Treatment-resistant DepressionPhase 2PSI-RISNCT05710237
Does Psilocybin Require Psychedelic Effects to Treat Depression?
A Phase 2 study testing Psilocybin 25 mg and Risperidone 1 MG in people with Treatment-resistant Depression, run by Centre for Addiction and Mental Health at 1 site in Canada.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Treatment-resistant Depression
- What is being tested?
- Psilocybin 25 mg and Risperidone 1 MG
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 41 participants
- Where
- 1 siteCanada
- Study dates
- 1 Jul 2023to 14 Apr 2026
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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 (an antidepressant resistance rating score of three or more is considered an adequate trial) based on the Antidepressant Treatment History Form (ATHF); there is no upper limit on the number of treatment failures;
- Ability to take oral medication;
- All bloodwork within normal limits or assessed as not clinically significant by study physicians and an eGFR above 40mL/min/1.73m2;
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- 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;
Who cannot join
- 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;
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- 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.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Does Psilocybin Require Psychedelic Effects to Treat Depression? A 4-Week, Double-Blind, Proof-of-Concept Randomized Controlled Trial
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.
Read the detailed description
This study is a three-arm, 4-week, double blind, proof-of concept RCT for investigating psilocybin-assisted psychotherapy (PAP) administered with risperidone in treating TRD. This three-arm "double dummy" design allows for an assessment of risperidone's anti-psychedelic effects, while allowing for an assessment of psilocybin's antidepressant effects alone and combined with risperidone, compared to an "active placebo" (i.e. placebo plus risperidone 1 mg).
Overview of Study Design:
A study team member will obtain informed consent from interested participants prior to study activities being initiated. Following this, participants will undergo a screening assessment where they will complete lab tests, and clinical and psychiatric assessments to determine eligibility. Following the screening visit, eligible participants will undergo a washout period where they will be tapered off concomitant medication over a period of 4 to 6 weeks. The length of the tapering period will depend on the type of medication the participant is being tapered off (based on the half-life of the medication) and the participant's preference for the length of the tapering period. Most medications will require a minimum of a 2-week tapering period before the baseline, with the exception of fluoxetine, which will require a minimum of 4-weeks. Additional time may be added at the discretion of the study investigator. During the tapering period, the study psychiatrist will see participants weekly (V1a, V1b, etc.) for at least 4 weeks to monitor for withdrawal and worsening of depressive symptoms and suicidality. Suicidality will be closely monitored using the Columbia Suicide Severity Rating Scale (C-SSRS). Participants and their family members/carers will be educated on the signs and symptoms of worsening depression and suicidality and will be given contact details of the study team in case of major decline in mental state.
At the Baseline visit (V2), which occurs the day before the dosing session, participants will complete clinical measures, and undergo a preparatory session (up to 4 hours) with the study therapists. These sessions will build a therapeutic alliance, provide psychoeducation about, and set intentions for, the psilocybin session. To reduce participant burden, baseline can be broken up into multiple days, however all assessments must be completed within 7-days of the intervention. Ideally, baseline occurs the day before the intervention is administered.
The psilocybin session (Day 0 [V3]) will last 5 to 6 hours and will be conducted in the existing psychedelic treatment suite developed at the Centre for Addiction and Mental Health (CAMH) Mood Disorder Service by Dr. Husain (PI). Two trained study therapists will be supporting each participant during the dosing session. Participants will receive psilocybin 25 mg plus risperidone 1 mg, or psilocybin 25 mg plus placebo, or placebo plus risperidone 1 mg. All participants will receive 10 hours of manualized supportive psychotherapy (which includes the 5-6 hour dosing session). After 5 hours of dose administration, participants will be evaluated for safety by the study psychiatrist and discharged home in the company of a caregiver or a family member.
After the dosing session, participants will be seen for two 1-hour integration sessions (Day 1 [V4], Week 1 [V5]). Thereafter, participants will be followed-up after 2 [V6], 3 [V7] and 4 weeks [V8] post-dosing (see Figure 1). A study psychiatrist will be available throughout the duration of the RCT to respond to any concerns or changes in mental/physical state. Participants will not start other interventions for MDD during the study.
