Psilocybin and Vagus Nerve Stimulation for Depression

(OPTIMIZE Trial)

Overseen By Program Manager

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Elaine Sandler

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

Disqualifiers: Psychotic disorder, Suicidal ideation, Substance use, 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: 12

141 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how psilocybin, a compound in certain mushrooms, can aid people with depression, especially when combined with specific follow-up activities. It examines whether adding a technique called taVNS, which gently stimulates a nerve in the ear, affects mood and behavior after psilocybin use. Participants will be divided into groups, with some receiving taVNS, a mock version of it, or no additional treatment after taking psilocybin. Suitable candidates have Major Depressive Disorder and have experienced depression for at least 60 days. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

Yes, you will need to stop taking any current prescription psychotropic medications (like antidepressants, antipsychotics, or mood stabilizers) for the duration of the trial.

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

Earlier studies have found psilocybin to be generally safe for humans. Some individuals experienced mild side effects such as headaches, nausea, or temporary changes in mood and perception, but these effects typically resolve quickly.

Research has shown that using a gentle electrical current on the ear, known as transcutaneous auricular Vagus Nerve Stimulation (taVNS), is also safe. Most people report only mild side effects like tingling or slight discomfort, which dissipate quickly.

Both treatments have been studied separately and appear safe for most individuals. However, since experiences can vary, it is important to consider personal health and consult a healthcare provider about any concerns before joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about psilocybin for depression because it offers a novel approach compared to traditional antidepressants, which mainly target neurotransmitter levels in the brain. Psilocybin works differently by inducing profound changes in brain connectivity and consciousness, potentially leading to rapid and lasting improvements in mood and mental health. Additionally, the trial explores the combination of psilocybin with transcutaneous auricular vagus nerve stimulation (taVNS), a technique that may enhance therapeutic outcomes by modulating brain activity. This combination could offer a faster-acting and more holistic treatment option for depression, addressing symptoms more comprehensively than standard medications like SSRIs or SNRIs.

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

Studies have shown that psilocybin can help reduce symptoms of depression in some people by affecting certain brain chemicals that influence mood and perception. Research indicates that even a single dose, when used with psychological support, can positively impact depression symptoms. In this trial, some participants will receive psilocybin alone, while others will receive it with transcutaneous auricular Vagus Nerve Stimulation (taVNS) or a sham version of taVNS.

Research shows that transcutaneous auricular Vagus Nerve Stimulation (taVNS) can improve depression by stimulating a nerve that helps regulate mood. Studies have found that taVNS can significantly lower depression scores compared to a placebo. Both treatments show promise for helping with depression, and combining them might enhance the effects. ^{1 2 3 4 5}

Who Is on the Research Team?

Charles Raison, MD

Principal Investigator

Vail Health Behavioral Health

Are You a Good Fit for This Trial?

This trial is for individuals with depression. Participants must meet certain health criteria to be included, but specific inclusion and exclusion details are not provided in the information given.

Inclusion Criteria

I can speak English or Spanish and can fill out forms in one of these languages.

I am generally in good health.

Montgomery-Åsberg Depression Rating Scale (MADRS) score ≥ 28

Exclusion Criteria

Endorses current active suicidal ideation with a specific plan in the prior 2 weeks

Abnormal electrocardiogram (ECG) at screening

I do not have a substance use disorder that would cause withdrawal symptoms during a 7-10 hour period.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Preparatory Sessions

Several hours of preparatory sessions prior to psilocybin dosing

1 week

Psilocybin Dosing

Participants receive a single 25 mg dose of psilocybin with psychological support

1 day

1 visit (in-person)

Post-Dosing Integration

Participants undergo integration sessions to process the psilocybin experience

2 weeks

3 visits (in-person)

taVNS/Sham/TAU

Participants receive 7 days of twice daily taVNS, sham taVNS, or treatment as usual

1 week

Follow-up

Participants are monitored for safety and effectiveness after treatment

8 weeks

Multiple assessments up to 8 weeks post-dose

What Are the Treatments Tested in This Trial?

Interventions

• Psilocybin
• Transcutaneous Auricular Vagus Nerve Stimulation (taVNS)

Trial Overview The study tests if psilocybin's antidepressant effects can be enhanced and prolonged by post-dose transcutaneous auricular Vagus Nerve Stimulation (taVNS). It compares usual treatment, taVNS, sham taVNS (placebo), and psilocybin with psychological support.

How Is the Trial Designed?

Group I: Group 1: Psilocybin + taVNS Experimental Treatment 2 Interventions

Participants in this arm will receive a single 25 mg dose of psilocybin, followed by twice-daily sessions of taVNS for 7 consecutive days. Each taVNS session will be paired with music and prompts related to the participant's psilocybin experience.

