Psilocybin for Mild Cognitive Impairment

Overseen By Ariel Graff, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Centre for Addiction and Mental Health

Must not be taking: Anticonvulsants, Antidepressants, Antipsychotics, others

Disqualifiers: Unstable medical illness, Major depression, Substance dependence, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 8

Duration: 2 weeks

60 Participants Needed

Trial Summary

What is the purpose of this trial?

The goal of this clinical trial is to investigate the effects of psilocybin on synaptic vesicular density (SVD) as measured by the positron emission tomography (PET) radiotracer, 18F-SynVesT-1, in participants with amnestic Mild Cognitive Impairment (aMCI) and healthy participants. The investigators hypothesize that SVD levels in the brain will be higher following the ingestion of psilocybin in comparison to placebo, and that increases in SVD will be associated with improvements in cognition. 60 participants (30 with aMCI, and 30 sex and age matched healthy volunteers) will: * Be randomized to receive either: 1. Two 25 mg macrodoses of psilocybin separated by 1 week. 2. Two placebo doses separated by 1 week. * Receive a baseline 18F-SynVesT-1 PET scan, clinical, and neuropsychological assessments. * Receive a 18F-SynVesT-1 PET scan one week after the last dose of treatment. * Receive a third PET scan at any time within 4 weeks of the screening visit to quantify tauopathy with the \[18F\]T807 radiotracer. * Receive clinical and neuropsychological testing 1, 4, and 12 weeks after the last treatment. Researchers will compare placebo vs. experimental groups to see if psilocybin will increase SVD, and if increases in SVD are associated with cognitive improvements.

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

The trial requires participants to be on a stable dose of medication for at least 2 months and unlikely to change during the study. However, certain medications like anticonvulsants, antidepressants, antipsychotics, mood stabilizers, opioids, benzodiazepines, and some others must be discontinued before participating.

What evidence supports the effectiveness of the drug psilocybin for mild cognitive impairment?

Research shows that psilocybin has been effective in improving mood and mental health, and it has shown promise in treating depression and other psychiatric disorders. While specific studies on mild cognitive impairment are limited, these findings suggest potential benefits for mental health conditions. ^{1 2 3 4 5}

Is psilocybin generally safe for humans?

Psilocybin, found in 'magic mushrooms,' has been studied for its potential in treating conditions like depression and addiction. While it can cause hallucinations and other effects on the nervous system, recent studies suggest it may be safe in controlled settings, but more research is needed to fully understand its safety profile. ^{3 6 7 8 9}

How does the drug psilocybin differ from other treatments for mild cognitive impairment?

Psilocybin is unique because it is a psychedelic compound that works by affecting serotonin receptors in the brain, which is different from traditional treatments for cognitive impairment. It has shown promise in treating other conditions like depression and addiction, suggesting it might offer novel benefits for cognitive issues. ^{3 4 7 10 11}

Research Team

Philip Gerretsen, MD, PhD

Principal Investigator

Centre for Addiction and Mental Health

Eligibility Criteria

This trial is for people aged 60-75 with mild cognitive impairment who can consent to participate, have a study partner, and are non-smokers. They must not have used psychedelic drugs before or be at risk of exceeding radiation exposure from PET scans. Participants cannot join if they're pregnant, breastfeeding, on certain medications like anticoagulants or antidepressants, or have had recent serious health issues like strokes.

Inclusion Criteria

I have been on the same dose of medication for at least 2 months and it's unlikely to change.

You have been diagnosed with Minor Neurocognitive Disorder (MCI) according to specific criteria set by doctors.

I am of any gender and from any racial or ethnic background.

Exclusion Criteria

You are currently having thoughts about hurting yourself or someone else.

A close family member has schizophrenia, bipolar disorder, or a psychotic disorder not caused by substances or medical conditions.

I have been diagnosed with major depression, bipolar disorder, intellectual disability, Alzheimer's, or a psychotic disorder.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Baseline Assessment

Participants receive a baseline 18F-SynVesT-1 PET scan, clinical, and neuropsychological assessments

1 week

1 visit (in-person)

Treatment

Participants receive two doses of either psilocybin or placebo, separated by one week

2 weeks

2 visits (in-person)

Post-Treatment Assessment

Participants receive a 18F-SynVesT-1 PET scan one week after the last dose of treatment

1 week

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment with clinical and neuropsychological testing at 1, 4, and 12 weeks after the last treatment

12 weeks

3 visits (in-person)

Treatment Details

Interventions

• Placebo
• Psilocybin

Trial Overview Researchers are testing whether psilocybin (a compound found in magic mushrooms) can increase synaptic vesicular density in the brain compared to a placebo. The study involves two doses of either psilocybin or placebo given one week apart and several PET scans and neuropsychological tests before and after treatment to measure changes.

