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Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1147 – 1166 www.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 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 East Africa 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’ or’qaad/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 . . . . . . . . . . . . . . . . . . . 1.1. Prevalence of use . . . . . . . . . . . . 1.2. Legal considerations . . . . . . . . . . . Methodology . . . . . . . . . . . . . . . . . . Analysis of active constituents of khat . . . . . 3.1. Active constituents of khat leaf . . . . . 3.2. Pharmacokinetics . . . . . . . . . . . . 3.3. Detection of khat alkaloids . . . . . . . Neuropharmacology of khat . . . . . . . . . . 4.1. Psychological sequelae of chewing khat. 4.1.1. Psychosis . . . . . . . . . . . . 4.1.2. Aggression . . . . . . . . . . . 4.1.3. Mood disorders. . . . . . . . . 4.1.4. Addiction . . . . . . . . . . . . 4.1.5. Khat-induced neurotoxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1148 1148 1149 1149 1149 1149 1150 1152 1152 1153 1153 1154 1154 1154 1155

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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: john.kelly@nuigalway.ie (J.P. Kelly). 0278-5846/$ - see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2007.12.033

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

Behavioural studies in animals . . . . . . . . . . . 4.2.1. Motor activity and stereotyped behaviour . 4.2.2. Analgesia . . . . . . . . . . . . . . . . . 4.2.3. Feeding behaviour. . . . . . . . . . . . . 4.2.4. Sexual behaviour . . . . . . . . . . . . . 4.2.5. Cathinone in animal models of addiction . 4.3. Khat and neurochemistry . . . . . . . . . . . . . . 5. Algorithms of laboratory/preclinical studies on khat . . . 6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . 7. Recommendations . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction Khat, Catha edulis Forsk, is an evergreen shrub or tree found 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: 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 are known as Abyssinian tea or Arabian tea (WHO, 2006). These many names attest to the widespread and presumably fairly old knowledge of C. 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 over 20 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 Madagascar 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 prestigious (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 (AlMotarreb et al., 2002). Recent reports suggest that 80–90% of the male adult and 10–60% 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 Internet has 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;

2006. 1983. Saha and Dollery. glycosides. where people publicly chew it and offer it to visitors as a mark of hospitality (Selassie and Gebre. Luqman and Danowski. Warfa et al. Elmi. 2002). 2007). zinc. Sweden and Norway (Widler et al.. Al-Hebshi and Skaug.. thiamine... 1997).A. 1987. Crombie. 1998). We also examined the reference sections of these articles to identify additional potentially relevant studies. German. Fasanmade et al. and the prevalence has been shown to reach 80% in Somali immigrants in London (Griffiths et al. Australia (Stevenson et al. Several authors have also suggested weighing the evidence dispassionately before sounding alarm on what is an important substance for sections of the immigrant population of many western countries (Weir and Thuriaux. Belgium. 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. . Switzerland and Canada (Vanwalleghem et al. Mathys and Brenneisen. 1994.. Yemen. Elmi.1. 1976. alanine and threonine (Szendrei. manganese (Halbach. and in small cities and towns all over the country it is brought to market as produce. Hattab and AngmarMånsson. 1990). 2003). 2002) and in some parts of Ethiopia it is consumed by government officials. 1972). iron (Hattab and AngmarMånsson. 2003) and a negligible amount of fluoride (Hattab and Angmar-Månsson.2.M. Alem et al. 1990). 2000. making its regulation very difficult.. Uganda. 1987.. 1988.A. 1983.. Norway. 1997).. 1988). A study was deemed to be ideal when it fulfils all the three criteria. terpenoids. Analysis of active constituents of khat 3.. Outside of Europe. In total 150 articles which belonged to the aforementioned areas were selected. 2007. 1996). 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. Recently. 2006).. Patel. edulis] (Nordal. Halbach. among which those that contained research on the epidemiology. 2004. and carotene (Nencini et al. edulis. and Canada but permissible in Australia (Saha and Dollery. 3. 1988). Kelly / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1147–1166 1149 Cunningham. Active constituents of khat leaf The leaves and young shoots of C.. Feyissa. 2007). 2003).K. a species of the plant family Celastraceae. Almost every small kiosk in Addis Ababa. 1996). Most taxonomists consider that the genus Catha consists of the single species Catha edulis (Nordal. 2004. For example.S. 1994. 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. Griffiths et al. Many different chemical substances are found in the leaves of khat and these include: • Alkaloids. and did not recommend the scheduling of khat (WHO. 1989. 2000. 70 original reports using khat and or its active principles in their in vitro. AlMotarreb et al.. 1985. 1992). which gained popularity during the first Persian Gulf crisis (Lurie et al. Legal considerations Khat circulates freely in Yemen.. The research only included articles available in English that were published from 1959 to 2007. Drake. Khat use has also been reported in East African communities in Italy (Nencini et al. Methodology A literature research was conducted via PubMed search engine with the search terms ‘khat’ or ‘qat’ or ‘miraa’ or ‘qaad/jaad’ or ‘cathinone’. 1980). Elmi. its status in European countries is not uniform (Kalix. 1972). The search was performed up to September 20. • Elements including calcium. khat is prohibited in Ireland. 2000. Kandela. France.. 1.. 1999). We also used these criteria to comment on the existing evidence of the effect of khat on human khat users. 2005). openly sells khat.. it is illegal in the U. 1980. 1992. From these 150 articles. 1976. 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. copper.. genus: Catha. 2000.. 2006) whilst it is legal in the U. animal studies were subjected to an algorithm for defining an ideal study on khat with regard to its relevance to humans.. J. Israel (Granek et al. Elmi. • More than 10 amino acids including tryptophan. tannins (7–14% by weight). A limited number of references that were not listed in the database were also used. glutamic acid. Elmi et al. 1989). glycine. 1972. Expert-based commentary papers and papers describing the pharmacological properties of khat were also included.. Ethiopia (despite the Orthodox Tewahdo Church prohibiting its use). 2006. One reason for this is that in Yemen (AlMotarreb et al. 2004. the Ethiopian capital. and in the Netherlands (Nielen et al. Ihunwo et al. niacin. Somalia and Ethiopia (Browne. 1987. 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 not significant enough to warrant international control. 1980). South Africa and Madagascar (Odenwald et al. Halbach. Switzerland. 2005. 1980. Somalia. analytical aspects or neuropharmacological properties of khat were identified. Although the active alkaloids of khat. are usually referred to as khat [Family: Celastraceae. and toxic metals like lead and cadmium (Matloob. 1994. 1983. 2000). is most prevalent amongst immigrants from Yemen. riboflavin. and Species C. Luqman and Danowski. 1983). Nielen et al. Khat is mainly grown in Ethiopia. Kenya. namely cathinone and cathine have been labeled as Schedule I and Schedule III substances respectively by WHO since 1971 (WHO.P. Cox and Rampes. Giannini et al. • Trace quantities of vitamins including ascorbic acid. Geisshüsler and Brenneisen. 2. Kalix and Braenden. sterols. whilst in the USA khat use. Holland. flavonoids.

(2004)1 Geisshüsler and Brenneisen (1987)2 Widler et al. Pharmacokinetics Khat is usually chewed. cathinone is enzymatically converted to cathine [(+) norpseudoephedrine] and (−)norephedrine (Al-Obaid et al. 1989.. the khat leaves are usually wrapped in banana leaves immediately after picking to retain their moisture (Yousef et al. 2003).. During the khat session the leaves and the bark of the plant are chewed slowly over several hours. Gugelmann et al.51 3.. 1980).9 ± 0. S. 2005). the Fig. isolated and identified the phenylalkylamine... Other alkaloids of phenylalkylamines in khat leaves include the phenylproanolamine diastereoisomers of cathine [1S. The chewers fill their mouths to capacity with the tenderest leaves and shoots and then chew intermittently to release the active components or keep it in buccal vestibules (Sawair et al. 1990) and their concentration is relatively low (Brenneisen and Geisshüsler. 1. which are mainly detected in khat leaves originating from Kenya (Brenneisen and Geisshüsler. The juice of the masticated leaves is swallowed. 1983. classified according to their relative molecular mass (Kite et al.09 ± 0. 2) (Sporkert et al. During chewing.02 ± 0. and norephedrine [1R.. there has been little investigation of the cathedulins to date (Kim et al. 2003. The phenylalkylamines and the cathedulins are the major alkaloids. During maturation. pseudomerucathine and merucathine. Kelly / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1147–1166 Table 1 Concentration of khat alkaloids from fresh khat leaves of various origin Cathinone 0. Accordingly. They seem to contribute less to the stimulant effects of khat (Kalix et al.60 ± 1. Recently. 2002)..8 0.8 1. 3).05 References Dimba et al. In certain khat samples. The leaves are removed from their branches and thoroughly chewed. 2007). Indeed. Fig. 2S-(+) norpseudoephedrine or (+) norpseudoephedrine]. . 1990. Another class of phenylalkylamine alkaloids found in khat leaves are the phenylpentenylamines.2). 2S-(−) norephedrine]. Alem et al. 4) (Kite et al. analyses of khat samples from Kenya and Ethiopia have shown that the commercial value of the material correlates with its cathinone content (Geisshüsler and Brenneisen. S-(+)-norpseudoephedrine (cathine) and R. J. 62 different cathedulins derived from fresh khat leaves were characterized (see Fig. Other classes of alkaloid in khat are the cathedulins.16 0.25 ± 1. 1987).74 ± 0. usually for 2–10 h and an average 100–500 g of khat is chewed (Nencini and Ahmed.47 ± 0. later named as S-(−)-cathinone as a major active constituent in fresh khat. 2005). Chemical structures of S-(−)-cathinone.. 2003).1150 A. Crombie. 2003). 1990.. as well as local traditions connected with cultivation and harvesting determine the chemical profile and general appearance of khat leaves (Nordal. 2003. 1987). Cathine and norephedrine occur mainly in older plants and is also formed by reduction of cathinone during drying and storage (see Fig.9 0. Szendrei (1980) at the UN Narcotics Laboratory. 2Khat samples from Ethiopia. 1984). Kalix. 2007). Elmi. S-(−)-norephedrine (MW = 151. 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.06 Norephedrine 0. Cathinone is transformed mainly to cathine in khat leaves and mainly to norephedrine by human metabolism. 1998).. to slow down the degradation process. 1985) which has the same absolute configuration as S-(+)-amphetamine (see Fig.. (−)-α-aminopropiophenene. and rarely smoked (Elmi.40 1. 1987) (Fig.. The plant contains the (–)-enantiomer of cathinone only (WHO. Though there has been much research on the phenyalkalymines. Chemical structure of S-(+)-amphetamine and S-(−)-cathinone (MW = 149.49 ± 0. Kenya.2). but not the residues (Toennes et al. (1994)1 Data given in mg per gram of khat leaf expressed as mean ± SD. 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. Feyissa. Matloob.11 Cathine 1.86 ± 0.M. Yemen and Madagascar. together with Schorno and Steinegger at the University of Berne.P. Goudie. 2003. 1980). The phenylalkylamine content of khat leaves varies widely.. 2006. 2. climate conditions. 1) (Kalix. 3. 1987). merucathinone. Al-Hebshi and Skaug.. occasionally brewed as a tea (Giannini et al. Modified from Sporkert et al. The environment.. 1983). 1999). 1992. 1Khat sample from Kenya. Switzerland. 2003). 1995).. Sunlight-induced or heat-induced degradation to cathine and norephedrine also occurs during extraction of cathinone in the laboratory (Banjaw et al. they are then kept for a while in the cheek as a ball of macerated material and later expectorated (Al-Motarreb et al.2.

