Classic psychedelics in obsessive–compulsive disorder: a circuit-based framework

LSD and psilocybin may help treat obsessive-compulsive disorder (OCD) by disrupting maladaptive brain circuits and enhancing neuroplasticity. OCD involves dysfunction in the cortico-striatal-thalamo-cortical circuit, default mode network, and salience network. Psychedelics acutely dysregulate the default mode network and increase connectivity between normally segregated networks, potentially breaking cycles of rumination and self-referential thought. They also modulate the cortico-striatal-thalamo-cortical circuit and rapidly promote dendritic spine formation via 5-HT2A receptors in rodents. These dual mechanisms could reset pathological patterns and support long-term restructuring of maladaptive circuits, but clinical trials with neuroimaging endpoints are needed to validate this framework.

Study at a glance

Abstract

Obsessive–compulsive disorder (OCD) is a psychiatric condition with high rates of treatment resistance. Emerging neuroimaging evidence implicates dysfunction in large-scale brain networks, particularly the cortico–striatal–thalamo–cortical (CSTC) circuit, default mode network (DMN) and salience network (SN). Lysergic acid diethylamide (LSD) and psilocybin induce acute dysregulation of the DMN and increase connectivity across normally segregated networks, potentially disrupting maladaptive rumination and self-referential loops. Furthermore, psychedelics may improve aberrant DMN–SN connectivity in OCD, improving functioning under the triple network model. Simultaneously, both LSD and psilocybin modulate CSTC function, particularly by modulating activity in the subthalamic nucleus and striatum, regions implicated in compulsive behavior. Beyond network disruption, psychedelics rapidly enhance neuroplasticity via 5-HT_2A-receptor-mediated pathways, promoting dendritic spine formation (rodents). These dual mechanisms may ‘reset’ pathological patterns and support long-term restructuring of maladaptive circuits. Future clinical trials with specific neuroimaging endpoints are needed to validate the presented framework for psychedelic action in OCD. In this Review, the authors explore how psychedelics such as LSD and psilocybin may disrupt maladaptive circuits and enhance neuroplasticity in obsessive–compulsive disorder (OCD), potentially offering a therapeutic approach for OCD by resetting pathological patterns and improving network connectivity.