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Methcathinone

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Methcathinone
Ball-and-stick model of the methcathinone molecule
Clinical data
Routes of
administration		Vaporized, insufflated, injected, orally
ATC code
  • none
Legal status
Legal status
Pharmacokinetic data
ExcretionUrine
Identifiers
  • (RS)-2-(methylamino)-1-phenyl-propan-1-one
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
CompTox Dashboard (EPA)
ECHA InfoCard100.024.630 Edit this at Wikidata
Chemical and physical data
FormulaC10H13NO
Molar mass163.220 g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
  • O=C(c1ccccc1)C(NC)C
  • InChI=1S/C10H13NO/c1-8(11-2)10(12)9-6-4-3-5-7-9/h3-8,11H,1-2H3 checkY
  • Key:LPLLVINFLBSFRP-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

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.[2] 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

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Methcathinone was first synthesized in 1928 in the United States[3] and was patented by Parke-Davis in 1957.[4] 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.[citation needed]

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.[5] In 1995, following US advice, China added the drug to its list of prohibited substances and discontinued its pharmaceutical use.[6]

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

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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 hydroxide 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.[7][unreliable source?] 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.[8]

Effects

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Methcathinone hydrochloride increases spontaneous rodent locomotor activity,[9] potentiates the release of dopamine from dopaminergic nerve terminals in the brain,[9] and causes appetite suppression.[citation needed] 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] The effects have been compared to those of cocaine, since it commonly causes hypertension (elevated blood pressure) and tachycardia (elevated heart rate).

Reported effects include:[medical citation needed]

  • 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

The effects of methcathinone usually last from four to six hours.[citation needed]

Pharmacology

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Monoamine release of methcathinone and related agents (EC50Tooltip Half maximal effective concentration, nM)
Compound NETooltip Norepinephrine DATooltip Dopamine 5-HTTooltip Serotonin Ref
Phenethylamine 10.9 39.5 >10,000 [10][11][12]
Amphetamine ND ND ND ND
  Dextroamphetamine 6.6–7.2 5.8–24.8 698–1,765 [13][14]
  Levoamphetamine 9.5 27.7 ND [11][12]
Methamphetamine ND ND ND ND
  Dextromethamphetamine 12.3–13.8 8.5–24.5 736–1,292 [13][15]
  Levomethamphetamine 28.5 416 4,640 [13]
Cathinone 23.6–25.6 34.8–83.1 6,100–7,595 [12][16][17]
  D-Cathinone 72.0 184 >10,000 [18]
  L-Cathinone 12.4–28 18–24.6 2,366–9,267 [19][20][18]
Methcathinone 22–26.1 12.5–49.9 2,592–5,853 [12][16][21][22][17]
  D-Methcathinone ND ND IA [23]
  L-Methcathinone 13.1 14.8 1,772 [19][24]
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: [25][26]

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.[27]

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.[citation needed] 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] These symptoms typically disappear quickly 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).[citation needed] Other routes of administration include oral, IV injection and smoking.

Illicit usage

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Methcathinone binges resemble amphetamine binges in that the user may not sleep or eat, and takes in little in the way of liquids. The methcathinone binge is followed by long periods of sleep, excess eating, long-lasting nosebleeds (insufflation of methcathinone is corrosive to the nasal mucosa in the same manner as methamphetamine) and, in some cases, depression.[citation needed]

Addiction

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In preclinical studies, methcathinone hydrochloride produces an abuse potential similar to that of the amphetamines.[28]

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

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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.[29]

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The Convention on Psychotropic Substances lists methcathinone as a Schedule I substance which restricts its use for government-approved medical and scientific uses.[30]

Australia

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Methcathinone is a Schedule 9 prohibited substance in Australia under the Poisons Standard (February 2021).[31] 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.[31]

United Kingdom

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In the United Kingdom, methcathinone is listed as a Class B drug with no clinical uses.[32]

United States

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In the United States, methcathinone is listed as a Schedule I drug, for which there is no clinical use.[33]

