Methedrone

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Not to be confused with methedrine, mephedrone, methadone, or methylone.
Methedrone
4-Methoxymethcathinone.svg
Systematic (IUPAC) name
(RS)-1-(4-Methoxyphenyl)-2-(methylamino)propan-1-one
Clinical data
  • I-P(Poland)[1]
Pharmacokinetic data
Half-life 26.2±0.7 (h)
Identifiers
530-54-1 YesY
None
PubChem CID 216281
ChemSpider 187475 YesY
Chemical data
Formula C11H15NO2
193.242 g/mol
 YesY (what is this?)  (verify)

Methedrone (para-methoxymethcathinone, 4-methoxymethcathinone, bk-PMMA, PMMC, methoxyphedrine, 4-MeOMC) is a recreational drug of the cathinone chemical class.[2] Chemically, methedrone is closely related to para-methoxymethamphetamine (PMMA), methylone and mephedrone.

History[edit]

Methedrone is a designer drug. Designer drugs are analogs to the original drug, created to mimic the effects of that drug. Because governments haven’t yet banned all these designer drugs, for the simple reason that these substances haven’t been researched enough to determine whether they should be illegal or not, these designer drugs are known as ‘legal highs’.[3][4]

Discovery[edit]

Since methedrone is a designer drug, the year of discovery remains unknown. So does the first creator of this chemical substance. Methedrone got most attention when in 2009 two young Swedish men died from a methedrone overdose. Both were found unconscious, one died on the way to the hospital, due to seizures. The other died after 16 hours in the hospital, because of complete organ failure.[3]

Structure and reactivity[edit]

Structure[edit]

Methedrone is a synthetic cathinone. It is related to the parent compound cathinone. Methedrone belongs closely to the phenethylamine family, which means there is a phenyl group attached to a linear carbon chain of two carbons.[5][6][7]

Reactivity[edit]

There are no articles found about the reactivity of Methedrone.

Synthesis[edit]

Figure 1: Synthesis of Methedrone

The synthesis of Methedrone is shown in figure 1. No articles describe the precise synthesis of Methedrone.[6][8] Mephedrone is a similar compound that has only one oxygen less and its synthesis is known.[9] Therefore, Methedrone is expected to have a similar synthesis.

First step is a bromination of 1-(4-methoxyphenyl)propan-1-one to 2-bromo-1-(4-methoxyphenyl)propan-1-one. The second step is a reaction with methylamine by which the 2-bromo-1-(4-methoxyphenyl)propan-1-one becomes 1-(4-methoxyphenyl)-2-(methylamino)propan-1-ol. The last step is a reaction with potassium permanganate and then finally we have Methedrone.

Availability[edit]

Methedrone can be purchased legally in Europe (except for Sweden) and in most states in the US on the internet, but also at head shops or at gas stations.[10] It is, along with other new synthetic drugs, commonly labeled as “bath salt” or “plant food”.[11]

Available forms[edit]

Methedrone is a powder. There are reports from a Drugs forum where two users describe Methedrone as a ‘yellow powder’. One of the reporter said it was ‘wet’ and the other one said that Methedrone has a ‘light and fluffy texture similar to flour’.[12] Methedrone can exist in two stereoisomeric forms, because of its asymmetric center.[6]

Administration[edit]

Methedrone is a synthetic drug used for its euphoric and stimulant properties, such as MDMA, and is administered through insufflation, oral, smoking, rectal and intravenous methods.[11]

Mechanism of Action[edit]

Methedrone is found to be a potent SERT and NET inhibitor, but a weak DAT inhibitor. The DAT/SERT ratio was smaller than 1. For other analog compounds, this is usually smaller than 0.5. Meaning that, unlike other MDMA-like compounds, Methedrone does not prefer inhibition of the NET and DAT over the SERT. It actually has the highest selectivity for the SERT of designer drugs yet known.[13]

Another effect of the drug is on the transporter mediated release of NE, DA and 5-HT from cells which were preloaded with transmitters. Methedrone releases all three monoamines (NE, DA and 5-HT). This means that the drug has an effect on the activity of the cells and thus affects the monoamine receptor binding profiles and interactions with monoamine transporters. It induces an efflux of monoamines.[13]

