Khat, a Cultural Chewing Drug: A Toxicokinetic and Toxicodynamic Summary.

Khat (Catha edulis) is a recreational, chewed herbal drug that has been used as a psychostimulant for centuries in East Africa and the Arabian Peninsula, namely in Somalia, Ethiopia, and Yemen. However, the growing worldwide availability of khat has produced widespread concern. The plant comprises a large number of active substances, among which cathinone, cathine, and norephedrine are the main constituents, which can be included in the group of sympathomimetics of natural origin. In fact, these compounds are amphetamine analogues, and, as such, they have amphetamine-like nervous system stimulant effects. Chewing the leaves gives people a sensation of well-being and increases energy, alertness, and self-confidence. The chronic use of khat is, however, associated with severe cardiac, neurological, psychological, and gastrointestinal complications. The psychological dependence and withdrawal symptoms of khat are the reasons for its prolonged use. The aim of this paper is to review current knowledge on the khat plant with toxicokinetic and toxicodynamic perspectives. Namely, this review paper addresses in vitro, in vivo, and human studies. The models used, as well as the concentrations and doses with the respective biological effects, are discussed. Additionally, the main drug interactions involved with khat are described.

Khat Induced Toxicity: Role on Its Modulating Effects on Inflammation and Oxidative Stability.

Long-term khat (Catha edulis Forsk.) chewing has negative effects on human body. Khat constituents appear to be capable of disturbing the delicate equilibrium between damaging and protective mechanisms of a cell that is essential for optimal activity, thereby producing oxidative damage. Therefore, the current study was designed to understand the role of khat on cell toxicity, oxidative stability, and inflammation. Khat was extracted using 60% methanol and assessed calorimetrically for its phenolic and flavonoid contents. 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging, oxygen radical absorbance capacity (ORAC), and ferric reducing/antioxidant power (FRAP) assays were used to assess the antioxidant properties. Lipopolysaccharide and interferon gamma induced murine monocytic macrophages cell line (RAW 264.7) were used to assess khat effects on cellular inflammation, oxidative stability, and viability. Khat possesses high content of polyphenols and flavonoids. The results showed a strong potency of antioxidants in DPPH, ORAC, and FRAP assays. Khat decreases the production of the proinflammatory nitric oxide and induces cytotoxicity and reactive oxygen species inhibition. Heavy khat consumption induced-toxicity and symptoms are probably due the harmful effects of its polyphenolic contents.

Khat chewing increases the risk for developing chronic liver disease: A hospital-based case-control study.

The chewing of the leaves of Catha edulis (khat) has been implicated in the development of liver disease, but no controlled observations have been undertaken. The objective of the present study was to determine whether khat chewing is associated with development of chronic liver disease (CLD). A case-control study was conducted at two public hospitals in Harar, Ethiopia, between April 2015 and April 2016. A consecutive sample of 150 adult hospital attendees with CLD were included as cases, and 300 adult hospital attendees without clinical or laboratory evidence of CLD were included as controls. Khat consumption was quantified in "khat years"; 1 khat year was defined as daily use of 200 g of fresh khat for 1 year. A logistic regression model was used to control for confounders. There was a significant association between chewing khat and the risk for developing CLD (crude odds ratio, 2.64; 95% confidence interval [CI], 1.56-4.58). In men, this risk, following adjustment for age, alcohol use, and chronic hepatitis B/C infection, increased with increasing khat exposure; thus, compared to never users the adjusted odds ratios were for low khat exposure 3.58 (95% CI 1.05-12.21), moderate khat exposure 5.90 (95% CI 1.79-19.44), and high khat exposure 13.03 (95% CI 3.61-47.02). The findings were robust in a post hoc sensitivity analysis in which individuals with identifiable risk factors for CLD were excluded. CONCLUSION: A significant association was observed between chewing khat and the risk for developing CLD, and in men the association was strong and dose-dependent, suggesting a causal relationship; as the prevalence of khat chewing is increasing worldwide, these findings have major public health implications. (Hepatology 2018;68:248-257).

