a review of the neuropharmacological properties of khat

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Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1147–1166www.elsevier.com/locate/pnpbp

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 2007Available 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 readilyavailable 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’ or’qaad/jaad’ or ‘cathinone’ was used to obtain articles relevant tokhat 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 whichinvestigated the entire plant extract in either in vitro or animal studies. In the majority of the studies it was reported that both cathinone andcathine, 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 morethorough examination of khat itself in well designed in vitro, animal and human studies with a range of comparator drugs before confirming theclaim that khat is a “natural amphetamine”.© 2008 Elsevier Inc. All rights reserved.

Keywords: Cathinone; Dopamine; Khat; Neuropharmacology; Psychosis

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11481.1. Prevalence of use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11481.2. Legal considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1149

2. Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11493. Analysis of active constituents of khat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1149

3.1. Active constituents of khat leaf . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11493.2. Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11503.3. Detection of khat alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1152

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

4.1.1. Psychosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11534.1.2. Aggression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11544.1.3. Mood disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11544.1.4. Addiction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11544.1.5. Khat-induced neurotoxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1155

Abbreviations: AUC, area under the curve; DOPAC, Dihydroxyphenylacetic acid; DRL, Differential reinforcement of low rates; GC–MS, 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).

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1148 A.M. Feyissa, J.P. Kelly / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1147–1166

4.2. Behavioural studies in animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11554.2.1. Motor activity and stereotyped behaviour . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11564.2.2. Analgesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11584.2.3. Feeding behaviour. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11584.2.4. Sexual behaviour . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11584.2.5. Cathinone in animal models of addiction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1159

4.3. Khat and neurochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11605. Algorithms of laboratory/preclinical studies on khat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11616. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11627. Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1162Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1163References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1163

1. Introduction

Khat, Catha edulis Forsk, is an evergreen shrub or treefound growing wild or cultivated in the east of a regionextending from Southern Africa to the Arabian Peninsula(Krikorian, 1984). The habit of khat chewing has prevailed forcenturies in this part of the world, being cited in certain ancienttexts, including the Old Testament (Cox and Rampes, 2003).The earliest scientific report on khat in the West was in theeighteenth century when the botanist Peter Forskal identifiedthe plant in Yemen and called it C. edulis. There are severalnames for the plant, depending on its origin: tchat—Ethiopia,qat—Yemen (Alem et al., 1999), qaad/jaad—Somalia (Elmi,1983), miraa—Kenya (Patel, 2000), mairungi—Uganda(Ihunwo et al., 2004), Muhulo—Tanzania, Hagigat—Hebrew(Bentur et al., 2007), cat, catha, gat, tohai, and muraa(Fasanmade et al., 2007). The dried leaves of khat areknown as Abyssinian tea or Arabian tea (WHO, 2006).These many names attest to the widespread and presumablyfairly old knowledge of C. edulis by native peoples of easternand Southeastern Africa (Krikorian, 1984). However, the mostcommon name is khat (Alem et al., 1999).

Recently published reviews on khat and cathinone focus onadverse health aspects and have only briefly addressed theirpharmacology (Cox and Rampes, 2003; Al-Hebshi and Skaug,2005; Al-Habori, 2005), or they investigate whether khat causesmental disorders in general (Warfa et al., 2007) or how it isspecifically linked to psychosis (Odenwald, 2007). In particular,there is a lack of emphasis on the pharmacokinetics andbehavioural pharmacology of khat. Thus the principal purposesof this review are to:

a) determine whether khat and its active principles arecomparable to other stimulants such as amphetamines; and

b) to detect gaps in our knowledge of the neuropharmacologyof khat.

To our knowledge, this review is the first in its kind in thearea to critically analyze past literature and to proposesuggestions for further investigation based on the limitationsidentified in this review.

1.1. Prevalence of use

Fresh leaves from khat trees are chewed daily by over20million people on the Arabian Peninsula and East Africa (Sahaand Dollery, 2006; Al-Motarreb et al., 2002). The khat chewinghabit is deeply rooted in the sociocultural traditions of thesecountries (Stevenson et al., 1996; Kennedy et al., 1983). Many ofthe users originate from countries between Sudan and Madagas-car and in the southwestern part of the Arabian Peninsula. Khatuse is particularlywidespread in Ethiopia, Kenya,Djibouti aswellas Yemen, where its use is socially sanctioned and even pres-tigious (Kalix, 1990; Belew et al., 2000). Khat is consumed atparties in combination with smoking cigarettes and drinking teaand soft drinks (Baron, 1999). The biggest population of chewersis in Yemen, where the plant is used as a social stimulant (Al-Motarreb et al., 2002). Recent reports suggest that 80–90% of themale adult and 10–60% of the female adult population in EastAfrica consume khat on a daily basis (Odenwald et al., 2005;Numan, 2004).

The use of khat has traditionally been confined to the regionswhere khat is grown (Yousef et al., 1995; Kalix and Khan, 1984;Al-Zubairi et al., 2003), because the shoots must be used fresh forthe desired effects (Kite et al., 2003). In recent years, however, theeconomic importance and consumption of khat leaves haveincreased dramatically (Sawair et al., 2007; Odenwald, 2007).This change is due to improved road and air transport, which hasallowed 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 andsell fresh khat leaves (Toennes and Kauert, 2002; Beyer et al.,2007; Bentur et al., 2007). In addition, the influx of immigrantsfrom East Africa and Arabian Peninsula, who continue to usekhat, has resulted in the importation of khat to countries wherethese immigrants have settled, including Europe and the UnitedStates (Toennes andKauert, 2004; Rousseau et al., 1998). In theseimmigrant communities, the khat party is an important socialevent and is a way for the participants to keep their ethnic identity(Stevenson et al., 1996; Nencini et al., 1989) and relieve the stressof living in a foreign country (Griffiths et al., 1997; Bhui et al.,2006, 2003). In theUK, khat is used by (mainlymale)members ofthe Somali and Yemeni community (Griffiths et al., 1997;

1149A.M. Feyissa, J.P. Kelly / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1147–1166

Cunningham, 1998), and the prevalence has been shown to reach80% in Somali immigrants in London (Griffiths et al., 1997),whilst in the USA khat use, which gained popularity during thefirst PersianGulf crisis (Lurie et al., 1994; Giannini et al., 1992), ismost prevalent amongst immigrants from Yemen, Somalia andEthiopia (Browne, 1990). Khat use has also been reported in EastAfrican communities in Italy (Nencini et al., 1989), Israel (Graneket al., 1988), Australia (Stevenson et al., 1996), Norway, Holland,Belgium,German, Switzerland andCanada (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 theOrthodox Tewahdo Church prohibiting its use), Somalia(though briefly banned during the six months rule of the UnitedIslamic Courts in Mogadishu in 2006) and some other EastAfrican countries (Widler et al., 1994; Hattab and Angmar-Månsson, 2000; Alem et al., 1999). Almost every small kiosk inAddis Ababa, the Ethiopian capital, openly sells khat, and insmall cities and towns all over the country it is brought tomarket as produce, where people publicly chew it and offer it tovisitors as a mark of hospitality (Selassie and Gebre, 1996). InYemen and Ethiopia there have been attempts to curtail the habitfor social and economic reasons but these have met with littlesuccess (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 isconsumed by government officials, making its regulation verydifficult.

Although the active alkaloids of khat, namely cathinone andcathine have been labeled as Schedule I and Schedule IIIsubstances respectively by WHO since 1971 (WHO, 2003), itsstatus in European countries is not uniform (Kalix, 1990). Forexample, 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 inAustralia (Saha and Dollery, 2006; Patel, 2000; Fasanmade etal., 2007). Recently, the WHO Committee reviewed the dataon khat and determined that the potential for abuse anddependence is low and the threat to public health is notsignificant enough to warrant international control, and did notrecommend the scheduling of khat (WHO, 2006). Severalauthors have also suggested weighing the evidence dispassio-nately before sounding alarm on what is an importantsubstance for sections of the immigrant population of manywestern countries (Weir and Thuriaux, 1988; Warfa et al.,2007).

2. Methodology

A literature research was conducted via PubMed search enginewith 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 limitednumber of references that were not listed in the database were alsoused. The search was performed up to September 20, 2007. Theresearch only included articles available in English that werepublished from 1959 to 2007. The full text of 284 articles or reportsthat provided original data on khat chewing or its activecomponents in animal and human studies were reviewed, amongwhich those that contained research on the epidemiology, analyticalaspects or neuropharmacological properties of khat were identified.Expert-based commentary papers and papers describing thepharmacological properties of khat were also included. In total150 articles which belonged to the aforementioned areas wereselected. From these 150 articles, 70 original reports using khat andor its active principles in their in vitro, animal studies weresubjected to an algorithm for defining an ideal study on khat withregard 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 before

subjects/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 threecriteria. We also used these criteria to comment on the existingevidence 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 consistsof 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 ofkhat and these include:

• Alkaloids, terpenoids, flavonoids, sterols, glycosides, tan-nins (7–14% by weight).

