Psilocybin-Assisted Psychotherapy for Depression

(PSI-1V2 Trial)

Overseen By Zoe Doyle, RN

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University Health Network, Toronto

Must not be taking: Antidepressants, Antipsychotics, Mood stabilizers, others

Disqualifiers: Mania, Psychosis, Substance use disorder, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 8 weeks

92 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether one or two doses of psilocybin, combined with therapy, can alleviate symptoms in people with treatment-resistant depression (TRD). Researchers aim to determine the safety of psilocybin and whether a second dose can enhance quality of life and cognitive function. Participants must have tried at least two antidepressants without success and currently experience moderate to severe depression. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

Yes, you will need to stop taking certain medications like antidepressants, antipsychotics, mood stabilizers, and stimulants at least one month before starting the trial, if your doctor says it's safe.

Is there any evidence suggesting that psilocybin is likely to be safe for humans?

Previous studies have generally shown that patients tolerate psilocybin well. Many participants reported mild to moderate side effects, such as temporary changes in perception, mood, and thought. These effects are common with psychedelic experiences. Some also experienced mild headaches or nausea, while serious side effects were rare.

Researchers are studying psilocybin for its potential to help with conditions like depression due to its effects on the brain. This substance is tested in controlled settings, with professional support, to ensure safety. Prospective trial participants can be assured that researchers will monitor and manage any side effects that may occur. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for depression?

Researchers are excited about psilocybin-assisted psychotherapy for depression because it offers a completely different approach compared to traditional antidepressants like SSRIs. Psilocybin, the active ingredient, is a psychedelic compound that has the potential to produce rapid and profound changes in mood by targeting serotonin receptors in the brain, possibly leading to faster relief from depressive symptoms. Traditional treatments often take weeks to show effects, while psilocybin could provide noticeable improvements after just one or two doses. This potential for quick and sustained relief, coupled with the therapeutic support of psychotherapy, makes psilocybin a promising alternative for those who haven’t responded well to existing treatments.

What evidence suggests that psilocybin-assisted psychotherapy could be effective for treatment-resistant depression?

Research shows that psilocybin, when combined with therapy, can ease symptoms of depression that resist other treatments. In earlier studies, participants who took psilocybin experienced a significant reduction in their depression symptoms. Some research found that just one dose can quickly lead to lasting improvements. This trial will compare two dosing regimens: one group will receive two doses of psilocybin, while another will receive a single dose. Although the exact mechanism of psilocybin remains unclear, it is thought to affect brain areas that control mood. Early results suggest that multiple doses might enhance these benefits, but further studies are needed to confirm this. Overall, psilocybin appears promising as a potential treatment for those unresponsive to standard depression therapies. ^{1 2 4 6 7}

Who Is on the Research Team?

Joshua Rosenblat, MD, MSc

Principal Investigator

University Health Network, Toronto

Are You a Good Fit for This Trial?

This trial is for individuals with treatment-resistant depression, meaning they haven't responded well to standard treatments. Participants must be adults who can safely receive psilocybin and are willing to undergo psychotherapy sessions.

Inclusion Criteria

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 in addition to monthly check-ins by study staff to determine the first day of their last menstrual period

Current MDE must be moderate to severe, as determined by a MADRS score greater than 21

I will use condoms or other methods to prevent pregnancy during the study.

Exclusion Criteria

Major neurocognitive disorder, as determined by clinical assessment, including administration of the Montreal Cognitive Assessment (MoCA)

Lifetime history of mania, hypomania or psychosis as determined by clinical psychiatric assessment and the MINI

Treatment with another investigational drug or other intervention within 30 days of Baseline (V2)

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive one or two doses of psilocybin in conjunction with psilocybin-assisted psychotherapy

8 weeks

2-4 visits (in-person) for dosing sessions

Follow-up

Participants are monitored for safety, effectiveness, and various secondary outcomes such as quality of life and cognitive function

6 months

Regular follow-up visits (in-person or virtual)

What Are the Treatments Tested in This Trial?

