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5-MeO-DMT modifies innate behaviors and promotes structural neural plasticity in mice

Neuropsychopharmacology volume 48, pages 1257–1266 (2023)Cite this article

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Abstract

Serotonergic psychedelics are gaining increasing interest as potential therapeutics for a range of mental illnesses. Compounds with short-lived subjective effects may be clinically useful because dosing time would be reduced, which may improve patient access. One short-acting psychedelic is 5-MeO-DMT, which has been associated with improvement in depression and anxiety symptoms in early phase clinical studies. However, relatively little is known about the behavioral and neural mechanisms of 5-MeO-DMT, particularly the durability of its long-term effects. Here we characterized the effects of 5-MeO-DMT on innate behaviors and dendritic architecture in mice. We showed that 5-MeO-DMT induces a dose-dependent increase in head-twitch response that is shorter in duration than that induced by psilocybin at all doses tested. 5-MeO-DMT also substantially suppresses social ultrasonic vocalizations produced during mating behavior. 5-MeO-DMT produces long-lasting increases in dendritic spine density in the mouse medial frontal cortex that are driven by an elevated rate of spine formation. However, unlike psilocybin, 5-MeO-DMT did not affect the size of dendritic spines. These data provide insights into the behavioral and neural consequences underlying the action of 5-MeO-DMT and highlight similarities and differences with those of psilocybin.

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Fig. 1: 5-MeO-DMT elicits a briefer duration of head-twitch response than psilocybin.
Fig. 2: Classical psychedelics and ketamine suppress the production of social ultrasonic vocalizations.
Fig. 3: 5-MeO-DMT increases the density of dendritic spines, but does not affect spine size, in the mouse medial frontal cortex.
Fig. 4: 5-MeO-DMT increases the formation rate of dendritic spines.

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Data availability

The data that support the findings and the code used to analyze the data in this study are available at https://github.com/Kwan-Lab.

Code availability

The data that support the findings and the code used to analyze the data in this study are available at https://github.com/Kwan-Lab.

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Acknowledgements

We thank Ling-Xiao Shao for advice on imaging, Neil Savalia for advice on statistical analyses, Gregg Castellucci and Katherine Tschida for advice on measuring ultrasonic vocalizations, Antonio Fonseca for advice on the VocalMat software, and Janghoo Lim for loaning equipment for recording ultrasonic vocalizations. 5-MeO-DMT-succinate was generously provided by Usona Institute’s Investigational Drug & Material Supply Program; the Usona Institute IDMSP is supported by Alexander Sherwood, Robert Kargbo, and Kristi Kaylo in Madison, WI. The behavioral experiments were supported by the Yale Program in Psychedelic Science, NIH/NIMH grant R01MH121848 (A.C.K.), NIH/NIMH grant R01MH128217 (A.C.K.), One Mind – COMPASS Rising Star Award (A.C.K.), and NIH/NIGMS medical scientist training grant T32GM007205 (P.A.D.). The imaging experiments were supported by a sponsored research project from Freedom Biosciences (C.P., S.J.J.), NIH/NINDS training grant T32NS041228 (C.L.), China Scholarship Council-Yale World Scholars Fellowship (H.W.), and NIH/NIMH training grant T32MH019961 (S.J.J.).

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Authors and Affiliations

  1. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, 06511, USA

    Sarah J. Jefferson, Ian Gregg, Mark Dibbs, Patrick H. Wehrle, Alfred P. Kaye, Christopher Pittenger & Alex C. Kwan

  2. Interdepartmental Neuroscience Program, Yale University School of Medicine, New Haven, CT, 06511, USA

    Clara Liao, Hao Wu & Pasha A. Davoudian

  3. Medical Scientist Training Program, Yale University School of Medicine, New Haven, CT, 06511, USA

    Pasha A. Davoudian

  4. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, 14853, USA

    Samuel C. Woodburn & Alex C. Kwan

  5. Freedom Biosciences, Tiburon, CA, 94920, USA

    Jeffrey S. Sprouse

  6. Usona Institute, Madison, WI, 53711, USA

    Alexander M. Sherwood

  7. VA National Center for PTSD Clinical Neuroscience Division, West Haven, CT, 06516, USA

    Alfred P. Kaye

  8. Child Study Center, Yale University School of Medicine, New Haven, CT, 06511, USA

    Christopher Pittenger

  9. Department of Neuroscience, Yale University School of Medicine, New Haven, CT, 06511, USA

    Alex C. Kwan

  10. Department of Psychiatry, Weill Cornell Medicine, New York, NY, 10065, USA

    Alex C. Kwan

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  1. Sarah J. Jefferson
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Contributions

SJJ, CP, and ACK designed the research. SJJ performed the two-photon imaging experiments and analyzed the data. IG performed the ultrasonic vocalization experiments and analyzed the data. MD performed the head-twitch response experiments and analyzed the data. CL and HW assisted in the two-photon imaging experiments. PAD worked with MD to make the equipment for using magnetic ear tags to measure head-twitch response and analyzed the data. SCW and PW contributed to behavioral experiments. JSS contributed to the experimental design. AMS synthesized and provided the 5-MeO-DMT succinate. CP and APK contributed to data interpretation. SJJ and ACK wrote the paper with input from other authors.

Corresponding author

Correspondence to Alex C. Kwan.

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Competing interests

ACK is a member of the Scientific Advisory Board of Empyrean Neuroscience and Freedom Biosciences. ACK has consulted for Biohaven Pharmaceuticals. No-cost compounds were provided to ACK for research by Usona Institute. CP has served as a consultant in the past year for Biohaven Pharmaceuticals, Teva Pharmaceuticals, and Brainsway Therapeutics and has performed research under contract with Biohaven and with Blackthorn Therapeutics, Ltd., on unrelated projects. CP and APK have performed research under contract with Transcend Therapeutics on unrelated projects. CP and SJJ have a sponsored research agreement with Freedom Biosciences. The sponsor of this research was not involved in the analyses or writing of the manuscript. The duties had no influence on the content of this article. The remaining authors have nothing to disclose.

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Jefferson, S.J., Gregg, I., Dibbs, M. et al. 5-MeO-DMT modifies innate behaviors and promotes structural neural plasticity in mice. Neuropsychopharmacol. 48, 1257–1266 (2023). https://doi.org/10.1038/s41386-023-01572-w

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