biostudies-literatureUnknown31(3)Puigseslloses PCurrent first-line antidepressants, such as selective serotonin reuptake inhibitors (SSRI), often present a delayed onset of action and fail to effectively treat a large proportion of patients, leaving a gap in the treatment of mood disorders. Psychedelics have recently emerged as promising alternatives due to their ability to produce fast-acting antidepressant effects through neuroplastic adaptations, but their hallucinogenic properties remain a major obstacle to their widespread therapeutic use. In this study, we characterized a novel class of halogenated DMT derivatives-5-F-DMT, 5-Cl-DMT, and 5-Br-DMT-for their pharmacological activity, behavioral effects, and therapeutic potential. Using a combination of in vitro assays, in silico modeling, and in vivo behavioral and gene expression stMolecular psychiatry1733-1745https://www.ebi.ac.uk/biostudies/studies/S-EPMC12916285biostudies-literatureNeuropharmacology of halogenated DMT analogs: psychoplastogenic and antidepressant properties of 5-Br-DMT, a psychedelic derivative with low hallucinogenic potential.PMC12916285Escubedo EPablo-Quesada APuigseslloses PLopez-Arnau ROrtigosa JRBerzosa XModenutti CPStove CNadal-Gratacos NPottie EFumas BPubill DRiera-Colomer CEttcheto MfalseNeuropharmacology of halogenated DMT analogs: psychoplastogenic and antidepressant properties of 5-Br-DMT, a psychedelic derivative with low hallucinogenic potential.Current first-line antidepressants, such as selective serotonin reuptake inhibitors (SSRI), often present a delayed onset of action and fail to effectively treat a large proportion of patients, leaving a gap in the treatment of mood disorders. Psychedelics have recently emerged as promising alternatives due to their ability to produce fast-acting antidepressant effects through neuroplastic adaptations, but their hallucinogenic properties remain a major obstacle to their widespread therapeutic use. In this study, we characterized a novel class of halogenated DMT derivatives-5-F-DMT, 5-Cl-DMT, and 5-Br-DMT-for their pharmacological activity, behavioral effects, and therapeutic potential. Using a combination of in vitro assays, in silico modeling, and in vivo behavioral and gene expression st2026-01-01T00:00:00Z2026 Mar2026-07-16T09:14:56.405Z2026-07-09T10:46:19.991ZS-EPMC129162854112073510.1038/s41380-025-03308-2