The purpose of this study is to assess the impact of psilocybin on cognitive inflexibility and neural plasticity in a cohort of people with obsessive-compulsive disorder (OCD).

This mechanistic study will utilise a within-subjects design, administering up to 10mg of psilocybin to participants with OCD (DSM-5 criteria) on two separate instances spaced four weeks apart. To ensure consistency and participant safety, dosing will occur under medical supervision with psychological support from two experienced therapists. Before and after each session, participants will engage in virtual preparation and integration sessions led by their therapists. Cognitive tasks will be administered in the days following each dosing session. Additionally, acute post-dosing EEG recordings will be conducted, and blood samples will be taken after each dosing session. OCD symptoms will also be assessed seven times throughout the trial by an external blinded psychiatrist, serving as a secondary outcome. Collectively, these measures aim to evaluate changes in cognitive inflexibility, decision-making abilities, neuroplasticity (peripheral blood markers and EEG measures), inflammation (peripheral blood markers), and symptomatology following each dosing session.

Key Inclusion Criteria:

• Aged 20 to 65 years;
• Any gender;
• A primary diagnosis of OCD (based on the Mini-International Neuropsychiatric Interview (M.I.N.I.));
• Has met diagnostic criteria for OCD for at least 12 months;
• Willing to comply with protocol and associated lifestyle restrictions;
• Adequate understanding of the English language to give informed consent and participate in the study;
• Participant can attend visits as an outpatient;
• Comfortable using a computer, access to internet from home, and willing to participate in some of the study visits via video-link.

Key Exclusion Criteria:

• Current or past history of dependent (according to ICD10 criteria) substance use (not including nicotine and/or caffeine), Tourette's syndrome, autism spectrum disorder, epilepsy, organic mental disorder, or a personality disorder apart from obsessive-compulsive personality disorder;
• Current or past history of psychosis or mania in themselves or a first-degree relative;
• Unstable physical health;
• Significantly abnormal clinical test result;
• Heavy smoker, or unable to attend the dosing days (including the subsequent recovery part) without a smoking break;
• Unwillingness to allow their GP or mental health practitioners to be informed of their participation (or, to allow study team access to Summary Care Record).

Study is single group, but participants are blinded to the fixed doses received on both dosing days (Dose A and Dose B), and the outcomes assessor responsible for evaluating OCD and depression symptoms using the Y-BOCS and MADRS is also blinded. Assessors evaluating all other outcomes are unblinded.

Note to editor: I ticked 'None (Open Label)' as advised, to avoid this being flagged and to be able to release this protocol; it is impossible to accurately describe our study's design with these options available. Please may this 'None (Open Label)' description be removed once it is published?