Psilocybin for the Treatment of Cluster Headache

Overseen By Christina Forte, BA

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Yale University

Must not be taking: Vasoconstrictives, Antiemetics, Antidepressants, Steroids

Disqualifiers: Psychotic disorders, Unstable medical conditions, others

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: 2 weeks

25 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests if taking psilocybin pills can help people with severe cluster headaches. Participants will take different doses of psilocybin and keep a diary of their headache experiences. The goal is to see if psilocybin can make these headaches less frequent and less intense. Psilocybin is a well-known substance with a long history of use by indigenous cultures and has shown potential in treating headache disorders.

Will I have to stop taking my current medications?

Yes, you may need to stop taking certain medications. The trial excludes participants who have used vasoconstrictive medications within five half-lives of test days, serotonergic antiemetics in the past 2 weeks, antidepressants in the past 6 weeks, and steroids or certain immunomodulatory agents in the past 2 weeks.

What evidence supports the effectiveness of the drug psilocybin?

Psilocybin has shown potential therapeutic benefits in palliative care, helping patients manage psychological distress, although it is not yet approved for therapeutic use in the United States. ^{1 2 3 4 5}

Is psilocybin generally safe for human use?

Psilocybin, found in magic mushrooms, has been studied for its effects on the brain and body. While it can cause hallucinations and other effects, studies suggest it can be safe under controlled conditions, though caution is advised, especially for those with heart conditions. ^{4 6 7 8 9}

How is the drug Psilocybin unique compared to other treatments?

Psilocybin is unique because it works by activating serotonin receptors in the brain, which can lead to psychedelic effects that are being explored for mental health conditions like depression and PTSD. Unlike traditional medications, it offers a novel approach by potentially altering consciousness and perception, which may provide therapeutic benefits. ^{10 11 12 13 14}

Eligibility Criteria

Inclusion Criteria

Episodic cluster headache with periods that are predictable and have a duration of approximately 2 months

You experience cluster headaches at least once a day on a regular basis.

You only use triptans (a type of medication for migraines) twice a week or less to manage your migraine attacks. You may use other methods, like applying heat or cold packs or using high-flow oxygen, to manage your migraines as well.

Exclusion Criteria

Axis I psychotic disorder (e.g. schizophrenia, bipolar I, depression with psychosis)

Use of antidepressant medications (i.e. amitriptyline, isocarboxazid, fluoxetine, citalopram) in the past 6 weeks

Use of steroids or certain other immunomodulatory agents (i.e. azathioprine) in the past 2 weeks

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive oral placebo, low dose psilocybin, or high dose psilocybin in three experimental sessions, each separated by 5 days

2 weeks

3 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment using a headache diary

6 months

Second Round (optional)

Participants may be invited for a second round of treatment with low dose or high dose psilocybin

2 weeks

Treatment Details

Interventions

• Psilocybin

Participant Groups

Group I: Psilocybin High Dose Active Control 1 Intervention

Group II: Psilocybin Low Dose Active Control 1 Intervention

Group III: Placebo Placebo Group 1 Intervention

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?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

Heffter Research Institute

Collaborator

Trials

15

Recruited

520+

Ceruvia Lifesciences

Collaborator

Trials

2

Recruited

40+

CH TAC LLC

Collaborator

Trials

1

Recruited

30+

Cluster Headache-Trigeminal Autonomic Cephalalgia (CH-TAC), LLC

Collaborator

Trials

1

Recruited

30+

Findings from Research

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]

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 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]

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]

This study found that the binding of serotonin 2A receptors (5-HT2AR) in the brain can predict how long the peak effects of psilocybin last and how quickly individuals return to normal consciousness after its effects wear off.

Higher levels of 5-HT2AR binding were associated with lower scores on the Mystical Experience Questionnaire, suggesting that individual differences in receptor availability may influence the subjective experience of psilocybin, which could have implications for its therapeutic use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brain serotonin 2A receptor binding predicts subjective temporal and mystical effects of psilocybin in healthy humans. Stenbæk, DS., Madsen, MK., Ozenne, B., 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]

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 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]

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]

Genomic analysis of five species of Psilocybe mushrooms revealed a much greater metabolic diversity than previously understood, indicating potential for discovering new compounds beyond psilocybin and psilocin.

Two species, P. cyanescens and P. mexicana, were identified as producers of aeruginascin, along with other metabolites like lumichrome and verpacamide A, which may help explain the pharmacological and toxicological effects associated with these mushrooms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genetic Survey of Psilocybe Natural Products. Dörner, S., Rogge, K., Fricke, J., et al.[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]

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]

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]

References

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

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

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

Psilocybin in Palliative Care: An Update. [2023]

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

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

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

The pharmacology of psilocybin. [2016]

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

Brain serotonin 2A receptor binding predicts subjective temporal and mystical effects of psilocybin in healthy humans. [2022]

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

[Hallucinogenic mushrooms]. [2018]

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

Intravenous mushroom poisoning. [2019]

8. 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]

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

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

10. Germany pubmed.ncbi.nlm.nih.gov

Genetic Survey of Psilocybe Natural Products. [2022]

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

DNA Authentication and Chemical Analysis of Psilocybe Mushrooms Reveal Widespread Misdeterminations in Fungaria and Inconsistencies in Metabolites. [2023]

14. 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]