• More than 10 amino acids including tryptophan, glutamicacid, glycine, alanine and threonine (Szendrei, 1980; Luq-man and Danowski, 1976; Halbach, 1972; Geisshüsler andBrenneisen, 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-Månsson, 2000; Halbach, 1972), manganese (Halbach,1972), copper, zinc, and toxic metals like lead and cadmium(Matloob, 2003) and a negligible amount of fluoride (Hattaband Angmar-Månsson, 2000).

Fig. 1. Chemical structure of S-(+)-amphetamine and S-(−)-cathinone(MW=149.2).

Table 1Concentration of khat alkaloids from fresh khat leaves of various origin

Cathinone Cathine Norephedrine References

0.74±0.40 1.49±0.51 0.9±0.16 Dimba et al. (2004)1

1.09±0.8 3.60±1.9 0.25±1.8 Geisshüsler and Brenneisen (1987)2

1.02±0.11 0.86±0.06 0.47±0.05 Widler et al. (1994)1

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


Most of our present knowledge on the constituents of khat isderived from studies in the late 1970s and 1980s followingrecommendation by the UN Commission on Narcotic Drugs(Kite et al., 2003). The phenylalkylamines and the cathedulinsare the major alkaloids. Szendrei (1980) at the UN NarcoticsLaboratory, together with Schorno and Steinegger at theUniversity of Berne, Switzerland, isolated and identified thephenylalkylamine, (−)-α-aminopropiophenene, later named asS-(−)-cathinone as a major active constituent in fresh khat. Theplant contains the (–)-enantiomer of cathinone only (WHO,2006; Gugelmann et al., 1985) which has the same absoluteconfiguration as S-(+)-amphetamine (see Fig. 1) (Kalix, 1990;Goudie, 1987). During maturation, cathinone is enzymaticallyconverted to cathine [(+) norpseudoephedrine] and (−)-norephedrine (Al-Obaid et al., 1998). Sunlight-induced orheat-induced degradation to cathine and norephedrine alsooccurs during extraction of cathinone in the laboratory (Banjawet al., 2005). Indeed, to slow down the degradation process, thekhat leaves are usually wrapped in banana leaves immediatelyafter picking to retain their moisture (Yousef et al., 1995).

Fig. 2. Chemical structures of S-(−)-cathinone, S, S-(+)-norpseudoephedrine(cathine) and R, S-(−)-norephedrine (MW=151.2). Cathinone is transformedmainly to cathine in khat leaves and mainly to norephedrine by humanmetabolism. Modified from Sporkert et al., 2003.

Other alkaloids of phenylalkylamines in khat leaves includethe phenylproanolamine diastereoisomers of cathine [1S, 2S-(+)norpseudoephedrine or (+) norpseudoephedrine], and norephe-drine [1R, 2S-(−) norephedrine]. Cathine and norephedrineoccur mainly in older plants and is also formed by reduction ofcathinone during drying and storage (see Fig. 2) (Sporkert et al.,2003). The environment, climate conditions, as well as localtraditions connected with cultivation and harvesting determinethe chemical profile and general appearance of khat leaves(Nordal, 1980). The phenylalkylamine content of khat leavesvaries widely. In certain khat samples, the phenyalkylaminefraction 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 ofkhat samples from Kenya and Ethiopia have shown that thecommercial value of the material correlates with its cathinonecontent (Geisshüsler and Brenneisen, 1987).

Another class of phenylalkylamine alkaloids found in khatleaves are the phenylpentenylamines; merucathinone, pseudo-merucathine and merucathine, which are mainly detected inkhat leaves originating from Kenya (Brenneisen and Geisshüs-ler, 1987) (Fig. 3). They seem to contribute less to the stimulanteffects of khat (Kalix et al., 1990) and their concentration isrelatively low (Brenneisen and Geisshüsler, 1987). Otherclasses of alkaloid in khat are the cathedulins, classifiedaccording to their relative molecular mass (Kite et al., 2003;Crombie, 1980). Recently, 62 different cathedulins derivedfrom fresh khat leaves were characterized (see Fig. 4) (Kiteet al., 2003). Though there has been much research on thephenyalkalymines, there has been little investigation of thecathedulins 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 thoroughlychewed; they are then kept for a while in the cheek as a ball ofmacerated 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 releasethe active components or keep it in buccal vestibules (Sawair et al.,2007). During the khat session the leaves and the bark of the plantare chewed slowly over several hours, usually for 2–10 h andan average 100–500 g of khat is chewed (Nencini and Ahmed,1989; Matloob, 2003; Kalix, 1990; Elmi, 1983; Al-Hebshi andSkaug, 2005). The juice of themasticated leaves is swallowed, butnot the residues (Toennes et al., 2003). During chewing, the

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


alkaloids from khat leaves are effectively liberated, with about80% of cathinone and cathine, and over 90% of norephedrinereleased following chewing (Toennes and Kauert, 2002). Theabsorption of the constituents of khat is said to have two phases,the first being at the buccal mucosa, plays a major role in theabsorption of alkaloids (Toennes et al., 2003). The second phase isfollowing swallowing of the juice, at the stomach and/or smallintestine (Toennes et al., 2003).

Fig. 4. Structure of K-19 (1), one of the most highly elaborated members of the catAdapted from White, 1994.

Cathinone has been determined in spiked human plasma inkhat naïve volunteers after 0administration of synthetic cathinone(Widler et al., 1994; Brenneisen et al., 1990) or after the chewingof khat leaves (Widler et al., 1994; Toennes et al., 2003; Halketet al., 1995). The pharmacokinetic parameters for cathinone andother ingredients of khat leaves have been determined over 8 h,with peak plasma levels attained after 1–3.5 h (Halket et al.,1995; Brenneisen et al., 1990). Similarly, maximal plasma

hedulin family with its polyhydroxylated sesquiterpenoid euonyminol core (2).


concentrations (tmax) of cathinone, cathine and norephedrine arereported to be reached at 2.3, 2.6 and 2.8 h respectively (Toenneset al., 2003). After ingestion of 0.8 mg/kg cathinone it wasreported that the total amount of cathinone absorbed in the bodyafter 9 h (AUC; area under the curve) was 25±13 μg min ml−1,and the terminal elimination half-life was 260±102 min (Widleret al., 1994). In another study, 8 h after four drug naïve volunteersingested khat (0.6 g/kg), the AUC of cathinone, cathine andnorephedrine was reported to be 245±49, 13±131, 710±173 μgmin ml−1 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; Geisshüslerand Brenneisen, 1987; Brenneisen et al., 1990). Metabolismof cathinone to cathine involves reduction of the ketone groupto 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 isexcreted unchanged in the urine (Toennes et al., 2003; Guantaiand Maitai, 1983), and is mainly excreted in the form ofnorephedrine and cathine (Toennes and Kauert, 2002; Kalixet al., 1990; Brenneisen and Geisshüsler, 1987). The amountof norephedrine excreted in urine is much higher than theamount ingested, indicating that (−) cathinone is alsometabolized to R, S-(−) norephedrine (Toennes and Kauert,2002). Cathine has been found in breast milk in severallactating 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 methodsare similar to those used for amphetamines because of theirstructural similarity (Sporkert et al., 2003). Analysis of urineand blood provides information on recent or current exposureto drug use, whilst analysis of hair samples provides detectionof long term and repeated use (Kim et al., 2007). Recently amulti anylate procedure has been developed to determinecathinone and other phenyalkylamines in plasma using LC-MS/MS [Liquid Chromatography/Mass Spectrometry/MassSpectrometry] (Beyer et al., 2007). Using this technique it hasbeen 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 layerchromatography), HPLC (High-performance liquid chromato-graphy), gas chromatography, and GC–MS [Gas chromato-graphy-mass spectrometry] (Mathys and Brenneisen, 1992;Guantai and Maitai, 1983; El-Haj et al., 2003). Toennes andKauert (2002) demonstrated that GC–MS, which could detectcathine and norephedrine for up to 80 h and cathinone for upto approximately 24 h after khat ingestion, is superior to theother techniques for screening and confirmation testing ofurine 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 urineanalysis (Toennes and Kauert, 2002). Therefore, khat use canbe confirmed only by the detection of cathinone in the absenceof N-alkylated homologs (e.g. methcathinone) from urinesamples (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 relativelylower incorporation rate into hair in comparison to otheramphetamines (Nakahara and Kikura, 1996). However, laterstudies in human hair from drug users using GC–MSseparation technique detected cathinone, cathine and norephe-drine (Sporkert et al., 2003; Kim et al., 2007). The proportionof alkaloids detected from the hair was in the same order asurine 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 andAhmed, 1989; Kebede et al., 2005). These effects, which havebeen observed in several clinical trials and animal studies withkhat and or cathinone (Widler et al., 1994; Kalix et al., 1990;Brenneisen et al., 1990), are similar to those observed withamphetamine (Halbach, 1979). The khat chewer believes thatthey think more clearly and quickly and are more alert, althoughtheir concentration and judgment are objectively impaired(Pantelis et al., 1989). In view of its potency and its higher lipidsolubility (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 ispredominately, or even exclusively due to the cathinone content ofthe leaves (Kalix, 1990). This is substantiated by the briefstimulation after khat chewing (Kalix et al., 1990), which is inagreement with the finding that cathinone is metabolized rapidly(Brenneisen and Geisshüsler, 1987). The major metabolites ofcathinone, i.e. cathine and norephedrine, possess weaker centralstimulant 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 aweak effect on dopamine release in dopamine prelabelled ratstriatal tissue (Kalix et al., 1990). The pharmacology ofcathedulins has not yet been well characterized in the CNS andother organs (Kite et al., 2003). Although other pathways couldnot be ruled out, there is enough scientific data to suggest khat/cathinone-induced psychostimulation is mediated primarily viathe meso–striato–cortico limbic dopaminergic pathway (Kalix,1990). This is further strengthened by the observation thatsubcutaneous administration of cathinone prevented the catalepsytypically 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, andanorexic effects of khat/cathinone are believed to be partlymediated via this pathway (Gosnell et al., 1996).


