Monoamine transporters In humans,<unk>  increases the amount of serotonin in the synaptic clefts of serotonergic neurons by inhibiting its uptake into neurons and by directly releasing it from the neurons. The released serotonin binds to various serotonin receptors and activates them in excess, which is the primary mechanism through which<unk>  causes intoxication.<unk>  also induces significant norepinephrine release. Extracellular<unk>  binds to presynaptic serotonin (SERT), norepinephrine (NET) and dopamine transporters (DAT) as a reuptake inhibitor, so that they uptake less of their namesake monoamine neurotransmitters. The efficacy of<unk>  inhibition is highest towards NET and SERT, and is much less towards DAT. As a result, more norepinephrine and serotonin remains in the synaptic cleft.<unk>  induced transporter reversal on human serotonin transporters (SERT), which leads to serotonin release. These monoamine transporters (SERT, NET and DAT) reuptake their respective neurotransmitters via ion gradient. Normally there is a high extracellular sodium (Na+) and chloride (Cl–) ion concentration, and low potassium (K+) ion concentration in respect to intracellular concentrations. In each reuptake cycle, one monoamine, Na+ and Cl– are simultaneously taken inside the cell. One intracellular K+ is then transported outside the cell. In experimental situations, high extracellular K+ concentration can cause reverse transport.<unk>  can substitute for K+ in this transport. Thus, high extracellular<unk>  can reverse the transport. This reversal is most notable with SERT and NET, which results in direct serotonin and norepinephrine release in exchange for cellular uptake of<unk> . VMAT2 and other effects In the serotonergic neurons of humans, extracellular<unk>  releases serotonin via serotonin transporters (SERT). Intracellular<unk>  inhibits VMAT2 and, to a much lesser extent, MAO-A. Intracellular<unk>  binds to VMAT2-proteins on synaptic vesicles as an inhibitor. Each VMAT2 transports cytosolic monoamines into the vesicle by dissipating proton gradient across the vesicular membrane. Thus, VMAT2 inhibition results in more free cytosolic monoamines like serotonin in the case of serotonergic neurons. These monoamines can then be released via monoamine transporters, which have been reversed by<unk>  (see below). Intracellular<unk>  can also bind to monoamine oxidase A (MAO-A) as an inhibitor, and thus prevent it from breaking down cytosolic serotonin. However, this effect is not significant in humans. Cortisol, prolactin, and oxytocin quantities in blood serum are increased by<unk> . Receptor binding In humans,<unk>  binds as an agonist to the following receptors: *5-HT1A-, 5-HT2A-, 5-HT2B- ja 5-HT2C-serotonin receptors *α1-, α2A-, β-adrenergic receptors *D1- ja D2-dopamine receptors *M1- ja M2-muscarinic receptors *H1-histamine receptor *TA1-receptor (TAAR1)<unk>  has two enantiomers, S-MDMA and R-MDMA. Mixture of the two (racemate) is typically used recreationally. S-MDMA causes the entactogenic effects of the racemate, because it releases serotonin, norepinephrine and dopamine much more efficiently via monoamine transporters. It also has higher affinity towards 5-HT2CR. R-MDMA has notable agonism towards 5-HT2AR, which supposedly contributes to the mild psychedelic hallucinations induced by high doses of<unk>  in humans.<unk>  racemate is a partial agonist towards human TAAR1, but this is not physiologically relevant due to low EC50. Relevant EC50 would be below 5 µM, but for humans it is 35 µM. However, the agonism is significant towards the TAAR1 of mice and rats (EC50 is 1–4 µM). Pharmacokinetics Main metabolic pathways of<unk>  in humans. The<unk>  concentration in the blood stream starts to rise after about 30 minutes, and reaches its maximal concentration in the blood stream between 1.5 and 3 hours after ingestion. It is then slowly metabolized and excreted, with levels of<unk>  and its metabolites decreasing to half their peak concentration over the next several hours. The duration of action of<unk>  is usually four to six hours, after which serotonin levels in the brain are depleted. Serotonin levels typically return to normal within 24–48 hours. Metabolites of<unk>  that have been identified in humans include 3,4-methylenedioxyamphetamine (MDA), 4-hydroxy-3-methoxymethamphetamine (HMMA), 4-hydroxy-3-methoxyamphetamine (HMA), 3,4-dihydroxyamphetamine (DHA) (also called alpha-methyldopamine (α-Me-DA)), 3,4-methylenedioxyphenylacetone (MDP2P), and 3,4-Methylenedioxy-N-hydroxyamphetamine (MDOH). The contributions of these metabolites to the psychoactive and toxic effects of<unk>  are an area of active research. 80% of<unk>  is metabolised in the liver, and about 20% is excreted unchanged in the urine.<unk>  is known to be metabolized by two main metabolic pathways: (1) O-demethylenation followed by catechol-O-methyltransferase (COMT)-catalyzed methylation and/or glucuronide/sulfate conjugation; and (2) N-dealkylation, deamination, and oxidation to the corresponding benzoic acid derivatives conjugated with glycine. The metabolism may be primarily by cytochrome P450 (CYP450) enzymes CYP2D6 and CYP3A4 and COMT. Complex, nonlinear pharmacokinetics arise via autoinhibition of CYP2D6 and CYP2D8, resulting in zeroth order kinetics at higher doses. It is thought that this can result in sustained and higher concentrations of<unk>  if the user takes consecutive doses of the drug.<unk>  and metabolites are primarily excreted as conjugates, such as sulfates and glucuronides.<unk>  is a chiral compound and has been almost exclusively administered as a racemate. However, the two enantiomers have been shown to exhibit different kinetics. The disposition of<unk>  may also be stereoselective, with the S-enantiomer having a shorter elimination half-life and greater excretion than the R-enantiomer. Evidence suggests that the area under the blood plasma concentration versus time curve (AUC) was two to four times higher for the (R)-enantiomer than the (S)-enantiomer after a 40 mg oral dose in human volunteers. Likewise, the plasma half-life of (R)-MDMA was significantly longer than that of the (S)-enantiomer (5.8 ± 2.2 hours vs 3.6 ± 0.9 hours). However, because<unk>  excretion and metabolism have nonlinear kinetics, the half-lives would be higher at more typical doses (100 mg is sometimes considered a typical dose).
MDMA
Phencyclidine
Theobromine
Benzocaine
Heroin
Cocaine
Cocaine 
Amphetamine