Psilocybin for Depression

(EMBRACE Trial)

Overseen By Sean Nestor, Dr

Age: 18 - 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Sunnybrook Health Sciences Centre

Must not be taking: Illicit drugs

Disqualifiers: Diabetes, Hypertension, Psychosis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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: 4

Duration: 3 weeks

50 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial team or your doctor to get a clear answer.

What data supports the effectiveness of the drug psilocybin for depression?

Several clinical trials have shown that psilocybin can reduce symptoms of depression, and it has been well tolerated with limited side effects. Some patients with treatment-resistant depression have experienced significant, long-term improvements after just one or a few sessions. ^{1 2 3 4 5}

Is psilocybin safe for human use?

Psilocybin, found in magic mushrooms, has been studied for its safety in humans. Research suggests that it can be safe under controlled conditions, but caution is advised with higher doses. Some studies have shown that it does not worsen certain heart conditions and may even protect against cell injury. ^{2 5 6 7 8}

How is the drug psilocybin unique in treating depression?

Psilocybin is unique because it acts quickly and is used in a few doses, unlike traditional antidepressants that require long-term use. It works by affecting serotonin receptors in the brain, which can lead to rapid improvements in depression symptoms. ^{1 2 4 9 10}

What is the purpose of this trial?

The goal of this neuroimaging clinical trial is to test whether psilocybin produces significant immediate changes in functional brain activity in networks associated with mood regulation and depression compared to placebo in patients with depression. The trial aims to determine if psilocybin: 1. Changes connectivity within brain networks associated with mood and depression 2. Changes blood flow in brain regions associated with mood and depression Participants will be attend two treatment sessions where they receive an oral medication and supportive psychotherapy. At each session, participants will undergo an MRI scan after drug administration but prior to psychotherapy. Participants will be randomly to assigned to one of two groups that will receive, 1) microcrystalline cellulose (25mg) at the first visit and psilocybin (25mg) at the second visit, or 2) psilocybin (25mg) at both visits, respectively. Differences between groups will be compared to understand what effects on brain activity are specific to psilocybin.

Research Team

Sean Nestor, Dr

Principal Investigator

Sunnybrook Health Sciences Centre

Eligibility Criteria

Adults aged 18-65 with a confirmed diagnosis of depression, experiencing a depressive episode for at least 3 months, and scoring >17 on the HAMD-17 scale. Participants must be able to attend all visits, have someone to monitor them post-treatment, and continue psychiatric care. Exclusions include pregnancy, severe heart conditions, significant arrhythmias or ECG abnormalities, recent drug abuse, certain psychiatric disorders like bipolar or schizophrenia, and those with a history of substance-induced psychosis.

Inclusion Criteria

Able and voluntarily willing to provide written informed consent at the screening visit

I can attend all study visits and complete tasks without help.

Mini International Neuropsychiatric Interview (MINI)-confirmed diagnosis of depressive disorder, recurrent or single episode, without psychotic features where the duration of the current episode is at least 3 months

Exclusion Criteria

Lifetime history of substance-induced psychosis

I haven't used psychedelics like psilocybin or LSD in the last year or during my current depressive episode.

I have had seizures, but only from childhood fevers or electroconvulsive therapy.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive oral medication and supportive psychotherapy during two treatment sessions, with MRI scans conducted after drug administration but prior to psychotherapy.

3 weeks

2 visits (in-person)

Follow-up

Participants are monitored for changes in depression and cognitive function using various scales and assessments.

3 weeks

2 visits (in-person)

Treatment Details

Interventions

• Niacin
• Psilocybin

Trial Overview This trial is examining if psilocybin affects brain activity related to mood in depressed patients compared to niacin (placebo). Participants will receive either two doses of psilocybin or one dose of niacin followed by psilocybin across two sessions. Brain scans are performed after each treatment before psychotherapy to observe changes in brain connectivity and blood flow.

Participant Groups

Group I: Staged Active Treatment Arm (Psilocybin-Psilocybin) Experimental Treatment 2 Interventions

This group will receive psilocybin (25mg) at the first and second treatment visit, along with supportive psychotherapy.

Group II: Placebo to Active Delayed-Start Treatment Arm (MCC-Psilocybin) Experimental Treatment 3 Interventions

This group will receive microcrystalline cellulose (25mg) at the first treatment visit and psilocybin (25mg) at the second treatment visit, along with supportive 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?

Sunnybrook Health Sciences Centre

Lead Sponsor

Trials

693

Recruited

1,569,000+

Findings from Research

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]

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, a serotonergic psychedelic, has shown promise in treating various psychiatric disorders, including depression and substance use disorders, with 9 clinical trials conducted between 2000 and 2020.

The treatment is generally well tolerated with limited side effects, and some patients with treatment-resistant conditions have experienced significant long-term improvements after just a few sessions, indicating its potential efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Treatment with psilocybin: applications for patients with psychiatric disorders]. Breeksema, JJ., Koolen, MHB., Somers, M., et al.[2021]

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]

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-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]

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]

In a study examining the effects of Psilocybe cubensis and Panaeolus cyanescens mushrooms on heart cells, the extracts did not worsen hypertrophy caused by endothelin-1 and provided protection against TNF-α-induced cell injury.

The findings suggest that these mushroom extracts can be safely used in controlled conditions for potential therapeutic benefits in heart disease, although caution is advised with higher concentrations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects and safety of Psilocybe cubensis and Panaeolus cyanescens magic mushroom extracts on endothelin-1-induced hypertrophy and cell injury in cardiomyocytes. Nkadimeng, SM., Steinmann, CML., Eloff, JN.[2021]

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, a prodrug for psilocin, shows strong agonist activity at the serotonin 5-HT2A receptor, which is responsible for its psychedelic effects, and has been shown to have nanomolar affinity for various serotonin receptor subtypes in both in vitro and in vivo studies.

In mouse experiments, psilocybin and related compounds induced head twitch responses, a sign of psychedelic activity, which were blocked by a 5-HT2A antagonist, confirming the involvement of this receptor in their effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Structure-Activity Relationships for Psilocybin, Baeocystin, Aeruginascin, and Related Analogues to Produce Pharmacological Effects in Mice. Glatfelter, GC., Pottie, E., Partilla, JS., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Assessing potential of psilocybin for depressive disorders. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

The pharmacology of psilocybin. [2016]

3. Netherlands pubmed.ncbi.nlm.nih.gov

[Treatment with psilocybin: applications for patients with psychiatric disorders]. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Single-dose psilocybin-assisted therapy in major depressive disorder: A placebo-controlled, double-blind, randomised clinical trial. [2023]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of Escalating Doses of Oral Psilocybin in Healthy Adults. [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

[Hallucinogenic mushrooms]. [2018]

7. United States pubmed.ncbi.nlm.nih.gov

Intravenous mushroom poisoning. [2019]

8. England pubmed.ncbi.nlm.nih.gov

Effects and safety of Psilocybe cubensis and Panaeolus cyanescens magic mushroom extracts on endothelin-1-induced hypertrophy and cell injury in cardiomyocytes. [2021]

9. United States 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. [2023]

10. United States pubmed.ncbi.nlm.nih.gov

Structure-Activity Relationships for Psilocybin, Baeocystin, Aeruginascin, and Related Analogues to Produce Pharmacological Effects in Mice. [2023]