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Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1147 – 1166

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Review article
A review of the neuropharmacological properties of khat
Anteneh M. Feyissa, John P. Kelly ⁎
Department of Pharmacology and Therapeutics, NUI Galway, Galway, Ireland
Received 5 October 2007; received in revised form 21 December 2007; accepted 23 December 2007
Available online 17 January 2008

Abstract

Background: The psychostimulant khat (Catha edulis Forsk), is a herbal drug cultivated and chewed as a recreational and socializing drug in 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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1148
1.1. Prevalence of use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1148
1.2. Legal considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1149
2. Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1149
3. Analysis of active constituents of khat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1149
3.1. Active constituents of khat leaf . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1149
3.2. Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1150
3.3. Detection of khat alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1152
4. Neuropharmacology of khat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1152
4.1. Psychological sequelae of chewing khat. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1153
4.1.1. Psychosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1153
4.1.2. Aggression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1154
4.1.3. Mood disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1154
4.1.4. Addiction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1154
4.1.5. Khat-induced neurotoxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1155

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

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

4.2.1. Motor activity and stereotyped behaviour . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1156
4.2.2. Analgesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1158
4.2.3. Feeding behaviour. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1158
4.2.4. Sexual behaviour . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1158
4.2.5. Cathinone in animal models of addiction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1159
4.3. Khat and neurochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1160
5. Algorithms of laboratory/preclinical studies on khat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1161
6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1162
7. Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1162
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1163
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1163

1. Introduction 1.1. Prevalence of use

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.
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 Madagas-
car and in the southwestern part of the Arabian Peninsula. Khat
use is particularly widespread in Ethiopia, Kenya, Djibouti as well
as Yemen, where its use is socially sanctioned and even pres-
tigious (Kalix, 1990; Belew et al., 2000). Khat is consumed at
parties in combination with smoking cigarettes and drinking tea
and soft drinks (Baron, 1999). The biggest population of chewers
is in Yemen, where the plant is used as a social stimulant (Al-
Motarreb et al., 2002). Recent reports suggest that 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;
 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 reach
80% in Somali immigrants in London (Griffiths et al., 1997),
whilst in the USA khat use, which gained popularity during the
first Persian Gulf crisis (Lurie et al., 1994; Giannini et al., 1992), is
most prevalent amongst immigrants from Yemen, Somalia and
Ethiopia (Browne, 1990). Khat use has also been reported in East
African communities in Italy (Nencini et al., 1989), Israel (Granek
et al., 1988), Australia (Stevenson et al., 1996), Norway, Holland,
Belgium, German, Switzerland and Canada (Vanwalleghem et al.,
2006; Nielen et al., 2004; Mathys and Brenneisen, 1992; Al-
Motarreb et al., 2002).
1.2. Legal considerations
Khat circulates freely in Yemen, Ethiopia (despite the
Orthodox Tewahdo Church prohibiting its use), Somalia
(though briefly banned during the six months rule of the United
Islamic Courts in Mogadishu in 2006) and some other East
African countries (Widler et al., 1994; Hattab and Angmar-
Månsson, 2000; Alem et al., 1999). Almost every small kiosk in
Addis Ababa, the Ethiopian capital, openly sells khat, and in
small cities and towns all over the country it is brought to
market as produce, where people publicly chew it and offer it to
visitors as a mark of hospitality (Selassie and Gebre, 1996). In
Yemen and Ethiopia there have been attempts to curtail the habit
for social and economic reasons but these have met with little
success (McKee, 1987; Kandela, 2000; Elmi et al., 1987; Elmi,
1983; Drake, 1988). One reason for this is that in Yemen (Al-
Motarreb et al., 2002) and in some parts of Ethiopia it is
consumed by government officials, making its regulation very
difficult.
Although the active alkaloids of khat, namely cathinone and
cathine have been labeled as Schedule I and Schedule III
substances respectively by WHO since 1971 (WHO, 2003), its
status in European countries is not uniform (Kalix, 1990). For
example, khat is prohibited in Ireland, France, Switzerland,
Sweden and Norway (Widler et al., 1994; Saha and Dollery,
2006) whilst it is legal in the U.K. and in the Netherlands
(Nielen et al., 2004; Griffiths et al., 1997). Outside of Europe,
it is illegal in the U.S.A. and Canada but permissible in
Australia (Saha and Dollery, 2006; Patel, 2000; Fasanmade et
al., 2007). Recently, the WHO Committee reviewed the data
on khat and determined that the potential for abuse and
dependence is low and the threat to public health is not
significant enough to warrant international control, and did not
recommend the scheduling of khat (WHO, 2006). Several
authors have also suggested weighing the evidence dispassio-
nately before sounding alarm on what is an important
substance for sections of the immigrant population of many
western countries (Weir and Thuriaux, 1988; Warfa et al.,
2007).
2. Methodology
A literature research was conducted via PubMed search engine
with the search terms ‘khat’ or ‘qat’ or ‘miraa’ or ‘qaad/jaad’ or
‘cathinone’. We also examined the reference sections of these
1149
articles to identify additional potentially relevant studies. A limited
number of references that were not listed in the database were also
used. The search was performed up to September 20, 2007. The
research only included articles available in English that were
published from 1959 to 2007. The full text of 284 articles or reports
that provided original data on khat chewing or its active
components in animal and human studies were reviewed, among
which those that contained research on the epidemiology, analytical
aspects or neuropharmacological properties of khat were identified.
Expert-based commentary papers and papers describing the
pharmacological properties of khat were also included. In total
150 articles which belonged to the aforementioned areas were
selected. From these 150 articles, 70 original reports using khat and
or its active principles in their in vitro, animal studies were
subjected to an algorithm for defining an ideal study on khat with
regard to its relevance to humans. The algorithm had three criteria:
(i) the study should use the entire khat extract
(ii) analysis of active alkaloids should be made before
subjects/treatments are exposed to the extract
(iii) the study should incorporate comparator drugs related to
their study question.
A study was deemed to be ideal when it fulfils all the three
criteria. We also used these criteria to comment on the existing
evidence of the effect of khat on human khat users.
3. Analysis of active constituents of khat
3.1. Active constituents of khat leaf
The leaves and young shoots of C. edulis, a species of 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 consists
of the single species Catha edulis (Nordal, 1980; Elmi, 1983).
Khat is mainly grown in Ethiopia, Kenya, Yemen, Somalia,
Uganda, South Africa and Madagascar (Odenwald et al., 2005;
Ihunwo et al., 2004; Elmi, 1983; Al-Hebshi and Skaug, 2005).
Many different chemical substances are found in the leaves of
khat and these include:
• Alkaloids, terpenoids, flavonoids, sterols, glycosides, tan-
nins (7–14% by weight).
• More than 10 amino acids including tryptophan, glutamic
acid, glycine, alanine and threonine (Szendrei, 1980; Luq-
man and Danowski, 1976; Halbach, 1972; Geisshüsler and
Brenneisen, 1987; Elmi, 1983; Crombie, 1980).
• Trace quantities of vitamins including ascorbic acid,
thiamine, riboflavin, niacin, and carotene (Nencini et al.,
1989; Luqman and Danowski, 1976; Kalix and Braenden,
1985; Cox and Rampes, 2003).
• Elements including calcium, iron (Hattab and Angmar-
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).
1150 A.M. Feyissa, J.P. Kelly / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1147–1166
Fig. 1. Chemical structure of S-(+)-amphetamine and S-(−)-cathinone
(MW = 149.2).
Most of our present knowledge on the constituents of khat is
derived from studies in the late 1970s and 1980s following
recommendation by the UN Commission on Narcotic Drugs
(Kite et al., 2003). The phenylalkylamines and the cathedulins
are the major alkaloids. Szendrei (1980) at the UN Narcotics
Laboratory, together with Schorno and Steinegger at the
University of Berne, Switzerland, isolated and identified the
phenylalkylamine, (−)-α-aminopropiophenene, later named as
S-(−)-cathinone as a major active constituent in fresh khat. The
plant contains the (–)-enantiomer of cathinone only (WHO,
2006; Gugelmann et al., 1985) which has the same absolute
configuration as S-(+)-amphetamine (see Fig. 1) (Kalix, 1990;
Goudie, 1987). During maturation, cathinone is enzymatically
converted to cathine [(+) norpseudoephedrine] and (−)-
norephedrine (Al-Obaid et al., 1998). Sunlight-induced or
heat-induced degradation to cathine and norephedrine also
occurs during extraction of cathinone in the laboratory (Banjaw
et al., 2005). Indeed, to slow down the degradation process, the
khat leaves are usually wrapped in banana leaves immediately
after picking to retain their moisture (Yousef et al., 1995).
Fig. 2. Chemical structures of S-(−)-cathinone, S, S-(+)-norpseudoephedrine
(cathine) and R, S-(−)-norephedrine (MW = 151.2). Cathinone is transformed
mainly to cathine in khat leaves and mainly to norephedrine by human
metabolism. Modified from Sporkert et al., 2003.
Table 1
Concentration of khat alkaloids from fresh khat leaves of various origin
Cathinone Cathine Norephedrine References
0.74 ± 0.40 1.49 ± 0.51 0.9 ± 0.16 Dimba et al. (2004)1
1.09 ± 0.8 3.60 ± 1.9 0.25 ± 1.8 Geisshüsler and Brenneisen (1987)2
1.02 ± 0.11 0.86 ± 0.06 0.47 ± 0.05 Widler et al. (1994)1
Data given in mg per gram of khat leaf expressed as mean ± SD; 1Khat sample
from Kenya; 2Khat samples from Ethiopia, Kenya, Yemen and Madagascar.
Other alkaloids of phenylalkylamines in khat leaves include
the phenylproanolamine diastereoisomers of cathine [1S, 2S-(+)
norpseudoephedrine or (+) norpseudoephedrine], and norephe-
drine [1R, 2S-(−) norephedrine]. Cathine and norephedrine
occur mainly in older plants and is also formed by reduction of
cathinone during drying and storage (see Fig. 2) (Sporkert et al.,
2003). The environment, climate conditions, as well as local
traditions connected with cultivation and harvesting determine
the chemical profile and general appearance of khat leaves
(Nordal, 1980). The phenylalkylamine content of khat leaves
varies widely. In certain khat samples, the phenyalkylamine
fraction consisted of up to 70% of (−) cathinone and that the (−)
cathinone content is correlated with the market price of khat
(see Table 1) (Kalix and Khan, 1984). Accordingly, analyses of
khat samples from Kenya and Ethiopia have shown that the
commercial value of the material correlates with its cathinone
content (Geisshüsler and Brenneisen, 1987).
Another class of phenylalkylamine alkaloids found in khat
leaves are the phenylpentenylamines; merucathinone, pseudo-
merucathine and merucathine, which are mainly detected in
khat leaves originating from Kenya (Brenneisen and Geisshüs-
ler, 1987) (Fig. 3). They seem to contribute less to the stimulant
effects of khat (Kalix et al., 1990) and their concentration is
relatively low (Brenneisen and Geisshüsler, 1987). Other
classes of alkaloid in khat are the cathedulins, classified
according to their relative molecular mass (Kite et al., 2003;
Crombie, 1980). Recently, 62 different cathedulins derived
from fresh khat leaves were characterized (see Fig. 4) (Kite
et al., 2003). Though there has been much research on the
phenyalkalymines, there has been little investigation of the
cathedulins to date (Kim et al., 2007).
3.2. Pharmacokinetics
Khat is usually chewed, occasionally brewed as a tea (Giannini
et al., 1992; Alem et al., 1999), and rarely smoked (Elmi, 1983).
The leaves are removed from their branches and thoroughly
chewed; they are then kept for a while in the cheek as a ball of
macerated material and later expectorated (Al-Motarreb et al.,
2002). The chewers fill their mouths to capacity with the ten-
derest leaves and shoots and then chew intermittently to release
the active components or keep it in buccal vestibules (Sawair et al.,
2007). During the khat session the leaves and the bark of the plant
are chewed slowly over several hours, usually for 2–10 h and
an average 100–500 g of khat is chewed (Nencini and Ahmed,
1989; Matloob, 2003; Kalix, 1990; Elmi, 1983; Al-Hebshi and
Skaug, 2005). The juice of the masticated leaves is swallowed, but
not the residues (Toennes et al., 2003). During chewing, the
 A.M. Feyissa, J.P. Kelly / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1147–1166 1151

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

alkaloids from khat leaves are effectively liberated, with about
80% of cathinone and cathine, and over 90% of norephedrine
released following chewing (Toennes and Kauert, 2002). The
absorption of the constituents of khat is said to have two phases,
the first being at the buccal mucosa, plays a major role in the
absorption of alkaloids (Toennes et al., 2003). The second phase is
following swallowing of the juice, at the stomach and/or small
intestine (Toennes et al., 2003).
Cathinone has been determined in spiked human plasma in
khat naïve volunteers after 0administration of synthetic cathinone
(Widler et al., 1994; Brenneisen et al., 1990) or after the chewing
of khat leaves (Widler et al., 1994; Toennes et al., 2003; Halket
et al., 1995). The pharmacokinetic parameters for cathinone and
other ingredients of khat leaves have been determined over 8 h,
with peak plasma levels attained after 1–3.5 h (Halket et al.,
1995; Brenneisen et al., 1990). Similarly, maximal plasma

