Editing Cathinone (section)

==Pharmacology==

===Pharmacodynamics===
{| class="wikitable floatright" style="font-size:small;"
|+ {{Nowrap|[[Monoamine releasing agent|Monoamine release]] of cathinone and related agents ({{Abbrlink|EC<sub>50</sub>|Half maximal effective concentration}}, nM)}}
|-
! Compound !! data-sort-type="number" | {{abbrlink|NE|Norepinephrine}} !! data-sort-type="number" | {{abbrlink|DA|Dopamine}} !! data-sort-type="number" | {{abbrlink|5-HT|Serotonin}} !! Ref
|-
| [[Phenethylamine]] || 10.9 || 39.5 || >10,000 || <ref name="ReithBLoughHong2015">{{cite journal | vauthors = Reith ME, Blough BE, Hong WC, Jones KT, Schmitt KC, Baumann MH, Partilla JS, Rothman RB, Katz JL | title = Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter | journal = Drug and Alcohol Dependence | volume = 147 | issue =  | pages = 1–19 | date = February 2015 | pmid = 25548026 | pmc = 4297708 | doi = 10.1016/j.drugalcdep.2014.12.005 }}</ref><ref name="Forsyth2012" /><ref name="Blough2008" />
|-
| [[Amphetamine]] || {{Abbr|ND|No data}} || {{Abbr|ND|No data}} || {{Abbr|ND|No data}} || {{Abbr|ND|No data}}
|-
| {{nbsp}}{{nbsp}}[[Dextroamphetamine]] || 6.6–7.2 || 5.8–24.8 || 698–1,765 || <ref name="RothmanBaumannDersch2001">{{cite journal | vauthors = Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, Partilla JS | title = Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin | journal = Synapse | volume = 39 | issue = 1 | pages = 32–41 | date = January 2001 | pmid = 11071707 | doi = 10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3 | url = }}</ref><ref name="BaumannPartillaLehner2013">{{cite journal | vauthors = Baumann MH, Partilla JS, Lehner KR, Thorndike EB, Hoffman AF, Holy M, Rothman RB, Goldberg SR, Lupica CR, Sitte HH, Brandt SD, Tella SR, Cozzi NV, Schindler CW | title = Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products | journal = Neuropsychopharmacology | volume = 38 | issue = 4 | pages = 552–562 | year = 2013 | pmid = 23072836 | pmc = 3572453 | doi = 10.1038/npp.2012.204 }}</ref>
|-
| {{nbsp}}{{nbsp}}[[Levoamphetamine]] || 9.5 || 27.7 || {{abbr|ND|No data}} || <ref name="Forsyth2012">{{cite journal | vauthors = Forsyth AN | title=Synthesis and Biological Evaluation of Rigid Analogues of Methamphetamines | website=ScholarWorks@UNO | date=22 May 2012 | url=https://scholarworks.uno.edu/td/1436/ | access-date=4 November 2024}}</ref><ref name="Blough2008">{{cite book | vauthors = Blough B | chapter = Dopamine-releasing agents | veditors = Trudell ML, Izenwasser S | title = Dopamine Transporters: Chemistry, Biology and Pharmacology | pages = 305–320 | date = July 2008 | isbn = 978-0-470-11790-3 | oclc = 181862653 | ol = OL18589888W | publisher = Wiley | location = Hoboken [NJ] | doi = | url = https://books.google.com/books?id=QCagLAAACAAJ | chapter-url = https://bitnest.netfirms.com/external/Books/Dopamine-releasing-agents_c11.pdf }}</ref>
|-
| [[Methamphetamine]] || {{Abbr|ND|No data}} || {{Abbr|ND|No data}} || {{Abbr|ND|No data}} || {{Abbr|ND|No data}}
|-
| {{nbsp}}{{nbsp}}[[Dextromethamphetamine]] || 12.3–13.8 || 8.5–24.5 || 736–1,292 || <ref name="RothmanBaumannDersch2001" /><ref name="BaumannAyestasPartilla2012">{{cite journal | vauthors = Baumann MH, Ayestas MA, Partilla JS, Sink JR, Shulgin AT, Daley PF, Brandt SD, Rothman RB, Ruoho AE, Cozzi NV | title = The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue | journal = Neuropsychopharmacology | volume = 37 | issue = 5 | pages = 1192–1203 | year = 2012 | pmid = 22169943 | pmc = 3306880 | doi = 10.1038/npp.2011.304 }}</ref>
|-
| {{nbsp}}{{nbsp}}[[Levomethamphetamine]] || 28.5 || 416 || 4,640 || <ref name="RothmanBaumannDersch2001" />
|-
| Cathinone || 23.6–25.6 || 34.8–83.1 || 6,100–7,595 || <ref name="Blough2008" /><ref name="BloughDeckerLandavazo2019">{{cite journal | vauthors = Blough BE, Decker AM, Landavazo A, Namjoshi OA, Partilla JS, Baumann MH, Rothman RB | title = The dopamine, serotonin and norepinephrine releasing activities of a series of methcathinone analogs in male rat brain synaptosomes | journal = Psychopharmacology | volume = 236 | issue = 3 | pages = 915–924 | date = March 2019 | pmid = 30341459 | pmc = 6475490 | doi = 10.1007/s00213-018-5063-9 }}</ref><ref name="FitzgeraldGannonWalther2024">{{cite journal | vauthors = Fitzgerald LR, Gannon BM, Walther D, Landavazo A, Hiranita T, Blough BE, Baumann MH, Fantegrossi WE | title = Structure-activity relationships for locomotor stimulant effects and monoamine transporter interactions of substituted amphetamines and cathinones | journal = Neuropharmacology | volume = 245 | issue = | pages = 109827 | date = March 2024 | pmid = 38154512 | doi = 10.1016/j.neuropharm.2023.109827 | pmc = 10842458 | url = }}</ref>
|-
