Recruitment

We will recruit via out-patient referrals from clinicians at CAMH and surrounding hospitals in the Greater Toronto Area. Regardless of recruitment method, all participants will be required to be under the care of a physician at CAMH to ensure clinical oversight; their usual treating psychiatrist will also be informed of their participation in the study. Participants who have expressed interest in the study will be contacted by the study team for a prescreening call where a description of the study will be given and a few short questions regarding psychiatric and medical history will be asked. The prescreen form will be reviewed by the principal investigator, and participants who are preliminarily deemed eligible will be contacted to schedule a consent and screening visit.

Informed consent and screening

Consent will be obtained in-person before the start of any research activities by trained study personnel. The principal investigator and/or therapists will not obtain informed consent. Each participant will be provided with a current copy of the research ethics board-approved informed consent form before the consent discussion. Research personnel will explain the clinical trial to the participant and answer any questions that may arise. Participants may take as much time as they need to make their decision, and may consult with others (e.g. family members, other healthcare providers, etc.) if they prefer.

Once consent is obtained, the screening process will begin. An outline of all assessments conducted during screening and throughout the study can be found in Table 2. The study physician will discuss tapering options with the patient based on the half-life of the medication and participant preference. Participants must be tapered off all concomitant medication 2 weeks before baseline to be eligible for the study.

Table 2

Overview of study activities and assessments

MRI, magnetic resonance imaging; TASS, Transcranial Magnetic Stimulation Adult Safety Screen; SCID-5, Structured Clinical Interview for DSM-5; fMRI, functional magnetic resonance imaging; YBOCS, Yale–-Brown Obsessive-–Compulsive Scale; C-SSRS, Columbia Suicide Severity Rating Scale; CGI, Clinical Global Impression scale; TMS, transcranial magnetic stimulation; CRF, case report form; MSI-BDP, Mclean Screening Instrument for Borderline Personality Disorder; 5D-ASC, 5-Dimensional Altered States of Consciousness scale; MEQ, Mystical Experiences Questionnaire; GAD-7, Generalised Anxiety Disorder-7; PHQ-9, Patient Health Questionnaire-9; WEMWBS, Warwick–Edinburgh Mental Wellbeing Scale; WHODAS 2.0, World Health Organization Disability Assessment Schedule 2.0; WHO-QOL-BREF, World Health Organization Quality of Life Questionnaire – Brief Version.

Study visits

The outline of study visits is shown in Fig. 1 and an overview of all study activities and assessments can be found in Table 2. After the tapering period, participants will participate in a minimum of ten study visits over the period of 13 weeks. Additional study visits may be added at the discretion of the study physician or visits may be separated to reduce the burden on participants. Across these study visits, participants will take part in one psilocybin dosing session (25 mg) and two fMRI scans. Participants will also complete two TMS-electroencephalogram sessions, and three electroencephalogram recordings (one of which will occur during the dosing session). There will be six follow-up visits, which will occur in the final 12 weeks of the study, at which baseline assessments will be repeated.

Fig. 1

Outline of study visits. fMRI, functional magnetic resonance imaging; PAP, psilocybin-assisted psychotherapy; TMS, transcranial magnetic stimulation.

Baseline, 1-week follow-up and 3-week follow-up

Baseline (visit 2) has similarities to both the 1-week and 3-week follow-up visit. All participants will undergo an fMRI scan at baseline and week 3. Electroencephalogram recordings (rest and task) and TMS-electroencephalogram will occur at baseline and 1–7 days post-dose, rather than at week 3. In addition, several assessments evaluating OCD symptom severity, anxiety, depression, well-being and quality of life, among others, will be administered at both time points. On the baseline day, preparatory therapy will be conducted, and the 1-week follow-up will include integration therapy for participants, both of which are outlined below.

