A Narrative Review of the Toxic Effects on Male Reproductive and Sexual Health of Chewing the Psychostimulant, Catha edulis (Khat).

Khat (Catha edulis Forsk) is a stimulating narcotic grown mainly in East and Southern Africa. The plant has a long history as a popular social behavior within these regions, and its active ingredient, cathinone, has been thought to cause an array of physical, psychological, and mental health complications. In 1980, the World Health Organization (WHO) classified it as an illicit substance due to the potential for psychological dependence. Subsequent investigations have found that its regular consumption can negatively impact the human central nervous system (CNS), systemic blood pressure, genitourinary system, and psychological health. This narrative review aims to discuss the reproductive toxicity and sexual dysfunction (SD) caused by regular khat usage in humans and experimental animals. Animal studies found dose-dependent impacts on male reproductive health: low levels increased testosterone production, whereas high levels had the opposite effects. Moderate intake was associated with reduced luteinizing hormone (LH) levels and heightened cortisol in blood plasma. In human studies, chronic users had dramatically lower semen volume, sperm motility, and count, as well as reduced libido or erectile dysfunction (ED). Khat can have serious implications for male fertility and sexual health: therefore, better understanding of its effects is paramount. This article aims to review the toxic effects on the male reproductive and sexual health of chewing the psychostimulant, Catha edulis (khat).

Cathine and cathinone disposition kinetics and neurotransmitter profile in several organs of rats exposed to a single dose of Catha edulis (Vahl) Forssk. ex Endl. extract.

OBJECTIVES: Catha edulis (Vahl) Forssk. ex Endl. (Khat) is a stimulant plant that contains cathine and cathinone, which its abuses induce euphoria, alertness, and motor activity. Since the toxicokinetics of these substances remain unclear, this study was carried out to investigate the disposition kinetics of cathine and cathinone, the neurotransmitter profile, following a single dose of C. edulis extract in rats. METHODS: Twenty-four adult male Wistar albino rats (250-300 g) were randomly selected and divided into six groups of four rats each. All groups received a single oral dose of 2,000 mg/kg body weight, and blood and tissue samples from the brain, lung, heart, liver, and kidney were obtained at intervals of 0.5, 1, 2.5, 5, 12, and 24 h. The cathine and cathinone concentrations were identified and quantified using ion trap ultra-high performance liquid chromatography (HPLC-IT/MS). The neurotransmitter profile was detected using the quadrupole time of flight UPLC-QTOF/MS method. RESULTS: The lung, liver, and heart tissues attained the highest levels of cathine, while the highest level of cathinone was determined in the heart. Cathine and cathinone concentrations in the blood and heart peaked at 0.5 h. The concentrations peaked in the brain 2.5 h later, indicating that the heart had an immediate effect, whereas the brain had a longer-lasting one. They have longer half-lives (2.68 and 5.07 h, respectively) and may remain in the brain for longer durations (3.31 and 2.31 h, respectively). The neurotransmitters epinephrine, dopamine, norepinephrine, and serotonin were detected in a delayed, prolonged and organ-specific manner. CONCLUSIONS: Cathine and cathinone were deposited in considerable concentrations in all tissues analyzed, with the highest Cmax in the lung and Tmax in the heart tissues but not in the brain. In addition, neurotransmitters such as adrenaline, dopamine, norepinephrine, and serotonin were differentially detected in all tested samples in a organ-specific fashion. More study is needed to identify cathine and cathinone's effects on neurotransmitter profiles. Nevertheless, these findings provided a further basis for experimental, clinical, and forensic investigations.

Effects of Catha Edulis Forsk on spatial learning, memory and correlation with serum electrolytes in wild-type male white albino rats.

