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.

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.

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.

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.

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.

Toxicological evaluation of Catha edulis leaves: a long term feeding experiment in animals.

In this study the long term (6 months) toxicological effect of varying levels of Catha edulis leaves were examined on the plasma concentration of liver enzymes as well as the histopathology of tissue sections of the liver. Both biochemical and histopathological data presented demonstrate signs of C. edulis toxicity. Our results show a significant increase in plasma levels of Alkaline phosphatase (ALP), Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) with all levels of C. edulis leaves tested and throughout the treatment period. The increase of ALP was more prominent than both ALT and AST at the higher level of 30%. Plasma levels of AST though were only moderately increased at the higher level of 30% at the early stage of treatment (3 months) it significantly increased with all levels of C. edulis leaves in the long term (4-6 months). In addition, a time-dependent gradual increase in indirect bilirubin with a concomitant decrease in direct bilirubin levels were observed with the lower level of C. edulis (10%) with no signs of haemolysis. Histopathology of tissue sections of liver display evidences of increasing chronic inflammation with porto-portal fibrosis in the tissue sections obtained from animals treated with both 20 and 30% C. edulis.

Effect of khat, its constituents and restraint stress on free radical metabolism of rats.

The leaves of khat (Catha edulis) are found to have stimulating and pleasurable effect and are chewed habitually by people of East Africa and Arabian Peninsula. Due to various toxic and psychostimulative effect of khat the present study was undertaken to evaluate the effect of intragastric khat alone or its major constituents flavonoids/alkaloids administration and before and after 4 h of immobilization stress in terms of alteration of free radical scavenging/metabolizing enzymes, uric acid and glucose in rats. Oral khat, alkaloid administration or 4 h restraint stress resulted in the decrease of the circulating levels of superoxide dismutase, catalase, glutathione-S-transferase and glucose with enhanced uric acid concentrations as compared with control rats. Oral treatment with flavonoid fraction of khat was found to enhance the activities of GST and catalase but showed no effect on SOD while the level of glucose was decreased and uric acid increased. The levels of these biochemical parameters were more altered in post stress khat/alkaloid treated rats than pre stress khat/alkaloid treated rats. The alteration in the levels of SOD, GST, catalase and uric acid in the pre stress khat treated rats were comparable with that of khat alone, except the level of glucose which was further decreased in pre stress khat treated rats. The flavonoid fraction of khat reduced the stress induced oxidative stress in terms of above mentioned biochemical parameters. The present study suggests that khat alone or khat/alkaloid consumption preceding stress may significantly decrease the levels of free radical metabolizing/scavenging enzymes and glucose leading to enhanced free radical concentration and toxicity of khat, which could be due to its alkaloid fraction as flavonoids were found to show antioxidant properties for oxidative stress generated during restraint stress.

Investigation into the toxicological effects of Catha edulis leaves: a short term study in animals.

In this study the short term (3 months) toxicological effects of varying levels of Catha edulis leaves were examined on the plasma concentration of liver enzymes and the histopathology of tissue sections of various organs including the liver, kidneys, spleen and testis. Both the biochemical and histopathological data demonstrated, initial signs of Catha edulis toxicity. Our results show a significant increase in plasma levels of alkaline phosphatase (ALP) and alanine aminotransferase (ALT) with all levels of Catha edulis leaves tested and throughout the treatment period. The increase of ALP was more prominent than that of ALT. The plasma levels of aspartate aminotransferase (AST) were only moderately increased at the higher dose (30%) in the later stages of treatment. In addition, a time-dependent gradual increase in indirect bilirubin with a concomitant decrease in direct bilirubin levels was observed with the 30% Catha edulis with no signs of haemolysis. The histopathology of tissue sections of the liver displayed evidence of congestion of the central liver veins as well as acute hepatocellular degenerative and regenerative activities in the tissue sections obtained from animals treated with both 20% and 30% Catha edulis. Similarly, histopathological examination of the tissue sections of the kidneys showed some lesions, and the degree of the lesion increased as the dose of Catha edulis leaves increased including: the presence of fat droplets particularly seen in the upper cortical tubules; acute cellular swelling; hyaline tubules; and acute tubular nephrosis. In contrast, Catha edulis treatment did not affect the spleen and increased the rate of spermatogenesis in male rabbits with the spermatozoa being quite evident, the Leydig cells were in good condition and were not affected by the doses given.