Cathinone

Discovery Khat has been cultivated in the Horn of Africa and Arabian Peninsula region of the world for thousands of years. It is most commonly chewed for the euphoric effect it produces. The active ingredient was first proposed in 1930, when cathine was identified as a predominant alkaloid in the plant. Cathine was thought to be the main active ingredient in khat until the 1960s, when it was found that the amount of cathine in the khat leaves is insufficient to produce the effects observed. In 1975, the United Nations Narcotic Laboratory analyzed khat leaves from Yemen, Kenya and Madagascar and found evidence of a different alkaloid, cathinone. The researchers analyzed the participants' moods, activity levels and blood pressure before and after consuming the khat or placebo. This analysis showed that cathinone produced amphetamine-like effects, leading the researchers to confirm that cathinone, not cathine, is the active ingredient in khat leaves. In order to produce its desired effects, khat leaves should be chewed fresh. The fresh leaves have a higher concentration of cathinone. Waiting too long after cultivation to chew the leaf will allow the cathinone to break down into its less potent form, cathine. Because of the need for quick chewing, it is a habit that has historically been prevalent only where the plant grows. However, in the recent years with improvements in road and air transport, khat chewing has spread to all corners of the world. The cultivation of khat in Yemen is a highly profitable industry for farmers. Khat plants will grow differently depending on the climate they are grown in and each one will produce different amounts of cathinone. It generally grows best in coastal, hot climates. In Yemen, the khat plant is named after the region in which it is grown. The Nehmi khat plant has the highest known concentration of cathinone, 342.5 mg/100 g. Circa 1993, the DEA added cathinone to the Controlled Substances Act's Schedule I. The sale of khat is legal in some jurisdictions, but illegal in others (see Khat (Regulation)). Substituted cathinones were also often used as the key ingredient of recreational drug mixes commonly known as "bath salts" in the United States. The table below shows the legality of khat and cathinone in various countries: ==Pharmacology==

Pharmacodynamics Cathinone has been found to stimulate the release of dopamine and inhibit the reuptake of epinephrine, norepinephrine and serotonin in the central nervous system (CNS). These neurotransmitters are all considered monoamines and share the general structure of an aromatic ring and an amine group attached by a two-carbon separator. It is more specifically a norepinephrine–dopamine releasing agent (NDRA) similarly to amphetamine. The effects of cathinone on the body can be countered by a preceding administration of a dopamine receptor antagonist. It can also induce dry mouth, blurred vision and increased blood pressure and heart rate. In contrast to cathinone however, most other cathinones are not human TAAR1 agonists. Pharmacokinetics Khat leaves are removed from the plant stalk and are kept in a ball in the cheek and chewed. Chewing releases juices from the leaves, which include the alkaloid cathinone. The absorption of cathinone has two phases: one in the buccal mucosa and one in the stomach and small intestine. The stomach and small intestine are very important in the absorption of ingested alkaloids. At approximately 2.3 hours after chewing khat leaves, the maximum concentration of cathinone in blood plasma is reached. The mean residence time is 5.2 ± 3.4 hours. The elimination half-life of cathinone is 1.5 ± 0.8 hours. A two-compartment model for absorption and elimination best describes this data. However, at most, only 7% of the ingested cathinone is recovered in the urine. This indicates that the cathinone is being broken down in the body. Cathinone has been shown to selectively metabolize into R,S-(-)-norephedrine and cathine. The reduction of the ketone group in cathinone will produce cathine. This reduction is catalyzed by enzymes in the liver. The spontaneous breakdown of cathinone is the reason it must be chewed fresh after cultivation. Effects on health The first documentation of the khat plant being used in medicine was in a book published by an Arabian physician in the 10th century. It was used as an antidepressant because it led to feelings of happiness and excitement. Chronic khat chewing can also create drug dependence, as shown by animal studies. In such studies, monkeys were trained to push a lever to receive the drug reward. As the monkeys' dependence increased, they pressed the lever at an increasing frequency. Khat chewing and the effects of cathinone on the body differ from person to person, but there is a general pattern of behavior that emerges after ingesting fresh cathinone: • Feelings of euphoria that last for one to two hours • Discussion of serious issues and increased irritability • Very active imagination • Depression • Irritability, loss of appetite and insomnia There are other effects not related to the CNS. The chewer can develop constipation and heartburn after a khat session. Long-term effects of cathinone can include gum disease or oral cancer, cardiovascular disease and depression. The withdrawal symptoms of cathinone include hot flashes, lethargy and a great urge to use the drug for at least the first two days. ==Chemistry==

Biosynthesis The synthesis of cathinone in khat begins with L-phenylalanine and the first step is carried out by L-phenylalanine ammonia lyase (PAL), which cleaves off an ammonia group and creates a carbon-carbon double bond, forming cinnamic acid. Aside from the beta- and non-beta-oxidative pathways, the biosynthesis of cathinone can proceed through a CoA-dependent pathway. The CoA-dependent pathway is actually a mix between the two main pathways as it starts like the beta-oxidative pathway and then when it loses CoA, it finishes the synthesis in the non-beta-oxidative pathway. In this pathway, the trans-cinnamic acid produced from L-phenylalanine is ligated to a Coenzyme A (CoA), just like the beginning of the beta-oxidative pathway. These dimers are pharmacologically inactive, and the rapid dimerization reduces active amounts of cathinone in non-fresh khat. Cathinone is structurally related to methcathinone, in much the same way as amphetamine is related to methamphetamine. Cathinone differs from amphetamine by possessing a ketone oxygen atom (C=O) on the β (beta) position of the side chain. Advancements in synthesizing cyclic cathinones based on α-tetralone have employed chiral HPLC-CD techniques to determine the absolute configuration of enantiomers, an approach that may contribute to the development of pharmaceutical analogs with antidepressant potential. The corresponding substance cathine, is a less powerful stimulant. The biophysiological conversion from cathinone to cathine is to blame for the depotentiation of khat leaves over time. Fresh leaves have a greater ratio of cathinone to cathine than dried ones, therefore having more psychoactive effects. There are many cathinone derivatives that include the addition of an R group to the amino end of the molecule. Some of these derivatives have medical uses as well. Bupropion is one of the most commonly prescribed antidepressants and its structure is Cathinone with a tertiary butyl group attached to the nitrogen and chlorine attached to the benzene ring meta- to the main carbon chain. Other cathinone derivatives are strong psychoactive drugs. One such drug is methylone, a drug structurally similar to MDMA. == See also ==