BACKGROUND: The burdens of psychostimulant use disorders are becoming a worldwide problem. One of the psychostimulants widely consumed in Ethiopia and East African countries is Catha edulis Forsk (khat). However, no studies have been conducted on the cognitive effects of khat and its correlation with serum electrolytes. The present study was aimed to evaluate the effects of khat on spatial learning and memory and their correlation with serum electrolytes. MATERIALS AND METHODS: Diethyl ether and chloroform (3:1v/v ratio) were solvents used to obtain the crude khat extract in this study. T80W was used to prepare the khat juice, fresh khat leave extract. The rats were received crude khat extract subchronically (KESC) (100 mg/kg, 200 mg/kg and 300 mg/kg b.w), khat juice (KHJ 2.5 mL/kg), 2% tween 80 in distilled water (T80W- v/v, vehicle) and khat extract subacutely (KESA) (300 mg/kg). For subchronic treatment, each rat was administered for twelve weeks before Morris water maze experiment has been started, while it was administered for a week for acute treatment. Spatial learning and memory were measured using the Morris water maze model and serum sodium, calcium, potassium, and chloride were evaluated using Cobas 6000. RESULTS: Spatial learning was improved with trials across the groups, while average escape latency (s) of rats received KESC 200 mg/kg (p<0.001), KESC 300 mg/kg (p<0.01) and KHJ 2.5 mL/kg (p<0.05) was significantly greater than rats that received vehicle. There was no significant difference in the latency between rats that received KESA 300mg/kg and vehicle (p>0.05). Thigmotaxis was significantly higher in rats that received all doses of khat extract (p<0.001). The time spent in the target quadrant in rats that received KESC 300 mg/kg was significantly reduced (p<0.05). Serum calcium level was inversely correlated with the escape latency (R = -0.417, p<0.05) in rats that received khat. CONCLUSIONS: Khat extract and juice administered subchronically, but not subacutely, impaired learning and memory and was associated with serum calcium reduction. The neuronal basis for such alteration should be investigated.

Studies on the ethnopharmacology, antimicrobial activity, and toxicity of Catha edulis (Vahl.) Endl., in Sprague Dawley rats.

Background: The Mbeere South community of Embu County consume leaves of Catha edulis for its stimulant and euphoretic actions. Other indigenous uses of the plant are undocumented. Information on the pharmacology and safety of this plant is also scanty. This study aimed to document the ethnopharmacology, antimicrobial properties, and toxicity of C. edulis leaves collected from the Mbeere South community in Kenya. Methods: Ethnopharmacological data was collected from 35 informants using semi-structured questionnaires. Leaf extracts of C. edulis were prepared using acetone, water, and methanol. The antimicrobial properties of these extracts were evaluated against Bacillus cereus, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Candida albicans. The toxicity of the aqueous extract was determined using hematological, biochemical, and histopathological parameters in male and female Sprague Dawley rats at 250 mg/kg, 500 mg/kg, and 1000 mg/kg doses over 28 days. p<0.05 was considered significant. Results: All informants were male, most were married, >50 years old, with >10 years of experience. The sources, local names, preparation, storage conditions, indications, frequency of use, dosage, and side effects of C. edulis were documented. All extracts were ineffective against E. coli, P. aeruginosa, and C. albicans. They had limited efficacy against B. cereus and S. aureus. Significant differences were observed in the hematological and biochemical parameters of rats at the tested doses. Low, intermediate, and high doses of the aqueous extract of C. edulis produced local congestion of the cardiac and hepatic vessels. Localized interstitial connective tissue proliferation, multifocal kidney interstitial hemorrhage, and localized tubular epithelium necrosis were also observed in female rats. Conclusions: The ethnobotanical uses of C. edulis among the Mbeere South community were documented for the first time. Limited antimicrobial efficacy and toxicity at high doses limit the use of leaves of C. edulis.

Effect of Biochar and Inorganic Fertilizer on the Soil Properties and Growth and Yield of Onion (Allium cepa) in Tropical Ethiopia.

Biochar is a carbon-rich product, which is processed by pyrolyzing biomass to improve soil properties and maintain environmental sustainability. This study aim was to investigate the effect of biochar and inorganic fertilizer on soil properties, growth, and yield. Four treatments and four replications have been used for the experimental plots using Randomized Complete Block Design (RCBD). Soil physiochemical properties have been investigated based on soil samples within 0-30 cm depth in each plot. The two types of biochar (grass and chat waste) have been used for the treatments. The pyrolyzing temperature required for grass and chat waste is 250°C and 1100°C, respectively. The plant height, total yield, and the marketable and nonmarketable yield of onion have been examined. The analysis showed that treatment with grass biochar and inorganic fertilizer had a similar effect on soil properties but chat (Catha edulis) biochar had a lower effect on soil properties. The total yield and days to 70% maturity have been increased due to the cumulative treatment of grass biochar and inorganic fertilizer. The biochar of grass and inorganic fertilizer have been significantly increased in marketable bulb yield, but unmarketable yield becomes decreased. The chat waste and controlled treatments shown an increased unmarketable yield and declined marketable bulb yield. Overall, biochar can substitute the inorganic fertilizer, which can help to improve the w soil fertility and environmental sustainability. Therefore, biochar has a win-win solution.

