There are numerous amphetamine derivatives, which derive from the same parent structure. Out of all of these compounds, 3,4-methilendioxymethamphetamine, also known as MDMA or Ecstasy, has gained the most popularity. It is a psychoactive drug with stimulant properties, which was first synthetized by Merk pharmaceuticals in 1912; no use was found for it until 1976, when Alexander Shulgin, chemist and pharmacologist, first described its mind-altering effects on humans. (Benzenhöfer and Passie, 2010).
MDMA structurally differs from amphetamine in a considerable manner. As depicted in Fig. 3, MDMA contains a methylendioxy group bound to positions 3 and 4 of the aromatic ring of the compound methamphetamine, which, in turn, results from the methylation of the primary amine of amphetamine.
Mechanism of Action of MDMA
MDMA is characterized by its empathogenic properties, providing a sense of emotional openness and affection towards others. These properties are a result of an increment in the levels of mostly serotonin in the neuronal synapse, together with other neurotransmitters (dopamine and norepinephrine) in lower proportions (Green et al., 1995).
As described for most amphetamine derivatives, this serotonin increase is mediated by a massive release from presynaptic vesicles, which runs in parallel with an inhibition of its reuptake through the serotonin transporter by direct competition with the substrate. The same mechanism applies for the release of the other monoamines, albeit to a lesser degree (White et al., 1996). MDMA also inhibits tyrosine hydroxylase, the limiting enzyme in the de novo synthesis of serotonin (Che et al., 1995). Furthermore, MDMA is a partial agonist on post- synaptic serotonin2A (5-HT2A) receptors, which endows it with light psychedelic properties. This is a shared characteristic with mescaline, with which it possesses a strong structural similarity (Fig. 3). How the activation of serotonin2A receptors leads to psychedelia is still unknown, but it likely somehow involves excitation of neurons in the prefrontal cortex.
Pharmacokinetics of MDMA
In Sprague-Dawley rats, after a single 10mg/kg intravenous dose, its half-life was 1.7h, with a distribution volume of approximately 7 L/Kg. It undergoes stereo- selective metabolism, favoring clearance of (S)-MDMA over (R)-MDMA, and is has been shown to possess non-linear pharmacokinetics (Mechan et al., 2006). In rats, its main metabolic route is that of N-demethylation, giving rise to 3.4- methylendioxyamphetamine (MDA), which is psychoactive. MDA can be found independently in the black market, as users have reported it to provide a slightly less empathogenic and more psychostimulant and psychedelic high to that of MDMA. Other metabolites that have been isolated in rats are 3-Hydroxy-4- methoxymethamphetamine, 3, 4-dihydroxymethamphetamine (HHMA), 4-hydroxy- 3-methoxyphenylacetone, 3,4-methylenedioxyphenylacetone (Lim and Foltz, 1988).
In humans, MDMA is easily absorbed through the gastrointestinal tract, reaching its plasmatic concentration peak 2 h post-administration (Farré et al., 2004). Nonetheless, some of the data on oral pharmacokinetics differ, due to the pharmaceutical form in which the compound is administered.
In humans, there are two preferred routes through which MDMA is metabolized. O- demethylation is the main route, which is regulated by a great number of cytochrome P450 isoforms, thus giving rise to HHMA. In addition, N-dealkylation takes place as a secondary route, generating MDA, which can, in turn, suffer O- demethylation, converting it into 3,4-dihydroxyamphetamine (HHA). Both HHMA and HHA are O-methylated into HMMA and HMA in a reaction that is regulated by catechol-O-methyltransferase (COMT), or form glucurono/sulfate conjugates (de la Torre et al. 2004). Furthermore, fractions of HHMA and HHA can suffer auto- oxidation, generating the corresponding ortho-quinones, which can be successively conjugated, forming glutathione adducts.