Catalysts for change: the cellular neurobiology of psychedelics

This review (2021) examines the psychoplastogenic effects (neural plasticity) of psychedelics and summarizes the current understanding of the cellular and subcellular mechanisms underlying their ability to produce long-term structural changes and reduce inflammation.

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 behavioural effects of classical psychedelics. We then summarize our current understanding of the cellular and subcellular mechanisms underlying these drugs’ behavioural effects, their effects on neural plasticity, and the roles of stress and inflammation in the acute and long-term effects of psychedelics. The signalling 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 behaviour 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 behaviour.”

Authors: Matthew I. Banks, Zarmeen Zahid, Nathan T. Jones, Ziyad W. Sultan & Cody J. Wenthur

Summary

INTRODUCTION

Human use of psychedelic drugs traces a remarkable historical arc, from prehistoric myth to modern day laboratories and clinical treatment rooms.

Evidence for human consumption of psychedelics in traditional medicine and religious ceremonies stretches back to prehistory. These naturally occurring psychedelics include ayahuasca, 5-MeO-DMT, and psilocybin, as well as lysergic acid diethylamide (LSD), which was first synthesized in 1938.

Over the past two decades, research has shown that psychedelics may help treat psychiatric disorders. This perspective discusses the neural mechanisms underlying psychedelics’ actions and the profound effects these drugs have on the human mind and body.

BEHAVIORAL AND PHYSIOLOGICAL EFFECTS OF PSYCHEDELICS IN HUMAN SUBJECTS

Psychedelics produce profound alteration in consciousness, with both pleasant and challenging aspects. There is no evidence for increased incidence of suicidality or psychiatric illnesses in the months following psychedelic experiences, and psychedelics present low addictive potential.

Multiple clinical trials have demonstrated the potential of psychedelics for treating psychiatric disorders, including depression and anxiety, substance use disorders, and obsessive-compulsive disorders. Psilocybin promotes long-lasting increases in well-being and positive perspective on life experiences in healthy subjects.

PHARMACOLOGY AND 5-HT2A RECEPTOR SIGNALING

Psychedelics are divided into two broad categories that differ in their receptor subtype specificity. The indolealkylamines exhibit less specificity for the 5-HT type 2A receptor (5-HT2AR) than the phenylalkylamines.

Psychedelics are strongly associated with 5-HT2A receptor occupancy in the central nervous system, and 5-HT2A antagonists block these effects. However, there is some evidence suggesting the involvement of other receptors in the neurophysiological effects of psychedelics.

Expression of 5-HT2AR mRNA and protein in the brain is widespread, and is associated with depression and other mood disorders, as well as with the administration of psychedelics.

The 5-HT2A receptor is a Class A, rhodopsin-like, G-protein – coupled receptor for 5-HT, which can couple with the Gq protein to mobilize intracellular calcium, activate calcineurin, and inhibit type 1.2 voltage-gated calcium channels.

BIASED AGONISM MODEL FOR PSYCHEDELIC ACTIONS

Psychedelic agonists of 5-HT2AR are associated with profound changes in perception and cognition, whereas nonpsychedelic agonists are not. This difference is explained using the ternary complex model of receptor activity, which suggests that drug molecules act to shift the equilibrium between a receptor’s different conformational states.

Psychedelic and nonpsychedelic agonists of 5-HT2AR activate several downstream pathways, including pPLC, pPKC, pERK, and pCREB, but the magnitude of these Gq-mediated responses is greater for psychedelic ligands. Non-Gq pathways likely contribute to psychedelic effects as well.

Beyond G-protein – coupled pathways, agonism at 5-HT2ARs can also engage in -arrestin signaling via PI3K, SRC, and AKT, although the relevance of such -arrestin – dependent signaling for promoting psychedelic effects is still unclear.

INTERACTION BETWEEN 5-HT2AR AND GLUTAMATE RECEPTOR SIGNALING

Glutamate signaling deficits are a prominent feature of schizophrenia and major depressive disorder, and can be ameliorated by antidepressant administration. Psychedelics cause an increase in extracellular glutamate in the PFC, which releases neurotrophic factors and activates ionotropic glutamate receptors, which promote neural plasticity.

Several studies indicate that 5-HT2AR and mGluR2 form heterodimeric complexes, which integrate glutamatergic and serotonergic signaling and modulate subsequent G-protein coupling and downstream effects. This heterodimeric complex may facilitate the rapid antidepressant effects observed with psychedelics.

CELLULAR AND NETWORK-LEVEL ELECTROPHYSIOLOGICAL EFFECTS OF PSYCHEDELICS

Psychedelics activate signaling pathways at the 5-HT2AR, which lead to structural changes in the brain following the psychedelic experience. These changes correlate with the phenomenology of the psychedelic experience, such as an increase in excitability and a switch from externally driven to internally driven neural activity in sensory areas.

Psychedelics alter connectivity in the brain, and this form of neural plasticity may underlie their therapeutic activity. Psychedelics alter connectivity in brain regions implicated in multiple psychiatric disorders, but the mechanisms of these changes and whether these changes persist postacutely remain areas of active inquiry.

NEURAL AND BEHAVIORAL PLASTICITY

Psychedelics induce changes in neural activity and connectivity in human subjects, as well as long-term structural changes in animal models. These changes include the growth of neurites and dendritic spines at synapses, and the formation of neurogenesis in the hippocampus.

Psychedelics induce changes in gene expression that are likely to be mediated at least in part by the neural plasticity – associated protein brain-derived neurotrophic factor (BDNF). Psychedelics may also promote neuroplastic changes that last for days or weeks.

Psychedelics can enhance learning and memory in vivo, and this suggests that they can be used to promote long-term changes in behavior in the absence of preconceived notions about their potential therapeutic benefit.

STRESS AND INFLAMMATION

Stress is a major precipitating factor in the etiology of many psychiatric disorders, and psychedelics have shown clinical efficacy in treating these disorders. It is intriguing that stress may play a role in promoting the neuroplastic effects of psychedelics in the context of treating these same disorders.

Psychedelics may act directly at 5-HT2ARs in the hypothalamus to induce expression and/or release of corticotrophin-releasing hormone, elevating plasma concentrations of stress-associated glucocorticoids. Alternatively, the altered state of consciousness itself may trigger the acute stress response.

Psychedelics may have therapeutic and pro-neuroplastic effects through their anti-inflammatory action, and 5-HT plays a key role in immune system function. This raises the possibility that systemically administered psychedelics could directly modulate microglial function, which becomes aberrant in mood disorders and neurodegenerative disorders.

CONCLUSIONS

Psychedelics have acute effects on gene expression, neurotransmitter and neuroendocrine release, neural activity, connectivity, perception and cognition, and long-term effects on mood and behavior. Understanding how these drugs work in clinical settings may provide needed insight into the neurobiological basis for psychiatric illnesses.

Studies should focus on neural plasticity, both its locus and acute and long-term mechanisms, and whether psychedelics open a window of neural plasticity that lasts and which signaling pathways are essential for facilitating neural plasticity.

GLOSSARY

Amygdala is a region of the brain involved in regulation and expression of emotions, memory and decision making, and is tightly coupled to the hippocampus and prefrontal cortex.

Glutamate signaling refers to communication between neurons via the neurotransmitter glutamate. G-protein – coupled receptors are commonly modified by neural plasticity.

Psychedelic experience is an acute psychological response to psychedelic drugs, which can include altered perception of time, altered sensory perception, heightened emotional response to music, hallucinations, and ego dissolution.