. plays a major role in the absorption of alkaloids (Toennes et al. 1995). 1990).. 1994. The absorption of the constituents of khat is said to have two phases. Brenneisen et al.. Structure of K-19 (1). Cathinone has been determined in spiked human plasma in khat naïve volunteers after 0administration of synthetic cathinone (Widler et al. J. at the stomach and/or small intestine (Toennes et al. The second phase is following swallowing of the juice. 2003). 4. the first being at the buccal mucosa..A. Kelly / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1147–1166 1151 Fig. with about 80% of cathinone and cathine..P.. maximal plasma Fig. Brenneisen et al. 2003).. . 1995. Feyissa. 2003.M. Summary of class of different alkaloids in khat leaves. Halket et al. 2002).5 h (Halket et al. Similarly. 1990) or after the chewing of khat leaves (Widler et al. Adapted from White. The pharmacokinetic parameters for cathinone and other ingredients of khat leaves have been determined over 8 h. and over 90% of norephedrine released following chewing (Toennes and Kauert. Toennes et al.. 3. 1994. alkaloids from khat leaves are effectively liberated. one of the most highly elaborated members of the cathedulin family with its polyhydroxylated sesquiterpenoid euonyminol core (2). with peak plasma levels attained after 1–3. 1994..

Analysis of urine and blood provides information on recent or current exposure to drug use.. Kim et al. These methods are similar to those used for amphetamines because of their structural similarity (Sporkert et al. which are available as over the counter anorectic and cold suppressant medications respectively. and GC–MS [Gas chromatography-mass spectrometry] (Mathys and Brenneisen. which have been observed in several clinical trials and animal studies with khat and or cathinone (Widler et al. The khat chewer believes that they think more clearly and quickly and are more alert. The major metabolites of cathinone.. 1990). Kalix et al.3. a fairly common metabolic pathway in humans. 2005). the dependence-producing potential. 2003). 1985. Feyissa. 2007).. 1990).8 mg/kg cathinone it was reported that the total amount of cathinone absorbed in the body after 9 h (AUC. However. anorexia.. Brenneisen and Geisshüsler. and the terminal elimination half-life was 260 ± 102 min (Widler et al. Brenneisen et al. cathine and norephedrine (Sporkert et al.P.. 2007). methcathinone) from urine samples (Toennes and Kauert.. possess weaker central stimulant properties because of their less lipophilic properties (Nencini and Ahmed. catalyzed by liver microsomal enzymes (Guantai and Maitai.. cathinone. 1994). 2002.. Detection of khat alkaloids (cathine.. Nencini and Ahmed. Analysis of cathinone in hair samples was measured in Dark-Agouti rats. 2002. Kebede et al.e. and increased sensory stimulation (Patel.6 and 2.. 2002). both cathine and norephedrine.. 2007). Other alkaloids such as phenylpentenylamines are of low concentration and were shown to have a weak effect on dopamine release in dopamine prelabelled rat striatal tissue (Kalix et al. gas chromatography. Recently a multi anylate procedure has been developed to determine cathinone and other phenyalkylamines in plasma using LCMS/MS [Liquid Chromatography/Mass Spectrometry/Mass Spectrometry] (Beyer et al. excitation. Guantai and Maitai. 1990... logorrhea. 1992. The amount of norephedrine excreted in urine is much higher than the amount ingested. 1990).. 1988). These effects. and hair samples (Kim et al. 2. However. Cathine has been found in breast milk in several lactating women who were chewing the leaves of khat (Kristiansson et al. 1990). it can be assumed that khat-induced psychostimulation is predominately. The pharmacology of cathedulins has not yet been well characterized in the CNS and other organs (Kite et al. there is enough scientific data to suggest khat/ cathinone-induced psychostimulation is mediated primarily via the meso–striato–cortico limbic dopaminergic pathway (Kalix. 1983... In view of its potency and its higher lipid solubility (Kalix and Braenden. The proportion of alkaloids detected from the hair was in the same order as urine samples i. Using this technique it has been reported that. is superior to the other techniques for screening and confirmation testing of urine samples from individuals with suspected khat use.e. 1983). are similar to those observed with amphetamine (Halbach. 1987. Geisshüsler and Brenneisen. could result in false positives in urine analysis (Toennes and Kauert. Kalix et al. 2007). or even exclusively due to the cathinone content of the leaves (Kalix. which may suggest a possible therapeutic relevance in management of Parkinson disease in the future (Banjaw et al. 1994. 4. blood. Neuropharmacology of khat The effects observed following khat consumption are generally of central stimulation and include euphoria..3. cathine and norephedrine was reported to be 245 ± 49.. 1979). 1996). 1983). increased respiration. There is a rapid stereoselective metabolism of S-(−) cathinone to norepehedrine and cathine following its administration to humans (Nencini and Ahmed. 1980). norephedrine N cathine N cathinone. and norephedrine) in urine has been performed by TLC (Thin layer chromatography). 1989. Guantai and Maitai. 1990).. hyperthermia. This is substantiated by the brief stimulation after khat chewing (Kalix et al. After ingestion of 0.8 h respectively (Toennes et al.. area under the curve) was 25 ± 13 μg min ml− 1. 2003. which could detect cathine and norephedrine for up to 80 h and cathinone for up to approximately 24 h after khat ingestion. 2003). Moreover. J. whilst analysis of hair samples provides detection of long term and repeated use (Kim et al. the AUC of cathinone. El-Haj et al. . 1996). which is in agreement with the finding that cathinone is metabolized rapidly (Brenneisen and Geisshüsler. i.. later studies in human hair from drug users using GC–MS separation technique detected cathinone. 2003). 1990.. 2003). Brenneisen et al. cathine and norephedrine are reported to be reached at 2. 1989). and is mainly excreted in the form of norephedrine and cathine (Toennes and Kauert. 2003).6 g/kg). 1989..g. and it was reported to have a relatively lower incorporation rate into hair in comparison to other amphetamines (Nakahara and Kikura. 2003). HPLC (High-performance liquid chromatography). Kelly / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1147–1166 concentrations (tmax) of cathinone. all the major alkaloids contained in the plant were detected in the plasma. 1987). Detection of khat alkaloids The biological material commonly used in forensic toxicology for phenylalkylamine derivatives are urine. 1989). Maitai and Dhadphale. 1987). 2002). 710 ± 173 μg min ml− 1 respectively (Toennes et al. facilitating access into the central nervous system (Zelger et al.. Only 7% or less of the absorbed (−)-cathinone is excreted unchanged in the urine (Toennes et al. 2000. This is further strengthened by the observation that subcutaneous administration of cathinone prevented the catalepsy typically found following administration of haloperidol to rats. 8 h after four drug naïve volunteers ingested khat (0.. Metabolism of cathinone to cathine involves reduction of the ketone group to an alcohol.. In another study. 2007). analgesia. 13 ± 131. 1990). analgesia. indicating that (−) cathinone is also metabolized to R. Toennes and Kauert (2002) demonstrated that GC–MS. Although other pathways could not be ruled out. Therefore. cathine and norephedrine. 1987). S-(−) norephedrine (Toennes and Kauert. and anorexic effects of khat/cathinone are believed to be partly mediated via this pathway (Gosnell et al. although their concentration and judgment are objectively impaired (Pantelis et al. khat use can be confirmed only by the detection of cathinone in the absence of N-alkylated homologs (e.1152 A. 3. Hassan et al. 2003. after ingestion of khat leaves.M.

