Neuropsychiatric Disease and Treatment
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Catha edulis chewing effects on treatment
of paranoid schizophrenic patients
Mohamed-i Kotb el-sayed
hatem-K amin
Department of Biochemistry
and Molecular Biology, Faculty
of Pharmacy, helwan University,
ain helwan, helwan, cairo, egypt
Background: The current study’s aim is to evaluate the possible interaction effects of khat
chewing on treatment of paranoid schizophrenic patients.
Patients and methods: In the study group, 42 male subjects suffered from paranoid
schizophrenia and were classified according to their khat chewing habits into two subgroups:
either khat-chewer subgroup (SKc; n=21; r=11, h=10) or non-khat-chewer subgroup (SNKc;
n=21, r=11, h=10). Each subgroup was further subdivided according to type of treatment into
r (risperidone) and h (haloperidol). Healthy male subjects (37) were subdivided into healthy
khat-chewer as positive controls (HKc, n=17) and healthy non-khat-chewer as negative controls
(HNKc, n=20). Plasma dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid,
5-hydroxytryptamine (serotonin), 5-hydroxyindoleacetic acid, epinephrine, and norepinephrine
were estimated.
Results: ANOVA and post hoc analysis showed that dopamine was illustrating significant
elevation in all khat chewing groups. DOPAC was illustrating significant decrease in all khat
chewing groups with an interesting outcome showing significant increase in DOPAC in SNKcr
group due to risperidone effect. Homovanillic acid, serotonin, hydroxyindoleacetic acid, and
norepinephrine were illustrating significant elevations in all khat chewing groups. Epinephrine
was illustrating significant elevation in all chewers than non-chewers groups. Unexpected significant decrease in epinephrine in the SNKcr group indicated that risperidone drug is decreasing
epinephrine through indirect mechanism involving calcium.
Conclusion: Khat chewing in schizophrenic patients is contraindicated because it aggravates
the disease symptoms, attenuates all used treatment medications, and deteriorates all biochemical markers of the patients.
Keywords: epinephrine, norepinephrine, dopamine, serotonin, schizophrenia, khat
Introduction
correspondence: Mohamed-i Kotb
el-sayed
Department of Biochemistry and
Molecular Biology, Faculty of Pharmacy,
helwan University, ain helwan, helwan,
PO Box 11790, cairo, egypt
Tel +20 114 040 0767
Fax +20 2 2554 1601
email mohamed.kotb71524@gmail.com
Schizophrenia is a severe neuropsychiatric mental disorder caused by inherent dysfunction of the brain, occurs in about 1% of the population, and is characterized by
hallucinations, delusions, and thinking or speech disturbances. Schizophrenia presents
positive symptoms such as auditory hallucination, mood abnormality, lack of insight
into the illness delusions, and initial vagueness in speech, whereas the negative symptoms present emotional apathy, lack of drive, and social withdrawal.1
Functional and structural disconnectivities are among the most reproducible neurophysiological abnormalities associated with schizophrenia and refer to macroscopic
neuroanatomical dynamics and are mainly measured by diffusion-tensor imaging,
tractography, volumetric magnetic resonance imaging, and magnetization-transfer
imaging.2
Neuroinflammatory mechanisms implicated in schizophrenia include glial (astroglial loss and activation, microglial activation, and priming), immunologic (cytokines,
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© 2015 Kotb El-Sayed and Amin. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0)
License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further
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Kotb el-sayed and amin
chemokines, and prostaglandins), and oxidative (reactive
oxygen and nitrogen species) aberrations. These mechanisms
are thought to result in glutamatergic (hypofunction) and
dopaminergic (limbic hyperfunction, frontal hypofunction)
dysregulations.3
Schizophrenia can be genetic, although in many cases of
identical twins, only one sibling developed schizophrenia.
