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3-Methylmethcathinone

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3-Methylmethcathinone (3-MMC), also known as metaphedrone,[4] is a designer drug from the substituted cathinone family. 3-MMC is a monoamine transporter substrate (a substance acted upon by monoamine transporters) that potently releases and inhibits the reuptake of dopamine and norepinephrine, as well as displaying moderate serotonin releasing activity.[5] Unlike some synthetic cathinones, 3-MMC has been evaluated in at least one large mammal study.[2]

3-Methylmethcathinone
Clinical data
Other names3-MMC; Metaphedrone; 3-Methyl-N-methylcathinone; 3,N-Dimethylcathinone; 3,N-Dimethyl-β-ketoamphetamine; 3,α,N-Trimethyl-β-ketophenethylamine
ATC code
  • None
Legal status
Legal status
Pharmacokinetic data
BioavailabilityOral: 5–9%[2]
Protein bindingLow[2]
Elimination half-life50 min (in pigs)[2]
Identifiers
  • 2-(Methylamino)-1-(3-methylphenyl)propan-1-one
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
CompTox Dashboard (EPA)
ECHA InfoCard100.259.777 Edit this at Wikidata
Chemical and physical data
FormulaC11H15NO
Molar mass177.247 g·mol−1
3D model (JSmol)
Melting point193.2 °C (379.8 °F) ± 0.2°C (hydrochloride salt)
Boiling point280.5 °C (536.9 °F) ± 23.0°C at 760 mm Hg
Solubility in waterSparingly soluble in PBS; slightly soluble in ethanol, dimethyl sulfoxide, and dimethyl formamide.[3] mg/mL (20 °C)
  • CC1=CC=CC(C(C(C)NC)=O)=C1
  • InChI=1S/C11H15NO/c1-8-5-4-6-10(7-8)11(13)9(2)12-3/h4-7,9,12H,1-3H3
  • Key:QDNXSIYWHYGMCD-UHFFFAOYSA-N

3-Methylmethcathinone is a structural isomer of mephedrone (4-methylmethcathinone), and as such is illegal via blanket bans in many countries that have banned mephedrone. However, 3-MMC has still appeared on the recreational drug market as an alternative to mephedrone, and was first identified being sold in Sweden in 2012.[6]

History

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3-MMC was first encountered in Sweden in 2012,[7] it was created as a designer drug following the control in many countries of the related compound mephedrone. It was sold as a research chemical, usually in powdered form. There is no known or reported medical use of 3-MMC, it is primarily used recreationally.

Chemistry

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Structure

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3-Methylmethcathinone's IUPAC name is 2-(methylamino)-1-(3-methylphenyl)propan-1-one). It is one of many synthetic cathinones, designer drugs related to amphetamines. It is a structural isomer of mephedrone, and controlled as such. It can also be seen as the β-keto analog of 3-methylmethamphetamine

3-MMC contains a chiral center at the C-2 carbon. Therefore two enantiomers exist, the R and S enantiomer. It is assumed that the S form is more potent due to its similarity to cathinone, but further research is needed to confirm this.[8]

Synthesis

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There are several ways to synthesize 3-MMC. One route adapted from Power et al[9] is to add ethylmagnesium bromide to 3-methylbenzaldehyde (I) to form the product 1-(3-methylphenyl)-1-propanol (II). This product is then oxidized by pyridinium chlorochromate (PCC) on silica gel to the ketone (III) and brominated with hydrobromic acid to yield the bromoketone (IV). This bromoketone is reacted with ethanolic methylamine to produce the 3-MMC free base (V), which can be converted to the hydrochloride salt (VI) by addition of ethereal hydrogen chloride (VI).[9]

 
One possible synthesis, starting from 3-methylbenzaldehyde

Pharmacology

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3-MMC potently inhibits the reuptake of monoamines in the human norepinephrine (NET) and dopamine (DAT) transporters. It also acts as a triple releasing agent of dopamine, serotonin, and norepinephrine, similar to many other cathinones. As a releasing agent, it is more selective for dopamine and especially norepinephrine, suggesting that it has stronger amphetamine-like stimulant properties compared to mephedrone or MDMA.[5]