4.1. Psychological sequelae of chewing khat

In recent decades, the traditional habit of chewing the leaves ofthe khat shrub has undergone profound changes in African andArab countries, from a socially regulated use pattern towardsuncontrolled 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 chewersdisplay a range of experiences, from minor reactions to thedevelopment of a psychotic illness. Minor reactions include over-talkativeness, hyperactivity, insomnia, anxiety, dizziness, impairedconcentration, irritability, agitation and aggression which usuallyoccur after a moderate intake of khat (Griffiths et al., 1997; Coxand Rampes, 2003), and bruxism (Walter, 1996). These minorpsychotoxic reactions to khat are so well known in Ethiopia forinstance, khat users displaying these features have been given thename jezba (Kalix, 1990). Among the several alkaloids in khat,cathinone is incriminated for most of psychological sequelaerelated with khat chewing (Elmi et al., 1987).

There are a number of reports of psychiatric disorderssecondary 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), inducedhypnagogic hallucinations (Granek et al., 1988), depression(Pantelis et al., 1989). In addition there have been reports ofpersonality disorders associated with long term khat use (Kalixand Braenden, 1985). Recently Odenwald et al. (2007) hasreported a positive association between Post Traumatic StressDisorder (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 khatchewing and subsequent intoxication phase, have been associatedwith self harm and suicide (Cox andRampes, 2003). Accordingly,two cases of homicide and combined homicide and suicide havebeen reported following consumption of khat (Pantelis et al.,1989; Alem and Shibre, 1997). Furthermore, khat chewers oftentake alcohol to counteract the stimulant and sleep depriving effectof khat, which raises the risk of interactions between alcohol andkhat (Omolo and Dhadphale, 1987; Kebede et al., 2005).

There is an ongoing international debate about a causalrelationship between khat use and mental illness (Warfa et al.,2007; Odenwald, 2007; Bimerew et al., 2007). Severalinvestigators claim that khat use is not necessarily linked topsychological morbidity; any association that is found mayreflect an interaction with other environmental factors (Warfa etal., 2007; Odenwald et al., 2005). Warfa et al. (2007) reviewedthe literature on the association between khat use and mentalillness 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 clearevidence as to the effects of khat use and the development ofmental illness'. Odenwald (2007) in a review of 45 articles in thisarea, has criticised that the majority of the reports andinformation about epidemiology and use patterns are merely

expert opinions and unsystematic observations, i.e. not sub-stantiated by rigorous clinical testing. However, he suggestedthat heavy khat chewing could induce brief psychosis and couldtrigger or exacerbate pre-existing schizophreniform spectrumdisorders (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 beattained after chewing (Giannini and Castellani, 1982). Secondly, itis thought that in khat-using areas where health facilities arelacking, people with psychotic symptoms are locked in their homesby families until the episode subsides (Yousef et al., 1995; Luqmanand Danowski, 1976). However, there have been growing reportsof khat-induced psychosis in khat producing areas and inimmigrants 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 tosocial dislocation, and abnormal patterns of drug use, and pre-existing stressful situations (Pantelis et al., 1989; Giannini andCastellani, 1982; Bhui et al., 2006, 2003). Pantelis et al. (1989) andYousef et al. (1995) summarized clinical features of khat-inducedpsychosis; most of the cases in Europe were Somali males with aminority of the cases having past psychiatric history and familypsychiatric history. Heavy khat consumption preceded thepsychotic episode and themajority of the cases had rapid resolutionwhen treated pharmacologically, usually by antipsychotic medica-tion of the phenothiazine type. There was a tendency for thepsychotic episodes to recur upon recommencement of khatchewing (Alem and Shibre, 1997). Few of the cases hadspontaneous resolution without pharmacological treatment oncethey stopped abusing khat (Yousef et al., 1995; Nielen et al., 2004;Alem and Shibre, 1997). The characteristics of psychosis followingthe use of khatweremainly of twomain types:manic psychosis andparanoid or schizophrenia spectrum disorder (Cox and Rampes,2003; Bimerew et al., 2007). The latter is very similar to paranoidpsychosis seen with chronic amphetamine and cocaine addicts(Pantelis et al., 1989; Ellison, 2002). It is postulated that khatconsumption precipitates psychosis by either increasing the risk inalready vulnerable individuals or affecting the course of a psychoticdisorder and themaintenance of symptoms (Odenwald et al., 2005).

To date the direction of causality between long term psychosisand khat use remains unclear. In general, previous investigationssuggesting a link have been criticised for they suffer from meth-odological problems and lack of quantitative data (for a review seeOdenwald, 2007). Nevertheless, recent studies using laboratoryanimal models of behavioural sensitization, which bears strikingsimilarities to the progressive development of psychosis andparanoia that develops in human addicts following repeatedpsychostimulant administration, suggest the possibility of positiveassociation between khat use and long term psychiatric morbidity.Accordingly, Banjaw and co-workers (2005) have reportedlocomotor sensitization and prepulse inhibition deficit, twoparadigms that have been widely studied as animal models of


psychosis, after intermittent oral administration of (−) cathinone orC. edulis extract in rats. In both instances there is progressiveaugmentation of either locomotor-stimulatory effects (locomotorsensitization) or deficit in prepulse inhibition (i.e. deficit in thestartle reducing effect of a weak prepulse preceding a startlestimulus by 30–200 ms) upon repeated administration ofpsychostimulants including amphetamine, cathinone and cocaine(Ellison, 2002; Banjaw et al., 2006). This finding suggests thathumans who useC. edulis over an extended period could be at highrisk of incurring neuropsychiatric diseases (Banjaw and Schmidt,2005). Clozapine, an atypical antipsychotic widely used to reversethese behavioural changes in animal models, was shown toattenuate these deficits (Banjaw et al., 2005). They also reportedincreased dopamine levels in prefrontal cortex with reduceddopamine and its metabolites in anterior putamen, and decrease in5-HT in nucleus accumbens and its metabolites in prefrontal cortex(Banjaw et al., 2005; Banjaw and Schmidt, 2005). The reduction indopamine and its metabolites is in contrast to amphetamines, whichare known to increase dopamine in the caudate putamen in thelocomotory sensitization paradigm. These results suggest that thebehavioural effects of C. edulis or cathinone are mediated, at leastin part, by dopamine in the meso–striato–cortico limbic pathway(Banjaw et al., 2005). This pathway is believed to play a central rolein the induction, maintenance and expression of sensitizationfollowing repeated administration of psychostimulants (Banjawand Schmidt, 2005). Indeed, psychosis due to cocaine andamphetamine, closely related drugs to cathinone, is similarlybelieved to be mediated via this pathway (Goudie, 1987; Ellison,2002).

4.1.2. AggressionPrevious literature reviews show that there are scant data on the

long-term relationship between khat abuse and aggression despitetraditional claims that prolonged abuse of this psychostimulantplant may influence the behavioural characteristics of individualsand lead to heinous violence (Cox and Rampes, 2003). However,there have been reports of khat-induced aggressive verbaloutbursts and violent behaviour in the past (Luqman andDanowski, 1976; Giannini and Castellani, 1982). Recently, in acommunity based study in Somalia, there was evidence of thepresence of disruptive and violent behaviour amongst chronic khatusers (Odenwald et al., 2005). Incidentally, Berardelli et al. (1980)observed a spontaneous burst of aggressive behaviour in rats afterintraperitoneal (ip) administration of cathinone, similar to that seenwith amphetamines. Recently, Banjaw et al. (2006) havereproduced this phenomenon using isolation induced aggressionparadigm, in which repeated oral administration of C. edulis or S(−) cathinone enhanced aggressive behaviour of isolated rats.Similar to amphetamine, neurochemical correlates revealeddepletion of serotonin and its corresponding metabolites in bothanterior and posterior striatum, which suggest that aggression inthis paradigm is enhanced presumably by decreasing the level ofserotonin and its metabolites (Banjaw et al., 2006).