Fig. 4. Structure of K-19 (1), one of the most highly elaborated members of the cathedulin family with its polyhydroxylated sesquiterpenoid euonyminol core (2).
Adapted from White, 1994.
1152 A.M. Feyissa, J.P. Kelly / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1147–1166
concentrations (tmax) of cathinone, cathine and norephedrine are
reported to be reached at 2.3, 2.6 and 2.8 h respectively (Toennes
et al., 2003). After ingestion of 0.8 mg/kg cathinone it was
reported that the total amount of cathinone absorbed in the body
after 9 h (AUC; area under the curve) was 25 ± 13 μg min ml− 1,
and the terminal elimination half-life was 260 ± 102 min (Widler
et al., 1994). In another study, 8 h after four drug naïve volunteers
ingested khat (0.6 g/kg), the AUC of cathinone, cathine and
norephedrine was reported to be 245 ± 49, 13 ± 131, 710 ± 173 μg
min ml− 1 respectively (Toennes et al., 2003).
There is a rapid stereoselective metabolism of S-(−)
cathinone to norepehedrine and cathine following its admin-
istration to humans (Nencini and Ahmed, 1989; Geisshüsler
and Brenneisen, 1987; Brenneisen et al., 1990). Metabolism
of cathinone to cathine involves reduction of the ketone group
to an alcohol, a fairly common metabolic pathway in humans,
catalyzed by liver microsomal enzymes (Guantai and Maitai,
1983). Only 7% or less of the absorbed (−)-cathinone is
excreted unchanged in the urine (Toennes et al., 2003; Guantai
and Maitai, 1983), and is mainly excreted in the form of
norephedrine and cathine (Toennes and Kauert, 2002; Kalix
et al., 1990; Brenneisen and Geisshüsler, 1987). The amount
of norephedrine excreted in urine is much higher than the
amount ingested, indicating that (−) cathinone is also
metabolized to R, S-(−) norephedrine (Toennes and Kauert,
2002). Cathine has been found in breast milk in several
lactating women who were chewing the leaves of khat
(Kristiansson et al., 1987).
3.3. Detection of khat alkaloids
The biological material commonly used in forensic
toxicology for phenylalkylamine derivatives are urine,
blood, and hair samples (Kim et al., 2007). These methods
are similar to those used for amphetamines because of their
structural similarity (Sporkert et al., 2003). Analysis of urine
and blood provides information on recent or current exposure
to drug use, whilst analysis of hair samples provides detection
of long term and repeated use (Kim et al., 2007). Recently a
multi anylate procedure has been developed to determine
cathinone and other phenyalkylamines in plasma using LC-
MS/MS [Liquid Chromatography/Mass Spectrometry/Mass
Spectrometry] (Beyer et al., 2007). Using this technique it has
been reported that, after ingestion of khat leaves, all the major
alkaloids contained in the plant were detected in the plasma.
Detection of khat alkaloids (cathine, cathinone, and norephe-
drine) in urine has been performed by TLC (Thin layer
chromatography), HPLC (High-performance liquid chromato-
graphy), gas chromatography, and GC–MS [Gas chromato-
graphy-mass spectrometry] (Mathys and Brenneisen, 1992;
Guantai and Maitai, 1983; El-Haj et al., 2003). Toennes and
Kauert (2002) demonstrated that GC–MS, which could detect
cathine and norephedrine for up to 80 h and cathinone for up
to approximately 24 h after khat ingestion, is superior to the
other techniques for screening and confirmation testing of
urine samples from individuals with suspected khat use.
However, both cathine and norephedrine, which are available
as over the counter anorectic and cold suppressant medica-
tions respectively, could result in false positives in urine
analysis (Toennes and Kauert, 2002). Therefore, khat use can
be confirmed only by the detection of cathinone in the absence
of N-alkylated homologs (e.g. methcathinone) from urine
samples (Toennes and Kauert, 2002; Maitai and Dhadphale,
1988). Analysis of cathinone in hair samples was measured in
Dark-Agouti rats, and it was reported to have a relatively
lower incorporation rate into hair in comparison to other
amphetamines (Nakahara and Kikura, 1996). However, later
studies in human hair from drug users using GC–MS
separation technique detected cathinone, cathine and norephe-
drine (Sporkert et al., 2003; Kim et al., 2007). The proportion
of alkaloids detected from the hair was in the same order as
urine samples i.e. norephedrine N cathine N cathinone.
4. Neuropharmacology of khat
The effects observed following khat consumption are
generally of central stimulation and include euphoria, excitation,
anorexia, increased respiration, hyperthermia, logorrhea, analge-
sia, and increased sensory stimulation (Patel, 2000; Nencini and
Ahmed, 1989; Kebede et al., 2005). These effects, which have
been observed in several clinical trials and animal studies with
khat and or cathinone (Widler et al., 1994; Kalix et al., 1990;
Brenneisen et al., 1990), are similar to those observed with
amphetamine (Halbach, 1979). The khat chewer believes that
they think more clearly and quickly and are more alert, although
their concentration and judgment are objectively impaired
(Pantelis et al., 1989). In view of its potency and its higher lipid
solubility (Kalix and Braenden, 1985; Hassan et al., 2007),
facilitating access into the central nervous system (Zelger et al.,
1980), it can be assumed that khat-induced psychostimulation is
predominately, or even exclusively due to the cathinone content of
the leaves (Kalix, 1990). This is substantiated by the brief
stimulation after khat chewing (Kalix et al., 1990), which is in
agreement with the finding that cathinone is metabolized rapidly
(Brenneisen and Geisshüsler, 1987). The major metabolites of
cathinone, i.e. cathine and norephedrine, possess weaker central
stimulant properties because of their less lipophilic properties
(Nencini and Ahmed, 1989). Other alkaloids such as phenylpen-
tenylamines are of low concentration and were shown to have a
weak effect on dopamine release in dopamine prelabelled rat
striatal tissue (Kalix et al., 1990). The pharmacology of
cathedulins has not yet been well characterized in the CNS and
other organs (Kite et al., 2003). Although other pathways could
not be ruled out, there is enough scientific data to suggest khat/
cathinone-induced psychostimulation is mediated primarily via
the meso–striato–cortico limbic dopaminergic pathway (Kalix,
1990). This is further strengthened by the observation that
subcutaneous administration of cathinone prevented the catalepsy
typically found following administration of haloperidol to rats,
which may suggest a possible therapeutic relevance in manage-
ment of Parkinson disease in the future (Banjaw et al., 2003).
Moreover, the dependence-producing potential, analgesia, and
anorexic effects of khat/cathinone are believed to be partly
mediated via this pathway (Gosnell et al., 1996).
 A.M. Feyissa, J.P. Kelly / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1147–1166
4.1. Psychological sequelae of chewing khat
In recent decades, the traditional habit of chewing the leaves of
the khat shrub has undergone profound changes in African and
Arab countries, from a socially regulated use pattern towards
uncontrolled consumption (Sawair et al., 2007; Bimerew et al.,
2007; Alem et al., 1999), which has become a special public
mental health concern (Bhui et al., 2006). In general, khat chewers
display a range of experiences, from minor reactions to the
development of a psychotic illness. Minor reactions include over-
talkativeness, hyperactivity, insomnia, anxiety, dizziness, impaired
concentration, irritability, agitation and aggression which usually
occur after a moderate intake of khat (Griffiths et al., 1997; Cox
and Rampes, 2003), and bruxism (Walter, 1996). These minor
psychotoxic reactions to khat are so well known in Ethiopia for
instance, khat users displaying these features have been given the
name jezba (Kalix, 1990). Among the several alkaloids in khat,
cathinone is incriminated for most of psychological sequelae
related with khat chewing (Elmi et al., 1987).
There are a number of reports of psychiatric disorders
secondary to khat chewing with features of manic-like psychosis
(Gough and Cookson, 1984; Giannini and Castellani, 1982),
schizophreniform psychosis (Yousef et al., 1995; McLaren, 1987;
Luqman and Danowski, 1976), paranoid psychosis (Nielen et al.,
2004; Critchlow and Seifert, 1987; Alem and Shibre, 1997),
Capgras and Fregoli syndrome (Yousef et al., 1995), induced
hypnagogic hallucinations (Granek et al., 1988), depression
(Pantelis et al., 1989). In addition there have been reports of
personality disorders associated with long term khat use (Kalix
and Braenden, 1985). Recently Odenwald et al. (2007) has
reported a positive association between Post Traumatic Stress
Disorder (PTSD) among Somali ex-combatants and higher levels
of khat abuse. Though it is difficult to incriminate khat use alone,
some of the cases with psychotic morbidity, occurring during khat
chewing and subsequent intoxication phase, have been associated
with self harm and suicide (Cox and Rampes, 2003). Accordingly,
two cases of homicide and combined homicide and suicide have
been reported following consumption of khat (Pantelis et al.,
1989; Alem and Shibre, 1997). Furthermore, khat chewers often
take alcohol to counteract the stimulant and sleep depriving effect
of khat, which raises the risk of interactions between alcohol and
khat (Omolo and Dhadphale, 1987; Kebede et al., 2005).
There is an ongoing international debate about a causal
relationship between khat use and mental illness (Warfa et al.,
2007; Odenwald, 2007; Bimerew et al., 2007). Several
investigators claim that khat use is not necessarily linked to
psychological morbidity; any association that is found may
reflect an interaction with other environmental factors (Warfa et
al., 2007; Odenwald et al., 2005). Warfa et al. (2007) reviewed
the literature on the association between khat use and mental
illness published over the last 50 years and concluded that
‘although excessive khat use appears to exacerbate psychologi-
cal problems caused by pre-existing stressors, there is no clear
evidence as to the effects of khat use and the development of
mental illness'. Odenwald (2007) in a review of 45 articles in this
area, has criticised that the majority of the reports and
information about epidemiology and use patterns are merely
1153
expert opinions and unsystematic observations, i.e. not sub-
stantiated by rigorous clinical testing. However, he suggested
that heavy khat chewing could induce brief psychosis and could
trigger or exacerbate pre-existing schizophreniform spectrum
disorders (Odenwald, 2007; Cox and Rampes, 2003).
4.1.1. Psychosis
Khat-induced psychosis (brief psychotic episodes) was con-
sidered by many authors to be a rare phenomenon (Halbach, 1972;
WHO, 1980; Kalix and Braenden, 1985). Halbach (1972)
suggested that this is due to the bulky nature of the khat leaves,
ensuring that only low plasma levels of its active ingredients can be
attained after chewing (Giannini and Castellani, 1982). Secondly, it
is thought that in khat-using areas where health facilities are
lacking, people with psychotic symptoms are locked in their homes
by families until the episode subsides (Yousef et al., 1995; Luqman
and Danowski, 1976). However, there have been growing reports
of khat-induced psychosis in khat producing areas and in
immigrants residing in Europe and USA (Yousef et al., 1995;
Pantelis et al., 1989; Bimerew et al., 2007; Alem and Shibre, 1997).
It is believed that immigrants are vulnerable to psychosis due to
social dislocation, and abnormal patterns of drug use, and pre-
existing stressful situations (Pantelis et al., 1989; Giannini and
Castellani, 1982; Bhui et al., 2006, 2003). Pantelis et al. (1989) and
Yousef et al. (1995) summarized clinical features of khat-induced
psychosis; most of the cases in Europe were Somali males with a
minority of the cases having past psychiatric history and family
psychiatric history. Heavy khat consumption preceded the
psychotic episode and the majority of the cases had rapid resolution
when treated pharmacologically, usually by antipsychotic medica-
tion of the phenothiazine type. There was a tendency for the
psychotic episodes to recur upon recommencement of khat
chewing (Alem and Shibre, 1997). Few of the cases had
spontaneous resolution without pharmacological treatment once
they stopped abusing khat (Yousef et al., 1995; Nielen et al., 2004;
Alem and Shibre, 1997). 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,
2003; Bimerew et al., 2007). The latter is very similar to paranoid
psychosis seen with chronic amphetamine and cocaine addicts
(Pantelis et al., 1989; Ellison, 2002). It is postulated that khat
consumption precipitates psychosis by either increasing the risk in
already vulnerable individuals or affecting the course of a psychotic
disorder and the maintenance of symptoms (Odenwald et al., 2005).
To date the direction of causality between long term psychosis
and khat use remains unclear. In general, previous investigations
suggesting a link have been criticised for they suffer from meth-
odological problems and lack of quantitative data (for a review see
Odenwald, 2007). Nevertheless, recent studies using laboratory
animal models of behavioural sensitization, which bears striking
similarities to the progressive development of psychosis and
paranoia that develops in human addicts following repeated
psychostimulant administration, suggest the possibility of positive
association between khat use and long term psychiatric morbidity.
Accordingly, Banjaw and co-workers (2005) have reported
locomotor sensitization and prepulse inhibition deficit, two
paradigms that have been widely studied as animal models of
1154 A.M. Feyissa, J.P. Kelly / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1147–1166
psychosis, after intermittent oral administration of (−) cathinone or
C. edulis extract in rats. In both instances there is progressive
augmentation of either locomotor-stimulatory effects (locomotor
sensitization) or deficit in prepulse inhibition (i.e. deficit in the
startle reducing effect of a weak prepulse preceding a startle
stimulus by 30–200 ms) upon repeated administration of
psychostimulants including amphetamine, cathinone and cocaine
(Ellison, 2002; Banjaw et al., 2006). This finding suggests that
humans who use C. edulis over an extended period could be at high
risk of incurring neuropsychiatric diseases (Banjaw and Schmidt,
2005). Clozapine, an atypical antipsychotic widely used to reverse
these behavioural changes in animal models, was shown to
attenuate these deficits (Banjaw et al., 2005). They also reported
increased dopamine levels in prefrontal cortex with reduced
dopamine and its metabolites in anterior putamen, and decrease in
5-HT in nucleus accumbens and its metabolites in prefrontal cortex
(Banjaw et al., 2005; Banjaw and Schmidt, 2005). The reduction in
dopamine and its metabolites is in contrast to amphetamines, which
are known to increase dopamine in the caudate putamen in the
locomotory sensitization paradigm. These results suggest that the
behavioural effects of C. edulis or cathinone are mediated, at least
in part, by dopamine in the meso–striato–cortico limbic pathway
(Banjaw et al., 2005). This pathway is believed to play a central role
in the induction, maintenance and expression of sensitization
following repeated administration of psychostimulants (Banjaw
and Schmidt, 2005). Indeed, psychosis due to cocaine and
amphetamine, closely related drugs to cathinone, is similarly
believed to be mediated via this pathway (Goudie, 1987; Ellison,
2002).
4.1.2. Aggression
Previous literature reviews show that there are scant data on 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, 2003). However,
there have been reports of khat-induced aggressive verbal
outbursts and violent behaviour in the past (Luqman and
Danowski, 1976; Giannini and Castellani, 1982). Recently, in a
community based study in Somalia, there was evidence of the
presence of disruptive and violent behaviour amongst chronic khat
users (Odenwald et al., 2005). Incidentally, Berardelli et al. (1980)
observed a spontaneous burst of aggressive behaviour in rats after
intraperitoneal (ip) administration of cathinone, similar to that seen
with amphetamines. Recently, Banjaw et al. (2006) have
reproduced this phenomenon using isolation induced aggression
paradigm, in which repeated oral administration of C. edulis or S
(−) cathinone enhanced aggressive behaviour of isolated rats.
Similar to amphetamine, neurochemical correlates revealed
depletion of serotonin and its corresponding metabolites in both
anterior and posterior striatum, which suggest that aggression in
this paradigm is enhanced presumably by decreasing the level of
serotonin and its metabolites (Banjaw et al., 2006).
4.1.3. Mood disorders
Khat chewing can induce a substantial degree of mood
disturbances, particularly depression in healthy subjects (Hassan
et al., 2002). Depression associated with khat chewing has been
reported by several authors (Pantelis et al., 1989; Nielen et al.,
2004; Hassan et al., 2002; Griffiths et al., 1997; Granek et al.,
1988). In most of the reports it is seen as a consequence of
cessation of khat chewing (reactive depressive mood). The
severity of depression varied from agitation and sleep dis-
turbances to severe depression with suicidality (Nielen et al.,
2004). Recently, Hassan et al. (2002) studied the effect of khat
chewing in human mood using the HAD (Hospital Anxiety and
Depression) Scale. They reported that khat chewing results in a
functional mood disorder consisting of predominantly reactive
depressive mood (seen an hour after acute khat administration),
and it might exacerbate symptoms in patients with pre-existing
mood disorder. It is thought to be mediated by the sympatho-
mimetic action of cathinone (Hassan et al., 2002). Other mood
disorders such as khat-induced behavioural syndrome described
as hypomania have also been reported by several authors
(Nencini et al., 1984a,b; Luqman and Danowski, 1976; Halbach,
1972). There are similar reports of mood disorders secondary to
repeated amphetamine use (Baker and Dawe, 2005).
4.1.4. Addiction
The use of khat often starts at a young age and can develop into
a compulsive daily habit lasting a lifetime (Patel, 2000). Khat
taking behaviour depends not only on the reinforcing psychos-
timulant action of khat, but also on deeply rooted cultural factors
(Nencini et al., 1989). Habitual use of khat is in many instances
compulsive, as indicated by the tendency of khat chewers to
secure their daily supply of the leaves at the expense of vital needs
and their behaviour at the markets (Nencini et al., 1988; Kalix and
Braenden, 1985). This is described as a psychological dependence
by many authors (Kalix, 1990; Gosnell et al., 1996; Connor et al.,
2002). In eastern African countries the prevalence of khat
dependence is estimated to be 5–15% of the population (Nielen
et al., 2004). The first documented case of khat addiction was that
of Amda Tsion, an Ethiopian ruler in the early 14th century, and
his subjects in the city of Mar'ade (Dillmann, 1884 as quoted by
Giannini et al., 1992). Giannini et al. (1992) reported two cases of
khat addiction which were effectively treated with bromocriptine
using a protocol developed for cocaine addiction. From their
description it could be inferred that both cases satisfy the Diag-
nostic and Statistical Manual of Mental Disorders, fourth edition
(DSM-IV) (American Psychiatric Association, 1994) criteria for
substance abuse. It is postulated that khat could have a higher
dependence potential than amphetamine (Kalix, 1990) because of
its less aversive nature (Foltin and Schuster, 1983; Goudie and
Newton, 1985), higher rate of self administration, and rapid onset
of action in discrimination experiments (Yanagita, 1979;
Johanson and Schuster, 1981) when compared to amphetamine
in various operant experiments (See Section 4.2.5). Although
cathinone is known to cause sensitization upon repeated
administration similar to amphetamines (See above), there are
reports of tolerance to the CNS stimulating effects of khat
chewing. This is alleged to be due to the physical limits on the
amount that can be chewed rather than the inherent property of
khat leaves (WHO, 1980). There are conflicting opinions
regarding the existence of a withdrawal syndrome. Generally it
 A.M. Feyissa, J.P. Kelly / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1147–1166
is believed that there is no physical withdrawal syndrome as
experienced with alcohol, morphine or barbiturates (Sulzer et al.,
2005; Luqman and Danowski, 1976; Kalix, 1984). Abandoning
the khat-chewing habit however is followed by symptoms
including lassitude, anergia, nightmares, slight trembling, and
depression (Luqman and Danowski, 1976; Elmi, 1983; Cox and
Rampes, 2003; Alem et al., 1999). Indeed, habitual users report
that they have no serious difficulties when moving to an area
where khat cannot be obtained (Kalix, 1990). However, there are
reports of social withdrawal symptoms after cessation of the habit,
described as ‘experiences of deprivation of joys and camaraderie
which khat session almost unfailingly provides’ (Stevenson et al.,
1996). As in the case of drug abuse in industrialized societies, khat
use is associated with simultaneous use of other drugs especially
cigarette and alcohol (Zein, 1988; Hassan et al., 2007). Cigarette
smoking is believed to enhance the effect obtained by chewing
khat and to reduce its bitter taste while alcohol is widely used to
counteract the stimulatory effects of khat. The concomitant use of
psychotropic agents such as hypnotics is also common (Zein,
1988).
4.1.5. Khat-induced neurotoxicity
There have been reports (albeit few) of severe and disabling
neurological illness associated with khat chewing. Morrish et al.
(1999) reported such a case in a 58 year old Somali man living
in UK who presented with leucoencephalopathy associated with
khat misuse. EEG and MRI findings indicated progressive
leucoencephalopathy but this could not be linked with khat use.
In addition, the CNS stimulating effect of khat has shown to
reach the level of acute and chronic toxicity as evidenced by
growing reports of psychiatric morbidity associated with khat
use (Nielen et al., 2004; Alem et al., 1999). However, there are
few studies which aimed at assessing the CNS toxicity of
different constituents of khat (Wagner et al., 1982; Al-Zubairi
et al., 2003). There is also a lack of information regarding the
effect of khat on the level of different neurotoxic/neuroprotec-
tive factors such as BDNF and lipid peroxidase in the brain. To
date, the main finding has been that khat/cathinone induces the
release of dopamine from presynaptic storage sites (Kalix and
Braenden, 1985) and chronic administration of either the whole
extract or cathinone (100 mg/kg) results in a significant
depletion of dopamine in several brain areas, particularly on
the nigrostriatal dopamine terminal projections (Wagner et al.,
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
†
Ideal study; 1ethanol, sildenafil and amphetamine used as a comparator; 2d-amphetamine used as comparator; PPI, prepulse inhibition; EEG, electroencephalogram;
✓ = Yes; ✗ = NO.
1155
1982; Banjaw et al., 2006). This is similar to the neurotoxic
effect of chronic amphetamine administration on the dopami-
nergic innervations of caudate, inducing their degeneration
(Ellison, 2002).
4.2. Behavioural studies in animals
For over the last 40 years Cathinone and/or khat extract have
been exposed to a wide array of behavioural experiments to
elucidate the behavioural pharmacology of this herbal psychos-
timulant. The behavioural models employed include; locomotor
activity (psychostimulation), feeding behaviour (anorexia), test
for analgesia (nociception), behavioural sensitization (psychosis),
isolation induced aggression paradigm (aggressive behaviour),
and several operant procedures (addiction/dependence). Since the
characteristic property of khat chewing is stimulation of the CNS,
the behavioural pharmacology is of particular interest. In most of
the behavioural experiments conducted in various animals
(chicken, mice, rat, and monkeys) cathinone/khat showed
qualitatively similar effects to amphetamine. Both khat extract
and cathinone have been shown to increase spontaneous
locomotor activity, stereotyped movement and anorexia (Kalix
and Braenden, 1985). In addition, khat extract (100 mg/kg) and
cathinone (5 mg/kg), have been reported to cause behavioural
sensitization in locomotor activity of rats similar to amphetamine
(Banjaw et al., 2006) (Table 2). When compared to amphetamine
the potency of cathinone was in the order of 1:2–1:5 except in
conditioned taste aversion, where cathinone was reported to be
very weak [1:17] (Mereu et al., 1983; Kalix, 1990; Goudie, 1987).
However, tolerance to the anorexgenic effect of cathinone
develops rapidly unlike that of amphetamine (Foltin and Schuster,
1983). In addition, cathinone was reported to have a more similar
profile to cocaine than to amphetamine in some behavioural
paradigms such as intravenous self administration and condi-
tioned taste aversion test (See Table 3 and Fig. 5). Cathine,
another psychoactive ingredient in khat, has also demonstrated
these behavioural features though less potently than cathinone, in
the range of 1:7–1:10 (Peterson et al., 1980; Eisenberg et al.,
1987). As to the neurotransmitters involved in mediating the
different behavioural effects of khat/cathinone, there appears to be
strong evidence to suggest the involvement of the dopaminergic
system (Zelger et al., 1980; Kalix, 1980a,b). Indeed, several
investigators have demonstrated that cathinone and cathine
Analysis made? Comparator used? References
✓ ✗ Banjaw et al. (2005)
✗ ✗ Saleh et al. (1988)
✓ ✗ Banjaw et al. (2006)
✓ ✗ Banjaw and Schmidt (2006)
✗ ✓1 Abdulwaheb et al. (2007)
✗ ✗ Connor et al. (2002)
✗ ✓2 Connor et al. (2000)
✓ ✓2 Banjaw and Schmidt (2005)†
1156 A.M. Feyissa, J.P. Kelly / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1147–1166