Netherlands

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

See also

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References

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  1. ^ Anvisa (2023-07-24). "RDC Nº 804 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 804 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-07-25). Archived from the original on 2023-08-27. Retrieved 2023-08-27.
  2. ^ Calkins RF, Aktan GB, Hussain KL (1995). "Methcathinone: the next illicit stimulant epidemic?". Journal of Psychoactive Drugs. 27 (3): 277–85. doi:10.1080/02791072.1995.10472472. PMID 8594170.
  3. ^ Hyde JF, Browning E, Adams R (1928). "Synthetic Homologs of d,l-Ephedrine". Journal of the American Chemical Society. 50 (8): 2287–2292. doi:10.1021/ja01395a032.
  4. ^ US Patent 2802865 -ETHYLAMINOPROPIOPHENONE COMPOUNDS
  5. ^ Erowid
  6. ^ "Chinese professor accused in 'Breaking Bad' drugs plot". BBC News. 20 May 2015.
  7. ^ The Clandestine Chemists Notebook
  8. ^ DeRuiter J, Hayes L, Valaer A, Clark CR, Noggle FT (1994). "Methcathinone and Designer Analogues: Synthesis, Stereochemical Analysis, and Analytical Properties". Journal of Chromatographic Science. 32 (12): 552–564. doi:10.1093/chromsci/32.12.552.
  9. ^ a b Glennon RA, Yousif M, Naiman N, Kalix P (1987). "Methcathinone: a new and potent amphetamine-like agent". Pharmacol. Biochem. Behav. 26 (3): 547–51. doi:10.1016/0091-3057(87)90164-X. PMID 3575369. S2CID 5890314.
  10. ^ Reith ME, Blough BE, Hong WC, Jones KT, Schmitt KC, Baumann MH, Partilla JS, Rothman RB, Katz JL (February 2015). "Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter". Drug and Alcohol Dependence. 147: 1–19. doi:10.1016/j.drugalcdep.2014.12.005. PMC 4297708. PMID 25548026.
  11. ^ a b Forsyth AN (22 May 2012). "Synthesis and Biological Evaluation of Rigid Analogues of Methamphetamines". ScholarWorks@UNO. Retrieved 4 November 2024.
  12. ^ a b c d Blough B (July 2008). "Dopamine-releasing agents" (PDF). In Trudell ML, Izenwasser S (eds.). Dopamine Transporters: Chemistry, Biology and Pharmacology. Hoboken [NJ]: Wiley. pp. 305–320. ISBN 978-0-470-11790-3. OCLC 181862653. OL 18589888W.
  13. ^ a b c Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, Partilla JS (January 2001). "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin". Synapse. 39 (1): 32–41. doi:10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3. PMID 11071707.
  14. ^ 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 (2013). "Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products". Neuropsychopharmacology. 38 (4): 552–562. doi:10.1038/npp.2012.204. PMC 3572453. PMID 23072836.
  15. ^ Baumann MH, Ayestas MA, Partilla JS, Sink JR, Shulgin AT, Daley PF, Brandt SD, Rothman RB, Ruoho AE, Cozzi NV (2012). "The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue". Neuropsychopharmacology. 37 (5): 1192–1203. doi:10.1038/npp.2011.304. PMC 3306880. PMID 22169943.
  16. ^ a b Blough BE, Decker AM, Landavazo A, Namjoshi OA, Partilla JS, Baumann MH, Rothman RB (March 2019). "The dopamine, serotonin and norepinephrine releasing activities of a series of methcathinone analogs in male rat brain synaptosomes". Psychopharmacology. 236 (3): 915–924. doi:10.1007/s00213-018-5063-9. PMC 6475490. PMID 30341459.
