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 is testing if combining psilocybin with a gentle nerve stimulation technique can make the positive effects of psilocybin last longer. The study involves adults who will receive a dose of psilocybin and either real or fake nerve stimulation. The goal is to see if the nerve stimulation helps keep the memories from the psilocybin experience vivid and beneficial.

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 the combination of psilocybin and taVNS generally safe for humans?

Psilocybin, found in magic mushrooms, can cause rapid effects on the central nervous system, including hallucinations and physical symptoms like ataxia (loss of control of body movements) and hyperkinesis (increased movement). While some studies suggest that psilocybin mushrooms may be safe under controlled conditions, they can also cause adverse reactions, especially if other substances like phenylethylamine are present. The safety of psilocybin in people with heart conditions is not fully known, and caution is advised. ^{1 2 3 4 5}

How is the drug psilocybin unique compared to other treatments?

Psilocybin is unique because it is a naturally occurring compound found in certain mushrooms that acts on the brain's serotonin receptors, leading to psychedelic experiences. Unlike traditional treatments, it rapidly affects the central nervous system and is being studied for its potential to enhance therapeutic experiences through its hallucinogenic effects. ^{1 6 7 8 9}

What data supports the effectiveness of the drug psilocybin in enhancing psychedelic experiences?

Research indicates that psilocybin, the active component in magic mushrooms, can produce rapid effects on the central nervous system, leading to hallucinations and other subjective experiences. These experiences are being studied for potential therapeutic benefits, particularly in palliative care, although psilocybin is not yet approved for therapeutic use in the United States. ^{1 2 8 10 11}

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

Clinically significant electrocardiogram (ECG)

I do not have any severe illnesses that would exclude me from the trial.

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]

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]

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 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]

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 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]

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]

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]

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]

Citations

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

The pharmacology of psilocybin. [2016]

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

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

6. England 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. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Presence of phenylethylamine in hallucinogenic Psilocybe mushroom: possible role in adverse reactions. [2019]

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

Intravenous mushroom poisoning. [2019]

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

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

10. England pubmed.ncbi.nlm.nih.gov

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