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3-Methylmethcathinone

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3-Methylmethcathinone
Clinical data
ATC code
  • None
Legal status
Legal status
Identifiers
  • 2-(Methylamino)-1-(3-methylphenyl)propan-1-one
CAS Number
PubChem CID
ChemSpider
UNII
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 water3-MMC is sparingly soluble in PBS; slightly soluble in ethanol, dimethyl sulfoxide, and dimethyl formamide.[1] 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, also known as 3-MMC and metaphedrone,[2] is a designer drug from the substituted cathinone family. 3-MMC is closely related in structure to the more commonly known illicit drug mephedrone (4-MMC), and is also illegal in most countries that have banned mephedrone due to 3-MMC being a structural isomer of 4-MMC. 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.[3] Unlike other legal highs 3-MMC was tested and characterized in large mammals,[4] providing much more knowledge about it than is known about other synthetic cathinones. 3-MMC is a monoamine transporter substrate that potently inhibits norepinephrine uptake and displays more pronounced dopaminergic vs. serotonergic activity.[5]

History

3-MMC was first encountered in Sweden in 2012,[6] 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 powder form. There is no known or reported medical use of 3-MMC and it is being used for recreation. Some fatal intoxications have been reported although only a few involved 3-MMC only.[1]

Structure

3-Methylmethcathinone (3-MMC) chemical name is 2-(methylamino)-1-(3-methylphenyl)propan-1-one) and is a cathinone derivative, which is a synthetic form of phenylethylamines. 3-MMC has a cathinone which is substituted with a methyl group at the 3 position which makes it a structural isomer of Mephedrone.

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 has to be done to confirm this.[7]

Synthesis

There are several ways to synthesize 3-MMC. One of ways to synthesize 3-MMC, which is adapted from Power et al, is to add ethyl magnesium bromide to 3-methylbenzaldehyde (I). The product (II) is then oxidized by pyridinium chlorochromate (PCC) on silica gel to the keton (III) and brominated with hydrobromic acid to yield the bromo ketone (IV). This bromo ketone 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).[8]

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Reactions

There are no simple conversions into controlled substances.[1]

Available forms

The most common form of 3-MMC is as a white crystalline powder or as white solid crystals. Sometimes however it is also sold as capsules filled with 3-MMC. There is no information available whether it is a racemate or enantiomerically pure.

Mechanism of action

The studies of pharmacology are currently lacking but it was found 3-MMC just like 4-MMC inhibits norepinephrine(NET), serotonin(SERT) and dopamine(DAT) transporters. 3-MMC inhibits SERT and NET and more potently than the DAT which suggests that 3-MMC has stronger amphetamine-like stimulant properties compared to mephedrone.[5]

3-MMC strongly binds to serotonin 5-HT1A, 5-HT2A and 5-HT2C receptors. In addition, 3-MMC binds weakly to the α1A and α2A adrenergic receptors.[9]

Metabolism

The metabolism pathway of 3-MMC is not yet fully known. From analysis of human pubic hair of a drug dealer it is known that 3-methylephedrine and 3-methylnorephedrine are metabolites of the drug. A possible metabolic pathway is β-keto-reduction followed by N-demethylation.[10]

Efficacy

Generally, 3-MMC is taken via inhalation, injection, insufflation or oral administration. Repeated use of 3-MMC in a single session, often via different routes, has also been seen. The dosages range from threshold, light, common, strong and heavy corresponding to 50 mg, 50–150 mg, 150–250 mg, 250–350 mg and 350+mg respectively. Most self-reported doses range from 50 to 150 mg or even up to 500 mg. Furthermore, most users report repeated usage in order to extend their euphoric experience often leading to 0.5g to 2g of 3-MMC consumed in one sitting or even within a few hours. The drug lasts from 4–6 hours with its peak being 2–3 hours long. In a questionnaire-based study of self-reported 3-MMC users in Slovenia, it was found that 88.8% of users insufflated the drug while 42.6% 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 g of 3-MMC in a single sitting and over 50% reported having consuming more than 0.5g in a single sitting.[11]

Effects

The desired effects of 3-MMC are stimulation, spontaneous bodily sensations, euphoria, enhancement of empathy, affection and sociability, happiness, awareness and an increased appreciation of music which are similar effects of other amphetamines and drugs of abuse.[12] The adverse effects can range from stuttering, fatigue, verbosity, reduced level of consciousness, depression, aggression, delirium and confusion, double vision, difficulty in concentration, headaches, dehydration, hallucinations, fear to more serious effects such as hyponatremia, diaphoresis, seizures, hyperthermia and rhabdomyolysis.[12][6]

Toxicity

Very few cases of overdoses have been recorded in literature for concentrations between 249 and 1600 ng/mL for 3-MMC. Since the concentration range is quite high in the literature, defining the concentration at which impairment or fatality occurs is very difficult. No correlation between the measured concentration and the type of intoxication was found. The most likely cause for this is the chemical instability of the drug.[13]

Effects on animals

In animals, 3-MMC has a rather high absorption rate with the peak concentration being achieved within 5 to 10 minutes after oral ingestion and a plasma half-life of 0.8 hours. The bioavailability was tested to be around 7% and 3-MMC levels dropped below detectable levels after 24 hours of oral ingestion. Moreover, 3-MMC caused a significant change in the feeding behaviour of animals often resulting in weight gain over time. Caution is needed when applying the data for human safety from the extrapolated animal data because of low sample size, lack of data and low dosage.[4]

3-MMC is currently being developed as a medicine by a publicly traded company MindMed Inc NASDAQ:MNMD based on a patent titled "Use of 3-methylmethcathinone"[14]

Since October 2015, 3-MMC is a controlled substance in China.[15]

3-MMC is banned in the Czech Republic.[16]

3-MMC was not banned by the United Nations Office on Drugs and Crime (UNODC) after a critical review.[17]

Effective 28 October 2021, 3-MMC has been scheduled under the Dutch Opium Law and is therefore illegal in the Netherlands.[18]

References

  1. ^ a b c "3-Methylmethcathinone (3-MMC) Critical Review Report" (PDF). World Health Organization.
  2. ^ 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.
  3. ^ EMCDDA 2012 Annual report on the state of the drugs problem in Europe
  4. ^ a b 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.
  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. ^ a b European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), Lisbon, Portugal (European Database on New Drugs)
  7. ^ 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.
  8. ^ 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.
  9. ^ 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.
  10. ^ 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.
  11. ^ 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.
  12. ^ a b "Experiences". Erowid. Retrieved 1 March 2021.
  13. ^ 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.
  14. ^ 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. 
  15. ^ "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.
  16. ^ "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.
  17. ^ "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.
  18. ^ "Designerdrug 3-MMC vanaf vandaag verboden" (in Dutch). Dutch government. 28 October 2021.


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