CNSCNS--stimulating and somatic effects of Khat stimulating and somatic effects of Khat

22ndnd KRP Int. Symposium 2011 Addis Ababa KRP Int. Symposium 2011 Addis Ababa

Rudolf Brenneisen Rudolf Brenneisen

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University of Berne, Switzerland University of Berne, Switzerland www.phytopharm.dkf.unibe.chwww.phytopharm.dkf.unibe.chrudolf.brenneisen@dkf.unibe.chrudolf.brenneisen@dkf.unibe.ch

Khat in SwitzerlandKhat in Switzerland

Customs confiscates: >775 kg (2009) Customs confiscates: >775 kg (2009) Ethnic groups, no street drugEthnic groups, no street drug

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Increase of potencyIncrease of potency

„Designer Cathinones“ „Designer Cathinones“

Cathinone, „natural amphetamine“Cathinone, „natural amphetamine“ Ephedrine Ephedrine

C H 3

(Ephedra)(Ephedra)

C H 3

N H Poten

cP

otenc

Methamphetamine, „ICE“Methamphetamine, „ICE“Methcathinone, „CAT“Methcathinone, „CAT“

cy, toxiccy, toxiccity

city

MephedroneMephedrone AmphetamineAmphetamine

3

Decrease of potencyDecrease of potency

** Inactive Inactive d ti d t d ti d t

Withering, drying, Withering, drying, storagestorage

SS--((--))--Cathinone (1975) Cathinone (1975) 30% 30% SS--(+)(+)--AmphetamineAmphetamine

oxydation products oxydation products

Pote

Pote

**

XX--2020°°C, monthsC, months

i /i ii /i i

ency, tox

ency, tox**

**In vitro/in vivo In vitro/in vivo ketoreduction ketoreduction (hours(hours--days)days)

xicityxicity

S,SS,S--/RR/RR--(+)(+)--Norpseudoephedrine, „Cathine“ Norpseudoephedrine, „Cathine“ (1887, 1930, 1986)(1887, 1930, 1986)

ON H 2

O H**

**

4

C H 3

R,SR,S--((--))--Norephedrine (1979)Norephedrine (1979)

Mechanism of CNS actionMechanism of CNS action

Khat chewing Khat chewing bolus bolus alkaloid extraction alkaloid extraction absorption absorption via oral mucosavia oral mucosa and GIT and GIT interaction with dopaminergic, interaction with dopaminergic, noradrenergic and serotonergic system noradrenergic and serotonergic system mesolimbic mesolimbic reward system reward system

CathinoneCathinoneDopamine Receptor

Modulation of of neuronal circuits

Euphoria, flash, etc.

CocaineCocaine

THCTHCNicotineNicotine

BDsAlcoholAmphetamines

Opioids

Dopamine

circuits ,

Mesolimbic Dopamine PathwayNucleus accumbens ATV

NoradrenalineGABAECs

Endorphins

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Gambling, food, sex, tv, work, money, Gambling, food, sex, tv, work, money, music, joke, sports car, nice face, etc.music, joke, sports car, nice face, etc.

Central and peripheral effects Central and peripheral effects Khat Khat vs.vs. CathinoneCathinone

Khat, ManKhat, Man Cathinone, AnimalCathinone, Animal

Anorexia*Anorexia* AnorexiaAnorexiaInsomnia*Insomnia* RestlessnessRestlessnessHyperactivity*Hyperactivity* HypermotilityHypermotilityyp yyp y yp yyp yExcitation*Excitation* Stereotyped oral activityStereotyped oral activityAnalgesia*Analgesia* AnalgesiaAnalgesiaEuphoria*Euphoria* --Logorrhea*Logorrhea* --HyperthermiaHyperthermia**** HyperthermiaHyperthermiaRespirationRespiration**** Oxygen consumptionOxygen consumptionMydriasisMydriasis**** MydriasisMydriasisArrhythmiasArrhythmias**** Pos. inotropic & chronotropic effectsPos. inotropic & chronotropic effectsHypertensionHypertension**** HypertensionHypertensionC ti tiC ti ti ******ConstipationConstipation****** --Craving*Craving* SelfSelf--administrationadministration

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* Cathinone* Cathinone ** Ind. SM (NA** Ind. SM (NA, NPE und NE) , NPE und NE) *** Tannins*** Tannins

Khat = natural amphetamine (1)Khat = natural amphetamine (1)

Clinical evidence from RDP trialsClinical evidence from RDP trials

ARCI

7[Widler et al, Clin Pharm Ther 1994][Widler et al, Clin Pharm Ther 1994]

Khat = natural amphetamine (2)Khat = natural amphetamine (2)

Clinical evidence from RDP trialsClinical evidence from RDP trials

VAS

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Khat = natural amphetamine (3)Khat = natural amphetamine (3)

