Modification of natural tryptamines for the treatment of neuropsychiatric diseases
Journal of Psychopharmacology – October 04, 2025
Source: OpenAlex
Summary
Tryptamines, a class of psychedelic substances, have shown promising efficacy in treating neuropsychiatric disorders with minimal adverse effects. Early clinical trials indicate that 70-80% of participants report significant improvements. However, the therapeutic impact may depend on the "psychedelic experience," raising questions about whether benefits can be achieved without these effects. The complex interactions of tryptamines with various serotonin receptors necessitate deeper investigation. This exploration aims to refine existing compounds and develop new psychedelic and non-psychedelic therapies, enhancing treatment options in neuropharmacology and psychology.
Abstract
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-HT2A receptor 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-HT1A and 5-HT2C receptor 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.