Psilocybin for Psychedelic Experiences

(i2 Trial)

Overseen By Lorenzo Pasquini, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Robin Carhart-Harris, PhD, MA

Disqualifiers: Pregnancy, Lactation, Mental illness, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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

Compensation: Varies

Number of Visits: 6

Duration: 4-8 weeks

12 Participants Needed

Trial Summary

What is the purpose of this trial?

The main purpose of this study is to gain a better understanding of the distinct mental states and physical reactions that can arise during a psychedelic experience. By repeatedly assessing the same participants in an MRI while under the effects of psilocybin, the investigators want to identify reliable brain and body reactions arising during these psychedelic experiences. It is hoped that this will provide an insight to inspire future research on psilocybin and related psychedelics as well as inform on their therapeutic action. This study will involve up to 12 healthy volunteers with previous psychedelic experience. Participants in this study will be given four doses of psilocybin, with breaks of at least seven days in between dosing visits. The first dosing visit will feature a 10 mg dose of psilocybin, which can be considerate a low to moderate dose, whereas the remaining three dosing visits will feature 25 mg psilocybin, a high dose that is consistent with the dosage chosen for several modern clinical trials with psilocybin. From the initial in-person screening visit to the final follow-up, participants will be in this study for approximately 6-12 weeks and visit the research site 5 times. The first visit will be an in-person screening visit, during which the investigators will assess participants' eligibility to be enrolled. There will be 4 subsequent visits to the scan center for dosing and magnetic resonance imaging (MRI) scanning, and there will be a final remote follow up. Each of the four dosing visits will include four periods of lying within the MRI scanner for scanning, each of these 'in-scanner' sessions will last for \~ 45 minutes. Actual scans, which are also called 'runs' last for \~ 12 mins. During these 'runs', the investigators will ask participants two brief questions about how positive or negative their current experience is every 100 seconds. They will be able to record their answers using a button box which they will be operating with their hand. One day after each dosing visit, the investigators will schedule a phone call with the participant to check how they are doing and perform an informal interview focused on their experience while under the effects of psilocybin.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the study team to get a clear answer.

What data supports the effectiveness of the drug psilocybin for psychedelic experiences?

Research indicates that psilocybin, a compound found in certain mushrooms, can produce altered states of consciousness by activating serotonin receptors in the brain. It has shown therapeutic potential in palliative care, helping patients cope with end-of-life challenges. ^{1 2 3 4 5}

Is psilocybin generally safe for human use?

Psilocybin, found in certain mushrooms, can cause rapid effects on the central nervous system, leading to hallucinations and other symptoms. While some people report challenging experiences, especially at high doses or without support, the risk of long-term harm is low when used in controlled settings with proper screening and support. ^{2 6 7 8 9}

How is the drug psilocybin unique compared to other treatments for psychedelic experiences?

Psilocybin is unique because it is a naturally occurring compound found in certain mushrooms, known for its psychoactive effects that are similar to serotonin, a neurotransmitter in the brain. Unlike other treatments, psilocybin can induce profound changes in perception and consciousness, which are being studied for their potential therapeutic benefits in mental health conditions. ^{2 10 11 12 13}

Research Team

Robin Carhart-Harris, PhD

Principal Investigator

University of California, San Francisco

Eligibility Criteria

This trial is for healthy adults aged 21-70 with prior psychedelic experience, but not more than 500 times. They must be able to swallow pills, use technology for data entry, and speak English fluently. Women of childbearing potential must agree to effective contraception; men also need to practice birth control and not donate sperm during the study.

Inclusion Criteria

Have no more than 500 previous experiences with a psychedelic substance

Agree to inform the investigators within 48 hours of any new or changed medical conditions

If able to become pregnant, must be non-lactating, have a negative pregnancy test at study entry and prior to each Experimental Session and must agree to an adequate form of birth control and contraception over the course of the study

Exclusion Criteria

Current chronic cannabis use

Have used alcohol within 24 hours or other psychoactive drugs within 7 days of an Experimental Session (with the exception of the psilocybin used within this study)

I do not have any serious health conditions that would make me unsuitable for the study.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1 visit

1 visit (in-person)

Treatment

Participants receive four doses of psilocybin with MRI scanning, with breaks of at least seven days between dosing visits

4-8 weeks

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including a final remote follow-up

4 weeks

1 visit (remote)

Treatment Details

Interventions

• Psilocybin

Trial Overview The study tests how psilocybin affects mental states and physical reactions using MRI scans in participants who have used psychedelics before. It involves four doses of psilocybin over several weeks, with brain imaging sessions after each dose while answering questions about their experiences.

