Advertisement
Browse Subject Areas
?

Click through the PLOS taxonomy to find articles in your field.

For more information about PLOS Subject Areas, click here.

  • Loading metrics

Khat Use Is Associated with Impaired Working Memory and Cognitive Flexibility

  • Lorenza S. Colzato ,

    colzato@fsw.leidenuniv.nl

    Affiliation Institute for Psychological Research and Leiden Institute for Brain and Cognition, Leiden University, Leiden, The Netherlands

  • Manuel J. Ruiz,

    Affiliation Institute for Psychological Research and Leiden Institute for Brain and Cognition, Leiden University, Leiden, The Netherlands

  • Wery P. M. van den Wildenberg,

    Affiliation Psychology Department, Amsterdam Center for the Study of Adaptive Control in Brain and Behaviour (Acacia), University of Amsterdam, Amsterdam, The Netherlands

  • Bernhard Hommel

    Affiliation Institute for Psychological Research and Leiden Institute for Brain and Cognition, Leiden University, Leiden, The Netherlands

Khat Use Is Associated with Impaired Working Memory and Cognitive Flexibility

  • Lorenza S. Colzato, 
  • Manuel J. Ruiz, 
  • Wery P. M. van den Wildenberg, 
  • Bernhard Hommel
PLOS
x

Abstract

Rationale

Khat consumption has increased during the last decades in Eastern Africa and has become a global phenomenon spreading to ethnic communities in the rest of the world, such as The Netherlands, United Kingdom, Canada, and the United States. Very little is known, however, about the relation between khat use and cognitive control functions in khat users.

Objective

We studied whether khat use is associated with changes in working memory (WM) and cognitive flexibility, two central cognitive control functions.

Methods

Khat users and khat-free controls were matched in terms of sex, ethnicity, age, alcohol and cannabis consumption, and IQ (Raven's progressive matrices). Groups were tested on cognitive flexibility, as measured by a Global-Local task, and on WM using an N-back task.

Result

Khat users performed significantly worse than controls on tasks tapping into cognitive flexibility as well as monitoring of information in WM.

Conclusions

The present findings suggest that khat use impairs both cognitive flexibility and the updating of information in WM. The inability to monitor information in WM and to adjust behavior rapidly and flexibly may have repercussions for daily life activities.

Introduction

The khat plant (Catha Edulis) is a flowering evergreen tree that grows at high altitudes. It is cultivated especially in East-Africa and the south west of the Arabian Peninsula, in countries such as Somalia, Kenya, Djibuti, Yemen, or Ethiopia. In those countries the chewing of khat is also very common; it is consumed as qat and kat in Yemen; eschat in Ethiopia; miraa, kijiti, gomba, mbachu or veve in Kenya; and as mairungi in Uganda.

Historically, khat leaves have been chewed since ancient times to alleviate fatigue, enhance work capacity, stay alert, reduce hunger, and to induce euphoria and enhanced self-esteem [1]; [2]. Khat has been appreciated for medical purposes too [3], and even for its aphrodisiac effects, but it is also used for recreational purposes [4]. It is habitually used in informal meetings (khat sessions) in which the participants are engaged in discussions and maintain social contact. During khat sessions, the leaves and the tender younger stalks of the plant are chewed slowly over several hours and they are kept in the side of the cheek until the mouth is filled with fresh leaves. The users then chew intermittently to release the active components and then spit out the residues [5].

The half life of khat is about 4 hours, depending on the amount of chewed khat. When the acute effects disappear, consumers experience feelings of depletion, insomnia, numbness, depression, lack of energy, and mental fatigue. Long-term, chronic (i.e. daily) use of khat is associated with increased blood pressure, development of gastrointestinal tract problems, cytotoxic effects on liver and kidneys, and keratotic lesions at the side of chewing [5].

Many authors have argued about the causal role of khat in exacerbating psychotic reactions. In psychotic patients, khat may aggravate thought disturbances (hallucinations and delusions), induce aggressive behavior, and create difficulties in treating these patients [6]; [7]. Regular users with a predisposition to psychotic symptoms, including schizotypal or schizoid traits and family disorders, also have an increased risk of khat-induced psychosis. The psychotic symptoms are abated rapidly when khat is withdrawn [8]; [9]. However, recently, Odenwald [10] challenged this assumption concluding that the causal relationship between general psychopathology and khat use remains unclear and that people with preexisting vulnerability should avoid using khat. Socio-economic and familiar problems may also arise in khat consumers [11]; [12]; [13]. Many men secure their daily portion of khat at the expense of vital needs, indicating dependence. Family life is harmed because of neglect, dissipation of family income, and inappropriate behaviour. In countries like Ethiopia or Kenya, khat-dependent individuals are the main group among those treated for drug problems [14].

The active ingredients of Catha Edulis are cathine (norpseudoephedrine) and cathinone (Benzoylethanamine). These alkaloids are similar in structure and pharmacological activity to amphetamines [15]. The acute effects of cathinone and cathine on neurotransmitters are basically comparable to amphetamines effects: both stimulate the CNS and suppress appetite. However, cathinone has a more rapid onset and a shorter half life than amphetamine. The two alkaloids act by increasing dopamine (DA), serotonin and noradrenaline [7]. For this reason khat is called a “natural amphetamine”. Even though the literature on the effect of Catha Edulis compounds on humans is scarce, khat is considered to increase blood pressure and heart rate, and is associated with euphoregenic and psychoestimulants effects [1].