which bears striking similarities to the progressive development of psychosis and paranoia that develops in human addicts following repeated psychostimulant administration. Luqman and Danowski. In general. 1990). Psychosis Khat-induced psychosis (brief psychotic episodes) was considered by many authors to be a rare phenomenon (Halbach. 2007. Several investigators claim that khat use is not necessarily linked to psychological morbidity. 2007.1. 1995. suggest the possibility of positive association between khat use and long term psychiatric morbidity. 2005).. 2003). 1985). However. Pantelis et al. Bimerew et al. 2007. 1999). (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 psychological problems caused by pre-existing stressors. Critchlow and Seifert.. Though it is difficult to incriminate khat use alone. schizophreniform psychosis (Yousef et al. it is thought that in khat-using areas where health facilities are lacking. previous investigations suggesting a link have been criticised for they suffer from methodological problems and lack of quantitative data (for a review see Odenwald. These minor psychotoxic reactions to khat are so well known in Ethiopia for instance.. 1997). Kelly / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1147–1166 1153 4. 1987.1. 2007). Psychological sequelae of chewing khat In recent decades. To date the direction of causality between long term psychosis and khat use remains unclear. hyperactivity... The characteristics of psychosis following the use of khat were mainly of two main types: manic psychosis and paranoid or schizophrenia spectrum disorder (Cox and Rampes. he suggested that heavy khat chewing could induce brief psychosis and could trigger or exacerbate pre-existing schizophreniform spectrum disorders (Odenwald. Cox and Rampes. Luqman and Danowski. impaired concentration. 1997). Alem and Shibre. 1987). Cox and Rampes. There was a tendency for the psychotic episodes to recur upon recommencement of khat chewing (Alem and Shibre. agitation and aggression which usually occur after a moderate intake of khat (Griffiths et al.. 1995.P.. 1988). Accordingly. Heavy khat consumption preceded the psychotic episode and the majority of the cases had rapid resolution when treated pharmacologically. Odenwald. Bimerew et al. 1976).. 2007. Minor reactions include overtalkativeness.. 2004. 1989). J. ensuring that only low plasma levels of its active ingredients can be attained after chewing (Giannini and Castellani. Giannini and Castellani.. (2007) has reported a positive association between Post Traumatic Stress Disorder (PTSD) among Somali ex-combatants and higher levels of khat abuse.. and abnormal patterns of drug use. 2007. Bimerew et al. 2006. 1987. There is an ongoing international debate about a causal relationship between khat use and mental illness (Warfa et al. Furthermore. any association that is found may reflect an interaction with other environmental factors (Warfa et al. 1980. There are a number of reports of psychiatric disorders secondary to khat chewing with features of manic-like psychosis (Gough and Cookson.. occurring during khat chewing and subsequent intoxication phase. insomnia. 1984.. some of the cases with psychotic morbidity. 2005).M. It is postulated that khat consumption precipitates psychosis by either increasing the risk in already vulnerable individuals or affecting the course of a psychotic disorder and the maintenance of symptoms (Odenwald et al. Halbach (1972) suggested that this is due to the bulky nature of the khat leaves. 1997). 2003). 1982).. there have been growing reports of khat-induced psychosis in khat producing areas and in immigrants residing in Europe and USA (Yousef et al. which raises the risk of interactions between alcohol and khat (Omolo and Dhadphale.. Among the several alkaloids in khat.. has criticised that the majority of the reports and information about epidemiology and use patterns are merely expert opinions and unsystematic observations. Accordingly. and bruxism (Walter. 1989. Nielen et al. In addition there have been reports of personality disorders associated with long term khat use (Kalix and Braenden.. 2007). 1989. Feyissa. 2007.. Alem and Shibre. 2006). cathinone is incriminated for most of psychological sequelae related with khat chewing (Elmi et al. which has become a special public mental health concern (Bhui et al. (1995) summarized clinical features of khat-induced psychosis. Giannini and Castellani. 1997). Kebede et al. 2004. 1997. However. 2005). 4. Alem and Shibre. people with psychotic symptoms are locked in their homes by families until the episode subsides (Yousef et al. the traditional habit of chewing the leaves of the khat shrub has undergone profound changes in African and Arab countries. Bhui et al. 1972. Kalix and Braenden. khat chewers often take alcohol to counteract the stimulant and sleep depriving effect of khat. It is believed that immigrants are vulnerable to psychosis due to social dislocation. 1995. induced hypnagogic hallucinations (Granek et al. 1982). (1989) and Yousef et al. dizziness. The latter is very similar to paranoid psychosis seen with chronic amphetamine and cocaine addicts (Pantelis et al. Nevertheless. 1989. 1985). depression (Pantelis et al. In general. Alem et al. Capgras and Fregoli syndrome (Yousef et al. two cases of homicide and combined homicide and suicide have been reported following consumption of khat (Pantelis et al. Recently Odenwald et al. 2007..1. 1995). from a socially regulated use pattern towards uncontrolled consumption (Sawair et al. WHO. Bimerew et al. McLaren. Odenwald et al. and preexisting stressful situations (Pantelis et al. recent studies using laboratory animal models of behavioural sensitization.. have been associated with self harm and suicide (Cox and Rampes. Secondly. khat users displaying these features have been given the name jezba (Kalix. 1989. not substantiated by rigorous clinical testing. Ellison. Odenwald (2007) in a review of 45 articles in this area.. usually by antipsychotic medication of the phenothiazine type. 1995. Few of the cases had spontaneous resolution without pharmacological treatment once they stopped abusing khat (Yousef et al. 2007). Warfa et al.A. Alem and Shibre. 1982... i.e. paranoid psychosis (Nielen et al. 1976).. 2002). 2003).. from minor reactions to the development of a psychotic illness. anxiety. 1996). 2003. Pantelis et al. khat chewers display a range of experiences. most of the cases in Europe were Somali males with a minority of the cases having past psychiatric history and family psychiatric history.. there is no clear evidence as to the effects of khat use and the development of mental illness'. 1997). 2003). 1987. two paradigms that have been widely studied as animal models of . Banjaw and co-workers (2005) have reported locomotor sensitization and prepulse inhibition deficit.. irritability..

. 1989. Mood disorders Khat chewing can induce a substantial degree of mood disturbances. The severity of depression varied from agitation and sleep disturbances to severe depression with suicidality (Nielen et al.. 2002). 2004). They also reported increased dopamine levels in prefrontal cortex with reduced dopamine and its metabolites in anterior putamen. after intermittent oral administration of (−) cathinone or C. 1990. neurochemical correlates revealed depletion of serotonin and its corresponding metabolites in both anterior and posterior striatum. These results suggest that the behavioural effects of C.. Clozapine. Nielen et al. and it might exacerbate symptoms in patients with pre-existing mood disorder. In eastern African countries the prevalence of khat dependence is estimated to be 5–15% of the population (Nielen et al. 2002). 2005). 1980). by dopamine in the meso–striato–cortico limbic pathway (Banjaw et al. 4. Although cathinone is known to cause sensitization upon repeated administration similar to amphetamines (See above).3. 1992). (2002) studied the effect of khat chewing in human mood using the HAD (Hospital Anxiety and Depression) Scale. in which repeated oral administration of C. and his subjects in the city of Mar'ade (Dillmann. 1997. there have been reports of khat-induced aggressive verbal outbursts and violent behaviour in the past (Luqman and Danowski. Recently. 1990) because of its less aversive nature (Foltin and Schuster. higher rate of self administration. cathinone and cocaine (Ellison. Similar to amphetamine. closely related drugs to cathinone. There are similar reports of mood disorders secondary to repeated amphetamine use (Baker and Dawe. Hassan et al. edulis or S (−) cathinone enhanced aggressive behaviour of isolated rats. The reduction in dopamine and its metabolites is in contrast to amphetamines. psychosis due to cocaine and amphetamine.2.M. in a community based study in Somalia. particularly depression in healthy subjects (Hassan et al. 2005). 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. (2006) have reproduced this phenomenon using isolation induced aggression paradigm.2. Banjaw et al.... 2002).1. This finding suggests that humans who use C. and rapid onset of action in discrimination experiments (Yanagita. Generally it .. Khat taking behaviour depends not only on the reinforcing psychostimulant action of khat. maintenance and expression of sensitization following repeated administration of psychostimulants (Banjaw and Schmidt.. 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. which suggest that aggression in this paradigm is enhanced presumably by decreasing the level of serotonin and its metabolites (Banjaw et al.. Banjaw et al. is similarly believed to be mediated via this pathway (Goudie. 1988). 1972).. at least in part. Luqman and Danowski. Habitual use of khat is in many instances compulsive.. 2005. an atypical antipsychotic widely used to reverse these behavioural changes in animal models. 1985). 1976. 1983. which are known to increase dopamine in the caudate putamen in the locomotory sensitization paradigm. 1996. 2003). Kalix and Braenden. Incidentally. edulis or cathinone are mediated. 1981) when compared to amphetamine in various operant experiments (See Section 4. Depression associated with khat chewing has been reported by several authors (Pantelis et al. They reported that khat chewing results in a functional mood disorder consisting of predominantly reactive depressive mood (seen an hour after acute khat administration).1. Ellison. 1979.. (1992) reported two cases of khat addiction which were effectively treated with bromocriptine using a protocol developed for cocaine addiction. 1982).. 1884 as quoted by Giannini et al. Halbach. 2005). Granek et al. 1985). 2006). Berardelli et al. Indeed. Gosnell et al. Giannini and Castellani. edulis extract in rats.. 2005). It is postulated that khat could have a higher dependence potential than amphetamine (Kalix. Griffiths et al. 2004. In most of the reports it is seen as a consequence of cessation of khat chewing (reactive depressive mood). 2004). 4.e. This is described as a psychological dependence by many authors (Kalix. Addiction The use of khat often starts at a young age and can develop into a compulsive daily habit lasting a lifetime (Patel. Recently. Kelly / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1147–1166 psychosis. Feyissa. 2006). 1984a. 2002. Connor et al. 1988. Goudie and Newton. J. 2005). was shown to attenuate these deficits (Banjaw et al. There are conflicting opinions regarding the existence of a withdrawal syndrome. 2005). This pathway is believed to play a central role in the induction. Recently. However. edulis over an extended period could be at high risk of incurring neuropsychiatric diseases (Banjaw and Schmidt. 4. Other mood disorders such as khat-induced behavioural syndrome described as hypomania have also been reported by several authors (Nencini et al. deficit in the startle reducing effect of a weak prepulse preceding a startle stimulus by 30–200 ms) upon repeated administration of psychostimulants including amphetamine. 1989). In both instances there is progressive augmentation of either locomotor-stimulatory effects (locomotor sensitization) or deficit in prepulse inhibition (i. Johanson and Schuster. 2005). there was evidence of the presence of disruptive and violent behaviour amongst chronic khat users (Odenwald et al. an Ethiopian ruler in the early 14th century.1154 A. Banjaw and Schmidt... fourth edition (DSM-IV) (American Psychiatric Association.5). 1976. It is thought to be mediated by the sympathomimetic action of cathinone (Hassan et al. (1980) observed a spontaneous burst of aggressive behaviour in rats after intraperitoneal (ip) administration of cathinone.. 1994) criteria for substance abuse. but also on deeply rooted cultural factors (Nencini et al. similar to that seen with amphetamines.. Aggression Previous literature reviews show that there are scant data on the long-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. Hassan et al. Giannini et al.. 2002).P.4. 2002.b. 2000). 1987... there are reports of tolerance to the CNS stimulating effects of khat chewing. From their description it could be inferred that both cases satisfy the Diagnostic and Statistical Manual of Mental Disorders. and decrease in 5-HT in nucleus accumbens and its metabolites in prefrontal cortex (Banjaw et al.1. The first documented case of khat addiction was that of Amda Tsion.

