Figure 19.6. Major metabolic pathways of racemic methylone, ethylone and butylone with enzymes involved, if known. SULT, Sulfotransferase; UGT, UDP-Glucuronyltransferase. Synthetic cathinones are heterogeneous in terms of mechanism of action. Butylone, ethylone, mephedrone, methylone and naphyron function similarly to cocaine and serve as non-selective inhibitors of monoamine reuptake. Butylone, ethylone, mephedrone and methylone cause the release of serotonin. Cathinone, methcathinone and flephedrone act similarly to amphetamines, preferentially causing dopamine release and inhibiting dopamine and norepinephrine reuptake (Simmler et al., 2013). Pyrovalerone and 3,4-methylenedioxypyrovalerone (MDPV) inhibit the transport of dopamine, serotonin and norepinephrine (Schifano et al., 2016), but – unlike amphetamines – do not induce the release of monoamines (Simmler et al., 2013). All cathinone derivatives, including mephedrone, methylone, methedron and MDPV, are Class B drugs under the Misuse of Drugs Act 1971. It is illegal to possess the drug and sell it.
Penalties for possession are up to five years` imprisonment and/or an unlimited fine. The procurement provides for penalties of up to 14 years` imprisonment and/or an unlimited fine. Bath salts refer to a group of previously over-the-counter but now illegal substances that contain 1 or more synthetic chemicals, similar to tacchinone, an amphetamine-like stimulant found in the khat plant. Bath salts, marketed under brand names (e.g. Lunar Wave, Cloud Nine, Vanilla Sky), are sold online or in pharmacies as white or brown crystalline powder and can be ingested, inhaled or injected. The most recent information on bath salt use among teens comes from the 2016 MTF survey of Grade 8, 10, and 12 students, who report consumption of 0.9%, 0.8%, and 0.8%, respectively. Synthetic cathinones in bath salts include methylone, mephedrone, and 3,4-methylenedioxypyrovalerone (MDPV), all of which are chemically similar to amphetamines and MDMA (ecstasy). Methylone (bk-MDMA), ethylone (bk-MDEA), butylone (bk-MBDB) and mephedrone (4-methylmethcathinone) are beta-keto-substituted analogues of the corresponding amphetamines and have emerged as a new class in the illicit drug market. Due to their chemical similarity to amphetamines or methcathinone and their use as an alternative to these drugs, pharmacological and toxicological effects similar to those described above could be postulated [6].
The metabolism of methylone and mephedrone has been studied in the urine of rats and aggressors and the metabolism of ethylone and butylone only in the urine of the aggressor [6]. Methylone, ethylone and butylone were metabolised similarly to their methylenedioxysubstituted amphetamine analogues (Fig. 19.6), namely by O-demethylation followed by methylation of one of the hydroxyl groups. N-demethylation and keto group reduction have been described as smaller metabolic steps. Mephedrone was degraded by reduction of the keto group, N-demethylation and oxidation of the tolyl group to corresponding alcohol and carboxylic acid. The metabolites of all active substances containing hydroxyl groups were conjugated to sulphates or glucuronides. Data on the kinetic CYP enzyme of methylone and in vitro incubations of mephedrone with a specific CYP inhibitor showed that CYP2D6, CYP1A2, 2B6 and 2C19 were more or less involved in the early metabolic steps [18,19]. Instrumental analysis was performed using HPLC-DAD [135], GC-MS [43,59,132–134, 137–139] or LC-MS(/MS) [59,73,86,87,137,138]. MS(/MS) instruments operated in full scan mode [43,50,59,132,137], SIM with three ions per link [59,132–134], MRM with at least two transitions per connection [59,73,86,87] or production scan mode [138]. As a result, the minimum criteria for identifying drugs based on MS were essentially met. Kamata et al.
