The psychoplastogen tabernanthalog induces neuroplasticity without proximate immediate early gene activation

Isak K Aarrestad^#^{1

2}, Lindsay P Cameron^#¹, Ethan M Fenton^{1

2}, Austen B Casey³, Daniel R Rijsketic^{3

4}, Seona D Patel⁵, Rohini Sambyal⁵, Shane B Johnson⁶, Calvin Ly⁵, Jayashri Viswanathan⁵, Eden V Barragan¹, Stephanie A Lozano^{1

2}, Nicolas Seban^{1

2}, Hongru Hu⁷, Noel A Powell⁸, Milan Chytil⁸, Retsina Meyer⁸, David Rose⁹, Chris Hempel⁹, Eric Olson^{9

10}, Hanne D Hansen¹¹, Clara A Madsen^{11

12}, Gitte M Knudsen^{11

12}, Chase Redd¹³, Damian G Wheeler¹³, Nathaniel Guanzon¹³, Jessie Muir^{14

15}, Joseph J Hennessey¹⁶, Gerald Quon¹⁷, John D McCorvy¹⁶, Sunil P Gandhi^{13

18}, Kurt Rasmussen⁸, Conor Liston⁶, John A Gray^{2

14

15

19}, Boris D Heifets^{3

20}, Alex S Nord^{2

14

19

21}, Christina K Kim^{2

14

15}, David E Olson^{22

23

24

25}

Affiliations

¹ Neuroscience Graduate Program, University of California, Davis, Davis, CA, USA.
² Institute for Psychedelics and Neurotherapeutics, University of California, Davis, Davis, CA, USA.
³ Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA.
⁴ Tensor Analytics, LLC, Salt Lake City, UT, USA.
⁵ Department of Chemistry, University of California, Davis, Davis, CA, USA.
⁶ Department of Psychiatry and Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
⁷ Integrative Genetics and Genomics Graduate Program, University of California, Davis, Davis, CA, USA.
⁸ Delix Therapeutics, Inc., Bedford, MA, USA.
⁹ Expressive Neuroscience, LLC, Syracuse, NY, USA.
¹⁰ Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA.
¹¹ Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
¹² Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹³ Translucence Biosystems, Inc., Irvine, CA, USA.
¹⁴ Center for Neuroscience, University of California, Davis, Davis, CA, USA.
¹⁵ Department of Neurology, School of Medicine, University of California, Davis, Sacramento, CA, USA.
¹⁶ Department of Cell Biology, Neurobiology and Anatomy, Neuroscience Research Center and Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA.
¹⁷ Department of Molecular and Cellular Biology, University of California, Davis, Davis, CA, USA.
¹⁸ Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA, USA.
¹⁹ Department of Psychiatry and Behavioral Sciences, School of Medicine, University of California, Davis, Sacramento, CA, USA.
²⁰ Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.
²¹ Department of Neurobiology, Physiology and Behavior, University of California, Davis, Davis, CA, USA.
²² Institute for Psychedelics and Neurotherapeutics, University of California, Davis, Davis, CA, USA. deolson@ucdavis.edu.
²³ Department of Chemistry, University of California, Davis, Davis, CA, USA. deolson@ucdavis.edu.
²⁴ Center for Neuroscience, University of California, Davis, Davis, CA, USA. deolson@ucdavis.edu.
²⁵ Department of Biochemistry & Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, CA, USA. deolson@ucdavis.edu.

^# Contributed equally.

PMID: 40760185
PMCID: PMC12373294 (available on 2026-08-04)
DOI: 10.1038/s41593-025-02021-1

The psychoplastogen tabernanthalog induces neuroplasticity without proximate immediate early gene activation

Isak K Aarrestad et al. Nat Neurosci. 2025 Sep.

. 2025 Sep;28(9):1919-1931.

doi: 10.1038/s41593-025-02021-1. Epub 2025 Aug 4.

