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Leaves of the Khat plant are widely consumed in the Horn of Africa, Yemen and the Jazan region of Saudi Arabia. I have investigated the mode of cardiovascular and autonomic actions of the stimulant cathine from Khat in terms of direct or indirect adrenergic actions in anaesthetised male and female rats, and in isolated tissues. Male and female rats were anaesthetised with pentobarbitone and changes in diastolic blood pressure and cardioaccelerator responses were examined in vehicle‐treated or chemically sympathectomised rats. Cathine produced marked tachycardia and smaller blood pressure responses in vehicle‐treated animals, with significant rises in heart rate occurring at cathine (0.1 mg/kg). In sympathectomised rats, cardiac actions were greatly attenuated in both male and female animals, with no differences between male and female rats. Although pressor responses to cathine were relatively small, sympathectomy significantly reduced these responses in female, but not male, rats. In rat aorta and spleen, cathine produced almost no direct contractions. It is concluded that cathine acts predominantly indirectly, presumably by the release of noradrenaline, in both male and female rats to produce cardiovascular actions. This may have implications for adverse cardiovascular actions of consumption of the plant Khat, particularly with dried Khat, in which actions of cathine may predominate over those of cathinone. [ABSTRACT FROM AUTHOR]

Khat leaves, indigenous to eastern Africa, have been chewed for centuries for their stimulant effects, attributed to alkaloids such as cathinone and cathine. Although associated with gastric disorders like gastritis and gastro-oesophageal reflux disease, the underlying molecular mechanisms remain unclear. This study aimed to examine the morpho-anatomy of khat leaves using light microscopy and histochemistry and to assess the effects of leaf extracts and alkaloids on human gastric epithelial cells (GES-1). The study identified specific cells in the palisade–spongy transition zone as storage sites for psychoactive alkaloids. Leaf extracts were prepared by mimicking the chewing process, including a prolonged salivary phase followed by a gastric phase. Cytotoxicity and cell viability were evaluated using LDH and MTT assays, respectively. Additionally, the impact on IL-8 secretion, a key chemokine in gastric inflammation, was analysed under normal and TNF-α-stimulated conditions. The results showed no increase in cytotoxicity up to 250 µg/mL. However, there was a significant decrease in cell metabolism and a reduction in both basal and TNF-α-induced IL-8 secretion, but cathinone and cathine were inactive. These findings suggest that khat may not directly cause the gastric issues reported in the literature, which would rather be attributed to other confounding factors, highlighting the need for further research to clarify its biological impacts. [ABSTRACT FROM AUTHOR]

Khat leaves, indigenous to eastern Africa, have been chewed for centuries for their stimulant effects, attributed to alkaloids such as cathinone and cathine. Although associated with gastric disorders like gastritis and gastro-oesophageal reflux disease, the underlying molecular mechanisms remain unclear. This study aimed to examine the morpho-anatomy of khat leaves using light microscopy and histochemistry and to assess the effects of leaf extracts and alkaloids on human gastric epithelial cells (GES-1). The study identified specific cells in the palisade–spongy transition zone as storage sites for psychoactive alkaloids. Leaf extracts were prepared by mimicking the chewing process, including a prolonged salivary phase followed by a gastric phase. Cytotoxicity and cell viability were evaluated using LDH and MTT assays, respectively. Additionally, the impact on IL-8 secretion, a key chemokine in gastric inflammation, was analysed under normal and TNF-α-stimulated conditions. The results showed no increase in cytotoxicity up to 250 µg/mL. However, there was a significant decrease in cell metabolism and a reduction in both basal and TNF-α-induced IL-8 secretion, but cathinone and cathine were inactive. These findings suggest that khat may not directly cause the gastric issues reported in the literature, which would rather be attributed to other confounding factors, highlighting the need for further research to clarify its biological impacts.

Khat (Catha edulis) is an evergreen shrub whose buds and leaves give a state of delight and euphoria when chewed. Cathinone, an amphetamine-like stimulant that is among the active ingredients in khat, is able to downregulate glutamate transporter subtype I (GLT-1). Neurobehavioral dysfunctions such as altered locomotor activity, anorexia, and nociception have been observed in animals exposed to cathinone. Interestingly, treatment with a β-lactam antibiotic such as ceftriaxone, which upregulates GLT-1, normalizes cathinone-induced conditioned place preference, and alters repetitive movements in rats. However, little is known about the role of the glutamatergic system in memory dysfunction and anxiety-like behaviors in mice exposed to khat. We found here that clavulanic acid, a β-lactam-containing compound and GLT-1 upregulator, would modulate the neurobehavioral changes, including memory impairment and anxiety-like behaviors, associated with repeated exposure of mice to khat. Our data supported that clavulanic acid could improve memory impairment and anxiety-like behaviors through upregulating GLT-1 in the nucleus accumbens (NAc), an effect abolished with a selective GLT-1 blocker. This upregulation was associated with restored glutamate/cystine antiporter expression in the NAc using a Western blotting assay. Cathine and cathinone were identified in khat extract using the gas chromatography technique. Our work provides preclinical insight into the efficacy of β-lactam-containing compounds for the attenuation of neurobehavioral changes induced by khat exposure. [ABSTRACT FROM AUTHOR]

