English: Schematic and simplified overview of the intracellular transduction cascades induced by 5-HT2AR TrkB and Sig-1R receptor activation by psychedelics. It is essential to emphasize that our understanding of the activation or inhibition of specific pathways and the precise molecular mechanisms responsible for triggering plasticity in specific neuron types remains incomplete. This figure illustrates the mechanisms associated with heightened plasticity within these pathways. Psychedelics (such as LSD, psilocin, and mescaline) bind to TrkB dimers, stabilizing their conformation. Furthermore, they enhance the localization of TrkB dimers within lipid rafts, thereby extending their signaling via PLCγ1. The BDNF/TrkB signaling pathway (black arrows) initiates with BDNF activating TrkB, prompting autophosphorylation of tyrosine residues within TrkB’s intracellular C-terminal domain (specifically Tyr490 and Tyr515), followed by the recruitment of SHC. This, in turn, leads to the binding of GRB2, which subsequently associates with SOS and GTPase RAS to form a complex, thereby initiating the ERK cascade. This cascade ultimately results in the activation of the CREB transcription factor. CREB, in turn, mediates the transcription of genes essential for neuronal survival, differentiation, BDNF production, neurogenesis, neuroprotection, neurite outgrowth, synaptic plasticity, and myelination. Activation of Tyr515 in TrkB also activates the PI3K signaling pathway through GAB1 and the SHC/GRB2/SOS complex, subsequently leading to the activation of protein kinase AKT and CREB. Both Akt and ERK activate mTOR, which is associated with downstream processes involving dendritic growth, AMPAR expression, and overall neuronal survival. Additionally, the phosphorylation of TrkB’s Tyr816 residue activates the phospholipase Cγ (PLCγ) pathway, generating IP3 and DAG. IP3 activates its receptor (IP3R) in the endoplasmic reticulum (ER), causing the release of calcium (Ca2+) from the ER and activating Ca2+/CaM/CaMKII which in turn activates CREB. DAG activates PKC, leading to ERK activation and synaptic plasticity. After being released into the extracellular space, glutamate binds to ionotropic glutamate receptors, including NMDA receptors (NMDARs) and AMPA receptors (AMPARs), as well as metabotropic glutamate receptors (mGluR1 to mGluR8), located on the membranes of both postsynaptic and presynaptic neurons. Upon binding, these receptors initiate various responses, such as membrane depolarization, activation of intracellular messenger cascades, modulation of local protein synthesis, and ultimately, gene expression. The surface expression and function of NMDARs and AMPARs are dynamically regulated through processes involving protein synthesis, degradation, and receptor trafficking between the postsynaptic membrane and endosomes. This insertion and removal of postsynaptic receptors provides a mechanism for the long-term modulation of synaptic strength [122]. Psychedelic compounds exhibit a high affinity for 5-HT2R, leading to the activation of G-protein and β-arrestin signaling pathways (red arrows). Downstream for 5-HT2R activation, these pathways intersect with both PI3K/Akt and ERK kinases, similar to the BDNF/TrkB signaling pathway. This activation results in enhanced neural plasticity. A theoretical model illustrating the signaling pathway of DMT through Sig-1R at MAMs suggests that, at endogenous affinity concentrations (14 μM), DMT binds to Sig-1R, triggering the dissociation of Sig-1R from BiP. This enables Sig-1R to function as a molecular chaperone for IP3R, resulting in an increased flow of Ca2+ from the ER into the mitochondria. This, in turn, activates the TCA cycle and enhances the production of ATP. However, at higher concentrations (100 μM), DMT induces the translocation of Sig-1Rs from the MAM to the plasma membrane (dashed inhibitory lines), leading to the inhibition of ion channels. BDNF = brain-derived neurotrophic factor; TrkB = tropomyosin-related kinase B; LSD = lysergic acid diethylamide; SHC = src homology domain containing; SOS = son of sevenless; Ras = GTP binding protein; Raf = Ras associated factor; MEK = MAP/Erk kinase; mTOR = mammalian target of rapamycin; ERK = extracellular signal regulated kinase; GRB2 = growth factor receptor bound protein 2; GAB1 = GRB-associated binder 1; PLC = phospholipase C γ; IP3 = inositol-1, 4, 5-triphosphate; DAG = diacylglycerol; PI3K = phosphatidylinositol 3-kinase; CaMKII = calcium/calmodulin-dependent kinase; CREB = cAMP-calcium response element binding protein; AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; Sig-1R = sigma-1 receptor; DMT = N,N-dimethyltryptamine; BiP = immunoglobulin protein; MAMs = mitochondria-associated ER membrane; ER = endoplasmic reticulum; TCA = tricarboxylic acid; AT P = adenosine triphosphate; ADP = adenosine diphosphate.