- Conditions
- Treatment-resistant Depression
- Being tested
- Psilocybin 25 mg, Risperidone 1 MG, Placebo
- Keywords
- Psilocybin, Psychedelics, Treatment-resistant depression, Clinical trial
- Medical subject headings
- Depressive Disorder, Treatment-Resistant
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Psilocybin 25 mgDrug
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.
Risperidone 1 MGDrug
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.
PlaceboDrug
The placebo will be administered once during the trial in combination with either risperidone 1 mg or psilocybin 25 mg.
| Study group | Role | What they receive |
|---|---|---|
| Risperidone 1 mg plus Psilocybin 25 mg | Experimental | Risperidone 1 mg plus Psilocybin 25 mg Receives: Drug: Psilocybin 25 mg; Drug: Risperidone 1 MG |
| Placebo plus Psilocybin 25 mg | Experimental | Placebo plus Psilocybin 25 mg Receives: Drug: Psilocybin 25 mg; Drug: Placebo |
| Risperidone 1 mg plus Placebo | Active comparator | Risperidone 1 mg plus Placebo Receives: Drug: Risperidone 1 MG; Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Feasibility of administering psilocybin (25mg) with risperidone (1mg)
Percentage of participants recruited, randomized, and retained.
Measured: 4 weeks
Tolerability and safety of administering psilocybin (25mg) with risperidone (1mg)
Frequency of dropouts attributed to adverse effects or serious adverse events
Measured: 4 weeks
Secondary outcomes (1)
Subjective psychedelic effects as measured by the 5-Dimensional Altered States of Consciousness (5D-ASC) Rating Scale
A visual analogue scale (0-100 millimeters in length) with higher scores indicating more intense effects.
Measured: Visit 3 (Day 0)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Feb 2023
- Study start1 Jul 2023
- Primary completion14 Apr 2026
- Study completion14 Apr 2026
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Treatment-resistant DepressionStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 41 participants (actual)
Sponsor and investigators
- Lead sponsor
- Centre for Addiction and Mental Health
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- M. Ishrat Husain, MBBS, MD, Principal investigator, Centre for Addiction and Mental Health
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05710237
- Sponsor's protocol ID
- 080-2022
- Acronym
- PSI-RIS
- Status last verified
- May 2026
- First submitted
- 24 Jan 2023
- Last updated
- 7 May 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 7 May 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Does Psilocybin Require Psychedelic Effects to Treat Depression? A 4-Week, Double-Blind, Proof-of-Concept Randomized Controlled Trial
- ClinicalTrials.gov ID
- NCT05710237
- Acronym / sponsor ID
- PSI-RIS / 080-2022
- Conditions
- Treatment-resistant Depression
- Keywords
- Psilocybin, Psychedelics, Treatment-resistant depression, Clinical trial
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 41 participants (actual)
- Lead sponsor
- Centre for Addiction and Mental HealthUniversity, hospital or other
- Study start
- 1 Jul 2023 (actual)
- Primary completion
- 14 Apr 2026 (actual)
- Study completion
- 14 Apr 2026 (actual)
- First posted
- 2 Feb 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
This study is a three-arm, 4-week, double blind, proof-of concept RCT for investigating psilocybin-assisted psychotherapy (PAP) administered with risperidone in treating TRD. This three-arm "double dummy" design allows for an assessment of risperidone's anti-psychedelic effects, while allowing for an assessment of psilocybin's antidepressant effects alone and combined with risperidone, compared to an "active placebo" (i.e. placebo plus risperidone 1 mg).
Overview of Study Design:
A study team member will obtain informed consent from interested participants prior to study activities being initiated. Following this, participants will undergo a screening assessment where they will complete lab tests, and clinical and psychiatric assessments to determine eligibility. Following the screening visit, eligible participants will undergo a washout period where they will be tapered off concomitant medication over a period of 4 to 6 weeks. The length of the tapering period will depend on the type of medication the participant is being tapered off (based on the half-life of the medication) and the participant's preference for the length of the tapering period. Most medications will require a minimum of a 2-week tapering period before the baseline, with the exception of fluoxetine, which will require a minimum of 4-weeks. Additional time may be added at the discretion of the study investigator. During the tapering period, the study psychiatrist will see participants weekly (V1a, V1b, etc.) for at least 4 weeks to monitor for withdrawal and worsening of depressive symptoms and suicidality. Suicidality will be closely monitored using the Columbia Suicide Severity Rating Scale (C-SSRS). Participants and their family members/carers will be educated on the signs and symptoms of worsening depression and suicidality and will be given contact details of the study team in case of major decline in mental state.
