Serotonergic Polypharmacology of 2-Halogenated Tryptamines.
Jeanine Yacoub, Elena Bray, Jude Bayyat, Grant C Glatfelter, Alex Leake, Emilia M Buitrago, Alexander D Maitland, John Partilla, Natalie G Cavalco, Serena S Schalk, Josie C Lammers, Michael H Baumann, John Mccorvy, James W Leahy, Danielle Gulick, Christopher G Witowski, Jacqueline L von Salm
bioRxiv : the preprint server for biology April 21, 2026 Peer reviewed DOI: 10.64898/2026.04.16.718915 via PubMed
Summary
2-halogenated derivatives of DMT and psilacetin were developed to reduce psychoactive effects and potential cardiotoxicity associated with serotonergic psychedelics. The study found that these compounds, particularly 2-Br-psilocin, showed decreased activity at certain serotonin receptors while maintaining therapeutic engagement with others. In tests on C57BL/6J mice, 2-Br-psilacetin did not induce head-twitch responses and improved stress-related behaviors, indicating a lower likelihood of psychedelic effects and safer profiles for cardiac health.
Study at a glance
| Population | C57BL/6J mice |
|---|---|
| Key finding | The 2-halogenated tryptamines exhibited reduced psychoactivity and safer cardiac profiles while showing improvements in stress-induced affective measures. |
Abstract
Serotonergic psychedelics such as N,N-dimethyltryptamine (DMT) and 4-phosphoryloxy-N,N-dimethyltryptamine (psilocybin) show therapeutic promise for psychiatric and neurodegenerative disorders but may be limited by liabilities from serotonin (5-HT)-2A mediated psychoactive effects and potential cardiotoxicity via 5-HT2B activation. To address these limitations, we designed and synthesized 2-halogenated derivatives of DMT and psilacetin to reduce 5-HT2A/5-HT2B activity while retaining engagement of therapeutically relevant targets, particularly 5-HT6, 5-HT2C, and 5-HT1B. This study demonstrated that 2-position halogenation decreased affinities, potencies, and efficacies at 5-HT2A and 5-HT1A receptors while preserving potent 5-HT6 agonism, especially for 2-Br-psilocin. The analogues exhibited reduced affinities at 5-HT2B and hERG ion channels, suggesting safer cardiac valve and cardiotoxic profiles. In C57BL/6J mice, 2-Br-psilacetin did not induce the head-twitch response and attenuated 2,5 dimethoxy-4-iodoamphetamine (DOI)-induced head-twitch behavior, suggesting a reduced potential for inducing psychedelic effects. Behavioral assays further revealed improvements in stress-induced affective measures and hippocampus-independent cued learning at intermediate doses. These findings identify 2-halogenated tryptamines as polypharmacological serotonergic ligands with reduced psychoactivity and cardiac valve and toxic liabilities, supporting their potential as next-generation psychedelic-inspired therapeutics.