Classic psychedelics in obsessive–compulsive disorder: a circuit-based framework
Saif S. Ali, Robin L. Carhart-Harris, Karl G. Sieg
Nature Mental Health April 1, 2026 Peer reviewed DOI: 10.1038/s44220-026-00626-4 via Springer Nature
Summary
Psychedelics like LSD and psilocybin may offer a therapeutic approach for obsessive-compulsive disorder (OCD) by disrupting maladaptive brain circuits and enhancing neuroplasticity. These substances can induce changes in the default mode network and improve connectivity in brain networks associated with compulsive behavior. The potential benefits stem from their ability to reset pathological patterns and promote long-term restructuring of neural pathways, suggesting a new avenue for treatment in patients with OCD.
Study at a glance
| Design | review |
|---|---|
| Population | not specified; focuses on OCD |
| Key finding | Psychedelics may disrupt maladaptive circuits and enhance neuroplasticity in OCD, potentially resetting pathological patterns. |
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.