Table 3
The effect of cathinone and khat on animal behaviour
Behavioural observation Cathinone Khat Reference
Operant behaviour
IV Self administration 0.025–1 mg/kg/infusion, in monkeys, Not examined Yanagita (1986), Woolverton
CATH ≈ COC and Johanson (1984)
Discriminative stimulus property⁎ 0.09–1.87 mg/kg (IP), 256 μg/kg (ICV), Not examined Schechter et al. (1984), Schechter (1990a)
in rats, generalizes to AMPH, COC,
and MDMA
Conditioned taste aversion 4–16 mg/kg, in rats, CATH:AMPH (1:17) Not examined Goudie (1987)
↓Food reinforced responding⁎ 1–4.7 mg/kg (IP) in rats, 0.008–0.1 Not examined Goudie (1985)
mg/kg/infusion in monkeys, CATH:AMPH (1:2–3)
Conditioned place preference 0.8 mg/kg (IP), in rats, ↑time spent Not examined Calcagnetti and Schechter (1993)
in non-preferred Side
Hypermotility⁎ 1–20 mg/kg in rats and mice (IP/SC/PO), 200–1600 mg/kg (PO) Banjaw et al. (2006)
20–64 μg/kg (IV) in rats, CATH:AMPH (1:2) in rats and mice
Stereotyped behaviour⁎ 1–20 mg/kg(IP/SC/PO) in rats and mice, 200–1600 mg/kg (PO) Berardelli et al. (1980), Zelger et al. (1980),
and chicken, CATH b AMPH in rats and mice Connor et al. (2002)
Anorexia⁎ 1–32 mg/kg(PO/IP), in monkeys and rats Not examined Zelger and Carlini (1980)
Analgesia 1–25 mg/kg(SC/IP) in mice in TFT and 200–1800 mg/kg (PO) Connor et al. (2002)
HPT CATH: AMPH (1:4–6) in mice
↑Sexual arousal 5 mg/kg(PO), for 15 days in SD rats 100 mg/kg (PO) Abdulwaheb et al. (2007)
for 15 days SD rats
↑Aggression 5 mg/kg (PO),for 4 weeks in SD rats 200 mg/kg (PO) Banjaw et al. (2006)
for 4 weeks in SD rats
N.B. dose range, animals species used, and when available potency comparisons with other psychostimulants is reported.⁎Cathine, also produced these effects though
less potent than cathinone; IP, intrapertoneal; SC, subcutaneous; PO, oral; IV, intravenous; AMPH, (+) amphetamine; CATH, Cathinone; COC, cocaine; TFT, tail flick
test; HPT, hot-plate test; SD, Sprague–Dawley rats.

primarily increase catecholamine release and secondarily inhibit
its reuptake (Wagner et al., 1982; Schechter, 1990a,b; Peterson
et al., 1980; Mereu et al., 1983). However, other neurotransmitters
could also be involved as well. For instance, the serotonergic
system is reported to be involved in khat/cathinone-induced
stereotyped movement, aggression, and sexual arousal (Connor et
al., 2002; Banjaw et al., 2006; Abdulwaheb et al., 2007).
Moreover, noradrenergic and opioid systems are suggested to be
involved in khat/cathinone induced analgesia and anorexia in
addition to the dopaminergic pathway (Nencini et al., 1984a,b;
Della Bella et al., 1985; Connor et al., 2000). (Tables 4 and 5).
4.2.1. Motor activity and stereotyped behaviour
The stimulatory effect of khat is perceived as an increase in
alertness and energy and relief from fatigue (Nencini and Ahmed,
1989). Indeed, these effects have been reproduced in rats after oral
administration of different concentrations of khat extract, in
which lower doses (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., 1988).
Similar EEG patterns were observed in rats after intraperitoneal
(ip) cathinone administration (Berardelli et al., 1980). The EEG
pattern resembles how users in a khat session would progress

