Psilocybin + Psychotherapy for Demoralization

(PATH Trial)

Overseen By Caitlin Brennan, PhD, GNP-BC

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Yvan Beaussant

Must not be taking: Antidepressants, Antipsychotics, Mood stabilizers, others

Disqualifiers: Chemotherapy, Schizophrenia, Bipolar, 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: 5

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests psilocybin, a psychedelic substance, to determine if it can reduce feelings of demoralization (a sense of hopelessness and helplessness) in patients receiving hospice care. Participants will receive one dose of psilocybin combined with supportive therapy sessions. This trial may suit those in home hospice care who feel significantly demoralized and have a caregiver present. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

You may need to stop taking certain medications, especially those that could interact with psilocybin, like antidepressants, antipsychotics, and mood stabilizers. If you are on these medications, they might be tapered off (gradually reduced) to avoid withdrawal effects before starting the trial.

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

Research has shown that psilocybin has been studied for its safety in humans. In past studies, participants generally tolerated psilocybin well, with most experiencing only mild to moderate side effects. Common side effects included temporary mood or perception changes, headaches, and nausea, which usually resolved on their own.

Psilocybin is also under investigation for treating other conditions, contributing to the understanding of its safety. Although research is still in the early stages for use with hospice patients, studies in other areas suggest it is relatively safe when administered in a controlled setting. ^{1 2 3 4 5}

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

Unlike the standard treatments for demoralization, which often include antidepressants and traditional talk therapy, psilocybin offers a novel approach. Psilocybin is derived from psychedelic mushrooms and works uniquely by potentially altering perception and mood through its action on serotonin receptors in the brain. This treatment is exciting because it involves just a single dose paired with targeted psychotherapy, which might lead to rapid and lasting improvements in symptoms. Researchers are particularly interested in its potential to quickly alleviate demoralization, a feature that sets it apart from conventional therapies that typically require longer periods to take effect.

What evidence suggests that psilocybin-assisted psychotherapy might be an effective treatment for demoralization?

Research has shown that psilocybin, when combined with therapy, may improve mood in people with severe depression. In this trial, participants will receive a single 25 mg dose of psilocybin along with supportive psychotherapy. Previous studies found that a single 25 mg dose of psilocybin significantly reduced symptoms of depression, with many participants experiencing improvement as soon as the day after administration. This treatment also appears to help individuals connect with their emotions and feel more empathy, without impairing their ability to think clearly. These findings suggest psilocybin could support individuals experiencing low mood during challenging times, such as in hospice care. ^{6 7 8 9 10}

Who Is on the Research Team?

Yvan Beaussant, MD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

This trial is for adults over 21 in hospice care with any terminal illness, experiencing moderate-to-severe demoralization. They must have a caregiver present after taking the study drug and not drive for 24 hours post-administration. Participants need to use contraception if of childbearing potential. Exclusions include those with certain psychiatric conditions or family history, significant suicide risk, allergies to similar drugs, or on medications that could interact poorly.

Inclusion Criteria

English proficiency

Moderate-to-severe demoralization as measured by Demoralization Scale-II ≥ 8

You have a very serious illness that cannot be cured.

Exclusion Criteria

You have a history of mental health conditions like schizophrenia, bipolar disorder, or personality disorders.

I have trouble eating or absorbing food.

My primary reason for hospice care is end-stage liver disease or cirrhosis.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Preparation

Participants undergo 2 preparation sessions as part of the supportive psychotherapy

2 weeks

2 visits (in-person)

Psilocybin Session

Participants receive a single administration of psilocybin 25 mg orally

1 day

1 visit (in-person)

Integration

Participants undergo 2 integration sessions as part of the supportive psychotherapy

2 weeks

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 weeks

Multiple visits (in-person and virtual)

What Are the Treatments Tested in This Trial?

Interventions

• Psilocybin
• Psychotherapy

Trial Overview The study tests psilocybin-assisted psychotherapy's effectiveness in reducing feelings of hopelessness among terminally ill patients receiving hospice care. Psilocybin is administered under controlled conditions alongside sessions of psychotherapy to evaluate its impact on demoralization.

How Is the Trial Designed?