Pharmacological and Toxicological Effects of Catha edulis F. (Khat).

Khat chewing is deeply rooted in the culture and tradition of communities in khat belt countries, and its consumption is spread to other countries through the suitcase trade. The aim of this article is to review current knowledge on the chemistry, social, pharmacology and toxicology of khat and its use. Khat produces effect invariably in every system, which is harmful or beneficial in some instances. Harmful effects are observed in heavy users, although firm evidence is lacking. Chewing khat acutely elicits states of euphoria, which is followed by low mood. Khat contains alkaloids with psychostimulant properties, but the effect cannot be totally explained by these alkaloids. It is also not clear whether the effect produced in some organs like liver could be attributed to khat or pesticides sprayed during farming. Although the evidence indicates that khat has adverse effects in most organs, our understanding of the complex interaction between use and effect is incomplete, and causal relationships have not yet been described. Moreover, khat has positioned itself well in the social, economic and political arena. Thus, a multidisciplinary research is required to understand the different dimensions and come up with ways that maximize the benefit while minimizing the risk. Copyright © 2017 John Wiley & Sons, Ltd.

Subchronic oral administration of crude khat extract (Catha edulis forsk) induces schizophernic-like symptoms in mice.

BACKGROUND: Chewing fresh leaves of the khat plant (Catha edulis forsk) is a deep rooted and widespread habit in East Africa and the Middle East. Although a body of knowledge exists about the adverse effects of khat on health, data are sparse with regard to the consequences of long-term khat chewing in resulting schizophrenic like symptoms. METHODS: A crude extract of khat at different doses (100 mg/kg (K (khat)100), 200 mg/kg (K200) and 400 mg/kg (K400)) were administered for experimental group of mice whereas standard (ketamine (KT) 10 mg/kg- positive controls (KT10)) and vehicle (2 % v/v Tween-80 in distilled water - negative control groups (CON)) were administered for control groups of mice daily for two months to evaluate subchronic oral administration of crude khat extract to induce schizophrenic-like symptoms in mice. Mice were subjected to a battery of behavioural tests and parameters like locomotor activity, total time spent in social interaction and level of cognition among different groups of mice were measured and analyzed. RESULTS: Khat at all doses significantly increased (p < 0.001) the mean locomotor activity score of mice compared to CON. However, the mean locomotor activity score of mice treated with khat was significantly lower (p < 0.001) compared to the mean locomotor activity score of KT10 mice (p < 0.001). The mean total time score (in seconds) spent in social interaction, mean total time score (in seconds) spent in sniffing and following the partner was significantly higher (p < 0.001) in CON groups of mice compared to khat and ketamine treated groups. Moreover, in spatial memory task, the mean latency score (in seconds) to find the platform of khat and ketamine treated mice was significantly higher (p < 0.05) when compared to CON. CONCLUSIONS: Subchronic oral administration of khat showed an enhanced locomotor activity, reduced social interaction and impaired cognitive function, which demonstrated that long-term use of khat is associated with schizophernic-like symptoms.

El Khat: usos, efectos secundarios y peligros de una planta psicoestimulante / Khat: Uses, side-effects and dangers of a psycho-stimulant plant

El Khat o Catha Edulis Forsk, es un arbusto que se emplea por sus propiedades euforizantes y estimulantes del sistema nervioso central y por su capacidad para aliviar la fatiga, sin embargo, su consumo abusivo produce efectos adversos sobre las funciones cognitivas. En este artículo de revisión se resume el origen, la producción, farmacología, toxicología, neuropsicología y los aspectos psicosociales del consumo del khat en un intento por aportar el mayor conocimiento posible sobre este arbusto, sus propiedades y efectos. Además, se centra especial atención en los aspectos psicológicos y neuropsicológicos que produce, entre los que se incluyen alteraciones leves del estado de ánimo y profundos trastornos que pueden variar tanto en intensidad como en duración. Pese a que se ha podido constatar que determinadas situaciones sociales pueden aumentar el consumo de determinadas drogas de precios asequibles, las consecuencias que producen en la sociedad hacen que sea necesaria una concienciación mayor sobre todos los aspectos que rodean su consumo. Existe un mercado legal e ilegal, con una parte de la población del cuerno de África y de la península arábiga bajo los efectos del Khat, que conlleva unas consecuencias graves para la salud

