Psilocybin for Depression

(EMBRACE Trial)

Overseen By EMBRACE Team

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how psilocybin, a compound found in certain mushrooms, affects brain activity related to mood and depression. Researchers aim to determine if psilocybin alters brain networks and blood flow in ways that could improve depression symptoms compared to a placebo. Participants will take oral doses of either a placebo or psilocybin during two sessions, each followed by an MRI scan to observe brain changes. Suitable candidates for this trial are adults who have experienced moderate to severe depression for at least three months without any psychotic symptoms. As a Phase 2 trial, this research measures how well psilocybin works in an initial, smaller group of people, offering participants a chance to contribute to important findings in depression treatment.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that psilocybin, the treatment under study, is generally safe for humans. In earlier studies, a single 25 mg dose of psilocybin significantly reduced depression symptoms but also caused mild to moderate side effects, such as headaches, nausea, and anxiety. These side effects were usually short-lasting.

Another study found that psilocybin greatly lowered depression scores compared to a low dose, with no serious health problems reported. This indicates no major negative health effects were observed.

Overall, these findings suggest that psilocybin is reasonably safe in clinical settings, especially in controlled doses. However, as with any treatment, individual experiences may vary, so discussing any concerns with the trial staff is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatment for depression?

Researchers are excited about psilocybin for depression because it offers a novel approach compared to standard treatments like selective serotonin reuptake inhibitors (SSRIs) and cognitive-behavioral therapy (CBT). Unlike traditional antidepressants that often take weeks to work, psilocybin has the potential to produce rapid effects, sometimes within hours or days. Additionally, psilocybin works by altering serotonin receptors in unique ways, potentially leading to profound shifts in mood and perception, which might offer relief for those who haven't responded to other treatments. This psychedelic compound, combined with supportive psychotherapy, could transform how we approach depression therapy by providing a faster, more profound impact.

What evidence suggests that psilocybin might be an effective treatment for depression?

Research has shown that psilocybin can help reduce symptoms of depression. One study found that a single 25 mg dose of psilocybin significantly lowered depression scores over three weeks compared to a very low dose. Another study discovered that the positive effects of a 25 mg dose lasted longer than lower doses over a year. Participants in these studies reported improvements in their mood. This trial will include a Staged Active Treatment Arm, where participants receive psilocybin (25 mg) at both treatment visits, and a Placebo to Active Delayed-Start Treatment Arm, where participants initially receive a placebo followed by psilocybin (25 mg). These findings suggest that psilocybin could be a promising treatment for depression. ^{2 3 4 5 6}

Who Is on the Research Team?

Sean M Nestor, PhD MD FRCPC

Principal Investigator

Sunnybrook Health Sciences Centre

Bradley J MacIntosh, PhD

Principal Investigator

Sunnybrook Research Institute

Are You a Good Fit for This Trial?

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 for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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, 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]

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]

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]

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]

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]

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 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 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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40047545/

Results From a Long-Term Observational Follow-Up Study ... Over 52 weeks, a single administration of 25 mg psilocybin suggested longer maintenance of antidepressant effect than both 1 mg and 10 mg.

2. compasspathways.com compasspathways.com/our-work/comp360-psilocybin-treatment-in-trd/

COMP360 psilocybin treatment in TRD The New England Journal of Medicine publishes results from phase 2b trial of investigational COMP360 psilocybin treatment for treatment-resistant depression.

3. nejm.org nejm.org/doi/full/10.1056/NEJMoa2206443

Single-Dose Psilocybin for a Treatment-Resistant Episode ... Psilocybin at a single dose of 25 mg, but not 10 mg, reduced depression scores significantly more than a 1-mg dose over a period of 3 weeks but was associated ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12226623/

Psilocybin therapy for treatment resistant depression MADRS score change at week 3 was the primary outcome of the study though a large reduction in depressive symptoms was evident on the day following psilocybin ...

5. psychiatrictimes.com psychiatrictimes.com/view/comp360-psilocybin-for-treatment-resistant-depression-positive-phase-3-efficacy-data

COMP360 Psilocybin for Treatment-Resistant Depression COMP360 showed a statistically significant reduction in TRD symptom severity compared to placebo, with a clinically meaningful MADRS score ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05624268

Efficacy, Safety, and Tolerability of COMP360 in ... Study Overview. Brief Summary. Efficacy, Safety, and Tolerability of a single administration of COMP360 in participants with treatment-resistant depression ( ...