Psilocybin for PTSD

(PSI-3PO Trial)

Overseen By Anna G Przybelski

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Johns Hopkins University

Must be taking: Serotonin reuptake inhibitors

Must not be taking: Monoamine oxidase inhibitors

Disqualifiers: Pregnancy, Cardiovascular conditions, Epilepsy, 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: 2

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if psilocybin, a compound found in some mushrooms, can ease PTSD symptoms in individuals who have had the condition for at least six months and are currently taking certain antidepressants. Researchers seek to assess psilocybin's safety, its impact on well-being, and whether combining it with trauma-focused therapy enhances its effects. Individuals who have maintained a stable dose of serotonin reuptake inhibitors for at least three months and have not used classic psychedelics in the last five years may be suitable candidates. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this innovative treatment.

Will I have to stop taking my current medications?

Participants must be on a stable dose of a serotonin reuptake inhibitor (like an SSRI or SNRI) for at least two weeks before the study. They must also refrain from using any nonprescription medications, nutritional supplements, or herbal supplements for one week before each drug session, unless approved by the study investigators.

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

Research has shown that psilocybin, when used in therapy, is generally safe. In earlier studies, a single 25 mg dose of COMP360 psilocybin, a lab-made version of the substance, did not cause any serious negative effects, meaning no major side effects required medical attention.

Participants in these studies reported that the treatment was manageable, especially with therapists providing support during sessions. Some common side effects, such as mild headaches or temporary feelings of anxiety, were noted, but these were neither severe nor long-lasting. These findings suggest that psilocybin can be safe when used in a controlled setting, such as a clinical trial. ^{1 2 3 4 5}

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

Researchers are excited about psilocybin for PTSD because it represents a novel approach to treatment. Unlike standard therapies like SSRIs or cognitive behavioral therapy, psilocybin is a psychedelic compound that may facilitate profound psychological insights and emotional breakthroughs. It works by targeting serotonin receptors in the brain, potentially leading to increased neuroplasticity and emotional processing. This unique mechanism might offer rapid relief from PTSD symptoms, which is particularly appealing compared to conventional treatments that can take weeks or months to show significant effects. Additionally, when combined with trauma-focused psychotherapy, psilocybin may enhance the therapeutic process, offering a potentially transformative experience for individuals with PTSD.

What evidence suggests that this trial's treatments could be effective for PTSD?

Research has shown that psilocybin can help reduce PTSD symptoms. In studies, participants who took just one dose of psilocybin reported fewer PTSD symptoms and an improved quality of life afterward. These positive effects were consistent and long-lasting. In this trial, participants will receive psilocybin followed by either standard psychological support or trauma-focused psychotherapy. Psilocybin is known to create deep emotional experiences, potentially aiding in more effective trauma processing. Overall, psilocybin has been well tolerated, with no serious side effects reported in these studies. ^{1 2 3 6 7}

Who Is on the Research Team?

Sandeep Nayak, MD

Principal Investigator

Johns Hopkins University

Are You a Good Fit for This Trial?

Adults aged 21-75 with chronic PTSD, diagnosed per DSM-5, and on a stable dose of serotonin reuptake inhibitors for at least two weeks. Participants must have a CAPS-5 score of >=35, be low risk for suicide, agree to consistent caffeine intake on session days, avoid psychoactive substances before sessions, and pass medical screenings.

Inclusion Criteria

I have signed a consent form for the trial.

I am between 21 and 75 years old.

I have been on a stable dose of antidepressants for at least two weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Preparatory Meetings

Participants undergo about 8 hours of preparatory meetings over approximately 2 weeks

2 weeks

Multiple visits (in-person)

Psilocybin Treatment

Participants receive 2 psilocybin sessions separated by approximately 2 weeks, with dose adjustments based on subjective effects

4 weeks

2 visits (in-person)

Therapeutic Integration

Participants meet with session facilitators at multiple scheduled time points for therapeutic integration of psilocybin experiences

4 weeks

Multiple visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

8 months

What Are the Treatments Tested in This Trial?

Interventions

• Psilocybin

Trial Overview The study is testing if psilocybin therapy can safely reduce PTSD symptoms and improve wellbeing when combined with trauma-focused psychotherapy. It's an open-label trial where all participants know they're receiving the treatment being studied.