In the current work, an enantioselective imprinting technique was used to develop a very selective adsorbent for the (+)‐cathine ((+)‐Cat) enantiomer. The phenolic sulfonamide produced from 2,4‐dihydroxybenzenesulfonic acid (HBS) and (+)‐Cat ((+)‐Cat‐HBS) was initially synthesized by triphenylphosphene activation and subsequently involved in condensation polymerization with resorcinol in the presence of formaldehyde under acidic conditions. Alkaline sulfonamide bond‐breaking was subsequently employed to separate the (+)‐Cat template from the polymer, and the resulting imprinted resin ((+)‐CIP) displayed high selectivity for the (+)‐Cat, with a capacity of 225 ± 2 mg/g. Studies of selectivity also showed that the (+)‐Cat enantiomer was preferred over its counterpart because of the development of configurationally matching receptors. In addition, the produced resin was used for the enantioresolution of (±)‐Cat racemate by column method, yielding a loading supernatant solution with an enantiomeric excess of (+)‐Cat 50% and a recovery eluant solution with an excess of (−)‐Cat 85%. [ABSTRACT FROM AUTHOR]

Novel psychoactive substances (NPS) are a very diverse group of recreational drugs that mimic effects of classic drugs of abuse and, at least at the beginning, are not usually prohibited. Representative of this group is mephedrone – a cathinone derivative. It is widely used as a recreational drug, particularly among club guests. Mephedrone`s effects are compared to effects of cocaine and MDMA but are more short-lived and include: psychostimulation, enhanced empathy, reduced feeling of tiredness, euphoria, hallucinations. This drug also exerts adverse effects, such as: anxiety, delusions, paranoia, psychosis, increased body temperature, elevated blood pressure, sleep disturbances. According to surveys performed on mephedrone users, it may be addictive. Those findings confirms a growing number of behavioural and molecular studies on animals. Mephedrone acts mainly via increasing monoamine transmission through increasing release of dopamine, serotonin and noradrenaline into synaptic cleft, inhibiting their re-uptake and reducing their metabolism. However, participation of other transmitters, modulators and pathways are investigated, including glutamate and nitric oxide. Favorable routes of administering mephedrone is intranasal and per os. Moreover, most often drug users use it in a binge way, e.g. taking repeated doses of a drug in a short period of time. According to animal studies, this pattern of mephedrone use leaves more neural injuries than taking it regularly, but in smaller doses. Our aim was to present a short, but essential, overview of the current knowledge on mephedrone, focusing on its effects, mechanism of action, animal studies evaluating its influence on the brain structures, toxicity and pharmacokinetics.

Interpreting fatalities involving khat is challenging due to a lack of data on cathinone and cathine reference concentrations in postmortem tissues. This study investigated the autopsy findings and toxicological results of fatalities involving khat in Saudi Arabia's Jazan region from 1 January 2018 to 31 December 2021. All confirmed cathine and cathinone results in postmortem blood, urine, brain, liver, kidney, and stomach samples were recorded and analyzed. Autopsy findings and the manner and cause of death of the deceased were assessed. Saudi Arabia's Forensic Medicine Center investigated 651 fatality cases over four years. Thirty postmortem samples were positive for khat's active constituents, cathinone and cathine. The percentage of fatalities involving khat was 3% in 2018 and 2019 and increased from 4% in 2020 to 9% in 2021, when compared with all fatal cases. They were all males ranging in age from 23 to 45. Firearm injuries (10 cases), hanging (7 cases), road traffic accident (2 cases), head injury (2 cases), stab wounds (2 cases), poisoning (2 cases), unknown (2 cases), ischemic heart disease (1 case), brain tumor (1 case), and choking (1 case) were responsible for the deaths. In total, 57% of the postmortem samples tested positive for khat only, while 43% tested positive for khat with other drugs. Amphetamine is the drug most frequently involved. The average cathinone and cathine concentrations were 85 and 486 ng/mL in the blood, 69 and 682 ng/mL in the brain, 64 and 635 ng/mL in the liver, and 43 and 758 ng/mL in the kidneys, respectively. The 10th–90th percentiles of blood concentrations of cathinone and cathine were 18–218 ng/mL and 222–843 ng/mL, respectively. These findings show that 90% of fatalities involving khat had cathinone concentrations greater than 18 ng/mL and cathine concentrations greater than 222 ng/mL. According to the cause of death, homicide was the most common fatality involving khat alone (77%). More research is required, especially toxicological and autopsy findings, to determine the involvement of khat in crimes and fatalities. This study may help forensic scientists and toxicologists investigate fatalities involving khat. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

Cathine is the stable form of cathinone, the major active compound found in khat (Catha edulis Forsk) plant. Khat was found to inhibit major phase I drug metabolizing cytochrome P450 (CYP) enzyme activities in vitro and in vivo. With the upsurge of khat consumption and the potential use of cathine to combat obesity, efforts should be channelled into understanding potential cathine-drug interactions, which have been rather limited. The present study aimed to assess CYPs activity and inhibition by cathine in a high-throughput in vitro fluorescence-based enzyme assay and molecular docking analysis to identify how cathine interacts within various CYPs' active sites. The half maximal inhibitory concentration (IC50) values of cathine determined for CYP2A6 and CYP3A4 were 80 and 90 μM, while CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP2J2 and CYP3A5 showed no significant inhibition. Furthermore, in Ki analysis, the Lineweaver-Burk plots depicted non-competitive mixed inhibition of cathine on both CYP2A6 and CYP3A4 with Ki value of 63 and 100 μM, respectively. Cathine showed negligible time-dependent inhibition on CYPs. Further, molecular docking studies showed that cathine was bound to CYP2A6 via hydrophobic, hydrogen and π-stacking interactions and formed hydrophobic and hydrogen bonds with active site residues in CYP3A4. Both molecular docking prediction and in vitro outcome are in agreement, granting more detailed insights for predicting CYPs metabolism besides the possible cathine-drug interactions. Cathine-drug interactions may occur with concomitant consumption of khat or cathine-containing products with medications metabolized by CYP2A6 and CYP3A4. [ABSTRACT FROM AUTHOR]