Cathinone is probably the main contributor to the stimulant effect of khat. Cathinone is an unstable molecule that rapidly transformes into cathine. Cathine is a less powerful stimulant and the pharmacological conversion from cathinone to cathine causes the decrease of stimulating properties of khat leaves over time. Fresh leaves have a greater ratio of cathinone to cathine than dried ones [16]. Therefore, the fresh leaves have more psychoactive effects and a number of techniques are in use to slow down the degradation process (e.g., wrapping the khat in banana leaves). To provide consumers with fresh leaves, khat is delivered by air around the world, commonly no later than five days after been harvested. When the leaves are chewed, cathinone is absorbed through the buccal mucosa and the stomach. After absorption it is metabolically transformed into norephedrine [17]. The effects of oral administration of cathinone occur more rapidly than the effects of amphetamine; roughly 15 minutes as compared to 30 minutes in amphetamine. Cathinone increases levels of DA in the brain by acting on the cathecholaminergic synapses, delaying DA reuptake inactivation and/or enhancing DA release [18]; [15], in particular in the striatum [19]. However, it is important to note that the consumption of cathinone in pure form is not entirely comparable with chewing khat leaves.

Studies addressing the neurobiological mechanism underlying the use of khat are still missing as well as studies that have systematically investigated the long-term cognitive effects of chronic khat use. Nevertheless, given the similarity of khat and amphetamine in structure and pharmacological activity, it makes sense to assume that the long-term use of khat affects the same neurotransmitter and brain structures as the chronic use of amphetamine (see [20]). At a structural level, one may thus expect white matter abnormalities, lower cortical gray matter volume, and higher striatal volume. In particular, higher striatal volumes might reflect a compensation for toxicity in the dopamine-rich basal ganglia. At a functional level, in turn, chronic khat use is likely to be associated with reduced functioning of Dopamine D2 (DAD2) receptors in the striatum and dysfunctions in prefrontal cortex (PFC) and orbitofrontal cortex (OFC)—areas that have been shown to play major roles in cognitive control [21].

Interestingly, DA has a key role in WM processes [22]; [23] and in the ability to flexibly alter cognitive representations [24]. According to Moustafa et al. [25], the striatum serves as a gate to modulate when and when not to update information into PFC. Consistent with this idea, Siessmeier et al. [26] found that administering DA agents to healthy subjects leads to a correlation between DA uptake in the striatum and dorso-lateral PFC (DLPFC) BOLD activity, suggesting that the striatum might drive activity in the PFC. Moreover, a PET study showed that working memory capacity predicts dopamine synthesis capacity in the striatum [27]. Consistent with these findings, previous studies on chronic amphetamine users and mice provided evidence for impairment on WM due to amphetamine use [28]; [20]; [29]; [30]. Similarly, studies investigating patients with Parkinson's disease (PD), a neurodegenerative disorder characterized by severe DA depletion in the striatum, showed decrements for the flexible alteration of cognitive representations [24]. Along the same lines, there is evidence of decreasing mental flexibility due to amphetamine use [31].

Khat consumption in Eastern Africa has increased during the last decades and has become a global phenomenon spreading to ethnic communities in the rest of the world, such as in the Netherlands, United Kingdom, Canada, and the United States [14]. Amsterdam airport, where a large amount of khat arrives weekly, has become a European distribution point [32]; [13]. In the Netherlands, khat bundles are commonly sold in restaurants, grocery stores and smartshops, which makes this country a suitable platform to investigate the effects of the drug.

Surprisingly, only one study has systematically looked into cognitive impairments in khat users so far. Colzato et al. [33] reported that khat users exhibit impairments in the inhibition of overt manual responses assumed to rely on proper dopaminergic functioning [34]. The ability to inhibit unwanted thoughts and actions is commonly considered an important part of executive control, but it represents just one of a larger set of cognitive control functions. In an attempt to categorize the available concepts and measures in a coherent fashion, Miyake and colleagues have investigated the psychometric relationships between the tests and tasks that are commonly used to assess cognitive control [35]; [36]; [37]. Their findings suggest the existence of three major, separable control functions: the “inhibition” of unwanted responses, the “shifting” between tasks and mental sets (also called “flexibility”), and the “updating” (and monitoring of) working memory (WM) representations. Miyake et al. 's model has been previously used to investigate cognitive impairments among recreational users of cocaine and MDMA [38]; [39].

Given the link between khat use and impaired inhibitory control, the current study focused on the two remaining cognitive control functions; flexibility and updating. Importantly for the current study, the above mentioned links between DA and “updating” (and monitoring of) WM representations and mental flexibility on the one hand, and between DA and khat on the other, suggest that WM monitoring and mental flexibility are impaired in khat users. We tested both hypotheses by comparing khat users and matched khat-free controls in a task assessing the efficiency of monitoring information in WM and a task that taps into cognitive flexibility.

Materials and Methods

Participants

Forty young healthy adults (36 men and 4 women) were compensated for their participation. They constituted the two groups of 20 khat users and 20 khat-free controls. The sample was drawn from 50 adults in the Leiden and The Hague metropolitan area, who volunteered to participate in studies of behavioral pharmacology. Participants were recruited via ads posted on community bulletin boards and by word of mouth. Participants were selected via a phone interview. Based on the interview, we excluded 10 of the 50 potential participants because of current medication use.

