Catalysts for change: the cellular neurobiology of psychedelics

Abstract

The resurgence of interest in the therapeutic potential of psychedelics for treating psychiatric disorders has rekindled efforts to elucidate their mechanism of action. In this Perspective, we focus on the ability of psychedelics to promote neural plasticity, postulated to be central to their therapeutic activity. We begin with a brief overview of the history and behavioral effects of the classical psychedelics. We then summarize our current understanding of the cellular and subcellular mechanisms underlying these drugs’ behavioral effects, their effects on neural plasticity, and the roles of stress and inflammation in the acute and long-term effects of psychedelics. The signaling pathways activated by psychedelics couple to numerous potential mechanisms for producing long-term structural changes in the brain, a complexity that has barely begun to be disentangled. This complexity is mirrored by that of the neural mechanisms underlying psychiatric disorders and the transformations of consciousness, mood, and behavior that psychedelics promote in health and disease. Thus, beyond changes in the brain, psychedelics catalyze changes in our understanding of the neural basis of psychiatric disorders, as well as consciousness and human behavior.

Classic Psychedelic Drugs: Update on Biological Mechanisms

“…Current psychological and cognitive studies of psychedelics drug effects in combination with functional human brain imaging in healthy volunteers suggest that psychedelics can profoundly change the sense of self, often experienced as a dissolution of the ordinary boundaries between the self and the world, enhance mood and shift emotion processing to the positive, and facilitate prosocial behavior 19 20 which is accompanied by modulation of neural circuits that are implicated in mood and affective disorders 21 22 23 24 25 . Psychedelics have also been shown to increase glutamate-driven neuroplastic adaptations in animals 26 which may provide a novel mechanism for the lasting beneficial outcomes reported in non-clinical and clinical populations 27 .…”

The Hallucinogenic Serotonin2A Receptor Agonist, 2,5-Dimethoxy-4-Iodoamphetamine, Promotes cAMP Response Element Binding Protein-Dependent Gene Expression of Specific Plasticity-Associated Genes in the Rodent Neocortex

“…There has been a renewal of interest in serotonergic psychedelics as potential rapid-acting antidepressants for the treatment of anxiety and depression (Nutt et al, 2020;Vollenweider and Preller, 2020;Banks et al, 2021;De Gregorio et al, 2021). Most serotonergic psychedelics target the serotonin 2A (5-HT 2A ) receptor, and agonist action at the 5-HT 2A receptor is implicated in the molecular, cytoarchitectural, hallucinogenic and mood-related behavioral effects of serotonergic psychedelics (Vollenweider et al, 1998;González-Maeso et al, 2003, 2007Martin and Nichols, 2016;López-Giménez and González-Maeso, 2018;Preller et al, 2018;Madsen et al, 2019;Slocum et al, 2021).…”

How to account for hallucinations in the interpretation of the antidepressant effects of psychedelics: a translational framework

“…For the sake of brevity, we will simply refer to these compounds as psychedelics. As for all other serotonergic psychedelics, these substances act primarily as (partial) agonists of the serotonin 2A (5-HT 2A ) receptor, yet they also show significant 5-HT 1A receptor agonistic activity (Banks et al 2021 ; Nichols 2016 ). Importantly, human studies with psilocybin and LSD often administered these substances in a pure synthetic form, whereas the effects of DMT have been tested mostly in the form of the Amazonian brew ayahuasca.…”