It has been found that the most MDMA-like, in terms of the monoamine transporter interaction, is Methedrone. However, the in vivo hyperthermic properties are stronger than MDMA’s. The properties of Methedrone have been linked to activation of the serotonergic receptor and therefore are able to cause hyperthermic complications when people are exposed to it too often.[13]

Metabolism[edit]

To consider how Methedrone (4-MeOMC) acts in a biological system, it is necessary to study the stability in an aqueous solution. Because, when tested directly in blood or urine, it is not known whether the compound will be degraded by enzymes available in the biological solutions or cause the chemical mechanisms, such as pH or dissolved oxygen. The length of the half-life of the compound has been examined and the percent remaining after 12 hours in buffers with various pH’s. The tested pHs were 4, 7, 10 and 12.[14] The conclusions are that Methedrone, just as most analogs, is stable in acid solutions. However, in neutral and basic solutions it is decomposed, where a stronger decomposing takes place as the solution turns more basic.

When comparing methdrone with its analogs, it’s been found that there are several factors which affect their stability:

  • The substituted group on the benzene ring.
  • The groups attached at the nitrogen atom, but this is not applicable for Methedrone.

Methedrone and four other analogs have their groups substituted in the meta- or para-positions. For these compounds the rate constant, k, has been determined and a Hammett plot was constructed by plotting the decomposition rate constant (0.693/half-life) in the pH of 12 against their Hammett constants, taken from literature. This again shows that Methedrone is a relative stable compound even in basic solution.

Another conclusion based on the results from the literature is that there is negative charge built up in the transition state during the rate determining step. This reasoning is based on the good linear correlation (r=0.9805) and the positive slope (determined as 1.76).[14]

There are two possible metabolites known for Methedrone:[15]

  • The carbon between the nitrogen group and R1, an H-atom in case of Methedrone, will be replaced. This will lead to a smaller compound.
  • The methylgroup bound to the oxygen at the benzene group will be replaced by an H-atom. This metabolite will lose the epoxide and turn into a hydroxy-compound.

Efficacy and Side Effects[edit]

Efficacy[edit]

In pharmacology, efficacy (Emax) is a term used to describe the maximum response achievable from a drug. There is little information available on Methedrone and its efficacy. According to users, the doses of Methedrone vary from 50 to 500 mg with a duration of effects range from 45 minutes to two hours. There are two cases known of fatal intoxications with Methedrone. In the first case, the postmortem femoral blood sample of the patient contained a concentration of 8.4 µg/g Methedrone, the patient died after 16 hours (but in addition, other toxic compounds such as diazepam were also detected in his blood). In the second case the concentration of Methedrone in the postmortem femoral blood sample was 9.6 µg/g and Methedrone was the only toxic compound detected. Recent studies[3] to these fatal cases suggest that the Methedrone alone was responsible for these deaths and that the concentrations in the femoral blood represent the fatal levels of Methedrone. Also, these studies show that there is little window range between a fatal dose and a non-fatal dose, this means that the safety gap is small. A fatal dose is more than 8 µg/g whereas the dose among the living cases which were studied varied from 0.1 to 4.8 µg/g blood.[3] Knowing this, it is concluded that the dose of efficacy of Methedrone is around 8 µg/g blood, leading to death.

Adverse effects[edit]

Anecdotal and case reports of human use of “bath salts”, such as Methedrone, suggest that these substances produce powerful psychological effects. These pshygological effects include psychotic behavior, paranoia, delusions, hallucinations and also self-injury.[16] There is very little known of the physical effects of Methedrone in human, but there have been some studies to the effects of Methedrone in animals, so we focused on the effects in mice. Studies to the effects of Methedrone in mice show that Methedrone produces a significant increase in circling, beam breaks and hyperactivity. Furthermore the mice also showed a significant increase in salivation, head weaving and stimulation. As already stated Methedrone is (nowadays) legal drug, however studies show that it shares major pharmacological properties with drugs that have been banned, such as mephedrone and methylone. Also, the effects of Methedrone are very similar to the effects of banned drugs in mice.[16] This suggests that Methedrone may be just as harmful as the drugs which are banned.

