Psilocybin for Treatment of Obsessive Compulsive Disorder

Study Overview
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Brief Summary
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This study will evaluate whether psilocybin, a hallucinogenic drug, improves symptoms of obsessive compulsive disorder (OCD), whether it is safely tolerated as treatment of OCD, and will investigate the mechanisms by which it works.

Detailed Description
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The study seeks to improve our ability to treat and improve the lives of people who have obsessive-compulsive disorder (OCD) by exploring the benefits of psilocybin, a mind-altering drug that changes activity in brain areas believed to be involved in OCD. Anecdotal reports and results from previous research support this idea. This two-phase study will enroll patients with symptomatic OCD who are not taking mind-altering medications or street drugs. During Phase One, neither participants nor the investigators will know which drugs or doses are administered. This information will be available if it is medically necessary to reveal which drugs and doses were administered. Five subjects in each group will receive study drug a total of four times, separated by one week. During Phase Two, participants will not know which drugs or doses they receive, but the investigators will know. All participants will receive psilocybin at some point during study participation. Participants will be randomly assigned to one of the following groups: Low dose (100 µg/kg) psilocybin, High dose (300 µg/kg) psilocybin, or Lorazepam (1 mg), a calming medication. Lorazepam is used often for anxiety and will be used to mask which drug participants receive. Participants will spend approximately 12 hours at the research site under observation during each visit, until they are free of the mind-altering effects of the drug and are determined by the psychiatrist to be safe to go home accompanied by a responsible adult. The effects of low versus high doses, and the additive effects of repeated doses will be analyzed and will be compared to the effects of lorazepam.

Official Title
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Psilocybin for Treatment of Obsessive Compulsive Disorder

Conditions
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Obsessive-compulsive Disorder (OCD)

