. and Canada but permissible in

Australia (Saha and Dollery, 2006; Patel, 2000; Fasanmade et

al., 2007). Recently, the WHO Committee reviewed the data

on khat and determined that the potential for abuse and

dependence is low and the threat to public health is notsignificant enough to warrant international control, and did not

recommend the scheduling of khat (WHO, 2006). Several

authors have also suggested weighing the evidence dispassio-

nately before sounding alarm on what is an important

substance for sections of the immigrant population of many

western countries (Weir and Thuriaux, 1988; Warfa et al.,

2007).

2. Methodology

A literature research was conducted via PubMed search engine

with the search terms khat or qat or miraa or qaad/jaad or

cathinone. We also examined the reference sections of these

articles to identify additional potentially relevant studies. A limited

number of references that were not listed in the database were also

used. The search was performed up to September 20, 2007. The

research only included articles available in English that were

published from 1959 to 2007. The full text of 284 articles or reports

that provided original data on khat chewing or its active

components in animal and human studies were reviewed, amongwhich those that contained researchon the epidemiology, analytical

aspects or neuropharmacological properties of khat were identified.

Expert-based commentary papers and papers describing the

pharmacological properties of khat were also included. In total

150 articles which belonged to the aforementioned areas were

selected. From these 150 articles, 70 original reports using khat and

or its active principles in their in vitro, animal studies were

subjected to an algorithm for defining an ideal study on khat with

regard to its relevance to humans. The algorithm had three criteria:

(i) the study should use the entire khat extract

(ii) analysis of active alkaloids should be made beforesubjects/treatments are exposed to the extract

(iii) the study should incorporate comparator drugs related to

their study question.

A study was deemed to be ideal when it fulfils all the three

criteria. We also used these criteria to comment on the existing

evidence of the effect of khat on human khat users.

3. Analysis of active constituents of khat

3.1. Active constituents of khat leaf

The leaves and young shoots of C. edulis, a species of theplant family Celastraceae, are usually referred to as khat [Family:

Celastraceae, genus: Catha, and Species C. edulis] (Nordal,

1980). Most taxonomists consider that the genus Catha consists

of the single species Catha edulis (Nordal, 1980; Elmi, 1983).

Khat is mainly grown in Ethiopia, Kenya, Yemen, Somalia,

Uganda, South Africa and Madagascar (Odenwald et al., 2005;

Ihunwo et al., 2004; Elmi, 1983; Al-Hebshi and Skaug, 2005).

Many different chemical substances are found in the leaves of

khat and these include:

Alkaloids, terpenoids, flavonoids, sterols, glycosides, tan-

nins (714% by weight). More than 10 amino acids including tryptophan, glutamic

acid, glycine, alanine and threonine (Szendrei, 1980; Luq-

man and Danowski, 1976; Halbach, 1972; Geisshsler and

Brenneisen, 1987; Elmi, 1983; Crombie, 1980).

Trace quantities of vitamins including ascorbic acid,

thiamine, riboflavin, niacin, and carotene ( Nencini et al.,

1989; Luqman and Danowski, 1976; Kalix and Braenden,

1985; Cox and Rampes, 2003).

Elements including calcium, iron (Hattab and Angmar-

Mnsson, 2000; Halbach, 1972), manganese (Halbach,

1972), copper, zinc, and toxic metals like lead and cadmium

(Matloob, 2003) and a negligible amount of fluoride (Hattab

and Angmar-Mnsson, 2000).

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Most of our present knowledge on the constituents of khat is

derived from studies in the late 1970s and 1980s following

recommendation by the UN Commission on Narcotic Drugs

(Kite et al., 2003). The phenylalkylamines and the cathedulins

are the major alkaloids. Szendrei (1980) at the UN Narcotics

Laboratory, together with Schorno and Steinegger at the

University of Berne, Switzerland, isolated and identified the phenylalkylamine, ()--aminopropiophenene, later named as

S-()-cathinone as a major active constituent in fresh khat. The

plant contains the ()-enantiomer of cathinone only (WHO,

2006; Gugelmann et al., 1985) which has the same absolute

configuration as S-(+)-amphetamine (see Fig. 1) (Kalix, 1990;

Goudie, 1987). During maturation, cathinone is enzymatically

converted to cathine [(+) norpseudoephedrine] and ()-

norephedrine (Al-Obaid et al., 1998). Sunlight-induced or

heat-induced degradation to cathine and norephedrine also

occurs during extraction of cathinone in the laboratory (Banjaw

et al., 2005). Indeed, to slow down the degradation process, the

khat leaves are usually wrapped in banana leaves immediately

after picking to retain their moisture (Yousef et al., 1995).

Other alkaloids of phenylalkylamines in khat leaves include

the phenylproanolamine diastereoisomers of cathine [1S, 2S-(+)

norpseudoephedrine or (+) norpseudoephedrine], and norephe-

drine [1R, 2S-() norephedrine]. Cathine and norephedrine

occur mainly in older plants and is also formed by reduction of

cathinone during drying and storage (see Fig. 2) (Sporkert et al.,

2003). The environment, climate conditions, as well as local

traditions connected with cultivation and harvesting determine

the chemical profile and general appearance of khat leaves

(Nordal, 1980). The phenylalkylamine content of khat leavesvaries widely. In certain khat samples, the phenyalkylamine

fraction consisted of up to 70% of () cathinone and that the ()

cathinone content is correlated with the market price of khat

(see Table 1) (Kalix and Khan, 1984). Accordingly, analyses of

khat samples from Kenya and Ethiopia have shown that the

commercial value of the material correlates with its cathinone

content (Geisshsler and Brenneisen, 1987).

Another class of phenylalkylamine alkaloids found in khat

leaves are the phenylpentenylamines; merucathinone, pseudo-

merucathine and merucathine, which are mainly detected in

khat leaves originating from Kenya (Brenneisen and Geisshs-

ler, 1987) (Fig. 3). They seem to contribute less to the stimulant

effects of khat (Kalix et al., 1990) and their concentration isrelatively low (Brenneisen and Geisshsler, 1987). Other

classes of alkaloid in khat are the cathedulins, classified

according to their relative molecular mass (Kite et al., 2003;

Crombie, 1980). Recently, 62 different cathedulins derived

from fresh khat leaves were characterized (see Fig. 4) (Kite

et al., 2003). Though there has been much research on the

phenyalkalymines, there has been little investigation of the

cathedulins to date (Kim et al., 2007).

3.2. Pharmacokinetics

Khat is usually chewed, occasionally brewed as a tea (Gianniniet al., 1992; Alem et al., 1999), and rarely smoked (Elmi, 1983).

The leaves are removed from their branches and thoroughly

chewed; they are then kept for a while in the cheek as a ball of

macerated material and later expectorated (Al-Motarreb et al.,

2002). The chewers fill their mouths to capacity with the ten-

derest leaves and shoots and then chew intermittently to release

the active components or keep it in buccal vestibules (Sawair et al.,

2007). During the khat session the leaves and the bark of the plant

are chewed slowly over several hours, usually for 210 h and

an average 100500 g of khat is chewed (Nencini and Ahmed,

1989; Matloob, 2003; Kalix, 1990; Elmi, 1983; Al-Hebshi and

Skaug, 2005). The juice of the masticated leaves is swallowed, but

not the residues (Toennes et al., 2003). During chewing, the

Fig. 1. Chemical structure of S-(+)-amphetamine and S-()-cathinone

(MW=149.2).

Fig. 2. Chemical structures of S-()-cathinone, S, S-(+)-norpseudoephedrine

(cathine) and R, S-()-norephedrine (MW=151.2). Cathinone is transformed

mainly to cathine in khat leaves and mainly to norephedrine by humanmetabolism. Modified from Sporkert et al., 2003.

