Relaxed Beliefs After Psychedelics: From Sensory Processing to Mystical States

Recent use of 5-HT2A psychedelics such as psilocybin and LSD weakens top-down modulation and increases bottom-up signaling in visual cortical circuits, shifting the balance of information flow. In human participants, this resulted in reduced express saccade production and a generalization of prediction errors. Mouse studies showed similar alterations, with enhanced bottom-up drive persisting for days. These findings support the Relaxed Beliefs under Psychedelics (ReBUS) model. 5-MeO-DMT, a 5-HT1A-selective psychedelic, produced distinct effects: altered saccade production but unaltered deviance detection, and a tendency toward hypo-connectivity states in resting-state brain networks, contrasting with the hyper-connectivity states seen after 5-HT2A use. The dissertation also proposes the ReBUS model as a framework for understanding mystical experiences beyond psychedelics and emphasizes the role of post-acute context in consolidating belief changes.

Study at a glance

Abstract

This dissertation explores the lasting impact of psychedelic use on brain networks, ranging from basic sensory processing to abstract mystical experiences. Recent research has highlighted the potential of these substances for treating psychiatric disorders, with therapeutic effects persisting weeks after a single dose. We focus on serotonergic psychedelics such as psilocybin and LSD, which are 5-HT2A receptor agonists, and the 5-HT1A-selective psychedelic 5-MeO-DMT. Through human electroencephalography and mouse electrophysiology, we explore how psychedelic use alters sensory processing and behavior. Using visual oddball and saccadic prediction paradigms, our findings demonstrate that recent 5-HT2A psychedelic use weakens top- down modulation and increases bottom-up signaling in visual cortical circuits. In our human participants, we observed reduced express saccade production and a generalization of prediction errors (deviance detection). Mouse studies reveal similar alterations, with disrupted deviance detection during the acute psychedelic experience and enhanced bottom-up drive persisting for days. These findings support the ‘Relaxed Beliefs under Psychedelics (ReBUS) Model’ by demonstrating that 5-HT2A psychedelics shift the balance from top-down to bottom-up information flow in sensory cortical circuits. Recent 5-MeO-DMT users displayed similar changes in saccade production but showed unaltered deviance detection, suggesting circuit-specific effects. Further distinct effects of 5-HT1A and 5-HT2A psychedelics were revealed in our resting-state global dynamic functional connectivity analysis. Recent 5-HT2A psychedelic users tended to shift between states more frequently and occupy hyper-connectivity states, while recent 5-HT1A users tended to occupy hypo-connectivity states. The distinct effects of 5-HT2A and 5-HT1A psychedelic use on sensory processing and brain network dynamics highlight unique mechanisms of 5-MeO- DMT that warrant further investigation. Additionally, we review mystical experiences across various induction methods. Based on shared phenomenology, consequences on beliefs, and some shared neural correlates, we propose the ReBUS model as a framework for understanding mystical experiences beyond just psychedelics. Finally, we emphasize the critical role of context in shaping 5-HT2A psychedelic outcomes, discussing the concept of the matrix —the post-acute environment—as crucial for consolidating belief changes