Interventions

• Psilocybin

Trial Overview The study is testing the effectiveness of one versus two doses of psilocybin in conjunction with psychotherapy on relieving symptoms of depression. It aims to determine which dosage level improves quality of life and cognitive functions more effectively.

How Is the Trial Designed?

Group I: Two Doses of Psilocybin Active Control 1 Intervention

Two psychedelic doses (25mg of psilocybin + 25mg of psilocybin) taken in conjunction with psilocybin-assisted psychotherapy

Group II: Single Dose of Psilocybin Placebo Group 1 Intervention

One psychedelic dose (1mg of psilocybin + 25mg of psilocybin) taken in conjunction with psilocybin-assisted psychotherapy

Psilocybin is already approved in United States, European Union for the following indications:

Approved in United States as Psilocybin for:

• Treatment-resistant depression (TRD) under Breakthrough Therapy designation

Approved in European Union as Psilocybin for:

• Treatment-resistant depression (TRD) under PRIME designation

Who Is Running the Clinical Trial?

University Health Network, Toronto

Lead Sponsor

Trials

1,555

Recruited

526,000+

Centre for Addiction and Mental Health

Collaborator

Trials

388

Recruited

84,200+

Published Research Related to This Trial

A meta-analysis of psilocybin studies found that higher doses of psilocybin are associated with stronger subjective experiences, particularly in areas like perceptual alterations and ego dissolution, based on data from standardized questionnaires.

Challenging experiences were less affected by dose, suggesting that individual and environmental factors also play a significant role in the psilocybin experience, indicating that these findings are most relevant in controlled settings rather than recreational use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose-response relationships of psilocybin-induced subjective experiences in humans. Hirschfeld, T., Schmidt, TT.[2022]

In a study involving 12 healthy adults, escalating doses of psilocybin (0.3, 0.45, and 0.6 mg/kg) were administered safely, with no serious adverse events reported, indicating a favorable safety profile for this psychedelic compound.

The pharmacokinetics of psilocin, the active metabolite of psilocybin, were linear across the tested doses, with an elimination half-life of about 3 hours, suggesting that no dose adjustments are necessary for individuals with mild to moderate renal impairment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of Escalating Doses of Oral Psilocybin in Healthy Adults. Brown, RT., Nicholas, CR., Cozzi, NV., et al.[2022]

Psilocybin, a hallucinogenic compound found in certain mushrooms, has been associated with increasing rates of drug abuse, highlighting the need for comprehensive pharmacological understanding.

Despite its historical use in the 1960s for experimental medical purposes, recent research has only begun to uncover the pharmacological properties of psilocybin, indicating a gap in knowledge that needs to be addressed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The pharmacology of psilocybin. Passie, T., Seifert, J., Schneider, U., et al.[2016]

Psilocybin has shown significant therapeutic effects in reducing symptoms of depression and anxiety in patients with life-threatening diseases, based on a systematic review and meta-analysis of clinical trials involving 92 patients.

The results indicate that psilocybin may be a safe and effective treatment option, particularly for cases resistant to conventional therapies, with significant improvements measured by the Beck Depression Inventory and State-Trait Anxiety Inventory.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Psilocybin as a New Approach to Treat Depression and Anxiety in the Context of Life-Threatening Diseases-A Systematic Review and Meta-Analysis of Clinical Trials. Vargas, AS., Luís, Â., Barroso, M., et al.[2020]

A 30-year-old man experienced severe symptoms, including vomiting and muscle pain, after receiving an intravenous injection of Psilocybe mushroom extract, highlighting the potential dangers of using hallucinogenic substances in non-traditional ways.

The patient showed rapid improvement with supportive care, suggesting that while the effects of Psilocybe mushrooms can be serious, timely medical intervention can effectively manage the symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravenous mushroom poisoning. Curry, SC., Rose, MC.[2019]

A single, moderate dose of psilocybin significantly reduced depressive symptoms in 52 participants with major depressive disorder, showing a decrease of 13.0 points on the MADRS scale compared to baseline, which was significantly greater than the placebo group.

