Psilocybin for Low Mood

(SnS Trial)

Overseen By Avery Ostrand, MSc

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Robin Carhart-Harris, PhD, MA

Must not be taking: SSRIs, MAO-Is, TCAs, lithium

Disqualifiers: Psychiatric disorders, Cardiovascular conditions, Drug use, others

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: 3

Duration: 1 day

120 Participants Needed

Trial Summary

What is the purpose of this trial?

One hundred twenty healthy participants, ages 21 to 70, who experience moderate-to-lower-than-average mental well-being will be evenly randomized into four different study arms, using a 2x2 factorial design. Depending on the study arm, participants will either receive an inactive placebo or up to 25mg psilocybin (oral dose), in one of two set and setting conditions; drug administration contexts that are predicted to modulate drug effects. The purpose of this study is to evaluate any interaction effects between an oral dose of psilocybin and the surrounding context (set and setting).

Do I have to stop taking my current medications to join the trial?

The trial requires participants to stop taking certain medications and substances, especially those with potential drug interactions like SSRIs, MAO-Is, TCAs, lithium, and serotonin-acting supplements such as St. John's wort. If you are currently taking any of these, you may need to stop before participating.

What evidence supports the effectiveness of the drug psilocybin for improving low mood?

Research shows that psilocybin can lead to significant and long-lasting improvements in mood for people with depression, even those who haven't responded to other treatments. It is generally well-tolerated with few side effects, making it a promising option for mood-related conditions. ^{1 2 3 4 5}

Is psilocybin safe for humans?

Psilocybin has been studied in clinical trials, showing promise for treating depression and substance use disorders. In a study with healthy adults, escalating doses of psilocybin were tested, and the safety profile was described, indicating it can be safe under controlled conditions. ^{6 7 8 9 10}

How is the drug psilocybin unique in treating low mood?

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. Unlike traditional antidepressants, psilocybin's effects are rapid, occurring within an hour of ingestion, and it is derived from natural sources like 'magic mushrooms'. ^{6 8 11 12 13}

Research Team

Robin Carhart-Harris, PhD

Principal Investigator

University of California, San Francisco

Jennifer Mitchell, PhD

Principal Investigator

University of California, San Francisco

Eligibility Criteria

This trial is for healthy individuals aged 21 to 70 who feel their mental well-being is moderate to low. Participants must not have any serious health issues and should be interested in how different environments might influence the effects of psilocybin, a substance being studied for its potential to improve mood.

Inclusion Criteria

Participants must agree to inform the investigators within 48 hours of any new or changed medical conditions

Participants must be fluent in speaking and reading English

Participants 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 over the course of the study

Exclusion Criteria

Participants with a positive alcohol breathalyzer test result on any study visit

Breastfeeding participants or participants with a positive pregnancy test

I am not taking any supplements or drugs that could interfere with the trial.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Baseline Assessment

Baseline assessments including psychological well-being and brain imaging

1 week

1 visit (in-person)

Treatment

Participants receive a single dose of either psilocybin or placebo in a controlled context

1 day

1 visit (in-person)

Follow-up

Participants are monitored for changes in mental well-being and brain activity

4 weeks

Multiple visits (in-person and virtual)

Treatment Details

Interventions

• Psilocybin

Trial Overview The study tests if the setting affects how psilocybin works on mood. One group gets a placebo (no active drug), while others get up to 25mg of psilocybin. They're placed in one of two different contexts designed to see if environment changes the drug's impact.

Participant Groups

Group I: Psilocybin C2 Experimental Treatment 2 Interventions

Following screening and a baseline assessment visit, healthy volunteers will receive one dose of up to 25mg psilocybin in a context (Context 2) that is hypothesized to modulate acute and post-acute drug effects.

Group II: Psilocybin C1 Experimental Treatment 2 Interventions

Following screening and a baseline assessment visit, healthy volunteers will receive one dose of up to 25mg psilocybin in a context (Context 1) that is hypothesized to modulate acute and post-acute drug effects.

Group III: Placebo C1 Placebo Group 2 Interventions

Following screening and a baseline assessment visit, healthy volunteers will receive one dose of an inactive placebo in a context (Context 1) that is hypothesized to modulate acute and post-acute drug effects.

Group IV: Placebo C2 Placebo Group 2 Interventions

Following screening and a baseline assessment visit, healthy volunteers will receive one dose of an inactive placebo in a context (Context 2) that is hypothesized to modulate acute and post-acute drug effects.

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, 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]

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]

In a study of 27 patients with moderate to severe major depressive disorder, psilocybin-assisted treatment showed significant and lasting antidepressant effects, with 75% of participants experiencing a treatment response and 58% achieving remission after 12 months.

There were no serious adverse events related to psilocybin, indicating a favorable safety profile, and participants reported meaningful personal and spiritual experiences that correlated with increased well-being, although these did not directly predict improvements in depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of psilocybin-assisted treatment for major depressive disorder: Prospective 12-month follow-up. Gukasyan, N., Davis, AK., Barrett, FS., 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]

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]

The study developed highly sensitive and accurate methods using liquid chromatography-mass spectrometry (LC-MS) and tandem mass spectrometry (LC-MS-MS) to effectively distinguish between psilocin and psilocybin, two active compounds in magic mushrooms.

Detection limits for these compounds were extremely low, ranging from 1 to 25 picograms, and the methods demonstrated high precision with low variability, making them suitable for analyzing psilocin and psilocybin content in various samples.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Liquid chromatography-mass spectrometric and liquid chromatography-tandem mass spectrometric determination of hallucinogenic indoles psilocin and psilocybin in "magic mushroom" samples. Kamata, T., Nishikawa, M., Katagi, M., 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]

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]

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]

P. samuiensis, a newly identified psychoactive mushroom species from Thailand, shows rapid mycelial growth and contains significant levels of psilocybin and psilocin, similar to other psychoactive fungi.

Laboratory analyses revealed that psilocybin concentrations in P. samuiensis ranged from 0.23% to 0.90%, with the highest levels found in the caps, indicating its potential for psychoactive effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ethnomycology, biochemistry, and cultivation of Psilocybe samuiensis Guzmán, Bandala and Allen, a new psychoactive fungus from Koh Samui, Thailand. Gartz, J., Allen, JW., Merlin, MD.[2019]

References

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

Psilocybin in Palliative Care: An Update. [2023]

2. Netherlands pubmed.ncbi.nlm.nih.gov

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

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

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

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

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

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

Efficacy and safety of psilocybin-assisted treatment for major depressive disorder: Prospective 12-month follow-up. [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

[Hallucinogenic mushrooms]. [2018]

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

The pharmacology of psilocybin. [2016]

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

Liquid chromatography-mass spectrometric and liquid chromatography-tandem mass spectrometric determination of hallucinogenic indoles psilocin and psilocybin in "magic mushroom" samples. [2016]

9. Switzerland pubmed.ncbi.nlm.nih.gov

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

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

Intravenous mushroom poisoning. [2019]

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

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

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

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

13. Ireland pubmed.ncbi.nlm.nih.gov

Ethnomycology, biochemistry, and cultivation of Psilocybe samuiensis Guzmán, Bandala and Allen, a new psychoactive fungus from Koh Samui, Thailand. [2019]