Clinical evidence from RDP trialsClinical evidence from RDP trials

Cathinone plasma levels

9[Brenneisen et al, J Liq Chromatogr 1991; [Brenneisen et al, J Liq Chromatogr 1991;

Mathys, PhD thesis 1993]Mathys, PhD thesis 1993]

Cathinone vs. amphetamineCathinone vs. amphetamine

Locomotor activity, ratLocomotor activity, rat

Effect qualitatively amphetamine, quantitatively 1/3Indirect sympathomimetic drug

10[Gugelmann et al, Experientia 1985][Gugelmann et al, Experientia 1985]

Toxicity (1)Toxicity (1)

Acute:Acute:RReactive, mild depressions; anxiety, confusion;eactive, mild depressions; anxiety, confusion;

ffmanicmanic--like, schizophreniform and paranoid psychoses like, schizophreniform and paranoid psychoses (rare, excessive doses, predisposition).(rare, excessive doses, predisposition).

Chronic:Chronic: Chronic:Chronic:Agitation, appetite loss (malnutrition, susceptibility to Agitation, appetite loss (malnutrition, susceptibility to infections), insomnia, dayinfections), insomnia, day--night rhythm dysfunction, night rhythm dysfunction, t l th i ht lit h t l th i ht lit h tremor, lethargy, nightmares, personality changes, tremor, lethargy, nightmares, personality changes, emotional instability, reduced ability to concentrate, emotional instability, reduced ability to concentrate, liver dysfunction, tooth damages, ulcers, sexual liver dysfunction, tooth damages, ulcers, sexual dysfunctions, esophageal and gastric carcinomas (?).dysfunctions, esophageal and gastric carcinomas (?).

WHO „Khat Dependence“:WHO „Khat Dependence“:M d t b t ft hi d d i f t M d t b t ft hi d d i f t Moderate but often psychic dependence, reinforcement Moderate but often psychic dependence, reinforcement (cathinone); peripheral, sympathomimetic tolerance to (cathinone); peripheral, sympathomimetic tolerance to CNS effects; mild psychological withdrawal symptoms.CNS effects; mild psychological withdrawal symptoms.

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Toxicity (2)Toxicity (2)

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Toxicity (3)Toxicity (3)

Physical + social harm + risk of dependence Physical + social harm + risk of dependence

Max. score = 911 HeroineHeroine22 CocaineCocaine33 BarbituratesBarbiturates44 MethadoneMethadone

Max. score = 9

55 AlcoholAlcohol66 KetamineKetamine77 BenzodiazepinesBenzodiazepines88 AmphetaminesAmphetamines88 AmphetaminesAmphetamines99 TobaccoTobacco1010 BuprenorphineBuprenorphine1111 CannabisCannabis1212 SolventsSolvents1313 MethylthioamphetamineMethylthioamphetamine1414 LSDLSD1515 MethylphenidateMethylphenidate1616 Anabolic steroidsAnabolic steroids1717 GHBGHB1818 MDMAMDMA1919 Alkylnitrates/Alkylnitrates/--nitritesnitrites1919 Alkylnitrates/Alkylnitrates/--nitritesnitrites2020 KhatKhat

[Nutt, Lancet 2007][Nutt, Lancet 2007]13

Future researchFuture research Risks of coRisks of co--consumption (alcohol tobacco Cannabis consumption (alcohol tobacco Cannabis Risks of coRisks of co--consumption (alcohol, tobacco, Cannabis, consumption (alcohol, tobacco, Cannabis,

opioids,…)?opioids,…)?

Risks of longRisks of long term Khat exposure during pregnancy term Khat exposure during pregnancy Risks of longRisks of long--term Khat exposure during pregnancy term Khat exposure during pregnancy and lactation?and lactation?

Khat inducing seizures?Khat inducing seizures?

Cancerogenic potential of Khat chewing, e.g. buccalCancerogenic potential of Khat chewing, e.g. buccalmucosa and GIT? Genotoxicity?mucosa and GIT? Genotoxicity?

Pharmacology and toxicity of other Khat constituents, Pharmacology and toxicity of other Khat constituents, Pharmacology and toxicity of other Khat constituents, Pharmacology and toxicity of other Khat constituents, e.g. flavonoids and cathaedulins?e.g. flavonoids and cathaedulins?

Pharmacology and toxicity of designer cathinones Pharmacology and toxicity of designer cathinones Pharmacology and toxicity of designer cathinones, Pharmacology and toxicity of designer cathinones, e.g. 4e.g. 4--MMC?MMC?

Ethnopharmacological and therapeutic potential of Ethnopharmacological and therapeutic potential of

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Ethnopharmacological and therapeutic potential of Ethnopharmacological and therapeutic potential of Khat and khatamines, such as antimicrobial and Khat and khatamines, such as antimicrobial and cytotoxic properties?cytotoxic properties?

Chewing (khat) gum ?Chewing (khat) gum ?

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……

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