4.1.3. Mood disordersKhat chewing can induce a substantial degree of mood

disturbances, particularly depression in healthy subjects (Hassan

et al., 2002). Depression associated with khat chewing has beenreported 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 ofcessation of khat chewing (reactive depressive mood). Theseverity 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 khatchewing in human mood using the HAD (Hospital Anxiety andDepression) Scale. They reported that khat chewing results in afunctional mood disorder consisting of predominantly reactivedepressive mood (seen an hour after acute khat administration),and it might exacerbate symptoms in patients with pre-existingmood disorder. It is thought to be mediated by the sympatho-mimetic action of cathinone (Hassan et al., 2002). Other mooddisorders such as khat-induced behavioural syndrome describedas 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. AddictionThe use of khat often starts at a young age and can develop into

a compulsive daily habit lasting a lifetime (Patel, 2000). Khattaking 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 instancescompulsive, as indicated by the tendency of khat chewers tosecure their daily supply of the leaves at the expense of vital needsand their behaviour at the markets (Nencini et al., 1988; Kalix andBraenden, 1985). This is described as a psychological dependenceby many authors (Kalix, 1990; Gosnell et al., 1996; Connor et al.,2002). In eastern African countries the prevalence of khatdependence is estimated to be 5–15% of the population (Nielenet al., 2004). The first documented case of khat addiction was thatof Amda Tsion, an Ethiopian ruler in the early 14th century, andhis subjects in the city of Mar'ade (Dillmann, 1884 as quoted byGiannini et al., 1992). Giannini et al. (1992) reported two cases ofkhat addiction which were effectively treated with bromocriptineusing a protocol developed for cocaine addiction. From theirdescription 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 forsubstance abuse. It is postulated that khat could have a higherdependence potential than amphetamine (Kalix, 1990) because ofits less aversive nature (Foltin and Schuster, 1983; Goudie andNewton, 1985), higher rate of self administration, and rapid onsetof action in discrimination experiments (Yanagita, 1979;Johanson and Schuster, 1981) when compared to amphetaminein various operant experiments (See Section 4.2.5). Althoughcathinone is known to cause sensitization upon repeatedadministration similar to amphetamines (See above), there arereports of tolerance to the CNS stimulating effects of khatchewing. This is alleged to be due to the physical limits on theamount that can be chewed rather than the inherent property ofkhat leaves (WHO, 1980). There are conflicting opinionsregarding the existence of a withdrawal syndrome. Generally it


is believed that there is no physical withdrawal syndrome asexperienced with alcohol, morphine or barbiturates (Sulzer et al.,2005; Luqman and Danowski, 1976; Kalix, 1984). Abandoningthe khat-chewing habit however is followed by symptomsincluding lassitude, anergia, nightmares, slight trembling, anddepression (Luqman and Danowski, 1976; Elmi, 1983; Cox andRampes, 2003; Alem et al., 1999). Indeed, habitual users reportthat they have no serious difficulties when moving to an areawhere khat cannot be obtained (Kalix, 1990). However, there arereports of social withdrawal symptoms after cessation of the habit,described as ‘experiences of deprivation of joys and camaraderiewhich khat session almost unfailingly provides’ (Stevenson et al.,1996).As in the case of drug abuse in industrialized societies, khatuse is associated with simultaneous use of other drugs especiallycigarette and alcohol (Zein, 1988; Hassan et al., 2007). Cigarettesmoking is believed to enhance the effect obtained by chewingkhat and to reduce its bitter taste while alcohol is widely used tocounteract the stimulatory effects of khat. The concomitant use ofpsychotropic agents such as hypnotics is also common (Zein,1988).

4.1.5. Khat-induced neurotoxicityThere 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 livingin UK who presented with leucoencephalopathy associated withkhat misuse. EEG and MRI findings indicated progressiveleucoencephalopathy but this could not be linked with khat use.In addition, the CNS stimulating effect of khat has shown toreach the level of acute and chronic toxicity as evidenced bygrowing reports of psychiatric morbidity associated with khatuse (Nielen et al., 2004; Alem et al., 1999). However, there arefew studies which aimed at assessing the CNS toxicity ofdifferent constituents of khat (Wagner et al., 1982; Al-Zubairiet al., 2003). There is also a lack of information regarding theeffect of khat on the level of different neurotoxic/neuroprotec-tive factors such as BDNF and lipid peroxidase in the brain. Todate, the main finding has been that khat/cathinone induces therelease of dopamine from presynaptic storage sites (Kalix andBraenden, 1985) and chronic administration of either the wholeextract or cathinone (100 mg/kg) results in a significantdepletion of dopamine in several brain areas, particularly onthe nigrostriatal dopamine terminal projections (Wagner et al.,

Table 2Algorithm for behavioural studies in animals that used the khat extract

Outcome reported Analys

PPI deficit and locomotor sensitization in Sprague–Dawley rats ✓EEG pattern in Wistar rat ✗↑Baseline aggressive behaviour in Sprague–Dawley rats ✓Ipsilateral rotation after 6-OHDA lesion in Sprague–Dawley rats ✓↑Sexual behaviour in Albino wistar rats ✗Motor behaviour in Albino mice ✗Analgesia in Albino mice ✗Locomotor sensitization in Sprague–Dawley rats ✓

†Ideal study; 1ethanol, sildenafil and amphetamine used as a comparator; 2d-ampheta✓=Yes; ✗=NO.

1982; Banjaw et al., 2006). This is similar to the neurotoxiceffect 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 havebeen exposed to a wide array of behavioural experiments toelucidate the behavioural pharmacology of this herbal psychos-timulant. The behavioural models employed include; locomotoractivity (psychostimulation), feeding behaviour (anorexia), testfor analgesia (nociception), behavioural sensitization (psychosis),isolation induced aggression paradigm (aggressive behaviour),and several operant procedures (addiction/dependence). Since thecharacteristic property of khat chewing is stimulation of the CNS,the behavioural pharmacology is of particular interest. In most ofthe behavioural experiments conducted in various animals(chicken, mice, rat, and monkeys) cathinone/khat showedqualitatively similar effects to amphetamine. Both khat extractand cathinone have been shown to increase spontaneouslocomotor activity, stereotyped movement and anorexia (Kalixand Braenden, 1985). In addition, khat extract (100 mg/kg) andcathinone (5 mg/kg), have been reported to cause behaviouralsensitization in locomotor activity of rats similar to amphetamine(Banjaw et al., 2006) (Table 2). When compared to amphetaminethe potency of cathinone was in the order of 1:2–1:5 except inconditioned taste aversion, where cathinone was reported to beveryweak [1:17] (Mereu et al., 1983; Kalix, 1990; Goudie, 1987).However, tolerance to the anorexgenic effect of cathinonedevelops rapidly unlike that of amphetamine (Foltin and Schuster,1983). In addition, cathinone was reported to have a more similarprofile to cocaine than to amphetamine in some behaviouralparadigms 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 demonstratedthese behavioural features though less potently than cathinone, inthe range of 1:7–1:10 (Peterson et al., 1980; Eisenberg et al.,1987). As to the neurotransmitters involved in mediating thedifferent behavioural effects of khat/cathinone, there appears to bestrong evidence to suggest the involvement of the dopaminergicsystem (Zelger et al., 1980; Kalix, 1980a,b). Indeed, severalinvestigators have demonstrated that cathinone and cathine

is made? Comparator used? References

✗ Banjaw et al. (2005)✗ Saleh et al. (1988)✗ Banjaw et al. (2006)✗ Banjaw and Schmidt (2006)✓1 Abdulwaheb et al. (2007)✗ Connor et al. (2002)✓2 Connor et al. (2000)✓2 Banjaw and Schmidt (2005)†

mine used as comparator; PPI, prepulse inhibition; EEG, electroencephalogram;

Table 3The effect of cathinone and khat on animal behaviour

Behavioural observation Cathinone Khat Reference

Operant behaviourIV Self administration 0.025–1 mg/kg/infusion, in monkeys,

CATH≈COCNot examined Yanagita (1986), Woolverton

and Johanson (1984)Discriminative stimulus property⁎ 0.09–1.87 mg/kg (IP), 256 μg/kg (ICV),

in rats, generalizes to AMPH, COC,and MDMA

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

Conditioned taste aversion 4–16 mg/kg, in rats, CATH:AMPH (1:17) Not examined Goudie (1987)↓Food reinforced responding⁎ 1–4.7 mg/kg (IP) in rats, 0.008–0.1

mg/kg/infusion in monkeys, CATH:AMPH (1:2–3)Not examined Goudie (1985)