Another postulation is the dopamine (DA) receptor’s abnormality, mainly D2 receptors. Other factors could implicate in
schizophrenia such as toxins, family environment, migration,
and socioeconomic factors.1
Khat leaves (Catha edulis Forsk) has a stimulant effect and
comes from West Asia and countries bordering the Red Sea in
east coast Africa. Khat is traditionally consumed by keeping
the slowly chewed leaves in the side of the cheek, releasing the
Khat active constituents, and swallowing with saliva.4,5
High consumption of Khat resulted in a state resembling
paranoid schizophrenia or maniac behavior. A short-lived
schizophrenic from psychotic illness and mania due to excessive khat chewing was documented presenting psychotic
paranoid delusions and manic-like psychosis.6–10
Khat contains cathinone and cathine, which have sympathomimetic effects mediated through cathinone-induced
catecholamine secretion by releasing catecholamines from
presynaptic storage sites, and inhibit catecholamines reuptake
and also monoamine oxidase enzyme (MAO). These amines
include DA and serotonin.11 Khat may have also MAO
inhibiting action.12
DA or β-(3,4-dihydroxyphenyl)ethylamine is an endogenous neurotransmitter catecholamine transmitting signals
between neurons that are separated by a synaptic cleft.13
Serotonin (5-hydroxytryptamine [5-HT]) is an indolamine
monoamine neurotransmitter in the central nervous system
(CNS), mainly in the basal ganglia and limbic system.14,15
Khat psychostimulant activity is mediated through release
of DA and 5-HT.16 The metabolism of serotonin is primarily done by MAO. The principle metabolite of serotonin is
hydroxyindoleacetic acid (HIAA).17
Intermittent oral administration of C. edulis extract
(200 mg/kg) induces DOPAC significant reduction with
increment of urinary catecholamine (HVA) indicating amine
oxidase activity inhibition.4,18,19
Khat effect is due to DA release rather than 5-HT
release.16,20 Cathinone (beta-keto analog of amphetamine) is
the main psychoactive alkaloid of fresh khat leaves and has
indirect sympathomimetic mechanism through modulating
the release of catecholamines, mainly DA from storage sites
in the synaptic terminal, and indirectly affects electrolyte
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balance by increasing copper and calcium and decreasing zinc plasma concentrations. Cathinone (-) isomer is
approximately three times more potent than (+) isomer at
DA terminals in the CNS.12,20–23
It was reported that cathinone may act on noradrenaline
transporters.24 Schizophrenia is treated by neuroleptic drugs,
which have an antipsychotic effect; haloperidol drug binds
preferentially to D2 and Alpha 1 receptors at low dose
(ED50 =0.13 mg/kg and 0.42 mg/kg, respectively) and
5-HT2 receptors at a higher dose (ED50 =2.6 mg/kg) with
pronounced DA antagonism. Haloperidol, a non-selective
DA antagonist, was found to reduce cathinone-induced biting
and licking movements.25 Risperidone is a second-generation
antipsychotic with more pronounced serotonin antagonism
than DA antagonism.26
This study was aimed to evaluate the interference of
Khat chewing with antipsychotic medications by assaying
DA, serotonin, epinephrine, norepinephrine, and their related
metabolites.
Patients and methods
ethical consideration
Written consent was taken from all participants as a routine
admission protocol. As the hospital is a mental and psychiatric health hospital (Al-Amal Hospital) in Sana’a, Yemen,
it is a charge-free governmental hospital, and all patients
were informed that their diagnosis and biological samples
taking during diagnosis will be recorded and could be used
anonymously for education and research purposes.
The research protocol followed all the ethical regulations
stated by the scientific research ethical committee in the
university. Protocol, consent format, recorded information,
and sampling procedures were approved by the committee.
The university and the hospital ethical regulations prohibit
disclosing names and personal information of any patients
without legislative procedure or applying any invasive protocol was not needed for the diagnosis such as tissue biopsy.
All our blood samples were collected during regular and
routine diagnosis procedure of patients without using any
invasive protocols. The authors are confirmed that they did
not administer khat in purpose for the patients. Khat groups
were classified by asking the patients during patient history
recording as khat is a common traditional medicine and being
used routinely in a widespread manner in Yemen.
study design
The current study was carried out as a case–control study.