2004. Kelly / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1147–1166 1155 is believed that there is no physical withdrawal syndrome as experienced with alcohol... feeding behaviour (anorexia). and depression (Luqman and Danowski. habitual users report that they have no serious difficulties when moving to an area where khat cannot be obtained (Kalix. 1980a. When compared to amphetamine the potency of cathinone was in the order of 1:2–1:5 except in conditioned taste aversion. 1ethanol. 1982.. and monkeys) cathinone/khat showed qualitatively similar effects to amphetamine. ✓ = Yes.... This is similar to the neurotoxic effect of chronic amphetamine administration on the dopaminergic innervations of caudate. Banjaw et al. Since the characteristic property of khat chewing is stimulation of the CNS. (2006) Banjaw and Schmidt (2006) Abdulwaheb et al. 1987). Goudie. electroencephalogram.M. 1983. there are reports of social withdrawal symptoms after cessation of the habit. 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. 2006). Kalix. Hassan et al. However. slight trembling. J. 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. Kalix. (2000) Banjaw and Schmidt (2005)† Ideal study.1. test for analgesia (nociception). nightmares. 1985). behavioural sensitization (psychosis). in the range of 1:7–1:10 (Peterson et al. 1982. anergia. To date. Both khat extract and cathinone have been shown to increase spontaneous locomotor activity. Cox and Rampes. Eisenberg et al. particularly on the nigrostriatal dopamine terminal projections (Wagner et al. EEG and MRI findings indicated progressive leucoencephalopathy but this could not be linked with khat use. The behavioural models employed include. rat. (1999) reported such a case in a 58 year old Somali man living in UK who presented with leucoencephalopathy associated with khat misuse. locomotor activity (psychostimulation). the main finding has been that khat/cathinone induces the release of dopamine from presynaptic storage sites (Kalix and Braenden. 2005. ✗ = NO... 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. where cathinone was reported to be very weak [1:17] (Mereu et al. Indeed. prepulse inhibition. (1988) Banjaw et al. Indeed. Alem et al. In most of the behavioural experiments conducted in various animals (chicken. the behavioural pharmacology is of particular interest. cathinone was reported to have a more similar profile to cocaine than to amphetamine in some behavioural paradigms such as intravenous self administration and conditioned taste aversion test (See Table 3 and Fig. As in the case of drug abuse in industrialized societies. 1996). there are few studies which aimed at assessing the CNS toxicity of different constituents of khat (Wagner et al. 2007). However.. morphine or barbiturates (Sulzer et al. Elmi. 1990. However. inducing their degeneration (Ellison. has also demonstrated these behavioural features though less potently than cathinone. 1999).A. PPI. 1976. sildenafil and amphetamine used as a comparator. (2002) Connor et al. 1990). and several operant procedures (addiction/dependence).P. Kalix. Alem et al.. 5). (2007) Connor et al. Morrish et al.b). there appears to be strong evidence to suggest the involvement of the dopaminergic system (Zelger et al. 1988. The concomitant use of psychotropic agents such as hypnotics is also common (Zein..2. 1988). 2006) (Table 2).5. 4. 1980. khat extract (100 mg/kg) and cathinone (5 mg/kg). 2d-amphetamine used as comparator. several investigators have demonstrated that cathinone and cathine Table 2 Algorithm for behavioural studies in animals that used the khat extract Outcome reported 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 † Analysis made? ✓ ✗ ✓ ✓ ✗ ✗ ✗ ✓ Comparator used? ✗ ✗ ✗ ✗ ✓1 ✗ ✓2 ✓2 References Banjaw et al. have been reported to cause behavioural sensitization in locomotor activity of rats similar to amphetamine (Banjaw et al. 2003). tolerance to the anorexgenic effect of cathinone develops rapidly unlike that of amphetamine (Foltin and Schuster.. 1980. Al-Zubairi et al. 4. Abandoning the khat-chewing habit however is followed by symptoms including lassitude. Khat-induced neurotoxicity There have been reports (albeit few) of severe and disabling neurological illness associated with khat chewing. . khat use is associated with simultaneous use of other drugs especially cigarette and alcohol (Zein. 1976. Feyissa. As to the neurotransmitters involved in mediating the different behavioural effects of khat/cathinone. 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 psychostimulant. 2003.. 1983. Cathine. In addition. (2005) Saleh et al. stereotyped movement and anorexia (Kalix and Braenden. isolation induced aggression paradigm (aggressive behaviour). There is also a lack of information regarding the effect of khat on the level of different neurotoxic/neuroprotective factors such as BDNF and lipid peroxidase in the brain. 2002). 1984). described as ‘experiences of deprivation of joys and camaraderie which khat session almost unfailingly provides’ (Stevenson et al.. 1999). 1983). 1987). another psychoactive ingredient in khat. Luqman and Danowski.. mice. In addition. EEG. In addition.