Table 1

Concentration of khat alkaloids from fresh khat leaves of various origin

Cathinone Cathine Norephedrine References

0.740.40 1.490.51 0.90.16 Dimba et al. (2004)1

1.090.8 3.601.9 0.251.8 Geisshsler and Brenneisen (1987)2

1.020.11 0.860.06 0.470.05 Widler et al. (1994)1

Data given in mg per gram of khat leaf expressed as meanSD; 1Khat samplefrom Kenya; 2Khat samples from Ethiopia, Kenya, Yemen and Madagascar.



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alkaloids from khat leaves are effectively liberated, with about

80% of cathinone and cathine, and over 90% of norephedrine

released following chewing (Toennes and Kauert, 2002). The

absorption of the constituents of khat is said to have two phases,

the first being at the buccal mucosa, plays a major role in the

absorption of alkaloids (Toennes et al., 2003). The second phase is

following swallowing of the juice, at the stomach and/or small

intestine (Toennes et al., 2003).

Cathinone has been determined in spiked human plasma in

khat nave volunteers after 0administration of synthetic cathinone

(Widler et al., 1994; Brenneisen et al., 1990) or after the chewing

of khat leaves (Widler et al., 1994; Toennes et al., 2003; Halket

et al., 1995). The pharmacokinetic parameters for cathinone and

other ingredients of khat leaves have been determined over 8 h,

with peak plasma levels attained after 13.5 h (Halket et al.,

1995; Brenneisen et al., 1990). Similarly, maximal plasma

Fig. 3. Summary of class of different alkaloids in khat leaves.

Fig. 4. Structure of K-19 (1), one of the most highly elaborated members of the cathedulin family with its polyhydroxylated sesquiterpenoid euonyminol core (2).Adapted from White, 1994.



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concentrations (tmax) of cathinone, cathine and norephedrine are

reported to be reached at 2.3, 2.6 and 2.8 h respectively (Toennes

et al., 2003). After ingestion of 0.8 mg/kg cathinone it was

reported that the total amount of cathinone absorbed in the body

after 9 h (AUC; area under the curve) was 2513 g min ml1,

and the terminal elimination half-life was 260102 min (Widler

et al., 1994). In another study, 8 h after four drug nave volunteersingested khat (0.6 g/kg), the AUC of cathinone, cathine and

norephedrine was reported to be 245 49, 13 131, 710 173g

min ml1 respectively (Toennes et al., 2003).

There is a rapid stereoselective metabolism of S-()

cathinone to norepehedrine and cathine following its admin-

istration to humans ( Nencini and Ahmed, 1989; Geisshsler

and Brenneisen, 1987; Brenneisen et al., 1990). Metabolism

of cathinone to cathine involves reduction of the ketone group

to an alcohol, a fairly common metabolic pathway in humans,

catalyzed by liver microsomal enzymes (Guantai and Maitai,

1983). Only 7% or less of the absorbed ()-cathinone is

excreted unchanged in the urine (Toennes et al., 2003; Guantaiand Maitai, 1983), and is mainly excreted in the form of

norephedrine and cathine (Toennes and Kauert, 2002; Kalix

et al., 1990; Brenneisen and Geisshsler, 1987). The amount

of norephedrine excreted in urine is much higher than the

amount ingested, indicating that () cathinone is also

metabolized to R, S-() norephedrine (Toennes and Kauert,

2002). Cathine has been found in breast milk in several

lactating women who were chewing the leaves of khat

(Kristiansson et al., 1987).

3.3. Detection of khat alkaloids

The biological material commonly used in forensictoxicology for phenylalkylamine derivatives are urine,

blood, and hair samples (Kim et al., 2007). These methods

are similar to those used for amphetamines because of their

structural similarity (Sporkert et al., 2003). Analysis of urine

and blood provides information on recent or current exposure

to drug use, whilst analysis of hair samples provides detection

of long term and repeated use (Kim et al., 2007). Recently a

multi anylate procedure has been developed to determine

cathinone and other phenyalkylamines in plasma using LC-

MS/MS [Liquid Chromatography/Mass Spectrometry/Mass

Spectrometry] (Beyer et al., 2007). Using this technique it has

been reported that, after ingestion of khat leaves, all the majoralkaloids contained in the plant were detected in the plasma.

Detection of khat alkaloids (cathine, cathinone, and norephe-

drine) in urine has been performed by TLC (Thin layer

chromatography), HPLC (High-performance liquid chromato-

graphy), gas chromatography, and GCMS [Gas chromato-

graphy-mass spectrometry] (Mathys and Brenneisen, 1992;

Guantai and Maitai, 1983; El-Haj et al., 2003). Toennes and

Kauert (2002) demonstrated that GCMS, which could detect

cathine and norephedrine for up to 80 h and cathinone for up

to approximately 24 h after khat ingestion, is superior to the

other techniques for screening and confirmation testing of

urine samples from individuals with suspected khat use.

However, both cathine and norephedrine, which are available

as over the counter anorectic and cold suppressant medica-

tions respectively, could result in false positives in urine

analysis (Toennes and Kauert, 2002). Therefore, khat use can

be confirmed only by the detection of cathinone in the absence

of N-alkylated homologs (e.g. methcathinone) from urine

samples (Toennes and Kauert, 2002; Maitai and Dhadphale,

1988). Analysis of cathinone in hair samples was measured inDark-Agouti rats, and it was reported to have a relatively

lower incorporation rate into hair in comparison to other

amphetamines ( Nakahara and Kikura, 1996). However, later

studies in human hair from drug users using GCMS

separation technique detected cathinone, cathine and norephe-

drine (Sporkert et al., 2003; Kim et al., 2007). The proportion

of alkaloids detected from the hair was in the same order as

urine samples i.e. norephedrineNcathineNcathinone.

4. Neuropharmacology of khat

The effects observed following khat consumption aregenerally of central stimulation and include euphoria, excitation,

anorexia, increased respiration, hyperthermia, logorrhea, analge-

sia, and increased sensory stimulation (Patel, 2000; Nencini and

Ahmed, 1989; Kebede et al., 2005). These effects, which have

been observed in several clinical trials and animal studies with

khat and or cathinone (Widler et al., 1994; Kalix et al., 1990;

Brenneisen et al., 1990), are similar to those observed with

amphetamine (Halbach, 1979). The khat chewer believes that

they think more clearly and quickly and are more alert, although

their concentration and judgment are objectively impaired

(Pantelis et al., 1989). In view of its potency and its higher lipid

solubility (Kalix and Braenden, 1985; Hassan et al., 2007),

facilitating access into the central nervous system (Zelger et al.,1980), it can be assumed that khat-induced psychostimulation is

predominately, or evenexclusively due to the cathinone content of

the leaves (Kalix, 1990). This is substantiated by the brief

stimulation after khat chewing (Kalix et al., 1990), which is in

agreement with the finding that cathinone is metabolized rapidly

(Brenneisen and Geisshsler, 1987). The major metabolites of

cathinone, i.e. cathine and norephedrine, possess weaker central

stimulant properties because of their less lipophilic properties

(Nencini and Ahmed, 1989). Other alkaloids such as phenylpen-

tenylamines are of low concentration and were shown to have a

weak effect on dopamine release in dopamine prelabelled rat

striatal tissue (Kalix et al., 1990). The pharmacology ofcathedulins has not yet been well characterized in the CNS and

other organs (Kite et al., 2003). Although other pathways could

not be ruled out, there is enough scientific data to suggest khat/

cathinone-induced psychostimulation is mediated primarily via

the mesostriatocortico limbic dopaminergic pathway (Kalix,

1990). This is further strengthened by the observation that

subcutaneous administration of cathinone prevented the catalepsy

typically found following administration of haloperidol to rats,

which may suggest a possible therapeutic relevance in manage-

ment of Parkinson disease in the future (Banjaw et al., 2003).

Moreover, the dependence-producing potential, analgesia, and

anorexic effects of khat/cathinone are believed to be partly

mediated via this pathway (Gosnell et al., 1996).