Khat (Catha edulis) is a shrub used for its euphoric and central nervous system- stimulating properties and for its ability to relieve fatigue. Its abusive consumption nevertheless produces adverse effects on cognitive functions. In this paper we provide a summarized review of the origin, production, pharmacology, toxicology, neuropsychology and psychosocial aspects of khat consumption, in an attempt to provide the best possible knowledge about the bush, its properties and effects. We also focus special attention on the psychological and neuropsychological aspects involved, including minor or major alterations of mood disorders. Although it has been shown that certain social situations can increase the consumption of certain drugs at affordable prices, the impact on several societies requires a greater awareness of all the aspects involved in its consumption. There is a legal and illegal market, with part of the population in the horn of Africa and the Arabian peninsula under the influence of Khat, with serious consequences for the health

Overview of literature and information on "khat-related" mortality: a call for recognition of the issue and further research.

During the past 20 years or so, more has become known about the properties of khat, its pharmacology, physiological and psychological effects on humans. However, at the same time its reputation of social and recreational use in traditional contexts has hindered the dissemination of knowledge about its detrimental effects in terms of mortality. This paper focuses on this particular deficit and adds to the knowledge-base by reviewing the scant literature that does exist on mortality associated with the trade and use of khat. We sought all peer-reviewed papers relating to deaths associated with khat. From an initial list of 111, we identified 15 items meeting our selection criteria. Examination of these revealed 61 further relevant items. These were supplemented with published reports, newspaper and other media reports. A conceptual framework was then developed for classifying mortality associated with each stage of the plant's journey from its cultivation, transportation, consumption, to its effects on the human body. The model is demonstrated with concrete examples drawn from the above sources. These highlight a number of issues for which more substantive statistical data are needed, including population-based studies of the physiological and psychological determinants of khat-related fatalities. Khat-consuming communities, and health professionals charged with their care should be more aware of the physiological and psychological effects of khat, together with the risks for morbidity and mortality associated with its use. There is also a need for information to be collected at international and national levels on other causes of death associated with khat cultivation, transportation, and trade. Both these dimensions need to be understood.

Khat a drug of abuse: roles of free radicals and antioxidants.

Many articles have reviewed the health impact of Khat consumption; however the role of free radicals in the pathogenesis associated with short- and long-term consumption of Khat is absent in the literature. As free radicals and antioxidants converge across various mechanisms in normal physiological function and in disease, this review attempts to uncover the role of endogenous free radicals and the mechanism of cellular injury associated with Khat consumption.

Khat alters the phenotype of in vitro-reconstructed human oral mucosa.

Khat-chewing has been associated with oral lesions including oral cancer, but the mechanisms leading to their development are not known. We hypothesized that khat interferes with the physiological processes of the oral mucosa, such as cell proliferation and differentiation, and aimed at investigating the effects of khat exposure on in vitro-reconstructed human normal buccal mucosa. Khat decreased cell proliferation, epithelial thickness, and cytokeratin 13 expression, while inducing premature expression of p21(Waf1/Cip1), transglutaminases, involucrin, and filaggrin. This suggests that khat is able to induce abnormal differentiation of the buccal epithelium. Khat-induced alterations were accompanied by increased levels of p38 and were reversed by p38 inhibition, pointing to p38 as the key player in this process. The morphological changes described herein mirror the in vivo changes previously described in khat users, and demonstrate for the first time that khat induces pathological alterations in human buccal mucosa, providing evidence that raises concerns about the effects of khat use on oral health.

Early loss of mitochondrial inner transmembrane potential in khat-induced cell death of primary normal human oral cells.

