Cathinone (; also known as β-ketoamphetamine) is a monoamine alkaloid found in the shrub Catha edulis (khat) and is chemically similar to ephedrine, cathine, methcathinone and other amphetamines. It is probably the main contributor to the stimulant effect of Catha edulis. Cathinone differs from many other amphetamines in that it has a ketone functional group. Other phenethylamines that share this structure include the stimulants methcathinone, MDPV, mephedrone and the antidepressant bupropion.
History
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:
{| class="wikitable"
|-http://www.who.int/countries/eri/en/
! Region !! Regulation
|-
| Eritrea || Legal
|-
| Ethiopia || Legal
|-
| Somalia || Legal
|-
| Djibouti || Legal
|-
| Kenya || Khat is legal but cathinone and cathine are classified as Class C substances
|-
| South Africa || Khat is a protected plant
|-
| China || Illegal
|-
| Israel || Legal – The khat plant leaves are allowed to be chewed and beverages containing khat are legal, but it is illegal to sell pills based on cathinone extracts
|-
| Malaysia || Illegal
|-
| Saudi Arabia || Illegal
|-
| Yemen || Khat is legal but the cultivation and selling of the plant is regulated by the government
|-
| Denmark || Illegal
|-
| Finland || Illegal
|-
| France || Khat is prohibited as a stimulant
|-
| Germany || Khat is illegal but a derivative of cathinone is available upon prescription
|-
| Ireland || Illegal unless authorized
|-
| Netherlands || Cathinone and cathine have been illegal but khat was announced as illegal in 2012
|-
| Norway || Illegal
|-
| Poland || Illegal
|-
| Sweden || Illegal
|-
| Switzerland || Illegal
|-
| United Kingdom || Illegal
|-
| Canada || Illegal to obtain unless approved by a medical practitioner
|-
| United States || Illegal
|-
| Australia || Illegal
|-
| New Zealand || Illegal
|-
| Georgia || The khat plant itself is allowed to be sold and chewed, but it is illegal to sell or make beverages containing khat
|-
| Turkey || Illegal
|-
| Bulgaria || Illegal under List I - "Plants and substances with a high risk to the public health due to their harmful effect of misuse, prohibited for use in human and veterinary medicine"
|}
Pharmacology
Pharmacodynamics
{| class="wikitable floatright" style="font-size:small;"
|+
|-
! Compound !! data-sort-type="number" | !! data-sort-type="number" | !! data-sort-type="number" | !! Ref
|-
| Phenethylamine || 10.9 || 39.5 || >10,000 ||
|-
| Levoamphetamine || 9.5 || 27.7 || ||
|-
| Methamphetamine || || || ||
|-
| Dextromethamphetamine || 12.3–13.8 || 8.5–24.5 || 736–1,292 ||
|-
| Levomethamphetamine || 28.5 || 416 || 4,640 ||
|-
| -Cathinone || 72.0 || 184 || >10,000 ||
|-
| -Cathinone || 12.4–28 || 18–24.6 || 2,366–9,267 ||
|-
| -Methcathinone || 13.1 || 14.8 || 1,772 ||
|-
| Cathine || 15.0 || 68.3 || >10,000 ||
|}
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.
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.