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4.1. Psychological sequelae of chewing khat

In recent decades, the traditional habit of chewing the leaves of

the khat shrub has undergone profound changes in African and

Arab countries, from a socially regulated use pattern towards

uncontrolled consumption (Sawair et al., 2007; Bimerew et al.,

2007; Alem et al., 1999), which has become a special publicmental health concern (Bhui et al., 2006). In general, khat chewers

display a range of experiences, from minor reactions to the

development of a psychotic illness. Minor reactions include over-

talkativeness, hyperactivity, insomnia, anxiety, dizziness, impaired

concentration, irritability, agitation and aggression which usually

occur after a moderate intake of khat (Griffiths et al., 1997; Cox

and Rampes, 2003), and bruxism (Walter, 1996). These minor

psychotoxic reactions to khat are so well known in Ethiopia for

instance, khat users displaying these features have been given the

name jezba (Kalix, 1990). Among the several alkaloids in khat,

cathinone is incriminated for most of psychological sequelae

related with khat chewing (Elmi et al., 1987).There are a number of reports of psychiatric disorders

secondary to khat chewing with features of manic-like psychosis

(Gough and Cookson, 1984; Giannini and Castellani, 1982),

schizophreniform psychosis (Yousef et al., 1995; McLaren, 1987;

Luqman and Danowski, 1976), paranoid psychosis (Nielen et al.,

2004; Critchlow and Seifert, 1987; Alem and Shibre, 1997),

Capgras and Fregoli syndrome (Yousef et al., 1995), induced

hypnagogic hallucinations (Granek et al., 1988), depression

(Pantelis et al., 1989). In addition there have been reports of

personality disorders associated with long term khat use (Kalix

and Braenden, 1985). Recently Odenwald et al. (2007) has

reported a positive association between Post Traumatic Stress

Disorder (PTSD) among Somali ex-combatants and higher levelsof khat abuse. Though it is difficult to incriminate khat use alone,

some of the cases with psychotic morbidity, occurring during khat

chewing and subsequent intoxication phase, have been associated

with self harm andsuicide (Cox andRampes,2003). Accordingly,

two cases of homicide and combined homicide and suicide have

been reported following consumption of khat (Pantelis et al.,

1989; Alem and Shibre, 1997). Furthermore, khat chewers often

take alcohol to counteract the stimulant and sleep depriving effect

of khat, which raises the risk of interactions between alcohol and

khat (Omolo and Dhadphale, 1987; Kebede et al., 2005).

There is an ongoing international debate about a causal

relationship between khat use and mental illness (Warfa et al.,2007; Odenwald, 2007; Bimerew et al., 2007). Several

investigators claim that khat use is not necessarily linked to

psychological morbidity; any association that is found may

reflect an interaction with other environmental factors (Warfa et

al., 2007; Odenwald et al., 2005). Warfa et al. (2007) reviewed

the literature on the association between khat use and mental

illness published over the last 50 years and concluded that

although excessive khat use appears to exacerbate psychologi-

cal problems caused by pre-existing stressors, there is no clear

evidence as to the effects of khat use and the development of

mental illness'. Odenwald (2007) in a review of 45 articles in this

area, has criticised that the majority of the reports and

information about epidemiology and use patterns are merely

expert opinions and unsystematic observations, i.e. not sub-

stantiated by rigorous clinical testing. However, he suggested

that heavy khat chewing could induce brief psychosis and could

trigger or exacerbate pre-existing schizophreniform spectrum

disorders (Odenwald, 2007; Cox and Rampes, 2003).

4.1.1. PsychosisKhat-induced psychosis (brief psychotic episodes) was con-

sidered by many authors to be a rare phenomenon (Halbach, 1972;

WHO, 1980; Kalix and Braenden, 1985). Halbach (1972)

suggested that this is due to the bulky nature of the khat leaves,

ensuring that only low plasma levels of its active ingredients can be

attained after chewing (Giannini and Castellani, 1982). Secondly, it

is thought that in khat-using areas where health facilities are

lacking, people with psychotic symptoms are locked in their homes

by families until the episode subsides (Yousef et al., 1995; Luqman

and Danowski, 1976). However, there have been growing reports

of khat-induced psychosis in khat producing areas and in

immigrants residing in Europe and USA (Yousef et al., 1995;Pantelis et al., 1989; Bimerew et al., 2007; Alem and Shibre, 1997).

It is believed that immigrants are vulnerable to psychosis due to

social dislocation, and abnormal patterns of drug use, and pre-

existing stressful situations (Pantelis et al., 1989; Giannini and

Castellani, 1982; Bhui et al., 2006, 2003). Pantelis et al. (1989) and

Yousef et al. (1995) summarized clinical features of khat-induced

psychosis; most of the cases in Europe were Somali males with a

minority of the cases having past psychiatric history and family

psychiatric history. Heavy khat consumption preceded the

psychotic episode and the majority of thecases had rapid resolution

when treated pharmacologically, usually by antipsychotic medica-

tion of the phenothiazine type. There was a tendency for the

psychotic episodes to recur upon recommencement of khatchewing (Alem and Shibre, 1997). Few of the cases had

spontaneous resolution without pharmacological treatment once

they stopped abusing khat (Yousef et al., 1995; Nielen et al., 2004;

Alem andShibre, 1997). The characteristics of psychosis following

the useof khat were mainly of two main types: manic psychosisand

paranoid or schizophrenia spectrum disorder (Cox and Rampes,

2003; Bimerew et al., 2007). The latter is very similar to paranoid

psychosis seen with chronic amphetamine and cocaine addicts

(Pantelis et al., 1989; Ellison, 2002). It is postulated that khat

consumption precipitates psychosis by either increasing the risk in

already vulnerable individualsor affecting the course of a psychotic

disorderand the maintenanceof symptoms (Odenwald et al., 2005).To date the direction of causality between long term psychosis

and khat use remains unclear. In general, previous investigations

suggesting a link have been criticised for they suffer from meth-

odological problems and lack of quantitative data (for a review see

Odenwald, 2007). Nevertheless, recent studies using laboratory

animal models of behavioural sensitization, which bears striking

similarities to the progressive development of psychosis and

paranoia that develops in human addicts following repeated

psychostimulant administration, suggest the possibility of positive

association between khat use and long term psychiatric morbidity.

Accordingly, Banjaw and co-workers (2005) have reported

locomotor sensitization and prepulse inhibition deficit, two

paradigms that have been widely studied as animal models of



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psychosis, after intermittent oral administration of () cathinone or

C. edulis extract in rats. In both instances there is progressive

augmentation of either locomotor-stimulatory effects (locomotor

sensitization) or deficit in prepulse inhibition (i.e. deficit in the

startle reducing effect of a weak prepulse preceding a startle

stimulus by 30200 ms) upon repeated administration of

psychostimulants including amphetamine, cathinone and cocaine(Ellison, 2002; Banjaw et al., 2006). This finding suggests that

humans who useC. edulis over an extended period could be at high

risk of incurring neuropsychiatric diseases (Banjaw and Schmidt,

2005). Clozapine, an atypical antipsychotic widely used to reverse

these behavioural changes in animal models, was shown to

attenuate these deficits (Banjaw et al., 2005). They also reported

increased dopamine levels in prefrontal cortex with reduced

dopamine and its metabolites in anterior putamen, and decrease in

5-HT in nucleus accumbens and its metabolites in prefrontal cortex

(Banjaw et al., 2005; Banjaw and Schmidt, 2005). The reduction in

dopamine andits metabolites is in contrast to amphetamines, which

are known to increase dopamine in the caudate putamen in thelocomotory sensitization paradigm. These results suggest that the

behavioural effects ofC. edulis or cathinone are mediated, at least

in part, by dopamine in the mesostriatocortico limbic pathway

(Banjawet al., 2005). This pathway is believed to play a central role

in the induction, maintenance and expression of sensitization

following repeated administration of psychostimulants (Banjaw

and Schmidt, 2005). Indeed, psychosis due to cocaine and

amphetamine, closely related drugs to cathinone, is similarly

believed to be mediated via this pathway (Goudie, 1987; Ellison,

2002).