Transporter EC50 [nM][10] IC50 [nM]
SERTTooltip Serotonin transporter 292 4500
NETTooltip Norepinephrine transporter 27 80
DATTooltip Dopamine transporter 70 270

Non-human studies

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The oral bioavailability of 3-methylmethcathinone was determined at 7%[2] in one pig study, with peak blood concentrations (Tmax) attained within 5 to 10 minutes, and a relatively short half-life of 50 minutes. Concentration in blood plasma dropped below detectability 24 hours after oral ingestion. Decreased feeding behavior resulted in weight loss for some.

Metabolism

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The metabolic pathway of 3-MMC is not well described. Known metabolites include 3-methylephedrine and 3-methylnorephedrine. A possible metabolic pathway is β-keto-reduction followed by N-demethylation.[11]

3-MMC also binds to serotonin 5-HT1A, 5-HT2A, 5-HT2C receptors and adrenergic α1A and α2A receptors.[12]

Toxicity

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A total of 27 fatalities with at least some exposure to 3-MMC have been confirmed as of March 2022. 18 of the 27 reported fatalities involved multiple drugs of abuse, usually opioids and uppers ("speedballs").[13] Of the 13 cases that specified gender, 12 deaths were male and 1 death was female. Of the 7 males whose age was reported, the median age was 27. The fatalities see a wide range of blood concentrations, from 249 to 1600 ng/mL.[14] The route of administration in any of these fatalities is not clear.

Of the presumably nine monointoxication deaths involving only 3-MMC that have occurred, two monointoxication cases were reported in the Netherlands and one was reported in France. The death in France was determined to be an accidental overdose.

In addition, there has been 291 reported cases of non-fatal 3-MMC intoxications. 213 of these cases (75%) were reported in Poland alone, and 50 cases (17%) were reported in Sweden.

The toxicokinetics of 3-MMC are thought to be similar to those for mephedrone. The dose-response curve of 3-MMC in humans is not well described in the literature, likely due to limited academic interest to date.

Recreational use

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Effects

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3-MMC as prepared for recreational use.

As with mephedrone, users of 3-MMC typically report effects such as an elevated mood, pleasant body sensations, feelings of love and empathy, euphoria, greater appreciation of music, heightened libido, and increased confidence and sociability.[15]

Adverse effects range from aggression, dry mouth, and jaw clenching, to more serious effects such as hyponatremia, seizures, hyperthermia and rhabdomyolysis.[15][7]

Abuse

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Due to its short duration and dopaminergic effects, 3-MMC is addictive and commonly abused. Repeated dosing within a sitting is typical, sometimes using different routes. Common self-reported doses range from 50 to 150 mg, up to single 500 mg doses. Intranasal administration, or snorting, is the most common route of administration, followed by oral administration. It can also be administered rectally and injected.

Users may dose repeatedly in order to extend the drugs duration, leading to 0.5—2 gram "sessions" that can span an evening. Single-dose effects last from 30 to 60 minutes, typically peaking around 10-minutes post-dose. In a questionnaire-based study of self-reported 3-MMC users in Slovenia, it was found that 88% of users insufflated the drug while 42% took it orally. The study did not find any instances of users injecting 3-MMC. Moreover, 26% of the users reported taking more than 1.5 grams of 3-MMC in a single sitting and over 50% reported having consumed more than 0.5 grams in a single sitting.[16]

Available forms

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3-Methylmethcathinone is commonly encountered as a white/off-white crystalline or pasty solid. It can be found sold in capsules. It is assumed to be a racemic mixture like mephedrone.

