Psilocybin for Depression

Overseen By Geena Fram

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Yale University

Must not be taking: MAOIs, Lithium, Methadone, others

Disqualifiers: Psychotic disorders, Hypertension, Cardiovascular disease, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 8

Duration: 1 day

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and effects of psilocybin, a compound found in magic mushrooms, to help individuals with psychiatric symptoms such as anxiety, mood problems, or addiction. The aim is to determine if psilocybin can reduce symptoms and improve daily functioning. Participants will take one dose and attend several follow-up visits to monitor changes. Individuals who have struggled with daily functioning due to these symptoms might be suitable for this study. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative treatment.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but it does mention that changes to psychotropic medication and/or dosages within the past 3 months are not allowed. Additionally, certain medications like MAOIs, Lithium, and methadone should not be used recently before enrollment. It's best to discuss your specific medications with the trial team.

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

Research has shown that a single 25 mg dose of psilocybin is well-tolerated. For example, one study with individuals who have treatment-resistant depression found that this dose eased symptoms without causing serious side effects. Another study also demonstrated that 25 mg of psilocybin significantly improved depression symptoms, with participants generally tolerating it well.

While psilocybin treatment can cause mild side effects, such as headaches or nausea, serious side effects were rare. This suggests that psilocybin at this dose is generally safe for most people. However, considering personal health and consulting healthcare professionals before joining a trial is always important. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike traditional antidepressants, which often target neurotransmitters like serotonin or norepinephrine, psilocybin is unique because it acts on serotonin receptors in a different way, potentially leading to profound changes in perception and mood. This psychedelic compound can promote rapid and long-lasting improvements in depression symptoms, sometimes after just a single dose, compared to the weeks or months it can take for conventional medications to become effective. Researchers are excited about psilocybin because it offers a new avenue for treatment with a distinct mechanism and the possibility of fewer side effects and quicker relief for patients suffering from depression.

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

Research has shown that psilocybin can greatly reduce depression symptoms. In one study, a single 25 mg dose lowered depression scores more effectively than smaller doses taken over three weeks. Another study found that this benefit could last up to a year. Other trials have also demonstrated that psilocybin significantly reduces symptom severity. Overall, these findings suggest that psilocybin might effectively treat depression. Participants in this trial will receive a 25 mg dose of psilocybin administered in an open-label format. ^{1 2 6 7 8}

Who Is on the Research Team?

Benjamin Kelmendi, MD

Principal Investigator

Yale University

Gabrielle Agin-Liebes, PhD

Principal Investigator

Yale University

Are You a Good Fit for This Trial?

This trial is for individuals with psychiatric symptoms causing functional impairment, such as mood, anxiety, trauma-related or addictive behaviors. Participants must be able to take oral pills, refrain from certain medications on dosing day, and have reliable transportation post-dosing. They should not be starting new psychiatric meds within 4 weeks after dosing.

Inclusion Criteria

I can swallow pills by mouth.

I have been diagnosed with a psychiatric condition that affects my daily life.

I can speak and understand English well enough to make informed decisions about my care.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive one dose of oral psilocybin (25 mg) with non-directive support before, during, and after treatment sessions

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment with follow-up visits at 1, 4, and 6 weeks post dosing

6 weeks

3 visits (in-person)

Long-term Follow-up (optional)

Participants may opt into long-term follow-up with reassessments at 3, 6, and 12 months post dosing

12 months

3 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Psilocybin

Trial Overview The study tests the safety and impact of a single dose of psilocybin (25mg) on various psychiatric symptoms and functional impairments. It's an open-label trial where participants know they're receiving psilocybin, followed by assessments at 1 week, 4 weeks, and 6 weeks post-dose.

How Is the Trial Designed?

Group I: Open-label Experimental Treatment 1 Intervention

Psilocybin will be administered in an opaque, size 2 gelatin capsule with approximately 180 ml of water to be orally ingested at Visit 5. The dose of psilocybin will be 25 mg.

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?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

Usona Institute

Collaborator

Trials

18

Recruited

1,100+

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]

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]

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]

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 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, 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 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]

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 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. 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 ... This is a phase III, international, multi-centre, randomised, parallel group, fixed single-dose, double-blind, placebo-controlled study.

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 ...