Fig. 5. Effects of Khat/Cathinone on animal behaviour when compared with known psycostimulants.
 A.M. Feyissa, J.P. Kelly / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1147–1166 1157

Table 4
Neurochemical effects of cathinone and khat
Nature of study Cathinone Khat extract Reference
In vitro studies
Synaptosomal preparations ↑Release and inhibition of uptake of [3H]DA, Not examined Wagner et al. (1982)
1–100 μM, CATH: AMPH (1:1.6)
Rabbit/rat striatal tissue Enhanced release of [3H] 5-HT, 12 μM ↑efflux Not examined Kalix (1981,
and inhibition of uptake of [3H]DA, 3–9 μM, 1982, 1983)
CATH: AMPH (1:2–6x)
Rat cerebral cortex Inhibits [3H] nisoxetine binding to NA transporter, Not examined Cleary and Docherty
2.5 μM, CATH ≈ COC ≈ MDMA (2003)
Rat atrial/ventricular strip Efflux of [3H]NA and inhibition of uptake of [3H] NA, Not examined Cleary and Docherty
1.2–2 μM, CATH ≈ COC ≈ MDMA (2003)
In vivo study in rats Inhibition of the firing rate of nigral DA neurons, Not examined Mereu et al. (1983)
0.4 mg/kg (IP), CATH ≈ AMPH ↓extracellular DOPAC
(NAc, SL), IP, 6 mg/kg ↓5-HT&5-HTP (NA, SL), IP, 6 mg/kg
Postmortem analysis in rats ↑DA (PFC), ↓DOPAC (PFC, NAc, CP) after 1.5 mg/kg (PO) ↑DA in PFC, PO 200 mg/kg, Banjaw et al. (2006)
for 10 days 10 days
↓5-HT&5-HIAA in PFC and anterior and posterior striatum, ↓5-HT&5-HIAA in PFC Banjaw and Schmidt
after 1.5 mg/kg (PO) for 4 weeks anterior and Posterior striatum (2005)
IP, intrapertoneal; PO, oral; AMPH, (+)amphetamine; COC, cocaine; CATH, cathinone; NAc, nucleus accumbens; SL, septi lateralis; CP, caudate Putamen.; NA,
noradrenaline; DA, dopamine; 5-HT, 5-hydroxytryptamine; DOPAC, Dihydroxyphenylacetic acid; 5-HIAA, 5-hydroxyindoalmineacid; PFC, prefrontal cortex.

from a state of stimulation and excitation to that of sedation,
anxiety and depression, as more khat is chewed (Kalix and
Braenden, 1985; Hassan et al., 2002).
Once cathinone was identified as an active constituent of khat,
there have been investigations of its effect on animal behaviour,
particularly on locomotor activity. Subcutaneous administration of
cathinone in rats (Yanagita, 1979; Kalix, 1980b; Gordon et al.,
1993; Banjaw et al., 2003) and mice (Zelger et al., 1980; Rosecrans
et al., 1979; Knoll, 1979) markedly increased spontaneous loco-
motor activity of the animals. It was reported that the potency of
cathinone was almost comparable with (+)-amphetamine (Kalix,
1990). Zelger et al. (1980) demonstrated that cathinone has a
stimulatory effect on locomotion in rats maximally after 15 to
30 min, in a similar fashion to amphetamine. Cathinone also
displayed hypermotility in hypophysectomized and unhypophy-
sectomized rats analogous to (+) amphetamine (Kalix, 1980b). In
addition, centrally administered cathinone increased spontaneous
activity when administrated directly into the nucleus accumbens,
but failed to demonstrate this effect when administered into the
substantia nigra in rats (Calcagnetti and Schechter, 1992a,b).
Similar increases in locomotor activity were observed after khat
extract administration in animals. Recently, it was reported that
acute and sub-chronic oral administration of C. edulis leaves or S-
(−) cathinone increased locomotor activity in rats (Banjaw and
Schmidt, 2005; Banjaw et al., 2006). In contrast, Connor et al.
(2002) reported a reduction in spontaneous motor activity in mice
after intragastric administration of khat extract. It was suggested
that the use of mice instead of rats and the difference in the source of
khat leaves could explain the observed variation (Connor et al.,
2002; Banjaw et al., 2006). For the first time Banjaw et al. (2006)
demonstrated the occurrence of strong behavioural sensitization
after repeated intermittent oral administration of C. edulis leaves or
cathinone in rats. The rats developed sensitization for locomotor
activity, rearing, upward and downward sniffing, and turning after
oral administration of the extract which was also observed with
cathinone and amphetamine.
Cathinone has also been found to be similar to amphetamine
with regard to induction of stereotyped behaviour in rats at higher
doses (Zelger et al., 1980; Peterson et al., 1980; Berardelli et al.,
1980; Banjaw et al., 2003; Banjaw and Schmidt, 2005), in mice
(Al-Meshal et al., 1991) and in young chickens (Bronson et al.,
1995). Stereotyped movements after administration of khat extract
or cathinone include biting, licking, pawing, sniffing, head
twitches, and rearing (Zelger et al., 1980; Connor et al., 2002;
Berardelli et al., 1980; Banjaw et al., 2006, 2005, 2003; Al-Meshal
et al., 1991). Moreover, there are some reports of cathinone-induced
tremor at a low dose and seizure at higher doses (Berardelli et al.,
1980). Cathine was considerably less potent, (1/7–1/10th), than