We made sure that the users met the following criteria: (1) khat consumption by chewing route for a minimum of 1 year; (2) no clinically significant medical disease and (3) no use of medication. All khat users met more than four of the seven criteria that according to the American psychiatric Association DSM-IV and the World Health Organization (ICD-10) define addiction: tolerance, withdrawal, difficulty controlling the use, negative consequences for job, family and health, significant time or emotional energy spent in searching/consuming the drug, put off or neglected activities because of the use, and desire to cut down the use. None of the khat-free controls reported any history of past or current khat use.

Participants were asked to refrain from taking any psychoactive drugs for at least 24 hours before the test, not to consume alcohol on the night before the experimental session, and to have a normal night rest. Participant's compliance with the instruction was encouraged by taking a (not further analyzed) saliva sample test at the beginning of the session (cf. [38]; [40]).

The two groups were matched for ethnicity (100% African), age, sex, IQ, (measured by Raven's Standard progressive matrices (SPM); [41]) and alcohol and cannabis consumption. Even though khat was the preferred drug for users, some of them drink alcohol (7) on a weekly base and used cannabis (3) on a monthly base. Khat users and non-users reported to have never used LSD, MDMA, cocaine, amphetamine, barbiturates, ketamine, GHB or speed. Demographic and drug use information are provided in Table 1. Written informed consent was obtained from all participants after the nature of the study was explained to them. The protocol and the remuneration arrangements of 25 Euro were approved by the institutional review board (Leiden University, Institute for Psychological Research).

thumbnail
Table 1. Demographic characteristics and self-reported use of khat and other psychoactive drugs.

https://doi.org/10.1371/journal.pone.0020602.t001

Computerized tasks

The tasks used in this study have been previously employed to systematically investigate the neurotoxic effects of recreational MDMA use [30]; [39] and recreational use of cocaine [42]; [38]. Similar to these studies and following Miyake et al. [37], we defined cognitive flexibility as the ability to adapt and restructure cognitive representations in response to changing situational demands (cf., [43]). We used the N-back task (see, [44], for a recent review) to assess the operational component of WM and a task-switching design [45] to assess flexibility.

All participants were tested individually. Individual IQs were determined by means of a 30-min reasoning-based intelligence test (SPM). The SPM assesses the individual's ability to create perceptual relations and to reason by analogy independent of language and formal schooling; it is a standard, widely-used test to measure Spearman's g factor and of fluid intelligence in particular [41]. Participants provided a saliva sample, completed the SPM, and subsequently performed the behavioral tasks measuring cognitive flexibility and WM capacity. Participants were allowed to take a short break (maximal 10 minutes) between task blocks. The experiment was controlled by a PC attached to a 17-inch monitor with a refresh rate of 120 Hz. Participants were seated approximately 0.5 m from the screen.

N-back task (WM monitoring).

Participants performed two N-back tasks consisting of the sequential visual presentation (stimulus onset asynchrony 2000 ms; duration of presentation 1000 ms) of single letters (B, C, D, G, P, T, F, N, L). Participants had to press the left or right shift-key of the computer-keyboard when the target or the non-target appeared, respectively. Target definition differed with respect to the experimental condition. In the 1-back condition, targets were defined as stimuli within the sequence that were identical to the immediately preceding one. In the 2-back condition, participants had to respond if the presented letter matched the one that was presented two trials before. The 1-back, and 2-back tasks differ in their amount of memory load and demands on executive control for the processing of information within working memory. Each block consisted of four cycles of the same task.

Task switching (flexibility).

Participants responded to randomly presented rectangles or squares by pressing a left or right response button, respectively. The target stimuli contained a global dimension (i.e., the overal shape was either a rectangle or a square) and a local dimension (the overall shape consisted either of small squares or small rectangles). Three blocks of trials were administered, two training blocks in which the instruction (global or local) was constant across all trials, followed by the experimental block in which participants switched between the global and the local task. In one of the two training blocks, participants responded to the local figure, in the other block they responded to the global figure. The order of the training blocks was randomized across participants and each block consisted of 50 trials. In the third block consisting of 160 trials, participants alternated between predictable sequences of four “local” and four “global” trials). A cue indicated to which dimension (global or local) the participants should respond. Cues that related to the global (local) dimension consisted of a big (small) square, presented at one side of the target stimulus, and a big (small) rectangle, presented at the other side of the target stimulus. The color of cues and target was red. Both remained on the screen until a response was given or 2500 ms had passed. The time interval between presentation of the cue and of the target stimulus varied between 400 ms and 500 ms and the interval between responses and the next presentation of the cue varied between 900 ms and 1100 ms ms.

Statistical analysis

We adopted a significance level of p<.05 for all statistical tests. Independent samples t-tests were used to analyze binary comparisons and ANOVAs otherwise.

T-tests were performed for Group analysis of age, sex, IQ and alcohol, and cannabis consumption and in the N-back task to assess differences between khat users and khat-free controls. For switching performance mean RTs and proportions of errors (PE) were analyzed by means of ANOVAs using Target level (global vs. local), the Congruency between the stimuli on the two levels (congruent vs. incongruent), and Task switch (i.e., same vs. different target level as in previous trial: task repetition vs. alternation) as within-participants factor and Group (khat users vs. khat-free controls) as between-participants factor. Spearman correlation coefficients were computed between the degree of exposure to khat and cognitive performance in order to test whether the magnitude of cognitive impairments is proportional to the amount of khat consumed. Effect magnitudes were assessed by calculating partial Eta squared (η2p) for repeated measures ANOVAs.

