Psilocybin for 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how psilocybin, a compound found in some mushrooms, might treat cluster headaches. Participants will receive either a placebo, a low dose, or a high dose of psilocybin in three sessions to assess its effects on headache frequency and intensity. It suits those with chronic cluster headaches who experience at least one attack daily or have predictable episodes lasting around two months, and who manage attacks without using triptans more than twice weekly (such as with oxygen or heat packs). As a Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this potentially groundbreaking treatment.

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.

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

Research shows that psilocybin, a substance found in certain mushrooms, is under study to assess its safety for people. Past studies have found that it is usually well-tolerated. Some research has noted mild to moderate side effects, such as nausea or temporary changes in mood and perception, which typically do not last long. Psilocybin is also being investigated for other health conditions, suggesting it might be safe enough for further research. However, since this study is in the early stages, the researchers are still collecting safety information. Participants should consider this when deciding whether to join the trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for cluster headaches, which typically include medications like verapamil, lithium, and corticosteroids, psilocybin is derived from psychedelic mushrooms and represents a novel approach. Researchers are excited about psilocybin because it potentially targets serotonin receptors in the brain differently, which could lead to rapid relief from headache symptoms. Additionally, the use of psilocybin could offer a new mechanism of action compared to traditional medications, possibly resulting in fewer side effects and a more profound effect on reducing headache frequency and intensity. With both high and low dose options being explored, psilocybin holds promise for providing flexible and effective relief for those suffering from this debilitating condition.

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

Research has shown that psilocybin might help with cluster headaches by affecting certain brain chemicals. Earlier studies found that psilocybin reduced the number and severity of headaches in some individuals. This trial will compare different doses of psilocybin, including high and low doses, to a placebo to evaluate its effectiveness. Although more information is needed, early evidence suggests psilocybin could be useful for treating cluster headaches. However, these findings are still new, and further research is underway to confirm them. ^{1 2 3 4 5}

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Psilocybin

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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-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, 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]

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]

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]

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 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]

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 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]

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 ...