Central Effect

of Khat
BY ESHETU
MULISA,AAU,S
OP
 Introduction

• The stimulant leaf khat (Catha edulis Forsk) comes from a tree
which grows in countries
– bordering the Red Sea, along the east coast of Africa and in
west Asia
• The earliest scientific in West was in the eighteenth century
– 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,jaad-Somalia,miraa-Kenya,Muhulo-
Tanzania, Haqiqat-Hebrew, cat, catha, tohai, and muraa
– attest to the widespread and presumably fairly old knowledge of C.
edulis by native peoples of eastern and Southeastern Africa
– But, the most common name is khat
 Botany
• An evergreen shrub cultivated as bush or small tree
• Grows in a variety of climates and soils
– Drought
History of Consumption in the Horn of
Africa
• Ethiopia is thought to be country of origin
– Starts from south then to north
• Northwestern Somalia (Rep. of Somaliland)
– British authorities in 1921 forbidding the cultivation, import, and sale of khat
– In 1936, official reports showed the Somaliland Protectorate imported 4000
bundles (approximately 4000 kg) of khat
– By 1945, according to the estimate of the British consul in Harer, about 3000 kg
of khat were smuggled daily into the Protectorate
• In Southern Somalia
– unknown prior to the Second World War
– 1941 British took control of all of Somali territories
• making business and cultural exchange possible
– In the 1950s,khat chewing spread to southern Somalia as more and more
Somalis took up the habit as an act of defiance against colonial authority
– in 1983 Somalia spent $57 million, an amount equivalent to 5.7 percent of the
GDP, on importing khat
• In Djibouti
– Since creation of Port (1969) by Yemeni Arabs
– Now ubiquitos
 Prevalence of Use
• In Yemen of the 27 410 patients who visited clinic, 90.3% of the males and 58.6% of
the females over the age of 12 chewed khat, but only 60.3% of the males and 34.9%
of the females were classified as ‘habitual chewers’
– Kennedy estimated that 80 –85% of the men and 50 –60% of the woman in
northern Yemen chewed khat more than once a week
• In Ethiopia
– Harar (widely)
– Prevalence of habit in the country in 1996 showed 30%
– one recent study with a sample size of 10 468 adults reported a prevalence of
50%
– study also reported a strong association between the habit and high educational
level
• Somalia
– in the south 18.3% were habitual chewers and 20.9% were occasional users
– in the north the respective figures were 55% and 29.3%
– Of the female population,habitual and occasional chewers collectively were
10.60% and 25.45% in the south and north, respectively
• Djibouti
– 90% of popn
• In the UK,khat is used by
– mainly male members of the Somali and Yemeni community and
– the prevalence has been shown to reach 80% in Somali immigrants in London
• In the USA khat use
– is most prevalent amongst immigrants from Yemen,Somalia and Ethiopia
• Khat use has also been reported in East African communities in Italy, Israel,
Australia,Norway, Holland,Belgium, German, Switzerland and Canada
Legal Aspects of Use
• Khat circulates freely in most of east African countries and western
asia
• its status in European countries is not uniform
– prohibited in Ireland, France,Switzerland,Sweden and Norway
– whilst it is legal in the U.K. and in the Netherlands
• illegal in the U.S.A. and Canada but permissible in Australia
• 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
 Pharmacology of Khat