Group I: PATH Experimental Treatment 2 Interventions

The research study procedures include screening for eligibility, and study intervention including preparation, evaluations, one psilocybin session and follow up visits. -The treatment regimen consists of a single administration of psilocybin 25 mg orally combined with a supportive psychotherapy including 2 preparation sessions and 2 integration sessions

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?

Yvan Beaussant

Lead Sponsor

Trials

1

Recruited

20+

Yvan Beaussant, MD, MSci

Lead Sponsor

Trials

2

Recruited

30+

Council on Spiritual Practices Fund at the San Francisco Foundation

Collaborator

Trials

1

Recruited

20+

Jack Smith

Collaborator

Trials

1

Recruited

20+

RiverStyx Foundation

Collaborator

Trials

2

Recruited

50+

Nikean Foundation

Collaborator

Trials

2

Recruited

70+

George Sarlo Foundation

Collaborator

Trials

1

Recruited

20+

RiverStyx Foundation

Collaborator

Trials

1

Recruited

20+

Oppenheimer Family Psychosocial Oncology and Palliative Care Research Grants

Collaborator

Trials

1

Recruited

20+

Usona Institute

Collaborator

Trials

18

Recruited

1,100+

Published Research Related to This Trial

Psilocybin is primarily a pro-drug that converts to the active compound psilocin in the body, which then interacts with serotonin receptors to produce its hallucinogenic effects.

The metabolism of psilocybin and psilocin varies significantly among individuals, affecting their dose-response and potential toxicity, highlighting the need for personalized approaches in therapeutic settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metabolism of psilocybin and psilocin: clinical and forensic toxicological relevance. Dinis-Oliveira, RJ.[2018]

Psychoactive compounds from fungi, like psilocin and muscimol, have been associated with both potential therapeutic benefits and significant neurotoxicity, raising concerns about their safety in medical applications.

Recent studies suggest that while hallucinogens may impair cognitive functions, substances like psilocin could also enhance perception and mental skills, complicating their use in therapy and increasing the risk of misuse.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fungal hallucinogens psilocin, ibotenic acid, and muscimol: analytical methods and biologic activities. Stebelska, K.[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, 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]

In a study involving 18 older long-term AIDS survivor men, psilocybin-assisted group therapy was found to be feasible and relatively safe, with no serious adverse reactions reported and only mild expected side effects experienced by some participants.

Participants showed a significant reduction in demoralization levels from baseline to a 3-month follow-up, indicating potential efficacy for psilocybin therapy in addressing psychological distress in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Psilocybin-assisted group therapy for demoralized older long-term AIDS survivor men: An open-label safety and feasibility pilot study. Anderson, BT., Danforth, A., Daroff, PR., et al.[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 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, 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]

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 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]

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

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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. 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 ...

3. 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 ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11612538/

Impact of psilocybin on cognitive function: A systematic ... Psilocybin was observed to enhance emotional empathy without significantly altering cognitive empathy and social cognition. Cognitive ...

5. 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 ...

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Psilocybin Psilocybin, also known as 4-phosphoryloxy-N,N-dimethyltryptamine (4-PO-DMT), is a naturally occurring tryptamine alkaloid and investigational drug found in ...

7. pubchem.ncbi.nlm.nih.gov pubchem.ncbi.nlm.nih.gov/compound/Psilocybin

Psilocybin | C12H17N2O4P | CID 10624 - PubChem - NIH Psilocybin is a tryptamine alkaloid that is N,N-dimethyltryptamine carrying an additional phosphoryloxy substituent at position 4. The major hallucinogenic ...

8. en.wikipedia.org en.wikipedia.org/wiki/Psilocin

Psilocin Psilocin, also known as 4-hydroxy-N,N-dimethyltryptamine (4-HO-DMT), is a substituted tryptamine alkaloid and a serotonergic psychedelic.

9. webbook.nist.gov webbook.nist.gov/cgi/cbook.cgi?ID=520-52-5

Psilocybine - the NIST WebBook Formula · C12H17N2O4P ; Molecular weight · 284.2481 ; Permanent link for this species. Use this link for bookmarking this species for future reference.

10. zfin.org zfin.org/CHEBI:8614

ZFIN ChEBI: psilocybin A tryptamine alkaloid that is N,N-dimethyltryptamine carrying an additional phosphoryloxy substituent at position 4. The major hallucinogenic alkaloid isolated ...