Previous studies suggest the use of khat, a psychostimulant plant used by millions of people in Middle East and Africa, as risk factor for oral cancer. We previously reported that khat is able to induce adverse affects, as cell cycle arrest and apoptosis, in normal human oral cells cultured in vitro. This study further investigates the more specific role played by mitochondria in khat-induced cell death and the kinetics of the events involved in this process. Exposure of primary normal human oral keratinocytes and fibroblasts to khat extract resulted in a swift and sustained decrease of the mitochondrial inner transmembrane potential occurring within 0.5-1h. Loss of mitochondrial membrane potential preceded all other biochemical and morphologic changes, and was associated with a significant decrease in cell survival. Subsequently, apoptosis-inducing factor was released from mitochondria into cytosol and relocated to nucleus. Cyclosporine A and bongkrekic acid delayed both the loss of mitochondrial inner transmembrane potential and the onset of cell death. This study describes a novel mechanism of khat-induced cell death in primary normal oral keratinocytes and fibroblasts involving an early pivotal effect on mitochondrial function and integrity.

Khat (Catha edulis) induces reactive oxygen species and apoptosis in normal human oral keratinocytes and fibroblasts.

Khat chewing is widely practiced in Eastern Africa and the Middle East. Khat is genotoxic to cells within the oral mucosa, and several studies have suggested an association between khat use and oral lesions like hyperkeratosis and oral cancer. This study investigated the mechanism of khat-induced cytotoxicity using primary normal human oral keratinocytes (NOK) and fibroblasts (NOF). Khat induced rounding up of cells, plasma membrane blebbing, and condensation of nuclear chromatin within 3-6 h of exposure. The cells also showed externalization of phosphatidylserine and fragmentation of DNA. Morphological and biochemical features were compatible with cell death by apoptosis. Khat also induced an increase in cytosolic reactive oxygen species (ROS) and a depletion of intracellular glutathione (GSH) within 1 h of exposure. Antioxidants reduced ROS generation, GSH depletion and delayed the onset of cytotoxicity in both cell types. Generally, NOF cells were more sensitive to khat-induced cytotoxicity than NOK cells. These effects were elicited at concentrations of khat expected to occur in the oral cavity during khat chewing. In summary, khat induced apoptotic cell death in primary normal oral keratinocytes and fibroblasts by an early effect on mechanisms that regulate oxidative stress.

Effect of Catha edulis (khat) on behaviour and its potential to induce seizures in Sprague Dawley rats.

BACKGROUND: Khat is a plant whose young shoots and leaves are habitually used in Eastern Africa and the Arabian Peninsula as a drug of recreation. Although it is used without any control in these regions, it contains two controlled substances, cathinone (schedule I) which is present in fresh khat and cathine (schedule VI) which is a degradation product of cathinone abundant in old khat. OBJECTIVE: To determine the effect of khat on locomotor behaviour and seizures in rats. DESIGN: Experimental study. SETTING: University of Nairobi. SUBJECTS: Adult male rats in groups of six were given fresh khat, old khat, methylphenidate and saline at varying doses and observed over three hours. RESULTS: Fresh khat at low doses and old khat at high doses stimulated locomotor activity. High doses of fresh and old khat induced stereotype behaviour and seizures. CONCLUSION: The results show that khat stimulates locomotor and stereotypic behavioural activity and can induce seizures; results similar to those observed with amphetamine analogs.

Socio-economic effects of khat chewing in north eastern Kenya.

BACKGROUND: The khat habit is a widespread phenomenon which has in the past two decades spread to parts of Western Europe and North America from Eastern Africa and the Arabian Peninsula. Although khat has been identified as one of the most commonly abused substances in Kenya, restrictions on cultivation, trade and usage have been non-existent since its legalisation in 1977. OBJECTIVE: To describe the socio-economic effects of khat chewing in Ijara District in the North Eastern Province of Kenya. DESIGN: Cross sectional study. SETTING: Ijara District, North Eastern Kenya. SUBJECTS: Fifty respondents were interviewed. RESULTS: Eighty eight percent of the respondents were khat chewers, and the majority (80%) had family members who engaged in the khat habit. There was a general lack of education on the negative effects of khat chewing. Due to reported mood changes and withdrawal symptoms when not chewing khat, many respondents used more than half of their domestic budgets on khat, but few (28%) perceived this as a waste of resources. Fifty four percent of khat chewers typically started the habit during the day, implying a waste of time for productive work. However, only 40% of the persons interviewed admitted that the drug affected work performance negatively. The khat habit was associated with strain on family relationships, anti-social behaviour and health effects such as insomnia. CONCLUSION: In spite of the negative socio-economic impact of khat in Ijara District, khat consumption remains a widespread habit.

