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A Review of the Neuropharmacological Properties of Khat[1]

A Review of the Neuropharmacological Properties of Khat[1]

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Review article
A review of the neuropharmacological properties of khat 
Anteneh M. Feyissa, John P. Kelly
 Department of Pharmacology and Therapeutics, NUI Galway, Galway, Ireland 
Received 5 October 2007; received in revised form 21 December 2007; accepted 23 December 2007Available online 17 January 2008
Abstract
 Background:
The psychostimulant khat (
Catha edulis Forsk 
), is a herbal drug cultivated and chewed as a recreational and socializing drug in East Africa and the Arabian Peninsula for centuries. Due to increasing air transportation and the loosening of customs restrictions, it is now readilyavailable in the Western Countries mainly used by immigrants from khat growing areas causing a concern to policy-makers.
Objective:
We conducted this review to further gain an insight to the neuropharmacological effects of khat.
 Methodology:
PubMed search engine with key terms
khat 
or 
qat 
or 
mirra
or 
qaad/jaad
or 
cathinone
was used to obtain articles relevant tokhat chewing. In total 284 English written articles published from 1959 to 2007 were screened.
 Results:
Most of the studies focused on cathinone, the postulated active psychostimulant alkaloid in khat. There were few studies whichinvestigated the entire plant extract in either 
in vitro
or animal studies. In the majority of the studies it was reported that both cathinone andcathine, another psychoactive constituent, have actions that are similar to those of amphetamine.
Conclusions:
It seems that the well investigated khat alkaloids have many features similar to amphetamines; however there is a need for a morethorough examination of khat itself in well designed
in vitro
, animal and human studies with a range of comparator drugs before confirming theclaim that khat is a
natural amphetamine
.© 2008 Elsevier Inc. All rights reserved.
 Keywords:
Cathinone; Dopamine; Khat; Neuropharmacology; Psychosis
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11481.1. Prevalence of use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11481.2. Legal considerations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11492. Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11493. Analysis of active constituents of khat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11493.1. Active constituents of khat leaf . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11493.2. Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11503.3. Detection of khat alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11524. Neuropharmacology of khat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11524.1. Psychological sequelae of chewing khat. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11534.1.1. Psychosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11534.1.2. Aggression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11544.1.3. Mood disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11544.1.4. Addiction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11544.1.5. Khat-induced neurotoxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1155
 Available online at www.sciencedirect.com
Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1147
1166www.elsevier.com/locate/pnpbp
 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
 