Interpreting fatalities involving khat is challenging due to a lack of data on cathinone and cathine reference concentrations in postmortem tissues. This study investigated the autopsy findings and toxicological results of fatalities involving khat in Saudi Arabia’s Jazan region from 1 January 2018 to 31 December 2021. All confirmed cathine and cathinone results in postmortem blood, urine, brain, liver, kidney, and stomach samples were recorded and analyzed. Autopsy findings and the manner and cause of death of the deceased were assessed. Saudi Arabia’s Forensic Medicine Center investigated 651 fatality cases over four years. Thirty postmortem samples were positive for khat’s active constituents, cathinone and cathine. The percentage of fatalities involving khat was 3% in 2018 and 2019 and increased from 4% in 2020 to 9% in 2021, when compared with all fatal cases. They were all males ranging in age from 23 to 45. Firearm injuries (10 cases), hanging (7 cases), road traffic accident (2 cases), head injury (2 cases), stab wounds (2 cases), poisoning (2 cases), unknown (2 cases), ischemic heart disease (1 case), brain tumor (1 case), and choking (1 case) were responsible for the deaths. In total, 57% of the postmortem samples tested positive for khat only, while 43% tested positive for khat with other drugs. Amphetamine is the drug most frequently involved. The average cathinone and cathine concentrations were 85 and 486 ng/mL in the blood, 69 and 682 ng/mL in the brain, 64 and 635 ng/mL in the liver, and 43 and 758 ng/mL in the kidneys, respectively. The 10th–90th percentiles of blood concentrations of cathinone and cathine were 18–218 ng/mL and 222–843 ng/mL, respectively. These findings show that 90% of fatalities involving khat had cathinone concentrations greater than 18 ng/mL and cathine concentrations greater than 222 ng/mL. According to the cause of death, homicide was the most common fatality involving khat alone (77%). More research is required, especially toxicological and autopsy findings, to determine the involvement of khat in crimes and fatalities. This study may help forensic scientists and toxicologists investigate fatalities involving khat.

Background Molecular docking is commonly used in the study of small-molecule–protein interaction. Amphetamine (AMPH), cathine (CATHI), and cathinone (CATHO) bind in silico with monoamine oxidase B (MAO B) with relatively low affinity. Objective The purpose of the study was to determine the binding modes of AMPH, CATHI, and CATHO with the enzyme MAO B. Molecular docking software, AutoDock 4.2, was used to study the interaction of these ligands with MAO B. Materials and methods Molecular docking was performed using the molecular docking software AutoDock, version 4.2. graphic user interface, AutoDock Tools, was used to prepare protein and ligands for docking. Results The estimated ΔG of binding (free energy of binding) was −6.25 kcal/mol for AMPH, −6.05 kcal/mol for CATHI, and −6.24 kcal/mol for CATHO. Respective Ki (inhibitor constant) values were 2.61×10−5 M, 3.69×10−5 M, and 2.69×10−5 M. All three ligands show similar interactions within active site which include hydrophobic and hydrogen-bonding interactions. When compared with binding affinity of known inhibitors of MAO, safinamide, the binding affinity of these inhibitors is substantially less. But, they bind in the same active site and share some common interactions with active site residues. Similarity in binding modes of AMPH, CATHI, and CATHO is due to their similar structures. Conclusion It can be speculated that nervous stimulant activity of AMPH, CATHI, and CATHO could be due to inhibition of MAO. This enzyme catalyzes the oxidative deamination of monoamine neurotransmitters such as serotonin and dopamine and reduces the level of these neurotransmitters. Inhibition of this enzyme might result in more sustained levels of these neurotransmitters. Our docking study shows that AMPH, CATHI, and CATHO inhibit MAO B with free energy ranging from −6.05 to −6.25 kcal/mol and Ki ranging from 2.61×10−5 to 3.69×10−5 M.

This letter is a response to Letter to the Editor (Corkery J, Schifano F, Guirguis A. Commentary on: Attafi IM, Albeishy MY, Oraiby ME, Khardali IA, Shaikhain GA, Fageeh MM. Postmortem Distribution of Cathinone and Cathine in Human Biological Specimens in a Case of Death Associated with Khat Chewing. Arab J Forensic Sci Forensic Med. 2018 Jun 7;1(7). Arab Journal of Forensic Sciences & Forensic Medicine. 2019 Dec 31;1(10):1473-1475).

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.

