Psilocybin for Depression

(SYNVEST 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

Disqualifiers: Pregnancy, Substance use disorder, Schizophrenia, 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: 5

Duration: 1 week

12 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how psilocybin, the active ingredient in "magic mushrooms," might help adults with treatment-resistant depression (TRD). Researchers aim to determine if psilocybin can alter brain activity related to depression using special imaging techniques. Participants will receive either psilocybin alone or a combination of psilocybin and the antipsychotic medication risperidone to assess effects on brain and mood changes. This trial is suitable for adults who have not found relief from depression despite trying at least two other antidepressant treatments. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to explore new treatment options.

Will I have to stop taking my current medications?

Yes, you will need to taper off your current antidepressant and antipsychotic medications for at least 2 weeks before starting the trial, as long as 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 clinical studies for its effects on depression. These studies found that psilocybin is generally safe, with most participants experiencing only mild side effects, such as temporary changes in mood and perception. Some may feel dizzy, nauseous, or have a headache, but these effects usually don't last long and are manageable.

In some studies, researchers use psilocybin with risperidone, a medication that reduces some of its psychedelic effects. This combination helps researchers understand how psilocybin works in the brain without causing strong hallucinations. Previous studies suggest that using risperidone in small doses with psilocybin is safe, though it might slightly increase the chance of feeling tired or mildly drowsy.

Overall, both psilocybin alone and with risperidone have been shown to be safe for many people in controlled settings. However, participants should discuss any concerns with the trial team to ensure it is a good fit for them. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for depression, which often include SSRIs, SNRIs, and other antidepressants that can take weeks to show effects, psilocybin offers a potentially faster and novel approach. Psilocybin, a compound found in certain mushrooms, acts on serotonin receptors in the brain, which might lead to transformative experiences and rapid improvement in mood. Researchers are particularly interested in psilocybin because it targets the brain in a fundamentally different way, possibly offering relief for those who haven't responded to traditional medications. In one treatment arm, psilocybin is combined with a low dose of risperidone, which could modulate its effects and offer a new dimension of treatment customization.

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

Studies have shown that psilocybin can significantly and lastingly reduce symptoms of depression. In several trials, patients with depression experienced noticeable improvements after taking psilocybin with therapy. This trial includes a treatment arm where participants receive psilocybin alone, suggesting that psilocybin might alter how the brain processes emotions and mood, offering new hope for those with treatment-resistant depression. Another arm in this trial administers risperidone before psilocybin. Previous studies found that this combination lessened the psychedelic effects, but the antidepressant benefits remain under investigation. Initial findings suggest psilocybin affects the brain's serotonin receptors, which play a key role in regulating mood. ^{1 2 3 4 5}

Who Is on the Research Team?

Muhammad Ishrat Husain, MBBS, MD

Principal Investigator

Centre for Addiction and Mental Health

Are You a Good Fit for This Trial?

This trial is for adults with treatment-resistant depression, meaning standard treatments haven't worked for them. Participants should be in good physical health and not currently using psychoactive or hormonal medications.

Inclusion Criteria

I can take pills by mouth.

Capable of becoming pregnant: must use highly effective contraception and agree to continue during study

My depression has not improved with treatment.

Exclusion Criteria

Pregnant, intending to become pregnant, or breastfeeding

I have a disability that stops me from completing study tasks.

I have a long QT interval or a history of Torsades de Pointes.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive psilocybin 25 mg with or without risperidone 1 mg, followed by PET imaging to assess synaptic density changes

1 week

3 visits (in-person)

Follow-up

Participants are monitored for changes in synaptic density and depression severity using MADRS and PET imaging

4 weeks

2 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Psilocybin
• Risperidone

Trial Overview The study tests if psilocybin (from 'magic mushrooms') affects synaptic density in the brain differently when taken alone versus with risperidone, a medication that blocks some of its effects. It involves PET imaging to track changes.

How Is the Trial Designed?

Group I: Risperidone (1 mg) + Psilocybin (25 mg) Experimental Treatment 2 Interventions

o One capsule of risperidone 1 mg will be taken first followed 60 minutes later by one capsule of psilocybin 25 mg. Both capsules will be taken orally with a glass of water.

Group II: Psilocybin (25 mg) Experimental Treatment 1 Intervention

One capsule of psilocybin 25 mg will be taken orally with a glass of water.

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 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 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 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]

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-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]

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, 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, 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 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]

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. 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.

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 ...