Models of psychedelic drug action: modulation of cortical-subcortical circuits

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.

Regional and cell type-specific afferent and efferent projections of the mouse claustrum

“…Neuromodulation via CLA influencing animal behaviors has recently been explored in humans. Psilocybin, a partial serotonin 2A (5-HT 2A ) receptor agonist, has been suggested to alter the functional connectivity of the CLA to cortical networks that support perception, memory, and attention (Barrett et al, 2020; Doss et al, 2021).…”

LSD and psilocybin flatten the brain’s energy landscape: insights from receptor-informed network control theory

“…A decade of neuroimaging studies has informed novel insights regarding psychedelic action in the brain 2 . One model, known as RElaxed Beliefs Under Psychedelics (REBUS) 3 ,integrates previous accounts of psychedelic action (the Entropic Brain Hypothesis) 4,5 with the view of the brain as a prediction engine, whereby perception and belief are shaped by both prior knowledge and incoming information.…”

Unique Effects of Sedatives, Dissociatives, Psychedelics, Stimulants, and Cannabinoids on Episodic Memory: A Review and Reanalysis of Acute Drug Effects on Recollection, Familiarity, and Metamemory

“…Whereas psychedelics may enhance familiarity by activating 5-HT 2A receptors on excitatory pyramidal neurons distributed throughout most of the cortex (Aghajanian and Marek, 1997; Martin and Nichols, 2016), psychedelics may impair recollection by shunting information flow to the hippocampus via activation of entorhinal 5-HT 2A receptors on inhibitory interneurons. Alternatively, activating 5-HT 2A receptors on inhibitory interneurons could disrupt entorhinal cortex’s gating of selective information to the hippocampus (Decurtis and Pare, 2004), thereby inundating hippocampal processing and resulting in catastrophic interference (similar to thalamic gating models of psychedelic drug action; Geyer and Vollenweider, 2008; Doss et al ., 2021). In contrast to blackouts or K-holes, psychedelics impairing recollection, which is associated with autonoetic consciousness, while sparing familiarity, which is associated with noetic consciousness, is consistent with the phenomenological state of ‘ego dissolution’ from which memories are formed with a noetic quality (Yaden et al ., 2017) but lack self-relevance (Conway, 2005; Letheby and Gerrans, 2017).…”