[137] also used SIM mode with one ion per compound, but only for LC-MS quantification of methylone and its metabolites after these were identified by GC-MS. In a preliminary study conducted in 2007 [45], the incorporation of methylone and other new synthetic drugs, namely methcathinone and N-methyl-1-(3,4-methylenedioxyphenyl)butan-2-amine (MBDB), into hair was performed in an animal model. The authors concluded that new synthetic drugs such as methylone and MBDB (but not methcathinone) are heavily incorporated into the keratin matrix. Methylone acts as a mixed inhibitor/release agent for the reuptake of serotonin, norepinephrine and dopamine. [2] [8] Compared to MDMA, it has about 3 times lower affinity for the serotonin transporter, while its affinity for norepinephrine and dopamine transporters is similar. [2] [8] Remarkably, methylone`s affinity for monoamine 2 vesicular transporter (VMAT2) is about 13 times lower than that of MDMA. [2] The results of these differences in pharmacology from MDMA are that methylone is less dose-effective, has more balanced catecholaminergic effects compared to serotonergic catecholaminergic effects, and behaves more like a reuptake inhibitor such as methylphenidate than as a delivery device such as amphetamine; However, methylone has relatively robust release capabilities,[8] possibly due to its ability to phosphorylate monoamine transporters, which are similar in efficacy to MDMA. [ref.needed] „This is not the first time cathinone has been sold as ecstasy at events in the UK. In 2014, shortly after the mephedrone ban, methylone made its debut on the British drug scene. After the methylone ban, N-ethylpentylon appeared in 2017. During the last festival season, three other cathinones raised their heads. In New Zealand, although methylone is not explicitly listed and does not fall under the strict definitions of an „amphetamine analogue“ in the Misuse of Drugs Act, it is considered „substantially similar“ to methcathinone and is therefore considered an illegal Class C drug by law enforcement agencies. Methylone was sold in New Zealand for approximately 6 months, from November 2005 to April 2006, as a substitute for MDMA under the name „Ease“. The product was withdrawn after a dispute with the government. [12] [13] Although not listed in Schedule 1[17], Health Canada reports that methylone is listed as an amphetamine analogue. However, methylone has the exact chemical difference between amphetamine and cathinone – and cathinone is listed as not an amphetamine analogue, which could mean that methylone is not planned in Canada. [18] The CDSA was updated as a result of the Safe Streets Act, which moved amphetamines from Schedule 3 to Schedule 1; However, methylone was not added.
[19] In October 2011, the DEA issued an emergency ban on methylone. Possession and distribution were declared illegal. [20] [21] On April 4, 2013, the DEA added methylone to the CSA as a Schedule 1 substance. [22] Synthetic cathinones could be divided into four main families: (1) compounds with an N-alkylated group originally synthesized for therapeutic purposes, such as methylone, ethylone, butylone and pentylone; (2) compounds with a methylenedioxy group added to the benzyl ring, such as MDMA, 3,4-methylenedioxy-N-ethylamphetamine (MDEA), N-methyl-1,3-benzodioxolylbutanamine (MBDB) and N-methyl-1,3-benzodioxolylpentanamine (MBDP); (3) compounds with a pyrrolidine group added to the nitrogen atom, such as α-PPP; and (4) compounds with a combination of methylenedioxy and N-pyrrolidine groups, such as MDPPP, MDPBP and MDPV (Valente et al., 2014). „Methylone“ is also a brand name for an injectable form of methylprednisolone, a corticosteroid hormone used to treat arthritis and severe allergic reactions; Therefore, methylone can be confused with it. Context aside, they can be distinguished by the fact that the name is usually capitalized when it comes to the prescription drug. The two main metabolic pathways of methylone in mammals 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). When 5 mg/kg methylone was administered to rats, approximately 26% was excreted as HMMC within the first 48 hours (less than 3% was excreted unchanged). [9] 4-Methylmethcathinone (mephedrone), 3,4-methylenedioxymethcathinone (methylone) and 3,4-methylenedioxyprovalerone (MDPV) are the most common synthetic cathinones, all derived from cathinone, an alkaloid with stimulating properties found in the leaves of Catha edulis and known as khat (German, Fleckenstein and Hanson, 2014; Valente, Guedes de Pinho, de Lourdes Bastos, Carvalho, & Carvalho, 2014). The synthesis of the first cathinone dates back to the 1920s. Methcathinone was the first to be synthesized in 1928 (Sanchez, 1929), but was not abused until the 1990s (Emerson & Cisek, 1993). Mephedrone was synthesized in 1929 (Sanchez, 1929) and MDPV in 1967 (G.m.b.H., 1967), while the more recent methylone was synthesized in 1996 (Jacob Peyton III, 1996).Nevertheless, it was not until the early 2000s that they were used in synthetic drugs and abused worldwide (German et al., 2014). The Sveriges riksdag added methylone to List I („Substances, plant materials and fungi not normally used medicinally“) as a narcotic drug in Sweden as from 1 October 2010, published by the Medical Products Agency in its prescription LVFS 2010:23 listed as metylone, 2-metylamino-1-(3,4-metylendioxiconyl)propane-1-one. [15] Methylone was first classified by the Sveriges riksdags Ministry of Health Statens folkhälsoinstitut [sv] as „dangerous to health“ under the Lagen om förbud mot vissa hälsofarliga varor [sv] (translated law on the prohibition of certain dangerous goods) from 1 November 2005 in its SFS Regulation 2005:733 as 3,4-metylendioximetkatinone (metylon). [16] Patients who are more likely to experience severe and uncontrolled agitation are those who abuse alcohol; sympathomimetics such as cocaine or methamphetamines or synthetic drugs such as ecstasy (MDMA), mephedrone or methylone (bath salts); and hallucinogenic drugs such as phencyclidine (PCP).