Toxicity[edit]

Acute toxicity[edit]

There is little research regarding the toxicity of methedrone. Research has been done by animal-testing on mice once.[16] Also the lethal doses of the two Swedish methedrone-victims has been compared to methedrone concentrations in the blood of petty drug offenders.[3]

The mean of the methedrone concentrations in the blood of the petty drug offenders was 1.3 μg/g blood. One of these persons had a very high concentration in the blood, that is 4.8 μg/g blood. The mean of the concentrations found in the blood of the deceased victims was 8.0 μg/g blood. None of the non-lethal doses or lethal doses is known, suggesting that the safety gap between a lethal and non-lethal dose of methedrone is probably very small. Thus making use of this drug dangerous because poisonings, and simultaneously death, are accidental.[3]

In a study of the effects of synthetic cathiones in ‘bath salts’ the effects of methedrone on mice were tested, these effects were compared to the effects of cocaine and methamphetamine. Different tests were performed to get insight into motor coordination, balance and overall behavioral effects. The mice did not show any difference in motor coordination or balance (doses administered were 10.0 mg/kg and 30.0 mg/kg). However significant changes were shown in overall behavioral effects. Administration of methedrone led to:[16]

  • Increase of repeated movement of the mouse in a circular manner
  • Hyperactivity
  • Excessive salivation
  • Increase of head weaving
  • Increase of stimulation, tense body

These effects are related with addiction potential.[17][18] Excessive salivation is not an effect that is typically reported in humans. It is suggested that methedrone increases salivation via brain systhems that primarily regulate autonomic responses.[3]

Compared with mephedrone, methylenedioxypyrovalerone (MDPV) and 4-fluoromethcathione (4-FMC), methedrone has a relatively slow onset. Thereby increasing the risk; because effects are not immediately shown, this could lead to an accidental overdose. It could also make the drug less popular, because humans tend to favor drugs that cause large, rapid initial increases in locomotor activity.[16]

Chronic toxicity[edit]

Even in comparison with acute toxicity, chronic toxicity is poorly researched. Only the post-mortem study did little investigation on this subject. The findings of this study only showed that hair of the deceased victims contained methedrone, however, no conclusions were made regarding these findings.[3]

No studies have examined the effect of methedrone-use during or before pregnancy by a pregnant female on the embryo, nor is the carcinogenicity researched.

Health risks[edit]

The health risks associated with methedrone are mostly unknown, but are expected to be similar to other cathinones.[19] Methedrone was almost immediately withdrawn from sale by initial vendors after reports of adverse health effects.[citation needed] Some amphetamine analogs containing a para-methoxy group are known to cause severe hyperthermia and even death due to concurrent MAOI and monoamine releasing action.[20]

Overdose[edit]

The deaths of two young men in southeast Sweden in 2009 were attributed to methedrone overdose.[3][21] Both were comatose when found. One suffered cardiorespiratory arrest on the way to the hospital, while the second survived for 16 hours in the emergency department.

Effects on Animals[edit]

Mice[edit]

Methedrone does not have an effect on the balance or motor coordination of mice. It does however have an effect on the overall behavior of mice. These effects include:[16]

  • Increase of repeated movement of the mouse in a circular manner
  • Hyperactivity
  • Excessive salivation
  • Increase of head weaving
  • Increase of stimulation, tense body

Legality[edit]

Its sale has been banned in Sweden since December 9, 2009.[3]

See also[edit]

References[edit]

