Psilocybin for Migraine

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether psilocybin, a compound found in certain mushrooms, can help reduce migraine headaches. Participants will take psilocybin and a placebo (a non-active substance) in separate sessions to assess their effects on migraines. The study will compare different doses of psilocybin to evaluate their effectiveness. Individuals who experience migraines about twice a week and manage them without frequent medication might be suitable candidates. The goal is to gather preliminary information to guide future, larger studies on psilocybin's impact on migraines. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new treatment.

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.

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

Research has shown that psilocybin, a substance found in certain mushrooms, has been studied for its safety in people. In a recent study, a single 25 mg dose of psilocybin was well tolerated, with no serious side effects reported. This suggests that psilocybin might be safe when used in controlled environments.

Other studies have examined psilocybin for treating depression that doesn't respond to other treatments. These studies also found that the treatment was generally well tolerated, with no unexpected safety issues.

However, it is important to note that this trial remains in the early stages of research. This means that the researchers are still learning about its safety, and the results from this trial will provide further understanding. Participants should consider this when deciding to take part. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for migraine?

Researchers are excited about psilocybin for migraine treatment because it offers a novel approach compared to standard therapies like triptans, NSAIDs, and beta-blockers. Unlike these conventional treatments that often focus on alleviating symptoms, psilocybin targets serotonin receptors in the brain, potentially addressing underlying migraine mechanisms. This psychedelic compound could offer relief with fewer doses and longer-lasting effects, reducing the frequency and severity of migraine episodes. Moreover, psilocybin's potential to improve mood and reduce anxiety may provide additional quality-of-life benefits for migraine sufferers.

What evidence suggests that psilocybin might be an effective treatment for migraine?

Research suggests that psilocybin might help with migraine headaches. Psilocybin, a substance found in certain mushrooms, affects serotonin, a brain chemical that influences mood and perception. By acting on serotonin, psilocybin may reduce the frequency and severity of headaches. Early studies in other conditions have shown that psilocybin can relieve symptoms like pain and discomfort. Although direct evidence for migraines remains limited, the potential benefits observed in similar conditions are encouraging. This trial will explore the effects of different psilocybin doses, with some participants receiving low or high doses alongside a placebo, to gather more solid data on psilocybin's effectiveness for migraines. ^{6 7 8 9 10}

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Placebo
• Psilocybin

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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, 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]

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]

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]

Citations

1. 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 ...

2. 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 ...

3. 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.

4. 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.

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

Psilocybine - the NIST WebBook Psilocybine. Formula: C12H17N2O4P ... 4-Phosphoryloxy-N,N-dimethyltryptamine; Psilocibin; Psilocin phosphate ester; Psilotsibin; Teonanacatl; Psylocybin ...

6. psychiatrictimes.com psychiatrictimes.com/view/comp360-psilocybin-for-treatment-resistant-depression-positive-phase-3-efficacy-data

COMP360 Psilocybin for Treatment-Resistant Depression Additionally, according to the Independent Data Safety Monitoring Board, who reviewed safety data for COMP360, there were no unexpected safety ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT05624268

Efficacy, Safety, and Tolerability of COMP360 in ... Psychological therapies cannot have been initiated within 30 days prior to Screening; Exposure to COMP360 psilocybin therapy prior to Screening. Ages Eligible ...

8. ir.compasspathways.com ir.compasspathways.com/News--Events-/news/news-details/2025/Compass-Pathways-Announces-Publication-of-Results-from-Phase-2-Study-of-COMP360-Psilocybin-for-Post-Traumatic-Stress-Disorder/default.aspx

News Details Open-label Phase 2 study shows a single 25 mg COMP360 psilocybin dose was well tolerated, with no serious adverse events observed, ...

9. clinicaltrials.gov clinicaltrials.gov/study/NCT04739865

NCT04739865 | The Safety and Efficacy Of Psilocybin as ... A recent open label study of the effects of psilocybin in participants with treatment-resistant depression (TRD) showed rapid significant decrease of depressive ...

10. compasspathways.com compasspathways.com/our-work/comp360-psilocybin-treatment-in-trd/

COMP360 psilocybin treatment in TRD This trial assessed the safety and efficacy of COMP360 psilocybin treatment in three doses: 1mg, 10mg, 25mg. The results, published in the New England ...