Psilocybin for Depression

(PSI-RIS Trial)

Overseen By Alexandria Coles, MSc

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Centre for Addiction and Mental Health

Must not be taking: Antidepressants, Antipsychotics, UGT inhibitors, others

Disqualifiers: Pregnancy, Substance use disorder, 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: 8

Duration: 1 day

60 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial uses a magic mushroom substance and therapy to treat people with depression that hasn't improved with other treatments. It aims to understand if the mind-altering effects are needed for its antidepressant benefits. Psilocybin, a compound derived from magic mushrooms, has shown potential in early trials for treating depression with relatively low side effects.

Will I have to stop taking my current medications?

Yes, you will need to stop taking your current antidepressant and antipsychotic medications, as well as certain enzyme inhibitors, for at least two weeks before starting the trial and throughout its duration, if your doctor confirms it's safe for you to do so.

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 generally safe for humans?

Psilocybin has been studied for its safety in humans, showing that it can be used safely under controlled conditions, although higher doses may pose risks. In healthy adults, escalating doses of psilocybin were generally well-tolerated, and extracts from magic mushrooms did not worsen certain heart conditions in lab studies. ^{2 3 6 7 8}

How is the drug psilocybin different from other treatments for depression?

Psilocybin is unique because it is a naturally occurring compound found in certain mushrooms and acts quickly to reduce depression symptoms, often with just one or two doses, unlike traditional antidepressants that require prolonged use. It works by affecting serotonin receptors in the brain, which can lead to psychedelic experiences that may help in therapeutic settings. ^{1 2 5 9 10}

Research Team

Ishrat Husain, MD

Principal Investigator

Centre for Addiction and Mental Health

Eligibility Criteria

Adults aged 18-65 with treatment-resistant depression, defined as not responding to two or more antidepressants, can join this trial. They must be able to consent and communicate in English, have normal bloodwork, use effective contraception if applicable, and safely stop current medications affecting the study.

Inclusion Criteria

I can safely stop my antidepressant and antipsychotic meds for the study.

I am between 18 and 65 years old.

Able to provide informed consent and read and communicate in English

Exclusion Criteria

I have a history of heart rhythm issues or risk factors for it.

I do not have a severe heart, kidney, liver condition, or an allergy to psilocybin.

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

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Washout

Participants undergo a washout period where they are tapered off concomitant medication over a period of 4 to 6 weeks.

4-6 weeks

Weekly visits (in-person)

Baseline

Participants complete clinical measures and undergo a preparatory session with study therapists.

Up to 7 days

1-2 visits (in-person)

Treatment

Participants receive psilocybin 25 mg plus risperidone 1 mg, or psilocybin 25 mg plus placebo, or placebo plus risperidone 1 mg during a 5-6 hour dosing session.

1 day

1 visit (in-person)

Integration

Participants attend two 1-hour integration sessions post-dosing.

1 week

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment.

4 weeks

3 visits (in-person)

Treatment Details

Interventions

• Psilocybin

Trial Overview The trial is testing whether psilocybin's effects on depression require its psychedelic aspect by comparing three groups: one taking psilocybin with risperidone (which may block psychedelic effects), another taking psilocybin with a placebo, and a third group receiving placebo plus risperidone.

Participant Groups

Group I: Risperidone 1 mg plus Psilocybin 25 mg Experimental Treatment 2 Interventions

Risperidone 1 mg plus Psilocybin 25 mg

Group II: Placebo plus Psilocybin 25 mg Experimental Treatment 2 Interventions

Placebo plus Psilocybin 25 mg

Group III: Risperidone 1 mg plus Placebo Active Control 2 Interventions

Risperidone 1 mg plus Placebo

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?

Centre for Addiction and Mental Health

Lead Sponsor

Trials

388

Recruited

84,200+

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]

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 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]

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. Switzerland pubmed.ncbi.nlm.nih.gov

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

4. Netherlands pubmed.ncbi.nlm.nih.gov

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

5. England pubmed.ncbi.nlm.nih.gov

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

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]