Psilocybin for Headaches

Overseen By Sarah Anthony, MSc

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Yale University

Must not be taking: Psychedelics, THC, Triptans, NSAIDs

Disqualifiers: Pregnancy, Psychotic disorder, Substance abuse, others

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

Compensation: Varies

Number of Visits: 1

Duration: 1 day

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

In previous clinical trial work, the investigators observed lasting reductions in headache burden after limited dosing of psilocybin. This purpose of this study is to examine potential sources for this observed effect. This study will measure brain resting state functional connectivity (fMRI), central synaptic density (SV2A PET), peripheral markers of inflammation, circadian rhythm (actigraphy), and sleep (sleep EEG) in both migraine and healthy control participants before and one week after the administration of psilocybin or an active control agent.

Will I have to stop taking my current medications?

You may need to stop taking certain medications to participate in this trial. Specifically, you should not use classic psychedelics, cannabis, triptans, ditans, serotonergic preventive therapies, or NSAIDs within specified time frames before and after certain procedures. Please consult with the trial team for guidance on your specific medications.

Is psilocybin 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) and hyperkinesis (increased movement). Some adverse reactions, such as vomiting and severe muscle pain, have been reported, especially when used recreationally. However, with proper medical supervision, these effects can be managed, and supportive care can lead to rapid improvement. ^{1 2 3 4 5}

How is the drug psilocybin unique in treating headaches?

Psilocybin is unique because it works by affecting the serotonin system in the brain, which is different from most traditional headache treatments. It acts quickly, within 30 minutes to an hour, and is known for its psychedelic effects, which are not typical of standard headache medications. ^{1 3 6 7 8}

What evidence supports the effectiveness of the drug psilocybin for treating headaches?

Research shows that psilocybin has been studied for various psychiatric disorders, including depression and anxiety, with patients sometimes experiencing significant, long-term improvements after treatment. Although not directly studied for headaches, these findings suggest potential benefits due to its effects on mood and perception. ^{3 9 10 11 12}

Are You a Good Fit for This Trial?

This trial is for individuals with headache disorders, specifically migraines. Participants should be healthy otherwise and willing to undergo brain imaging and sleep studies before and after taking psilocybin or a placebo. The exact eligibility criteria are not provided.

Inclusion Criteria

I have been diagnosed with migraines according to ICHD-3 or I am a healthy volunteer.

I am between 21 and 70 years old.

Exclusion Criteria

Substance abuse in the prior 3 months

I haven't taken NSAIDs like ibuprofen a week before or will not take them a week after my PET scan.

Urine toxicology positive to drugs of abuse

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive psilocybin or an active control agent, with various physiological and psychological measures taken before and after administration

1 day

1 visit (in-person)

Follow-up

Participants are monitored for changes in physiological and psychological markers, including sleep and inflammation, after drug administration

14 days

Long-term Follow-up

Participants are monitored for adverse events and long-term changes in physiological markers

3 months

What Are the Treatments Tested in This Trial?

Interventions

• Psilocybin

Trial Overview The study tests the effects of psilocybin on headaches by comparing it to a placebo. It measures changes in brain connectivity, synaptic density, inflammation markers, circadian rhythms, and sleep patterns before and one week after administration.

How Is the Trial Designed?

Group I: Migraine psilocybin Experimental Treatment 1 Intervention

Migraine participants randomized to receive 10 mg psilocybin (oral)

Group II: Healthy control psilocybin Experimental Treatment 1 Intervention

Healthy control participants randomized to receive 10 mg psilocybin (oral)

Group III: Migraine placebo Placebo Group 1 Intervention

Migraine participants randomized to receive 2.5 mg THC (oral)

Group IV: Healthy control placebo Placebo Group 1 Intervention

Healthy control participants randomized to receive 2.5 mg THC

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+

Wallace Research Foundation

Collaborator

Trials

4

Recruited

90+

The Wallace Foundation

Collaborator

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, 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 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 serotonergic psychedelic, has shown promise in treating various psychiatric disorders, including depression and substance use disorders, with 9 clinical trials conducted between 2000 and 2020.

The treatment is generally well tolerated with limited side effects, and some patients with treatment-resistant conditions have experienced significant long-term improvements after just a few sessions, indicating its potential efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Treatment with psilocybin: applications for patients with psychiatric disorders]. Breeksema, JJ., Koolen, MHB., Somers, M., et al.[2021]

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]

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]

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]

P. samuiensis, a newly identified psychoactive mushroom species from Thailand, shows rapid mycelial growth and contains significant levels of psilocybin and psilocin, similar to other psychoactive fungi.

Laboratory analyses revealed that psilocybin concentrations in P. samuiensis ranged from 0.23% to 0.90%, with the highest levels found in the caps, indicating its potential for psychoactive effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ethnomycology, biochemistry, and cultivation of Psilocybe samuiensis Guzmán, Bandala and Allen, a new psychoactive fungus from Koh Samui, Thailand. Gartz, J., Allen, JW., Merlin, MD.[2019]

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]

Citations

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

Psilocybin in Palliative Care: An Update. [2023]

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

The pharmacology of psilocybin. [2016]

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

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

4. England pubmed.ncbi.nlm.nih.gov

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

5. Netherlands pubmed.ncbi.nlm.nih.gov

[Treatment with psilocybin: applications for patients with psychiatric disorders]. [2021]

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

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

9. 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]

10. Ireland pubmed.ncbi.nlm.nih.gov

Ethnomycology, biochemistry, and cultivation of Psilocybe samuiensis Guzmán, Bandala and Allen, a new psychoactive fungus from Koh Samui, Thailand. [2019]

11. 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]

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

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