Accumulating evidence indicates that the plasticity-inducing effects of conventional antidepressant drugs are mediated by their direct binding to TrkB. In addition, it has recently been reported that psychedelics LSD and psilocybin, also bind to TrkB with higher affinity than antidepressants. In this study, we investigated whether psychedelics and classical antidepressants promote TrkB dimerization and neurotrophic signalling in a differential manner. The effects of psychedelics on the TrkB dimerization dynamics and neurotrophic signalling associated with plasticity were studied treating N2a cells and primary cortical neuronal cultures with LSD or fluoxetine. Dimerization of the TrkB receptor in the presence of the drugs is assayed by protein-fragment complementation assay (PCA). N2a cells are transiently transfected with TrkB constructs that are C-terminally tagged with either half of Gaussian luciferase and treated with LSD or fluoxetine for 40 minutes. The phosphorylation state of the neuronal TrkB receptor in different tyrosines was checked as a marker of its activation by Western blot. Primary cortical cultures (DIV21) were treated with fluoxetine (10µM) or LSD (100nM) for 1 hour. This experiment showed a significant increase of phosphorylation in TrkB Y816 after LSD treamtnet in cortical neuronal cultures while fluoxetine treatment showed no significant effect. Together, these results suggest that psychedelics that bind to TrkB are more potent than classical antidepressants inducing TrkB-signalling. Overall, this study provides further evidence that TrkB is a critical mediator of psychedelics's actions on neurotrophic signalling, and highlights the common and differential mechanisms used by psychedelics and conventional antidepressants to produce their therapeutic effects.