Table 5
The in vitro affinity table for cathinone and comparator compounds
Receptor/transporter/enzyme Cathinone IC50/EC50 Cathinone vs. comparator compounds Reference
Dopamine transporter 0.85 uM AMPH N Cocaine N CATH Fleckenstein et al. (1999)
α-receptorsa N10 uM CATH ≈ Ephedrine Rothman et al. (2003)
Noradrenaline transporter 0.9 uM Cocaine ≈ MDMA ≈ CATH Cleary and Docherty (2003)
5-HT receptorsb 3 uM CATH ≈ 4X AMPH Glennon and Liebowitz (1982)
Serotonin transporter 0.014 uM Cocaine N AMPH ≈ CATH Fleckenstein et al. (1999)
Monoamine-oxidase 50 uM CATH ≈ 100X AMPH Nencini et al. (1984b)
a
Human receptors bfrom rat fundus; IC50, half maximal inhibitory concentration; EC50, half maximal effective concentration; AMPH, amphetamine; CATH,
cathinone N.B there is no data as to the affinity of cathinone to dopamine and β-adrenergic receptors.
1158 A.M. Feyissa, J.P. Kelly / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1147–1166
cathinone at inducing both spontaneous locomotion and stereo-
typed movement (Zelger et al., 1980; Woolverton, 1986; Peterson
et al., 1980; Kalix, 1983; Eisenberg et al., 1987). Another con-
stituent of khat alkaloid, norephedrine, failed to show stimulatory
effect in the open field test (Eisenberg et al., 1987). Taken together,
these findings indicate that cathinone is the constituent of khat that
is mainly responsible for the stimulatory effect of the plant and that
it is a potent amphetamine-like compound. Nevertheless, effects of
an entire khat extract, with its many constituents, would differ from
amphetamine with regard to the production of motor, and probably
other behaviours (Connor et al., 2002).
4.2.2. Analgesia
Khat leaves and its constituents have been shown to have
analgesic properties in animal experiments (Nencini and Ahmed,
1982; Nencini et al., 1998; Knoll, 1979; Della Bella et al., 1985;
Connor et al., 2002). This property is shared by amphetamine
(WHO, 1980; Nencini et al., 1998). Khat extract was shown to
exert analgesic effects in mice, albeit at high doses relative to
ibuprofen and amphetamine (Connor et al., 2000). It produced
analgesic effects in the tail flick test and hot plate test at a lower
dose (200 mg/kg and 600 mg/kg) and in acetic acid-induced
abdominal constriction assays at a higher dose (1800 mg/kg).
Cathinone has also been shown to cause a long lasting analgesic
activity in mice and rats (Nencini and Ahmed, 1982). This was
reversibly antagonized by naloxone, a pure opioid antagonist,
and by the noradrenaline synthesis inhibitors, α-MPT (α-methyl-
p-tyrosine) and diethyldithiocarbamate. Furthermore, cathine, a
metabolite of cathinone in humans, has been shown to enhance
the analgesic effect of morphine in hot plate and formalin test in
mice (Nencini et al., 1998).
4.2.3. Feeding behaviour
Anorexia, a characteristic effect of amphetamine-like sub-
stances, is a consequence of khat chewing (Halbach, 1972). This
feature of khat has been used for centuries to alleviate the sensation
of hunger (Zelger and Carlini, 1980; Kalix, 1983). Therapeutically,
the khat alkaloid cathine (norpseudoephedrine) and norephedrine
have been widely used as appetite suppressants in the modern world
(Kalix and Braenden, 1985). This anorectic effect of cathinone and
cathine has been observed in rhesus monkeys (Yanagita, 1979;
Foltin and Schuster, 1983), in rats (Zelger and Carlini, 1980; Knoll,
1979; Islam et al., 1990; Foltin et al., 1983; Eisenberg et al., 1987),
and in late pregnant guinea pigs (Jansson et al., 1988). Both isomers
of cathinone and cathine markedly inhibited the food intake of rats
at intracerebroventricular doses of 300 and 500 μg per animal
respectively (Knoll, 1979). Both cathine and (−)-cathinone were
reported to be more potent than amphetamine in this regard (WHO,
1980). Systemic acute as well as chronic administration of the two
alkaloids in rats showed similar effects, however they were reported
to be less potent than (+)-amphetamine in this order of potency:
amphetamineN cathinone N cathine (Zelger and Carlini, 1980). On
the other hand, when cathinone was administered to rats via the
intargastric route, it was reported to be a more potent anorectic than
amphetamine and cocaine (Foltin et al., 1983). It was reported that
within a week there was development of tolerance to this effect of
cathinone, and the weight reducing effect disappeared within 3–
4 weeks (Zelger and Carlini, 1980; Nencini, 1988; Nencini et al.,
1988; Foltin and Schuster, 1983). This is in contrast to
amphetamine in which tolerance developed only after 2 weeks
and its effect persisted for more than 7 weeks (Zelger and Carlini,
1980). Total and/or partial cross-tolerance was also observed
among all the three drugs. A similar pattern of cross tolerance
between (−) cathinone and (+) amphetamine was reported by
Schuster and Johanson (1979). Anorexic effects of the other khat
alkaloid, norephedrine, have also been demonstrated in rats
(Eisenberg et al., 1987). In this study it was reported that both
cathine and norephedrine have a potency of one tenth that of
cathinone. Tolerance to the anorectic effects of khat alkaloids has
been extended to include cathine (Zelger and Carlini, 1980). Taken
together, individual khat alkaloids have been shown to possess
anorexic properties, yet there has been no study so far where the
entire khat extract has been investigated for these properties in
animals.
Two models have been proposed to explain the reduction in
food intake of psychostimulants like cathinone (Wolgin and
Munoz, 2006). According to some who advocate the Pavlovian
homeostatic model, the suppression of intake is due to loss of
appetite, which results in a failure to seek food (appetitive
behaviour) or to eat it (consummatory behaviour). Tolerance is
mediated by a compensatory increase in the motivation to eat.
Nencini et al. (1988), using this model, suggested that tolerance to
the anorectic effect of cathinone is associated with a sensitization to
endogenous kappa-opiate mediated activation of feeding. Indeed,
after 10 days of cathinone treatment, kappa agonist-induced
increase in food intake was about twice that induced by the same
dose of cathinone administered acutely (Nencini, 1988; Nencini
et al., 1988). On the other hand, Wolgin and Munoz (2006)
suggested drug-induced locomotion and or stereotyped response to
interfere with the appetitive phase of feeding i.e. locating,
approaching, and orienting to food (the instrumental learning
model). They elegantly demonstrated that acute cathinone
injection produced decreased milk intake in bottle-but not in
cannula-fed rats, while motor activity increased in both groups.
They also showed that, after the tolerance phase, switching form
bottle to cannula feeding produced a further increase in intake,
whereas switching form cannula to bottle feeding produced
decreased intake.
4.2.4. Sexual behaviour
Khat and its alkaloid cathinone have been reported to affect
male sexual potency. There are contradictory reports regarding the
association between khat chewing and sexuality. Khat has been
reported to be used as an aphrodisiac (Krikorian, 1984; Giannini
et al., 1992; Browne, 1990; Bentur et al., 2007), and to treat
premature ejaculation (Luqman and Danowski, 1976). Similarly,
in females, khat chewing has been reported to increase sexual
desire (Elmi, 1983). Recently it was reported that a capsule
containing illicit cathinone have been marketed in Israel as a
stimulant and an aphrodisiac drug (Bentur et al., 2007). On the
other hand, impairment of sexuality (WHO, 1980; Halbach, 1972),
inability to sustain erection (Elmi, 1983), loss of libido (Krikorian,
1984; Kervingant, 1959), and spermatorrhea due to khat chewing
have been reported (Halbach, 1972; Granek et al., 1988; Elmi,
 A.M. Feyissa, J.P. Kelly / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1147–1166
1983). Taha et al. (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. Recently, Abdulwaheb et al.
(2007) reported that low doses of khat extract (200 mg/kg/day)
exerted enhanced sexual motivation/arousal, characterized by
reduced mounting latency (ML) and intromission latency (IL),
while high doses of the extract (400 mg/kg/day) produced opposite
effects on both sexual motivation/arousal and performance in male
rats. In addition, concurrent administration of the low dose extract
followed by ethanol was found to enhance male rat sexual
motivation/arousal (Abdulwaheb et al., 2007). This is similar to
amphetamine, which at low dose is reported to evoke penile
erection, though its effect at high dose is inconclusive (Taha et al.,
1995). It was suggested that alteration of both dopamine (at low
dose) and or serotonin (at high dose) levels in the CNS could
explain the biphasic sexual behaviour of rats after khat adminis-
tration, although the role of testosterone cannot be ruled out (Taha
et al., 1995; Abdulwaheb et al., 2007).
4.2.5. Cathinone in animal models of addiction
Animal models of addiction that mimic the human condition in
an informative way are critical for advances in the study of
addiction (Schramm-Sapyta, 2004). The various animal models
used to examine the neurobiological basis of drug addiction have
helped us to understand the role of cathinone/khat in the
development and maintenance of addiction. Cathinone has been
compared to amphetamine and cocaine in a wide array of
procedures of operant behaviour, and it is generally found to have
similar effects to amphetamine and cocaine (Woolverton and
Johanson, 1984). Indeed, cathinone has been shown to have
reinforcing potential in self administration studies (to demonstrate
the dependence-producing potential of cathinone), drug discri-
mination procedures (to elucidate its similarity to other
psychostimulants such as amphetamine), food reinforced
responding, conditioned taste aversion test, and conditioned
place preference test (to assess the rewarding and motivational
effects of cathinone). These animal studies suggest that cathinone
has abuse potential as great as that of cocaine and probably greater
than that of amphetamine (Goudie, 1987). In addition to the
pharmacological properties of khat, the complex rituals of a khat
party could be used by consumers as environmental cues to
identify the appropriate conditions in which they enjoy khat
chewing (place, partner, and music) and could also be partly
responsible for khat's euphorogenic effects, through ‘placebo’
mechanisms (Nencini et al., 1986).
4.2.5.1. Self administration. Khat chewing has been described
as ‘pleasurable’ and the behaviour of repetitive chewing of khat
leaves has been labelled as from of ‘psychic dependence’
(Halbach, 1979), characterized by compulsive khat consumption
(Kalix, 1983). Self administration studies are particularly useful
for the evaluation of the dependence potential of pharmacological
substances and are believed to have high predictive validity in
predicting abuse potential (Woolverton and Johanson, 1984). Self
1159
administration studies using (−) cathinone have illustrated the role
of this alkaloid as a dependence producing compound among the
khat alkaloids (Kalix, 1983) enhancing the behaviour of animals
that gives them access to the substance (Kalix and Braenden,
1985). Johanson and Schuster (1981) and Yanagita (1986) have
reported that intravenous infusions of cathinone will maintain
responding in rhesus monkeys, which had been previously trained
to lever press for cocaine injections. When monkeys were given
the choice of self administering cathinone and cocaine, they chose
both equally often (Woolverton and Johanson, 1984; Johanson
and Schuster, 1981). The self administration pattern was reported
to be of the spree type, like cocaine and amphetamine, in which
monkeys took the drug frequently day and night, stopping only
when exhausted (Yanagita, 1979, 1986). They relapsed after a
period of rest of less than 24 h. This pattern corresponds to that
seen in amphetamine dependent humans (Kalix and Braenden,
1985). Similar results were obtained in rhesus monkeys, which
were first trained to self-administer cocaine intravenously by lever
presses, after which progressive ratio tests were conducted
(Yanagita, 1979). Progressive ratio tests, which utilize the
breaking point generated by increasing the fixed-ratio require-
ment, are important measures of motivation to take the drug (i.e.,
how hard the individual will work for it) and to compare the
reinforcement magnitude of several psychostimulants (Willner,
1997). The final ratios obtained for (−) cathinone were similar
with amphetamine, and roughly half of those of cocaine in
monkeys (Yanagita, 1986).
Since self administration in primates is considered highly
predictive of abuse in humans, it is possible that abuse potential
of cathinone is as great as cocaine (Nencini and Ahmed, 1989).
This contention is further strengthened by the weak aversive
nature of cathinone, which, despite being an amphetamine-like
drug, possesses unexpectedly weak aversive properties (Goudie,
1987). Indeed, in the condition taste aversion procedure, which is
thought to be the animal analogue of aversive effects of drugs in
man which limit the intake of drug of abuse, cathinone was less
potent (1:17) than amphetamine (Goudie and Newton, 1985;
Goudie, 1987; Foltin and Schuster, 1982). In addition to the
aforementioned studies on primates, Gosnell et al. (1996) have
demonstrated intravenous self administration of cathinone in rats
under a continuous (FR1) reinforcement schedule. In contrast to
the primate models, however, when compared with amphetamine
and cocaine, cathinone produced a pattern of responding more
closely resembling amphetamine. This was characterized by
more frequent infusions at the beginning of the session than in the
middle or final portion of the sessions. They also reported that
pre-treatment with D1-type receptor antagonist SCH 23390,
increased the number of infusions, which suggests a role for D1
type dopamine receptors in mediating its reinforcing effects.
4.2.5.2. Discriminative stimulus properties. The discrimina-
tive stimulus properties of drugs in animals are considered to be
predictive of their subjective effects in humans (Goudie, 1987,
1991). Further they allow us to investigate the subjective effects of
the training drug as a function of time and dose, and to explore its
mode of action by the use of appropriate antagonists and
other pharmacological manipulations (Willner, 1997). (+)
1160 A.M. Feyissa, J.P. 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., 1984; Schechter, 1986a,b; Rosecrans et al.,
1979; Nielsen and Schechter, 1985; Kalix and Glennon, 1986;
Huang and Wilson, 1986; Glennon et al., 1984). Similarly,
animals trained to detect cathinone react as if they had received
cathinone when injected with amphetamine and cocaine but not
when injected with opioids, benzodiazepines or fenfluramine
(Goudie et al., 1986). In fact, the only difference between
cathinone, amphetamine and cocaine have been shown to be
temporal (Schechter, 1989; Schechter and Glennon, 1985).
Similarly, in rats trained to discriminate the interoceptive cues
produced by (−) cathinone, the administration of (+) cathinone
and (+) cathine produced (−) cathinone like responding, an
ability known as ‘generalization’ (Schechter, 1990a; Pehek and
Schechter, 1990; Glennon et al., 1984). Moreover, direct
microinjection of cathinone into the nucleus accumbens (NAc)
was reported to produce discriminative stimuli (Schechter et al.,