In all, 79 Yemeni male subjects were recruited (aged
Neuropsychiatric Disease and Treatment 2015:11
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39.64±0.44 years, body mass index averaged 8±1.2 kg/m2,
and were nonsmokers), out of which 42 subjects suffered from
late-onset paranoid schizophrenia. They were examined and
treated during temporary remission in the psychiatric department and were classified according to their khat chewing
habits into two main subgroups: either khat-chewer subgroup
(SKc; n=21, r=11, h=10), patients chewed khat during treatment (when they were discharged for holidays), or non-khatchewer subgroup (SNKc; n=21, r=11, h=10). Each subgroup
further subdivided according to type of treatment into r (risperidone) and h (haloperidol). The daily doses of risperidone
and haloperidol were 5 mg and 10 mg, respectively.
Healthy subjects who chewed khat and were not suffering
from paranoid schizophrenia were taken as positive controls
(HKc, n=17). Healthy subjects who did not chew khat and
were not suffering from paranoid schizophrenia were taken
as negative controls (HNKc, n=20).
All subjects (in groups HKc or SKc) were demonstrating
khat chewing habits, determined as daily abuse with duration
of 4–8 hours, and khat chewing habit was highly comparable
within the patient groups in quantity (average 100–120 g).
Patients’ inclusion criteria considered age, sex, onset of
disease, previous readmission to hospital, past history of mental illness, family history of mental illness, and date of admission of each patient, while the exclusion criteria excluded
dementia or mental retardation diagnosis, any intermittent
therapy (on/off), and any patient exposed to severe drug side
effects, shifted from one drug to another, or administered any
concomitant psychotropic medications.
sociodemographic and clinical
characteristics
On admission, all patients underwent a routine clinical
interview with specialist psychiatrist to register psychotic
symptoms using the rating instrument that assesses even
different symptoms of schizophrenia instrument; positive and negative syndrome scale (PANSS)27 comprises
three components: positive (P), negative (N), and cognitive or general psychopathology (G). Positive syndrome
is composed of symptoms such as delusions, hallucinations, and disorganized thinking. Negative syndrome is
characterized by deficits in cognitive, affective, and social
functions, including blunting affect and passive withdrawal.
General psychopathology is composed of many deficits in
cognition such as disorientation, poor attention, lack of
insight, and active social avoidance. Positive and negative subscales each contain seven items (P1–P7, N1–N7);
General psychopathology subscale contains 16 items with
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effects of khat chewing on schizophrenia treatment
the major emphasis on cognition (G1–G16). Diagnosis at
discharge was given according to the ICD-10 classification
of mental and behavioral disorders.28
sample collection
Venous blood samples were collected 2 hours after lunch
in the HNKc group, 1 hour after treatment in the SNKc
group, 1 hour after treatment and starting of continued khat
chewing in SKc, and 1 hour after starting of continued
khat chewing in HKc (they chewed the khat outside the
hospital before coming to outpatient psychiatric department
and then underwent blood drawing) using vacutainer. Blood
samples were collected on EDTA tubes and immediately
centrifuged at 3,500× g for 10 minutes, and separated plasma
was divided into six separated aliquots in Eppendorf (micro
centrifuge) tubes and stored at -70°C for later analysis of
DA (Cat No CEA851Ge), homovanillic acid (HVA) (Cat
No CED717Ge), 5-hydroxytryptamine (serotonin) (Cat No
CEA808Ge), 5-HIAA (Cat No CEB005Ge), epinephrine (Cat
No CEA858Ge), and norepinephrine (Cat No CEA907Ge)
using ELISA kits from Cloud-Clone Corp Company
(Houston, TX, USA) and following the manufacturer instructions, while 3,4-dihydroxyphenylacetic acid (DOPAC) was
measured using microdialysis-HPLC as described by Dethy
et al.29
Data analysis
Data were collected and analyzed using SPSS version 15
(SPSS Inc., Chicago, IL, USA). One-way ANOVA was used
to assess the difference between frequencies (the associations between khat chewing and paranoid schizophrenia).
Tukey’s post hoc test was used to test the difference between
subgroup means, and F value test tested the multivariate
effect of investigated subjects using multivariate Pillai’s
trace, Wilks’ lambda, Hotelling trace, and Roy’s largest
root tests. These tests are based on the linearly independent
pairwise comparisons among the estimated marginal means.