Therapy

This study involves up to 6 h of manualised therapy administered before and after the dosing session, along with up to 8 h of supportive therapy during dosing. Therapy will be administered by two trained therapists who will be trained in PAP; therapists will have continunity with participants for the duration of the trial. The manual used for training is the Yale Manual for Psilocybin-assisted Therapy for OCD, delivered by a clinician who is an expert in OCD. Briefly, preparatory therapy will occur before dosing and will be used to answer participant questions, educate the participant regarding what to expect from the therapy, set boundaries and safety protocols for the dosing session and set intentions for the dosing session. On the dosing day, participants will lay on a bed with the option of using eyeshades. To enhance inward reflection, a pre-selected music playlist will be played quietly. All participants will listen to the same playlist, which is preset specifically for the standardisation of PAP sessions across all other psilocybin studies in our institution. Therapists will offer support and encourage inward reflection during the experience. At 1 day and 1 week after the dosing session, participants will participate in integration therapy, which is expected to last 1–3 h.

Dosing session

Participants will be administered a high dose of psilocybin (25 mg) in the form of a capsule. We chose this dose for standardisation across the study participants, as it is the most frequently chosen dose in other psilocybin research studies, with almost guaranteed and observed psychedelic effects. ^{Reference MacCallum, Lo, Pistawka and Deol32} A recent study reported no significant differences in weight-adjusted dosing versus fixed dosing. ^{Reference Garcia-Romeu, Barrett, Carbonaro, Johnson and Griffiths33} Furthermore, advantages of fixed dosing outweigh the potential minimal advantage of weight-adjusted dosing, given that fixed dosing incurs a lower cost. Although the acute effects of orally ingested psilocybin typically last 4–6 h, participants will be expected to remain in the dosing suite for at least 5 h. There will be at least one therapist present at all times during the dosing session, and a medical professional will be on site to oversee medical care and approve patient discharge at the end of the day. In addition, participants will undergo an electroencephalogram recording, which will begin 5-min before drug administration and last for a total of 120 min. At the end of the dosing day, participants will be released to a caregiver, who will transport them home and remain with them for 24 h post-dose. For safety purposes, both the participant and caregiver will be provided with the contact information of a study team member who will be on-call should support be required.

Follow-up visits

Remote or in-person follow-up visits to assess changes on secondary outcome measures will occur at 1 day post-dose, as well as at 1, 3, 6, 9 and 12 weeks post-dose. These visits will be short, with the primary focus being the administration of the secondary assessment measures described below.

Feasibility outcomes

Feasibility will be assessed through recruitment and retention rates. Drop-out rates during three periods will be evaluated, namely (a) the screening period, in which the participant undergoes medication tapering and washout; (b) during the acute course of the study intervention and (c) during the follow-up period. A CONSORT diagram will be presented displaying participant retention rates throughout each phase of the trial, including recruitment. For full transparency, we will provide reasons for screening failures, withdrawals and drop-out.

Tolerability and safety outcomes

To evaluate the co-primary outcome of the safety of PAP in participants with treatment-resistant OCD, standardised adverse event monitoring will be conducted at all time points, starting from the first screening visit through to the final follow-up visit. During the dosing session, adverse events will be assessed both before and after the intervention, as well as the following morning when the participant returns for integration therapy. The Principal Investigator will closely monitor and assess all reported adverse events on the same day and will document them promptly in the adverse events log, to ensure the safety of all participants. The adverse event log is pre-approved by CAMH to be used in clinical trials. All adverse events will be assessed by the physician and Principal Investigator, and recorded in the log, detailing seriousness, unexpectedness, relatedness to the psilocybin, severity, actions taken with the psilocybin drug and any medications administered. This will ensure comprehensive documentation of the tolerability of psilocybin. Throughout the time periods mentioned above, we will prioritise the close and thorough evaluation of the acute and subacute psychological safety profile. The Columbia Suicide Severity Rating Scale (C-SSRS) will be administered at every study visit. The C-SSRS is a semi-structured interview designed to assess the severity and intensity of suicidal ideation, suicidal behaviour and non-suicidal injurious behaviour over the time period between study visits. ^{Reference Posner, Brown, Stanley, Brent, Yershova and Oquendo31} There will be a psychiatrist on call to assess participants with active suicidal ideation, plans and/or intent, and standard of care will be provided. Adverse events will be classified based on severity, causality and expectedness by the study investigator. Serious adverse events are defined as any event that occurs which results in death, is life threatening, requires admission to hospital results in persistent or significant disability. All serious adverse events will be reported to the Principal Investigator, ethics committee, drug manufacturer and regulatory bodies within 24 h of the study team being made aware of the event, or according to the necessary reporting requirements of each department.

