Methylone
Group of stereoisomers From Wikipedia, the free encyclopedia
Methylone, also known as 3,4-methylenedioxy-N-methylcathinone (MDMC), is an entactogen and stimulant drug of the amphetamine, cathinone, and benzodioxole families related to 3,4-methylenedioxymethamphetamine (MDMA; "ecstasy").[5][1][6] It is the β-keto or cathinone analogue of MDMA.[6][1] Methylone is usually taken orally, but is also used by other routes.[5][1]
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| Other names | 3,4-Methylenedioxy-N-methylcathinone; 3,4-Methylenedioxymethcathinone; MDMC; MDMCAT; β-Keto-MDMA; βk-MDMA; M1; TSND-201; TSND201; MeONE; EASE; EMM; Explosion |
| Routes of administration | Common: oral, insufflation[1] Uncommon: IV or IM injection, rectal[1] |
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| Onset of action | 0.5 hours[4] |
| Elimination half-life | 5.8–6.9 hours[4] |
| Duration of action | 2.5–3.0 hours[4] |
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| Formula | C11H13NO3 |
| Molar mass | 207.229 g·mol−1 |
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| Solubility in water | 357 mg/mL (20 °C) |
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The drug acts as a serotonin–norepinephrine–dopamine releasing agent (SNDRA).[5][7][8][9] It has much less activity at the vesicular monoamine transporter 2 (VMAT2) than MDMA[5][10] and may have less serotonergic neurotoxicity.[5][11][12][7] In contrast to certain other entactogens like MDMA, methylone does not appear to be a significant agonist of the serotonin 5-HT2 receptors.[5][12][13][14] Methylone is similar in its effects to MDMA, producing entactogenic effects and euphoria, but has a reputation of being gentler than MDMA and only lasts about half as long.[5][15] Side effects of methylone include tachycardia, hangover, and insomnia.[5] It may have reduced negative after-effects compared to MDMA.[5] Methylone's onset is about 0.5 hours and its duration is about 2 to 3 hours.[5][4]
Methylone was first synthesized by Peyton Jacob III and Alexander Shulgin in the mid-1990s[16] and was first described in the literature in 1996.[1][17] It was patented by Jacob and Shulgin as a potential antidepressant and antiparkinsonian agent, but was never developed or marketed for such uses.[1][17] Methylone was encountered as a designer and recreational drug by 2004 and has become a controlled substance in many countries.[6][1] Similarly to MDMA, it is being developed for the treatment of post-traumatic stress disorder (PTSD).[18][19][20]
Chemistry
Methylone is the substituted cathinone analogue of 3,4-methylenedioxymethamphetamine (MDMA) and the 3,4-methylenedioxy analog of methcathinone. The only structural difference of methylone with respect to MDMA is the substitution of 2 hydrogen atoms by 1 oxygen atom in the β position of the phenethylamine core, forming a ketone group.[10]
Effects
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Perspective
Resemblance to MDMA
Left: amphetamine, methamphetamine and methcathinone.
Right: MDA, MDMA, and methylone
Methylone substitutes for MDMA in drug discrimination tests in rodents. Methylone does not substitute for the stimulant amphetamine or for the hallucinogen DOM in animal drug discrimination tests.[21] Further, also in common with MDMA, methylone acts on monoaminergic systems. In vitro, methylone has one third the potency of MDMA at inhibiting platelet serotonin accumulation and about the same in its inhibiting effects on the dopamine and noradrenaline transporters.[22][23][10]
In spite of these behavioral and pharmacological similarities between methylone and MDMA, the observed subjective effects of both drugs are not completely identical. Alexander Shulgin wrote of the former:[15]
"[Methylone] has almost the same potency of MDMA, but it does not produce the same effects. It has an almost antidepressant action, pleasant and positive, but not the unique magic of MDMA."