Results

Participants

No significant group differences were obtained for age, t(38) = 0.306, p = 0.761, intelligence, t(38) = −0.973, p = 0.337, alcohol consumption, t(38) = 0.478, p = 0.521, or cannabis consumption, t(38) = 0.169, p = 1.00. Table 1 shows drug-use profiles for the two groups.

Tasks

The results per cognitive task are summarized below and in Table 2. The data of two male khat-users were excluded in both tasks because of their excessive error rates in the task-switching paradigm (PE>45%).

thumbnail
Table 2. Means responses latencies (in milliseconds), error rates (in percent), and standard deviations of all relevant measures for the N-back task and task switching.

https://doi.org/10.1371/journal.pone.0020602.t002

Task switching.

Analyses of Mean RT showed three reliable main effects (see Table 2). First, the effect of Task switch, F(1,36) = 38.30, p<.0001, MSE  = 7916.15, η2p  = 0.52, was due to that repeating the task allowed for faster responding than switching between target levels (475 vs. 537 ms). Second, the effect of Target level, F(1,36) = 23.52, p<.0001, MSE  = 8728.09, η2p  = 0.39, reflected the well-known global preference [46], that is, faster responses to globally than locally defined targets (480 vs. 532 ms). Third, the Congruency effect, F(1,36) = 7.46, p<.01, MSE  = 10881.70, η2p = 0.17, indicated interference from the non-target level, that is, faster responses if the stimulus at the currently irrelevant level was congruent (e.g., a global square shape consisting of local squares) with the present target than if that stimulus was incongruent (e.g., a global square consisting of local rectangles; 489 vs. 522 ms, respectively).

More important for present purposes, the size of the Switch effect varied by Group, F(1,36) = 5.68, p<.05, MSE  = 8073.45, η2p  = 0.14: khat users showed more pronounced switching costs (i.e., a greater difference in RT between alternation trials and repetition trials) than khat-free controls. No other interaction was reliable.

Analyses of error rates revealed three reliable main effects. First, an effect of Group, F(1,36) = 73.91, p<.0001, MSE  = 3065.69, η2p  = 0.67: khat users committed significantly more errors than khat-free controls (21.3% vs. 4.0%). Second, the effect of Congruency, F(1,36) = 83.49, p<.0001, MSE  = 322.34, η2p  = 0.70, reflecting the interference of the irrelevant target level, as indicated by a smaller proportion of errors on congruent as compared to incongruent trials (3.3% vs. 22.1%). Third, the effect of Target level, F(1,36) = 5.17, p<.05, MSE  = 686.91, η2p  = 0.13, suggesting less errors to globally than locally defined targets (10.1% vs. 15.2%). No other effect was significant.

N-back task.

Mean RTs and accuracy—with the latter commonly being the more reliable measure in this task—were submitted to independent t-tests, see Table 2 for means. As expected, khat users committed significantly more errors in both the 1-back, t(36)  = 4.72, p = 0.001, and 2-back conditions, t(36)  =  .75, p = 0.001, see Table 2. RTs revealed no significant group differences in the 1-back, t(36)  = 0.53, p = 0.59, and 2-back conditions, t(36)  = 1.37, p = 0.18.

Correlations

To test whether the magnitude of cognitive impairments is proportional to the amount of khat consumed, we computed Pearson correlation coefficients between the individual life time khat exposure, hours chewing and number of bundles used in a khat session and switching costs, as well as accuracy in the n-back task. No significant correlations were obtained, probably due to the limited variability across users.

Discussion

This study tested, for the first time, whether khat use is associated with a detectable selective impairment in cognitive flexibility and WM. As expected, khat users showed increased switching costs, suggesting that recreational use is associated with impaired cognitive flexibility. Performance in khat users differed from performance in non-users also with respect to WM updating (the executive component of WM). We attribute these deficits to the possibility that long-term use of cathinone, the active ingredient of khat, is associated with dysfunctions in PFC and a reduced DA level in the striatum—the neurotransmitter that plays a crucial role in cognitive flexibility and updating of WM [24]; [25]; [47]. Bearing in mind the similarity between cathinone and amphetamine, our results are also consistent with previous studies in humans showing impairments in WM [28]; [29]; [30]; [48] and cognitive flexibility [31] as consequences of long-term amphetamine and methamphetamine use.

Given that khat users committed significantly more errors also in the 1-back task, a condition that requires hardly any active maintenance of information, we suggest that khat use may be associated with impairment of the updating rather than the maintenance component of WM. Khat users may thus not necessarily process or store fewer items than khat-free controls but, rather, are less selective with regard to what they store [49]. In an N-back task, this would imply that khat users are less efficient in discriminating targets from non-targets, which means that non-targets are more likely to enter WM and interfere with target information.

Bearing in mind the similarity between cathinone and amphetamine, our results are also consistent with previous studies in humans showing impairments in WM [28]; [29]; [30]; [48] and cognitive flexibility [31] as consequences of long-term amphetamine and methamphetamine use. Together with our previous observation of impaired inhibitory control in khat users [33], this suggests that khat use may be associated with a general decrement in cognitive control. Another, not necessarily exclusive possibility is that the impairments on tasks measuring mental flexibility and WM were the result of transitory khat-induced withdrawal symptoms. Indeed, chronic khat users experience withdrawal symptoms during the first days, especially sleeping problems, depressive states, attentional problems, and intense cravings [5]. Moreover, given that cathine stays longer than 24 hours in the body, it cannot be excluded that our pattern of results is due to possible acute effects potentially masking or potentiating longer-term effects [5].

