Psilocybin for Demoralization

(PT2PC Trial)

Recruiting at 2 trial locations

Overseen By Brian T Anderson, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Charles S. Grob, M.D.

Must not be taking: Antipsychotics, Antidepressants, Dopamine agonists, others

Disqualifiers: Cognitive impairment, Uncontrolled hypertension, Pregnancy, 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: 4

Duration: 1 week

100 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

You may need to stop taking certain medications, like antipsychotics, antidepressants, dopamine agonists, or any drugs that interact badly with psilocybin or ketamine. It's best to discuss your current medications with the study team to see if any changes are needed.

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

Research shows that psilocybin has been studied in clinical trials for various psychiatric disorders, including demoralization, and is generally well tolerated with limited side effects. Some patients, even those with treatment-resistant conditions, have shown significant long-term improvements after just one or a few sessions. ^{1 2 3 4 5}

Is psilocybin safe for human use?

Psilocybin, found in certain mushrooms, can cause challenging experiences, including hallucinations and risky behavior, especially at high doses or without support. However, in controlled settings with screened participants, the risk of lasting psychological distress is very low. Some adverse reactions may be due to other substances in the mushrooms, like phenylethylamine. ^{2 6 7 8 9}

How is the drug psilocybin unique in treating demoralization?

Psilocybin is unique because it works by activating serotonin receptors in the brain, particularly the 5-HT2A receptor, which can lead to psychedelic effects and potentially improve mood and outlook. Unlike traditional treatments, psilocybin's effects are rapid, occurring within 30 minutes to an hour, and it is derived from natural sources like certain mushrooms. ^{2 4 8 10 11}

What is the purpose of this trial?

This multicenter, triple-blind, phase 2, randomized controlled trial will evaluate the efficacy and safety of psilocybin therapy compared to an active control in treating demoralization in adults near the end of life (≤2 years life expectancy).

Research Team

Charles S. Grob, M.D.

Principal Investigator

Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center

Eligibility Criteria

Adults over 18 with a life-threatening illness and an estimated life expectancy of 2 years or less, who are experiencing moderate-to-severe feelings of hopelessness (demoralization), can join this trial. They must be able to take oral medication and consent to research.

Inclusion Criteria

I can swallow pills and liquids.

Is currently a patient in a study-engaged clinical site

My doctor says I have up to 2 years to live due to my illness.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single dose of oral psilocybin or ketamine along with 4-5 sessions of brief existential psychotherapy

1 week

1 visit (in-person) for drug administration

Follow-up

Participants are monitored for safety and effectiveness after treatment, with assessments at 1, 2, and 5 weeks post-drug administration

5 weeks

3 visits (in-person or virtual) for assessments

Open-label extension (optional)

Participants who received the active control may opt for another course of talk therapy plus psilocybin

Varies

Treatment Details

Interventions

• Ketamine
• Psilocybin

Trial Overview The trial is testing the effectiveness and safety of psilocybin therapy versus ketamine in reducing feelings of demoralization in palliative care patients. It's a phase 2 study where participants are randomly assigned to one treatment without knowing which they're receiving (triple-blind).

Participant Groups

Group I: Psilocybin Experimental Treatment 1 Intervention

A single moderate-to-high dose of oral psilocybin, plus 4-5 sessions of a brief, existential psychotherapy.

Group II: Ketamine Active Control 1 Intervention

A single low-to-moderate dose of oral liquid ketamine, plus 4-5 sessions of a brief, existential psychotherapy.

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?

Charles S. Grob, M.D.

Lead Sponsor

Trials

1

Recruited

100+

University of California, San Francisco

Collaborator

Trials

2,636

Recruited

19,080,000+

Findings from Research

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 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 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]

This study found that the binding of serotonin 2A receptors (5-HT2AR) in the brain can predict how long the peak effects of psilocybin last and how quickly individuals return to normal consciousness after its effects wear off.

Higher levels of 5-HT2AR binding were associated with lower scores on the Mystical Experience Questionnaire, suggesting that individual differences in receptor availability may influence the subjective experience of psilocybin, which could have implications for its therapeutic use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brain serotonin 2A receptor binding predicts subjective temporal and mystical effects of psilocybin in healthy humans. Stenbæk, DS., Madsen, MK., Ozenne, B., et al.[2022]

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]

This study identified phenylethylamine in Psilocybe semilanceata mushrooms, which may contribute to adverse reactions during psilocybin intoxication, as evidenced by a case involving three young men who experienced severe symptoms.

The levels of phenylethylamine in these mushrooms can vary significantly, with the highest concentration found in the case of hospitalization, suggesting that this compound could play a role in the tachycardia and other symptoms not directly linked to psilocybin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Presence of phenylethylamine in hallucinogenic Psilocybe mushroom: possible role in adverse reactions. Beck, O., Helander, A., Karlson-Stiber, C., et al.[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]

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 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]

The study successfully utilized GLC-mass spectrometry to analyze psilocin and psilocybin, two hallucinogenic compounds, by converting them into trimethylsilyl derivatives for better detection.

This method was specifically applied to an extract of the Psilocybe cubensis mushroom, indicating its potential for accurately identifying and quantifying these psychoactive substances in natural samples.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

GLC-mass spectral analysis of psilocin and psilocybin. Repke, DB., Leslie, DT., Mandell, DM., et al.[2019]

References

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

Psilocybin in Palliative Care: An Update. [2023]

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

The pharmacology of psilocybin. [2016]

3. Netherlands pubmed.ncbi.nlm.nih.gov

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

4. England pubmed.ncbi.nlm.nih.gov

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

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

Brain serotonin 2A receptor binding predicts subjective temporal and mystical effects of psilocybin in healthy humans. [2022]

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

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

7. England pubmed.ncbi.nlm.nih.gov

Presence of phenylethylamine in hallucinogenic Psilocybe mushroom: possible role in adverse reactions. [2019]

8. Switzerland pubmed.ncbi.nlm.nih.gov

[Hallucinogenic mushrooms]. [2018]

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

Intravenous mushroom poisoning. [2019]

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

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

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

GLC-mass spectral analysis of psilocin and psilocybin. [2019]