 | |
 | |
| Clinical data | |
|---|---|
| Other names | β-Ketoamphetamine; Benzoylethanamine[1] |
| Dependence liability | Physical: no dataPsychological: Low–moderate[2] |
| ATC code |
|
| Legal status | |
| Legal status |
|
| Pharmacokinetic data | |
| Eliminationhalf-life | 0.7–2.3 h[4] |
| Identifiers | |
| |
| CAS Number | |
| PubChemCID | |
| DrugBank |
|
| ChemSpider |
|
| UNII | |
| KEGG |
|
| ChEBI | |
| ChEMBL | |
| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.163.927 |
| Chemical and physical data | |
| Formula | C9H11NO |
| Molar mass | 149.193 g·mol−1 |
| 3D model (JSmol) | |
| |
| |
 N Y (what is this?) (verify) | |
Cathinone (/ˈkæθɪnoʊn/; also known asβ-ketoamphetamine) is amonoaminealkaloid found in theshrubCatha edulis (khat) and is chemically similar toephedrine,cathine,methcathinone and otheramphetamines. It is probably the main contributor to thestimulant effect ofCatha edulis. Cathinone differs from many other amphetamines in that it has aketonefunctional group. Other phenethylamines that share this structure include the stimulantsmethcathinone,MDPV,mephedrone and theantidepressantbupropion.
Khat has been cultivated in theHorn of Africa andArabian Peninsula region of the world for thousands of years. It is most commonly chewed for theeuphoric effect it produces. The active ingredient was first proposed in 1930, whencathine was identified as a predominant alkaloid in the plant.[5] 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 fromYemen,Kenya andMadagascar and found evidence of a different alkaloid, cathinone.[5] Cathinone is molecularly similar to cathine, but is much more abundant in younger plants. This finding caused scientists to speculate that cathinone was the true active ingredient in khat.[5]
A study was conducted in 1994 to test the effects of cathinone. Six volunteers who had never chewed khat were given an active khat sample and a cathinone-freeplacebo sample.[6] 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.[6]
Over 20 million people in theArabian Peninsula andEast Africa chew khat leaves daily. It is an important piece of the culture and economy in this region, especially inEthiopia (where khat is said to have originated), Kenya,Djibouti, Somalia and Yemen. Men usually chew it during parties or other social gatherings while smoking cigarettes and drinking tea. Farmers and other workers also use khat in the afternoon to reduce fatigue and hunger as the day goes on. It functions like thecaffeine in a strong cup of coffee as an anti-fatigue drug. Students and drivers have been known to use it to stay alert for longer periods of time.[7]
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.[8] 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.[8]
Internationally, cathinone is aSchedule I drug under theConvention on Psychotropic Substances.[9] Circa 1993, theDEA added cathinone to theControlled Substances Act's Schedule I.
The sale of khat is legal in some jurisdictions, but illegal in others (seeKhat (Regulation)).Substituted cathinones were also often used as the key ingredient of recreational drug mixes commonly known as "bath salts" in the United States.[10][11][12][13]
The table below shows the legality of khat and cathinone in various countries:
| 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[14] |
| 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"[15] |
| Compound | NETooltip Norepinephrine | DATooltip Dopamine | 5-HTTooltip Serotonin | Ref |
|---|---|---|---|---|
| Phenethylamine | 10.9 | 39.5 | >10,000 | [16][17][18] |
| Amphetamine | ND | ND | ND | ND |
| Dextroamphetamine | 6.6–7.2 | 5.8–24.8 | 698–1,765 | [19][20] |
| Levoamphetamine | 9.5 | 27.7 | ND | [17][18] |
| Methamphetamine | ND | ND | ND | ND |
| Dextromethamphetamine | 12.3–13.8 | 8.5–24.5 | 736–1,292 | [19][21] |
| Levomethamphetamine | 28.5 | 416 | 4,640 | [19] |
| Cathinone | 23.6–25.6 | 34.8–83.1 | 6,100–7,595 | [18][22][23] |
| D-Cathinone | 72.0 | 184 | >10,000 | [24] |
| L-Cathinone | 12.4–28 | 18–24.6 | 2,366–9,267 | [25][26][24] |
| Methcathinone | 22–26.1 | 12.5–49.9 | 2,592–5,853 | [18][22][27][28][23] |
| D-Methcathinone | ND | ND | IA | [29] |
| L-Methcathinone | 13.1 | 14.8 | 1,772 | [25][30] |
| Cathine | 15.0 | 68.3 | >10,000 | [25] |