  1. ^ "Ustawa z dnia 15 kwietnia 2011 r. o zmianie ustawy o przeciwdziałaniu narkomanii ( Dz.U. 2011 nr 105 poz. 614 )". Internetowy System Aktów Prawnych. Retrieved 17 June 2011. 
  2. ^ "Cathinone and its analogues (e.g. mephedrone, methedrone, α- pyrrolidinovalerophenone)". World Antidoping Agency. 
  3. ^ a b c d e f g h i j Wikström, Maria, et al. "Two fatal intoxications with the new designer drug methedrone (4-methoxymethcathinone)." Journal of analytical toxicology 34.9 (2010): 594-598.
  4. ^ http://www.emcdda.europa.eu/publications/drugnet/online/2010/69/article3, European Monitoring Centre for Drugs and Drug Addiction, Drugnet Europe, visited on 19-03-2015
  5. ^ European Monitoring Centre for Drugs and Drug Addiction http://www.emcdda.europa.eu/publications/drug-profiles/synthetic-cathinones, Visited 17-03-2015
  6. ^ a b c TECHNICAL PROFILE OF METHEDRONE from European Monitoring Centre for Drugs and Drug Addiction, https://ewsd.wiv-isp.be/Publications%20on%20new%20psychoactive%20substances/Methedrone /Methedrone_Tech_Prof_EMCDDA_Mar_2010.pdf, Visited 17-03-02015
  7. ^ Emerging drugs of abuse: current perspectives on substituted cathinones published in Dove Press Journal: Substance Abuse and Rehabilitation 26 may 2014 by Magalie Paillet-Loilier, Alexandre Cesbron, Reynald Le Boisselier, Joanne Bourgine and Daniele Debruyne.
  8. ^ Drugs-Forum https://drugs-forum.com/forum/showwiki.php?title=Methedrone, Visited 19-03-2015
  9. ^ Academia.edu http://www.academia.edu/528001/Mephedrone_4-methylmethcathinone_meow_meow_ chemical_pharmacological_and_clinical_issues, Visited 17-03-2015
  10. ^ DEA (Drug Enforcement Agency). Synthetic cathinones – DEA request for information posted 3/31/11; 2011 [retrieved 28.07.11].
  11. ^ a b Psychonaut Research Web Mapping Project, MDPV report, London, UK: Institute of Psychiatry, King's College London; 2009.
  12. ^ Drugs-forum https://drugs-forum.com/forum/showthread.php?t=101305, Visited 18-03-2015
  13. ^ a b c Uptake and release effects of diethylpropion and its metabolites with biogenic amine transporters Han Yua, Richard B Rothmanb, Christina M Derschb, John S Partillab, Kenner, C Ricea
  14. ^ a b Degradation pathways of 4-methylmethcathinone in alkaline solution and stability of methcathinone analogs in various pH solutions Kenji Tsujikawa a, *, Toshiyasu Mikuma b, Kenji Kuwayama a, Hajime Miyaguchi a, Tatsuyuki Kanamori a, Yuko T. Iwata a, Hiroyuki Inoue a Forensic Science International 220 (2012) 103–110
  15. ^ Generation of metabolites by an automated online metabolism method using human liver microsomes with subsequent identification by LC-MS(n), and metabolism of 11 cathinones Daniel M. Mueller & Katharina M. Rentsch
  16. ^ a b c d e f Marusich, Julie A., et al. "Effects of synthetic cathinones contained in “bath salts” on motor behavior and a functional observational battery in mice."Neurotoxicology 33.5 (2012): 1305-1313.
  17. ^ Calabrese, Edward J. "Addiction and dose response: the psychomotor stimulant theory of addiction reveals that hormetic dose responses are dominant." CRC Critical Reviews in Toxicology 38.7 (2008): 599-617.
  18. ^ Wise, Roy A., and Michael A. Bozarth. "A psychomotor stimulant theory of addiction." Psychological review 94.4 (1987): 469
  19. ^ Prosser JM, Nelson LS (2012). "The toxicology of bath salts: a review of synthetic cathinones". J Med Toxicol 8 (1): 33–42. doi:10.1007/s13181-011-0193-z. PMID 22108839. 
  20. ^ Becker J, Neis P, Rohrich J, Zorntlein S (2003). "A fatal paramethoxymethamphetamine intoxication". Legal Medicine (Tokyo) 5 (Suppl 1): S138–41. PMID 12935573. 
  21. ^ "Two die of legal drug overdose". The Local. October 14, 2009.