Participant Groups

Group I: Healthy Participants Receiving Psilocybin Experimental Treatment 1 Intervention

Receiving 2 doses of 25mg of psilocybin separated by 1 week.

Group II: Amnestic Mild Cognitive Impairment Participants Receiving Psilocybin Experimental Treatment 1 Intervention

Receiving 2 doses of 25mg of psilocybin separated by 1 week.

Group III: Healthy Participants Receiving Placebo Placebo Group 1 Intervention

Receiving 2 doses of placebo separated by 1 week.

Group IV: Amnestic Mild Cognitive Impairment Participants Receiving Placebo Placebo Group 1 Intervention

Receiving 2 doses of placebo separated by 1 week.

Who Is Running the Clinical Trial?

Centre for Addiction and Mental Health

Lead Sponsor

Trials

388

Recruited

84,200+

Findings from Research

In a study of 953 psilocybin microdosers and 180 non-microdosing comparators over 30 days, participants reported small- to medium-sized improvements in mood and mental health, consistent across different demographics.

Combining psilocybin with lion's mane mushrooms and niacin showed specific psychomotor performance benefits in older adults, suggesting potential advantages of this combination, although further research is needed to confirm these effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Psilocybin microdosers demonstrate greater observed improvements in mood and mental health at one month relative to non-microdosing controls. Rootman, JM., Kiraga, M., Kryskow, P., et al.[2022]

Psilocybin has shown promise in clinical trials for reducing symptoms of depression, indicating its potential as a novel treatment option.

Patients with treatment-resistant depression (TRD) may benefit the most from psilocybin therapy, although the risks associated with its use are still not fully understood.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessing potential of psilocybin for depressive disorders. Kozak, Z., Johnson, MW., Aaronson, ST.[2023]

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]

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]

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, 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 compound found in 'magic mushrooms', has shown potential in recent studies for treating various mental health conditions, including obsessive-compulsive disorder, alcohol and tobacco addiction, and major depressive disorder, particularly in terminally ill cancer patients.

Despite its classification as a Schedule I drug in 1970, which halted much research, there is a renewed interest in psilocybin's therapeutic effects, highlighting its importance in both historical and contemporary neuroscience.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

DARK Classics in Chemical Neuroscience: Psilocybin. Geiger, HA., Wurst, MG., Daniels, RN.[2019]

Psilocybin, derived from Psilocybe cubensis mushrooms, is being investigated as a novel treatment for major depression, with a focus on its safety and efficacy compared to traditional antidepressants.

The proposed study will include both preclinical toxicity evaluations in mice and a clinical trial assessing the safety and pharmacokinetics of psilocybin in healthy adults, followed by an open trial in patients with major depressive disorder, aiming to provide comprehensive data on its therapeutic potential.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Proposal to Study the Safety and Efficacy of Psilocybe cubensis in Preclinical and Clinical Studies as a Therapeutic Alternative for Major Depressive Disorder. Escamilla, R., González-Trujano, ME., González Mariscal, JM., 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]

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 (PY) is rapidly converted to its active form, psilocin (PI), in the body, with peak plasma levels occurring approximately 105 minutes after oral administration and 1.9 minutes after intravenous injection, indicating a quick onset of action.

The study found that psilocin has an estimated absolute bioavailability of about 52.7% when taken orally, suggesting that a significant portion of the drug is effectively absorbed into the bloodstream.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Determination of psilocin and 4-hydroxyindole-3-acetic acid in plasma by HPLC-ECD and pharmacokinetic profiles of oral and intravenous psilocybin in man. Hasler, F., Bourquin, D., Brenneisen, R., et al.[2019]

References

1. England pubmed.ncbi.nlm.nih.gov

Psilocybin microdosers demonstrate greater observed improvements in mood and mental health at one month relative to non-microdosing controls. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Assessing potential of psilocybin for depressive disorders. [2023]

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

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

4. Switzerland pubmed.ncbi.nlm.nih.gov

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

5. Netherlands pubmed.ncbi.nlm.nih.gov

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

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

The pharmacology of psilocybin. [2016]

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

DARK Classics in Chemical Neuroscience: Psilocybin. [2019]

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

A Proposal to Study the Safety and Efficacy of Psilocybe cubensis in Preclinical and Clinical Studies as a Therapeutic Alternative for Major Depressive Disorder. [2023]

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

[Hallucinogenic mushrooms]. [2018]

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. Switzerland pubmed.ncbi.nlm.nih.gov

Determination of psilocin and 4-hydroxyindole-3-acetic acid in plasma by HPLC-ECD and pharmacokinetic profiles of oral and intravenous psilocybin in man. [2019]