Comparing single- and repeat-dose psilocybin with active placebo for migraine prevention in an exploratory randomized controlled clinical trial

[Craigo]

Comparing single- and repeat-dose psilocybin with active placebo for migraine prevention in an exploratory randomized controlled clinical trial

Emmanuelle A D Schindler, Christopher H Gottschalk, Brian P Pittman, Deepak C D'Souza

Published in Headache on December 29, 2025
Link: https://headachejournal.onlinelibrary.wiley.com/doi/10.1111/head.70024

Abstract:
Objective: The goals of this study were to examine the therapeutic effects and safety of psilocybin given as a pulsed regimen for the prevention of migraine and to consider the blinding integrity of an active control agent.

Background: The administration of a single low dose of psilocybin was observed to have lasting therapeutic effects in one small pilot trial in migraine, although the ability of a pulse dose regimen, as practiced by patients with cluster headache, to potentially improve magnitude and/or duration of transitional preventive effects has not been studied. Furthermore, comparison to an active placebo agent that adequately mimics the acute subjective effects of psilocybin is required to improve blinding integrity and measure placebo effects.

Methods: In an exploratory randomized, double-blind, placebo-controlled, parallel group study, adults with migraine having at least two weekly migraine days at baseline (n = 18) participated in two drug administration sessions separated by 7 days during which they received zero, one, or two doses of psilocybin (10 mg; psi). Whenever participants did not receive psilocybin, they received diphenhydramine (25 mg; diph). Participant recruitment took place between September 2021 and August 2023. The primary outcome measure was a change in migraine frequency using headache diary data collected starting 2 weeks before and continuing through 8 weeks after the second drug session.

Results: In the 2 weeks after completion of the two drug administration sessions, the change from baseline in migraine days/week was not significantly different among groups [diph-diph: -0.7 (95% confidence interval, -1.5 to 0.2); diph-psi: -2.0 (-3.0 to -1.0); psi-psi: -1.7 (-4.1 to 0.7); Χ2 (2) = 4.56, p = 0.102], despite large effect sizes against the placebo group in the those receiving one (diph-psi; d = 1.66) or two (psi-psi; d = 0.69) doses of psilocybin. Similar reductions in migraine frequency approximating 50% were seen in all groups over the 8 weeks measured. The difference in 50% response rate among groups over 2 weeks, however, approached significance (diph-diph: 17%; diph-psi: 80%; psi-psi: 80%; p = 0.087). Drug confidence ratings (i.e., blinding integrity) suggested that diphenhydramine partially substituted for the acute effects of psilocybin. No correlations were observed between changes in migraine frequency after psilocybin and drug confidence, acute general drug effects, or acute psychedelic effects. No serious or unexpected adverse events occurred.

Conclusion: This exploratory study found similar reductions in migraine frequency with single-dose psilocybin, a two-dose pulse of psilocybin, or diphenhydramine placebo. Whereas blinding was incomplete in this study, this important topic is highlighted in the study design and findings. The potential for psilocybin to serve as a transitional treatment in migraine remains but will require careful planning in future studies to separate drug and non-drug effects. Furthermore, the inclusion of headache specialists in the design and execution of these future studies is necessary to preserve the viability of psilocybin treatment in headache medicine.

[Craigo]

Thank-you to the researchers. The study was exploratory and only had 18 participants split into three groups so the lack of statistical power is the likely reason for the discrepancy where the single-dose group showed a large effect size against placebo yet the primary outcome for the trial failed to reach statistical significance. 

And the single dose group reported greater improvement than the two dose group... could be just simply random variability again due to the small sample.

Diphenhydramine was used to mimic the effects of psilocybin yet they found it only "partially substituted" for them, do they mean the participants may have been able to distinguish the active from placebo and potentially biased the self-reported headache diary results? i.e. expectation bias.

Given the placebo performed unexpectedly well, should we be asking if diphenhydramine has therapeutic potential for migraine? Batch has previously said the neuropeptides involved in migraine and CH such as CGRP, PACAP, SP etc can trigger mast cell degranulation, histamine release and a self-sustaining feedback loop hence the early recommendation to take Benadryl (diphenhydramine) or more recently the full monty supplements with the D3 regimen for CH.

Looking forward to larger trials. Welcome to read the study at link above or interact with it in NotebookLM (AI) below. 

https://notebooklm.google.com/notebook/94236d69-1463-4b24-93a4-a3870f7e9701?authuser=1

[jon019]

...at one point (cannot enumerate) there was a reluctance(?) official or non by researchers to placebo arm studies with active HA patients. understandable, but obviously limiting. any thoughts? was this just an understanding or are there study protocols (besides life or death) concerning pain or perhaps intractable pain that have been superseded/modified?

Edited January 1 by jon019

[Craigo]

17 hours ago, jon019 said:

...at one point (cannot enumerate) there was a reluctance(?) official or non by researchers to placebo arm studies with active HA patients. understandable, but obviously limiting. any thoughts? was this just an understanding or are there study protocols (besides life or death) concerning pain or perhaps intractable pain that have been superseded/modified?

HNY and right on Jon, exactly - CH is pretty much a stress-test for Helsinki and CIOMS. I can only imagine the complexities of designing CH studies that advance knowledge but always place the well-being of the study participant first, let alone sitting on the ethics committees that have to review and approve them.

Check out the below, part 33.

World Medical Association Declaration of Helsinki Ethical Principles for Medical Research Involving Human Subjects

https://jamanetwork.com/journals/jama/fullarticle/1760318

And the Council for International Organizations of Medical Sciences, guideline 5.

https://www.ncbi.nlm.nih.gov/books/NBK614415/

I saw a few posts on socials in recent weeks venting that there isn't enough research on CH and I get it but I also want to acknowledge that like the lead author of this study, we have some amazing researchers in our corner and I am so thankful for that as well as excited to see what happens in 2026. I feel we saw some real advancement in our understanding in 2025. Thank-you for bringing up this very relevant point.