Pearson’s chi-squared test was used to test the significant
differences between PANSS scores from study baseline and
after 6 weeks and 12 weeks duration; Phi and Cramer’s V
were used as symmetric measures to evaluate the chi-square
correlation strength. Observed difference was considered to
be significant at P,0.05.
Results
All analyzed data in the ANOVA table (Table 1) and multivariate tests table (Table 2) are showing highly significant
correlations between groups and within groups.
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Kotb el-sayed and amin
Table 1 One-way aNOVa analysis showing correlation between groups and within groups
Dopamine
DOPac
hVa
serotonin
hiaa
epinephrine
Norepinephrine
Between groups
Within groups
Total
Between groups
Within groups
Total
Between groups
Within groups
Total
Between groups
Within groups
Total
Between groups
Within groups
Total
Between groups
Within groups
Total
Between groups
Within groups
Total
Sum of squares
df
Mean square
F
P-value*
21,635.444
947.772
22,583.215
26.917
12.567
39.484
1,060.951
63.133
1,124.084
140,676.456
8,380.961
149,057.418
21,429.771
3,436.963
24,866.734
1,879.219
1,524.224
3,403.443
24,655,933.049
339,146.419
24,995,079.468
5
73
78
5
73
78
5
73
78
5
73
78
5
73
78
5
73
78
5
73
78
4,327.089
12.983
333.284
0.000
5.383
0.172
31.271
0.000
212.190
0.865
245.353
0.000
28,135.291
114.808
245.065
0.000
4,285.954
47.082
91.032
0.000
375.844
20.880
18.000
0.000
4,931,186.610
4,645.841
1,061.419
0.000
Note: *The mean difference is signiicant at the P,0.05 level.
Abbreviations: ANOVA, analysis of variance; Sig, signiicance; DOPAC, 3,4-dihydroxyphenylacetic acid; HVA, homovanillic acid; HIAA, hydroxyindoleacetic acid.
Post hoc tests for all tested groups (multiple comparisons,
Tukey’s HSD) in Tables 3–5 show (Figure 1A) significant
elevation in DA in all khat chewing groups, while SKch and
SKcr groups are showing significant elevation in DA level
than HKc group, exhibiting the significant positive effect
of khat on DA increment in both SKch and SKcr groups.
DOPAC (Figure 1B) is illustrating significant decrease in
all khat chewing groups with an interesting outcome, the
unexpected significant increase in SNKcr group. HVA is
illustrating significant elevation in all khat chewing groups;
SKch group is illustrating significant increase in HVA than
SKcr group (Figure 1C).
Serotonin (Figure 2A) is illustrating significant elevation
in all khat chewing groups with significant increase in both
SKch and SKcr groups, and HIAA (Figure 2B) is illustrating
significant elevation in all khat chewing groups with significant increase in SKch and SKcr groups.
Norepinephrine (Figure 3A) is illustrating significant elevation in all khat chewing groups with significant increase in both
SKch and SKcr groups. Epinephrine (Figure 3B) is illustrating
significant elevation in all chewers than non-chewers. Another
interesting finding is encountered in the unexpected significant
decrease in epinephrine in the SNKcr group, indicating that
risperidone drug is possibly decreasing plasma epinephrine.
Table 6 shows the improvement/deterioration in symptoms
according to khat chewing within 12 weeks duration. Table 7
shows the sociodemographic and clinical characteristics.
Discussion
In vitro studies reported that cathinone may act on noradrenaline transporters and serotonin receptors and induce motor
activities and was found to have four times higher affinity
than racemic amphetamine for serotonin receptors in isolated
rat fundus.24,30,31
Table 2 Multivariate tests
Pillai’s trace
Wilks’ lambda
hotelling trace
roy’s largest root
Value
F
Hypothesis df
Error df
P-value
Partial eta squared
2.566
0.001
116.720
110.248
10.696
39.703
218.100
1,118.228
35.000
35.000
35.000
7.000
355.000
284.273
327.000
71.000
0.000
0.000
0.000
0.000
0.513
0.775
0.959
0.991
Notes: each F tests the multivariate effect of subject. These tests are based on the linearly independent pairwise comparisons among the estimated marginal means.
