The study investigates the structural pharmacology and therapeutic potential of 5-methoxytryptamines (5-MeO-tryptamines), a class of psychedelic compounds, focusing on their interactions with serotonin receptors, particularly 5-HT1A and 5-HT2A. Using cryo-EM, the researchers determined the structures of 5-MeO-DMT and LSD-bound 5-HT1A-Gi signaling complexes, revealing distinct binding modes and interactions. They also explored the structure-activity relationship (SAR) of 5-MeO-tryptamines, identifying key residues and modifications that affect potency and selectivity. The study found that 5-MeO-DMT and its selective analogue, 4-F,5-MeO-PyrT, bind to 5-HT1A with high potency and selectivity, respectively, and exhibit anxiolytic and antidepressant-like effects in a mouse model of social defeat stress. These findings suggest that 5-HT1A plays a crucial role in the therapeutic effects of 5-MeO-tryptamines, providing insights into the development of new medications for neuropsychiatric disorders.The study investigates the structural pharmacology and therapeutic potential of 5-methoxytryptamines (5-MeO-tryptamines), a class of psychedelic compounds, focusing on their interactions with serotonin receptors, particularly 5-HT1A and 5-HT2A. Using cryo-EM, the researchers determined the structures of 5-MeO-DMT and LSD-bound 5-HT1A-Gi signaling complexes, revealing distinct binding modes and interactions. They also explored the structure-activity relationship (SAR) of 5-MeO-tryptamines, identifying key residues and modifications that affect potency and selectivity. The study found that 5-MeO-DMT and its selective analogue, 4-F,5-MeO-PyrT, bind to 5-HT1A with high potency and selectivity, respectively, and exhibit anxiolytic and antidepressant-like effects in a mouse model of social defeat stress. These findings suggest that 5-HT1A plays a crucial role in the therapeutic effects of 5-MeO-tryptamines, providing insights into the development of new medications for neuropsychiatric disorders.