seminar on central effect of khat

8/8/2019 Seminar on Central Effect of Khat

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Central Effect

of Khat

BY ESHETU

MULISA,AAU,S

OP


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Introduction

The stimulant leaf khat (Catha edulis Forsk) comes from a treewhich 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


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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 ofAfrica

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 4000bundles (approximately 4000 kg) of khat

By 1945, according to the estimate of the British consul in Harer, about 3000 kgof khat were smuggled daily into the Protectorate


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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 moreSomalis 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 theGDP, on importing khat

In Djibouti

Since creation of Port (1969) by Yemeni Arabs

Now ubiquitos


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Prevalence of Use In Yemen of the 27 410 patients who visited clinic, 90.3% of the males and 58.6% ofthe 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


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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 CanadaLegal 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


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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 islow

and the threat to public health is not significant enough to warrant internationalcontrol, and did not recommend the scheduling of khat


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Pharmacology of KhatActive Constituents of Khat Leaf different chemical substances are found in the leaves of khat

Alkaloids,terpenoids,flavonoids,sterols,glycosides, Tannins (714% 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


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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 andnoradrenaline

Cathinone is

the constituent that is mainly responsible for central effects of khat andmost potent

is active constituent in fresh khat

Khat contains the ()-enantiomer of cathinone only which has the sameabsolute configuration as S-(+)-amphetamine


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Therefore,

environment, climate conditions, as well as local traditions connected withcultivation and harvesting determine the chemical profile and generalappearance 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 themarket 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


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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


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Only 7% or less of the absorbed ()- cathinone is excreted unchanged inthe urine

is mainly excreted in the form of norephedrine and cathine

amount of norephedrine excreted in urine is much higher than theamount ingested,

Indicates that () cathinone is also metabolized to R, S-() norephedrine

Cathine has been found in breast milk in several lactating women whowere chewing the leaves of khat


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Modes of Action of KhatOverview of Amphetamine Action

AMPH induces the release of catecholamines, but not ATP

two non-exclusive hypotheses that may explain the mechanism by whichAMPH redistributes vesicular monoamines to the cytosol

The weak base hypothesis

All sympathomimetics are weak bases with amine moieties that are capable ofaccepting protons with pKs in the range of ~8 to 10

Secretory vesicles are acidic; maintain a pH of 5.05.6

AMPH is a lipophilic weak base with a pK of 9.9 and is thus protonated in acidicorganelles 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


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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 itstyrosine hydroxylase-binding site from where it exerts feedbackinhibition


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Similarly the mechanism of AMPHs tyrosine hydroxylase inhibition at higherlevels remains unknown

although it has long been suggested to be due to feedback inhibition fromincreased 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


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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 toamphetamine

It has also been demonstrated that khat /cathinone promote release of 5-HT


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High doses of cathinone result in

depletion of dopamine and also have neurotoxic effecs on dopamineneurons

Long-term administration of cathinone deplete norepinephrine or serotonin

However in contrast to amphetamine, there is in vitro evidence thatcathinone-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 inrats

Cathinone, similar to amphetamines, has also been shown to inhibitmonoamine oxidase (MAO) activity in vitro


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level of the neurotransmitter in different brain regions was differentwhen khat extract is used instead of cathinone

may be due to the fact that

C. edulis contains (besides S-()-cathinone) othercompounds, such as cathine and different metabolites

The additional compounds existing in the crude extract mighthave substantially altered behavioural and neurochemical

effects


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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 evenexclusively 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

striatocortico limbic dopaminergic pathway Moreover,the dependence-producing potential,analgesia, and anorexic effects of

khat/cathinone are believed to be partly mediated via this pathway


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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 (311 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 isequivalent to a single dose)

Symptoms subsided spontaneously within about 8 hours of chewing

Drake (1988) also described a case of mania following prolonged chewing


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Admissions to hospital due to khat-induced psychosis are notinfrequent,

Presentations are frequently similar to an amphetamine-likepsychosis,with disturbed behavior

