## Psychedelics Promote Structural and Functional Neural Plasticity

Astral X Neural Plasticity, 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. Padd, Whitney C. Duim, Megan Y. Dennis, A. Kimberley McAllister, Kassandra M. Ori-McKenney, John A. Gray and David E. Olson

Experiment Findings, February 2018

https://www.researchgate.net/publication/331396378

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.

### In Brief

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 disorder

### INTRODUCTION

Neuropsychiatric diseases, including mood and anxiety disorders, are some of the leading causes of dis ability worldwide and place an enormous economic burden on society ( Gustavsson et al., 2011 ; Whiteford et al., 2013 ). Approximately one-third of patients will not respond to current antidepressant drugs, and those who do will usually require at least 2–4 weeks of treatment before they experience any beneficial effects ( Rush et al., 2006 ). Depression, post-traumatic stress disorder (PTSD), and addiction share common neural circuitry ( Arnsten, 2009 ; Russo et al., 2009 ; Peters et al., 2010 ; Russo and Nestler, 2013 ) and have high comorbidity ( Kelly and Daley, 2013 ). A preponderance of evidence from a combination of human imaging, postmortem studies, and animal models suggests that atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiology of depression and related disorders and is precipitated and/or exacerbated by stress ( Arnsten, 2009 ; Autry and Monteggia, 2012 ; Christoffel et al., 2011 ; Duman and Aghajanian, 2012 ; Duman et al., 2016 ; Izquierdo et al., 2006 ; Pittenger and Duman, 2008 ; Qiao et al., 2016 ; Russo and Nestler, 2013 ). These structural changes, such as the retraction of neurites, loss of dendritic spines, and elimination of synapses, can potentially be counteracted by compounds capable of promoting structural and functional neural plasticity in the PFC ( Castrén and Antila, 2017 ; Cramer et al., 2011 ; Duman, 2002 ; Hayley and Litteljohn, 2013 ; Kolb and Muhammad, 2014 ; Krystal et al., 2009 ; Mathew et al., 2008 ), providing a general solution to treating all of these related diseases. However, only a relatively small number of compounds capable of promoting plasticity in the PFC have been identified so far, each with significant drawbacks ( Castrén and Antila, 2017 ). Of these, the dissociative anesthetic ketamine has shown the most promise, revitalizing the field of molecular psychiatry in recent years. Ketamine has demonstrated remarkable clinical potential as a fast-acting antidepressant ( Berman et al., 2000 ; Ionescu et al., 2016 ; Zarate et al., 2012 ), even exhibiting efficacy in treatment-resistant populations ( DiazGranados et al., 2010 ; Murrough et al., 2013 ; Zarate et al., 2006 ). Additionally, it has shown promise for treating PTSD ( Feder et al., 2014 ) and heroin addiction ( Krupitsky et al., 2002 ). Animal models suggest that its therapeutic effects stem from its ability to promote the growth of dendritic spines, increase the synthesis of synaptic proteins, and strengthen synaptic responses ( Autry et al., 2011 ; Browne and Lucki, 2013 ; Li et al., 2010 ). Like ketamine, serotonergic psychedelics and entactogens have demonstrated rapid and long-lasting antidepressant and anxiolytic effects in the clinic after a single dose ( Bouso et al., 2008 ; Carhart-Harris and Goodwin, 2017 ; Grob et al., 2011 ; Mithoefer et al., 2013 , 2016 ; Nichols et al., 2017 ; Sanches et al., 2016 ; Osório et al., 2015 ), including in treatment-resistant populations ( Carhart-Harris et al., 2016 , 2017 ; Mithoefer et al., 2011 ; Oehen et al., 2013 ; Rucker et al., 2016 ). In fact, there have been numerous clinical trials in the past 30 years examining the therapeutic effects of these drugs ( Dos Santos et al., 2016 ), with 3,4-methylenedioxymethamphetamine (MDMA) recently receiving the “breakthrough therapy” designation by the Food and Drug Administration for treating PTSD. Furthermore, classical psychedelics and entactogens produce antidepressant and anxiolytic responses in rodent behavioral tests, such as the forced swim test ( Cameron et al., 2018 ) and fear extinction learning ( Cameron et al., 2018 ; Catlow et al., 2013 ; Young et al., 2015 ), paradigms for which ketamine has also been shown to be effective ( Autry et al., 2011 ; Girgenti et al., 2017 ; Li et al., 2010 ). Despite the promising antidepressant, anxiolytic, and anti-addictive properties of serotonergic psychedelics, their therapeutic mechanism of action remains poorly understood, and concerns about safety have severely limited their clinical usefulness. Because of the similarities between classical serotonergic psychedelics and ketamine in both preclinical models and clinical studies, we reasoned that their therapeutic effects might result from a shared ability to promote structural and functional neural plasticity in cortical neurons. Here, we report that serotonergic psychedelics and entactogens from a variety of chemical classes (e.g., amphetamine, tryptamine, and ergoline) display plasticity-promoting properties comparable to or greater than ketamine. Like ketamine, these compounds stimulate structural plasticity by activating the mammalian target of rapamycin (mTOR). To classify the growing number of compounds capable of rapidly promoting induced plasticity ( Castrén and Antila, 2017 ), we introduce the term “psychoplastogen, ” from the Greek roots psych- (mind), -plast (molded), and -gen (producing). Our work strengthens the growing body of literature indicating that psychoplastogens capable of promoting plasticity in the PFC might have value as fast-acting antidepressants and anxiolytics with efficacy in treatment-resistant populations and suggests that it may be possible to use classical psychedelics as lead structures for identifying safer alternatives.

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PsychedelicsPromoteStructuralandFunctionalNeuralPlasticity