Active Constituents of Khat Leaf

• different chemical substances are found in the leaves of khat
– Alkaloids,terpenoids,flavonoids,sterols,glycosides,
– Tannins (7–14% by weight)
– Amino acids
• asparaginic acid, threonine, serine,glutaminic acid…
• Choline was to the extent of about 0.05 % in the dried plant
– Vitamins
• ascorbic acid content of khat is high
• Ash 1.6%
• Fibre 2.7%
• Protein 5.2%
• Niacin 14.8 mg
• Thiamine <0.05 mg
• Riboflavin <0.05 mg
• B-carotene 1.8 mg
• Calcium 290 mg
• Iron 18.5 mg
• Among all these chemicals in khat,alkaloids are the most important
– three main alkaloids are
• (-)-S- cathinone (S-alpha-aminopropiophenone)
• norpseudoephedrine (cathine)
• Norephedrine
– phenylpropylamines structurally related to amphetamine and
noradrenaline
• Cathinone is
– the constituent that is mainly responsible for central effects of khat and
most potent
– is active constituent in fresh khat
– Khat contains the (–)-enantiomer of cathinone only which has the same
absolute configuration as S-(+)-amphetamine
• During the maturation of the leaves or decomposition of the plant through
drying and storage
– cathinone is enzymatically converted to cathine[(+) norpseudoephedrine and (−)-
norephedrin
– utilized NADPH as cofactor to catalyze the reduction of (−)-cathinone to (+)-
cathine and (−)-norephedrine
– Sunlight-induced or heat also causes degradation of cathinone in lab
• to slow down the degradation process,
– the khat leaves are usually wrapped in banana leaves immediately after
picking to retain their moisture
– Therefore,
• environment, climate conditions, as well as local traditions connected with
cultivation and harvesting determine the chemical profile and general
appearance of khat leaves
– 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
– Accordingly, analyses of khat samples from Kenya and Ethiopia have shown that
the commercial value of the material correlates with its cathinone content
 Pharmacokinetics
• 100 –500g Catha edulis are used over a period of 3 – 4 h
• During chewing,the alkaloids from khat leaves are effectively
liberated
– with about 80% of cathinone and cathine, and
– over 90% of norephedrine released following chewing
• absorption of the constituents have two phases
– first being at the buccal mucosa
• plays a major role in the absorption of alkaloids
– second phase is following swallowing of the juice
• at the stomach and/or small intestine
• T max of cathinone, cathine and norephedrine
– reached at 2.3, 2.6 and 2.8 h respectively
• Only 7% or less of the absorbed (−)- cathinone is excreted unchanged in
the urine
– is mainly excreted in the form of norephedrine and cathine
– amount of norephedrine excreted in urine is much higher than the
amount ingested,
• Indicates that (−) cathinone is also metabolized to R, S-(−) norephedrine
– Cathine has been found in breast milk in several lactating women who
were chewing the leaves of khat
Modes of Action of Khat
Overview of Amphetamine Action
• AMPH induces the release of catecholamines, but not ATP
• two non-exclusive hypotheses that may explain the mechanism by which
AMPH redistributes vesicular monoamines to the cytosol
• The weak base hypothesis
– All sympathomimetics are weak bases with amine moieties that are capable of
accepting protons with pK’s in the range of ~8 to 10
– Secretory vesicles are acidic; maintain a pH of 5.0–5.6
– AMPH is a lipophilic weak base with a pK of 9.9 and is thus protonated in acidic
organelles including catecholamine vesicles:once charged,it is less membrane
permeable and accumulates in the acidic structure
– acidic pH gradient in secretory vesicles provides the energy to accumulate
transmitter against its concentration gradient
– is a substrate for both VMATs
• alkalinize the existing acidic pH gradient and thus decrease the energy that
provides accumulation of neurotransmitter
VMAT competition
• Competition for uptake
Other Action of Amphetamine
• inhibiting of MAOs
• enhance dopamine synthesis
– this is due enhancement of tyrosine hydroxylase activity
– Mechanism is unknown
– An alternate possibility is that AMPH may substitute for dopamine at its
tyrosine hydroxylase-binding site from where it exerts feedback
inhibition
 – Similarly the mechanism of AMPH’s tyrosine hydroxylase inhibition at higher
levels remains unknown
• although it has long been suggested to be due to feedback inhibition from
increased levels of cytosolic dopamine
• AMPH acutely regulates DAT cell surface expression
– AMPH acutely reduced cell surface expression of human DAT in cell lines,
leading to a concomitant loss of DAT activity
• AMPH and its derivatives appear to regulate VMAT2 function
– apparent inhibition of VMAT2 is due to D2 autoreceptor activation following
dopamine release
Action of Khat
• stimulant effects of khat
– mediated through monoamine neurotransmitter systems
• Cathinone induces release of monoamines through membrane transporters
• It causes release of dopamine in the striatum and nucleus accumbens
– with similar potency to amphetamine in low micromolar concentrations
– Consequently,increases are seen in extracellular levels of the metabolite 3,4-
dihydroxyphenylacetic(DOPAC) in the caudate nucleus, nucleus accumbens,
and frontal cortex
• Norpseudoephedrine also induces release of catecholamines
• Cathinone decreases firing of substantia nigra neurons, similar to
amphetamine
• It has also been demonstrated that khat /cathinone promote release of 5-HT
• High doses of cathinone result in
– depletion of dopamine and also have neurotoxic effecs on dopamine
neurons
• Long-term administration of cathinone deplete norepinephrine or serotonin
• However in contrast to amphetamine, there is in vitro evidence that
cathinone-induced dopamine release is regulated by calcium channels
– pre-treatment with isradipine, a potent dihydropyridine calcium channel
(L-type) blocker attenuated the activity elevating effect of cathinone in
rats
• Cathinone, similar to amphetamines, has also been shown to inhibit
monoamine oxidase (MAO) activity in vitro
 – about 150–200 times more effective than amphetamine in this
regard
– cathinone exhibited inhibition of MAO-B activity more than MAO-
A
– Inhibition of MAO activity
• is supported by the observation of increment of urinary
catecholamine (HVA) associated with khat chewing in humans
• Recently,it was documented that S-(−)-cathinone acts as well on
noradrenaline transporters
– Therefore,neurochemical mechanisms other than dopamine
could explain the central actions of khat or S-(−)-cathinone
• level of the neurotransmitter in different brain regions was different
when khat extract is used instead of cathinone
– may be due to the fact that
• C. edulis contains (besides S-(−)-cathinone) other
compounds, such as cathine and different metabolites
• The additional compounds existing in the crude extract might
have substantially altered behavioural and neurochemical
effects
Central Effects of Khat