In acute pharmacological studies of methylone (50–300 mg) in humans, the drug produced physiological and psychological effects including increased blood pressure, heart rate, body temperature, pupil dilation, stimulation, euphoria, feelings of well-being, enhanced empathy, increased sociability, and altered perception.[24][25] The studies found that the effects of methylone were similar to or milder than those of MDMA.[24][25] Methylone had a faster onset of action and its subjective effects wore off sooner than MDMA, which might lead to a redosing pattern of use.[24] The misuse potential of methylone, as measured by for instance drug liking responses, appeared to be similar to that of MDMA.[24] However it also has less off-target effects than MDMA which may be an advantage for medical applications.[26][24][27]
Pharmacology
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Perspective
Pharmacodynamics
Methylone acts as a mixed releasing agent and reuptake inhibitor of serotonin, norepinephrine, and dopamine.[10][28] In comparison to MDMA, it has approximately 3-fold lower affinity for the serotonin transporter, while its affinity for the norepinephrine and dopamine transporters is similar.[10][28] Notably, methylone's affinity for the vesicular monoamine transporter 2 (VMAT2) is about 13-fold lower than that of MDMA.[10] The results of these differences in pharmacology relative to MDMA are that methylone is less potent in terms of dose, has more balanced catecholaminergic effects relative to serotonergic, and behaves more like a reuptake inhibitor like methylphenidate than a releaser like amphetamine; however, methylone still has relatively robust releasing capabilities.[28]
In contrast to MDMA, methylone and its metabolites lack significant affinity for the serotonin 5-HT2A and 5-HT2C receptors and similarly do not activate the serotonin 5-HT2B receptor.[12][13][14] This may make methylone safer than MDMA, for instance in terms of long-term cardiac valvulopathy risk.[29][30][31] Methylone is inactive at the mouse and rat trace amine-associated receptor 1 (TAAR1).[32][14]
Methylone has been found to produce psychoplastogenic effects in preclinical research and showed greater effects than MDMA.[33]
Similarly to MDMA, methylone has been found to be a monoaminergic neurotoxin in animals.[11] It has specifically been found to produce serotonergic and dopaminergic neurotoxicity in rodents.[11] However, in one study, moderate doses of MDMA produced serotonergic neurotoxicity in rodents whereas methylone and mephedrone did not do so, suggesting that cathinones like methylone may be less neurotoxic than their corresponding amphetamine counterparts like MDMA.[12][7]
| Compound | 5-HT | NE | DA | Ref |
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| Dextroamphetamine | 698–1,765 | 6.6–7.2 | 5.8–24.8 | [34][8] |
| Dextromethamphetamine | 736–1,292 | 12.3–13.8 | 8.5–24.5 | [34][7] |
| MDA | 160–162 | 47–108 | 106–190 | [35][36][37] |
| MDMA | 49.6–72 | 54.1–110 | 51.2–278 | [34][7][38][35][37] |
| Cathinone | 6,100–7,595 | 23.6–25.6 | 34.8–83.1 | [36][39][40] |
| Methcathinone | 2,592–5,853 | 22–26.1 | 12.5–49.9 | [36][39][41][42][40] |
| MDC | 966 | 394 | 370 | [9] |
| Methylone (MDMC) | 234–708 | 140–270 | 117–220 | [7][8][43][44][9] |
| Mephedrone | 118.3–122 | 58–62.7 | 49.1–51 | [7][8][39][42][45] |
| 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: [46][47] | ||||
Pharmacokinetics
The two major metabolic pathways in mammals for methylone are N-demethylation to methylenedioxycathinone (MDC), and demethylation followed by O-methylation of the 3- or 4-hydroxy group to 4-hydroxy-3-methoxymethcathinone (HMMC) or 3-hydroxy-4-methoxymethcathinone (3-OH-4-MeO-MC). Another metabolite is 3,4-dihydroxymethcathinone (HHMC).[9][14] When 5 mg/kg of methylone was administered to rats, it was found that around 26% was excreted as HMMC within the first 48 hours (less than 3% excreted unchanged).[48] The mean elimination half-lives of methylone in humans following oral administration of doses of 50 to 200 mg ranged from 5.8 to 6.9 hours.[4] The onset of action and duration of action of methylone in humans are 0.5 hours and 2.5 to 3.0 hours, respectively.[4]
History
Methylone was first synthesized by Peyton Jacob III and Alexander Shulgin in the mid-1990s.[16][1][17] This was after the publication of Shulgin's PiHKAL (1991), and so methylone is not included in this book.[49] However, it was subsequently included in The Shulgin Index (2011).[6] The drug was patented by Jacob and Shulgin as a potential antidepressant and antiparkinsonian agent, but was never developed or marketed.[1][17] This was the first time that methylone was described in the literature.[17] The drug was first described in the scientific literature by 1997.[21] Methylone was encountered as a designer and recreational drug by 2004.[6][1] It has become a controlled substance in many countries.[1]
Society and culture
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Perspective
Names and etymology
"Methylone" is also a trademarked brand name for an injectable form of methylprednisolone, a corticosteroid hormone used to treat arthritis and severe allergic reactions; hence, methylone may be confused with it. Aside from context, they can be distinguished by the fact that the name will usually be capitalized when referring to the prescription drug.
A proposed alternate name is βk-MDMA, or beta-keto-MDMA. While this nomenclature has not caught on because the name "methylone" became widely used before the conflicting Methylone trademark was noticed, the analogous names for related chemicals βk-MDEA and βk-MBDB have become the established names for those substances.
Commercial distribution
Analysis of "Explosion" has confirmed that the active ingredient is methylone.[50][unreliable source?] Many other formulations marketed as household chemicals, as well as the pure powder, have been sold.
Legal status
Netherlands
In the Netherlands, methylone is not yet listed under the Opium Law, but is covered under the medicine act. Because methylone is not registered officially, it is forbidden to trade in methylone. The Minister of Health has asked the Coordination point Assessment and Monitoring new drugs group (CAM) to gather information about this substance, resulting possibly in an official risk assessment.[51] Until now, no research has been conducted on the toxicity of methylone, so nothing is known about the harmfulness of this new drug.