Clinical outcomes

The preliminary clinical effects of PAP will be measured according to change in the primary outcome measure, from baseline to week 1 total scores: the YBOCS will be employed. The YBOCS comprises ten items with total scores ranging from 0 to 40. Higher scores indicate greater symptom severity. The scale is clinician-rated, with interviewers providing a rating from 0 (‘no symptoms’) to 4 (‘extreme symptoms’) on each item.

Exploratory clinical effects outcomes

The clinical effects of PAP will also be investigated in the context of response and remission rates by comparing baseline to week 1 total scores on the YBOCS. Response is defined as a 35% reduction or more on the YBOCS. ^{Reference Mataix-Cols, de la Cruz, Nordsletten, Lenhard, Isomura and Simpson34} Remission is defined as as score of ≤7 on the YBOCS for patients with OCD. ^{Reference Mataix-Cols, de la Cruz, Nordsletten, Lenhard, Isomura and Simpson34} We will also analyse changes in YBOCS score from baseline to day 1 and weeks 3, 6, 9 and 12. In addition, baseline scores on various assessment measures to evaluate overall functioning, anxiety, depression, quality of life, disability and wellbeing will be compared with week 1. Anxiety will be measured with the Generalised Anxiety Disorder-7 (GAD-7) scale which is a brief self-report measure of generalised anxiety that has demonstrated good psychometric properties and is a widely used research instrument for assessing adult anxiety. ^{Reference Spitzer, Kroenke, Williams and Löwe35} The Patient Health Questionnaire-9 (PHQ-9) is a nine-item brief self-report questionnaire that will be employed to evaluate the presence and severity of depression. ^{Reference Kroenke, Spitzer and Williams36} Quality of life will be evaluated with the World Health Organization Quality of Life Questionnaire – Short Version (WHO-QoL-BREF). The WHO-QoL-BREF is a self-report measure developed by the World Health Organization. ³⁷ It uses a five-point Likert scale to assess quality of life in the following areas: physical, psychological, level of independence, social relationships, environment and spirituality/religion/personal beliefs. ³⁷ The Disability Assessment Schedule (WHODAS 2.0) is a 12-item self-report questionnaire that assesses health status and disability across different cultures and settings. ^{Reference Üstün, Chatterji, Kostanjsek, Rehm, Kennedy and Epping-Jordan38} Participants will rate themselves on a Likert scale from 1 (‘none’) to 4 (‘extreme’) across six different domains of functioning: cognition, mobility, self-care, getting along, life activities and participation. ^{Reference Üstün, Chatterji, Kostanjsek, Rehm, Kennedy and Epping-Jordan38} The Clinical Global Impression scale (CGI) will also be used as a secondary outcome measure. The CGI is a brief observer-rated instrument that measures the clinician’s view of the patient’s global functioning before and after initiating the study medication. ^{Reference Guy39} Well-being will be assessed withthe Warwick–Edinburgh Mental Wellbeing Scale (WMWBS), a self-report scale that consists of positively worded statements covering feelings and functioning aspects of mental well-being. ^{Reference Tennant, Hiller, Fishwick, Platt, Joseph and Weich40}

Psychedelic experience

Potential response predictors, including the psychedelic experience itself, will be assessed as mediators/moderators of the primary outcome. The Five Dimension Altered States of Consciousness Questionnaire (5D-ASC) and the Mystical Experiences Questionnaire (MEQ) will be assessed for correlations with the primary and secondary outcomes as possible predictors of response. The 5D-ASC is a 94-item self-rated measure that consists of five subscales used to evaluate the psychedelic experience: (a) oceanic boundlessness, (b) anxious ego dissolution, (c) visionary re-structuralisation, (d) auditory alterations and (e) reduction of vigilance. ^{Reference Dittrich41,Reference Studerus, Gamma and Vollenweider42} The MEQ consists of a subset of 30 items from a larger scale that assesses four factors: mystical experiences (including ‘internal unity’, ‘external unity’, ‘noetic quality’ and ‘sacredness’), positive mood (awe, joy, peace and tranquillity), transcendence of time and space (sense of being outside of time, in a realm of no space boundaries, sense of timelessness) and ineffability (e.g. inability to adequately describe one’s experience in words). ^{Reference Barrett, Johnson and Griffiths29,Reference MacLean, Leoutsakos, Johnson and Griffiths43}