• Cathinone is potent and have higher lipid solubility

– facilitates its access into the central nervous system
– So khat-induced psychostimulation is predominately,or even
exclusively due to the cathinone content of the leaves
• cathine and norephedrine, possess weaker central stimulant properties
– because of their less lipophilic properties
• phenylpentenylamines are of low concentration and were shown to have a
weak effect on dopamine release in dopamine prelabelled rat striatal tissue
• Cathedulins has not yet been well characterized in the CNS and other
organs
• Although other pathways could not be ruled out
– khat/cathinone-induced psychostimulation is mediated primarily via the meso–
striato–cortico limbic dopaminergic pathway
– Moreover,the dependence-producing potential,analgesia, and anorexic effects of
khat/cathinone are believed to be partly mediated via this pathway
• Psychosis
– Consequence of psychosis by khat was assumed as a rare
phenomenon by many researcher
– due to the bulky nature of the khat leaves
• only low plasma levels of its active ingredients can be attained after
chewing
– Recent work among Somali people in war zones
• khat use appears to correlate strongly with measures of psychosis
and that the two may be linked
– two main types
• paranoid or schizophrenia spectrum disorder (similar to
amphetamine like psychosis) and
• a manic psychosis
– Schizophreniform psychosis
 • paranoid delusions, fear, a hostile perception of the environment,
auditory hallucinations, ideas of reference, thought alienation and a
tendency to isolate themselves
• If khat consumption is ceased at this time, resolution of symptoms
usually occurs within a short period (3–11 days)
– a manic-type psychosis
• The first case was in USA
• The patient presented with hyperactivity, shouting, pressure of speech,
grandiose delusions with flight of ideas and tangential thought processes,
and a labile mood varying from euphoria to anger
• The patient had used khat for the first time, chewing about 24 leaves (this is
equivalent to a single dose)
• Symptoms subsided spontaneously within about 8 hours of chewing
• Drake (1988) also described a case of mania following prolonged chewing
– Admissions to hospital due to khat-induced psychosis are not
infrequent,
• Presentations are frequently similar to an amphetamine-like
psychosis,with disturbed behavior
– Banjaw et al. found that
• that repeated oral administration of cathinone or C. edulis extract to
rats
– enhanced locomotor and exploratory activity and lead to a gradual
deficit in prepulse inhibition
• finding showed that psychostimulants including amphetamine,
cathinone and cocaine can cause
– delusions,hallucinations and thought disorder
– could be reversed by administration of clozapine
• Neurotransmitter level analyses according to their report showed
– significant increase in the level of dopamine in the prefrontal cortex and
reduced dopamine and its metabolites in anterior putamen
– a significant decrease in the level 5-HT in the nucleus accumbens and
its metabolite, 5-hydroxyindole acetic acid (5-HIAA) in the prefrontal
cortex
– concluded that according to the dopamine hypothesis of schizophrenia
» psychotic symptoms may be related to excessive dopaminergic
activity in the limbic system
» whereas negative symptoms and cognitive deficits may be related,
in part to reduced dopaminergic activity in the PFC
 • So C. edulis or cathinone exert its behavioural effects by dopamine
in the meso–striato–cortico limbic pathway
• This pathway is believed to play a central role in the induction,
maintenance and expression of sensitization following repeated
administration of psychostimulants
• Aggression
– 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. (2005) 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
– Neurochemical studies 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
•Mood Disorders
– Recently,Hassan et al. (2002) studied the effect of khat chewing
in human mood
• reported that khat chewing results in a functional mood disorder
consisting of predominantly reactive depressive mood
– seen an hour after acute khat administration
– it might exacerbate symptoms in patients with pre-existing mood
disorder
– The severity of depression varied from agitation and sleep disturbances
to severe depression with suicidality
– mediated by the sympathomimetic action of cathinone and due
to its depletion of 5-HT
– Other mood disorders such as khat-induced behavioural
syndrome described as
 • hypomania have also been reported by several authors
• There are similar reports of mood disorders secondary to repeated
amphetamine use
• Addiction
– Deep rooted cultural factors have also major contribution to khat
taking behaviour
– Because the use of khat often starts at a young age and can
develop into a compulsive daily habit lasting a lifetime
– This compulsive behaviour, as indicated by the tendency of khat
chewers to secure their daily supply of the leaves at the expense
of vital needs is described as a psychological dependence by
many researchers
– In eastern African countries the prevalence of khat dependence
is estimated to be 5–15% of the population
 – When using khat it takes about 2–3 h to reach maximal plasma levels
• hence khat has less reinforcing properties than other stimulants such as
amphetamine and cocaine when taken for short period

