Chemistry:Methcathinone

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Methcathinone /ˌmɛθˈkæθɪˌnoʊn/ (α-methylamino-propiophenone or ephedrone) (sometimes called "cat" or "jeff" or "catnip" or "M-Kat" or "kat" or "intash") is a monoamine alkaloid and psychoactive stimulant, a substituted cathinone. It is used as a recreational drug due to its potent stimulant and euphoric effects and is considered to be addictive, with both physical and psychological withdrawal occurring if its use is discontinued after prolonged or high-dosage administration.[1] It is usually snorted, but can be smoked, injected, or taken orally.

Methcathinone is listed as a Schedule I controlled substance by the Convention on Psychotropic Substances and the United States' Controlled Substances Act, and as such it is not considered to be safe or effective in the treatment, diagnosis, prevention, or cure of any disease, and has no approved medical use. Possession and distribution of methcathinone for the purpose of human consumption is illegal under any/all circumstances in the United States and is either illegal or highly regulated in most jurisdictions worldwide.

History

Methcathinone was first synthesized in 1928 in the United States[2] and was patented by Parke-Davis in 1957.[3] It was used in the Soviet Union during the 1930s and 1940s as an anti-depressant (under the name Эфедрон—ephedrone). Methcathinone has long been used as a drug of abuse in the Soviet Union and Russia. Circa 1994, the United States government recommended to the UN Secretary-General that methcathinone should be listed as a Schedule I controlled substance in the Convention on Psychotropic Substances.[4] In 1995, following US advice, China added the drug to its list of prohibited substances and discontinued its pharmaceutical use.[5]

It is currently a Schedule III drug in Canada along with codeine, anabolic steroids, and testosterone. It is legal to possess in Canada, but illegal to purchase. Methcathinone used to have the nick-name "bath salts", to avoid restrictions on importation.

Chemistry

Methcathinone is a beta-keto N-methylamphetamine and is closely related to the naturally occurring compounds, cathinone and cathine. It is also very closely related to methamphetamine, differing by only the β-ketone substituent and differing from amphetamine by both a keto and N-methyl substituent. Its carbon skeleton is identical to pseudoephedrine and methamphetamine. It differs from pseudoephedrine in that the hydroxyl beta to the aromatic ring is oxidized to a ketone.

Methcathinone possesses a chiral carbon atom, and therefore two enantiomers are possible. When it is made semi-synthetically from pseudo/ephedrine as a starting material, then only a single enantiomer is produced. Given that the chiral center has an alpha hydrogen and adjacent the carbonyl group, the molecule will racemize in solution via an enol intermediate. This process is known as keto–enol tautomerism.

Methcathinone production utilizes the oxidation of pseudoephedrine or ephedrine, the former being preferred because of much higher yields achieved. Oxidation of pseudoephedrine to methcathinone requires little chemistry experience, making it (relatively) easy to synthesize.[6] Potassium permanganate (KMnO4) is most commonly used as the oxidant.

In clandestine laboratories, synthesizing methcathinone using potassium permanganate is considered undesirable because of the low yields and the high toxicity of this oxidant (see Manganese toxicity); however, if done in a proper laboratory using the proper procedures potassium permanganate can be a high-yielding reactant. A method that yields more methcathinone is oxidizing (pseudo)ephedrine with chromium (VI) compounds, which are far more toxic than permanganate compounds.

Methcathinone as free base is very unstable; it easily loses its ketone group, which is substituted with a hydroxyl group, yielding pseudoephedrine, in the reverse of the typical synthesis reaction. Structurally, this occurs when the C=O bond at the Rβ-position is converted into a C-OH bond. Additionally, a dimerization reaction has been observed in solutions of freebase methcathinone, which yields a biologically inactive compound.[7]

Effects

Methcathinone hydrochloride increases spontaneous rodent locomotor activity,[8] potentiates the release of dopamine from dopaminergic nerve terminals in the brain,[8] and causes appetite suppression. Users can easily forget to consume fluids leading to increased thirst and dehydration. The effects of methcathinone are similar to those of methamphetamine, initially deemed to be less intense by the inexperienced user, and often more euphoric.{{Citation needed|date=April 2010} o those of cocaine, since it commonly causes hypertension (elevated blood pressure) and tachycardia (elevated heart rate).