1992). Cathine was also shown to have discriminative stimulus
properties in a two choice food motivated, drug discrimination
paradigm (Pehek and Schechter, 1990). Recently, Li et al. (2006)
have demonstrated that when cathinone was given before or
concurrently with cocaine to rats in a drug discrimination proce-
dure, the cocaine dose effect function was shifted to the left
suggesting cathinone generalizes to cocaine.
The drug discrimination procedure is used not only to test the
similarity and dissimilarity of psychoactive drugs, but it can
also be used to investigate the production of tolerance after
chronic treatment of trained rats (Schechter, 1990a). Indeed, it
was reported that tolerance tends to develop to cathinone in their
ability to control discriminative behaviour, indicated by deficits
in discriminative performance and shift of the dose response
curve to the right (Schechter and McBurney, 1991; Schechter,
1986a,b). Similarly, Schechter (1990a) reported an acute
tolerance effect of cathine in their ability to control discrimi-
native behaviour, indicated by deficits in discriminative
performance.
4.2.5.3. Food-reinforced responding. Similar to amphetamine,
cathinone interferes with the reinforcing properties of food. This
modification of food-motivated behaviour has been demonstrated
in rats (Yanagita, 1979; Peterson et al., 1980; Goudie, 1985) and
in monkeys (Schuster and Johanson, 1979). Initially it was
demonstrated that cathinone (0.5 mg/kg) increased the response
rate in rats under a differential reinforcement of low rates of
responding schedule [e.g. DRL 20 s] (Yanagita, 1979).
Differential reinforcement of low rate schedules are known to
produce low rates of responding as only those responses that
occur after a minimum time interval after a previous response are
reinforced. Subsequently, it was reported that large dose of
cathinone suppresses operant responding in rats under fixed
interval and fixed ratio schedule of food delivery (Peterson et al.,
1980; Goudie, 1985). Goudie (1985) illustrated that the effect of
cathinone, like (+) amphetamine is rate dependent; i.e. has a
tendency to increase low rates of responding and decrease high
rate of responding. The potency ratio of cathinone and (+)
amphetamine in this regard was similar (1:3) to that reported for
other behavioural tests (Peterson et al., 1980; Johanson and
Schuster, 1981; Goudie, 1985). Similar results have been obtained
in monkeys, where both amphetamine and cathinone were shown
to suppress responding maintained by a multiple fixed interval
and fixed ratio schedule for the delivery of food reward in a rate
dependent manner (Johanson and Schuster, 1981). Cathine,
though less potent than cathinone, was also shown to produce
similar effect on food reinforced responding (Peterson et al.,
1980). The suppression of overall food reinforced responding
may be explained in terms of drug-induced behavioural disruption
and response competition (Goudie, 1985).
4.2.5.4. Conditioned place preference. Conditioned place
preference is a method of assessing the rewarding and
motivational effects of drugs of abuse (Willner, 1997). This
behavioural task, which involves the pairing of drug cues with a
distinctive environment, has been shown to produce a dose-
response location preference with ip cathinone, similar to
cocaine and amphetamine in rats (Schechter and Meehan, 1993;
Schechter, 1991). Furthermore, intracerebroventricular injec-
tion of cathinone to rats, when paired with confinement in the
non-preferred side of the conditioned place preference appara-
tus, increased the time spent on that side, which suggest that this
behaviour is of central in origin (Calcagnetti and Schechter,
1993). It is generally believed that cathinone-induced condi-
tioned place preference is mediated by dopaminergic neurons
(Kalix, 1990; Calcagnetti and Schechter, 1993). This contention
is supported by evidence that pre-treatment with a dopamine
release inhibitor attenuates place preference induced by
cathinone (Schechter, 1991, 1990b; Calcagnetti and Schechter,
1993).
4.3. Khat and neurochemistry
The stimulatory effect of cathinone is believed to be mediated
by the dopaminergic system, similar to amphetamine (see Table 4)
(Kalix and Braenden, 1985). In support of this, it has been
demonstrated that substantial release of radioactivity induced by
low dose cathinone in a dose-dependent manner, similar to
amphetamine, from isolated rabbit caudate nucleus prelabelled
with [3H] dopamine (Kalix and Glennon, 1986; Kalix, 1983,
1981, 1980b). Moreover, pretreatment with cocaine, which is
known to prevent the induction of release by amphetamine,
inhibited the efflux increase caused by cathinone (Kalix, 1981). In
a similar manner, cathinone increased efflux from isolated rat
caudate nucleus (Kalix, 1982) and striata (Zelger and Carlini,
1981) prelabelled with [3H] dopamine. Three known catecho-
lamine reuptake inhibitors, nomifensine, mazindol and benz-
tropine that have been shown to inhibit amphetamine induced
circling behaviour were found to inhibit (block) cathinone
induced [3 H] dopamine release from these tissues (Kalix,
1982). This suggests that (−) cathinone has to penetrate to
intraneuronal sites in order to evoke release, and that the uptake
inhibitors prevent this penetration. Moreover, support for the
hypothesis that cathinone/khat requires an intact dopaminergic
system to exert their effect upon activity has been evidenced
by reports that dopamine antagonists (Zelger et al., 1980),
 A.M. Feyissa, J.P. Kelly / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1147–1166
dopamine release inhibitors (Calcagnetti and Schechter,
1992b), or pretreatment with the relatively selective dopami-
nergic neurotoxin 6-OHDA (Zelger and Carlini, 1981; Banjaw
and Schmidt, 2006), into mesolimbic pathways significantly
attenuates cathinone induced activity.
Zelger et al. (1980) has demonstrated that pre-treatment with
reserpine (monoamine store depleting agent) or methyl-p-
tyrosine (MPT, a catecholamine synthesis inhibitor), abolished
locomotor and increased stereotyped behaviour induced by
cathinone. On the other hand pretreatment with haloperidol, a
non selective dopamine antagonist was found to reduce biting
and licking movements caused by cathinone. In addition,
administration of khat or cathinone to rats after unilateral lesion
of substantia nigra with 6-hydroxydopamine (6-OHDA)
induced ipsilateral rotation, in a similar fashion to amphetamine,
suggesting that they have indirect dopamine releasing actions
on the CNS (Zelger and Carlini, 1981; Banjaw and Schmidt,
2006). In agreement with this, in vivo microdialysis in rats after
acute intraperitoneal administration of (−) cathinone, in a
similar fashion to (+) amphetamine, increased levels of
dopamine but decreased level of metabolites in a dose
dependent manner (Pehek et al., 1990). These findings are in
agreement with those previously described for synaptosomal
preparations, in which cathinone released and blocked the
uptake of tritiated dopamine (Wagner et al., 1982).
In a similar fashion to amphetamine, cathinone was also
shown to decrease dopamine transporter function following in
vivo administration in rats (Fleckenstein et al., 1999). On the
other hand, it was found that chronic administration of cathinone
to rats leads to significant reduction in the dopamine levels
(Wagner et al., 1982) although acute administration of cathinone
was insufficient to produce detectable decrease in dopamine
(Nielsen, 1985; Mereu et al., 1983). The result of the later studies
showed that there is reduction in the dopamine metabolite
DOPAC, a parameter that is generally taken as reflecting the
amount of dopamine released and captured by the nerve endings
(Pehek et al., 1990). This is similar to amphetamine and cocaine,
which have been shown to cause depletion of dopamine upon
chronic administration (Ellison, 2002). In addition, Mereu et al.
(1983) have demonstrated that (−) cathinone inhibited the firing
rate of dopaminergic cells in the substantia nigra which was
reversed by haloperidol. Once more these finding suggests that
cathinone, like amphetamine, releases dopamine from nerve
terminals and blocks its reuptake (Mereu et al., 1983). It has also
been shown that intermittent oral administration of C. 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, 2005). However
in contrast to amphetamine, there is in vitro evidence that
cathinone-induced dopamine release is regulated by calcium
channels (Vislobokov et al., 1993). This is attested by the fact that
pre-treatment with isradipine, a potent dihydropyridine calcium
channel (L-type) blocker attenuated the activity elevating effect
of intracerebroventricularly administered cathinone in rats
(Calcagnetti and Schechter, 1992a,b).
So far there is no clear cut evidence on the role of serotonergic
and/or other pathways in the stimulatory effect of cathinone. Some
1161
investigators have reported that levels of serotonin in rat brain are
not altered by repeated administration of cathinone (Wagner et al.,
1982; Nielsen, 1985). In contrast, 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. Interestingly, cathinone was also
found to have four times higher affinity than racemic amphetamine
for serotonin receptors in isolated rat fundus (Glennon and
Liebowitz, 1982). Connor et al. (2002) have reported that
pretreatment with methysergide, 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. In addition,
deterioration of visual stimuli after ip administration of cathinone
to cats, which was antagonized by methysergide and p-chlorphe-
nyalanine (5-HT synthesis blockers), supports the hypothesis that
the serotonergic pathway as well could play a role (Babayan et al.,
1983). Moreover, cathinone was shown to decrease serotonin
transporter function, though low in magnitude when compared with
amphetamine and methamphetamine (Fleckenstein et al., 1999).
Cathinone, similar to amphetamines, has also been shown to
inhibit monoamine-oxidase (MAO) activity in vitro (Nencini et al.,
1984b). In fact, cathinone (Ki = 0.05 mM) appears to be about 150–
200 times more effective than amphetamine (Ki =7.9 mM) in this
regard (See Table 5). In line with this, Osorio-Olivares and co-
workers (2004) have reported that cathinone exhibited inhibition
of MAO-B activity more than MAO-A. 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., 1984b). Recently, it was documented that
S-(−)-cathinone acts as well on noradrenaline transporters (Cleary
and Docherty, 2003; Rothman et al., 2003). Therefore, at this
juncture, neurochemical mechanisms other than dopamine could
explain the neuropharmacological actions of khat or S-(−)-
cathinone (Banjaw et al., 2006).
Finally, 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., 2002; Banjaw et al., 2006, 2005). The
apparent difference between the extract and the active principle,
S-(−)-cathinone, may be attributed to the fact that C. edulis
contains (besides S-(−)-cathinone) other compounds, such as
cathine and different metabolites (Schechter, 1990b). The
additional compounds existing in the crude extract might have
substantially altered behavioural and neurochemical effects
(Schechter, 1990b; Banjaw et al., 2006).
5. Algorithms of laboratory/preclinical studies on khat
After reviewing each article, which we obtained through one of
the previously mentioned methods, we made an attempt to critically
analyse the relevance and possibility of translation of the preclinical
studies to human khat users (Fig. 6). For the analysis, original
studies conducted on khat or its active principles in vitro and in vivo
were used. Articles which emphasized the epidemiology, pre-
valence and socioeconomic aspects of khat were excluded from this
assessment. Moreover, studies addressing solely the analytical
1162 A.M. Feyissa, J.P. Kelly / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1147–1166
Fig. 6. Algorithms used to identify an ideal study on khat for khat use in humans.
aspects were not incorporated in the analysis. Thus the only papers
included in the final analysis were original studies (animal/in
vitro) that dealt with the neuropharmacological aspects of khat.
About a third of the studies analyzed had used a comparator
compound in their studies irrespective of whether they use khat
extract or not. In most instances the comparator used was
amphetamine; however cocaine and/or MDMA were also used
in few of the studies as a comparator psychostimulant. Only 8
(11%) out of the 70 studies have used the extract instead of
either cathinone or cathine. And among those eight studies only
half of them have made analysis of the extract before they
carried out the experiment. And only a single study (1.4%) used
a comparator drug (d-amphetamine), and was deemed to be an
ideal study (Banjaw et al., 2005). From the analysis it is clear
that a few studies used the entire extract instead of cathinone.
Interestingly, Banjaw and co-workers have made analysis of the
extract in most of their work.
6. Conclusions
The leaves of the tree C. edulis, known as khat, have for
centuries been chewed for psychostimulant and socializing
effects by people living in east African and Arabian Peninsula.
Recently, this deep rooted socio-cultural tradition has also
spread to East African and Middle Eastern communities in
Europe and North America. The ingredients of khat leaves are
numerous, but the major and most abundant active constituents
include six major alkaloids, tannins (7–14%) and flavonoids. To
date, urine measurement of cathinone and cathine using GC–
MS is the most accepted method available for screening
individuals with suspected khat use.
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. There seems to be considerable
circumstantial evidence to suggest that khat chewing can cause
brief psychosis and could exacerbate pre-existing psychopathol-
ogies. However, the current data is not sufficient enough to
imply a causal relationship between khat chewing and long-term
psychopathology. Studies claiming such associations have been
criticized for not being based on rigorous clinical evaluations.
Cathinone is more effective than cathine and other alkaloids
in khat on brain neurochemistry and behaviour; similar to (+)
amphetamine in many aspects, although quantitative differences
are noticeable. Cathinone, the psychoactive active alkaloid in
khat, 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. At this
juncture the role of the serotonergic (via 5-HT receptors;
cathinone N amphetamine), noradrenergic (via adrenergic recep-
tors and transporters) and opioid systems cannot be ruled out in
the neuropharmacological actions of khat/(−) cathinone.
Although numerous studies have investigated the pharma-
cological effects of cathinone, only few studies have dealt with
the effects of whole material, as normally taken by users, or
complex mixtures of chemical found in its extracts. For those
that used the extract, very few have analysed the extract and
used comparator drugs, raising a question on the validity of the
claim that khat is a “natural amphetamine”.
7. Recommendations
Although a number of investigations have been carried out
using cathinone, the psychoactive component of khat, these may
not wholly reflect the effect observed after administering khat in a
dose similar to those used traditionally. Human addicts take the
drug in its entirety; hence any translation from experimental
studies could only be feasible when the entire extract is used. A