The impact of catha edulis (vahl) forssk. ex endl. (celestraceae) (khat) on pharmacokinetics of clinically used drugs.

INTRODUCTION: Catha edulis (Vahl) Forssk. ex Endl. (Celestraceae) is used as a recreational drug on daily basis for its euphoric and psychostimulant effects. It is also chewed by individuals who are on medications, raising the possibility of drug-khat interaction. However, limited data are available in the literature, although clinically significant interactions are expected, as khat contains a complex mixture of pharmacologically active constituents. AREAS COVERED: It provides an overview of the phytochemistry, pharmacokinetics, pharmacodynamics, and pharmacogenetics of khat based on the literature mined from PubMed, Google Scholar, and Cochrane databases. It also presents a detailed account of drug-khat interactions with specific examples and their clinical significance. The interactions mainly occur at the pharmacokinetics level and particular attention is paid for the phases of absorption and cytochrome P450 enzyme-mediated metabolism. EXPERT OPINION: Despite the increasing trend of khat chewing with medications among the populace and the potential risk for the occurrence of clinically significant interactions, there is paucity of data in the literature demonstrating the magnitude of the risk. The available data, however, clearly demonstrate that the consequence of drug-khat interaction is dependent on genotype. Genotyping, where feasible, could be used to improve clinical outcome and minimize adverse reactions.

Qualitative ultrastructural analysis of the submandibular salivary glands after administration of khat: in vivo study.

OBJECTIVE: Khat (Catha edulis Forssk) plant has been widely chewed for its psychostimulatory effects in the African and Arabian Peninsula, particularly in Yemen. Considering the khat leaves are gradually chewed without swallowing, while its active constituents are extracted into saliva, studying the effect of khat on salivary glands is necessary. This work is an extension of the previously published work that studied the effect of khat extract on the rats' submandibular salivary glands in terms of histological and immunohistochemical evaluations. The current research note aimed to better understand this effect on the ultrastructure of submandibular salivary gland cells by using transmission electron microscope. RESULTS: Oral administration of khat extract produced degenerative changes in the secretory and ductal cells of rats' submandibular salivary glands. These changes involved irregular boundaries of variable sized-nuclei, dilated RER, cytoplasmic vacuoles as well as swollen and degenerated mitochondria.

Khat Chewing and Lipid Profile in Human and Experimental Animals.

BACKGROUND: Catha edulis, also known as khat or qat, is a plant that grows in East Africa and southern Arabia. Several millions of people chew the leaves and twigs of khat plant for their central stimulating amphetamine-like effects. Khat chewing is becoming more common in Europe and the United States, owing to worldwide migration. OBJECTIVE: This review examines the khat ingredients, global prevalence, and legal status as well as its effects on lipid profile. Methodology. A literature search was performed using PubMed, Scopus, and Google Scholar to collect information within articles published up to April 2021 with the goal of identifying relevant studies. The proposed mechanisms of cathinone effects on total cholesterol and triglyceride were also discussed. CONCLUSION: The khat chewing habit is considered as a serious economic and health issue that needs specialized programs to assist those people to quit or reducing this habit.

In vitro effects of 95% khat ethanol extract (KEE) on human recombinant cytochrome P450 (CYP)1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2E1, CYP2J2 and CYP3A5.