Authors

Affiliations

¹ Neuroscience Graduate Program, University of California, Davis, Davis, CA, USA.
² Institute for Psychedelics and Neurotherapeutics, University of California, Davis, Davis, CA, USA.
³ Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA.
⁴ Tensor Analytics, LLC, Salt Lake City, UT, USA.
⁵ Department of Chemistry, University of California, Davis, Davis, CA, USA.
⁶ Department of Psychiatry and Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
⁷ Integrative Genetics and Genomics Graduate Program, University of California, Davis, Davis, CA, USA.
⁸ Delix Therapeutics, Inc., Bedford, MA, USA.
⁹ Expressive Neuroscience, LLC, Syracuse, NY, USA.
¹⁰ Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA.
¹¹ Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
¹² Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹³ Translucence Biosystems, Inc., Irvine, CA, USA.
¹⁴ Center for Neuroscience, University of California, Davis, Davis, CA, USA.
¹⁵ Department of Neurology, School of Medicine, University of California, Davis, Sacramento, CA, USA.
¹⁶ Department of Cell Biology, Neurobiology and Anatomy, Neuroscience Research Center and Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA.
¹⁷ Department of Molecular and Cellular Biology, University of California, Davis, Davis, CA, USA.
¹⁸ Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA, USA.
¹⁹ Department of Psychiatry and Behavioral Sciences, School of Medicine, University of California, Davis, Sacramento, CA, USA.
²⁰ Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.
²¹ Department of Neurobiology, Physiology and Behavior, University of California, Davis, Davis, CA, USA.
²² Institute for Psychedelics and Neurotherapeutics, University of California, Davis, Davis, CA, USA. deolson@ucdavis.edu.
²³ Department of Chemistry, University of California, Davis, Davis, CA, USA. deolson@ucdavis.edu.
²⁴ Center for Neuroscience, University of California, Davis, Davis, CA, USA. deolson@ucdavis.edu.
²⁵ Department of Biochemistry & Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, CA, USA. deolson@ucdavis.edu.

^# Contributed equally.

PMID: 40760185
PMCID: PMC12373294 (available on 2026-08-04)
DOI: 10.1038/s41593-025-02021-1

Abstract

Nonhallucinogenic psychoplastogens, such as tabernanthalog (TBG), are being developed as potentially safer, more scalable alternatives to psychedelics for promoting neuronal growth and treating various brain conditions. Currently, it is unclear whether 5-hydroxytryptamine 2A (5-HT_2A) receptors and immediate early gene (IEG) activation have a role in the neuroplasticity-promoting effects of nonhallucinogenic psychoplastogens. Here, we use pharmacological and genetic tools in rodents to show that nonhallucinogenic psychoplastogens promote cortical neuroplasticity through the same biochemical pathway-involving 5-HT_2A, TrkB, mTOR and AMPA receptor activation-as classic psychedelics and that TBG-induced cortical spinogenesis is required for the sustained antidepressant-like behavioral effect of TBG. In contrast to psychedelics, TBG does not induce an immediate glutamate burst or IEG activation. As these effects have been assumed to be necessary for psychedelic-induced neuroplasticity, our results shed light on the mechanisms by which certain psychoplastogens can promote cortical neuroplasticity in the absence of hallucinogenic effects.

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Conflict of interest statement

Competing interests: D.E.O. is a cofounder of Delix Therapeutics, Inc., serves as the chief innovation officer and head of the scientific advisory board, and has had sponsored research agreements with Delix Therapeutics. Delix Therapeutics has licensed TBG-related technology from the University of California, Davis. C. Liston is a member of the scientific advisory board of Delix Therapeutics. The sponsors of this research were not involved in the conceptualization, design, decision to publish or preparation of the manuscript. However, several employees of Delix Therapeutics are coauthors of this article as they collected and analyzed data and approved the final version of the manuscript. Within the last 3 years, G.M.K. has been an advisor for Sanos, Onsero, Pangea Botanica, Gilgamesh and Seaport. At the time of manuscript submission, H.D.H. was employed by H. Lundbeck A/S. B.D.H. is on the scientific advisory board of Osmind and Journey Clinical and is a paid advisor to Arcadia Medicine, Inc. The other authors declare no competing interests.

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The psychoplastogen tabernanthalog induces neuroplasticity without proximate immediate early gene activation

Affiliations

The psychoplastogen tabernanthalog induces neuroplasticity without proximate immediate early gene activation

Authors

Affiliations

Abstract

Conflict of interest statement

References

METHODS ONLY REFERENCES

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Research Materials

Miscellaneous