PSI-RIS: Does Psilocybin Require Psychedelic Effects to Treat Depression?

Sponsor

Centre for Addiction and Mental Health (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05710237

Collaborator

(none)

Enrollment

Location

Arms

Anticipated Duration (Months)

1.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Psilocybin, the chemical component of "magic mushrooms", has been administered with psychotherapy in several randomized clinical trials (RCTs) showing large and sustained antidepressant effects. In healthy volunteers, the psychedelic effects of psilocybin have been shown to be blocked by administration of serotonin (5HT)2A receptor antagonists such as risperidone.

The purpose of this "double dummy" proof-of-concept trial is to evaluate whether psilocybin's antidepressant effects are dependent on its psychedelic effects. Sixty participants with treatment-resistant depression will be randomly assigned to one of three groups: 1) Psilocybin 25 mg plus risperidone 1 mg; 2) Psilocybin 25 mg plus placebo; and 3) Placebo plus risperidone 1 mg. The investigator's hypothesize that the combination of psilocybin and risperidone will be well tolerated, safe, and will block the psychedelic effects of psilocybin in patients diagnosed with treatment-resistant depression.

Condition or Disease	Intervention/Treatment	Phase
Treatment-resistant Depression	Drug: Psilocybin 25 mg Drug: Risperidone 1 MG Drug: Placebo	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

60 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

Patients, their families, the study investigator, study therapists, and research assistants carrying out assessments will be concealed from allocation.

Primary Purpose:

Treatment

Official Title:

Does Psilocybin Require Psychedelic Effects to Treat Depression? A 4-Week, Double-Blind, Proof-of-Concept Randomized Controlled Trial

Anticipated Study Start Date :

Feb 1, 2023

Anticipated Primary Completion Date :

Feb 1, 2026

Anticipated Study Completion Date :

Feb 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Risperidone 1 mg plus Psilocybin 25 mg	Drug: Psilocybin 25 mg The psilocybin used in this study meets quality specifications suitable for human research use. The active drug is encapsulated using a hydroxypropyl methylcellulose (HPMC) capsule and contains 25 mg of psilocybin. The psilocybin will be administered once during the trial in combination with either risperidone 1 mg or place. It will also be administered in conjunction with supportive therapy. Drug: Risperidone 1 MG The risperidone is encapsulated using a cellulose capsule and contains 1 mg of risperidone. The risperidone will be administered once during the trial in combination with either psilocybin 25 mg or placebo. It will also be administered with supportive therapy.
Experimental: Placebo plus Psilocybin 25 mg	Drug: Psilocybin 25 mg The psilocybin used in this study meets quality specifications suitable for human research use. The active drug is encapsulated using a hydroxypropyl methylcellulose (HPMC) capsule and contains 25 mg of psilocybin. The psilocybin will be administered once during the trial in combination with either risperidone 1 mg or place. It will also be administered in conjunction with supportive therapy. Drug: Placebo The placebo will be administered once during the trial in combination with either risperidone 1 mg or psilocybin 25 mg.
Active Comparator: Risperidone 1 mg plus Placebo	Drug: Risperidone 1 MG The risperidone is encapsulated using a cellulose capsule and contains 1 mg of risperidone. The risperidone will be administered once during the trial in combination with either psilocybin 25 mg or placebo. It will also be administered with supportive therapy. Drug: Placebo The placebo will be administered once during the trial in combination with either risperidone 1 mg or psilocybin 25 mg.

Arm

Intervention/Treatment

Experimental: Risperidone 1 mg plus Psilocybin 25 mg

Drug: Psilocybin 25 mg

The psilocybin used in this study meets quality specifications suitable for human research use. The active drug is encapsulated using a hydroxypropyl methylcellulose (HPMC) capsule and contains 25 mg of psilocybin. The psilocybin will be administered once during the trial in combination with either risperidone 1 mg or place. It will also be administered in conjunction with supportive therapy.

Drug: Risperidone 1 MG

The risperidone is encapsulated using a cellulose capsule and contains 1 mg of risperidone. The risperidone will be administered once during the trial in combination with either psilocybin 25 mg or placebo. It will also be administered with supportive therapy.

Experimental: Placebo plus Psilocybin 25 mg

Drug: Psilocybin 25 mg

Drug: Placebo

The placebo will be administered once during the trial in combination with either risperidone 1 mg or psilocybin 25 mg.