OBJECTIVES: Khat, a natural amphetamine-like psychostimulant plant, are widely consumed globally. Concurrent intake of khat and xenobiotics may lead to herb-drug interactions and adverse drug reactions (ADRs). This study is a continuation of our previous study, targeted to evaluate the in vitro inhibitory effects of khat ethanol extract (KEE) on human cytochrome (CYP) 1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2E1, CYP2J2, and CYP3A5, major human drug metabolizing enzymes. METHODS: In vitro fluorescence enzyme assays were employed to assess CYPs inhibition with the presence and absence of various KEE concentrations. RESULTS: KEE reversibly inhibited CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2E1, CYP2J2 and CYP3A5 but not CYP1A2 with IC50 values of 25.5, 99, 4.5, 21, 27, 17, and 10 µg/mL respectively. No irreversible inhibition of KEE on all the eight CYPs were identified. The Ki values of CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2E1, CYP2J2 and CYP3A5 were 20.9, 85, 4.8, 18.3, 59.3, 3, and 21.7 µg/mL, respectively. KEE inhibited CYP2B6 via competitive or mixed inhibition; CYP2E1 via un-competitive or mixed inhibition; while CYP2A6, CYP2C8, CYP2C19, CYP2J2 and CYP3A5 via non-competitive or mixed inhibition. CONCLUSIONS: Caution should be taken by khat users who are on medications metabolized by CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2E1, CYP2J2, and CYP3A5.

Effect of Khat (Catha edulis Forsk) extract on testicular maturation in pre-pubertal and pubertal rats: A morphological and biochemical study.

The present study aimed at analysing the effect of Khat plant extract on rat testicular development. Thirty-two weaned male albino rats (4 weeks old) were divided into four groups consisting of eight animals each. While control animals received normal saline, rats of groups I, II and III received 100, 200 and 300 mg Khat extract per kg body weight dissolved in distilled water by oral gavage daily for 8 weeks, respectively. Blood samples were collected in separate heparinized tubes by cardiac puncture from each rat and processed for measuring plasma levels of reproductive hormones LH, FSH, testosterone and prolactin. Five-µm sections were stained with haematoxylin and eosin and examined by light microscope. Some sections were immunostained for protamine-1 representing a biomarker for intact sperm differentiation. The present study clearly demonstrated that Khat extract has a pronounced effect on testicular maturation of developing albino rats at both the morphological and functional levels. Khat-treated groups revealed a significantly low serum testosterone level and severe impairment of spermatogenesis when compared with control animals. The current findings also verified, for the first time, that the final stages of sperm maturation (spermiogenesis) were strongly impaired after administration of Khat extract to experimental rats particularly at a higher dose (300 mg/kg body weight). This was proved by the very weak, if any, expression of protamine-1 in the maturing spermatids in Khat-treated rats.

Khat Chewing Effect on the International Normalized Ratio in Patients with Mechanical Heart Valves under Warfarin Therapy.

BACKGROUND AND OBJECTIVE: Khat is a plant that contains the alkaloids cathine and cathinone which have some amphetamine-like properties. It is cultivated and it's leaves chewed for their euphoric effect. This study intended to elucidate the effect of khat chewing on blood coagulation by using the International Normalized Ratio (INR) value as a calculable benchmark. MATERIALS AND METHODS: In this cohort study, 146 patients with Mechanical Heart Valves (MHV) were assessed for two consecutive visits at one-month intervals. For each visit, the date of surgery, the patient's compliance, the dose of warfarin and the INR reading were assessed by the researcher. RESULTS: Out of 146 patients with MHV, the mean age was 33.72±12.43 years (range, 14-65 years); 82 (56.2%) were female and 64 (43.8%) were male. The results revealed that the mean of absolute INR readings was lower in khat-chewers than non-chewers by average 0.2 on the first and second visits (p = 0.038 and 0.002, respectively). CONCLUSION: Khat chewing has a significant coagulant effect. There was a significant decrease in the value of INR for khat chewers patients with MHV when compared to non-khat chewers.

Prevalence of hypertension and associated factors among adult residents in Arba Minch Health and Demographic Surveillance Site, Southern Ethiopia.