(2002) Zelger and Carlini (1980) Connor et al.1. 1985. Kelly / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1147–1166 Table 3 The effect of cathinone and khat on animal behaviour Behavioural observation Operant behaviour IV Self administration Discriminative stimulus property⁎ Cathinone 0. 1989). (2007) Banjaw et al. CATH:AMPH (1:2) 1–20 mg/kg(IP/SC/PO) in rats and mice. dose range. (1980). COC. 5. also produced these effects though less potent than cathinone. 2006. Effects of Khat/Cathinone on animal behaviour when compared with known psycostimulants. cocaine. in rats.M. J. 2007). Banjaw et al. HPT.8 mg/kg (IP).for 4 weeks in SD rats Khat Not examined Not examined Reference Yanagita (1986).⁎Cathine.2. (1984). Peterson et al. The EEG pattern resembles how users in a khat session would progress Fig. the serotonergic system is reported to be involved in khat/cathinone-induced stereotyped movement. Indeed. Sprague–Dawley rats. (1980). COC.7 mg/kg (IP) in rats. in which lower doses (50–100 mg/kg) caused a stimulatory EEG pattern whilst higher doses (400 mg/kg) caused initial cortical activation followed by EEG depression (Saleh et al. in monkeys and rats 1–25 mg/kg(SC/IP) in mice in TFT and HPT CATH: AMPH (1:4–6) 5 mg/kg(PO). (Tables 4 and 5). ↑time spent in non-preferred Side 1–20 mg/kg in rats and mice (IP/SC/PO). and MDMA 4–16 mg/kg. 1984a.. 4.1 mg/kg/infusion in monkeys.025–1 mg/kg/infusion.87 mg/kg (IP).B. AMPH. Moreover. PO. CATH:AMPH (1:2–3) 0... other neurotransmitters could also be involved as well. CATH:AMPH (1:17) 1–4. 1988). IV.09–1. animals species used.b.008–0. 20–64 μg/kg (IV) in rats. Abdulwaheb et al.. oral. (2002) Abdulwaheb et al.. and sexual arousal (Connor et al. in monkeys. 1980. and chicken.. (2006) N. . For instance. intravenous. intrapertoneal. 1982. SD. Connor et al. subcutaneous. Feyissa. CATH ≈ COC 0. 256 μg/kg (ICV). these effects have been reproduced in rats after oral administration of different concentrations of khat extract. Della Bella et al.. SC. 1983). primarily increase catecholamine release and secondarily inhibit its reuptake (Wagner et al. (+) amphetamine. Connor et al. aggression. 2002. 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. in rats.. IP. 1990a. CATH.. Cathinone. generalizes to AMPH. tail flick test. Mereu et al. Similar EEG patterns were observed in rats after intraperitoneal (ip) cathinone administration (Berardelli et al. 1980). (2006) Berardelli et al.b. Woolverton and Johanson (1984) Schechter et al. Schechter (1990a) Conditioned taste aversion ↓Food reinforced responding⁎ Conditioned place preference Hypermotility⁎ Stereotyped behaviour⁎ Anorexia⁎ Analgesia ↑Sexual arousal ↑Aggression Not examined Not examined Not examined 200–1600 mg/kg (PO) in rats and mice 200–1600 mg/kg (PO) in rats and mice Not examined 200–1800 mg/kg (PO) in mice 100 mg/kg (PO) for 15 days SD rats 200 mg/kg (PO) for 4 weeks in SD rats Goudie (1987) Goudie (1985) Calcagnetti and Schechter (1993) Banjaw et al. Zelger et al. hot-plate test. and when available potency comparisons with other psychostimulants is reported.. 0. for 15 days in SD rats 5 mg/kg (PO).. TFT. However. in rats.P. CATH b AMPH 1–32 mg/kg(PO/IP). 2000). 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. Schechter.1156 A.

2–2 μM. amphetamine. CATH ≈ COC ≈ MDMA Efflux of [3H]NA and inhibition of uptake of [3H] NA. cocaine.4 mg/kg (IP).85 uM N10 uM 0. head twitches.. 2005.. edulis leaves or S(−) cathinone increased locomotor activity in rats (Banjaw and Table 5 The in vitro affinity table for cathinone and comparator compounds Receptor/transporter/enzyme Dopamine transporter α-receptorsa Noradrenaline transporter 5-HT receptorsb Serotonin transporter Monoamine-oxidase a Schmidt. 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. Knoll. in mice (Al-Meshal et al. 2006). it was reported that acute and sub-chronic oral administration of C. CATH ≈ AMPH ↓extracellular DOPAC (NAc. In addition. 2006). as more khat is chewed (Kalix and Braenden. (2002) reported a reduction in spontaneous motor activity in mice after intragastric administration of khat extract.. 3–9 μM. anxiety and depression. particularly on locomotor activity..P. 1980.. 1992a. Berardelli et al. COC. EC50. 1979. Recently. 0. caudate Putamen. 1993. 2002. 6 mg/kg ↓5-HT&5-HTP (NA. dopamine. Cathine was considerably less potent. Banjaw et al. CATH: AMPH (1:1. Hassan et al. 1991) and in young chickens (Bronson et al.. IP.. 2005. ↓DOPAC (PFC. (+)amphetamine. in a similar fashion to amphetamine. prefrontal cortex.. (1980) demonstrated that cathinone has a stimulatory effect on locomotion in rats maximally after 15 to 30 min. For the first time Banjaw et al.b).014 uM 50 uM Cathinone vs.9 uM 3 uM 0. 1980. CP. Banjaw et al. J. IC50. AMPH. 1980. (2006) demonstrated the occurrence of strong behavioural sensitization after repeated intermittent oral administration of C.. (1999) Nencini et al. DOPAC.5 mg/kg (PO) for 4 weeks Khat extract Not examined Not examined Reference 1157 Wagner et al. Connor et al. and turning after oral administration of the extract which was also observed with cathinone and amphetamine. Berardelli et al. than Cathinone IC50/EC50 0.. 2006. NAc. . Once cathinone was identified as an active constituent of khat. PO.. centrally administered cathinone increased spontaneous activity when administrated directly into the nucleus accumbens. 1982. AMPH. 1985. half maximal effective concentration. IP. 5-hydroxytryptamine.. SL).B there is no data as to the affinity of cathinone to dopamine and β-adrenergic receptors.5 mg/kg (PO) for 10 days ↓5-HT&5-HIAA in PFC and anterior and posterior striatum. Kalix.. 2002). 1991). (2003) Cleary and Docherty (2003) Glennon and Liebowitz (1982) Fleckenstein et al. 1990). CATH ≈ COC ≈ MDMA Inhibition of the firing rate of nigral DA neurons. 6 mg/kg ↑DA (PFC). there have been investigations of its effect on animal behaviour. there are some reports of cathinone-induced tremor at a low dose and seizure at higher doses (Berardelli et al. Banjaw and Schmidt. NAc. PFC. 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. after 1. SL. pawing. DA. 5-hydroxyindoalmineacid. sniffing.. 2002. 1980. CATH: AMPH (1:2–6x) Inhibits [3H] nisoxetine binding to NA transporter. Kelly / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1147–1166 Table 4 Neurochemical effects of cathinone and khat Nature of study In vitro studies Synaptosomal preparations Rabbit/rat striatal tissue Cathinone ↑Release and inhibition of uptake of [3H]DA. Peterson et al. 1980b). Similar increases in locomotor activity were observed after khat extract administration in animals. 1980b. 2003) and mice (Zelger et al. 5-HIAA. It was reported that the potency of cathinone was almost comparable with (+)-amphetamine (Kalix. noradrenaline. (2006) Banjaw and Schmidt (2005) IP. half maximal inhibitory concentration. 1979. Moreover. Banjaw et al. 1. NA. 1979) markedly increased spontaneous locomotor activity of the animals.. 2003. 1980. 1–100 μM. (1999) Rothman et al. nucleus accumbens. (1983) Rat cerebral cortex Rat atrial/ventricular strip In vivo study in rats Not examined Not examined Not examined Postmortem analysis in rats ↑DA in PFC. 1980). cathinone. SL). (1982) Kalix (1981. CP) after 1. CATH. edulis leaves or cathinone in rats. 1983) Cleary and Docherty (2003) Cleary and Docherty (2003) Mereu et al. 10 days ↓5-HT&5-HIAA in PFC anterior and Posterior striatum Banjaw et al. Banjaw et al. oral..A. (1984b) Human receptors bfrom rat fundus.. Al-Meshal et al. 1995).M. comparator compounds AMPH N Cocaine N CATH CATH ≈ Ephedrine Cocaine ≈ MDMA ≈ CATH CATH ≈ 4X AMPH Cocaine N AMPH ≈ CATH CATH ≈ 100X AMPH Reference Fleckenstein et al. but failed to demonstrate this effect when administered into the substantia nigra in rats (Calcagnetti and Schechter.. CATH. cathinone N. 2005). Zelger et al. 12 μM ↑efflux and inhibition of uptake of [3H]DA. 2003. In contrast. Stereotyped movements after administration of khat extract or cathinone include biting.. Dihydroxyphenylacetic acid. licking. Cathinone also displayed hypermotility in hypophysectomized and unhypophysectomized rats analogous to (+) amphetamine (Kalix. 5-HT. septi lateralis. PO 200 mg/kg. The rats developed sensitization for locomotor activity. Banjaw et al. intrapertoneal. 1980. Gordon et al. Connor et al. upward and downward sniffing.. Feyissa. (1/7–1/10th).6) Enhanced release of [3H] 5-HT. Rosecrans et al. and rearing (Zelger et al.5 μM. from a state of stimulation and excitation to that of sedation.. 2. rearing. Subcutaneous administration of cathinone in rats (Yanagita.