Intervention / Treatment
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* Drug: Psilocybin 100 mcg/kg
* Drug: Psilocybin 300 mcg/kg
* Drug: Lorazepam 1 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have moderate to severe OCD (DSM-5) after diagnostic interview using the Structured Clinical Interview for DSM-5 Research Version (SCID-R). Failed at least one adequate attempted routine care treatment. Considered safe for independent living Exclusion Criteria: Concurrent psychosis, active substance use disorder, or a personal history of psychosis. Medical illness based on physical examination and routine blood testing that may complicate cardiovascular safety or drug metabolism or excretion, such as uncontrolled hypertension, severe cardiac disease, or kidney or liver failure. Unstable Chronic Obstructive Pulmonary Disease (COPD) or severe sleep apnea Psychiatric comorbidity that may represent an acute risk to their own or others' safety. Subjects may not be using antidepressant medication for OCD for at least two weeks before receiving study drug, and they cannot require any sedative, narcotic, or neuroleptic medications on a regular basis. Any of these medications they have taken should have been stopped long enough in the past to allow for their elimination and safe withdrawal prior to starting administration of the study drug. The specific time required will be dependent on the medication the patient was previously receiving. Women who are pregnant, breastfeeding, or unwilling/unable to practice medically acceptable birth control during the study. Allergy to lorazepam.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: All participants will be randomly assigned to administration of low dose (100 µg/kg) psilocybin, High dose (300 µg/kg) psilocybin, or Lorazepam (1 mg). Eight different sessions divided in two phases will ensure all subjects are exposed to psilocybin at some point during the study in a blinded fashion.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High-dose Psilocybin<br>Psilocybin 300 mcg/kg once per week, every week, for 8 weeks | Drug: Psilocybin 300 mcg/kg<br>* Psilocybin belongs to the class of hallucinogen or psychedelic drugs. It is one of the major psychoactive components in mushrooms of the Psilocybe genus (magic mushrooms).<br>* Other names: Psilocybine, magic mushrooms;|
| Experimental: High- or Low-dose Psilocybin<br>Psilocybin 100 mcg/kg or psilocybin 300 mcg/kg once per week, every week, for 8 weeks | Drug: Psilocybin 100 mcg/kg<br>* Psilocybin belongs to the class of hallucinogen or psychedelic drugs. It is one of the major psychoactive components in mushrooms of the Psilocybe genus (magic mushrooms).<br>* Other names: Psilocybine, magic mushrooms;Drug: Psilocybin 300 mcg/kg<br>* Psilocybin belongs to the class of hallucinogen or psychedelic drugs. It is one of the major psychoactive components in mushrooms of the Psilocybe genus (magic mushrooms).<br>* Other names: Psilocybine, magic mushrooms;|
| Placebo Comparator: High-dose Psilocybin or Lorazepam<br>Psilocybin 300 mcg/kg or Lorazepam 1 mg once per week, every week, for 8 weeks | Drug: Psilocybin 300 mcg/kg<br>* Psilocybin belongs to the class of hallucinogen or psychedelic drugs. It is one of the major psychoactive components in mushrooms of the Psilocybe genus (magic mushrooms).<br>* Other names: Psilocybine, magic mushrooms;Drug: Lorazepam 1 mg<br>* A medication used to treat anxiety belonging to a class of drugs known as benzodiazepines, which act on the central nervous system to produce a calming effect. This drug works by enhancing the effects of a certain natural chemical in the body (GABA).<br>* Other names: Ativan, Intensol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment-phase effects on Obsessive-Compulsive symptom severity | Prospective Assessment of YBOCS (Yale-Brown Obsessive Compulsive Scale) score comparing each psilocybin dose and active placebo (Lorazepam). | weekly Y-BOCS rating prior to ingestion of study drug on Week 1 through 8, and week 9 (follow up week 1) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute Incidence of Treatment Emergent Adverse Events | Prospective active inquiry of adverse events with the SAFTEE-GI (Systematic Assessment For Treatment Emergent Events-General Inquiry) comparing each psilocybin dose and active placebo (Lorazepam) | At 0, and 24 hours after blinded medication ingestion | 
| Duration of Effects on Obsessive-Compulsive symptom severity | Prospective Naturalistic Assessment of YBOCS (Yale-Brown Obsessive Compulsive Scale) after repeated administration of study drug. | Follow-up assessments will be conducted weekly over the phone weekly (± 3 days) for one month after last dose, monthly (± 7 days) for three months beginning 28 days after last dose, and then once at 6 months after last dose (± 7 days). | 
| Long Term Incidence and Duration of Treatment Emergent Psychiatric Adverse Events | Prospective Assessment with SCID-I (Structured Clinical Interview for DSM-5 Disorders) psychotic screening tool will assess for onset of psychopathology or hallucinogen induced disorders after repeated use. | Follow-up assessments will be conducted weekly over the phone (± 3 days) for one month after last dose, monthly (± 7 days) for three months beginning 28 days after last dose, and then once at 6 months after last dose (± 7 days). | 
| Changes in the magnitude of Error Related Negativity (an electroencephalographic biomarker of OCD) assessed by Error-related negativity (voltage) and mid-frontal theta power (time-frequency approach) | Prospective Assessment of Error Related brain activity comparing each psilocybin dose and active placebo (Lorazepam). | Baseline, and 9-10 hours after ingestion of study dose 1, 4, and 8. | 
| Prospective Self-Assessment of Depression Symptoms | Prospective Assessment of Quick Inventory of Depressive Symptomatology (QIDS) Score comparing each psilocybin dose and active placebo (Lorazepam). | Baseline, 24 hours after each dose during 8 week active phase, and during the follow-up phase (weekly for one month after last dose, monthly for three months beginning 28 days after last dose, and then once at 6 months after last dose. | 
| Prospective Clinician-Rated Assessment of Depression Symptoms | Prospective Assessment of Montgomery-Asberg Depression Rating Scale (MADRS) Score comparing each psilocybin dose and active placebo (Lorazepam). | Baseline, 4 weeks, 8 weeks, and during the follow-up phase (weekly for one month after last dose, monthly for three months beginning 28 days after last dose, and then once at 6 months after last dose | 
| Changes in functional connectivity: 1) between the Caudate Nucleus (CN) and Orbital Frontal Cortex (OFC); 2) within the default mode network (DMN). | Prospective Assessment of Functional Connectivity in CN and OFC and in DMN comparing each psilocybin dose and active placebo (Lorazepam). Also examining whether magnitude of symptom reduction is related to changes in functional connectivity. | Imaging at baseline, and 9-10 hours post ingestion on weeks 1, 4, and 8. YBOCS at baseline and 8 hours after ingestion at weeks 1, 4, and 8. |