Abbreviation: Sig, signiicance.
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effects of khat chewing on schizophrenia treatment
Table 3 effects of khat chewing and paranoid schizophrenia on plasma levels of dopamine and its related metabolites (DOPac and
hVa), in comparison with healthy non-khat-chewer subjects
Variables
Dopamine (pg/ml)
DOPac (ng/ml)
hVa (ng/ml)
Healthy subjects (n=37)
Schizophrenic subjects (n=42)
HNKc
(n=20)
HKc
(n=17)
SNKc (n=21)
SNKch (10 mg/day)
(n=10)
SNKcr (5 mg/day)
(n=11)
SKch (10 mg/day)
(n=10)
SKcr (5 mg/day)
(n=11)
24.30±0.63
3.0±0.10
9.29±0.17
50.5±1.24***
2.46±0.15**
12.56±0.31***
23.2±1.11
2.03±0.05▼▼▼
10.05±0.39
19.82±0.48▼
2.97±0.07
9.72±0.10
61.3±1.25***,◊◊◊
1.48±0.05*,◊◊◊
19.25±0.23***,◊◊◊
57.0±0.93***,◊◊◊
1.65±0.08***,◊◊◊
17.3±0.19***,◊◊◊
SKc (n=21)
Notes: each value represents as mean ± seM. *For comparison between khat-chewers and non-chewers between groups and within groups, ▼for comparison between
sNKch or sNKcr and hNKc, and ◊for comparison between SKch or SKcr and HKc. Note that mostly rest of all other comparisons were signiicant. *,▼P,0.05; **P,0.01;
***,▼▼▼,◊◊◊P,0.001.
Abbreviations: s, schizophrenic; K, khat; c, chewing; N, non; r, risperidone; h, haloperidol; DOPac, 3,4-dihydroxyphenylacetic acid; hVa, homovanillic acid; seM, standard
error of the mean.
Repeated doses of amphetamines 5 mg/kg twice daily
for successive 5 days in rats induce behavioral sensitization
phenomenon due to DA release.32,33
In addition, administration of khat or cathinone
to rats after unilateral lesion of substantia nigra with
6-hydroxydopamine induced ipsilateral rotation, in a similar
fashion to amphetamine, suggesting that they have indirect
DA-releasing actions on the CNS.34
Several preclinical studies on rats treated with cathinone
(3.2 mg/kg) showed increase in DA efflux measured by
microdialysis (55%), and the behavioral effect of cathinone in
animals is attributed to increasing the level of DA release or
inhibiting its reuptake,12,35,36 and this might explain the khatinducing behavioral sensitization phenomenon. Locomotor
sensitization and deficits in prepulse inhibition induced by
psychostimulants are two paradigms that have been widely
studied as animal behavioral models of amphetamine psychosis. Repeated oral administration of a standardized C. edulis
extract (containing a dose of 1 mg cathinone per kilogram
body weight) or (-) cathinone (1.5 mg/kg) to rats induced
a strong locomotor sensitization and led to a gradual deficit
in prepulse inhibition.4
Chronic administration of either the whole khat extract
or cathinone in rats results in a significant depletion of DA
in several brain areas, particularly on the nigrostriatal DA
terminal projections,4 and exhibits the same neurotoxic effect
of chronic amphetamine administration on the dopaminergic
innervations of caudate, inducing their degeneration.37
Cathinone has to penetrate to intraneuronal sites in order
to evoke release, and the uptake inhibitors prevent this
penetration; therefore, DA release inhibitors or pretreatment with the relatively selective dopaminergic neurotoxin
6-hydroxydopamine significantly attenuates cathinoneinduced effects,25,32 while Zelger et al38 have demonstrated
that pretreatment with reserpine (monoamine store depleting agent) or methyl-p-tyrosine (a catecholamine synthesis
inhibitor) abolished locomotor and increased stereotyped
behavior induced by cathinone. On the other hand, pretreatment with haloperidol, a non-selective DA antagonist, was
found to reduce biting and licking movements caused by
cathinone.