Neuroimaging

Participants will complete a 1 h MRI scan before and following PAP, including a T1 MRI, 28 min of resting-state fMRI, and a multi-shell diffusion MRI scan for exploratory analyses. Data will be collected with state-of-the-art MRI protocols developed as part of the Adolescent Brain Cognitive Development study, including hyperband sequences. MRI scans will undergo rigorous quality control checks, and will be cleaned using an extensive noise regression procedure, and normalised into surface-space with the Human-Connectome analysis tools. For resting fMRI, leading eigenvector dynamics analysis will be applied to examine dynamic functional connectivity, as was done in prior work on the effects of psilocybin in major depressive disorder. ^{Reference Olsen, Lykkebo-Valløe, Ozenne, Madsen, Stenbæk and Armand44} We will examine changes in dynamic connectivity measures related to specific ‘brain states’ from pre to post treatment. We hypothesise that we will see a greater repertoire of dynamic changes, associated with a reduction in overexpressed pathological brain states.

Neurophysiology

There are several exploratory neurophysiological measures in this study. The ongoing electroencephalogram recordings during the dosing session will be used to investigate changes of brain dynamics (spectral changes, changes in connectivity, changes in complexity measures) associated with psilocybin under acute conditions in patients with OCD. TMS-electroencephalogram measurements will be acquired as additional markers of the brain response to perturbation, targeting both the dorsomedial prefrontal cortex and dorsolateral prefrontal cortex. In addition, changes in resting-state electroencephalogram, task electroencephalogram and TMS-electroencephalogram between baseline, provocation of OCD symptoms and up to 1 week post-dose will also be used to investigate correlations between changes in electroencephalogram and TMS-electroencephalogram measures and changes in symptom severity.

During each of the two neurophysiology visits (one before and one after the intervention), resting-state electroencephalogram, task-related electroencephalogram and TMS-electroencephalogram (targeting two anatomical areas) will be collected, alternating between neutral and symptom provocation phases. OCD symptoms will be provoked by using an individualised external provocation method; ^{Reference Blair Simpson, Tenke, Towey, Liebowitz and Bruder30,Reference Tendler, Sisko, Barnea-Ygael, Zangen and Storch45} For example, participants may be asked to touch a surface they perceive as unclean. The severity of OCD symptoms will be assessed during each phase by using an 11-point visual analogue scale (VAS). A provoked session will aim to elicit a VAS score between 4 and 7, as scores above 7 may cause significant distress, whereas scores below 4 may not sufficiently activate the brain regions associated with OCD symptoms. During the neutral phase, participants will engage in breathing exercises to relax and aim to bring their VAS score below 4. These two phases will then be repeated when targeting the other brain region. The duration of the electroencephalogram and TMS-electroencephalogram measurements will be approximately 80 min.

For the rest electroencephalogram, the participant will be seated comfortably with their eyes open, looking at a fixation target, for a period of 5 min. For task electroencephalogram, the participant will additionally perform an auditory oddball task consisting of 600 auditory stimuli (sinus tones, intensity of 80 dB, duration 40 ms) delivered binaurally through headphones, with an interstimulus interval of 1500 ms. ^{Reference Andreou, Faber, Leicht, Schoettle, Polomac and Hanganu-Opatz28} The duration of this measurement will be about 15 min.

TMS-electroencephalogram will also be applied in blocks consisting of 150 biphasic single pulses of TMS with an inter-pulse interval ≥2.5 s, using masking noise to reduce the auditory-evoked electroencephalogram potential. Target stimulation sites will be left dorsomedial prefrontal cortex and left dorsolateral prefrontal cortex (the order will be counterbalanced between different study participants, but remain consistent in any given study participant). In total, the TMS-electroencephalogram procedure will take about 20 min.

Finally, functional connectivity change profiles associated with the neurobiological effects of PAP will be investigated by examining functional connections, using electroencephalogram at baseline compared with 1–7 days post-dose, and fMRI at baseline compared with week 3.