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

Nature Mental Health volume 4, pages 540–550 (2026) Cite this article

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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-HT2A-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.

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Fig. 1: Proposed CSTC circuit modulation by successful treatment in OCD.
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Fig. 2: Proposed triple network model of OCD and the potential therapeutic impact of psychedelic therapy.
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Fig. 3: Psilocybin-induced brain network changes in depression.
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Fig. 4: Therapeutic overview: model for psychedelic action in OCD.
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Acknowledgements

We thank S. Karkare and A. Corbett for their feedback and editorial suggestions during the preparation of this manuscript.

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Authors and Affiliations

  1. University of Central Florida College of Medicine, Orlando, FL, USA

    Saif S. Ali & Karl G. Sieg

  2. Department of Neurology, Psychiatry and Behavioral Sciences, University of California, San Francisco, CA, USA

    Robin L. Carhart-Harris

  3. Centre for Psychedelic Research, Imperial College London, London, UK

    Robin L. Carhart-Harris

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  1. Saif S. Ali
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  2. Robin L. Carhart-Harris
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  3. Karl G. Sieg
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Contributions

S.S.A. conceived the project, conducted the literature review, developed the therapeutic framework, prepared the figures, and drafted and revised the manuscript. R.L.C.-H. provided critical feedback on the manuscript and guidance on conceptual framing. K.G.S. provided faculty supervision and feedback on the manuscript. Final approval of the submitted manuscript was given by all authors.

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Correspondence to Saif S. Ali.

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Competing interests

R.L.C.-H. has served as scientific advisor to Entropy Neurodynamics, Atai Beckley, Red Light Holland and Otsuka. The other authors declare no competing interests.

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Nature Mental Health thanks Goi Khia Eng, Pengchong Wang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Ali, S.S., Carhart-Harris, R.L. & Sieg, K.G. Classic psychedelics in obsessive–compulsive disorder: a circuit-based framework. Nat. Mental Health 4, 540–550 (2026). https://doi.org/10.1038/s44220-026-00626-4

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