Reported effects include:

  • Feelings of euphoria
  • Increased alertness
  • Slurred speech
  • Shaking of the limbs
  • Increased heart rate
  • Increased blood pressure, risk of stroke or heart attack
  • Increased empathy and sense of communication
  • Both decreased and increased sexual function and desire
  • Bruxism

Pharmacology

Pharmacodynamics

Monoamine release of methcathinone and related agents (EC50, nM)
Compound NE DA 5-HT Ref
Phenethylamine 10.9 39.5 >10,000 [9][10][11]
Amphetamine ND ND ND ND
  Dextroamphetamine 6.6–7.2 5.8–24.8 698–1,765 [12][13]
  Levoamphetamine 9.5 27.7 ND [10][11]
Methamphetamine ND ND ND ND
  Dextromethamphetamine 12.3–13.8 8.5–24.5 736–1,292 [12][14]
  Levomethamphetamine 28.5 416 4,640 [12]
Cathinone 23.6–25.6 34.8–83.1 6,100–7,595 [11][15][16]
  D-Cathinone 72.0 184 >10,000 [17]
  L-Cathinone 12.4–28 18–24.6 2,366–9,267 [18][19][17]
Methcathinone 22–26.1 12.5–49.9 2,592–5,853 [11][15][20][21][16]
  D-Methcathinone ND ND IA [22]
  L-Methcathinone 13.1 14.8 1,772 [18][23]
Notes: The smaller the value, the more strongly the drug releases the neurotransmitter. The assays were done in rat brain synaptosomes and human potencies may be different. See also Monoamine releasing agent § Activity profiles for a larger table with more compounds. Refs:[24][25]

Methcathinone is a norepinephrine–dopamine releasing agent (NDRA). Methcathinone has very strong affinities for the dopamine transporter (DAT) and the norepinephrine transporter (NET). Its affinity for the serotonin transporter (SERT) is less than that of methamphetamine.[26]

The C=O bond at the Rβ-position (directly right of the phenyl ring) is slightly polar, and as a result the drug does not cross the lipid blood–brain barrier quite as well as amphetamine. Nevertheless, it is a potent central nervous system (CNS) stimulant and dopamine reuptake inhibitor. Chronic high dosage use may result in acute mental confusion ranging from mild paranoia to psychosis.{{citation needed|date=February 2013} uickly if use is stopped.

Anecdotal reports have provided some information on patterns of methcathinone use. The most common route of administration is via nasal insufflation (snorting). Other routes of administration include oral, IV injection and smoking.

Illicit usage

Addiction

In preclinical studies, methcathinone hydrochloride produces an abuse potential similar to that of the amphetamines.[27]

Methcathinone can be highly psychologically addictive, and can produce a methamphetamine-like withdrawal.

In drug discrimination studies, methcathinone hydrochloride evokes responses similar to those induced by both dextro­amphetamine sulfate and cocaine hydrochloride.

Intravenous usage

Injecting this substance has been associated with symptoms similar to those seen in patients with Parkinson's disease (manganism) due to the compound manganese dioxide which is a byproduct of synthesis with permanganate.[28]

The Convention on Psychotropic Substances lists methcathinone as a Schedule I substance which restricts its use for government-approved medical and scientific uses.[29]

Australia

Methcathinone is a Schedule 9 prohibited substance in Australia under the Poisons Standard (February 2021).[30] A Schedule 9 substance is defined as a substance which may be abused or misused, the manufacture, possession, sale or use of which should be prohibited by law except when required for medical or scientific research, or for analytical, teaching or training purposes with approval of Commonwealth and/or State or Territory Health Authorities.[30]

United Kingdom

In the United Kingdom, methcathinone is listed as a Class B drug with no clinical uses.[31]

United States

In the United States, methcathinone is listed as a Schedule I drug, for which there is no clinical use.[32]

Netherlands

In the Netherlands, methcathinone is listed as a Level I substance of the Opium Law, for which there is no clinical use.

