Psilocybin for Demoralization

(PT2PC Trial)

Recruiting at 4 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test the effectiveness and safety of psilocybin, a psychedelic compound, in helping individuals who feel demoralized, particularly those with a serious illness and less than two years to live. Participants will receive either psilocybin or ketamine (an anesthetic and dissociative drug), both paired with several psychotherapy sessions. Suitable candidates have a life-threatening illness, a short life expectancy, and experience deep demoralization. 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, 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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that psilocybin is generally safe. Clinical trials have demonstrated a strong safety record, with participants often experiencing mood improvements without serious side effects. Studies have found that psilocybin can help reduce mental distress in people with serious illnesses.

For ketamine, past studies indicate it is well-tolerated at low-to-moderate doses. Some people might feel dizzy or a bit confused, but these effects usually don't last long. Overall, both treatments have been studied and are considered safe for use in clinical settings. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Psilocybin is unique in treating demoralization because it is a psychedelic compound that can induce profound changes in perception and mood. Unlike typical antidepressants, which often take weeks to show effectiveness, psilocybin can produce significant emotional and psychological shifts after just one session. Researchers are excited because psilocybin works by affecting serotonin receptors in the brain, potentially leading to a rapid and sustained improvement in mood and outlook, which is a novel approach compared to traditional medications. Additionally, when combined with existential psychotherapy, it may help individuals find meaning and purpose, addressing the root causes of demoralization more directly.

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

This trial will compare psilocybin therapy with ketamine therapy for demoralization. Studies have shown that psilocybin therapy can significantly reduce depression, anxiety, and distress in patients. Improvements appeared soon after treatment and persisted over time. In individuals with serious illnesses, a small dose of psilocybin reduced mental distress without major side effects. Research also suggests that psilocybin therapy can effectively treat anxiety, depression, and life-related distress. These findings indicate that psilocybin may help ease hopelessness in those nearing the end of life. ^{1 2 3 6 7}

Who Is on the Research Team?

Charles S. Grob, M.D.

Principal Investigator

Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center

Are You a Good Fit for This Trial?

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 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 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

What Are the Treatments Tested in This Trial?

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).

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40259688/

Evaluating the effectiveness of psilocybin in alleviating ... Psilocybin therapy consistently showed significant reductions in depression, anxiety, and existential distress, with improvements sustained over ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT07063862

Study Details | NCT07063862 | Psilocybin Microdose for ... Our results showed psilocybin microdose improved psychological distress in most participants with advanced illness, without serious side effects. Our next step ...

3. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2023-04798

Psilocybin-Assisted Psychotherapy for the Treatment of ... This phase IIb trial studies the safety and effectiveness of psilocybin-assisted psychotherapy in treating anxiety, depression, and existential distress

4. hopkinsmedicine.org hopkinsmedicine.org/psychiatry/research/psychedelics-research

Psychedelics Research and Psilocybin Therapy 2022 (Milestone) : Psilocybin Treatment for Major Depression May be Effective for Up to a Year. Previous studies by Johns Hopkins Medicine researchers showed ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9833165/

Psilocybin mushrooms for psychological and existential ... Improvement was observed in 3 subscales (existential, psychological, social) 18 days after the high-dose psilocybin session; results were sustained to follow-up ...

6. apm.amegroups.org apm.amegroups.org/article/view/127674/html

Psilocybin-assisted psychotherapy for existential distress Psilocybin administration to adult participants in clinical trials has an excellent clinical safety record, both from the perspective of psychological and ...

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0165178124001719

Efficacy and safety of psychedelics for the treatment ... Our analyses suggest that psychedelics reduce negative mood, and have potential efficacy in other mental disorders, such as substance-use disorders and PTSD.