Psilocybin for Depression

Not currently recruiting at 2 trial locations

Overseen By Audrey Shoultz

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Sheppard Pratt Health System

Disqualifiers: Veterans only, 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: 1

Duration: 1 day

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests psilocybin, a compound found in some mushrooms, to determine if it can improve symptoms in people with severe treatment-resistant depression (TRD). The researchers aim to discover if a 25 mg dose of psilocybin can benefit those who haven't succeeded with other depression treatments. Participants should have at least moderate major depressive disorder (MDD) that significantly affects their daily life. Those who have tried multiple depression treatments without relief might be a good fit for this study. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering hope for those seeking new solutions.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

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

Research has shown that psilocybin, the main ingredient in magic mushrooms, may help treat depression that doesn't respond to other treatments. One study found that a 25 mg dose of psilocybin significantly lowered depression scores compared to a smaller dose, though some people experienced side effects like headaches and nausea.

Another study tested doses of 1 mg, 10 mg, and 25 mg. The 25 mg dose reduced depression symptoms, but some participants experienced mild to moderate side effects, such as anxiety and temporary increases in blood pressure.

Overall, psilocybin appears generally safe when used in a controlled environment, though some people might still experience side effects. As research continues, scientists aim to better understand its safety. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about psilocybin for depression because it offers a novel approach compared to traditional treatments like SSRIs and SNRIs, which primarily target serotonin reuptake. Psilocybin, the active ingredient in certain types of mushrooms, acts on the brain's serotonin receptors in a different way, potentially leading to rapid and profound changes in mood and perception. Unlike traditional antidepressants, which can take weeks to show effects, psilocybin has the potential to deliver noticeable improvements after just one or two doses. This could make it a game-changer for individuals who have not responded well to conventional therapies.

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

Research has shown that psilocybin can effectively reduce symptoms of depression. In this trial, participants will receive a single 25 mg dose of psilocybin. One study found that this dose significantly lowered depression scores over three weeks compared to a smaller dose. Another study demonstrated that this single dose maintained its antidepressant effects for up to 52 weeks, longer than the effects of smaller doses. Additionally, psilocybin has significantly reduced the severity of symptoms in people with treatment-resistant depression (TRD). These findings suggest that psilocybin could be a promising treatment for those with severe depression that hasn't improved with other treatments. ^{3 4 6 7 8}

Who Is on the Research Team?

Scott Aaronson, MD

Principal Investigator

Sheppard Pratt Health System

Are You a Good Fit for This Trial?

This trial is specifically for veterans who have been diagnosed with moderate to severe Major Depressive Disorder (MDD) and haven't found relief from standard treatments. It's not suitable for individuals with other significant health conditions.

Inclusion Criteria

Only Veterans are Eligible

You have been diagnosed with moderate or severe Major Depressive Disorder (MDD).

Exclusion Criteria

You have other health conditions in addition to the one being studied.

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 25 mg psilocybin under supportive conditions

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 weeks

Multiple visits (in-person)

Re-dosing (optional)

Participants at the CA site may receive a re-dose if depressive symptoms exacerbate, at least 12 months post-initial dosing

Long-term

What Are the Treatments Tested in This Trial?

Interventions

• Psilocybin

Trial Overview The study is testing the effects of a single dose of psilocybin (25 mg), given in a supportive setting, on improving symptoms in participants with treatment-resistant depression.

How Is the Trial Designed?

Group I: Psilocybin Experimental Treatment 1 Intervention

25mg of Psilocybin Note: CA site only is re-dosing participants with an exacerbation in depressive symptoms at a minimum of 12 months post-initial dosing.

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?

Sheppard Pratt Health System

Lead Sponsor

Trials

23

Recruited

7,800+

COMPASS Pathways

Industry Sponsor

Trials

15

Recruited

1,400+

Published Research Related to This Trial

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]

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 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]

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 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, 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 ... 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 ...