Conditioned place preference 0.8 mg/kg (IP), in rats, ↑time spentin non-preferred Side

Not examined Calcagnetti and Schechter (1993)

Hypermotility⁎ 1–20 mg/kg in rats and mice (IP/SC/PO),20–64 μg/kg (IV) in rats, CATH:AMPH (1:2)

200–1600 mg/kg (PO)in rats and mice

Banjaw et al. (2006)

Stereotyped behaviour⁎ 1–20 mg/kg(IP/SC/PO) in rats and mice,and chicken, CATHbAMPH

200–1600 mg/kg (PO)in rats and mice

Berardelli et al. (1980), Zelger et al. (1980),Connor et al. (2002)

Anorexia⁎ 1–32 mg/kg(PO/IP), in monkeys and rats Not examined Zelger and Carlini (1980)Analgesia 1–25 mg/kg(SC/IP) in mice in TFT and

HPT CATH: AMPH (1:4–6)200–1800 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 thoughless potent than cathinone; IP, intrapertoneal; SC, subcutaneous; PO, oral; IV, intravenous; AMPH, (+) amphetamine; CATH, Cathinone; COC, cocaine; TFT, tail flicktest; HPT, hot-plate test; SD, Sprague–Dawley rats.


primarily increase catecholamine release and secondarily inhibitits reuptake (Wagner et al., 1982; Schechter, 1990a,b; Petersonet al., 1980;Mereu et al., 1983). However, other neurotransmitterscould also be involved as well. For instance, the serotonergicsystem is reported to be involved in khat/cathinone-inducedstereotypedmovement, aggression, and sexual arousal (Connor etal., 2002; Banjaw et al., 2006; Abdulwaheb et al., 2007).Moreover, noradrenergic and opioid systems are suggested to beinvolved in khat/cathinone induced analgesia and anorexia inaddition to the dopaminergic pathway (Nencini et al., 1984a,b;Della Bella et al., 1985; Connor et al., 2000). (Tables 4 and 5).

Fig. 5. Effects of Khat/Cathinone on animal behavio

4.2.1. Motor activity and stereotyped behaviourThe 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 oraladministration of different concentrations of khat extract, inwhich lower doses (50–100 mg/kg) caused a stimulatory EEGpattern whilst higher doses (400 mg/kg) caused initial corticalactivation 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 EEGpattern resembles how users in a khat session would progress

ur when compared with known psycostimulants.

Table 4Neurochemical effects of cathinone and khat

Nature of study Cathinone Khat extract Reference

In vitro studiesSynaptosomal preparations ↑Release and inhibition of uptake of [3H]DA,

1–100 μM, CATH: AMPH (1:1.6)Not examined Wagner et al. (1982)

Rabbit/rat striatal tissue Enhanced release of [3H] 5-HT, 12 μM ↑effluxand inhibition of uptake of [3H]DA, 3–9 μM,CATH: AMPH (1:2–6x)

Not examined Kalix (1981,1982, 1983)

Rat cerebral cortex Inhibits [3H] nisoxetine binding to NA transporter,2.5 μM, CATH≈COC≈MDMA

Not examined Cleary and Docherty(2003)

Rat atrial/ventricular strip Efflux of [3H]NA and inhibition of uptake of [3H] NA,1.2–2 μM, CATH≈COC≈MDMA

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), CATH≈AMPH ↓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 PFCanterior 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.


from a state of stimulation and excitation to that of sedation,anxiety and depression, as more khat is chewed (Kalix andBraenden, 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 ofcathinone in rats (Yanagita, 1979; Kalix, 1980b; Gordon et al.,1993; Banjaw et al., 2003) andmice (Zelger et al., 1980; Rosecranset al., 1979; Knoll, 1979) markedly increased spontaneous loco-motor activity of the animals. It was reported that the potency ofcathinone was almost comparable with (+)-amphetamine (Kalix,1990). Zelger et al. (1980) demonstrated that cathinone has astimulatory effect on locomotion in rats maximally after 15 to30 min, in a similar fashion to amphetamine. Cathinone alsodisplayed hypermotility in hypophysectomized and unhypophy-sectomized rats analogous to (+) amphetamine (Kalix, 1980b). Inaddition, centrally administered cathinone increased spontaneousactivity when administrated directly into the nucleus accumbens,but failed to demonstrate this effect when administered into thesubstantia nigra in rats (Calcagnetti and Schechter, 1992a,b).Similar increases in locomotor activity were observed after khatextract administration in animals. Recently, it was reported thatacute and sub-chronic oral administration of C. edulis leaves or S-(−) cathinone increased locomotor activity in rats (Banjaw and

Table 5The in vitro affinity table for cathinone and comparator compounds

Receptor/transporter/enzyme Cathinone IC50/EC50 Cath

Dopamine transporter 0.85 uM AMPα-receptorsa N10 uM CATNoradrenaline transporter 0.9 uM Coca5-HT receptorsb 3 uM CATSerotonin transporter 0.014 uM CocaMonoamine-oxidase 50 uM CAT

aHuman receptors bfrom rat fundus; IC50, half maximal inhibitory concentrationcathinone N.B there is no data as to the affinity of cathinone to dopamine and β-ad

Schmidt, 2005; Banjaw et al., 2006). In contrast, Connor et al.(2002) reported a reduction in spontaneous motor activity in miceafter intragastric administration of khat extract. It was suggestedthat the use ofmice instead of rats and the difference in the source ofkhat 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 sensitizationafter repeated intermittent oral administration ofC. edulis leaves orcathinone in rats. The rats developed sensitization for locomotoractivity, rearing, upward and downward sniffing, and turning afteroral administration of the extract which was also observed withcathinone and amphetamine.

Cathinone has also been found to be similar to amphetaminewith regard to induction of stereotyped behaviour in rats at higherdoses (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 extractor cathinone include biting, licking, pawing, sniffing, headtwitches, and rearing (Zelger et al., 1980; Connor et al., 2002;Berardelli et al., 1980; Banjaw et al., 2006, 2005, 2003; Al-Meshalet al., 1991).Moreover, there are some reports of cathinone-inducedtremor at a low dose and seizure at higher doses (Berardelli et al.,1980). Cathine was considerably less potent, (1/7–1/10th), than

inone vs. comparator compounds Reference

HNCocaineNCATH Fleckenstein et al. (1999)H≈Ephedrine Rothman et al. (2003)ine≈MDMA≈CATH Cleary and Docherty (2003)H≈4X AMPH Glennon and Liebowitz (1982)ineNAMPH≈CATH Fleckenstein et al. (1999)H≈100XAMPH Nencini et al. (1984b)

; EC50, half maximal effective concentration; AMPH, amphetamine; CATH,renergic receptors.


cathinone at inducing both spontaneous locomotion and stereo-typed movement (Zelger et al., 1980; Woolverton, 1986; Petersonet al., 1980; Kalix, 1983; Eisenberg et al., 1987). Another con-stituent of khat alkaloid, norephedrine, failed to show stimulatoryeffect in the open field test (Eisenberg et al., 1987). Taken together,these findings indicate that cathinone is the constituent of khat thatis mainly responsible for the stimulatory effect of the plant and thatit is a potent amphetamine-like compound. Nevertheless, effects ofan entire khat extract, with its many constituents, would differ fromamphetamine with regard to the production of motor, and probablyother behaviours (Connor et al., 2002).

4.2.2. AnalgesiaKhat 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 toexert analgesic effects in mice, albeit at high doses relative toibuprofen and amphetamine (Connor et al., 2000). It producedanalgesic effects in the tail flick test and hot plate test at a lowerdose (200 mg/kg and 600 mg/kg) and in acetic acid-inducedabdominal constriction assays at a higher dose (1800 mg/kg).Cathinone has also been shown to cause a long lasting analgesicactivity in mice and rats (Nencini and Ahmed, 1982). This wasreversibly antagonized by naloxone, a pure opioid antagonist,and by the noradrenaline synthesis inhibitors, α-MPT (α-methyl-p-tyrosine) and diethyldithiocarbamate. Furthermore, cathine, ametabolite of cathinone in humans, has been shown to enhancethe analgesic effect of morphine in hot plate and formalin test inmice (Nencini et al., 1998).