4.1.2. Aggression

Previous literature reviews show that there are scant data on thelong-term relationship between khat abuse and aggression despite

traditional claims that prolonged abuse of this psychostimulant

plant may influence the behavioural characteristics of individuals

and lead to heinous violence (Cox and Rampes, 2003). However,

there have been reports of khat-induced aggressive verbal

outbursts and violent behaviour in the past (Luqman and

Danowski, 1976; Giannini and Castellani, 1982). Recently, in a

community based study in Somalia, there was evidence of the

presence of disruptive and violent behaviour amongst chronic khat

users (Odenwald et al., 2005). Incidentally, Berardelli et al. (1980)

observed a spontaneous burst of aggressive behaviour in rats after

intraperitoneal(ip) administration of cathinone, similar to that seenwith amphetamines. Recently, Banjaw et al. (2006) have

reproduced this phenomenon using isolation induced aggression

paradigm, in which repeated oral administration ofC. edulis or S

() cathinone enhanced aggressive behaviour of isolated rats.

Similar to amphetamine, neurochemical correlates revealed

depletion of serotonin and its corresponding metabolites in both

anterior and posterior striatum, which suggest that aggression in

this paradigm is enhanced presumably by decreasing the level of

serotonin and its metabolites (Banjaw et al., 2006).

4.1.3. Mood disorders

Khat chewing can induce a substantial degree of mood

disturbances, particularly depression in healthy subjects (Hassan

et al., 2002). Depression associated with khat chewing has been

reported by several authors (Pantelis et al., 1989; Nielen et al.,

2004; Hassan et al., 2002; Griffiths et al., 1997; Granek et al.,

1988). In most of the reports it is seen as a consequence of

cessation of khat chewing (reactive depressive mood). The

severity of depression varied from agitation and sleep dis-

turbances to severe depression with suicidality (Nielen et al.,2004). Recently, Hassan et al. (2002) studied the effect of khat

chewing in human mood using the HAD (Hospital Anxiety and

Depression) Scale. They reported that khat chewing results in a

functional mood disorder consisting of predominantly reactive

depressive mood (seen an hour after acute khat administration),

and it might exacerbate symptoms in patients with pre-existing

mood disorder. It is thought to be mediated by the sympatho-

mimetic action of cathinone (Hassan et al., 2002). Other mood

disorders such as khat-induced behavioural syndrome described

as hypomania have also been reported by several authors

(Nencini et al., 1984a,b; Luqman and Danowski, 1976; Halbach,

1972). There are similar reports of mood disorders secondary torepeated amphetamine use (Baker and Dawe, 2005).

4.1.4. Addiction

The use of khat often starts at a young age and can develop into

a compulsive daily habit lasting a lifetime (Patel, 2000). Khat

taking behaviour depends not only on the reinforcing psychos-

timulant action of khat, but also on deeply rooted cultural factors

(Nencini et al., 1989). Habitual use of khat is in many instances

compulsive, as indicated by the tendency of khat chewers to

secure their daily supply of the leaves at the expense of vital needs

and their behaviour at the markets (Nencini et al., 1988; Kalix and

Braenden, 1985). This is described as a psychological dependence

by many authors ( Kalix, 1990; Gosnell et al., 1996; Connor et al.,2002). In eastern African countries the prevalence of khat

dependence is estimated to be 515% of the population (Nielen

et al., 2004). The first documented case of khat addiction was that

ofAmda Tsion, an Ethiopian ruler in the early 14th century, and

his subjects in the city of Mar'ade (Dillmann, 1884 as quoted by

Giannini et al., 1992). Giannini et al. (1992) reported two cases of

khat addiction which were effectively treated with bromocriptine

using a protocol developed for cocaine addiction. From their

description it could be inferred that both cases satisfy the Diag-

nostic and Statistical Manual of Mental Disorders, fourth edition

(DSM-IV) (American Psychiatric Association, 1994) criteria for

substance abuse. It is postulated that khat could have a higherdependence potential than amphetamine (Kalix, 1990) because of

its less aversive nature (Foltin and Schuster, 1983; Goudie and

Newton, 1985), higher rate of self administration, and rapid onset

of action in discrimination experiments (Yanagita, 1979;

Johanson and Schuster, 1981) when compared to amphetamine

in various operant experiments (See Section 4.2.5). Although

cathinone is known to cause sensitization upon repeated

administration similar to amphetamines (See above), there are

reports of tolerance to the CNS stimulating effects of khat

chewing. This is alleged to be due to the physical limits on the

amount that can be chewed rather than the inherent property of

khat leaves (WHO, 1980). There are conflicting opinions

regarding the existence of a withdrawal syndrome. Generally it



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is believed that there is no physical withdrawal syndrome as

experienced with alcohol, morphine or barbiturates (Sulzer et al.,

2005; Luqman and Danowski, 1976; Kalix, 1984). Abandoning

the khat-chewing habit however is followed by symptoms

including lassitude, anergia, nightmares, slight trembling, and

depression (Luqman and Danowski, 1976; Elmi, 1983; Cox and

Rampes, 2003; Alem et al., 1999). Indeed, habitual users reportthat they have no serious difficulties when moving to an area

where khat cannot be obtained (Kalix, 1990). However, there are

reports of social withdrawal symptomsafter cessation of the habit,

described as experiences of deprivation of joys and camaraderie

which khat session almost unfailingly provides (Stevenson et al.,

1996). As in the case of drug abusein industrializedsocieties,khat

use is associated with simultaneous use of other drugs especially

cigarette and alcohol (Zein, 1988; Hassan et al., 2007). Cigarette

smoking is believed to enhance the effect obtained by chewing

khat and to reduce its bitter taste while alcohol is widely used to

counteract the stimulatory effects of khat. The concomitant use of

psychotropic agents such as hypnotics is also common (Zein,1988).

4.1.5. Khat-induced neurotoxicity

There have been reports (albeit few) of severe and disabling

neurological illness associated with khat chewing. Morrish et al.

(1999) reported such a case in a 58 year old Somali man living

in UK who presented with leucoencephalopathy associated with

khat misuse. EEG and MRI findings indicated progressive

leucoencephalopathy but this could not be linked with khat use.

In addition, the CNS stimulating effect of khat has shown to

reach the level of acute and chronic toxicity as evidenced by

growing reports of psychiatric morbidity associated with khat

use (Nielen et al., 2004; Alem et al., 1999). However, there arefew studies which aimed at assessing the CNS toxicity of

different constituents of khat (Wagner et al., 1982; Al-Zubairi

et al., 2003). There is also a lack of information regarding the

effect of khat on the level of different neurotoxic/neuroprotec-

tive factors such as BDNF and lipid peroxidase in the brain. To

date, the main finding has been that khat/cathinone induces the

release of dopamine from presynaptic storage sites (Kalix and

Braenden, 1985) and chronic administration of either the whole

extract or cathinone (100 mg/kg) results in a significant

depletion of dopamine in several brain areas, particularly on

the nigrostriatal dopamine terminal projections (Wagner et al.,

1982; Banjaw et al., 2006). This is similar to the neurotoxic

effect of chronic amphetamine administration on the dopami-

nergic innervations of caudate, inducing their degeneration

(Ellison, 2002).

