The last decade represented a period of unprecedented interest in, and development of, traditional psychedelic substances for the treatment of a variety of neuropsychiatric disorders. While early clinical trials of classical psychedelics, several of the major ones being tryptamines, have demonstrated robust efficacy in patients with minimal adverse effects, many of these molecules have properties that may limit their broad utility in clinical practice or require more complex methods of delivery. The functional role and importance of a "psychedelic experience" for therapeutic efficacy remain enigmatic. If the mechanism of action is reduced to mere 5-HTreceptor activation, this raises the question if whether therapeutic efficacy is achievable without the psychedelic effects. Furthermore, as this class of molecules typically interacts with many other members of the serotonin receptor family, including the 5-HTand 5-HTreceptor subtypes (receptors proven to be relevant to a multitude of neuropsychiatric disorders), as well as non-serotonergic receptors, the polypharmacological aspect of psychedelic tryptamines needs further scrutiny and understanding. In this perspective, the authors will review the limitations of the current classical non-conjugated tryptamines (excludes lysergic acid diethylamide, ibogaine, and similar molecules), highlighting approaches that have been explored to improve the molecules, as well as approaches to develop new generation psychedelic and "non-psychedelic" compounds. Further, the authors will review the latest thoughts within the field on the pharmacology that could be underlying these potentially field changing therapies. 2A1A2C