Khat (Catha edulis)-an updated review.

The habit of chewing fresh leaves and twigs of khat (Catha edulis) for their stimulating amphetamine-like effects is highly prevalent in East Africa and southwest on the Arabic peninsula. There is an extensive literature on khat providing information about its history, botany, production, geographical distribution, chemistry and pharmacology, and exploring the social, economic, medical, psychological and oral aspects related to its use. Some of this literature dates as early as the 11th century; however, most of it appeared after the first scientific description of khat by Peter Forskal in 1775. This review provides a panorama of khat and the various aspects of its use. A non-technical description of the plant chemistry and pharmacology is included. The medical, psychological and oral aspects are emphasized, and the current knowledge about the microbiological effects of khat is also presented.

Long-term feeding effects of Catha edulis leaves on blood constituents in animals.

In this study, the long-term (6 months) biochemical effects of varying levels of Catha edulis leaves on the plasma concentration of glucose, triglycerides, cholesterol, HDL-cholesterol, total protein, albumin, uric acid, urea and creatinine were examined. Our results demonstrated a significant decrease in plasma cholesterol throughout the treatment period by all levels of C. edulis leaves tested. This significant decrease in plasma cholesterol was halved at the end of the treatment period and corresponded with a significant increase in plasma HDL-cholesterol and a significant decrease in plasma glucose and triglycerides concentrations. Moreover, C. edulis treatment increased plasma uric acid significantly, in a time-dependent manner with the higher concentrations (20% and 30%) of C. edulis leaves. Only plasma albumin was decreased significantly at the end of the treatment period, with no significant effect on plasma total protein. This also coincided with a significant, dose-dependent decrease in plasma urea at month 6, with no significant effect on plasma creatinine concentration.

Exploration of adverse psychological symptoms in Yemeni khat users by the Symptoms Checklist-90 (SCL-90).

AIM: The present study was aimed at assessing associations between psychological symptoms and khat use in the Yemeni population. SETTING: The survey was performed in 2000/2001, in different zones including three urban and three rural areas. PARTICIPANTS: The survey was carried out in 800 Yemeni adults (15-76), both male and female, representing mainly urban populations of students, state employees and housewives. DESIGN: A cross-sectional survey was undertaken using face-to-face interviews and no preset selection criteria regarding profession, socio-economic status, age or gender. MEASUREMENT: The Symptoms Checklist-90 (SCL-90) was used containing 90 items, which cover nine scales of the following domains: somatization, depression, anxiety, phobia, hostility, interpersonal sensitivity, obsessive-compulsive, hostility, interpersonal sensitivity, paranoia and psychoticism. Details of khat use and socio-demographic data were also collected. FINDINGS: At least one life-time episode of khat use was reported in 81.6% of men and 43.3% of women. Male users tended to use more frequently. The incidence of adverse psychological symptoms was not greater in khat users; in fact, there was a negative association between the incidence of phobic symptoms and khat use. CONCLUSIONS: Khat use is very common in the Yemeni population, particularly men, but it is not associated with adverse psychological symptoms.

Las consecuencias del consumo del Khat: Una revisión de la literatura

El Khat es un árbol de hoja perenne que crece en determinados lugares del Este de África y de la Península Arábiga. Las hojas del Khat contienen efectos estimulantes y se mastican con frecuencia en aquellos países en donde crece. Debido a la disponibilidad del transporte aéreo, esta droga se ha extendido a la Europa Occidental y a América. En este artículo revisaremos todos aquellos aspectos relacionados con las consecuencias del Khat, su uso y su abuso en los diferentes lugares del mundo (AU)