4.2. Behavioural studies in animals

For over the last 40 years Cathinone and/or khat extract have

been exposed to a wide array of behavioural experiments to

elucidate the behavioural pharmacology of this herbal psychos-

timulant. The behavioural models employed include; locomotor

activity (psychostimulation), feeding behaviour (anorexia), test

for analgesia (nociception), behavioural sensitization (psychosis),

isolation induced aggression paradigm (aggressive behaviour),

and several operant procedures (addiction/dependence). Since the

characteristic property of khat chewing is stimulation of the CNS,

the behavioural pharmacology is of particular interest. In most of

the behavioural experiments conducted in various animals

(chicken, mice, rat, and monkeys) cathinone/khat showedqualitatively similar effects to amphetamine. Both khat extract

and cathinone have been shown to increase spontaneous

locomotor activity, stereotyped movement and anorexia (Kalix

and Braenden, 1985). In addition, khat extract (100 mg/kg) and

cathinone (5 mg/kg), have been reported to cause behavioural

sensitization in locomotor activity of rats similar to amphetamine

(Banjaw et al., 2006) (Table 2). When compared to amphetamine

the potency of cathinone was in the order of 1:21:5 except in

conditioned taste aversion, where cathinone was reported to be

very weak [1:17] (Mereu et al., 1983; Kalix, 1990; Goudie, 1987).

However, tolerance to the anorexgenic effect of cathinone

develops rapidly unlike that of amphetamine (Foltin and Schuster,

1983). In addition, cathinone was reported to have a more similar profile to cocaine than to amphetamine in some behavioural

paradigms such as intravenous self administration and condi-

tioned taste aversion test (See Table 3 and Fig. 5). Cathine,

another psychoactive ingredient in khat, has also demonstrated

these behavioural features though less potently than cathinone, in

the range of 1:71:10 (Peterson et al., 1980; Eisenberg et al.,

1987). As to the neurotransmitters involved in mediating the

different behavioural effectsof khat/cathinone, there appears to be

strong evidence to suggest the involvement of the dopaminergic

system (Zelger et al., 1980; Kalix, 1980a,b). Indeed, several

investigators have demonstrated that cathinone and cathine

Table 2

Algorithm for behavioural studies in animals that used the khat extract

Outcome reported Analysis made? Comparator used? References

PPI deficit and locomotor sensitization in SpragueDawley rats Banjaw et al. (2005)

EEG pattern in Wistar rat Saleh et al. (1988)

Baseline aggressive behaviour in SpragueDawley rats Banjaw et al. (2006)

Ipsilateral rotation after 6-OHDA lesion in SpragueDawley rats Banjaw and Schmidt (2006)

Sexual behaviour in Albino wistar rats 1 Abdulwaheb et al. (2007)

Motor behaviour in Albino mice Connor et al. (2002)

Analgesia in Albino mice 2 Connor et al. (2000)

Locomotor sensitization in SpragueDawley rats 2 Banjaw and Schmidt (2005)

Ideal study;

1

ethanol, sildenafil and amphetamine used as a comparator;

2

d-amphetamine used as comparator; PPI, prepulse inhibition; EEG, electroencephalogram; = Yes; =NO.



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primarily increase catecholamine release and secondarily inhibit

its reuptake (Wagner et al., 1982; Schechter, 1990a,b; Peterson

et al., 1980; Mereu et al., 1983). However, other neurotransmitters

could also be involved as well. For instance, the serotonergic

system is reported to be involved in khat/cathinone-induced

stereotyped movement, aggression, and sexual arousal (Connor etal., 2002; Banjaw et al., 2006; Abdulwaheb et al., 2007).

Moreover, noradrenergic and opioid systems are suggested to be

involved in khat/cathinone induced analgesia and anorexia in

addition to the dopaminergic pathway (Nencini et al., 1984a,b;

Della Bella et al., 1985; Connor et al., 2000). (Tables 4 and 5).

4.2.1. Motor activity and stereotyped behaviour

The stimulatory effect of khat is perceived as an increase in

alertness and energy and relief from fatigue (Nencini and Ahmed,

1989). Indeed, these effects have been reproduced in rats after oral

administration of different concentrations of khat extract, in

which lower doses (50100 mg/kg) caused a stimulatory EEG pattern whilst higher doses (400 mg/kg) caused initial cortical

activation followed by EEG depression (Saleh et al., 1988).

Similar EEG patterns were observed in rats after intraperitoneal

(ip) cathinone administration (Berardelli et al., 1980). The EEG

pattern resembles how users in a khat session would progress

Table 3

The effect of cathinone and khat on animal behaviour

Behavioural observation Cathinone Khat Reference

Operant behaviour

IV Self administration 0.0251 mg/kg/infusion, in monkeys,

CATHCOC

Not examined Yanagita (1986), Woolverton

and Johanson (1984)

Discriminative stimulus property

0.09

1.87 mg/kg (IP), 256 g/kg (ICV),in rats, generalizes to AMPH, COC,

and MDMA

Not examined Schechter et al. (1984), Schechter (1990a)

Conditioned taste aversion 416 mg/kg, in rats, CATH:AMPH (1:17) Not examined Goudie (1987)

Food reinforced responding 14.7 mg/kg (IP) in rats, 0.0080.1

mg/kg/infusion in monkeys, CATH:AMPH (1:23)

Not examined Goudie (1985)

Conditioned place preference 0.8 mg/kg (IP), in rats, time spent

in non-preferred Side

Not examined Calcagnetti and Schechter (1993)

Hypermotility 120 mg/kg in rats and mice (IP/SC/PO),

2064 g/kg (IV) in rats, CATH:AMPH (1:2)

2001600 mg/kg (PO)

in rats and mice

Banjaw et al. (2006)

Stereotyped behaviour 120 mg/kg(IP/SC/PO) in rats and mice,

and chicken, CATHbAMPH

2001600 mg/kg (PO)

in rats and mice

Berardelli et al. (1980), Zelger et al. (1980),

Connor et al. (2002)

Anorexia 132 mg/kg(PO/IP), in monkeys and rats Not examined Zelger and Carlini (1980)

Analgesia 125 mg/kg(SC/IP) in mice in TFT and

HPT CATH: AMPH (1:46)

2001800 mg/kg (PO)

in mice

Connor et al. (2002)

Sexual arousal 5 mg/kg(PO), for 15 days in SD rats 100 mg/kg (PO)for 15 days SD rats

Abdulwaheb et al. (2007)

Aggression 5 mg/kg (PO),for 4 weeks in SD rats 200 mg/kg (PO)

for 4 weeks in SD rats


N.B. dose range, animals species used, and when available potency comparisons with other psychostimulants is reported.Cathine, also produced these effects though

less potent than cathinone; IP, intrapertoneal; SC, subcutaneous; PO, oral; IV, intravenous; AMPH, (+) amphetamine; CATH, Cathinone; COC, cocaine; TFT, tail flick

test; HPT, hot-plate test; SD, SpragueDawley rats.

Fig. 5. Effects of Khat/Cathinone on animal behaviour when compared with known psycostimulants.



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from a state of stimulation and excitation to that of sedation,

anxiety and depression, as more khat is chewed (Kalix and

Braenden, 1985; Hassan et al., 2002).

Once cathinone was identified as an active constituent of khat,

there have been investigations of its effect on animal behaviour,

particularly on locomotor activity. Subcutaneous administration of

cathinone in rats (Yanagita, 1979; Kalix, 1980b; Gordon et al.,

1993; Banjaw et al., 2003) andmice (Zelger et al., 1980; Rosecrans

et al., 1979; Knoll, 1979) markedly increased spontaneous loco-

motor activity of the animals. It was reported that the potency of

cathinone was almost comparable with (+)-amphetamine (Kalix,1990). Zelger et al. (1980) demonstrated that cathinone has a

stimulatory effect on locomotion in rats maximally after 15 to

30 min, in a similar fashion to amphetamine. Cathinone also

displayed hypermotility in hypophysectomized and unhypophy-

sectomized rats analogous to (+) amphetamine (Kalix, 1980b). In

addition, centrally administered cathinone increased spontaneous

activity when administrated directly into the nucleus accumbens,

but failed to demonstrate this effect when administered into the

substantia nigra in rats (Calcagnetti and Schechter, 1992a,b).

Similar increases in locomotor activity were observed after khat

extract administration in animals. Recently, it was reported that

acute and sub-chronic oral administration ofC. edulis leaves or S-() cathinone increased locomotor activity in rats (Banjaw and

Schmidt, 2005; Banjaw et al., 2006). In contrast, Connor et al.