A similar pattern of cross tolerance between (−) cathinone and (+) amphetamine was reported by Schuster and Johanson (1979). 1987). using this model. 1983). 1998). Foltin and Schuster. Two models have been proposed to explain the reduction in food intake of psychostimulants like cathinone (Wolgin and Munoz. In this study it was reported that both cathine and norephedrine have a potency of one tenth that of cathinone. This feature of khat has been used for centuries to alleviate the sensation of hunger (Zelger and Carlini. 1983. 1988. 1983). 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). norephedrine.3. 1983). On the other hand. a pure opioid antagonist. Nevertheless. Islam et al. these findings indicate that cathinone is the constituent of khat that is mainly responsible for the stimulatory effect of the plant and that it is a potent amphetamine-like compound.. Furthermore. Nencini et al. Knoll. Taken together. Kalix. 1988. 1984. 1998). Kervingant. Kelly / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1147–1166 cathinone at inducing both spontaneous locomotion and stereotyped movement (Zelger et al. 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. 1980). 1982). in rats (Zelger and Carlini. 1990. 4. Cathinone has also been shown to cause a long lasting analgesic activity in mice and rats (Nencini and Ahmed. This anorectic effect of cathinone and cathine has been observed in rhesus monkeys (Yanagita. would differ from amphetamine with regard to the production of motor. 1980). 1987). which results in a failure to seek food (appetitive behaviour) or to eat it (consummatory behaviour). in females.. 1980. Foltin et al. Khat extract was shown to exert analgesic effects in mice. 1983). There are contradictory reports regarding the association between khat chewing and sexuality. 1985).P. whereas switching form cannula to bottle feeding produced decreased intake. Eisenberg et al. Sexual behaviour Khat and its alkaloid cathinone have been reported to affect male sexual potency. Knoll.. 1983).. Similarly. Tolerance is mediated by a compensatory increase in the motivation to eat. 1972). 2002). 2006).. 1988. This property is shared by amphetamine (WHO. switching form bottle to cannula feeding produced a further increase in intake. approaching. Connor et al. failed to show stimulatory effect in the open field test (Eisenberg et al. has been shown to enhance the analgesic effect of morphine in hot plate and formalin test in mice (Nencini et al. when cathinone was administered to rats via the intargastric route. 1980. locating. Nencini et al. a characteristic effect of amphetamine-like substances. and the weight reducing effect disappeared within 3– 4 weeks (Zelger and Carlini. Both cathine and (−)-cathinone were reported to be more potent than amphetamine in this regard (WHO. 1986. 1987).. Indeed. 1979. 1990. Granek et al.. Another constituent of khat alkaloid. 2000). kappa agonist-induced increase in food intake was about twice that induced by the same dose of cathinone administered acutely (Nencini. and in late pregnant guinea pigs (Jansson et al. (1988). They also showed that. however they were reported to be less potent than (+)-amphetamine in this order of potency: amphetamineN cathinone N cathine (Zelger and Carlini. Tolerance to the anorectic effects of khat alkaloids has been extended to include cathine (Zelger and Carlini. and to treat premature ejaculation (Luqman and Danowski. cathine. Wolgin and Munoz (2006) suggested drug-induced locomotion and or stereotyped response to interfere with the appetitive phase of feeding i.. 1980. Feeding behaviour Anorexia. albeit at high doses relative to ibuprofen and amphetamine (Connor et al. loss of libido (Krikorian. 1983). Giannini et al. Systemic acute as well as chronic administration of the two alkaloids in rats showed similar effects.1158 A.2. 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. 1984. 1988.. 1982. Halbach.2. and spermatorrhea due to khat chewing have been reported (Halbach. after the tolerance phase. a metabolite of cathinone in humans. 2002). Elmi.. Browne. 1988). Analgesia Khat leaves and its constituents have been shown to have analgesic properties in animal experiments (Nencini and Ahmed. α-MPT (α-methylp-tyrosine) and diethyldithiocarbamate. 1972. individual khat alkaloids have been shown to possess anorexic properties. Foltin and Schuster. On the other hand. Nencini et al. This was reversibly antagonized by naloxone.. effects of an entire khat extract. Both isomers of cathinone and cathine markedly inhibited the food intake of rats at intracerebroventricular doses of 300 and 500 μg per animal respectively (Knoll. 2007). Woolverton. Anorexic effects of the other khat alkaloid.M. the khat alkaloid cathine (norpseudoephedrine) and norephedrine have been widely used as appetite suppressants in the modern world (Kalix and Braenden.. 1980. Kalix. and by the noradrenaline synthesis inhibitors. Therapeutically. According to some who advocate the Pavlovian homeostatic model. have also been demonstrated in rats (Eisenberg et al. It was reported that within a week there was development of tolerance to this effect of cathinone. impairment of sexuality (WHO. norephedrine. 1972). 2007). khat chewing has been reported to increase sexual desire (Elmi. 1992. yet there has been no study so far where the entire khat extract has been investigated for these properties in animals. 1980).. with its many constituents. 1987). Nencini. 1980. Total and/or partial cross-tolerance was also observed among all the three drugs. Khat has been reported to be used as an aphrodisiac (Krikorian.. . Nencini et al. is a consequence of khat chewing (Halbach....2. while motor activity increased in both groups. inability to sustain erection (Elmi. 1979). 1980. Bentur et al. and probably other behaviours (Connor et al. 4. On the other hand. the suppression of intake is due to loss of appetite. 1980.. and orienting to food (the instrumental learning model). after 10 days of cathinone treatment. 1979. 1988). 1976).4.. suggested that tolerance to the anorectic effect of cathinone is associated with a sensitization to endogenous kappa-opiate mediated activation of feeding. Eisenberg et al. Peterson et al. Taken together. They elegantly demonstrated that acute cathinone injection produced decreased milk intake in bottle-but not in cannula-fed rats. 1983. 1979. 1985.2. J. Nencini et al. Feyissa. it was reported to be a more potent anorectic than amphetamine and cocaine (Foltin et al. 1980). 1959). Della Bella et al. 4...e. 1998...

Abdulwaheb et al. despite being an amphetamine-like drug. they chose both equally often (Woolverton and Johanson. cathinone produced a pattern of responding more closely resembling amphetamine. 1979. They also reported that pre-treatment with D1-type receptor antagonist SCH 23390. This contention is further strengthened by the weak aversive nature of cathinone. which at low dose is reported to evoke penile erection. 1987). (1995) demonstrated that oral treatment of cathinone (5 mg/kg/day) and its combination with caffeine (50 mg/ 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.. the complex rituals of a khat party could be used by consumers as environmental cues to identify the appropriate conditions in which they enjoy khat chewing (place. 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. 4. 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. This was characterized by more frequent infusions at the beginning of the session than in the middle or final portion of the sessions.2. The self administration pattern was reported to be of the spree type. 1981). cathinone has been shown to have reinforcing potential in self administration studies (to demonstrate the dependence-producing potential of cathinone). Foltin and Schuster. through ‘placebo’ mechanisms (Nencini 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). Progressive ratio tests.2. When monkeys were given the choice of self administering cathinone and cocaine. however. Indeed. Johanson and Schuster. and to explore its mode of action by the use of appropriate antagonists and other pharmacological manipulations (Willner. 1983) enhancing the behaviour of animals that gives them access to the substance (Kalix and Braenden. 1997).2.5. Cathinone has been compared to amphetamine and cocaine in a wide array of procedures of operant behaviour. and conditioned place preference test (to assess the rewarding and motivational effects of cathinone). cathinone was less potent (1:17) than amphetamine (Goudie and Newton. 1986). in the condition taste aversion procedure.M. characterized by compulsive khat consumption (Kalix.. which were first trained to self-administer cocaine intravenously by lever presses. 1984).e.A. which is thought to be the animal analogue of aversive effects of drugs in man which limit the intake of drug of abuse. stopping only when exhausted (Yanagita. (+) . and roughly half of those of cocaine in monkeys (Yanagita. 4. 1987. when compared with amphetamine and cocaine.. 1984). 2007). J. Since self administration in primates is considered highly predictive of abuse in humans. Discriminative stimulus properties. 1995). are important measures of motivation to take the drug (i. and music) and could also be partly responsible for khat's euphorogenic effects.2. Gosnell et al.. This pattern corresponds to that seen in amphetamine dependent humans (Kalix and Braenden. 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. 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. (1996) have demonstrated intravenous self administration of cathinone in rats under a continuous (FR1) reinforcement schedule. Similar results were obtained in rhesus monkeys. The final ratios obtained for (−) cathinone were similar with amphetamine. 1979). after which progressive ratio tests were conducted (Yanagita. food reinforced responding. Indeed. which utilize the breaking point generated by increasing the fixed-ratio requirement. drug discrimination procedures (to elucidate its similarity to other psychostimulants such as amphetamine).. 1991). 1979). in which monkeys took the drug frequently day and night.. Recently. 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 administration. Self administration studies using (−) cathinone have illustrated the role of this alkaloid as a dependence producing compound among the khat alkaloids (Kalix. 1986). Taha et al. Kelly / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1147–1166 1159 1983). Abdulwaheb et al. In contrast to the primate models. They relapsed after a period of rest of less than 24 h.P. Goudie. Further they allow us to investigate the subjective effects of the training drug as a function of time and dose. concurrent administration of the low dose extract followed by ethanol was found to enhance male rat sexual motivation/arousal (Abdulwaheb et al.5. possesses unexpectedly weak aversive properties (Goudie.5. and it is generally found to have similar effects to amphetamine and cocaine (Woolverton and Johanson. The discriminative stimulus properties of drugs in animals are considered to be predictive of their subjective effects in humans (Goudie. In addition to the aforementioned studies on primates. partner. 4. Johanson and Schuster (1981) and Yanagita (1986) have reported that intravenous infusions of cathinone will maintain responding in rhesus monkeys. In addition. This is similar to amphetamine. 1989). Feyissa. These animal studies suggest that cathinone has abuse potential as great as that of cocaine and probably greater than that of amphetamine (Goudie. 1986). 1997). like cocaine and amphetamine. which had been previously trained to lever press for cocaine injections. 1982). though its effect at high dose is inconclusive (Taha et al. it is possible that abuse potential of cathinone is as great as cocaine (Nencini and Ahmed. In addition to the pharmacological properties of khat. conditioned taste aversion test. how hard the individual will work for it) and to compare the reinforcement magnitude of several psychostimulants (Willner. which.1. 2004). 1987. 1983). 1985). which suggests a role for D1 type dopamine receptors in mediating its reinforcing effects. 1985). increased the number of infusions. Self administration. 2007). 1995. although the role of testosterone cannot be ruled out (Taha et al. 1985. 1987). while high doses of the extract (400 mg/kg/day) produced opposite effects on both sexual motivation/arousal and performance in male rats. 1984.

