Psilocybin + taVNS for Enhancing Psychedelic Experiences

(ENHANCE Trial)

Overseen By Program Manager

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Wisconsin, Madison

Must not be taking: Psychedelics, others

Disqualifiers: Hypertension, Tachycardia, Pregnancy, 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: Unknown

108 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether combining a dose of psilocybin with a non-invasive treatment that stimulates the ear's vagus nerve (taVNS) can enhance the long-term benefits of psilocybin. Researchers aim to determine if this combination helps individuals retain important insights from their psychedelic experiences better than psilocybin alone. Individuals who have experienced a modest decline in emotional well-being and are medically healthy may be suitable for this study. Participants will be divided into groups to compare the effects of real and sham nerve stimulation both before and after taking psilocybin. As a Phase 1 trial, the research focuses on understanding how the treatment works in people.

Will I have to stop taking my current medications?

Yes, you will need to stop taking any drugs or medications that may interact with psilocybin before participating in the trial.

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

Research has shown that psilocybin is usually safe for humans. In past studies, most participants experienced only mild to moderate side effects, such as temporary mood changes and some anxiety, while serious side effects were rare. Psilocybin is also being researched for other uses, indicating growing interest in its safety.

For transcutaneous auricular vagus nerve stimulation (taVNS), less safety information is available. However, taVNS is non-invasive, meaning it doesn't involve surgery or needles, which generally suggests a lower risk of serious side effects. Participants in studies who used taVNS reported mild effects like tingling at the application site.

Since this trial is in its early stages, it primarily focuses on safety, aiming to identify any major safety issues. Overall, earlier research has shown promise for the combination of psilocybin and taVNS, but understanding their combined safety remains ongoing. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about psilocybin combined with taVNS (transcutaneous auricular vagus nerve stimulation) because it offers a potentially novel way to enhance psychedelic experiences for therapeutic benefits. Unlike traditional treatments that primarily involve medications or psychotherapy alone, this combination targets the vagus nerve, which plays a crucial role in mood regulation and stress response. By pairing psilocybin, a psychedelic compound known for its potential in treating depression and anxiety, with taVNS, researchers aim to amplify its effects and improve patient outcomes. This approach is distinct because it could lead to more rapid and profound improvements in mental health conditions compared to conventional therapies.

What evidence suggests that this trial's treatments could be effective for enhancing psychedelic experiences?

This trial will explore the effects of combining psilocybin with transcutaneous auricular vagus nerve stimulation (taVNS) in various ways. Research has shown that psilocybin, a compound found in certain mushrooms, can strongly affect the mind, causing hallucinations and potentially reducing anxiety and depression. Studies suggest it can help individuals better understand their thoughts and feelings.

In this trial, some participants will receive psilocybin with active taVNS, while others will receive psilocybin with sham taVNS. Transcutaneous auricular vagus nerve stimulation (taVNS) is a technique that might enhance brain plasticity, the brain's ability to change and adapt. This could potentially extend the effects of psilocybin by helping individuals remember their insights more clearly. While early research appears promising, further studies are needed to fully understand the effectiveness of this combination. ^{1 2 4 5 6}

Who Is on the Research Team?

Charles Raison, MD

Principal Investigator

University of Wisconsin, Madison

Are You a Good Fit for This Trial?

This trial is for English-speaking, medically healthy individuals who can swallow pills and agree to use contraception if they are sexually active. They should have a slight decrease in emotional well-being but no current serious medical conditions, psychiatric diagnoses, abnormal lab results, heart issues like hypertension or tachycardia, and not be pregnant or breastfeeding.

Inclusion Criteria

I am willing and able to follow all study requirements.

I am generally in good health with no major medical conditions.

English speaking

Exclusion Criteria

Pregnancy and currently breastfeeding

Current DSM-5 psychiatric diagnosis

Clinically significant safety lab abnormalities (i.e., Complete Blood Count with Differential, Comprehensive Metabolic Panel, and urinalysis)

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Preparation

Participants undergo 2-4 hours of preparation within a 'set and setting' framework of psychological support

1 day

Psilocybin Dosing

Participants receive a single open-label 25 mg dose of psilocybin with a 6- to 8-hour dosing session

1 day

taVNS/Sham taVNS

Participants receive twice daily sessions of either active or sham taVNS for 7 days, depending on group allocation

7 days

Integration

Participants attend an hour-long integration session 1 day and 9 days post-psilocybin dosing

9 days

Follow-up

Participants are monitored for safety and effectiveness, including assessments of adverse events and memory experiences

8 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Psilocybin
• Sham taVNS
• Transauricular Vagus Nerve Stimulation (taVNS)
• Treatment as Usual (TAU)

Trial Overview The study tests if transauricular vagus nerve stimulation (taVNS) can make the positive effects of psilocybin last longer. Participants will take a single dose of psilocybin and then receive either real taVNS treatment, sham taVNS treatment without actual stimulation, or usual care with no additional intervention.

How Is the Trial Designed?

Group I: Group 1: Sham taVNS + Psilocybin + taVNS Experimental Treatment 3 Interventions

Group 1 will receive twice daily sham taVNS for 7 days immediately prior to psilocybin dosing. Post-psilocybin dosing, they will receive twice-daily taVNS paired with psychedelic session contextual cues for 7 days.

Group II: Group 3: Sham taVNS + Psilocybin + Psychosocial Support Alone Active Control 3 Interventions

Group 3 will receive twice daily sham taVNS for 7 days immediately prior to psilocybin dosing. Post-psilocybin dosing, they will receive psychosocial support alone, comprised of an integration session 1 day and 1-week post-psilocybin dosing. They will not receive active or sham taVNS post-psilocybin.

Group III: Group 4: taVNS + Psilocybin + Sham taVNS Active Control 3 Interventions

Group 4 will receive twice daily taVNS for 7 days immediately prior to psilocybin dosing. Post-psilocybin dosing, they will receive twice-daily sham taVNS paired with psychedelic session contextual cues for 7 days.

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

Group 2 will receive twice daily sham taVNS for 7 days immediately prior to psilocybin dosing. Post-psilocybin dosing, they will receive twice-daily sham taVNS paired with psychedelic session contextual cues for 7 days.

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 Wisconsin, Madison

Lead Sponsor

Trials

1,249

Recruited

3,255,000+

Tiny Blue Dot Foundation

Collaborator

Trials

10

Recruited

660+

Tiny Blue Dot Foundation

Collaborator

Trials

9

Recruited

640+

Published Research Related to This Trial

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]

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]

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]

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]

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 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]

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-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]

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]

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]

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]

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

Psilocybine - the NIST WebBook Psilocybine's formula is C12H17N2O4P, molecular weight is 284.2481, CAS number is 520-52-5, and also known as Psilocybin.

4. 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 ...

5. cancer.gov cancer.gov/publications/dictionaries/cancer-drug/def/psilocybine

Definition of psilocybine - NCI Drug Dictionary A tryptamine alkaloid, isolated from various genera of fungi including the genus Psilocybe, with hallucinogenic, anxiolytic, and psychoactive activities.

6. 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.