Abstract Background Khat (Catha edulis Forsk) is an evergreen shrub of the Celastraceae family. It is widely cultivated in Yemen and East Africa, where its fresh leaves are habitually chewed for their momentary pleasures and stimulation as amphetamine-like effects. The main psychostimulant constituents of khat are the phenylpropylamino alkaloids: cathinone, cathine and norephedrine. Results In this study, simple procedures based on preparative HPLC and salting-out assisted liquid–liquid extraction (SALLE) based methods were developed respectively for large scale isolation and the extraction of psychoactive phenylpropylamino alkaloids; cathinone, cathine and norephedrine, from khat (Catha edulis Forsk) chewing leaves, a stimulant and drug of abuse plant. The three khat alkaloids were directly isolated from the crude oxalate salt by preparative HPLC–DAD method with purity > 98%. In addition, a modified (SALLE) method has been developed and evaluated for the extraction efficiency of psychoactive phenylpropylamino alkaloids from khat (Catha edulis Forsk) chewing leaves. An in situ two steps extraction protocol was followed without dispersive SPE clean up. The method involves extraction of the samples with 1% HAc and QuEChERS salt (1.0 g of CH3COONa and 6.0 g of MgSO4) followed by subsequent in situ liquid–liquid partitioning by adding ethyl acetate and NaOH solution. The optimized method allowed recoveries of 80–86% for the three alkaloids from khat sample with relative standard deviation (RSD) values less than 15% and limits of detection (0.85–1.9 μg/mL). Conclusion The method was found to be simple, cost-effective and provides cleaner chromatogram with good selectivity and reproducibility. The SALLE based protocol provided as good results as the conventional extraction method (ultrasonic assisted extraction followed by solid phase extraction, UAE–SPE) and hence the method can be applicable in forensic and biomedical sectors.

Objective: To investigate the efficacy and safety of increasing doses of cathine (nor-pseudoephedrine) as a weight-lowering agent in patients with obesity. Methods: Overweight and obese patients (n = 241, mean BMI 34.6 ± 3.4 kg/m²) were randomly allocated to one of three doses of cathine (16 mg, 32 mg, 53.3 mg) or placebo in addition to a multimodal lifestyle intervention program in a multicenter, double-blind, controlled, dose-finding study for 24 weeks. Primary outcome was weight loss. Results: Treatment with the 3 doses of cathine resulted in a significantly greater weight loss compared to placebo over 24 weeks: 6.5 ± 4.2 kg for 16 mg cathine, 6.2 ± 4.7 kg for 32 mg cathine, and 9.1 ± 5.4 kg for 53.3 mg cathine versus 2.4 ± 4.4 kg for placebo (each p 5% / >10% of initial body weight was significantly greater for all doses of cathine than for placebo (each p Conclusion: Cathine appears to be an effective weight-lowering agent for adjunct treatment of obesity, but additional clinical studies on its efficacy and safety are required.

Toxicology screening of unusual poisons is important. We report a case of death of a young female suspected to die due to drug overdose. Medico legal autopsy was indicative of cerebral hemorrhage. The deceased had no previous history of drug dependence. Toxicological analysis revealed the presence of cathine {(+)-norpseudoephedrine} and alcohol in the blood. The concentration of ethyl alcohol in blood was determined as 85.57 mg per dL. An overview of toxicology of cathine and its side effects are presented. The reports due to fatal intoxication of cathine in combination with alcohol are rarely reported. The present case substantiates that an intake of low potent drug like cathine in combination with alcohol can cause fatal intoxication.

Background: Cathinone is a natural stimulant found in the Catha edulis plant. Its derivatives make up the largest group of new psychoactive substances. In order to better understand its effects, it is imperative to investigate its distribution, pharmacokinetics, and metabolic profile. However, the existing literature on cathinone remains limited., Objective: This study aimed to investigate the disposition kinetics and metabolic profile of cathinone and its metabolite cathine through a single oral dose of cathinone administration in rats., Methods: Cathinone and cathine concentrations were identified and quantified using ion trap liquid chromatography- mass spectrometry (LC-IT/MS). The metabolic profile in the serum, brain, lung, liver, kidney, and heart was analyzed at specific time points (0, 0.5, 2.5, 6, 12, 24, 48, and 72 hours) using the ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS) method., Results: The highest concentration of cathinone was found in the kidney (1438.6 μg/L, which gradually decreased to 1.97 within 48 h and disappeared after 72 h. Cathinone levels in the lungs, liver, and heart were 859, 798.9, and 385.8 μg/L, respectively, within half an hour. However, within 2.5 hours, these levels decreased to 608.1, 429.3, and 309.1 μg/L and became undetectable after 24 h. In the rat brain, cathinone levels dropped quickly and were undetectable within six hours, decreasing from 712.7 μg/L after 30 min. In the brain and serum, cathine reached its highest levels at 2.5 hours, while in other organs, it peaked at 0.5 hours, indicating slower conversion of cathinone to cathine in the brain and serum., Conclusion: This study revealed a dynamic interplay between cathinone disposition kinetics and its impact on organ-specific metabolic profiles in rats. These results have significant implications for drug development, pharmacovigilance, and clinical practices involving cathinone. Investigating the correlation between the changes in biomarkers found in the brain and the levels of cathinone and cathine is essential for informed decision- making in medical practices and further research into the pharmacological properties of cathinone., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Chewing khat leaves has been associated with several adverse health effects, and there are very few case reports of cardiotoxicity, stroke and death resulting from this. In addition, postmortem distribution of cathine and cathinone, active components of khat, are not yet fully clear. This postmortem case report aimed to identify and determine the concentration of cathine and cathinone in different body organs and green chewed plants found in the mouth of the deceased. Immunoassay and non-targeted GC-MS analysis showed that samples were only positive for amphetamine type stimulants. LC-MS/MS quantitative analysis confirmed that samples were positive for cathinone and cathine. The results showed that cathinone concentration was 0.03, 0.03, 0.06, 0.07, 1.85 and 31 μg/ml in brain, liver, blood, vitreous humor, stomach and chewed green plant, respectively. Whereas, the concentration of cathine was 0.31, 3.28, and 141 μg/ml in kidney, stomach and chewed green plant, respectively. Cathine and cathinone concentrations were found to be changed with respect to site of sampling. The results suggest that stomach and chewed green plants are considered as good samples to show the concentration for both cathine and cathinone at the time of death of the khat chewer.