It is important to emphasize that the causal relation between cognitive impariment and the regular use of khat is not necessarily straightforward. For instance, we cannot exclude that pre-existing genetic or neurodevelopmental factors may play a mediating role. What we can exclude are contributions from other drugs, to which our khat users were barely exposed, and from individual characteristics as age or intelligence, which do impact performance on working-memory tasks [50]; [51]; [52]; [53] but were controlled in this study.

Although data on the density of DA receptors in khat users are not yet available, one may speculate that khat users suffer from the impaired functioning of dopaminergic receptors in the frontostriatal circuit. Indeed, the striatum is assumed to underlie the ability to flexibly alter cognitive representations [24] and to serve as a gate to modulate when to update information in the PFC structures subserving WM [25].

The present findings raise the question whether khat users also show impairments in other cognitive control functions, such as strategic planning and decision making [8]. The acute effect of khat on cognitive functions needs to be investigated as well. Moreover, it would very useful to explore the direct effect of khat use on the brain. It remains to be demonstrated, for instance, that khat use produces changes at the neuromodulatory (reduced functioning of DAD2 receptors) and functional level (dysfunction in PFC and striatum) that may be proportional to the degree of behavioural performance deficits. Of particular interest would be to investigate whether khat users suffer from impulsive behaviour—given that cathinone has been found to enhance aggressive behavior in isolated rats [54] and that dysfunctional impulsivity has been associated with genetic markers of striatal dopamine [34].

As pointed out, the observations that khat use is apparently associated with all three major functions of cognitive control (WM monitoring/updating, flexibility, and inhibition: [37]) suggest a broad and general impact of khat use on human cognition. Accordingly, using khat can be expected to affect a broad range of everyday behavior, ranging from car driving to work performance and social behavior.

Acknowledgments

We thank Lucy Chodota for her enthusiasm and invaluable assistance in recruiting the participants of this study.

Author Contributions

Conceived and designed the experiments: LSC. Performed the experiments: MJR. Analyzed the data: WVDW. Contributed reagents/materials/analysis tools: WVDW. Wrote the paper: LSC BH.

