Psychedelics Promote Structural and Functional Neural Plasticity
Calvin Ly,
Alexandra C. Greb,
Lindsay P. Cameron,
Jonathan M. Wong,
Eden V. Barragan,
Paige C. Wilson,
Kyle F. Burbach,
Sina Soltanzadeh Zarandi,
Alexander Sood,
Michael R. Paddy,
Whitney C. Duim,
Megan Y. Dennis,
A. Kimberley McAllister,
Kassandra M. Ori-McKenney,
John A. Gray,
David E. Olson
Affiliations
Calvin Ly
Department of Chemistry, University of California, Davis, Davis, CA 95616, USA
Alexandra C. Greb
Department of Chemistry, University of California, Davis, Davis, CA 95616, USA
Lindsay P. Cameron
Neuroscience Graduate Program, University of California, Davis, Davis, CA 95618, USA
Jonathan M. Wong
Neuroscience Graduate Program, University of California, Davis, Davis, CA 95618, USA
Eden V. Barragan
Neuroscience Graduate Program, University of California, Davis, Davis, CA 95618, USA
Paige C. Wilson
Department of Molecular and Cellular Biology, University of California, Davis, Davis, CA 95616, USA
Kyle F. Burbach
Genome Center, University of California, Davis, Davis, CA 95616, USA
Sina Soltanzadeh Zarandi
Department of Chemistry, University of California, Davis, Davis, CA 95616, USA
Alexander Sood
Center for Neuroscience, University of California, Davis, Davis, CA 95618, USA
Michael R. Paddy
Department of Molecular and Cellular Biology, University of California, Davis, Davis, CA 95616, USA
Whitney C. Duim
Department of Chemistry, University of California, Davis, Davis, CA 95616, USA
Megan Y. Dennis
Genome Center, University of California, Davis, Davis, CA 95616, USA; Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA; MIND Institute, University of California, Davis, Sacramento, CA 95817, USA
A. Kimberley McAllister
Center for Neuroscience, University of California, Davis, Davis, CA 95618, USA; Department of Neurology, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA; Department of Neurobiology, Physiology, and Behavior, University of California, Davis, Davis, CA 95616, USA
Kassandra M. Ori-McKenney
Department of Molecular and Cellular Biology, University of California, Davis, Davis, CA 95616, USA
John A. Gray
Center for Neuroscience, University of California, Davis, Davis, CA 95618, USA; Department of Neurology, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA
David E. Olson
Department of Chemistry, University of California, Davis, Davis, CA 95616, USA; Center for Neuroscience, University of California, Davis, Davis, CA 95618, USA; Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA; Corresponding author
Summary: Atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiology of depression and related disorders. The ability to promote both structural and functional plasticity in the PFC has been hypothesized to underlie the fast-acting antidepressant properties of the dissociative anesthetic ketamine. Here, we report that, like ketamine, serotonergic psychedelics are capable of robustly increasing neuritogenesis and/or spinogenesis both in vitro and in vivo. These changes in neuronal structure are accompanied by increased synapse number and function, as measured by fluorescence microscopy and electrophysiology. The structural changes induced by psychedelics appear to result from stimulation of the TrkB, mTOR, and 5-HT2A signaling pathways and could possibly explain the clinical effectiveness of these compounds. Our results underscore the therapeutic potential of psychedelics and, importantly, identify several lead scaffolds for medicinal chemistry efforts focused on developing plasticity-promoting compounds as safe, effective, and fast-acting treatments for depression and related disorders. : Ly et al. demonstrate that psychedelic compounds such as LSD, DMT, and DOI increase dendritic arbor complexity, promote dendritic spine growth, and stimulate synapse formation. These cellular effects are similar to those produced by the fast-acting antidepressant ketamine and highlight the potential of psychedelics for treating depression and related disorders. Keywords: neural plasticity, psychedelic, spinogenesis, synaptogenesis, depression, LSD, DMT, ketamine, noribogaine, MDMA