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In the United States, 3-MMC is illegal as a positional isomer of the controlled substance mephedrone[17] It was explicitly designated as a controlled substance on 13 December 2023.[18]

Since October 2015, 3-MMC is a controlled substance in China.[19]

3-MMC is banned in the Czech Republic.[20]

3-MMC was not banned in 2016 by the United Nations Office on Drugs and Crime (UNODC) after a critical review.[21] However, following its subsequent abuse beginning in 2019, this decision was overturned and it was placed into schedule II of the 1971 convention in March 2023.[1]

Effective 28 October 2021, 3-MMC has been scheduled under the Dutch Opium Law and is therefore illegal in the Netherlands.[22]

3-MMC was given narcotic status in India on 8 February 2024.

Research

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3-MMC is under development for use as a pharmaceutical drug in the potential treatment of dyskinesias.[23] As of August 2023, it is in preclinical research for this indication.[23] The drug is being developed by Clearmind Medicine.[23]

3-MMC is currently being developed as a medicine by the American biotech company MindMed. They have filed for a patent to use 3-MMC for problems such as social anxiety disorder, post-traumatic stress disorder (PTSD), and as an adjunct in couples therapy.[24]

3-MMC is also undergoing clinical trials for its use in treating menstrual symptoms.[25] A successful trial has been completed in the University of Maastricht. These efforts are led by the small Dutch company Period Pill.[26] The company has filed for patent coverage in Canada, Mexico, Croatia, the United States, Morocco, Japan, Brazil, Poland, Hungary, and Korea.

