Figure 2.

MDMA acts as an inhibitor of NET, DAT, SERT and of VMAT2, resulting in increased levels of the three monoamines DA, NE, and 5HT. The latter consequently increases the blood levels of prolactin, DHEA, oxytocin, and cortisol. MDMA also binds D1-D2 receptors and acts as an agonist of H1, 5HT2A, and B receptors. Its effects are also explained by the interaction with TAAR1, alpha2, and Sigma1. S- and R-ketamines increase glutamate release into the synaptic cleft, activating AMPAR and contributing to further synaptogenesis and dendritogenesis. S-ketamine binds NMDARs expressed in GABAergic interneurons, leading to a depolarization of cortical excitatory neurons. This depolarization causes glutamate and BDNF release, which bind to TrkB receptors. TrkB activates the mTORC1 signaling pathway, leading to the upregulation of synaptogenesis and dendritogenesis. S-ketamine binds to extrasynaptic NMDARs, disinhibiting mTORC1 signaling by deactivating eEFK2. Binding to mu-opioid receptors may facilitate antidepressant effects. R-ketamine affects microglial signaling and, by increasing BDNF release through TrkB, activates the ERK signaling pathway, resulting in synaptogenesis and dendritogenesis.