(2002) reported a reduction in spontaneous motor activity in mice

after intragastric administration of khat extract. It was suggested

that the use of mice instead of rats and the difference in the source of

khat leaves could explain the observed variation (Connor et al.,

2002; Banjaw et al., 2006). For the first time Banjaw et al. (2006)

demonstrated the occurrence of strong behavioural sensitization

after repeated intermittent oral administration ofC. edulis leaves or

cathinone in rats. The rats developed sensitization for locomotor

activity, rearing, upward and downward sniffing, and turning after

oral administration of the extract which was also observed withcathinone and amphetamine.

Cathinone has also been found to be similar to amphetamine

with regard to induction of stereotyped behaviour in rats at higher

doses (Zelger et al., 1980; Peterson et al., 1980; Berardelli et al.,

1980; Banjaw et al., 2003; Banjaw and Schmidt, 2005), in mice

(Al-Meshal et al., 1991) and in young chickens (Bronson et al.,

1995). Stereotyped movements after administration of khat extract

or cathinone include biting, licking, pawing, sniffing, head

twitches, and rearing (Zelger et al., 1980; Connor et al., 2002;

Berardelli et al., 1980; Banjaw et al., 2006, 2005, 2003; Al-Meshal

et al., 1991). Moreover, there are somereportsof cathinone-induced

tremor at a low dose and seizure at higher doses (Berardelli et al.,1980). Cathine was considerably less potent, (1/71/10th), than

Table 4

Neurochemical effects of cathinone and khat

Nature of study Cathinone Khat extract Reference

In vitro studies

Synaptosomal preparations Release and inhibition of uptake of [3H]DA,

1100 M, CATH: AMPH (1:1.6)

Not examined Wagner et al. (1982)

Rabbit/rat striatal tissue Enhanced release of [3

H] 5-HT, 12 M effluxand inhibition of uptake of [3H]DA, 39 M,

CATH: AMPH (1:26x)

Not examined Kalix (1981,1982, 1983)

Rat cerebral cortex Inhibits [3H] nisoxetine binding to NA transporter,

2.5 M, CATHCOCMDMA

Not examined Cleary and Docherty

(2003)

Rat atrial/ventricular strip Efflux of [3H]NA and inhibition of uptake of [3H] NA,

1.22 M, CATHCOCMDMA

Not examined Cleary and Docherty

(2003)

In vivo study in rats Inhibition of the firing rate of nigral DA neurons,

0.4 mg/kg (IP), CATHAMPH extracellular DOPAC

(NAc, SL), IP, 6 mg/kg 5-HT&5-HTP (NA, SL), IP, 6 mg/kg

Not examined Mereu et al. (1983)

Postmortem analysis in rats DA (PFC), DOPAC (PFC, NAc, CP) after 1.5 mg/kg (PO)

for 10 days

DA in PFC, PO 200 mg/kg,

10 days


5-HT&5-HIAA in PFC and anterior and posterior striatum,

after 1.5 mg/kg (PO) for 4 weeks

5-HT&5-HIAA in PFC

anterior and Posterior striatum

Banjaw and Schmidt

(2005)

IP, intrapertoneal; PO, oral; AMPH, (+)amphetamine; COC, cocaine; CATH, cathinone; NAc, nucleus accumbens; SL, septi lateralis; CP, caudate Putamen.; NA,

noradrenaline; DA, dopamine; 5-HT, 5-hydroxytryptamine; DOPAC, Dihydroxyphenylacetic acid; 5-HIAA, 5-hydroxyindoalmineacid; PFC, prefrontal cortex.

Table 5

The in vitro affinity table for cathinone and comparator compounds

Receptor/transporter/enzyme Cathinone IC50/EC50 Cathinone vs. comparator compounds Reference

Dopamine transporter 0.85 uM AMPHNCocaineNCATH Fleckenstein et al. (1999)

-receptorsa N10 uM CATHEphedrine Rothman et al. (2003)

Noradrenaline transporter 0.9 uM CocaineMDMACATH Cleary and Docherty (2003)

5-HT receptorsb 3 uM CATH4X AMPH Glennon and Liebowitz (1982)

Serotonin transporter 0.014 uM CocaineNAMPHCATH Fleckenstein et al. (1999)

Monoamine-oxidase 50 uM CATH100XAMPH Nencini et al. (1984b)

a

Human receptors

b

from rat fundus; IC50, half maximal inhibitory concentration; EC50, half maximal effective concentration; AMPH, amphetamine; CATH,cathinone N.B there is no data as to the affinity of cathinone to dopamine and -adrenergic receptors.



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cathinone at inducing both spontaneous locomotion and stereo-

typed movement (Zelger et al., 1980; Woolverton, 1986; Peterson

et al., 1980; Kalix, 1983; Eisenberg et al., 1987). Another con-

stituent of khat alkaloid, norephedrine, failed to show stimulatory

effect in the open field test (Eisenberg et al., 1987). Taken together,

these findings indicate that cathinone is the constituent of khat that

is mainly responsible for the stimulatory effect of the plant and thatit is a potent amphetamine-like compound. Nevertheless, effects of

an entire khat extract, with its many constituents, would differ from

amphetamine with regard to the production of motor, and probably

other behaviours (Connor et al., 2002).

4.2.2. Analgesia

Khat leaves and its constituents have been shown to have

analgesic properties in animal experiments (Nencini and Ahmed,

1982; Nencini et al., 1998; Knoll, 1979; Della Bella et al., 1985;

Connor et al., 2002). This property is shared by amphetamine

(WHO, 1980; Nencini et al., 1998). Khat extract was shown to

exert analgesic effects in mice, albeit at high doses relative toibuprofen and amphetamine (Connor et al., 2000). It produced

analgesic effects in the tail flick test and hot plate test at a lower

dose (200 mg/kg and 600 mg/kg) and in acetic acid-induced

abdominal constriction assays at a higher dose (1800 mg/kg).

Cathinone has also been shown to cause a long lasting analgesic

activity in mice and rats (Nencini and Ahmed, 1982). This was

reversibly antagonized by naloxone, a pure opioid antagonist,

and by the noradrenaline synthesis inhibitors, -MPT (-methyl-

p-tyrosine) and diethyldithiocarbamate. Furthermore, cathine, a

metabolite of cathinone in humans, has been shown to enhance

the analgesic effect of morphine in hot plate and formalin test in

mice (Nencini et al., 1998).

4.2.3. Feeding behaviour

Anorexia, a characteristic effect of amphetamine-like sub-

stances, is a consequence of khat chewing (Halbach, 1972). This

feature of khat has been used for centuries to alleviate the sensation

of hunger (Zelger and Carlini, 1980; Kalix, 1983). Therapeutically,

the khat alkaloid cathine (norpseudoephedrine) and norephedrine

have been widely used as appetite suppressants in the modern world

(Kalix and Braenden, 1985). This anorectic effect of cathinone and

cathine has been observed in rhesus monkeys (Yanagita, 1979;

Foltin and Schuster, 1983), inrats(Zelger and Carlini, 1980; Knoll,

1979; Islam et al., 1990; Foltin et al., 1983; Eisenberg et al., 1987),

andin late pregnant guinea pigs (Jansson et al., 1988). Both isomersof cathinone and cathine markedly inhibited the food intake of rats

at intracerebroventricular doses of 300 and 500 g per animal

respectively (Knoll, 1979). Both cathine and ()-cathinone were

reported to be more potent than amphetamine in this regard (WHO,

1980). Systemic acute as well as chronic administration of the two

alkaloids in ratsshowed similar effects, howevertheywere reported

to be less potent than (+)-amphetamine in this order of potency:

amphetamineNcathinoneNcathine (Zelger and Carlini, 1980). On

the other hand, when cathinone was administered to rats via the

intargastric route, it was reported to be a more potent anorectic than

amphetamine and cocaine (Foltin et al., 1983). It was reported that

within a week there was development of tolerance to this effect of

cathinone, and the weight reducing effect disappeared within 3

4 weeks (Zelger and Carlini, 1980; Nencini, 1988; Nencini et al.,

1988; Foltin and Schuster, 1983). This is in contrast to

amphetamine in which tolerance developed only after 2 weeks

and its effect persisted for more than 7 weeks (Zelger and Carlini,

1980). Total and/or partial cross-tolerance was also observed

among all the three drugs. A similar pattern of cross tolerance

between () cathinone and (+) amphetamine was reported bySchuster and Johanson (1979). Anorexic effects of the other khat

alkaloid, norephedrine, have also been demonstrated in rats

(Eisenberg et al., 1987). In this study it was reported that both

cathine and norephedrine have a potency of one tenth that of

cathinone. Tolerance to the anorectic effects of khat alkaloids has

been extended to include cathine ( Zelger and Carlini, 1980). Taken

together, individual khat alkaloids have been shown to possess

anorexic properties, yet there has been no study so far where the

entire khat extract has been investigated for these properties in

animals.