In vivo microdialysis in rats after acute intraperitoneal
administration of cathinone, in a similar fashion to
amphetamine, increased levels of DA but decreased levels
Table 4 effects of khat chewing and paranoid schizophrenia on plasma levels of serotonin (5-hT) and its metabolite (hiaa), in
comparison with healthy non-khat-chewer subjects
Variables
Healthy subjects (n=37)
Schizophrenic subjects (n=42)
HNKc
(n=20)
SNKc (n=21)
SKc (n=21)
SNKch (10 mg/day) SNKcr (5 mg/day)
(n=10)
(n=11)
SKch (10 mg/day) SKcr (5 mg/day)
(n=10)
(n=11)
HKc
(n=17)
serotonin (5-hT) (ng/ml) 199.40±2.78 262.18±2.05*** 221.3±1.89▼▼▼
5-hiaa (nmol/l)
58.10±1.18 85.41±1.62*** 64.3±4.19
206.36±3.16
59.09±1.42
309.5±5.03***,◊◊◊
99.6±1.8***,◊◊◊
297.6±2.27***,◊◊◊
93.82±0.93***,◊
Notes: each value represents as mean ± seM. *For comparison between khat-chewers and non-chewers between groups and within groups, ▼for comparison
between sNKch or sNKcr and hNKc, and ◊for comparison between SKch or SKcr and HKc. Note that mostly rest of all other comparisons were signiicant. ◊P,0.05;
***,▼▼▼,◊◊◊P,0.001.
Abbreviations: 5-hT, 5-hydroxytryptamine; hiaa, hydroxyindoleacetic acid; s, schizophrenic; K, khat; c, chewing; N, non; r, risperidone; h, haloperidol; seM, standard
error of the mean.
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Kotb el-sayed and amin
Table 5 effects of khat chewing and paranoid schizophrenia on plasma levels of norepinephrine and epinephrine, in comparison with
healthy non-khat-chewer subjects
Variables
Healthy subjects (n=37)
Schizophrenic subjects (n=42)
HNKc
(n=20)
SNKc (n=21)
HKc
(n=17)
SKc (n=21)
SNKch (10 mg/day) SNKcr (5 mg/day) SKch (10 mg/day) SKcr (5 mg/day)
(n=10)
(n=11)
(n=10)
(n=11)
Norepinephrine (pg/ml) 863.70±7.28 1,902.88±26.31*** 906.5±6.5
epinephrine (pg/ml)
108.95±1.42 115.12±1.23**
111.3±1.07
2,092.5±34.4***,◊◊◊
119.5±0.72**
889.45±2.96
102.72±1.13▼▼
2,041.45±13.3***,◊◊◊
113.45±0.64***
Notes: each value represents as mean ± seM. *For comparison between khat-chewers and non-chewers between groups and within groups, ▼for comparison between sNKch
or sNKcr and hNKc, and ◊for comparison between SKch or SKcr and HKc. Note that mostly rest of all other comparisons were signiicant. **,▼▼P,0.01; ***,◊◊◊P,0.001.
Abbreviations: s, schizophrenic; K, khat; c, chewing; N, non; r, risperidone; h, haloperidol; seM, standard error of the mean.
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Figure 1 effects of khat chewing and paranoid schizophrenia on plasma level of dopamine (A) and its related metabolites, DOPac (B) and hVa (C).
Notes: each value represents as mean ± seM. *For comparison between khat-chewers and non-chewers between groups and within groups, ▼for comparison between
sNKch or sNKcr and hNKc, and ◊for comparison between SKch or SKcr and HKc. Note that mostly rest of all other comparisons were signiicant. *,▼P,0.05; **P,0.01;
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Abbreviations: h, healthy; N, non; K, khat; c, chewing; s, schizophrenic; h, haloperidol; r, risperidone; DOPac, 3,4-dihydroxyphenylacetic acid; hVa, homovanillic acid;
se, standard error; seM, standard error of the mean.
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Neuropsychiatric Disease and Treatment 2015:11
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effects of khat chewing on schizophrenia treatment
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Figure 2 effects of khat chewing and paranoid schizophrenia on plasma level of serotonin (A) and its related metabolite hiaa (B).