  17. ^ a b Fitzgerald LR, Gannon BM, Walther D, Landavazo A, Hiranita T, Blough BE, Baumann MH, Fantegrossi WE (March 2024). "Structure-activity relationships for locomotor stimulant effects and monoamine transporter interactions of substituted amphetamines and cathinones". Neuropharmacology. 245: 109827. doi:10.1016/j.neuropharm.2023.109827. PMC 10842458. PMID 38154512.
  18. ^ a b Hutsell BA, Baumann MH, Partilla JS, Banks ML, Vekariya R, Glennon RA, Negus SS (February 2016). "Abuse-related neurochemical and behavioral effects of cathinone and 4-methylcathinone stereoisomers in rats". Eur Neuropsychopharmacol. 26 (2): 288–297. doi:10.1016/j.euroneuro.2015.12.010. PMC 5331761. PMID 26738428.
  19. ^ a b Rothman RB, Vu N, Partilla JS, Roth BL, Hufeisen SJ, Compton-Toth BA, Birkes J, Young R, Glennon RA (October 2003). "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. doi:10.1124/jpet.103.053975. PMID 12954796. S2CID 19015584.
  20. ^ Shalabi AR, Walther D, Baumann MH, Glennon RA (June 2017). "Deconstructed Analogues of Bupropion Reveal Structural Requirements for Transporter Inhibition versus Substrate-Induced Neurotransmitter Release". ACS Chem Neurosci. 8 (6): 1397–1403. doi:10.1021/acschemneuro.7b00055. PMC 7261150. PMID 28220701.
  21. ^ 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.
  22. ^ Walther D, Shalabi AR, Baumann MH, Glennon RA (January 2019). "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. doi:10.1021/acschemneuro.8b00524. PMC 8269283. PMID 30354055.
  23. ^ 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.
  24. ^ Glennon RA, Dukat M (2017). "Structure-Activity Relationships of Synthetic Cathinones". Curr Top Behav Neurosci. Current Topics in Behavioral Neurosciences. 32: 19–47. doi:10.1007/7854_2016_41. ISBN 978-3-319-52442-9. PMC 5818155. PMID 27830576.
  25. ^ Rothman RB, Baumann MH (October 2003). "Monoamine transporters and psychostimulant drugs". Eur J Pharmacol. 479 (1–3): 23–40. doi:10.1016/j.ejphar.2003.08.054. PMID 14612135.
  26. ^ Rothman RB, Baumann MH (2006). "Therapeutic potential of monoamine transporter substrates". Current Topics in Medicinal Chemistry. 6 (17): 1845–1859. doi:10.2174/156802606778249766. PMID 17017961.
  27. ^ Rothman RB, Vu N, Partilla JS, Roth BL, Hufeisen SJ, Compton-Toth BA, et al. (October 2003). "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. doi:10.1124/jpet.103.053975. PMID 12954796. S2CID 19015584.
  28. ^ Kaminski BJ, Griffiths RR (April 1994). "Intravenous self-injection of methcathinone in the baboon". Pharmacol. Biochem. Behav. 47 (4): 981–3. doi:10.1016/0091-3057(94)90307-7. PMID 8029273. S2CID 40584010.
  29. ^ De Bie RM, Gladstone RM, Strafella AP, Ko JH, Lang AE (Jun 2007). "Manganese-induced Parkinsonism associated with methcathinone (Ephedrone) abuse". Archives of Neurology. 64 (6): 886–9. doi:10.1001/archneur.64.6.886. PMID 17562938.
  30. ^ "Convention on Psychotropic Substances, 1971" (PDF). United Nations Office on Drugs and Crime. Retrieved 9 January 2013.
  31. ^ a b "Poisons Standard February 2021". Therapeutic Goods Administration. Australian Government Department of Health. February 2021.
  32. ^ "The Misuse of Drugs Act 1971 (Modification) Order 1998 (SI 1998 No. 750)". Statutory Instrument. Ministry of Justice. 1998-03-18. Retrieved 2008-07-06.[permanent dead link‍]
  33. ^ "Methcathinone - Partnership for Drug-Free Kids". Drugfree.org. Retrieved 2015-12-23.
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