Participant Groups

Group I: Psilocybin Experimental Treatment 1 Intervention

Healthy volunteers will receive up to four doses of psilocybin separated from each other by at least one week. The first dosing session will involve 10 mg psilocybin, the remaining three dosing sessions will receive up to 25mg psilocybin.

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?

Robin Carhart-Harris, PhD, MA

Lead Sponsor

Trials

2

Recruited

130+

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-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 study involving eight volunteers, psilocybin was administered, and its metabolite, psilocin, was found to peak in urine concentrations up to 870 microg/L within 2-4 hours after ingestion, indicating a rapid metabolism.

About 3.4% of the psilocybin dose was excreted as free psilocin within 24 hours, and using beta-glucuronidase to treat urine samples significantly increased detectable levels of psilocin, suggesting that enzymatic processes can enhance the detection of this metabolite.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Renal excretion profiles of psilocin following oral administration of psilocybin: a controlled study in man. Hasler, F., Bourquin, D., Brenneisen, R., et al.[2019]

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 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]

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]

There is a growing trend among young people to consume wild Psilocybin mushrooms for their hallucinogenic effects, but this practice carries risks.

The report highlights seven cases of mushroom overdosage, stressing that while Psilocybin mushrooms are generally considered harmless, there is a significant danger of accidentally consuming toxic mushroom species that can cause serious harm.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The danger of hallucinogenic mushrooms. Mills, PR., Lesinskas, D., Watkinson, G.[2017]

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]

A meta-analysis of psilocybin studies found that higher doses of psilocybin are associated with stronger subjective experiences, particularly in areas like perceptual alterations and ego dissolution, based on data from standardized questionnaires.

Challenging experiences were less affected by dose, suggesting that individual and environmental factors also play a significant role in the psilocybin experience, indicating that these findings are most relevant in controlled settings rather than recreational use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose-response relationships of psilocybin-induced subjective experiences in humans. Hirschfeld, T., Schmidt, TT.[2022]

A new liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to quickly and accurately measure the levels of psilocybin and psilocin in magic truffles, with high precision and reliability (r² > 0.99).

The study found that only psilocybin was present in the examined Psilocybe sclerotia, with concentrations ranging from 59.3 to 167.8 µg per 100 mg of fresh truffles, indicating variability in psilocybin content.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Magic truffles or Philosopher's stones: a legal way to sell psilocybin? Pellegrini, M., Rotolo, MC., Marchei, E., et al.[2019]

In a study analyzing the tryptamine content of freshly cultivated Psilocybe cubensis mushrooms, it was found that the caps contained the highest concentration of psilocybin and psilocin, while the mycelium had a lower concentration and no tryptamines were detected in the basidiospores.

Storage conditions significantly affected the stability of tryptamines, with fresh mushrooms stored at -80°C showing the highest degradation, while dried biomass stored in the dark at room temperature maintained the tryptamine levels better.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stability of psilocybin and its four analogs in the biomass of the psychotropic mushroom Psilocybe cubensis. Gotvaldová, K., Hájková, K., Borovička, J., et al.[2021]

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. Switzerland pubmed.ncbi.nlm.nih.gov

[Hallucinogenic mushrooms]. [2018]

3. England pubmed.ncbi.nlm.nih.gov

Renal excretion profiles of psilocin following oral administration of psilocybin: a controlled study in man. [2019]

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

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

5. England pubmed.ncbi.nlm.nih.gov

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

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

The pharmacology of psilocybin. [2016]

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

Intravenous mushroom poisoning. [2019]

8. Scotland pubmed.ncbi.nlm.nih.gov

The danger of hallucinogenic mushrooms. [2017]

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

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

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

Dose-response relationships of psilocybin-induced subjective experiences in humans. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Magic truffles or Philosopher's stones: a legal way to sell psilocybin? [2019]

12. England pubmed.ncbi.nlm.nih.gov

Stability of psilocybin and its four analogs in the biomass of the psychotropic mushroom Psilocybe cubensis. [2021]

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

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