Notes: each value represents as mean ± seM. *For comparison between khat-chewers and non-chewers between groups and within groups, ▼for comparison between sNKch
or sNKcr and hNKc, and ◊for comparison between SKch or SKcr and HKc. Note that mostly rest of all other comparisons were signiicant. ◊P,0.05; ***,▼▼▼,◊◊◊P,0.001.
Abbreviations: h, healthy; N, non; K, khat; c, chewing; s, schizophrenic; h, haloperidol; r, risperidone; hiaa, hydroxyindoleacetic acid; se, standard error; seM, standard
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of DA metabolite DOPAC in a dose-dependent manner,19
and similar to amphetamine, cathinone led to depletion of
serotonin and its corresponding metabolites in both anterior
and posterior striatum, which suggests that aggression in this
paradigm is enhanced presumably by decreasing the level of
serotonin and its metabolites.34
In human, khat induces hypomanic illness with grandiose delusions and paranoid or schizophrenic psychosis
with persecutory delusions associated with mainly auditory
hallucinations, fear, and anxiety, resembling amphetamine
psychosis,21,39 and induced psychotic states have been described
in over 20 case reports,40 while recent community-based stud-
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6WXGLHGJURXSV
+1.F
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6WXGLHGJURXSV
Figure 3 effects of Khat chewing and paranoid schizophrenia on plasma level of norepinephrine (A), and epinephrine (B).
Notes: each value represents as mean ± seM. *For comparison between khat-chewers and non-chewers between groups and within groups, ▼for comparison between sNKch
or sNKcr and hNKc, and ◊for comparison between SKch or SKcr and HKc. Note that mostly rest of all other comparisons were signiicant. **,▼▼P,0.01; ***,◊◊◊P,0.001.
Abbreviations: h, healthy; N, non; K, khat; c, chewing; s, schizophrenic; h, haloperidol; r, risperidone; se, standard error; seM, standard error of the mean.
Neuropsychiatric Disease and Treatment 2015:11
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Variables
Schizophrenic subjects (n=42)
SNKc (n=21)
Positive (P) (M ± seM)
Negative (N) (M ± seM)
general psychopathology
(g) (M ± seM)
Kotb el-sayed and amin
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Table 6 Positive, negative syndrome, and general psychopathology scales of patients with paranoid schizophrenia receiving haloperidol or risperidone across 12-week study period
SKc (n=21)
SNKch (10 mg/day) (n=10)
SNKcr (5 mg/day) (n=11)
SKch (10 mg/day) (n=10)
SKcr (5 mg/day) (n=11)
Baseline
Week 6
Week 12
Baseline
Week 6
Week 12
Baseline
Week 6
Week 12
Baseline
Week 6
Week 12
27±0.39
29.5±0.34
60.3±0.36
25±0.39
27.2±0.29**
55.8±0.38**
24±0.39
24.9±0.99**
51.8±0.38**
28±0.42
29±0.43
60.9±0.43
25±0.23**
27±0.44**
56±0.35**
23±0.44**
24±0.44**
50.8±0.32**
27.6±0.47
29.9±0.37
61.5±0.37
26.7±0.3
28.9±0.48
60.2±0.44**
26±0.29
29.1±0.43
58±0.42**
29.6±0.33
31.18±0.44
59.7±0.42
27.7±0.4
30.9±0.31
57±0.31**
27.2±0.35
29.6±0.41
54.9±0.25**
Notes: each value represents as mean ± seM. *For comparison between subjects within each group at 6 weeks or 12 weeks of treatment and baseline. **P,0.05.
Abbreviations: s, schizophrenic; K, khat; c, chewing; N, non; r, risperidone; h, haloperidol; seM, standard error of the mean; M, mean.
Table 7 sociodemographic and clinical characteristics
Variables
Schizophrenic subjects (n=42)
HKc
(n=17)
SNKc (n=21)
38.4±92
0.0±0.0
36.64±1.0
0.0±0.0
SKc (n=21)
SNKch (10 mg/day)
(n=10)
SNKcr (5 mg/day)
(n=11)
SKch (10 mg/day)
(n=10)
SKcr (5 mg/day)
(n=11)
39.9±1.4
1.5±0.16
40.18±0.6
2.09±0.25
42.1±0.56
3.5±0.30
43.09±0.6
3.36±0.33
2.5±0.16
2.54±0.15
0.0±0.0
0.0±0.0
1.6±0.16
1.54±0.15
No family history of mental and psychiatric illness for all subjects involved in the current study
all subjects involved in the current study were males
Note: each value represents as mean ± seM.