| {{nbsp}}{{nbsp}}{{Small|D}}-Cathinone || 72.0 || 184 || >10,000 || <ref name="HutsellBaumannPartilla2016">{{cite journal | vauthors = Hutsell BA, Baumann MH, Partilla JS, Banks ML, Vekariya R, Glennon RA, Negus SS | title = Abuse-related neurochemical and behavioral effects of cathinone and 4-methylcathinone stereoisomers in rats | journal = Eur Neuropsychopharmacol | volume = 26 | issue = 2 | pages = 288–297 | date = February 2016 | pmid = 26738428 | pmc = 5331761 | doi = 10.1016/j.euroneuro.2015.12.010 | url = }}</ref>
|-
| {{nbsp}}{{nbsp}}{{Small|L}}-Cathinone || 12.4–28 || 18–24.6 || 2,366–9,267 || <ref name="RothmanVuPartilla2003">{{cite journal | vauthors = Rothman RB, Vu N, Partilla JS, Roth BL, Hufeisen SJ, Compton-Toth BA, Birkes J, Young R, Glennon RA | title = In vitro characterization of ephedrine-related stereoisomers at biogenic amine transporters and the receptorome reveals selective actions as norepinephrine transporter substrates | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 307 | issue = 1 | pages = 138–145 | date = October 2003 | pmid = 12954796 | doi = 10.1124/jpet.103.053975 | s2cid = 19015584 }}</ref><ref name="ShalabiWaltherBaumann2017">{{cite journal | vauthors = Shalabi AR, Walther D, Baumann MH, Glennon RA | title = Deconstructed Analogues of Bupropion Reveal Structural Requirements for Transporter Inhibition versus Substrate-Induced Neurotransmitter Release | journal = ACS Chem Neurosci | volume = 8 | issue = 6 | pages = 1397–1403 | date = June 2017 | pmid = 28220701 | pmc = 7261150 | doi = 10.1021/acschemneuro.7b00055 | url = }}</ref><ref name="HutsellBaumannPartilla2016" />
|-
| [[Methcathinone]] || 22–26.1 || 12.5–49.9 || 2,592–5,853 || <ref name="Blough2008" /><ref name="BloughDeckerLandavazo2019" /><ref name="Shalabi2017">{{cite thesis | vauthors = Shalabi AR | title=Structure-Activity Relationship Studies of Bupropion and Related 3-Substituted Methcathinone Analogues at Monoamine Transporters | publisher = Virginia Commonwealth University | via = VCU Scholars Compass | date=14 December 2017 | doi=10.25772/M4E1-3549 | url=https://scholarscompass.vcu.edu/etd/5176/ | access-date=24 November 2024}}</ref><ref name="WaltherShalabiBaumann2019">{{cite journal | vauthors = Walther D, Shalabi AR, Baumann MH, Glennon RA | title = Systematic Structure-Activity Studies on Selected 2-, 3-, and 4-Monosubstituted Synthetic Methcathinone Analogs as Monoamine Transporter Releasing Agents | journal = ACS Chem Neurosci | volume = 10 | issue = 1 | pages = 740–745 | date = January 2019 | pmid = 30354055 | pmc = 8269283 | doi = 10.1021/acschemneuro.8b00524 | url = }}</ref><ref name="FitzgeraldGannonWalther2024" />
|-
| {{nbsp}}{{nbsp}}{{Small|D}}-Methcathinone || {{abbr|ND|No data}} || {{abbr|ND|No data}} || {{abbr|IA|Inactive}} || <ref name="Davies2019">{{cite thesis | vauthors = Davies RA | title=Structure-Activity Relationship Studies of Synthetic Cathinones and Related Agents | publisher = Virginia Commonwealth University Virginia Commonwealth Universityvcu| via = VCU Scholars Compass | date=10 July 2019 | doi=10.25772/TZSA-0396 | url=https://scholarscompass.vcu.edu/etd/5953/ | access-date=24 November 2024}}</ref>
|-
| {{nbsp}}{{nbsp}}{{Small|L}}-Methcathinone || 13.1 || 14.8 || 1,772 || <ref name="RothmanVuPartilla2003" /><ref name="GlennonDukat2017">{{cite book | vauthors = Glennon RA, Dukat M | title = Neuropharmacology of New Psychoactive Substances (NPS) | chapter = Structure-Activity Relationships of Synthetic Cathinones | series = Current Topics in Behavioral Neurosciences | volume = 32 | pages = 19–47 | date = 2017 | publisher = Springer | pmid = 27830576 | pmc = 5818155 | doi = 10.1007/7854_2016_41 | isbn = 978-3-319-52442-9 | chapter-url = }}</ref>
|-
| [[Cathine]] || 15.0 || 68.3 || >10,000 || <ref name="RothmanVuPartilla2003" />
|-
| colspan="5" style="width: 1px; background-color:#eaecf0; text-align: center;" | '''Notes:''' The smaller the value, the more strongly the drug releases the neurotransmitter. The [[bioassay|assay]]s were done in rat brain [[synaptosome]]s and human [[potency (pharmacology)|potencies]] may be different. See also [[Monoamine releasing agent#Activity profiles|Monoamine releasing agent § Activity profiles]] for a larger table with more compounds. '''Refs:''' <ref name="RothmanBaumann2003">{{cite journal | vauthors = Rothman RB, Baumann MH | title = Monoamine transporters and psychostimulant drugs | journal = Eur J Pharmacol | volume = 479 | issue = 1–3 | pages = 23–40 | date = October 2003 | pmid = 14612135 | doi = 10.1016/j.ejphar.2003.08.054 | url = }}</ref><ref name="RothmanBaumann2006">{{cite journal | vauthors = Rothman RB, Baumann MH | title = Therapeutic potential of monoamine transporter substrates | journal = Current Topics in Medicinal Chemistry | volume = 6 | issue = 17 | pages = 1845–1859 | year = 2006 | pmid = 17017961 | doi = 10.2174/156802606778249766 | url = https://zenodo.org/record/1235860 }}</ref>
|}