| Notes: The smaller the value, the more strongly the drug releases the neurotransmitter. Theassays were done in rat brainsynaptosomes and humanpotencies may be different. See alsoMonoamine releasing agent § Activity profiles for a larger table with more compounds.Refs:[31][32] | ||||
Cathinone has been found to stimulate the release ofdopamine and inhibit the reuptake ofepinephrine,norepinephrine andserotonin in thecentral nervous system (CNS). Theseneurotransmitters are all consideredmonoamines and share the general structure of anaromatic ring and anamine group attached by a two-carbon separator.[8] Because cathinone is ahydrophobic molecule, it can easily cross cell membranes and other barriers, including theblood–brain barrier.[33] This property allows it to interact with the monoamine transporters in thesynaptic cleft betweenneurons. Cathinone induces the release ofdopamine from brain striatal preparations that are prelabelled either with dopamine or its precursors.[34] It is more specifically anorepinephrine–dopamine releasing agent (NDRA) similarly toamphetamine.[31][32]
The metabolites of cathinone, cathine and norephedrine, also possess CNS stimulation, but create much weaker effects.[35] The effects of cathinone on the body can be countered by a preceding administration of adopamine receptor antagonist.[35] The antagonist prevents synaptic dopamine released by cathinone from exerting its effect by binding to dopamine receptors.
Cathinone can also affect cholinergic concentrations in the gut and airways by blocking prejunctionaladrenergic receptors (α2 adrenergic) and activating5-HT7 receptors, thereby inhibitingsmooth muscle contraction.[33] It can also induce dry mouth, blurred vision and increased blood pressure and heart rate.[8]
Cathinone is a weak agonist of the mouse, rat, and humantrace amine-associated receptor 1 (TAAR1).[36][37] In contrast to cathinone however, most othercathinones are not human TAAR1 agonists.[38][37] TAAR1 activation may auto-inhibit and constrain themonoaminergic effects ofmonoamine releasing agents possessing TAAR1 agonism.[38][39]
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 thebuccal mucosa and one in thestomach andsmall intestine.[6] The stomach and small intestine are very important in the absorption of ingested alkaloids.[6] 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.[6] The elimination half-life of cathinone is 1.5 ± 0.8 hours.[6] 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.[6] 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 theketone 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.[6]
The first documentation of the khat plant being used in medicine was in a book published by an Arabian physician in the 10th century.[8] It was used as anantidepressant because it led to feelings of happiness and excitement. Chronic khat chewing can also create drug dependence, as shown by animal studies.[8] 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.[8]
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:[8]
There are other effects not related to the CNS. The chewer can developconstipation andheartburn after a khat session. Long-term effects of cathinone can includegum disease ororal cancer,cardiovascular disease anddepression.[8] Thewithdrawal symptoms of cathinone includehot flashes,lethargy and a great urge to use the drug for at least the first two days.[8]
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, formingcinnamic acid.[40] After this, the molecule can either go through a beta-oxidative pathway or a non-beta-oxidative pathway. The beta-oxidative pathway producesbenzoyl-CoA while the non-beta-oxidative pathway producesbenzoic acid.[40] Both of these molecules can be converted to 1-phenylpropane-1,2-dione by acondensation reaction catalyzed by a ThDP-dependent enzyme (Thiamine diphosphate-dependent enzyme) withpyruvate and producing CO2.[40] 1-phenylpropane-1,2-dione goes through a transaminase reaction to replace a ketone with an ammonia group to form (S)-cathinone. (S)-Cathinone can then undergo a reduction reaction to produce the less potent but structurally similar cathine or norephedrine, which are also found in the plant.[40]
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 aCoenzyme A (CoA), just like the beginning of the beta-oxidative pathway.[40] It then undergoeshydration at the double bond. This product then loses the CoA to producebenzaldehyde, an intermediate of the non-beta-oxidative pathway. Benzaldehyde is converted into benzoic acid and proceeds through the rest of the synthesis.[40]
