Methylone, also known as 3,4-methylenedioxy-N-methylcathinone (MDMC), is an entactogen and stimulant drug of the amphetamine, cathinone, and MDxx families related to 3,4-methylenedioxymethamphetamine (MDMA; "ecstasy"). It is the β-keto or cathinone analogue of MDMA. The drug is usually taken orally, but can also be administered by other routes. It acts as a serotonin–norepinephrine–dopamine releasing agent (SNDRA). The drug has much less activity at the vesicular monoamine transporter 2 (VMAT2) than MDMA and may have less serotonergic neurotoxicity. In contrast to certain other entactogens like MDMA, methylone does not appear to be a significant agonist of the serotonin 5-HT2 receptors. 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. Side effects of methylone include tachycardia, hangover, and insomnia. It may have reduced negative after-effects compared to MDMA. Methylone's onset is about 0.5 hours and its duration is about 2 to 3 hours. Methylone was first synthesized by Peyton Jacob III and Alexander Shulgin in the mid-1990s and was first described in the literature in 1996. It was patented by Jacob and Shulgin as a potential antidepressant and antiparkinsonian agent, but was never developed or marketed for such uses. Methylone was encountered as a designer and recreational drug by 2004 and has become a controlled substance in many countries. Similarly to MDMA, it is being developed for the treatment of post-traumatic stress disorder (PTSD).
Use and effects
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. 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. 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:
"[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. The studies found that the effects of methylone were similar to or milder than those of MDMA. 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. The misuse potential of methylone, as measured by for instance drug liking responses, appeared to be similar to that of MDMA. However it also has less off-target effects than MDMA which may be an advantage for medical applications.
Interactions
Pharmacology
Pharmacodynamics Methylone acts as a releasing agent and reuptake inhibitor of serotonin, norepinephrine, and dopamine. 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. Notably, methylone's affinity for the vesicular monoamine transporter 2 (VMAT2) is about 13-fold lower than that of MDMA. 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 effects, and behaves more like a mixed releaser and reuptake inhibitor than a predominant releaser, though methylone still has relatively robust releasing capabilities. In addition to its monoamine-releasing actions, similarly to MDMA, methylone is a variable-potency partial agonist of the serotonin 5-HT1A, 5-HT1B, and 5-HT1D receptors. In contrast to MDMA however, methylone and its metabolites lack significant affinity for the serotonin 5-HT2A and 5-HT2C receptors and do not activate the serotonin 5-HT2B receptor. On the other hand, a subsequent study found that methylone indeed showed no affinity for or agonistic activity at the serotonin 5-HT2A and 5-HT2B receptors, but was a potent and near-full agonist of the serotonin 5-HT2C receptor Gαq pathway, though not of the other assessed Gα pathways of the receptor. The absence of serotonin 5-HT2A receptor agonism with methylone may explain its absence of psychedelic effects. The lack of serotonin 5-HT2B receptor agonism with methylone may make it safer than MDMA, for instance in terms of long-term cardiac valvulopathy risk. Methylone is inactive at the mouse and rat trace amine-associated receptor 1 (TAAR1). Similarly to MDMA, methylone does not produce the head-twitch response, a behavioral proxy of psychedelic effects, in rodents. On the other hand, it has been found to produce psychoplastogenic effects in preclinical research, and showed greater effects in this regard than MDMA. Similarly to MDMA, methylone has been found to be a monoaminergic neurotoxin in animals. It has specifically been found to produce serotonergic and dopaminergic neurotoxicity in rodents. 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.
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