4.2. Behavioural studies in animals. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11554.2.1. Motor activity and stereotyped behaviour. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11564.2.2. Analgesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11584.2.3. Feeding behaviour. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11584.2.4. Sexual behaviour . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11584.2.5. Cathinone in animal models of addiction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11594.3. Khat and neurochemistry. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11605. Algorithms of laboratory/preclinical studies on khat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11616. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11627. Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1162Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1163References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1163
1. Introduction
Khat,
Catha edulis Forsk 
, is an evergreen shrub or treefound growing wild or cultivated in the east of a regionextending from Southern Africa to the Arabian Peninsula(Krikorian, 1984). The habit of khat chewing has prevailed 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 theeighteenth century when the botanist Peter Forskal identifiedthe plant in Yemen and called it 
C. edulis
. There are severalnames for the plant, depending on its origin: tchat 
Ethiopia,qat 
Yemen (Alem et al., 1999), qaad/jaad
Somalia (Elmi,1983), miraa
Kenya (Patel, 2000), mairungi
Uganda(Ihunwo et al., 2004), Muhulo
Tanzania, Hagigat 
Hebrew(Bentur et al., 2007), cat, catha, gat, tohai, and muraa(Fasanmade et al., 2007). The dried leaves of khat areknown as Abyssinian tea or Arabian tea(WHO, 2006). These many names attest to the widespread and presumablyfairly old knowledge of 
C. edulis
by native peoples of easternand Southeastern Africa (Krikorian, 1984). However, the most common name is khat (Alem et al., 1999).Recently published reviews on khat and cathinone focus onadverse health aspects and have only briefly addressed thei pharmacology (Cox and Rampes, 2003; Al-Hebshi and Skaug,2005; Al-Habori, 2005), or they investigate whether khat causesmental disorders in general (Warfa et al., 2007) or how it isspecifically linked to psychosis (Odenwald, 2007). In particular,there is a lack of emphasis on the pharmacokinetics and behavioural pharmacology of khat. Thus the principal purposesof this review are to:a) determine whether khat and its active principles arecomparable to other stimulants such as amphetamines; and b) to detect gaps in our knowledge of the neuropharmacologyof khat.To our knowledge, this review is the first in its kind in thearea to critically analyze past literature and to proposesuggestions for further investigation based on the limitationsidentified in this review.
1.1. Prevalence of use
Fresh leaves from khat trees are chewed daily by ove20millionpeopleontheArabianPeninsulaandEastAfrica(Sahaand Dollery, 2006; Al-Motarreb et al., 2002). The khat chewinghabit is deeply rooted in the sociocultural traditions of thesecountries (Stevenson et al., 1996; Kennedy et al.,1983). Many of the users originate from countries between Sudan and Madagas-car and in the southwestern part of the Arabian Peninsula. Khat useisparticularlywidespreadinEthiopia,Kenya,Djiboutiaswellas Yemen, where its use is socially sanctioned and even pres-tigious (Kalix, 1990; Belew et al., 2000). Khat is consumed at  parties in combination with smoking cigarettes and drinking teaand softdrinks(Baron, 1999).The biggest population of chewersis in Yemen, where the plant is used as a social stimulant (Al-Motarrebetal.,2002).Recentreports suggest that80
90% ofthemale 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 regionswhere khat is grown (Yousef et al., 1995; Kalix and Khan, 1984;Al-Zubairietal.,2003),becausetheshootsmustbeusedfreshfothedesiredeffects(Kiteetal.,2003).Inrecentyears,however,theeconomic importance and consumption of khat leaves haveincreased dramatically (Sawair et al., 2007; Odenwald, 2007).This change is due to improved road and air transport, which hasallowed a much wider distribution (Mathys and Brenneisen,1992; Cox and Rampes, 2003). Moreover, the use of the Internet has seen the emergence of several websites which advertise andsell fresh khat leaves (Toennes and Kauert, 2002; Beyer et al.,2007; Bentur et al., 2007). In addition, the influx of immigrantsfrom East Africa and Arabian Peninsula, who continue to usekhat, has resulted in the importation of khat to countries wherethese immigrants have settled, including Europe and the UnitedStates(ToennesandKauert,2004;Rousseauetal.,1998).Intheseimmigrant communities, the khat party is an important socialevent andisa wayfor the participantstokeeptheir ethnicidentity(Stevensonetal.,1996;Nencinietal.,1989)andrelievethestressof living in a foreign country (Griffiths et al., 1997; Bhui et al.,2006,2003).IntheUK,khatisusedby(mainlymale)membersof the Somali and Yemeni community (Griffiths et al., 1997;
1148
A.M. Feyissa, J.P. Kelly / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1147 
 – 
1166 
 