case in point is cathedulins and the phenypentenylamine
 A.M. Feyissa, J.P. Kelly / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1147–1166
alkaloids, which have not been studied well, yet could
significantly contribute to the pharmacology of khat. Along the
same line, in different experiments there were variations in
outcome when C. edulis extract is used instead of cathinone.
Therefore, other constituents of khat merit investigation as well
before any firm conclusion is made.
As most experimental investigations on khat and cathinone
have been short term acute studies, there is lack of important
information on the long term use of khat. For instance several
reports claim khat to cause psychosis, nevertheless data lacks on
acute and long term neurotoxicity of khat. Further toxicological
studies are warranted, in particular, on the central nervous
system. It would be interesting to see the long term effect of the
entire extract and/or cathinone in level of various neuroprotec-
tive and neurotoxic biomarkers in the brain to elucidate the
neurotoxic potential of khat chewing.
Problems related with khat chewing especially khat induced
psychosis in immigrants could pose a problem on substance
abuse treatment centres in the West. This is attested by growing
reports of khat-induced psychosis among immigrants residing
in Western countries few of the cases culminating in suicide and
homicide. It would, therefore, appear highly desirable for the
international community to promote co-operation in the area of
khat control not only for the sake of saving the populations of
countries at present affected by this harmful phenomenon, but
also to protect possible new recruits of khat chewers in other
parts of the world.
As the khat-chewing habit has for centuries been limited to
the same geographical area where it has been traditionally
grown and habitually consumed, one could argue that the
problem will always remain within communities from khat
growing nations. However, in a world where rapid changes are
taking place in the way of thinking and of life, this assumption
may prove to be dangerously wrong. Although at this time it
seems unlikely for Western people to indulge in this habit, it
worth recalling the case of cocaine which started in a similar
mode as khat. It is tempting to forecast this, considering the
resemblance between cocaine and cathinone as positive
reinforcers. If synthetic cathinone becomes popular in the
near future which we believe is likely considering the story of
different versions of cocaine, previous works on cathinone
could be valuable. Khat leaves may be extracted by chemical
processing to produce a purer (cathinone); more concentrated
form for administration by other perhaps more addicting routes.
The emergence of popularity of methcathinone (methyl version
of cathinone) in countries like Russia and USA should ring
some alarm bells (Gosnell et al., 1996). That being said, it is
important to be aware of the fact that khat has an important
economic significance to countries which are involved in its
production. The khat sector today feeds millions of farmers and
people involved in its trade (Odenwald, 2007). It is believed that
the sector has a major contribution to the national GDP of
developing nations like Ethiopia, Kenya, and Yemen who
produce khat in large scale for domestic and export use. Hence,
we suggest a multidisciplinary research involving economists,
anthropologists, and sociologist is needed in addition to
Pharmacologists and Clinicians.
1163
Acknowledgments
AM was supported in this research with a scholarship award
from the NUI Galway International Scholarship Programme.
References
Abdulwaheb M, Makonnen E, Debella A, Abebe D. Effect of Catha edulis
foresk (khat) extracts on male rat sexual behavior. J Ethnopharmacol
2007;110:250–6.
Alem A, Shibre T. Khat induced psychosis and its medico-legal implication:
a case report. Ethiop Med J 1997;35:137–9.
Alem A, Kebede D, Kullgren G. The prevalence and socio-demographic
correlates of khat chewing in Butajira, Ethiopia. Acta Psychiatr Scand Suppl
1999;397:84–91.
Al-Habori M. The potential adverse effects of habitual use of Catha edulis
(khat). Expert Opin Drug Saf 2005;4:1145–54.
Al-Hebshi NN, Skaug N. Khat (Catha edulis)—an updated review. Addict Biol
2005;10:299–307.
Al-Meshal IA, Qureshi S, Ageel AM, Tariq M. The toxicity of Catha edulis
(khat) in mice. J Subst Abuse 1991;3:107–15.
Al-Motarreb A, Baker K, Broadley KJ. Khat: pharmacological and medical
aspects and its social use in Yemen. Phytother Res 2002;16:403–13.
Al-Obaid AM, al-Tamrah SA, Aly FA, Alwarthan AA. Determination of (S) (−)-
cathinone by spectrophotometric detection. J Pharm Biomed Anal
1998;17:321–6.
Al-Zubairi A, Al-Habori M, Al-Geiry A. Effect of Catha edulis (khat) chewing
on plasma lipid peroxidation. J Ethnopharmacol 2003;87:3–9.
American Psychiatric Association. Diagnostic and Statistical Manual for Mental
Disorders. fourth edition. Washington, DC: American Psychiatric Press;
1994 (DSM-IV).
Babayan EA, Barkov NK, Machula AI. Mediator mechanisms of cathinone
effects on animal behaviour. Drug Alcohol Depend 1983;12:31–5.
Banjaw MY, Schmidt WJ. Behavioural sensitisation following repeated
intermittent oral administration of Catha edulis in rats. Behav Brain Res
2005;156:181–9.
Banjaw MY, Schmidt WJ. Catha edulis extract and its active principle cathinone
induce ipsilateral rotation in unilaterally lesioned rats. Behav Pharmacol
2006;17:615–20.
Banjaw MY, Mayerhofer A, Schmidt WJ. Anticataleptic activity of cathinone
and MDMA (Ecstasy) upon acute and subchronic administration in rat.
Synapse 2003;49:232–8.
Banjaw MY, Fendt M, Schmidt WJ. Clozapine attenuates the locomotor
sensitisation and the prepulse inhibition deficit induced by a repeated oral
administration of Catha edulis extract and cathinone in rats. Behav Brain
Res 2005;160:365–73.
Banjaw MY, Miczek K, Schmidt WJ. Repeated Catha edulis oral administration
enhances the baseline aggressive behavior in isolated rats. J Neural Transm
2006;113:543–56.
Baker A, Dawe S. Amphetamine use and co-occurring psychological problems:
Review of the literature and implications for treatment. Aust Psychol
2005;40:87–94.
Baron DN. The qat party. BMJ 1999;319:500.
Belew M, Kebede D, Kassaye M, Enquoselassie F. The magnitude of khat use
and its association with health, nutrition and socio-economic status. Ethiop
Med J 2000;38:11–26.
Berardelli A, Capocaccia L, Pacitti C, Tancredi V, Quinteri F, Elmi AS.
Behavioural and EEG effects induced by an amphetamine like substance
(cathinone) in rats. Pharmacol Res Commun 1980;12:959–64.
Bentur Y, Bloom-Krasik A, Raikhlin-Eisenkraft B. Illicit cathinone (“Hagigat”)
poisoning. Clin Toxicol 2007;15:1–5.
Beyer J, Peters FT, Kraemer T, Maurer HH. Detection and validated quantification
of nine herbal phenalkylamines and methcathinone in human blood plasma by
LC–MS/MS with electrospray ionization. J Mass Spectrom 2007;42:150–6.
Bhui K, Abdi A, Abdi M, Pereira S, Dualeh M, Robertson D, et al. Traumatic
events, migration characteristics and psychiatric symptoms among Somali
refugees. Soc Psychiatry Psychiatr Epidemiol 2003;38:35–43.
1164 A.M. Feyissa, J.P. Kelly / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1147–1166
Bhui K, Craig T, Mohamud S, Warfa N, Stansfeld SA, Thornicroft G, et al.
Mental disorders among Somali refugees: developing culturally appropriate
measures and assessing socio-cultural risk factors. Soc Psychiatry Psychiatr
Epidemiol 2006;41:400–8.
Bimerew MS, Sonn FC, Kortenbout WP. Substance abuse and the risk of
readmission of people with schizophrenia at Amanuel Psychiatric Hospital,
Ethiopia. Curationis 2007;30:74–81.
Brenneisen R, Geisshüsler S. Phenylpentenylamines from Catha edulis. J Nat
Prod 1987;50:1188–9.
Brenneisen R, Fisch HU, Koelbing U, Geisshüsler S, Kalix P. Amphetamine-
like effects in humans of the khat alkaloid cathinone. Br J Clin Pharmacol
1990;30:825–8.
Bronson ME, Jiang W, DeRuiter J, Clark CR. A behavioral comparison of Nexus,
cathinone, BDB, and MDA. Pharmacol Biochem Behav 1995;51:473–5.
Browne DL. Qat use in New York City. NIDA Res Monogr 1990;105:464–5.
Calcagnetti DJ, Schechter MD. Increases in the locomotor activity of rats after
intracerebral administration of cathinone. Brain Res Bull 1992a;29:843–6.
Calcagnetti DJ, Schechter MD. Psychostimulant-induced activity is attenuated
by two putative dopamine release inhibitors. Pharmacol Biochem Behav
1992b;43:1023–31.
Calcagnetti DJ, Schechter MD. Place preference for the psychostimulant
cathinone is blocked by pretreatment with a dopamine release inhibitor. Prog
Neuropsychopharmacol Biol Psychiatry 1993;17:637–49.
Cleary L, Docherty JR. Actions of amphetamine derivatives and cathinone at the
noradrenaline transporter. Eur J Pharmacol 2003;476:31–4.
Connor J, Makonnen E, Rostom A. Comparison of analgesic effects of khat
(Catha edulis Forsk.) extract, D-amphetamine and ibuprofen in mice.
J Pharm Pharmacol 2000;52:107–10.
Connor JD, Rostom A, Makonnen E. Comparison of effects of khat extract and
amphetamine on motor behaviors in mice. J Ethnopharmacol 2002;81:65–71.
Cox G, Rampes R. Adverse effects of khat: a review. Adv Psychiatr Treat
2003;9:456–63.
Critchlow S, Seifert R. Khat-induced paranoid psychosis. Br J Psychiatry
1987;150:247–9.
Crombie L. The cathedulin alkaloids. Bull Narc 1980;32:37–50.
Cunningham T. Culture of khat. Nurs Stand 1998;13:25.
Della Bella D, Carenzi A, Frigeni V, Reggiani A, Zambon A. Involvement of
monoaminergic and peptidergic components in cathinone-induced analge-
sia. Eur J Pharmacol 1985;114:231–4.
Dimba EA, Gjertsen BT, Bredholt T, Fossan KO, Costea DE, Francis GW, et al.
Khat (Catha edulis)-induced apoptosis is inhibited by antagonists of
caspase-1 and-8 in human leukaemia cells. Br J Cancer 2004;91:1726–34.
Drake PH. Khat-chewing in the Near East. Lancet 1988;8584:532–3.
Eisenberg MS, Maher TJ, Silverman HI. A comparison of the effects of
phenylpropanolamine, d-amphetamine and d-norpseudoephedrine on open-
field locomotion and food intake in the rat. Appetite 1987;9:31–7.
El-Haj BM, Al-Amri AM, Hassan MH, Ali HS, Bin Khadem RK. The use of
cyclohexanone as a “derivatizing” reagent for the GC–MS detection of
amphetamines and ephedrines in seizures and the urine. Forensic Sci Int
2003;135:16–26.
Ellison G. Neural degeneration following chronic stimulant abuse reveals a
weak link in brain, fasciculus retroflexus, implying the loss of forebrain
control circuitry. Eur Neuropsychopharmacol 2002;12:287–97.
Elmi AS. The chewing of khat in Somalia. J Ethnopharmacol 1983;8:163–76.
Elmi AS, Ahmed YH, Samatar MS. Experience in the control of khat-chewing
in Somalia. Bull Narc 1987;39:51–7.
Fasanmade A, Kwok E, Newman L. Oral squamous cell carcinoma associated
with khat chewing. Oral Surg Oral Med Oral Pathol Oral Radiol Endod
2007;104:53–5.
Fleckenstein AE, Haughey HM, Metzger RR, Kokoshka JM, Riddle EL,
Hanson JE, et al. Differential effects of psychostimulants and related agents
on dopaminergic and serotonergic transporter function. Eur J Pharmacol
1999;382:45–9.
Foltin RW, Schuster CR. Behavioral tolerance and cross-tolerance to dl cathinone
and d-amphetamine in rats. J Pharmacol Exp Ther 1982;222:126–31.
Foltin RW, Schuster CR. Interaction between the effects of intragastric
meals and drugs on feeding in rhesus monkeys. J Pharmacol Exp Ther
1983;226:405–10.
Foltin RW, Woolverton WL, Schuster CR. Effects of psychomotor stimulants,
alone and in pairs, on milk drinking in the rat after intraperitoneal and
intragastric administration. J Pharmacol Exp Ther 1983;226:411–8.
Geisshüsler S, Brenneisen R. The content of psychoactive phenylpropyl and
phenylpentenyl khatamines in Catha edulis Forsk. of different origin.
J Ethnopharmacol 1987;19:269–77.
Giannini AJ, Castellani S. A manic-like psychosis due to khat (Catha edulis
Forsk.). J Toxicol Clin Toxicol 1982;19:455–9.
Giannini AJ, Miller NS, Turner CE. Treatment of khat addiction. J Subst Abuse
Treat 1992;9:379–82.
Glennon RA, Liebowitz SM. Serotonin receptor affinity of cathinone and related
analogues. J Med Chem 1982;25:393–7.
Glennon RA, Schechter MD, Rosecrans JA. Discriminative stimulus properties
of S(−)-and R(+)-cathinone, (+)-cathine and several structural modifica-
tions. Pharmacol Biochem Behav 1984;21:1–3.
Gordon TL, Meehan SM, Schechter MD. Differential effects of nicotine but not
cathinone on motor activity of P and NP rats. Pharmacol Biochem Behav
1993;44:657–9.
Gosnell BA, Yracheta JM, Bell SM, Lane KE. Intravenous self administration of
cathinone by rats. Behav Pharmacol 1996;7:526–31.
Goudie AJ. Comparative effects of cathinone and amphetamine on fixed-interval
operant responding: a rate-dependency analysis. Pharmacol Biochem Behav
1985;23:355–65.
Goudie AJ. Importing khat, legal but dangerous. Lancet 1987;8571:1340–1.
Goudie AJ. Discriminative stimulus properties of amphetamine, cathinone, and
related agents. NIDA Res Monogr 1991;116:45–60.
Goudie AJ, Newton T. The puzzle of drug-induced conditioned taste aversion:
comparative studies with cathinone and amphetamine. Psychopharmacology
1985;87:328–33.
Goudie AJ, Atkinson J, West CR. Discriminative properties of the psychosti-
mulant dl-cathinone in a two lever operant task. Lack of evidence for
dopaminergic mediation. Neuropharmacology 1986;25:85–94.
Gough SP, Cookson IP. Khat-induced schizophreniform psychosis in UK.
Lancet 1984;8374:455.
Granek M, Shalev A, Weingarten AM. Khat-induced hypnagogic hallucinations.
Acta Psychiatr Scand 1988;78:458–61.
Griffiths P, Gossop M, Wickenden S, Dunworth J, Harris K, Lloyd C. A
transcultural pattern of drug use: qat (khat) in the UK. Br J Psychiatry
1997;170:281–4.
Guantai AN, Maitai CK. Metabolism of cathinone to d norpseudoephedrine in
humans. J Pharm Sci 1983;72:1217–8.
Gugelmann R, von Allmen M, Brenneisen R, Porzig H. Quantitative differences
in the pharmacological effects of (+)- and (−)-cathinone. Experientia
1985;41:1568–71.
Halbach H. Medical aspects of the chewing of khat leaves. Bull World Health
Organ 1972;47:21–9.
Halbach H. Khat-the problem today. NIDA Res Monogr 1979;27:318–9.
Halket JM, Karasu Z, Murray-Lyon IM. Plasma cathinone levels fol-
lowing chewing khat leaves (Catha edulis Forsk.). J Ethnopharmacol
1995;49:111–3.
Hassan NA, Gunaid AA, El Khally FM, Murray-Lyon IM. The subjective effects
of chewing qat leaves in human volunteers. Saudi Med J 2002;23:850–3.
Hassan NA, Gunaid AA, Murray-Lyon IM. Khat (Catha edulis): health aspects
of khat chewing. East Mediterr Health J 2007;13:706–18.
Hattab FN, Angmar-Månsson B. Fluoride content in khat (Catha edulis)
chewing leaves. Arch Oral Biol 2000;45:253–5.
Huang D, Wilson MC. Comparative discriminative stimulus properties of dl-
cathinone, d-amphetamine, and cocaine in rats. Pharmacol Biochem Behav
1986;24:205–10.
Ihunwo AO, Kayanja FI, Amadi-Ihunwo UB. Use and perception of the
psychostimulant, khat (Catha edulis) among three occupational groups in
south western Uganda. East Afr Med J 2004;81:468–73.
Islam MW, Tariq M, Ageel AM, el-Feraly FS, al-Meshal IA, Ashraf I. An
evaluation of the male reproductive toxicity of cathinone. Toxicology
1990;60:223–34.
Jansson T, Kristiansson B, Qirbi A. Effect of khat on uteroplacental blood flow
in awake, chronically catheterized, late-pregnant guinea pigs. J Ethnophar-
macol 1988;23:19–26.
 A.M. Feyissa, J.P. Kelly / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1147–1166
Johanson CE, Schuster CR. A comparison of the behavioral effects of l- and dl-