Finland

Methcathinone is illegal in Finland. It is scheduled in the "government decree on substances, preparations and plants considered to be narcotic drugs".[33]

See also

References

  1. ↑ "Methcathinone: the next illicit stimulant epidemic?". Journal of Psychoactive Drugs 27 (3): 277–85. 1995. doi:10.1080/02791072.1995.10472472. PMID 8594170. 
  2. ↑ "Synthetic Homologs of d,l-Ephedrine". Journal of the American Chemical Society 50 (8): 2287–2292. 1928. doi:10.1021/ja01395a032. Bibcode: 1928JAChS..50.2287H. 
  3. ↑ US Patent 2802865 – Ethylaminopropiophenone compounds
  4. ↑ Erowid
  5. ↑ "Chinese professor accused in 'Breaking Bad' drugs plot". BBC News. 20 May 2015. https://www.bbc.com/news/world-asia-china-32812621. 
  6. ↑ The Clandestine Chemists Notebook
  7. ↑ "Methcathinone and Designer Analogues: Synthesis, Stereochemical Analysis, and Analytical Properties". Journal of Chromatographic Science 32 (12): 552–564. 1994. doi:10.1093/chromsci/32.12.552. 
  8. ↑ 8.0 8.1 "Methcathinone: a new and potent amphetamine-like agent". Pharmacol. Biochem. Behav. 26 (3): 547–51. 1987. doi:10.1016/0091-3057(87)90164-X. PMID 3575369. 
  9. ↑ "Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter". Drug and Alcohol Dependence 147: 1–19. February 2015. doi:10.1016/j.drugalcdep.2014.12.005. PMID 25548026. 
  10. ↑ 10.0 10.1 Synthesis and Biological Evaluation of Rigid Analogues of Methamphetamines. 22 May 2012. https://scholarworks.uno.edu/td/1436/. Retrieved 4 November 2024. 
  11. ↑ 11.0 11.1 11.2 11.3 "Dopamine-releasing agents". Dopamine Transporters: Chemistry, Biology and Pharmacology. Hoboken [NJ]: Wiley. July 2008. pp. 305–320. ISBN 978-0-470-11790-3. OCLC 181862653. https://bitnest.netfirms.com/external/Books/Dopamine-releasing-agents_c11.pdf. 
  12. ↑ 12.0 12.1 12.2 "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin". Synapse 39 (1): 32–41. January 2001. doi:10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3. PMID 11071707. 
  13. ↑ "Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products". Neuropsychopharmacology 38 (4): 552–562. 2013. doi:10.1038/npp.2012.204. PMID 23072836. 
  14. ↑ "The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue". Neuropsychopharmacology 37 (5): 1192–1203. 2012. doi:10.1038/npp.2011.304. PMID 22169943. 
  15. ↑ 15.0 15.1 "The dopamine, serotonin and norepinephrine releasing activities of a series of methcathinone analogs in male rat brain synaptosomes". Psychopharmacology 236 (3): 915–924. March 2019. doi:10.1007/s00213-018-5063-9. PMID 30341459. 
  16. ↑ 16.0 16.1 "Structure-activity relationships for locomotor stimulant effects and monoamine transporter interactions of substituted amphetamines and cathinones". Neuropharmacology 245. March 2024. doi:10.1016/j.neuropharm.2023.109827. PMID 38154512. 
  17. ↑ 17.0 17.1 "Abuse-related neurochemical and behavioral effects of cathinone and 4-methylcathinone stereoisomers in rats". Eur Neuropsychopharmacol 26 (2): 288–297. February 2016. doi:10.1016/j.euroneuro.2015.12.010. PMID 26738428. 
  18. ↑ 18.0 18.1 "In vitro characterization of ephedrine-related stereoisomers at biogenic amine transporters and the receptorome reveals selective actions as norepinephrine transporter substrates". The Journal of Pharmacology and Experimental Therapeutics 307 (1): 138–145. October 2003. doi:10.1124/jpet.103.053975. PMID 12954796. 