Background: Catha edulis is an evergreen plant belonging to the Celastraceae family, used by the people of Africa, Yemen, and some part of Saudi Arabia as a recreational plant. They chew it alone or in combination with alcohol for attaining euphoria. Objective: There are contradictory studies in the genotoxic potential of the leaves of this plant. So far, the accomplished studies were conducted with much high doses. Hence, the current study has been designed to check the genotoxicity of khat-leaves extract with subcytotoxic concentration in human peripheral blood lymphocytes. Materials and Methods: We have employed comet assay, micronuclei (MN) analysis, and Ames test to evaluate the objectives. Results: The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay has revealed that there is a dose-dependent reduction in cell viability with an IC50value of 76.5 μg/ml at 24-h treatment. The results of the comet assay have showed a nonsignificant difference between control and treatment up to 40 μg/ml extract. There was no dose-dependent increase in the frequency of binucleated cells with MN and reduction of cell proliferation in all the doses. The extract showed no mutagenic effect, in both TA98 and TA100 strains even with S9 activation. Conclusion: Under the experimental conditions employed in the present study, khat has been found to be nongenotoxic at subcytotoxic level. Abbreviations used: DMSO: Dimethyl sulfoxide; GIT: gastrointestinal tract; HPBL: Human peripheral blood lymphocytes; KCL: Potassium chloride; LCQ: Low-content quantification; MMC: Mitomycin C; RPMI: Roswell park memorial institute; SWGDRUG: Scientific working group for seized drugs. [ABSTRACT FROM AUTHOR]

Background: Khat ( Catha edulis Forsk) is an evergreen shrub of the Celastraceae family. It is widely cultivated in Yemen and East Africa, where its fresh leaves are habitually chewed for their momentary pleasures and stimulation as amphetamine-like effects. The main psychostimulant constituents of khat are the phenylpropylamino alkaloids: cathinone, cathine and norephedrine. Results: In this study, simple procedures based on preparative HPLC and salting-out assisted liquid-liquid extraction (SALLE) based methods were developed respectively for large scale isolation and the extraction of psychoactive phenylpropylamino alkaloids; cathinone, cathine and norephedrine, from khat ( Catha edulis Forsk) chewing leaves, a stimulant and drug of abuse plant. The three khat alkaloids were directly isolated from the crude oxalate salt by preparative HPLC-DAD method with purity > 98%. In addition, a modified (SALLE) method has been developed and evaluated for the extraction efficiency of psychoactive phenylpropylamino alkaloids from khat ( Catha edulis Forsk) chewing leaves. An in situ two steps extraction protocol was followed without dispersive SPE clean up. The method involves extraction of the samples with 1% HAc and QuEChERS salt (1.0 g of CHCOONa and 6.0 g of MgSO) followed by subsequent in situ liquid-liquid partitioning by adding ethyl acetate and NaOH solution. The optimized method allowed recoveries of 80-86% for the three alkaloids from khat sample with relative standard deviation (RSD) values less than 15% and limits of detection (0.85-1.9 μg/mL). Conclusion: The method was found to be simple, cost-effective and provides cleaner chromatogram with good selectivity and reproducibility. The SALLE based protocol provided as good results as the conventional extraction method (ultrasonic assisted extraction followed by solid phase extraction, UAE-SPE) and hence the method can be applicable in forensic and biomedical sectors. [ABSTRACT FROM AUTHOR]

Objective: To investigate the efficacy and safety of increasing doses of cathine (nor-pseudoephedrine) as a weight-lowering agent in patients with obesity. Methods: Overweight and obese patients (n = 241, mean BMI 34.6 ± 3.4 kg/m²) were randomly allocated to one of three doses of cathine (16 mg, 32 mg, 53.3 mg) or placebo in addition to a multimodal lifestyle intervention program in a multicenter, double-blind, controlled, dose-finding study for 24 weeks. Primary outcome was weight loss. Results: Treatment with the 3 doses of cathine resulted in a significantly greater weight loss compared to placebo over 24 weeks: 6.5 ± 4.2 kg for 16 mg cathine, 6.2 ± 4.7 kg for 32 mg cathine, and 9.1 ± 5.4 kg for 53.3 mg cathine versus 2.4 ± 4.4 kg for placebo (each p < 0.01, ANCOVA). The percentage of patients losing > 5% / >10% of initial body weight was significantly greater for all doses of cathine than for placebo (each p < 0.01, chi-square test). Heart rate increased dose-dependently (by 1.2 bpm under 16 mg, 5.8 bpm under 32 mg, and 6.2 bpm under 53.3 mg cathine), but no suspected unexpected serious adverse reactions were noted. The overall dropout rate was 24.9%, with the highest rate in the placebo group (42.3%). Conclusion: Cathine appears to be an effective weight-lowering agent for adjunct treatment of obesity, but additional clinical studies on its efficacy and safety are required. [ABSTRACT FROM AUTHOR]

