Models of psychedelic drug action: modulation of cortical-subcortical circuits
This theory-building paper (2021) presents a new model of how psychedelic drugs may act in the brain. The new model, the cortico-clasustro-cortical model (CCC model), proposes that psychedelics disrupt 5-HT2A-mediated network coupling between the claustrum (a region of the brain where 5-HT2A receptors are densely expressed) and the cortex, leading to attenuation of canonical cortical networks. This model is discussed in relation to two previously described models, the CSTC and REBUS.
Authors
- Roland Griffiths
- Frederick Barrett
- Alaina Doss
Published
Abstract
Classic psychedelic drugs such as psilocybin and lysergic acid diethylamide (LSD) have recaptured the imagination of both science and popular culture, and may have efficacy in treating a wide range of psychiatric disorders. Human and animal studies of psychedelic drug action in the brain have demonstrated the involvement of the serotonin 2A (5-HT2A) receptor and the cerebral cortex in acute psychedelic drug action, but different models have evolved to try to explain the impact of 5-HT2A activation on neural systems. Two prominent models of psychedelic drug action (the cortico-striatal thalamo-cortical, or CSTC, model and relaxed beliefs under psychedelics, or REBUS, model) have emphasized the role of different subcortical structures as crucial in mediating psychedelic drug effects. We describe these models and discuss gaps in knowledge, inconsistencies in the literature, and extensions of both models. We then introduce a third circuit-level model involving the claustrum, a thin strip of grey matter between the insula and the external capsule that densely expresses 5-HT2A receptors (the cortico-claustro-cortical, or CCC, model). In this model, we propose that the claustrum entrains canonical cortical network states, and that psychedelic drugs disrupt 5-HT2A-mediated network coupling between the claustrum and the cortex, leading to attenuation of canonical cortical networks during psychedelic drug effects. Together, these three models may explain many phenomena of the psychedelic experience, and using this framework, future research may help to delineate the functional specificity of each circuit to the action of both serotonergic and non-serotonergic hallucinogens.
Research Summary of 'Models of psychedelic drug action: modulation of cortical-subcortical circuits'
Introduction
Psychedelic drugs that act as agonists or partial agonists at the serotonin 2A (5-HT2A) receptor—examples include psilocybin and lysergic acid diethylamide (LSD)—produce profound alterations in perception and cognition and have renewed interest because of possible therapeutic benefits across mood, substance use and headache disorders. Prior animal and human work implicates cortical 5-HT2A signalling, especially in layer V pyramidal cells, in initiating cascades that alter cortical and subcortical function; complementary findings include increased cortical glutamate, changes in interneuron activity, and the requirement of 5-HT2A signalling for many subjective and behavioural effects of classic psychedelics. Despite this progress, there is no single accepted circuit-level model that accounts for the range of neural and behavioural effects reported, and multiple, sometimes conflicting, models have emerged focusing on different subcortical hubs and mechanisms of network disruption. Doss and colleagues set out to review and compare three circuit-level models of psychedelic action: the cortico‑striatal‑thalamo‑cortical (CSTC) model, the relaxed beliefs under psychedelics (REBUS) model, and a newly proposed cortico‑claustro‑cortical (CCC) model centred on the claustrum. They describe the anatomical and physiological bases of each model, review behavioural and neuroimaging evidence bearing on them, identify inconsistencies and gaps in the literature, and suggest how these frameworks might be revised or integrated to guide future research into both serotonergic and non‑serotonergic hallucinogens.
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Doss, M. K., Madden, M. B., Gaddis, A., Nebel, M. B., Griffiths, R. R., Mathur, B. N., & Barrett, F. S. (2022). Models of psychedelic drug action: modulation of cortical-subcortical circuits. Brain, 145(2), 441-456. https://doi.org/10.1093/brain/awab406
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