See also

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References

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  1. ^ a b "News: March 2023 – UNODC: Seven NPS "scheduled" at the 66th Session of the Commission on Narcotic Drugs". United Nations Office on Drugs and Crime (UNODC). United Nations Office on Drugs and Crime. Retrieved 29 May 2024.
  2. ^ a b c d e Shimshoni JA, Britzi M, Sobol E, Willenz U, Nutt D, Edery N (June 2015). "3-Methyl-methcathinone: Pharmacokinetic profile evaluation in pigs in relation to pharmacodynamics". Journal of Psychopharmacology. 29 (6): 734–43. doi:10.1177/0269881115576687. PMID 25804420. S2CID 26012927.
  3. ^ "3-Methylmethcathinone (3-MMC) Critical Review Report" (PDF). World Health Organization. Archived from the original (PDF) on 11 November 2021.
  4. ^ Preedy V (26 April 2016). Neuropathology of Drug Addictions and Substance Misuse Volume 2: Stimulants, Club and Dissociative Drugs, Hallucinogens, Steroids, Inhalants and International Aspects (2 ed.). London: King's College. ISBN 978-0-12-800212-4.
  5. ^ a b Luethi D, Kolaczynska KE, Docci L, Krähenbühl S, Hoener MC, Liechti ME (May 2018). "Pharmacological profile of mephedrone analogs and related new psychoactive substances" (PDF). Neuropharmacology. 134 (Pt A): 4–12. doi:10.1016/j.neuropharm.2017.07.026. PMID 28755886. S2CID 28786127.
  6. ^ "EMCDDA 2012 Annual report on the state of the drugs problem in Europe" (PDF). Archived from the original (PDF) on 23 April 2014. Retrieved 17 April 2014.
  7. ^ a b European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), Lisbon, Portugal (European Database on New Drugs)
  8. ^ Ferreira B, Dias da Silva D, Carvalho F, de Lourdes Bastos M, Carmo H (February 2019). "The novel psychoactive substance 3-methylmethcathinone (3-MMC or metaphedrone): A review". Forensic Science International. 295: 54–63. doi:10.1016/j.forsciint.2018.11.024. PMID 30572220. S2CID 58638238.
  9. ^ a b Power JD, McGlynn P, Clarke K, McDermott SD, Kavanagh P, O'Brien J (October 2011). "The analysis of substituted cathinones. Part 1: chemical analysis of 2-, 3- and 4-methylmethcathinone". Forensic Science International. 212 (1–3): 6–12. doi:10.1016/j.forsciint.2011.04.020. PMID 21601387.
  10. ^ 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.
  11. ^ Frison G, Frasson S, Zancanaro F, Tedeschi G, Zamengo L (August 2016). "Detection of 3-methylmethcathinone and its metabolites 3-methylephedrine and 3-methylnorephedrine in pubic hair samples by liquid chromatography-high resolution/high accuracy Orbitrap mass spectrometry". Forensic Science International. 265: 131–7. doi:10.1016/j.forsciint.2016.01.039. PMID 26901638.
  12. ^ Schmidt KT, Weinshenker D (April 2014). "Adrenaline rush: the role of adrenergic receptors in stimulant-induced behaviors". Molecular Pharmacology. 85 (4): 640–50. doi:10.1124/mol.113.090118. PMC 3965894. PMID 24499709.
  13. ^ Report on the risk assessment of 2-(methylamino)-1-(3-methylphenyl)propan-1-one (3-methylmethcathinone, 3-MMC) in accordance with Article 5c of Regulation (EC) No 1920/2006 (as amended). European Monitoring Centre for Drugs and Drug Addiction. 17 March 2022.{{cite book}}: CS1 maint: date and year (link)
  14. ^ Ameline A, Dumestre-Toulet V, Raul JS, Kintz P (March 2019). "Determination of a threshold fatal 3-MMC concentration in human: mission impossible". Psychopharmacology. 236 (3): 865–867. doi:10.1007/s00213-018-4941-5. PMID 29876621. S2CID 46978121.
  15. ^ a b "3-Methylmethcathinone". Erowid. Retrieved 11 April 2024.
  16. ^ Sande M (January 2016). "Characteristics of the use of 3-MMC and other new psychoactive drugs in Slovenia, and the perceived problems experienced by users". The International Journal on Drug Policy. 27: 65–73. doi:10.1016/j.drugpo.2015.03.005. PMID 25908121.
  17. ^ "Lists of: Scheduling Actions Controlled Substances Regulated Chemicals" (PDF). U.S. Department of Justice. February 2023. Retrieved 5 March 2023.
  18. ^ "eCFR :: 21 CFD 1308.11 (Dec 12, 2023) -- Schedule I." Electronic Code of Federal Regulations. Retrieved 21 December 2023.
  19. ^ "关于印发《非药用类麻醉药品和精神药品列管办法》的通知" (in Chinese). China Food and Drug Administration. 27 September 2015. Archived from the original on 1 October 2015. Retrieved 1 October 2015.
  20. ^ "Látky, o které byl doplněn seznam č. 4 psychotropních látek (příloha č. 4 k nařízení vlády č. 463/2013 Sb.)" (PDF) (in Czech). Ministerstvo zdravotnictví. Archived from the original (PDF) on 9 March 2016. Retrieved 6 February 2016.
  21. ^ "Extract from the Report of the 38 th Expert Committee on Drug Dependence, convened from 14 to 18 November 2016, at WHO headquarters in Geneva" (PDF). Commission on Narcotic Drugs. Retrieved 7 December 2016.
  22. ^ "Designerdrug 3-MMC vanaf vandaag verboden" (in Dutch). Dutch government. 28 October 2021.
  23. ^ a b c "3-Methylmethcathinone - Clearmind Medicine - AdisInsight". adisinsight.springer.com.
  24. ^ WO 2019026019, Golan E, Haden M, Van Wettum R, "Use of 3-methylmethcathinone", published 7 February 2019, assigned to Therapeutic Adjuncts Inc. and Recraceutical Corp. B.V. 
  25. ^ WO2021038460A1, JANSSEN, Merel; JANSSEN, Jochem & Golan, Ezekiel, "Treatment of menstrual cycle-induced symptoms", issued 2021-03-04 
  26. ^ "Period Pill • Fixing the Uncomforts of PMS & PMDD". Period Pill. Retrieved 8 May 2024.
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