Toxicology screening of unusual poisons is important. We report a case of death of a young female suspected to die due to drug overdose. Medico legal autopsy was indicative of cerebral hemorrhage. The deceased had no previous history of drug dependence. Toxicological analysis revealed the presence of cathine {(+)-norpseudoephedrine} and alcohol in the blood. The concentration of ethyl alcohol in blood was determined as 85.57 mg per dL. An overview of toxicology of cathine and its side effects are presented. The reports due to fatal intoxication of cathine in combination with alcohol are rarely reported. The present case substantiates that an intake of low potent drug like cathine in combination with alcohol can cause fatal intoxication. [ABSTRACT FROM AUTHOR]

The study demonstrated that by freezing or drying under different conditions, cathinone could be detected in the khat (Catha edulis Forsk) samples that have been harvested for more than four months. Freeze drying or freezing in the refrigerator (-20 oC) yielded more than 73% of cathinone. Air drying, sun drying or oven drying at 60 oC resulted in a cathinone composition of 57%, 42% and 36%, respectively. The study confirmed that, freshly harvested tender leaves of khat contained exclusively of cathinone but upon sun drying, part of it decomposes to cathine and norephedrine leaving cathinone as a major component. Thus it is wrong to assume that sun drying the leaves can result complete conversion of cathinone to cathine and norephedrine. Furthermore, the results of the study confirmed that it was possible to preserve khat samples for longer periods after freeze drying or deep freezing without significant loss of cathinone.DOI: http://dx.doi.org/10.4314/bcse.v27i3.3

Khat ( Catha edulis) belongs to Celastraceae family which contains 60-70 genera and 850-900 species. It is an indigenous plant to Ethiopia and Yemen as the countries of origin. It is also found in many other east and southern African countries. Khat leaves are chewed by the local people for their stimulant action. The main active ingredient compounds those are responsible for this action is cathinone and a mild stimulant cathine. In addition to these khat contains several phytochemicals such as alkaloids (phenylalkylamines and cathedulins), flavonoids, steroid and triterpenoids, monoterpenes and volatile aromatic compounds, and other miscellaneous compounds like vitamins and amino acids. Hence, this paper presents a comprehensive and unified review of literatures which concerned on the phytochemical composition of khat plant. And it also provides the isolated compounds with their chemical structures. [ABSTRACT FROM AUTHOR]

A molecularly imprinted polymer (MIP) was prepared using (−)-norephedrine as the template, methacrylic acid as the functional monomer, ethylene glycol dimethacrylate as the cross-linker and chloroform as the porogen. The MIP was used as a selective sorbent in the molecularly imprinted solid-phase extraction (MIP-SPE) of the psychoactive phenylpropylamino alkaloids, norephedrine and its analogs, cathinone and cathine, from Khat ( Catha edulis Vahl. Endl.) leaf extracts prior to HPLC-DAD analysis. The MIP was able to selectively extract the alkaloids from the aqueous extracts of Khat. Loading, washing and elution of the alkaloids bound to the MIP were evaluated under different conditions. The clean baseline of the Khat extract obtained after MIP-SPE confirmed that a selective and efficient sample clean-up was achieved. Good recoveries (90.0-107%) and precision (RSDs 2.3-3.2%) were obtained in the validation of the MIP-SPE-HPLC procedure. The content of the three alkaloids in Khat samples determined after treatment with MIP-SPE and a commercial Isolute C18 (EC) SPE cartridge were in good agreement. These findings indicate that MIP-SPE is a reliable method that can be used for sample pre-treatment for the determination of Khat alkaloids in plant extracts or similar matrices and could be applicable in pharmaceutical, forensic and biomedical laboratories. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

