DescriptionMain mechanisms of action of MDMA in humans.svg
English: In humans, MDMA (3,4-methylenedioxy-N-methylamphetamine) increases serotonin (5HT) concentrations inside synaptic clefts at least via three ways:
Extracellular MDMA is taken inside presynaptic serotonergic neurons via serotonin transporters (SERT). In the absence of MDMA, SERT would constantly take 5HT from the synaptic cleft and transport it inside the neuron. High extracellular MDMA concentration reverses the SERT function: each extracellular MDMA molecule transported via SERT causes the SERT to release one intracellular serotonin (5HT) into the synaptic cleft. Inside the cleft, 5HT can bind to a dendritic 5HT-receptor and activate it. Mass activation of 5HT-receptors by excess 5HT is the primary reason for the intoxication that MDMA ingestion causes.
Intracellular MDMA can bind to VMAT2-proteins of synaptic vesicles. In the absence of MDMA, synaptic vesicles store 5HT inside themselves via VMAT2 in exchange for protons (H+). H+ gradient of the vesicles is sustained by H+-ATPases. VMAT2 inhibition by MDMA increases free 5HT concentration inside cytoplasm. This excess 5HT can be released via SERTs which have been reversed by MDMA.
Intracellular MDMA partially inhibits some of the outer mitochondrial membrane-bound monoamine oxidase A enzymes (MAO-A). Thus, less 5HT is transformed inactive by MAO-A. However, this effect has only minor relevance with regards to MDMA intoxication (see Reyes-Parada M).
Sources:
Oeri E: Beyond ecstasy: alternative entactogens to 3,4-methylenedioxymethamphetamine with potential applications in psychotherapy. Journal of Psychopharmacology. 2020. PMID32909493. doi:10.1177/0269881120920420.
Reyes-Parada M, Iturriaga-Vasquez P, Cassels BK: Amphetamine derivatives as monoamine oxidase inhibitors. Frontiers in Pharmacology. 2020;10:1590. PMC6989591. doi:10.3389/fphar.2019.01590.
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