Psilocybin for Demoralization

Overseen By Peter S Hendricks, PhD

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: University of Alabama at Birmingham

Must not be taking: ADHD meds, Antidepressants, Antipsychotics, others

Disqualifiers: Hypertension, Pregnancy, Psychotic disorders, others

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 9

Duration: 5 weeks

60 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of the present study is to evaluate the feasibility, initial signals of efficacy, and potential mechanisms of action of "microdoses" of psilocybin (i.e., low doses of psilocybin that are not believed to produce mystical-type, transcendent, hallucinogenic, or other overtly salient subjective effects that limit functionality) in the treatment of moderate to severe demoralization (feelings of hopelessness and meaningless that frequently accompany medical illness and other life hardship).

Will I have to stop taking my current medications?

Yes, you will need to stop taking certain medications, including those for ADHD, anxiety, depression, mood stabilization, and any with serotonin activity, as they are part of the exclusion criteria for this trial.

What data supports the effectiveness of the drug psilocybin for treating 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 with psilocybin. ^{1 2 3 4 5}

Is psilocybin generally safe for humans?

Psilocybin can cause challenging experiences, including hallucinations and risky behavior, especially at high doses or without support. However, in controlled settings with screened and supported participants, the risk of enduring psychological distress is extremely low. ^{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 naturally occurring mushrooms, offering a novel approach to mental health conditions. ^{2 4 6 10 11}

Eligibility Criteria

This trial is for English-speaking adults aged 25-65 who feel hopeless and meaningless, scoring over 8 on the Demoralization Scale-II. Participants must be in good health, have not used hallucinogens recently (or at all), can secure a ride home post-session, and are not pregnant or breastfeeding. Exclusions include recent mental health treatment, substance abuse, certain medical conditions like hypertension or neurological issues, and those taking various medications for mood disorders.

Inclusion Criteria

I have someone or a way to get home after my treatment sessions.

I am between 25 and 65 years old.

Ability to read and write in English

Exclusion Criteria

History of immoderate alcohol consumption within the past 3 months per NIAAA definitions: more than 4 drinks per day or 14 drinks per week for men; more than 3 drinks per day or 7 drinks per week for women

I am not pregnant or breastfeeding.

I am either 24 years old or younger, or 66 years old or older.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1 week

1 visit (telephone)

Baseline Intake

Participants complete a demographic questionnaire, psychiatric interview, and provide a urine sample. Medical history interview and physical examination including EKG and blood panel are conducted.

1 week

1 visit (in-person)

Orientation

Participants attend a psychoeducational orientation session and complete baseline questionnaires and neuropsychological assessments.

1 week

1 visit (in-person)

Treatment

Participants receive psilocybin or placebo once per week for 5 weeks. Each session includes drug administration, VAS questions, blood pressure monitoring, EEG tasks, and neuropsychological measures.

5 weeks

5 visits (in-person)

Study Termination

Completion of questionnaires and a semi-structured qualitative interview. EKG is repeated.

1 week

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment.

4 weeks

Treatment Details

Interventions

• Psilocybin

Trial Overview The study tests if low doses of psilocybin can help with feelings of demoralization without causing significant mind-altering effects. It's an exploratory study comparing the effects of 'microdoses' of psilocybin to a placebo in controlled settings.

Participant Groups

Group I: 5 mg psilocybin Experimental Treatment 1 Intervention

Participants in this arm will receive 5 mg psilocybin once per week for 5 weeks.

Group II: 2.5 mg psilocybin Experimental Treatment 1 Intervention

Participants in this arm will receive 2.5 mg psilocybin once per week for 5 weeks.

Group III: 1 mg psilocybin Experimental Treatment 1 Intervention

Participants in this arm will receive 1 mg psilocybin once per week for 5 weeks.

Group IV: Placebo (0 mg psilocybin) Placebo Group 1 Intervention

Participants in this arm will receive 0 mg of psilocybin once per week for 5 weeks.

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?

University of Alabama at Birmingham

Lead Sponsor

Trials

1,677

Recruited

2,458,000+

Diamond Therapeutics Inc.

Industry Sponsor

Trials

1

Recruited

60+

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]

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]

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 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. Switzerland pubmed.ncbi.nlm.nih.gov

[Hallucinogenic mushrooms]. [2018]

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

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

8. England pubmed.ncbi.nlm.nih.gov

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

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]