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.

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.

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.