Is toad toxin the next antidepressant?

Embargoed until: Publicly released: 2024-05-09 01:00

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Modifying the psychedelic compounds found in the toxin of a poisonous toad could be an effective treatment for depression and anxiety, say US researchers who trialled the toxic toad drug on mice. Recent research has found that certain psychedelics such as LSD have a positive effect on our mental health by interacting with a specific receptor in our brains, and in this study, the team found the toad toxin to have similar effects on the receptor as the hallucinogens did; without the hallucinogenic effects.

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From: Springer Nature

Medicine: Evaluating a potent psychedelic for treatment of neuropsychiatric disorders

A modified psychedelic found in the venom of a poisonous toad could be an effective treatment option for depression and anxiety, reports a study involving mice published in Nature.

Recent scientific research has shown the potential of psychedelics in treating conditions such as depression and anxiety. These are thought to act via an interaction with serotonin receptors. The majority of research has focused on a serotonin receptor called 5-HT2A, with less effort focused on investigating the role of 5-HT1A in the effects of these compounds.

Daniel Wacker and colleagues investigated the mechanism by which the hallucinogen 5-MeO-DMT (found in the poison of the Colorado River toad and associated with intense psychedelic experiences) interacts with a serotonin receptor called 5-HT1A. They examine its structure and modify specific sites in the compound to evaluate its potential as a therapeutic agent, performing tests in mouse models of depression.

The researchers developed a variant of 5-MeO-DMT that was then tested for efficacy in mice. When tested against LSD and existing 5-HT1A agonists in clinical use, the compound was found to produce similar antidepressant-like activity. Importantly, this effect was accomplished without the hallucinogenic effects of the unaltered compound. The variant also demonstrated an 800-fold selectivity for 5-HT1A over 5-HT2A, which suggests that the benefits of this drug are probably driven by interactions with the 5-HT1A receptor, validating its potential as a therapeutic target.

These findings provide clarity on the ways in which this type of psychedelic can modulate the receptors in the brains of mammals and suggest a potential avenue for the development of medications for neuropsychiatric disorders. Further research is needed to assess whether these findings might translate to humans.

Journal/
conference: Nature

Research:Paper

Organisation/s: Icahn School of Medicine at Mount Sinai, New York, NY, USA

Funder: This work was supported by NIH grant R35GM133504, a Sloan Research Fellowship in Neuroscience, an Edward Mallinckrodt, Jr Foundation Grant, a McKnight Foundation Scholars Award, an Irma T. Hirschl/Monique Weill-Caulier Trust Research Award all to D.W.); an NIH F31 MH132317 (A.L.W), and T32 Training Grant GM062754 and DA053558 (A.L.W and G.Z.); the G. Harold & Leila Y. Mathers Charitable Foundation, the NIH grant R01DA050613, G.L. Freeman, and Columbia University for support of this work (all to D.S.); and the following NIH grants: R01MH127820 and R01MH104559 (S.R.). L.F.P is supported by the Leon Levy Foundation and the Brain and Behavior Research Foundation. Some of this work was performed at the National Center for CryoEM Access and Training (NCCAT) and the Simons Electron Microscopy Center located at the New York Structural Biology Center, supported by the NIH Common Fund Transformative High Resolution Cryo-Electron Microscopy program (U24 GM129539) and by grants from the Simons Foundation (SF349247) and NY State Assembly. We further acknowledge cryo-EM resources at the National Resource for Automated Molecular Microscopy located at the New York Structural Biology Center, supported by grants from the Simons Foundation (SF349247), NYSTAR, and the NIH National Institute of General Medical Sciences (GM103310) with additional support from Agouron Institute (F00316) and NIH (OD019994). For additional data collection, we are grateful to staff at the Laboratory for BioMolecular Structure (LBMS), which is supported by the DOE Office of Biological and Environmental Research (KP160711). This work was supported in part through the computational and data resources and staff expertise provided by Scientific Computing and Data at the Icahn School of Medicine at Mount Sinai and supported by the Clinical and Translational Science Awards (CTSA) grant ULTR004419 from the National Center for Advancing Translational Sciences.

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