A literature criticism is given on methods using currently gas chromatography mass spectrometry (GC/MS) to determine cathine (CAT), cathinone (CTN) and norephedrine (NE), jointly khatamines. In this study, khatamines’ oximation, trimethylsilylation and mass fragmentation properties—applying N -Methyl- N -(trimethylsilyl)trifluoroacetamide (MSTFA), its trimethyliodosilane (TMIS) catalyst containing version (MSTFA TMIS ), N , O -bis(trimethylsilyl)trifluoroacetamide (BSTFA) and hexamethyldisilazane (HMDS)—was highlighted, at first. Derivatization, mass fragmentation and quantitation related, optimized model investigations have been carried out as a function of the reaction times and conditions. Special emphasis was put (i) on the stability of the primarily formed (CAT-2TMS, NE-2TMS, CTN-TMS(TMS-oximes) 1,2 ), then transformed, fully derived (CAT-3TMS, NE-3MTS, CTN-2TMS(TMS-oximes) 1,2 ) species, and, (ii) on the proportionally formed stable products, suitable to selective quantitation of all three natural amines, simultaneously. Results, as novelty to the field confirmed that (i) TMIS catalyzed trimethylsilyation triggers to form fully derivatized species unfortunately, in part only; while, (ii) khatamines’ simultaneous quantitation needs to be carried out in a two steps derivatization process consisting of oximation (1st step, hydroxylamine in pyridine) and trimethylsilylation (2nd step, MSTFA), to the CAT-2TMS, NE-2TMS, CTN-TMS(TMS-oximes) 1,2 . These species were characterized with their retention, mass fragmentation and analytical performance properties, in model solutions and in the presence of plant tissues, as well: R 2 , limit of quantitation (LOQ) data, expressed in pg/1 μL injection basis, proved to be 62.5 pg (CAT), 20 pg (NE) and 62.5 pg (CTN), respectively. The practical utility of proposal was enormously enhanced by the novel, direct sample preparation method. In this process, the freshly harvested, freeze-dried, then pulverized leaves of Catha edulis FORKS were directly derivatized, in the presence of the matrix. Reproducibility (in average 2.07 RSD% varying between 0.15 and 5.5 RSD%), linearity (0.9990–0.9994) and recovery (95.7–99.1%) values of the new sample preparation protocol was confirmed by the standard addition method for CAT, NE and CTN equally. From plant leaf, 0.061 w/w% CAT and 0.014 w/w% NE contents were obtained. In this tissue CTN was not found. Very likely attributable to the unfavorable climate for the plant: grown in Hungary of temperate zone and naturalized in the tropical Africa. [ABSTRACT FROM AUTHOR]

Highlights: [•] GC/MS and GC/FID analysis of Catha edulis vegetable material seized in Italy in 2012. [•] Optimization and validation of the analytical method. [•] Determination of cathinone, cathine and phenylpropanolamine. [Copyright &y& Elsevier]

A capillary electrophoretic method, which allowed the detection and separation of the active principles of Catha edulis, i.e. cathinone, cathine and phenylpropanolamine, was developed. A suitable internal standard (nicotinamide), which permitted the quantification of the analytes reducing the variability of the migration times due to EOF changes, was identified. The analytical method was validated, assessing linearity, sensitivity and repeatability, showing optimal features for the analysis of the vegetable material. Moreover extraction conditions were investigated to achieve the exhaustion of the plant material in the fastest and most efficient way to meet the requirements of the Court. [ABSTRACT FROM AUTHOR]

A fast and simple procedure based on matrix solid-phase dispersion was developed for the extraction of psychoactive phenylpropylamino alkaloids; cathinone, cathine and norephedrine, from khat ( Catha edulis Forsk) chewing leaves, a stimulant and drug of abuse plant. Determination of the alkaloids was carried out by high performance liquid chromatography with diode array detection. Several extraction parameters, such as type of dispersant, type and volume of elution solvent and the ratio of sample to sorbent material were evaluated and optimized. Mean recoveries ranging from 89 to 92 % with relative SD of less than 6 % were obtained. A marked diversity in the phenylpropylamino alkaloid content and composition was found in seventeen different cultivars of Ethiopian khat. ANOVA results showed the existence of significant differences between the alkaloids profiles among samples of different varieties from different geographical locations in Ethiopia. The proposed method is simpler, faster and comparably more efficient than the frequently reported maceration followed by liquid-liquid extraction but as good and efficient as ultrasonic assisted extraction followed by solid-phase extraction. [ABSTRACT FROM AUTHOR]

Due to its stimulatory effects on the central nervous system, and its structural similarity to banned stimulants such as ephedrine and methamphetamine, pseudoephedrine (PSE) at high doses is considered as an ergogenic aid for boosting athletic performance. However, the status of PSE in the International Standard of the Prohibited List as established under the World Anti-Doping Code has changed over the years, being prohibited until 2003 at a urinary cut-off value of 25 µg/ml, and then subsequently removed from the Prohibited List during the period 2004-2009. The re-consideration of this position by the World Anti-Doping Agency (WADA) List Expert Group has led to the reintroduction of PSE in the Prohibited List in 2010. In this manuscript, we present the results of two WADA-sponsored clinical studies on the urinary excretion of PSE and its metabolite cathine (CATH) following the oral administration of different PSE formulations to healthy individuals at therapeutic regimes. On this basis, the current analytical urinary threshold for the detection of PSE as a doping agent in sport has been conservatively established at 150 µg/ml Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: In the last years, all the vegetable material supposed to belong to the Catha Edulis species, seized at the Malpensa and Orio al Serio airports, were analyzed in our laboratory on behalf of the Tribunals of Busto Arsizio and Bergamo, respectively. After a preliminary botanic examination, the quali–quantitative determination of the active principles cathinone, cathine and phenylpropanolamine (PPA) was carried out by means of GC/MS and GC/FID techniques, which meet the requirements of the forensic analyses. We developed a fast, effective and reliable derivatization procedure which allowed to simultaneously detect cathine and PPA, whose discrimination is mandatory since PPA is not a psychoactive agent. Cathine was distributed in the various parts of the plant (leaves and stems) and its quantity ranged from 0.03% to 0.17% of the weight of the vegetable material; PPA was not detected in the twigs and its quantity in the leaves ranged from 0.07% to 0.16%. The quantitative determination of cathinone was carried out directly on the methanol solution after maceration of the vegetable material, its quantity ranging from 0.02% to 0.10%. No significant difference in the content of the two active principles was found between the fresh and the dried material. [Copyright &y& Elsevier]