4.2.3. Feeding behaviourAnorexia, a characteristic effect of amphetamine-like sub-

stances, is a consequence of khat chewing (Halbach, 1972). Thisfeature of khat has been used for centuries to alleviate the sensationof hunger (Zelger and Carlini, 1980; Kalix, 1983). Therapeutically,the khat alkaloid cathine (norpseudoephedrine) and norephedrinehave beenwidely used as appetite suppressants in themodernworld(Kalix and Braenden, 1985). This anorectic effect of cathinone andcathine has been observed in rhesus monkeys (Yanagita, 1979;Foltin and Schuster, 1983), in rats (Zelger and Carlini, 1980; Knoll,1979; Islam et al., 1990; Foltin et al., 1983; Eisenberg et al., 1987),and in late pregnant guinea pigs (Jansson et al., 1988). Both isomersof cathinone and cathine markedly inhibited the food intake of ratsat intracerebroventricular doses of 300 and 500 μg per animalrespectively (Knoll, 1979). Both cathine and (−)-cathinone werereported to bemore potent than amphetamine in this regard (WHO,1980). Systemic acute as well as chronic administration of the twoalkaloids in rats showed similar effects, however theywere reportedto be less potent than (+)-amphetamine in this order of potency:amphetamineNcathinoneNcathine (Zelger and Carlini, 1980). Onthe other hand, when cathinone was administered to rats via theintargastric route, it was reported to be a more potent anorectic thanamphetamine and cocaine (Foltin et al., 1983). It was reported thatwithin a week there was development of tolerance to this effect ofcathinone, 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 toamphetamine in which tolerance developed only after 2 weeksand its effect persisted for more than 7 weeks (Zelger and Carlini,1980). Total and/or partial cross-tolerance was also observedamong all the three drugs. A similar pattern of cross tolerancebetween (−) cathinone and (+) amphetamine was reported bySchuster and Johanson (1979). Anorexic effects of the other khatalkaloid, norephedrine, have also been demonstrated in rats(Eisenberg et al., 1987). In this study it was reported that bothcathine and norephedrine have a potency of one tenth that ofcathinone. Tolerance to the anorectic effects of khat alkaloids hasbeen extended to include cathine (Zelger and Carlini, 1980). Takentogether, individual khat alkaloids have been shown to possessanorexic properties, yet there has been no study so far where theentire khat extract has been investigated for these properties inanimals.

Two models have been proposed to explain the reduction infood intake of psychostimulants like cathinone (Wolgin andMunoz, 2006). According to some who advocate the Pavlovianhomeostatic model, the suppression of intake is due to loss ofappetite, which results in a failure to seek food (appetitivebehaviour) or to eat it (consummatory behaviour). Tolerance ismediated by a compensatory increase in the motivation to eat.Nencini et al. (1988), using this model, suggested that tolerance tothe anorectic effect of cathinone is associatedwith a sensitization toendogenous kappa-opiate mediated activation of feeding. Indeed,after 10 days of cathinone treatment, kappa agonist-inducedincrease in food intake was about twice that induced by the samedose of cathinone administered acutely (Nencini, 1988; Nenciniet 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 learningmodel). They elegantly demonstrated that acute cathinoneinjection produced decreased milk intake in bottle-but not incannula-fed rats, while motor activity increased in both groups.They also showed that, after the tolerance phase, switching formbottle to cannula feeding produced a further increase in intake,whereas switching form cannula to bottle feeding produceddecreased intake.

4.2.4. Sexual behaviourKhat and its alkaloid cathinone have been reported to affect

male sexual potency. There are contradictory reports regarding theassociation between khat chewing and sexuality. Khat has beenreported to be used as an aphrodisiac (Krikorian, 1984; Gianniniet al., 1992; Browne, 1990; Bentur et al., 2007), and to treatpremature ejaculation (Luqman and Danowski, 1976). Similarly,in females, khat chewing has been reported to increase sexualdesire (Elmi, 1983). Recently it was reported that a capsulecontaining illicit cathinone have been marketed in Israel as astimulant and an aphrodisiac drug (Bentur et al., 2007). On theother 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 chewinghave been reported (Halbach, 1972; Granek et al., 1988; Elmi,


1983). Taha et al. (1995) demonstrated that oral treatment ofcathinone (5mg/kg/day) and its combinationwith caffeine (50mg/kg/day) for 15 days increased sexual arousal (motivation) in malerats as evidenced by increased mounting performance andanogenital investigatory behaviour with no stimulatory effect onerectile 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 byreduced mounting latency (ML) and intromission latency (IL),while high doses of the extract (400mg/kg/day) produced oppositeeffects on both sexual motivation/arousal and performance in malerats. In addition, concurrent administration of the low dose extractfollowed by ethanol was found to enhance male rat sexualmotivation/arousal (Abdulwaheb et al., 2007). This is similar toamphetamine, which at low dose is reported to evoke penileerection, though its effect at high dose is inconclusive (Taha et al.,1995). It was suggested that alteration of both dopamine (at lowdose) and or serotonin (at high dose) levels in the CNS couldexplain the biphasic sexual behaviour of rats after khat adminis-tration, although the role of testosterone cannot be ruled out (Tahaet al., 1995; Abdulwaheb et al., 2007).

4.2.5. Cathinone in animal models of addictionAnimalmodels of addiction thatmimic the human condition in

an informative way are critical for advances in the study ofaddiction (Schramm-Sapyta, 2004). The various animal modelsused to examine the neurobiological basis of drug addiction havehelped us to understand the role of cathinone/khat in thedevelopment and maintenance of addiction. Cathinone has beencompared to amphetamine and cocaine in a wide array ofprocedures of operant behaviour, and it is generally found to havesimilar effects to amphetamine and cocaine (Woolverton andJohanson, 1984). Indeed, cathinone has been shown to havereinforcing potential in self administration studies (to demonstratethe dependence-producing potential of cathinone), drug discri-mination procedures (to elucidate its similarity to otherpsychostimulants such as amphetamine), food reinforcedresponding, conditioned taste aversion test, and conditionedplace preference test (to assess the rewarding and motivationaleffects of cathinone). These animal studies suggest that cathinonehas abuse potential as great as that of cocaine and probably greaterthan that of amphetamine (Goudie, 1987). In addition to thepharmacological properties of khat, the complex rituals of a khatparty could be used by consumers as environmental cues toidentify the appropriate conditions in which they enjoy khatchewing (place, partner, and music) and could also be partlyresponsible for khat's euphorogenic effects, through ‘placebo’mechanisms (Nencini et al., 1986).

4.2.5.1. Self administration. Khat chewing has been describedas ‘pleasurable’ and the behaviour of repetitive chewing of khatleaves has been labelled as from of ‘psychic dependence’(Halbach, 1979), characterized by compulsive khat consumption(Kalix, 1983). Self administration studies are particularly usefulfor the evaluation of the dependence potential of pharmacologicalsubstances and are believed to have high predictive validity inpredicting abuse potential (Woolverton and Johanson, 1984). Self

administration studies using (−) cathinone have illustrated the roleof this alkaloid as a dependence producing compound among thekhat alkaloids (Kalix, 1983) enhancing the behaviour of animalsthat gives them access to the substance (Kalix and Braenden,1985). Johanson and Schuster (1981) and Yanagita (1986) havereported that intravenous infusions of cathinone will maintainresponding in rhesusmonkeys,which had been previously trainedto lever press for cocaine injections. When monkeys were giventhe choice of self administering cathinone and cocaine, they choseboth equally often (Woolverton and Johanson, 1984; Johansonand Schuster, 1981). The self administration pattern was reportedto be of the spree type, like cocaine and amphetamine, in whichmonkeys took the drug frequently day and night, stopping onlywhen exhausted (Yanagita, 1979, 1986). They relapsed after aperiod of rest of less than 24 h. This pattern corresponds to thatseen in amphetamine dependent humans (Kalix and Braenden,1985). Similar results were obtained in rhesus monkeys, whichwere first trained to self-administer cocaine intravenously by leverpresses, after which progressive ratio tests were conducted(Yanagita, 1979). Progressive ratio tests, which utilize thebreaking 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 thereinforcement magnitude of several psychostimulants (Willner,1997). The final ratios obtained for (−) cathinone were similarwith amphetamine, and roughly half of those of cocaine inmonkeys (Yanagita, 1986).