At the Baseline visit (V2), which occurs the day before the dosing session, participants will complete clinical measures, and undergo a preparatory session (up to 4 hours) with the study therapists. These sessions will build a therapeutic alliance, provide psychoeducation about, and set intentions for, the psilocybin session. To reduce participant burden, baseline can be broken up into multiple days, however all assessments must be completed within 7-days of the intervention. Ideally, baseline occurs the day before the intervention is administered.
The psilocybin session (Day 0 [V3]) will last 5 to 6 hours and will be conducted in the existing psychedelic treatment suite developed at the Centre for Addiction and Mental Health (CAMH) Mood Disorder Service by Dr. Husain (PI). Two trained study therapists will be supporting each participant during the dosing session. Participants will receive psilocybin 25 mg plus risperidone 1 mg, or psilocybin 25 mg plus placebo, or placebo plus risperidone 1 mg. All participants will receive 10 hours of manualized supportive psychotherapy (which includes the 5-6 hour dosing session). After 5 hours of dose administration, participants will be evaluated for safety by the study psychiatrist and discharged home in the company of a caregiver or a family member.
After the dosing session, participants will be seen for two 1-hour integration sessions (Day 1 [V4], Week 1 [V5]). Thereafter, participants will be followed-up after 2 [V6], 3 [V7] and 4 weeks [V8] post-dosing (see Figure 1). A study psychiatrist will be available throughout the duration of the RCT to respond to any concerns or changes in mental/physical state. Participants will not start other interventions for MDD during the study.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Risperidone 1 mg plus Psilocybin 25 mg | Experimental | Drug: Psilocybin 25 mg, Drug: Risperidone 1 MGRisperidone 1 mg plus Psilocybin 25 mg |
| Placebo plus Psilocybin 25 mg | Experimental | Drug: Psilocybin 25 mg, Drug: PlaceboPlacebo plus Psilocybin 25 mg |
| Risperidone 1 mg plus Placebo | Active comparator | Drug: Risperidone 1 MG, Drug: PlaceboRisperidone 1 mg plus Placebo |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- 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 (an antidepressant resistance rating score of three or more is considered an adequate trial) based on the Antidepressant Treatment History Form (ATHF); there is no upper limit on the number of treatment failures;
- Ability to take oral medication;
Key exclusion criteria (12 listed)
- 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;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Psilocybin 25 mgThe 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 plus Psilocybin 25 mg, Risperidone 1 mg plus Psilocybin 25 mg |
| Risperidone 1 MGThe 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 | Risperidone 1 mg plus Placebo, Risperidone 1 mg plus Psilocybin 25 mg |
| PlaceboThe placebo will be administered once during the trial in combination with either risperidone 1 mg or psilocybin 25 mg. | Drug | Placebo plus Psilocybin 25 mg, Risperidone 1 mg plus Placebo |
Primary outcome
Feasibility of administering psilocybin (25mg) with risperidone (1mg)
Time frame: 4 weeks
Percentage of participants recruited, randomized, and retained.
Tolerability and safety of administering psilocybin (25mg) with risperidone (1mg)
Time frame: 4 weeks
Frequency of dropouts attributed to adverse effects or serious adverse events
1 secondary outcome
Subjective psychedelic effects as measured by the 5-Dimensional Altered States of Consciousness (5D-ASC) Rating Scale
Time frame: Visit 3 (Day 0)
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 May 2026.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
M. Ishrat Husain, MBBS, MD principal investigator
Centre for Addiction and Mental Health
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Psilocybin 25 mg and Risperidone 1 MG in people with Treatment-resistant Depression, run by Centre for Addiction and Mental Health at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 7 May 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Feasibility of administering psilocybin (25mg) with risperidone (1mg) (time frame: 4 weeks). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 May 2026.