How Is the Trial Designed?

Group I: Trauma-focused psychotherapy treatment condition Experimental Treatment 3 Interventions

Individuals in this arm will undergo procedures related to trauma-focused psychotherapy (combined with standard psychological support) beginning after receipt of psilocybin.

Group II: Standard psychological support treatment condition Active Control 2 Interventions

This condition represents typical support following the experimental administration of psilocybin therapy.

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?

Johns Hopkins University

Lead Sponsor

Trials

2,366

Recruited

15,160,000+

Steven & Alexandra Cohen Foundation

Collaborator

Trials

10

Recruited

320+

Usona Institute

Collaborator

Trials

18

Recruited

1,100+

Published Research Related to This Trial

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]

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 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]

A single dose of psilocybin significantly reduced fear responses in mice, indicating its potential to facilitate fear extinction, which is crucial for treating PTSD.

Psilocybin promoted hippocampal neuroplasticity by improving dendritic complexity, spine density, and levels of neuroplasticity-related proteins, suggesting it could enhance the effectiveness of exposure-based therapies for PTSD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Psilocybin facilitates fear extinction in mice by promoting hippocampal neuroplasticity. Du, Y., Li, Y., Zhao, X., et al.[2023]

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]

A meta-analysis of psilocybin studies found that higher doses of psilocybin are associated with stronger subjective experiences, particularly in areas like perceptual alterations and ego dissolution, based on data from standardized questionnaires.

Challenging experiences were less affected by dose, suggesting that individual and environmental factors also play a significant role in the psilocybin experience, indicating that these findings are most relevant in controlled settings rather than recreational use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose-response relationships of psilocybin-induced subjective experiences in humans. Hirschfeld, T., Schmidt, TT.[2022]

A single dose of 5-MeO-DMT, derived from the bufotoxin of the Sonoran Desert Toad, resulted in significant and sustained improvements in PTSD symptoms for a 23-year-old female patient, with effects lasting up to 12 months.

The treatment was generally safe, with no serious adverse events reported, although the patient did experience some side effects like nausea and night terrors, highlighting the need for further research to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

5-MeO-DMT for post-traumatic stress disorder: a real-world longitudinal case study. Ragnhildstveit, A., Khan, R., Seli, P., et al.[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]

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 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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12146596/

Clinical conceptualisation of PTSD in psilocybin treatment Studies have shown that psilocybin can facilitate profound psychological experiences characterised by heightened emotional processing and ...

2. ir.compasspathways.com ir.compasspathways.com/News--Events-/news/news-details/2025/Compass-Pathways-Announces-Publication-of-Results-from-Phase-2-Study-of-COMP360-Psilocybin-for-Post-Traumatic-Stress-Disorder/default.aspx

News Details Open-label Phase 2 study shows a single 25 mg COMP360 psilocybin dose was well tolerated, with no serious adverse events observed, ...

3. journals.sagepub.com journals.sagepub.com/doi/10.1177/02698811251362390

Investigating the safety and tolerability of single-dose ... Secondary outcomes (PTSD symptom severity, functional impairment and quality of life) revealed consistent and durable pre-post treatment ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT05312151

NCT05312151 | The Safety and Tolerability of COMP360 in ... Results Posted Record History. Study Overview. Brief Summary. The Safety and Tolerability of COMP360 in Participants with Post-traumatic Stress Disorder.

5. finance.yahoo.com finance.yahoo.com/news/compass-pathways-announces-publication-results-103000296.html

Compass Pathways Announces Publication of Results from ... Open-label Phase 2 study shows a single 25 mg COMP360 psilocybin dose was well tolerated, with no serious adverse events observed, ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40883964/

A nonrandomized open-label clinical trial Aims: The trial's primary outcome was to investigate the safety and tolerability of single-dose psilocybin in participants with PTSD. Methods: ...

7. hra.nhs.uk hra.nhs.uk/planning-and-improving-research/application-summaries/research-summaries/safety-and-tolerability-of-comp360-in-post-traumatic-stress-disorder/

Safety and Tolerability of COMP360 in Post-traumatic ... Research suggests that psilocybin may help in treating PTSD. COMP360 is a synthetic form of psilocybin, a chemical compound found in some species of mushrooms.