References

  1. 1. Brenneisen R, Fisch HU, Koelbing U, Geisshüsler S, Kalix P (1990) Amphetamine-like effects in humans of the khat alkaloid cathinone. Br J Clin Pharmacol 30: 825–828.R. BrenneisenHU FischU. KoelbingS. GeisshüslerP. Kalix1990Amphetamine-like effects in humans of the khat alkaloid cathinone.Br J Clin Pharmacol30825828
  2. 2. Kalix P (1996) Catha edulis, a plant that has amphetamine effects. Pharm World Sci 18: 69–73.P. Kalix1996Catha edulis, a plant that has amphetamine effects.Pharm World Sci186973
  3. 3. Carrier N (2008) Is miraa a drug? Categorizing Kenyan khat. Subst Use Misuse 43: 803–818.N. Carrier2008Is miraa a drug? Categorizing Kenyan khat.Subst Use Misuse43803818
  4. 4. Krikorian AD (1984) Kat and its use: an historical perspective. J Ethnopharmacol 12: 115–178.AD Krikorian1984Kat and its use: an historical perspective.J Ethnopharmacol12115178
  5. 5. Al-Habori M (2005) The potential adverse effects of habitual use of Catha edulis (khat). Expert Opin Drug Saf 4: 1145–1154.M. Al-Habori2005The potential adverse effects of habitual use of Catha edulis (khat).Expert Opin Drug Saf411451154
  6. 6. Hassan NAGM, Gunaid AA, Murray-Lyon IM (2007) Khat (Catha edulis): health aspects of khat chewing. East Mediterr Health J 13: 706–718.NAGM HassanAA GunaidIM Murray-Lyon2007Khat (Catha edulis): health aspects of khat chewing.East Mediterr Health J13706718
  7. 7. Kalix P, Braenden O (1985) Pharmacological aspects of the chewing of khat leaves. Pharmacol Rev 37: 149–164.P. KalixO. Braenden1985Pharmacological aspects of the chewing of khat leaves.Pharmacol Rev37149164
  8. 8. Hoffman R, al'Absi , M (2010) Khat use and neurobehavioral functions: Suggestions for future studies. J Ethnopharmacol 132: 554–563.R. Hoffmanal'AbsiM2010Khat use and neurobehavioral functions: Suggestions for future studies.J Ethnopharmacol132554563
  9. 9. Pantelis C, Hindler CG, Taylor JC (1989) Use and abuse of khat (Catha edulis): A review of the distribution, pharmacology, side effects and a description of psychosis attributed to khat chewing. Psychol Med 19: 657–668.C. PantelisCG HindlerJC Taylor1989Use and abuse of khat (Catha edulis): A review of the distribution, pharmacology, side effects and a description of psychosis attributed to khat chewing.Psychol Med19657668
  10. 10. Odenwald M (2007) Chronic khat use and psychotic disorders: A review of the literature and future prospects. Sucht 53: 9–22.M. Odenwald2007Chronic khat use and psychotic disorders: A review of the literature and future prospects.Sucht53922
  11. 11. Balint EE, Falkay G, Balint GA (2009) Khat - a controversial plant. Wiener Klinische Wochenschrift 121: 604–614.EE BalintG. FalkayGA Balint2009Khat - a controversial plant.Wiener Klinische Wochenschrift121604614
  12. 12. Cox G, Rampes H (2003) Adverse effects of khat: a review. Adv Psychiatr Treat 9; 456-463: G. CoxH. Rampes2003Adverse effects of khat: a review.Adv Psychiatr Treat 9;456-463
  13. 13. Pennings EJM, Opperhuizen A, van Amsterdam JGC (2008) Risk assessment of khat use in the Netherlands: A review based on adverse health effects, prevalence, criminal involvement and public order. Regul Toxicol Pharmacol 52: 199–207.EJM PenningsA. OpperhuizenJGC van Amsterdam2008Risk assessment of khat use in the Netherlands: A review based on adverse health effects, prevalence, criminal involvement and public order.Regul Toxicol Pharmacol52199207
  14. 14. UNODCUNODCWorld Drug Report 2010 (United Nations Publication, Sales No. E.10.XI.13). World Drug Report 2010 (United Nations Publication, Sales No. E.10.XI.13).
  15. 15. Wagner GC, Preston K, Ricaurte GA, Schuster CR, Seiden LS (1982) Neurochemical similarities between d,l-cathinone and d-amphetamine. Drug Alcohol Depend 9: 279–284.GC WagnerK. PrestonGA RicaurteCR SchusterLS Seiden1982Neurochemical similarities between d,l-cathinone and d-amphetamine.Drug Alcohol Depend9279284
  16. 16. Chappell JS, Lee MM (2010) Cathinone preservation in khat evidence via drying. Forensic Sci Int 195: 108–120.JS ChappellMM Lee2010Cathinone preservation in khat evidence via drying.Forensic Sci Int195108120
  17. 17. Feyissa AM, Kelly JP (2008) A review of the neuropharmacological properties of khat. Prog Neuropsychopharmacol Biol Psychiatry 32: 1147–1166.AM FeyissaJP Kelly2008A review of the neuropharmacological properties of khat.Prog Neuropsychopharmacol Biol Psychiatry3211471166
  18. 18. Patel NB (2000) Mechanism of action of cathinone: the active ingredient of khat (Catha edulis). East Afr Med J 77: 329–332.NB Patel2000Mechanism of action of cathinone: the active ingredient of khat (Catha edulis).East Afr Med J77329332
  19. 19. Zelger J, Carlini E (1981) Influence of cathinone ([alpha]-aminopropiophenone) and cathine (phenylpropanolamine) on circling behavior and on the uptake and release of [3H]dopamine in striatal slices of rats. Neuropharmacology 20: 839–843.J. ZelgerE. Carlini1981Influence of cathinone ([alpha]-aminopropiophenone) and cathine (phenylpropanolamine) on circling behavior and on the uptake and release of [3H]dopamine in striatal slices of rats.Neuropharmacology20839843
  20. 20. Berman S, O'Neill J, Fears S, Bartzokis G, London ED (2008) Abuse of amphetamines and structural abnormalities in the brain. Ann N Y Acad Sci 1141: 195–220.S. BermanJ. O'NeillS. FearsG. BartzokisED London2008Abuse of amphetamines and structural abnormalities in the brain.Ann N Y Acad Sci1141195220
  21. 21. Miller EK (2000) The prefrontal cortex and cognitive control. Nat Rev Neurosci 1: 59–65.EK Miller2000The prefrontal cortex and cognitive control.Nat Rev Neurosci15965
