Psilocybin for Depression

Overseen By Sarah G Richter, M.A.

Age: 18 - 65

Sex: Any

Trial Phase: Phase 3

Sponsor: Sharmin Ghaznavi

Must not be taking: Benzodiazepines, Anticoagulants, others

Disqualifiers: Schizophrenia, Bipolar, Substance abuse, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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: 2

Duration: 1 day

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how a single dose of psilocybin, a compound found in certain mushrooms, affects individuals with major depressive disorder, focusing on repetitive negative thinking (rumination) and brain activity. The study uses fMRI brain scans to observe brain activity before and after treatment. Suitable participants are those with moderate major depressive disorder for at least three months who have not found relief from one to four different antidepressant medications during their current depressive episode. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to a potentially groundbreaking treatment for depression.

Will I have to stop taking my current medications?

Yes, participants will need to stop taking all psychotropic medications (medications that affect mood, perception, or behavior) under the supervision of a study psychiatrist, and this must be completed at least 2 weeks before the baseline scan.

Is there any evidence suggesting that psilocybin is likely to be safe for humans?

Research has shown that psilocybin can be safe for treating depression. One study found that people with depression unresponsive to other treatments experienced a noticeable drop in symptoms after taking a single 25 mg dose of psilocybin. However, some participants experienced side effects like headaches and nausea, which were common and usually mild.

Other research suggests that psilocybin is generally well-tolerated. While side effects can occur, serious problems are rare. The advanced stage of this study indicates that earlier research found psilocybin to be fairly safe. Prospective participants should consult a healthcare provider to understand the risks and benefits before joining a trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for depression?

Most treatments for depression, such as SSRIs and SNRIs, work by altering the levels of neurotransmitters like serotonin in the brain, and they often take weeks to show results. Psilocybin is unique because it is a psychedelic compound that acts on serotonin receptors in a novel way, potentially offering rapid improvement in depressive symptoms. Researchers are excited about psilocybin because it may provide relief within hours or days, offering a fast-acting alternative to traditional antidepressants. Additionally, psilocybin is being studied for its potential to create lasting changes in mood and cognition after just one or a few doses, unlike the daily regimen required by standard antidepressants.

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

Research has shown that a single 25 mg dose of psilocybin, which participants in this trial will receive, can greatly reduce depression symptoms. One study found that people who took this dose felt better over three weeks compared to those who took a smaller dose. Long-term results suggest that this positive effect can last up to a year. Psilocybin has significantly lessened the severity of depression symptoms. Several studies support its potential to help with major depressive disorder, making it a promising treatment option. ^{3 4 6 7 8}

Who Is on the Research Team?

Sharmin Ghaznavi, M.D., Ph.D.

Principal Investigator

Massachusetts General Hospital

Are You a Good Fit for This Trial?

This trial is for adults aged 18-55 with major depressive disorder who haven't improved after trying 1-4 different depression treatments. They must score high on specific depression scales, not have borderline personality disorder, and be able to stop taking current psychotropic meds two weeks before the study starts. Participants need to read well in English, follow the study plan without help, and be right-handed.

Inclusion Criteria

My reading and comprehension score is above 40.

I can complete all study tasks and attend all visits on my own.

My MSI-BPD score is below 7.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single dose of 25mg psilocybin and undergo fMRI scans to assess effects on rumination and neural correlates

1 day

1 visit (in-person)

Follow-up

Participants are monitored for changes in rumination, depression, and neural activity through various assessments and questionnaires

12 weeks

Multiple visits (in-person and virtual) at 1 day, 1 week, 2 weeks, 3 weeks, 6 weeks, 9 weeks, and 12 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Psilocybin

Trial Overview The trial tests how a single dose of psilocybin affects self-focused thinking (rumination) in people with depression. It involves brain scans using fMRI technology before and after treatment to see what changes occur in brain activity related to these thought patterns.

How Is the Trial Designed?

Group I: Psilocybin Experimental Treatment 1 Intervention

25mg Psilocybin

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?

Sharmin Ghaznavi

Lead Sponsor

Trials

1

Recruited

20+

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

COMPASS Pathways

Industry Sponsor

Trials

15

Recruited

1,400+

Published Research Related to This Trial

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]

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]

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, 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 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]

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]

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]

Citations

1. 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 ...

2. 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.

3. ir.compasspathways.com ir.compasspathways.com/News--Events-/news/news-details/2025/Compass-Pathways-Successfully-Achieves-Primary-Endpoint-in-First-Phase-3-Trial-Evaluating-COMP360-Psilocybin-for-Treatment-Resistant-Depression/default.aspx

News Details A single administration of COMP360 demonstrated a highly statistically significant and clinically meaningful reduction in symptom severity ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0165032724020494

The role of the psychedelic experience in psilocybin ... Several exploratory trials have suggested that an exemplar, psilocybin, can reduce symptoms of major depressive disorder (MDD), including in ...

5. 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.

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 ( ...

7. 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 ...

8. 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 ...