Group II: Group 3: Psilocybin + No taVNS Active Control 1 Intervention

Participants in this arm will receive a single 25 mg dose of psilocybin, followed by no additional intervention. They will receive the standard psychological support related to their psilocybin experience, but no taVNS or sham device will be used.

Group III: Group 2: Psilocybin + Sham taVNS Placebo Group 2 Interventions

Participants in this arm will receive a single 25 mg dose of psilocybin, followed by twice-daily sham taVNS sessions for 7 consecutive days. Each sham session will be paired with music and prompts related to the participant's psilocybin experience.

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?

Elaine Sandler

Lead Sponsor

Trials

1

Recruited

140+

Charles Raison

Lead Sponsor

Trials

1

Recruited

140+

Usona Institute

Collaborator

Trials

18

Recruited

1,100+

Emory University

Collaborator

Trials

1,735

Recruited

2,605,000+

Steadman Philippon Research Institute

Collaborator

Trials

11

Recruited

700+

Tiny Blue Dot Foundation

Collaborator

Trials

9

Recruited

640+

Tiny Blue Dot Foundation

Collaborator

Trials

10

Recruited

660+

Published Research Related to This Trial

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 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 examining the effects of Psilocybe cubensis and Panaeolus cyanescens mushrooms on heart cells, the extracts did not worsen hypertrophy caused by endothelin-1 and provided protection against TNF-α-induced cell injury.

The findings suggest that these mushroom extracts can be safely used in controlled conditions for potential therapeutic benefits in heart disease, although caution is advised with higher concentrations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects and safety of Psilocybe cubensis and Panaeolus cyanescens magic mushroom extracts on endothelin-1-induced hypertrophy and cell injury in cardiomyocytes. Nkadimeng, SM., Steinmann, CML., Eloff, JN.[2021]

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 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, a psychedelic drug, shows promising safety and efficacy in treating major depression and treatment-resistant depression (TRD), with initial phase 2 trials indicating positive outcomes when combined with psychological support.

The first international randomized controlled trial in 2022 found that a 25 mg dose of psilocybin was effective compared to an active placebo, and phase 3 trials are set to begin in 2023, suggesting a growing interest in psilocybin as a viable treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The development of psilocybin therapy for treatment-resistant depression: an update. Borissova, A., Rucker, JJ.[2023]

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 single, moderate dose of psilocybin significantly reduced depressive symptoms in 52 participants with major depressive disorder, showing a decrease of 13.0 points on the MADRS scale compared to baseline, which was significantly greater than the placebo group.

54% of participants in the psilocybin group met the criteria for remission of depression 14 days after treatment, and no serious adverse events were reported, indicating a favorable safety profile for this novel treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-dose psilocybin-assisted therapy in major depressive disorder: A placebo-controlled, double-blind, randomised clinical trial. von Rotz, R., Schindowski, EM., Jungwirth, J., et al.[2023]

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]

A single dose of psilocybin (0.5-20 mg/kg) significantly increases the expression of genes related to neuroplasticity in the prefrontal cortex and hippocampus, suggesting its potential therapeutic effects for mental health disorders.

The study highlights that psilocybin's effects on gene expression are dose-dependent and predominantly observed in the prefrontal cortex, emphasizing the need to assess both gene expression and protein translation to understand its rapid effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcriptional regulation in the rat prefrontal cortex and hippocampus after a single administration of psilocybin. Jefsen, OH., Elfving, B., Wegener, G., et al.[2022]

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]

Citations

1. en.wikipedia.org en.wikipedia.org/wiki/Psilocybin

Psilocybin Psilocybin, also known as 4-phosphoryloxy-N,N-dimethyltryptamine (4-PO-DMT), is a naturally occurring tryptamine alkaloid and investigational drug found in ...

2. pubchem.ncbi.nlm.nih.gov pubchem.ncbi.nlm.nih.gov/compound/Psilocybin

Psilocybin | C12H17N2O4P | CID 10624 - PubChem - NIH Psilocybin is a tryptamine alkaloid that is N,N-dimethyltryptamine carrying an additional phosphoryloxy substituent at position 4. The major hallucinogenic ...

3. en.wikipedia.org en.wikipedia.org/wiki/Psilocin

Psilocin Psilocin, also known as 4-hydroxy-N,N-dimethyltryptamine (4-HO-DMT), is a substituted tryptamine alkaloid and a serotonergic psychedelic.

4. webbook.nist.gov webbook.nist.gov/cgi/cbook.cgi?ID=520-52-5

Psilocybine - the NIST WebBook Formula · C12H17N2O4P ; Molecular weight · 284.2481 ; Permanent link for this species. Use this link for bookmarking this species for future reference.

5. zfin.org zfin.org/CHEBI:8614

ZFIN ChEBI: psilocybin A tryptamine alkaloid that is N,N-dimethyltryptamine carrying an additional phosphoryloxy substituent at position 4. The major hallucinogenic alkaloid isolated ...