Abstract: In this study molecular imprinting technology was employed to prepare a specific affinity sorbent for the resolution of Cathine, a chiral drug product. The molecularly imprinted polymer (MIP) was prepared by non-covalent molecular imprinting with either (+) or (−)-Cathine (threo-2-amino-1-hydroxy-1-phenyl propane; norpseudoephedrine) as the template. Methacrylic acid and ethylene glycol di-methacrylate were copolymerized in the presence of the template molecule. The bulk polymerization was carried out in chloroform with 2,2′-azobisisobutyronitrile as the initiator, at 5°C and under UV radiation. The resulting MIP was ground into powders, which were slurry packed into analytical columns. After removal of template molecules, the MIP-packed columns were found to be effective for the resolution of (±)-Cathine racemates. The separation factor for the enantiomers ranged between 1.5 and 2.4 when the column was packed with MIP prepared with (+)-Cathine as the template. A separation factor ranging from 1.6 to 2.9 could be achieved from the column packed with MIP, prepared with (−)-Cathine as the template. Although the separation factor was higher with that previously obtained from reversed-phase column chromatography following derivatization with a chiral agent, elution peaks were broader due to the heterogeneity of binding sites on MIP particles and the possible non-specific interaction. [Copyright &y& Elsevier]

Aim of the study: To review the information available on the use of khat (Catha edulis) in the EU, and to assess the future use of this drug and related substances. Material and methods: Khat is not controlled by international law and it has not been systematically included in the list of illicit drugs monitored in the EU. The current principal source of information on khat use in Europe is the early-warning system set up to monitor new and emerging drugs. Further information was obtained from official national reports to the EMCDDA and from the scientific literature. Results: Across Europe, the use of khat is low. Khat use is limited to countries with immigrant communities from countries where khat use is common (such as Ethiopia, Somalia and Kenya). Information on the prevalence of khat use in the general population is scarce. Data on seizures provide an insight on the situation, though these may be difficult to interpret. The most recent estimates suggest that Europe accounts for about 40% of the khat seized worldwide. Conclusion: The shortage of data on the use and patterns of use of khat in Europe does not allow an evaluation of the needs for health and social interventions in communities in which the drug is used. But seizures of the plant are increasing in the EU, and more synthetic derivatives of the pharmacologically active ingredients of the plant (cathine and cathinone) are appearing on the market. Some of these, like mephedrone, have significant potential for future diffusion, and are likely to play a greater role on the European drug scene of the future. [Copyright &y& Elsevier]

Abstract: A primary concern with the forensic analysis of the khat plant (Catha edulis) has been the need to preserve the principle psychoactive component, cathinone, which converts to the less-active substance, cathine, after harvesting. The loss of cathinone has serious legal implications since it is a Schedule I controlled substance under federal regulations in the United States, while cathine is Schedule IV. A common misconception is that cathinone is highly unstable once the plant is harvested, and may be undetectable upon drying and prolonged storage. However, drying the plant material will preserve cathinone. Numerous seizures of a dried form of khat (referred to as “graba” in the United States) have been made in recent years, suggesting that drying the plant material is a viable approach to preserve khat evidence for both storage and reanalysis. A qualitative and quantitative study of the composition of khat samples seized as dried plant material has found the khat alkaloids to be relatively stable for a monitored period of 3 years, and cathinone has remained identifiable while stored at room temperature for over 10 years. Studies of green khat (received moist) have also determined that drying the moist leaves at either room temperature or by the application of heat are suitable methods to preserve cathinone in the dried material. These findings demonstrate that cathinone persists in dried khat for a time frame of several years, and simple drying techniques are an effective means to preserve seized khat evidence for long-term storage. [Copyright &y& Elsevier]

Abstract: Hallucinogenic mushrooms (e.g. Psilocybe and Panaeolus species) as well as leaves and young shoots of the khat tree (Catha edulis Forsk) are illicit drugs in many countries. The exact concentration of the hallucinogenic alkaloids psilocin and psilocybin in mushrooms and the sympathomimetic alkaloids cathinone and cathine in khat is usually essential for jurisdiction. Facing an increasing number of mushroom and khat seizures by German customs authorities, a convenient comprehensive quantitative HPLC method based on cation-exchange liquid chromatography for these rather “exotic” drugs has been developed which avoids time-consuming multi-step sample preparation or chemical derivatization procedures. Using this method a number of different hallucinogenic fungi species and products that are mainly distributed via the internet have been analysed (dried and fresh Psilocybe cubensis Singer as well as P. cubensis collected from “grow boxes”, Panaeolus cyanescens Berkeley and Broome and so-called “philosopher stones” (sclerotia of Psilocybe species)). Highest total amounts of psilocin have been detected in dried P. cyanescens reaching up to 3.00±0.24mg per 100mg. The distribution of khat alkaloids in different parts of the khat shoots has been studied. High concentrations of cathinone have not only been detected in leaves but also in green parts and barks of stalks. Additionally, the sample treatment for fresh mushroom and khat samples has been optimised. Highest amounts of alkaloids were found when fresh material was freeze-dried. [Copyright &y& Elsevier]