Cathine was also shown to have discriminative stimulus properties in a two choice food motivated. This suggests that (−) cathinone has to penetrate to intraneuronal sites in order to evoke release.e. when paired with confinement in the non-preferred side of the conditioned place preference apparatus. 1990. 1982) and striata (Zelger and Carlini. Glennon et al. amphetamine and cocaine have been shown to be temporal (Schechter.2.. . Glennon et al. which is known to prevent the induction of release by amphetamine. which involves the pairing of drug cues with a distinctive environment. 1990. Rosecrans et al. cathinone interferes with the reinforcing properties of food. Schechter. Khat and neurochemistry The stimulatory effect of cathinone is believed to be mediated by the dopaminergic system. 1990a.5 mg/kg) increased the response rate in rats under a differential reinforcement of low rates of responding schedule [e. i. 1985).. 1984).b). 1989. 1991. Initially it was demonstrated that cathinone (0. animals trained to detect cathinone react as if they had received cathinone when injected with amphetamine and cocaine but not when injected with opioids. 1984. Similarly. benzodiazepines or fenfluramine (Goudie et al. which suggest that this behaviour is of central in origin (Calcagnetti and Schechter. 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.P. cathinone increased efflux from isolated rat caudate nucleus (Kalix. similar to cocaine and amphetamine in rats (Schechter and Meehan. Furthermore. 1985. 1993). Nielsen and Schechter. Johanson and Schuster. Li et al. mazindol and benztropine that have been shown to inhibit amphetamine induced circling behaviour were found to inhibit (block) cathinone induced [3 H] dopamine release from these tissues (Kalix. like (+) amphetamine is rate dependent.. it has been demonstrated that substantial release of radioactivity induced by low dose cathinone in a dose-dependent manner. Similarly.4. 1980. 1980. In fact. Goudie (1985) illustrated that the effect of cathinone. 1979). inhibited the efflux increase caused by cathinone (Kalix. it was reported that tolerance tends to develop to cathinone in their ability to control discriminative behaviour. Schechter (1990a) reported an acute tolerance effect of cathine in their ability to control discriminative behaviour.. The drug discrimination procedure is used not only to test the similarity and dissimilarity of psychoactive drugs. (2006) have demonstrated that when cathinone was given before or concurrently with cocaine to rats in a drug discrimination procedure. 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.g. from isolated rabbit caudate nucleus prelabelled with [3H] dopamine (Kalix and Glennon. Subsequently.. 4. Peterson et al. 1991). Calcagnetti and Schechter. 1986).5. 1997).M. 1986. In a similar manner. Moreover. Goudie. 1993). Cathine. was also shown to produce similar effect on food reinforced responding (Peterson et al. 1986. Moreover. the only difference between cathinone. 1990a). Goudie. direct microinjection of cathinone into the nucleus accumbens (NAc) was reported to produce discriminative stimuli (Schechter et al. Conditioned place preference is a method of assessing the rewarding and motivational effects of drugs of abuse (Willner. drug discrimination paradigm (Pehek and Schechter. 1979. in rats trained to discriminate the interoceptive cues produced by (−) cathinone.. In support of this.2. 1986. Schechter. 1991. Pehek and Schechter. Similarly. Three known catecholamine reuptake inhibitors. 1980.. 1992). the administration of (+) cathinone and (+) cathine produced (−) cathinone like responding. Huang and Wilson. has a tendency to increase low rates of responding and decrease high rate of responding. Feyissa. 1985). the cocaine dose effect function was shifted to the left suggesting cathinone generalizes to cocaine. Moreover. Kalix. 1980b). 1981). nomifensine. 1980). Calcagnetti and Schechter. 1985). The suppression of overall food reinforced responding may be explained in terms of drug-induced behavioural disruption and response competition (Goudie. 1984). 1986a. 1993. increased the time spent on that side. This modification of food-motivated behaviour has been demonstrated in rats (Yanagita. and that the uptake inhibitors prevent this penetration. Recently.. 1981). indicated by deficits in discriminative performance and shift of the dose response curve to the right (Schechter and McBurney. 1983.1160 A.. 1981. indicated by deficits in discriminative performance. Conditioned place preference.5. similar to amphetamine (see Table 4) (Kalix and Braenden. Indeed.. DRL 20 s] (Yanagita. 1981) prelabelled with [3H] dopamine. J.. 1985). Goudie. 1980). Kalix and Glennon. pretreatment with cocaine. It is generally believed that cathinone-induced conditioned place preference is mediated by dopaminergic neurons (Kalix. This contention is supported by evidence that pre-treatment with a dopamine release inhibitor attenuates place preference induced by cathinone (Schechter. 1979). Kelly / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1147–1166 amphetamine trained rats responded as if they were given (+) amphetamine when various doses of cathinone were administered ip (Schechter et al. This behavioural task. Schechter and Glennon. 1993). intracerebroventricular injection of cathinone to rats. has been shown to produce a doseresponse location preference with ip cathinone.b.3. 1990). 1985). 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. similar to amphetamine. 1981. Schechter. an ability known as ‘generalization’ (Schechter. Similar results have been obtained in monkeys. but it can also be used to investigate the production of tolerance after chronic treatment of trained rats (Schechter. though less potent than cathinone. 4. 4. Similar to amphetamine. Food-reinforced responding. 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. 1986a.3. The potency ratio of cathinone and (+) amphetamine in this regard was similar (1:3) to that reported for other behavioural tests (Peterson et al. 1990b. 1985) and in monkeys (Schuster and Johanson. 1982).

Interestingly. supports the hypothesis that the serotonergic pathway as well could play a role (Babayan et al. For the analysis. 1990b).. Zelger et al. On the other hand. edulis extract (200 mg/kg) significantly reduced the level of dopamine and its metabolites in caudate putamen in rats which displayed locomotor sensitization (Banjaw and Schmidt. a known 5-HT receptor blocker depressed both head twitches and spontaneous activity in rats that were treated by oral khat extract or (−) cathinone suggesting a possible role of 5-HT mediated motor activity. a potent dihydropyridine calcium channel (L-type) blocker attenuated the activity elevating effect of intracerebroventricularly administered cathinone in rats (Calcagnetti and Schechter. 1985. In contrast. Rothman et al. neurochemical mechanisms other than dopamine could explain the neuropharmacological actions of khat or S-(−)cathinone (Banjaw et al. 1985). in a similar fashion to (+) amphetamine. 1984b). Mereu et al. 2006). However in contrast to amphetamine. Kelly / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1147–1166 1161 dopamine release inhibitors (Calcagnetti and Schechter.A.. In agreement with this. In addition. 2002. J. 1993).. abolished locomotor and increased stereotyped behaviour induced by cathinone. 2002). 2006). a non selective dopamine antagonist was found to reduce biting and licking movements caused by cathinone. 1999). Banjaw and Schmidt. 1990).. On the other hand pretreatment with haloperidol. In a similar fashion to amphetamine. Connor et al.. The apparent difference between the extract and the active principle. 1984b). similar to amphetamines. prevalence and socioeconomic aspects of khat were excluded from this assessment. S-(−)-cathinone. administration of khat or cathinone to rats after unilateral lesion of substantia nigra with 6-hydroxydopamine (6-OHDA) induced ipsilateral rotation. 6). Banjaw et al. 1999). cathinone was also found to have four times higher affinity than racemic amphetamine for serotonin receptors in isolated rat fundus (Glennon and Liebowitz. such as cathine and different metabolites (Schechter. (1983) have demonstrated that (−) cathinone inhibited the firing rate of dopaminergic cells in the substantia nigra which was reversed by haloperidol. It has also been shown that intermittent oral administration of C. 2003.. Nielsen.9 mM) in this regard (See Table 5). at this juncture. Moreover. 2003). Inhibition of amine oxidase activity is supported by the observation of increment of urinary catecholamine (HVA) associated with khat chewing in humans (Nencini et al.. 1982). Therefore. In addition. Once more these finding suggests that cathinone. Algorithms of laboratory/preclinical studies on khat After reviewing each article. This is attested by the fact that pre-treatment with isradipine. 2005). Mereu et al... 1990b. which was antagonized by methysergide and p-chlorphenyalanine (5-HT synthesis blockers). 1981. 1992b). it was found that chronic administration of cathinone to rats leads to significant reduction in the dopamine levels (Wagner et al. original studies conducted on khat or its active principles in vitro and in vivo were used. in a similar fashion to amphetamine.P. Feyissa. (2002) have reported that pretreatment with methysergide. Banjaw and Schmidt. deterioration of visual stimuli after ip administration of cathinone to cats. suggesting that they have indirect dopamine releasing actions on the CNS (Zelger and Carlini. The result of the later studies showed that there is reduction in the dopamine metabolite DOPAC. in which cathinone released and blocked the uptake of tritiated dopamine (Wagner et al. This is similar to amphetamine and cocaine. These findings are in agreement with those previously described for synaptosomal preparations... Cathinone. 5...b). or pretreatment with the relatively selective dopaminergic neurotoxin 6-OHDA (Zelger and Carlini. 1981. Recently. in vivo microdialysis in rats after acute intraperitoneal administration of (−) cathinone. Moreover. 1982. though low in magnitude when compared with amphetamine and methamphetamine (Fleckenstein et al. 2006). cathinone (Ki = 0. Osorio-Olivares and coworkers (2004) have reported that cathinone exhibited inhibition of MAO-B activity more than MAO-A. we made an attempt to critically analyse the relevance and possibility of translation of the preclinical studies to human khat users (Fig. 2006). which have been shown to cause depletion of dopamine upon chronic administration (Ellison.. studies addressing solely the analytical .M. 1983).05 mM) appears to be about 150– 200 times more effective than amphetamine (Ki =7. Banjaw et al. 1992a. cathinone was also shown to decrease dopamine transporter function following in vivo administration in rats (Fleckenstein et al. edulis contains (besides S-(−)-cathinone) other compounds. So far there is no clear cut evidence on the role of serotonergic and/or other pathways in the stimulatory effect of cathinone... 1983). has also been shown to inhibit monoamine-oxidase (MAO) activity in vitro (Nencini et al. there is in vitro evidence that cathinone-induced dopamine release is regulated by calcium channels (Vislobokov et al. In fact. it was documented that S-(−)-cathinone acts as well on noradrenaline transporters (Cleary and Docherty. Finally. 1990). (1980) has demonstrated that pre-treatment with reserpine (monoamine store depleting agent) or methyl-ptyrosine (MPT. releases dopamine from nerve terminals and blocks its reuptake (Mereu et al. like amphetamine. 1982). 1983). Kalix (1984) reported that cathinone had a 5-HT releasing effect (like amphetamine) in rat caudate nucleus prelablled with [3H] serotonin and it was one third as potent as (+) amphetamine. 2006. which we obtained through one of the previously mentioned methods. increased levels of dopamine but decreased level of metabolites in a dose dependent manner (Pehek et al. In line with this. Some investigators have reported that levels of serotonin in rat brain are not altered by repeated administration of cathinone (Wagner et al.. may be attributed to the fact that C. 2005). a catecholamine synthesis inhibitor). cathinone was shown to decrease serotonin transporter function. 1982) although acute administration of cathinone was insufficient to produce detectable decrease in dopamine (Nielsen. In addition. into mesolimbic pathways significantly attenuates cathinone induced activity. a parameter that is generally taken as reflecting the amount of dopamine released and captured by the nerve endings (Pehek et al. The additional compounds existing in the crude extract might have substantially altered behavioural and neurochemical effects (Schechter. it is important to note that in various behavioural experiments the neurotransmitter level in different brain regions was slightly different when khat extract is used instead of cathinone (Connor et al. Articles which emphasized the epidemiology..