Active Comparator: Risperidone 1 mg plus Placebo

Drug: Risperidone 1 MG

Drug: Placebo

The placebo will be administered once during the trial in combination with either risperidone 1 mg or psilocybin 25 mg.

Outcome Measures

Primary Outcome Measures

Feasibility of administering psilocybin (25mg) with risperidone (1mg) [4 weeks]
Percentage of participants recruited, randomized, and retained.
Tolerability and safety of administering psilocybin (25mg) with risperidone (1mg) [4 weeks]
Frequency of dropouts attributed to adverse effects or serious adverse events

Secondary Outcome Measures

Subjective psychedelic effects as measured by the 5-Dimensional Altered States of Consciousness (5D-ASC) Rating Scale [Visit 3 (Day 0)]
A visual analogue scale (0-100 millimeters in length) with higher scores indicating more intense effects.

Other Outcome Measures

Change in the Montgomery-Åsberg Depression Rating Scale (MADRS) from Baseline to 1-week post-treatment. [Baseline (Day -1) to visit 5 (Day 7)]
The Montgomery-Åsberg Depression Rating Scale is a clinician-rated scale that measures depression severity. It is 10-items which are scored from 0 (not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Outpatient adults 18 to 65 years old;
Able to provide informed consent and read and communicate in English;
Primary DSM-5 diagnosis of non-psychotic MDD, single or recurrent, based on the Structured Clinical Interview for DSM-5 (SCID-5);
Diagnosis of treatment-resistant depression defined as a baseline HamD-17 score > 14 and have not responded to two or more separate trials of antidepressants at an adequate dosage and duration;
Ability to take oral medication;
All bloodwork within normal limits and an eGFR above 40mL/min/1.73m2;
Individuals who are capable of becoming pregnant: use of highly effective contraception for at least 1 month prior to screening and agreement to use such a method during study participation;
Willing to and have tapered off current antidepressant and antipsychotic medications for a minimum of 2-weeks (or more depending on the medication) prior to baseline and for the duration of the study and whose physician confirms that it is safe for them to do so; AND
Willing to and have tapered off current inhibitors of 5'-diphospho-glucuronosyltransferase (UGT)1A9 and 1A10, aldehyde dehydrogenase inhibitors (ALDHs) and alcohol dehydrogenase inhibitors (ADHs) for a minimum of 2-weeks (or more depending on the medication) prior to baseline and for the duration of the study and whose physician confirms that it is safe for them to do so;

Exclusion Criteria:

Pregnant or individual's that intend to become pregnant during the study or are breastfeeding;
Treatment with another investigational drug or other intervention within 30 days of screening;
Have initiated psychotherapy in the preceding 12 weeks prior to screening;
Have a DSM-5 diagnosis of substance use disorder (recreational use of tobacco, alcohol, cannabis and prescribed opioids are permitted) within the preceding 6-months;
Have active suicidal ideation with intent and plan as determined by item 3 of the HamD-17;
Any DSM-5 lifetime diagnosis of a schizophrenia-spectrum disorder, obsessive-compulsive disorder, psychotic disorder (unless substance induced or due to a medical condition), bipolar I or II disorder, paranoid personality disorder, borderline personality disorder, or neurocognitive disorder as determined by medical history and the SCID-5 clinical interview;
Any first-degree relative with a diagnosis of schizophrenia-spectrum disorder; psychotic disorder (unless substance-induced or due to a medical condition); or bipolar I or II disorder;
Presence of a relative or absolute contraindication to psilocybin, including a drug allergy, recent stroke history, uncontrolled hypertension, low or labile blood pressure, recent myocardial infarction, cardiac arrhythmic, severe coronary artery disease, or moderate to severe renal or hepatic impairment;
Presence of baseline prolonged QTc or Torsade de Pointes as measured by the ECG or a history of long QTc syndrome or related risk factors;
History of allergy or contraindication to risperidone including insulin-dependent diabetes, history of hypoglycemia on oral hypoglycemic agent(s)
Lifetime use of serotonergic psychedelic drugs; OR
Any other clinically significant physical illness including chronic infectious diseases or any other major concurrent illness that, in the opinion of the investigator, may interfere with the interpretation of the study results or constitute a health risk for the participant if they take part in the study.