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The psychoplastogen tabernanthalog induces neuroplasticity without proximate immediate early gene activation.
Peer-reviewed Human StudyObservationalPubMedJournal ArticleSeptember 4, 2025PMID: 40760185DOI
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-HT2A) 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-HT2A, 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.
Authors (38)
LeadNeuroscience Graduate Program, University of California, Davis, Davis, CA, USA.
Neuroscience Graduate Program, University of California, Davis, Davis, CA, USA.
Neuroscience Graduate Program, University of California, Davis, Davis, CA, USA.
Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA.
Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA.
Department of Chemistry, University of California, Davis, Davis, CA, USA.
Department of Chemistry, University of California, Davis, Davis, CA, USA.
Department of Psychiatry and Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
Department of Chemistry, University of California, Davis, Davis, CA, USA.
Department of Chemistry, University of California, Davis, Davis, CA, USA.
Neuroscience Graduate Program, University of California, Davis, Davis, CA, USA.
Neuroscience Graduate Program, University of California, Davis, Davis, CA, USA.
Neuroscience Graduate Program, University of California, Davis, Davis, CA, USA.
Integrative Genetics and Genomics Graduate Program, University of California, Davis, Davis, CA, USA.
Delix Therapeutics, Inc., Bedford, MA, USA.
Delix Therapeutics, Inc., Bedford, MA, USA.
Delix Therapeutics, Inc., Bedford, MA, USA.
Expressive Neuroscience, LLC, Syracuse, NY, USA.
Expressive Neuroscience, LLC, Syracuse, NY, USA.
Expressive Neuroscience, LLC, Syracuse, NY, USA.
Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
Translucence Biosystems, Inc., Irvine, CA, USA.
Translucence Biosystems, Inc., Irvine, CA, USA.
Translucence Biosystems, Inc., Irvine, CA, USA.
Center for Neuroscience, University of California, Davis, Davis, CA, USA.
Department of Cell Biology, Neurobiology and Anatomy, Neuroscience Research Center and Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA.
Department of Molecular and Cellular Biology, University of California, Davis, Davis, CA, USA.
Department of Cell Biology, Neurobiology and Anatomy, Neuroscience Research Center and Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA.
Translucence Biosystems, Inc., Irvine, CA, USA.
Delix Therapeutics, Inc., Bedford, MA, USA.
Department of Psychiatry and Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
Institute for Psychedelics and Neurotherapeutics, University of California, Davis, Davis, CA, USA.
Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA.
Institute for Psychedelics and Neurotherapeutics, University of California, Davis, Davis, CA, USA.
Institute for Psychedelics and Neurotherapeutics, University of California, Davis, Davis, CA, USA.
Institute for Psychedelics and Neurotherapeutics, University of California, Davis, Davis, CA, USA. deolson@ucdavis.edu.