Psilocybin for Treatment-Resistant Depression

Recruiting at 43 trial locations

Overseen By Ziad Nahas, MD

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: COMPASS Pathways

Disqualifiers: Bipolar disorder, Schizophrenia, Borderline personality, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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: Unknown

255 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing a new medication called COMP360 to help people with severe depression that hasn't improved with other treatments. The study involves adults aged 18 and older. Researchers want to see if a single dose of COMP360 can reduce depression symptoms when given with psychological support.

Do I need to stop my current medications for the trial?

Yes, you will need to stop taking all prohibited medications before participating in the trial.

What evidence supports the effectiveness of the drug psilocybin for treatment-resistant depression?

Research shows that psilocybin can lead to significant and lasting improvements in depression symptoms, even in patients who haven't responded to other treatments. It has been well tolerated with minimal side effects, and studies have demonstrated its rapid and enduring antidepressant effects after just one or two doses. ^{1 2 3 4 5}

Is psilocybin safe for human use?

Psilocybin has been studied for its safety in humans, showing that it does not worsen certain heart conditions and may protect against cell injury at controlled doses. However, its safety in people with cardiovascular diseases is not fully known, and caution is advised with higher doses. ^{1 6 7 8 9}

How is the drug psilocybin unique in treating treatment-resistant depression?

Psilocybin is unique because it acts quickly and is used in a single or few doses, unlike traditional antidepressants that require daily intake. It works by affecting serotonin receptors in the brain, and it has shown promise in reducing depression symptoms even in those who haven't responded to other treatments. ^{5 10 11 12 13}

Eligibility Criteria

Adults over 18 with treatment-resistant depression (TRD), who haven't responded to at least two different antidepressants, can join this trial. They must have moderate to severe depression without psychotic features and agree to stop taking any prohibited medications. The current depressive episode should be their first or ongoing for 3 months to 2 years.

Inclusion Criteria

My first major depression episode has lasted between 3 months and 2 years.

I have tried 2-4 different depression medications without success.

I am 18 years old or older.

Exclusion Criteria

I have not used ECT, DBS, or VNS for my current depression.

Current enrolment in a psychological therapy programme that will not remain stable for the duration of the study. Psychological therapies cannot have been initiated within 30 days prior to Screening

I have not had transcranial magnetic stimulation in the last 6 months.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

3-10 weeks

Treatment (Part A)

Participants receive a single administration of COMP360 or placebo with psychological support

6 weeks

Single visit for administration, followed by monitoring

Follow-up (Part A)

Participants are monitored for safety and effectiveness after initial treatment

6 weeks

Re-treatment (Part B)

Participants receive a single-dose re-treatment in a double-blind manner

20 weeks

Open-label treatment (Part C)

Participants receive open-label treatment to assess long-term safety and efficacy

26 weeks

Treatment Details

Interventions

• Psilocybin

Trial Overview The trial is testing the effectiveness, safety, and tolerability of a single dose of COMP360 psilocybin in individuals with TRD. It aims to see if this one-time treatment can help where standard antidepressants have failed.

Participant Groups

Group I: 25 mg COMP360 Psilocybin Experimental Treatment 1 Intervention

25 mg COMP360 Psilocybin

Group II: Placebo Placebo Group 1 Intervention

Matched 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?

COMPASS Pathways

Lead Sponsor

Trials

15

Recruited

1,400+

Findings from Research

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]

In a study of 27 patients with moderate to severe major depressive disorder, psilocybin-assisted treatment showed significant and lasting antidepressant effects, with 75% of participants experiencing a treatment response and 58% achieving remission after 12 months.

There were no serious adverse events related to psilocybin, indicating a favorable safety profile, and participants reported meaningful personal and spiritual experiences that correlated with increased well-being, although these did not directly predict improvements in depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of psilocybin-assisted treatment for major depressive disorder: Prospective 12-month follow-up. Gukasyan, N., Davis, AK., Barrett, FS., et al.[2022]

In a placebo-controlled study involving individuals with moderate to severe major depressive disorder, psilocybin (0.3 mg/kg) showed larger antidepressant effect sizes compared to placebo, with 66.7% of participants responding and 46.7% achieving remission after treatment.

The antidepressant effects of psilocybin persisted for an average of 2 months, indicating its potential as a long-lasting treatment option for depression, although the strength of the mystical experience during dosing did not correlate with these effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Psilocybin-assisted therapy for major depressive disorder: An exploratory placebo-controlled, fixed-order trial. Sloshower, J., Skosnik, PD., Safi-Aghdam, H., et al.[2023]

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-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]

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]

A single dose of psilocybin (0.5-20 mg/kg) significantly increases the expression of genes related to neuroplasticity in the prefrontal cortex and hippocampus, suggesting its potential therapeutic effects for mental health disorders.

The study highlights that psilocybin's effects on gene expression are dose-dependent and predominantly observed in the prefrontal cortex, emphasizing the need to assess both gene expression and protein translation to understand its rapid effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcriptional regulation in the rat prefrontal cortex and hippocampus after a single administration of psilocybin. Jefsen, OH., Elfving, B., Wegener, G., et al.[2022]

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 feasibility trial involving 12 patients with treatment-resistant depression, psilocybin was found to be well tolerated, with no serious adverse events reported, although some patients experienced transient anxiety and confusion.

Patients showed significant reductions in depressive symptoms one week and three months after receiving high doses of psilocybin, indicating its potential efficacy as a treatment for unipolar depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. Carhart-Harris, RL., Bolstridge, M., Rucker, J., et al.[2022]

Psilocybin has been rigorously tested in a randomized trial for its safety and efficacy in treating treatment-resistant depression, confirming its positive effects seen in previous studies.

The paper discusses psilocybin's mechanism of action and highlights its relative safety and lack of addiction potential, suggesting it could be a promising option for larger trials aimed at establishing its risk-benefit ratio in depression treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Return of the psychedelics: Psilocybin for treatment resistant depression. Patra, S.[2017]

In a phase II study involving 19 adults with treatment-resistant depression, a single 25 mg dose of synthetic psilocybin (COMP360) showed a significant reduction in depression scores, with a mean change of -14.9 on the MADRS scale after 3 weeks.

The treatment was generally safe, with 63.2% of participants experiencing mild treatment-emergent adverse events, but no serious adverse events or increased suicidal thoughts were reported, indicating a favorable safety profile for psilocybin in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Psilocybin for treatment resistant depression in patients taking a concomitant SSRI medication. Goodwin, GM., Croal, M., Feifel, D., 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]

References

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

The pharmacology of psilocybin. [2016]

2. Netherlands pubmed.ncbi.nlm.nih.gov

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

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

Efficacy and safety of psilocybin-assisted treatment for major depressive disorder: Prospective 12-month follow-up. [2022]

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

Psilocybin-assisted therapy for major depressive disorder: An exploratory placebo-controlled, fixed-order trial. [2023]

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

Assessing potential of psilocybin for depressive disorders. [2023]

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

[Hallucinogenic mushrooms]. [2018]

7. 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]

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

Transcriptional regulation in the rat prefrontal cortex and hippocampus after a single administration of psilocybin. [2022]

9. Switzerland pubmed.ncbi.nlm.nih.gov

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

10. England pubmed.ncbi.nlm.nih.gov

Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. [2022]

11. Netherlands pubmed.ncbi.nlm.nih.gov

Return of the psychedelics: Psilocybin for treatment resistant depression. [2017]

12. England pubmed.ncbi.nlm.nih.gov

Psilocybin for treatment resistant depression in patients taking a concomitant SSRI medication. [2023]

13. England pubmed.ncbi.nlm.nih.gov

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