Cathinone can be synthetically produced from propiophenone through aFriedel-Crafts acylation of propionic acid and benzene.[33] The resultingpropiophenone can be brominated, and the bromine can be substituted with ammonia to produce a racemic mixture of cathinone. A different synthetic strategy must be employed to produce enantiomerically pure (S)-cathinone. This synthetic route starts out with the N-acetylation of theoptically activeamino acid, S-alanine.[33] Then,phosphorus pentachloride (PCl5) is used to chlorinate thecarboxylic acid forming an acyl chloride. At the same time, a Friedel-Crafts acylation is preformed on benzene withaluminum chloride catalyst. Finally, theacetyl protecting group is removed by heating withhydrochloric acid to form enantiomerically pure S-(-)-cathinone.[33]
Cathinone can be extracted fromCatha edulis (khat), or synthesized fromα-bromopropiophenone (which is easily made frompropiophenone). Because cathinone is both aprimary amine and aketone, it is very prone todimerization, especially as a free base isolated from plant matter.[41][42] These dimers arepharmacologically inactive, and the rapid dimerization reduces active amounts of cathinone in non-fresh khat.[41][42] The rapid formation of dimers also applies to other non-N-substituted cathinones such asmethylenedioxycathinone (MDC; normethylone).[41][42]
The structure of cathinone is very similar to that of other molecules. By reducing the ketone, it becomes cathine if it retains its stereochemistry, or norephedrine if its stereochemistry is inverted. Cathine is a less potent version of cathinone and cathinone's spontaneous reduction is the reason that older khat plants are not as stimulating as younger ones. Cathinone and amphetamine are closely related in that amphetamine is only lacking the ketone C=O group.[43] Cathinone is structurally related tomethcathinone, in much the same way asamphetamine is related tomethamphetamine. Cathinone differs from amphetamine by possessing aketoneoxygen atom (C=O) on theβ (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.[44] The corresponding substancecathine, is a less powerful stimulant. The biophysiological conversion from cathinone to cathine is to blame for the depotentiation ofkhat 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 ringmeta- to the main carbon chain.[43]
Other cathinone derivatives are strong psychoactive drugs. One such drug ismethylone, a drug structurally similar toMDMA.
Another feature that distinguishes [synthetic cathinones (SCs)] from amphetamines is their negligible interaction with the trace amine associated receptor 1 (TAAR1). Activation of this receptor reduces the activity of dopaminergic neurones, thereby reducing psychostimulatory effects and addictive potential (Miller, 2011; Simmler et al., 2016). Amphetamines are potent agonists of this receptor, making them likely to self‐inhibit their stimulating effects. In contrast, SCs show negligible activity towards TAAR1 (Kolaczynska et al., 2021; Rickli et al., 2015; Simmler et al., 2014, 2016). [...] It is worth noting, however, that for TAAR1 there is considerable species variability in its interaction with ligands, and it is possible that the in vitro activity of [rodent TAAR1 agonists] may not translate into activity in the human body (Simmler et al., 2016). The lack of self‐regulation by TAAR1 may partly explain the higher addictive potential of SCs compared to amphetamines (Miller, 2011; Simmler et al., 2013).
Interestingly, the concentrations of amphetamine found to be necessary to activate TAAR1 are in line with what was found in drug abusers [3, 51, 52]. Thus, it is likely that some of the effects produced by amphetamines could be mediated by TAAR1. Indeed, in a study in mice, MDMA effects were found to be mediated in part by TAAR1, in a sense that MDMA auto-inhibits its neurochemical and functional actions [46]. Based on this and other studies (see other section), it has been suggested that TAAR1 could play a role in reward mechanisms and that amphetamine activity on TAAR1 counteracts their known behavioral and neurochemical effects mediated via dopamine neurotransmission.