Abbreviations: s, schizophrenic; K, khat; c, chewing; N, non; r, risperidone; h, haloperidol; seM, standard error of the mean.
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age (years)
Onset of disease (paranoid schizophrenia
with depression) (years)
Previous readmission to hospital (times)
Family history of mental illness
sex
Healthy subjects (n=37)
HNKc
(n=20)
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ies showed that khat use is associated with severe psychiatric
problems.41
There are a number of reports of psychiatric disorders
secondary to khat chewing with features of manic-like
psychosis6 and paranoid psychosis.7,8
Accordingly, two cases of homicide and combined homicide and suicide have been reported following consumption
of khat.7,39
In addition to cathinone, other khat cathine alkaloid or
d-norpseudoephedrine has been identified as an additional
psychoactive ingredient with psychostimulant properties.42
Khat withdrawal syndrome includes dysphoria, depression, irritability, anxiety, poor concentration, hypersomnia,
fatigue, paranoia, akathisia, and drug craving.43,44
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.10
This study’s results come in agreement with all the previous
studies, as schizophrenic patients khat chewing groups (SKch
and SKcr) for treated patients showed significant increase in
DA, DA metabolite HVA, serotonin, serotonin metabolites
HIAA, epinephrine, and norepinephrine than schizophrenic
patients non-khat chewing groups (SNKch and SNKcr) and
control healthy groups (HNKc and HKc). This outcome was
explained by khat induction release effect on both DA and
serotonin through khat cathinone and cathine alkaloids.
This study revealed two interesting outcomes. The first
one was the significant increase in DOPAC in the SNKcr
group and was expected to show the same decrement pattern
like other non-khat-chewer group, SNKch, and this outcome
could be explained as risperidone treatment induced a decrement in plasma DA levels and increment in plasma DOPAC
in the schizophrenic patients.45 Khat chewing in the SKcr
group had compensated the induction effect of risperidone,
and the DOPAC plasma level was declined. This might
deeply explain the mechanism of action for risperidone
through affecting DA biosynthesis and metabolism.
The second interesting outcome was the marked significant decrease in epinephrine in the SNKcr group than other
groups, particularly SNKch and HNKc groups, and this
could be explained as serotonin concentration dependent can
increase Ca2+ and its effect is blocked by a broad-spectrum
5-HT antagonist (metergoline). Calcium triggers the exocytosis of chromaffin granules, releasing epinephrine into the
bloodstream.46–48 Risperidone is a 5-HT antagonist; therefore,
it blocks Ca2+ elevation by serotonin and consequently blocks
release of epinephrine into the bloodstream.
Neuropsychiatric Disease and Treatment 2015:11
effects of khat chewing on schizophrenia treatment
According to PANSS scores assessed at study startup,
after 6 weeks, and then after 12 weeks duration (Table 6),
khat chewing prohibited the improvements in SKcr PANSS
positive and PANSS negative and significantly deteriorated
the PANSS general scale.
This study showed two limitations: we could not confirm
the khat effect on SKch PANSS positive because the SNKch
group showed non-significant mild improvement and the
other limitation is the discontinuation of khat administration
during hospitalization periods.
In conclusion, khat chewing in schizophrenic patients is
contraindicated because it aggravates the disease symptoms,
attenuates all used treatment medications, and deteriorates
all biochemical markers of the patients.
Acknowledgment
We would like to express our gratitude to medical staff of
Al-Amal Hospital for their cooperation during the study.
Author contributions
Both authors were involved and contributed to the proposal
design, conception, and design of the manuscript; analyzed,
collected, assembled, and interpreted the data; provided the
study material, intellectual content, and graphics design; and
were involved in manuscript writing and the final approval
of the manuscript.
Disclosure
We declare no conflict of interests with any other party. This
study was completely covered financially by the authors,
and no grants or funds by any type either governmental or
industrial were received.
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