cathinone and d-amphetamine. J Pharmacol Exp Ther 1981;219:355–62.
Kalix P. A constituent of khat leaves with amphetamine-like releasing
properties. Eur J Pharmacol 1980a;68:213–5.
Kalix P. Hypermotility of the amphetamine type induced by a constituent of khat
leaves. Br J Pharmacol 1980b;68:11–3.
Kalix P. Cathinone, an alkaloid from khat leaves with an amphetamine-like
releasing effect. Psychopharmacology 1981;74:269–70.
Kalix P. The amphetamine-like releasing effect of the alkaloid (−)cathinone on
rat nucleus accumbens and rabbit caudate nucleus. Prog Neuropsychophar-
macol Biol Psychiatry 1982;6:43–9.
Kalix P. A comparison of the catecholamine releasing effect of the khat alkaloids
(−)-cathinone and (+)-norpseudoephedrine. Drug Alcohol Depend
1983;11:395–401.
Kalix P. Effect of the alkaloid (−)-cathinone on the release of radioactivity from
rat striatal tissue prelabelled with 3H-serotonin. Neuropsychobiology
1984;12:127–9.
Kalix P. Pharmacological properties of the stimulant khat. Pharmacol Ther
1990;48:397–416.
Kalix P, Braenden O. Pharmacological aspects of the chewing of khat leaves.
Pharmacol Rev 1985;37:149–64.
Kalix P, Glennon RA. Further evidence for an amphetamine-like mechanism of
action of the alkaloid cathinone. Biochem Pharmacol 1986;35:3015–9.
Kalix P, Khan I. Khat: an amphetamine-like plant material. Bull World Health
Organ 1984;62:681–6.
Kalix P, Geisshusler S, Brenneisen R, Koelbing U, Fisch HU. Cathinone, a
phenylpropylamine alkaolid from khat leaves that has amphetamine effects
in humans. NIDA Res Monogr 1990;105:289–90.
Kandela P. Women's rights, a tourist boom, and the power of khat in Yemen.
Lancet 2000;9213:1437.
Kebede D, Alem A, Mitike G, Enquselassie F, Berhane F, Abebe Y, et al. Khat
and alcohol use and risky sex behaviour among in-school and out-of-school
youth in Ethiopia. BMC Public Health 2005;5:109.
Kennedy JG, Teague J, Rokaw W, Cooney E. A medical evaluation of the use of
qat in North Yemen. Soc Sci Med 1983;17:783–93.
Kervingant D. The consumption of khat in French Somaliland. Bull Narc
1959;32:42.
Kim JY, Jung KS, Kim MK, Lee JI, In MK. Simultaneous determination of
psychotropic phenylalkylamine derivatives in human hair by gas chromato-
graphy/mass spectrometry. Rapid Commun Mass Spectrom 2007;21:1705–20.
Kite GC, Ismail M, Simmonds MS, Houghton PJ. Use of doubly protonated
molecules in the analysis of cathedulins in crude extracts of khat (Catha
edulis) by liquid chromatography/serial mass spectrometry. Rapid Commun
Mass Spectrom 2003;17:1553–64.
Knoll J. Studies on the central effects of (−) Cathinone. NIDA Res Monogr
1979;27:322–3.
Krikorian AD. Khat and its use: an historical perspective. J Ethnopharmacol
1984;12:115–78.
Kristiansson B, Abdul Ghani N, Eriksson M, Garle M, Qirbi A. Use of khat in
lactating women: a pilot study on breast-milk secretion. J Ethnopharmacol
1987;21:85–90.
Li SM, Campbell BL, Katz JL. Interactions of cocaine with dopamine uptake
inhibitors or dopamine releasers in rats discriminating cocaine. J Pharmacol
Exp Ther 2006;317:1088–96.
Luqman W, Danowski TS. The use of khat (Catha edulis) in Yemen. Social and
medical observations. Ann Intern Med 1976;85:246–9.
Lurie IS, Klein RF, Dal Cason TA, LeBelle MJ, Brenneisen R, Weinberger RE.
Chiral resolution of cationic drugs of forensic interest by capillary
electrophoresis with mixtures of neutral and anionic cyclodextrins. Anal
Chem 1994;66:4019–26.
Maitai CK, Dhadphale M. Khat-induced paranoid psychosis. Br J Psychiatry
1988;152:294.
Mathys K, Brenneisen R. Determination of (S)-(−)-cathinone and its metabolites
(R,S)-(−)-norephedrine and (R,R)-(−)-norpseudoephedrine in urine by high-
performance liquid chromatography with photodiode-array detection.
J Chromatogr 1992;593:79–85.
Matloob MH. Determination of cadmium, lead, copper and zinc in Yemeni khat
by anodic stripping voltammetry. East Mediterr Health J 2003;9:28–36.
1165
McKee CM. Medical and social aspects of qat in Yemen: a review. J R Soc Med
1987;80:762–5.
McLaren P. Khat psychosis. Br J Psychiatry 1987;150:712.
Mereu GP, Pacitti C, Argiolas A. Effect of (−)-cathinone, a khat leaf constituent,
on dopaminergic firing and dopamine metabolism in the rat brain. Life Sci
1983;32:1383–9.
Morrish PK, Nicolaou N, Brakkenberg P, Smith PE. Leukoencephalopathy
associated with khat misuse. J Neurol Neurosurg Psychiatry 1999;67:
556.
Nakahara Y, Kikura R. Hair analysis for drugs of abuse. XIII. Effect of structural
factors on incorporation of drugs into hair: the incorporation rates of
amphetamine analogs. Arch Toxicol 1996;70:841–9.
Nencini P. The role of opiate mechanisms in the development of tolerance
to the anorectic effects of amphetamines. Pharmacol Biochem Behav
1988;30:755–64.
Nencini P, Ahmed AM. Naloxone-reversible antinociceptive activity of
cathinone, the active principle of khat, in the mouse and rat. Pharmacol
Res Commun 1982;14:759–70.
Nencini P, Ahmed AM. Khat consumption: a pharmacological review. Drug
Alcohol Depend 1989;23:19–29.
Nencini P, Ahmed AM, Amiconi G, Elmi AS. Tolerance develops to
sympathetic effects of khat in humans. Pharmacology 1984a;28:150–4.
Nencini P, Amiconi G, Befani O, Abdullahi MA, Anania MC. Possible
involvement of amine oxidase inhibition in the sympathetic activation
induced by khat (Catha edulis) chewing in humans. J Ethnopharmacol
1984b;11:79–86.
Nencini P, Ahmed AM, Elmi AS. Subjective effects of khat chewing in humans.
Drug Alcohol Depend 1986;18:97–105.
Nencini P, Johanson CE, Schuster CR. Sensitization to kappa opioid
mechanisms associated with tolerance to the anorectic effects of cathinone.
J Pharmacol Exp Ther 1988;245:147–54.
Nencini P, Grassi MC, Botan AA, Asseyr AF, Paroli E. Khat chewing spread to
the Somali community in Rome. Drug Alcohol Depend 1989;23:255–8.
Nencini P, Fraioli S, Pascucci T, Nucerito CV. (−) Norpseudoephedrine, a
metabolite of cathinone with amphetamine-like stimulus properties,
enhances the analgesic and rate decreasing effects of morphine, but inhibits
its discriminative properties. Behav Brain Res 1998;92:11–20.
Nielsen JA. Cathinone affects dopamine and 5-hydroxytryptamine neurons in
vivo as measured by changes in metabolites and synthesis in four forebrain
regions in the rat. Neuropharmacology 1985;24:845–52.
Nielsen JA, Schechter MD. Behavioral and neurochemical effects of (−)- and (+/−)-
cathinone: dose-response and time-course. Prog Neuropsychopharmacol Biol
Psychiatry 1985;9:739–43.
Nielen RJ, van der Heijden FM, Tuinier S, Verhoeven WM. Khat and mushrooms
associated with psychosis. World J Biol Psychiatry 2004;5: 49–53.
Nordal A. Khat: pharmacognostical aspects. Bull Narc 1980;32:51–64.
Numan N. Exploration of adverse psychological symptoms in Yemeni khat users
by the Symptoms Checklist-90 (SCL-90). Addiction 2004;99:61–5.
Odenwald M. Chronic khat use and psychotic disorders: a review of the
literature and future prospects. Sucht 2007;53:9–22.
Odenwald M, Neuner F, Schauer M, Elbert T, Catani C, Lingenfelder B, et al.
Khat use as risk factor for psychotic disorders: a cross-sectional and case-
control study in Somalia. BMC Med 2005;12:3–5.
Odenwald M, Lingenfelder B, Schauer M, Neuner F, Rockstroh B, Hinkel H,
et al. Screening for posttraumatic stress disorder among somali ex-
combatants: a validation study. Confl Health 2007;1:10.
Omolo OE, Dhadphale M. Alcohol use among khat (Catha) chewers in Kenya.
Br J Addict 1987;82:97–9.
Osorio-Olivares M, Rezende MC, Sepúlveda-Boza S, Cassels BK, Fierro A.
MAO inhibition by arylisopropylamines: the effect of oxygen substituents at
the beta-position. Bioorg Med Chem 2004;12:4055–66.
Pantelis C, Hindler CG, Taylor JC. Use and abuse of khat (Catha edulis): a
review of the distribution, pharmacology, side effects and a description of
psychosis attributed to khat chewing. Psychol Med 1989;19:657–68.
Patel NB. Mechanism of action of cathinone: the active ingredient of khat
(Catha edulis). East Afr Med J 2000;77:329–32.
Pehek EA, Schechter MD. Discriminative stimulus properties of (+)cathine, an
alkaloid of the khat plant. Pharmacol Biochem Behav 1990;36:267–71.
1166 A.M. Feyissa, J.P. Kelly / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1147–1166
Pehek EA, Schechter MD, Yamamoto BK. Effects of cathinone and
amphetamine on the neurochemistry of dopamine in vivo. Neuropharma-
cology 1990;29:1171–6.
Peterson DW, Maitai CK, Sparber SB. Relative potencies of two phenylalkylamines
found in the abused plant Catha edulis, khat. Life Sci 1980;27:2143–7.
Rosecrans JA, Campbell OL, Dewey WL, Harris LS. Discriminative stimulus
and neurochemical mechanisms of cathinone: a preliminary study. NIDA
Res Monogr 1979;27:328–9.
Rothman RB, Vu N, Partilla JS, Roth BL, Hufeisen SJ, Compton-Toth BA, et al.
In vitro characterization of ephedrine-related stereoisomers at biogenic amine
transporters and the receptorome reveals selective actions as norepinephrine
transporter substrates. J Pharmacol Exp Ther 2003;307:138–45.
Rousseau C, Said TM, Gagné MJ, Bibeau G. Between myth and madness: the
premigration dream of leaving among young Somali refugees. Cult Med
Psychiatry 1998;22:385–411.
Saha S, Dollery C. Severe ischaemic cardiomyopathy associated with khat
chewing. J R Soc Med 2006;99:316–8.
Saleh M, Mekkawy H, el-Komy F. Acute effects of a khat extract on the rat
electroencephalogram. J Ethnopharmacol 1988;23:291–8.
Sawair FA, Al-Mutwakel A, Al-Eryani K, Al-Surhy A, Maruyama S, Cheng J,
et al. High relative frequency of oral squamous cell carcinoma in Yemen:
qat and tobacco chewing as its aetiological background. Int J Environ
Health Res 2007;17:185–95.
Schechter MD. Induction of and recovery from tolerance to the discriminative
stimulus properties of l-cathinone. Pharmacol Biochem Behav 1986a;25:13–6.
Schechter MD. Dopaminergic mediation of a behavioral effect of l-cathinone.
Pharmacol Biochem Behav 1986b;25:337–40.
Schechter MD. Temporal parameters of cathinone, amphetamine and cocaine.
Pharmacol Biochem Behav 1989;34:289–92.
Schechter MD. Rats become acutely tolerant to cathine after amphetamine or
cathinone administration. Psychopharmacology 1990a;101:126–31.
Schechter MD. Dopaminergic nature of acute cathine tolerance. Pharmacol
Biochem Behav 1990b;36:817–20.
Schechter MD. Effect of learned behavior upon conditioned place preference to
cathinone. Pharmacol Biochem Behav 1991;38:7–11.
Schechter MD, Glennon RA. Cathinone, cocaine and methamphetamine:
similarity of behavioral effects. Pharmacol Biochem Behav 1985;22:913–6.
Schechter MD, McBurney D. Effect of repeated administrations upon cathinone
discrimination and conditioned place preference. Gen Pharmacol
1991;22:779–82.
Schechter MD, Meehan SM. Conditioned place preference produced by the
psychostimulant cathinone. Eur J Pharmacol 1993;232:135–8.
Schechter MD, Rosecrans JA, Glennon RA. Comparison of behavioral effects of
cathinone, amphetamine and apomorphine. Pharmacol Biochem Behav
1984;20:181–4.
Schechter MD, Schechter JB, Calcagnetti DJ. Direct microinjection of cathinone
into the rat brain produces discriminative stimuli. Pharmacol Biochem
Behav 1992;42:619–23.
Schuster CR, Johanson CE. Behavioral studies of cathinone in monkeys and
rats. NIDA Res Monogr 1979;27:324–5.
Schramm-Sapyta NL. Drug addiction: what can animal models teach us?
Preclinica 2004;2:417–21.
Selassie SG, Gebre A. Rapid assessment of drug abuse in Ethiopia. Bull Narc
1996;48:53–63.
Sporkert F, Pragst F, Bachus R, Masuhr F, Harms L. Determination of cathinone,
cathine and norephedrine in hair of Yemenite khat chewers. Forensic Sci Int
2003;133:39–46.
Stevenson M, Fitzgerald J, Banwell C. Chewing as a social act: cultural
displacement and khat consumption in the East African communities of
Melbourne. Drug Alcohol Rev 1996;15:73–82.
Sulzer D, Sonders MS, Poulsen NW, Galli A. Mechanisms of neurotransmitter
release by amphetamines: a review. Prog Neurobiol 2005;75:406–33.
Szendrei K. The chemistry of khat. Bull Narc 1980;32:5–35.
Taha SA, Ageel AM, Islam MW, Ginawi OT. Effect of (−)-cathinone, a
psychoactive alkaloid from khat (Catha edulis Forsk.) and caffeine on
sexual behaviour in rats. Pharmacol Res 1995;31:299–303.
Toennes SW, Kauert GF. Excretion and detection of cathinone, cathine, and
phenylpropanolamine in urine after kath chewing. Clin Chem 2002;48:1715–9.
Toennes SW, Kauert GF. Driving under the influence of khat-alkaloid concentrations
and observations in forensic cases. Forensic Sci Int 2004;140:85–90.
Toennes SW, Harder S, Schramm M, Niess C, Kauert GF. Pharmacokinetics of
cathinone, cathine and norephedrine after the chewing of khat leaves. Br J
Clin Pharmacol 2003;56:125–30.
Vanwalleghem IE, Vanwalleghem PW, De Bleecker JL. Khat chewing can cause
stroke. Cerebrovasc Dis 2006;22:198–200.
Vislobokov AI, Mantsev VV, Kuzmin AV. Cocaine, amphetamine and cathinone,
but not nomifensine and pargyline increase calcium inward current in internally
perfused neurons. Life Sci 1993;52:261–5.
Wagner GC, Preston K, Ricaurte GA, Schuster CR, Seiden LS. Neurochemical
similarities between d,l-cathinone and d-amphetamine. Drug Alcohol Depend
1982;9:279–84.
Walter HP. Drink-drive: broken jaw, lager and khat ingestion. J Clin Forensic
Med 1996;3:51–3.
Warfa N, Klein A, Bhui K, Leavey G, Craig T, Alfred SS. Khat use and mental
illness: a critical review. Soc Sci Med 2007;65:309–18.
Weir S, Thuriaux MC. Importing khat. Lancet 1988;8582:414.
White JD. The chemistry of khat. An approach to the synthesis of euonyminol.
Pure Appl Chem 1994;66:2183–8.
WHO. Review of the pharmacology of khat. Report of a WHO advisory group.
Bull Narc 1980;32:83–93.
WHO. WHO Expert Committee on Drug Dependence. World Health Organ
Tech Rep Ser 2003;915:1–26.
WHO. WHO Expert Committee on Drug Dependence. World Health Organ
Tech Rep Ser 2006;942:1–21.
Widler P, Mathys K, Brenneisen R, Kalix P, Fisch HU. Pharmacodynamics
and pharmacokinetics of khat: a controlled study. Clin Pharmacol Ther
1994;55:556–62.
Willner P. Animal models of addiction. Hum Psychopharmacol Clin Exp
1997;12(S2):59–68.
Wolgin DL, Munoz JR. Role of instrumental learning in tolerance to cathinone
hypophagia. Behav Neurosci 2006;120:362–70.
Woolverton WL. A review of the effects of repeated administration of selected
phenylethylamines. Drug Alcohol Depend 1986;17:143–50.
Woolverton WL, Johanson CE. Preference in rhesus monkeys given a choice
between cocaine and d,l-cathinone. J Exp Anal Behav 1984;41:35–43.
Yanagita T. Studies on cathinones: cardiovascular and behavioral effects in rats
and self-administration experiment in rhesus monkeys. NIDA Res Monogr
1979;27:326–7.
Yanagita T. Intravenous self-administration of (−)-cathinone and 2-amino-1-
(2,5-dimethoxy-4-methyl)phenylpropane in rhesus monkeys. Drug Alcohol
Depend 1986;17:135–41.
Yousef G, Huq Z, Lambert T. Khat chewing as a cause of psychosis. Br J Hosp
Med 1995;54:322–6.
Zein ZA. Polydrug abuse among Ethiopian university students with particular
reference to khat (Catha edulis). J Trop Med Hyg 1988;91:71–5.
Zelger JL, Carlini EA. Anorexigenic effects of two amines obtained from Catha
edulis Forsk. (Khat) in rats. Pharmacol Biochem Behav 1980;12:701–5.
Zelger JL, Carlini EA. Influence of cathinone (alpha-aminopropiophenone) and
cathine (phenylpropanolamine) on circling behavior and on the uptake and
release of [3H] dopamine in striatal slices of rats. Neuropharmacology
1981;20:839–43.
Zelger JL, Schorno HX, Carlini EA. Behavioural effects of cathinone, an amine
obtained from Catha edulis Forsk.: comparisons with amphetamine, norpseu-
doephedrine, apomorphine and nomifensine. Bull Narc 1980;32:67–81.