Two models have been proposed to explain the reduction in

food intake of psychostimulants like cathinone (Wolgin andMunoz, 2006). According to some who advocate the Pavlovian

homeostatic model, the suppression of intake is due to loss of

appetite, which results in a failure to seek food (appetitive

behaviour) or to eat it (consummatory behaviour). Tolerance is

mediated by a compensatory increase in the motivation to eat.

Nencini et al. (1988), using this model, suggested that tolerance to

theanorectic effect of cathinone is associated with a sensitization to

endogenous kappa-opiate mediated activation of feeding. Indeed,

after 10 days of cathinone treatment, kappa agonist-induced

increase in food intake was about twice that induced by the same

dose of cathinone administered acutely ( Nencini, 1988; Nencini

et al., 1988). On the other hand, Wolgin and Munoz (2006)

suggested drug-induced locomotion and or stereotyped response tointerfere with the appetitive phase of feeding i.e. locating,

approaching, and orienting to food (the instrumental learning

model). They elegantly demonstrated that acute cathinone

injection produced decreased milk intake in bottle-but not in

cannula-fed rats, while motor activity increased in both groups.

They also showed that, after the tolerance phase, switching form

bottle to cannula feeding produced a further increase in intake,

whereas switching form cannula to bottle feeding produced

decreased intake.

4.2.4. Sexual behaviour

Khat and its alkaloid cathinone have been reported to affectmale sexual potency. There are contradictory reports regarding the

association between khat chewing and sexuality. Khat has been

reported to be used as an aphrodisiac (Krikorian, 1984; Giannini

et al., 1992; Browne, 1990; Bentur et al., 2007), and to treat

premature ejaculation (Luqman and Danowski, 1976). Similarly,

in females, khat chewing has been reported to increase sexual

desire (Elmi, 1983). Recently it was reported that a capsule

containing illicit cathinone have been marketed in Israel as a

stimulant and an aphrodisiac drug (Bentur et al., 2007). On the

other hand, impairment of sexuality(WHO, 1980; Halbach, 1972),

inability to sustain erection (Elmi, 1983), loss of libido (Krikorian,

1984; Kervingant, 1959), and spermatorrhea due to khat chewing

have been reported (Halbach, 1972; Granek et al., 1988; Elmi,



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1983). Taha et al. (1995) demonstrated that oral treatment of

cathinone (5 mg/kg/day) and itscombination with caffeine (50mg/

kg/day) for 15 days increased sexual arousal (motivation) in male

rats as evidenced by increased mounting performance and

anogenital investigatory behaviour with no stimulatory effect on

erectile and ejaculatory responses. Recently, Abdulwaheb et al.

(2007) reported that low doses of khat extract (200 mg/kg/day)exerted enhanced sexual motivation/arousal, characterized by

reduced mounting latency (ML) and intromission latency (IL),

while high doses of the extract (400 mg/kg/day) produced opposite

effects on both sexual motivation/arousal and performance in male

rats. In addition, concurrent administration of the low dose extract

followed by ethanol was found to enhance male rat sexual

motivation/arousal (Abdulwaheb et al., 2007). This is similar to

amphetamine, which at low dose is reported to evoke penile

erection, though its effect at high dose is inconclusive (Taha et al.,

1995). It was suggested that alteration of both dopamine (at low

dose) and or serotonin (at high dose) levels in the CNS could

explain the biphasic sexual behaviour of rats after khat adminis-tration, although the role of testosterone cannot be ruled out (Taha

et al., 1995; Abdulwaheb et al., 2007).

4.2.5. Cathinone in animal models of addiction

Animal models of addiction that mimic the human condition in

an informative way are critical for advances in the study of

addiction (Schramm-Sapyta, 2004). The various animal models

used to examine the neurobiological basis of drug addiction have

helped us to understand the role of cathinone/khat in the

development and maintenance of addiction. Cathinone has been

compared to amphetamine and cocaine in a wide array of

procedures of operant behaviour, and it is generally found to have

similar effects to amphetamine and cocaine (Woolverton andJohanson, 1984). Indeed, cathinone has been shown to have

reinforcing potential in self administration studies (to demonstrate

the dependence-producing potential of cathinone), drug discri-

mination procedures (to elucidate its similarity to other

psychostimulants such as amphetamine), food reinforced

responding, conditioned taste aversion test, and conditioned

place preference test (to assess the rewarding and motivational

effects of cathinone). These animal studies suggest that cathinone

has abuse potential as greatas that of cocaine andprobably greater

than that of amphetamine (Goudie, 1987). In addition to the

pharmacological properties of khat, the complex rituals of a khat

party could be used by consumers as environmental cues toidentify the appropriate conditions in which they enjoy khat

chewing (place, partner, and music) and could also be partly

responsible for khat's euphorogenic effects, through placebo

mechanisms (Nencini et al., 1986).

4.2.5.1. Self administration. Khat chewing has been described

as pleasurable and the behaviour of repetitive chewing of khat

leaves has been labelled as from of psychic dependence

(Halbach, 1979), characterized by compulsive khat consumption

(Kalix, 1983). Self administration studies are particularly useful

for the evaluation of the dependence potential of pharmacological

substances and are believed to have high predictive validity in

predicting abuse potential (Woolverton and Johanson, 1984). Self

administration studies using () cathinone have illustrated the role

of this alkaloid as a dependence producing compound among the

khat alkaloids (Kalix, 1983) enhancing the behaviour of animals

that gives them access to the substance (Kalix and Braenden,

1985). Johanson and Schuster (1981) and Yanagita (1986) have

reported that intravenous infusions of cathinone will maintain

responding in rhesus monkeys,which had been previouslytrainedto lever press for cocaine injections. When monkeys were given

the choice of self administering cathinone and cocaine, theychose

both equally often (Woolverton and Johanson, 1984; Johanson

and Schuster, 1981). The self administration pattern was reported

to be of the spree type, like cocaine and amphetamine, in which

monkeys took the drug frequently day and night, stopping only

when exhausted (Yanagita, 1979, 1986). They relapsed after a

period of rest of less than 24 h. This pattern corresponds to that

seen in amphetamine dependent humans (Kalix and Braenden,

1985). Similar results were obtained in rhesus monkeys, which

were first trained to self-administer cocaine intravenously by lever

presses, after which progressive ratio tests were conducted(Yanagita, 1979). Progressive ratio tests, which utilize the

breaking point generated by increasing the fixed-ratio require-

ment, are important measures of motivation to take the drug (i.e.,

how hard the individual will work for it) and to compare the

reinforcement magnitude of several psychostimulants (Willner,

1997). The final ratios obtained for () cathinone were similar

with amphetamine, and roughly half of those of cocaine in

monkeys (Yanagita, 1986).

Since self administration in primates is considered highly

predictive of abuse in humans, it is possible that abuse potential

of cathinone is as great as cocaine (Nencini and Ahmed, 1989).