• Khat Neurotoxicity
– khat/cathinone induces the release of dopamine from
presynaptic storage sites 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
• similar to the neurotoxic effect of chronic amphetamine
administration on the dopaminergic innervations of caudate,
inducing their degeneration
 Animals’ Behavioural Studies

• 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)
• the behavioural pharmacology is of particular interest
– Since the characteristic property of khat chewing is stimulation of the CNS
Motor and Stereotyped
Activity
• Kalix was the first to find an increase in the locomotor activity both in
rats and in mice following parenteral administration of cathinone
– Subcutaneous administration of cathinone in rats and mice markedly
increased spontaneous locomotor activity of the animals
 – potency of cathinone was almost comparable with (+)-amphetamine
– Zelger etal demonstrated that cathinone was less potent than
amphetamine
• role of dopaminergic mechanisms in the motor effects of cathinone
has been confirmed
– by the findings that intracerebroventricular administration of the drug or
its bilateral microinjection into the nucleus accumbens elicit a dose-
related increase in locomotor activity in rats
– but failed to demonstrate this effect when administered into the
substantia nigra in rats
• Striatal tissue is essential for the stereotyped oral activities induced by
amphetamine, and because compulsive licking and gnawing had indeed
been observed upon administration of cathinone
• In contrast,the hypermotility produced by compounds of the amphetamine
type is believed to be mediated by the nucleus accumbens
• Khat extract induced head twitches in mice in a dose-dependent
manner
• depressed the locomotor activity also in a dose-dependent manner
– methysergide,a nonselective blocker of serotonin receptors, was found
capable of depressing the twitch response but not the spontaneous
activity
• it is assumed that serotonin play role in mediating some of the motor
effects of khat
– But dopaminergic transmission might underlie the effects of khat extract
on spontaneous activity,but not head twitches
Analgesia
• Cathinone shares analgesic properties with other psychostimulant
substances
– reduces the motor reaction aroused by painful thermal or irritative
stimuli,hence showing an inhibitory effect on the pain perception
 – 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)
• increase the reaction time of mice in the hot plate and in the tail flick test
– Cathinone is also active in the writhing test, however, quite high doses
are needed to suppress the pain reaction under these conditions
• characteristic for psychostimulant analgesics which,in contrast to true
analgesics, are generally more potent in the hot plate than in the writhing
• 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
Feeding
• Anorexia is a consequence of khat chewing
– alleviate the sensation of hunger
– cathine (norpseudoephedrine) and norephedrine widely used as
appetite suppressant in modern world
• Both isomers of cathinone and cathine cause a
– decrease in rats’ food intake when acutely administered and also a loss
in body weight when given chronically at intracerebroventricular doses
of 300 and 500 μg per animal respectively
– in terms of potency amphetamine>cathinone>cathine
• On the other hand,when cathinone was administered to rats via the
intergastric route,
– reported to be a more potent anorectic than amphetamine and cocaine
– within a week there was development of tolerance to this effect of
cathinone
– the weight reducing effect disappeared within 3–4 weeks
• cathine and norephedrine have a potency of one tenth that of cathinone
• Two models have been proposed to explain the reduction in food
intake
– appetitive behaviour model
• which results in a failure to seek food

