Psychedelics such as psilocybin and LSD are promising treatments for depression and anxiety. Psychedelics are thought to exert their antidepressant and hallucinatory effects through the serotonin 2A receptor (5-HT2A), although they have high affinity for most of the 15 serotonin receptors in the human body. Despite their therapeutic promise, we still do not understand how they work at a cellular level or how the signalling induced by psychedelics differs from that of serotonin. We hypothesised that psychedelics act by signalling from intracellular localised serotonin receptors following their internalisation by endocytosis, in contrast to prototypical receptor signalling from the cell surface. Using live cell imaging with nanobody tags to specifically track receptor internalisation, we showed that 5-HT2A endocytosis is constitutive irrespective of the receptor being treated with serotonin, LSD, psilocin (the active metabolite of psilocybin) or left untreated. This constitutive endocytosis delivers 5-HT2A to the trans-Golgi network, from where receptor recycling occurs. Using genetically encoded biosensors we found that the G protein coupled receptor signalling effector, G-alpha q, is rapidly recruited to the cell surface following serotonin, but not with LSD or psilocin treatment. Consistent with this, Protein kinase-C, a downstream G-alpha q signalling effector, is only recruited to the cell surface with serotonin treatment. Further, G-alpha q is recruited to 5-HT2A endosomes with serotonin, but not LSD or psilocin treatment, indicating that only serotonin induces 5-HT2A endosomal signalling through canonical signalling pathways, in contrast to our hypothesis. Altogether, our results are consistent with recent pharmacology studies indicating psychedelics are only partial agonists of 5-HT2A and suggest that they activate entirely different cellular signalling pathways to serotonin. Plasma membrane and endosomal proteomics studies are currently underway to reveal the identity of these psychedelic-specific signalling pathways.