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 [[monoamine]]s and share the general structure of an [[aromatic ring]] and an [[amine]] group attached by a two-carbon separator.<ref name="Al-Motarreb"/> Because cathinone is a [[hydrophobic]] molecule, it can easily cross cell membranes and other barriers, including the [[blood–brain barrier]].<ref name="Hugins"/> This property allows it to interact with the monoamine transporters in the [[synaptic cleft]] between [[neurons]]. Cathinone induces the release of [[dopamine]] from brain striatal preparations that are prelabelled either with dopamine or its precursors.<ref name="pmid6791236">{{cite journal | vauthors = Kalix P | title = Cathinone, an alkaloid from khat leaves with an amphetamine-like releasing effect | journal = Psychopharmacology | volume = 74 | issue = 3 | pages = 269–270 | year = 1981 | pmid = 6791236 | doi = 10.1007/BF00427108 | s2cid = 20621923 }}</ref> It is more specifically a [[norepinephrine–dopamine releasing agent]] (NDRA) similarly to [[amphetamine]].<ref name="RothmanBaumann2003" /><ref name="RothmanBaumann2006" />

The metabolites of cathinone, cathine and norephedrine, also possess CNS stimulation, but create much weaker effects.<ref name="drugbank">{{cite web|title=Cathinone|url=http://www.drugbank.ca/drugs/DB01560|website=Drug Bank|access-date=10 March 2015|url-status=live|archive-url=https://web.archive.org/web/20150423165202/http://www.drugbank.ca/drugs/DB01560|archive-date=23 April 2015}}</ref> The effects of cathinone on the body can be countered by a preceding administration of a [[dopamine receptor antagonist]].<ref name="drugbank"/> 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 prejunctional [[adrenergic receptor]]s (α<sub>2</sub> adrenergic) and activating [[5-HT7]] receptors, thereby inhibiting [[smooth muscle]] contraction.<ref name="Hugins">{{cite web| vauthors = Hugins KB |title=Cathinone: History, Synthesis, and Human Applications|url=http://www.slideshare.net/KevinHugins/cathinone-history-synthesis-and-human-applications|website=slideshare|date=17 July 2014|access-date=8 March 2015|url-status=live|archive-url=https://web.archive.org/web/20150704030825/http://www.slideshare.net/KevinHugins/cathinone-history-synthesis-and-human-applications|archive-date=4 July 2015}}</ref> It can also induce dry mouth, blurred vision and increased blood pressure and heart rate.<ref name="Al-Motarreb"/>

