Fig. (3).

Mechanisms of MDMA. Left: Typical neurotransmission. Right: MDMA acts by increasing synaptic monoamine concentrations through three mechanisms: (1) inhibition of presynaptic membranal monoamine transporters with relative selectivity for NET > SERT > DAT [326, 328]; (2) reversal of monoamine transporters by MDMA entering presynaptic nerve terminals during ion exchange in place of extracellular K⁺ and directly stimulating efflux of cytoplasmic monoamines; (3) binding as a substrate for vesicular monoamine transporter VMAT2 causing efflux of monoamines from vesicles into the cytoplasm and inhibiting uptake of monoamines into the vesicles. In addition to the above, MDMA demonstrates affinity as an agonist at various receptors, including 5HT1A, 5HT2A, 5HT2B, 5HT2C, 5HT4, adrenergic, dopamine D1 and D2, among others [326, 329, 330]. Bottom Right: Within the hypothalamus, the supraoptic nucleus (SON) and paraventricular nucleus (PVN) contain cell bodies of oxytocinergic neurons [330, 331]. These neurons contain presynaptic 5-HT₄ and postsynaptic 5-HT_1A receptors that, when stimulated by serotonin, trigger the release of oxytocin [329, 330]. Oxytocin (OT) has several downstream targets that are thought to contribute to a wide range of behavioral and physiological effects [332] associated with MDMA and potentially underlie some of the therapeutic efficacy of MDMA-AT for PTSD [333, 334].