This contention is further strengthened by the weak aversive

nature of cathinone, which, despite being an amphetamine-likedrug, possesses unexpectedly weak aversive properties (Goudie,

1987). Indeed, in the condition taste aversion procedure, which is

thought to be the animal analogue of aversive effects of drugs in

man which limit the intake of drug of abuse, cathinone was less

potent (1:17) than amphetamine (Goudie and Newton, 1985;

Goudie, 1987; Foltin and Schuster, 1982). In addition to the

aforementioned studies on primates, Gosnell et al. (1996) have

demonstrated intravenous self administration of cathinone in rats

under a continuous (FR1) reinforcement schedule. In contrast to

the primate models, however, when compared with amphetamine

and cocaine, cathinone produced a pattern of responding more

closely resembling amphetamine. This was characterized bymore frequent infusions at the beginning of the session than in the

middle or final portion of the sessions. They also reported that

pre-treatment with D1-type receptor antagonist SCH 23390,

increased the number of infusions, which suggests a role for D1type dopamine receptors in mediating its reinforcing effects.

4.2.5.2. Discriminative stimulus properties. The discrimina-

tive stimulus properties of drugs in animals are considered to be

predictive of their subjective effects in humans (Goudie, 1987,

1991). Further theyallow us to investigate the subjective effects of

the training drug as a function of time and dose, and to explore its

mode of action by the use of appropriate antagonists and

other pharmacological manipulations (Willner, 1997). (+)



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amphetamine trained rats responded as if they were given (+)

amphetamine when various doses of cathinone were administered

ip (Schechter et al., 1984; Schechter, 1986a,b; Rosecrans et al.,

1979; Nielsen and Schechter, 1985; Kalix and Glennon, 1986;

Huang and Wilson, 1986; Glennon et al., 1984). Similarly,

animals trained to detect cathinone react as if they had received

cathinone when injected with amphetamine and cocaine but notwhen injected with opioids, benzodiazepines or fenfluramine

(Goudie et al., 1986). In fact, the only difference between

cathinone, amphetamine and cocaine have been shown to be

temporal (Schechter, 1989; Schechter and Glennon, 1985).

Similarly, in rats trained to discriminate the interoceptive cues

produced by () cathinone, the administration of (+) cathinone

and (+) cathine produced () cathinone like responding, an

ability known as generalization (Schechter, 1990a; Pehek and

Schechter, 1990; Glennon et al., 1984). Moreover, direct

microinjection of cathinone into the nucleus accumbens (NAc)

was reported to produce discriminative stimuli (Schechter et al.,

1992). Cathine was also shown to have discriminative stimulusproperties in a two choice food motivated, drug discrimination

paradigm (Pehek and Schechter, 1990). Recently, Li et al. (2006)

have demonstrated that when cathinone was given before or

concurrently with cocaine to rats in a drug discrimination proce-

dure, the cocaine dose effect function was shifted to the left

suggesting cathinone generalizes to cocaine.

The drug discrimination procedure is used not only to test the

similarity and dissimilarity of psychoactive drugs, but it can

also be used to investigate the production of tolerance after

chronic treatment of trained rats (Schechter, 1990a). Indeed, it

was reported that tolerance tends to develop to cathinone in their

ability to control discriminative behaviour, indicated by deficits

in discriminative performance and shift of the dose responsecurve to the right (Schechter and McBurney, 1991; Schechter,

1986a,b). Similarly, Schechter (1990a) reported an acute

tolerance effect of cathine in their ability to control discrimi-

native behaviour, indicated by deficits in discriminative

performance.

4.2.5.3. Food-reinforced responding. Similar to amphetamine,

cathinone interferes with the reinforcing properties of food. This

modification of food-motivated behaviour has been demonstrated

in rats (Yanagita, 1979; Peterson et al., 1980; Goudie, 1985) and

in monkeys (Schuster and Johanson, 1979). Initially it was

demonstrated that cathinone (0.5 mg/kg) increased the responserate in rats under a differential reinforcement of low rates of

responding schedule [e.g. DRL 20 s] (Yanagita, 1979).

Differential reinforcement of low rate schedules are known to

produce low rates of responding as only those responses that

occur after a minimum time interval after a previous response are

reinforced. Subsequently, it was reported that large dose of

cathinone suppresses operant responding in rats under fixed

interval and fixed ratio schedule of food delivery (Peterson et al.,

1980; Goudie, 1985). Goudie (1985) illustrated that the effect of

cathinone, like (+) amphetamine is rate dependent; i.e. has a

tendency to increase low rates of responding and decrease high

rate of responding. The potency ratio of cathinone and (+)

amphetamine in this regard was similar (1:3) to that reported for

other behavioural tests (Peterson et al., 1980; Johanson and

Schuster, 1981; Goudie, 1985). Similar resultshavebeenobtained

in monkeys, where both amphetamine and cathinone were shown

to suppress responding maintained by a multiple fixed interval

and fixed ratio schedule for the delivery of food reward in a rate

dependent manner (Johanson and Schuster, 1981). Cathine,

though less potent than cathinone, was also shown to producesimilar effect on food reinforced responding (Peterson et al.,

1980). The suppression of overall food reinforced responding

may be explained in terms of drug-inducedbehavioural disruption

and response competition (Goudie, 1985).

4.2.5.4. Conditioned place preference. Conditioned place

preference is a method of assessing the rewarding and

motivational effects of drugs of abuse (Willner, 1997). This

behavioural task, which involves the pairing of drug cues with a

distinctive environment, has been shown to produce a dose-

response location preference with ip cathinone, similar to

cocaine and amphetamine in rats (Schechter and Meehan, 1993;Schechter, 1991). Furthermore, intracerebroventricular injec-

tion of cathinone to rats, when paired with confinement in the

non-preferred side of the conditioned place preference appara-

tus, increased the time spent on that side, which suggest that this

behaviour is of central in origin (Calcagnetti and Schechter,

1993). It is generally believed that cathinone-induced condi-

tioned place preference is mediated by dopaminergic neurons

(Kalix, 1990; Calcagnetti and Schechter, 1993). This contention

is supported by evidence that pre-treatment with a dopamine

release inhibitor attenuates place preference induced by

cathinone (Schechter, 1991, 1990b; Calcagnetti and Schechter,

1993).

4.3. Khat and neurochemistry

The stimulatory effect of cathinone is believed to be mediated

by the dopaminergic system, similar to amphetamine (see Table4)

(Kalix and Braenden, 1985). In support of this, it has been

demonstrated that substantial release of radioactivity induced by

low dose cathinone in a dose-dependent manner, similar to

amphetamine, from isolated rabbit caudate nucleus prelabelled

with [3H] dopamine (Kalix and Glennon, 1986; Kalix, 1983,

1981, 1980b). Moreover, pretreatment with cocaine, which is

known to prevent the induction of release by amphetamine,

inhibited the efflux increase caused by cathinone (Kalix, 1981).Ina similar manner, cathinone increased efflux from isolated rat

caudate nucleus (Kalix, 1982) and striata (Zelger and Carlini,

1981) prelabelled with [3H] dopamine. Three known catecho-

lamine reuptake inhibitors, nomifensine, mazindol and benz-

tropine that have been shown to inhibit amphetamine induced

circling behaviour were found to inhibit (block) cathinone

induced [3H] dopamine release from these tissues (Kalix,

1982). This suggests that () cathinone has to penetrate to

intraneuronal sites in order to evoke release, and that the uptake

inhibitors prevent this penetration. Moreover, support for the

hypothesis that cathinone/khat requires an intact dopaminergic

system to exert their effect upon activity has been evidenced

by reports that dopamine antagonists (Zelger et al., 1980),



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dopamine release inhibitors (Calcagnetti and Schechter,

1992b), or pretreatment with the relatively selective dopami-

nergic neurotoxin 6-OHDA (Zelger and Carlini, 1981; Banjaw

and Schmidt, 2006), into mesolimbic pathways significan

Documents

A Review of the Neuropharmacological Properties of Khat[1]