Hypertension is the leading risk factor for mortality and it is also one of the major risk factors for other non-communicable diseases (NCDs). The objective of the study was to assess the prevalence of hypertension and its associated factors among adults residing in Arba Minch health and demographic surveillance site (HDSS), Southern Ethiopia. A community-based cross-sectional survey was conducted in 2017 on the estimated sample size of 3,368 adults at Arba Minch Health and Demographic Surveillance site (HDSS). Data were collected using the WHO STEPS survey tools. Bivariate analysis was done to detect candidate variables at P-value less than 0.25 and entered into the final model to identify the independent predictors of hypertension. The prevalence of hypertension was 18.92% (95% CI: 17.63-20.28). The magnitude increase among respondents in the older age group [AOR 1.39 (95%CI: 1.05-1.84), 1.68 (95% CI: 1.26-2.23) and 2.67 (95%CI: 2.01-3.56) for age group 35-44, 45-54 and 55-64, respectively, compared to 25-34 years old group] and those with the higher wealth index [AOR 1.86 (95%CI: 1.33-2.59), 2.68 (95% CI: 1.91-3.75) and 2.97 (95%CI: 2.08-4.25) for 3rd quantile, 4th quantile and 5th quantile, respectively, compared to 1st quantile]. The odds of hypertension reduce among married participants (AOR 0.66, 95%CI: 0.51-0.85). Respondents with overweight (AOR 1.44, 95%CI: 1.02-2.02), khat chewing (AOR3.31, 95%CI: 1.94-5.64), low fruit and/or vegetable consumption (AOR 1.27, 95%CI: 1.05-1.53) and those who do not use coffee and tea (AOR 1.52, 95%CI: 1.03-2.24) had significantly higher likelihood of hypertension. Nearly one out of five participants have hypertension in this population. As hypertension is one of the silent killers, it is advisable to develop a system for enabling early detection and monitoring in the older age groups and overweight individuals.

Khat (Catha edulis) upregulates lipolytic genes in white adipose tissue of male obese mice (C57BL/6J).

ETHNOPHARMACOLOGICAL RELEVANCE: Khat (Catha edulis (Vahl) Forssk.) is a herb from the Celastraceae family (also known as qat, gaad, or mirra) that is widely-consumed in East Africa and in the Arabian peninsula. The green leaves and small stems are consumed primarily at recreational and social gatherings, and medicinally for their antidiabetic and appetite-suppression effects. AIMS: The objectives of this study were to determine the effects of khat and its active alkaloid, cathinone, on food intake and body weight in mice maintained on a high-fat diet, and to investigate its mechanism of action in white adipose tissue and in the hypothalamus. MATERIALS & METHOD: Adult male mice (C57BL/6J) were fed a high fat diet (HFD) for 8 weeks (n = 30), then divided into 5 groups and treated daily for a further 8 weeks with HFD + vehicle [control (HFD)], HFD + 15 mg/kg orlistat (HFDO), HFD + 200 mg/kg khat extract (HFDK200), HFD + 400 mg/kg khat extract (HFDK400) and HFD + 3.2 mg/kg cathinone (HFDCAT). Treatments were carried out once daily by gastric gavage. Blood and tissue samples were collected for biochemical, hormonal and gene expression analyses. RESULTS: Khat extracts and orlistat treatment significantly reduced weight gain as compared to control mice on HFD, and cathinone administration completely prevented weight gain in mice fed on HFD. Khat treatment caused a marked reduction in body fat and in serum triglycerides. A dose-dependent effect of khat was observed in reducing serum leptin concentrations. Analysis of gene expression in adipose tissue revealed a significant upregulation of two lipolysis pathway genes:(adipose triglyceride lipase (PNPLA-2) and hormone-sensitive lipase (LIPE). In the hypothalamic there was a significant (P < 0.05) upregulation of agouti-related peptide (AgRP) and cocaine-amphetamine regulated transcript (CART) genes in the HFDK400 and HFDCAT groups. CONCLUSION: Cathinone treatment blocked body weight gain, while high dose khat extract significantly reduced the weight gain of mice on an obesogenic diet through stimulation of lipolysis in white adipose tissue.

Evaluation of Khat (Catha edulis) Use as a Risk Factor of Cancer: A Systematic Review.