Since self administration in primates is considered highlypredictive of abuse in humans, it is possible that abuse potentialof cathinone is as great as cocaine (Nencini and Ahmed, 1989).This contention is further strengthened by the weak aversivenature of cathinone, which, despite being an amphetamine-likedrug, possesses unexpectedly weak aversive properties (Goudie,1987). Indeed, in the condition taste aversion procedure, which isthought to be the animal analogue of aversive effects of drugs inman which limit the intake of drug of abuse, cathinone was lesspotent (1:17) than amphetamine (Goudie and Newton, 1985;Goudie, 1987; Foltin and Schuster, 1982). In addition to theaforementioned studies on primates, Gosnell et al. (1996) havedemonstrated intravenous self administration of cathinone in ratsunder a continuous (FR1) reinforcement schedule. In contrast tothe primate models, however, when compared with amphetamineand cocaine, cathinone produced a pattern of responding moreclosely resembling amphetamine. This was characterized bymore frequent infusions at the beginning of the session than in themiddle or final portion of the sessions. They also reported thatpre-treatment with D1-type receptor antagonist SCH 23390,increased the number of infusions, which suggests a role for D1

type 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 bepredictive of their subjective effects in humans (Goudie, 1987,1991). Further they allow us to investigate the subjective effects ofthe training drug as a function of time and dose, and to explore itsmode of action by the use of appropriate antagonists andother pharmacological manipulations (Willner, 1997). (+)


amphetamine trained rats responded as if they were given (+)amphetamine when various doses of cathinone were administeredip (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 receivedcathinone when injected with amphetamine and cocaine but notwhen injected with opioids, benzodiazepines or fenfluramine(Goudie et al., 1986). In fact, the only difference betweencathinone, amphetamine and cocaine have been shown to betemporal (Schechter, 1989; Schechter and Glennon, 1985).Similarly, in rats trained to discriminate the interoceptive cuesproduced by (−) cathinone, the administration of (+) cathinoneand (+) cathine produced (−) cathinone like responding, anability known as ‘generalization’ (Schechter, 1990a; Pehek andSchechter, 1990; Glennon et al., 1984). Moreover, directmicroinjection 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 discriminationparadigm (Pehek and Schechter, 1990). Recently, Li et al. (2006)have demonstrated that when cathinone was given before orconcurrently with cocaine to rats in a drug discrimination proce-dure, the cocaine dose effect function was shifted to the leftsuggesting cathinone generalizes to cocaine.

The drug discrimination procedure is used not only to test thesimilarity and dissimilarity of psychoactive drugs, but it canalso be used to investigate the production of tolerance afterchronic treatment of trained rats (Schechter, 1990a). Indeed, itwas reported that tolerance tends to develop to cathinone in theirability to control discriminative behaviour, indicated by deficitsin discriminative performance and shift of the dose responsecurve to the right (Schechter and McBurney, 1991; Schechter,1986a,b). Similarly, Schechter (1990a) reported an acutetolerance effect of cathine in their ability to control discrimi-native behaviour, indicated by deficits in discriminativeperformance.

4.2.5.3. Food-reinforced responding. Similar to amphetamine,cathinone interferes with the reinforcing properties of food. Thismodification of food-motivated behaviour has been demonstratedin rats (Yanagita, 1979; Peterson et al., 1980; Goudie, 1985) andin monkeys (Schuster and Johanson, 1979). Initially it wasdemonstrated that cathinone (0.5 mg/kg) increased the responserate in rats under a differential reinforcement of low rates ofresponding schedule [e.g. DRL 20 s] (Yanagita, 1979).Differential reinforcement of low rate schedules are known toproduce low rates of responding as only those responses thatoccur after a minimum time interval after a previous response arereinforced. Subsequently, it was reported that large dose ofcathinone suppresses operant responding in rats under fixedinterval and fixed ratio schedule of food delivery (Peterson et al.,1980; Goudie, 1985). Goudie (1985) illustrated that the effect ofcathinone, like (+) amphetamine is rate dependent; i.e. has atendency to increase low rates of responding and decrease highrate 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 andSchuster, 1981;Goudie, 1985). Similar results have been obtainedin monkeys, where both amphetamine and cathinone were shownto suppress responding maintained by a multiple fixed intervaland fixed ratio schedule for the delivery of food reward in a ratedependent 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 respondingmay be explained in terms of drug-induced behavioural disruptionand response competition (Goudie, 1985).

4.2.5.4. Conditioned place preference. Conditioned placepreference is a method of assessing the rewarding andmotivational effects of drugs of abuse (Willner, 1997). Thisbehavioural task, which involves the pairing of drug cues with adistinctive environment, has been shown to produce a dose-response location preference with ip cathinone, similar tococaine and amphetamine in rats (Schechter and Meehan, 1993;Schechter, 1991). Furthermore, intracerebroventricular injec-tion of cathinone to rats, when paired with confinement in thenon-preferred side of the conditioned place preference appara-tus, increased the time spent on that side, which suggest that thisbehaviour 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 contentionis supported by evidence that pre-treatment with a dopaminerelease inhibitor attenuates place preference induced bycathinone (Schechter, 1991, 1990b; Calcagnetti and Schechter,1993).

4.3. Khat and neurochemistry

The stimulatory effect of cathinone is believed to be mediatedby the dopaminergic system, similar to amphetamine (see Table 4)(Kalix and Braenden, 1985). In support of this, it has beendemonstrated that substantial release of radioactivity induced bylow dose cathinone in a dose-dependent manner, similar toamphetamine, from isolated rabbit caudate nucleus prelabelledwith [3H] dopamine (Kalix and Glennon, 1986; Kalix, 1983,1981, 1980b). Moreover, pretreatment with cocaine, which isknown 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 ratcaudate 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 inducedcircling behaviour were found to inhibit (block) cathinoneinduced [3H] dopamine release from these tissues (Kalix,1982). This suggests that (−) cathinone has to penetrate tointraneuronal sites in order to evoke release, and that the uptakeinhibitors prevent this penetration. Moreover, support for thehypothesis that cathinone/khat requires an intact dopaminergicsystem to exert their effect upon activity has been evidencedby reports that dopamine antagonists (Zelger et al., 1980),


dopamine release inhibitors (Calcagnetti and Schechter,1992b), or pretreatment with the relatively selective dopami-nergic neurotoxin 6-OHDA (Zelger and Carlini, 1981; Banjawand Schmidt, 2006), into mesolimbic pathways significantlyattenuates cathinone induced activity.

Zelger et al. (1980) has demonstrated that pre-treatment withreserpine (monoamine store depleting agent) or methyl-p-tyrosine (MPT, a catecholamine synthesis inhibitor), abolishedlocomotor and increased stereotyped behaviour induced bycathinone. On the other hand pretreatment with haloperidol, anon selective dopamine antagonist was found to reduce bitingand licking movements caused by cathinone. In addition,administration of khat or cathinone to rats after unilateral lesionof substantia nigra with 6-hydroxydopamine (6-OHDA)induced ipsilateral rotation, in a similar fashion to amphetamine,suggesting that they have indirect dopamine releasing actionson the CNS (Zelger and Carlini, 1981; Banjaw and Schmidt,2006). In agreement with this, in vivo microdialysis in rats afteracute intraperitoneal administration of (−) cathinone, in asimilar fashion to (+) amphetamine, increased levels ofdopamine but decreased level of metabolites in a dosedependent manner (Pehek et al., 1990). These findings are inagreement with those previously described for synaptosomalpreparations, in which cathinone released and blocked theuptake of tritiated dopamine (Wagner et al., 1982).

In a similar fashion to amphetamine, cathinone was alsoshown to decrease dopamine transporter function following invivo administration in rats (Fleckenstein et al., 1999). On theother hand, it was found that chronic administration of cathinoneto rats leads to significant reduction in the dopamine levels(Wagner et al., 1982) although acute administration of cathinonewas insufficient to produce detectable decrease in dopamine(Nielsen, 1985; Mereu et al., 1983). The result of the later studiesshowed that there is reduction in the dopamine metaboliteDOPAC, a parameter that is generally taken as reflecting theamount of dopamine released and captured by the nerve endings(Pehek et al., 1990). This is similar to amphetamine and cocaine,which have been shown to cause depletion of dopamine uponchronic administration (Ellison, 2002). In addition, Mereu et al.(1983) have demonstrated that (−) cathinone inhibited the firingrate of dopaminergic cells in the substantia nigra which wasreversed by haloperidol. Once more these finding suggests thatcathinone, like amphetamine, releases dopamine from nerveterminals and blocks its reuptake (Mereu et al., 1983). It has alsobeen shown that intermittent oral administration of C. edulisextract (200 mg/kg) significantly reduced the level of dopamineand its metabolites in caudate putamen in rats which displayedlocomotor sensitization (Banjaw and Schmidt, 2005). Howeverin contrast to amphetamine, there is in vitro evidence thatcathinone-induced dopamine release is regulated by calciumchannels (Vislobokov et al., 1993). This is attested by the fact thatpre-treatment with isradipine, a potent dihydropyridine calciumchannel (L-type) blocker attenuated the activity elevating effectof intracerebroventricularly administered cathinone in rats(Calcagnetti and Schechter, 1992a,b).

