Classic psychedelics are compounds that target the 5-hydroxytryptamine receptor type 2A (5-HT2AR), inducing profound changes in consciousness. Although these compounds most closely resemble the natural neurotransmitter serotonin, their therapeutic and psychoactive action is still not well understood. Therefore, a quantitative atomistic description of their interaction in the 5-HT2AR receptor is required to shed light into their mode of action. In this work, we performed a computational characterization of the orthosteric binding pocket for classical and photoswitchable psychedelics by means of semi-flexible molecular docking, classical molecular dynamics and binding free energy computations to identify the interactions with the key protein residues. Two nearly degenerate binding poses were observed inside the orthosteric pocket. 5-HT (5-hydroxytryptamine) and LSD (lysergic acid diethylamide) show a preference for the canonical crystallized pose of the 5-HT2AR-LSD structure, in contrast to N,N-DMT (N,N-dimethyltryptamine) and 4-OH-N,N-DMT (4-hydroxy-N,N-dimethyltryptamine), which show a small preference for the newly identified pose. The photoswitchable analogs trans- and cis- AzobenzeneDMT (AzoDMT) interact similarly to N,N-DMT, with the cis-AzoDMT isomer being the most stable. Finally, the azobenzene domain of both cis- and trans-AzoDMT interact with the same key residue (L229) responsible for the extracellular loop closure of LSD. Our simulations clarify the nature of intermolecular drug/protein interactions, which can help to develop new classes of classical and photoswitchable psychedelics.