BACKGROUND: Conducting systematic review to evaluate plant use as a risk factor to cancer could be challenging. A systematic and well-balanced method should be applied to accommodate in vivo and in vitro studies to make a final decision. In this article, khat, a recreational plant used in some Arabic and African regions, was employed as an example to systematically determine its relationships to the premalignant and cancerous conditions. METHODS: Systematic database search was performed to recruit original human, animal or in vitro studies on khat and cancer. Sixteen studies fulfilled the inclusion criteria and subjected to assessment using Risk of Bias (RoB). Office of Health and Translation (OHAT) approach was used to rate the confidence level in the body of evidence. The evidence was integrated to establish the relationships between khat, premalignant conditions and cancer. RESULTS: Seven out of eight studies showed that khat causes premalignant oral lesions with moderate evidence level. Four studies showed that khat causes cancer with low evidence level and another three studies showed that khat has anti-cancer effect with moderate to high evidence level. Only one study suggested that khat is unrelated to cancer. CONCLUSION: RoB and OHAT approach are reliable systematic tools to evaluate plant risk to cancer and provide objective and uniform summary regardless of the study type. In conclusion, our pooled analysis did not find a direct relationship between khat and cancer but anti-cancer effect would require to be proofed on human studies.

Determination of chiral cathinone in fresh samples of Catha edulis.

The main psychoactive compound in Khat is cathinone which consists of two enantiomers, S-(-)-cathinone being more stimulant than its R antipode. This study aimed to the enantioseparation and determination of these two stereoisomers in different parts of fresh Catha edulis. The samples were solvent extracted and cathinone was derivatized with menthyl chloroformate. The separation of the two diastereomeric derivatives was carried out by gas chromatography and showed an excellent resolution, while their structure was confirmed by mass spectrometry. The quantitative determination of both enantiomers showed a different distribution in various investigated parts of the plant, as shown in their enantiomeric excess. Unlike the results published in some previous articles, the current study confirmed the presence of both S and R cathinone in all parts of the fresh plant. The concentration of S-cathinone was higher in stems while its values were lower in leaves. The obtained concentrations were in the ranges 0.081-0.290 and 0.087-0.211 mg/g for S and R antipodes, respectively. Also, S-cathinone which is the most psychoactive stereoisomer showed an increasing concentration from lower to upper stems of the plant. The present study is the first quantitative investigation of the two cathinone enantiomers in different parts of fresh Catha edulis.

Involvement of CB2 Receptors in the Neurobehavioral Effects of Catha Edulis (Vahl) Endl. (Khat) in Mice.

There is behavioral evidence for the interaction between crude khat extract and the endocannabinoid system, whereby the endocannabinoid system alters khat extract-mediated behavioral effects through modulation of the monoaminergic system. The objective of this study was to investigate the role of the endocannabinoid system on the neurobehavioral effect of khat extract in mice following concomitant administration of khat extract and the CB2R agonist, JWH133. Locomotor activity test, immunohistochemistry, and reverse transcriptase polymerase chain reaction technique were utilized to assess locomotor activity, tyrosine hydroxylase immunoreactivity, and expression of dopamine transporter mRNA gene. The results show sub-acute administration of khat extract alone increased locomotor activity in mice and co-administration of the CB2R agonist, JWH133, reduced khat extract induced hyperlocomotor activity. The data revealed that cell type specific deletion of CB2Rs on dopaminergic neurons increased the hyperlocomotor behavior of khat extract. Furthermore, the results revealed that khat extract attenuated MPTP induced motor deficits, which is enhanced by JWH133. Khat extract also increased expression of tyrosine hydroxylase positive cells and expression of dopamine transporter mRNA gene in wild type mice. Nevertheless, JWH133 did not alter the effect of khat extract on tyrosine hydroxylase immunoreactivity and dopamine transporter mRNA expression when given together with khat extract. Taken together, the results suggest that the CB2Rs selectively interact with khat extract-mediated locomotor effects and could be utilized as therapeutic target in central nervous system movement disorders associated with dopamine dysregulation.

Flavonoids in a crude extract of Catha edulis inhibit rat intestinal contraction via blocking Ca2+ channels.