Thus the only papers included in the final analysis were original studies (animal/in vitro) that dealt with the neuropharmacological aspects of khat. urine measurement of cathinone and cathine using GC– MS is the most accepted method available for screening individuals with suspected khat use. 6.. Human addicts take the drug in its entirety. Recently.4%) used a comparator drug (d-amphetamine). have for centuries been chewed for psychostimulant and socializing effects by people living in east African and Arabian Peninsula. Kelly / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1147–1166 Fig. mediate the neuropharmacology of khat primarily by evoking dopamine release and secondarily by inhibiting its uptake (there by prolonging the action of dopamine on its receptors) from dopamine containing synaptic endings. Cathinone is more effective than cathine and other alkaloids in khat on brain neurochemistry and behaviour. tannins (7–14%) and flavonoids. From the analysis it is clear that a few studies used the entire extract instead of cathinone. Although numerous studies have investigated the pharmacological effects of cathinone. Studies in animals suggest that cathinone has a potential for abuse at least as great as cocaine and probably greater than amphetamine causing persistent psychic dependence with minimal withdrawal symptoms. very few have analysed the extract and used comparator drugs. 2005). these may not wholly reflect the effect observed after administering khat in a dose similar to those used traditionally. The ingredients of khat leaves are numerous. raising a question on the validity of the claim that khat is a “natural amphetamine”. aspects were not incorporated in the analysis. Cathinone.M. Studies claiming such associations have been criticized for not being based on rigorous clinical evaluations. but the major and most abundant active constituents include six major alkaloids. this deep rooted socio-cultural tradition has also spread to East African and Middle Eastern communities in Europe and North America. and was deemed to be an ideal study (Banjaw et al. although quantitative differences are noticeable. For those that used the extract. At this juncture the role of the serotonergic (via 5-HT receptors. 6. Feyissa. known as khat. similar to (+) amphetamine in many aspects. To date.P. A case in point is cathedulins and the phenypentenylamine . There seems to be considerable circumstantial evidence to suggest that khat chewing can cause brief psychosis and could exacerbate pre-existing psychopathologies. as normally taken by users. Algorithms used to identify an ideal study on khat for khat use in humans. About a third of the studies analyzed had used a comparator compound in their studies irrespective of whether they use khat extract or not. Banjaw and co-workers have made analysis of the extract in most of their work. only few studies have dealt with the effects of whole material. However. edulis. And only a single study (1. Only 8 (11%) out of the 70 studies have used the extract instead of either cathinone or cathine. In most instances the comparator used was amphetamine. or complex mixtures of chemical found in its extracts. the psychoactive active alkaloid in khat. the psychoactive component of khat. Interestingly. noradrenergic (via adrenergic receptors and transporters) and opioid systems cannot be ruled out in the neuropharmacological actions of khat/(−) cathinone. the current data is not sufficient enough to imply a causal relationship between khat chewing and long-term psychopathology. Conclusions The leaves of the tree C. And among those eight studies only half of them have made analysis of the extract before they carried out the experiment. 7.1162 A. however cocaine and/or MDMA were also used in few of the studies as a comparator psychostimulant. J. hence any translation from experimental studies could only be feasible when the entire extract is used. cathinone N amphetamine). Recommendations Although a number of investigations have been carried out using cathinone.

For instance several reports claim khat to cause psychosis.P. Khat induced psychosis and its medico-legal implication: a case report. As most experimental investigations on khat and cathinone have been short term acute studies. and sociologist is needed in addition to Pharmacologists and Clinicians. Kullgren G. Alem A. Baker K. Bhui K. Belew M. It would be interesting to see the long term effect of the entire extract and/or cathinone in level of various neuroprotective and neurotoxic biomarkers in the brain to elucidate the neurotoxic potential of khat chewing. Elmi AS. Khat: pharmacological and medical aspects and its social use in Yemen. 2007). J Ethnopharmacol 2007.319:500. Debella A. Bloom-Krasik A. Miczek K. Aust Psychol 2005. Ethiopia. on the central nervous system. Enquoselassie F. Hence. Ethiop Med J 1997. Al-Habori M. Banjaw MY. Capocaccia L. Schmidt WJ. considering the resemblance between cocaine and cathinone as positive reinforcers. Drug Alcohol Depend 1983.38:35–43. Berardelli A. Abdi M. Catha edulis extract and its active principle cathinone induce ipsilateral rotation in unilaterally lesioned rats. Addict Biol 2005. fourth edition. It is believed that the sector has a major contribution to the national GDP of developing nations like Ethiopia. Schmidt WJ. Determination of (S) (−)cathinone by spectrophotometric detection. Traumatic events. Banjaw MY.17:321–6. Behavioural sensitisation following repeated intermittent oral administration of Catha edulis in rats. Kraemer T.M. The potential adverse effects of habitual use of Catha edulis (khat). Al-Habori M. Pereira S. . Baron DN. Peters FT. migration characteristics and psychiatric symptoms among Somali refugees. Makonnen E.A. Ageel AM. we suggest a multidisciplinary research involving economists. Al-Hebshi NN. Soc Psychiatry Psychiatr Epidemiol 2003. Diagnostic and Statistical Manual for Mental Disorders. there is lack of important information on the long term use of khat.3:107–15. and Yemen who produce khat in large scale for domestic and export use. Banjaw MY. J Ethnopharmacol 2003. previous works on cathinone could be valuable. Therefore. Beyer J. Synapse 2003. BMJ 1999.397:84–91. Mediator mechanisms of cathinone effects on animal behaviour. Clozapine attenuates the locomotor sensitisation and the prepulse inhibition deficit induced by a repeated oral administration of Catha edulis extract and cathinone in rats.16:403–13. Acknowledgments AM was supported in this research with a scholarship award from the NUI Galway International Scholarship Programme. Khat leaves may be extracted by chemical processing to produce a purer (cathinone). Illicit cathinone (“Hagigat”) poisoning.12:31–5.110:250–6. Kassaye M. J Mass Spectrom 2007. more concentrated form for administration by other perhaps more addicting routes. Pharmacol Res Commun 1980. Qureshi S. in particular. Shibre T. J Pharm Biomed Anal 1998. Further toxicological studies are warranted. nevertheless data lacks on acute and long term neurotoxicity of khat. Problems related with khat chewing especially khat induced psychosis in immigrants could pose a problem on substance abuse treatment centres in the West. one could argue that the problem will always remain within communities from khat growing nations.113:543–56.. However.40:87–94. therefore. Amphetamine use and co-occurring psychological problems: Review of the literature and implications for treatment. It is tempting to forecast this. Abebe D.4:1145–54. The qat party. in different experiments there were variations in outcome when C. Effect of Catha edulis (khat) chewing on plasma lipid peroxidation. As the khat-chewing habit has for centuries been limited to the same geographical area where it has been traditionally grown and habitually consumed. It would. 1996). Quinteri F. 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