Banjaw et al. found that

that repeated oral administration of cathinone orC. edulisextract to

rats enhanced locomotor and exploratory activity and lead to a gradual

deficit in prepulse inhibition


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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 andreduced dopamine and its metabolites in anterior putamen

a significant decrease in the level 5-HT in the nucleus accumbens andits metabolite, 5-hydroxyindole acetic acid (5-HIAA) in the prefrontalcortex

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


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So C. edulis or cathinone exert its behavioural effects by dopaminein the mesostriatocortico limbic pathway

This pathway is believed to play a central role in the induction,maintenance and expression of sensitization following repeatedadministration 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 usingisolation induced aggression paradigm,in which repeated oraladministration of C. edulis or S-()-cathinone enhanced aggressivebehaviour of isolated rats

Neurochemical studies revealed depletion of serotonin and itscorresponding 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


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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 dueto its depletion of 5-HT Other mood disorders such as khat-induced behavioural

syndrome described as


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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 expenseof vital needs is described as a psychological dependence bymany researchers

In eastern African countries the prevalence of khat dependenceis estimated to be 515% of the population


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When using khat it takes about 23 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 frompresynaptic storage sites and

chronic administration of either the whole extract or cathinone(100 mg/kg) results in a significant depletion of dopamine inseveral 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


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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 StereotypedActivity

Kalix was the first to find an increase in the locomotor activity both inrats and in mice following parenteral administration of cathinone Subcutaneous administration of cathinone in rats and mice markedly

increased spontaneous locomotor activity of the animals


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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 thesubstantia nigra in rats

Striatal tissue is essential for the stereotyped oral activities induced by

amphetamine, and because compulsive licking and gnawing had indeedbeen observed upon administration of cathinone

In contrast,the hypermotility produced by compounds of the amphetaminetype is believed to be mediated by the nucleus accumbens


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Khat extract induced head twitches in mice in a dose-dependentmanner

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 spontaneousactivity

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 psychostimulantsubstances reduces the motor reaction aroused by painful thermal or irritative

stimuli,hence showing an inhibitory effect on the pain perception


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It produced analgesic effects in the tail flick test and hot plate test at alower dose (200 mg/kg and 600 mg/kg) and in acetic acid-inducedabdominal 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 dosesare needed to suppress the pain reaction under these conditions

characteristic for psychostimulant analgesics which,in contrast to trueanalgesics, are generally more potent in the hot plate than in the writhing

Cathine,a metabolite of cathinone in humans, has been shown to enhancethe 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 asappetite suppressant in modern world


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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 dosesof 300 and 500 g 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 ofcathinone

the weight reducing effect disappeared within 34 weeks

cathine and norephedrine have a potency of one tenth that of cathinone


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Two models have been proposed to explain the reduction in foodintake

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 motivationto 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


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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 thedopaminergic transmission in the positive reinforcing effects ofpsychostimulants

it is expected that dopamine antagonists should affect cathinoneself-administration


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+

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 reinforcingproperties of the drug


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Discriminative StimulusProperties (+) 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 butnot 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 tothe left suggesting cathinone generalizes to cocaine


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Conditioned Place

Preference is a method of assessing the rewarding and motivational effects ofdrugs 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 ipcathinone, similar to cocaine and amphetamine in rats

Furthermore,intracerebroventricular injection of cathinone to rats, whenpaired with confinement in the non-preferred side of the conditionedplace preference apparatus, increased the time spent on that side

which suggest that this behaviour is of central in origin


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It is generally believed that cathinone-induced conditioned placepreference is mediated by dopaminergic neurons supported by evidence that pre-treatment with a dopamine release

inhibitor attenuates place preference induced by cathinone


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AMPHETAMINE LIKE HYPERMOTILITY STEREOTYPED FOOD SUPPRESSION IPSILATERAL ROTATION

COCAINE LIKE SELF ADMINISTRATION IN MONKEY

-CONDITIONED TEST AVERSION SHARED ANALGESIA ANOREXIA DISCRINATI

PLACE REFERNCE


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variation in symptoms of various neuropsychiatric disordersacross 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 incharacterizing 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 geneticinfluences may play in the neurocognitive domains of impulsivity,risk taking, and stress responsivity which are central to theinvestigation of stimulant drugs such as khat


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seminar on central effect of khat

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