Cunningham, 1998), and the prevalence has been shown to reach80% in Somali immigrants in London(Griffiths et al., 1997), whilst in the USA khat use, which gained popularity during thefirstPersianGulfcrisis(Lurieetal.,1994;Gianninietal.,1992),ismost prevalent amongst immigrants from Yemen, Somalia andEthiopia (Browne, 1990). Khat use has also been reported in East AfricancommunitiesinItaly( Nencinietal.,1989),Israel(Granek  etal.,1988),Australia(Stevensonetal.,1996),Norway,Holland, Belgium,German,SwitzerlandandCanada(Vanwalleghemetal.,2006; Nielen et al., 2004; Mathys and Brenneisen, 1992; Al-Motarreb et al., 2002).
1.2. Legal considerations
Khat circulates freely in Yemen, Ethiopia (despite theOrthodox Tewahdo Church prohibiting its use), Somalia(though briefly banned during the six months rule of the UnitedIslamic Courts in Mogadishu in 2006) and some other East African countries (Widler et al., 1994; Hattab and Angmar-Månsson, 2000; Alem et al., 1999). Almost every small kiosk inAddis Ababa, the Ethiopian capital, openly sells khat, and insmall cities and towns all over the country it is brought tomarket as produce, where people publicly chew it and offer it tovisitors as a mark of hospitality (Selassie and Gebre, 1996). InYemen and Ethiopia there have been attempts to curtail the habit for social and economic reasons but these have met with littlesuccess (McKee, 1987; Kandela, 2000; Elmi et al., 1987; Elmi,1983; Drake, 1988). One reason for this is that in Yemen (Al-Motarreb et al., 2002) and in some parts of Ethiopia it isconsumed by government officials, making its regulation verydifficult.Although the active alkaloids of khat, namely cathinone andcathine have been labeled as Schedule I and Schedule IIIsubstances respectively by WHO since 1971 (WHO, 2003), itsstatus in European countries is not uniform (Kalix, 1990). For example, khat is prohibited in Ireland, France, Switzerland,Sweden and Norway (Widler et al., 1994; Saha and Dollery,2006) whilst it is legal in the U.K. and in the Netherlands( Nielen et al., 2004; Griffiths et al., 1997). Outside of Europe,it is illegal in the U.S.A. and Canada but permissible inAustralia (Saha and Dollery, 2006; Patel, 2000; Fasanmade et al., 2007). Recently, the WHO Committee reviewed the dataon khat and determined that the potential for abuse anddependence is low and the threat to public health is not significant enough to warrant international control, and did not recommend the scheduling of khat (WHO, 2006). Severalauthors have also suggested weighing the evidence dispassio-nately before sounding alarm on what is an important substance for sections of the immigrant population of manywestern countries (Weir and Thuriaux, 1988; Warfa et al.,2007).
2. Methodology
A literature research was conducted via PubMed search enginewith the search terms
khat 
or 
qat 
or 
miraa
or 
qaad/jaad
or 
cathinone
. We also examined the reference sections of thesearticles to identify additional potentially relevant studies. A limitednumber of references that were not listed in the database were alsoused. The search was performed up to September 20, 2007. Theresearch only included articles available in English that were publishedfrom1959to2007.Thefulltextof284articlesorreportsthat provided original data on khat chewing or its activecomponents in animal and human studies were reviewed, amongwhichthosethatcontainedresearchontheepidemiology,analyticalaspectsorneuropharmacologicalpropertiesofkhatwereidentified.Expert-based commentary papers and papers describing the pharmacological properties of khat were also included. In total150 articles which belonged to the aforementioned areas wereselected.Fromthese150articles,70originalreportsusingkhatandor its active principles in their 
in vitro
, animal studies weresubjected to an algorithm for defining an ideal study on khat withregard to its relevance to humans. The algorithm had three criteria:(i) the study should use the entire khat extract (ii) analysis of active alkaloids should be made beforesubjects/treatments are exposed to the extract (iii) the study should incorporate comparator drugs related totheir study question.A study was deemed to be ideal when it fulfils all the threecriteria. We also used these criteria to comment on the existingevidence of the effect of khat on human khat users.
3. Analysis of active constituents of khat
3.1. Active constituents of khat leaf  
The leaves and young shoots of 
C. edulis
, a species of the plant family Celastraceae, are usually referred to as khat [Family:Celastraceae, genus:
Catha
, and Species
C. edulis
]( Nordal,1980). Most taxonomists consider that the genus
Catha
consistsof the single species
Catha edulis
( Nordal, 1980; Elmi, 1983).Khat is mainly grown in Ethiopia, Kenya, Yemen, Somalia,Uganda, South Africa and Madagascar (Odenwald et al., 2005;Ihunwo et al., 2004; Elmi, 1983; Al-Hebshi and Skaug, 2005).Many different chemical substances are found in the leaves of khat and these include:
Alkaloids, terpenoids, flavonoids, sterols, glycosides, tan-nins (7
14% by weight).
More than 10 amino acids including tryptophan, glutamicacid, glycine, alanine and threonine (Szendrei, 1980; Luq-man and Danowski, 1976; Halbach, 1972; Geisshüsler andBrenneisen, 1987; Elmi, 1983; Crombie, 1980).
Trace quantities of vitamins including ascorbic acid,thiamine, riboflavin, niacin, and carotene ( Nencini et al.,1989; Luqman and Danowski, 1976; Kalix and Braenden,1985; Cox and Rampes, 2003).
Elements including calcium, iron (Hattab and Angmar-Månsson, 2000; Halbach, 1972), manganese (Halbach,1972), copper, zinc, and toxic metals like lead and cadmium(Matloob, 2003) and a negligible amount of fluoride (Hattab and Angmar-Månsson, 2000).
1149
 A.M. Feyissa, J.P. Kelly / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1147 
 – 
1166 

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