54% of participants in the psilocybin group met the criteria for remission of depression 14 days after treatment, and no serious adverse events were reported, indicating a favorable safety profile for this novel treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-dose psilocybin-assisted therapy in major depressive disorder: A placebo-controlled, double-blind, randomised clinical trial. von Rotz, R., Schindowski, EM., Jungwirth, J., et al.[2023]

Psilocybin, derived from Psilocybe cubensis mushrooms, is being investigated as a novel treatment for major depression, with a focus on its safety and efficacy compared to traditional antidepressants.

The proposed study will include both preclinical toxicity evaluations in mice and a clinical trial assessing the safety and pharmacokinetics of psilocybin in healthy adults, followed by an open trial in patients with major depressive disorder, aiming to provide comprehensive data on its therapeutic potential.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Proposal to Study the Safety and Efficacy of Psilocybe cubensis in Preclinical and Clinical Studies as a Therapeutic Alternative for Major Depressive Disorder. Escamilla, R., González-Trujano, ME., González Mariscal, JM., et al.[2023]

Psilocybin-containing mushrooms, commonly known as hallucinogenic or 'magic' mushrooms, rapidly affect the central nervous system within 0.5-1 hour of ingestion, leading to effects such as ataxia, hyperkinesis, and hallucinations.

The review discusses the significant toxicity associated with these mushrooms, highlighting the need for awareness and understanding of their pharmacology, clinical effects, and potential treatment for adverse reactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Hallucinogenic mushrooms]. Reingardiene, D., Vilcinskaite, J., Lazauskas, R.[2018]

Psilocybin has shown promise in clinical trials for reducing symptoms of depression, indicating its potential as a novel treatment option.

Patients with treatment-resistant depression (TRD) may benefit the most from psilocybin therapy, although the risks associated with its use are still not fully understood.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessing potential of psilocybin for depressive disorders. Kozak, Z., Johnson, MW., Aaronson, ST.[2023]

Citations

1. en.wikipedia.org en.wikipedia.org/wiki/Psilocybin

Psilocybin Psilocybin, also known as 4-phosphoryloxy-N,N-dimethyltryptamine (4-PO-DMT), is a naturally occurring tryptamine alkaloid and investigational drug found in ...

2. pubchem.ncbi.nlm.nih.gov pubchem.ncbi.nlm.nih.gov/compound/Psilocybin

Psilocybin | C12H17N2O4P | CID 10624 - PubChem - NIH Psilocybin is a tryptamine alkaloid that is N,N-dimethyltryptamine carrying an additional phosphoryloxy substituent at position 4. The major hallucinogenic ...

3. webbook.nist.gov webbook.nist.gov/cgi/cbook.cgi?ID=520-52-5

Psilocybine - the NIST WebBook Psilocybine's formula is C12H17N2O4P, molecular weight is 284.2481, CAS number is 520-52-5, and also known as Psilocybin.

4. zfin.org zfin.org/CHEBI:8614

ZFIN ChEBI: psilocybin A tryptamine alkaloid that is N,N-dimethyltryptamine carrying an additional phosphoryloxy substituent at position 4. The major hallucinogenic alkaloid isolated ...

5. cancer.gov cancer.gov/publications/dictionaries/cancer-drug/def/psilocybine

Definition of psilocybine - NCI Drug Dictionary A tryptamine alkaloid, isolated from various genera of fungi including the genus Psilocybe, with hallucinogenic, anxiolytic, and psychoactive activities.

6. en.wikipedia.org en.wikipedia.org/wiki/Psilocin

Psilocin Psilocin, also known as 4-hydroxy-N,N-dimethyltryptamine (4-HO-DMT), is a substituted tryptamine alkaloid and a serotonergic psychedelic.

7. consensus.app consensus.app/home/blog/what-is-psilocybin-other-names-psilocibin-psilocybine-psilocin-phosphate-ester/

Psilocibin, Psilocybine, Psilocin Phosphate Ester Psilocybin is a naturally occurring psychedelic compound found in certain species of mushrooms, commonly referred to as “magic mushrooms.”