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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether the antidepressant effects of psilocybin, a compound in "magic mushrooms," depend on its psychedelic effects. Participants will be divided into three groups to receive different combinations of psilocybin, risperidone (a medication that can block psychedelic effects), and placebo. The study aims to determine if psilocybin can alleviate depression even when its mind-altering effects are blocked. Individuals diagnosed with depression that hasn't improved with at least two other treatments might be suitable for this trial. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

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

Research has shown that psilocybin, the active ingredient in "magic mushrooms," has been tested in several studies for its effects on depression. These studies found that psilocybin can significantly reduce depression symptoms for an extended period. In terms of safety, psilocybin is generally well-tolerated in clinical settings, with most side effects being mild and temporary, such as nausea or mood changes.

Additionally, some research has combined risperidone, a medication often used for certain mental health conditions, with psilocybin. This combination is being tested to determine if it can lessen the mind-altering effects of psilocybin without reducing its antidepressant benefits.

Overall, studies suggest that using psilocybin with risperidone is expected to be safe. However, anyone considering joining a trial should understand that all treatments can have side effects, and discussing any concerns with the study team is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for depression because they include psilocybin, a compound found in magic mushrooms, which offers a new approach compared to traditional antidepressants like SSRIs. Unlike standard treatments that primarily adjust serotonin levels over several weeks, psilocybin targets serotonin receptors in the brain directly, potentially providing rapid relief. The combination of psilocybin with either a placebo or risperidone (an antipsychotic) explores different pathways to enhance its effects or minimize side effects. This novel mechanism and the potential for quick symptom alleviation are why psilocybin is generating significant interest in the scientific community.

What evidence suggests that this trial's treatments could be effective for depression?

Research has shown that psilocybin, the active ingredient in "magic mushrooms," can have strong and lasting effects in treating depression. In several studies, people with depression who took psilocybin experienced significant improvements in their symptoms. These positive effects often lasted for weeks or even months after just a few doses. The treatment affects serotonin receptors in the brain, which help regulate mood. Some studies suggest that the psychedelic experience itself may enhance psilocybin's effectiveness for depression. However, more research is needed to understand exactly how these effects are connected. In this trial, participants will receive either Psilocybin 25 mg with a placebo, Psilocybin 25 mg with Risperidone 1 mg, or Risperidone 1 mg with a placebo to evaluate the effectiveness of these combinations. ^{1 2 3 4 5}

Who Is on the Research Team?

Ishrat Husain, MD

Principal Investigator

Centre for Addiction and Mental Health

Are You a Good Fit for This Trial?

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 can take pills by mouth.

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 for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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-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 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 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 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]

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]

Citations

1. 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.

2. 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 ...

3. 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 ...

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

Psilocybine - the NIST WebBook Formula · C12H17N2O4P ; Molecular weight · 284.2481 ; Permanent link for this species. Use this link for bookmarking this species for future reference.

5. 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 ...