New Zealand
In New Zealand, although methylone is not explicitly scheduled and falls outside the strict definitions of an "amphetamine analogue" in the Misuse of Drugs Act, it is considered to be "substantially similar" to methcathinone and is thus considered by law enforcement authorities to be a Class C illegal drug. Methylone was sold in New Zealand for around 6 months from November 2005 to April 2006 as an MDMA substitute, under the name "Ease". The product was withdrawn after legal disputes with the government.[52][53]
United Kingdom
In the United Kingdom, methylone is illegal since the 16/04/2010 revision of the misuse of drugs act. Before this it was not specifically mentioned in United Kingdom (U.K.) law as the β-ketone was not covered under the Misuse of Drugs Act. In March 2010, plans were announced to make methylone and other cathinones, Class B drugs, "within weeks". While delayed by dissatisfaction in the Advisory Council on the Misuse of Drugs, the revision was rushed through by the government with little regard for the views of the council. The importation of the compound was banned immediately.[54]
Sweden
Sveriges riksdag added methylone to schedule I ("substances, plant materials and fungi which normally do not have medical use") as narcotics in Sweden as of Oct 1, 2010, published by Medical Products Agency in their regulation LVFS 2010:23 listed as Metylon, 2-metylamino-1-(3,4-metylendioxifenyl)propan-1-on.[55] Methylone was first classified by Sveriges riksdags health ministry Statens folkhälsoinstitut as "health hazard" under the act Lagen om förbud mot vissa hälsofarliga varor (translated Act on the Prohibition of Certain Goods Dangerous to Health) as of Nov 1, 2005, in their regulation SFS 2005:733 listed as 3,4-metylendioximetkatinon (Metylon).[56]
Canada
Although not listed as a Schedule 1[57] substance, Health Canada reports that methylone falls under the scheduling as an analogue of amphetamine. However, Methylone bears the exact chemical difference between amphetamine and cathinone – and cathinone is listed as not being an analogue of amphetamine, possibly implying that methylone is unscheduled in Canada.[58] The CDSA was updated as a result of the Safe Streets Act changing amphetamines from Schedule 3 to Schedule 1; however, methylone was not added.[59]
United States
In October 2011, the DEA issued an emergency ban on methylone. It was made illegal to possess and distribute.[60][61] On April 4, 2013, the DEA placed methylone as a Schedule 1 substance under the CSA.[62]
- Arizona:
- Effective February 16, 2012, methylenedioxymethcathinone (methylone) was classified as a dangerous drug, making it a felony to knowingly possess, use, possess for sale, manufacture, administer, transport for sale, import into the state, or offer to transport for sale or import into this state, sell, transfer or offer to sell or transfer. A.R.S. 13-3401(6)(c)(xliii), 2012 Ariz. Legis. Serv. Ch. 1 (H.B. 2356).
- Florida:
- In January 2011, it was reported that Florida Attorney General Pam Bondi issued an emergency ban on MDPV, Methylone, Mephedrone, 3-methoxymethcathinone, 3-fluoromethcathinone, and 4-fluoromethcathinone as media attention on products labeled as "bath salts" grew. These chemicals are now Schedule I under Florida law.[63]
- Louisiana:
- In January 2011, Louisiana Governor Bobby Jindal emergency scheduled 3,4-methylenedioxymethcathinone (methylone), 3,4-methyenedioxypyrovalerone (MDPV), 4-methylmethcathinone (mephedrone), 4-methoxymethcathinone (methedrone), 4-fluoromethcathinone (flephedrone), and 3-fluoromethcathinone (3-FMC).
- Tennessee:
- On May 5, 2011, Tennessee Governor Bill Haslam signed a law making it a crime to knowingly produce, manufacture, distribute, sell, offer for sale or possess with intent produce, manufacture, distribute, sell, or offer for sale any product containing 3,4-methylenedioxymethcathinone (methylone), 3,4-methyenedioxypyrovalerone (MDPV), 4-methylmethcathinone (mephedrone), 4-methoxymethcathinone (methedrone), 4-fluoromethcathinone (flephedrone), and 3-fluoromethcathinone (3-FMC).[64]
- Texas:
- In September 2011, Texas added 3,4-methylenedioxy-N-methylcathinone to the Penalty Group 2 listing of the Health and Safety Code. Possession of a substance in penalty group 2 is a minimum of a state jail felony.
- Michigan:
- Schedule 1 controlled substance in 2012.
Research
Post-traumatic stress disorder
Under the developmental code TSND-201, methylone is under development by Transcend Therapeutics for the treatment of post-traumatic stress disorder (PTSD).[18][19][20] As of July 2024, it is in phase 2 clinical trials for this indication.[18][19]
References
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