  22. 22. Braver TS, Cohen JD Monsell S, Driver J, editors. (2000) On the control of control: The role of dopamine in regulating prefrontal function and working memory. Control of cognitive processes: Attention and performance XVIII 713–737: Cambridge MA, MIT Press. TS BraverJD Cohen2000On the control of control: The role of dopamine in regulating prefrontal function and working memory.S. MonsellJ. DriverControl of cognitive processes: Attention and performance XVIII713–737Cambridge MA, MIT Press
  23. 23. Sawaguchi T, Goldman-Rakic PS (1991) D1 dopamine receptors in prefrontal cortex: Involvement in working memory. Science 251: 947–950.T. SawaguchiPS Goldman-Rakic1991D1 dopamine receptors in prefrontal cortex: Involvement in working memory.Science251947950
  24. 24. Cools R (2006) Dopaminergic modulation of cognitive function – Implication for L-DOPA therapy in Parkinson's disease. Neurosci Biobehav Rev 30: 1–34.R. Cools2006Dopaminergic modulation of cognitive function – Implication for L-DOPA therapy in Parkinson's disease.Neurosci Biobehav Rev30134
  25. 25. Moustafa AA, Sherman SJ, Frank MJ (2008) A dopaminergic basis for working memory, learning and attentional shifting in Parkinsonism. Neuropsychologia 46: 3144–3156.AA MoustafaSJ ShermanMJ Frank2008A dopaminergic basis for working memory, learning and attentional shifting in Parkinsonism.Neuropsychologia4631443156
  26. 26. Siessmeier T, Kienast T, Wrase J, Larsen JL, Braus , DF , Smolka MN, et al. (2006) Net influx of plasma 6-[18F]fluoro-l-DOPA (FDOPA) to the ventral striatum correlates with prefrontal processing of affective stimuli. Eur J Neurosci 24: 305–313.T. SiessmeierT. KienastJ. WraseJL LarsenBrausDFMN Smolka2006Net influx of plasma 6-[18F]fluoro-l-DOPA (FDOPA) to the ventral striatum correlates with prefrontal processing of affective stimuli.Eur J Neurosci24305313
  27. 27. Cools R, Gibbs SE, Miyakawa A, Jagust W, D'Esposito M (2008) Working memory capacity predicts dopamine synthesis capacity in the human striatum. J Neurosci 28: 1208–1212.R. CoolsSE GibbsA. MiyakawaW. JagustM. D'Esposito2008Working memory capacity predicts dopamine synthesis capacity in the human striatum.J Neurosci2812081212
  28. 28. Baicy K, London ED (2007) Corticolimbic dysregulation and chronic methamphetamine abuse. Addiction 102: 5–15.K. BaicyED London2007Corticolimbic dysregulation and chronic methamphetamine abuse.Addiction102515
  29. 29. Daumann J, Schnitker R, Weidemann J, Schnell K, Thron A, Gouzoulis-Mayfrank E (2003) Neural correlates of working memory in pure and polyvalent ecstasy (MDMA) users. Neuroreport 14: 1983–1987.J. DaumannR. SchnitkerJ. WeidemannK. SchnellA. ThronE. Gouzoulis-Mayfrank2003Neural correlates of working memory in pure and polyvalent ecstasy (MDMA) users.Neuroreport1419831987
  30. 30. Daumann J, Fischermann T, Heekeren K, Thron A, Gouzoulis-Mayfrank E (2004) Neural mechanisms of working memory in ecstasy (MDMA) users who continue or discontinue ecstasy and amphetamine use: Evidence from an 18-month longitudinal functional magnetic resonance imaging study. Biol Psychiatry 56: 349–355.J. DaumannT. FischermannK. HeekerenA. ThronE. Gouzoulis-Mayfrank2004Neural mechanisms of working memory in ecstasy (MDMA) users who continue or discontinue ecstasy and amphetamine use: Evidence from an 18-month longitudinal functional magnetic resonance imaging study.Biol Psychiatry56349355
  31. 31. van der Plas EAA, Crone EA, van den Wildenberg WPM, Tranel D, Bechara A (2009) Executive control deficits in substance-dependent individuals: A comparison of alcohol, cocaine, and methamphetamine, and of men and women. J Clin Exp Neuropsychol 31: 706–719.EAA van der PlasEA CroneWPM van den WildenbergD. TranelA. Bechara2009Executive control deficits in substance-dependent individuals: A comparison of alcohol, cocaine, and methamphetamine, and of men and women.J Clin Exp Neuropsychol31706719
  32. 32. Beckerleg S (2008) Khat special edition introduction. Subst Use Misuse 43: 749–761.S. Beckerleg2008Khat special edition introduction.Subst Use Misuse43749761
  33. 33. Colzato LS, Ruiz MJ, van den Wildenberg WPM, Bajo MT, Hommel B (2011) Decreased inhibitory control among khat users. Frontiers in Psychology, 1: 219.LS ColzatoMJ RuizWPM van den WildenbergMT BajoB. Hommel2011Decreased inhibitory control among khat users.Frontiers in Psychology,1219
  34. 34. Colzato LS, van den Wildenberg WPM, van der Does WAJ, Hommel B (2010c) Genetic markers of striatal dopamine predict individual differences in dysfunctional, but not functional impulsivity. Neurosci 170: 782–788.LS ColzatoWPM van den WildenbergWAJ van der DoesB. Hommel2010cGenetic markers of striatal dopamine predict individual differences in dysfunctional, but not functional impulsivity.Neurosci170782788
  35. 35. Friedman NP, Miyake A (2004) The relations among inhibition and interference control functions: a latent-variable analysis. J Exp Psychol Gen 133: 101–135.NP FriedmanA. Miyake2004The relations among inhibition and interference control functions: a latent-variable analysis.J Exp Psychol Gen133101135
  36. 36. Friedman NP, Miyake A, Corley RP, Young SE, Defries JC, Hewitt JK (2006) Not all executive functions are related to intelligence. Psychol Sci17: 172–179.NP FriedmanA. MiyakeRP CorleySE YoungJC DefriesJK Hewitt2006Not all executive functions are related to intelligence.PsycholSci17172179
  37. 37. Miyake A, Friedman NP, Emerson MJ, Witzki AH, Howerter A, Wager TD (2000) The unity and diversity of executive functions and their contributions to complex "Frontal Lobe" tasks: a latent variable analysis. Cogn Psychol 41: 49–100.A. MiyakeNP FriedmanMJ EmersonAH WitzkiA. HowerterTD Wager2000The unity and diversity of executive functions and their contributions to complex "Frontal Lobe" tasks: a latent variable analysis.Cogn Psychol4149100