  19. ↑ "Deconstructed Analogues of Bupropion Reveal Structural Requirements for Transporter Inhibition versus Substrate-Induced Neurotransmitter Release". ACS Chem Neurosci 8 (6): 1397–1403. June 2017. doi:10.1021/acschemneuro.7b00055. PMID 28220701. 
  20. ↑ Shalabi, Abdelrahman R. (14 December 2017). Structure-Activity Relationship Studies of Bupropion and Related 3-Substituted Methcathinone Analogues at Monoamine Transporters. VCU Scholars Compass (Thesis). doi:10.25772/M4E1-3549. Retrieved 24 November 2024.
  21. ↑ "Systematic Structure-Activity Studies on Selected 2-, 3-, and 4-Monosubstituted Synthetic Methcathinone Analogs as Monoamine Transporter Releasing Agents". ACS Chem Neurosci 10 (1): 740–745. January 2019. doi:10.1021/acschemneuro.8b00524. PMID 30354055. 
  22. ↑ Davies, Rachel A (10 July 2019). Structure-Activity Relationship Studies of Synthetic Cathinones and Related Agents. VCU Scholars Compass (Thesis). doi:10.25772/TZSA-0396. Retrieved 24 November 2024.
  23. ↑ "Structure-Activity Relationships of Synthetic Cathinones". Neuropharmacology of New Psychoactive Substances (NPS). Current Topics in Behavioral Neurosciences. 32. Springer. 2017. pp. 19–47. doi:10.1007/7854_2016_41. ISBN 978-3-319-52442-9. 
  24. ↑ "Monoamine transporters and psychostimulant drugs". Eur J Pharmacol 479 (1–3): 23–40. October 2003. doi:10.1016/j.ejphar.2003.08.054. PMID 14612135. 
  25. ↑ "Therapeutic potential of monoamine transporter substrates". Current Topics in Medicinal Chemistry 6 (17): 1845–1859. 2006. doi:10.2174/156802606778249766. PMID 17017961. https://zenodo.org/record/1235860. 
  26. ↑ "In vitro characterization of ephedrine-related stereoisomers at biogenic amine transporters and the receptorome reveals selective actions as norepinephrine transporter substrates". The Journal of Pharmacology and Experimental Therapeutics 307 (1): 138–145. October 2003. doi:10.1124/jpet.103.053975. PMID 12954796. 
  27. ↑ "Intravenous self-injection of methcathinone in the baboon". Pharmacol. Biochem. Behav. 47 (4): 981–3. April 1994. doi:10.1016/0091-3057(94)90307-7. PMID 8029273. 
  28. ↑ "Manganese-induced Parkinsonism associated with methcathinone (Ephedrone) abuse". Archives of Neurology 64 (6): 886–9. Jun 2007. doi:10.1001/archneur.64.6.886. PMID 17562938. 
  29. ↑ "Convention on Psychotropic Substances, 1971". United Nations Office on Drugs and Crime. https://www.unodc.org/pdf/convention_1971_en.pdf. 
  30. ↑ 30.0 30.1 "Poisons Standard February 2021". Australian Government Department of Health. February 2021. https://www.legislation.gov.au/Details/F2021C00098. 
  31. ↑ "The Misuse of Drugs Act 1971 (Modification) Order 1998 (SI 1998 No. 750)". Statutory Instrument. Ministry of Justice. 1998-03-18. http://www.statutelaw.gov.uk/content.aspx?ActiveTextDocId=2810429. 
  32. ↑ "Methcathinone". Partnership for Drug-Free Kids. Drugfree.org. http://www.drugfree.org/drug-guide/methcathinone. 
  33. ↑ "Valtioneuvoston asetus huumausaineina pidettävistä aineista, valmisteista ja kasveista | 543/2008 | Lainsäädäntö | Finlex". https://www.finlex.fi/fi/lainsaadanto/2008/543. 

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