In vitro and In silico studies of interactions of cathinone with human recombinant cytochrome P450 CYP(1A2), CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2E1, CYP2J2, and CYP3A5.

Cathinone is the psychostimulatory major active ingredient of khat (Catha edulis Forsk) and are often co-abused with alcohols and polydrugs. With the increased consumption of khat and cathinones on a global scale, efforts should be channelled into understanding and minimising the excruciating effects of possible khat-drug interactions. This study aimed to determine the in vitro inhibitory effects of cathinone on CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2E1, CYP2J2 and CYP3A5 and the in silico identification of their type of interactions and residues involved. The activities of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2E1, CYP2J2 and CYP3A5 were examined by fluorescence based assays using recombinant cDNA-expressed human CYPs in Vivid® P450 screening kits. Cathinone reversibly inhibited CYP1A2, CYP2A6 and CYP3A5 via competitive, uncompetitive and noncompetitive modes with inhibition constant (Ki) values of 57.12, 13.75 and 23.57 µM respectively. Cathinone showed negligible inhibitory effects on CYP2B6, CYP2C8, CYP2C19, CYP2E1 and CYP2J2. Cathinone showed negligible time dependent inhibition on all 8 CYPs. Docking studies was performed on cathinone with CYP1A2, CYP2A6 and CYP3A5 following their inhibition in vitro. Cathinone is bound to a few key amino acid residues in the active sites while π-π interactions are formed in aromatic clusters of CYP1A2 and CYP3A5. These findings offer valuable reference for the use of cathinones and khat when combined with therapeutic drugs that are metabolised by CYP enzymes especially patients on medications metabolised by CYP1A2, CYP2A6 and CYP3A5.

Catha edulis Forsk and Ascorbic Acid Effects on Hematological Indices in Rat.

BACKGROUND: The prevalence of chewing Catha edulis Forsk and the use of ascorbic acid is increasing from time to time. Their subchronic effects on hematological indices are not well examined. The present study was aimed to investigate their subchronic effects on hematological indices in rats. MATERIALS AND METHODS: A total of 36 adult (7-8 weeks) wild-type rats weighing between 213 and 229g were used in this study. They received Catha edulis Forsk extract (Ce) (100 milligrams/kilogram, 200 milligram/kilogram and 300 milligram/kilogram b.w), Catha edulis Forsk juice (2.5 mL/kg), ascorbic acid (AA 200 milligram/kilogram), and 2% tween 80 in distilled water (T80W- v/v) for twelve weeks. Hematological indices were measured with Sysmex KX-21. Data were analyzed by SPSS version 21.0 and Microsoft Excel. RESULTS: Neutrocytes (p < 0.01), lymphocytes (p < 0.05), plateletcrit (p < 0.05), average size of platelets (p < 0.05), platelet size variability (p < 0.01), platelet-large cell ratio (p < 0.05) and neutrocytes/lymphocytes ratio (p < 0.001) were significantly greater, while hemoglobin concentration per red blood cell (p < 0.05) and hemoglobin concentration per volume of red blood cells were significantly reduced (p < 0.05) in rats received khat. The red cell distribution width (p < 0.05), platelet size variability (p < 0.05) and platelet-large cell ratio (p < 0.01) were significantly greater in rats received ascorbic acid. CONCLUSION: Crude Catha edulis Forsk extract and juice changed some hematological indices and increased platelet activities. The platelet activity was also increased by ascorbic acid. The mechanisms for these changes need to be investigated.

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.

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.

"Natural Amphetamine" Khat: A Cultural Tradition or a Drug of Abuse?

Khat, Catha edulis Forsk, is among the most widely used plant-based psychoactive substance in the world. Grown in Eastern Africa, Horn of Africa, and southwestern part of the Arabian Peninsula, its fresh young leaves and twigs are used daily by over 20 million people for the psychostimulatory effects it produces in the user, a practice deeply rooted in the history, tradition, and culture of the indigenous population. Once hardly known outside the regions where it is grown and used, khat use has now spread to other countries. This review will cover the, phytochemistry, pharmacokinetics of the active ingredients-cathinone, cathine, norephedrine, neurochemistry, effects on cognitive and executive functions as well as its ability to produce dependency in the user. Whether it is an innocuous cultural practice or a drug of abuse is debatable as the preclinical and clinical data needed to arrive at an authoritative conclusion is lacking.