  38. 38. Colzato LS, Huizinga M, Hommel B (2009) Recreational cocaine polydrug use impairs cognitive flexibility but not working memory. Psychopharmacology 207: 225–234.LS ColzatoM. HuizingaB. Hommel2009Recreational cocaine polydrug use impairs cognitive flexibility but not working memory.Psychopharmacology207225234
  39. 39. von Geusau NA, Stalenhoef P, Huizinga M, Snel J, Ridderinkhof KR (2004) Impaired executive function in male MDMA (“ecstasy”) users. Psychopharmacology 175: 331–341.NA von GeusauP. StalenhoefM. HuizingaJ. SnelKR Ridderinkhof2004Impaired executive function in male MDMA (“ecstasy”) users.Psychopharmacology175331341
  40. 40. Colzato LS, Erasmus V, Hommel B (2004) Moderate alcohol consumption in humans impairs feature binding in visual perception but not across perception and action. Neurosci Lett 360: 103–105.LS ColzatoV. ErasmusB. Hommel2004Moderate alcohol consumption in humans impairs feature binding in visual perception but not across perception and action.Neurosci Lett360103105
  41. 41. Raven JC, Court JH, Raven J (1988) Manual for Raven's progressive matrices and vocabulary scales. London: Lewis. JC RavenJH CourtJ. Raven1988Manual for Raven's progressive matrices and vocabulary scales.LondonLewis
  42. 42. Colzato LS, van den Wildenberg WPM, Hommel B (2007) Impaired inhibitory control in recreational cocaine users. PLoS ONE 2(11): e1143.LS ColzatoWPM van den WildenbergB. Hommel2007Impaired inhibitory control in recreational cocaine users.PLoS ONE211e1143
  43. 43. Monsell S (1996) Control of mental processes. In: Bruce V, editor. Unsolved mysteries of the mind. Hove: Erlbaum. pp. 93–148.S. Monsell1996Control of mental processes.V. BruceUnsolved mysteries of the mindHove: Erlbaum93148
  44. 44. Kane MJ, Conway , ARA , Miura TK, Colflesh , GJH (2007) Working memory, attention control, and the N-back task: A question of construct validity. J Exp Psychol Learn Mem Cogn 33: 615–622.MJ KaneConwayARATK MiuraColfleshGJH2007Working memory, attention control, and the N-back task: A question of construct validity.J Exp Psychol Learn Mem Cogn33615622
  45. 45. Colzato LS, van Leeuwen PJA, van den Wildenberg WPM, Hommel B (2010b) DOOM'd to switch: Superior cognitive flexibility in players of first person shooter games. Front Psychol 1(8).LS ColzatoPJA van LeeuwenWPM van den WildenbergB. Hommel2010bDOOM'd to switch: Superior cognitive flexibility in players of first person shooter games.Front Psychol18
  46. 46. Navon D (1977) Forest before trees. The precedence of global features in visual perception. Cognitive Psych 9: 353–383.D. Navon1977Forest before trees. The precedence of global features in visual perception.Cognitive Psych9353383
  47. 47. Colzato LS, Waszak F, Nieuwenhuis ST, Posthuma D, Hommel B (2010a) The flexible mind is associated with the Catechol-O-methyltransferase (COMT) Val158Met polymorphism: Evidence for a role of dopamine in the control of task switching. Neuropsychologia 48: 2764–2768.LS ColzatoF. WaszakST NieuwenhuisD. PosthumaB. Hommel2010aThe flexible mind is associated with the Catechol-O-methyltransferase (COMT) Val158Met polymorphism: Evidence for a role of dopamine in the control of task switching.Neuropsychologia4827642768
  48. 48. Nordahl TE, Salo R, Leamon M (2003) Neuropsychological effects of chronic methamphetamine use on neurotransmitters and cognition: A review. J Neuropsychiatry Clin Neurosci 15: 317–325.TE NordahlR. SaloM. Leamon2003Neuropsychological effects of chronic methamphetamine use on neurotransmitters and cognition: A review.J Neuropsychiatry Clin Neurosci15317325
  49. 49. Vogel EK, McCollough AW, Machizawa MG (2005) Neural measures reveal individual differences in controlling access to visual working memory. Nature 438: 500–503.EK VogelAW McColloughMG Machizawa2005Neural measures reveal individual differences in controlling access to visual working memory.Nature438500503
  50. 50. Ackerman PL, Beier ME, Boyle MO (2005) Working memory and intelligence: The same or different constructs? Psychol Bull 131: 30–60.PL AckermanME BeierMO Boyle2005Working memory and intelligence: The same or different constructs?Psychol Bull1313060
  51. 51. Colzato LS, van Wouwe NC, Lavender TJ, Hommel , B (2006) Intelligence and cognitive flexibility: fluid intelligence correlates with feature "unbinding" across perception and action. Psychon Bull Rev 13: 1043–1048.LS ColzatoNC van WouweTJ LavenderHommelB2006Intelligence and cognitive flexibility: fluid intelligence correlates with feature "unbinding" across perception and action.Psychon Bull Rev1310431048
  52. 52. Hartman M, Warren LH (2005) Explaining age differences in temporal working memory. Psychol Aging 20: 645–656.M. HartmanLH Warren2005Explaining age differences in temporal working memory.Psychol Aging20645656
  53. 53. Kray J, Li KZH, Lindenberger U (2002) Age-related changes in task-switching components: the role of task uncertainty. Brain Cogn 49: 363–381.J. KrayKZH LiU. Lindenberger2002Age-related changes in task-switching components: the role of task uncertainty.Brain Cogn49363381
  54. 54. Banjaw MY, Schmidt WJ (2005) Behavioural sensitisation following repeated intermittent oral administration of Catha edulis in rats. Behav Brain Res 156: 181–189.MY BanjawWJ Schmidt2005Behavioural sensitisation following repeated intermittent oral administration of Catha edulis in rats.Behav Brain Res156181189