Psilocybin-Assisted Therapy for Depression

Overseen By Brittania Ricketts

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: University of North Carolina, Chapel Hill

Must not be taking: MAOIs, Antipsychotics, Tramadol, others

Disqualifiers: Bipolar, Schizophrenia, Substance use, 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: 3

Duration: 2 weeks

23 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether psilocybin-assisted therapy can alleviate depression. Participants will receive one or two doses of psilocybin, a psychedelic compound, and attend therapy sessions to monitor changes in their symptoms. Researchers aim to determine if one or two treatment sessions are more effective and how long the benefits persist. Individuals who have experienced depression for at least three months and have not found relief with at least two different depression medications may be suitable candidates. As a Phase 3 trial, this study represents the final step before FDA approval, providing participants an opportunity to contribute to a potentially groundbreaking treatment for depression.

Will I have to stop taking my current medications?

The trial requires stopping certain medications, like Monoamine oxidase inhibitors (MAOIs), antipsychotics, and tramadol, at least 4 weeks before psilocybin administration. Other medications may be allowed at the investigator's discretion.

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

Research shows that psilocybin is generally well-tolerated when used to treat depression. Studies have found that a 25 mg dose can help reduce symptoms in people with treatment-resistant depression. Most participants in these studies did not experience serious side effects. Some had mild to moderate reactions, such as headaches or nausea, which are common with many medications.

Earlier trials carefully studied the safety of psilocybin. Some participants reported temporary anxiety or confusion during treatment, but these effects were usually brief and managed with help from the therapy team. This suggests that psilocybin is relatively safe when administered in a controlled setting with professional supervision.

Overall, data from past studies suggest that psilocybin, especially at the doses being tested, is safe for most people. However, as with any treatment, discussing any concerns with the research team before joining the study is important. ^{1 2 3 4 5}

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

Psilocybin is unique because it offers a novel approach to treating depression by using a psychedelic compound found in certain mushrooms, rather than traditional antidepressants like SSRIs or SNRIs. Unlike most depression treatments that require regular dosing over weeks or months, psilocybin might show results after just one or two sessions, potentially providing faster relief. Researchers are excited about psilocybin-assisted therapy because it targets serotonin receptors in the brain differently, possibly leading to lasting improvements in mood and emotional processing with minimal doses.

What evidence suggests that psilocybin-assisted therapy could be an effective treatment for depression?

Research has shown that psilocybin can help reduce depression symptoms. One study found that a single 25 mg dose of psilocybin significantly eased symptoms in people whose depression didn't improve with other treatments. Another study discovered that this benefit lasted up to a year for some individuals. In this trial, participants will receive either a single psilocybin treatment or two psilocybin treatments. Several studies have consistently found that psilocybin reduces depression symptoms with few side effects. These findings suggest that therapy using psilocybin could be a promising way to treat depression. ^{1 6 7 8 9}

Who Is on the Research Team?

Robert K McClure, MD

Principal Investigator

Director of Interventional Psychiatry

Are You a Good Fit for This Trial?

This trial is for individuals with depression that hasn't improved with standard treatments. Participants will undergo screening visits, receive psilocybin in one or two sessions, and attend follow-ups over a year to monitor changes in their symptoms.

Inclusion Criteria

Provision of signed and dated informed consent form

Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-V) diagnosis of major depressive disorder

Use of effective contraception throughout the study by those with child-bearing potential

Exclusion Criteria

Borderline personality disorder, defined by DSM-V criteria, that in the judgement of the Investigator is likely to complicate the assessment of clinical response to study treatments or limits the patient's ability to comply with study procedures

I am currently taking tramadol.

I have not used esketamine, ketamine, psilocybin, or LSD in the last 6 months or more than 10 times ever.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

2 visits (in-person)

Treatment

Participants receive one or two doses of a 25mg capsule of psilocybin

2 weeks

1-2 visits (in-person)

Follow-up

Participants attend follow-up sessions and complete forms and surveys to assess changes in symptoms over the following year

12 months

Multiple visits (in-person and virtual)

What Are the Treatments Tested in This Trial?

Interventions

• Psilocybin

Trial Overview The study tests the effectiveness of psilocybin-assisted therapy on improving depressive symptoms and how long these benefits last. It compares the outcomes between receiving one versus two treatment sessions.

How Is the Trial Designed?

Group I: Single Psilocybin Treatment Experimental Treatment 1 Intervention

Participants will be administered one dose of a 25mg capsule of psilocybin. This will be administered one time.

Group II: Two Psilocybin Treatments Active Control 1 Intervention

Participants will be administered one dose of a 25mg capsule of psilocybin. Two weeks later, the participant will be administered one more dose of a 25mg capsule of 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?

University of North Carolina, Chapel Hill

Lead Sponsor

Trials

1,588

Recruited

4,364,000+

Foundation of Hope, North Carolina

Collaborator

Trials

18

Recruited

670+

Published Research Related to This Trial

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 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]

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]

Psilocybin shows promising effects in alleviating anxiety, depression, and emotional distress in palliative care patients, with a favorable safety profile, based on recent studies and reports.

Despite its potential benefits, psilocybin is not yet approved for therapeutic use in the U.S., and significant barriers exist for access, particularly for vulnerable populations like the elderly and those in palliative care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Psilocybin in Palliative Care: An Update. Whinkin, E., Opalka, M., Watters, C., 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]

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 psychedelic drug, shows promising safety and efficacy in treating major depression and treatment-resistant depression (TRD), with initial phase 2 trials indicating positive outcomes when combined with psychological support.

The first international randomized controlled trial in 2022 found that a 25 mg dose of psilocybin was effective compared to an active placebo, and phase 3 trials are set to begin in 2023, suggesting a growing interest in psilocybin as a viable treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The development of psilocybin therapy for treatment-resistant depression: an update. Borissova, A., Rucker, JJ.[2023]

In a survey of 1993 individuals who experienced challenging psilocybin trips, 39% rated their experience as one of the most difficult of their lives, with 11% reporting risks of physical harm, particularly influenced by dose and lack of support.

Despite the challenges, 84% of respondents felt they benefited from the experience, suggesting that while adverse effects can occur, the overall incidence of serious psychological distress is low, especially in controlled settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Survey study of challenging experiences after ingesting psilocybin mushrooms: Acute and enduring positive and negative consequences. Carbonaro, TM., Bradstreet, MP., Barrett, FS., et al.[2018]

Citations

1. nejm.org nejm.org/doi/full/10.1056/NEJMoa2206443

Single-Dose Psilocybin for a Treatment-Resistant Episode ... In this phase 2 trial involving participants with treatment-resistant depression, psilocybin at a single dose of 25 mg, but not 10 mg, reduced ...

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. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10811389/

Psilocybin, an Effective Treatment for Major Depressive ... It was found that every study significantly favoured the use of psilocybin in reducing depressive symptoms, with few side effects.

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. 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 ...

6. compasspathways.com compasspathways.com/our-work/comp360-psilocybin-treatment-in-trd/

COMP360 psilocybin treatment in TRD This trial assessed the safety and efficacy of COMP360 psilocybin treatment in three doses: 1mg, 10mg, 25mg. The results, published in the New England Journal ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT05624268

Efficacy, Safety, and Tolerability of COMP360 in ... This is a phase III, international, multi-centre, randomised, parallel group, fixed single-dose, double-blind, placebo-controlled study.

8. 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 ...

9. 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 ...