– consummatory behaviour model

• to eat it
• Tolerance is mediated by a compensatory increase in the motivation
to eat
– Nencini et al. suggested that tolerance to the anorectic effect of
cathinone
• a sensitization to endogenous kappa-opiate mediated activation of feeding
Addiction Model
• Self administration
– Johanson and Schuster (1981) compared the ability of
• i.v. L-cathinone, DL-cathinone, and D-amphetamine in maintaining
responding
• Results showed that,relative to amphetamine, lower doses of L-
cathinone maintained responding
• whereas the function for DL-cathinone was shifted to the right with
respect to amphetamine
• This finding is consistent with the notion that in the case of
cathinone,the maximal pharmacological activity is owned by the L-
steroisomer
– Taken into account the well-established key role of the
dopaminergic transmission in the positive reinforcing effects of
psychostimulants
• it is expected that dopamine antagonists should affect cathinone
self-administration
 +

– pretreatment with D1 selective antagonist SCH-23,390

» causes a significant increase in the number of infusions,
– whereas D2 antagonist spiperone determined only a slight
increase in the self-administration
– Note that in these conditions an augmentation of the number of
infusions is usually interpreted as a discount of the reinforcing
properties of the drug
• Discriminative Stimulus
Properties
– (+) Amphetamine trained rats responded as if they were given (+)
amphetamine when various doses of cathinone were administered ip
– 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
– Moreover,direct microinjection of cathinone into the nucleus accumbens
(NAc) was reported to produce discriminative stimuli
– Cathine was also shown to have discriminative stimulus properties in a
two choice food motivated, drug discrimination paradigm
– Recently,reaserchers (2006) have demonstrated that when cathinone
was given before or concurrently with cocaine to rats in a drug
discrimination procedure,the cocaine dose effect function was shifted to
the left
• suggesting cathinone generalizes to cocaine
• Conditioned Place
Preference
– is a method of assessing the rewarding and motivational effects of
drugs of abuse
– 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
– Furthermore,intracerebroventricular injection of cathinone to rats, when
paired with confinement in the non-preferred side of the conditioned
place preference apparatus, increased the time spent on that side
• which suggest that this behaviour is of central in origin
– It is generally believed that cathinone-induced conditioned place
preference is mediated by dopaminergic neurons
• supported by evidence that pre-treatment with a dopamine release
inhibitor attenuates place preference induced by cathinone
• AMPHETAMINE LIKE
– HYPERMOTILITY
– STEREOTYPED
– FOOD SUPPRESSION
– IPSILATERAL ROTATION
• COCAINE LIKE
– SELF ADMINISTRATION IN MONKEY
– -CONDITIONED TEST AVERSION
• SHARED
– ANALGESIA
– ANOREXIA
– DISCRINATI
– PLACE REFERNCE
 Suggested Future
Research with Chronic
Khat Users
• Multiple areas of neurocognitive deficit have been identified with chronic
users of stimulants, such as amphetamines and methamphetamines
• A substantial body of evidence has demonstrated a wide range of learning
and memory impairments in chronic amphetamine and methamphetamine
users
• Recent evidence from rodent research implicates a similar association
– between daily khat use and spatial learning and memory
– future studies examining these same domains of cognitive functioning in
chronic khat users and abstinent khat users appears to be warranted
• it would be worthwhile to investigate the potential role of hormones
(particularly estrogen) as mediating factors
– A number of recent studies in both humans and non human primates
suggest that changes in DA receptor availability may be involved in
 variation in symptoms of various neuropsychiatric disorders
across the menstrual cycle,including differences in sensitivity
to the abuse-related effects of stimulants
• Pharmacogenetics related to drug response and human
molecular genetics plays as an intervening variable in
characterizing the response to addictive substances,
including
– opiates, cocaine,and stimulants
– therefore,it creates another emerging area of considerable
interest in stimulant research and addiction.
– Particularly salient for khat researchers is the role that genetic
influences may play in the neurocognitive domains of impulsivity,
risk taking, and stress responsivity which are central to the
investigation of stimulant drugs such as khat