So far there is no clear cut evidence on the role of serotonergicand/or other pathways in the stimulatory effect of cathinone. Some

investigators have reported that levels of serotonin in rat brain arenot altered by repeated administration of cathinone (Wagner et al.,1982; Nielsen, 1985). In contrast, Kalix (1984) reported thatcathinone had a 5-HT releasing effect (like amphetamine) in ratcaudate nucleus prelablled with [3H] serotonin and it was one thirdas potent as (+) amphetamine. Interestingly, cathinone was alsofound to have four times higher affinity than racemic amphetaminefor serotonin receptors in isolated rat fundus (Glennon andLiebowitz, 1982). Connor et al. (2002) have reported thatpretreatment with methysergide, a known 5-HT receptor blockerdepressed both head twitches and spontaneous activity in rats thatwere treated by oral khat extract or (−) cathinone suggesting apossible role of 5-HT mediated motor activity. In addition,deterioration of visual stimuli after ip administration of cathinoneto cats, which was antagonized by methysergide and p-chlorphe-nyalanine (5-HT synthesis blockers), supports the hypothesis thatthe serotonergic pathway as well could play a role (Babayan et al.,1983). Moreover, cathinone was shown to decrease serotonintransporter function, though low inmagnitudewhen comparedwithamphetamine and methamphetamine (Fleckenstein et al., 1999).

Cathinone, similar to amphetamines, has also been shown toinhibit monoamine-oxidase (MAO) activity in vitro (Nencini et al.,1984b). In fact, cathinone (Ki=0.05mM) appears to be about 150–200 times more effective than amphetamine (Ki=7.9 mM) in thisregard (See Table 5). In line with this, Osorio-Olivares and co-workers (2004) have reported that cathinone exhibited inhibitionof MAO-B activity more than MAO-A. Inhibition of amineoxidase activity is supported by the observation of increment ofurinary catecholamine (HVA) associated with khat chewing inhumans (Nencini et al., 1984b). Recently, it was documented thatS-(−)-cathinone acts as well on noradrenaline transporters (Clearyand Docherty, 2003; Rothman et al., 2003). Therefore, at thisjuncture, neurochemical mechanisms other than dopamine couldexplain the neuropharmacological actions of khat or S-(−)-cathinone (Banjaw et al., 2006).

Finally, it is important to note that in various behaviouralexperiments the neurotransmitter level in different brain regionswas slightly different when khat extract is used instead ofcathinone (Connor et al., 2002; Banjaw et al., 2006, 2005). Theapparent difference between the extract and the active principle,S-(−)-cathinone, may be attributed to the fact that C. eduliscontains (besides S-(−)-cathinone) other compounds, such ascathine and different metabolites (Schechter, 1990b). Theadditional compounds existing in the crude extract might havesubstantially altered behavioural and neurochemical effects(Schechter, 1990b; Banjaw et al., 2006).

5. Algorithms of laboratory/preclinical studies on khat

After reviewing each article, which we obtained through one ofthe previouslymentionedmethods,wemade an attempt to criticallyanalyse the relevance and possibility of translation of the preclinicalstudies to human khat users (Fig. 6). For the analysis, originalstudies conducted on khat or its active principles in vitro and in vivowere used. Articles which emphasized the epidemiology, pre-valence and socioeconomic aspects of khatwere excluded from thisassessment. Moreover, studies addressing solely the analytical

Fig. 6. Algorithms used to identify an ideal study on khat for khat use in humans.


aspects were not incorporated in the analysis. Thus the only papersincluded in the final analysis were original studies (animal/invitro) that dealt with the neuropharmacological aspects of khat.

About a third of the studies analyzed had used a comparatorcompound in their studies irrespective of whether they use khatextract or not. In most instances the comparator used wasamphetamine; however cocaine and/or MDMA were also usedin few of the studies as a comparator psychostimulant. Only 8(11%) out of the 70 studies have used the extract instead ofeither cathinone or cathine. And among those eight studies onlyhalf of them have made analysis of the extract before theycarried out the experiment. And only a single study (1.4%) useda comparator drug (d-amphetamine), and was deemed to be anideal study (Banjaw et al., 2005). From the analysis it is clearthat a few studies used the entire extract instead of cathinone.Interestingly, Banjaw and co-workers have made analysis of theextract in most of their work.

6. Conclusions

The leaves of the tree C. edulis, known as khat, have forcenturies been chewed for psychostimulant and socializingeffects by people living in east African and Arabian Peninsula.Recently, this deep rooted socio-cultural tradition has alsospread to East African and Middle Eastern communities inEurope and North America. The ingredients of khat leaves arenumerous, but the major and most abundant active constituentsinclude six major alkaloids, tannins (7–14%) and flavonoids. Todate, urine measurement of cathinone and cathine using GC–MS is the most accepted method available for screeningindividuals with suspected khat use.

Studies in animals suggest that cathinone has a potential forabuse at least as great as cocaine and probably greater thanamphetamine causing persistent psychic dependence withminimal withdrawal symptoms. There seems to be considerable

circumstantial evidence to suggest that khat chewing can causebrief psychosis and could exacerbate pre-existing psychopathol-ogies. However, the current data is not sufficient enough toimply a causal relationship between khat chewing and long-termpsychopathology. Studies claiming such associations have beencriticized for not being based on rigorous clinical evaluations.

Cathinone is more effective than cathine and other alkaloidsin khat on brain neurochemistry and behaviour; similar to (+)amphetamine in many aspects, although quantitative differencesare noticeable. Cathinone, the psychoactive active alkaloid inkhat, mediate the neuropharmacology of khat primarily byevoking dopamine release and secondarily by inhibiting itsuptake (there by prolonging the action of dopamine on itsreceptors) from dopamine containing synaptic endings. At thisjuncture the role of the serotonergic (via 5-HT receptors;cathinoneNamphetamine), noradrenergic (via adrenergic recep-tors and transporters) and opioid systems cannot be ruled out inthe neuropharmacological actions of khat/(−) cathinone.

Although numerous studies have investigated the pharma-cological effects of cathinone, only few studies have dealt withthe effects of whole material, as normally taken by users, orcomplex mixtures of chemical found in its extracts. For thosethat used the extract, very few have analysed the extract andused comparator drugs, raising a question on the validity of theclaim that khat is a “natural amphetamine”.

7. Recommendations

Although a number of investigations have been carried outusing cathinone, the psychoactive component of khat, these maynot wholly reflect the effect observed after administering khat in adose similar to those used traditionally. Human addicts take thedrug in its entirety; hence any translation from experimentalstudies could only be feasible when the entire extract is used. Acase in point is cathedulins and the phenypentenylamine


alkaloids, which have not been studied well, yet couldsignificantly contribute to the pharmacology of khat. Along thesame line, in different experiments there were variations inoutcome when C. edulis extract is used instead of cathinone.Therefore, other constituents of khat merit investigation as wellbefore any firm conclusion is made.

As most experimental investigations on khat and cathinonehave been short term acute studies, there is lack of importantinformation on the long term use of khat. For instance severalreports claim khat to cause psychosis, nevertheless data lacks onacute and long term neurotoxicity of khat. Further toxicologicalstudies are warranted, in particular, on the central nervoussystem. It would be interesting to see the long term effect of theentire extract and/or cathinone in level of various neuroprotec-tive and neurotoxic biomarkers in the brain to elucidate theneurotoxic potential of khat chewing.

Problems related with khat chewing especially khat inducedpsychosis in immigrants could pose a problem on substanceabuse treatment centres in the West. This is attested by growingreports of khat-induced psychosis among immigrants residinginWestern countries few of the cases culminating in suicide andhomicide. It would, therefore, appear highly desirable for theinternational community to promote co-operation in the area ofkhat control not only for the sake of saving the populations ofcountries at present affected by this harmful phenomenon, butalso to protect possible new recruits of khat chewers in otherparts of the world.

As the khat-chewing habit has for centuries been limited tothe same geographical area where it has been traditionallygrown and habitually consumed, one could argue that theproblem will always remain within communities from khatgrowing nations. However, in a world where rapid changes aretaking place in the way of thinking and of life, this assumptionmay prove to be dangerously wrong. Although at this time itseems unlikely for Western people to indulge in this habit, itworth recalling the case of cocaine which started in a similarmode as khat. It is tempting to forecast this, considering theresemblance between cocaine and cathinone as positivereinforcers. If synthetic cathinone becomes popular in thenear future which we believe is likely considering the story ofdifferent versions of cocaine, previous works on cathinonecould be valuable. Khat leaves may be extracted by chemicalprocessing to produce a purer (cathinone); more concentratedform for administration by other perhaps more addicting routes.The emergence of popularity of methcathinone (methyl versionof cathinone) in countries like Russia and USA should ringsome alarm bells (Gosnell et al., 1996). That being said, it isimportant to be aware of the fact that khat has an importanteconomic significance to countries which are involved in itsproduction. The khat sector today feeds millions of farmers andpeople involved in its trade (Odenwald, 2007). It is believed thatthe sector has a major contribution to the national GDP ofdeveloping nations like Ethiopia, Kenya, and Yemen whoproduce khat in large scale for domestic and export use. Hence,we suggest a multidisciplinary research involving economists,anthropologists, and sociologist is needed in addition toPharmacologists and Clinicians.

Acknowledgments

AM was supported in this research with a scholarship awardfrom the NUI Galway International Scholarship Programme.

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a review of the neuropharmacological properties of khat

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