Psilocybin for the Treatment of Migraine Headache

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

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 2

Duration: 4 weeks

14 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

You may need to stop taking certain medications before participating in the trial. Specifically, you should not use vasoconstrictive medications close to the test days, and you must avoid serotonergic antiemetics and certain antidepressants and immunomodulatory agents for a few weeks before the trial.

What data supports the effectiveness of the drug psilocybin?

Research indicates that psilocybin, found in magic mushrooms, affects the brain's serotonin receptors, which can lead to altered states of consciousness. While its therapeutic benefits are still being studied, it has shown potential in producing beneficial health outcomes through its psychoactive effects. ^{1 2 3 4 5}

Is psilocybin generally safe for human use?

Psilocybin, found in certain mushrooms, can cause rapid effects on the central nervous system, including hallucinations and physical symptoms like ataxia (loss of control of body movements). While some people report positive experiences, there are risks of challenging experiences, and a small percentage may experience lasting psychological effects or require medical help. Safety is generally higher in controlled, supportive environments. ^{1 4 6 7 8}

What makes psilocybin unique compared to other drugs?

Psilocybin is unique because it is a psychedelic drug that works by activating serotonin 2A receptors in the brain, leading to altered states of consciousness and mystical experiences. Unlike traditional treatments, it offers a novel approach to mental health care, particularly for conditions like depression and PTSD, by inducing profound psychological effects. ^{1 5 9 10 11}

What is the purpose of this trial?

This trial is testing whether a substance from 'magic mushrooms' called psilocybin can help people who suffer from migraines. Participants will take psilocybin to see if it reduces their headache frequency and intensity. The study will help understand if psilocybin can be an effective treatment for migraines. Psilocybin is a well-characterized classic hallucinogen with a long history of religious use by indigenous cultures and has shown potential in treating cluster headaches and chronic pain.

Eligibility Criteria

Inclusion Criteria

Diagnosis of migraine headache per ICHD-3beta criteria

Age 21 to 65

You have frequent migraine attacks, occurring at least twice a week.

Exclusion Criteria

Unstable medical condition, severe renal, cardiac or hepatic disease, pacemaker, or serious central nervous system pathology

Urine toxicology positive to drugs of abuse

Use of vasoconstrictive medications (i.e. sumatriptan, pseudoephedrine, midodrine) within 5 half-lives of test days

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a dose of placebo and a dose of psilocybin approximately 14 days apart, with randomization to the order of treatment and dosage level

4 weeks

2 visits (in-person)

Follow-up

Participants maintain a headache diary to document headache frequency and intensity, as well as associated symptoms

4 weeks

Long-term Follow-up

Participants' quality of life is assessed using the CDC Health-Related Quality of Life Scale

3 months

Treatment Details

Interventions

• Placebo
• Psilocybin

Participant Groups

Group I: Placebo/Low Dose Psilocybin Experimental Treatment 2 Interventions

Subjects in this arm receive placebo in the first session and low dose psilocybin in the second session.

Group II: Placebo/High Dose Psilocybin Experimental Treatment 2 Interventions

Subjects in this arm receive placebo in the first session and high dose psilocybin in the second session.

Group III: Low Dose Psilocybin/Placebo Experimental Treatment 2 Interventions

Subjects in this arm receive low dose psilocybin in the first session and placebo in the second session.

Group IV: High Dose Psilocybin/Placebo Experimental Treatment 2 Interventions

Subjects in this arm receive high dose psilocybin in the first session and placebo in the second session.

Who Is Running the Clinical Trial?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

Ceruvia Lifesciences

Collaborator

Trials

2

Recruited

40+

Findings from Research

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 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 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]

In a survey of 1993 individuals who experienced challenging psilocybin trips, 39% rated their experience as one of the most difficult of their lives, with 11% reporting risks of physical harm, particularly influenced by dose and lack of support.

Despite the challenges, 84% of respondents felt they benefited from the experience, suggesting that while adverse effects can occur, the overall incidence of serious psychological distress is low, especially in controlled settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Survey study of challenging experiences after ingesting psilocybin mushrooms: Acute and enduring positive and negative consequences. Carbonaro, TM., Bradstreet, MP., Barrett, FS., et al.[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]

Psilocybin, derived from Psilocybe cubensis mushrooms, is being investigated as a novel treatment for major depression, with a focus on its safety and efficacy compared to traditional antidepressants.

The proposed study will include both preclinical toxicity evaluations in mice and a clinical trial assessing the safety and pharmacokinetics of psilocybin in healthy adults, followed by an open trial in patients with major depressive disorder, aiming to provide comprehensive data on its therapeutic potential.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Proposal to Study the Safety and Efficacy of Psilocybe cubensis in Preclinical and Clinical Studies as a Therapeutic Alternative for Major Depressive Disorder. Escamilla, R., González-Trujano, ME., González Mariscal, JM., et al.[2023]

Psilocin, isolated from psychotropic mushrooms, showed varying levels of acute toxicity, with the highest toxicity observed at an LD50 of 293.07 mg/kg for pure psilocin, compared to 316.87 mg/kg for Pholiotina cyanopus and 324.37 mg/kg for Psilocybe semilanceata.

Both psilocin and mushroom extracts acted as agonists on the serotonergic system, with psilocin significantly reducing head-twitch responses in mice, indicating its potential effects on serotonin pathways, which are linked to hallucinogenic activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Research on acute toxicity and the behavioral effects of methanolic extract from psilocybin mushrooms and psilocin in mice. Zhuk, O., Jasicka-Misiak, I., Poliwoda, A., et al.[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]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

[Hallucinogenic mushrooms]. [2018]

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

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

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

Survey study of challenging experiences after ingesting psilocybin mushrooms: Acute and enduring positive and negative consequences. [2018]

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

Intravenous mushroom poisoning. [2019]

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

A Proposal to Study the Safety and Efficacy of Psilocybe cubensis in Preclinical and Clinical Studies as a Therapeutic Alternative for Major Depressive Disorder. [2023]

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

Research on acute toxicity and the behavioral effects of methanolic extract from psilocybin mushrooms and psilocin in mice. [2018]

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

Structure-Activity Relationships for Psilocybin, Baeocystin, Aeruginascin, and Related Analogues to Produce Pharmacological Effects in Mice. [2023]

11. 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]