BACKGROUND: Animal studies show that Catha edulis inhibits gastrointestinal tract motility. However, there is little or no information on its effect on colon motility and the mechanism of action and active constituents responsible for this effect. This study therefore attempted to discern the effect, suggest the mechanism, and identify the active compounds from the crude extract. METHODS: A crude extract of Catha edulis was fractionated and subfractionated using column chromatography and HPLC. The activity of all fractions and subfractions was evaluated on rat colon longitudinal muscle. Nuclear magnetic resonance (NMR) spectroscopic data elucidations were used to identify the active compounds. An ileal segment preparation was used to investigate the possible mechanism of action. RESULTS: The crude extract of Catha edulis (0.05-0.5 mg/mL) inhibited spontaneous contraction of rat colon and ileum (P < 0.05), and tetrodotoxin (TTX, 10 µmol/L) failed to block this effect. Similar to verapamil (0.01-0.1 µmol/L), the Catha edulis extract (0.05-0.5 mg/mL) inhibited high K+ (80 mmol/L)-induced sustained ileal contraction and decreased the response to Ca2+ . Analysis of the NMR data showed that quercetin, kaempferol, and myricetin were the active phytochemicals. All the identified compounds were flavonoids and significantly inhibited (P < 0.05) spontaneous contraction of the rat colon longitudinal muscle compared to controls. CONCLUSIONS: The crude extract of Catha edulis has a spasmolytic effect on the rat ileum, which is mediated through blocking Ca2+ channels, and quercetin, kaempferol, and myricetin were found to be the causative compounds.

Kaurene as the major constituent of the essential oils of the narcotic plant, Khat (Catha edulis Forsk).

Khat (Catha edulis Forsk) is a narcotic plant which contains significant amounts of amphetamines, like alkaloids. Herein, analysis of the essential oil composition showed that Khat has useful volatile chemicals in addition to its alkaloids. Results indicated that among 35 identified constituents including mono and sesquiterpenes, the diterpene kaurene, comprises the major part of the essential oil, around 50 percent of total. Kaurene is known as a potent biological agent for the treatment of cancer patients. The presence of kaurene at high levels indicates that the essential oil of Catha edulis can potentially be more effectively exploited rather than its narcotic stimulant amphetamine-like alkaloids.

Effect of 95% Ethanol Khat Extract and Cathinone on in vitro Human Recombinant Cytochrome P450 (CYP) 2C9, CYP2D6, and CYP3A4 Activity.

BACKGROUND AND OBJECTIVE: A significant number of people worldwide consume khat on daily basis. Long term of khat chewing has shown negative impact on several organ systems. It is likely that these people are co-administered khat preparations and conventional medication, which may lead to khat-drug interactions. This study aimed to reveal the inhibitory potencies of khat ethanol extract (KEE) and its major active ingredient (cathinone) on human cytochrome P450 (CYP) 2C9, CYP2D6, and CYP3A4 enzymes activities, which are collectively responsible for metabolizing 70-80% clinically used drugs. METHODS: In vitro fluorescence-based enzyme assays were developed and the CYP enzyme activities were quantified in the presence and absence of KEE and cathinone employing Vivid® CYP450 Screening Kits. RESULTS: KEE inhibited human CYP2C9, CYP2D6, and CYP3A4 enzyme activities with IC50 of 42, 62, and 18 µg/ml. On the other hand, cathinone showed negligible inhibitory effect on these CYPs. Further experiments with KEE revealed that KEE inhibited CYP2C9 via non-competitive or mixed mode with Ki of 14.7 µg/ml, CYP2D6 through competitive or mixed mode with Ki of 17.6 µg/ml, CYP3A4 by mixed inhibition mode with Ki of 12.1 µg/ml. CONCLUSION: Khat-drug interactions are possible due to administration of clinical drugs metabolized by CYP2C9/CYP2D6/CYP3A4 together with khat chewing. Further in vivo studies are required to confirm our findings and identify the causative constituents of these inhibitory effects.

Khat (Catha edulis Forsk) - And now there are three.

For centuries, a large number of people living in the southwestern part of the Arabian Peninsula and eastern Africa have chewed the fresh leaves and twigs of the plant Catha edulis Forsk, more commonly known as khat, for its psychostimulatory effect. The main active compound in khat is cathinone, whose synthetic derivatives form a part of the new psychoactive substances list. This review summaries the prevalence of khat use, its harvesting and consumption, the biosynthetic pathway in khat, the mechanism of action, the results from animal and human studies, and its dependence potential. It is unlikely that khat use will be prohibited in countries where it is traditionally consumed and socially acceptable unlike in other countries of the world where both the importation and the consumption of khat and cathinone is banned. Khat users being mainly Muslims prohibited from using alcohol or other drugs probably represent the largest global number of mono-drug users of an amphetamine-like stimulant. Thus, khat use represents a unique situation and a neglected area of research in Africa.