Cathinone is a weak agonist of the mouse, rat, and human [[trace amine-associated receptor 1]] (TAAR1).<ref name="GainetdinovHoenerBerry2018">{{cite journal | vauthors = Gainetdinov RR, Hoener MC, Berry MD | title = Trace Amines and Their Receptors | journal = Pharmacol Rev | volume = 70 | issue = 3 | pages = 549–620 | date = July 2018 | pmid = 29941461 | doi = 10.1124/pr.117.015305 | url = | doi-access = free }}</ref><ref name="SimmlerBuchyChaboz2016">{{cite journal | vauthors = Simmler LD, Buchy D, Chaboz S, Hoener MC, Liechti ME | title = In Vitro Characterization of Psychoactive Substances at Rat, Mouse, and Human Trace Amine-Associated Receptor 1 | journal = J Pharmacol Exp Ther | volume = 357 | issue = 1 | pages = 134–144 | date = April 2016 | pmid = 26791601 | doi = 10.1124/jpet.115.229765 | url = https://web.archive.org/web/20250509235235/https://d1wqtxts1xzle7.cloudfront.net/74120533/eae6c6e62565b82d46b4d111bbea0f77b9c2-libre.pdf?1635931703=&response-content-disposition=inline%3B+filename%3DIn_Vitro_Characterization_of_Psychoactiv.pdf&Expires=1746838268&Signature=Sy4fJ90yUhxs68314NxYsW5PAaNrBGePRu35WRR4PIF-3YC7Z~sLdnCn5wfqqbLg9bDEGdt~oW55ugMP3D3jgA0BoRI~~GOb0NQOwrtfUEQK1PQs1uuN9qg5Y1ct8z5NsABm44RgtukkwRMdU6fO7OlfIsQ68hOiFk129Ll7UYqldxD2f1xhE2fTTfsxSpb8cMCJzHn7-ItqLdwnAUPFK7WggDIjmY1kCnaHLwIxMwdJCAq8L6DYzSTg7pZkbR8qlou~GXbTPQt~gYpyZTJp5hgW-7V6K5wLlQ7Z2xE7B0f9wEfuc1W1QNafg125Tr-vvAe4LEGKXV58bnn1bpfWKw__&Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA}}</ref> In contrast to cathinone however, most other [[substituted cathinone|cathinone]]s are not human TAAR1 agonists.<ref name="KuropkaZawadzkiSzpot2023">{{cite journal | vauthors = Kuropka P, Zawadzki M, Szpot P | title = A narrative review of the neuropharmacology of synthetic cathinones-Popular alternatives to classical drugs of abuse | journal = Hum Psychopharmacol | volume = 38 | issue = 3 | pages = e2866 | date = May 2023 | pmid = 36866677 | doi = 10.1002/hup.2866 | url = | quote = 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). }}</ref><ref name="SimmlerBuchyChaboz2016" /> TAAR1 activation may auto-inhibit and constrain the [[monoaminergic]] effects of [[monoamine releasing agent]]s possessing TAAR1 agonism.<ref name="KuropkaZawadzkiSzpot2023" /><ref name="EspinozaGainetdinov2014">{{cite book | vauthors = Espinoza S, Gainetdinov RR | title=Taste and Smell | chapter=Neuronal Functions and Emerging Pharmacology of TAAR1 | series=Topics in Medicinal Chemistry | publisher=Springer International Publishing | publication-place=Cham | volume=23 | date=2014 | isbn=978-3-319-48925-4 | doi=10.1007/7355_2014_78 | pages=175–194 | quote = 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. }}</ref>

===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]].<ref name="Wilder"/> The stomach and small intestine are very important in the absorption of ingested alkaloids.<ref name="Wilder"/> 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&nbsp;±&nbsp;3.4 hours.<ref name="Wilder"/> The elimination half-life of cathinone is 1.5&nbsp;±&nbsp;0.8 hours.<ref name="Wilder"/> 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.<ref name="Wilder"/> 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.<ref name="Wilder"/>

===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.<ref name="Al-Motarreb"/> 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.<ref name="Al-Motarreb"/> 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.<ref name="Al-Motarreb"/>

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:<ref name="Al-Motarreb"/>

# 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 (mood)|depression]].<ref name="Al-Motarreb"/> The [[withdrawal symptoms]] of cathinone include [[hot flashes]], [[lethargy]] and a great urge to use the drug for at least the first two days.<ref name="Al-Motarreb"/>