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

15 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests a treatment using psilocybin, a substance from certain mushrooms, combined with talk therapy for hospice patients feeling demoralized. The goal is to see if this approach can safely reduce their emotional distress. Psilocybin recently received breakthrough status by the FDA for its use in treatment of depression.

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.

What data supports the effectiveness of the drug psilocybin for treating demoralization?

Research shows that psilocybin, a compound found in certain mushrooms, has been studied in clinical trials for various psychiatric disorders, including demoralization. It is generally well tolerated and can lead to significant, long-lasting improvements even in patients who haven't responded to other treatments. ^{1 2 3 4 5}

Is psilocybin safe for use in humans?

Psilocybin, found in magic mushrooms, can cause challenging experiences, but when used in controlled settings with support, the risk of harm is very low. Some people report enduring psychological benefits, though a small number have experienced lasting distress or risky behavior. Safety in people with heart conditions is not fully known, but studies suggest it may be safe under controlled conditions. ^{2 6 7 8 9}

How is psilocybin different from other drugs for demoralization?

Psilocybin is unique because it is a psychedelic drug that works by affecting serotonin receptors in the brain, potentially leading to rapid and long-lasting improvements in mood and perception after just one or a few sessions, unlike traditional treatments that may require ongoing use. ^{2 4 10 11 12}

Research Team

Yvan Beaussant, MD

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

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

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)

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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 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 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-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 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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Metabolism of psilocybin and psilocin: clinical and forensic toxicological relevance. [2018]

2. United States pubmed.ncbi.nlm.nih.gov

The pharmacology of psilocybin. [2016]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of Escalating Doses of Oral Psilocybin in Healthy Adults. [2022]

4. Netherlands pubmed.ncbi.nlm.nih.gov

[Treatment with psilocybin: applications for patients with psychiatric disorders]. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Psilocybin in Palliative Care: An Update. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

Intravenous mushroom poisoning. [2019]

7. Switzerland pubmed.ncbi.nlm.nih.gov

[Hallucinogenic mushrooms]. [2018]

8. United States pubmed.ncbi.nlm.nih.gov

Survey study of challenging experiences after ingesting psilocybin mushrooms: Acute and enduring positive and negative consequences. [2018]

9. England 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. [2021]

10. England 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. [2023]

11. United States pubmed.ncbi.nlm.nih.gov

Fungal hallucinogens psilocin, ibotenic acid, and muscimol: analytical methods and biologic activities. [2016]

12. United States pubmed.ncbi.nlm.nih.gov

Structure-Activity Relationships for Psilocybin, Baeocystin, Aeruginascin, and Related Analogues to Produce Pharmacological Effects in Mice. [2023]